Cordycepin derivatives or a pharmaceutically acceptable salt thereof as pan-antiviral agents

Abstract

The present invention relates to a cordycepin derivative or a pharmaceutically acceptable salt thereof, where in the cordycepin derivative having a formula (I), and a use of said derivative for inhibiting viruses as a pan-antiviral agent (I) wherein, X is a heteroatom; Y is selected from hydrogen or halogen; Ar is selected from unsubstituted C6 to C20-aryl group or, C6e to C20-aryl group having one or two substituent groups; R1 is selected from hydroxyl group (OH), amide group (-CO-NH2), hydrogen (-H), amine (-NH, -NH2, or -NH3), carboxyl group (COOH) or an R group representing a nonpolar group; R2 is selected from 2-ethylbutyl group (-CH2CH(C2H5) C2H5) or tert-butyl group (- C(CH3)3) according to structure (a) and (b), respectively. The present invention modifies the structure of cordycepin into a form of nucleotide by incorporating a phosphate group having a protective group, into said structure. This modification aims to enhance the drug efficacy and cell permeability, enabling more effective viral inhibition and a rapid response to cellular changes.

Description

[0001] CORDYCEPIN DERIVATIVES OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AS PAN-ANTIVIRAL AGENTS

[0002] FIELD OF INVENTION

[0003] This invention relates to organic chemistry and biotechnology, more particularly, to a cordycepin derivative or a pharmaceutically acceptable salt thereof, as a pan-antiviral agent.

[0004] BACKGROUND OF THE INVENTION

[0005] Cordycepin, a natural product derived from cordyceps, exhibits various properties such as anti-inflammatory, anticancer, antimicrobial, and antiviral activities, particularly against RNA viruses. Several reports have mentioned its activities against influenza, plant, human immunodeficiency (HIV), and Epstein Barr viruses. When considering the chemical structure of cordycepin, it is classified in the nucleoside group with the chemical name of 3’-deoxyadenosine. Previous studies have shown that cordycepin, which is effective in inhibiting RNA synthesis of viruses, must be in the form of cordycepin-triphosphate. This compound can inhibit the activity of RNA polymerase. However, the addition of a phosphate group to the first position of cordycepin rarely occurs in cells. Also, cordycepin has limited ability to enter cells. Therefore, there are several reports indicating that using cordycepin to inhibit the production of viral RNA requires a significantly high dosage to demonstrate efficacy.

[0006] Recently, drugs belonging to the groups of nucleoside and nucleotide derivatives have been utilized in a treatment of viral infections and their development is ongoing. Examples of such drugs are anti-HIV drugs, anti-herpes and shingles drugs, anti-Ebola drugs, or anti-C0VID19 drugs. The development of nucleoside drugs consisting solely of nucleic acid and sugar, has led to the emergence of a new generation of nucleotide -based drugs. This includes the addition of a phosphate group to enhance efficacy and promote better cell permeability. The technology for designing and synthesizing latest generations of antiviral drugs is expected to integrate phosphate groups into the molecular structure.

[0007] The present invention studies and modifies the structure of cordycepin into a nucleotide form by incorporating a phosphate group having a protective group in the cordycepin structure in order to enhance the drug efficacy and their cell permeability. Consequently, these modifications facilitate the more effective inhibition of viruses, enabling a rapid response to cellular changes. SUMMARY OF THE INVENTION

[0008] The present invention relates to a cordycepin derivative of Formula I, or a pharmaceutically acceptable salt thereof, and a use of said derivative for inhibiting viruses as a pan-antiviral agent wherein:

[0009] X is a heteroatom;

[0010] Y is selected from hydrogen or halogen;

[0011] Ar is selected from unsubstituted C6to C20-aryl group or, C6to C20-aryl group having one or two substituent groups;

[0012] R1is selected from hydroxyl group (OH), amide group (-CO-NH2), hydrogen (-H), amine (-NH, -NH2, or -NH3), carboxyl group (COOH) or an R group representing nonpolar group;

[0013] R2is selected from 2-ethylbutyl group (-CH2CH( C2H5) C2H5) or tert-butyl group (- C(CH3)3) according to structure (a) and (b), respectively.

[0014] The objective of the present invention is to study and modify the structure of cordycepin into a form of nucleotide by incorporating a phosphate group having a protective group, into said structure. This modification aims to enhance the drug efficacy and cell permeability, enabling more effective viral inhibition and a rapid response to cellular changes.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 shows a proposed mechanism of metabolic pathway of BION-157 and BION-158.

[0017] Figure 2 shows an ester hydrolysis by carboxypeptidase enzyme; Y type of BION-157.

[0018] Figure 3 shows an ester hydrolysis by carboxypeptidase enzyme; Y type of BION-158.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention relates to a novel cordycepin derivative or a pharmaceutically acceptable salt thereof, including a use of said cordycepin derivative for inhibiting viruses as a pan-antiviral agent, which will be detailed in the following description.

[0021] Any aspects described herein shall encompass modification to other aspects of this invention, unless stated otherwise.

[0022] Technical terms or scientific terms used herein are defined to the understanding of persons skilled in the art, unless stated otherwise. Any apparatus, equipment, methods, or chemicals named here refer to apparatus, equipment, methods, or chemicals being commonly operated or used by persons skilled in the art, unless stated otherwise. Any mention of equipment, apparatus, methods, or chemicals specifically used in this invention will be clearly specified.

[0023] When the term “comprising” is used in the claims or the specification, singular or plural nouns should be interpreted as “one” or “one or more,” “at least one,” and “one or more than one.”

[0024] All compositions and / or methods disclosed and claimed in this application are intended to encompass variations involving any actions, operations, modifications, or adjustments to any parameters, provided that they do not significantly deviate from experiments conducted, examples provided, or data presented in this invention and they achieve similar objectives, utilities and results as described in the present invention, as understood by persons skilled in the art although without specifically stated in claims. Therefore, substitutable or similar modifications to the present invention, including any minor modifications or adjustments that are apparent to persons skilled in the art should be construed as remains in spirit, scope, and concept of invention as appeared in appended claims.

[0025] Throughout this application, term “about” refers to any value appeared or presented herein that may vary or deviate due to factors such as equipment deviation, methodological error, or differences between individual operators implementing the apparatus or methods.

[0026] Hereafter, following embodiments of the present invention are presented without intending to limit the scope of the invention in any manner.

[0027] In one embodiment of the invention, the present invention relates to a cordycepin derivative or a pharmaceutically acceptable salt thereof, as a pan-antiviral agent, wherein said cordycepin derivative for use as a pan-antiviral agent has a Formula I wherein

[0028] X is a heteroatom;

[0029] Y is selected from hydrogen or halogen;

[0030] Ar is selected from unsubstituted C6to C20-aryl group or, C6to C20-aryl group having one or two substituent groups; R1is selected from hydroxyl group (OH), amide group (-CO-NH2), hydrogen (-H), amine (-NH, -NH2, or -NH3), carboxyl group (COOH) or an R group representing a nonpolar group;

[0031] R2is selected from 2-ethylbutyl group (-CH2CH(C2H5) C2H5) or tert-butyl group (- C(CH3)3) having structure (a) and (b), respectively.

[0032] Notes C6to C20-aryl group represents an aryl group having carbon 6 to 20 atoms.

[0033] In a preferred exemplary embodiment of the invention, X is selected from oxygen or sulfur.

[0034] In a preferred exemplary embodiment of the invention, Y is selected from hydrogen, fluorine, chlorine, bromine, or iodine.

[0035] In a preferred exemplary embodiment of the invention, Ar is selected from phenyl, 1- naphthyl, 2-naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3 -bromophenyl, or 4-bromophenyl.

[0036] In a preferred exemplary embodiment of the invention, R1is selected from methyl, methylethyl, 1 -methylpropyl, 2-methylpropyl, or benzyl.

[0037] In a particularly preferred exemplary embodiment of the invention, X is oxygen.

[0038] In a particularly preferred exemplary embodiment of the invention, Y is hydrogen or fluorine.

[0039] In a particularly preferred exemplary embodiment of the invention, Ar is phenyl.

[0040] In a particularly preferred exemplary embodiment of the invention, R1is methyl.

[0041] In an exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is in a diastereomer form selected from diastereomer mixture of Sp-isomcr and Rp-isomer, diastereomer of pure Sp-isomer, or diastereomer of pure Rp-isomer.

[0042] In a preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is in the diastereomer form of pure Sp-isomer.

[0043] In a preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is in the diastereomer form of pure Rp-isomer. In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is tert-butyl ((S)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

[0044] In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is tert-butyl ((R)-(((2S,4R,5R)-5-( 6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2 - yl)methoxy) (phenoxy )pho sphory 1) -L-alaninate .

[0045] In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is 2- ethylbutyl ((S)-(((2S,4R,5R)-5 - ( 6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2 - yl) methoxyXphenoxy) phosphoryl)-L-alaninate.

[0046] In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is 2- ethylbutyl ((R)-(((2 S,4 R,5 R)-5 - ( 6 - amino-9 H-purin-9 - yl)-4 - hydroxytetrahydrofuran-2 - yl) methoxyXphenoxy) phosphoryl)-L-alaninate.

[0047] In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is 2 - ethylbutyl ((S )-(((2 S ,4 R, 5 R)-5 - (6 - amino-2 - fluoro-9 H-purin-9 - yl)-4 -hydroxytetrahydrofuran-2 - yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

[0048] In a particularly preferred exemplary embodiment of the invention, the cordycepin derivative or pharmaceutically acceptable salt thereof, as a pan-antiviral agent which is 2 - ethylbutyl ((R)-(((2S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate.

[0049] In an embodiment of the invention, the present invention also relates to a use of the cordycepin derivative or pharmaceutically acceptable salt thereof according to the present invention for manufacture of a pan-antiviral agent.

[0050] In an embodiment of the invention, the present invention also relates to a use of the cordycepin derivative or pharmaceutically acceptable salt thereof according to the present invention for manufacture of a medicament in a form of tablets, injections, or spays. EXAMPLES

[0051] Examples of synthesizing cordycepin derivatives according to the present invention are shown in a diagram below. The synthesis method is known to a person skilled in the art.

[0052] Synthesis diagram 1

[0053] Synthesis diagram 2

[0054] Step 1 Addition reaction of silyl protecting group to hydroxy group

[0055] About 1 part of cordycepin, about 3.3 parts of tert-butyldimethylsilyl chloride, and about 6.6 parts of imidazole in a 3 -neck round bottom flask were added with dimethylformamide to obtain a volume of about 2.3 mL / mmol of starting material. The reaction mixture was stirred at room temperature under a nitrogen atmosphere. Upon completion of the reaction, a saturated solution of ammonium chloride with a volume of approximately 7.5 mL per millimole of the starting material was added. The resulting mixture was then subjected to extraction five times with ethyl acetate. The organic layer was dehydrated by adding sodium sulfate. The organic solvent was subsequently evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of dichloromethane: methanol in a range of 100: 0 to 95: 5. The resulting product appeared as a white solid.

[0056] Step 2 Deprotection of silyl protecting group on primary hydroxy group

[0057] About 1 part of Compound (3) was dissolved in tetrahydrofuran about 6 mL / mmol of starting material at 0 °C. A mixed solvent of trifluoroacetic acid: water in a ratio of 1: 1 with a volume of about 3 mL / mmol of starting material was then added, and the reaction mixture was stirred at about -5 to 0 °C. Upon completion of the reaction, the pH of the reaction was adjusted to 7 by adding dropwise of saturated solution of sodium hydrogen carbonate. The reaction mixture was then subjected to extraction with ethyl acetate 3 times. The organic layer was separated, and moisture was removed by adding sodium sulfate. The organic solvent was subsequently evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of dichloromethane: methanol in the range of 100: 0 to 90: 10. The resulting product appeared as a white solid. Step 3 Phosphorylation reaction

[0058] A mixture of about 1 part of Compound (4), about 1.5 parts of phosphoramidate derivative, and about 1.5 parts of magnesium chloride in tetrahydrofuran (about 5 mL / mmol of starting material) was stirred at 50 °C for 10 min. Subsequently, about 2.5 parts of N, N- diisopropylethylamine was added to the reaction mixture, and stirring continued at 50 °C. Upon completion of the reaction, the reaction mixture was subjected to extraction with ethyl acetate 3 times and washed with the saturated solution of sodium chloride 1 time. The organic layer was then evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of dichloromethane: methanol in the range of 100: 0 to 100: 2. The resulting product appeared as a white solid.

[0059] Step 4 Deprotection of silyl protecting group on secondary hydroxy group

[0060] About 1 part of Compound (5) was dissolved in tetrahydrofuran with a volume of about 4.5 mL / mmol of the starting material at 0 °C. A mixed solvent of trifluoroacetic acid: water in the ratio of 1: 1 with a volume of about 9 mL / mmol of starting material was then added, and the reaction mixture was stirred at 0 °C. Upon completion of the reaction, the solvent was evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of ethyl acetate: methanol in the range of 100: 0 to 95: 5. The resulting product appeared as a white solid.

[0061] Step 5 Separation of diastereomer mixture

[0062] Compound (6) was separated into diastereomer using chiral column chromatography technique employing puriFlash® 5.250, interchim with Lux5 micromolar Cellulose-2 column, LC Column 250 x 21.2 mm using a mixed mobile phase of acetonitrile: methanol or acetonitrile: water.

[0063] Example 1

[0064] 2’-O-(tert-butyldimethylsilyl)cordycepin (4) a) 2’,5’-bis-Q-(tert-butyldimethylsilyl)cordycepin

[0065] About 5 g of cordycepin (19.9 mmol), about 9.90 g of tert-butyldimethylsilyl chloride (65.67 mmol), and about 8.94 g of imidazole (131.34 mmol) in a 3-neck round bottom flask were added with about 46 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Subsequently, about 150 mL of saturated solution of ammonium chloride was introduced. The resulting mixture was then subjected to extraction with ethyl acetate 5 times. The organic layer was separated, and moisture was removed by adding sodium sulfate. The organic solvent was subsequently evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of dichloromethane: methanol (100: 0 to 95: 5). The resulting product appeared as a white solid yielded about 8.63 g (90%):1H NMR (500 MHz, DMSO-de): 8 (ppm) 8.30 (s, 1H), 8.13 (s, 1H), 7.29 (br s, 2H), 5.88 (d, J = 2.3 Hz, 1H), 4.73 - 4.67 (m, 1H), 4.43 - 4.35 (m, 1H), 3.94 (dd, J = 11.5, 3.0 Hz, 1H), 3.76 (dd, J = 11.5, 3.6 Hz, 1H), 2.33 - 2.25 (m, 1H), 1.96 - 1.89 (m, 1H), 0.88 (s, 9H), 0.82 (s, 9H), 0.06 (s, 6H), 0.00 (s, 3H), -0.00 (s, 3H);13C NMR (126 MHz, DMSO-J6): 6 (ppm) 155.99, 152.61, 148.97, 138.25, 118.91, 90.31, 80.08, 76.52, 63.93, 33.99, 25.84, 25.55, 18.09, 17.64, -5.03, -5.14, -5.45, -5.47. b) 2’-O-(tert-butyldimethylsilyl)cordycepin

[0066] About 6.52 g of 2’,5’-bis-O-(tert-butyldimethylsilyl)cordycepin (13.6 mmol) was dissolved in about 81.6 mL of tetrahydrofuran at 0 °C. A mixed solvent of trifluoroacetic acid: water in the ratio of 1: 1 with a volume of about 40.8 mL was then added. The reaction mixture was stirred at about -5 to 0 °C for about 4 hours. Subsequently, the pH of the reaction mixture was adjusted to 7 by adding dropwise a saturated solution of sodium hydrogen carbonate. The reaction mixture was then subjected to extraction with ethyl acetate 3 times. The organic layer was separated, and moisture was removed by adding sodium sulfate. The organic solvent was subsequently evaporated under low pressure. The obtained crude product was purified by column chromatography using a mixed mobile phase of dichloromethane: methanol in the range of 100: 0 to 90: 10. The resulting product appeared as a white solid yielded about 3.98 g (80%):1H NMR (500 MHz, DMSO-de): 8 (ppm) 8.38 (s, 1H), 8.14 (s, 1H), 7.32 (br s, 2H), 5.84 (d, J = 3.0 Hz, 1H), 5.30 - 5.23 (m, 1H), 4.79 - 4.73 (m, 1H), 4.39 - 4.31 (m, 1H), 3.72 (d, J = 12.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 2.32 - 2.24 (m, 1H), 1.97 - 1.90 (m, 1H), 0.81 (s, 9H), -0.03 (s, 3H), -0.05 (s, 3H);13C NMR (126 MHz, DMSO-J6): 8 (ppm) 156.04, 152.44, 148.80, 139.06, 119.15, 90.63, 80.36, 75.84, 62.56, 34.37, 25.54, 17.63, -5.10, -5.16. Example 2 (BION-157 and BION-158)

[0067] 2-ethylbutyl ((S)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methoxy) (phenoxy )phosphoryl)-L-alaninate (BION-157) and

[0068] 2-ethylbutyl ((R)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2- yl)methoxy) (phenoxy )phosphoryl)-L-alaninate (BION-158) a) 2-ethylbutyl((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetra hydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)-L-alaninate

[0069] The reaction was carried out following Step 3 (phosphorylation reaction) using about 1.10 g of Compound (4) (3 mmol), about 2.02 g of 2-ethylbutyl ((4-nitrophenoxy)(phenoxy) phosphoryl)-L-alaninate) (4.5 mmol), about 0.43 g of magnesium chloride (4.5 mmol), and about 1.31 mL of N, N-diisopropylethylamine (7.5 mmol). The reaction mixture was then reacted for 5 h. The resulting product appeared as a white solid yielded about 1.70 g (84%):1H NMR (500 MHz, DMSO-de): 8 (ppm) 8.27 - 8.25 (m, 1H), 8.14 (s, 1H), 7.37 - 7.26 (m, 4H), 7.22 - 7.13 (m, 3H), 6.09 - 5.98 (m, 1H), 5.89 (dd, J = 7.5, 2.3 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.58 - 4.45 (m, 1H), 4.33 - 4.10 (m, 2H), 3.97 - 3.76 (m, 3H), 2.35 - 2.26 (m, 1H), 2.04 - 1.94 (m, 1H), 1.46 - 1.36 (m, 1H), 1.30 - 1.15 (m, 7H), 0.86 - 0.72 (m, 15H), 0.02 - -0.07 (m, 6H);31P NMR (202 MHz, DMSO- d6): 6 (ppm) 3.91 (Rp), 3.62 (Sp). b) 2-ethylbutyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy)phosphoryl)-L-alaninate

[0070] The reaction was carried out following Step 4 (deprotection of silyl protecting group on secondary hydroxy group) using about 1.51 g of 2-ethylbutyl ((((2S,4R,5R)-5-(6-amino-9H-purin- 9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (2.23 mmol). The resulting product appeared as a white solid yielded about 0.845 g (67%). c) separation of diastereomer of 2 - ethylbutyl ((((2S,4R,5R)-5-( 6-amino-9H-purin-9-yl)-4- hvdroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)-L-alaninate

[0071] The diastereomer of 2-ethylbutyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy tetrahydrofuran-2-yl)methoxy) (phenoxy )phosphoryl)-L-alaninate was separated following Step 5 using a mixed mobile phase of acetonitrile: methanol (95: 5 to 93: 7) with a flow rate of 6 mL / min to obtain:

[0072] BION-158 (Rp-isomer): retention time (RT) 41 min:1H NMR (500 MHz, MeOD): 6 (ppm) 8.28 (s, 1H), 8.21 (s, 1H), 7.34 - 7.28 (m, 2H), 7.22 - 7.13 (m, 3H), 6.02 (d, J = 1.8 Hz, 1H), 4.74 - 4.66 (m, 2H), 4.51 - 4.43 (m, 1H), 4.34 - 4.27 (m, 1H), 4.07 - 3.95 (m, 2H), 3.94 - 3.84 (m, 1H), 2.40 - 2.29 (m, 1H), 2.14 - 2.04 (m, 1H), 1.53 - 1.42 (m, 1H), 1.37 - 1.25 (m, 7H), 0.86 (t, J = 7.5 Hz, 6H);13C NMR (101 MHz, MeOD): 8 (ppm) 175.18, 175.14, 157.24, 153.72, 152.16, 152.09, 150.17, 140.51, 130.74, 126.16, 121.47, 121.42, 120.47, 93.18, 80.48, 80.39, 76.63, 68.34, 68.29, 68.05, 51.70, 41.74, 34.68, 24.23, 24.21, 20.44, 20.37, 11.33, 11.29;31P NMR (202 MHz, MeOD): 8 (ppm) 3.98;

[0073] BION-157 (Sp-isomer): retention time (RT) 48 min:1H NMR (500 MHz, MeOD): 8 (ppm) 8.27 (s, 1H), 8.21 (s, 1H), 7.36 - 7.29 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 6.01 (d, J = 1.6 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.69 - 4.62 (m, 1H), 4.43 - 4.36 (m, 1H), 4.31 - 4.24 (m, 1H), 4.00 (dd, J = 10.9, 5.8 Hz, 1H), 3.96 - 3.86 (m, 2H), 2.41 - 2.32 (m, 1H), 2.13 - 2.05 (m, 1H), 1.49 - 1.39 (m, 1H), 1.36 - 1.25 (m, 7H), 0.93 - 0.76 (m, 6H);13C NMR (126 MHz, MeOD): 8 (ppm) 174.99, 174.95, 157.33, 153.85, 152.17, 152.11, 150.18, 140.51, 130.76, 126.14, 121.40, 121.36, 120.51, 93.29, 80.46, 80.39, 76.64, 68.67, 68.63, 68.07, 51.54, 41.72, 34.92, 24.23, 24.20, 20.63, 20.57, 11.33, 11.27;31P NMR (202 MHz, MeOD): 8 (ppm) 3.78

[0074] Example 3 (BION-171 and BION-172)

[0075] (tert-butyl ((S)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl) methoxyXphenoxy) phosphoryl)-L-alaninate (BION-171) and tert-butyl ((R)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl) methoxyXphenoxy) phosphoryl)-L-alaninate (BION-172) a) tert-butyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl) -L-alaninate

[0076] The reaction was carried out following Step 3 (phosphorylation reaction) using about 0.73 g of Compound (4) (2 mmol), about 1.27 g of tert-butyl ((4-nitrophenoxy)(phenoxy)phosphoryl)- L-alaninate) (3 mmol), about 0.29 g of magnesium chloride (3 mmol), and about 0.87 mL of N, N- diisopropylethylamine (5 mmol). The reaction mixture was then reacted for 5 h. The resulting product appeared as a white solid yielded about 1.00 g (77%):1H NMR (500 MHz, MeOD): 6 (ppm) 8.31 - 8.26 (m, 1H), 8.22 - 8.18 (m, 1H), 7.37 - 7.29 (m, 2H), 7.26 - 7.13 (m, 3H), 5.99 - 5.95 (m, 1H), 4.91 - 4.87 (m, 1H), 4.71 - 4.61 (m, 1H), 4.48 - 4.38 (m, 1H), 4.34 - 4.26 (m, 1H), 3.84 - 3.74 (m, 1H), 2.40 - 2.31 (m, 1H), 2.11 - 2.05 (m, 1H), 1.43 - 1.39 (m, 9H), 1.30 - 1.22 (m, 3H), 0.89 - 0.86 (m, 9H), 0.08 - 0.01 (m, 6H);31P NMR (202 MHz, MeOD): 8 (ppm) 4.10 (Rp), 3.90 (Sp). b) tert-butyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetra hydrofuran-2- yl)methoxy)(phenoxy) phosphoryl)-L-alaninate

[0077] The reaction was carried out following Step 4 (deprotection of silyl protecting group on secondary hydroxy group) using about 0.973 g of tert-butyl ((((2S,4R,5R)-5-(6-amino-9H-purin- 9-yl)-4-hydroxytetra hydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (1.5 mmol). The resulting product appeared as a white solid yielded about 0.510 g (63.5%). c) separation of diastereomer of tert-butyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4- hydroxytetra hydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate

[0078] The diastereomer of tert-butyl ((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetra hydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate was separated following Step 5 using a mixed mobile phase of acetonitrile: water (98: 2), with flow rate of 10 mL / min, to obtain: BION-172 (Rp-isomer): RT 19 min:1H NMR (500 MHz, MeOD): 8 (ppm) 8.27 (s, 1H), 8.21 (s, J = 4.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.23 - 7.13 (m, 3H), 6.01 (d, J = 1.8 Hz, 1H), 4.75 - 4.67 (m, 2H), 4.49 - 4.44 (m, 1H), 4.35 - 4.28 (m, 1H), 3.80 - 3.69 (m, 1H), 2.40 - 2.32 (m, 1H), 2.12

[0079] - 2.05 (m, 1H), 1.41 (s, 9H), 1.24 (d, J = 7.1 Hz, 3H);31P NMR (202 MHz, MeOD): 8 (ppm) 4.06; BION-171 (Sp-isomer): RT 20 min:1H NMR (500 MHz, MeOD): 8 (ppm) 8.27 (s, 1H), 8.21 (s, 1H), 7.35 - 7.30 (m, 2H), 7.24 - 7.15 (m, 3H), 6.01 (d, J = 1.8 Hz, 1H), 4.75 - 4.71 (m, 1H), 4.70

[0080] - 4.64 (m, 1H), 4.43 - 4.38 (m, 1H), 4.30 - 4.25 (m, 1H), 3.84 - 3.75 (m, 1H), 2.44 - 2.37 (m, 1H), 2.14 - 2.06 (m, 1H), 1.40 (s, J = 8.0 Hz, 9H), 1.27 (d, J = 7.0 Hz, 3H);31P NMR (202 MHz, MeOD): 8 (ppm) 3.95. Example 4

[0081] (2S,4R ,5R )-5-(6-amino-2-fluoro-9H -purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran- 2-yl) methanol (9) a) (9-((2R ,3R ,5S)-3-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetra hydrofuran -2-yl)-2-fluoro-9H -purin-6-amine

[0082] The reaction was carried out following Step 1 (addition reaction of silyl protecting group to hydroxy group) using about 0.85 g of Compound (7) (1.30 mmol), about 1.57 g of tertbutyldimethylsilyl chloride (10.4 mmol), and about 1.29 g of imidazole (18.9 mmol). The reaction mixture was then reacted for 19 h. The resulting product appeared as a white solid yielded about

[0083] I.14 g (72%):1H NMR (400 MHz, CDC13): 6 (ppm) 8.31 (s, 1H), 6.49 (br s, 2H), 5.91 (d, J = 1.4 Hz, 1H), 4.61 - 4.59 (m, 1H), 4.58 - 4.54 (m, 1H), 4.14 (dd, J = 11.6, 2.6 Hz, 1H), 3.78 (dd, J =

[0084] I I.6, 2.6 Hz, 1H), 2.28 - 2.21 (m, 1H), 1.85 (ddd, J = 13.0, 5.5, 2.1 Hz, 1H), 0.95 (s, 9H), 0.91 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H). b) (2S,4R , 5R )-5-(6-amino-2-fluoro-9H -purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)tetra hydrofuran-2-yl)methanol

[0085] The reaction was carried out following Step 2 (deprotection of silyl protecting group on primary hydroxy group) using about 0.75 g of Compound (8) (1.51 mmol). The resulting product appeared as a white solid yielded about 0.445 g (77%):1H NMR (400 MHz, MeOD): 6 (ppm) 8.36 (s, 1H), 5.82 (d, J = 3.1 Hz, 1H), 4.81 - 4.78 (m, 1H), 4.52 - 4.47 (m, 1H), 3.92 (dd, J = 12.3, 2.7 Hz, 1H), 3.66 (dd, J = 12.3, 3.4 Hz, 1H), 2.35 - 2.28 (m, 1H), 2.06 - 2.00 (m, 1H), 0.88 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H). Example 5 (BION-293)

[0086] BION-293

[0087] 2-ethylbutyl ((S)-(((2S,4R,5R)-5-(6-amino-2-fluoro-9 / Z-purin-9-yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate (BION-293) a) 2-ethylbutyl ((((2S,4R,5R)-5-(6-amino-2-fhioro-9.H-purin-9-yl)-4-((tert-butyldimethylsilyl) oxy) tetrahydro furan-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate

[0088] The reaction was carried out following Step 3 (phosphorylation reaction) using about 0.25 g of Compound (9) (0.65 mmol), about 0.44 g of 2-ethylbutyl ((S)-(4-nitrophenoxy) (phenoxy )phosphoryl)-L-alaninate (1 mmol), about 0.093 g of magnesium chloride (1 mmol) and about 0.29 mL of N, N- diisopropylethylamine ( 1.62 mmol). The reaction mixture was then reacted for 5 h. The resulting product appeared as a white solid yielded about 0.28 g (60%):1H NMR (400 MHz, MeOD): 8 (ppm) 8.22 (s, 1H), 7.38 - 7.33 (m, 2H), 7.27 - 7.24 (m, 2H), 7.22 - 7.17 (m, 1H), 5.87 (d, J = 2.2 Hz, 1H), 4.85 - 4.82 (m, 1H), 4.67 - 4.62 (m, 1H), 4.45 - 4.40 (m, 1H), 4.33

[0089] - 4.27 (m, 1H), 4.05 - 4.00 (m, 1H), 3.97 - 3.91 (m, 2H), 2.34 - 2.27 (m, 1H), 2.07-2.01 (m, 1H), 1.49-1.43 (m, 1H), 1.37-1.29 (m, 7H), 0.91 (s, 9H), 0.89 (s, 3H), 0.87 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H). b) 2-ethylbutyl ((S,)-(((2S,,4R,5R)-5-(6-amino-2-fluoro-9H -purin-9-yl)-4-hydroxytetrahydrofuran- 2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate

[0090] The reaction was carried out following Step 4 (deprotection of silyl protecting group on secondary hydroxy group) using about 0.27 g of Compound (10) (0.39 mmol). The resulting product appeared as a white solid yielded about 0.15 g (65%):1H NMR (400 MHz, MeOD): 6 (ppm) 8.20 (s, 1H), 7.34 - 7.29 (m, 2H), 7.21-7.19 (m, 2H), 7.17-7.13 (m, 1H), 5.90 (s, 1H), 4.72

[0091] - 4.69 (m, 1H), 4.67 - 4.63 (m, 1H), 4.42 - 4.37 (m, 1H), 4.30 - 4.24 (m, 1H), 4.02-3.97 (m, 1H), 3.95-3.88 (m, 2H), 2.39 - 2.31 (m, 1H), 2.09-2.04 (m, 1H), 1.46-1.40 (m, 1H), 1.32-1.27 (m, 7H), 0.86-0.82 (m, 6H);31P NMR (162 MHz, MeOD): 8 (ppm) 3.63;19F NMR (470 MHz, MeOD): 8 (ppm) -77.63. Efficacy test against influenza virus in Madin-Darby canine kidney cells (MDCK)

[0092] Madin-Darby canine kidney cells (MDCK) were prepared at a density of about 1.5xl04cells / well in a 96-well plate overnight. Subsequently, MDCK cells were infected with influenza virus strain H1N1 influenza A / Puerto Rico / 8 / 34 (PR8) at a concentration of 100 plaque forming unit (pfu) / well for 1 h. The viruses were washed with a PBS solution, and the synthesized compounds underwent serial dilution in a DMSO solution within the concentration range of 100 to 0.78 μM with a volume of approximately 100 pL / well. The MDCK cells were incubated in an incubator at 37 °C with 5% CO2for 24 h.

[0093] The MDCK cells, which were tested with the synthesized compounds as mentioned above, were fixed with an 80% aqueous acetone solution. A blocking solution (1% bovine serum albumin (BSA) in PBS solution with 0.05% Tween20; PBST) and monoclonal antibody: nucleoprotein of the influenza virus were added and then incubated at room temperature for 1 h. Subsequently, horseradish peroxidase (HRP)-conjugated secondary antibodies were added and incubated at room temperature for 1 h. The MDCK cells were washed in a well plate with PBST solution at each step to eliminate non-specific binding. After that, a substrate of the HRP enzyme was added. Virus- infected samples underwent the reaction that converted the substrate into a compound with an absorbance at 450 nm. The reaction was stopped using about 0.5 M of sulfuric acid solution (H2SO4) and then the absorbance at 450 nm (OD450) was read. The OD450 was used to calculate the efficacy percentage of influenza virus infectious inhibition. The obtained values were used to calculate a half maximal inhibitory concentration (IC50) of each synthesized compound.

[0094] Based on the results of the efficacy test against the influenza virus, it was observed that cordycepin exhibited the half maximal inhibitory concentration (IC50) of 10.46 μM. BION- 157 exhibited a lower inhibitory activity on the influenza virus compared to cordycepin, with an I C 50 value of 65.59 μM. BION- 158, a compound in Rp-isomer form, exhibited greater inhibitory activity against the influenza virus compared to BION-157, approximately 2.7 fold greater. It, however, still demonstrated less inhibitory potency than cordycepin with an I C 50 value of 24.25 μM.

[0095] Efficacy test against SAR-CoV-2 in Vero E6 cells

[0096] An inhibitory activity test of SAR-CoV-2 proliferation using a phenotypic screening technique through high-content imaging analysis was performed.

[0097] Vero E6 cells at approximately 10,000 cells / well were cultured in a 96-black well plate, coated with collagen type 1, and incubated at 37 °C with 5% CO2for 24 h. Subsequently, SARS- CoV-2 was introduced to the Vero E6 cells, causing infection at levels of 25-fold TCID50 (50% tissue culture infectious dose). The infected Vero E6 cells were incubated at 37 °C with 5% CO2 for 2 hours and then transferred to a medium mixed with post-treatment agent. The infected Vero E6 cells were then incubated with the post-treatment agent at 37 °C with 5% CO2for 48 h, utilizing patient serum as a positive control, which demonstrated 100% efficacy.

[0098] After 48 h, staining was performed using a fluorescence dye specific to SARS-CoV-2 , followed by imaging with a high-content imaging system. As shown in Figure 1, the Vero E6 cells in the 96-black well plate were fixed and permeabilized with 50% (v / v) acetone in cold methanol for 20 min. The Vero E6 cells were then rinsed in PBS buffer with 0.05% Tween20 (Tween® detergent: PBST) and blocked with 2% bovine serum albumin (BSA) for 1 hour at room temperature. Subsequently, the primary antibody specific to SARS-CoV Nucleoprotein (NP) was added in a ratio of 1: 500 for 1 hour at 37 °C, followed by the secondary antibody of goat antirabbit IgG (H+L) (Alexa 488) at a ratio of 1: 500. Nucleus staining (Hoechst) was performed for analysis with the high-content imaging screening system technique (Kanjanasirirat P. el al, 2020).

[0099] Based on the results of the efficacy test against the SAR-CoV-2 in the Vero E6 cells, it was demonstrated that cordycepin exhibited a slight inhibitory activity with IC50 value exceeding 200 μM. BION-157 exhibited a greater inhibitory activity with IC50 value of 69.82 μM, while BION- 158 demonstrated a slightly higher inhibitory activity ability than BION-157 (ICso is 49.42 μM). Efficacy test against dengue virus

[0100] The synthesized compounds were tested against the dengue virus using a fluorescent dengue virus system on K562 cells with virus’s receptor CD209 (K562-CD209).

[0101] The dengue viruses expressing mCherry and eGFP fluorescences (DENV2-mCherry and DENVl-eGFP) were obtained from a DENV2-mCherry and DENVl-eGFP plasmid prepared using an extraction kit (Qiagen miniprep kit). About 20 pg of the DENV2-mCherry or DENVl- eGFP insert was introduced into BHK21-rtTA3 cells, comprising about 2x107cells in a 100 mL cell culture plate by chemical transfection with lipofectamine-2000. The BHK21-rtTA3 cells containing DENV2-mCherry or DENVl-eGFP were then cultured in an ISF1 medium with doxycycline at 1 pg / mL for 3 days, with a daily change of medium. Subsequently, the medium containing DENV2-mCherry or DENVl-eGFP was centrifuged at 9,100 x g at 4 °C for 20 min to eliminate dead cells. The resulting DENV2-mCherry or DENVl-eGFP was then cultured in Vero cells in a T75 flask overnight. The following day, the ISF1 medium was changed, and subsequent medium changes occurred every other day. On day 3 to 4, the medium containing DENV2- mCherry or DENVl-eGFP particles were collected, centrifuged at 9,100 x g at 4 °C for 20 min to eliminate dead cells. Fetal bovine serum, previously incubated at 56 °C for 20 min, was added (reaching a final concentration of 20%) before dividing the solution into 1.5 mL tubes and stored at -70 °C. The K562-CD209 cells cultured in the 96-well plate, were used for the efficacy test. Approximately 10,000 cells / well of the K562-CD209 cells were mixed with DENV2-mCherry or DENVl-eGFP at about MOI = 0.1 in a volume of 150 pL / well in a medium (RPMI containing 10% heat-inactivate fetal serum), and the mixture was incubated at 37 °C, with 5% CO2for 1 hour to induce infection in the K562-CD209 cells. Subsequently, various synthesized compounds at concentrations of 32,000 μM, 8000 μM, 2000 μM, 500 μM, 125 μM, 31.25 μM, 7.81 μM, and 1 .95 μM were prepared by serial dilution with a RPMI medium containing 10% heat-inactivate fetal serum and DMSO for use as a control. The synthesized compounds were then mixed with the K562-CD209 cells in the 96-well plate (50 pL / well). The obtained K562-CD209 cells were diluted 1 : 4 to final concentrations of 8,000 μM, 2,000 μM, 500 μM, 125 μM, 31.25 μM, 7.81 μM, 1.95 μM, and 0. 48 μM, respectively. After that, the K562-CD209 cells were incubated at 37 °C with 5% CO2for 3 days to measure virus inhibitory level of the synthesized compounds. This was done by assessing mean fluorescent intensity (MFI) of mCherry or eGFP protein from DENV2-mCherry or DENVl-eGFP using flow cytometry (BD LSRFortessa) with HTS mode to measure the dengue virus proliferation level in the K562-CD209 cells. The K562-CD209 cells were centrifuged at 1,000 x g at 4 °C for 5 min and fixed with 3.7% formaldehyde. The relationship between the concentration of synthesized compounds and the measured fluorescence level was analyzed with ECCpy program to determine IC50 value of each synthesized compound. The IC50 value indicated the efficacy of inhibiting the dengue virus of each synthesized compound.

[0102] Based on the results of efficacy test against the dengue virus K562 cells having the virus’s receptor CD209 ( K562 - CD209 ) , it was observed that cordycepin exhibited the dengue virus inhibitory activity with the I C50value of 33.61 μM for DENV2-mCherry and 44.67 μM for DENVl-eGFP, while BION-157 exhibited clearly greater efficacy of inhibition with the IC50 value of 3.96 μM for DENV2-mCherry and 4.47 μM for DENVl-eGFP. In the case of BION-158, which is only tested with DENVl-eGFP, it shows notably reduced efficacy, with an IC50 value of 186.2 μM compared to BION-157.

[0103] Toxicity test in human keratinocytes (HaCaT) cells

[0104] Toxicity test was conducted by culturing human keratinocyte (HaCaT) cells in DMEM / F12 medium mixed with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin in the incubator at 37 °C, 5% CO2. Upon reaching 80% confluence of HaCaT cells in the T-75 flask, the cells were detached from the T-75 flask surface by trypsinization. Subsequently, the HaCaT cells were plated in the 96-well plate at approximately 50,000 cells / well and cultured at 37 °C, 5% CO2for 24 h. After that, the HaCaT cells were exposed to synthesized compounds. These compounds were diluted in DMEM / F12 medium mixed with 10% FBS and 1% penicillin / streptomycin at concentrations ranging from 100 to 200 |iM. The incubation continued at 37 °C, 5% CO2for 48 h. Then, the toxicity of the synthesized compounds to the HaCaT cells was measured using MTT cell viability assay by incubating the cells with tetrazolium MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5- diphenyltetrazolium bromide) for 3 h. The MTT solution changed into a purple crystal of formazan by succinate dehydrogenase in mitochondria of viable cells. After 3 h, the solution was removed, and DMSO was added to dissolve the purple crystals. The absorbance was measured at a wavelength of 570 nm to calculate a cell survival rate using the equation: % cell survival rate = (A570 nm treated cells) / (A570 nm untreated cells) x 100.

[0105] Based on the toxicity test in the HaCaT cells, it was demonstrated that cordycepin at a concentration of 200 μM, exhibited the cell survival rate of 23.9%, indicating toxicity to the HaCaT cells. In contrast, BION-157 and 158 exhibited lower toxicity, as at the concentration of 200 μM, the HaCaT cells could survive more than 50% (CC50). This value is acceptable for further conducting drug development due to its specificity in inhibiting infection rather than inhibiting cell growth.

[0106] Metabolic pathway of BION-157 and BION-158 compounds

[0107] Approximately 5 mg of BION-157 compound was dissolved in ^-acetone about 0.15 mL. Subsequently, about 0.30 mL of trizma buffer at pH 7.4 and about 0.1 mL of carboxypeptidase Y type dissolved in trizma buffer solution of 0.15 mL were added. The resulting mixture was analyzed using 3 IP NMR technique by monitoring the reaction every 15 min until a completion after 5 h. The methods for the metabolic pathway test of BION-158 compound were conducted in a similar manner to those for BION-157 compound.

[0108] Analysis of metabolic pathway test results of BION-157 and BION-158

[0109] The metabolic pathways of BION-157 and BION-158 were studied to determine the effect of deprotection of various protective groups of amino esters in ProTides form. These compounds, when employed as antiviral drugs in the nucleotide analogue ProTide, could be absorbed into cells. Subsequently, ester hydrolysis reaction by esterase or carboxypeptidase led to the formation of a carboxylate ion (COO ), which is a critical step allowing the substance in the nucleotide analogue ProTide group to transform into bioactive compounds. As shown in Figure 1, a proposed mechanism of the metabolic pathway of BION-157 and BION-158 demonstrated that when BION-157 and BION-158 compounds underwent carboxypeptidase for the deprotection of the protective group, intermediate A was produced. Subsequently, formation of a five-membered cyclic structure resulted in intermediate B. Following this, hydrolysis reaction occurred again, breaking the P-N bond and leading to the monophosphate form, followed by phosphorylation reaction resulting in the production of triphosphate form, which is the bioactive compounds. The31P NMR analysis of BION-157 and BION-158 revealed a correlation between signal intensity and chemical shift of BION-157 and BION-158 at 3.95 and 3.56 ppm, respectively (Figure 2 and 3). Upon the addition of carboxypeptidase Y type and monitoring the reaction every 15 min, the signal intensity and the chemical shift of BION-157 gradually disappeared within 3 hours while the chemical shift BION-158 disappeared within 5 hours, with new signal intensity values of 4.67 and 7.12 ppm, indicating intermediate A and intermediate C, respectively. It was concluded that BION-157, being the Sp- isomer compound, underwent ester hydrolysis by carboxypeptidase Y type faster than BION-158, the Rp- isomer compound. Therefore, the design of the nucleotide analogue ProTide in a P-chiral manner was essential for stability and the resulting metabolic pathway. Specifically, the Sp-isomcr was rapidly converted to the bioactive compound, making it suitable for local actions such as lung infection, with application methods for local drug delivery like sprays for SARS-CoV-2 infection. On the other hand, the Rp-isomer was more stable and suitable for systemic action or infections in multiple areas in the body, such as dengue infection, where drug stability was crucial for gradual action throughout the body. BEST MODE OF THE INVENTION

[0110] The best mode or preferred embodiment of the invention is as described in the detailed description.

Claims

CLAIMS1. A cordycepin derivative or a pharmaceutically acceptable salt thereof as a pan-antiviral agent, where in the cordycepin derivative having a formula (I),whereinX is a heteroatom;Y is selected from hydrogen or halogen;Ar is selected from unsubstituted C6to C20-aryl group or, C6to C20-aryl group having one or two substituent groups;R1is selected from hydroxyl group (OH), amide group (-CO-NH2), hydrogen (-H), amine (-NH, -NH2, or -NH3), carboxyl group (COOH) or an R group representing a nonpolar group;R2is selected from 2-ethylbutyl group (-CH2CH(C2H5) C2H5) or tert-butyl group (-C(CH3)3) having structure (a) and (b), respectively.(a) (b)2. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1, wherein X is selected from oxygen or sulfur.

3. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1, wherein Y is selected from hydrogen, fluorine, chlorine, bromine or iodine.

4. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1, wherein Ar is selected from phenyl, 1 -naphthyl, 2-naphthyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3 -chlorophenyl, 4- chlorophenyl, 2-bromophenyl, 3 -bromophenyl, or 4-bromophenyl.

5. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1, wherein R1is selected from methyl, methylethyl, 1 -methylpropyl, 2- methylpropyl, or benzyl.

6. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 2, wherein X is oxygen.

7. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 3, wherein Y is hydrogen or fluorine.

8. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 4, wherein Ar is phenyl.

9. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 5, wherein R1is methyl.

10. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to any one of claims 1 to 9 which is in a diastereomer form selected from diastereomer mixture of Sp-isomcr and Rp-isomer, diastereomer of pure Sp-isomer, or diastereomer of pure Rp-isomer.

11. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 10 which is in a diastereomer form of pure Sp-isomcr.

12. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 10 which is in a diastereomer form of pure Rp-isomer.

13. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is tert-butyl ((S)-(((2S,4R,5 R)-5 -(6 -amino-9H-purin-9 -yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

14. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is tert-butyl ((R)-(((2S,4R,5 R)-5 -(6 -amino-9H-purin-9 -yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

15. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is 2-ethylbutyl ((S)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

16. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is 2-ethylbutyl ((R)-(((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4- hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

17. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is 2-ethylbutyl ((S)-(((2S,4R,5R)-5-(6-amino-2-fluoro-9H-purin- 9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

18. The cordycepin derivative or pharmaceutically acceptable salt thereof as a pan-antiviral agent according to claim 1 which is 2-ethylbutyl ((R)-(((2S,4R,5R)-5-(6-amino-2-fluoro-9H-purin- 9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)-L-alaninate.

19. A use of the cordycepin derivative or pharmaceutically acceptable salt thereof according to claim 1 for manufacture of a pan-antiviral agent.

20. The use of the cordycepin derivative or pharmaceutically acceptable salt thereof according to claims 1 for manufacture of a medicament in a form of tablets, injections, or spays.

Images