Purine compound as well as preparation method and application thereof

Abstract

The invention relates to the field of medicinal chemistry, and particularly discloses purine compounds as well as a preparation method and application thereof. The purine compound provided by the invention is a compound as shown in a formula (I) or pharmaceutically acceptable salt thereof: # imgabs0 #. The purine compound disclosed by the invention is designed based on a novel purine skeleton structure, and the anti-herpes simplex virus type 1 (HSV-1) activity of the purine compound is verified through an in-vitro antiviral experiment. Experimental data show that the HSV-1 median inhibitory concentration (EC50) of the series of compounds to HSV-1 is obviously superior to that of a clinical first-line drug acyclovir, and the series of compounds show better virus inhibition efficiency on the premise of keeping a similar selectivity index (SI = CC50 / EC50). The technical scheme breaks through the molecular framework limitation of the existing anti-HSV-1 drugs (such as acyclovir, famciclovir and the like), and has good clinical transformation value.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to novel compounds containing purine structures and their application in the preparation of antiviral drugs as inhibitors of herpes simplex virus type 1 (HSV-1). Background Art

[0002] Herpes simplex virus type 1 (HSV-1), as a neurotropic alpha herpesvirus, its infection can cause various diseases such as oral herpes, keratitis, and fatal encephalitis, posing a major threat to global public health.

[0003] Currently, the first-line drug for the treatment of HSV-1 in clinical practice is still acyclovir, but its application is increasingly showing limitations. Studies have shown that the oral bioavailability of acyclovir is only 15%-20%, and the cerebrospinal fluid / plasma concentration ratio is as low as 0.15-0.25, making it difficult to effectively control the progression of HSV encephalitis. More seriously, the acyclovir resistance rate in immunosuppressed patients has reached 12.3%. Currently reported anti-HSV-1 compounds are still mainly natural products, with fewer structural types, and it is particularly urgent to develop novel non-nucleoside small molecule HSV-1 inhibitors with novel structures. Summary of the Invention

[0004] Based on the current technical status, the purpose of the present invention is to provide a class of novel compounds containing purine structures with good anti-herpes simplex virus type 1 (HSV-1) virus activity and low toxicity; another purpose is to provide its preparation method and its application as an antiviral drug in inhibiting HSV-1.

[0005] To achieve the purpose of the present invention, the purine compound of the present invention has a molecular structure as shown in formula (I):

[0006]

[0007] Wherein, R1 is an aryl or heteroaryl.

[0008] The aryl is an unsubstituted or arbitrarily substituted phenyl; the substituent can be any one of halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, amino, or nitro.

[0009] The heteroaryl is an unsubstituted or arbitrarily substituted pyridyl or furyl; the substituent can be any one of halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, amino, or nitro.

[0010] Preferably: R1 is a mono-substituted or di-substituted halogenated phenyl.

[0011] More preferably: R1 is a mono-substituted halogenated phenyl; the halogen is more preferably fluorine or chlorine.

[0012] Preferably, the purine compound is selected from compounds of the following structures or pharmaceutically acceptable salts thereof, denoted as compounds 4a-g in sequence:

[0013]

[0014] When the compounds developed in the present invention are used in drug development and applications, they can also be in the form of pharmaceutically acceptable salts, and those skilled in the art can make reasonable selections according to needs. Further, the pharmaceutically acceptable salt is one of hydrochloride, hydrobromide, sulfate, phosphate, borate, mesylate, tosylate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate, phenylacetate of the hydroxamic acid compounds.

[0015] The synthesis method is as follows:

[0016]

[0017] (1) Place the raw materials 2,6-dichloropurine, substituted benzenethiol and organic base in a reaction flask, add an alcohol solvent to dissolve, stir and react. After the reaction is completed, filter by suction, wash the obtained solid, and obtain intermediate 2, which is directly used in the next step without purification.

[0018] (2) Place intermediate 2, tert-butyl (4-methylpiperidin-4-yl)carbamate and organic base in a reaction flask, add an alcohol solvent to dissolve, heat and react. After the reaction is completed, remove the solvent under reduced pressure, extract, and concentrate under reduced pressure to obtain a crude product of intermediate 3, which is purified by recrystallization to obtain a pure product.

[0019] (3) Place intermediate 3 in a reaction flask, add an organic solvent to dissolve, then add an organic acid or a solvent that dissolves acidic gas, stir and react. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain a crude product, which is purified by recrystallization to obtain the target compound.

[0020] In the present invention, there is no special limitation on the selection of the solvent, and it only needs to ensure the dissolution of the reaction raw materials and the normal progress of the reaction. Preferably, the substituted benzenethiol in step (1) is one of 3-fluorobenzenethiol, 3-chlorobenzenethiol, 3-bromobenzenethiol, 2-chlorobenzenethiol, 4-chlorobenzenethiol, 2,3-dichlorobenzenethiol, 3,4-dichlorobenzenethiol; the organic base in steps (1) and (2) is one or more of triethylamine, pyridine, piperidine, N,N-diisopropylethylamine; the alcoholic organic solvent in steps (1) and (2) is one or more of methanol, ethanol, ethylene glycol, isopropanol, tert-butanol, n-butanol; the organic acid in step (3) is one or more of formic acid, acetic acid, propionic acid, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid; the acidic gas is one or more of hydrogen chloride, hydrogen bromide; the organic solvent in step (3) is one or more of methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile, methyl tert-butyl ether.

[0021] The present invention also provides the application of such purine compounds in the preparation of inhibitors or antiviral drugs based on the HSV-1 target. The small molecule compounds developed in the present invention show stronger virus inhibitory activity than acyclovir in in vitro experiments, and their half maximal inhibitory concentration (EC 50 ) is reduced by nearly 6 times. Moreover, the compounds of the present invention have a selection index close to that of acyclovir, and no adverse reactions such as liver and kidney damage are shown in the acute toxicity test. Their unique chemical skeleton design breaks through the structural limitations of traditional nucleoside analogs, has excellent blood-brain barrier penetration ability and drug resistance barrier, and provides important scientific value and clinical application prospects for the research and development of anti-HSV-1 drugs.

[0022] Advantages and innovations of the present invention: The present invention optimizes and designs novel compounds based on the purine skeleton, and significant breakthroughs have been made in anti-HSV-1 activity and safety. In vitro experiments show that the EC50 of the optimized compound against HSV-1 is nearly 6 times higher than that of the clinical first-line drug acyclovir, and the therapeutic index is close to that of the positive control drug acyclovir, with a good safety window. The present invention can not only provide compounds with better inhibitory effects on HSV-1 virus, but also is expected to avoid the drug resistance problem of traditional drugs, and is expected to be developed into an efficient, broad-spectrum and safe anti-HSV-1 drug. In addition, the synthesis method of the present invention has a simple route and a high yield, reaching more than 83%. Detailed implementation manners

[0023] The present invention will be further described below in conjunction with embodiments. These embodiments are only used to illustrate the present invention and do not limit the scope of the present invention.

[0024] In the following examples, unless otherwise specified, the percentages are all mass percentages. The compound structures were determined by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The nuclear magnetic resonance instrument used was a Bruker DPX-400 superconducting nuclear magnetic resonance instrument from Sweden, with tetramethylsilane (TMS) as the internal standard; the high-resolution mass spectrometry used was a Q-Tof mass spectrometer from Waters-Micromass. The 16 compounds involved in the examples are all new compounds synthesized in the present invention, and their structures were confirmed by modern spectroscopic means such as melting point determination, 1 1H NMR, 13 13C NMR and HRMS.

[0025] Acyclovir (ACV) was purchased from GlpBio (Montclair, USA). The primary antibodies against herpes simplex virus ICP4 and gD proteins were purchased from Abcam (UK). The antibodies against Cleaved PRAP, Cleaved Caspase-3, Bax, Bcl-2, STING, and Phospho-NF-κB (P65) were purchased from Cell Signaling Technology (CST; USA). The antibody against GAPDH was purchased from Abbkine (California, USA). Human laryngeal carcinoma epithelial cells (HEp-2) were purchased from Beijing Beina Chuanglian Biotechnology Research Institute (Beijing, China). Mouse BV2 microglial cell line (BV2) cells were purchased from Shanghai Qiyun Biotechnology Co., Ltd. (Shanghai, China) and cultured in Dulbecco's Modified Eagle Medium (DMEM; Hyclone, USA) containing 10% fetal bovine serum (FBS; Gibco, USA) at 37 °C and 5% CO2. Herpes simplex virus type 1 KOS strain (HSV-1 / KOS) was purchased from the American Type Culture Collection (ATCC; Manassas, USA).

[0026] The hydroxamic acid compounds involved in the following examples are denoted as compounds 4a-g in sequence, and their structural formulas are as follows:

[0027]

[0028] Example 1

[0029] The preparation processes of compounds 4a-g are similar. Now, 4a is taken as an example for illustration.

[0030]

[0031] (1) Preparation of intermediate 2a

[0032] 2,6-Dichloropurine (500 mg, 1.0 eq.), 3-fluorobenzenethiol (509 mg, 1.5 eq.), and triethylamine (402 mg, 1.5 eq.) were placed in a 100 mL eggplant-shaped flask and dissolved with 30 mL of ethanol. After stirring at room temperature for 1.5 h, a large amount of solid precipitated. The reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, the solid was filtered by suction, and the solid was rinsed with ethanol 2 - 3 times to obtain the crude product of intermediate 2a, which could be directly used in the next reaction without purification.

[0033] (2) Preparation of intermediate 3a

[0034] Intermediate 2a (762 mg, 1.0 eq.), tert-butyl (4-methylpiperidin-4-yl)carbamate (872 mg, 1.5 eq.), and N,N-diisopropylethylamine (456 mg, 1.3 eq.) were placed in a 100 mL eggplant-shaped flask and dissolved with 45 mL of n-butanol. After refluxing at 120 °C for 5 h, the reaction was monitored by TLC (PE:EA = 1:2). After the reaction was completed, most of the n-butanol was removed by distillation under reduced pressure. The system was dissolved with ethyl acetate and extracted with water 3 - 4 times. The crude product of intermediate 3a was obtained by concentration under reduced pressure. The crude product of intermediate 3a was purified by recrystallization with ethyl acetate to obtain intermediate 3a.

[0035] (3) Preparation of intermediate 4a

[0036] Intermediate 3a (540 mg, 1.0 eq.) was placed in a 100 mL eggplant-shaped flask, dissolved with 5 mL of ethyl acetate, and then 15 mL of hydrochloric acid-ethyl acetate solution was added. After stirring at room temperature for 4 h, the reaction was monitored by TLC (PE:EA = 1:4). After the reaction was completed, the solution was concentrated under reduced pressure. Subsequently, the system was dissolved with ethyl acetate multiple times and the solvent was removed. Finally, the crude product was obtained. The crude product was purified by recrystallization with ethyl acetate to finally obtain compound 4a.

[0037] Compound 4a: 1-(6-((3-fluorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. White solid, yield 95%, melting point 285.4 - 287.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.26 (s, 3H), 7.58–7.51 (m, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.41–7.35 (m, 1H), 3.90 (d, J = 13.8 Hz, 2H), 3.28 (t, J = 10.4 Hz, 2H), 1.68–1.53 (m, 4H), 1.33 (s, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 163.63, 161.18, 158.07, 157.28, 152.35, 141.00, 132.17, 132.14, 131.38, 131.30, 129.37, 122.89, 117.02, 52.65, 34.45, 22.96. HR-MS (ESI): Calcd. C 17 H 19 FN6S, [M+H] + m / z: 359.1456, found: 359.1456.

[0038] Example 2

[0039] The purine compound of this example has the structural formula as shown in Compound 4b, and its preparation process is basically the same as that of Example 1, except that: 3-fluorobenzenethiol in step (1) is replaced by 3-chlorobenzenethiol.

[0040] Compound 4b: 1-(6-((3-chlorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. White solid, yield 83%, melting point 291.5 - 293.1 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.34 (s, 3H), 7.76 (d, J = 1.7 Hz, 1H), 7.63–7.50 (m, 3H), 3.91 (d, J = 12.6 Hz, 2H), 3.36–3.24 (m, 2H), 1.73–1.52 (m, 4H), 1.34 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 158.04, 157.06, 152.33, 141.02, 135.60, 134.44, 133.70, 131.29, 130.02, 129.41, 52.63, 34.49, 22.99. HR-MS (ESI): Calcd. C 17 H 19 ClN6S, [M+H] + m / z: 375.1160, found: 375.1160.

[0041] Example 3

[0042] The purine compound of this example has the structural formula as shown in Compound 4c, and its preparation process is basically the same as that of Example 1, except that: 3-fluorobenzenethiol in step (1) is replaced by 3-bromobenzenethiol.

[0043] Compound 4c: 1-(6-((3-bromophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. Pink solid, yield 83%, melting point 282.4 - 283.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.32 (s, 3H), 7.89 (t, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.0, 1.9 Hz, 1H), 7.66–7.61 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H), 3.92 (d, J = 13.7 Hz, 2H), 3.37–3.25 (m, 2H), 1.74–1.53 (m, 4H), 1.34 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 158.07, 157.04, 152.29, 141.02, 138.38, 134.71, 132.87, 131.58, 129.61, 122.03, 52.63, 34.55, 23.01. HR-MS (ESI): Calcd. C 17 H 19 BrN6S, [M + H] + m / z: 419.0655, found: 419.0657.

[0044] Example 4

[0045] The purine compound of this example has the structural formula shown in Compound 4d, and its preparation process is basically the same as that of Example 1, with the only difference being that: 3-fluorobenzenethiol in step (1) is replaced by 2-chlorobenzenethiol.

[0046] Compound 4d: 1-(6-((2-chlorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. White solid, yield 90%, melting point 292.2 - 294.3 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.31 (s, 3H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H), 3.83 (d, J = 13.4 Hz, 2H), 3.22 (s, 2H), 1.69–1.47 (m, 4H), 1.32 (s, 3H). 13CNMR(101MHz, DMSO-d6) δ 157.98, 156.64, 152.37, 140.92, 139.60, 138.94, 138.46, 132.49, 130.47, 128.46, 126.60, 52.62, 34.50, 22.92. HR-MS(ESI): Calcd. C 17 H 19 ClN6S, [M + H] + m / z: 375.1160, found: 375.1162.

[0047] Example 5

[0048] The purine compound of this example has the structural formula as shown in Compound 4e. Its preparation process is basically the same as that of Example 1, except that: 3-fluorobenzenethiol in step (1) is replaced by 4-chlorobenzenethiol.

[0049] Compound 4e: 1-(6-((4-chlorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. White solid, yield 83%, melting point 272.6 - 273.1 °C. 1 H NMR(400MHz, DMSO-d6) δ 8.38(s, 1H), 8.23(s, 3H), 7.66–7.56(m, 4H), 3.87(s, 2H), 3.26(t, J = 11.0Hz, 2H), 1.67–1.51(m, 4H), 1.32(s, 3H). 13 CNMR(101MHz, DMSO-d6) δ 158.12, 157.48, 152.19, 140.94, 137.97, 135.16, 129.65, 126.25, 52.64, 34.49, 22.98. HR-MS(ESI): Calcd. C 17 H 19 ClN6S, [M + H] + m / z: 375.1160, found: 375.1160.

[0050] Example 6

[0051] The purine compound of this example has the structural formula as shown in Compound 4f. Its preparation process is basically the same as that of Example 1, except that: 3-fluorobenzenethiol in step (1) is replaced by 2,3-dichlorobenzenethiol.

[0052] Compound 4f: 1-(6-((2,3-dichlorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. White solid, yield 90%, melting point 259.6 - 261.3 °C.1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.24 (s, 3H), 7.84 (dd, J = 8.1, 1.5 Hz, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 3.83 (d, J = 13.6 Hz, 2H), 3.22 (s, 2H), 1.64–1.50 (m, 4H), 1.32 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 157.94, 155.97, 152.44, 141.05, 137.71, 137.38, 133.09, 132.84, 129.39, 129.20, 52.63, 34.53, 23.01. HR-MS (ESI): Calcd. C 17 H 18 Cl2N6S, [M + H] + m / z: 409.0771, found: 409.0747.

[0053] Example 7

[0054] The purine compound of this example has the structural formula as shown in Compound 4g, and its preparation process is basically the same as that of Example 1, except that: 3-fluorobenzenethiol in step (1) is replaced by 3,4-dichlorobenzenethiol.

[0055] Compound 4g: 1-(6-((3,4-dichlorophenyl)thio)-9H-purin-2-yl)-4-methylpiperidin-4-amine. Milky white solid, yield 83%, melting point 267.9 - 269.3 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.26 (s, 3H), 7.97 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 3.32 (d, J = 11.4 Hz, 2H), 1.70–1.55 (m, 4H), 1.34 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 158.04, 156.63, 152.37, 141.14, 137.54, 135.85, 133.01, 131.86, 131.51, 128.19, 52.63, 34.49, 23.04. HR-MS (ESI): Calcd. C 17 H 18 Cl2N6S, [M + H] +m / z: 409.0771, found: 409.0772.

[0056] Example 8 Anti-HSV-1 Activity and Cytotoxicity Screening

[0057] Anti-HSV-1 activity experimental method:

[0058] Inoculate Hep-2 cells into a 96-well plate at a density of 1.5×10 4 cells per well. When the cells grow to 80% confluence, infect the cells with a 100 TCID 50 virus suspension. Then, add compounds with different concentrations to the cells and incubate for 72 hours. Measure the absorbance at a wavelength of 490 nm (OD 490 ) using MTT. The calculation formula for the virus inhibition rate is as follows:

[0059] Inhibition rate (%) = (OD of the compound group 490 - OD of the virus control group 490 ) / (OD of the blank group 490 - OD of the virus control group 490 ) × 100%

[0060] Input the inhibition rate and the corresponding compound concentration into SPSS 26 software to calculate the EC 50 of the compound.

[0061] Cytotoxicity screening experimental method:

[0062] Use the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Beijing Solarbio Science & Technology Co., Ltd.) to measure cell viability. Inoculate Hep-2 cells into a 96-well plate at a density of 1.5×10 4 cells per well. When the cells grow to 80% confluence, add compounds with different concentrations to each well. After incubating in an incubator for 72 hours, measure the absorbance at a wavelength of 490 nm (OD 490 ) using MTT. The calculation formula for cell viability is as follows:

[0063] Cell viability (%) = OD of the compound group 490 / OD of the blank control group 490 × 100%

[0064] Input the cell viability and the corresponding compound concentration into SPSS 26 software to calculate the CC 50 of the compound.

[0065] The antiviral activity and cytotoxicity of the compounds in the present invention against HSV are summarized in Table 1.

[0066] Table 1. Screening Results of the Antiviral Activity and Cytotoxicity of Compounds

[0067]

[0068] a CC 50 : Median cytotoxic concentration.

[0069] b EC 50 : Median effective inhibitory concentration.

[0070] c SI: (Selectivity Index) = CC 50 / EC 50 .

[0071] As can be seen from the above table, compounds 4a, 4b, and 4d all showed significantly better antiviral activity than the positive control drug acyclovir. Among them, compound 4d showed the strongest virus inhibitory ability (EC 50 1.67 ± 0.79 μM), and its antiviral efficacy was nearly 6 times higher than that of acyclovir (EC 50 9.62 ± 3.06 μM). It is worth noting that although the cytotoxicity of 4d (CC 50 32.82 ± 6.08 μM) was slightly higher than that of acyclovir (CC 50 283.34 ± 22.82 μM), its therapeutic index (SI = 19.65) was very close to that of the positive control drug acyclovir (SI = 29.45), showing good development potential and clinical treatment prospects.

[0072] In summary, a series of purine compounds were successfully developed in this invention, and compound 4d showed good clinical transformation value. This compound not only has significantly better antiviral efficacy than the first-line drug acyclovir (EC 50 = 1.95 vs 9.62 μM), but is more likely to achieve a synergistic therapeutic effect through a dual mechanism of action. The compounds developed in this invention highlight the potential as therapeutic drugs for HSV-1-related diseases, not only providing a new strategy for the treatment of HSV-1, but also opening up a new direction for the development of drugs for the herpes virus family.

Claims

1. A purine compound, characterized in that: It is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: Wherein, R1 is a mono-substituted or di-substituted halogenated phenyl group.

2. The purine compound according to claim 1, characterized in that R1 is a monosubstituted halogenated phenyl group; the halogen is selected from fluorine or chlorine.

3. The purine compound according to claim 1 or 2, characterized in that The pharmaceutically acceptable salt is one of hydrochloride, hydrobromide, sulfate, phosphate, borate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, benzenesulfonate, citrate, lactate, pyruvate, tartrate, acetate, trifluoroacetate, maleate, succinate, mandelate, fumarate, salicylate, and phenylacetate.

4. The purine compound according to claim 1, characterized in that Selected from compounds having the following structures:

5. A method for preparing a purine compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: R1 is consistent with claim 1; (1) placing the raw materials 2,6-dichloropurine, substituted thiophenol and organic base in a reaction flask, heating an alcohol solvent to dissolve, stirring to react, and filtering after the reaction, washing the obtained solid to obtain intermediate 2, which is directly used in the next step without purification; (2) placing intermediate 2, tert-butyl (4-methylpiperidin-4-yl)carbamate and an organic base in a reaction flask, adding an alcohol solvent to dissolve, heating to react, removing the solvent under reduced pressure after the reaction, extracting, concentrating under reduced pressure to obtain a crude intermediate 3, and purifying by recrystallization to obtain a pure product; (3) The intermediate 3 is placed in a reaction flask, an organic solvent is added to dissolve it, and then an organic acid or a solvent that dissolves acidic gas is added, and the reaction is stirred. After the reaction is completed, the mixture is concentrated under reduced pressure to remove the solvent to obtain a crude product, which is then purified by recrystallization to obtain the target compound.

6. The method for preparing a purine compound according to claim 5, characterized in that: The substituted thiophenol in step (1) is selected from one of 3-fluorothiophenol, 3-chlorothiophenol, 3-bromothiophenol, 2-chlorothiophenol, 4-chlorothiophenol, 2,3-dichlorothiophenol and 3,4-dichlorothiophenol.

7. Use of a purine compound as claimed in any one of claims 1 to 4 in the preparation of an antiviral drug, characterized in that: It is used as an active ingredient to prepare an anti-herpes simplex virus type 1 HSV-1 drug.

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