Orthopoxvirus inhibitor and its application

Abstract

The present invention discloses an orthopoxvirus inhibitor and its application. The present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Compared with cidofovir or brincidofovir, the compound of the present application has higher anti-AdV14 activity and higher exposure in hepatocytes and lung cells.

Description

Technical Field

[0001] The present invention relates to the antiviral field, and in particular to an orthopoxvirus inhibitor and application thereof. Background Art

[0002] Orthopoxviruses belong to the Poxviridae family, a class of double-stranded DNA viruses. There are many viruses in this genus that can infect humans and cause disease, such as smallpox, cowpox, vaccinia, and monkeypox. Monkeypox is a zoonotic disease caused by the monkeypox virus. Monkeypox occurs in monkeys in the rainforests of central and western Africa, and can also infect other animals and occasionally humans. The clinical manifestations are similar to smallpox, but the condition is milder. The disease is caused by the monkeypox virus, which can be transmitted from animals to humans through direct close contact, and can also be spread from person to person.

[0003] Since smallpox was eradicated, monkeypox has become the orthopoxvirus with the greatest threat to human life and health, with a mortality rate of about 1% to 11% in unvaccinated populations. The main epidemic areas of the virus are central and western Africa. According to WHO statistics, more than 1,300 cases of monkeypox occurred in central and western Africa from December 15, 2021 to May 1, 2022, of which about 60 patients died. In addition, since the first case of monkeypox was reported in the UK on May 7, 2022, the number of patients in non-monkeypox epidemic areas around the world has increased rapidly, which has also attracted the attention of governments around the world. Therefore, it is of great significance to develop safe and effective anti-monkeypox drugs.

[0004] Cidofovir (Cidofovir, recorded in patent US5142051) is a kind of acyclic nucleoside phosphonate (ANP) analog, is essentially a nucleoside monophosphate analog, has the advantage of metabolic stability. Current research has proved that Cidofovir has a broad spectrum activity against all DNA viruses, including adenovirus, polyomavirus, papillomavirus and poxvirus. Because the phosphonate part of Cidofovir is negatively charged under physiological pH, Cidofovir cannot pass through the cell membrane rich in lipid, which hinders its antiviral activity and bioavailability, and causes serious nephrotoxicity, causing it to be difficult to be widely used. Brincidofovir (Brincidofovir, abbreviated as BCV, recorded in patent US8962829) is a phospholipid prodrug of Cidofovir. As an improvement of Cidofovir, Brincidofovir improves the activity of Cidofovir and also improves its oral bioavailability. However, the absorption of Brincidofovir in vivo, the exposure amount of cells still has defects. Prévost J, Sloan A,Deschambault Y, et al. Treatment Efficacy of Cidofovir and Brincidofovir against Clade II Monkeypox Virus isolates. Antiviral Res reported that cidofovir and brincidofovir have high antiviral activity against monkeypox virus.

[0005] Therefore, there is still a need in the art to further develop safe and effective orthopoxvirus inhibitors for the treatment of diseases caused by orthopoxvirus infection. Summary of the invention

[0006] To further develop safe and effective orthopoxvirus inhibitors for the treatment of diseases caused by orthopoxvirus infection. The compounds of the present application and brincidofovir are both prodrugs of cidofovir. Compared with cidofovir or brincidofovir, the compounds of the present application have higher anti-AdV14 activity. There is a higher exposure in liver cells and lung cells.

[0007] The present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008] ;in,

[0009] R 1 is hydrogen or metal ion;

[0010] R 2 for or , where R 3 and R 3'are independently H or C1-C4 alkyl, R 4 For C8-C 20 alkyl.

[0011] In one embodiment, the metal ion is a potassium ion or a sodium ion.

[0012] In one embodiment, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0013] In one embodiment, the C8-C 20 The alkyl group is a linear or branched alkyl group, and is preferably a linear alkyl group.

[0014] In one embodiment, the C8-C 20 Alkyl is C 12 -C 20 Alkyl groups, such as C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl or C 20 alkyl.

[0015] In one scenario, R 1 It is hydrogen, potassium ion or sodium ion, preferably hydrogen.

[0016] In one scenario, R 2 for , , , , or .

[0017] In one scenario, R 4 -(CH2) 14 CH3, -(CH2) 15 CH3, -(CH2) 16 CH3, -(CH2) 17 CH3, -(CH2) 18 CH3 or -(CH2) 19 CH3.

[0018] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (I-1):

[0019] ;in,

[0020] R 3 and R 3' are independently H or methyl;

[0021] R 4 C 12 -C 20 alkyl.

[0022] In one embodiment, the compound represented by formula (I) is a compound represented by the following formula (I-2):

[0023] ;in,

[0024] R 3 and R 3' are independently H or methyl;

[0025] R 4 C 12 -C 20 alkyl.

[0026] In one embodiment, the compound represented by formula (I) is any of the following compounds:

[0027] , , , , , , , , , , or .

[0028] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient.

[0029] The present invention also provides a use of the compound represented by the above formula (I), its stereoisomers or pharmaceutically acceptable salts or the above pharmaceutical composition in the preparation of drugs for treating and / or preventing adenovirus, vaccinia virus or monkeypox virus infection.

[0030] In one embodiment, the vaccinia virus may be vaccinia virus VP13 strain.

[0031] In one embodiment, the adenovirus may be adenovirus AdV5 strain or adenovirus AdV14 strain.

[0032] Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-C4 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3 or 4 carbon atoms.

[0033] As used herein, numerical ranges defined in substituents such as 1-4, 8-20, 12-20, etc. indicate integers within the range, such as 12-20 is 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0034] Those skilled in the art will understand that according to the conventions used in the art, the “ " means that the corresponding group R is connected to other fragments and groups in the compound through this site.

[0035] Unless otherwise indicated, keys with a solid wedge shape ( ) and dotted wedge bonds ( ) represents the absolute configuration of a stereocenter.

[0036] In the present invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. For example, C1-C4 alkyl refers to an alkyl group having 1 to 4 carbon atoms, which is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl. 20 The alkyl group refers to an alkyl group having 8 to 20 carbon atoms, preferably an alkyl group having 12 to 20 carbon atoms. 12 -C 20 Alkyl, more preferably C 12 -C 20 Straight chain alkyl, such as -(CH2) 14 CH3, -(CH2) 15 CH3, -(CH2) 16 CH3, -(CH2) 17 CH3, -(CH2) 18 CH3 or -(CH2) 18 CH3.

[0037] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the invention as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0038] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0039] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0040] The term "treat" refers to removing the cause or alleviating the symptoms.

[0041] The term "prevention" refers to reducing the risk of developing a disease.

[0042] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0043] The reagents and raw materials used in the present invention are commercially available.

[0044] The positive and progressive effect of the present invention is that compared with cidofovir or brincidofovir, the compound of the present application has higher anti-AdV14 activity and higher exposure in liver cells and lung cells. DETAILED DESCRIPTION

[0045] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0046] The list of example compounds is shown in Table 1 below:

[0047] Table 1

[0048]

[0049]

[0050] Example 1 Synthesis of Compound 1

[0051]

[0052] Synthesis of Compound 1-3:

[0053] Compound 1-2 (7.2 g, 0.056 mol, 1.4 eq) and pyridine (5.8 g, 0.074 mol, 1.8 eq) were added to a mixture of compound 1-1 (10.0 g, 0.04 mol, 1 eq) in cyclohexane (400 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with PE (50 mL x 3), and the combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to obtain compound 1-3 (13.0 g, 97%) as a white solid.

[0054] Synthesis of compound 1:

[0055] S1 (0.3 g, 1.08 mmol, 1.0 eq) was added to DMF (5 mL), and DIEA (277 mg, 2.15 mmol, 2 eq) and compound 1-3 (1.08 g, 3.2 mmol, 3.0 eq) were added. The mixture was reacted at 70 °C for 10 h and directly purified by prep-TLC (DCM: MeOH=3:1) to obtain compound 1 (45.7 mg, 7%) as a white solid.

[0056] LCMS: [M+1] + = 578.5.

[0057] 1 H NMR (400 MHz, CD3OD) δ 7.85 (d, J = 4.6 Hz, 1H), 5.99 (d, J = 4.6Hz, 1H), 5.55–5,51 (m, 2H), 4.21–4.10 (m, 3H), 3.80–3.75 (m, 4H), 3.72–3.51(m, 2H), 1.66–1.62 (m, 2H), 1.30–1.25 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H).

[0058] The following compounds in Table 2 were synthesized using a similar method:

[0059] Table 2

[0060]

[0061] Example 2 Synthesis of Compound 9

[0062]

[0063] Synthesis of compound 9-3:

[0064] To a stirred solution of compound 9-2 (2.3 g, 26.1 mmol, 1eq) in THF (100 mL) was added 2 mol / L LDA (2M, 32.9 mL, 65.8 mmol, 2.5eq) at 0°C N2 atmosphere. The resulting mixture was stirred at 25°C N2 atmosphere for 2h. A solution of compound 9-1 (10 g, 26.32 mmol, 1eq) in THF (30mL) was added dropwise to the above mixture at 0°C N2 atmosphere for 15 minutes. The resulting mixture was stirred at 25°C N2 atmosphere for 2h. The reaction was quenched with 1 mol / L HCl at 0°C. The resulting mixture was extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with [PE:EA] (100:0~90:10) to obtain compound 9-3 (6.0 g, 67%) as a white solid.

[0065] 1 H NMR (400 MHz, CDCl3) δ 1.50 (t, J = 5.9 Hz, 2H), 1.25–1.20 (m,28H), 1.17 (s, 6H), 0.89 (t, J = 5.9 Hz, 3H).

[0066] Synthesis of compound 9-5:

[0067] Compound 9-3 (6.0 g, 17.6 mmol, 1 eq), (n-Bu4N)2SO4 (1.023 g, 1.765mmol, 0.1eq) and K2CO3 (9.742g, 70.60 mmol, 4 eq) were dissolved in DCM (90 mL) and H2O (90mL) and stirred at 0°C for 5 minutes. Compound 9-4 (3.5 g, 21.2 mmol, 1.2 eq) was added dropwise to the above mixture at 0°C for 10 minutes. The resulting mixture was stirred at 25°C under N2 atmosphere for 16 hours. The resulting mixture was extracted with DCM (200mL x 3). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EA = 100:0~98:2) to obtain compound 9-5 (5.5 g, 80%) as a white solid.

[0068] 1 H NMR (400 MHz, CDCl3) δ 5.71(s, 2H), 1.57–1.41 (m, 2H), 1.30–1.22(m, 28H), 1.19 (s, 6H), 0.88 (t, J = 6.7 Hz, 3H).

[0069] Synthesis of compound 9

[0070] To a stirred solution of compound 9-5 (2.0 g, 5.2 mmol, 2.5 eq) and s1 (0.764 g, 2.1 mmol, 1.0 eq) in DMF (40 mL) was added DIEA (1.6 g, 12.4 mmol, 6.0 eq) at 25 °C. The resulting mixture was stirred at 60 °C under N2 atmosphere for 24 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with [DCM / MeOH] = (90 / 10~80 / 20) to give CG-1914 (67.1 mg, 4.5%) as a white solid.

[0071] LCMS: [M+1] + = 604.4

[0072] 1H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 7.4 Hz, 1H), 5.90 (d, J = 7.4Hz, 1H), 5.52 (d, J = 12.0 Hz, 2H), 4.14–4.07 (m, 1H), 3.81–3.58 (m, 5H), 3.54–3.47 (m, 1H), 1.51 (t, J = 7.6 Hz, 2H), 1.30–1.25 (m, 28H), 1.15 (s, 6H), 0.90–0.85 (t, J = 7.6 Hz, 3H).

[0073] The following compounds in Table 3 were synthesized using a similar method:

[0074] Table 3

[0075]

[0076] Activity Test Example 1 In vitro anti-vaccinia virus activity test

[0077] This study used the cytopathic effect (CPE) assay to detect the in vitro anti-vaccinia virus (Vaccinia) VP13 activity of the test samples, and also tested the toxicity of the samples to HFF-1 cells.

[0078] HFF-1 (ATCC, Catalog No. SCRC-1041) cells were seeded into 96-well test plates at a density of 6,000 cells per well and 100 μL per well, and cultured overnight in a 5% CO2, 37 °C incubator. The culture medium was DMEM medium supplemented with 20% fetal bovine serum, 1% double antibody, 1% non-essential amino acids and 1% sodium pyruvate. On the second day, for the anti-vaccinia virus experiment, the compounds of the examples and comparative examples (cidofovir and brincidofovir) and viruses (CCTCC, Catalog No. GDV088) were added after multiple dilutions. For the toxicity test of HFF-1 cells, the compounds of the examples and comparative examples (cidofovir and brincidofovir) were added after multiple dilutions. Cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium) were set up. The final concentration of DMSO in the culture medium was 0.5%. The cells were cultured in a 5% CO2, 37°C incubator for 4 days. On the sixth day, the cell viability was detected using the cell viability detection kit CCK8 (Shanghai Liji Biotechnology Co., Ltd., Cat. No. AC11L057). The antiviral activity and cytotoxicity of the tested samples were expressed by the inhibition rate (%) of the virus-induced cytopathic effect and the cell viability (%) of the samples at different concentrations, respectively. The calculation formula is as follows:

[0079]

[0080] GraphPad Prism was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the samples and calculate the half effective concentration (EC 50 ) and the half cytotoxic concentration (CC 50 ) values. The corresponding results are shown in Table 4.

[0081] Table 4

[0082]

[0083] EC 50 : A: <100 nM, B: 100~1000nM, C: >1000nM.

[0084] Activity Test Example 2 In vitro activity test against adenovirus AdV 5 strains

[0085] This experiment used the cytopathic effect (CPE) experiment to detect the in vitro anti-adenovirus AdV 5 strain activity of the test samples, and also detected the toxicity of the samples to 293A cells.

[0086] 293A (Invitrogen, P / N 51-0036) cells were seeded into 96-well test plates at a density of 20,000 cells per well and 100 μL per well, and cultured overnight in a 5% CO2, 37 °C incubator. The culture medium was DMEM medium supplemented with 10% fetal bovine serum, 1% L-glutamine, 1% double antibody, 1% non-essential amino acids and 1% sodium pyruvate. The next day, for the anti-adenovirus experiment, the compounds of the examples and comparative examples (cidofovir and brincidofovir) and viruses (ATCC, P / N VR-1516) were added after multiple dilutions. For the toxicity test of 293A cells, the compounds of the examples and comparative examples (cidofovir and brincidofovir) were added after multiple dilutions. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with viruses, no compound treatment) and culture medium controls (only culture medium) were set up. The final concentration of DMSO in the culture medium was 0.5%. The cells were cultured in a 5% CO2, 37°C incubator for 5 days. On the 7th day, the cell viability was detected using the cell viability detection kit CCK8 (Shanghai Liji Biotechnology Co., Ltd., catalog number AC11L057). The antiviral activity and cytotoxicity of the tested samples were expressed by the inhibition rate (%) of the virus-induced cytopathic effect and the cell viability (%) of the samples at different concentrations, respectively. The calculation formula is as follows:

[0087]

[0088] GraphPad Prism was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the samples and calculate the half effective concentration (EC 50 ) and the half cytotoxic concentration (CC 50 The corresponding results are shown in Table 5.

[0089] Table 5

[0090]

[0091] EC 50 : A: <100 nM, B: 100~1000nM, C: >1000nM.

[0092] Activity Test Example 3 In vitro activity test against adenovirus AdV 14 strain

[0093] This experiment used the cytopathic effect (CPE) experiment to detect the in vitro anti-adenovirus AdV 14 strain activity of the test samples, and also detected the toxicity of the samples to A549 cells.

[0094] A549 (ATCC, Catalog No. CCL-185) cells were seeded into 96-well test plates at a density of 4,000 cells per well and 100 μL per well, and cultured overnight in a 5% CO2, 37 °C incubator. The culture medium was RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% double antibody, and 1% non-essential amino acids. The next day, for the anti-adenovirus experiment, the compounds of the examples and comparative examples (cidofovir and brincidofovir) and viruses (ATCC, Catalog No. VR-15) were added after multiple dilutions. For the toxicity test of A549 cells, the compounds of the examples and comparative examples (cidofovir and brincidofovir) were added after multiple dilutions. Cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium) were set. The final concentration of DMSO in the culture medium was 0.5%. The cells were cultured in a 5% CO2, 37 °C incubator for 5 days. On the 7th day, the cell viability was detected using the cell viability detection kit CTB (Promega, catalog number G8081). The antiviral activity and cytotoxicity of the tested samples were expressed by the inhibition rate (%) of the virus-induced cytopathic effect and the cell viability (%) of the samples at different concentrations, respectively. The calculation formula is as follows:

[0095]

[0096] GraphPad Prism was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the samples and calculate the half effective concentration (EC 50 ) and the half cytotoxic concentration (CC 50The corresponding results are shown in Table 6.

[0097] Table 6

[0098]

[0099] EC 50 : A: <100 nM, B: 100~1000nM, C: >1000nM.

[0100] Activity Test Example 4 Evaluation of Prodrug Conversion in Hep G2 Cells

[0101] Hep G2 (ATCC, Catalog No. HB-8065) ​​cells were used to evaluate the efficiency of prodrug conversion into nucleoside triphosphates. 6 / mL density was resuspended in EMEM (Procell, PM150467) medium containing 10% PBS (ExCell, FND500). 1mL of cell suspension and 1.5mL of culture medium were added to a 6-well plate and cultured overnight in a 37°C / 5% CO2 incubator. After the cells adhered to the wall, the culture medium was discarded, and culture medium containing 5µM of the example and comparative example compounds (cidofovir and brincidofovir) was added respectively, and culture was continued at 37°C / 5% CO2 for 1, 2, 4, and 6 hours. At the corresponding time point, the culture medium was discarded and washed twice with 3mL PBS. 100µL of 0.25% trypsin-0.53mM EDTA (Sigma-Aldrich, T4049) solution was added for dissociation for 5min. After the dissociation was completed, 500 µL of 70% methanol (pre-cooled at 4°C) was added to digest the cells. The digested cells were transferred to a 1.5 mL centrifuge tube and centrifuged at 10,000 rpm and 4°C for 10 min. 500 µL of the supernatant was transferred to a 96-well plate and dried with nitrogen. 200 µL of the initial mobile phase (10% ACN in H2O) was added to reconstitute and transferred to an LC-MS (Waters liquid chromatograph coupled to an ABSciex mass spectrometer) for detection. The intracellular triphosphorylated metabolites of the compound at each time point were calculated. The corresponding results are shown in Table 7.

[0102] Activity Test Example 5 Evaluation of Prodrug Conversion in A549 Cells

[0103] A-549 (ATCC, Cat. No. CCL-185) cells were used to evaluate the efficiency of prodrug conversion into nucleoside triphosphates. 6 / mL density was resuspended in F-12K (Procell, PM150912) medium containing 10% PBS (ExCell, FND500). 1mL of cell suspension and 1.5mL of culture medium were added to a 6-well plate and cultured overnight in a 37°C / 5% CO2 incubator. After the cells adhered to the wall, the culture medium was discarded, and culture medium containing 5µM of the example and comparative example compounds (cidofovir and brincidofovir) was added respectively, and culture was continued at 37°C / 5% CO2 for 1, 2, 4, and 6 hours. At the corresponding time point, the culture medium was discarded and washed twice with 3mL PBS. 100µL of 0.25% trypsin-0.53mM EDTA (Sigma-Aldrich, T4049) solution was added for 5min of dissociation. After the dissociation was completed, 500 µL of 70% methanol (pre-cooled at 4°C) was added to digest the cells. The digested cells were transferred to a 1.5 mL centrifuge tube and centrifuged at 10,000 rpm and 4°C for 10 min. 500 µL of the supernatant was transferred to a 96-well plate and dried with nitrogen. 200 µL of the initial mobile phase (10% ACN in H2O) was added for reconstitution and transferred to an LC-MSMS (Waters liquid chromatograph coupled to an AB Sciex mass spectrometer) instrument for detection. The intracellular triphosphorylated metabolites of the compound at each time point were calculated. The corresponding results are shown in Table 7.

[0104] Table 7

[0105]

[0106] C: <200nM, B: 200~500nM, A: >500nM.

Claims

1. A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ;in, R 1 is hydrogen or metal ion; R 2 for or , where R 3 and R 3' are independently H or methyl, R 4 C 15 -C 19 alkyl; The C 15 -C 19 The alkyl group is a straight chain alkyl group.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The metal ions are potassium ions or sodium ions.

3. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The C 15 -C 19 Alkyl is C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl or C 19 alkyl.

4. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound satisfies one or more of the following conditions: (1) R 1 It is hydrogen, potassium or sodium ion; (2) R 2 for , , , , or ; and (3) R 4 -(CH2) 14 CH3, -(CH2) 15 CH3, -(CH2) 16 CH3, -(CH2) 17 CH3 or -(CH2) 18 CH3.

5. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1 For hydrogen.

6. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound satisfies one of the following schemes 1 or 2: Option 1: The compound represented by formula (I) is a compound represented by the following formula (I-1), ;in, R 3 and R 3' are independently H or methyl; R 4 C 15 -C 19 alkyl; Option 2: The compound represented by formula (I) is a compound represented by the following formula (I-2), ;in, R 3 and R 3' are independently H or methyl; R 4 C 15 -C 19 alkyl.

7. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following compounds: , , , , , , , , , or .

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as described in any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient.

9. Use of a compound of formula (I) as described in any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 8 in the preparation of a medicament for treating and / or preventing infection by adenovirus AdV5 strain, adenovirus AdV14 strain or vaccinia virus.

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