Cordycepin-based derivatized compound with anti-tumor effect

Abstract

Disclosed in the present invention is a cordycepin-derivatized compound with an anti-tumor effect, which has a structure as represented by formula I. The cordycepin derivative and a pharmaceutical com

Description

The present invention belongs to the field of biomedicine, and particularly relates to a cordyc epin-based derived compound, a preparation method thereof and an application thereof in preparing a product for preventing and treating a disease related to variation caused by a cell functional da mage. BACKGROUND With the stimulation of external environment and the accumulation of cell damage, the adapta bility of cells in a body is changed, wherein one case is the loss of cell adaptability, which event ually evolves into aging, and the other case is the abnormal enhancement of cell adaptability, whic h turns into a cancer. Cancer is a common disease endangering human life and health, and an inc idence rate and a death rate of the cancer have been increased all over the world. At present, trea tment methods for malignant tumors mainly comprise surgery, radiotherapy and chemotherapy, whe rein a synthetic drug is mainly used in the chemotherapy. An inhibition effect of a chemotherapeut ic drug on tumors is worthy of recognition, and the chemotherapeutic drug is also one of more ef fective and widely used treatment methods for malignant tumors, but has extensive and serious tox ic and side effects, and a drug resistance problem. In addition, the chemotherapeutic drug has poor selectivity to tumor cells and normal cells, can damage the growth of the normal cells while killi ng or inhibiting the tumor cells, may have a direct impact on functions of heart, liver, kidney and nervous system, and has certain toxicity' to human body. Therefore, it is very necessary- to find a n anti-tumor drug with low toxicity and high efficiency in tumor treatment. Nucleoside, as one of most important endogenous compounds in human body, plays an import ant role in a metabolic process of the body. Modify ing and derivatizing the nucleoside compound is one of main ways to prepare the anti-tumor drag, and at present, nucleoside anti-tumor drugs o n the market comprise Forodesine, Fludarabine, Cladribine, Clofarabine, Fludarabine phosphate, Tro xacitabine and the like. Cordycepin (3'-deoxyadenosine) is a main active ingredient of Cordyceps si nensis, which belongs to a nucleoside analogue, and has excellent effects on the change of cell ad aptivity (anti-aging and anti-cancer) during metabolism in the body, immune regulation and inflam mation elimination. An anti-cancer mechanism of the cordycepin is mainly to induce cell apoptosis, regulate a cell cycle and interfere with the expression of matrix metalloproteinase (MMP), thus inhibiting the inv asion and metastasis of the tumor cells. A signal pathway related to the induction of apoptosis of the tumor cells comprises an NF-kB signal pathway and a mitogen-activated protein kinase (MAP K) signal pathway. The regulation of the cell cycle is mainly manifested in the cancer cells, and t he cordycepin shortens a G1 phase and prolongs a G2 phase and an M phase in the cell cycle, s o that cell cycle arrest occurs in the G2 / M phase, thus inhibiting cell proliferation. A generating p rocess of matrix metalloproteinase expression is mainly intervened through inhibiting the NF-kB sig nal pathway, thus finally inhibiting the expression of MMP-9. However, the nucleoside analogue h as poor fat solubility, is difficult to absorb and easily inactivated by deaminase metabolism, and h as a short half-life and low targeting, and some tumor cells or viruses are prone to drug resistanc e, all of which greatly reduce a use effect of the nucleoside drug. SUMMARY Object of invention: the technical problem to be solved by the present invention is to provide a series of nucleoside analogues (cordycepin derivatives) chemically modified with cordycepin tak en as a parent nucleus in combination with natural pharmacological activity of the cordycepin in v iew of shortcomings of existing nucleoside drugs. The technical problem to be further solved by the present invention is to provide a compositi on comprising the nucleoside analogue above. The technical problem to be further solved by the present invention is to provide an applicati on of the nucleoside analogue above and a composition thereof in a product for preventing and tr eating a disease related to variation caused by a cell functional damage in a mammal or a human body. The technical problem to be finally solved by the present invention is to provide a preparatio n method of the nucleoside analogue above. In order to solve the first technical problem above, the present invention discloses a cordycepi n derivative, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a solvate, a prodrug, or a metabolite thereof; I 17 03 25 wherein the cordycepin derivative is selected from the group consisting of compound 24 compound 20 NH- The cordycepin derivative of the present invention is selected from the following compound 24, or the following compound 20. The cordycepin derivative of the present invention is shown as Compounds 20 and 24 below. The other structures are shown for reference purposes. Compound 1: Compound 2: Compound 3: Compound 4: nh2 HO^. V0^ OH Z—A X / , V Z—V Z H Z^ Z---Tu X J o I 1 0-0.=0 6 T Z—A x / / V Z—V z Th ° I o O=^° o X \ 73 "\x° b 1 ° O-L / a z --z xz 17 03 25 Compound 5: Compound 6: Compound 7: Compound 8: nh2 . vj......% r । । 7 Cd ..V iH 0 KS V2 ' j V A VJ H A—OMe >—f 0 OH nh2 / V I ° w vAp A oh nh2 ji n-Vni HVoW°J HO^ .........................f OH Compound 9: Compound 10: Compound 11: Compound 12: nh2 Vj 0 j N HO OH V Nh2 6V zV oz xo 0 1 x z12 n-^Vn U j N hok^ OH o hn'^! N>Aw V' m A OH o HN'><YV Vj N AT HO AV OH Compound 13: Compound 14: Compound 15: Compound 16: nh2 N^Aw hoT f-rT P—0. 0 OH nh2 NnAm n i HoT FT"SH P—0. o OH nh2 V HOplo At 11 7 ° V"o">i F OH nh2 / Aft 1 ° n-Vn7 w'o 1 j) CN Compound 17: Compound 18: Compound 19: Compound 20: nh2 U V "'^N^F Av Vy0 OH 0 nh2 VprA 0 o t J, I A^K V-°-j V Hh 0 nh2 vVn 0 0 -t, II "-. N M SH -M » 0 nh2 O 1 2 Vn^F via Kv VV °h Compound 21: Compound 22: Compound 23: Compound 24: 0 av HN Ki 1 x 12 <A j A ”' OH 0 HN^V—'Pp' 1 ' j2 O j ~z. Cl OH 0 HN 'Az, pVn o 4 0 °> V°V V V 0 0 * / z. HN -0 N An Pn 1 ° 'V KA OH Compound 25: Compound 26: Compound 27: Compound 28: nh2 V HCtlo T 11 7 n O V ° Z n3 OH nh2 7.....rV 0 0 7-7.7 7..... p 1 1—r -—y n3 oh 0 nh2 7.......A | 9 V-V Wp A A OH o Ip: pl pn i ° w YrPp A / n3 oh Compound 29: Compound 30: Compound 31: Compound 32: nh2 HO. ___0^1 < NH2 O ' nh2 0.,,0 I N ho^QhV'0 7 f NH2 0 ' O HN' lY HO ohPN > f NH2 °A-r 0 1 o An f NH2 o- Y. / A Y o 1 Compound 33: Compound 34: Compound 35: Compound 36: NH2 ho., ? O NH / Y / Ox O 0 Y HO. 1 kd O / OvY Xv Ar- 0 0 HN”AfY (Il HO.?H P— "in 0 k 7 OH nh2 A^f ■<4-4 HO OH Compound 37: Compound 38: Compound 39: Compound 40: nh2 O O \Y -J 4 £ NO—’ 7-.,° 0H 0 nh2 ZN~AN HO N' 0 OH 4 / 44: 21, 21-----I 1 ) o I 1 0-0-=0 d T nh2 HO OH In order to solve the second technical problem above, the present invention discloses a pharm 17 03 25 aceutical composition, which comprises at least one cordycepin derivative, or the pharmaceutically acceptable salt, the stereoisomer, the tautomer, the solvate, the prodrug, or the metabolite thereof a bove; and at least one immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from a PD-1 and / or CTLA 4 monoclonal antibody. In some embodiments, a mass ratio of the cordycepin derivative, or the pharmaceutically acce ptable salt, the stereoisomer, the tautomer, the solvate, the prodrug, or the metabolite thereof to th e immune checkpoint inhibitor is 1: 0.2 to 10, in some embodiments, the mass ratio is 1: 0.2 to 8, in some embodiments, the mass ratio is 1: 0.2 to 5, in some embodiments, the mass ratio is 1: 0.2 to 3, in some embodiments, the mass ratio is 1: 0.2 to 2, in some embodiments, the mass ra tio is 1: 0.5 to 1.5, in some embodiments, the mass ratio is 1: 0.8 to 1.2, and in some embodime nts, the mass ratio is 1: 1. In some embodiments, a dosage form of the pharmaceutical composition is selected from a ta blet, a pill, a capsule, a dripping pill, a syrup, a disintegrant, an injection, a sustained to Release agent, or a kit. In order to solve the third technical problem above, the present invention discloses the cordyc cpin derivative, or the pharmaceutically acceptable salt, the stereoisomer, the tautomer, the solvate, the prodrug, or the metabolite thereof above, or the pharmaceutical combination above for use in t he treatment of a disease related to variation caused by a cell functional damage in a mammal or a human body. In some embodiments, the disease related to the variation caused by the cell functional damag e is a tumor; in some embodiments, the tumor comprises, but is not limited to, a gastric cancer, a pancreatic cancer, a liver cancer, a small cell lung cancer, a non-small cell lung cancer, a colore ctal cancer, an esophageal cancer, a prostate cancer, melanoma, glioma, and an ovarian cancer; and in some embodiments, the tumor is any one of the gastric cancer, the pancreatic cancer, the liver -4- 17 03 25 cancer, the small cell lung cancer, the colorectal cancer, the melanoma and the ovarian cancer. In some embodiments, the product comprises, but is not limited to, a drug. In order to solve the fourth technical problem above, the present invention discloses a prepara tion method of the cordycepin derivative above, the preparation method is a synthetic method of c orresponding modification, considering that the cordycepin or other active groups in modified cordy cepin molecules may participate in the reaction in the reaction process, the cordycepin should be p roperly protected, a protection method involved in the present invention comprises protection and d eprotection of hydroxyl and amino, wherein protection and deprotection means are both convention al means in the art, and other reaction systems need to be protected by adding protective gas, whi ch are all conventional means in the experimental process in the art. Specifically: A. Modification of Ri Ri is selected from phosphate group, phosphate ester group substituted, phosphonate group, ph osphonate ester group substituted, alkyl alcohol group, amino acid alkyl ester group, amino acid al kyl alcohol ester group, alkyl acid alkyl ester group, or cycloalkyl polyol group in formula I, whe rein the substitution refers to substituting with any one or more functional groups of alkoxyl, alko xyl substituted by halogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alky 1 acid oxy; and the preparation method of the cordycepin derivative as shown in formula I compri ses: using a compound I-R-l as a raw material for a chemical reaction in an organic solvent to p repare the cordycepin derivative as shown in formula I; in formula I-R-l, R2 to R? are the same as R2 to R? in formula I, or are independently selec ted from protecting groups respectively. When Ri is selected from the phosphate group in formula I, in some embodiments, the prepar ation method of the cordycepin derivative as shown in formula I comprises: reacting the compoun d I-R-l with a modifier phosphorus oxychloride in trimethyl phosphite and / or triethyl phosphite, in some embodiments, a dosage ratio of the compound I-R-l to the modifier and the organic solven t is 1 mmol: 3 mmol to 6 mmol: 15 mL to 30 mL, in some embodiments, a temperature of the reaction is -10°C to 5°C, and in some embodiments, the reaction lasts for 0.5 hour to 2 hours. When R is selected from the phosphate ester group substituted in formula I, in some embodi ments, the preparation method of the cordycepin derivative as shown in formula I comprises: reach ng the compound I-R-l with nitrophenyl phosphate substituted by a modifier in anhydrous N,N-di methylformamide and / or tetrahydrofuran with tert-butyl magnesium chloride as a catalyst, wherein t he substitution refers to substituting with any one or more functional groups of alkoxyl, alkoxyl su bstituted by halogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alkyl acid oxy, in some embodiments, a dosage ratio of the compound I-R-l to the modifier, the catalyst an d the organic solvent is 1 mmol: 1 mmol to 3 mmol: 1 mmol to 2 mmol: 9 mL to 15 mL, in s ome embodiments, a temperature of the reaction is 20°C to 40°C, and in some embodiments, the r 17 03 25 eaction lasts for 2 hours to 5 hours. When Ri is selected from the phosphonate group or the phosphonate ester group substituted, i n some embodiments, the preparation method of the cordycepin derivative as shown in formula I c omprises: reacting the compound I-R-l with p-toluenesulfonyloxymethyl phosphate substituted or no n-substituted by a modifier in anhydrous N,N-dimethylformamide with NaH as a catalyst, wherein the substitution refers to substituting with any one or more functional groups of alkoxyl, alkoxyl s ubstituted by halogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alkyl aci d oxy, in some embodiments, a dosage ratio of the compound I-R-l to the modifier, the catalyst a nd the organic solvent is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 100 mL to 200 m L, in some embodiments, the dosage ratio is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 150 mL, in some embodiments, a temperature of the reaction is -20°C to 0 °C, and in some em bodiments, the reaction lasts for 0.5 hour to 6 hours. When Ri is selected from alkyl alcohol group, amino acid alkyl ester group, amino acid alkyl alcohol ester group, alkyl acid alkyl ester group, or cycloalkyl polyol group in formula I, in som e embodiments, the preparation method of the cordycepin derivative as shown in fonnula I compri ses: reacting the compound I-R-l with a modifier in butanone with potassium carbonate as a catal yst, wherein the modifier is alkyl alcohol substituted by halogen, amino acid alkyl ester, amino aci d alkyl alcohol ester, alkyl acid alkyl ester or cycloalkyl polyol, in some embodiments, the haloge n is bromine or chlorine, in some embodiments, a dosage ratio of the compound I-R-l to the mod ifier, the catalyst and the organic solvent is 1 mmol: 0.5 mmol to 1.5 mmol: 1 mmol to 3 mmol: 5 mL to 8 mL, in some embodiments, the dosage ratio is I mmol: 1 mmol: I mmol to 3 mmol: 5 mL to 8 mL, in some embodiments, a temperature of the reaction is 40°C to 100 °C, and in s ome embodiments, the reaction lasts for 8 hour to 20 hours. B. Modification of R2 When R2 is selected from the azido in fonnula I, the preparation method of the cordycepin d erivative as shown in fonnula 1 comprises: using a compound I-R-2 as a raw material for a cycliz ation reaction in an organic solvent to prepare an intermediate I-R-2a, which is 5-(6-amino-9H-puri ne-9-yl)-l,4-dioxopyrrole[2.4]heptane-6-alcohol or a derivative thereof; and subjecting the obtained i ntermediate I-R-2a to a ring-opening reaction in the organic solvent to prepare the cordycepin deri vative as shown in formula I; in formula I-R-2, Ri and R3 to R7 are the same as Ri and R3 to R7 in formula I, or are in dependently selected from protecting groups respectively. In some embodiments, the preparation method of the intermediate I-R-2a comprises: subjecting the compound I-R-2 to a cyclization reaction under catalysis of phosphorus pentoxide and m-chlor operoxybenzoic acid in dichloromethane, in some embodiments, a dosage ratio of the compound I-R-2 to the phosphorus pentoxide, the m-chloroperoxybenzoic acid and the dichloromethane is 1 m mol: 1.2 mmol to 2 mmol: 2 mmol to 3 mmol: 10 mL to 20 mL, in some embodiments, a temp erature of the cyclization reaction is 20°C to60°C, and in some embodiments, the cyclization reach on lasts for 3 hours to 10 hours. In some embodiments, the preparation method of the cordycepin derivative as shown in formu la I comprises: subjecting the intermediate I-R-2a to a ring-opening reaction with sodium azide in anhydrous dimethylformamide, in some embodiments, a dosage ratio of the compound I-R-2a to th e sodium azide and the dimethylformamide is 1 mmol: 4 mmol to 5 mmol: 2 mL to 5 mL, in so me embodiments, a temperature of the ring-opening reaction is 100°C to 120 °C, and in some em bodiments, the ring-opening reaction lasts for 12 horn to 16 hours. C. Modification of Rs When Rs is selected from the fluorine, the chlorine or the azido in formula I, the preparation method of the cordycepin derivative as shown in formula I comprises: using a compound I-R-3 a s a raw material for a chemical reaction in an organic solvent to prepare the cordycepin derivative as shown in formula I; 17 03 25 in formula I-R-3, Ri, Rs, and Rs to R? are the same as Ri, Rs, and Rs to R? in formula I, o r are independently selected from protecting groups respectively; when Rs is selected from the fluorine or the chlorine in formula I, in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the co mpound I-R-3 with trifluoromethanesulfonic anhydride in pyridine and dichloromethane to prepare a n intermediate I-R-3a, which is 5-(6-amino-9H-purine-9-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydrofur an-3-yl trifluoromethane sulfonate or a derivative thereof; and subjecting the intermediate I-R-3a to a substitution reaction with hydrofluoric acid, sulfur trifluoride or hydrochloric acid in ethyl acetat e to prepare the cordycepin derivative as shown in formula I; wherein, in the preparation method of the intermediate I-R-3a, in some embodiments, a dosage ratio of the compound I-R-3 to the trif luoromethanesulfonic anhydride, the pyridine and the dichloromethane is 1 mmol: 1 mmol to 1.5 mmol: 0.15 mL to 0.2 mL: 10 mL to 20 mL, in some embodiments, a temperature of the reactio n is -5°C to 5°C, in some embodiments, the temperature is 0°C, and in some embodiments, the re action lasts for 1 hour to 3 hours; wherein, in the preparation method of the cordycepin derivative as shown in formula I, in some embodiments, the intermediate I-R-3a is subjected to the substitut ion reaction with a triethylamine solution of 37% hydrofluoric acid or diethylamino sulfur trifluorid e or hydrochloric acid, in some embodiments, a dosage ratio of the intermediate I-R-3a to the triet hylamine solution of 37% hydrofluoric acid or diethylamino sulfur trifluoride or hydrochloric acid and the ethyl acetate is 1 mmol: 2 mmol to 3 mmol: 4 mL to 10 mL, in some embodiments, a t empterature of the reaction is 60°C to 80°C, and in some embodiments, the reaction lasts for 8 ho urs to 10 hours. When R3 is selected from the azido in formula I, in some embodiments, the preparation meth od of the cordycepin derivative as shown in formula I comprises: subjecting the compound I-R-3 t 0 a cyclization reaction under catalysis of triphenylphosphorus and diisopropyl azodicarboxylate in N,N-dimethylformamide to prepare an intermediate I-R-3b, which is 4-(6-amino-9H-purine 9-yl)-3,6-dioxane [3.1.0]hexane-2-yl)m ethanol or a derivative thereof; and subjecting the intermediate I-R-3b t o a cyclization reaction with sodium azide in dimethylformamide to prepare the cordycepin derivati ve as shown in formula I; wherein, in the preparation method of the intermediate I-R-3b, in some embodiments, a dosage ratio of the compound I-R-3 to the triphenylphosphorus, the diisopropyl a zodicarboxylate and the N,N-dimethylformamide is 10.0 mmol: 16 mmol to 28 mmol: 1.6 mmol to 2.8 mmol: 15 mL to 50 mL, in some embodiments, the dosage ratio is 10.0 mmol: 22 mmol: 2. 2 mmol: 15 mL to 50 mL, in some embodiments, a temperature of the reaction is 10°C to 60 °C, and in some embodiments, the cyclization reaction lasts for 1 hour to 5 hours; in some embodim ents, in the preparation method of the cordycepin derivative as shown in formula I, a dosage ratio of the intermediate I-R-3b to the sodium azide and the dimethylformamide is 1 mmol: 4 mmol t o 5 mmol: 2 mL to 5 mL, in some embodiments, a tempterature of the cyclization reaction is 10 0°C to 120 °C, and in some embodiments, the cyclization reaction lasts for 12 hours to 16 hours. D. Modification of R4 17 03 25 When R4 is selected from the cyano, the P-amide-y-cyclosulfonyloxy, the amino acid carboxyli c ester group, the amino acid alkyl ester phenyl phosphonate group, or the amino acid alkyl ester phenyl phosphonate group in formula I, the preparation method of the cordycepin derivative as sho wn in formula I comprises: using a compound I-R-4 as a raw material for a chemical reaction in an organic solvent to prepare the cordycepin derivative as shown in formula I; I-R-4 I-R-4a I-R-4b I-R-4c in formula I-R-4, Ri to R3 and R5 to R7 are the same as Ri to R3 and Rs to R? in formula I, or are independently selected from protecting groups respectively. When R4 is selected from the cyano in formula I, in some embodiments, the preparation meth od of the cordycepin derivative as shown in formula I comprises: stirring the compound I-R-4, trif luoromethanesulfonic acid and trimethylsilyl triflate in dichloromethane at -50°C to -30°C, and then reacting the mixture with trimethylnitrile silane and triethylamine; in some embodiments, a dosage ratio of the compound I-R-4 to the trifluoromethanesulfonic acid, the trimethylsilyl triflate and the dichloromethane is 10 mmol: 0.8 mL to 1.8 mL: 2.2 mL to 3.2 mL: 90 mL to IIO mL, in som e embodiments, the dosage ratio is 10 mmol: 1.3 mL: 2.7 mL: 100 mL, and in some embodiment s, the stirring lasts for 20 minutes to 40 minutes, in some embodiments, the stirring lasts for 30 minutes; in some embodiments, a dosage ratio of the compound I-R-4 to the trimethylnitrile silane and the triethylamine is 10 mmol: 3.4 g to 4.3 g: 3 mL to 4 mL, in some embodiments, a temp erature of the reaction is 20°C to 30°C, in some embodiments, the temperature is room temperatur e, and in some embodiments, the reaction lasts for 2 hours to 4 hours. When R4 is selected from the P-amide-y-cyclosulfonyloxy, in some embodiments, the preparati on method of the cordycepin derivative as shown in formula I comprises: subjecting the compound I-R-4 to an oxidation reaction to prepare an intermediate I-R-4a, which is 2-(6-amino-l,6-dihydro- 17 03 25 9H-purin-9-yl)-5-(hydroxymethyl)dihydrofuran-3(2H)-one or a derivative thereof, then subjecting the intermediate I-R-4a to a cyanation reaction to prepare an intermediate I-R-4b, which is 2-(6-amino-l,6-dihydro-9H-purin-9-yl)-5-(hydroxymethyl)-3-isocyanatotetrahydrofuran-3-ol or a derivative thereof, then subjecting the intermediate I-R-4b to methylsulfonic acid esterification to prepare an intermed iate I-R-4c, which is 2-(6-amino-l,6-dihydro-9H-purine-9-yl)-5-(hydroxymethyl)-3-isocyanatotetrahydro furan-3-ylmethane sulfonate or a derivative thereof, and finally subjecting the intermediate I-R-4c t o a ring-closure reaction to prepare the cordycepin derivative as shown in formula I; in some emb odiments, the preparation method of the intermediate I-R-4a comprises: reacting the compound I-R-4 with a Jones reagent 2.2 M chromium trioxide in acetone, in some embodiments, a dosage ratio of the compound I-R-4 to the Jones reagent and the acetone is 20 mmol: 5 mL to 8 mL: 50 m L to 100 mL, in some embodiments, a temperature of the reaction is 0°C to 40°C, and in some e mbodiments, the reaction lasts for 1 hour to 4 hours; in some embodiments, the preparation metho d of the intermediate I-R-4b comprises: reacting the intermediate I-R-4a with trimethylsilyl cyanide and boron trifluoride diethyl ether in dichloromethane, in some embodiments, a dosage ratio of th e intermediate I-R-4a to the trimethylsilyl cyanide, the boron trifluoride diethyl ether and the dichl oromethane is 20 mmol: 20 mmol to 40 mmol: 10 mmol to 30 mmol: 50 mL to 100 mL, in so me embodiments, the dosage ratio is 20 mmol: 20 mmol to 40 mmol: 20 mmol: 50 mL to 100 mL, and in some embodiments, a temperature of the reaction is 0°C to 40°C, and in some embodi ments, the reaction lasts for 1 hour to 4 hours; in some embodiments, the preparation method of t he intermediate I-R-4c comprises: reacting the intermediate I-R-4b with triethylamine and methanes ulfonyl chloride in anhydrous dichloromethane, in some embodiments, a dosage ratio of the interm ediate I-R-4b to the triethylamine, the methanesulfonyl chloride and the anhydrous dichloromethane is 2.2 mmol: 10 mmol to 15 mmol: 4 mmol to 8 mmol: 5 mL to 10 mL, in some embodiments, a temperature of the reaction is -30°C to 0°C, and in some embodiments, the reaction lasts for 2 hours to 4 hours; and in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the intermediate I-R-4c with cesium carbonate in anhy drous acetonitrile, in some embodiments, a dosage ratio of the intermediate I-R-4c to the cesium c arbonate and the anhydrous acetonitrile is 1 mmol: 0.5 mmol to 2.5 mmol: 3 mL to 10 mL, in s ome embodiments, the dosage ratio is 1 mmol: 1.5 mmol: 3 mL to 10 mL, in some embodiments, a temperature of the reaction is 0°C to 40°C, and in some embodiments, the reaction lasts for 2 hours to 4 hours. When R4 is selected from the amino acid carboxylic ester group in formula I, in some embod iments, the preparation method of the cordycepin derivative as shown in formula I preferably com prises: reacting the compound I-R-4 with amino acid acyl chloride in anhydrous pyridine to prepar e the cordycepin derivative as shown in formula I: in some embodiments, a dosage ratio of the co mpound I-R-4 to the amino acid acyl chloride and the pyridine is 10 mmol: 5 mmol to 15 mmol: 50 mL to 100 mL, in some embodiments, the dosage ratio is 10 mmol: 10 mmol: 50 mL to 10 0 mL, in some embodiments, a temperature of the reaction is 20°C to 60°C, in some embodiments, the temperature is 40°C, and in some embodiments, the reaction lasts for 6 hours to 20 hours. When R4 is selected from the amino acid alkyl ester phenyl phosphonate group in formula I, in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the compound I-R-4 with phenyl p-toluenesulfonyloxymethyl phosphate substitut ed by a modifier amino acid alkyl ester in anhydrous N,N-dimethylformamide with NaH as a catal 17 03 25 yst, in some embodiments, a dosage ratio of the compound I-R-4 to the modifier, the NaH and th e anhydrous N,N-dimethylformamide is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 100 mL to 200 mL, in some embodiments, the dosage ratio is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 150 mL, in some embodiments, a temperature of the reaction is -20°C to 0 °C, and in some embodiments, the reaction lasts for 0.5 hour to 6 hours. When R4 is selected from the amino acid alkyl ester phenyl phosphonate group in formula 1, in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the compound l-R-4 with nitrophenyl phosphate substituted by a modifier in an hydrous N,N-dimethylformamide and / or tetrahydrofuran with tert-butyl magnesium chloride as a cat alyst, wherein the substitution refers to substituting with any one or more functional groups of aryl oxy and methyl alkyl ester oxy, in some embodiments, a dosage ratio of the compound I-R-4 to t he modifier, the catalyst and the organic solvent is 1 mmol: 1 mmol to 3 mmol: 1 mmol to 2 m mol: 9 mL to 15 mL, in some embodiments, a temperature of the reaction is 20°C to 40°C, and i n some embodiments, the reaction lasts for 2 hours to 5 hours. E. Modification of R5 When R5 is selected from the bromvinyl, the mercapto, the methyl, the fluorine, or the chlori ne in formula I, the preparation method of the cordycepin derivative as shown in formula I compr ises: using a compound I-R-5 as a raw material for a chemical reaction in an organic solvent to p repare the cordycepin derivative as shown in formula I; in formula I-R-5, Ri to R4 and Re to R7 are the same as Ri to R; and Re to R? in formula I, or are independently selected from protecting groups respectively. When R5 is selected from the bromvinyl in formula I, in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: subjecting the compound I-R-5 to an iodization reaction to prepare an intermediate I-R-5a, which is 2-(6-amino-2-iodine-l,6-di hydro-9H-purine-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol or a derivative thereof, subjecting the in termediate I-R-5 a to a substitution reaction with methyl acrylate to prepare an intermediate I-R-5b, which is methyl(E)-3-(6-amino-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6,9-dihydro-lH-puri ne-2-yl)acrylate or a derivative thereof, hydrolyzing the intermediate l-R-5b to prepare an intermedi ate I-R-5c, which is (E)-3-(6-amino-9-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-6,9-dihydro-lH-purine-2-yl)acrylic acid or a derivative thereof, and subjecting the intermediate I-R-5c to a bro mination reaction with N-bromosuccinimide to prepare the cordycepin derivative as shown in formu la I; in some embodiments, the preparation method of the intermediate I-R-5a comprises: subjectin g the compound I-R-5 to an iodination reaction with iodine in dilute nitric acid to prepare the int ermediate I-R-5a, in some embodiments, a dosage ratio of the compound I-R-5 to the iodine is 1 mmol: 0.5 mmol to 0.8 mmol, in some embodiments, a temperature of the reaction is 100°C to 1 20°C, in some embodiments, the temperature is 110°C, and in some embodiments, the reaction last 17 03 25 s for 4 hours to 6 hours; in some embodiments, the preparation method of the intennediate I-R-5b comprises: reacting the intermediate I-R-5a with methyl acrylate and triethylamine in under cataly sis of palladium acetate and triphenylphosphine in 1,4-dioxane, in some embodiments, a dosage rati o of the intermediate I-R-5a to the methyl acrylate, the triethylamine, the palladium acetate, the tri phenylphosphine and the 1,4-dioxane is 1 mmol: 3 mmol to 4 mmol: 0.1 mL to 0.5 mL: 0.01 m mol to 0.09 mmol: 0.05 mmol to 0.15 mmol: 10 mL to 20 mL, in some embodiments, the dosag e ratio is 1 mmol: 3 mmol to 4 mmol: 0.1 mL to 0.5 mL: 0.05 mmol: 0.01 mmol: 10 mL to 20 mL, in some embodiments, a temperature of the reaction is 50°C to 90°C, and in some embodim ents, the reaction lasts for 0.5 hour to 2 hours; in some embodiments, the preparation method of t he intermediate I-R-5c comprises: hydrolyzing the intermediate I-R-5b with a sodium hydroxide sol ution, in some embodiments, a concentration of the sodium hydroxide solution is 0.5 mol / L to 3.5 mol / L, in some embodiments, the concentration is 2 mol / L, in some embodiments, a dosage ratio of the intermediate I-R-5b to the sodium hydroxide solution is 1 g: 10 mL to 14 mL, in some e mbodiments, the dosage ratio is 1 g: 12 mL, in some embodiments, a temperature of the reaction is 20°C to 30°C, in some embodiments, the temperature is room temperature, and in some embodi ments, the reaction lasts for 3 hours to 5 hours; and in some embodiments, the preparation metho d of the cordycepin derivative as shown in formula I comprises: reacting the intermediate I-R-5c with N-bromosuccinimide under catalysis of potassium carbonate in a mixed solvent of water and acetone, in some embodiments, a dosage ratio of the intennediate I-R-5c to the N-bromosuccinimid e, the potassium carbonate and the mixed solvent is 1 mmol: 1 mmol to 3 mmol: 1 mmol to 3 mmol: 15 mL to 30 mL, in some embodiments, a volume ratio of the water to the acetone is 1: 4 to 8, and in some embodiments, the volume ratio is 1: 6. I-R-5b I-R-5c I-R-5a In some embodiments, the unmodified cordycepin is directly modified by bromovinyl, with a r eaction path as follows: When Rs is selected from the mercapto in formula I, in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: making the compound I-R-5 react with hydrogen peroxide in acetic acid to prepare an intennediate I-R-5d, which is IN-oxidiz 17 03 25 ed-3'-deoxyadenosine or a derivative thereof, heating and refluxing the intermediate I-R-5d in a hy drochloric acid aqueous solution to prepare an intermediate I-R-5e, which is 5-amino-N'-hydroxy-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-lH-imidazole-4-carboxamide or a derivative thereof, dissolving the intermediate I-R-5e in water, making the mixture react in a hydrogen environment u nder catalysis of raney nickel to prepare an intermediate I-R-5f, which is 5-amino-3-hydroxy-5-(hyd roxymethyl)tetrahydrofuran-2-yl)-lH-imidazole-4-carboxamide or a derivative thereof, and reacting th e intermediate I-R-5f with methanol, methanol and carbon disulfide to prepare the cordycepin deriv ative as shown in formula I; in some embodiments, the preparation method of the intermediate 1-R -5d comprises: making the compound I-R-5 react with the acetic acid in the hydrogen peroxide, in some embodiments, a concentration of the hydrogen peroxide is 20% to 40%, in some embodime nts, the concentration is 30%, and in some embodiments, a dosage ratio of the compound I-R-5 to the hydrogen peroxide and the acetic acid is 1 mmol: 2 mol to 3 mol: 1 mL to 6 mL, in some embodiments, a temperature of the reaction is 30°C to 50°C, and in some embodiments, the react ion lasts for 2 days to 4 days; in some embodiments, the preparation method of the intermediate I -R-5e comprises: heating and refluxing the intermediate I-R-5d in the hydrochloric acid aqueous so lution, in some embodiments, a concentration of the hydrochloric acid aqueous solution is 1 mol / L to 5 mol / L, in some embodiments, the concentration is 3 mol / L, in some embodiments, a dosage ratio of the intermediate I-R-5d to the hydrochloric acid aqueous solution is 1 mmol: 3 mL to 5 mL, and in some embodiments, the heating and refluxing last for 10 minutes to 30 minutes; whe rein, in the preparation method of the intennediate 1-R-5L in some embodiments, a dosage ratio of the intermediate I-R-5e to the raney nickel and the water is 1 mmol: 0.08 g to 0.2 g: 10 mL to 20 mL, in some embodiments, a temperature of the reaction is 50°C to 70°C, and in some embo diments, the reaction lasts for 2 days to 5 days; and wherein, in the preparation method of the co rdycepin derivative as shown in formula I, in some embodiments, a dosage ratio of the intermediat e I-R-5f to the methanol, the pyridine and the carbon disulfide is 1 mmol: 5 mL to 10 mL, in so me embodiments, a volume dosage ratio of the methanol to the pyridine and the carbon disulfide i s 4: 3 to 7: 0.5 to 3.5, in some embodiments, the volume dosage ratio is 4: 5: 2, in some embo diments, a temperature of the reaction is 30°C to 50°C, in some embodiments, the temperature is 40°C, and in some embodiments, the reaction lasts for 3 days to 5 days. LR-5d In some embodiments, the unmodified cordycepin is directly modified by sulfydryl, with a rea ction method as follows: When R5 is selected from the methyl in formula I, in some embodiments, the preparation met 17 03 25 hod of the cordycepin derivative as shown in formula I comprises: reacting the compound I-R-5 w ith methyl iodide and potassium carbonate in a dichloromethane solvent, in some embodiments, a dosage ratio of the compound I-R-5 to the methyl iodide, the potassium carbonate and the dichlor omethane solvent is 1 mmol: 1 mmol to 2 mmol: 1.5 mmol to 3 mmol: 5 mL to 10 mL, in som e embodiments, a temperature of the reaction is 20°C to 50 °C, and in some embodiments, the re action lasts for 3 hours to 10 hours. When Rs is selected from the fluorine or the chlorine in formula I, the preparation method of the cordycepin derivative as shown in fonnula I comprises: subjecting the compound I-R-5 to a n itro derivatization reaction to prepare a nitration intermediate I-R-5g, which is 2-(6-amino-2-nitro-l, 6-dihydro-9H-purine-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, and then subjecting the intermediate to a substitution reaction to prepare the cordycepin derivative as shown in formula I; in some em bodiments, the preparation method of the intermediate I-R-5g comprises: reacting the compound I-R-5 with tetrabutylammonium nitrate under catalysis of trifluoroacetic anhydride in dichloromethane, in some embodiments, a dosage ratio of the compound I-R-5 to the tetrabutylammonium nitrate, t he trifluoroacetic anhydride and the dichloromethane is 1 mmol: 1.4 mmol to 2 mmol: 1 mmol to 2 mmol: 15 mL to 35 mL, in some embodiments, a temperature of the reaction is -10°C to 1 0°C, and in some embodiments, the reaction lasts for 0.5 hour to 20 hours; in some embodiments, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting th e nitration intermediate I-R-5g with tetrabutylammonium fluoride or tetrabutylammonium chloride in acetonitrile, in some embodiments, a dosage ratio of the nitration intermediate I-R-5g to the tetra butylammonium fluoride or the tetrabutylammonium chloride and the acetonitrile is I mmol: 1.3 m mol to 1.5 mmol: 30 mL to 50 mL, a temperature of the reaction is -5°C to 5°C, in some embod iments, the temperature is 0°C, and in some embodiments, the reaction lasts for 20 minutes to 30 minutes. Re r3 r4 I-R-5g F. Modification of Re When Re is selected from the formamido substituted in formula I, wherein the substitution ref ers to substituting with any one or more functional groups of alkyl, aryl, cycloalkyl, fund and pyr idyl; and the preparation method of the cordycepin derivative as shown in fonnula I comprises: us ing a compound I-R-6 as a raw material for a chemical reaction in an organic solvent to prepare the cordycepin derivative as shown in formula I; in formula I-R-6, Ri, Rs and R7 are the same as Ri, Rs and R7 in formula 1, or are indepen dently selected from protecting groups respectively. In some embodiments, the preparation method of the cordycepin derivative as shown in formu la I comprises: reacting the compound I-R-6 with acyl chloride substituted under anhydrous pyridin e, wherein the substitution refers to substituting with any one or more functional groups of alkyl, anl. cycloalkyl, furyl and pyridyl, in some embodiments, a dosage ratio of the compound I-R-6 to the acyl chloride substituted and the anhydrous pyridine is I mmol: I mmol to 2 mmol: 5 mL t 0 10 mL, in some embodiments, a temperature of the reaction is 0°C to 60°C, and in some embo diments, the reaction lasts for 2 hours to 20 hours. G. Modification of R7 When R7 is selected from the isopropyl amino in formula I, the preparation method of the co rdycepin derivative as shown in formula I comprises: using a compound I-R-7 as a raw material f or a chemical reaction in an organic solvent to prepare the cordycepin derivative as shown in for mula I; 17 03 25 I-R-7 in formula I-R-7, Ri to Rs are the same as Ri to Rs in fonnula I, or are independently selec ted from protecting groups respectively. In some embodiments, the preparation method of the cordycepin derivative as shown in formu la I comprises: subjecting the compound I-R-7 to a substitution reaction with 2-propylamina in dio xane, in some embodiments, a dosage ratio of the compound I-R-7 to the 2-propylamina and the dioxane is 10 mmol: 10 mmol to 30 mmol: 50 mL to 100 mL, in some embodiments, a temperat ure of the reaction is 60°C to 120 °C, and in some embodiments, the reaction lasts for 10 hours t 0 30 hours. In the present invention, the protecting groups comprise, but are not limited to, -OTBS, -OAc, -NHCbz, -OTBPS and -OTBDPS; in some embodiments, R4 is the same as R4 in formula I or is selected from -OTBS, -OAc and -OTBDPS; and in some embodiments, R(, is the same as Re in fonnula 1 or is selected from -NHCbz. In the present invention, the nitrophenyl phosphate substituted (the substitution refers to substit uting with any one or more functional groups of alkoxyl, alkoxyl substituted by halogen, aryloxy. amino acid ester acylamino, alkyl ester group and methyl alkyl acid oxy) is prepared according to the following method or other methods in the prior art. In anhydrous dichloromethane, phenyl chlorophosphate, p-nitrophenol and corresponding alcohol or amine substituted are prepared under catalysis of triethylamine at 0°C to 25 °C, wherein the su bstitution refers to substituting with any one or more functional groups of alkoxyl, alkoxyl substitu ted by halogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alkyl acid oxy, in some embodiments, a molar volume ratio of the phenyl chlorophosphate to the p-nitrophenol, t he corresponding substituent, the triethylamine and the anhydrous dichloromethane is 1 mmol: 1 m 17 03 25 mol: 1 mmol to 2 mmol: 2 mmol to 5 mmol: 5 mL to 10 mL. In the present invention, the p-toluenesulfonyloxymethyl phosphate substituted (the substitution refers to substituting with any one or more functional groups of alkoxyl, alkoxyl substituted by hal ogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alkyl acid oxy) is prepare d according to the following method or other methods in the prior art. In toluene, corresponding chlorophosphate substituted, p-toluenesulfonyl chloride and formaldeh yde are prepared under catalysis of triethylamine at 0°C to 105 °C, wherein the chlorophosphate s ubstituted is chlorophosphate substituted by any one or more functional groups of alkoxyl, alkoxyl substituted by halogen, aryloxy, amino acid ester acylamino, alkyl ester group and methyl alkyl aci d oxy, in some embodiments, a molar volume ratio of the corresponding chlorophosphate substitute d to the p-toluenesulfonyl chloride, the formaldehyde, the triethylamine and the toluene is 1 mol: 1 mol: 0.8 mol to 1.2 mol: 180 mL to 210 mL: 500 mL to 800 mL. Those skilled in the art can easily understand that Ri to R? are modified with groups based on the cordycepin in the present invention, and when Ri is hydrogen, R2 is hydrogen, R3 is hydro gen, R5 is hydrogen, R7 is hydrogen, R4 is hydroxyl, or Re is amino, it is unnecessary to modify Ri to R7. In the preparation method of tire present invention, the above substituents may be modif ied according to a priority order of stability of the prepared intermediates without violating the co mmon sense in the art, so as to obtain various embodiments of the present invention, for example, modifications without ester group, phosphate group and phosphonate group may be carried out fir st, such as modifying -CN, -N3, -F, -SH, and the like, then modification with ester group is carrie d out, and finally, modification with phosphate group or phosphonate group is carried out. The tenn "prevention" in the present invention means that the compounds or preparations des cribed in the present application are administered to prevent a disease or one or more symptoms r elated to the disease, and comprises: preventing a disease or a disease state from appearing in ma mmals, especially when these mammals are prone to induce related cancer symptoms. The term "pharmaceutically acceptable" in the present invention aims at those compounds, ma terials, compositions and / or dosage forms, which are within the range of reliable medical judgment and are suitable for contact with human and animal tissues without excessive toxicity , irritation, a llergic reaction or other problems or complications, thus being commensurate with a reasonable be nefit / risk ratio. The compounds of the present invention may exist in specific geometric or stereoisomeric for ms. All such compounds are proposed in the present invention, comprising cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)-isomers, (L)-isomers, racem ic mixtures thereof and other mixtures, such as mixtures enriched with the enantiomers or the dias tereomers, and all these mixtures are within the scope of the present invention. There may be othe r asymmetric carbon atoms in substituents such as alkyl. All these isomers and mixtures thereof ar e included in the scope of the present invention. Beneficial effects: compared with the prior art, the present invention has the following advant ages: The cordycepin derivative and the pharmaceutical composition thereof provided by the present invention have a good anti-tumor proliferation effect. Compared with a parent drug, the cordycepi n derivative has better affinity to cell membranes, so that a half-life period of in-vivo metabolism of the drug is longer, and in-vivo remaining time of the drug is longer. Compared with other nucl 17 03 25 eoside anti-tumor drugs, the cordycepin derivative and the pharmaceutical composition thereof provi ded by the invention have wider types and action ranges of tumors, have excellent inhibition effec ts on a gastric cancer, a pancreatic cancer, a liver cancer, a small cell lung cancer, a colorectal ca ncer, melanoma, an ovarian cancer and the like, and have lower side effects and better curative ef fects. DESCRIPTION OF THE DRAWINGS FIG. 1 shows anti-tumor effects of a blank group, a cordycepin control group and a compoun d group on a mouse model transplanted with liver cancer cells Hep-1-6. FIG. 2 shows inhibition effects of a control group and various compound groups on a tumorbearing zebrafish model of small cell lung cancer H446 cells. FIG. 3 shows inhibition effects of a compound 16 and an immune checkpoint inhibitor on a mouse model transplanted with colon cancer MC38 cells. FIG. 4 shows anti-tumor effects of the control group and the compound group on a mouse m odel transplanted with melanoma B16-F10. FIG. 5 shows inhibition effects of a compound 24 and the immune checkpoint inhibitor on a homotransplanted tumor model of a mouse with an ID 8 ovarian cancer. FIG. 6 shows anti-tumor effects of the control group and the compound group on a mouse m odel transplanted with gastric cancer BGC-823 cells. FIG. 7 shows anti-tumor effects of the control group and the compound group on a mouse m odel transplanted with pancreatic cancer Pan02-luc cells. DETAILED DESCRIPTION The experimental methods described in the following embodiments are all conventional method s unless otherwise specified. The reagents and materials can all be obtained commercially unless ot herwise specified. The cell models and animal models in the drug evaluation experiments can be o btained commercially unless otherwise specified. The cordycepin in the present invention is prepared by biological fermentation (CN 111117896 B), wherein the cordycepin or the derivative thereof is prepared according to the method in the sp ecification, and the post-treatment method mainly adopts a conventional organic experiment post-tre atment operation method which comprises, but is not limited to, filtration, quenching, extraction, ro tary steaming, recrystallization, column chromatography and the like. The preparation methods of th e compounds mentioned in the embodiments do not comprise all compounds, and only a few repre sentative compounds are listed herein for the convenience of explanation. In the embodiments, not all the animal model experiments on anti-cancer related cells of the cordycepin or the derivative thereof have effective experimental results, the animal model experime nts are only related experiments listed to illustrate the effects, and the drug evaluation experiments comprise cell model and animal model experiments following ethical rules. The feeding of the mouse model in the dnig evaluation follows that: mice are fed and treated in a laminar flow cabinet, with 5 nude mice in each cage, drinking water and feedstuffs are add ed once eveiy 3 days, and paddings are replaced once a week; a number of mice kept in each ca ge is no more than 5, the mice in separate cages are kept in groups as far as possible, and the mice should not be kept in a single cage; the animal management must conform to the relevant n 17 03 25 ational standards on animal feeding management, and the behavioral needs of animals should be c oncemed at the same time to avoid unnecessary stress; the normal physiological and behavioral ne eds of animals, such as defecation, urination, constant body temperature maintenance, normal activi ties, posture adjustment and reproduction are met; good ventilation and dry animals are kept; the a nimals can access to drinking water and food at will, and supplementation, replacement and cleani ng operations are easily carried out; a solid and safe environment is provided to avoid accidents o f animals, such as escaping or limb trapping in a gap; the animals are avoided from being damag ed by sharp edges or protrusions; and the animals are not disturbed during observation. The zebrafish model is a wild-type AB-line zebrafish from College of Biotechnology and Phar maceutical Engineering, Nanjing Tech University, and is carried out by a natural mating reproducti on method, with 30 zebrafish of 2 dpf in each experimental group. The zebrafish is fed in fish cu Iture water at 28°C (water quality: 200 mg of instant sea salt and CaCO?, are added into 1 L of r everse osmosis water with a conductivity of 480 uS / cm to 510 uS / cm, a pH value of 6.9 to 7.2, and a hardness of 53.7 mg / L to 71.6 mg / L), and the feeding management meets the requirements of international AAALAC certification. The method for determining inhibitory activities of the compounds on the proliferation of turn or cells by an MTT method is as follows: a bottle of cells in a good state in an exponential gro wth phase is added with 0.25% trypsin digestive juice, the digestion makes adherent cells fall off, with 2 to 4><104 cells / mL, and a cell suspension is prepared. The cell suspension is inoculated on a 96-well plate, with 90 uL well, and cultured in a constant-temperature CO: incubator for 24 ho urs. The prepared compounds are added for testing, with 10 uL well, and cultured for 72 hours. A n MTT reagent is added into a 96-w-ell plate, with 10 pL / well, and reacts in an incubator for 4 h ours to absorb a supernatant, and then dimethyl sulfoxide is added, with 100 pL / well. After a crys tai is dissolved, an absorbance of each well at a wavelength of 570 nm is measured by an enzym e-linked immunosorbent assay instrument, and a cell inhibition rate is calculated. An S curve is m ade with a compound concentration and a corresponding inhibition rate. Therefore, IC50 of a corres ponding compound is obtained. Embodiment 1: preparation of compound: 2-(6-amino-9H-purin-9-yl)-5-(2-hydroxyethoxy)methyl)tetra hydrofuran-3-ol (1) Protection and deprotection methods for hydroxyl in cordycepin la protection and deprotection methods for hydroxyl at Ri and R4 sites of cordycepin were as follows. Protection: 0.251 g (1 mmol) of cordycepin, 0.3618 g (2.4 mmol) of TBSCL and 0.3404 g (5 mmol) of imidazole were added into 10 mL of DMF, stirred at room temperature for 10 hours, and extracted with water and ethyl acetate after the reaction, and an organic phase was concentrate d to obtain 0.4607 g of la, with a yield of 96.03%, and MSI-MS: 480.8 [M+H]+. Deprotection: 10 mL of (tetrabutylainmonium fluoride: THF = 2: 1) solvent was prepared, add ed with 0.48 g (1 mmol) of la, stirred at room temperature for 5 hours, and extracted with water and ethyl acetate after the reaction, and an organic phase was concentrated, and recrystallized to obtain 0.246 g of cordycepin, with a yield of 97.96%. lb protection and deprotection methods for hydroxyl at Ri site of cordycepin were as follows. 17 03 25 1b Protection: 0.251 g (1 mmol) of cordycepin, 0.3618 g (2.4 mmol) of TBSCL and 0.3404 g (5 mmol) of imidazole were added into 10 mL of DMF, stirred at room temperature for 10 hours, and extracted with water and ethyl acetate after the reaction, and an organic phase was concentrate d to obtain 0.4607 g of la, with a yield of 96.03%. In addition, subsequently, 10 mL of (acetic a cid: water: THF = 13: 7: 3.) solvent was prepared, added with 0.48 g (1 mmol) of la, stirred at room temperature for 15 hours, and extracted with water and ethyl acetate after the reaction, and an organic phase was concentrated, and subjected to column chromatography to obtain 0.293 g of lb, with a yield of 79.99%, MSI-MS: 366.5 [M+H]+. Deprotection: 10 mL of 0.1 M hydrochloric acid methanol solution was added with 0.366 g (1 mmol) of lb, and stirred at room temperature for 10 hours, pH of the mixture was adjusted to be neutral with 0.1 M sodium carbonate aqueous solution after the reaction, the mixture was extr acted with ethyl acetate, and an organic phase was concentrated, rotationally evaporated and recryst allized to obtain 0.215 g of cordycepin, with a yield of 85.56%. 1c protection and deprotection methods for hydroxyl at Ri site of cordycepin were as follows. 1c Protection: 1.256 g (5 mmol) of cordycepin was added into 10 mL of dichloromethane and 1 0 mL of diisopropylethylamine under protection of nitrogen, then dropwise added with 0.451 g (1. 6 mmol) of TBDPSC1, stirred at room temperature for 2 hours, concentrated and then purified by column chromatography to obtain 2.20 g of 1c, with a yield of 89.9%, and MSI-MS: 366.5 [M+H] + Deprotection: 10 mL of (tetrabutylammonium fluoride: THF = 2: 1) solvent was prepared, add ed with 0.490 g (1 mmol) of Ie, stirred at room temperature for 5 hours, and extracted with wate r and ethyl acetate after the reaction, and an organic phase was concentrated, and recrystallized to 17 03 25 obtain 0.244 g of cordycepin, with a yield of 97.01%. (2) Specific preparation method of compound: 2-(6-amino-9H-purin-9-yl)-5-(2-hydroxyethoxy)me thy l)tetrahy drofuran-3 -ol The compound lb was used as a raw material, 3.65 g (10 mmol) of lb and 0.81 g (10 mmo 1) of compound 2-chloro-ethanol were placed in a round-bottomed flask, and added with 60 mL of butanone, and the reactant was heated and dissolved, and additionally added with 2.07 g (15 mm ol) of potassium carbonate. The reaction was carried out at 80°C for 8 hours, and the reaction wa s monitored by TLC. The reaction solution was filtered and concentrated after the reaction, and ex tracted twice with 60 mL of water and 60 mL of ethyl acetate, organic phases were combined, an d rotationally evaporated under a reduced pressure to obtain a viscous liquid, and the viscous liqui d was deprotected and subjected to column chromatography to obtain a compound 1, with a weigh t of 2.24 g and a yield of 76%. Detection results of the prepared compound 1 were as follows: 1 H NMR (400 MHz, DMSO-d6) 5 8.56 (s, 1H), 8.35 (s, 1H), 7.09 (s, 2H), 6.14 (d, 1H), 5.47-5.3 (d, 2H), 5.01 (m, 1H), 4.12 (m, 1H), 3.74 (m. 1H), 3.61-3.56 (m, 4H), 3.51-3.46 (m, 2H), 2.04-1.92 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 156.1, 152.4, 149.8, 140.1, 119.6, 95.2, 82.1, 7 5.2, 74.7, 70.4, 61.1, 34.5. MSI-MS: 296.3 [M+H]+. Embodiment 2: preparation of compound: (5-(6-amino-9H-purine-9-yl)-4-hydroxytetrahydrofuran-2-yl) dihydromethyl phosphate According to the protection method in Embodiment 1, 3.65 g (10 mmol) of compound lb w as added with 150 mL of triethyl phosphite and 4.62 g (30 mmol) of phosphorus oxychloride in i ce bath. The reaction was carried out at 0°C for 2 hours, after the reaction, the mixture was adde d with 1,000 mL of water in the ice bath for a quenching reaction, and added with dichlorometha ne for multiple extractions, organic phases were combined, and rotationally evaporated to remove a solvent, so as to obtain a viscous liquid, the prepared viscous liquid was separated and purified b y a preparative liquid phase (Cl8 preparative column, Waters preparative liquid phase, mobile phas e of 30% acetonitrile aqueous solution, flow rate of 2 mL / min), and an effluent of a peak segmen t of a sample was concentrated and then weighed to obtain a phosphorylated compound, which wa s 3.02 g in total, with a yield of 70%. A compound 2 was prepared according to the deprotection solution of lb in Embodiment 1. Detection results of the prepared compound 2 were as follows:'H NMR (400 MHz, DMSO-d6) 8 8.54 (s, 1H), 8.36 (s, 1H), 7.11(s, 2H), 6.19 (d, 1H), 5.15 (d, 1H), 4.28-4.23 (m, 2H), 4.2 (s, 2H), 4.02 (m, 1H), 3.71 (m, 1H), 2.06-1.90 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 156.2, 152.7, 149.5, 140.2, 119.3, 97.2, 76.1, 74.6, 69.5, 34.5. MSI-MS: 332.2 [M+H|\ Embodiment 3: ((((5-(6-amino-9H-purine-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)methyl)phospho nic acid 17 03 25 36.5 g (100 mmol) of compound lb was added into a 500 mL reaction flask, added with 15 0 mL of DMF as a solvent, and heated and dissolved. After rapid cooling to room temperature, 6. 4 g (267 mmol) of 80% NaH was added in batches under stirring, and stirred at room temperatur e for 15 minutes. The reaction solution was cooled to -10°C in a low-temperature reactor, dropwis e added with 45.1 g (140 mmol) of diethyl p-toluenesulfonyloxymethyl phosphate, stirred for reacti on at this temperature for 1 hour after dropwise adding, and then gradually subjected to temperatu re rise to room temperature and stirred for 4 hours. After the reaction, glacial acetic acid was dro pwise added to adjust pH to be neutral, the reaction solution was filtered, and washed with dichlo romethane, the filtrate was extracted with water (60 mL) thrice, dichloromethane phases were com bined, and evaporated under a reduced pressure to remove a solvent, and toluene was added into t he residue for recrystallization. A crystallization mother liquor was filtered, the filter cake was drie d at 50°C under a reduced pressure to obtain a white powdery solid 3a, with a weight of 26.87 g and a yield of 52%, and MSI-MS: 540.6 [M+23]+. 5.17 g (10 mmol) of compound 3a was added into a 100 mL reaction flask, added with 20 mL of n-butyronitrile, and dropwise added with 6.52 g (60 mmol) of trimethylchlorosilane at room temperature, and the reaction solution was subjected to temperature rise and refluxed for reaction for 24 hours after dropwise adding. The solvent was concentrated to be dry by distillation under a reduced pressure after the reaction, 20 mL of water was added into the residue, 2 M sodium hyd roxide was additionally added to adjust pH of the mixture to be about 8, then the mixture was ex traded thrice with ethyl acetate (50 mL), and a water phase was neutralized with 1 M hydrochlori c acid to make pH equal to 3 to 4. Subsequently, the mixture was heated to 70°C to 80°C for cr ystallization to obtain a compound 3b, with a weight of 3.40 g and a yield of 74%, and MSI-MS: 460.6 [M+H]+. The compound 3b was treated according to the deprotection solution of lb in Embodiment 1 to obtain a compound 3. Detection results of the prepared compound were as follows:'H NMR (4 00 MHz, DMSO-d6) 8 8.58 (s, 1H), 8.32 (s, 1H), 7.13 (s, 2H), 6.12 (d, 1H), 5.39 (d, 1H), 4.81 (s, 2H), 4.02 (m, 1H), 3.98 (m, 1H), 3.74 (d, 2H), 3.63-3.56 (m, 2H), 2.08-1.94 (m, 2H). 13C N MR (100 MHz, DMSO-d6) 3 156.7, 152.6, 149.1, 140.4, 119.5, 98.2, 81.1, 76.3, 74.3, 73.1, 34.7. MSI-MS: 346.3 [M+H]+. Embodiment 4: preparation of compound: (5-(6-amino-9H-purine-9-yl)-4-hydroxytetrahydrofuran-2-yl) diisobutyl methylphosphate 3.65 g (10 mmol) of compound lb was added into a 500 mL reaction flask, dissolved in 100 mL of anhydrous DMF, and additionally added with 4.96 g (15 mmol) of diisobutyl phosphate(4-nitrophenyl). In addition, 1.17 g (10 mmol) of tert-butyl magnesium chloride was dissolved in 20 mL of THF, and the solution was slowly dropwise added into the reaction solution above. The rea ction solution w-as gradually subjected to temperature rise to room temperature for reaction for 2 h ours, and the reaction was monitored by a TLC plate. After the reaction, the obtained mixture was allowed to stand for reaction, diluted with 100 mL of ethyl acetate, washed and extracted thrice with saturated sodium bicarbonate aqueous solution, with 50 mL each time, and then extracted wit h 50 mL of saturated sodium chloride aqueous solution. An organic layer was dried on anhydrous sodium sulfate, and concentrated under a reduced pressure. The obtained oil was purified by silic a gel column chromatography (eluent: dichloro / methanol =10: 1) to obtain a compound 4a, with a weight of 4.24 g and a yield of 76%. The 4a was treated according to the deprotection method of lb in Embodiment 1 to obtain a compound 4. Detection results of the prepared compound 4 were as follows: ’H NMR (400 MHz, DMSO-d6) 8 8.52 (s, 1H), 8.31 (s, 1H), 7.11 (s, 2H), 6.15 (d, 1H), 5.33 (d, 1H), 4.24-4.05 (m,2 H), 4.02 (m, 1H), 3.93 (m, 4H), 3.77 (m, 1H), 2.08-1.83 (m, 2H), 1.33 (m, 2H), 0.90 (d, 12H). 1 3C NMR (100 MHz, DMSO-d6) 8 154.3, 151.7, 148.4, 141.9, 119.2, 98.2, 74.1, 74.0, 73.5, 68.1, 34.2, 28.6, 19.5. MSI-MS: 466.7 [M+Na]+. Embodiment 5: preparation of compound: (((((((5-(6-amino-9H-purine-9-yl)-4-hydroxytetrahydrofuran- 17 03 25 2-yl)methoxy)methyl)phosphoryl) bis(oxy)bis(methylene)bis(2-methylpropionic acid)) A compound 5 was prepared according to the preparation method of 3 a in Embodiment 3 in combination with the deprotection method of lb in Embodiment 1, wherein diethyl p-toluenesulfo nyloxymethyl phosphate was replaced by ((tolyloxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2-m ethylpropionic acid) in equivalent amount, and a total yield of the prepared compound 5 was 74%. Detection results of the prepared compound 5 were as follows: 'H NMR (400 MHz, DMSO-d6) 8 8.57 (s, 1H), 8.33 (s. 1H), 7.11 (s, 2H), 6.84 (d, 4H), 6.18 (d, 1H), 5.46 (d, 1H), 4.12 (m, 1H), 3.94 (m, 1H), 3.81 (d, 2H), 3.60-3.44 (m, 2H), 2.55 (m, 2H), 2.08-1.82 (m, 2H), 1.14 (d, 12H). 13C NMR (100 MHz, DMSO-d6) 8 174.2, 155.7, 153.6, 149.5, 141.2, 119.5, 99.4, 93.2, 77.4, 74.5, 74.1, 71.5, 34.2, 33.6, 19.3. MSI-MS: 546.5 [M+H]+. Embodiment 6: preparation of compound: methyl((5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofura n-2-yl)methoxy)(phenoxy)phosphoryl)-D-valine, with a preparation process as follows. 17 03 25 A preparation method of methyl((4-nitrophenoxy)(phenoxy)phosphoryl)-D-valine was as follows. 1.17 g (10 mmol) of valine was dissolved in 50 mL of dichloromethane. The solution was co oled to about 0°C, added with 2.11 g (10 mmol) of phenyl phosphate dichloride, and then slowly dropwise added with 2.02 g (20 mmol) of triethylamine, the reaction was subjected to temperature rise to room temperature, and the mixture was stirred for 80 minutes. 1.39 g (10 mmol) of react ant p-nitrophenol was added, then dropwise added with 2.02 g (20 mmol) of triethylamine, and sti rred at room temperature for 180 minutes. After the reaction, the mixture was washed with ether, and filtered to remove a generated solid. The filtrate was concentrated on a rotary evaporator, and an obtained sample was purified by silica gel column chromatography (eluent: n-hexane / ethyl acet ate (1: 1)). Detection results of the prepared compound were as follows: 'H NMR (400 MHz, DM SO-d6) 5 8.25 (d, 2H), 7.40 (m, 2H), 7.35 (d, 2H), 7.20 (m, 3H), 3.68 (s, 1H), 3.65 (s, 3H), 3.3 5 (m, 1H), 1.90 (m, 2H), 0.86 (m, 3H). 13C NMR (100 MHz, DMSO-d6) 8 171.6, 156.5, 150.5, 141.1, 130.2, 126.5, 121.7, 121.4, 120.4, 52.2, 51.9, 26.4, 9.6. MS1-MS: 395.3 [M+H]+. A compound 6 was prepared according to the preparation method of 4a in Embodiment 4 in combination with the deprotection method of lb in Embodiment 1, wherein diisobutyl p-phosphate (4-nitrophenyl) was replaced by methyl((4-nitrophenoxy)(phenoxy)phosphoryl)-D-valine in equivalent amount, and a yield of the prepared compound 6 was 68%. Detection results of the finally prepa red compound 6 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.33 (s, 1H), 7. 43 (m, 2H), 7.20 (m, 3H) 7.08 (s, 2H), 6.15 (d, 1H), 5.47 (d, 1H), 4.26-4.12 (m, 2H), 4.02 (m, 1H), 3.75 (m, 1H), 3.67 (d, 1H), 3.62 (s, 3H), 3.28 (d, 1H), 2.41 (m. 1H), 2.08-1.96 (m, 2H), 0.9 8 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 8 173.6, 154.9, 151.5, 150.6, 149.8, 141.3, 132.7, 123. 3, 120.8, 119.2, 98.2, 76.1, 74.5, 72.0, 57.6, 52.3, 35.2, 32.4, 20.1. MSI-MS: 521.4 [M+H]+. Embodiment 7: preparation of compound: isopropyl(((((((5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahyd rofuran-2-yl)methoxy)methyl)(phenoxy)phosphoryl)alanine ester, with a preparation process as follow 17 03 25 A preparation method of isopropyl(phenoxy((tolyloxy)methyl)phosphoryl)alanine ester was as fo Hows. 216.15 g (1.65 mol) of isopropyl alanine, 155 g (1.65 mol) of phenol and 240 mL of chlorof orm were added into a 1,000 mL reaction flask, and stirred at about 5°C in ice salt bath and then dropwise added with 138.8 g (1 mol) of phosphorus trichloride, and a reaction temperature was k ept at 5°C to 10°C. After dropwise adding the phosphorus trichloride, the mixture was continuous! y stirred for 30 minutes and removed from the ice salt bath, and gradually subjected to temperatur e rise to room temperature and continuously stirred for 2 hours, and then, hydrogen chloride gas was removed under a reduced pressure at 50°C. The reaction was cooled to room temperature, the mixture was slowly added with 80 mL of saturated sodium bicarbonate aqueous solution, and the n added with sodium bicarbonate solid powder to adjust a pH value of the reaction solution to be 7 to 8. Precipitated salt was removed by filtering, the filtrate was placed in a separatory funnel t o separate a chloroform layer, a water layer was extracted with 100 mL of chloroform once, orga nic phases were combined, and washed with saturated sodium bicarbonate solution and water once in sequence, the chloroform layer w-as distilled under a reduced pressure, and the residue was a t arget product phenyl chlorophosphate alanine isopropyl ester, with a yield of 87%. 306 g (1 mol) of phenyl chlorophosphate alanine isopropyl ester, 40.6 g (1.35 mol) of parafor maldehyde, 14 mL of triethylamine and 260mL of toluene were put into a 1,000 mL reaction flas k. The reaction was slowly subjected to temperature rise to 105°C under protection of nitrogen, th e reaction was intense at the moment, and the mixture was refluxed for reaction for 3 hours. Afte r the reaction, the ice salt bath was cooled to 0°C, the mixture was added with 169.5 g (0.9 mol) of p-toluenesulfonyl chloride, added with 220 mL of toluene, and additionally dropw-ise added wit h 177 mL of triethylamine, the reaction temperature was kept at 0°C and the mixture was stirred for 2 horns, and the mixture was gradually subjected to temperature rise to room temperature and stirred for 12 hours. The mixture was filtered after the reaction, the filter cake was washed with t oluene (50 mLx3), and mother liquors were combined and washed with 5% sodium carbonate aqu eous solution (200 mL*2) and water (200 mLx2) in sequence, and then layered to obtain an orga nic phase. The organic phase was distilled under a reduced pressure to obtain a light yellow oil s ubstance, which was isopropyl(phenoxy((tolyloxy)methyl)phosphoryl)alanine ester and used for subse quent reaction, with a weight of 291 g and a yield of 64%. Detection results of the prepared com pound were as follows: 'H NMR (400 MHz, DMSO-d6) 5 7.74 (d, 2H), 7.45-7.39 (m, 4H), 7.22 (m, 3H), 4.95 (m, 1H), 3.91 (d, 2H), 3.65 (s, 1H), 3.57 (m, 1H), 2.42 (s, 3H), 1.28 (d, 3H), 1.18 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 5 171.6, 150.4, 144.4, 140.3, 130.5, 130.1, 128.5, 121. 4, 120.2, 69.6, 63.8, 50.5, 21.7, 21.5, 19.2. MSI-MS: 456.5 [M+H]+. A compound 7 was prepared according to the preparation method of 3a in Embodiment 3 in combination with the deprotection method of lb in Embodiment 1, wherein diethyl p-toluenesulfon yloxymethyl phosphate was replaced by the isopropyl(phenoxy((tolyloxy)methyl)phosphoryl)alanine e ster in equivalent amount, and a yield of the prepared compound 7 was 52%. Detection results of the prepared compound 7 were as follows: 'H NMR (400 MHz, DMSO-d6) 5 8.59 (s, 1H), 8.37 (s, 1H), 7.45 (m, 2H), 7.24 (m, 3H), 7.12 (s, 2H), 6.16 (d, 1H), 5.33 (d, 1H), 4.98 (m, 1H), 4.0 8-3.99 (m, 2H), 3.84 (m, 1H), 3.77 (m, 2H), 3.58-3.42 (m, 3H), 2.08-1.96 (m, 2H), 1.29 (d, 3H), 1.16 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 6 172.1, 156.3, 152.5, 150.4, 149.8, 140.1, 130.2, 122.1, 120.5, 119.1, 98.2, 79.1, 74.8, 74.7, 73.1, 69.6, 52.3, 34.5, 22.5, 18.8. MSI-MS: 535.6 [M +H]+. Embodiment 8: 2-(-5 -(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)-3 -hydroxypropyl valine salt 17 03 25 A compound lb was used as a raw material, 3.65 g (10 mmol) of lb and 2.10 g (10 mmol) of compound 2-chloro-3-hydroxypropyl valine were placed in a round-bottomed flask, and added with 60 mL of butanone, and the reactant was heated and dissolved, and additionally added with 2.07 g (15 mmol) of potassium carbonate. The reaction was carried out at 80°C for 10 hours, and the reaction was monitored by TLC. The reaction solution was filtered and concentrated after the reaction, and extracted twice with 60 mL of water and 60 mL of ethyl acetate, organic phases w ere combined, and rotationally evaporated under a reduced pressure to obtain a viscous liquid, and the viscous liquid was subjected to column chromatography to obtain a compound 8a, with a wei ght of 3.24 g and a yield of 52%, and MSI-MS: 539.6 [M+H]+. The compound 8a was used as a substrate, which was treated by the deprotection method of lb in Embodiment 1 to prepare a compound 8, with a yield of 91%. Detection results of the pre pared compound 8 were as follows: ’H NMR (400 MHz, DMSO-d6) 6 8.88 (s, 2H), 8.54 (s, 1H), 8.37 (s, 1H), 7.14 (s, 2H), 6.18 (d, 1H), 5.57 (d, 1H), 4.33-4.11 (m, 3H) 4.03 (m, 1H), 3.96-3.8 9 (m, 3H), 3.61-3.36 (m, 4H), 2.37 (m, 1H), 2.08-1.82 (m, 2H), 0.98 (d, 6H). 13C NMR (100 M Hz, DMSO-d6) 5 173.5, 154.6, 153.5, 150.4, 141.3, 119.6, 99.5, 85.6, 75.7, 74.0, 73.1, 63.3, 62.5, 58.7, 34.7, 30.8, 18.8. MSI-MS: 425.4 [M+H]+. Embodiment 9: preparation of compound: (4-amino-6-(6-amino-9H-purin-9-yl)-2,2-dioxide-l ,7-dioxane -2-thiespiro[4.4]non-3-ene-8-yl)dihydromethyl phosphate, with a preparation method as follows. A compound 2 was used as a raw' material, 9.00 g (27.2 mmol) of compound 2 and 4.88 g 17 03 25 (27.2 mmol) of CbzCl were added into 38.5 mL of toluene and 38.5 mL of water, and additional! y added with 4.70 g (34 mmol) of K2CO3, and the mixture was vigorously stirred at a temperatur e below 25 °C. Subsequently, the mixture was stirred at room temperature for 3 hours, and then ad ded with 0.275 g (2.72 mmol) of triethylamine and 5.78 g of sodium chloride in sequence, and th e mixture was continuously stirred for 30 minutes. An organic layer was separated and concentrate d to obtain a required oil product 9a, with a weight of 11.38 g, and a yield of 90%, and MSI-M S: 488.7 [M+Na]+. 9.3 g (20 mmol) of compound 9a was stirred and dissolved in 60 mL of acetone at room te mperature, and 5.50 mL (2.2 M chromium trioxide, 12.1 mmol) of Jones reagent was added into t he solution, which was dropwise added at room temperature for 2 hours. The obtained reaction mi xture was continuously stirred at room temperature for 1 hour, filtered, and concentrated under a r educed pressure to obtain an oil liquid. The liquid was dissolved in 30 mL of ether, washed with 30 mL of saturated ammonium chloride solution once, dried with anhydrous magnesium sulfate, c oncentrated under a reduced pressure and then subjected to column chromatography to obtain a co mpound 9b, with a weight of 3.98 g, and a yield of 43%, and MSI-MS: 464.4 [M+H]+. 4 mL (30 mmol) of trimethylsilyl cyanide and 2.53 mL (20 mmol) of boron trifluoride dieth yl ether were added into 50 mL of dichloromethane solution of 9.26 g (20 mmol) of 9b. The mix hire was stirred at room temperature for 2 hours, and the solvent was evaporated to be dry. An 0 btained slag was dissolved in 100 mL of ethyl acetate, washed with 50 mL of brine twice and dri ed (with Na2SO4). The solvent was filtered and evaporated, and then purified by column chromato graphy (n-hexane / ethyl acetate, 1:2) to obtain a white compound 9c, with a weight of 7.45 g, and a yield of 76%, and MSI-MS: 491.9 [M+H]+. 1.9 mL of EtsN (14 mmol) was added into 5 mL of anhydrous dichloromethane, and 1.08 g (2.2 mmol) of compound 9c was added into the solution for dissolution. The mixture was cooled to -30°C, and then slowly added with 460 uL (6 mmol) of methanesulfonyl chloride. The mixhire was stirred at -20°C for 1 hour, and stirred at 0°C for 1 hour. Subsequently, the mixture was c oncentrated under a reduced pressure to remove a volatile, and a slag was dissolved in 10 mL of ethyl acetate, and then consecutively washed with 10 mL of water and 10 mL of brine twice. An organic phase (NaiSCU) was dried and concentrated under a reduced pressure, and purified by col umn chromatography (n-hexane: ethyl acetate, 10: 1) to obtain a white amorphous solid 9d, with a weight of 0.975 g, and a yield of 78%. Preparation results were detected as follows: 'H NMR (4 00 MHz, DMSO-d6) 8 10.45 (s, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.34-7.32 (s, 5H), 6.12 (s, 1H), 4.65 (s, 2H), 4.30-4.03 (m, 4H), 3.74 (m ,1H), 3.15 (s, 3H), 2.41-2.16 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 153.6, 152.5, 151.7, 149.8, 140.2, 136.4, 128.9, 127.7, 127.2, 123.5, 120.4, 97. 4, 71.6, 69.2, 68.2, 66.9, 38.2, 37.8. MSI-MS: 569.4 [M+H]+. 490 mg (1.5 mmol) of cesium carbonate was added into 3 mL of anhydrous acetonitrile susp ension of 0.568 g (1 mmol) of 9d, and the mixhire was stirred at room temperature for 2 hours. The solvent was removed, and an obtained residue was dissolved in 20 mL of ethyl acetate, and washed with 10 mL of water and 10 mL of brine twice in sequence. An organic phase (Na2SO4) was dried and filtered, then concentrated under a reduced pressure, and purified by column chroma tography (n-hexane / ethyl acetate, 3:1) to obtain a white solid 9c. with a weight of 4.49 g, and a yield of 79%, and MSI-MS: 569.4 [M+H]+. 5.68 g of compound 9e (10 mmol) was dissolved in 200 mL of methanol. Subsequently, 1.5 g of ammonium formate (30 mmol) and 0.75 g of 10% Pd-C were added, and the reaction mixt ure was stirred at room temperature for 10 minutes, and then heated and refluxed for 45 minutes. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to be dry to obtain 4.12 g of compound 9, with a yield of 95%. Detection results of the prepared compound 9 were as follows: 'H NMR (400 MHz, DMSO-d6) 5 8.59 (s, 1H), 8.38 (s, 1H), 7.14 (s, 2H), 6. 88 (s, 2H), 6.16 (d, 1H), 5.25 (s, 1H), 4.28 (m, 1H), 4.18 (s, 2H), 4.02 (m, 1H), 3.74 (m, 1H), 2.09-1.96 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 5 168.5, 155.1, 151.4, 147.8, 141.1, 119.4, 9 8.2, 88.9, 86.1, 73.0, 68.1, 37.9. MSI-MS: 435.3 [M+H]+. Embodiment 10: preparation of compound: N-(3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purine-6-yl)octadecylamine OAc 10a 17 03 25 2.51 g (10 mmol) of cordycepin was added with 40.00 mL of anhydrous pyridine and 8.5 m L of acetic anhydride in ice bath. The reaction was monitored by HPLC, and the reaction was en ded after reacting for about 5 hours. The solvent was removed to obtain a viscous liquid 10a, wit h a weight of 2.68 g, and a yield of 80%, and MSI-MS: 358.6 [M+Na]+. 3.35 g (10 mmol) of compound 10a and 2.89 g (10 mmol) of octadecyl chloride were added with 60 mL of anhydrous pyridine in ice bath, the reaction was gradually subjected to temperatur e rise to 40°C for reaction for 10 hours, the reaction was monitored by TLC, water and ethyl ace tate were added for extraction after the reaction, an organic phase was reverse-extracted, the organi c phase was collected for rotary evaporation to obtain an oil liquid 10b, and the oil liquid 10b w as purified by column chromatography to obtain 5.40 g of purified product of 10b, with a yield o f 90%, and MSI-MS: 624.4 [M+Na]+. 6.01 g (10 mmol) of compound 10b was dissolved in 450 mL of ammonia methanol solution for reaction, and stirred at room temperature, the reaction was detected by thin layer chromatogra phy, and the reaction was stopped 4 hours later. The solvent was removed to obtain a target prod uct 10, and 4.67 g of the compound was weighed, with a yield of 90%. Alternatively, protection and deprotection were carried out according to the preparation method of la in Embodiment 1, wherein the protected la was subjected to an acylation reaction in the s econd step herein, and then subjected to deprotection to prepare a compound 10. Detection results of the prepared compound 10 were as follows: 'H NMR (400 MHz, DMSO-d6) 5 10.55 (s, 1H), 8.64 (s, 1H), 8.38 (s, 1H), 6.18 (d, 1H), 5.35 (d, 1H), 5.04 (m, 1H), 4.02 (m, 1H), 3.76 (m, 1H), 3.58 (m, 1H), 3.52 (m,lH), 2.35 (m, 2H), 2.07-1.94 (m, 2H), 1.58 (m, 2H), 1.30-1.26 (m, 28H), 0.89 (m, 3H). 13C NMR (100 MHz, DMSO-d6) 8 173.5, 153.3, 152.5, 148.8, 141.0, 122.6, 99.2, 84.1, 74.3, 63.8, 38.5, 34.8, 31.5, 29.5, 28.8, 25.6, 22.4, 14.7. (Some alkyl peaks were overlapped) MSI-MS: 540.7 [M+Na]+. 17 03 25 Embodiment 11: N-(3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purine-6-yl)cyclopentane car boxamide According to the method of Embodiment 10, cordycepin was subjected to steps of protection, acylation and deprotection to prepare a compound 11, wherein the octadecanoyl chloride was repla ced by cyclopentyl formyl chloride, with an overall yield of 72%. Detection results of the prepare d compound 11 were as follows: ’H NMR (400 MHz, DMSO-d6) S 10.52 (s, 1H), 8.66 (s. 1H), 8.38 (s, 1H), 6.16 (d, 1H), 5.28 (d, 1H), 5.01 (m, 1H), 4.01 (m, 1H), 3.77 (m, 1H), 3.57-3.46 (m, 2H), 2.46 (m, 1H), 2.08-1.88 (m, 2H), 1.80-1.55 (m, 8H). 13C NMR (100 MHz, DMSO-d6) 8 17 2.5, 153.3, 151.5, 149.5, 139.8, 123.6, 98.4, 82.1, 74.9, 63.8, 49.5, 34.5, 32.4, 24.5. MSI-MS: 348. 2 [M+H]+. Embodiment 12: N-(3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purine-6-yl)isonicotinamide According to the method of Embodiment 10, cordycepin was subjected to steps of protection, acylation and deprotection to prepare a compound 12, wherein the octadecanoyl chloride was repl aced by pyridine-3-formyl chloride, with an overall yield of 76%. Detection results of the prepared compound 12 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 11.05 (s, 1H), 8.86 (d, 2H), 8. 41 (s, 1H), 8.22 (s, 1H), 8.01(d, 2H), 6.15 (d, 1H), 5.22 (d, 1H), 4.98 (m, 1H), 4.02 (m, 1H), 3. 75 (m, 1H), 3.58-3.46 (m, 2H), 2.08-1.88 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 165.5, 152. 3, 151.9, 149.8, 149.7, 140.9, 140.4, 123.4, 120.5, 99.4, 82.8, 74.7, 63.8, 35.4. MSI-MS: 357.3 [M +H]+. Embodiment 13: (5-(6-amino-2-fluoro-9H-piirine-9-yl)-4-hydroxytetrahydrofuran-2-yl)dihydromethyl ph osphate 193 pL (1.39mmol) of 2,2,2-trifluoroacetic anhydride was added into a solution of dry dichlo romethane (15 mL) containing 428 mg (1.40 mmol) of tetrabutylammonium nitrate at 0°C to prepa re a nitration mixture. After reacting at 0°C for 45 minutes, the solution was slowly added into dr y dichloromethane (15 mL) of 480 mg (1 mmol) of compound la. After reacting at room tempera tore in the dark for 14 hours, the reaction mixture was poured into a cold mixture of H;O (50 m L), saturated NaHCOs (35 mL) and CH2CI2: Et2O (1: 2, 30 mL) for extraction, and extracted with CH2Q2: Et2O (1: 2, 30 mL) twice. An organic extract was washed with brine, dried with anhydr ous Na2SO4, and dried in vacuum (the temperature was kept below 40°C). A crude product was p urified by column chromatography, and eluted with CH2Q2, and then a compound 13a was obtaine d by using CH2Q2: acetone (99: 1 to 95: 5), with a weight of 273 mg, and a yield of 52%, and MSI-MS: 525.4 |M+H|'. TBAF (equivalent amount of 1.3, 600 pL, 0.6 mmol) was dropwise added into a suspension of dry acetonitrile (15 mL) containing 236 mg (0.45 mmol) of 13a within 1 minute at 0°C. The mixture was stirred for 20 minutes, and an obtained solution was evaporated in vacuum without h eating. A crude product was purified by column chromatography (CH2Q2: acetone, 100: 0 to 90: 10) to obtain a compound 13b, with a weight of 78 mg, and a yield of 35%, and MSI-MS: 498.8 [M+H]+. The prepared compound 13b was treated by the phosphorylation method in Embodiment 2 an d the deprotection method in Embodiment 1 to obtain a compound 13, with a yield of 65%. Dete ction results of the prepared compound 13 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 8.3 8 (s, 1H), 6.98 (s, 2H), 6.16 (d, 1H), 5.36 (d, 1H), 4.28 (m, 1H), 4.21 (s, 2H), 4.02 (m, 1H), 3.9 5 (m, 1H), 3.74 (m, 1H), 2.02-1.82 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 5 158.3, 157.2, 14 8.8, 141.5, 118.6, 97.2, 74.9, 74.6, 67.1, 35.5. MSI-MS: 372.2 [M+Na]+. Embodiment 14: (5-(6-amino-2-mercapto-9H-purine-9-yl)-4-hydroxytetrahydrofuran-2-yl)dihydromethyl phosphate 17 03 25 14d 4.80 g (10 mmol) of compound la was added into 60 mL of acetic acid, and stirred at 40°C and dissolved. After the solution was cooled to room temperature, 5 mL (25 mmol) of 30% hydr ogen peroxide was added. The solution was stirred at 40°C for 3 days, and filtered, and a solid w as recrystallized in water to obtain a compound 14a, with a weight of 3.37 g, and a yield of 68%, and MSI-MS: 497.4 [M+H]+. 4.96 g (10 mmol) of 14a was added into 40 mL of 3 M hydrochloric acid aqueous solution, heated and refluxed until the solid was completely dissolved, continuously refluxed for 10 minutes, and then cooled to room temperature, and 20 mL of ethanol was added after removing the solve nt. A precipitated crystal was filtered and dried to obtain a compound 14b, with a weight of 2.92 g, and a yield of 62%, and MSI-MS: 487.5 [M+H]+. 4.86 g (10 mmol) of compound 14b was dissolved in 100 mL of water, added with 1.0 g of activated Raneyni in batches, and introduced with hydrogen. The reaction mixture was stirred at 55°C for reaction for 4 days. The introduction of hydrogen was stopped, inorganic salt was remov ed by filtration, and then the solvent was removed by distillation under a reduced pressure. A cru de product was washed with ethanol and ether respectively, and dried to obtain a gray solid 14c, with a weight of 3.30 g, and a yield of 70%, and MSI-MS: 495.8 [M+Na]+. Methanol, pyridine and carbon disulfide were mixed according to a volume ratio of 4: 5: 2 to obtain 50 mL of solution, and added with 4.72 g (10 mmol) of 14c, and a balloon was sleeved on a reflux condensing tube to prevent carbon disulfide from volatilizing. The reaction mixture wa s stirred at 40 °C for reaction for 4 days, and filtered. A crude product was heated and refluxed i n 5% sulfuric acid aqueous solution for 20 minutes, filtered while the mixture was hot to remove impurities, cooled to room temperature, and then filtered and dried to obtain a gray crystal 14d, w ith a weight of 2.82 g, and a yield of 55%. The prepared compound 14d was treated by the phos phon lalion method in Embodiment 2 and the deprotection method in Embodiment 1 to obtain a c ompound 14, with a yield of 71%. Detection results of the prepared compound 14 were as follow s: ’H NMR (400 MHz, DMSO-d6) 8 12.22 (s, 1H), 8.36 (s, 1H), 6.99 (s, 2H), 6.16 (d, 1H), 5.33 (d, 1H), 4.30 (m, 1H),4.21 (s, 2H), 4.02 (m, 1H), 3.94 (m, 1H), 3.71 (m, 1H), 2.06-1.88 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) 8 154.3, 152.1, 149.2, 139.8, 118.6, 99.2, 74.8, 74.3, 67.1, 3 5.1. MSI-MS: 364.3[M+H]+. Embodiment 15: (5-(6-amino-9H-purine-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)dihydromethyl ph osphate 17 03 25 2.67 g (10 mmol) of adenosine, 3.618 g (24 mmol) of TBSCL and 3.95 g (50 mmol) of pyr idine were added into 10 mL of DMF, stirred at room temperature for 10 hours, and extracted wi th water and ethyl acetate after the reaction, and an organic phase was concentrated and subjected to column chromatography to obtain 2.33 g of 15a, with a yield of 47%, and MSI-MS: 497.7 [M+H]+. The solution of dichloromethane (100 mL) containing 4.96 g (10 mmol) of 15a and pyridine (1.5 mL) was stirred and cooled to -5°C under protection of nitrogen, dropwise added with 2.5 mL (15 mmol) of trifluoromethanesulfonic anhydride for continuous reaction at 0°C for 2 hours, p cured into ice water (100 mL) after complete reaction was shown in TLC, and stirred and layered, and a water phase was extracted with dichloroalkane (100 mL). Dichloromethane phases were co mbined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then filtered, the filtrate was concentrated under a reduced pressure, and petroleum ether (40 mL) was added into the residue for recrystallization, filtered and then dried to obtain 15b, with a weig ht of 5.65 g, and a yield of 90%. Preparation results were detected as follows: 'H NMR (400 M Hz, DMSO-d6) 8 8.59 (s, 1H), 8.35 (s, IH), 7.11 (s, 2H), 6.15 (d ,1H), 5.05 (m. 1H), 4.55 (m, 1 H), 4.12 (m, IH), 4.02-3.79 (m, 2H), 0.99 (s, 18H), 0.20 (s, 12H). 13C NMR (100 MHz, DMSO-d6) 8 156.2, 152.5, 149.7, 140.2, 119.5, 118.4, 96.5, 86.4, 83.5, 73.8, 63.2, 30.8, 30.6, 25.8, 0. M SI-MS: 628.8 [M+H]+. 6.28 g (10 mmol) of 15b was dissolved in ethyl acetate (40 mL) under protection of nitroge n, added with 10 mL (22 mmol) of triethylamine solution of 37% hydrofluoric acid, stirred and su bjected to temperature rise to 70°C for reaction for about 8 hours. The mixture was cooled to roo m temperature after complete reaction was shown in TLC, washed with saturated sodium bicarbona te solution to be neutral, then washed with saturated sodium chloride solution, dried with anhydrou s sodium sulfate, and filtered, the filtrate was concentrated under a reduced pressure, and the resid ue was recrystallized with anhydrous methanol (30 mL) to obtain a solid 15c, with a weight of 2. 04 g, and a yield of 41%. The prepared compound 15c was treated by the phosphorylation metho d in Embodiment 2 and the deprotection method in Embodiment 1 to obtain a compound 15, with a yield of 77%. Detection results of the prepared compound 15 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.37 (s, 1H), 7.07 (s, 2H), 6.15 (d, 1H), 5.33 (d, 1H), 4.70 (m, 1H), 4.44 (m, 1H), 4.28 (m, 1H), 4.18 (s, 2H), 4.02 (m, 1H) 3.55 (m, 1H). 13C NMR (100 MH z, DMSO-d6) 5 155.3, 151.4, 148.9, 141.1, 119.6, 97.2, 90.1, 79.0, 73.4, 61.5. MS1-MS: 350.2 [M +H]+. Embodiment 16: isopropyl ((((((5-(6-amino-9H-purin-9-yl)-4-cyano tetrahydrofuran-2-yl)methoxy)meth yl)(phenoxy)phosphoryl)alanine ester 17 03 25 A compound 7 was prepared according to the method in Embodiment 7, and the compound 7 was used as a raw material to prepare a compound 16. 5.34 g (10 mmol) of compound 7 was dissolved in 100 mL of dichloromethane solution, and then added with 1.3 mL (1.50 g, 10 mmol) of trifluoromethylsulfonic acid. After reacting and being stirred for 10 minutes, 2.7 mL of trimeth ylsilyl triflate (10 mmol) was slowly drop wise added into the solution, and the obtained mixture w as stirred at -40°C for 30 minutes. Subsequently, 3.96 g (40 mmol) of trimethylnitrile silane was s lowly added, and the mixture was stirred for 2 hours. Subsequently, 3.5 mL of triethylamine was dropwise added, and the reaction mixture was heated to room temperature. Subsequently, 5.5 g of solid sodium bicarbonate and 20.7 mL of water were added, and the obtained mixture was stirred for 10 minutes. Subsequently, the mixture was extracted with dichloromethane and water to obtain an organic extract, and the organic extract was washed with brine, then dried with anhydrous sod ium sulfate, and concentrated under a reduce pressure. A crude slag was purified by column chro matography to obtain a product compound 16 of a gray solid, with a weight of 1.71 g, and a yiel d of 32%. Detection results of the prepared compound 16 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 8.57 (s, 1H), 8.36 (s, 1H), 7.41 (m, 2H), 7.22 (m, 3H), 7.09 (s, 2H), 6.17 (d, 1H), 4.99 (d, 1H), 3.97 (m, 1H), 3.74-3.33 (m, 6H), 2.88 (m, 1H), 2.04-1.92 (m, 2H), 1.28-1.14 (d, 9 H). 13C NMR (100 MHz, DMSO-d6) 5 173.4, 155.3, 152.5, 150.2, 149.8, 141.3, 130.2, 121.6, 120. 5,118.2, 92.2, 77.4, 75.0, 73.1, 69.1, 51.2, 26.5, 25.8, 22.4, 20 I. MSI-MS: 544.5 [M+H]+. Embodiment 17: (((((((5-(6-amino-2-fluoro-9H-purine-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)met hyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionic acid) A compound 13b was prepared according to the method in Embodiment 13, the 13b was use d as a raw material to prepare a compound 17a according to the protection method of lb in Emb odiment 1, and the compound 17a was used as a raw material to prepare a compound 17 accordin g to the preparation method of 3a in Embodiment 3, wherein diethyl p-toluenesulfonyl methyl pho sphonate was replaced by (((tolyloxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropi onic acid) in equivalent amount, and the lb was replaced by the 17a in equivalent amount, with a total yield of 61%. Detection results of the prepared compound 17 were as follows: H NMR (40 0 MHz, DMSO-d6) 6 8.33 (s, 1H), 6.99 (s, 2H), 6.88 (s, 4H), 6.16 (d, 1H), 5.37 (d, 1H), 4.02 (m, 1H), 3.95 (m, 1H),3.85 (s, 2H), 3.61-3.42 (m, 2H), 2.05-1.88 (m, 2H), 1.25 (s, 18H). 13C NM R (100 MHz, DMSO-d6) 8 175.2, 158.3, 157.5, 148.6, 140.3, 119.2, 99.2, 92.2, 79.1, 74.8, 74.3, 71.2, 38.5, 35.8 26.8. MSI-MS: 592.5 [M+H]+. 17 03 25 Embodiment 18: (((((5-(6-amino-9H-purine-9-yl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)methoxy)meth yl)phosphoiyl)bis (oxy))bis(methylene)bis(2,2- dimethylpropionic acid) o 15c 18a A compound 18b was prepared according to the method in Embodiment 15 and the protection method of lb in Embodiment 1, and the compound 18a was used as a raw material to prepare a compound 18 according to the preparation method of 3 a in Embodiment 3, wherein diethyl p-tolu enesulfonyl methyl phosphonate was replaced by (((tolyloxy)methyl)phosphoryl)bis(oxy))bis(methylen e)bis(2,2- dimethylpropionic acid) in equivalent amount, and the lb was replaced by the 18a in eq uivalent amount, with a total yield of 34%. Detection results of the prepared compound 18 were a s follows: 'H NMR (400 MHz, DMSO-d6) 6 8.59 (s, 1H), 8.32 (s, 1H), 7.09 (s, 2H), 6.84 (s, 4 H), 6.15 (d, 1H). 5.35 (d, 1H), 4.71-4.64 (m. 2H), 3.85(m, 2H), 3.60-3.33 (m, 3H), 1.27 (s. 18H). 13C NMR (100 MHz, DMSO-d6) 8 175.9, 157.3, 151.5, 149.8, 141.3, 118.9, 98.2, 92.8, 91.5, 79. 4, 73.3, 71.4, 70.5, 38.6, 27.8. MSI-MS: 592.4 [M+H]+. Embodiment 19: (((((5-(6-amino-2-mercapto-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)met hyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2- dimethylpropionic acid) A compound 14d was prepared according to the method in Embodiment 14, the 14d was use d as a raw material to prepare a compound 19a according to the protection method of lb in Emb odiment 1, and the compound 19a was used as a raw material to prepare a compound 19 accordin g to the preparation method of 3a in Embodiment 3, wherein diethyl p-toluenesulfonyl methyl pho sphonate was replaced by (((tolyloxy)methyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2- dimethylpropi onic acid) in equivalent amount, and the lb was replaced by the 19a in equivalent amount, with a total yield of 18%. Detection results of the prepared compound 19 were as follows: ’H NMR (40 0 MHz, DMSO-d6) 8 12.12 (s, 1H), 8.34 (s, 1H), 7.01 (s, 2H), 6.84 (s, 4H), 6.12 (d, 1H), 5.35 (d, 1H), 4.01 (m, 1H), 3.93 (m, 1H), 3.85 (s, 2H), 3.63-3.37 (m, 2H), 2.06-1.85 (m, 2H), 1.27 (s, 18H). 13C NMR (100 MHz, DMSO-d6) 8 175.8, 155.4, 152.5, 149.7, 140.5, 118.9, 98.7, 92.8, 78. 1, 74.9, 74.7, 71.2, 38.7, 34.5, 27.5. MSI-MS: 606.6 [M+H]+. 17 03 25 Embodiment 20: isopropyl((((5 -(6-amino-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methox y (methyl ((phenoxy )phosphoiyl (alanine ester A compound 17b was prepared according to the methods in Embodiment 13 and Embodiment 17, and a compound 20 was prepared according to the method in Embodiment 7, wherein diethyl p-toluenesulfonyl methyl phosphonate was replaced by isopropyl(phenoxy((tolyloxy)methyl)phosphor yl)alanine ester in equivalent amount, and the lb was replaced by the 17a, with a total yield of 6 7%. Detection results of the prepared compound 20 were as follows: *H NMR (400 MHz, DMSO-d6) 8 8.37 (s, 1H), 7.40 (m, 2H), 7.20 (m. 3H), 7.02 (s, 2H), 6.15 (d, 1H), 5.38 (s, 1H), 4.94 (m, 1H), 4.00 (m, 1H), 3.95 (m, 1H), 3.71-3.53 (m, 5H), 3.34 (m, IH), 2.06-1.82 (m, 2H), 1.28-1. 14 (d, 9H). 13C NMR (100 MHz, DMSO-d6) 8 172.1, 157.3, 156.8, 150.0, 149.8, 140.2, 121.3, 12 0.6, 119.2, 97.4, 76.6, 75.0, 74.8, 72.1, 69.4, 50.1, 34.5, 21.7, 19.5. MSI-MS: 553.5 [M+H]+. Embodiment 21: N-(2-fluoro-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purine-6-yl)octadec ylamine A compound 13b was prepared according to the method in Embodiment 13, the 13b was use d as a raw material to prepare a compound 21a according to the preparation method of 10b from 10a in Embodiment 10, and the 21a was used as a raw material to prepare a compound 21 acco rding to the deprotection method of la in Embodiment 1, with a total yield of 74%. Detection res ults of the prepared compound 21 were as follows:1!! NMR (400 MHz, DMSO-d6) 5 10.53(s, 1H), 8.34 (s, 1H), 6.15 (d, 1H), 5.6 (d, 1H), 5.02 (in, 1H), 4.01 (m, 1H), 3.78 (m, 1H), 3.57 (m, 1 H), 3.51 (m,lH), 2.35 (m, 2H), 2.09-1.91 (m, 2H), 1.52 (m, 2H), 1.33-1.25 (m, 28H), 0.88 (m, 3 H). 13C NMR (100 MHz, DMSO-d6) 6 172.5. 153.5, 152.7, 148.6, 141.2, 122.4, 99.1, 84.5, 74.6, 63.4, 37.3, 34.2, 32.3, 29.4, 28.7, 25.7, 22.3, 14.5. (Some alkyl peaks were overlapped) MS1-MS: 536.6 [M+H]+. 17 03 25 Embodiment 22: N-(4-chloro-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purine-6-yl)octadec ylamine Adenosine was used as a raw material to prepare 15b according to the method in Embodime nt 15, the 15b was used as a raw material, and 6.28 g (10 mmol) of 15b was dissolved in ethyl acetate (40 mL) under protection of nitrogen, added with 10 mL (22 mmol) of triethylamine soluti on of 37% hydrochloric acid, stirred and subjected to temperature rise to 70°C for reaction for ab out 8 hours. The mixture was cooled to room temperature after complete reaction was shown in T LC, washed with saturated sodium bicarbonate solution to be neutral, then washed with saturated s odium chloride solution, dried with anhydrous sodium sulfate, and filtered, the filtrate was concentr ated under a reduced pressure, and the residue was recrystallized with anhydrous methanol (30 mL) to obtain a solid 22a, with a weight of 1.95 g, and a yield of 38%, and MSLMS: 515.2 [M+H] + The 22a was used as a raw material to prepare a compound 22 according to the preparation method of 10b from 10a in Embodiment 10 in combination with the deprotection method of la in Embodiment 1, with a total yield of 79%. Detection results of the prepared compound 22 were a s follows: 'H NMR (400 MHz, DMSO-d6) 6 10.60 (s, 1H), 8.67 (s, 1H), 8.35 (s, 1H), 6.15 (d, 1 H), 5.33 (d, 1H), 4.98 (m, 1H), 4.31 (m, 1H), 4.02 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.53 (m,lH), 2.32 (m, 2H), 1.51 (m, 2H), 1.34-1.21 (m, 28H), 0.87 (m, 3H). 13C NMR (100 MHz, D MSO-d6) 5 171.4, 152.5, 151.6, 148.4, 140.5, 121.4, 98.7, 77.5, 74.3, 68.1, 59.4, 38.2, 33.7, 31.5, 28.1, 27.5, 25.4, 22.1, 14.6. (Some alkyl peaks were overlapped) MSI-MS: 553.2 [M+H]+. Embodiment 23: (((((4-hydroxy-5 -(6-(isoniazid)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)methyl)pho sphoryl)bis (oxy))bis(methylene)bis(2,2- dimethylpropionic acid) 17 03 25 A compound 12 was used as a raw material to prepare a compound 23 a according to the pro tection method of lb in Embodiment 1, the compound 23a was used as a raw material to prepare a compound 23 according to the preparation process of 17 from 17a in Embodiment 17, the 17a was replaced by the 23 a in equivalent amount in the reaction, and a total yield of the reaction w as 81%. Detection results of the prepared compound 23 were as follows: ]H NMR (400 MHz, D MSO-d6) 5 11.05, (s, 1H), 8,85 (d, 2H), 8.34 (s, 1H), 8.18 (s, 1H), 8.00(d, 2H), 6.84 (s, 4H), 6.1 4 (d, 1H), 5.35 (d, 1H), 4.01 (m, 1H), 3.94 (m, 1H),3.86 (s, 2H), 3.60-3.38 (m, 2H), 2.06-1.84 (m, 2H), 1.27 (s, 18H). 13C NMR (100 MHz, DMSO-d6) 5 175.8, 165.1, 152.4, 151.5, 149.8, 149. 6, 140.7, 140.2, 121.2, 120.1, 99.5, 92.8, 78.1, 74.7, 74.5, 71.4, 38.7, 34.5, 27.2. MSI-MS: 679.6 [M+H]+. Embodiment 24: isopropyl((((4-hydroxy-5-(6-(isonicotinamide)-9H-purin-9-yl)tetrahydrofuran-2-yl)meth oxy)methyl)(phenoxy)phosphoryl)alanine ester 23a A compound 23a was prepared according to the method in Embodiment 23, and the 23a was used as a raw material to prepare a compound 24 according to the method in Embodiment 7, wh erein the compound lb was replaced by the 23a in equivalent amount, with a total yield of 85%. Detection results of the prepared compound 24 were as follows: 'H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 8.81(d, 2H), 8.36 (s, 1H), 8.18 (s, 1H), 8.02 (d ,2H), 7.42 (m, 2H), 7.21 (m, 3 H), 6.16 (d, 1H), 5.35 (s, 1H), 4.92 (m, 1H), 4.01-3.95 (m, 2H), 3.65-3.54 (m, 5H), 3.35 (m, 1H), 2.04-1.84 (m, 2H), 1.25-1.18 (d, 9H). 1JC NMR (100 MHz, DMSO-d6) 8 171.1, 165.2, 152.7, 15 1.8, 150.4, 149.8, 149.5, 140.5, 140.1, 130.4, 123.2, 121.8, 121.4, 120.2, 99.3, 76.7, 74.8, 74.5, 72. 5, 69.8, 50.4, 34.7, 21.5, 19.3. MSI-MS: 640.6 [M+H]+. Embodiment 25: (5-(6-amino-9H-purinc-9-yl)-3-azide-4-hydroxytctrahydrofuran-2-yl)dihydromethyl pho sphate 17 03 25 2.67 g (10.0 mmol) of adenosine and 5.78 g (22 mmol) of PPh? were added into a round-bo ttomed flask under an argon atmosphere, and then added with 18 mL of DMF, and the obtained mixture was stirred at room temperature until a solid was completely dissolved. The solution was cooled to 10°C, and quickly dropwise added with 4.4 ml (2.2 mmol) of diisopropyl azodiformate (DIAD), so that the reaction mixture reached room temperature. The mixture was stirred at 40°C f or 2 hours, then DMF was evaporated under a reduced pressure to obtain a viscous liquid, and th e mixture was allocated between 150 mL of water and 100 mL of ether. A water layer was colic cted and washed with 100 mL of ether. An organic phase was concentrated under a reduced press ure, and a crude product was purified by column chromatography, and eluted with a mixture of D CM and an acetone solvent (3: 1 to 2: 3) to obtain a compound 25 a of a white solid, with a wei ght of 1.84 g, and a yield of 74%, and detection results of the prepared compound were as folio ws: ’H NMR (400 MHz, DMSO-d6) 5 8.57 (s, 1H), 8.36 (s, 1H), 7.10 (s ,2H), 6.37 (d, 1H), 4.5 9 (m, 1H), 3.95 (s, 1H), 3.57-3.50 (m, 2H), 2.62-2.55 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 156.3, 152.5, 149.9, 140.5, 119.5, 90.4, 82.6, 63.5, 60.8, 59.6. MSI-MS: 250.2 [M+H]+. 2.49 g (10 mmol) of compound 25a and 2.6 g (40 mmol) of sodium azide were added into a flask, and additionally added with 20 mL of DMF as a solvent, the reaction was carried out at 120°C for 16 hours, and the reaction was monitored by a TLC plate. Water was added for quench ing after the reaction, a water phase was extracted with ethyl acetate (180 mL) thrice, organic pha ses were combined, and washed with water, and the solvent was removed under a reduced pressur e to obtain a foamed solid 25b, with a weight of 2.22 g, and a yield of 76%, and MSI-MS: 293. 2 [M+H]+. The 25b was used as a raw material to prepare 25c according to the protection method of 1 b in Embodiment 1, and the 25c was used as a raw material to prepare a compound 25 according to the method in Embodiment 2, wherein the lb was replaced by the 25c in equivalent amount, with a yield of 76%. Detection results of the prepared compound 25 were as follows: 'H NMR (4 00 MHz, DMSO-d6) 8 8.57 (s, 1H), 8.38 (s, 1H), 7.09 (s, 2H), 6.17 (d, 1H), 5.35 (d, 1H), 4.27-4.24 (m, 2H), 4.19 (s, 2H), 4.02 (m, 1H), 3.81 (m, 1H), 1.75 (m, 1H). :C NMR (100 MHz, DM SO-d6) 8 158.2, 152.4, 149.8, 140.5, 119.4, 101.2, 78.1, 73.2, 68.4, 57.5. MSI-MS: 373.2 [M+H]+. Embodiment 26: (((((5-(6-amino-9H-purine-9-yl)-3 -azide-4-hydroxytetrahydrofuran-2-yl)methoxy)methy 1) phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionic acid) A compound 25c was prepared according to the preparation method in Embodiment 25, the 2 5c was used as a raw material to prepare a compound 26a according to the preparation method of 17 from 17a in Embodiment 17, and a compound 26 was prepared according to the deprotection method of lb in Embodiment 1, wherein the 25c was replaced by the 17a in equivalent amount, with a total yield of 54%. Detection results of the prepared compound 26 were as follows: 'H N MR (400 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.34 (s, 1H), 7.04 (s, 2H), 6.82 (s, 4H), 6.15 (d, 1H), 5.35 (d, 1H), 4.00 (m, 2H), 3.85 (s, 2H), 3.62-3.41 (m, 2H), 1.84 (m, 1H), 1.26 (s, 18H). BC N MR (100 MHz, DMSO-d6) 6 175.4, 157.3, 152.5, 149.7, 140.2, 119.5, 99.8, 92.8, 79.0, 72.3, 71.5, 71.1, 56.5, 38.8 27.6. MSI-MS: 615.6 [M+H]+. 17 03 25 Embodiment 27: isopropyl((((5-(6-amino-9H-purine-9-yl)-3 -azide-4-hydroxytetrahydrofuran-2-yl)methox y)methyl)(phenoxy)phosphoryl)alanine ester 25c A compound 25c was prepared according to the protection method in Embodiment 25, and th e 25c was used as a raw material to prepare a compound 27 according to the preparation method in Embodiment 7, wherein the lb was replaced by the 25c in equivalent amount, with a total yie Id of 43%. Detection results of the prepared compound 27 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.34 (s, 1H), 7.42 (m, 2H), 7.21 (m, 3H), 7.07 (s, 2H), 6.15 (d, 1H), 5.34 (s ,1H), 4.95 (d, 1H), 3.99 (m, 2H), 3.76-3.34 (m, 6H), 1.88 (m, 1H), 1.27-1.16 (d, 9H). 13C NMR (100 MHz, DMSO-d6) 5 171.4, 156.4, 152.1, 150.1,149.5, 140.3, 130.5, 121.2, 120.5,119.4, 100.5, 78.4, 72.8, 72.0, 71.5, 69.1, 57.2, 50.5, 21.5, 19.1. MSI-MS: 576.5 [M+H]+. Embodiment 28: isopropyl((((3-azide-4-hydroxy-5-(6-(isoniazid)-9H-purin-9-yl)tetrahydrofuran-2-yl)met hoxy)methyl)(phenoxy)phosphoryl)alanine ester 28a The prepared compound T! was used as a raw material, a compound 28a was prepared accor ding to the protection method of la or lb in Embodiment 1, and the compound 28a was used as a raw material to prepare a compound 28 according to the preparation method in Embodiment 12, wherein cordycepin or the lb was replaced by the compound 28 in equivalent amount, with a tot al yield of 37%. Detection results of the prepared compound 28 were as follows: ’H NMR (400 MHz, DMSO-d6) 8 11.07 (s, 1H), 8.83 (d, 2H), 8.35 (s, 1H), 8.20 (s, 1H), 8.01 (d, 2H), 7.41 (m, 2H), 7.21 (m, 3H), 6.15 (d, 1H), 5.35 (s ,1H), 4.94 (d, 1H), 4.00 (m, 2H), 3.72-3.32 (m, 6H), 1. 82 (m, 1H), 1.24-1.17 (d, 9H). 13C NMR (100 MHz, DMSO-d6) 8 171.5, 164.5, 152.1, 151.6, 150. 1, 149.8, 149.4, 140.7, 140.3, 130.2, 122.2, 121.5, 121.1, 120.4, 100.4, 78.7, 72.5, 72.1, 71.5, 69.2, 57.4, 50.8, 21.6, 19.2. MSI-MS: 681.6 [M+H]+. Embodiment 29: 2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl valine salt 17 03 25 A compound 1c was prepared according to the protection method of 1c in Embodiment 1, the 1c was used as a raw material for further reaction, 9.95 g (27.2 mmol) of compound 1c and 4.8 8 g (27.2 mmol) of CbzCl were added into 38.5 mL of toluene and 38.5 mL of water, and additi onally added with 4.70 g (34 mmol) of K2CO3, and the mixture was vigorously stirred at a tempe rature below 25 °C. Subsequently, the mixture was stirred at room temperature for 3 hours, and the n added with 0.275 g (2.72 mmol) of triethylamine and 5.78 g of sodium chloride in sequence, a nd the mixture was continuously stirred for 30 minutes. An organic layer was separated and conce ntrated to obtain a required oil product 29a, with a weight of 13.1 g, and a yield of 90%, and M SI-MS: 522.6 [M+Na]+. 4.99 g (10 mmol) of compound 29a and 1.36 g (10 mmol) of valine acyl chloride were add ed with 60 mL of anhydrous pyridine in ice bath, the reaction was gradually subjected to temperat ure rise to 40°C for reaction for 10 hours, the reaction was monitored by TLC, water and ethyl a cetate were added for extraction after the reaction, an organic phase was reverse-extracted, the org anic phase was collected for rotary evaporation to obtain an oil liquid 10b, and the oil liquid 10b was purified by column chromatography to obtain 5.03 g of purified product of 29b, with a yield of 84%, and MSI-MS: 625.5 [M+Na]+. 5.99 g of compound 29b (10 mmol) was dissolved in 200 mL of methanol. Subsequently, 1. 5 g of ammonium formate (30 mmol) and 0.75 g of 10% Pd-C were added, and the reaction mix ture was stirred at room temperature for 10 minutes, and then heated and refluxed for 45 minutes. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to be dry to obtain 4.41 g of compound 29c, with a yield of 95%. The 29c was used as a raw material to pr epare a compound 29 by deprotection according to the method of 1c in Embodiment 1, with a yie Id of 90%. Detection results of the prepared compound 29 were as follows: 'll NMR (400 MHz, DMSO-d6) 8 8.89 (s, 2H), 8.58 (s, 1H), 8.37 (s, 1H), 7.05 (s, 2H), 6.73 (d, 1H), 5.01 (m, 1H), 4. 92 (s, 1H), 4.27 (m, 1H), 3.75 (m, 1H), 3.56-3.47 (m, 2H), 2.38 (m, 1H), 2.13 (m, 1H), 1.89 (m, 1H), 0.98 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 8 172.1, 156.0, 152.3, 149.5, 140.1, 119.4, 102.2, 82.5, 74.4, 63.7, 59.5, 33.1, 30.5, 19.1. MSI-MS: 351.3 [M+H]+. Embodiment 30: 2-(6-amino-9H-purin-9-yl)-5-(phosphonoxy)methyl)tetrahydrofuran-3-yl valine salt A compound 29 was used as a raw material to prepare a compound 30 by reaction accordin g to the method in Embodiment 2, wherein the lb was replaced by the 29 in equivalent amount t o prepare the compound 30, with a yield of 84%. Detection results of the prepared compound 30 were as follows: 'H NMR (400 MHz, DMSO-d6) 6 8.90 (s, 2H), 8.56 (s, 1H), 8.33 (s, 1H), 7.04 (s, 2H), 6.75 (d, 1H), 5.00 (m, 1H), 4.27-4.02 (m, 5H), 3.73 (m, 1H), 2.36 (m, 1H), 2.16 (m, 1 H), 1.88 (m, 1H), 0.96 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 8 172.4, 156.3, 152.5, 149.8, 14 0.2, 119.5, 101.2, 76.1, 74.2, 68.7, 59.3, 32.1, 30.4, 19.0. MSI-MS: 431.3 [M+H]+. 17 03 25 Embodiment 31: 2-(6-(isonicotinamide)-9H-purin-9-yl)-5-(phosphonyl)methyl)tetrahydrofuran-3-yl valin e salt A compound 30 was used as a raw material to prepare a compound 31 according to the pre paration method in Embodiment 12, wherein the la was replaced by the compound 30 in equivale nt amount, with a yield of 91%. Detection results of the prepared compound 31 were as follows: 'H NMR (400 MHz, DMSO-d6) 8 11.08 (s, 1H), 8.92 (s, 2H), 8.82 (d, 2H), 8.34 (s, 1H), 8.20 (s, 1H), 8.02(d, 2H), 6.73 (d, 1H), 5.03 (m, 1H), 4.29-4.01 (m, 5H), 3.75 (m, 1H), 2.39 (m, 1H), 2.15 (m, 1H), 1.88 (m, 1H), 0.97 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 8 171.4, 164.5, 152. 3, 151.1, 149.9, 149.7, 140.5, 140.1, 123.7, 121.5, 101.7, 77.1, 74.5, 68.2, 59.8, 32.4, 30.8, 19.2. MSI-MS: 558.4 |M+Na]\ Embodiment 32: (((5-(6-(isonicotinamide)-9H-purine-9-yl)-4-(pentoxy)tetrahydrofuran-2-yl)methoxy)met hyl)phosphonic acid o 29 32a A compound 29 was used as a raw material to prepare a compound 32a according to the pr eparation method in Embodiment 3, wherein the compound lb was replaced by the compound 29 in equivalent amount, with a yield of 77%. The compound 32a was used as a substrate to prepare a compound 32 according to the preparation method in Embodiment 12, wherein the la was repl aced by the compound 32a in equivalent amount, with a yield of 90%. Detection results of the pr epared compound 32 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 11.05 (s, 1H), 8.91 (s. 2 H), 8.84 (d, 2H), 8.35 (s, 1H), 8.18 (s, 1H), 8.01 (d, 2H), 6.75 (d, 1H), 5.01 (m, 1H), 4.81 (s, 2 H), 4.24 (m, 1H), 3.95 (m, 1H), 3.73 (d, 2H), 3.60-3.35 (m, 2H), 2.37 (m, 1H), 2.14 (m, 1H), 1. 89 (m, 1H), 0.96 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 5 171.5, 165.5, 152.4, 151.1, 149.8, 1 40.7, 140.1, 123.5, 121.7, 102.7, 76.8, 76.6, 75.5, 74.3, 59.5, 32.5, 30.5, 18.9. MSI-MS: 550.4 [M +H]t Embodiment 33: methyl(((2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(pheno xy (phosphon 1 (alanine salt 17 03 25 A compound 1c was used as a raw material to prepare a compound 33a according to the pr eparation method in Embodiment 6, wherein the compound lb was replaced by the compound 1c i n equivalent amount, with a yield of 62%, and a compound 33 was prepared by reacting the 33a according to the deprotection solution of 1c in Embodiment 1, with a yield of 90%. Detection res ults of the prepared compound 33 were as follows: !H NMR (400 MHz, DMSO-d6) 5 8.58 (s. 1 H), 8.33 (s, 1H), 7.42 (m, 2H), 7.21 (m, 3H), 7.08 (s, 2H), 6.15 (d, 1H), 5.00 (m, 1H), 4.02 (m, 1H), 3.71-3.48 (m, 8H), 2.24-1.98 (m, 2H), 1.25 (d, 3H). 13C NMR (100 MHz, DMSO-d6) 8 17 2.1, 156.1, 152.4, 149.9, 149.6, 140.3, 131.0, 121.5, 120.2, 119.6, 101.8, 82.1, 74.3, 63.4, 52.1, 46. 2, 32.5, 19.2. MSI-MS:439.4 [M+H]+. Embodiment 34: methyl(((5-(hydroxymethyl)-2-(6-(isonicotinamide)-9H-purin-9-yl)tetrahydrofuran-3-yl) oxy)(phcnoxy (phosphoryl (alanine salt 17 03 25 A compound 33a was prepared according to the process in Embodiment 33, and the 33a was used as a raw material to prepare a compound 34 according to the preparation method in Embod iment 12, wherein the la was replaced by the compound 33a in equivalent amount, with a total y ield of 83%. Detection results of the prepared compound 34 were as follows: ’H NMR (400 MHz, DMSO-d6) 5 11.02 (s, 1 H), 8.81 (d, 2H), 8.34 (s, 1H), 8.17 (s, 1H), 8.02 (d, 2H), 7.41 (m, 2 H), 7.23 (m, 3H), 6.16 (d, 1H), 4.98 (m, 1H), 4.01 (m, 1H), 3.78-3.47 (m, 8H), 2.25-1.97 (m, 2 H), 1.27 (d, 3H). 13C NMR (100 MHz, DMSO-d6) 5 171.4, 163.8, 152.1, 151.5, 150.4, 149.8, 14 9.7, 140.8, 140.5, 130.2, 122.5, 121.7, 121.2, 119.9, 102.4, 82.5, 74.5, 63.5, 51.7, 46.3, 32.7, 19.4. MSI-MS:598.5 [M+H]+. Embodiment 35: (5-(2-((E)-2-bromocarbonyl)-6-(isonicotinamide)-9H-purin-9-yl)-4-hydroxytetrahydrofu 2.51 g (10 mmol) of cordycepin was dissolved in dilute nitric acid, heated to 110°C, and add ed with 1.26 g (5 mmol) of elemental iodine for reaction for 4 hours, and the reaction was monit ored by TLC. The mixture was extracted with petroleum ether after the reaction, a water phase w as collected, an organic phase solution was extracted with deionized water, and water phases were 17 03 25 combined for rot an evaporation to obtain a compound 35a, with a weight of 2.72 g, and a yield of 72%, and MSI-MS: 378.2 [M+H]+. 100 mL of anhydrous 1,4-dioxane was added into a reactor, introduced with argon for protect! on, heated to 70°C, added with 0.11 g (0.5 mmol) of palladium acetate, 0.26 g (1 mmol) of triph enylphosphine and 1.8 mL of triethylamine in sequence, and stirred for about 30 minutes. 3.77 g (10 mmol) of compound 35a and 2.59 g (30 mmol) of methyl acrylate were added, the reaction was carried out at 80°C for 2 hours and then finished, the mixture was filtered, and the filtrate w as collected, allowed to stand, and then filtered again to obtain a white flocculent solid, which wa s a compound 35b, with a weight of 2.41 g, and a yield of 72.7%, and MSI-MS: 336.4 [M+H]+. 1.00 g of compound 35b was dropwise added with 12 mL of sodium hydroxide solution (2 mol / L), stirred at room temperature for 3 hours, and then dropwise added with concentrated hydro chloric acid in ice bath until a pH value was 1. At the moment, a large number of white precipit ates were generated. A white solid 35c was obtained by suction filtration, with a weight of 0.88 g, and a yield of 92%, and MSI-MS: 322.6 |M+H|\ 3.21 g (10 mmol) of compound 35c was added into 120 mL of water, heated to 100°C and s tirred, and then added with 2.07 g (15 mmol) of anhydrous potassium carbonate, 2.67 g (15 mmol) of NBS was dissolved in 22.5 mL of acetone and 22.5 mL of water respectively, and the mixed solution was dropwise added into a flask, which was finished within 135 minutes. The mixture w as stirred for 3 hours, the reaction was stopped, a half of the solvent was removed, and the remai ning solution was placed in a refrigerator overnight. A large number of needle-like brown crystals were precipitated and subjected to suction filtration to obtain a compound 35d, with a weight of 1. 78 g. and a yield of 50%, and MSI-MS: 357.3 [M+H]+. 1.78 g (5 mmol) of compound 35d was added with 40.00 mL of anhydrous pyridine and 8.5 mL of acetic anhydride in ice bath. The reaction was monitored by HPLC, and the reaction was e nded after reacting for about 5 hours. The solvent was removed to obtain a viscous liquid 35e, wi th a weight of 1.76 g, and a yield of 80%. The compound 35e was prepared into a compound 35 f by the method in Embodiment 16, with a yield of 95%; and the compound 35f was prepared in to a compound 35 by the phosphorylation method in Embodiment 2 and the deprotection method i n Embodiment 1, with a yield of 72%. Detection results of the prepared compound 35 were as fo Hows: ’H NMR (400 MHz, DMSO-d6) 8 11.05 (s, 1H), 8.84 (d, 2H), 8.31 (s, 1H), 8.02 (d, 2H), 7.11 (d, 1H), 6.70 (d,lH), 6.11 (d, 1H), 5.35 (s, 1H), 4.31-4.02 (m, 5H), 3.76 (m, 1H), 2.07-1.84 (m, 2H). 13C NMR (100 MHz, DMSO-d6) 8 164.5, 152.6, 151.8, 149.8, 149.7, 140.9, 140.3, 134. 5, 124.3, 123.4, 121.5, 98.5, 74.5, 74.3, 68.5, 34.7. MSI-MS: 542.2 |MlH|. Embodiment 36: 3-((5-(6-amino-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-y I (methoxy)-5-(hyd roxymethyljcyclopentane-1,2-diol OTBS H0 A compound 17a was prepared according to the method in Embodiment 17, and the 17a was used as a raw material to prepare a compound 36a according to the preparation method in Embo diment 8, wherein 2-chloro-3-hydroxypropyl valine was replaced by 3-chloro-5-(hydroxymethyl)cyclo pentane-1,2-diol in equivalent amount, and a compound 36 was prepared after deprotecting the co mpound 36a, with a total yield of 41%. Detection results of the prepared compound 36 were as f ollows: ’H NMR (400 MHz, DMSO-d6) 8 8.37 (s, 1H), 7.01 (s, 2H), 6.15 (d, 1H), 5.92 (s, 1H), 5.37 (d, 1H), 4.38 (s, 1H), 4.25 (s, 1H), 4.02 (m, 2H), 3.84 (m, 1H), 3.65-3.31 (m, 6H), 2.07-1.8 2 (m, 2H), 1.70-1.44 (m, 3H). 13C NMR (100 MHz, DMSO-d6) 8 156.1, 153.5, 149.8, 140.3, 119. 5, 99.2, 83.5, 81.2, 76.2, 75.7, 74.8, 73.1, 64.1, 34.9, 34.7, 31.5. MS1-MS: 416.8 [M+H]+. Embodiment 37: preparation of compound: (((((5-(6-amino-9H-purine-9-yl)-2-azide-4-hydroxytetrahydr ofuran-2-yl)methoxy)methyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2- dimethylpropionic acid), with a preparation process as follows. 1b 37a 37b 17 03 25 3.65 g (10 mmol) of compound lb and 3.44 g (20 mmol) of m-chloroperoxybenzoic acid we re added into a reaction flask, added with 100 mL of anhydrous dichloromethane for dissolution, a nd additionally added with 2.13 g (15 mmol) of phosphorus pentoxide in ice bath, and the reactio n was gradually subjected to temperature rise to 40°C for 3 hours. The mixture was filtered after the reaction, added with 100 mL of saturated sodium bicarbonate for a quenching reaction, additio nally washed with 50 mL of dichloromethane twice, and reversely extracted with 60 mL of saturat ed sodium bicarbonate twice, organic phases were combined, concentrated under a reduced pressure, and subjected to column chromatography to obtain a compound 37a, with a weight of 1.49 g, an d a yield of 41%. The prepared compound was detected as follows: 'H NMR (400 MHz, DMSO-d6) 3 8.56 (s, 1H), 8.36 (s, 1H), 7.10 (s, 2H), 6.16 (d, 1H), 4.02 (s, 1H), 2.75-2.45 (m ,2H), 2.1 3 (d ,2H), 0.99 (s, 9H), 0.22 (s, 6H). 13C NMR (100 MHz, DMSO-d6) 8 156.5, 152.5, 149.8, 14 0.4, 119.6, 102.5, 85.9, 69.3, 52.7, 42.5, 30.8, 25.8, 0. MSLMS: 364.5 [M+H]+. 3.63 g (10 mmol) of compound 37a and 2.6 g (40 mmol) of sodium azide were added into a flask, and additionally added with 20 mL of DMF as a solvent, the reaction was carried out at 120°C for 16 hours, and the reaction was monitored by a TLC plate. Water was added for quench ing after the reaction, a water phase was extracted with ethyl acetate (180 mL) thrice, organic pha ses were combined, and washed with water, and the solvent was removed under a reduced pressur e to obtain a foamed solid 37b, with a weight of 2.77 g, and a yield of 68%. The 37b was used as a raw material to prepare a compound 37 according to the preparation method of the compou nd 17 from the compound 17a in Embodiment 17, wherein the compound 37b was replaced by th e 17a in equivalent amount, with a total yield of 50%. Detection results of the prepared compoun d 37 were as follows: *H NMR (400 MHz, DMSO-d6) 8 8.58 (s, 1H), 8.34 (s, 1H), 7.07 (s, 2H), 6.82(d, 4H), 6.15 (d. 1H), 5.34 (d, 1H), 4.02 (m, 1H), 3.84 (d, 2H), 3.61-3.42 (m, 2H), 2.11-1.8 0 (m, 2H), 1.28(d, 18H). 13C NMR (100 MHz, DMSO-d6) 8 175.2, 156.3, 152.6, 149.9, 140.2. 11 9.4, 100.3, 93.1, 90.2, 81.0, 71.5, 68.8, 38.6, 36.2, 27.4. MSLMS: 637.6 [M+Na]+. Embodiment 38: preparation of compound: (5-(6-amino-2-((E)-2-bromocarbonyl)-9H-purine-9-yl)-4-hy droxytetrahydrofuran-2-yl)dihydromethyl phosphate, with a reaction process as follows. 2 A compound 2 was used as a raw material to prepare a compound 38 from the compound 2 according to the method in Embodiment 35, with an overall yield of 24%. Detection results of th e prepared compound 38 were as follows: 'H NMR (400 MHz, DMSO-d6) 8 8.35 (s, 1H), 7.09 (d, 1H), 6.95 (s, 2H), 6.68 (d, 1H), 6.15 (d, 1H), 5.35 (s, 1H), 4.27-4.02 (m, 5H), 3.74 (m, 1H), 2.07-1.84(m, 2H). 13C NMR (100 MHz, DMSO-d6) 3 156.1, 152.3, 149.8, 140.2, 134.9, 124.2, 11 9.5, 98.7, 74.9, 74.3, 68.1, 34.5. MS1-MS: 458.3 IM+N]+. Embodiment 39: preparation of compound: (5-(6- amino-8-(isopropylamino)-9H-purin-9-yl)-4-hydroxy tetrahydrofuran-2-yl)dihydromethyl phosphate, with a preparation process as follows. 17 03 25 A compound lb was used as a raw material to prepare a compound 39. 3.65 g (10 mmol) o f compound lb and 1.18 g (20 mmol) of 2-propylamine were added into a reaction flask first, an d added with 60 mL of dioxane as a solvent, the mixture was refluxed at 80°C for reaction for 2 0 hours, and the reaction was monitored by TLC. The reaction solution was concentrated after the reaction, and then added with 50 mL of water and 50 mL of ethyl acetate for extraction twice, organic phases were combined, and concentrated under a reduced pressure to obtain an oil liquid, and the oil liquid was purified by column chromatography to obtain a light yellow oil liquid, whic h was a compound 39a, with a weight of 1.44 g and a yield of 34%. The compound 39a was used as a raw material to prepare a compound 39 according to the preparation method in Embodiment 2, wherein the lb was replaced by the 39a in equivalent amou nt, with a yield of 91%. Detection results of the prepared compound 39 were as follows: 'H NM R (400 MHz, DMSO-d6) 8 8.15 (s, 1H), 7.05 (s, 2H), 6.15 (d, 1H), 5.98 (s, 1H), 5.38 (s, 1H), 4. 28-3.95 (m, 6H), 3.75 (m, 1H), 2.05-1.81 (m, 2H), 1.18 (d, 6H). 13C NMR (100 MHz, DMSO-d6) 8 153.1, 152.3, 151.5, 149.8, 118.5, 99.7, 74.8, 74.5, 68.5, 46.5, 34.3, 23.5. MSI-MS: 389.3 [M+ H]+. Embodiment 40: preparation of compound: 3-((5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl (methoxy )-5-(hydroxymcthyl)cyclopcntanc-1.2-dioL with a preparation process as follow s. A compound lb was used as a raw material to prepare a compound 40 according to the prep aration method in Embodiment 8, wherein 2-chloro-3-hydroxypropyl valine was replaced by 3-chlor o-5-(hydroxymethyl)cyclopentane-l,2-diol in equivalent amount, with a total yield of 46%. Detection results of the prepared compound 40 were as follows: ’H NMR (400 MHz, DMSO-d6) 8 8.58 (s, 1H), 8.37 (s, 1H), 7.04 (s, 2H), 6.15 (d, 1H), 5.91 (s, 1H), 5.37 (d, 1H), 4.37 (s, 1H), 4.25 (s, 1H), 4.00 (m, 2H), 3.82 (m, 1H), 3.63-3.32 (m, 6H), 2.08-1.81 (m, 2H), 1.71-1.45 (m, 3H). 13C N MR (100 MHz, DMSO-d6) 5 156.3, 153.4, 149.7, 140.2, 119.4, 99.5, 83.4, 81.1, 76.1, 75.5, 74.9, 73.6, 64.4, 34.9, 34.7, 31.6. MSI-MS: 382.3 [M+H]+. 17 03 25 Embodiment 41: Anti-tumor experimental effect of modified derivative of cordycepin on liver canc er A mouse transplanted liver cancer model was established and a dnig was evaluated. 2.5x10'' Hep-1-6 liver cancer cells were suspended in 100 pL of PBS to be inoculated into an outer side of thigh of left lower limb of C57BL / 6j nude mice. One week later, wEen the transplanted tumor reached about 100 mm3, the mice were randomly divided into 12 groups, with 10 mice in each gr oup, comprising a blank group, a cordycepin control group and drug groups (compounds 2, 3, 5, 7, 15, 24, 27, 31, 35, and 40). The blank group was intragastrically administrated with a nutrition al agent such as a com steep liquor and DMSO as a solvent control every other day, and the cor dycepin control group and the drug groups were intragastrically administrated with a compound dr ug (500 ug / time / animal) respectively every other day, and the groups were continuously observed f or 14 days. Changes of tumor sizes of liver tumors in the two groups of mice were observed, the mice were killed after the experiment, blood and corresponding tissue samples were collected, tu mor bodies were immediately photographed and weighed, and some tumor tissues were fixed in a formalin solution to be further detected. Two vertical diameters (length and width) of the transplan ted tumor were measured with a caliper every two days to calculate a size of the transplanted tu mor. Experimental results of changes of tumor volumes and tumor results treated in the blank gro up, the cordycepin control group and the drug groups within 14 days were shown in FIG. 1. The volume was calculated according to formula: tumor volume (mm3) = 1 / 2* (lengthxwidth)2. The ex perimental results show that the separate use of the drug groups can obviously inhibit the growth of tumors in mice, with an effect better than that of the cordycepin control group, wherein the co mpound 24 has an excellent anti-tumor effect (reduced from 900 mm3 to <100 mm3)(P<0.001), ind icating that the compound drug groups have an efficacy of killing the liver cancer cells or an effi cacy of activating tumor immunity. Embodiment 42: Anti-tumor experimental effect of modified derivative of cordycepin on small cell lung cancer Anti-tumor dose-effect relationship curves of cordycepin and compounds 1, 2, 4, 5, 7, 8, 10, 12, 16, 18, 21, 23, 24, 35 and 38 in small cell lung cancer cell lines H1048, H446 and H69 wer e analyzed by an MTT experimental method. Calculation results of median inhibitory concentration (IC50) were summarized as shown in the table below. Results of an in-vitro anti-tumor experiment s show that, compared with the cordycepin, an effective concentration of a modified cordycepin de rivative on tumor cells is reduced, wherein the compounds 35 and 38 both have a strong killing e ffect on the three lines of cells in vitro, but the compounds also have higher toxicity, followed by the compounds 18 and 21. The IC50 values of the cordycepin in the small cell lung cancer cell 1 ines H1048 and H446 are both higher than 100 pM, with a high concentration of action, so that a large amount of drug may be needed to take effect in practical application. 17 03 25 Table 1: IC50 (pM) of compounds in three lines of small cell lung cancer cells Compound number H446 H1048 H69 Cordycepin 123.10 171.60 63.12 1 23.77 27.45 20.59 2 76.75 55.33 50.17 4 54.34 42.14 43.17 5 43.34 40.92 53.39 7 20.46 12.10 9.59 8 10.45 14.47 14.78 10 12.14 10.41 9.48 12 18.12 22.17 19.47 16 19.06 25.54 23.30 18 6.53 4.31 6.74 21 4.58 6.38 2.95 23 16.45 1 7.35 20.17 24 17.16 24.38 25.48 35 21.43 32.57 21.48 38 0.97 1.37 1.25 Embodiment 43: Determination of maximum tolerance dose of modified derivative of cordycepin to in-vivo experiment of zebrafish 240 3 dpf wild-type AB-line zebrafish were randomly selected in an 8-well plate, with 30 zeb rafish in each well, and 3 mL of fish culture water in each well, the cordycepin was diluted acco rding to a maximum lethal dose, dissolved in DMSO, and added into each well according to a co ncentration gradient (the maximum lethal dose was diluted by 100 times, in which 8 concentration gradient values were taken for the experiment), and meanwhile, a normal control group, a solvent control group G (5% glucose) and a solvent control group D (DMSO) were set. During the expe riment, the zebrafish in each group were cultured at 3 5 °C, after the zebrafish were treated to be 5 dpf with a sample to be tested, lethal and developmental malformation conditions of the zebrafish in different doses were investigated respectively, and a maximum tolerance dose (MTD) of the sa mple to be tested to normal zebrafish was determined under a concentration when survival rate>9 0% and teratogenicity<20%. The cordycepin was selected as the control group, and other compoun ds 2, 5, 6, 7, 9, 11, 13, 20, 24, 25, 28, 35, 36, 37 and 39 were selected to test the MTD to the zebrafish according to the above method. Test results were shown in Table 2. Table 2: Maximum tolerance doses (MTD) of natural products and positive control drug in zebrafi sh model Compound number MTD Compound number MTD Cordycepin 995 pM 20 120 nM 2 845 pM 24 5 pM 5 525 pM 25 12 pM 6 384 pM 28 5 pM 7 62 pM 35 25 nM 9 14 pM 36 20 nM 11 75 pM 37 170 nM 13 50 nM 39 28 pM 17 03 25 Embodiment 44: In-vivo inhibition effect of modified derivative of cordycepin on zebrafish sufferin g from small cell lung cancer Models of zebrafish bearing transplanted tumors of small cell lung cancers of H69, H446 and H1048 cells were respectively established: l><106mL suspensions of the H69, H446 and H1048 c ells were respectively prepared and placed in a serum-free cell culture medium, 5 mL of red fluor escent dye (CM-Dil) cell labeling solution was added into each milliliter of cell suspension, mixed gently and evenly, incubated at 37°C for 20 minutes, centrifuged at 1,500 rpm for 5 minutes to r emove a supernatant, and added with the serum-free culture medium again for resuspension, and th en the above steps were repeated twice to obtain a cell suspension to be labeled. The cell suspens ion was transplanted into yolk sacs of the zebrafish by micro-injection, each zebrafish was transpla nted with about 100 cells, a transplanted tumor model of a zebrafish-human small cell lung cancer sensitive strain was established, and the zebrafish injected with ovarian cancer cells were cultured to be 3 dpf at 35°C. Value-added effects of the cordycepin and the prepared compounds 2, 5, 6, 7, 9, 11, 13, 20, 24, 25, 28, 35, 36, 37 and 39 on anti-small cell lung cancer of the zebrafish in vivo were tested: when the tumor-bearing zebrafish model was inhibited to be 3 dpf, the zebrafish with good consi stency in transplanted tumor were selected under a microscope, and randomly distributed into a 6-well plate, with 30 zebrafish in each well. In the case of 3 dpf, the above compounds were dilute d according to the MTD dose, dissolved in DMSO and added into each well. Meanwhile, a norma 1 control group, a model control group and a solvent control group (DMSO) were set, with 3 mL of fish culture water in each well. After the zebrafish in each experimental group were continuou sly cultured at 35°C to be 5 dpf, 10 zebrafish in each experimental group were randomly selected, observed under a fluorescence microscope, and photographed, images were saved, and analyzed b y Nikon NIS-Elements 13.10 advanced image processing software, and fluorescence intensities (S) o f transplanted tumors of the zebrafish were calculated. Inhibition results were shown in Table 3 be low, wherein inhibition results of the control group, the cordycepin group, the compound 24 and c ompound 35 groups on H446 small cell lung cancer-transplanted zebrafish were as shown in FIG. 2. Growth inhibition effects of a Xiaoaiping injection and paclitaxel applied alone on a zebrafish-h uman ovarian cancer sensitive strain were calculated by overall fluorescence intensity according to a formula as follows: Tumor growth inhibition effect (%) = S (model control group)-S (drug group) / S (model control gr oup)*100% Table 3: Effects of various compounds on pro iferation of three cell ines in zebrafish model Compound number H69 M ± SEM (%) H446 M ± SEM (%) H1048 M ± SEM (%) Cordycepin (995 p 57.53 ± 11.08 61.19 ± 7.62 60.32 ± 4.95 M) 2 (845 pM) 63.93 ± 5.37 65.42 ± 7.45 65.74 ± 4.41 5 (125 pM) 67.70+ 6.97 75.02 ± 9.54 76.72 ± 4.55 6 (384 pM) 64.20+ 3.23 67.04 ± 4.75 71.43 ± 4.78 7 (62 pM) 68.41+ 4.22 71.30 ± 4.27 67.34 ± 4.07 9 (14 pM) 70.32 ± 6.84 76.53 ± 10.43 74.89 ± 10.52 11 (75 pM) 79.06 ± 7.43 74.37+ 4.39 87.67 ± 6.12 13 (50 nM) 64.09 ± 1.23 66.64+ 4.43 68.74 ± 5.05 20 (120 nM) 70.41+ 2.34 68.76+ 3.52 70.16 l 3.14 24 (5 pM) 68.62 ± 4.79 84.92+ 2.69 83.41 ± 5.83 25 (12 pM) 68.74 ± 3.47 66.41 ± 3.59 70.15 ±4.08 28 (5 pM) 83.55 ± 4.59 76.46 ± 8.03 99.61 ± 8.81 35 (25 nM) 69.55 ± 6.28 79.06 ± 2.28 81.91 ± 6.37 36 (20 nM) 78.36+ 4.59 76.07+ 4.16 78.37+ 4.75 37 (170 nM) 72.24+ 2.49 71.74+ 3.18 73.48+ 3.87 39 (28 pM) 64.17+ 3.16 65.65+ 4.07 68.52+ 4.14 17 03 25 Embodiment 45: Inhibition experiment effect of modified derivative of cordycepin on colon cancer A mouse transplanted colon cancer model was established and a drug was evaluated. 2.5* 106 MC-38 colon cancer cells were suspended in 100 pL of PBS to be inoculated into an outer side of thigh of left lower limb of C57BL / 6j nude mice. One week later, when the transplanted tumor reached about 100 mm3, the mice were randomly divided into seven groups, with 8 mice in each group, comprising a control group IgG, a compound 16 drug+IgG group, a PD-1 antibody treatme nt group, a CTLA4 monoclonal antibody treatment group, a compound 16 drug+PD-1 combined tre atment group and a compound 16 drug+CTLA4 monoclonal antibody combined treatment group res pectively. The control group IgG was intragastrically administrated with immunoglobulin G (IgG) (500 ug / time / animal) every day for 28 consecutive days. The cordycepin+IgG was intragastrically a dministrated with the immunoglobulin G (IgG) and the cordycepin (500 ug / time / animal in both ca ses) every day for 28 consecutive days. The compound 16 drug+IgG group was intragastrically ad ministrated with the immunoglobulin G (IgG) and a compound 16 drug (500 ug / time / animal in b oth cases) even’ day for 28 consecutive days. The antibody treatment group was intragastrically ad ministrated with an antibody (500 ug / time / animal) every 4 days for 28 consecutive days. The com pound 16 drug+antibody combined treatment group was intragastrically administrated an immunoglo bulin compound 16 drug (500 ug / time / animal) every day, and intragastrically administrated the anti body (500 ug / time / animal) every 4 days for 28 consecutive days. The mice were killed after the e xperiment, blood and corresponding tissue samples were collected, tumor bodies were immediately photographed and weighed, and some tumor tissues were fixed in a formalin solution to be further detected. Two vertical diameters (length and width) of the transplanted tumor were measured with a caliper every two days to calculate a size of the transplanted tumor, and a tumor value was ca Iculated according to a formula: tumor volume (mm3) = 1 / 2 * (lengthxwidth)2, and changes of tumor sizes of colon cancer in seven groups of mice were observed. Results were shown in FIG. 3. 28 days later, the experimental results show that the cordycepin has an anti-proliferation effect on th e colon cancer (the size is reduced from 1.300 mm3 to 730 mm3), the compound 16 used alone h as a more obvious anti-tumor growth effect than the cordycepin (the size is reduced from 1,300 m m3 to 480 mm’)(P<0.01), and immune checkpoint inhibitors PD-1 and CTLA4 used alone also hav e a significant anti-tumor growth effect (the size is reduced from 1,300 mm3 to about 448 mm3) -47- 17 03 25 (P<0.01). When the compound 16 and the immune checkpoint inhibitors PD-1 and CTLA4 are res pectively used at the same time, a synergistic effect of them can greatly improve the anti-tumor ef feet (the size is reduced from 1,300 mm’ to about 260 mm3). Embodiment 46: Inhibition experiment effect of modified derivative of cordycepin on melanoma A mouse transplanted melanoma model was established and a drug was evaluated. 2.5 IO5 Bl 6-F10 melanoma cells were suspended in 100 pL of PBS to be inoculated into an outer side of t high of left lower limb of C57BL / 6j nude mice. One week later, when the transplanted tumor reac hed about 100 mm3, the mice were randomly divided into ten groups, with 10 mice in each group, comprising a blank control group, a cordycepin group, a compound 13 group, a compound 14 gr oup, a compound 17 group, a compound 19 group, a compound 22 group, a compound 26 group, a compound 29 group and a compound 34 group respectively. The blank control group was intra gastrically administrated with a nutritional agent such as a com steep liquor and DMSO as a solv ent control even’ day for 24 consecutive days, and the compound groups were intragastrically adm inistrated with corresponding compounds (500 ug / time / animal in all cases) every other day for 24 consecutive days. Changes of melanoma sizes in the ten groups of mice were observed every 4 da ys in an early stage and every two days in a late stage. The mice were killed after the experimen t, blood and corresponding tissue samples were collected, tumor bodies were immediately photogra phed and weighed, and some tumor tissues were fixed in a formalin solution to be further detecte d. Two vertical diameters (length and width) of the transplanted tumor w ere measured with a calip er every two days to calculate a size of the transplanted tumor, and a tumor value w as calculated according to a formula: tumor volume (mm3) = l / 2x(lengthxwidth)2. Experimental results were sh own in FIG. 4. The experimental results show that the cordycepin itself can inhibit the proliferatio n of melanoma (reduced from 1760 mm3 to 600 mm3), and the modified derivative of the cordyce pin has a better effect than the cordycepin (reduced from 1760 mm3 to <560 mm3), wherein the c ompounds 19 and 34 used alone can obviously inhibit the tumor growth of the mice (reduced fro m 1760 mm3 to about 240 mm3) P<0.001). The above results suggest that the synthesized product has the effect of killing tumor cells. Embodiment 46-1: a compound 27 was used to inhibit melanoma by the above method, which had the same inhibition effect as a compound 26. Embodiment 47: Inhibition experiment effect of modified derivative of cordycepin on ovarian cance r A mouse transplanted ovarian cancer model was established and a drug was evaluated. 2.5x10 6 ID8 ovarian cancer cells were suspended in 100 pL of PBS to be inoculated into an outer side of thigh of left lower limb of C57BL / 6j nude mice. About one week later, when the transplanted tumor reached about 100 mm3, the mice were randomly divided into five groups, with 10 mice in each group, comprising a control group, a cordycepin group, a compound 24 drug group, a PD-1 +TIM3 antibody treatment group, a compound 24 drug+PD-l+TIM3 antibody treatment group respe ctively. The control group was intragastrically administrated with immunoglobulin G (IgG) (500 ug / time / animal) even7 day for 15 consecutive days. The cordycepin group was intragastrically administ rated with the cordycepin (500 ug / time / animal) every day under configuration with PBS for 15 co 17 03 25 nsecutive days. The compound 24 drug group was intragastrically administrated with the compound 24 (500 ug / time / animal) every day under configuration with PBS for 15 consecutive days. The P D-1+TIM3 antibody treatment group was intragastrically administrated with antibody PD-1+TIM3 (5 00 ug / time / animal respectively) every 4 days for 15 consecutive days. The compound 24 drug+PD-1+TIM3 antibody treatment group was intragastrically administrated an immunoglobulin compound 24 drug (500 ug / time / animal) every day, and intragastrically administrated the antibody PD-1+TIM3 (500 ug / time / animal respectively) every 4 days for 15 consecutive days. Changes of sizes of ovari an tumors in five groups of mice were observed every two days. The mice were killed after the e xperiment, blood and corresponding tissue samples were collected, tumor bodies were immediately photographed and weighed, and some tumor tissues were fixed in a formalin solution to be further detected. Two vertical diameters (length and width) of the transplanted tumor were measured with a caliper every two days to calculate a size of the transplanted tumor, and a tumor value was ca Iculated according to a formula: tumor volume (mm3) = l / 2x(length width)'. Results were shown i n FIG. 5. The experimental results show' that the cordycepin has an anti-proliferation effect on the ovarian cancer (the size is reduced by 1.5 times in 15 days), the compound 24 used alone has a more obvious anti-tumor growth effect than the cordycepin (the size is reduced by about 2 times in 15 days), and immune checkpoint inhibitors PD-1 and CTLA4 used alone also have a significa nt anti-tumor growth effect (the size is reduced by more than 2 times in 15 days). When the com pound 24 and the immune checkpoint inhibitors PD-1 and CTLA4 are respectively used at the sa me time, the anti-tumor effect can be greatly improved (the size is reduced by about 4 times in 1 5 days). Embodiment 48: Inhibition experiment effect of modified derivative of cordycepin on in-vitro-gastri c cancer cells Anti-tumor dose-effect relationship curves of the cordycepin and 40 compounds prepared in ga stric cancer cell lines AGS and BGC-823 were analyzed by an MTT experimental method. Calcula tion results of median inhibitory concentration (IC50) were summarized as shown in Table 4 below. Results of an in-vitro anti-tumor experiments show that, compared with the cordycepin, an effecti ve concentration of a modified cordycepin derivative on tumor cells is reduced. Table 4: IC50 (pM) of cordycepin and modified compounds of cordycepin in gastric cancer cells Compound AGS BGC-823 Compound AGS BGC-823 Cordycepin 372 235 21 2.46 4.38 1 81.67 64.41 22 45.04 53.73 2 142 209 23 0.89 1.31 3 86.72 61.39 24 0.13 0.09 4 64.33 86.16 25 47.56 58.47 5 72.74 91.48 26 57.41 46.58 6 66.77 73.16 T1 8.42 10.17 7 2.46 1.61 28 3.47 5.42 8 27.78 18.82 29 32.48 41.39 9 0.46 1.24 30 75.42 64.17 10 136 82.41 31 41.25 33.64 II 13.03 10.31 32 23.04 19.82 12 1.23 1.34 33 36.47 29.51 13 32.45 36.75 34 19.37 24.16 14 12.87 18.57 35 69.42 71.03 15 18.43 20.72 36 103 90.24 16 0.14 0.19 37 64.23 56.11 17 1.32 2.39 38 134 104 18 0.41 0.69 39 187 167 19 0.46 0.76 40 164 189 20 0.94 1.37 17 03 25 Embodiment 49: In-vivo tumor inhibition experimental effect of modified derivative of cordycepin on gastric cancer-mouse model A mouse transplanted gastric cancer model was established and a drug was evaluated. 2^107 BGC-823 gastric cancer cells were suspended in 100 pL of PBS to be inoculated into an anterior chest wall of C57BL / 6j nude mice, disinfection was carried out with 75% ethanol, and the most o bvious part of apical impulse was touched with hand to inoculate the cells to a left ventricle in a second intercostal space about 3 mm to the left of the sternum. About one week later, when the transplanted tumor reached about 100 mm3, the mice were randomly divided into five groups, wit h 10 mice in each group, comprising a control group, a cordycepin group, and compound 16, com pound 18 and compound 24 drug groups respectively. The control group was intragastrically admin istrated with a nutritional agent such as a com steep liquor and DMSO as a solvent control every day; the cordycepin group was intragastrically administrated with the cordycepin (500 ug / time / ani mal) every day under configuration with DMSO; and the compound dnig groups were intragastrica lly administrated with the compounds (500 ug / time / animal) every day under configuration with DM SO. The administration was carried out for 18 consecutive days. Changes of gastric tumor sizes in the five groups of mice were observed even7 two days, the mice were killed after the experiment, blood and corresponding tissue samples were collected, and tumor bodies were immediately photo graphed and weighed. Weighing experimental results were shown in FIG. 6. It can be seen from t he experimental results that the cordycepin can effectively inhibit the proliferation of gastric tumor s, which is about 4 times lower than that of the control group (reduced from 1.73 g to 0.46 g), a nd the modified cordycepin has a more obvious effect than the cordycepin, wherein the compound 24 group is about 12 times lower than that of the control group (reduced from 1.73 g to 0.14 g)- Embodiment 50: In-vivo tumor inhibition experimental effect of modified derivative of cordycepin on pancreatic cancer-mouse model A mouse transplanted pancreatic cancer model was established and a drug was evaluated: pan creatic cancer Pan02-luc cells were placed in a DMEM culture medium containing 10% fetal bovi ne serum in a CO2 incubator at 37°C. Trypsin ED-TA was subjected to digestive passage, and wa s passaged even7 2 days to 3 days. When a number of the cells reached a required number, the c ells in logarithmic growth period were resuspended with the culture medium to be lxlO7 / mL. C57 BL / 6j nude mice were fed under a pathogen-free condition, and when the mice grew to 6 weeks, 200 uL of pancreatic cancer Pan02-uc cells were subcutaneously injected into a right dorsal axil 0 f each mouse, and a transplanted tumor appeared within about one week, indicating that the model was established successfully. The mice were randomly divided into five groups, with 10 mice in each group, comprising a control group, a cordycepin group, and compound 11, compound 16 and compound 24 drug groups respectively. The control group was intragastrically administrated with a nutritional agent such as a com steep liquor and DMSO as a solvent control every day; the cor dycepin group was intragastrically administrated with the cordycepin (500 ug / time / animal) every da y under configuration with DMSO; and the compound drug groups were intragastrically administrat ed with the compounds (500 ug / time / animal) every day under configuration with DMSO. The admi nistration was continuously performed for 24 days. Subsequently, survival rates of the five groups of mice were observed every day, and median survival time was studied. Experimental results wer e shown in FIG. 7. The experimental results show that the cordycepin administrated alone has sig nificantly prolonged the survival time of the tumor-bearing mice (increased from 41 days to 52 da ys), and the compound groups further prolong the survival time of the tumor-bearing mice (increas ed from 41 days to >58 days), wherein the compound 24 has the best effect, which prolongs the survival time of the tumor-bearing mice by nearly half (increased from 41 days to 76 days). The above is only the preferred embodiments of the present invention, and it should be point ed out that those of ordinary skills in the art may further make several improvements and decorati ons without departing from the principle of the present invention, and these improvements and dec orations should also be regarded as falling within the scope of protection of the present invention as defined by the appended Claims 17 03 25

Claims

1. A cordycepin derivative, or a pharmaceutically acceptable salt thereof; wherein the cordycepinderivative is selected from the group consisting of17 03 252. A pharmaceutical composition, wherein the pharmaceutical composition comprises at least one co rdycepin derivative, or the pharmaceutically acceptable salt thereof of claim 1; and at least one immune checkpoint inhibitor, the immune checkpoint inhibitor is selected from a PD-1 and / or CTLA4 monoci onal antibody.

3. The pharmaceutical composition according to claim 2, the immune checkpoint inhibitor is selected from a PD-1 and / or CTLA4 monoclonal antibody.

4. The pharmaceutical composition according to claim 2, cordycepin derivative, or the pliarmaceutically acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.2 to 10.

5. The pharmaceutical composition according to claim 2, cordycepin derivative, or the cally acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.2 to 8.

6. The pharmaceutical composition according to claim 2, cordycepin derivative, or the cally acceptable salt thereof to the immune checkpoint inhibitor is I: 0.2 to 5.

7. The pharmaceutical composition according to claim 2, cordycepin derivative, or the cally acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.2 to 3.

8. The pharmaceutical composition according to claim 2, cordycepin derivative, or the cally acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.2 to 2.

9. The pharmaceutical composition according to claim 2, cordycepin derivative, or thepharmaceuti pliarmaceuti pharmaceuti pharmaceuti pharmaceutically acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.5 to 1.5.

10. The pharmaceutical composition according to claim 2, cordycepin derivative, or the pharmaccu tically acceptable salt thereof to the immune checkpoint inhibitor is 1: 0.8 to 1.2.

11. The pharmaceutical composition according to claim 2, cordycepin derivative, or the pharmaceutically acceptable salt thereof to the immune checkpoint inhibitor is 1: 1.

12. The pharmaceutical composition according to claim 2, a dosage form of the pharmaceutical co mposition is selected from a tablet, a pill, a capsule, a dripping pill, a syrup, a disintegrant, an injectio n. a sustained to Release agent, or a kit.

13. The cordycepin derivative, or the pharmaceutically acceptable salt thereof of claim I. or the ph armaceutical composition of claim 2 for use in the treatment of a disease related to variation caused bya cell functional damage in the human body; the disease related to the variation caused by the cell fu nctional damage is a tumor.

14. The cordycepin derivative, or the pharmaceutically acceptable salt thereof of claim 1, or the p harmaceutical composition of claim 2 for use according to claim 13, wherein the tumor is selected fro m tire group consisting of a gastric cancer, a pancreatic cancer, a liver cancer, a small cell lung cancer, a non-small cell lung cancer, a colorectal cancer, an esophageal cancer, a prostate cancer, melanoma, glioma, and an ovarian cancer.

15. The cordycepin derivative, or the pharmaceutically acceptable salt thereof of claim 1, or the p harmaceutical composition of claim 2 for use according to claim 13, wherein the tumor is selected fro m the group consisting of the gastric cancer, the pancreatic cancer, the liver cancer, the small cell lung cancer, the colorectal cancer, the melanoma and the ovarian cancer.

16. The cordycepin derivative, or the pharmaceutically acceptable salt thereof of claim 1, or the p harmaceutical composition of claim 2 for use according to claim 13. wherein the tumor is selected fro m the group consisting of the gastric cancer, the pancreatic cancer, the liver cancer, the small cell lung cancer and the ovarian cancer.

17. A preparation method of the cordycepin derivative according to any one of claims 1, wherein.17 03 25r3 r4I-R-l;in formula I-R-l, R2 to R- are the same as R2 to R? in formula I;the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the compound I-R-l with a modifier in anhydrous N,N-dimethylformamide with NaH as a catalyst; the mod ifier is as follows:a dosage ratio of the compound I-R-l to the modifier, the catalyst and anhydrous N. N-dimethylfor mamide is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 100 mL to 200 mL, a temperature of the reaction is -20°C to 0 °C.

18. The method according to claim 17, wherein a dosage ratio of the compound I-R-l to the modi fier, the catalyst and anhydrous N, N-dimethylformamide is 0.1 mol: 0.1 mol to 0.15 mol: 0.2 mol to 0.03 mol: 150 mL.

19. The method according to claim 17, wherein, the reaction lasts for 0.5 hour to 6 hours.

20. A preparation method of the cordycepin derivative according to any one of claims 1, wherein, when R5 is selected from the fluorine or the chlorine in formula I, the formula of the process comprise s: using a compound I-R-5 as a raw material for a chemical reaction in an organic solvent to prepare t he cordycepin derivative as shown in formula I;Ri^ 'T—0Fty]—17 03 25r3 r4I-R-5;in formula I-R-5, Ri to R3 and R are the same as Ri to R? and R- in formula I; R4 is selected from -OTB-OAc, -OTBDPS; R6 is the same as RI in formula I or is selected from -NHCbz.

21. The method according to claim 20, wherein, the formula I of the process comprises: subjectin g the compound I-R-5 to a nitro derivatization reaction to prepare a nitration intermediate I-R-5g, and t hen subjecting the intermediate to a substitution reaction to prepare the cordycepin derivative as shown in fonnula I;I-R-5g;in fonnula I-R-5g. Ri to R4 and Re to R? are the same as R to R4 and Re to R in formula I.

22. The method according to claim 21. wherein, the preparation method of the intermediate I-R-5g comprises: reacting the compound I-R-5 with tetrabutylammonium nitrate under catalysis of trifluoroace tic anhydride in dichloromethane.

23. The method according to claim 22, wherein, a dosage ratio of the compound I-R-5 to the tetra butylammonium nitrate, the trifluoroacetic anhydride and the dichloromethane is 1 mmol: 1.4 mmol to 2 mmol: 1 mmol to 2 mmol: 15 mL to 35 mL.

24. The method according to claim 21, wherein, the preparation method of the cordycepin derivativ e as shown in formula I comprises: reacting the nitration intermediate I-R-5g with tetrabutylammonium fluoride or tetrabutylammonium chloride in acetonitrile.

25. The method according to claim 24, wherein, a dosage ratio of the nitration intermediate I-R-5g to the tetrabutylammonium fluoride or tetrabuty lammonium chloride and the acetonitrile is 1 mmol:

1. 3 mmol to 1.5 mmol: 30 mL to 50 mL, a temperature of the reaction is -5°C to 5°C.

26. The method according to claim 24, wherein, a temperature of the reaction is 0°C.

27. The method according to claim 24, wherein, the reaction lasts for 20 minutes to 30 minutes.

28. A preparation method of the cordycepin derivative according to any one of claims 1, wherein, when Re is selected from pyridine formamido in formula I. the preparation method of the cordycepin d erivative as shown in formula I comprises: using a compound I-R-6 as a raw material for a chemical r eaction in an organic solvent to prepare the cordycepin derivative as shown in formula I;I-R-6;17 03 25in formula I-R-6, Ri to R3, Rs and R? are the same as Ri to R3, Rs and R7 in formula I; in form ula I-R-6, R4 is the same as R4 in formula I, or selected from -OTBS^ -OAc^ -OTBDPS.

29. A process according to claim 28, wherein, the preparation method of the cordycepin derivative as shown in formula I comprises: reacting the compound I-R-6 with pyridyl substituted acyl chloride.

30. The process according to claim 29, wherein, a dosage ratio of the compound I-R-6 to pyridyl substituted acyl chloride and the anhydrous pyridine is 1 mmol: 1 mmol to 2 mmol: 5 mL to 10 mL.

31. The process according to claim 29, wherein, a temperature of the reaction is 0°C to 60°C.

32. The process according to claim 29. wherein, the reaction lasts for 2 hours to 20 hours.

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