Antiviral nucleoside analogue, preparation method and application thereof

Abstract

The invention discloses a nucleoside analogue as shown in a formula I and pharmaceutically acceptable salts thereof, and a preparation method and medical application of the nucleoside analogue and the pharmaceutically acceptable salts thereof, pharmacological experiments prove that the nucleoside analogue and the pharmaceutically acceptable salts thereof have relatively good inhibitory activity on RNA-dependent RNA polymerase, and can inhibit replication of various RNA viruses in the aspect of inhibiting virus replication, so that the nucleoside analogue and the pharmaceutically acceptable salts thereof have good application prospects. Particularly, the compound has relatively good biological activity for treating influenza virus and vesicular stomatitis virus infection. Therefore, the compound provided by the invention has good broad-spectrum antiviral activity, can be used as a broad-spectrum antiviral drug to treat various virus infections, and enriches the inventory of antiviral drugs. The nucleoside analogue has anti-RNA (Ribonucleic Acid) virus activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, in particular to a nucleoside analogue, a preparation method thereof and uses thereof. BACKGROUND

[0002] Viruses can be classified into DNA viruses and RNA viruses by their structure. Among them, some RNA viruses have caused many global public health emergencies in recent years.

[0003] Nucleoside analogues refer to a class of molecules similar in chemical structure to natural nucleosides. Therefore, nucleoside analogues have the potential to resist a variety of viruses. Nucleoside analogues are widely used in the treatment of acute and chronic viral infections. These drugs inhibit viral replication through one or several different mechanisms, one of which is that nucleoside analogues act as chain terminators, preventing the synthesis of viral DNA, RNA or subsequent transcription after entering host cells. The structural changes made by nucleoside analogues to mimic natural nucleosides often result in premature termination of viral RNA replication, thereby exerting antiviral activity.

[0004] Common nucleotide analogue drugs include remdesivir, sofosbuvir, ribavirin, monapaviravir, etc. They have been marketed as antiviral drugs and have contributed to the human antiviral cause. However, as the types of viruses and the disease outbreaks caused by viruses become more and more severe, it is crucial to develop a new type of antiviral nucleoside analogue for human public health and health care, and it also plays a key role in the stable development of the national economy. SUMMARY

[0005] The technical purpose of the present application is to provide a class of nucleoside analogues and pharmaceutically acceptable salts thereof, a preparation method and medical uses thereof, which have antiviral activity against RNA viruses.

[0006] According to one aspect of the present application, one object of the present application is to provide a nucleoside analogue represented by the following formula I and a pharmaceutically acceptable salt thereof:

[0007]

[0008] R1and R2are each independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-6 alkoxy;

[0009] with the proviso that R1and R2are not hydrogen at the same time and not hydroxyl at the same time;

[0010] R3is selected from hydroxyl, amino, hydroxylamine, C 1-6 alkoxyamine, oxo (O=);

[0011] R4 is selected from hydrogen, hydroxyl, cyano, substituted or unsubstituted C 1-6 linear or branched alkyl, 4- to 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S, substituted or unsubstituted C 1-6 alkanoyl, substituted or unsubstituted C 1-6 alkanoylamino, substituted or unsubstituted C 1-6 alkyl oxime, substituted or unsubstituted C 1-6 alkyl-O-C 1-6 alkyl oxime, C 1-6 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by one or more substituents selected from hydroxylamino, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxylamino, halogen, hydroxyl, amino, C 6-10 aryl, C 1-6 alkyl C 6-10 aryl, C 1-6 alkoxy C 6-10 aryl, halogenated C 1-6 alkyl C 6-10 aryl, C 1-6 alkoxy C 6-10 aryloxy, 4- to 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S;

[0012] or R3 and R4 together with the carbon atom to which they are attached form a 4- to 9-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S or a 4- to 9-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S;

[0013] R5 is selected from hydrogen;

[0014] or R4 and R5 together with the carbon atom to which they are attached form C 4-8 cycloalkyl, 4- to 9-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S or a 4- to 9-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S.

[0015] Preferably, R1 is selected from hydrogen, halogen, substituted or unsubstituted C 1-4 alkoxy.

[0016] Preferably, R1 is selected from hydrogen, halogen.

[0017] Preferably, R2 is selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C 1-4 alkoxy.

[0018] Preferably, R2 is selected from hydrogen, hydroxyl, halogen.

[0019] Preferably, R3 is selected from hydroxyl, amino, hydroxylamino, C1-3 alkoxyamino, oxo (O=).

[0020] Preferably, R3 is selected from hydroxyl, amino, hydroxylamino, methoxyamino, oxo (O=).

[0021] Preferably, R4 is selected from hydrogen, hydroxyl, cyano, substituted or unsubstituted C 1-4 linear or branched alkyl, 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S, substituted or unsubstituted C 1-4 alkanoyl, substituted or unsubstituted C 1-4 alkanoylamino, substituted or unsubstituted C 1-4 alkyl oxime, substituted or unsubstituted C 1-4 alkyl-O-C 1-4 alkyl oxime, C 1-4 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted with 1 to 3 groups selected from hydroxylamino, C 1-4 alkyl, hydroxyl C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylhydroxylamino, halogen, hydroxyl, amino, C 6-10 aryl, C 1-4 alkyl C 6-10 aryl, C 1-4 alkoxy C 6-10 aryl, halogenated C 1-4 alkyl C 6-10 aryl, C 1-4 alkoxy C 6-10 aryloxy, 4- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S;

[0022] Preferably, R4 is selected from hydrogen, hydroxyl, cyano, substituted or unsubstituted C 1-3 linear or branched alkyl, 5- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N, substituted or unsubstituted C 1-3 alkanoyl, substituted or unsubstituted C 1-3 alkanoylamino, substituted or unsubstituted C 1-3 alkyl oxime, substituted or unsubstituted C 1-3 alkyl-O-C 1-3 alkyl oxime, C 1-3 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted with 1 to 3 groups selected from hydroxylamino, C 1-3 alkyl, hydroxyl C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylhydroxylamino, halogen, hydroxyl, amino, phenyl, C 1-3 alkylphenyl, C 1-4alkyl, C 1-4 alkyl, C 1-4 alkoxyphenoxy, 5- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N;

[0023] Preferably, R4 is selected from hydrogen, hydroxyl, cyano, substituted or unsubstituted C 1-3 linear or branched alkyl, 5- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N, substituted or unsubstituted C 1-3 alkanoyl, substituted or unsubstituted C 1-3 alkanoylamino, substituted or unsubstituted C 1-3 alkyl oxime, substituted or unsubstituted C 1-3 alkyl-O-C 1-3 alkyl oxime, C 1-3 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by 1 or 2 groups selected from hydroxylamino, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, methylhydroxylamino, ethylhydroxylamino, propylhydroxylamino, halogen, hydroxyl, amino, phenyl, tolyl, mesityl, ethylphenyl, t-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, methoxyphenoxy, ethoxyphenoxy, 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from O and N;

[0024] Preferably, R4 is selected from the following groups:

[0025]

[0026] Preferably, R3 and R4 together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S or a 5- to 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S.

[0027] Preferably, R3 and R4 together with the carbon atom to which they are attached form a 5- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from O and N or a 5- to 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from O and N.

[0028] Preferably, R3 and R4 together with the carbon atom to which they are attached form

[0029] Preferably, R4 and R5 together with the carbon atom to which they are attached form a C4-C6cycloalkyl, a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O or N or a 4- to 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O and N;

[0030] R4and R5together with the carbon atom to which they are attached form a C5-C6cycloalkyl, a 5- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from O or N, or a 5- to 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from O and N;

[0031] R4and R5together with the carbon atom to which they are attached form a C5-C6cycloalkyl, a 5- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from O or N, or a 5- to 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from O and N;

[0032] Preferably, the halogen is selected from F, Cl, Br, I, preferably from F, Cl, Br.

[0033] More preferably, the compound of formula I and the pharmaceutically acceptable salts thereof are selected from any one of the following compounds A1 to A46 of the following structures:

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] According to another aspect of the present application, another object of the present application is to provide a method for preparing the nucleoside analog of formula I and the pharmaceutically acceptable salts thereof, which is prepared according to the following Reaction Scheme 1:

[0040]

[0041] Reaction Scheme I

[0042] As shown in the above Reaction Scheme 1, the method comprises the following steps:

[0043] i-1) reducing compound 1a to form compound 2a;

[0044] i-2) acylating compound 2a to form compound 3a;

[0045] i-3) Vorbrüggen glycosylation of compound 3a to form compound 5a;

[0046] i-4) removing the corresponding acyl protecting group of compound 5a to form compound 1.

[0047] In the above Reaction Scheme I, the definitions of substituents R1, R2, R3, R4, R5are the same as those in the above general formula 1.

[0048] Preferably, in steps i-1) and i-2), lithium tri-tert-butoxyaluminum hydride is used as a reducing agent, acetic anhydride is used as an acylating agent, and the reaction is carried out at -40°C.

[0049] Preferably, in step i-3), N,O-bistrimethylsilylacetamide and trimethylsilyl triflate are used, and the reaction is carried out at 60°C.

[0050] Preferably, in step i-4), the deprotecting agent used is amine / methanol, and the reaction is carried out at room temperature.

[0051] According to another aspect of the present application, another object of the present application is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned nucleoside analogue and pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients.

[0052] According to another aspect of the present application, another object of the present application is to provide the use of the above-mentioned nucleoside analogue and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating viral infection.

[0053] Among them, the virus is a coronavirus, an influenza virus, a rhabdovirus, a paramyxovirus, a respiratory syncytial virus, a flaviviridae virus, a filoviridae virus, a porcine epidemic diarrhea virus, a bunyaviridae virus or a arenavirus.

[0054] Preferably, the virus is an influenza virus, a rhabdovirus or a coronavirus.

[0055] Preferably, the influenza virus includes Influenza A virus, Influenza B virus and Influenza C virus.

[0056] Preferably, the coronavirus subtype is SARS-CoV (SARS coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV-2 (2019 novel coronavirus), HCoV-229E, HCoV-NL63, CCoV-HuPn-2018 (Canine coronavirus).

[0057] According to another aspect of the present application, another object of the present application is to provide a method for treating viral infection diseases, the method comprising administering a therapeutically effective amount of the above-mentioned nucleoside analogue and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition to a subject in need thereof.

[0058] Advantages

[0059] The present application relates to nucleoside analogues and pharmaceutically acceptable salts thereof. It is verified by pharmacological experiments that the compounds of the present application have better inhibitory activity on RNA-dependent RNA polymerase, and can inhibit the replication of various RNA viruses, especially the influenza virus and vesicular stomatitis virus, and have better biological activity in treating the infection of the influenza virus and the vesicular stomatitis virus. Therefore, the compounds of the present application have good broad-spectrum antiviral activity, and can be used as broad-spectrum antiviral drugs to treat various viral infections, and enrich the stock of antiviral drugs. DETAILED DESCRIPTION

[0060] Hereinafter, the present application will be described in detail. Before proceeding with the description, it should be understood that the terms used in the specification and the appended claims should not be construed as limiting to the general and dictionary meanings and should be construed as having a meaning and concepts corresponding to the technical aspects of the present application based on the principle that the inventor is allowed to define the terms in order to best explain the application. Therefore, the description presented herein is merely a preferred example for the purpose of illustration and should not be intended to limit the scope of the present application, so it should be understood that other equivalent ways or modifications can be derived from the application without departing from the spirit and scope of the present application.

[0061] In this document, the terms "comprise", "comprising", "have", "having", "include", "including", or "contain", "containing" or any other similar term are open-ended connective words that are intended to encompass non-exclusive inclusion, for example, a composition or an article containing elements not expressly listed or inherent to such composition or article. In addition, unless specifically stated otherwise, the term "or" refers to inclusive "or", not exclusive "or". For example, any of the following conditions satisfy the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), A and B are both true (or exist). In addition, in this document, the terms "comprise", "comprising", "have", "having", "include", "including", "contain", "containing" are interpreted as having been specifically disclosed and encompassing "consist of" and "consist essentially of" closed or semi-closed connectives.

[0062] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0063] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0064] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0065] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0066] In the structure of the nucleoside analogs of Formula I and pharmaceutically acceptable salts thereof according to the present application, the oxime structure (HO-N=CH2-) and the hydroxylamine structure (HO-NH=CH-) are tautomers, for example, the compound of Formula I-3 is equivalent to the compound of Formula I-3' and is a tautomer, and the hydroxylamine group at the 4-position of the pyrimidine base can be represented by a hydroxyl imine.

[0067]

[0068] The compound of Formula I-4 is equivalent to the compound of Formula I-4' and is a tautomer, and the hydroxyl imine group at the 5-position of the pyrimidine base can be represented by an N'-hydroxyacetimidate.

[0069]

[0070] Definitions

[0071] The compounds of the present disclosure can contain one or more asymmetric centers and / or axial chirality, and can therefore exist in various isomeric forms (e.g., enantiomeric and / or diastereomeric forms). For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, atropisomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis. The present disclosure additionally encompasses the individual isomers substantially free of other isomers, and, optionally, mixtures of the various isomers including racemic mixtures. When stereochemistry is specifically depicted, it will be understood that, for that particular chiral center or axial chirality, the compound primarily exists in the stereo isomeric form depicted, e.g., the amount of other stereo isomers is less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC area, or both, or is not detectable. One skilled in the art, in light of the present disclosure, can determine the presence and / or amount of stereo isomers, including by using chiral HPLC.

[0072] The compounds of the disclosure can have atropisomers. In any of the embodiments described herein, when applicable, the compounds of the disclosure can exist as a mixture of atropisomers in any ratio. In some embodiments, when applicable, the compounds can exist as individual atropisomers isolated substantially free (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC area, or both, or containing an undetectable amount) of other atropisomers. Some exemplary isolated atropisomers of the compounds of the disclosure are shown in the Examples section. As understood by one skilled in the art, when rotation about a single bond (e.g., an aryl-aryl single bond) is restricted, the compound can exist as a mixture of atropisomers, and each individual atropisomer is isolatable.

[0073] When a range of values is listed, then it is intended to include each value and sub-range within the range. For example, “C 1-6 ” is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 .

[0074] The term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon radical (“C 1-20 alkyl”) having from 1 to 20 carbon atoms. In some embodiments, the alkyl group has from 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, the alkyl group has from 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, the alkyl group has from 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, the alkyl group has from 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, the alkyl group has from 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, the alkyl group has from 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, the alkyl group has from 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, the alkyl group has from 1 to 2 carbon atoms (“C 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., a halogen, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-20 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-20 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0075] "Alkenyl" refers to a group consisting of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. 2-20 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6Examples of alkenyl groups include the aforementioned C 2-4 alkenyl groups. Each example of alkenyl is, unless otherwise specified, independently optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In certain embodiments, alkenyl is unsubstituted C 2-10 alkenyl. In certain embodiments, alkenyl is substituted C 2-10 alkenyl. In alkenyl groups, the C=C double bond for which stereochemistry is not specified (e.g., -CH=CHCH3or ) can be an (E)- or (Z)-double bond.

[0076] “Alkynyl” refers to a straight or branched chain hydrocarbon group (“C 2-20 alkynyl”) having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. In some embodiments, alkynyl has 2 to 10 carbon atoms (“C 2-10 alkynyl”). In some embodiments, alkynyl has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, alkynyl has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, alkynyl has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In some embodiments, alkynyl has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, alkynyl has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, alkynyl has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, alkynyl has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, alkynyl has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2-6 Examples of alkenyl groups include the aforementioned C 2-4 alkynyl groups. Each example of alkynyl is, unless otherwise specified, independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In certain embodiments, alkynyl is unsubstituted C2-10 alkynyl. In certain embodiments, alkynyl is substituted C 2-10 alkynyl.

[0077] "Cycloalkyl" or "carbocyclyl" refers to a non-aromatic ring system having from 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl") and zero heteroatoms. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl"). Exemplary C 3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), and the like. Exemplary C 3-10 carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decyl (C 10 ), and the like. As shown by the foregoing examples, in certain embodiments, a carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the point of attachment is on the carbocyclic ring of a carbocyclic ring system as defined above with one or more aryl or heteroaryl groups, and in this case the carbon number continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ( "substituted carbocyclyl") with one or more substituents. In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 carbocyclyl. In certain embodiments, a carbocyclyl group is a substituted C 3-10Cycloalkyl.

[0078] In some embodiments, "cycloalkyl" is a monocyclic saturated carbocyclic radical ("C 3-10 cycloalkyl") having from 3 to 10 ring carbon atoms. In some embodiments, cycloalkyl has from 3 to 8 ring carbon atoms ("C 3-8 cycloalkyl"). In some embodiments, cycloalkyl has from 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, cycloalkyl has from 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, cycloalkyl has from 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl").C 5-6 Examples of cycloalkyl include cyclopentyl (C5) and cyclohexyl (C6).C 3-6 Examples of cycloalkyl include the foregoing C 5-6 cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4).C 3-8 Examples of cycloalkyl include the foregoing C 3-6 cycloalkyl as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise indicated, each instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, cycloalkyl is unsubstituted C 3-10 cycloalkyl. In certain embodiments, cycloalkyl is substituted C 3-10 cycloalkyl.

[0079] “Heterocyclyl” or “heterocyclic” refers to a group of 3- to 10-membered nonaromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3- to 10-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valence permits. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”) or fused, bridged, or spiro ring systems, e.g., bicyclic ring systems (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems in which a heterocycle as defined above is fused with one or more carbocyclyl groups at a ring carbon of the carbocyclyl or heterocycle, or a heterocycle as defined above is fused with one or more aryl or heteroaryl groups at a ring heteroatom of the heterocycle, and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclyl”) or substituted with one or more substituents (“substituted heterocyclyl”). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0080] In some embodiments, a heterocyclyl group is a 5- to 10-membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 8-membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 6-membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, a 5- to 6-membered heterocyclyl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0081] “Aryl” refers to a group of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C 10Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0082] "Aryl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group that is optionally substituted with an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0083] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) containing a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0084] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In certain embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.

[0085] The term “administering” means implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0086] The term “treatment” means reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment can be administered in the absence of visible signs or symptoms of the disease. For example, treatment can be administered to a susceptible subject pre-symptomatically (e.g., based on history of symptoms and / or based on exposure to a pathogen) to delay or prevent occurrence of the disease. Treatment can also continue after symptoms have resolved, such as to delay or prevent recurrence.

[0087] An “effective amount” of a compound described herein means an amount sufficient to elicit the desired biological response, i.e., to treat a disorder. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound described herein can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the manner of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the combined amount of a compound described herein in multiple doses.

[0088] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a disorder, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0089] The term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4alkyl)4-salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0090] The following examples are set forth by way of illustration only and not as limitations of the present application, and those skilled in the art will readily understand that modifications can be made within the scope of the present application without departing from the spirit and scope thereof. Unless otherwise indicated, the reagents and instruments used in the following examples are commercially available.

[0091] Example 1: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-5-((E)-1-(hydroxyimino)ethyl)pyrimidin-2(1H)-one A1

[0092]

[0093] Compound 3a-1 (4.9 g, 10 mmol) was added to acetonitrile (100 mL), 5- acetyluracil (1.54 g, 10 mmol) and N,O-bistrimethylsilylacetamide (4 mL, 15 mmol) were added, after addition, the reaction was refluxed for 30 min. Cooled to room temperature, added trimethylsilyl trifluoromethanesulfonate (1.9 mL, 10 mmol) under ice bath. Then reacted at 60 °C for 3 h, TLC showed that the reaction was complete. The reaction was diluted with ethyl acetate (100 mL), and NaHCO3 saturated aqueous solution (5 mL) was added to quench the reaction. The organic phase was separated, and the organic phase was washed with NaHCO3 saturated aqueous solution and saturated brine in turn, and dried over anhydrous sodium sulfate. After filtration, the solvent was rotary evaporated, and silica gel column chromatography was performed with DCM:PE:EA = 1:1:1 to obtain compound 4a-1 as a white solid (4.4 g, 73.5%). 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.55 (s, 1H), 8.03 - 7.85 (m, 6H), 7.64 (q, J = 7.3 Hz, 3H), 7.51 - 7.40 (m, 6H), 6.29 (d, J = 3.4 Hz, 1H), 6.08 - 5.87 (m, 2H), 4.90 - 4.74 (m, 1H), 4.74 - 4.56 (m, 2H), 2.42 (s, 3H).

[0094] Compound 4a-1 (4g, 6.7mmol) was added to methanol 100 mL, hydroxylamine hydrochloride (558.7mg, 8mmol) was added. Then the reaction was stirred at room temperature for 8 hours, TLC showed the reaction was complete, filtered, DCM:PE:EA=1:1:2 silica gel column chromatography to give compound 5a-1, light yellow solid (2.4g, 58.9%). 1 H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 11.09 (s, 1H), 8.01 - 7.96 (m, 2H), 7.94 - 7.85 (m, 5H), 7.68 - 7.61 (m, 3H), 7.47 (dt, J = 24.8, 7.7 Hz, 7H), 6.21 (d, J = 3.6 Hz, 1H), 6.01 - 5.82 (m, 2H), 4.74 (td, J = 5.5, 3.8 Hz, 1H), 4.71 - 4.57 (m, 2H), 1.95 (s, 3H).

[0095] Compound 5a-1 (2.2g, 3.6mmol) was added to (70mL) dichloromethane, triethylamine (729mg, 7.2mmol) and 4-dimethylaminopyridine (22mg, 0.18mmol) were added, then acetic anhydride (550mg, 5.4mmol) was added dropwise. Then the reaction was stirred at room temperature for 8 hours, TLC showed the reaction was complete, ethanol (5mL) was added to quench the reaction. DCM:EA=2:1 silica gel column chromatography to give compound 6a-1, light yellow solid (2.25g, 95.3%).

[0096] Compound 6a-1 (1g, 1.53mmol) was added to acetonitrile (15mL), N-methylpyrrolidine (2.5mL, 23mmol) was added, stirred at room temperature for 30 minutes under nitrogen protection. Under ice bath, phosphorus oxychloride (0.3mL, 3.06mmol) was added and reacted for 30 minutes under ice bath, then reacted for 2 hours at room temperature. TLC showed the reaction was complete, dichloromethane (10mL) was added to dilute the reaction, 0.5M phosphate / triethylamine buffer (30mL) was added to quench the reaction, the organic phase was separated, the organic phase was dried with anhydrous sodium sulfate. Filtered, 0.5M amine in 1,4-dioxane (5mL) was added to the filtrate, stirred at room temperature overnight. TLC showed the reaction was complete, the reaction was rotary evaporated, DCM:EA=1:2 silica gel column chromatography to give compound 7a-1, white solid (650mg, 64.9%). 1H NMR (400 MHz, DMSO-d6) δ 14.03 (s, 1H), 11.30 (s, 1H), 8.44 (s, 2H), 8.25 - 8.13 (m, 1H), 8.10 (s, 1H), 8.04 - 7.84 (m, 6H), 7.64 (qd, J = 7.1, 1.5 Hz, 3H), 7.53 - 7.34 (m, 6H), 6.15 (d, J = 2.4 Hz, 1H), 6.11 - 5.99 (m, 2H), 4.84 - 4.54 (m, 3H), 2.00 (s, 3H).

[0097] Compound 7a-1 (400 mg, 0.61 mmol) was added to 7M amine in methanol (10 mL) and stirred at room temperature overnight. TLC showed the reaction was complete, the reaction was spin dried and compound Al was obtained as a white solid (130 mg, 70.9%) by DCM:MeOH = 3:1 silica gel column chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.44 (s, 1H), 8.34 (d, J = 4.3 Hz, 1H), 7.87 (d, J = 4.6 Hz, 1H), 5.80 (d, J = 2.9 Hz, 1H), 5.43 (d, J = 5.0 Hz, 1H), 5.31 (t, J = 4.6 Hz, 1H), 5.01 (d, J = 5.9 Hz, 1H), 4.07 - 3.94 (m, 2H), 3.89 (dd, J = 5.6, 3.0 Hz, 1H), 3.68 (dddd, J = 62.2, 12.1, 4.7, 2.4 Hz, 2H), 2.05 (s, 3H). MS m / z = 301.1 [M+H] +

[0098] Example 2: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-5-((E)-1-(hydroxyimino)ethyl)pyrimidin-2(1H)-one A2

[0099]

[0100] Compound 7a-2 was prepared according to a similar method to that described in Reference Example 1 for 7a-1 as a white solid (200 mg,

[0101] 19.5%. 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.39 (s, 1H), 9.99 (s, 1H), 8.09 - 7.81 (m, 7H), 7.71 - 7.60 (m, 3H), 7.55 - 7.38 (m, 7H), 7.14 (s, 1H), 6.17 - 6.08 (m, 1H), 5.96 - 5.74 (m, 2H), 4.74 - 4.57 (m, 3H), 1.91 (s, 3H).

[0102] Compound A2 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 21.2%. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.26 (s, 1H), 9.62 (s, 1H), 7.08 (s, 1H), 5.76 (s, 1H), 5.28 (d, J = 6.2 Hz, 1H), 5.05 (d, J = 4.6 Hz, 1H), 4.97 (t, J = 5.0 Hz, 1H), 3.98 (q, J = 6.1 Hz, 1H), 3.91 (dt, J = 8.0, 3.7 Hz, 1H), 3.78 (q, J = 3.2 Hz, 1H), 3.52 (dq, J = 9.4, 5.1, 4.6 Hz, 2H), 1.93 (s, 3H). MS m / z = 317.1 [M+H] +

[0103] Example 3: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-((E)-1-(methoxyimino)ethyl)pyrimidin- 2(1H)-one A3

[0104]

[0105] Compound 4a-1 (1 g, 1.67 mmol) was added methanol (25 mL), methoxyamine hydrochloride (167 mg, 2 mmol). Then the reaction was allowed to proceed at room temperature overnight, TLC showed the reaction was complete, filtered, the filtrate was rotary evaporated, compound 5a-3 was obtained by silica gel column chromatography with PE:EA = 2:1, light yellow solid (420 mg, 59.8%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.11 - 7.80 (m, 7H), 7.80 - 7.58 (m, 3H), 7.58 - 7.34 (m, 6H), 6.25 (d, J = 3.1 Hz, 1H), 6.08 - 5.94 (m, 2H), 4.78 (td, J = 5.1, 3.2 Hz, 1H), 4.74 - 4.56 (m, 2H), 3.72 (s, 3H), 1.94 (s, 3H).

[0106] Compound 7a-3 was prepared according to a similar method as described for 7a-1 in Reference Example 1, as a white solid (260 mg, 54.9% yield).

[0107] 64.8%. 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 16.4 Hz, 3H), 8.08 - 7.96 (m, 2H), 7.88 (ddd, J = 11.9, 8.3, 1.4 Hz, 4H), 7.64 (dddt, J = 11.3, 8.8, 7.5, 1.4 Hz, 3H), 7.54 - 7.34 (m, 6H), 6.13 (d, J = 2.6 Hz, 1H), 6.05 (dd, J = 4.1, 1.3 Hz, 2H), 4.77 - 4.55 (m, 3H), 3.89 (s, 3H), 2.01 (s, 3H).

[0108] Compound A3 was prepared according to a similar method as described for Al in Reference Example 1, as a white solid, 54.9% yield. 1 H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.99 (dd, J = 105.1, 3.9 Hz, 2H), 5.80 (d, J = 2.8 Hz, 1H), 5.43 (d, J = 5.0 Hz, 1H), 5.30 (t, J = 4.6 Hz, 1H), 4.99 (d, J = 6.0 Hz, 1H), 4.06 - 3.93 (m, 2H), 3.89 (s, 4H), 3.68 (dddd, J = 78.3, 12.2, 4.7, 2.5 Hz, 2H), 2.07 (s, 3H). MS m / z

[0109] = 315.1 [M+H] +

[0110] Example 4: l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-5-((E)-l-(methoxyimino)ethyl)pyrimidin-2(lH)-one A4

[0111]

[0112] Compound 7a-4 was prepared in analogy to the preparation of 7a-1 in Reference Example 1 as a white solid (133 mg, 54.1% yield).

[0113] 52.0%). 1 H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.03 - 7.99 (m, 2H), 7.93 - 7.89 (m, 2H), 7.88 - 7.84 (m, 2H), 7.69 - 7.62 (m, 4H), 7.51 (t, J = 7.8 Hz, 2H), 7.45 (dt, J = 11.1, 7.8 Hz, 5H), 7.13 (s, 1H), 6.14 (d, J = 4.5 Hz, 1H), 5.95 - 5.86 (m, 2H), 4.75 - 4.57 (m, 3H), 3.71 (s, 3H), 3.56 (s, 3H), 1.89 (s, 3H).

[0114] Compound A4 was prepared in analogy to the preparation of A1 in Reference Example 1 as a white solid in 54.1% yield. 1 H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.01 (s, 1H), 8.03 - 7.99 (m, 2H), 7.93 - 7.89 (m, 2H), 7.88 - 7.84 (m, 2H), 7.69 - 7.62 (m, 4H), 7.51 (t, J = 7.8 Hz, 2H), 7.45 (dt, J = 11.1, 7.8 Hz, 5H), 7.13 (s, 1H), 6.14 (d, J = 4.5 Hz, 1H), 5.95 - 5.86 (m, 2H), 4.75 - 4.57 (m, 3H), 3.71 (s, 3H), 3.56 (s, 3H), 1.89 (s, 3H). +

[0115] Example 5: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (methoxyamino)-5-((E)-1-(methoxyimino)ethyl)pyrimidin-2(1H)-one A5

[0116]

[0117] Compound 7a-5 was prepared in analogy to the preparation of 7a-1 in Reference Example 1 as a white solid (200 mg, 76.5% yield).

[0118] 76.5%). 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.04 - 7.82 (m, 6H), 7.69 - 7.60 (m, 3H), 7.56 - 7.41 (m, 6H), 7.20 (s, 1H), 6.15 (d, J = 4.6 Hz, 1H), 5.90 (qd, J = 6.4, 4.8 Hz, 2H), 4.72 (td, J = 5.0, 3.4 Hz, 1H), 4.68 (dd, J = 12.1, 3.4 Hz, 1H), 4.61 (dd, J = 12.1, 5.0 Hz, 1H), 3.70 (d, J = 5.9 Hz, 6H), 1.90 (s, 3H).

[0119] Compound A5 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 71.8%. 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.29 (s, 1H), 5.74 (d, J = 6.2 Hz, 1H), 5.29 (d, J = 5.9 Hz, 1H), 5.03 (d, J = 4.7 Hz, 1H), 5.00 (t, J = 4.8 Hz, 1H), 4.00 (q, J = 5.8 Hz, 1H), 3.93 (td, J = 4.9, 3.1 Hz, 1H), 3.81 (s, 4H), 3.69 (s, 3H), 3.62 - 3.47 (m, 2H), 1.96 (s, 3H). MS m / z

[0120] = 345.1 [M+H] +

[0121] Example 6: 5-acetyl-l-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-4-(methoxyamino)pyrimidin-2(lH)- one A6 (mch-1242)

[0122]

[0123] Compound 7a-6 was prepared in analogy to the preparation of 7a-5 in Reference Example 5, light yellow solid, yield 14.3%.

[0124] 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.05 - 7.83 (m, 7H), 7.71 - 7.59 (m, 3H), 7.54 - 7.39 (m, 6H), 6.17 (d, J = 3.5 Hz, 1H), 5.91 (dd, J = 3.9, 2.1 Hz, 2H), 4.73 (td, J = 5.1, 3.7 Hz, 1H), 4.67 - 4.61 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H).

[0125] Compound A6 was prepared by analogy to the preparation of A1 in Reference Example 1, light yellow solid, yield 47.8%. 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.03 (s, 1H), 5.76 (d, J = 5.6 Hz, 1H), 5.37 (d, J = 5.7 Hz, 1H), 5.20 - 5.03 (m, 2H), 4.01 (p, J = 5.3 Hz, 1H), 3.95 (q, J = 4.7 Hz, 1H), 3.84 (q, J = 3.2 Hz, 1H), 3.75 (s, 3H), 3.57 (qdd, J = 11.6, 4.7, 3.0 Hz, 2H), 2.40 (s, 3H). MS m / z = 316.1 [M+H] +

[0126] Example 7: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-((E)-1- (methoxyimino)ethyl)pyrimidine-2,4(1H,3H)-dione A7 (mch-1441)

[0127]

[0128] Compound A7 was prepared by analogy to the preparation of A1 in Reference Example 1, light yellow solid, yield 73.3%, starting from compound 5a-3. 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.09 (s, 1H), 5.79 (d, J = 5.2 Hz, 1H), 5.40 (d, J = 5.6 Hz, 1H), 5.08 (t, J = 4.7 Hz, 2H), 4.06 (q, J = 5.3 Hz, 1H), 3.98 (hept, J = 4.4 Hz, 1H), 3.87 (q, J = 3.2 Hz, 1H), 3.82 (s, 3H), 3.68 - 3.50 (m, 2H), 2.00 (s, 3H). MS m / z = 316.1 [M+H] +

[0129] Example 8: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- ((E)-1-(hydroxyimino)ethyl)pyrimidine-2,4(1H,3H)-dione A8

[0130]

[0131] Compound A8 was prepared by the similar procedure as described in Reference Example 1 for the preparation of A1 using compound 5a-1 as the starting material, in yield of 59.9% as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.74 (s, 1H), 8.59 (s, 1H), 8.05 - 7.84 (m, 6H), 7.71 - 7.59 (m, 3H), 7.54 - 7.38 (m, 6H), 6.28 (d, J = 3.5 Hz, 1H), 6.10 - 5.91 (m, 2H), 4.80 (ddd, J = 6.5, 5.0, 3.5 Hz, 1H), 4.75 - 4.61 (m, 2H). +

[0132] Example 9: (E)-4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-2-oxo-1,2-dihydropyrimidine-5-carbaldehyde O-methyl A9

[0133]

[0134] Compound 4a-9 was prepared by the similar procedure as described in Reference Example 1 for the preparation of 4a-1, in yield of 85.5% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.74 (s, 1H), 8.59 (s, 1H), 8.05 - 7.84 (m, 6H), 7.71 - 7.59 (m, 3H), 7.54 - 7.38 (m, 6H), 6.28 (d, J = 3.5 Hz, 1H), 6.10 - 5.91 (m, 2H), 4.80 (ddd, J = 6.5, 5.0, 3.5 Hz, 1H), 4.75 - 4.61 (m, 2H).

[0135] Compound 4a-9 (1 g, 1.7 mmol) was added to dichloromethane (10 mL), methoxyamine hydrochloride (172 mg, 2.05 mmol) and triethylamine (207 mg, 2.05 mmol) were added, stirred at room temperature overnight. TLC showed the reaction was complete, filtered, the filtrate was washed with 10 mL saturated sodium bicarbonate and 10 mL saturated brine in turn, the organic phase was separated, dried over anhydrous sodium sulfate. Filtered, the solvent was evaporated, silica gel column chromatography with PE:EA = 1.5:1 to obtain compound 5a-9 as a white solid (974 mg, 93.4%). 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.24 (s, 1H), 8.05 - 7.99 (m, 2H), 7.93 - 7.87 (m, 4H), 7.86 (s, 1H), 7.69 - 7.62 (m, 3H), 7.55 - 7.39 (m, 6H), 6.27 (d, J = 3.7 Hz, 1H), 6.03 - 5.92 (m, 2H), 4.78 (td, J = 5.2, 3.4 Hz, 1H), 4.73 - 4.61 (m, 2H), 3.68 (s, 3H).

[0136] Compound 7a-9 was prepared by a similar method to that of 7a-1 in Reference Example 1, white solid, yield 92.6%. 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 3.3 Hz, 1H), 8.19 (s, 1H), 8.03 - 7.98 (m, 2H), 7.96 (s, 1H), 7.93 - 7.89 (m, 2H), 7.89 - 7.83 (m, 2H), 7.64 (dddd, J = 16.4, 9.4, 3.1, 1.7 Hz, 4H), 7.52 - 7.38 (m, 6H), 6.14 (d, J = 3.3 Hz, 1H), 6.00 - 5.92 (m, 2H), 4.77 (ddd, J = 6.6, 5.4, 3.7 Hz, 1H), 4.72 (dd, J = 12.1, 3.7 Hz, 1H), 4.64 (dd, J = 12.0, 5.5 Hz, 1H), 3.85 (s, 3H).

[0137] Compound A9 was prepared by a similar method to that of A1 in Reference Example 1, white solid, yield 61.2%. 1HNMR (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.06 (d, J = 3.3 Hz, 1H), 8.01 (s, 1H), 7.53 - 7.43 (m, 1H), 5.75 (d, J = 2.8 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 5.12 (t, J = 5.3 Hz, 1H), 5.00 (d, J = 5.3 Hz, 1H), 3.96 (h, J = 5.0 Hz, 2H), 3.85 (s, 4H), 3.65 (dddd, J = 78.1, 12.2, 5.3, 3.2 Hz, 2H). MS m / z = 301.1 [M+H] +

[0138] Example 10: (E)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (methoxyamino)-2-oxo-1,2-dihydropyrimidine-5-carbaldehyde O-methyl oxime A10

[0139]

[0140] Compound 7a-10 was prepared by a similar method to that described in Reference Example 1 for 7a-1, white solid, yield 63.0%.1HNMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.09 - 7.81 (m, 6H), 7.77 (s, 1H), 7.71 - 7.61 (m, 3H), 7.58 (s, 1H), 7.55 - 7.36 (m, 6H), 6.18 (t, J = 4.5 Hz, 1H), 5.90 (dd, J = 8.6, 3.3 Hz, 2H), 4.85 - 4.71 (m, 1H), 4.65 (tq, J = 9.3, 5.0, 4.3 Hz, 2H), 3.73 (d, J = 5.8 Hz, 3H), 3.66 (s, 3H).

[0141] Compound A10 was prepared by a similar method to that described in Reference Example 1 for A1, white solid, yield 97.3%. 1 HNMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 5.78 - 5.74 (m, 1H), 5.31 (d, J = 5.8 Hz, 1H), 5.08 - 5.02 (m, 2H), 4.00 (p, J = 5.9 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.88 (s, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.64 - 3.46 (m, 3H). MS m / z = 331.1 [M+H] +

[0142] Example 11: (E)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-2-oxo-1,2-dihydropyrimidine-5-carbaldehyde O-methyl oxime A11

[0143]

[0144] Compound 11 was prepared in analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 24.0%. 1 HNMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.16 (s, 1H), 8.05 - 7.83 (m, 6H), 7.79 (s, 1H), 7.74 - 7.61 (m, 3H), 7.59 - 7.37 (m, 7H), 6.28 - 6.12 (m, 1H), 6.04 - 5.84 (m, 2H), 4.83 - 4.70 (m, 1H), 4.70 - 4.59 (m, 2H), 3.67 (s, 3H).

[0145] Compound A11 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 48.8%. 1 HNMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.82 (s, 1H), 7.81 (s, 1H), 7.58 (s, 1H), 5.76 (d, J = 6.1 Hz, 1H), 5.30 (d, J = 5.8 Hz, 1H), 5.09 - 4.91 (m, 2H), 4.01 (q, J = 5.7 Hz, 1H), 3.95 (td, J = 5.0, 3.3 Hz, 1H), 3.80 (s, 4H), 3.56 (dddd, J = 33.5, 11.9, 5.0, 3.4 Hz, 2H). MS m / z

[0146] = 317.1 [M+H] +

[0147] Example 12: (E)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-methyl oxime A12

[0148]

[0149] Compound A12 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 65.9%. 1HNMR (500 MHz, DMSO-d6) δ 8.75 (d, J = 319.8 Hz, 1H), 7.60 (d, J = 275.4 Hz, 1H), 5.82 (dd, J = 34.2, 5.1 Hz, 1H), 5.43 (dd, J = 5.5, 1.3 Hz, 1H), 5.13 (dt, J = 7.3, 3.7 Hz, 1H), 5.11 - 4.95 (m, 1H), 4.05 (dd, J = 9.5, 4.7 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.93 - 3.87 (m, 3H), 3.82 (s, 2H), 3.63 - 3.51 (m, 2H). MS m / z = 302.1 [M+H] +

[0150] Example 13: (E)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime A13

[0151]

[0152] Compound 4a-9 (1.44 g, 2.5 mmol) was added to a mixture solvent of ethanol (40 mL) and water (15 mL), hydroxylamine hydrochloride (206 mg, 2.96 mmol) was added, stirred at room temperature overnight. TLC showed that the reaction was complete, diluted with water (50 mL) and stirred for 1 hour, filtered, and the filter cake was oven dried to obtain compound 5a-13 as a white solid (1320 mg, 89.4%). 1 H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 11.16 (s, 1H), 8.21 (s, 1H), 8.04 - 7.86 (m, 6H), 7.83 (s, 1H), 7.71 - 7.59 (m, 3H), 7.53 - 7.40 (m, 6H), 6.24 (d, J = 3.8 Hz, 1H), 5.98 (dd, J = 6.4, 3.9 Hz, 1H), 5.93 (t, J = 6.4 Hz, 1H), 4.75 (td, J = 6.1, 5.7, 4.0 Hz, 1H), 4.69 - 4.63 (m, 2H).

[0153] Compound A13 was prepared according to the preparation of A1 in Reference Example 1, white solid, yield 20.9%. 1H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.14 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 5.82 (d, J = 5.4 Hz, 1H), 5.41 (d, J = 5.6 Hz, 1H), 5.11 - 5.02 (m, 2H), 4.01 (dq, J = 48.7, 5.2 Hz, 2H), 3.87 (q, J = 3.5 Hz, 1H), 3.64 - 3.50 (m, 2H). MS m / z = 288.1 [M+H] +

[0154] Example 14: 4-amino-l-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-(l,3-dioxolan-2-yl)pyrimidin- 2(lH)-one A14

[0155]

[0156] Compound 4a-9 (1 g, 1.71 mmol) was added to toluene (15 mL), ethylene glycol (0.5 mL) was added, Amberlite IR120 (100 mg) was added, and the reaction was heated to reflux for 2 hours. TLC showed the reaction was complete, after cooling, the reaction was filtered, the organic phase was washed with 30 mL water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The compound 5a-14 was obtained as a white solid (990 mg, 92.1%) by silica gel column chromatography using PE:EA = 1:1. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.06 - 7.97 (m, 2H), 7.97 - 7.82 (m, 5H), 7.71 - 7.61 (m, 3H), 7.55 - 7.40 (m, 6H), 6.32 - 6.12 (m, 1H), 6.01 - 5.92 (m, 2H), 5.58 (s, 1H), 4.76 (td, J = 5.2, 3.1 Hz, 1H), 4.73 - 4.55 (m, 2H), 3.90 - 3.70 (m, 4H).

[0157] Compound 7a-14 was prepared according to a similar method as described in Reference Example 1 for 7a-1, white solid, 89.6% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.05 - 7.96 (m, 2H), 7.94 - 7.84 (m, 5H), 7.73 (s, 1H), 7.70 - 7.61 (m, 3H), 7.52 - 7.40 (m, 6H), 6.73 - 6.56 (m, 1H), 6.13 (d, J = 3.8 Hz, 1H), 5.98 (t, J = 6.3 Hz, 1H), 5.93 (dd, J = 6.4, 3.8 Hz, 1H), 5.40 (s, 1H), 4.78 - 4.67 (m, 2H), 4.61 (dd, J = 11.8, 5.2 Hz, 1H), 4.01 - 3.94 (m, 2H), 3.80 (td, J = 5.0, 4.6, 1.4 Hz, 2H).

[0158] Compound A14 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 48.0%. 1 H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.45 (s, 1H), 6.45 (s, 1H), 5.76 (d, J = 3.2 Hz, 1H), 5.48 (s, 1H), 5.38 - 5.28 (m, 1H), 5.10 (t, J = 5.0 Hz, 1H), 5.03 - 4.90 (m, 1H), 4.09 - 4.00 (m, 2H), 3.93 (qd, J = 4.8, 3.5 Hz, 2H), 3.90 - 3.81 (m, 3H), 3.68 (ddd, J = 12.1, 5.1, 3.0 Hz, 1H), 3.55 (ddd, J = 12.1, 5.0, 3.1 Hz, 1H). MS m / z = 316.1 [M+H] +

[0159] Example 15: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(1,3-dioxolan-2-yl)-4-(hydroxyamino)pyrimidin-2(lH)-one A15

[0160]

[0161] Compound 7a-15 was prepared in analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 85.4%. 1HNMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.93 (s, 1H), 8.07 - 7.81 (m, 6H), 7.75 - 7.59 (m, 3H), 7.59 - 7.39 (m, 6H), 7.16 (s, 1H), 6.14 (d, J = 4.7 Hz, 1H), 5.90 (qd, J = 6.3, 4.8 Hz, 2H), 5.52 (d, J = 0.7 Hz, 1H), 4.79 - 4.56 (m, 3H), 3.81 - 3.69 (m, 4H).

[0162] Compound A15 was prepared by analogy to the preparation of A1 in Reference Example 1, white solid, yield 80.63%. 1 HNMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.93 (s, 1H), 8.07 - 7.81 (m, 6H), 7.75 - 7.59 (m, 3H), 7.59 - 7.39 (m, 6H), 7.16 (s, 1H), 6.14 (d, J = 4.7 Hz, 1H), 5.90 (qd, J = 6.3, 4.8 Hz, 2H), 5.52 (d, J = 0.7 Hz, 1H), 4.79 - 4.56 (m, 3H), 3.81 - 3.69 (m, 4H). +

[0163] Example 16: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(1,3-dioxolan-2-yl)-4-(methoxyamino)pyrimidin-2(lH)-one A16

[0164]

[0165] Compound 7a-16 was prepared by analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 79.5%. 1 HNMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.93 (s, 1H), 8.07 - 7.81 (m, 6H), 7.75 - 7.59 (m, 3H), 7.59 - 7.39 (m, 6H), 7.16 (s, 1H), 6.14 (d, J = 4.7 Hz, 1H), 5.90 (qd, J = 6.3, 4.8 Hz, 2H), 5.52 (d, J = 0.7 Hz, 1H), 4.79 - 4.56 (m, 3H), 3.81 - 3.69 (m, 4H).

[0166] Compound A16 was prepared by a similar method to that of A1 in Reference Example 1, white solid, yield 88.1%. 1 HNMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.43 (s, 1H), 5.75 (d, J = 5.9 Hz, 1H), 5.60 (s, 1H), 5.28 (d, J = 5.8 Hz, 1H), 5.03 (dt, J = 4.9, 2.5 Hz, 2H), 4.00 - 3.89 (m, 4H), 3.82 (qd, J = 6.3, 5.5, 2.2 Hz, 3H), 3.69 (s, 3H), 3.55 (qdd, J = 11.8, 4.8, 3.1 Hz, 2H). MS m / z = 346.0 [M+H] +

[0167] Example 17: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(1,3-dioxolan-2-yl)pyrimidine-2,4(1H,3H)-dione A17

[0168]

[0169] Compound A17 was prepared by a similar method to that of A1 in Reference Example 1, white solid, yield 88.3%. 1 HNMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.15 (s, 1H), 5.79 (d, J = 5.0 Hz, 1H), 5.66 (s, 1H), 5.40 (d, J = 5.5 Hz, 1H), 5.14 (t, J = 4.6 Hz, 1H), 5.08 (d, J = 5.1 Hz, 1H), 4.02 (q, J = 5.1 Hz, 1H), 3.96 (tdd, J = 7.3, 4.5, 1.6 Hz, 3H), 3.89 - 3.86 (m, 1H), 3.86 - 3.81 (m, 2H), 3.61 (dddd, J = 41.6, 12.0, 4.7, 2.9 Hz, 2H). MS m / z = 317.1 [M+H] +

[0170] Example 18: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(dimethoxymethyl)pyrimidin-2(1H)-one A18

[0171]

[0172] Compound 4a-9 (600 mg, 1.03 mmol) was added to methanol (20 mL), Amberlite IR120 (100 mg) was added, stirred at room temperature overnight. TLC showed the reaction was complete, filtered, solvent was evaporated, PE:EA = 1.5:1 silica gel column chromatography to give compound 5a-18 as a white solid (250 mg, 38.6%). 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.14

[0173] -7.82 (m, 6H), 7.79 (s, 1H), 7.66 (dddt, J = 14.3, 8.9, 7.3, 1.3 Hz, 3H), 7.60 - 7.41 (m, 6H), 6.32

[0174] -6.19 (m, 1H), 6.02 - 5.86 (m, 2H), 5.17 (d, J = 0.7 Hz, 1H), 4.76 (td, J = 4.8, 3.1 Hz, 1H), 4.73 - 4.56 (m, 2H), 3.16 (s, 3H), 3.11 (s, 3H).

[0175] Compound 7a-18 was prepared by a similar method to 7a-1 in Reference Example 1, white solid, yield 60.2%. 1 H NMR (500 MHz, DMSO-d6) δ 8.08 - 8.01 (m, 2H), 7.93 - 7.89 (m, 2H), 7.89 - 7.84 (m, 2H), 7.79 (s, 1H), 7.70 - 7.59 (m, 4H), 7.54 - 7.41 (m, 6H), 6.61 (s, 1H), 6.18 (d, J = 4.1 Hz, 1H), 6.00 (t, J = 6.2 Hz, 1H), 5.94 (dd, J = 6.3, 4.1 Hz, 1H), 5.14 (s, 1H), 4.80 - 4.64 (m, 2H), 4.61 (dd, J = 12.0, 5.1 Hz, 1H), 3.16 (s, 3H), 3.12 (s, 3H).

[0176] Compound A18 was prepared by a similar method to A1 in Reference Example 1, white solid, yield 37.7%. 1HNMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.39 (d, J = 22.3 Hz, 1H), 6.39 (s, 1H), 5.76 (d, J = 3.7 Hz, 1H), 5.32 (d, J = 5.0 Hz, 1H), 5.11 (s, 1H), 5.05 (t, J = 4.9 Hz, 1H), 4.98 (d, J = 5.3 Hz, 1H), 3.93 (h, J = 4.9 Hz, 2H), 3.84 (dt, J = 5.3, 3.1 Hz, 1H), 3.61 (dddd, J = 64.8, 11.9, 5.0, 3.2 Hz, 2H), 3.24 (s, 6H). MS m / z = 318.1 [M+H] +

[0177] Example 19: l-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- (dimethoxymethyl)-4-(hydroxyamino)pyrimidin-2(lH)-one A19

[0178]

[0179] Compound 19 was prepared by a similar method to that described in Reference Example 1 for 7a-1, white solid, yield 81.6%. 1 HNMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.86 (s, 1H), 8.12 - 8.01 (m, 2H), 8.00 - 7.92 (m, 2H), 7.88 - 7.80 (m, 2H), 7.73 - 7.60 (m, 3H), 7.57 - 7.39 (m, 6H), 7.15 - 7.06 (m, 1H), 6.18 (d, J = 5.2 Hz, 1H), 6.04 - 5.76 (m, 2H), 5.07 (d, J = 0.8 Hz, 1H), 4.73 (td, J = 4.6, 3.2 Hz, 1H), 4.70 - 4.57 (m, 2H), 3.12 (s, 3H), 3.07 (s, 3H).

[0180] Compound A19 was prepared by a similar method to that described in Reference Example 1 for Al, white solid, yield 78.0%. 1HNMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.52 (s, 1H), 7.18 (d, J = 0.8 Hz, 1H), 5.76 (d, J = 6.2 Hz, 1H), 5.25 (d, J = 5.9 Hz, 1H), 5.07 (d, J = 0.8 Hz, 1H), 5.03 (d, J = 4.7 Hz, 1H), 4.94 (t, J = 4.8 Hz, 1H), 4.02 - 3.89 (m, 2H), 3.79 (q, J = 3.3 Hz, 1H), 3.51 (tdd, J = 11.7, 4.8, 3.4 Hz, 2H), 3.23 (d, J = 2.0 Hz, 6H). MS m / z = 332.1 [M-H] +

[0181] Example 20: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- (dimethoxymethyl)-4-(methoxyamino)pyrimidin-2(lH)-one A20

[0182]

[0183] Compound 7a-20 was prepared by analogy to the procedure described in Reference Example 1 for 7a-1, white solid, yield 65.5%. 1 HNMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.09 - 8.01 (m, 2H), 7.98 - 7.92 (m, 2H), 7.88 - 7.79 (m, 2H), 7.71 - 7.59 (m, 3H), 7.56 - 7.38 (m, 6H), 7.16 (s, 1H), 6.18 (d, J = 5.3 Hz, 1H), 6.00 - 5.78 (m, 2H), 5.07 (s, 1H), 4.74 (td, J = 4.6, 3.1 Hz, 1H), 4.70 - 4.55 (m, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 3.07 (s, 3H).

[0184] Compound A20 was prepared by analogy to the procedure described in Reference Example 1 for Al, white solid, yield 79.5%. 1HNMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.28 (s, 1H), 5.75 (d, J = 6.1 Hz, 1H), 5.27 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 5.04 (d, J = 4.7 Hz, 1H), 4.96 (t, J = 4.7 Hz, 1H), 3.96 (q, J = 5.7 Hz, 1H), 3.91 (td, J = 4.9, 3.1 Hz, 1H), 3.80 (q, J = 3.3 Hz, 1H), 3.69 (s, 3H), 3.56 - 3.48 (m, 2H), 3.24 (d, J = 2.0 Hz, 6H). MS m / z = 346.0 [M-H] +

[0185] Example 21 : 1 -((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- (dimethoxymethyl)pyrimidine-2,4(1 H,3H)-dione A21

[0186]

[0187] Compound A21 was prepared according to a similar method to that described for the preparation of A1 in Reference Example 1, white solid, yield 68.7%. 1 HNMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.28 (s, 1H), 5.75 (d, J = 6.1 Hz, 1H), 5.27 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 5.04 (d, J = 4.7 Hz, 1H), 4.96 (t, J = 4.7 Hz, 1H), 3.96 (q, J = 5.7 Hz, 1H), 3.91 (td, J = 4.9, 3.1 Hz, 1H), 3.80 (q, J = 3.3 Hz, 1H), 3.69 (s, 3H), 3.56 - 3.48 (m, 2H), 3.24 (d, J = 2.0 Hz, 6H). MS m / z = 346.0 [M-H] +

[0188] Example 22: 5-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)isoxazolo[5,4- d]pyrimidin-6(5H)-one A22

[0189]

[0190] Compound 5a-13 (200 mg, 0.33 mmol) was added to THF (10 mL), triphenylphosphine (131.1 mg, 0.5 mmol) and diisopropyl azodicarboxylate (101.2 mg, 0.5 mmol) were added and stirred at room temperature overnight. TLC showed the reaction was complete, filtered, solvent was evaporated and compound 7a-22 was obtained as a white solid (169 mg, 87.0) % by silica gel column chromatography with PE:EA = 1.5:1. 1 HNMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.81 (s, 1H), 8.04 - 7.96 (m, 2H), 7.94 - 7.88 (m, 2H), 7.85 - 7.81 (m, 2H), 7.71 - 7.59 (m, 3H), 7.53 - 7.37 (m, 6H), 6.20 (d, J = 3.1 Hz, 1H), 6.00 - 5.89 (m, 2H), 4.79 (td, J = 5.7, 3.8 Hz, 1H), 4.75 - 4.66 (m, 2H), 1.18 (d, J = 6.3 Hz, 5H).

[0191] Compound A22 was prepared by a similar method to that of A1 in Reference Example 1, white solid, yield 64.8%. 1 HNMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.96 (s, 1H), 5.65 (d, J = 2.8 Hz, 1H), 5.52 (d, J = 4.9 Hz, 1H), 5.39 (t, J = 4.7 Hz, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.05 (td, J = 4.8, 2.8 Hz, 1H), 4.02 - 3.93 (m, 1H), 3.93 - 3.85 (m, 1H), 3.68 (dddd, J = 83.4, 12.2, 4.7, 2.6 Hz, 2H). MS m / z

[0192] = 270.0 [M+H] +

[0193] Example 23: 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide A23

[0194]

[0195] Compound 3a’-23 was synthesized by a reported method (Eur J Med Chem. 2011; 46(9):4178- 4183.).

[0196] 5-ureidomethyl-2-oxo-1,2-dihydropyrimidine-5-carboxamide (368.3 mg, 2 mmol) was added to dichloroethane (10 mL) and N,O-bistrimethylsilylacetamide (0.8 mL, 3 mmol) was added and the reaction was refluxed for 2 hours. The reaction was cooled and a solution of compound 3a'-24 (804.1 mg. 1.9 mmol) in 5 mL of dichloroethane was added and the reaction was refluxed overnight. The reaction was neutralized with saturated aqueous NaHC03solution and the organic phase was separated and washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated after filtration and the residue was purified by column chromatography on silica gel using DCM:MeOH = 20:1 to give compound 4a-23 as a white solid (500 mg, 47.5) %.

[0197] Compound A23 was prepared by a similar method to that described for A1 in Reference Example 1 as a white solid in 33% yield.1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.09 (d, J = 3.7 Hz, 1H), 7.61 (d, J = 3.7 Hz, 1H), 6.12 (dd, J = 17.6, 3.7 Hz, 1H), 5.94 (d, J = 4.9 Hz, 1H), 5.26 - 4.93 (m, 2H), 4.22 (dtd, J = 19.1, 4.7, 2.4 Hz, 1H), 3.86 (q, J = 4.9 Hz, 1H), 3.60 (hept, J = 6.3 Hz, 2H). MS m / z = 290.0 [M+H] +

[0198] Example 24: 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidine-5- carboxamide A24

[0199]

[0200] Compound 7a-24 was prepared by a similar method to that described for 7a-1 in Reference Example 1 as a white solid in 72.3% yield.

[0201] Compound A24 was prepared by a similar method to that described for A1 in Reference Example 1 as a white solid in 52.8% yield. 1HNMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.11 (d, J = 3.5 Hz, 1H), 7.73 (d, J = 3.4 Hz, 1H), 6.11 (dd, J = 16.3, 3.9 Hz, 1H), 5.90 (d, J = 4.9 Hz, 1H), 5.17 (q, J = 6.3, 5.8 Hz, 1H), 5.06 (dt, J = 52.3, 3.3 Hz, 1H), 4.27 - 4.18 (m, 1H), 3.87 (q, J = 4.7 Hz, 1H), 3.76 (s, 3H), 3.68 - 3.54 (m, 2H). MS m / z = 304.1 [M+H] +

[0202] Example 25: Methyl 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-4-(methoxyamino)-2-oxo-1,2-dihydropyrimidine-5-carboxylate A25

[0203]

[0204] Compound 4a-25 was prepared by analogy with the preparation of 4a-1 in Reference Example 1, white solid, yield 55.7%. 1 HNMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.05 - 7.98 (m, 2H), 7.89 (ddd, J = 17.1, 8.2, 1.4 Hz, 4H), 7.70 - 7.60 (m, 3H), 7.52 - 7.39 (m, 6H), 6.27 (d, J = 3.5 Hz, 1H), 6.01 (dq, J = 7.6, 6.0, 4.9 Hz, 2H), 4.81 (td, J = 5.2, 3.4 Hz, 1H), 4.73 - 4.60 (m, 2H), 4.05 (dq, J = 10.9, 7.1 Hz, 1H), 3.92 (dq, J = 10.9, 7.1 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H).

[0205] Compound 7a-25 was prepared by analogy with the preparation of 7a-1 in Reference Example 1, white solid, yield 88.5%. 1 HNMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.05 - 7.98 (m, 2H), 7.89 (ddd, J = 17.1, 8.2, 1.4 Hz, 4H), 7.70 - 7.60 (m, 3H), 7.52 - 7.39 (m, 6H), 6.27 (d, J = 3.5 Hz, 1H), 6.01 (dq, J = 7.6, 6.0, 4.9 Hz, 2H), 4.81 (td, J = 5.2, 3.4 Hz, 1H), 4.73 - 4.60 (m, 2H), 4.05 (dq, J = 10.9, 7.1 Hz, 1H), 3.92 (dq, J = 10.9, 7.1 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H).

[0206] 12.4, 7.0, 1.4 Hz, 4H), 7.70 - 7.61 (m, 3H), 7.54 - 7.42 (m, 6H), 6.20 - 6.15 (m, 1H), 5.96 - 5.91 (m, 2H), 4.80 - 4.72 (m, 1H), 4.70 - 4.59 (m, 2H), 3.95 (ddq, J = 56.5, 10.9, 7.1 Hz, 2H), 3.73 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H).

[0207] Compound A25 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 85.5%. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.24 (s, 1H), 5.74 (d, J = 5.3 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 5.12 (t, J = 4.6 Hz, 1H), 5.08 (d, J = 4.9 Hz, 1H), 4.03 - 3.93 (m, 2H), 3.85 (q, J = 3.0 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.64 - 3.50 (m, 2H). MS m / z = 332.0 [M+H] +

[0208] Example 26: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- methoxy-4-(methoxyamino)pyrimidin-2(lH)-one A26

[0209]

[0210] Compound 4a-26 was prepared in analogy to the preparation of 4a-1 in Reference Example 1, white solid, yield 71.6%. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.24 (s, 1H), 5.74 (d, J = 5.3 Hz, 1H), 5.37 (d, J = 5.6 Hz, 1H), 5.12 (t, J = 4.6 Hz, 1H), 5.08 (d, J = 4.9 Hz, 1H), 4.03 - 3.93 (m, 2H), 3.85 (q, J = 3.0 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.64 - 3.50 (m, 2H). MS m / z = 332.0 [M+H]

[0211] Compound 7a-26 was prepared in analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 82.4%. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.07 - 7.82 (m, 6H), 7.73 - 7.60 (m, 3H), 7.57 - 7.40 (m, 6H), 6.69 (s, 1H), 6.17 (d, J = 4.8 Hz, 1H), 5.92 (t, J = 4.2 Hz, 2H), 4.71 (dq, J = 7.0, 3.5 Hz, 2H), 4.68 - 4.61 (m, 1H), 3.71 (s, 3H), 3.47 (s, 3H).

[0212] Compound A26 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 69.2%. 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 6.96 (s, 1H), 5.76 (d, J = 5.6 Hz, 1H), 5.24 (d, J = 5.9 Hz, 1H), 5.16 (t, J = 4.8 Hz, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.06 - 3.95 (m, 2H), 3.81 (q, J = 3.1 Hz, 1H), 3.71 (s, 3H), 3.66 - 3.52 (m, 5H). MS m / z = 304.1 [M+H] +

[0213] Example 27: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-5-methoxyprimidine-2(lH)-one A27

[0214]

[0215] Compound 7a-27 was prepared in analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 71.2%. 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.07 - 7.82 (m, 6H), 7.73 - 7.60 (m, 3H), 7.57 - 7.40 (m, 6H), 6.69 (s, 1H), 6.17 (d, J = 4.8 Hz, 1H), 5.92 (t, J = 4.2 Hz, 2H), 4.71 (dq, J = 7.0, 3.5 Hz, 2H), 4.68 - 4.61 (m, 1H), 3.71 (s, 3H), 3.47 (s, 3H).

[0216] Compound A27 was prepared by a similar method to the preparation of A1 in Reference Example 1, white solid, yield 28.0%. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.40 (s, 1H), 6.86 (s, 1H), 5.76 (d, J = 5.8 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H), 5.14 (t, J = 4.8 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.04 (q, J = 5.7 Hz, 1H), 3.97 (td, J = 5.0, 3.4 Hz, 1H), 3.80 (q, J = 3.1 Hz, 1H), 3.66 - 3.50 (m, 5H). MS m / z

[0217] = 290.1 [M+H] +

[0218] Example 28: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione A28

[0219]

[0220] Compound 4a-28 was prepared by a similar method to the preparation of 4a-1 in Reference Example 1, white solid, yield 58.7%. 1 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.71 (dd, J = 4.8, 1.9 Hz, 1H), 8.41 (dd, J = 7.7, 1.9 Hz, 1H), 7.98 - 7.90 (m, 4H), 7.85 - 7.77 (m, 2H), 7.71 - 7.55 (m, 3H), 7.51 - 7.30 (m, 8H), 6.27 (d, J = 3.8 Hz, 2H), 4.82 - 4.64 (m, 2H), 4.56 (dd, J = 12.0, 5.3 Hz, 1H).

[0221] Compound A28 was prepared by a similar method to the preparation of A1 in Reference Example 1, white solid, yield 65.7%. 1HNMR (400 MHz, Chloroform-d) δ 11.81 (s, 1H), 8.70 (dd, J = 4.7, 1.9 Hz, 1H), 8.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.38 (dd, J = 7.7, 4.8 Hz, 1H), 6.67 (s, 1H), 5.08 (d, J = 5.0 Hz, 1H), 4.91 (d, J = 6.6 Hz, 1H), 4.64 (dt, J = 19.6, 5.6 Hz, 2H), 4.24 (d, J = 6.6 Hz, 1H), 3.74 (td, J = 6.5, 3.3 Hz, 1H), 3.65 (ddd, J = 11.7, 5.3, 3.4 Hz, 1H), 3.46 (dt, J = 11.7, 6.4 Hz, 1H). MS m / z = 296.0 [M+H] +

[0222] Example 29: 4-amino-l-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)pyrido[2,3-d]pyrimidin-2(lH)-one A29

[0223]

[0224] Compound 7a-29 was prepared by analogy to the procedure for the preparation of 7a-1 in Reference Example 1, white solid, yield 56.1%. 1 HNMR (400 MHz, Chloroform-d) δ 11.81 (s, 1H), 8.70 (dd, J = 4.7, 1.9 Hz, 1H), 8.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.38 (dd, J = 7.7, 4.8 Hz, 1H), 6.67 (s, 1H), 5.08 (d, J = 5.0 Hz, 1H), 4.91 (d, J = 6.6 Hz, 1H), 4.64 (dt, J = 19.6, 5.6 Hz, 2H), 4.24 (d, J = 6.6 Hz, 1H), 3.74 (td, J = 6.5, 3.3 Hz, 1H), 3.65 (ddd, J = 11.7, 5.3, 3.4 Hz, 1H), 3.46 (dt, J = 11.7, 6.4 Hz, 1H). MS m / z = 296.0 [M+H]

[0225] Compound A29 was prepared by analogy to the procedure for the preparation of Al in Reference Example 1, white solid, yield 55.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (dd, J = 4.7, 1.7 Hz, 1H), 8.49 (dd, J = 8.0, 1.8 Hz, 1H), 8.28 - 8.13 (m, 2H), 7.31 (dd, J = 7.9, 4.7 Hz, 1H), 6.73 (s, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.81 (d, J = 6.4 Hz, 1H), 4.74 - 4.62 (m, 2H), 4.24 (q, J = 6.2 Hz, 1H), 3.74 (td, J = 6.1, 3.0 Hz, 1H), 3.64 (ddd, J = 11.7, 4.8, 3.1 Hz, 1H), 3.53 - 3.39 (m, 1H). MS m / z = 295.1 [M+H] +

[0226] Example 30: l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)pyrido[2,3-d]pyrimidin-2(lH)-one A30

[0227]

[0228] Compound 7a-30 was prepared by analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 54.0%. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.42 (s, 1H), 8.44 (dd, J = 4.8, 1.8 Hz, 1H), 8.20 (dd, J = 7.8, 1.8 Hz, 1H), 7.92 (td, J = 8.9, 8.3, 3.5 Hz, 4H), 7.83 (d, J = 7.7 Hz, 2H), 7.68 - 7.56 (m, 3H), 7.42 (dt, J = 32.4, 7.6 Hz, 7H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 6.24 (d, J = 5.7 Hz, 2H), 4.78 - 4.62 (m, 2H), 4.54 (dd, J = 11.9, 5.3 Hz, 1H).

[0229] Compound A30 was prepared by analogy to the preparation of Al in Reference Example 1, white solid, yield 59.1%. 1HNMR(400MHz,DMSO-d6)δ10.79(s,1H),10.07(s,1H),8.43(dd,J=4.9,1.9Hz,1H),8.15 (dd,J=7.8,1.8Hz,1H),7.20(dd,J=7.8,4.8Hz,1H),6.53(s,1H),5.05(d,J=5.0Hz,1H) ,4.84(d,J=6.6Hz,1H),4.62(q,J=5.0,4.5Hz,2H),4.20(d,J=6.5Hz,1H),3.70(td,J=6 .4,3.3Hz,1H),3.63(ddd,J=11.6,5.2,3.4Hz,1H),3.44(dt,J=11.6,6.4Hz,1H).MSm / z

[0230] =311.1[M+H] +

[0231] Example 31: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(methoxyamino)pyrido[2,3-d]pyrimidin-2(1H)-one A31

[0232]

[0233] Compound 7a-31 was prepared using a similar method to that used for 7a-1 in Example 1. It was a white solid with a yield of 82.3%. 1 HNMR(400MHz,DMSO-d6)δ10.71(s,1H),8.51–8.42(m,1H),8.19(dd,J=7.6,1.5Hz,1H),7.99–7.76(m,7H),7.67–7.56(m,3H),7.4 1(dt,J=33.2,7.6Hz,7H),7.24(dd,J=7.9,4.7Hz,1H),6.23(s,2H),4.76–4.63(m,2H),4.54(dd,J=11.6,5.2Hz,1H),3.87(s,3H).

[0234] Compound A31 was prepared using a similar method to that used for A1 in Example 1. It was a white solid with a yield of 89.9%. 1HNMR (400 MHz, Chloroform-d) δ 10.40 (s, 1H), 8.46 (dd, J = 4.7, 1.8 Hz, 1H), 8.15 (dd, J = 7.8, 1.9 Hz, 1H), 7.21 (dd, J = 7.8, 4.8 Hz, 1H), 6.54 (s, 1H), 5.05 (d, J = 5.1 Hz, 1H), 4.85 (d, J = 6.6 Hz, 1H), 4.61 (td, J = 5.6, 3.7 Hz, 2H), 4.20 (q, J = 6.5 Hz, 1H), 3.84 (s, 3H), 3.71 (td, J = 6.5, 3.3 Hz, 1H), 3.63 (ddd, J = 11.6, 5.3, 3.4 Hz, 1H), 3.44 (dt, J = 11.6, 6.4 Hz, 1H). MS m / z

[0235] = 325.1 [M+H] +

[0236] Example 32: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1,5,6,7-tetrahydro-2H- cyclopenta[d]pyrimidin-2-one A32

[0237]

[0238] Compound 4a-32 was prepared by analogy with the procedure described for 4a-1 in Reference Example 1, white solid, yield 75.4%. 1 HNMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.99 (dd, J = 8.2, 1.4 Hz, 2H), 7.88 (ddd, J = 9.7, 8.1, 1.4 Hz, 4H), 7.68 - 7.59 (m, 3H), 7.53 - 7.39 (m, 6H), 6.11 - 5.95 (m, 2H), 5.85 (d, J = 1.7 Hz, 1H), 4.78 - 4.62 (m, 2H), 4.56 (dd, J = 12.8, 5.8 Hz, 1H), 2.92 (q, J = 6.6 Hz, 2H), 2.54 (d, J = 7.4 Hz, 2H), 1.96 (p, J = 7.6 Hz, 2H).

[0239] Compound 7a-32 was prepared by analogy with the procedure described for 7a-1 in Reference Example 1, white solid, yield 70.4%. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 7.7 Hz, 2H), 7.88 (dd, J = 7.7, 4.6 Hz, 4H), 7.69 - 7.56 (m, 3H), 7.52 (s, 1H), 7.49 - 7.34 (m, 6H), 7.04 (s, 1H), 6.12 (t, J = 7.2 Hz, 1H), 6.04 (dd, J = 6.6, 2.0 Hz, 1H), 5.78 (d, J = 2.1 Hz, 1H), 4.66 (dq, J = 10.4, 3.8 Hz, 2H), 4.60 - 4.50 (m, 1H), 2.86 (t, J = 7.8 Hz, 2H), 2.54 (t, J = 7.7 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H).

[0240] Compound A32 was prepared by analogy to the preparation of A1 in Reference Example 1, white solid, yield 66.2%. 1 H NMR (400 MHz, Chloroform-d) δ 6.91 (s, 1H), 5.38 (d, J = 5.5 Hz, 1H), 5.09 (d, J = 6.2 Hz, 1H), 4.99 (dd, J = 7.9, 3.8 Hz, 1H), 4.92 (d, J = 5.6 Hz, 1H), 4.58 (q, J = 5.8 Hz, 1H), 4.06 (q, J = 5.4 Hz, 1H), 3.76 (q, J = 3.9 Hz, 1H), 3.59 (dt, J = 11.9, 3.3 Hz, 1H), 3.45 (ddd, J = 12.0, 7.9, 4.3 Hz, 1H), 2.87 (dtd, J = 24.6, 16.9, 8.4 Hz, 2H), 2.56 - 2.51 (m, 2H), 2.00 (p, J = 7.5 Hz, 2H). MS m / z = 284.1 [M+H] +

[0241] Example 33: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1,5,6,7-tetrahydro-2H- cyclopenta[d]pyrimidin-2-one A33

[0242]

[0243] Compound 7a-33 was prepared by analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 67.7. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.84 (s, 1H), 8.05 - 7.95 (m, 2H), 7.88 (ddd, J = 12.2, 8.3, 1.5 Hz, 4H), 7.72 - 7.59 (m, 3H), 7.54 - 7.34 (m, 7H), 6.09 - 5.95 (m, 2H), 5.70 (d, J = 1.8 Hz, 1H), 4.71 - 4.59 (m, 2H), 4.59 - 4.49 (m, 1H), 2.75 (t, J = 7.7 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.96 (dd, J = 14.2, 6.9 Hz, 2H).

[0244] Compound A33 was prepared by analogy to the preparation of A1 in Reference Example 1, white solid, yield 38.6%. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.39 (s, 1H), 5.32 (d, J = 5.1 Hz, 1H), 5.13 (d, J = 5.8 Hz, 1H), 4.90 (d, J = 6.1 Hz, 1H), 4.70 (dd, J = 6.4, 5.2 Hz, 1H), 4.39 (q, J = 5.7 Hz, 1H), 3.98 (q, J = 5.9 Hz, 1H), 3.66 (td, J = 5.4, 3.6 Hz, 1H), 3.58 (ddd, J = 11.8, 5.1, 3.7 Hz, 1H), 3.44 (dt, J = 11.8, 5.9 Hz, 1H), 2.84 - 2.61 (m, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.96 (ddt, J = 12.9, 8.6, 4.6 Hz, 2H). MS m / z = 300.1 [M+H] +

[0245] Example 34: 1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 1,5,6,7-tetrahydro-2H-cyclopenta[d]pyrimidine-2,4(3H)-dione A34

[0246]

[0247] Compound 1a-34 (10 g, 26.6 mmol) was added to a mixed solvent of tetrahydrofuran (80 mL) and methyl tert-butyl methyl ether (20 mL), and a tetrahydrofuran solution (1.0 M, 29.6 mL) of lithium tri-tert-butoxyaluminum hydride was added dropwise at -20 °C. The reaction was continued at -20 °C for 3 hours. 4-Dimethylaminopyridine (1.6 g, 13.3 mmol) and acetic anhydride (1.49 g, 14.6 mmol) were added to the reaction solution, and the reaction was continued at -20 °C for 1 hour. The reaction solution was diluted with ethyl acetate (300 mL), and the organic phase was washed with water (100 mL x 3) and a saturated brine solution (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The product 3a-34 was obtained as a white solid (8 g, 71.6%) by recrystallization with n-hexane.1H NMR (400 MHz, Chloroform-d) δ 8.22-7.96 (m, 4H), 7.67-7.61 (m, 1H), 7.60-7.53 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.45-7.36 (m, 2H), 6.28 (d, J = 7.1 Hz, 1H), 5.91 (dt, J = 14.7, 7.4 Hz, 1H), 4.76 (ddd, J = 12.1, 3.7, 1.2 Hz, 1H), 4.58 (dt, J = 7.3, 4.2 Hz, 1H), 4.50 (dd, J = 12.2, 4.7 Hz, 1H), 2.00 (s, 3H).

[0248] Compound 6,7-dihydro-1H-cyclopenta[D]pyrimidine-2,4(3H,5H)-dione (912.9 mg, 6 mmol) was added to chlorobenzene (30 mL), and N,O-bistrimethylsilylacetamide (3.36 mL, 13.5 mmol) was added. The reaction was continued at 80 °C for 2 hours, and a solution of 3a-35 (227. mg, 5.4 mmol) in chlorobenzene (15 mL) was added. Tin tetrachloride (3.6 mL, 30 mmol) was added at ice bath, and the reaction was continued at 80 °C overnight. TLC showed that the reaction was complete, and the reaction solution was diluted with 40 mL of ethyl acetate. The pH of the reaction solution was adjusted to 6-7 with a saturated sodium bicarbonate solution, and the organic phase was separated. The organic phase was washed with a saturated brine solution (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. Compound 4a-34 was obtained as a white solid (600 mg, 19.5%) by silica gel column chromatography with PE:EA = 2:1.

[0249] Compound A34 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 20.8%.1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 6.13 (d, J = 22.4 Hz, 1H), 6.02 (d, J = 6.3 Hz, 1H), 5.55 (d, J = 4.4 Hz, 1H), 4.12 - 3.87 (m, 1H), 3.79 (d, J = 26.5 Hz, 1H), 3.66 - 3.49 (m, 2H), 3.07 - 2.79 (m, 2H), 2.42 (td, J = 14.8, 7.2 Hz, 2H), 1.93 - 1.79 (m, 2H). MS m / z = 305.1 [M+H] +

[0250] Example 35: 1-((2R,3R,4S,5S)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-1,5,6,7-tetrahydro-2H-cyclopenta[d]pyrimidine-2,4(3H)-dione A35

[0251]

[0252] Compound 4a-35 was prepared in analogy to the preparation of 4a-24 in Reference Example 24, white solid, yield 19.2%.

[0253] Compound A35 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 86.3%.1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 5.81 (d, J = 5.6 Hz, 1H), 5.70 (dd, J = 23.9, 5.5 Hz, 1H), 5.61 (dt, J = 10.9, 5.2 Hz, 1H), 4.83 (dd, J = 6.4, 4.8 Hz, 1H), 4.27 (ddt, J = 23.7, 8.7, 5.8 Hz, 1H), 4.20 - 4.11 (m, 1H), 3.60 (ddd, J = 13.8, 4.4, 1.8 Hz, 1H), 3.44 (ddd, J = 12.3, 6.4, 4.5 Hz, 1H), 2.97 - 2.76 (m, 2H), 2.53 (d, J = 1.7 Hz, 2H), 1.99 (p, J = 7.5 Hz, 2H). MS m / z = 287.0 [M+H] +

[0254] Example 36: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5,6,7,8-tetrahydroquinolin-2(1H)-one A36

[0255]

[0256] Compound 4a-36 was prepared in analogy to the preparation of 4a-1 in Reference Example 1, white solid, yield 29.2%. 1 HNMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.02 - 7.96 (m, 2H), 7.94 - 7.89 (m, 2H), 7.87 - 7.81 (m, 2H), 7.66 - 7.58 (m, 3H), 7.51 - 7.37 (m, 7H), 6.13 - 6.04 (m, 2H), 6.00 (d, J = 1.4 Hz, 1H), 4.67 - 4.60 (m, 2H), 4.59 - 4.47 (m, 1H), 2.61 - 2.52 (m, 2H), 2.35 - 2.12 (m, 2H), 1.79 - 1.36 (m, 4H).

[0257] Compound 7a-36 was prepared in analogy to the preparation of 7a-1 in Reference Example 1, white solid, yield 55.1%. 1 HNMR (400 MHz, DMSO-d6) δ 8.01 - 7.95 (m, 2H), 7.92 - 7.81 (m, 4H), 7.61 (td, J = 7.5, 6.0 Hz, 3H), 7.52 - 7.35 (m, 7H), 6.90 (s, 1H), 6.16 (dd, J = 8.0, 6.6 Hz, 1H), 6.09 (dd, J = 6.5, 1.6 Hz, 1H), 5.94 (d, J = 1.8 Hz, 1H), 4.63 (dt, J = 10.3, 4.0 Hz, 2H), 4.59 - 4.47 (m, 1H), 2.57 (d, J = 6.6 Hz, 2H), 2.19 (qd, J = 15.8, 8.0 Hz, 2H), 1.78 - 1.49 (m, 4H).

[0258] Compound A36 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 80.1%. 1HNMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 6.77 (s, 1H), 5.44 (d, J = 4.5 Hz, 1H), 5.05 (d, J = 5.7 Hz, 1H), 4.91 (dd, J = 7.8, 3.7 Hz, 1H), 4.86 (d, J = 6.1 Hz, 1H), 4.65 (td, J = 5.9, 4.4 Hz, 1H), 4.13 (q, J = 5.9 Hz, 1H), 3.74 (td, J = 4.9, 2.6 Hz, 1H), 3.66 - 3.38 (m, 2H), 2.72 - 2.51 (m, 2H), 2.20 (tq, J = 17.0, 10.5, 8.1 Hz, 2H), 1.63 (dddd, J = 38.9, 26.5, 11.8, 5.9 Hz, 4H). MS m / z = 298.1 [M+H] +

[0259] Example 37: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-5,6,7,8-tetrahydroquinazolin-2(lH)-one A37 (mch-1139)

[0260]

[0261] Compound 7a-37 was prepared according to a similar method to that described in Reference Example 1 for 7a-1, white solid, yield 36.1%. 1 HNMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 6.77 (s, 1H), 5.44 (d, J = 4.5 Hz, 1H), 5.05 (d, J = 5.7 Hz, 1H), 4.91 (dd, J = 7.8, 3.7 Hz, 1H), 4.86 (d, J = 6.1 Hz, 1H), 4.65 (td, J = 5.9, 4.4 Hz, 1H), 4.13 (q, J = 5.9 Hz, 1H), 3.74 (td, J = 4.9, 2.6 Hz, 1H), 3.66 - 3.38 (m, 2H), 2.72 - 2.51 (m, 2H), 2.20 (tq, J = 17.0, 10.5, 8.1 Hz, 2H), 1.63 (dddd, J = 38.9, 26.5, 11.8, 5.9 Hz, 4H). MS m / z = 298.1 [M+H]

[0262] Compound A37 was prepared according to a similar method to that described in Reference Example 1 for Al, white solid, yield 55.0%. 1HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.37 (s, 1H), 5.28 (d, J = 3.9 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.84 (d, J = 6.6 Hz, 1H), 4.64 (dd, J = 6.6, 5.0 Hz, 1H), 4.52 (td, J = 5.7, 3.9 Hz, 1H), 4.04 (q, J = 6.3 Hz, 1H), 3.71 - 3.52 (m, 2H), 3.41 (dt, J = 12.1, 6.3 Hz, 1H), 2.48 - 2.27 (m, 2H), 2.22 - 2.01 (m, 2H), 1.80 - 1.43 (m, 4H). MS m / z = 314.1 [M+H] +

[0263] Example 38: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (hydroxyamino)-5-(hydroxymethyl)pyrimidin-2(lH)-one A38 (mch-0850)

[0264]

[0265] Compound 4a-38 was prepared in analogy to the preparation of 4a-1 in Reference Example 1, white solid, yield 56.3%. 1 HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.37 (s, 1H), 5.28 (d, J = 3.9 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.84 (d, J = 6.6 Hz, 1H), 4.64 (dd, J = 6.6, 5.0 Hz, 1H), 4.52 (td, J = 5.7, 3.9 Hz, 1H), 4.04 (q, J = 6.3 Hz, 1H), 3.71 - 3.52 (m, 2H), 3.41 (dt, J = 12.1, 6.3 Hz, 1H), 2.48 - 2.27 (m, 2H), 2.22 - 2.01 (m, 2H), 1.80 - 1.43 (m, 4H). MS m / z = 314.1 [M+H]

[0266] Compound 6a-38 was prepared in analogy to the preparation of 6a-1 in Reference Example 1, white solid, yield 86.1%. 1 HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.37 (s, 1H), 5.28 (d, J = 3.9 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.84 (d, J = 6.6 Hz, 1H), 4.64 (dd, J = 6.6, 5.0 Hz, 1H), 4.52 (td, J = 5.7, 3.9 Hz, 1H), 4.04 (q, J = 6.3 Hz, 1H), 3.71 - 3.52 (m, 2H), 3.41 (dt, J = 12.1, 6.3 Hz, 1H), 2.48 - 2.27 (m, 2H), 2.22 - 2.01 (m, 2H), 1.80 - 1.43 (m, 4H). MS m / z = 314.1 [M+H]

[0267] Compound 7a-38 was prepared by a similar method to the preparation of 7a-1 in Reference Example 1, white solid, yield 27.2%. 1 HNMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.01 (s, 1H), 8.07 - 7.99 (m, 2H), 7.88 (ddt, J = 14.0, 7.0, 1.4 Hz, 4H), 7.72 - 7.60 (m, 3H), 7.55 - 7.39 (m, 6H), 7.26 (s, 1H), 6.13 (d, J = 4.5 Hz, 1H), 5.89 (qd, J = 6.5, 4.8 Hz, 2H), 4.78 - 4.66 (m, 2H), 4.65 - 4.51 (m, 3H), 1.96 (s, 3H).

[0268] Compound A38 was prepared by a similar method to the preparation of A1 in Reference Example 1, white solid, yield 63.4%. 1 HNMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.46 (s, 1H), 6.97 (d, J = 1.5 Hz, 1H), 5.78 - 5.72 (m, 1H), 5.23 (d, J = 6.1 Hz, 1H), 5.05 (d, J = 4.6 Hz, 1H), 4.94 (t, J = 5.2 Hz, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.10 - 4.04 (m, 2H), 3.98 (q, J = 5.9 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.77 (q, J = 3.7 Hz, 1H), 3.51 (tq, J = 11.7, 5.9, 4.4 Hz, 2H). MS m / z = 290.1 [M+H] +

[0269] Example 39: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- (hydroxymethyl)-4-(methoxyamino)pyrimidin-2(lH)-one A39 (mch-1005)

[0270]

[0271] Compound 7a-39 was prepared by a similar method to the preparation of 7a-1 in Reference Example 1, white solid, yield 38.4%. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.06 - 7.83 (m, 6H), 7.72 - 7.59 (m, 3H), 7.55 - 7.39 (m, 6H), 7.31 (s, 1H), 6.13 (d, J = 4.4 Hz, 1H), 5.89 (p, J = 6.2 Hz, 2H), 4.78 - 4.47 (m, 5H), 3.70 (s, 3H), 1.97 (s, 3H).

[0272] Compound A39 was prepared in analogy to the preparation of A1 in Reference Example 1, white solid, yield 83.3%. 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.06 (d, J = 1.4 Hz, 1H), 5.76 (d, J = 6.4 Hz, 1H), 5.24 (d, J = 6.1 Hz, 1H), 5.06 (d, J = 4.7 Hz, 1H), 4.95 (t, J = 5.1 Hz, 1H), 4.87 (t, J = 5.6 Hz, 1H), 4.05 (dt, J = 5.7, 1.2 Hz, 2H), 3.97 (q, J = 6.0 Hz, 1H), 3.91 (td, J = 5.0, 3.1 Hz, 1H), 3.77 (q, J = 3.6 Hz, 1H), 3.69 (s, 3H), 3.59 - 3.44 (m, 2H). MS m / z = 304.1 [M+H] +

[0273] Example 40: 4-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-5-(isopropoxymethyl)pyrimidin-2(1H)-one A40 (mch-1427)

[0274]

[0275] Compound 4a-38 (1000 mg, 1.7 mmol) was added to isopropanol (50 mL), concentrated hydrochloric acid (0.5 mL) was added, and the reaction was stirred at 80 °C overnight. TLC showed the reaction was complete, the reaction was cooled, stirred in ice bath for 30 min, filtered to give compound 6a-40 as a white solid (932 mg, 87.0%). 1H NMR(400MHz,Chloroform-d)δ11.58(s,1H),8.05–7.99(m,2H),7.89(ddd,J=14 .2,8.3,1.4Hz,4H),7.77(s,1H),7.71–7.62(m,3H),7.55–7.41(m,6H),6.31–6 .18(m,1H),5.99–5.89(m,2H),4.76(td,J=5.1,3.1Hz,1H),4.66(qd,J=12.1,4 .4Hz,2H),4.11–3.93(m,2H),3.54(hept,J=6.1Hz,1H),1.02(t,J=5.8Hz,6H).

[0276] Compound 7a-40 was prepared using a similar method to 7a-1 in Example 1, and was a white solid with a yield of 92.4%. 1 HNMR(400MHz,DMSO-d6)δ8.07–7.96(m,2H),7.88(ddd,J=8.4,4.9,1.4Hz,4 H),7.74(s,1H),7.65(dt,J=9.3,7.5Hz,4H),7.55–7.40(m,6H),6.70(s,1H) ,6.13(d,J=3.8Hz,1H),6.04–5.90(m,2H),4.81–4.67(m,2H),4.67–4.57(m ,1H),4.15–4.03(m,2H),3.57(p,J=6.1Hz,1H),1.05(dd,J=6.1,1.6Hz,6H).

[0277] Compound A40 was prepared using a similar method to that used for A1 in Example 1. It was a white solid with a yield of 69.6%. 1 HNMR(400MHz, DMSO-d6)δ7.91(s,1H),7.36(s,1H),6.47(s,1H),5.79–5.67(m,1H),5.35–5.22(m,1H),5.09(t,J=5.1Hz,1H),5.03–4.92( m,1H),4.14(d,J=2.4Hz,2H),3.99–3.90(m,2H),3.82(dt,J=5.2,3.2Hz,1H),3.71–3.49(m,3H),1.10(d,J=6.1Hz,6H).MSm / z=316.1[M+H] +

[0278] Example 41: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-N-(2- morpholinoethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide A41 (mch-0827)

[0279]

[0280] Compound 4a-41 was prepared according to the similar procedure of 4a-1 in Reference Example 1, white solid, yield 70.4%. 1 HNMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 12.23 (s, 1H), 8.75 (s, 1H), 8.13 - 7.95 (m, 2H), 7.89 (ddt, J = 12.2, 6.8, 1.4 Hz, 4H), 7.64 (qt, J = 7.6, 1.3 Hz, 3H), 7.46 (dq, J = 15.4, 7.9 Hz, 6H), 6.30 (d, J = 3.6 Hz, 1H), 6.11 - 5.88 (m, 2H), 4.80 (ddd, J = 6.5, 5.0, 3.6 Hz, 1H), 4.75 - 4.60 (m, 2H).

[0281] Compound 4a-41 (300 mg, 0.5 mmol) was added to N,N-dimethylformamide (2 mL), 1-hydroxybenzotriazole (81 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) were added under ice bath, stirred for 20 min, 4-(2- aminoethyl)morpholine (65 mg, 0.5 mmol) was added, then stirred overnight. TLC showed the reaction was complete, the reaction solution was added to 80 mL water, extracted with ethyl acetate, the organic phase was rotary evaporated, EA:MeOH = 20:1 silica gel column chromatography to give compound 5a-42 as a white solid (167 mg, 46.9%). 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.87 (t, J = 5.4 Hz, 1H), 8.67 (s, 1H), 8.05 - 7.99 (m, 2H), 7.92 - 7.85 (m, 4H), 7.70 - 7.61 (m, 3H), 7.52 - 7.39 (m, 6H), 6.32 (d, J = 3.7 Hz, 1H), 6.02 - 5.88 (m, 2H), 4.78 (dt, J = 6.6, 4.4 Hz, 1H), 4.67 (d, J = 4.4 Hz, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.36 (q, J = 6.0 Hz, 2H), 2.40 (dt, J = 13.6, 5.6 Hz, 6H).

[0282] Compound A41 was prepared by analogy to the preparation of A1 in Reference Example 1, white solid, yield 49.1%. 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (t, J = 5.4 Hz, 1H), 8.74 (s, 1H), 5.81 (d, J = 4.9 Hz, 1H), 5.43 (s, 1H), 5.10 (s, 2H), 4.07 (t, J = 4.9 Hz, 1H), 4.02 - 3.86 (m, 2H), 3.69 - 3.52 (m, 6H), 3.30 (s, 2H), 2.40 (dt, J = 17.2, 5.6 Hz, 6H). MS m / z = 401.1 [M+H] +

[0283] Example 42: N-(2-bromo-4-methylphenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- carboxamide A42 (mch-0822)

[0284]

[0285] Compound 5a-42 was prepared by analogy to the preparation of 5a-42 in Reference Example 42, white solid, yield 92.4%.

[0286] Compound A42 was prepared by analogy to the preparation of A1 in Reference Example 1, white solid, yield 32.2%. 1HNMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 11.19 (s, 1H), 9.01 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 2.0, 0.9 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 5.82 (d, J = 4.3 Hz, 1H), 5.48 (d, J = 5.3 Hz, 1H), 5.17 (t, J = 4.5 Hz, 1H), 5.13 (d, J = 5.5 Hz, 1H), 4.11 (q, J = 4.8 Hz, 1H), 3.99 (q, J = 5.1 Hz, 1H), 3.94 (dt, J = 5.3, 3.0 Hz, 1H), 3.65 (dddd, J = 54.2, 11.8, 4.6, 3.0 Hz, 2H), 2.27 (s, 3H). MS m / z = 256.0 [M+H] +

[0287] Example 43: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2,4-dioxo-N-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide A43 (mch-0823)

[0288]

[0289] Compound 5a-43 was prepared by analogy with the preparation of 5a-42 in Reference Example 42, white solid, yield 61.8%.

[0290] Compound A43 was prepared by analogy with the preparation of A1 in Reference Example 1, white solid, yield 40.7%. 1 HNMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 11.19 (s, 1H), 9.01 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 2.0, 0.9 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 5.82 (d, J = 4.3 Hz, 1H), 5.48 (d, J = 5.3 Hz, 1H), 5.17 (t, J = 4.5 Hz, 1H), 5.13 (d, J = 5.5 Hz, 1H), 4.11 (q, J = 4.8 Hz, 1H), 3.99 (q, J = 5.1 Hz, 1H), 3.94 (dt, J = 5.3, 3.0 Hz, 1H), 3.65 (dddd, J = 54.2, 11.8, 4.6, 3.0 Hz, 2H), 2.27 (s, 3H). MS m / z = 256.0 [M+H] +

[0291] Example 44: N-(4-(tert-butyl)phenyl)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- carboxamide A44 (mch-0824)

[0292]

[0293] Compound 5a-44 was prepared by analogy with the method described for the preparation of 5a-42 in Reference Example 42, white solid, yield 81.7%.

[0294] Compound A44 was prepared by analogy with the preparation of A1 in Reference Example 1, white solid, yield 39.1%. 1 H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.84 (s, 1H), 8.94 (s, 1H), 7.60 - 7.51 (m, 2H), 7.40 - 7.33 (m, 2H), 5.83 (d, J = 4.6 Hz, 1H), 5.47 (d, J = 5.3 Hz, 1H), 5.18 (q, J = 5.3, 4.5 Hz, 1H), 5.13 (d, J = 5.4 Hz, 1H), 4.12 (q, J = 4.9 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.93 (dt, J = 5.1, 3.0 Hz, 1H), 3.72 - 3.56 (m, 2H), 1.27 (s, 9H). MS m / z = 420.1 [M+H] +

[0295] Example 45: 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)- N-(2-(2-methoxyphenoxy)ethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide A45 (mch-0818)

[0296]

[0297] Compound 5a-45 was prepared by analogy with the method described for the preparation of 5a-42 in Reference Example 42, white solid, yield 72.5%.

[0298] Compound A45 was prepared by analogy with the preparation of A1 in Reference Example 1, white solid, yield 63.5%. 1HNMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.97 (t, J = 5.7 Hz, 1H), 8.79 (s, 1H), 7.04 - 6.80 (m, 4H), 5.81 (d, J = 4.8 Hz, 1H), 5.44 (d, J = 5.5 Hz, 1H), 5.16 - 5.06 (m, 2H), 4.08 (q, J = 5.1 Hz, 1H), 4.03 (t, J = 5.7 Hz, 2H), 3.96 (q, J = 4.9 Hz, 1H), 3.90 (q, J = 3.5 Hz, 1H), 3.75 (s, 3H), 3.66 - 3.53 (m, 4H). MS m / z = 438.0 [M+H] +

[0299] Example 46: 1-((2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4- (methoxyamino)-2-oxo-1,2-dihydropyrimidine-5-carbonitrile A46 (mch-1615)

[0300]

[0301] Compound 4a-46 was prepared by analogy with the procedure described for 4a-1 in Reference Example 1, white solid, yield 86.6%. 1 HNMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.82 (s, 1H), 8.01 - 7.97 (m, 2H), 7.95 - 7.89 (m, 2H), 7.85 - 7.80 (m, 2H), 7.70 - 7.60 (m, 3H), 7.49 (td, J = 7.7, 5.4 Hz, 5H), 7.40 (t, J = 7.8 Hz, 2H), 6.20 (d, J = 2.9 Hz, 1H), 5.98 - 5.90 (m, 2H), 4.79 (td, J = 5.6, 3.6 Hz, 1H), 4.74 - 4.65 (m, 2H).

[0302] Compound 7a-46 was prepared by analogy with the procedure described for 7a-1 in Reference Example 1, white solid, yield 76.3%. 1HNMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.24 (s, 1H), 8.05 - 7.96 (m, 2H), 7.87 (ddt, J = 7.2, 5.8, 1.3 Hz, 4H), 7.65 (dtd, J = 11.3, 7.3, 6.5, 2.9 Hz, 3H), 7.54 - 7.37 (m, 6H), 6.11 (d, J = 3.8 Hz, 1H), 5.96 - 5.80 (m, 2H), 4.78 - 4.60 (m, 3H), 3.76 (s, 3H).

[0303] Compound A46 was prepared by analogy with the preparation of A1 in Reference Example 1, white solid, yield 79.2%. 1 HNMR (400 MHz, DMSO-d6) δ 10.79 - 10.60 (m, 1H), 8.29 (s, 1H), 5.65 (d, J = 4.3 Hz, 1H), 5.39 (d, J = 5.1 Hz, 1H), 5.25 (t, J = 4.9 Hz, 1H), 5.05 (d, J = 5.2 Hz, 1H), 3.98 (dq, J = 14.2, 5.0 Hz, 2H), 3.83 (dt, J = 4.8, 2.9 Hz, 1H), 3.73 (s, 3H), 3.62 (dddd, J = 48.0, 12.0, 4.9, 3.0 Hz, 2H). MS m / z = 299.1 [M+H] +

[0304] Test Example 1: Anti-vesicular stomatitis virus (VSV) activity screening

[0305] Test principle: The green fluorescence signal of recombinant vesicular stomatitis virus inserted with green fluorescent protein (GFP) was determined in African green monkey kidney cells (Vero) as host cells, so as to measure the inhibition efficiency of the sample.

[0306] Test materials and methods:

[0307] Virus strain: Vesicular stomatitis virus with green fluorescent protein reporter gene, cultured and passed in African green monkey kidney cells (Vero), -80°C.

[0308] Cell culture medium: MEM medium (CM50011, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biotech).

[0309] Sample treatment: The sample was configured into a mother liquor with DMSO, and then diluted with cell culture solution.

[0310] Positive control drug: Favipiravir, Shanghai Bide Pharmaceutical Technology Co., Ltd. (Batch number: 152DGA).

[0311] Test method: Vero cells 2x104 / well were inoculated in 96-well culture plates and incubated at 37°C in 5% CO2. After 12 h, the culture medium was replaced with a culture medium containing drugs or DMSO, and the cells were pretreated for 2 h. The diluted virus suspension was added, and the cells were incubated at 37°C in 5% CO2. After 24 h, the GFP signal was detected using a fluorescence microplate reader at an excitation wavelength of 488 nm and an emission wavelength of 535 nm. The inhibition rate was calculated according to the formula: inhibition rate = 1-[(fluorescence intensity of drug group-background fluorescence intensity) / (fluorescence intensity of DMSO group-background fluorescence intensity)]. The cell viability was tested by the cck-8 method for the drug mock group. The test results are shown in Table 1 below, and the effect of the drug on cell viability is shown in Table 2 below.

[0312] Table 1

[0313]

[0314]

[0315] Table 2

[0316]

[0317]

[0318] Test Example 2: Anti-influenza A virus (IAV) RNA-dependent RNA polymerase (RdRp) target activity test

[0319] Test principle: An A549 cell line stably expressing IAV RdRp complex and viral small genomic RNA was used, and Gaussia luciferase (Gluc) was encoded in the viral small genome and expressed under the control of IAV RdRp. Gluc was used as a reporter gene to monitor the activity of IAV RdRp.

[0320] Test materials: Ribavirin (RBV), Shanghai Tao Shu Biological Technology Co., Ltd., batch number (158104). Secrete-Pair Gaussia Luciferase Assay Kit, GeneCopoiea Company. The culture medium used was DMEM high-sugar culture medium (CM10017, MACGENE) containing 10% fetal bovine serum (fetal bovine serum, HQ30071-T500, Hongquan Biological) and 2 μg / mL puromycin.

[0321] Specific implementation method:

[0322] The construction of cell lines is described in the reference (PLoS One. 2015; 10(7): e0133558.). A549-5Ps cells were seeded at 2 x 104cells per well in 96-well plates and incubated at 37°C in 5% CO2. After 12 h, the culture medium was replaced with fresh medium containing the drug or DMSO at three concentrations of 0.1 μM, 1 μM and 10 μM, respectively. The cells were incubated at 37°C in 5% CO2for 72 h. The chemiluminescence signal was detected for 2 s using a stable Gaussia luciferase detection kit. The luminescence signal value was used to report the expression of RdRp complex, and the relative Gluc activity was calculated. The calculation formula was: relative Gluc activity (%) = Gluc signal value of the drug group / Gluc signal value of the DMSO control group. The test results are shown in Table 3.

[0323] Table 3

[0324]

[0325]

[0326] The above merely describes specific embodiments of the present application, but the protection scope of the present application is not limited thereto. Any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A nucleoside analogue represented by Formula I and pharmaceutically acceptable salts thereof: Formula I wherein: R 1 and R 2 are independently selected from hydrogen, hydroxyl, halogen, C 1-C 6 alkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkyl, C 1-C 6 haloalkoxy, C 3-C 6 cycloalkyl, C 3-C 6 halocycloalkyl, C 2-C 6 alkenyl, C 2-C 6 haloalkenyl, C 2-C 6 alkynyl, C 2-C 6 haloalkynyl, C 1-C 6 alkylamino, C 1-C 6 haloalkylamino, C 1-C 6 alkylthio, C 1-C 6 haloalkylthio, C 1-C 6 alkylsulfinyl, C 1-C 6 haloalkylsulfinyl, C 1-C 6 alkylsulfonyl, C 1-C 6 haloalkylsulfonyl, C 1-C 6 alkylsulfonyloxy, C 1-C 6 haloalkylsulfonyloxy, C 1-C 6 alkylsulfonamidyl, C 1-C 6 haloalkylsulfonamidyl, C 1-C 6 alkylcarbonyl, C 1-C 6 haloalkylcarbonyl, C 1-C 6 alkoxycarbonyl, C 1-C 6 haloalkoxycarbonyl, C 1-C 6 alkylcarbonyloxy, C 1-C 6 haloalkylcarbonyloxy, C 1-C 6 alkylcarbonylamino, C 1-C 6 haloalkylcarbonylamino, C 1-C 6 alkylaminocarbonyl, C 1-C 6 haloalkylaminocarbonyl, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, C 1-C 6 haloalkylcarbonyloxyimino, C 1-C 6 alkylcarbonyloxyimino, R1and R2are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-6 alkoxy; ​ R3is selected from the group consisting of hydroxyl, amino, hydroxylamino, C 1-6 alkoxyamino, oxo (O=); R4is selected from the group consisting of hydrogen, hydroxyl, cyano, substituted or unsubstituted C 1-6 linear or branched alkyl, 4- to 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S, substituted or unsubstituted C 1-6 alkanoyl, substituted or unsubstituted C 1-6 alkanoylamino, substituted or unsubstituted C 1-6 alkyl oxime, substituted or unsubstituted C 1-6 alkyl-O-C 1-6 alkyl oxime, C 1-6 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by one or more substituents selected from the group consisting of hydroxylamino, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylhydroxylamino, halogen, hydroxyl, amino, C 6-10 aryl, C 1-6 alkyl C 6-10 aryl, C 1-6 alkoxy C 6-10 aryl, halogenated C 1-6 alkyl C 6-10 aryl, C 1-6 alkoxy C 6-10 aryloxy, 4- to 9-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N and S, substituted; ​ ​ or R4and R5together with the carbon atom to which they are attached form C 4-8 cycloalkyl, 4- to 9-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, N and S or 4- to 9-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from O, N and S. ​ Preferably, R1is selected from hydrogen, halogen, substituted or unsubstituted C 1-4 alkoxy; ​ Preferably, R2is selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-4 alkoxy; ​ Preferably, R3is selected from hydroxyl, amino, hydroxylamino, C 1-3 alkoxyamino, oxo (O=); ​ Preferably, R4 is selected from hydrogen, hydroxyl, cyano, substituted or unsubstituted C4. 1-4 Straight-chain or branched alkyl groups, 4- to 7-membered heterocyclic groups containing 1 to 3 heteroatoms selected from O, N, and S, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkamide group, substituted or unsubstituted C 1-4 Alkyl oxime, substituted or unsubstituted C 1-4 Alkyl-OC 1-4 Alkyl oxime, C 1-4 alkyl-O(O=)C-, wherein the substitution refers to the group being further replaced by 1 to 3 groups selected from hydroxylamine, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl hydroxylamine, halogen, hydroxyl, amino, C 6-10 Aryl, C 1-4 Alkyl C 6-10 Aryl, C 1-4 Alkoxy C 6-10 Aryl, Halogenated C 1-4 Alkyl C 6-10 Aryl, C 1-4 Alkoxy C 6-10 Aryloxy group, containing 1 to 3 4- to 7-membered heterocyclic groups selected from O, N and S heteroatoms; R4 is selected from hydrogen, hydroxy, cyano, substituted or unsubstituted C 1-3 straight-chain or branched alkyl, 5- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N, substituted or unsubstituted C 1-3 alkanoyl, substituted or unsubstituted C 1-3 alkanoylamino, substituted or unsubstituted C 1-3 alkyl oxime, substituted or unsubstituted C 1-3 alkyl-O-C 1-3 alkyl oxime, C 1-3 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by 1 to 3 substituents selected from hydroxylamino, C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylhydroxylamino, halogen, hydroxy, amino, phenyl, C 1-3 alkylphenyl, C 1-4 alkoxyphenyl, halogenated C 1-4 alkylphenyl, C 1-4 alkoxyphenoxy, 5- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from O and N; R4 is selected from hydrogen, hydroxy, cyano, substituted or unsubstituted C 1-3 straight-chain or branched alkyl, 5- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N, substituted or unsubstituted C 1-3 alkanoyl, substituted or unsubstituted C 1-3 alkanoylamino, substituted or unsubstituted C 1-3 alkyloxime, substituted or unsubstituted C 1-3 alkyl-O-C 1-3 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by 1 or 2 substituents selected from hydroxylamine, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, methylhydroxylamine, ethylhydroxylamine, propylhydroxylamine, halogen, hydroxy, amino, phenyl, tolyl, mesityl, ethylphenyl, t-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, methoxyphenoxy, ethoxyphenoxy, 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from O and N; 1-3 alkyl-O(O=)C-, wherein the substitution means that the group is further substituted by 1 or 2 substituents selected from hydroxylamine, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, methylhydroxylamine, ethylhydroxylamine, propylhydroxylamine, halogen, hydroxy, amino, phenyl, tolyl, mesityl, ethylphenyl, t-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethoxyphenyl, methoxyphenoxy, ethoxyphenoxy, 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from O and N; ​ ​ ​ Preferably, R3and R4together with the carbon atom to which they are attached form ​ ​ Preferably, R4and R5together with the carbon atom to which they are attached form ​ 3. The nucleoside analogue and pharmaceutically acceptable salts thereof according to claim 1 or 2, characterized in that, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 6. A pharmaceutical composition comprising a therapeutically effective amount of the nucleoside analogue according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients.

7. Use of the nucleoside analogue according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof or the pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment of viral infections; wherein the virus is a coronavirus, an influenza virus, a rhabdovirus, a paramyxovirus, a respiratory syncytial virus, a flaviviridae virus, a filoviridae virus, a porcine epidemic diarrhea virus, a bunyaviridae virus or an arenavirus.

8. Use according to claim 7, characterized in that, the virus is an influenza virus, a rhabdovirus or a coronavirus; preferably, the influenza virus comprises Influenza A virus, Influenza B virus and Influenza C virus; preferably, the coronavirus subtype is SARS-CoV (SARS coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV-2 (2019 novel coronavirus), HCoV-229E, HCoV-NL63, CCoV-HuPn-2018 (Canine coronavirus).

9. A method of treating a viral infection disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the nucleoside analogue according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof or the pharmaceutical composition according to claim 6.

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