6-Mercaptopurine nucleoside analogs

Abstract

The compound has the following formula (I) or formula (II), its isomer, tautomer, its acceptable solvate or its pharmaceutically acceptable prodrug.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 746,701, filed on October 17, 2018, which is incorporated by reference into this application as if fully set forth herein. Technical Field

[0002] The present invention relates to 6-mercaptopurine nucleoside analogs which are useful for treating various diseases, such as cancer and viral infections. Background Art

[0003] Nucleoside analogs are effective in treating a variety of diseases, such as cancer and viral infections such as herpes simplex virus (HSV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Nucleoside analogs are also used to selectively target telomerase activity. Most normal cells do not have telomerase activity.

[0004] There are many nucleoside analog drugs on the market that can treat cancer and viral infections. After entering the cell, the nucleoside analog is activated by nucleoside and nucleotide kinases to form phosphorylated nucleoside analogs. Phosphorylated nucleoside analogs exert their therapeutic effects.

[0005] However, nucleoside analog drugs also have some disadvantages. The phosphorylation of nucleoside analogs is usually inefficient. Due to low intestinal permeability, the oral bioavailability of nucleoside analogs is poor; resistance has developed to some nucleoside analogs. To overcome these limitations, it is necessary to find highly efficient and bioavailable nucleoside analogs. Summary of the invention

[0006] The present invention provides a compound having the following formula (I), an isomer, a tautomer, a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug thereof.

[0007]

[0008] In formula (I), X1 is -O- or -NH-; R7 is -H, alkyl, alkyl substituted by one or more -OH or halogen; alkenyl, alkenyl substituted by one or more -OH or halogen; alkynyl, alkynyl substituted by one or more -OH or halogen; cycloalkyl, cycloalkyl substituted by one or more -OH or halogen; aryl, substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl

[0009] Aryl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heteroaryl, heteroaryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heterocyclyl, heterocyclyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; CH(CH3)COOCH(CH3)2, or R4 is -H, -OH, -CH3, -Cl, -F, -N3, -OCH3, alkenyl or alkynyl; R5 is -H, -OH, -CH3, -Cl, -F, -N3, -OCH3, alkenyl or alkynyl; R 10 is -LM, wherein L is -O-, -O-CH2-, -S-, -NH-, -CO-, -SO-, or -CH2-, and M is alkyl, alkyl substituted by one or more -OH or halogen groups; alkenyl, alkenyl substituted by one or more -OH or halogen; alkynyl, alkynyl substituted by one or more -OH or halogen; alkoxy, alkoxy substituted by one or more -OH or halogen; cycloalkyl, cycloalkyl substituted by one or more -OH or halogen; aryl, aryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heteroaryl, heteroaryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heterocyclyl, or heterocyclyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl.

[0010] In another embodiment, in Formula (I), X1 is -O-; R7 is or R4 is -H; R5 is -H; R 10 is -LM, wherein L is -O- or -O-CH2-; M is alkynyl, alkynyl substituted by one or more -OH or halogen groups; aryl, aryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heterocyclyl, heterocyclyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl.

[0011] In another embodiment, the compound of formula (I) is selected from the group consisting of: 2-amino-9-((2S,4aR,6R,7aS)-2-((4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy)-2-oxidotrihydro-4H-furan[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-((2S,4aR,6R,7aS)-2-((4S,5S)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy)-2-oxidotetrahydro-4H-furan[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-((2R,4aR,6R,7aS)-2-((4S,5S)-5-(benzyloxy)-1,2-dithio-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-(((2R,4aR,6R,7aS)-2-((((4R,5R)-5-(benzyloxy)-1,2-dithio-4-yl)oxy]-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione 6-thione; S-(3-((((2R,4aR,6R,7aS)-6-(2-amino-6-thio-1,6-dihydro-9H-purin-9-yl)-2-oxidotetrahydro-4H-furan[3,2-d][1,3,2]dioxaphosphin(-2-yl)oxy)propyl)2,2-dimethyl-3-propoxypropane sulfate; S-(3-((((2S,4aR,6R,7aS)-6-(2-amino-6-thio-1,6-dihydro-9H-purin-9-yl)-2-oxidotetrahydro-4H-furan[3,2-d][1,3,2]dioxaphosphin(-2-yl)oxy)propyl)2,2-dimethyl-3-propoxypropane sulfate Esters; 2-amino-9-(((2S,4aR,6R,7aS)-2-((((4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl]oxy]4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-(((2R,4aR,6R,7aS)-2-((((4R,5R)-5-((2-methylbenzyl)oxy)-1,2-dithiox-4-yl]oxy])-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione;2-amino-9-((2R,4aR,6R,7aS)-2-oxido-2-((4R,5R)-5-(prop-2-yn-1-yloxy)-1,2-dithio-4-yl)oxy)tetrahydro-4H-furano[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-(((2R,4aR,6R,7aS)-2-((((4R,5R)-5-methoxy-1,2-diethyl-4-yl)oxy]-2 -2-Oxidized-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; and 2-amino-9-(((2R,4aR,6R,7aS)-2-oxidized-2-((((4R,5R)-5-(pyridin-4-ylmethoxy)-1,2-dithioxo-4-(yl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione.;

[0012] In one embodiment, the present application provides a compound having the following formula (II), an isomer, a tautomer, a pharmaceutically acceptable solvate or a pharmaceutically acceptable prodrug thereof.

[0013]

[0014] In formula (II), X2 is -O- or -NH-; X3 is -O- or -NH-; X4 is -CH2- or none; Y is -O-, -S- or -SO2-; R8 and R9 are independently selected from the group consisting of: -H, alkyl, alkyl substituted by one or more -OH or halogen groups; alkenyl, alkenyl substituted by one or more -OH or halogen groups; alkynyl, alkynyl substituted by one or more -OH or halogen groups; cycloalkyl, cycloalkyl substituted by one or more -OH or halogen groups; aryl, aryl substituted by one or more -OH or halogen groups; aryl, substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heteroaryl, heteroaryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heterocyclyl, heterocyclyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; -CH(CH3)COOCH(CH3)2, or or a five-membered or six-membered heterocyclic ring formed by R8 and R9, or a five-membered or six-membered heterocyclic ring substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy, benzyl, or benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy, or haloalkyl; R4 is -H, -OH, -CH3, -Cl, -F, -N3, -OCH3, alkenyl, or alkynyl; R5 is -H, -OH, -CH3, -Cl, -F, -N3, -OCH3, alkenyl, or alkynyl; R 10 is -LM, wherein L is -O-, -O-CH2-, -S-, -NH-, -CO-, -SO- or -CH2-; M is alkyl, alkyl substituted by one or more -OH or halogen groups; alkenyl, alkenyl substituted by one or more -OH or halogen groups; alkynyl, alkynyl substituted by one or more -OH or halogen groups; alkoxy, alkoxy substituted by one or more -OH or halogen groups; cycloalkyl, cycloalkyl substituted by one or more -OH or halogen groups; aryl , aryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heteroaryl, heteroaryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heterocyclyl, or heterocyclyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl.

[0015] In another embodiment, in formula (II), R8 and R9 are independently selected from the group consisting of: -H, alkyl, alkyl substituted by one or more -OH or halogen; aryl, aryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl, -CH(CH3)COOCH(CH3)2, -COCH3, or R4 is -H; R5 is -H; R 10 It is -LM, wherein L is -O- or -O-CH2-, and M is alkynyl, alkynyl substituted by one or more -OH or halogen; aryl, aryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; benzyl, benzyl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; heteroaryl, heteroaryl substituted by one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl.

[0016] In another embodiment, in Formula (II), R8 and R9 form a five-membered or six-membered heterocyclic ring; a five-membered or six-membered heterocyclic ring substituted with one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy, benzyl, benzyl substituted with one or more -OH, halogen, -CN, -NO2, alkyl, alkoxy or haloalkyl; R4 is -H; and R5 is -H.

[0017] In another embodiment, the compound of formula (II) is selected from the group consisting of isopropyl ((((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-ylmethoxy)(phenoxy)phosphoryl)-L-alaninate; acetic acid ((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methylphenylphosphoryl) anhydride; isopropyl (2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl(phenoxy)phosphoryl)-L-alaninate diphenyl((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; 2-(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-4-(3-chlorophenyl)-1,3,2-dioxaphosphirane 2-oxide; ((((((((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphoryl)bis(oxy))bis(methylene)diisopropyl Bis(carbonate); diethyl (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; ((((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid; phenyl hydrogen (((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-ylphenyl ((((2R,3S,5R)-5 -(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithio-4-yl-((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-N-benzylphosphonamide; (4R,5R)-5-(prop-2-yn-1-propoxy)-1,2-dithio-4-yl-((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-N-benzylphosphonamide;(4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(4-fluorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(4-fluorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester -6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(3-chlorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(3-chlorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; 1,2-dithio-4-yl-o-tolyl((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (((((((((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphoryl)bis(oxy 2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methylphosphonic acid) anhydride; diethyl (2S, 3S, 5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)thio)phosphonic acid methyl ester. ; DETAILED DESCRIPTION

[0018] The present invention provides a compound having the following formula (I).

[0019]

[0020] X1, R7, R4, R5 and R 10 is defined as above.

[0021] The present invention also provides a compound having the following formula (II).

[0022]

[0023] X2, X3, X4, Y, R8 and R9 are as defined above.

[0024] In formula (I) and (II), P may be a chiral or achiral phosphorus atom. The compounds of formula (I) and (II) may be separated into their individual diastereomers by fractional crystallization in a suitable solvent (e.g., methanol or ethyl acetate or a mixture thereof), or by chiral chromatography using an optically active stationary phase. The absolute stereochemistry may be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which may be derivatized, if desired, with a reagent containing an asymmetric center of known absolute configuration.

[0025] Alternatively, any stereoisomer of the compounds of general formula (I) and (II) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0026] If desired, the racemic mixture of the compound can be separated so as to isolate the individual enantiomers. Separation can be performed by methods well known in the art, such as coupling the racemic mixture of the compound with an enantiomerically pure compound to form a diastereomeric mixture, and then separating the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is usually to form a salt using an enantiomerically pure acid or base, and the diastereomeric derivatives can then be converted to pure enantiomers by breaking the increased chiral residue. The racemic mixture of the compound can also be directly separated by chromatographic methods using a chiral stationary phase, which is well known in the art.

[0027] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0028] Some of the compounds described herein exist as tautomers, which have different hydrogen attachment points and are accompanied by one or more double bond displacements. For example, a ketone and its enol form are keto-enol tautomers. The compounds of formula (I) and (II) include individual tautomers and mixtures thereof. Examples of tautomers intended to be included in the compounds of the present invention are as follows:

[0029]

[0030] As used herein, the following definitions apply.

[0031] Unless otherwise defined, "alkyl" and other groups with the prefix "alk", such as alkoxy and alkanoyl, refer to carbon chains that may be straight or branched, and combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. When the number of carbon atoms is specified, C 3-10 When used herein, the term alkyl also includes cycloalkyl groups, and combinations of straight or branched alkyl chains in conjunction with cycloalkyl structures.

[0032] "Haloalkyl" refers to straight-chain or branched alkyl groups, in which some or all of the hydrogen atoms in these groups may be replaced by halogen atoms.

[0033] "Alkenyl" refers to a straight or branched chain olefin of 2 to 20 carbon atoms, or any number within this range. Examples of alkenyl include ethenyl, propenyl, butenyl, pentenyl, oleyl, and the like.

[0034] "Cycloalkyl" is a subset of "alkyl" and refers to a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, among others. Unless otherwise specified, cycloalkyl groups are typically monocyclic. Unless otherwise defined, cycloalkyl groups are saturated.

[0035] "Aryl" refers to a cyclic aromatic hydrocarbon radical having from 1 to 3 aromatic rings, including phenyl and naphthyl. Aryl groups may be fused to a second or third ring which is a heterocyclic, cycloalkyl or heteroaryl ring, provided that in this case the point of attachment will be on the aryl portion of the ring system.

[0036] "Heteroaryl" refers to an aromatic or partially aromatic heterocycle containing at least one heteroatom selected from O, S and N. Heteroaryl thus includes heteroaryls fused to other types of rings, such as aryls, cycloalkyls and non-aromatic heterocycles. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiazolyl, dihydrobenzofuranyl, dihydroindolyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothiophenyl, indolizinyl, cinnozinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxy, quinoxalinyl, purinyl, furazolidyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like.

[0037] "Heterocyclyl" or "heterocycle" refers to a fully saturated or partially unsaturated non-aromatic ring group (e.g., a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 16-membered tricyclic ring system) having at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, wherein the nitrogen and / or sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. As indicated above, for cycloalkyl groups, the heterocyclic ring may have carbon ring atoms substituted with carbonyl (C=O) groups.

[0038] "Halogen group" refers to -F, -Cl, -Br and -I.

[0039] The compounds of the present application can be prepared from known or easily prepared starting materials according to methods known to those skilled in the art of organic synthesis. Methods that can be used to prepare compounds of the general formula are listed in the following examples and summarized in the following schemes A, B, and C. For those skilled in the art of organic synthesis, alternative synthetic pathways and similar structures will be apparent.

[0040] Scheme A shows a method for preparing a nucleoside compound of formula A4, which corresponds to a compound of formula (II). In Scheme A, R1, R2, R3 and R6 are independently-H, alkyl, alkenyl, cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl; R4 and R5 are independently-H,-OH,-CH3,-Cl,-F,-N3,-OCH3, alkenyl or alkynyl.

[0041] Plan A

[0042]

[0043] A1 type compound can react with A2 to obtain A3, and then deprotected by TBS to obtain A4 type compound.

[0044] Scheme B shows a method for preparing a nucleoside compound of formula B4 corresponding to a compound of formula (I). In Scheme B, R 10 , R4 and R5 are the same as R in formula (II) 10 , R4 and R5 have the same definition.

[0045] Plan B

[0046]

[0047] Compounds of type B1 can react with B2 to form compounds of type B3, and then the following protecting groups are removed to form compounds of type B4.

[0048] Scheme C shows a method for preparing formula C4 and C5 nucleoside compounds, which correspond to formula (II) compounds. In formula C4 and C5, R1, R2 are independently-H, alkyl, alkenyl, cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted, substituted aryl or form an unsubstituted or substituted five-membered or six-membered heterocycle, and R4 and R5 are independently-H,-OH,-CH3,-Cl,-F,-N3,-OCH3, alkenyl or alkynyl.

[0049] Plan C

[0050]

[0051] Compounds of type C1 can be reacted with TsOCH2P(O)OR1OR2 to give C2, followed by conversion of Cl to SH as C3, followed by removal of the protecting groups to provide compounds of type C4, and further deprotection of the protecting groups R1 and R2 to provide compounds of type C5.

[0052] General procedure:

[0053] Preparative thin layer chromatography (PTLC) was performed on 20 x 20 cm plates (500 micron thick silica gel). Silica gel chromatography was performed on a Biotage Horizon flash chromatography system.

[0054] 1 H and 31 P NMR spectra were recorded on a Bruker Ascend™ 400 spectrometer at 298 K, 400 MHz, and chemical shifts are given in parts per million (ppm) relative to the residual proton signal of the deuterated solvent CHCl 3 : δ = 7.26 ppm and CH 3 OH or CH 3 OD, δ = 3.30 ppm.

[0055] LCMS spectra were performed on an Agilent Technologies 1260 Infinity or 6120 quadrupole spectrometer. An SBC1850 mm × 4.6 mm × 2.7 μm capillary column was used, the mobile phase was acetonitrile (A) and water (B), containing 0.01% formic acid, and the elution gradient was 5-95% A in 6.0 min, 60-95% A in 5.0 min, 80-100% A in 5.0 min, and 85-100% A in 10 min.

[0056] Mass spectra (MS) were measured by electrospray ionization mass spectrometry (ESI). All temperatures are in degrees Celsius unless otherwise stated.

[0057] HPLC mass spectrometry conditions:

[0058] LC1: Column: SB-C18 50mm×4.6mm×2.7μm

[0059] Temperature: 50℃

[0060] Eluent: 5:95 v / v acetonitrile / water + 0.01% formic acid over 6 minutes

[0061] Flow rate: 1.5mL / min, injection 5μL

[0062] Detection: PDA, 200-600nm

[0063] MS: mass range 150-750 amu; m / z (mass). Positive ion electrospray ionization

[0064] LC2: Column: SB-C18 50mm×4.6mm×2.7μm

[0065] Temperature: 50℃

[0066] Eluent: 5:95 to 95:5 v / v acetonitrile / water + 0.05% TFA in 3.00 min.

[0067] Flow rate: 1.5mL / min, injection 5μL

[0068] Detection: PDA, 200-600nm

[0069] MS: mass range 150-750 amu; m / z (mass). Positive ion electrospray ionization

[0070] LC3: Column: SB-C18 50mm×4.6mm×2.7μm

[0071] Temperature: 50℃

[0072] Eluent: 10:90 to 98:2 v / v acetonitrile / water + 0.05% TFA in 3.75 min.

[0073] Flow rate: 1.0mL / min, injection 10μL

[0074] Detection: PDA, 200-600nm

[0075] MS: mass range 150-750 amu; m / z (mass). Positive ion electrospray ionization

[0076] In the following examples, schemes and tables the following abbreviations are used: AcOH = acetic acid; Aq = aqueous solution; Alk = alkyl; Ar = aryl; Boc = tert-butyloxycarbonyl; br = broad; CH2Cl2 = dichloromethane; d = doublet; dd = two doublets; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DMA = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EA = ethyl acetate; EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; ESI = electrospray ionization; Et = ethyl; Et3N = triethylamine; EtOAc = ethyl acetate Ester; EtOH = ethanol; h = hour; HPLC = high performance liquid chromatography; HOAc = acetic acid; LiOH = lithium hydroxide; m = multiplet; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MgSO4 = magnesium sulfate; min = minute; MS = mass spectrum; NaCl = sodium chloride; NaOH = sodium hydroxide; Na2SO4 = sodium sulfate; NMI = N-methylimidazole; NMR = nuclear magnetic resonance spectroscopy; PE = petroleum ether; PG = protecting group; Ph = phenyl; q = quartet; rt = room temperature; s = singlet; t = triplet; TBME = tert-butyl dimethyl ether; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Ts = p-toluenesulfonyl (tosyl).

[0077] The following examples provide conditions for preparing the compounds of this invention, and the examples provided are not intended to limit the scope of the present invention in any way, and should not be so interpreted. It will be readily appreciated by those skilled in the art that the conditions of the following preparation methods and known variations of technology can be used to prepare these and other compounds of the present invention.

[0078] Embodiment 1:

[0079]

[0080] 2-Amino-9-[2-(5-(benzyloxy)-1,2-dithiox-4-yl)oxy]-2-oxytetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl]-1,9-dihydro-6H-purine-6-thione

[0081]

[0082] Step 1: Intermediate 2

[0083] A mixture of 1 (15.2 g, 26.7 mmol), trityl mercaptan (11.1 g, 40.0 mmol) and K2CO3 (7.4 g, 53.3 mmol) in DMF (91 mL) was heated at 80°C for 3 hours. The reaction mixture was cooled and poured into cold water, and the resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with water, brine, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc=3 / 1-5 / 3) to give 2 (12.2 g, white amorphous solid, 56.5%).

[0084] 1 H NMR (400MHz, DMSO-d6) δ8.69 (1H, s), 7.29-7.20 (15H, m), 6.34 (1H, t, J = 6.8Hz), 5.36-5.33 (1H, m), 4.28-4. 21(2H,m),4.15-4.08(1H,m),3.12-3.05(1H,m),2.58-2.52(1H,m),2.06(3H,s),1.96(3H,s),1.30(18H,s).

[0085] Step 2: Intermediate 3

[0086] To a solution of 2 (12.2 g, 15.1 mmol) in THF (125 mL) was added a solution of LiOH·H2O (3.16 g, 75.3 mmol) in water (25 mL). The reaction was stirred at room temperature overnight and then poured into water. The resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2 SO4 and concentrated under reduced pressure. The residue was suspended in tert-butyl methyl ether (80 mL) and stirred vigorously for 30 minutes. The slurry was filtered and washed with tert-butyl methyl ether (40 mL). The filter cake was collected and dried under reduced pressure to give 3 (9.4 g, white solid, 86.2%).

[0087] 1 H NMR (400MHz, DMSO-d6) δ8.68(1H,s),7.32-7.19(15H,m),6.29(1H,t,J=6.8Hz),5.32(1H,d,J=3.6Hz),4.92(1H,b rs),4.41-4.35(1H,m),3.86-3.82(1H,m),3.59-3.43(2H,m),2.70-2.64(1H,m),2.32-2.26(1H,m),1.30(18H,s).

[0088] Step 3: Intermediate 5

[0089] To the reaction solution of 3 above were added 4 (3369 mg, 4.64 mmol) and DBU (1882 mg, 12.4 mmol). The reaction was stirred at room temperature for 2 hours and then heated at 44°C overnight. Most of the solvent was evaporated and the residue was directly purified by column chromatography (PE / EtOAc=3 / 2-4 / 5) to give 5 (520 mg, light yellow amorphous solid, two-step yield 16.6%).

[0090] Step 4: Final Product 6

[0091] TFA (8 mL) was added to a DCM (10 mL) solution of 5 (790 mg, 0.781 mmol) and triethylsilane (454 mg, 3.9 mmol). The reaction was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was azeotroped with DCM twice. The resulting residue was purified by column chromatography (DCM / MeOH=50 / 1-33 / 1-25 / 1) to give a crude product. The crude product was suspended in MeOH (4 mL) and stirred for 30 minutes. The slurry was filtered and washed with MeOH (2 mL). The filter cake was collected and dried under reduced pressure to give 6 (101.4 mg, white solid, 22.8%).

[0092] LCMS: for C 21 H 24 N5O6PS3,calculated 569.1,found 570.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.03,12.01(1H,s),8.20,8.06(1H,s,ratio 1:2),7.39-7.11(5H,m),6.87,6.82(1H,brs),6.27-6.20(1H,m),5.06-4.99,4.92-4.85(1H,m),4.73-4.26(5H,m),4.02 -3.93(1H,m),3.78-3.72(1H,m),3.61-3.42(2H,m),3.26-3.17(1H,m),3.01-2.94(1H,m),2.87-2.59,2.35-2.28(2H,m).

[0093] Example 2-13

[0094] The compounds in Table 1 can be prepared by the same method as described in Example 1.

[0095] Table 1: Compounds of Examples 2-12

[0096]

[0097]

[0098] Embodiment 13

[0099]

[0100] 2-{[5-(2-Amino-6-mercapto-purin-9-yl)-3-hydroxy-tetrahydrofuran-2-ylmethoxy]-phenoxyphosphorylamino}-propionic acid isopropyl ester

[0101]

[0102] Step 1: 3',5'-O-di-tert-butyldimethylsilyl-2'-deoxythioguanine (1):

[0103] To a solution of 2'-deoxythioguanine (2.3 g, 8.13 mmol) and imidazole (3.65 g, 53.66 mmol) in anhydrous DMF (15 ml) was added 3.90 g (26.0 mmol) of tert-butyldimethylsilyl chloride (TBDMS-Cl). The reaction mixture was stirred at room temperature for 20 hours. The resulting mixture was poured into water (100 mL), filtered, and the precipitate was collected, rinsed with a cooled mixture of ethanol and water (1:2), and dried under reduced pressure to obtain 3.6 g of the title compound 1 as a gray solid (yield 85%).

[0104] LC-MS:(ES,m / z):[M+H] + =512. 1 H NMR (400MHz, DMSO) δ12.01(s,1H),8.11(s,1H),6.87(s,2H),6.14(t,J=6.5Hz,1H),4.52(s,1H),3.85(s,1H),3.7 9–3.66(m,2H),2.73–2.63(m,1H),2.29(dd,J=7.5,3.9Hz,1H),0.91(d,J=4.6Hz,18H),0.13(s,6H),0.08(s,6H).

[0105] Step 2: 3'-O-tert-Butyldimethylsilyl-5'-hydroxy-2'-deoxythioguanine (2):

[0106] To a stirred solution of 1 (1.05 g, 1.96 mmol) in tetrahydrofuran (40 mL) was added TFA-H2O (10 mL, 1:1 v / v) at 0°C. The reaction mixture was stirred at this temperature for 2 hours. Saturated sodium bicarbonate solution was added to neutralize to pH 8. Filtered, washed with cooling water, and dried under reduced pressure to give product 2 (0.67 g, yield 84%) as a light grey powder.

[0107] LC-MS:(ES,m / z):[M+H] + =398. 1 H NMR (400MHz, DMSO) δ11.95(s,1H),8.08(s,1H),6.67(s,2H),6.10(t,J=6.7Hz,1H),5.07(s,1H),4.51(s,1 H),3.81(s,1H),3.51(d,J=8.6Hz,2H),2.70–2.59(m,1H),2.20(d,J=9.0Hz,1H),0.89(s,9H),0.10(s,6H).

[0108] Step 3: Intermediate 4

[0109] At room temperature, under stirring, a solution of protected 2'-deoxythioguanine (2, 0.81 g, 2.05 mmol) in anhydrous THF-NMP (20 mL, 1:1 v / v) was added dropwise with 1.0 M tert-butyl magnesium chloride in THF (4.5 mL, 4.51 mmol), the white suspension was stirred at this temperature for 30 minutes, and a THF solution of commercially available phosphate 3 (1.1 g, 2.45 mmol) was added. The mixture was stirred at this temperature overnight. The reaction mixture was quenched with saturated NH4Cl (aqueous solution) and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography, eluted with dichloromethane / methanol (20:1) to give the title compound 4 (0.75 g, yield 55%).

[0110] LC-MS:(ES,m / z):[M+H] + =667. 1H NMR (400MHz, DMSO) δ11.98(s,1H),8.10(s,1H),7.36(t,J=7.8Hz,2H),7.18(dd,J=15.3,7.7Hz,3H),6.82 (br,2H),6.13(t,J=6.9Hz,1H),6.06(dd,J=12.8,10.3Hz,1H),4.83(dt,J=12.5,6.3Hz,1H),4.52(s,1H) ,4.23–4.14(m,1H),4.07–3.95(m,2H),3.77(dd,J=17.2,10.0Hz,1H),3.17(d,J=5.1Hz,1H),2.75–2.61( m,1H),2.25(dd,J=12.0,4.8Hz,1H),1.20(d,J=7.0Hz,3H),1.16–1.08(m,6H),0.87(s,9H),0.08(s,6H). 31 P NMR (400 MHz, DMSO) δ 3.70.

[0111] Step 4: 2-{[5-(2-amino-6-mercaptopurin-9-yl)-3-hydroxy-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester (5)

[0112] At room temperature, 20mL fresh methanol solution of hydrogen chloride (prepared by 5mL acetyl chloride added in 500mL anhydrous methanol) is added in the corresponding phosphoramidate 4.The reaction is stirred 40 hours, then quenched with saturated sodium acetate aqueous solution.The gained mixture is extracted with dichloromethane.The combined organic layer is washed with salt water, and anhydrous Na2SO4 is used.The solvent is removed under reduced pressure, and the crude product is purified by Prep-TLC to obtain final product 5 (40mg, yield 24%).

[0113] LC-MS:(ES,m / z):[M+H] + =553. 1H NMR (400MHz, DMSO) δ11.96(s,1H),8.04(s,1H),7.36(t,J=7.4Hz,2H),7.18(dd,J=16.6,7.6 Hz,3H),6.81(s,2H),6.14(t,J=6.4Hz,1H),6.00(t,J=11.5Hz,1H),5.44(d,J=2.8Hz,1H),4. 89–4.77(m,1H),4.38(s,1H),4.19(d,J=4.5Hz,1H),4.03(dd,J=20.3,9.5Hz,2H),3.78(d,J= 7.1Hz,1H),2.56(d,J=6.6Hz,1H),2.26(s,1H),1.20(d,J=6.7Hz,3H),1.13(d,J=3.3Hz,6H). 31 P NMR (400 MHz, DMSO) δ 3.80.

[0114] Embodiment 14

[0115]

[0116] ((((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid

[0117]

[0118] Step 1: Methyl diethyl ((((2R,3S,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)phosphonate (2)

[0119] Under argon, a mixture of 1 (685 mg, 1.71 mmol), (diethoxyphosphoryl) 4-methylbenzenesulfonic acid methyl ester (1.10 g, 3.43 mmol), t-BuO2Mg (1.16 g, 6.84 mmol) in anhydrous DMSO (20 mL) was stirred at 70°C for 3 hours. After cooling, the mixture was poured into a cooled ammonium chloride solution (50 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude product was purified by column chromatography, eluting with dichloromethane / methanol (50:1) to give 2 (660 mg, yield 69%).

[0120] LC-MS:(ES,m / z):[M+H] + =551.1 1H NMR(400MHz, CDCl3)δ8.04(s,1H),6.27(dd,J=7.4,6.3Hz,1H),5.44(s,2H),4.64–4.55(m ,1H),4.25–4.11(m,4H),4.06(dd,J=6.4,3.6Hz,1H),3.94(dd,J=10.5,4.2Hz,1H),3.90– 3.78(m,2H),3.73(dd,J=10.5,3.6Hz,1H),2.81(ddd,J=13.2,7.7,5.7Hz,1H),2.28(ddd, J=13.1,6.0,2.8Hz,1H),1.33(dt,J=9.5,7.1Hz,6H),0.90(s,9H),0.10(d,J=6.1Hz,6H). 31 P NMR (400 MHz, CDCl3): δ 20.86.

[0121] Step 2: Diethyl (2R, 3S, 5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)methyl)phosphate (3)

[0122] To a mixture of 2 (660 mg, 1.20 mmol) in dry DMF (10 mL) was added anhydrous NaHS (289 mg, 7.20 mmol) at 0°C, and the mixture was stirred for 2 hours. It was then neutralized with 10% aqueous acetic acid (2 mL). The resulting precipitate was filtered and dried under vacuum to give the desired product 3 (320 mg, 58.7% yield).

[0123] LC-MS:(ES,m / z):[M+H] + =548.1. 1 H NMR (400MHz, DMSO) δ11.95(s,1H),8.06(s,1H),6.82(s,2H),6.12(t,J=6.9Hz,1H),4.48(s,1H),4.11–3.98(m,4H),3.93(s,1H),3.87(d,J=8 .1Hz,2H),3.68(ddd,J=45.8,10.3,4.7Hz,2H),2.71–2.62(m,1H),2.27–2.19(m,1H),1.23(td,J=6.9,4.1Hz,6H),0.88(s,9H),0.10(s,6H). 31 P NMR (400 MHz, DMSO): δ 21.23.

[0124] Step 3: Methyl diethyl ((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonate (4)

[0125] To a solution of 3 (140 mg, 0.256 mmol) in dry THF (10 mL) was added TBAF (0.38 mL, 0.383 mmol) dropwise at room temperature, and the mixture was stirred for 3 hours. The resulting mixture was concentrated in vacuo at room temperature and purified by Prep-HPLC to give 4 (70 mg).

[0126] LC-MS:(ES,m / z):[M+H]+=434.1.1H NMR (400MHz, DMSO) δ7.64 (d, J=4.7Hz, 1H), 6.12 (dd, J=7.9, 6.2Hz, 1H), 5.31 (s,1H),5.23(s,2H),4.37–4.25(m,1H),4.10–3.97(m,4H),3.87(dd,J=9.8,5 .3Hz,3H),3.74(dd,J=10.5,4.5Hz,1H),3.63(dd,J=10.5,5.2Hz,1H),2.64– 2.54(m,1H),2.12(ddd,J=13.0,6.0,2.6Hz,1H),1.23(td,J=7.1,3.7Hz,6H). 31 P NMR (400 MHz, DMSO): δ 21.32.

[0127] Step 4: (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid (5).

[0128] To a mixture of 4 (50 mg, 0.115 mmol) and 2,6-dimethylpyridine (308 mg, 2.88 mmol) in dry DCM (5 mL) was added TMSBr (352 mg, 2.31 mmol) dropwise at room temperature, and the mixture was stirred overnight. The resulting mixture was concentrated under vacuum and purified by Pre-HPLC to give 5 (5.0 mg, yield 10.2%). LC-MS: (ES, m / z): [MH]-=376.1, 1H NMR (400MHz, DMSO) δ11.92(s,1H),8.10(s,1H),6.83(s,2H),6.17–6.09(m,1H),4.40–4.32(m,1H),3.93(d,J=2.3 Hz,1H),3.75(dd,J=10.5,4.5Hz,1H),3.59(d,J=8.5Hz,3H),2.63(dd,J=13.3,7.8Hz,1H),2.24–2.16(m,1H).31P NMR (400MHz, DMSO): δ16.39.

[0129] Examples 15-32

[0130] The compounds in Table 2 can be prepared by the same methods as described in Examples 13 and 14.

[0131] Table 2: Compounds of Examples 15-32

[0132]

[0133]

[0134]

[0135] Embodiment 32

[0136] The compounds of Examples 1-31 were tested in a xenograft animal model using A549 cells at an oral dose of 5 mg / kg for 21 days, with 6-thiol-dG as a control. The compounds of Examples 1-31 showed good anti-tumor growth efficacy. More importantly, the toxicity of these compounds is much less than that of 6-thio-dG. These compounds can be used to treat various diseases, such as cancer and viral infections.

[0137] Although the present invention has been described and illustrated for specific embodiments, it will be understood by those skilled in the art that various changes, modifications and substitutions may be made therein without departing from the spirit and scope of the present invention. For example, due to changes in the responsiveness of the person being treated to cancer or other diseases, effective doses other than the above preferred doses may also be applicable. Similarly, the pharmacological responses observed may vary according to and depend on the specific active compound selected or the presence or absence of a drug carrier and the type and mode of administration of the preparation used, and changes or differences in the results may be expected according to the purposes and practices of the present invention. Therefore, the intent of the present invention is limited only by the scope of the appended claims, and such claims should be interpreted as broadly as reasonably possible.

Claims

1. A compound having the following formula (I), in X1 is -O-; R7 is R4 is -H; R5 is -H; and R 10 is -LM, wherein L is -O- or -O-CH2-, and M is phenyl, methyl, ethynyl or pyridyl.

2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 2-amino-9-(((2S,4aR,6R,7aS)-2-((((4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy]-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-(((2S,4aR,6R,7aS)-2-((((4S,5S)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy]-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-Amino-9-((2R,4aR,6R,7aS)-2-((4S,5S)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy)-2-oxidotrihydro-4H-furan[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-Amino-9-((2R,4aR,6R,7aS)-2-((4S,5S)-5-(benzyloxy)-1,2-dithiox-4-yl)oxy)-2-oxidotrihydro-4H-furan[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione Hydrogen-6H-purine-6-thione; S-(3-(((2R,4aR,6R,7aS)-6-(2-amino-6-thio-1,6-dihydro-9H-purin-9-yl)-2-oxidotrihydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-2-yl)oxy)propyl)2,2-dimethyl-3-propoxypropane sulfate; S-(3-((((2S,4aR,6R,7aS)-6-(2-amino-6-thio-1,6-dihydro-9H-purin-9-yl)-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin(-2-yl)oxy)propyl)2,2-dimethyl-3-propoxypropane sulfate Esters; 2-amino-9-(((2S,4aR,6R,7aS)-2-((((4R,5R)-5-(benzyloxy)-1,2-dithiodithio-4-yl]oxy]-2-thioxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-((2R,4aR,6R,7aS)-2-((4R,5R)-5-((2-methylbenzyl)oxy)-1,2-dithiodithio-4-yl)oxy)-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione;2-amino-9-((2R,4aR,6R,7aS)-2-oxido-2-((4R,5R)-5-(prop-2-yn-1-yloxy)-1,2-dithiox-4-yl)oxy)-2-tetrahydro-4H-furano[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; 2-amino-9-((2R,4aR,6R,7aS)-2-((4R,5R)-5-methoxy-1,2-dithiox-4-yl)oxy) -2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione; and 2-amino-9-(((2R,4aR,6R,7aS)-2-oxidotetrahydro-2-((((4R,5R)-5-(pyridin-4-ylmethoxy)-1,2-dithiox-4-yl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphin-6-yl)-1,9-dihydro-6H-purine-6-thione.; 3. A compound having the following formula (II), in X2 is -O- or -NH-; X3 is -O- or -NH-; X4 is -CH2- or none; Y is -O- or -S-; R8 and R9 are independently selected from the group consisting of: -H, phenyl, ethyl, -COCH3, Or R8 and R9 form a chlorobenzene-substituted six-membered heterocyclic ring; R4 is -H; R5 is -H; and R 10 It is -LM, wherein L is -O- or -O-CH2-; and M is phenyl or ethynyl.

4. The compound according to claim 3, wherein the compound is selected from the group consisting of the following compounds: isopropyl ((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; acetic (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methylphenylphosphonic) anhydride; isopropyl (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)(phenoxy)phosphoryl)-L-alaninate 2-((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid methyl ester; 2-(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-4-(3-chlorophenyl)-1,3,2-dioxaphosphirane 2-oxide; (((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonylbis(oxy)bis(methylene)diisopropyl bis(carbonate); diethyl (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phosphonic acid; phenyl hydrogen (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-ylphenyl ((((2R,3S,5R)-5-( (4R,5R)-5-(benzyloxy)-1,2-dithio-4-yl-p-(((2R,3S,5R)-5-(2-amino-6-thio-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-N-benzylphosphonamide; (4R,5R)-5-(prop-2-yn-1-propoxy)-1,2-dithio-4-yl-p-((2R,3S,5R)-5-(2-amino-6-thio-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)methyl)-N-benzylphosphonamide;(4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(4-fluorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(4-fluorophenyl)((((2R,3S,5R)-5-(2 ((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(3-chlorophenyl)(((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (4R,5R)-5-(benzyloxy)-1,2-dithiox-4-yl(3-chlorophenyl) (Benzyloxy)-1,2-dithiox-4-yl-o-tolyl((((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonic acid methyl ester; (((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)phosphonyl)bis(oxy)bis (Methylene)bis(2,2-dimethylpropionate); acetic ((2R,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methylphosphonic) anhydride and diethyl (((((((2S,3S,5R)-5-(2-amino-6-mercapto-9H-purin-9-yl)-3-hydroxytetrahydrofuran-2-yl)methyl)thio)phosphonic acid methyl ester.;

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