Non-natural nucleoside analogs and uses thereof

Abstract

The application discloses a kind of non-natural nucleoside analogues as shown in the following formula 1 and its pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer, tautomer and solvate, and pharmaceutical composition comprising them, and its purposes in preparing antiviral infection and antitumor drug and its use method.The non-natural nucleoside analogues have good broad-spectrum antiviral activity or antitumor cytotoxicity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and in particular, relates to a class of unnatural nucleoside analogs and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof, as well as pharmaceutical compositions containing them, and their use in the preparation of antiviral and antitumor drugs and methods of use thereof. The unnatural nucleoside analogs have good broad-spectrum antiviral activity or cytotoxicity. BACKGROUND

[0002] Nucleoside compounds refer to a class of molecules similar in chemical structure to natural nucleosides. As such, nucleoside compounds have the potential to inhibit the replication of a variety of viruses. For example, Favipiravir was approved for marketing in Japan in 2014 and has good in vivo or in vitro antiviral activity against influenza virus, flavivirus, coronavirus, etc. Molnupiravir is also a class of nucleoside analogs that can reduce the risk of severe illness in patients infected with the new coronavirus (Clin Infect Dis. 2023; 76(1): 165-171). Generally speaking, nucleoside analogs act as chain terminators and prevent the synthesis of viral DNA, RNA or subsequent transcription after entering host cells. The structural changes made by nucleoside analogs to mimic natural nucleosides often result in premature termination of viral RNA replication, thereby exerting antiviral activity.

[0003] In summary, developing broad-spectrum antiviral drugs against RdRp of RNA viruses is an effective strategy, and nucleoside analogs are small molecule inhibitors that effectively exert broad-spectrum antiviral activity. Discovering new unnatural nucleoside analogs has important social significance and value. In addition, nucleoside compounds can interfere with the synthesis of RNA or DNA, and therefore also have antitumor effects, such as gemcitabine, etc. SUMMARY

[0004] The present application discloses a series of novel small molecule compounds with good antiviral activity.

[0005] According to one aspect of the present application, one object of the present application is to provide an unnatural nucleoside analog as shown in the following formula 1 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof:

[0006]

[0007] X is selected from C, N;

[0008] R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C6straight or branched chain alkyl, C2-C6straight or branched chain alkenyl, C2-C6straight or branched chain alkynyl, -0(C=0)Ra, with the proviso that R1and R2are not hydrogen at the same time;

[0009] Ra is selected from the group consisting of substituted or unsubstituted C1-C6straight or branched chain alkyl, substituted or unsubstituted C2-C6straight or branched chain alkenyl, substituted or unsubstituted C6-C14aryl, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein the substitution means containing 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C14aryl, C1-C6straight or branched chain alkyl, C1-C6straight or branched chain alkoxy, -0(C=0)C1-C6alkyl ester group;

[0010] R3and R4are each independently selected from the group consisting of hydroxyl, -0(C=0)Rb;

[0011] Rb is selected from the group consisting of substituted or unsubstituted C1-C6straight or branched chain alkyl, substituted or unsubstituted C2-C6straight or branched chain alkenyl, substituted or unsubstituted C6-C14aryl, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein the substitution means containing 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C14aryl, C1-C6straight or branched chain alkyl, C1-C6straight or branched chain alkoxy, -0(C=0)C1-C6alkyl ester group;

[0012] R5is selected from the group consisting of amino, cyano, guanidino, ureido, hydroxylamine, N'-hydroxy imidic amide, -NH(C=0)Rc, -(C=0)NHRd, -0(C=0)Re, -(C=0)ORf, carboxyl, wherein Rc, Rd, Reand Rfare each independently selected from the group consisting of C1-C6straight or branched chain alkyl, halogenated C1-C6straight or branched chain alkyl;

[0013] R6is selected from the group consisting of hydrogen, cyano, halogen, amino, nitro, substituted or unsubstituted C1-C6straight or branched chain alkyl, wherein substituted means containing 1 to 3 substituents selected from the group consisting of cyano, halogen, amino, nitro, with the proviso that R6is not present when X is N;

[0014] R7is selected from the group consisting of hydrogen, amino, cyano, guanidino, ureido, hydroxylamine, N'-hydroxy imidic amide, -NH(C=0)Rc, -(C=0)NHRd, carboxyl, substituted or unsubstituted C1-C6straight or branched chain alkyl, wherein Rcand Rdare each independently selected from the group consisting of C1-C6straight or branched chain alkyl, halogenated C1-C6straight or branched chain alkyl.

[0015] Preferably, R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C4linear or branched alkyl, C2-C4linear or branched alkenyl, C2-C4linear or branched alkynyl, -0(C=0)Ra, with the proviso that R1and R2are not hydrogen at the same time;

[0016] Ra is selected from the group consisting of substituted or unsubstituted C1-C4linear or branched alkyl, substituted or unsubstituted C2-C4linear or branched alkenyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C10aryl, C1-C4linear or branched alkyl, C1-C4linear or branched alkoxy, -0(C=0)C1-C4alkyl ester.

[0017] Further preferably, R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C3linear or branched alkyl, -0(C=0)Ra, with the proviso that R1and R2are not hydrogen at the same time;

[0018] Ra is selected from the group consisting of substituted or unsubstituted C1-C3linear or branched alkyl, substituted or unsubstituted C2-C4linear or branched alkenyl, substituted or unsubstituted C6-C10aryl, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C10aryl, C1-C3linear or branched alkyl, C1-C3linear or branched alkoxy, -0(C=0)C1-C3alkyl ester.

[0019] Further preferably, R1and R2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, -0(C=0)Ra, with the proviso that R1and R2are not hydrogen at the same time;

[0020] Ra is selected from the group consisting of substituted or unsubstituted methyl, ethyl, n-propyl, i-propyl, substituted or unsubstituted ethenyl, substituted or unsubstituted phenyl, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, -0(C=0) methyl ester, -0(C=0) ethyl ester, -0(C=0) n-propyl ester, -0(C=0) i-propyl ester.

[0021] Further preferably, R1and R2are each independently selected from the group consisting of hydrogen, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, -0(C=0) methyl ester, -0(C=0) ethyl ester, -0(C=0) n-propyl ester, -0(C=0) i-propyl ester,

[0022] Preferably, R3and R4are each independently selected from the group consisting of hydroxyl, -0(C=0)Rb, wherein Rbis selected from the group consisting of substituted or unsubstituted C1-C4linear or branched alkyl, substituted or unsubstituted C2-C4linear or branched alkenyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C10aryl, C1-C4linear or branched alkyl, C1-C4linear or branched alkoxy, -0(C=0)C1-C4alkyl ester;

[0023] More preferably, R3and R4are each independently selected from the group consisting of hydroxyl, -0(C=0)Rb, wherein Rbis selected from the group consisting of substituted or unsubstituted C1-C3linear or branched alkyl, substituted or unsubstituted C2-C3linear or branched alkenyl, substituted or unsubstituted C6-C10aryl, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, C6-C10aryl, C1-C3linear or branched alkyl, C1-C3linear or branched alkoxy, -0(C=0)C1-C3alkyl ester;

[0024] Further preferably, R3and R4are each independently selected from the group consisting of hydroxyl, -0(C=0)Rb, wherein Rbis selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, substituted or unsubstituted ethenyl, substituted or unsubstituted phenyl, wherein the substitution means containing 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, cyano, phenyl, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, -0(C=0) methyl ester, -0(C=0) ethyl ester, -0(C=0) n-propyl ester, -0(C=0) i-propyl ester.

[0025] Further preferably, R3and R4are each independently selected from the group consisting of hydroxyl, -0(C=0) methyl ester, -0(C=0) ethyl ester, -0(C=0) n-propyl ester, -0(C=0) i-propyl ester,

[0026] Preferably, R5is selected from the group consisting of amino, cyano, guanidino, ureido, hydroxylamino, N'-hydroxyformimidamide, -NH(C=0)Rc, -(C=0)NHRd, -0(C=0)Re, -(C=0)ORf, carboxyl, wherein Rc, Rd, Reand Rfare each independently selected from the group consisting of C1-C4linear or branched alkyl, halogenated C1-C4linear or branched alkyl.

[0027] More preferably, R5is selected from the group consisting of amino, cyano, guanidino, ureido, hydroxylamine, N'-hydroxyformimidamide, -NH(C=0)methyl, -NH(C=0)ethyl, -NH(C=0)n-propyl, -NH(C=0)isopropyl, -(C=0)NH methyl, -(C=0)NH ethyl, -(C=0)NH n-propyl, -(C=0)NH isopropyl, -0(C=0)methyl, -0(C=0)ethyl, -0(C=0)n-propyl, -0(C=0)isopropyl, -(C=0)O methyl, -(C=0)O ethyl, -(C=0)O n-propyl, -(C=0)O isopropyl, -NH(C=0)trifluoromethyl, -(C=0)NH trifluoromethyl, -0(C=0)trifluoromethyl, -(C=0)O trifluoromethyl.

[0028] Preferably, R6is selected from the group consisting of hydrogen, cyano, halogen, amino, nitro, C1-C4linear or branched alkyl.

[0029] More preferably, R6is selected from the group consisting of hydrogen, cyano, halogen, amino, nitro, methyl, ethyl, n-propyl, isopropyl.

[0030] Preferably, R7is selected from the group consisting of hydrogen, amino, cyano, guanidino, ureido, hydroxylamine, N'-hydroxyformimidamide, -NH(C=0)Rc, -(C=0)NHRd, substituted or unsubstituted C1-C4linear or branched alkyl, wherein Rcand Rdare each independently selected from the group consisting of C1-C4linear or branched alkyl, halogenated C1-C4linear or branched alkyl.

[0031] More preferably, R7is selected from the group consisting of hydrogen, amino, cyano, guanidino, ureido, hydroxylamine, N'-hydroxyformimidamide, methyl, ethyl, n-propyl, isopropyl, -NH(C=0)methyl, -NH(C=0)ethyl, -NH(C=0)n-propyl, -NH(C=0)isopropyl, -(C=0)NH methyl, -(C=0)NH ethyl, -(C=0)NH n-propyl, -(C=0)NH isopropyl, trifluoromethyl, -NH(C=0)trifluoromethyl, -(C=0)NH trifluoromethyl.

[0032] The non-natural nucleoside analogues according to the present application and their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates are selected from the following compounds A1 to A43:

[0033]

[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 unnatural nucleoside analogues of Formula 1 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof according to one of the following methods. The following methods are only exemplary, and those skilled in the art can make corresponding adjustments to the following preparation methods according to the structure of the product combined with the known synthesis method.

[0040] Method I,

[0041]

[0042] As shown in the above reaction formula, the method comprises the following steps:

[0043] i-1) Compound 1a is subjected to a reduction reaction to generate compound 2a,

[0044] i-2) Compound 2a is subjected to an acylation reaction to generate compound 3a,

[0045] i-3) Compound 3a is subjected to a Vorbrüggen glycosylation to generate compound 4a,

[0046] i-4) The nitro group in compound 4a is subjected to a reduction to generate compound 5a,

[0047] i-5) Compound 5a is subjected to a di-tert-butyloxycarbonyl guanylation to generate compound 6a,

[0048] i-6) Compound 6a is subjected to a di-tert-butyloxycarbonyl protecting group removal to generate compound II-1,

[0049] i-7) Compound 6a is subjected to a benzoyl protecting group removal to generate compound 7a,

[0050] i-8) Compound 8a is subjected to a reaction with a corresponding acid or acid anhydride to generate compound 8a,

[0051] i-9) Compound 9a is subjected to a di-tert-butyloxycarbonyl protecting group removal to generate compound II-2.

[0052] In the above reaction formula, the substituents R1, R2, R3, R4, R6, R7 are as defined in Formula 1.

[0053] 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;

[0054] Preferably, in step i-3), the reaction is carried out at 80°C using N, O-bistrimethylsilylacetamide and tin tetrachloride.

[0055] Preferably, in step i-4), the reaction is carried out at room temperature using palladium on carbon and hydrogen.

[0056] Preferably, in step i-5), the reaction is carried out at room temperature using N, N'-di-BOC-S-methylisothiourea as guanidination reagent and triethylamine as acid scavenger.

[0057] Preferably, in step i-6), the reaction is carried out at room temperature using trifluoroacetic acid as deprotection reagent.

[0058] Preferably, in step i-7), the reaction is carried out at room temperature using sodium methoxide / methanol as deprotection reagent.

[0059] Preferably, in step i-8), the reaction is carried out at room temperature using an acid anhydride as acylating reagent and dimethylaminopyridine as acid scavenger.

[0060] Preferably, in step i-8), the reaction is carried out at room temperature using a carboxylic acid as acylating reagent, 1-ethyl-carbodiimide hydrochloride as condensing agent and dimethylaminopyridine as acid scavenger.

[0061] Preferably, in step i-9), the reaction is carried out at room temperature using trifluoroacetic acid as deprotection reagent.

[0062] ii-1) compound 5a is subjected to a nucleophilic addition to yield compound 9a,

[0063] ii-2) compound 1b is subjected to removal of the benzoyl protecting group to yield compound II-3,

[0064] In the above reaction scheme, the substituents R1, R2, R6, R7are defined as in formula 1.

[0065] Preferably, in step ii-1), the nucleophilic reaction is carried out at room temperature using sodium cyanate.

[0066] Preferably, in step ii-2), the removal of the benzoyl protecting group is carried out at room temperature using sodium methoxide.

[0067] Method two,

[0068]

[0069] iii-1) compound 3a is subjected to a Vorbrüggen glycosidation to yield compound 10a,

[0070] iii-2) compound 1c is subjected to a nucleophilic addition to yield compound 11a,

[0071] iii-3) removing the benzoyl protecting group of compound Id to form compound II-4.

[0072] In the above reaction formula, substituent groups R1, R2, R6 are as defined in formula 1.

[0073] Preferably, in step iii-1), the N, O-bistrimethylsilylacetamide and trimethylsilyl triflate used undergo Vorbrüggen glycosidation, and the reaction is carried out at 80°C.

[0074] Preferably, in step iii-2), the hydroxylamine hydrochloride used undergoes nucleophilic addition, and the reaction is carried out at room temperature.

[0075] Preferably, in step iii-3), the sodium methoxide used removes the benzoyl protecting group, and the reaction is carried out at room temperature.

[0076] 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 unnatural nucleoside analogue according to the present application and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof, and optionally a pharmaceutically acceptable carrier.

[0077] According to another aspect of the present application, another object of the present application is to provide the use of the unnatural nucleoside analogue and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof or the pharmaceutical composition according to the present application in the manufacture of a medicament for preventing and / or treating viral infection.

[0078] According to the use of the medicament for preventing and / or treating viral infection according to the present application, the virus is preferably 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, an arenavirus.

[0079] Preferably, the virus is an influenza virus, a rhabdovirus or a coronavirus.

[0080] Further preferably, the influenza virus subtype is H1N1.

[0081] Further preferably, the coronavirus subtype is HCoV-229E.

[0082] According to another aspect of the present application, another object of the present application is to provide the use of the unnatural nucleoside analogue and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates thereof or the pharmaceutical composition according to the present application in the manufacture of a medicament for preventing and / or treating tumor.

[0083] According to the use in the medicament for preventing and / or treating tumors according to the present application, wherein the tumors are non-central nervous system solid tumors, including ovarian cancer, breast cancer, bladder cancer, cervical cancer, liver cancer, biliary tract cancer, nasopharyngeal cancer, testicular tumor, lymphoma, mesothelioma, lung cancer, and head and neck cancer, etc.

[0084] According to another aspect of the present application, another object of the present application is to provide a method for treating a disease or disorder associated with viral infection, the method comprising administering to a patient in need thereof a therapeutically effective amount of the unnatural nucleoside analogs and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof according to the present application or the pharmaceutical composition according to the present application.

[0085] According to another aspect of the present application, another object of the present application is to provide a method for treating tumors, the method comprising administering to a patient in need thereof a therapeutically effective amount of the unnatural nucleoside analogs and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof according to the present application or the pharmaceutical composition according to the present application.

[0086] Advantages

[0087] The present application relates to nucleoside analogs and pharmaceutically acceptable salts thereof. It has been verified through pharmacological experiments that the compounds of the present application have better inhibitory activity on RNA-dependent RNA polymerase, and can inhibit the replication of a variety of RNA viruses, especially have better biological activity in treating influenza virus and vesicular stomatitis virus infections. Therefore, the compounds of the present application have good broad-spectrum antiviral activity, and can be used as broad-spectrum antiviral drugs to treat a variety of viral infections. BRIEF DESCRIPTION OF DRAWINGS

[0088] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the specific embodiments or prior art description will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0089] Figure 1 Show the effect of compound A17 prepared in Example 15 on inhibiting influenza virus replication in MDCK cells DETAILED DESCRIPTION

[0090] Hereinafter, the present application will be described in detail. Before undertaking the description below, it should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It will be further understood that where a specific number of steps, or materials or conditions are named herein, it should be recognized that the number of steps, or materials and conditions could be more than or less than those specifically named, and still be in accordance with various embodiments of the present application. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Thus, the description herein is not intended to be limited to the preferred embodiments, but is to be accorded the full scope of the claims.

[0091] Definitions

[0092] As used herein, the term "alkyl," used alone or as part of another group, refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl group can contain from 1 to 8 carbon atoms (i.e., C1-8alkyl) or the specified number of carbon atoms (i.e., C1alkyl (such as methyl), C2alkyl (such as ethyl), C3alkyl (such as propyl or isopropyl), and the like). In one embodiment, the alkyl group is a straight chain C1-6alkyl. In another embodiment, the alkyl group is a straight chain C1-4alkyl. For example, C1-4alkyl as used herein refers to a group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, t-butyl, and isobutyl. Optionally substituted C1-4alkyl refers to a C1-4alkyl group as defined, which is optionally substituted with one or more permissible substituents as described herein. As used herein, the term "alkylene," used alone or as part of another group, refers to a divalent group derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, and the like.

[0093] As used herein, the term "alkenyl," used alone or as part of another group, refers to an alkyl group as defined above containing 1, 2, or 3 carbon-carbon double bonds. In one embodiment, the alkenyl group is a C2-6alkenyl. In another embodiment, the alkenyl group is a C2-4alkenyl. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0094] As used herein, the term "alkynyl," used alone or as part of another group, refers to an alkyl group as defined above containing 1 to 3 carbon-carbon triple bonds. In one embodiment, the alkynyl group has 1 carbon-carbon triple bond. In one embodiment, the alkynyl group is a C2-6alkynyl. In another embodiment, the alkynyl group is a C2-4alkynyl. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

[0095] As used herein, the term "alkoxy," used alone or as part of another group, refers to a group of the formula OR ’ wherein R' is alkyl as defined above.

[0096] As used herein, the term "alkanoyl," used alone or as part of another group, refers to a group of the formula R ’ CO, wherein R' is alkyl as defined above.

[0097] As used herein, the term "alkanoyloxy," used alone or as part of another group, refers to a group of the formula R ’ COO, wherein R ’ is alkyl as defined above.

[0098] The term "halo," used alone or as part of another group, refers to a group of a compound in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine, bromine, and / or iodine. For example, a haloalkyl is an alkyl group substituted with 1, 2, or 3 fluorine atoms.

[0099] "Heterocyclyl" or "heterocycle," used alone or as part of another group, refers to a group of a 5- to 9-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-9 membered heterocyclyl"). Where valence permits, in a heterocyclyl group containing one or more nitrogen or oxygen atoms, the point of attachment can be a carbon or a nitrogen or oxygen atom. The heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, e.g., a bicyclic ring system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. The heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes where a heterocycle as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the ring system on the carbocyclyl or heterocycle, or where a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the ring system on the heterocycle, and in this case the number of ring members continues to designate the number of ring members in the heterocycle system.

[0100] "Aryl," used alone or as part of another group, refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, 14, or 18 π electrons shared in a cyclic array) having 6-18 carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6-18 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C14 aryl"; e.g., anthryl). "Aryl" also includes where an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the ring system of the aryl ring, and in this case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system.

[0101] "Heteroaryl," used alone or as part of another group, refers to 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) having ring carbon atoms and 1-4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5-10 membered heteroaryl"). Where valence permits, in heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes where a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the ring system of the heteroaryl ring, and in this case the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes where a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the ring system of the aryl or heteroaryl ring, and in this case the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl).

[0102] The compounds of the present application or pharmaceutically acceptable salts thereof can exist as hydrates, solvates, or prodrugs. Thus, hydrates, solvates, or prodrugs of the compounds of the present application or pharmaceutically acceptable salts thereof are included within the scope of this application.

[0103] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0104] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is within the scope of sound medical judgment, of a compound of the present application having particular substituents discovered in the present application, with a relatively nontoxic acid or base. Alkali addition salts are obtained by contacting the neutral form of such compounds, in either solution or pure form, with a sufficient amount of the desired alkali to produce the salt. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. Acid addition salts are obtained by contacting the neutral form of such compounds, in either solution or pure form, with a sufficient amount of an acid to produce the salt (i.e., a pharmaceutically acceptable salt), examples of which include inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, bisulfic, hydroiodic, phosphorous, and the like, and organic acids such as benzoic, 2-hydroxyethanesulfonic, sulfamic, benzenesulfonic, phenylacetic, mandelic, malonic, propionic, oxalic, p-aminobenzoic, p-toluenesulfonic, galactonic, isethionic, malic, malonic, maleic, fumaric, gluconic, glutamic, succinic, methanesulfonic, tartaric, ascorbic, phthalic, salicylic, citric, malic, tartaric, gluconic, glucuronic, glycolic, lactic, lactobionic, dodecylsulfonic, pamoic, palmoic, salicylic, stearic, sulfonic, sulfanilic, and the like; similar acids such as ascorbic, adipic, ethane sulfonic, isobutyric, stearic, and the like; salts of amino acids such as arginate, and the like; and salts of organic acids like glucuronic, and the like (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application contain both basic and acidic functionalities as a result of which, the compounds can be converted into either alkali or acid addition salts. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.

[0105] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present application, does not interfere with the biological activity of the active substance, and is nontoxic to the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like. Their formulation is well known to those skilled in the art of cosmetics or topical pharmaceuticals. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0106] The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to achieve the intended effect without being toxic to the subject. With respect to the oral dosage forms of the present application, an "effective amount" of one active substance in a composition means the amount needed to achieve the intended effect when used in conjunction with another active substance in the composition. The determination of an effective amount will vary from subject to subject, depending on the age and general condition of the subject, as well as the particular active substance, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art with routine experimentation.

[0107] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, which can include deuterium and variations of hydrogen, provided that the valency of the designated atom is not exceeded and that the substituted compound is stable. When the substituent group is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups

[0108] When a range of values is listed, then each value and sub-range within the range is intended to be included. For example, "Ci-6" is intended to encompass Ci, C2, C3, C4, C5, C6, Ci-6, Ci-5, Ci-4, Ci-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.

[0109] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure. The pharmaceutical composition can optionally comprise a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula I of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are well known in the art. Suitable excipients include, and are not limited to, for example, encapsulating material or additives, such as absorption accelerators, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, effervescent agents, fillers, flavorants, humectants, lubricants, odorants, preservatives, propellants, release agents, sterilants, sweeteners, solubilizers, wetting agents, and mixtures thereof.

[0110] The pharmaceutical compositions described herein can be prepared by any of the methods known to pharmacology. In general, such preparative methods include the step of bringing into association active ingredients, e.g., salts of the present application, with a carrier or excipient and / or one or more other accessory ingredients, if desired and / or appropriate, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0111] The pharmaceutical compositions can be prepared as single unit dosage and / or as multiple single unit dosages in bulk, packaged, and / or sold. A "unit dosage" is a discrete amount of the pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is typically equal to the dosage of the active ingredient to be administered to a subject and / or a fraction of such a dosage, such as one-half or one-third of the dosage.

[0112] The relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any other ingredients in a pharmaceutical composition described herein can vary, depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is to be administered. The composition can comprise between 0.1% and 100% (w / w) of the active ingredient.

[0113] Pharmaceutically acceptable excipients that can be used to manufacture pharmaceutical compositions herein include, for example, inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweetening, flavoring, and perfuming agents can also be present in the composition.

[0114] The pharmaceutical composition can be formulated for any route of administration, such as oral administration. Typically, the pharmaceutical composition is a solid dosage form. However, in some embodiments, other dosage forms, such as liquid, suspension, or semi-solid dosage forms, can also be used.

[0115] The application will be further described below with reference to the accompanying drawings. The following examples are only used to more clearly illustrate the technical solutions of the application, and cannot be used to limit the protection scope of the application.

[0116] The experimental methods in the following examples are all conventional methods unless otherwise specified.

[0117] The materials, reagents and the like in the following examples can be obtained from commercial channels unless otherwise specified.

[0118] Example 1: 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H- imidazol-4-yl)guanidine A1

[0119]

[0120] Compound 3a-1 (9.3 g, 18.5 mmol) was added to acetonitrile (50 mL), 4-nitroimidazole (2 g, 17.6 mmol) and N,O-bistrimethylsilylacetamide (7.1 g, 35.2 mmol) were added, after addition, refluxed for 30 min. Cooled to room temperature, added trimethylsilyl trifluoromethanesulfonate (4.7 g, 21.1 mmol) under ice bath. Then reacted at 60°C for 3 hours, TLC showed that the reaction was complete. Added saturated aqueous NaHCO3 solution (5 mL) to quench the reaction. Diluted the reaction solution with ethyl acetate (200 mL), separated the organic phase, and washed the organic phase with saturated aqueous NaHCO3 solution and saturated brine successively, and dried over anhydrous sodium sulfate. After filtration, the solvent was rotary evaporated, ethanol (100 mL) was added, and after ultrasonic extraction, the filtrate was obtained. Compound 4a-1 was a white solid (8.1 g, 82.46%). 1 H NMR (400 MHz, Chloroform-d) δ 8.11-8.05 (m, 2H), 8.05-7.97 (m, 3H), 7.97-7.91 (m, 2H), 7.77 (d, J = 1.6 Hz, 1H), 7.67-7.57 (m, 3H), 7.54-7.36 (m, 6H), 6.11 (d, J = 3.9 Hz, 1H), 5.78 (p, J = 5.5 Hz, 2H), 4.94-4.85 (m, 2H), 4.78-4.69 (m, 1H).

[0121] Compound 4a-1 (2 g, 3.6 mmol) was added to a mixed solution of ethanol (30 mL) and tetrahydrofuran (30 mL), and palladium on carbon was added. The reaction was carried out under hydrogen atmosphere at room temperature and 1 atm overnight. Filtration, rotary evaporation of the solvent. Compound 5a-1 was obtained as a light brown solid (1.83 g, 96.7%). MS m / z = 528.0 [M+1] + .

[0122] Compound 5a-1 (1.8 g, 3.4 mmol) was taken in dichloromethane (50 mL), N,N'-di-BOC-S-methyl isothiourea (1.2 g, 4 mmol), silver nitrate (751 mg, 4.4 mmol) and triethylamine (404 mg, 4 mmol) were added and the reaction was carried out at room temperature overnight. TLC showed the completion of the reaction, filtered, the filtrate was evaporated, silica gel column chromatography using PE:EA = 3:1 gave compound 6a-1 as a white solid (1.76 g, 67.01 %). 1 H NMR (400 MHz, Chloroform-d) δ 11.38 (s, 1H), 10.50 (s, 1H), 8.11 - 8.05 (m, 2H), 7.95 (ddd, J = 8.3, 6.5, 1.4 Hz, 4H), 7.59 - 7.53 (m, 4H), 7.45 (d, J = 7.6 Hz, 2H), 7.39 (td, J = 7.6, 4.7 Hz, 5H), 6.08 (d, J = 4.1 Hz, 1H), 5.87 (p, J = 5.3 Hz, 2H), 4.78 (dt, J = 10.1, 2.8 Hz, 2H), 4.71 (dd, J = 12.8, 4.7 Hz, 1H), 1.52 (s, 9H), 1.45 (s, 9H).

[0123] Compound 6a-1 (1 g, 1.3 mmol) was taken in methanol (20 mL), potassium carbonate (10 mg) was added and the reaction was carried out at room temperature overnight. TLC showed the completion of the reaction, Dowex 50WX 50-100(H) was added until the pH reached 5-6. Filtered, the solvent was evaporated, tert-butyl methyl ether (30 mL) was added, stirred for 1 h, filtered to get compound 7a-1 as a white solid (538 mg, 90.53 %). 1 H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.17 (s, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 5.52 (d, J = 5.7 Hz, 1H), 5.45 (d, J = 6.3 Hz, 1H), 5.17 (d, J = 4.8 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.10 (q, J = 5.7 Hz, 1H), 4.00 (td, J = 4.9, 3.4 Hz, 1H), 3.89 (q, J = 3.9 Hz, 1H), 3.62 - 3.46 (m, 2H), 1.51 (s, 9H), 1.44 (s, 9H).

[0124] Compound 7a-1 (275 mg, 0.6 mmol) was added to dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was allowed to proceed at room temperature for 3 hours. TLC showed that the reaction was complete, the solvent was evaporated, and methanol was used as the mobile phase to obtain compound A1 as a light yellow solid (132 mg, 85.67%). 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.83 (s, 3H), 7.14 (d, J = 1.5 Hz, 1H), 5.56 (d, J = 5.6 Hz, 1H), 5.47 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 4.9 Hz, 1H), 5.06 (t, J = 5.3 Hz, 1H), 4.16 (q, J = 5.1 Hz, 1H), 4.04 (q, J = 3.6 Hz, 1H), 3.92 (d, J = 3.6 Hz, 1H), 3.57 (dddd, J = 20.8, 12.0, 5.1, 2.6 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 155.08, 137.92, 134.83, 105.48, 90.37, 85.29, 75.84, 69.63, 60.60. MS m / z = 258.1 [M+l] +

[0125] Example 2: 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- methyl-1H-imidazol-4-yl)guanidine A2 Compound No: DXY-1043

[0126]

[0127] The target compound A2 was prepared according to the method of Example 1, a light yellow solid, with a yield of 5.5%, except that the corresponding starting material was replaced. 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.71 (s, 3H), 7.05 (s, 1H), 5.52 (d, J = 6.0 Hz, 1H), 5.44 (s, 1H), 5.26 (s, 1H), 5.05 (t, J = 5.3 Hz, 1H), 4.09 (s, 1H), 4.01 (s, 1H), 3.90 (d, J = 3.4 Hz, 1H), 3.55 (t, J = 4.8 Hz, 2H), 2.35 (s, 3H); 13C NMR (101 MHz, DMSO) δ 155.64, 142.44, 135.23, 104.26, 88.63, 86.13, 75.86, 70.82, 61.75, 13.33. MS m / z = 272.1 [M+l] +

[0128] Example 3: 1 -(5-cyano-1 -((2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1 H-imidazol-4-yl)guanidine Compound No. DXY-0927

[0129]

[0130] The target compound was prepared according to the method of Example 1, pale yellow solid, yield 10.1 %. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1 H), 6.64 (s, 2H), 5.79 (s, 2H), 5.66 (d, J = 6.9 Hz, 1 H), 5.52 (d, J = 6.7 Hz, 1 H), 5.36 - 5.18 (m, 2H), 4.08 (t, J = 4.6 Hz, 1 H), 4.02 (q, J = 6.5 Hz, 1 H), 3.94 (q, J = 3.1 Hz, 1 H), 3.66 (dq, J = 8.4, 5.5, 3.5 Hz, 2H), 3.17 (s, 1 H). MS m / z = 283.0 [M+l] +

[0131] Example 4: 1 -(1 -((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-1 H-1,2,4-triazol-3-yl)

[0132] Compound No. DXY-1325

[0133]

[0134] The compound 5a-5 was prepared according to the preparation of 4a-1 in Reference Example 1. White solid, yield 72.7%. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (ddt, J = 11.0, 7.0, 1.4 Hz, 4H), 7.90 - 7.80 (m, 2H), 7.74 - 7.68 (m, 1H), 7.68 - 7.59 (m, 2H), 7.53 (dt, J = 9.4, 7.7 Hz, 4H), 7.41 (t, J = 7.8 Hz, 2H), 6.88 (d, J = 1.3 Hz, 1H), 6.21 (dd, J = 7.9, 5.2 Hz, 1H), 6.08 (p, J = 1.5 Hz, 3H), 4.87 (dt, J = 8.1, 4.2 Hz, 1H), 4.58 (ddd, J = 42.0, 12.2, 4.2 Hz, 2H), 3.87 (s, 3H).

[0135] Compound 6a-5 was prepared according to the preparation of 6a-1 in Reference Example 1. White solid, yield 17.7%. 1 H NMR (400 MHz, Chloroform-d) δ 11.03 (s, 1H), 10.16 (s, 1H), 8.08 - 8.03 (m, 2H), 8.00 (s, 1H), 7.98 - 7.84 (m, 2H), 7.61 - 7.46 (m, 4H), 7.46 - 7.35 (m, 5H), 7.32 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 1.7 Hz, 1H), 6.28 (dd, J = 5.4, 1.9 Hz, 1H), 6.21 (dd, J = 7.2, 5.4 Hz, 1H), 4.94 - 4.81 (m, 1H), 4.75 (dd, J = 12.1, 3.9 Hz, 1H), 4.63 (dd, J = 12.1, 5.5 Hz, 1H), 3.99 (s, 3H), 1.54 (d, J = 9.4 Hz, 18H).

[0136] Compound A5 was prepared according to the preparation of 7a-1 and A1 in Reference Example 1. White solid, yield 91.1%. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 6.22 (s, 4H), 5.58 (d, J = 3.7 Hz, 1H), 5.42 (s, 1H), 5.11 (s, 1H), 4.88 (s, 1H), 4.29 (t, J = 4.3 Hz, 1H), 4.12 (t, J = 5.0 Hz, 1H), 3.88 (q, J = 4.7 Hz, 1H), 3.59 (dd, J = 12.7, 3.8 Hz, 1H), 3.51 - 3.42 (m, 1H). 13C NMR (101 MHz, DMSO) δ 167.17, 157.20, 142.52, 91.44, 85.52, 74.53, 70.95, 62.33. MS m / z = 259.1 [M+l] +

[0137] Example 5: 1-(1-((2R,3S,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H- imidazol-4-yl)guanidine A6

[0138]

[0139] Compound 3a’-6 was synthesized according to the reported method (Eur J Med Chem. 2011; 46(9):4178-4183.).

[0140] 4-Nitroimidazole (1.8 g, 15.1 mmol) was added to acetonitrile (60 mL), N,O-bistrimethylsilylacetamide (6.1 g, 30.2 mmol) was added, and the reaction was refluxed for 30 min. After cooling, compound 3a’-6 (4.9 g, 11.6 mmol) was added, and the reaction was refluxed for 36 h. The solvent was removed, and silica gel column chromatography with PE:EA = 3:1 gave compound 4a-6 as a white solid (1.8 g, 34.1%). 1 HNMR (400 MHz, Chloroform-d) δ 8.12 - 8.00 (m, 5H), 7.72 (s, 1H), 7.63 (dt, J = 24.3, 7.4 Hz, 2H), 7.49 (dt, J = 13.5, 7.7 Hz, 4H), 6.18 (dd, J = 20.1, 2.7 Hz, 1H), 5.71 (dd, J = 16.3, 2.7 Hz, 1H), 5.34 (dd, J = 49.8, 2.7 Hz, 1H), 4.79 (d, J = 4.6 Hz, 2H), 4.61 (q, J = 4.2 Hz, 1H).

[0141] Compound 5a-6 was prepared according to the preparation of 5a-1 in Example 1, which was used directly in the next step.

[0142] Compound 6a-6 was prepared according to the preparation of 6a-1 in Example 1. White solid, yield 41.7%. 1H NMR (400 MHz, Chloroform-d) δ 11.27 (s, 1H), 8.00 (ddt, J = 18.5, 7.0, 1.4 Hz, 4H), 7.63 - 7.55 (m, 1H), 7.52 - 7.47 (m, 3H), 7.46 - 7.32 (m, 5H), 5.94 (dd, J = 21.7, 2.7 Hz, 1H), 5.61 (dd, J = 15.9, 2.7 Hz, 1H), 5.16 (dd, J = 49.9, 2.6 Hz, 1H), 4.67 (d, J = 4.9 Hz, 2H), 4.43 (td, J = 4.8, 2.7 Hz, 1H), 1.44 (d, J = 6.5 Hz, 18H).

[0143] Compound 7a-6 was prepared according to the preparation of 7a-1 in Reference Example 1. White solid, yield 58.7%. 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 10.18 (s, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 6.09 (dd, J = 15.8, 4.2 Hz, 1H), 5.90 (d, J = 4.7 Hz, 1H), 5.20 - 4.90 (m, 2H), 4.26 (dt, J = 18.2, 4.4 Hz, 1H), 3.78 (d, J = 5.1 Hz, 1H), 3.68 - 3.54 (m, 1H), 1.48 (d, J = 28.6 Hz, 18H).

[0144] Compound A6 was prepared according to the preparation of Al in Reference Example 1. White solid, yield 95.6%. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.89 (s, 1H), 7.83 (s, 3H), 7.11 (s, 1H), 6.12 (dd, J = 14.0, 4.4 Hz, 1H), 6.01 - 5.54 (m, 2H), 5.10 (dt, J = 52.4, 4.4 Hz, 1H), 4.32 (dt, J = 18.3, 4.6 Hz, 1H), 3.80 (t, J = 5.0 Hz, 1H), 3.61 (qd, J = 12.0, 4.5 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 155.63, 136.49, 134.56, 106.72, 96.79, 94.88, 84.98 (d, J = 16.8 Hz), 83.98 (d, J = 4.7 Hz), 72.66 (d, J = 23.2 Hz), 60.58. MS m / z = 260.0 [M+l] +

[0145] Example 6: 1-(1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-1H-imidazol-4-yl)guanidine A7 Compound No. DXY-0935

[0146]

[0147] Compound 1a-7 (5 g, 13.3 mmol) was added to a mixed solvent of tetrahydrofuran (40 mL) and methyl tert-butyl methyl ether (10 mL), and a tetrahydrofuran solution (1.0 M, 14.58 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 (200 mL), and the organic phase was washed with water (100 mL x 3) and a saturated aqueous sodium chloride solution (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The product 3a-7 was obtained as a white solid by recrystallization with n-hexane (4.9 g, 87.7%). 1 H 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).

[0148] 4-Nitroimidazole (312 mg, 2.8 mmol) was added to pyridine (5 mL), and hexamethyldisilazane (720 mg, 4.6 mmol) was added, and refluxed for 30 minutes. The solvent was distilled off to obtain a white powder, which was added to chlorobenzene (15 mL). Compound 3a-7 (970 mg, 2.3 mmol) and tetrabutylammonium bromide (57 mg, 0.18 mmol) were added. Tin tetrachloride (3.48 g, 13.8 mmol) was added under nitrogen protection, and the reaction was continued at 120 °C for 3 hours. TLC detection showed that the reaction was complete, 1 mL of a saturated aqueous sodium bicarbonate solution was added, and the reaction solution was poured into a beaker containing 10 g of sodium bicarbonate and sodium chloride, and stirred and filtered. The filtrate was subjected to silica gel column chromatography with PE:EA = 2:1 to obtain compound 4a-7 as a white solid (576 mg, 52.7%). 1H NMR (400 MHz, Chloroform-d) δ 8.08 (t, J = 7.0 Hz, 4H), 7.97 (s, 1H), 7.74 - 7.58 (m, 3H), 7.50 (dt, J = 12.6, 7.6 Hz, 4H), 5.98 (dd, J = 11.0, 5.6 Hz, 1H), 5.73 (ddd, J = 13.1, 4.9, 2.7 Hz, 1H), 4.84 (dd, J = 12.6, 3.5 Hz, 1H), 4.76 (dd, J = 12.5, 4.3 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H).

[0149] Compound 5a-7 was prepared according to the procedure described in Reference Example 1 for the preparation of 5a-1 and used directly in the next step.

[0150] Compound 6a-7 was prepared according to the procedure described in Reference Example 1 for the preparation of 6a-1 and was obtained as a white solid in 41.5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (t, J = 7.0 Hz, 4H), 7.97 (s, 1H), 7.74 - 7.58 (m, 3H), 7.50 (dt, J = 12.6, 7.6 Hz, 4H), 5.98 (dd, J = 11.0, 5.6 Hz, 1H), 5.73 (ddd, J = 13.1, 4.9, 2.7 Hz, 1H), 4.84 (dd, J = 12.6, 3.5 Hz, 1H), 4.76 (dd, J = 12.5, 4.3 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H).

[0151] Compound A7 was prepared according to the procedure described in Reference Example 1 for the preparation of A1 and was obtained as a white solid in 32.1% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (t, J = 7.0 Hz, 4H), 7.97 (s, 1H), 7.74 - 7.58 (m, 3H), 7.50 (dt, J = 12.6, 7.6 Hz, 4H), 5.98 (dd, J = 11.0, 5.6 Hz, 1H), 5.73 (ddd, J = 13.1, 4.9, 2.7 Hz, 1H), 4.84 (dd, J = 12.6, 3.5 Hz, 1H), 4.76 (dd, J = 12.5, 4.3 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H). +

[0152] Example 7: 1-(1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)-1H-imidazol-4-yl)guanidine A8 Compound No. DXY-1710

[0153]

[0154] Compound 1a-8 (10 g, 27.0 mmol) was added to tetrahydrofuran (150 mL), and a tetrahydrofuran solution (1.0 M, 34 mL) of lithium tri-tert-butoxyaluminum hydride was added dropwise at -20 °C. The reaction was continued at -20 °C for 3 h. 4-Dimethylaminopyridine (3.3 g, 27.0 mmol) and acetic anhydride (2.73 g, 27.0 mmol) were added to the reaction solution, and the reaction was continued at -20 °C for 1 h. The reaction solution was diluted with ethyl acetate (300 mL), and the organic phase was washed with water (150 mL x 3) and a saturated aqueous sodium chloride solution (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. Column chromatography on a silica gel (PE:EA = 10:1) gave the product 3a-8 as a white solid (8.1 g, 72.4%). 1 H NMR (400 MHz, Chloroform-d) δ 8.11 - 8.05 (m, 2H), 8.04 - 7.98 (m, 2H), 7.65 - 7.52 (m, 2H), 7.51 - 7.37 (m, 4H), 6.18 (d, J = 2.1 Hz, 1H), 5.26 (t, J = 5.9 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.69 (dd, J = 12.2, 3.7 Hz, 1H), 4.56 (dd, J = 12.2, 4.9 Hz, 1H), 2.19 (s, 3H), 1.71 (d, J = 22.4 Hz, 3H).

[0155] 4-Nitroimidazole (930 mg, 8.0 mmol) was added to acetonitrile (40 mL), and N,O-bistrimethylsilylacetamide (3.2 g, 16.0 mmol) was added. The reaction was continued at reflux for 30 min. After cooling to room temperature, compound 3a-8 (2.2 g, 5.3 mmol) and tetrabutylammonium bromide (136 mg, 0.4 mmol) were added, and tin tetrachloride (2.0 g, 8.0 mmol) was added under nitrogen protection. The reaction was continued at 80 °C overnight. TLC showed that the reaction was complete, 2 mL of a saturated aqueous sodium bicarbonate solution was added, and the reaction solution was poured into a beaker containing 30 g of sodium bicarbonate and sodium chloride, and stirred and filtered. The filtrate was distilled off, and recrystallized from 95% ethanol to give compound 4a-8 as a white solid (1.3 g, 52.4%). 1H NMR (400MHz, chloroform-d) δ8.07(d,J=1.0Hz,1H),8.02(dt,J=6.0,2.3Hz,5H),7.62( t,J=7.5Hz,1H),7.58(t,J=7.5Hz,1H),7.45(dt,J=15.8,7.7Hz,5H),6.92(d,J =14.5Hz,1H),5.74(dd,J=18.0,7.5Hz,1H),4.92(dt,J=7.9,4.3Hz,1H),4.74 (dd,J=12.3,3.7Hz,1H),4.60(dd,J=12.3,4.6Hz,1H),1.64(d,J=22.3Hz,3H).

[0156] Compound 5a-8 was prepared by referring to the preparation of 5a-1 in Example 1 and can be directly used in the next reaction.

[0157] Compound 6a-8 was prepared according to the preparation of 6a-1 in Example 1, and was a white solid with a yield of 57.6%. 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 8.11–8.06 (m, 3H), 8.01–7.94 (m, 3H), 7.80 (d, J = 2.8 Hz,1H),7.62(t,J=7.3Hz,2H),7.53(d,J=7.4Hz,1H),7.48(d,J=7.7Hz,3H),7.38(t,J=7.7 Hz,3H),7.13(s,1H),5.75(d,J=19.9Hz,1H),5.72–5.63(m,1H),4.88(dt,J=8.6,4.4Hz,1 H), 4.61 (ddd, J=54.6, 12.1, 4.3Hz, 3H), 1.60 (d, J=22.0Hz, 3H), 1.49 (s, 9H), 1.43 (s, 9H).

[0158] Compound A8 was prepared according to the preparation of A1 in Example 1, and was a light brown solid with a yield of 75.4%. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 3.0 Hz, 1H), 7.55 (s, 4H), 6.97 (s, 1H), 5.76 (d, J = 5.9 Hz, 1H), 5.67 (d, J = 20.8 Hz, 1H), 4.89 (t, J = 5.4 Hz, 1H), 4.08 (q, J = 2.3 Hz, 1H), 3.70 (dd, J = 11.8, 3.5 Hz, 1H), 3.51 (dt, J = 12.3, 4.6 Hz, 1H), 3.17 (s, 1H), 1.32 (d, J = 21.9 Hz, 3H). 13 CNMR (101 MHz, DMSO) δ 157.85, 136.94, 99.27, 97.37, 86.59 (d, J = 15.1 Hz), 83.04, 72.79 (d, J = 17.2 Hz), 60.64, 49.05, 17.01 (d, J = 25.1 Hz). MS m / z = 278.1 [M+l] +

[0159] Example 8: 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H- imidazol-4-yl)urea A9 Compound No: DXY-0904

[0160]

[0161] Compound A25 (421 mg, 0.74 mmol) was added to methanol (15 mL), sodium methoxide (10 mg, 0.22 mmol) was added, and the reaction was carried out at 60 °C overnight. Dowex 50WX 50-100(H) was added until the pH reached 5-6. Filtration, and the solvent was rotary evaporated. Water (50 mL) was added for dilution, and dichloromethane (10 mL x 3) was washed. The water phase was rotary evaporated, and Sephadex LH-20 column chromatography was used to obtain compound A9 as a white solid (98 mg, 51.4%). 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 6.96 (s, 1H), 5.90 (s, 2H), 5.43 (d, J = 5.9 Hz, 1H), 5.35 (d, J = 6.3 Hz, 1H), 5.13 (d, J = 4.6 Hz, 1H), 4.96 (t, J = 5.3 Hz, 1H), 4.09 (q, J = 5.8 Hz, 1H), 3.98 (q, J = 4.4 Hz, 1H), 3.84 (q, J = 3.9 Hz, 1H), 3.62 - 3.47 (m, 2H). MS m / z = 259.1 [M+l] +

[0162] Example 9: N-(l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-lH-imidazol-4-yl)-2,2,2-trifluoroacetamide A10 Compound No. DXY-0648-2

[0163]

[0164] Compound 5a-1 (100 mg, 0.19 mmol) was added to dichloromethane (5 mL), trifluoroacetic anhydride (37 mg, 0.285 mmol) and triethylamine (40 mg, 0.47 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. The reaction solution was subjected to silica gel column chromatography using PE:EA = 2; 1 to obtain compound A26 (62 mg, 52,5%).

[0165] Compound A26 (590 mg, 0.95 mmol) was added to methanol (30 mL), sodium methoxide (16 mg, 0.29 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. Dowex 50WX 50-100(H) was added until the pH reached 5-6. Filtration and column chromatography using DCM:MeOH = 10:1 yielded compound A10 as a white solid (30 mg, 10.1%). 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 5.55 (d, J = 5.9 Hz, 1H), 5.39 (d, J = 6.4 Hz, 1H), 5.15 (d, J = 4.6 Hz, 1H), 5.00 (t, J = 5.2 Hz, 1H), 4.15 (q, J = 5.9 Hz, 1H), 4.03 (td, J = 4.7, 3.0 Hz, 1H), 3.90 (q, J = 3.6 Hz, 1H), 3.56 (qdd, J = 11.8, 5.2, 3.8 Hz, 2H). MS m / z = 312.1 [M+l] +

[0166] Example 10: l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5- nitro-lH-imidazole-4-carboxamide A12 Compound No. DXY-0443

[0167]

[0168] The target compound A12 was prepared according to the method of Example 1, except that the corresponding reaction starting material was replaced. White solid, yield 18.6%. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 5.60 (dd, J = 17.3, 5.1 Hz, 2H), 5.25 (d, J = 5.3 Hz, 1H), 5.13 (t, J = 5.2 Hz, 1H), 4.27 (q, J = 4.9 Hz, 1H), 4.08 (q, J = 5.0 Hz, 1H), 3.93 (d, J = 4.4 Hz, 1H), 3.68 (dt, J = 11.9, 4.4 Hz, 1H), 3.57 (dt, J = 12.2, 4.5 Hz, 1H). MS m / z = 599.0 [2M+Na] +

[0169] Example 11: (Z)-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-N'-hydroxy-1H-imidazole-4-carboxamide A13 Compound No. DXY-0801

[0170]

[0171] Compound A29 (100 mg, 0.175 mmol) was added to methanol (8 mL), sodium methoxide (3 mg, 0.053 mmol) was added and the reaction was left to react at room temperature overnight. Dowex 50WX 50-100(H) was added until the pH reached 5-6. Filtration, recrystallization in isopropyl alcohol gave compound A13 as a white solid (32 mg, 70.7%). 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 5.59 (d, J = 5.9 Hz, 1H), 5.45 (d, J = 6.3 Hz, 1H), 5.21 (d, J = 4.6 Hz, 1H), 5.03 (t, J = 5.3 Hz, 1H), 4.15 (q, J = 5.8 Hz, 1H), 4.04 (dd, J = 4.8, 3.1 Hz, 1H), 3.91 (q, J = 3.6 Hz, 1H), 3.56 (qt, J = 11.9, 4.6 Hz, 2H), 3.17 (d, J = 4.2 Hz, 1H). MS m / z = 281.1 [M+Na] +

[0172] Example 12: (Z)-5-cyano-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-N'-hydroxy-1H-imidazole-4-carboxamide A14 Compound No. DXY-0911

[0173]

[0174] The target compound A14 was prepared according to the method of Example 11 except that the corresponding starting material was replaced. White solid, yield 22.2%. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.40 (s, 1H), 5.74 - 5.61 (m, 4H), 5.34 (d, J = 4.9 Hz, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 5.4 Hz, 1H), 4.07 (q, J = 4.5 Hz, 1H), 3.96 (d, J = 3.9 Hz, 1H), 3.67 - 3.52 (m, 2H). MS m / z = 284.1 [M+l] +.

[0175] Example 13: 1-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methyl-1H-imidazol-4-yl)guanidine A15 Compound No. DXY-1127

[0176]

[0177] The target compound A15 was prepared according to the method of Example 1 except that the corresponding starting material was replaced. Pale yellow solid, yield 3.3%. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.40 (s, 1H), 5.74 - 5.61 (m, 4H), 5.34 (d, J = 4.9 Hz, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 5.4 Hz, 1H), 4.07 (q, J = 4.5 Hz, 1H), 3.96 (d, J = 3.9 Hz, 1H), 3.67 - 3.52 (m, 2H). MS m / z = 284.1 [M+l] 2+

[0178] Example 14: 3-amino-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-5-carboxylic acid methyl ester A16 Compound No. DXY-1119

[0179]

[0180] The target compound A16 was prepared according to the method of Example 11, white solid, yield 34.8% except replacing the corresponding starting material. 1 H NMR (400 MHz, DMSO-d6) δ 6.31 (d, J = 3.6 Hz, 1H), 5.82 (s, 2H), 5.40 (d, J = 5.5 Hz, 1H), 5.12 (d, J = 5.7 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.35 (td, J = 5.3, 3.7 Hz, 1H), 4.15 (q, J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.86 (t, J = 5.5 Hz, 1H), 3.54 (ddd, J = 11.7, 5.4, 4.3 Hz, 1H), 3.41 (dt, J = 11.9, 6.2 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ 163.56, 158.33, 143.66, 90.47, 85.66, 74.42, 71.26, 62.84, 53.29. MS m / z = 282.1 [M+Na] +

[0181] Example 15: (2R, 3R, 4R, 5R)-2-((benzoyloxy)methyl)-5-(4-guanidino-1H-imidazol-1- yl)tetrahydrofuran-3, 4-diyl dibenzoate A17 Compound No: DXY-0722

[0182]

[0183] Compound 6a-1 (100 mg, added into dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 3 hours. The solvent was rotary evaporated, and DCM:MeOH = 20:1 column chromatography to obtain compound A17, white solid (56 mg, 75.7%). 1 H NMR (400 MHz, DMSO-d6) δ 6.31 (d, J = 3.6 Hz, 1H), 5.82 (s, 2H), 5.40 (d, J = 5.5 Hz, 1H), 5.12 (d, J = 5.7 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.35 (td, J = 5.3, 3.7 Hz, 1H), 4.15 (q, J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.86 (t, J = 5.5 Hz, 1H), 3.54 (ddd, J = 11.7, 5.4, 4.3 Hz, 1H), 3.41 (dt, J = 11.9, 6.2 Hz, 1H). 13C NMR (101 MHz, DMSO) δ 165.94, 165.10, 164.88, 155.83, 137.30, 134.92, 134.54, 134.41, 134.07, 129.85, 129.83, 129.73, 129.63, 129.28, 129.24, 129.22, 128.99, 128.65, 105.97, 87.94, 80.01, 74.82, 71.33, 64.39. MS m / z = 570.1 [M+H] +

[0184] Example 16: (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-guanidino-2-methyl-1 H- imidazol-1 -yl)tetrahydrofuran-3,4-diyl dibenzoate A18 Compound No. DXY-1137

[0185]

[0186] The target compound A18 was prepared according to the method of Example 1 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 5.9%. 1 H NMR (400 MHz, Chloroform-d) δ 10.52 (s, 1H), 8.82 (s, 1H), 8.16 - 8.05 (m, 2H), 7.93 (ddd, J = 11.9, 8.2, 1.5 Hz, 4H), 7.65 - 7.52 (m, 3H), 7.50 - 7.31 (m, 7H), 6.79 (s, 1H), 6.00 (d, J = 5.8 Hz, 1H), 5.82 (dd, J = 5.8, 4.2 Hz, 1H), 5.73 (t, J = 5.8 Hz, 1H), 4.78 (dd, J = 11.9, 2.8 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.66 (dd, J = 11.9, 4.0 Hz, 1H), 2.42 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 166.18, 165.22, 164.89, 155.63, 142.14, 136.98, 133.92, 133.79, 133.57, 129.77, 129.65, 129.04, 128.66, 128.61, 128.57, 128.23, 101.63, 86.87, 80.58, 75.17, 71.26, 63.60, 13.35. MS m / z = 584.2 [M+H] +

[0187] Example 17: (2R, 3R, 4R, 5R)-2-((benzoyloxy)methyl)-5-(5-cyano-4-guanidino- 1 H-imidazol- 1 -yl)tetrahydrofuran-3,4-diyl dibenzoate A19 Compound No. DXY-0922

[0188]

[0189] The target compound A19 was prepared according to the method of Example 1 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 14.1%. 1 H NMR (400 MHz, Chloroform-d) δ 11.28 (s, 1H), 8.05 - 7.98 (m, 2H), 7.96 - 7.88 (m, 4H), 7.75 (s, 1H), 7.53 (ddd, J = 9.3, 7.5, 4.6 Hz, 3H), 7.44 - 7.27 (m, 7H), 6.14 (d, J = 5.5 Hz, 1H), 5.85 (dd, J = 5.9, 4.2 Hz, 1H), 5.79 (t, J = 5.7 Hz, 1H), 4.82 (dd, J = 11.8, 3.3 Hz, 1H), 4.78 (q, J = 3.9 Hz, 1H), 4.69 (dd, J = 11.8, 4.2 Hz, 1H), 3.06 (s, 2H). MS m / z = 595.2 [M+H] +

[0190] Example 18: (2R, 3R, 4R, 5R)-2-((benzoyloxy)methyl)-5-(2-guanidino-1 H-imidazol- 1 -yl)tetrahydrofuran-3,4-diyl dibenzoate A20 Compound No. DXY-1010

[0191]

[0192] The target compound A20 was prepared according to the method of Example 1 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 14.1%. 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 4H), 8.03 (d, J = 7.7 Hz, 2H), 7.98 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 2H), 7.69 (q, J = 8.3, 7.7 Hz, 3H), 7.60 - 7.40 (m, 6H), 7.40 - 7.25 (m, 2H), 6.38 (d, J = 5.6 Hz, 1H), 5.93 - 5.79 (m, 2H), 4.81 - 4.56 (m, 3H). MS m / z = 570.1 [M+H] +

[0193] Example 19: (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(5-guanidino-3- (methoxycarbonyl)-1H-1,2,4-triazol-1-yl)tetrahydrofuran-3,4-diyl dibenzoate A21 Compound No. DXY-1315

[0194]

[0195] The target compound A21 was prepared according to the method of Example 1 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 13.7%. 1 H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.02 - 7.98 (m, 2H), 7.92 - 7.87 (m, 2H), 7.86 - 7.81 (m, 2H), 7.74 - 7.69 (m, 1H), 7.67 - 7.60 (m, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.45 (dt, J = 17.7, 7.8 Hz, 4H), 7.00 (d, J = 1.2 Hz, 1H), 6.21 (s, 2H), 4.94 (dd, J = 6.9, 4.0 Hz, 1H), 4.71 (dd, J = 12.3, 3.8 Hz, 1H), 4.57 (dd, J = 12.3, 4.5 Hz, 1H), 3.94 (s, 3H). MS m / z = 629.1 [M+H] +

[0196] Example 20: Methyl ((2R,3R,4S,5R)-3-(benzoyloxy)-4-fluoro-5-(4-guanidino-1H- imidazol-1-yl)tetrahydrofuran-2-yl)benzoate A22 Compound No. DXY-1550

[0197]

[0198] The target compound A22 was prepared according to the method of Example 5 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 9.4%. 1 H NMR (400 MHz, Chloroform-d) δ 10.21 - 9.94 (m, 1H), 7.92 (t, J = 8.4 Hz, 4H), 7.57 - 7.38 (m, 3H), 7.31 (dt, J = 20.4, 7.7 Hz, 4H), 6.81 (s, 1H), 5.86 (d, J = 21.0 Hz, 1H), 5.48 (d, J = 16.9 Hz, 1H), 5.08 (d, J = 50.5 Hz, 1H), 4.57 (s, 2H), 4.34 (q, J = 4.2 Hz, 1H). 13C NMR (101 MHz, CDC13) δ 166.38, 165.08, 155.57, 134.11, 133.43, 129.83, 129.68, 129.17, 128.66, 128.48, 128.07, 116.12 (d, J = 290.6 Hz), 93.63, 86.76 (d, J = 17.7 Hz), 81.01, 63.21. MS m / z = 468.1 [M+H] +

[0199] Example 21: ((2R,3R,5R)-3-(benzoyloxy)-4,4-difluoro-5-(4-guanidino-1H-imidazol-1- yl)tetrahydrofuran-2-yl)methyl benzoate A23 Compound No. DXY-0929

[0200]

[0201] The target compound A23 was prepared according to the method of Example 6 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 12.7%. 1 H NMR (400 MHz, Chloroform-d) δ 10.88 (s, 1H), 8.81 (s, 1H), 8.18 - 7.96 (m, 4H), 7.64 (t, J = 7.5 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.43 (t, J = 7.6 Hz, 3H), 6.86 (s, 1H), 5.83 (dd, J = 11.8, 5.4 Hz, 1H), 5.65 (ddd, J = 13.4, 4.9, 2.1 Hz, 1H), 4.73 (qd, J = 12.4, 4.3 Hz, 2H), 4.60 (q, J = 4.4 Hz, 1H), 2.12 (s, 1H). MS m / z = 486.0 [M+H] +

[0202] Example 22: ((2R,3R,4R,5R)-3-(benzoyloxy)-4-fluoro-5-(4-guanidino-1H-imidazol-1-yl)- 4-methyltetrahydrofuran-2-yl)methyl benzoate A24 Compound No. DXY-1707

[0203]

[0204] The target compound A24 was prepared according to the method of Example 7 and Example 15 except that the corresponding reaction starting materials were replaced. White solid, yield 12.7%. 1H NMR (400 MHz, Chloroform-d) δ 9.95 (s, 1H), 8.11 (d, J = 3.4 Hz, 1H), 8.07 - 8.00 (m, 2H), 7.96 - 7.87 (m, 3H), 7.76 - 7.69 (m, 1H), 7.63 - 7.56 (m, 3H), 7.45 (s, 1H), 7.14 (s, 1H), 6.12 (d, J = 20.1 Hz, 1H), 5.98 - 5.90 (m, 1H), 4.89 (dt, J = 9.2, 5.0 Hz, 1H), 4.59 (t, J = 4.8 Hz, 2H), 1.48 (d, J = 22.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 166.37, 165.40, 158.24, 134.50, 133.94, 130.05, 129.68, 129.56, 129.35, 129.11, 128.93, 118.90, 115.94, 97.93 (d, J = 194.2 Hz), 86.27 (d, J = 15.0 Hz), 77.54, 74.90, 64.12, 17.13 (d, J = 24.2 Hz). MS m / z = 482.1 [M+H] +

[0205] Example 23: (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-ureido-lH-imidazol-l- yl)tetrahydrofuran-3,4-diyl dibenzoate A25 Compound No. DXY-0819

[0206]

[0207] Compound 5a-1 (2.4 g, 4.6 mmol) was added to ethanol (45 mL), sodium cyanate (442 mg, 0.68 mmol) aqueous solution 5 mL was added under ice bath, dropwise glacial acetic acid. The reaction was carried out at room temperature overnight. 5 mL saturated aqueous sodium bicarbonate was added to quench the reaction. The ethanol was removed, diluted with ethyl acetate (40 mL), the organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate. DCM:MeOH = 15: 1 silica gel column chromatography to obtain compound A25 as a light brown solid (1.0 g, 38.5%). 1H NMR (400 MHz, Chloroform-d) δ 8.07 (ddd, J = 8.4, 6.7, 1.4 Hz, 2H), 7.97 - 7.95 (m, 2H), 7.95 - 7.92 (m, 2H), 7.56 (ddd, J = 10.0, 6.3, 1.7 Hz, 4H), 7.49 - 7.42 (m, 2H), 7.42 - 7.34 (m, 5H), 6.03 (dd, J = 6.5, 4.3 Hz, 1H), 5.90 - 5.77 (m, 2H), 4.87 - 4.74 (m, 2H), 4.67 (ddd, J = 12.1, 6.2, 3.6 Hz, 1H), 1.19 (s, 1H). MS m / z = 571.1 [M+l] +

[0208] Example 24: (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(2-(2,2,2- trifluoroacetamido)-lH-imidazol-l-yl)tetrahydrofuran-3,4-diyl dibenzoate A27 Compound No. DXY-1049

[0209]

[0210] The target compound A27 was prepared according to the procedure of Example 9 except that the corresponding starting materials were replaced. Off-white solid, yield 74.1%. 1 H NMR (400 MHz, Chloroform-d) δ 11.97 (s, 1H), 8.10 (d, J = 7.7 Hz, 2H), 7.97 (dd, J = 14.7, 7.7 Hz, 4H), 7.79 (dd, J = 44.8, 7.6 Hz, 1H), 7.57 (dq, J = 12.3, 7.7 Hz, 3H), 7.42 (ddd, J = 30.7, 15.3, 7.7 Hz, 6H), 6.86 (s, 1H), 6.78 (s, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.01 (t, J = 5.1 Hz, 1H), 5.83 (t, J = 5.9 Hz, 1H), 4.86 (d, J = 12.0 Hz, 1H), 4.78 (q, J = 3.9 Hz, 1H), 4.71 (dd, J = 12.3, 4.1 Hz, 1H). MS m / z = 624.1 [M+H] +

[0211] Example 25: (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-(4-((Z)-N'- hydroxycarbamimidamido)-lH-imidazol-l-yl)tetrahydrofuran-3,4-diyl dibenzoate A29 Compound No. DXY-0823

[0212]

[0213] Compound 4a-12 was prepared according to the preparation of 4a-1 in Reference Example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 - 8.05 (m, 2H), 8.01 - 7.92 (m, 5H), 7.83 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.52 (dd, J = 8.4, 7.1 Hz, 2H), 7.44 - 7.38 (m, 4H), 6.09 (d, J = 4.4 Hz, 1H), 5.83 - 5.73 (m, 2H), 4.89 - 4.82 (m, 2H), 4.72 - 4.67 (m, 1H).

[0214] Hydroxylamine hydrochloride (50 mg, 0.7 mmol) was added to water (2.5 mL), sodium carbonate (37 mg, 0, 35 mmol) was added, a solution of compound 4a-12 (400 mg, 0.7 mmol) in ethanol (8 mL) was added and the reaction was left to react overnight at 70 °C. TLC showed that the reaction was complete, the solvent was evaporated, dichloromethane was added and filtered. The solvent was evaporated and recrystallized from methyl tert-butyl ether to obtain compound A29 as a white solid (380 mg, 89.5%). 1 H NMR (400 MHz, Chloroform-d) δ 8.08 - 8.05 (m, 2H), 8.01 - 7.92 (m, 5H), 7.83 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.52 (dd, J = 8.4, 7.1 Hz, 2H), 7.44 - 7.38 (m, 4H), 6.09 (d, J = 4.4 Hz, 1H), 5.83 - 5.73 (m, 2H), 4.89 - 4.82 (m, 2H), 4.72 - 4.67 (m, 1H). +

[0215] Example 26: (2R, 3R, 4R, 5R)-2-((benzoyloxy)methyl)-5-(5-cyano-4-((Z)-N'- hydroxycarbamimidamido)-lH-imidazol-l-yl)tetrahydrofuran-3,4-diyl dibenzoate A30 Compound No: DXY-0911

[0216]

[0217] The target compound A30 was prepared according to the method of Example 11 except that the corresponding reaction starting material was replaced. White solid, yield 40.6%. 1 H NMR (400 MHz, Chloroform-d) δ 8.14 - 8.05 (m, 2H), 8.04 - 7.95 (m, 4H), 7.90 (s, 1H), 7.68 - 7.54 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 7.8 Hz, 3H), 6.27 (d, J = 6.4 Hz, 1H), 5.93 (dd, J = 5.8, 3.5 Hz, 1H), 5.79 (t, J = 6.0 Hz, 1H), 5.22 (s, 2H), 4.89 (dd, J = 12.2, 2.9 Hz, 1H), 4.82 (q, J = 3.5 Hz, 1H), 4.76 (dd, J = 12.1, 4.1 Hz, 1H). MS m / z = 596.1 [M+l] +

[0218] Example 27: (2R,3R,4R,5R)-2-(((2-acetyloxybenzoyl)oxy)methyl)-5-(4-guanidino-1H- imidazol-1-yl)tetrahydrofuran-3,4-diyl bis(2-acetylbenzoate) A31 Compound No. DXY-1324

[0219]

[0220] Compound 7a-1 (150 mg, 0.33 mmol) was added to dichloromethane (10 mL), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.465 mmol), 4- dimethylaminopyridine (210 mg, 1.72 mmol) and m-acetybenzoic acid (210 mg, 1.17 mmol) were added. The reaction was carried out at room temperature overnight. TLC showed that the reaction was completed, diluted with dichloromethane (30 mL), the organic phase was washed successively with saturated aqueous ammonium chloride solution (10 mL x 3) and saturated brine (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. Filtration, PE:EA = 1:1 column chromatography to obtain compound 6a-23, white solid (266 mg, 86.0%). 1H NMR (400 MHz, Chloroform-d) δ 11.39 (s, 1H), 10.50 (s, 1H), 8.08 - 7.86 (m, 2H), 7.84 - 7.76 (m, 3H), 7.70 (d, J = 1.7 Hz, 1H), 7.66 (dt, J = 10.2, 1.9 Hz, 2H), 7.54 (dd, J = 5.0, 1.9 Hz, 1H), 7.43 (dtd, J = 16.1, 8.1, 2.3 Hz, 3H), 7.38 - 7.31 (m, 2H), 6.06 (d, J = 4.8 Hz, 1H), 5.85 (dt, J = 22.9, 5.2 Hz, 2H), 4.78 - 4.64 (m, 3H), 2.39 - 2.21 (m, 9H), 1.54 - 1.44 (m, 18H).

[0221] Compound A31 was prepared according to the procedure described in Example 27, white solid, yield 54.0%. 1 H NMR (400 MHz, Chloroform-d) δ 11.39 (s, 1H), 10.50 (s, 1H), 8.08 - 7.86 (m, 2H), 7.84 - 7.76 (m, 3H), 7.70 (d, J = 1.7 Hz, 1H), 7.66 (dt, J = 10.2, 1.9 Hz, 2H), 7.54 (dd, J = 5.0, 1.9 Hz, 1H), 7.43 (dtd, J = 16.1, 8.1, 2.3 Hz, 3H), 7.38 - 7.31 (m, 2H), 6.06 (d, J = 4.8 Hz, 1H), 5.85 (dt, J = 22.9, 5.2 Hz, 2H), 4.78 - 4.64 (m, 3H), 2.39 - 2.21 (m, 9H), 1.54 - 1.44 (m, 18H). +

[0222] Example 28: (2R, 3R, 4R, 5R)-2-(((3-acetyloxy-4-methoxybenzoyl)oxy)methyl)-5-(4- guanidino-1H-imidazol-1-yl)tetrahydrofuran-3,4-diyl bis(3-acetyl-4-methylbenzoate) A32 Compound No. DXY-1341

[0223]

[0224] The target compound A32 was prepared according to the procedure described in Example 27, white solid, yield 54.0%, except that the corresponding starting materials were replaced. 1H NMR (400 MHz, Chloroform-d) δ 8.15 - 8.04 (m, 1H), 7.96 (ddt, J = 20.3, 8.6, 2.0 Hz, 1H), 7.90 - 7.72 (m, 4H), 7.72 - 7.66 (m, 1H), 7.62 (dd, J = 4.4, 2.2 Hz, 1H), 7.57 (dd, J = 11.0, 1.9 Hz, 1H), 7.50 (t, J = 1.8 Hz, 1H), 7.07 - 6.89 (m, 4H), 6.72 (dd, J = 6.6, 1.6 Hz, 1H), 5.95 (dd, J = 5.2, 2.7 Hz, 1H), 5.81 - 5.60 (m, 2H), 4.98 - 4.75 (m, 1H), 4.75 - 4.65 (m, 1H), 4.53 - 4.34 (m, 1H), 3.92 - 3.83 (m, 9H), 2.39 - 2.22 (m, 9H). 13 C NMR (101 MHz, CDC13) δ 169.90, 168.79, 168.63, 164.90, 164.26, 164.09, 163.02, 162.67, 155.93, 155.83, 155.53, 139.48, 139.37, 138.65, 130.07, 129.65, 125.02, 124.43, 124.32, 121.67, 120.96, 120.62, 118.16, 115.25, 112.11, 111.93, 88.48, 80.78, 77.36, 77.24, 77.04, 76.72, 71.15, 62.98, 56.19, 56.13, 20.62, 20.56, 20.48. MS m / z = 834.2 [M+H] +

[0225] Example 29: (2R,3R,4R,5R)-2-(((E)-3-(3,4-dimethoxyphenyl)acryloyl)oxy)methyl)-5-(4- guanidino-1H-imidazol-1-yl)tetrahydrofuran-3,4-diyl (2E,2'E)-bis(3-(3,4- dimethoxyphenyl)acrylate) A34 Compound No. DXY-1311

[0226]

[0227] The target compound A34 was prepared according to the method of Example 27 except that the corresponding reaction starting materials were replaced. White solid, yield 70.8%. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.79 (s, 4H), 7.70 - 7.59 (m, 3H), 7.43 - 7.23 (m, 5H), 7.19 (ddd, J = 7.6, 5.3, 1.9 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.67 - 6.53 (m, 3H), 6.19 (d, J = 5.5 Hz, 1H), 5.78 (t, J = 4.6 Hz, 1H), 5.70 - 5.58 (m, 1H), 4.66 - 4.45 (m, 3H), 3.80 (s, 6H), 3.79 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H). MS m / z = 828.3 [M+H] +

[0228] Example 30: (2R,3R,4R,5R)-2-((((E)-3-(3-acetyloxy-4-methoxyphenyl)acryloyl)oxy)methyl)-5-(4-guanidino-1H-imidazol-1-yl)tetrahydrofuran-3,4-diyl (2E,2'E)-bis(3-(3-acetyl-4-methylphenyl)acrylate) A36 Compound No.: DXY-1226

[0229]

[0230] The target compound A36 was prepared according to the method of Example 27 except that the corresponding reaction starting materials were replaced. White solid, yield 74.3%. 1 H NMR (400 MHz, Chloroform-d) δ 10.79 (s, 1H), 7.64 - 7.55 (m, 4H), 7.39 (dd, J = 8.6, 2.1 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 2H), 7.25 - 7.21 (m, 3H), 6.96 (s, 1H), 6.94 - 6.91 (m, 1H), 6.91 - 6.88 (m, 2H), 6.33 - 6.24 (m, 3H), 5.86 (d, J = 3.7 Hz, 1H), 5.61 (q, J = 4.1, 2.6 Hz, 2H), 4.70 (dd, J = 12.5, 2.9 Hz, 1H), 4.59 (q, J = 3.3 Hz, 1H), 4.39 (dd, J = 12.3, 3.2 Hz, 1H), 3.84 (d, J = 4.7 Hz, 9H), 2.98 - 2.39 (m, 3H), 2.36 - 2.23 (m, 9H). MS m / z = 912.3 [M+H] +

[0231] Example 31: (2R, 3R, 4R, 5R)-2-(4-guanidino-1H-imidazol-1-yl)-5-((isobutoxy) methyl)tetrahydrofuran-3, 4-diyl bis(2-methylpropanoate) A38 Compound No. DXY-1547

[0232]

[0233] 7a-1 (150 mg, 0.33 mmol) was added to dichloromethane (10 mL), acetic anhydride (134 mg, 1.32 mmol), triethylamine (143 mg, 1.416 mmol) and 4-dimethylaminopyridine (4 mg, 0.033 mmol) were added and the reaction was left to stir at room temperature overnight. TLC showed the reaction was complete and the product was purified by silica gel column chromatography with PE:EA = 3:1 to give compound 6a-38 as a white solid (81 mg, 83.6%).

[0234] Compound A38 was prepared according to the preparation of A17 in Reference Example 15. White solid, yield 77.1%. 1 H NMR (400 MHz, Chloroform-d) δ 10.98 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 5.75 (d, J = 4.9 Hz, 1H), 5.33 (t, J = 3.8 Hz, 2H), 4.50 - 4.27 (m, 3H), 2.21 - 2.08 (m, 9H). 13 C NMR (101 MHz, CDC13) δ 175.21, 170.61, 169.65, 169.52, 155.50, 138.38, 132.26, 88.34, 80.57, 74.63, 70.41, 62.83, 20.73, 20.49, 20.30. MS m / z = 384.1 [M+H] +

[0235] Example 32: ((2R, 3S, 4R, 5R)-5-(4-guanidino-1H-imidazol-1-yl)-3, 4-dihydroxytetrahydrofuran-2-yl) isobutyrate methyl ester A40 Compound No. DXY-1146

[0236]

[0237] 7a-1 (510 mg, 1.1 mmol) was added to acetone (15 mL), 2,2-dimethoxypropane (580 mg, 5.5 mmol) and p-toluenesulfonic acid (39 mg, 0,22 mmol) were added and the reaction was left to react overnight at 50 °C. TLC showed that the reaction was complete, silica gel column chromatography with PE:EA = 1 : 1 gave 9a-40 as a white solid (270 mg, 48.68%). 1 H NMR (400 MHz, Chloroform-d) δ 11.35 (s, 1H), 10.50 (s, 1H), 7.77 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 5.75 (d, J = 2.8 Hz, 1H), 4.92 (ddd, J = 28.9, 6.2, 2.6 Hz, 2H), 4.38 (q, J = 2.8 Hz, 1H), 3.92 (dd, J = 12.1, 2.6 Hz, 1H), 3.79 (dd, J = 12.0, 3.5 Hz, 1H), 3.34 (s, 1H), 1.59 (s, 3H), 1.52 (s, 9H), 1.51 (s, 9H), 1.36 (s, 3H).

[0238] 9a-40 (170 mg, 0.34 mmol) was added to dichloromethane, isobutyric anhydride (81 mg, 0.51 mmol), triethylamine (69 mg, 0.68 mmol) and 4-dimethylaminopyridine (4.1 mg, 0.034 mmol) were added. The reaction was left to react at room temperature for 3 hours. Dilution with dichloromethane and the solvent was evaporated. Silica gel column chromatography with PE:EA = 2: 1 gave compound 10a-40 as a white solid (105 mg, 54.14%). 1 H NMR (400 MHz, Chloroform-d) δ 11.22 (s, 1H), 7.26 (s, 1H), 7.08 (s, 1H), 5.59 (d, J = 2.4 Hz, 1H), 4.72 (dd, J = 6.3, 2.5 Hz, 1H), 4.57 (dd, J = 6.4, 3.5 Hz, 1H), 4.24 (q, J = 4.2 Hz, 1H), 4.12 - 3.94 (m, 2H), 2.42 - 2.34 (m, 1H), 1.41 (s, 3H), 1.34 (s, 18H), 1.19 (s, 3H), 1.01 - 0.92 (m, 6H).

[0239] A40 was prepared following the preparation of A17 in Example 15. White solid, yield 86.7%. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.97 (s, 1H), 7.74 (s, 4H), 7.21 (s, 1H), 5.84 - 5.73 (m, 1H), 5.59 (d, J = 6.6 Hz, 1H), 5.28 (s, 1H), 5.20 (dd, J = 5.6, 2.3 Hz, 1H), 4.44 (q, J = 5.8 Hz, 1H), 4.06 (t, J = 3.1 Hz, 1H), 2.61 (q, J = 7.0 Hz, 1H), 1.18 - 1.07 (m, 6H). 13 C NMR (101 MHz, DMSO) δ 175.92, 155.50, 137.11, 134.77, 105.20, 90.08, 83.90, 74.16, 73.51, 61.61, 33.70, 19.35, 19.23. MS m / z = 328.2 [M+H] +

[0240] Example 33: (2R,3R,4R,5R)-2-(4-guanidino-1H-imidazol-1-yl)-5-((isobutoxy)methyl)tetrahydrofuran-3,4-diyl bis(2-methylpropanoate) A41 Compound No. DXY-1303

[0241]

[0242] 6a-41 was prepared according to the preparation of 6a-38 in Example 31. White solid, yield 89.5%. 1 H NMR (400 MHz, Chloroform-d) δ 11.40 (s, 1H), 10.53 (s, 1H), 7.55 (s, 1H), 7.48 (d, J = 1.6 Hz, 1H), 5.79 (d, J = 5.0 Hz, 1H), 5.40 (t, J = 4.3 Hz, 2H), 4.39 (t, J = 3.2 Hz, 1H), 4.35 (d, J = 3.2 Hz, 2H), 2.69 - 2.53 (m, 3H), 1.52 (s, 9H), 1.51 (s, 9H), 1.23 - 1.17 (m, 18H).

[0243] A41 was prepared according to the preparation of A17 in Example 15. White solid, yield 54.52%. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.97 (s, 1H), 7.80 (s, 2H), 7.14 (s, 1H), 7.07 (s, 1H), 6.04 (d, J = 5.9 Hz, 1H), 5.47 (t, J = 5.8 Hz, 1H), 5.38 (d, J = 4.5 Hz, 1H), 4.39 (q, J = 4.0 Hz, 1H), 4.34 - 4.28 (m, 2H), 2.65 - 2.57 (m, 3H), 1.15 - 1.07 (m, 18H). MS m / z = 468.1 [M+H] +

[0244] Example 34: (2R,3R,4S,5R)-4-Fluoro-5-(4-guanidino-1H-imidazol-1-yl)-2- ((isobutoxy)methyl)tetrahydrofuran-3-yl isobutyrate A42 Compound No: DXY-1712

[0245]

[0246] The target compound A42 was prepared according to the method of Example 5 and Example 33, white solid, yield: 56.83% except that the corresponding starting materials were replaced. 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.92 (s, 4H), 7.84 (s, 1H), 7.05 (s, 1H), 6.21 (dd, J = 19.9, 3.3 Hz, 1H), 5.48 - 5.31 (m, 1H), 5.30 (d, J = 3.4 Hz, 1H), 4.41 - 4.28 (m, 2H), 4.24 (q, J = 4.4 Hz, 1H), 2.61 (dp, J = 14.0, 7.0 Hz, 2H), 1.13 (dd, J = 14.7, 7.0 Hz, 12H). 13 C NMR (101 MHz, DMSO) δ 176.33, 175.61, 155.68, 136.93, 134.79, 106.48, 93.19 (d, J = 191.1 Hz), 85.80 (d, J = 16.4 Hz), 79.36, 75.50 (d, J = 29.2 Hz), 62.93, 33.64, 33.45, 19.12, 19.10, 18.96, 18.92. MS m / z = 400.1 [M+H] +

[0247] Example 35: (2R,3R,4R,5R)-2-((cinnamoyloxy)methyl)-5-(4-guanidino-1H- imidazol-1-yl)tetrahydrofuran-3,4-diyl (2E,2'E)-bis(3-phenylacrylate) A43 Compound No. DXY-1321

[0248]

[0249] The target compound A43 was prepared according to the method of Example 27, except that the corresponding reaction starting material was replaced. White solid, yield 54.2%. 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.83 - 7.71 (m, 8H), 7.70 - 7.64 (m, 4H), 7.49 - 7.35 (m, 9H), 7.33 (d, J = 1.5 Hz, 1H), 6.82 - 6.54 (m, 3H), 6.23 (d, J = 5.6 Hz, 1H), 5.79 (t, J = 5.7 Hz, 1H), 5.74 - 5.66 (m, 1H), 4.63 (p, J = 4.5 Hz, 1H), 4.57 (dd, J = 7.2, 4.4 Hz, 1H), 1.23 (s, 1H). MS m / z = 648.2 [M+H] +

[0250] Test Example 1: Anti-vesicular stomatitis virus (VSV) activity screening

[0251] Test principle: The green fluorescence signal of the 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.

[0252] Test materials and methods:

[0253] Virus strain: Vesicular stomatitis virus with green fluorescent protein reporter gene, cultured and passaged in African green monkey kidney cells (Vero), and stored at -80°C.

[0254] Cell culture medium: MEM medium (CM50011, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biotech).

[0255] Sample treatment: The sample was configured into a mother liquor with DMSO, and then diluted with cell culture solution.

[0256] Positive control drug: Favipiravir, Shanghai Bide Pharmaceutical Technology Co., Ltd. (Batch number: 152DGA).

[0257] Test method: 2 x 104 Cells were seeded in 96-well plates and incubated at 37°C with 5% CO2. After 12 hours, the culture medium was replaced with a solution of drug (20 μM) or DMSO, and the cells were pretreated for 2 hours. Diluted virus suspension was added, and the cells were incubated at 37°C with 5% CO2. After 24 hours, GFP signals were 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 as: Inhibition rate = 1 - [(Fluorescence intensity of drug group - Background fluorescence intensity) / (Fluorescence intensity of DMSO group - Background fluorescence intensity)]. Cell viability was assessed using the CCK-8 assay 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. The effect on cell viability can serve as a reference for antiviral activity and also reflects the potential application of drug cytotoxicity in antitumor treatment, because nucleoside molecules can replace natural human nucleosides and participate in the DNA or RNA chains during cell replication, thereby producing cytotoxicity. Compared to normal cells, tumor cells proliferate rapidly, and their DNA and RNA replicate quickly and extensively. Therefore, the probability of the nucleoside molecules of this invention being incorporated into the DNA and RNA chains is high, which can achieve selective tumor cell toxicity. Thus, the compounds of this invention can be used for the treatment of solid tumors outside the central nervous system, including ovarian cancer, breast cancer, bladder cancer, cervical cancer, liver cancer, biliary tract cancer, nasopharyngeal carcinoma, testicular tumors, lymphoma, mesothelioma, lung cancer, and head and neck cancer.

[0258] Table 1

[0259]

[0260] Table 2

[0261]

[0262]

[0263] Test Example 2: Assay for RNA-dependent RNA polymerase (RdRp) target activity against influenza A virus (IAV)

[0264] Assay Principle: Using the A549 cell line stably expressing the IAV RdRp complex and viral small genomic RNA, Gaussia luciferase (Gluc) is encoded in the viral small genome and expressed under the control of IAV RdRp. Gluc serves as a reporter gene to monitor IAV RdRp activity.

[0265] Test material: Ribavirin (RBV), Shanghai Tao Shu Biological Technology Co., Ltd., batch number (158104). Secrete-Pair Gaussia Luciferase Assay Kit, GeneCopoiea Company. The culture medium adopts DMEM high-sugar culture medium (CM10017, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biological) and 2 μg / mL puromycin.

[0266] Implementation:

[0267] The construction of the cell line is described in the reference (PLoS One. 2015; 10 (7): e0133558.). A549-5Ps cells 2 million per hole are inoculated in a 96-hole culture plate and cultured at 37°C in 5% CO2. After 12 hours, the culture solution containing the drug (three concentrations 0.1 μM, 1.0 μM, 10 μM) or DMSO is used to replace the culture solution, obtaining three concentration gradient experimental groups of 0.1 μM, 1 μM, and 10 μM. Cultured at 37°C in 5% CO2 for 72 hours. The stable Gaussia luciferase detection kit is used to detect the chemiluminescence signal for 2 seconds. The luminescence signal value reports the expression of RdRp complex, and the relative Gluc activity is calculated. The calculation formula is: relative Gluc activity (%) = drug group Gluc signal value / DMSO control group Gluc signal value. The test results are shown in Table 3.

[0268] Table 3

[0269]

[0270] Test Example 3: Cytotoxicity experiment for detecting the inhibition of influenza virus replication

[0271] Test principle: The Madin-Darby canine kidney (MDCK) cells are used as the virus host to determine the degree of cytopathic effect (CPE) caused by the inhibition of the virus by the sample.

[0272] Tested cells: MDCK cells (purchased from ATCC Company).

[0273] Virus strain: Influenza virus A / PR / 8 / 34 (H1N1), cultured in chicken embryo allantoic cavity and passed (2018.3), stored at -80°C.

[0274] Test material:

[0275] Culture solution: DMEM high-sugar culture medium (CM10017, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biological).

[0276] The sample was prepared into DMSO mother liquor before use, and was diluted twice with culture solution, and five dilutions were prepared.

[0277] Test method: 3.5 x 10 4 The cells were seeded in 96-well plates and cultured for 12 h. A solvent control group, a PR8 control group, and a drug administration group were set. The PR8 control group and the drug administration group were infected with PR8 virus with a titer of 100 TCID 50 MDCK cells were cultured at 5% CO2 and 37℃ for 2 h, and were shaken every 30 min. After adsorption, the virus solution was discarded, and the cells were washed once with PBS (10010049, Thermo). Then, the 96-well plate was added with a compound, 1 μg / mL TPCK (T1426, Sigma), serum-free high-glucose DMEM medium (CM10017, MACGENE), and was placed in a cell culture box for culture for 48 h. When the virus control group was completely lesioned, 100 μL of MTS (G3580, Promega) detection solution was added to each well to detect cell viability, so as to characterize the antiviral effect of the compound. The virus inhibition rate (%) = 1-[(no pr8 control group OD value-drug administration group OD value) / (no pr8 control group OD value-solvent control group)] x 100%. The test results are shown in the following Figure 1 . The half inhibitory concentration of A17 was 9.95 μM, which was better than that of the positive drug ribavirin (IC 50 = 11.43 μM).

[0278] 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, and all of them 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 non-natural nucleoside analogue and pharmaceutically acceptable salts thereof, selected from the group consisting of: 。 2. A pharmaceutical composition comprising a therapeutically effective amount of a non-natural nucleoside analogue and pharmaceutically acceptable salts thereof according to claim 1, and optionally a pharmaceutically acceptable carrier.

3. Use of a non-natural nucleoside analogue and pharmaceutically acceptable salts thereof according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and / or treatment of a viral infection, the virus being an influenza virus or a rhabdovirus.

4. The use according to claim 3 in a medicament for the prevention and / or treatment of viral infections, characterized in that, The influenza virus subtype is H1N1.

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