Five-membered sulfur-containing heterocyclic nucleoside lead compounds and their application in anti-HIV drugs

Abstract

This invention discloses five-membered sulfur-containing heterocyclic nucleoside derivatives and their application in anti-HIV drugs, belonging to the field of medicinal chemistry. A series of five-membered sulfur-containing heterocyclic nucleoside compounds were synthesized via a Sulfa-Michael / Aldol tandem reaction. Results showed that in anti-HIV virus testing, the five-membered sulfur-containing heterocyclic nucleoside lead compound 42a exhibited the best anti-HIV-1 activity, providing a new structural unit for candidate antiviral drug molecules.

Description

Technical Field

[0001] This invention relates to five-membered sulfur-containing heterocyclic nucleoside lead compounds and their application in anti-HIV active drugs, belonging to the field of medicinal chemistry. Background Technology

[0002] Viruses pose a serious threat to human life and health, and are one of the leading causes of death. The development of antiviral drugs has always been a crucial direction in drug development. Synthetically synthesized nucleoside compounds are structurally similar to natural nucleoside compounds and, after entering the human body, can inhibit the replication of viruses or tumor cells, achieving antiviral or antitumor effects.

[0003] The research and development of nucleoside antitumor and antiviral drugs is receiving increasing attention. Five-membered thioheterocyclic nucleosides are a unique class of nucleoside compounds with distinctive physicochemical properties, and have become a key focus in nucleoside drug development.

[0004] Five-membered thioheterocyclic nucleoside compounds are an important class of marketed antiviral drugs, but research on their antiviral activity is relatively limited. Innovative research on five-membered thioheterocyclic nucleoside antiviral drugs has significant scientific importance and potential application prospects. Summary of the Invention

[0005] To overcome the aforementioned technical deficiencies, this invention provides nucleoside lead compounds with more functional structures, and discloses five-membered thioheterocyclic nucleoside lead compounds with anti-HIV activity. In terms of synthesis methods: a series of five-membered thioheterocyclic nucleoside compounds were synthesized through reactions such as the Sulfa-Michael / Aldol tandem reaction.

[0006] The present invention discloses a five-membered thioheterocyclic nucleoside lead compound comprising its racemic form and a chiral compound, wherein the chiral compound has an ee value of 0-100% and is composed of a single enantiomer or a mixture of two enantiomers in different proportions. Its general structural formula is as follows:

[0007]

[0008] Where: R 1 Selected from hydrogen, halogen, amino, C1-C20 alkyl, C1-C20 alkoxy; R 2 Selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, C1-20 alkylthio, C2-C20 alkynthio, halogenated C1-C20 alkylthio, benzylthio, phenylthio, substituted phenylthio, di(C1-C8 alkyl)amino, X = CH2, O, S, NH, N-(C1-C4) alkyl; n = 0-5; R3 =C1-C8 alkyl, halogen, trifluoromethyl, benzyl, substituted phenylmethyl, morpholino; wherein the substituent in the substituted phenyl group is a halogen or a C1-C8 alkyl; R is selected from hydrogen and C1-C20 alkyl.

[0009] Furthermore, under preferred conditions, R 1 Selected from hydrogen, halogen, amino, C1-C20 alkyl, C1-C20 alkoxy; R 2 Selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, C1-20 alkylthio, C2-C20 alkynthio, halogenated C1-C20 alkylthio, benzylthio, phenylthio, substituted phenylthio, di(C1-C8 alkyl)amino, X = CH2, O, S, NH, N-(C1-C4) alkyl; n = 0-5; R = C1-C8 alkyl, halogen, trifluoromethyl, benzyl, substituted phenylmethyl, morpholino; wherein the substituent in the substituted phenyl group is a halogen or a C1-C8 alkyl group; R is selected from ethyl.

[0010] Furthermore, under preferred conditions, R 1 Selected from hydrogen, halogen, and amino; R 2 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-6 alkylthio, C2-C4 alkynthio, halo-C1-C4 alkylthio, benzylthio, phenylthio, substituted phenylthio, di(C1-C2 alkyl)amino, X = CH2, O, S, NH, N-(C1-C4) alkyl; n = 1 - 3; R 3 =C1-C4 alkyl, halogen, trifluoromethyl, benzyl, substituted phenylmethyl, morpholino; wherein the substituent in the substituted phenyl group is a halogen or a C1-C4 alkyl group; R is selected from ethyl.

[0011] Furthermore, under optimal conditions, the structure of the five-membered thioheterocyclic nucleoside lead compound is as follows:

[0012]

[0013] This invention also provides a method for synthesizing a five-membered thioheterocyclic nucleoside lead compound, comprising the following steps:

[0014]

[0015] Compound 1-42A was reacted in the presence of triphenylphosphine, sodium acetate, acetic acid and propargyl ester to give compound 1-42B; compound 1-42B was then reacted with 1,4-dithiane-2,5-diol in the presence of triethylamine to give 1a-42a and 1b-42b; the corresponding chiral compounds were then separated by a chiral separation column.

[0016] Furthermore, in the above technical solution, the solvent for the first reaction is toluene, and the reaction temperature is 110℃.

[0017] Furthermore, in the above technical solution, the solvent for the second step reaction is dichloromethane, and the reaction temperature is 0-30℃.

[0018] Furthermore, in the above technical solution, the chiral separation column is used for separation using a CHI RALPAK IF (IF00CE-RL017, 0.46cm IDx 25cm L) chromatographic column (injection volume 10μL, mobile phase MeOH / DCM-95 / 5 (V / V), flow rate 1.0mL / min, wavelength UV 254nm, column temperature 35℃, HPLC: Shimadzu LC-20AD CP-HPLC-08), and the chiral compounds after separation are all greater than 98% ee.

[0019] This invention also provides the application of five-membered thioheterocyclic nucleoside lead compounds in the preparation of antiviral drugs.

[0020] Furthermore, in the above technical solution, the antiviral agent is an anti-HIV-1 virus.

[0021] This invention also provides the application of a five-membered thioheterocyclic nucleoside lead compound in the preparation of drugs for treating AIDS.

[0022] The present invention also provides a pharmaceutical composition containing the above-mentioned five-membered thioheterocyclic nucleoside lead compound.

[0023] Beneficial effects of the invention:

[0024] 1. The raw materials used are simple and readily available, and have broad application prospects.

[0025] 2. Antiviral activity tests were conducted on the products, and it was found that compound 42a (LZ-42a) had good anti-HIV-1 activity. Attached Figure Description

[0026] Figure 1 Image showing the anti-HIV-1 viral activity of 42a (LZ-42a);

[0027] Figure 2 The diagram shows the anti-HIV-1 viral activity of 11a (LZ-11a). Detailed Implementation

[0028] Example 1

[0029]

[0030] Synthesis of 1a / 1b-42a / 42b. Reagents and conditions: (a) PPh3, NaOAc, HOAc, Ethyl propiolate, toluene, 110℃, 12h. (b) 1,4-dithiane-2,5-diol, Et3N (20mol%), CH2Cl2, rt, 4h.

[0031] Typical procedure of step one: In a round-bottom flask, purine compound A (10 mmol), triphenylphosphine (0.0521 g, 0.2 mL), sodium acetate (0.1641 g, 2 mmol), acetic acid (0.3 mL, 2 mmol), and ethyl propynate (1.21 mL, 12 mmol) were added to toluene (100 mL). Under nitrogen protection, the mixture was heated and stirred at 110 °C for 12 h. The reaction mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by silica gel (PE / EA = 2 / 1) column chromatography to obtain product B.

[0032] The second step, a typical procedure, involves adding α-heterocyclic acrylate B (0.05 mmol) and 1,4-dithionane-2,5-diol (0.03 mmol) to a round-bottom flask. Then, 20 mmol% triethylamine is added, and the mixture is stirred at room temperature for 4 hours. The reaction products are detected by thin-layer chromatography, and the solvent is removed by silica gel (PE / EA = 2 / 1) column chromatography to obtain products a and b.

[0033] Structural characterization of representative compounds:

[0034] 1.2.1.(±)-Ethyl-4-hydroxy-3-(9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(1a,1b)

[0035] 1a: white solids, 41.2% yield. 1H NMR(600MHz,CDCl3)δ9.18(s,1H),8.95(s,1H),8.42(s,1H),5.42(d,J=42.6Hz,2H),4.24-4.16(m,2H),3.96(d,J=12.6Hz,1H),3.59(d,J=12Hz,1H),3.19(dd,J=4.8Hz,J=7.2Hz,1H),2.86(dd,J=4.8Hz,J=11.4Hz,1H),1.08(t,J=6.6Hz,3H). 13 C NMR(150MHz,CDCl3)δ169.3,152.4,151.5,149.6,144.0,134.3,78.9,74.0,63.3,35.5,35.4,13.9.ESI-HRMS(m / z)calcd C 12 H 15 N4O3S(M+H) + ,295.0859;found,295.0856.HPLC purity:97.7%.1b:white solids,52.4%yield. 1 H NMR(600MHz,CDCl3)δ9.06(s,1H),8.83(s,1H),8.51(s,1H),5.49(t,J=6.0Hz,1H),4.22-4.15(m,2H),3.74(dd,J=12Hz,J=30.0Hz,2H),3.34(q,J=5.4Hz,1H),2.89(q,J=6,1H),1.12(t,J=7.2Hz,3H), 13 C NMR(150MHz,CDCl3)δ168.1,152.1,151.7,148.9,145.0,133.7,76.3,73.8,63.1,34.7,34.0,13.8;ESI-HRMS(m / z)calcdC 12 H 14 N4O3SNa(M+Na) + ,317.0679;found,317.0678.HPLCpurity:98.0%.

[0036] 1.2.2.(±)-Ethyl-3-(6-chloro-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxy late(2a,2b)

[0037] 2a:colorless 1iquid,42.4%yield. 1 HNMR(600MHz,CDCl3)δ8.70(s,1H),8.56(s,1H),5.46(s,1H),4.23(t,J=7.2Hz,2H),3.79(d,J=11.4Hz,1H),3.64(d,J=11.4Hz,1H),3.32(q,J=6.0Hz,1H),2.83(dd,J=6.6Hz,J=11.4Hz,1H)1.17(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ167.9,152.2,152.0,151.8,144.7,131,7,74.0,63.5,34.9,33.7,14.0;ESI-HRMS(m / z)calcd C 12 H 13 N4ClO3SNa(M+Na) + ,351.0281;found,351.0289.HPLC purity:98.3%.2b:colorless 1iquid,58.3%yield. 1 H NMR(600 MHz,CDCl3)δ8.71(s,1H),8.48(s,1H),5.34(s,1H),5.14(s,1H),4.20(d,J=6.6 Hz,2H),3.97(d,J=12.6 Hz,1H),3.15(dd,J=4.2 Hz,J=12,1H),2.82(dd,J=4.8 Hz,J=11.4 Hz,1H),1.09(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.1,152.1,151.8,151.7,143.8,132.0,78.8,74.2,63.5,53.6,35.5,35.4,14.0;ESI-HRMS(m / z)calcd C 12 H 13 N4ClO3SNa(M+Na) + ,351.0289;found,351.0294.HPLC purity:98.8%.

[0038] 1.2.3.(±)-Ethyl-3-(6-bromo-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxy late(3a,3b)

[0039] 3a:white solid,30.1%yield. 1 H NMR(400 MHz,CDCl3)δ8.61(s,1H),8.58(s,1H),5.46(s,1H),4.27-4.17(m,2H),4.15-4.12(m,1H),3.73(dd,J=12.0 Hz,J=28.4 Hz,2H),3.33(q,J=5.6 Hz,1H),2.84(dd,J=6.4 Hz,J=11.2 Hz,1H),1.14(t,J=7.2Hz,3H). 13 C NMR(100 MHz,CDCl3)δ167.9,151.7,150.9,144.8,143.9,134.1,74.1,63.4,34.7,33.9,13.9.ESI-HRMS(m / z)calcd C 12 H 13 N4BrO3SNa(M+Na)+,394.9784;found,394.9782.HPLC purity:95.5%.3b:white solid,41.2%yield. 1 H NMR(400 MHz,CDCl3)δ8.66(s,1H),8.50(s,1H),5.34(s,1H),5.12(s,1H),4.20(q,J=7.2 Hz,2H),3.96(d,J=12.4 Hz,1H),3.58(d,J=12.8 Hz,1H),3.15(dd,J=4.0 Hz,J=11.6 Hz,1H),2.81(dd,J=4.8 Hz,J=11.6 Hz,1H),1.10(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.0,151.7,150.4,144.1,143.7,134.5,78.7,74.3,63.5,35.5,35.3,13.9.ESI-HRMS(m / z)calcd C 12 H 13 N4BrO3SNa(M+Na) +,394.9784;fou nd,394.9789.HPLC purity:98.1%.

[0040] 1.2.4.(±)-Ethyl-3-(6-(dimethylamino)-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(4a,4b)

[0041] 4a:white solid,38.1%yield. 1 H NMR(400 MHz,CDCl3)δ8.49(s,1H),8.19(s,1H),5.84(s,1H),5.32(t,J=5.2 Hz,1H),4.23-4.15(m,8H),3.93(d,J=12.4 Hz,1H),3.57(d,J=12.0 Hz,1H),3.21(q,J=5.2 Hz,1H),2.89(dd,J=5.2 Hz,J=11.6 Hz,1H),1.10(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ69.4,161.6,152.0,151.9,141.0,121.8,79.3,74.1,63.1,54.6,35.6,35.3,14.0.ESI-HRMS(m / z)calcd C 14 H 20 N5O3S(M+H) + ,338.1281;found,338.1272.HPLC purity:98.9%.4b:white solid,59.2%yield. 1 H NMR(600 MHz,CDCl3)δ8.22(s,1H),8.00(s,1H),6.28(s,1H),5.40(t,J=6.6,1H),4.25-4.18(m,2H),3.74(d,J=12 Hz,1H),3.54-3.44(m,7H),3.22(dd,J=6.6Hz,J=10.8 Hz,1H),2.81(dd,J=7.2 Hz,J=10.8 Hz,1H),1.18(t,J=7.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ168.6,155.2,151.8,150.4,137.8,120.1,73.9,63.0,35.3,33.3,14.0.ESI-HRMS(m / z)calcd C 14 H 20 N5O3S(M+H) + ,338.1281;found,338.1280.HPLC purity:95.2%.

[0042] 1.2.5.(±)-Ethyl-4-hydroxy-3-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(5a,5b)

[0043] 5a:white solid,41.7%yield. 1 H NMR(400 MHz,CDCl3)δ8.24(s,1H),7.90(s,1H),5.25(t,J=5.6 Hz,1H),4.28-4.15(m,6H),3.87(d,J=12.0 Hz,1H),3.53(d,J=12.0Hz,1H),3.25(dd,J=6.0,J=11.2 Hz,1H),2.94(dd,J=11.2,J=5.2 Hz,1H),1.76-1.69(m,6H),1.15(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.8,154.1,151.9,150.9,136.8,119.8,79.7,74.0,63.0,35.9,35.1,26.3,24.9,14.1.ESI-HRMS(m / z)calcdC 17 H 24 N5O3S(M+H) + ,378.1594;found,378.1597.HPLC purity:98.7%.5b:white solid,51.1%yield. 1H NMR(600 MHz,CDCl3)δ8.19(s,1H),7.99(s,1H),5.39(t,J=6.6,1H),4.24-4.18(m,6H),3.72(d,J=12,1H),3.44(d,J=12,1H),3.21(q,J=6,1H),2.80(q,J=7.2,1H),1.74-1.67(m,6H),1.18(t,J=6.6,3H). 13 C NMR(150 MHz,CDCl3)δ168.6,154.1,151.9,150.7,137.5,119.6,73.8,63.0,35.2,33.4,26.3,24.8,14.0.ESI-HRMS(m / z)calcdC 17 H 23 N5O3SNa(M+Na) + ,400.1414;found,400.1410.HPLC purity:95.8%.

[0044] 1.2.6.(±)-Ethyl-3-(6-ethoxy-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxy late(6a,6b)

[0045] 6a:white solid,39.1%yield. 1 H NMR(600 MHz,CDCl3)δ8.47(s,1H),8.17(s,1H),5.90(d,J=2.4 Hz,1H),5.31(t,J=5.4 Hz,1H),4.69-4.63(m,2H),4.23-4.15(m,2H),3.92(d,J=12.6 Hz,1H),3.67(d,J=12.0 Hz,1H),3.21(q,J=5.4 Hz,1H),2.89(dd,J=4.8 Hz,J=11.4 Hz,1H),1.51(t,J=7.2 Hz,3H),1.10(t,J=7.2 Hz,3H). 13 C NMR(100MHz,CDCl3)δ169.8,161.7,152.4,152.4,141.3,122.1,79.7,74.5,64.0,63.5,36.1,35.7,15.0,14.4.ESI-HRMS(m / z)calcd C 14 H 18 N4O4SNa(M+Na)+ ,361.0941;found,361.0938.HPLCpurity:95.4%.6b:white solid,53.2%yield. 1 H NMR(600 MHz,CDCl3)δ8.43(s,1H),8.22(s,1H),5.46(t,J=6.0 Hz,1H),4.64(q,J=7.2 Hz,2H),4.23-4.63(m,2H),4.23-4.16(m,2H),3.74(d,J=12.0 Hz,1H),3.59(d,J=11.4 Hz,1H),3.30(q,J=6.0 Hz,1H),2.87(dd,J=6.0 Hz,J=7.2 Hz,1H),1.51(t,J=7.2 Hz,3H),1.15(t,J=7.2 Hz,3H). 13 C NMR(100MHz,CDCl3)δ168.3,161.2,152.0,151.9,141.8,121.4,76.7,74.1,63.6,63.1,35.0,33.8,14.6,13.9.ESI-HRMS(m / z)calcd C 14 H 18 N4O4SNa(M+Na) + ,361.0941;found,361.0936.HPLCpurity:96.0%.

[0046] 1.2.7.(±)-Ethyl-4-hydroxy-3-(6-methoxy-9H-purin-9-yl)tetrahydrothiophene-3-carbox ylate(7a,7b)

[0047] 7a:light yellow solid,32.8%yield. 1 H NMR(600 MHz,CDCl3)δ8.49(s,1H),8.19(s,1H),5.31(t,J=7.8 Hz,1H),4.21-4.15(m,5H),3.92(d,J=18.6 Hz,1H),3.57(d,J=18 Hz,1H),3.20(dd,J=7.8 Hz,J=17.4 Hz,1H),2.89(dd,J=7.2 Hz,J=17.4Hz,1H),1.09(t,J=10.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ169.8,155.2,151.9,150.7,137.1,120.1,79.7,74.0,62.9,53.6,35.9,35.1,14.1.ESI-HRMS(m / z)calcd C 13 H 16 N4O4SNa(M+Na) + ,347.0784;found,347.0786.HPLC purity:95.1%.7b:light yellow solid,54.1%yield. 1 H NMR(400 MHz,CDCl3)δ8.47(s,1H),8.25(s,1H),5.46(t,J=6.4 Hz,1H),4.21(t,J=7.2 Hz,5H),3.76(d,J=11.6 Hz,1H),3.57(d,J=11.2 Hz,1H),3.29(q,J=5.6 Hz,1H),2.86(dd,J=6.4 Hz,J=11.2 Hz,1H),1.16(t,J=7.2 Hz,3H). 13 C NMR(100MHz,CDCl3)δ168.3,161.6,152.0,151.9,141.9,74.0,63.2,54.6,35.1,33.7,14.0.ESI-HRMS(m / z)calcd C 13 H 16 N4O4SNa(M+Na) + ,347.0784;found,347.0778.HPLC purity:95.7%.

[0048] 1.2.8.(±)-Ethyl-4-hydroxy-3-(6-(propylthio)-9H-purin-9-yl)tetrahydrothiophene-3-ca rboxylate(8a,8b)

[0049] 8a:yellow solid,31.2%yield. 1H NMR(400 MHz,CDCl3)δ8.63(s,1H),8.28(s,1H),5.48(t,J=6.0 Hz,1H),4.22(q,J=7.2 Hz,2H),3.78(d,J=12.0 Hz,1H),3.56(d,J=11.6 Hz,2H),3.37(t,J=7.2 Hz,2H),3.29(dd,J=6.0 Hz,J=11.2,1H),2.86(dd,J=6.8 Hz,J=11.2 Hz,1H),1.81.78(m,2H),1.18(t,J=7.2 Hz,3H),1.09(t,J=7.6,3H). 13 CNMR(100 MHz,CDCl3)δ168.3,163.0,151.5,148.4,142.2,131.3,74.0,63.2,35.1,33.6,30.9,22.9,14.0,13.6.ESI-HRMS(m / z)calcd C 15 H 20 N4O3S2Na(M+Na) + ,391.0869;found,391.0870.HPLC purity:98.0%.8b:yellow solid,yield:54.1%. 1 H NMR(400 MHz,CDCl3)δ8.64(s,1H),8.22(s,1H),5.32(t,J=4.8 Hz,1H),4.25-4.14(m,2H),3.92(d,J=12.4Hz,1H),3.56(d,J=12.4 Hz,1H),3.42-3.31(m,2H),3.19(dd,J=5.2 Hz,J=11.6 Hz,1H),2.87(dd,J=4.8 Hz,J=11.6 Hz,1H),1.86-1.77(m,2H),1.13-1.06(m,6H). 13 C NMR(100 MHz,CDCl3)δ169.4,162.9,151.5,148.3,141.2,131.5,79.2,74.0,63.2,35.6,35.3,30.9,22.9,14.0,13.5.ESI-HRMS(m / z)calcd C 15 H 20 N4O3S2Na(M+Na) + ,391.0869;found,391.0865.HPLC purity:96.4%.

[0050] 1.2.9.(±)-Ethyl-4-hydroxy-3-(6-morpholino-9H-purin-9-yl)tetrahydrothiophene-3-ca rboxylate(9a,9b)

[0051] 9a:white solid,24.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.27(s,1H),7.94(s,1H),5.26(t,J=5.6 Hz,1H),4.31(s,4H),4.26-4.15(m,2H),3.88(d,J=12.4 Hz,1H),3.83(d,J=4.0 Hz,4H),3.53(d,J=12.0 Hz,1H),3.23(q,J=6.0 Hz,1H),2.92(dd,J=5.2 Hz,J=11.6 Hz,1H),1.15(t,J=6.8 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.7,154.1,151.9,151.1,137.3.120.0,79.6,74.0,67.1,63.0,35.8,35.2,14.1.ESI-HRMS(m / z)calcdC 16 H 22 N5O4S(M+H) + ,380.1387;found,380.1390.HPLC purity:97.9%.9b:white solid,45.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.23(s,1H),8.02(s,1H),5.94(s,1H),5.40(t,J=6.4 Hz,1H),4.29(s,4H),4.21(q,J=7.2 Hz,2H),3.81(t,J=4.8 Hz,4H),3.73(d,J=11.6 Hz,1H),3.46(d,J=11.6 Hz,1H),3.23(dd,J=6.0 Hz,J=10.8 Hz,1H),2.80(dd,J=7.2 Hz,J=10.8 Hz,1H),1.18(t,J=6.8Hz,3H). 13C NMR(100 MHz,CDCl3)δ168.5,154.1,151.8,150.9,138.1,119.8,77.3,73.8,67.1,63.0,35.2,33.4,14.0.ESI-HRMS(m / z)calcd C 16 H 21 N5O4SNa(M+Na) + ,402.1206;found,402.1196.HPLC purity:99.4%.

[0052] 1.2.10.(±)-Ethyl-4-hydroxy-3-(6-thiomorpholino-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(10a,10b)

[0053] 10a:white solid,30.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.27(s,1H)7.94(s,1H),5.27(t,J=5.6 Hz,1H),4.59(s,4H),4.26-4.18(m,2H),3.88(d,J=12 Hz,1H),3.54(d,J=12 Hz,1H),3.24(q,J=6 Hz,1H),2.93(dd,J=5.2 Hz,J=11.2 Hz,1H),2.76(t,J=5.2 Hz,4H),1.16(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ160.7,153.9,151.9,151.2,137.3,120.0,79.6,74.0,63.0,35.9,35.2,27.5,14.1.ESI-HRMS(m / z)calcdC 16 H 22 ClN5O3S2(M+H) + ,396.1159;found,396.1149.HPLC purity:96.1%.10b:white solid,45.2%yield. 1H NMR(600 MHz,CDCl3)δ8.27(s,1H),7.94(s,1H),6.46(s,1H),5.27(t,J=6Hz,1H)4.59(s,4H),4.25-4.19(m,2H),3.88(d,J=12 Hz,1H),3.54(d,J=12 Hz,1H),3.24(q,J=6 Hz,1H),2.93(q,J=5.4 Hz,1H),2.77(t,J=4.8 Hz,4H),1.16(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.7,153.9,151.9,151.2,120.0,79.6,74.0,63.0,35.9,35.2,27.5,14.1.ESI-HRMS(m / z)calcd C 16 H 21 ClN5O3S2Na(M+Na) + ,418.0978;found,418.0980.HPLC purity:97.4%.

[0054] 1.2.11.(±)-Ethyl-4-hydroxy-3-(6-(4-methylpiperidin-1-yl)-9H-purin-9yl)tetrahydro thiophene-3-carboxylate(11a,11b)

[0055] 11a:white solid,32.7%yield. 1 H NMR(600 MHz,CDCl3)δ8.23(s,1H),7.89(s,1H),6.66(s,1H),5.41(s,2H),5.24(t,J=8.4 Hz,1H),4.24-4.16(m,2H),3.86(d,J=18Hz,1H),3.52(d,J=17.4 Hz,1H)3.24(dd,J=6.6 Hz,J=9 Hz,1H),3.08(s,2H),2.93(q,J=7.8 Hz,1H),1.82-1.66(m,2H),1.31-1.19(2H),1.14(t,J=10.2 Hz,3H),0.97(d,J=10.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ169.8,154.0,151.9,150.9,136.8,119.8,82.3,79.6,73.9,62.9,35.9,35.1,34.4,31.3,22.0,14.0.ESI-HR MS(m / z)calcdC 18 H 25 ClN5O3SNa(M+Na) + ,392.1751;found,392.1744.HPLC purity:95.4%.11b:whitesolid,31.5%yield. 1 H NMR(400 MHz,CDCl3)δ8.21(s,1H),8.00(s,1H),5.40(t,J=6.8Hz,4H),4.22(dd,J=7.2 Hz,J=15.6 Hz,2H),3.74(d,J=12 Hz,1H),3.43(d,J=12 Hz,1H),3.22(dd,J=6.0 Hz,J=10.8 Hz,1H),3.09(s,2H),2.81(dd,J=7.2 Hz,J=10.8 Hz,1H),1.83-1.70(m,2H),1.32-1.27(m,2H),1.19(t,J=7.2 Hz,3H),0.98(d,J=6.4 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.7,154.1,151.9,150.7,137.5,119.7,73.8,63.0,35.3,34.5,33.3,31.4,22.0,14.0.ESI-HRMS(m / z)calcd C 18 H 25 ClN5O3SNa(M+Na) + ,392.1751;found,392.1746.HPLC purity:96.7%.

[0056] 1.2.12.(±)-Ethyl-3-(6-(4-fluoropiperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro thiophene-3-carboxylate(12a,12b)

[0057] 12a:white solid,42.3%yield. 1H NMR(600 MHz,CDCl3)δ8.21(s,1H),7.90(s,1H),6.48(s,1H),5.21(t,J=6 Hz,1H),4.93-4.84(m,1H),4.46(s,2H)4.19-4.13(m,4H),3.83(d,J=12 Hz,1H),3.50(d,J=12.6 Hz,1H),3.18(q,J=6 Hz,1H),2.89(dd,J=4.8Hz,J=11.4 Hz,1H),1.99-1.90(m,4H),1.10(t,J=7.2 Hz,3H). 13 C NM R(150 MHz,CDCl3)δ169.5,153.8,151.8,150.9,137.0,119.7,88.6,87.5,79.4,73.9,62.8,42.3,35.7,35.0,31.4(Jc-F=19.7),13.9. 19 F NMR(376MHz,CDCl3)δ-181.58.ESI-HRMS(m / z)calcdC 17 H 22 FN5O3SNa(M+Na) + ,396.1500;found,396.1506.HPLC purity:98.9%.12b:whitesolid,53.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.24(s,1H),8.03(s,1H),6.10(s,1H),5.41(t.J=6.0 Hz,1H),5.03-4.86(m,1H),4,54(s,2H),4.22(q,J=7.2 Hz,4H),3.75(d,J=12Hz,1H),3.44(d,J=11.6 Hz,1H),3.23(dd,J=10.8 Hz,J=6.0 Hz,1H),2.81(dd,J=10.8Hz,J=7.2 Hz,1H),2.05-1.95(m,4H),1.20(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.6,154.1,151.9,150.9,137.9,119.8,87.3,73.8,63.1,35.3,33.3,31.6(d,J C-F =20.2Hz),14.0. 19F NMR(376MHz,CDCl3)δ-181.68.ESI-HRMS(m / z)calcd C 17 H 22 FN5O3SNa(M+Na) + ,396.1500;found,396.1508.HPLC purity:97.2%.

[0058] 1.2.13.(±)-Ethyl-4-hydroxy-3-(6-(4-(trifluoromethyl)piperidin-1-yl)-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(13a,13b)

[0059] 13a:yellow solid,42.1%yield. 1 H NMR(400 MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),6.44(s,1H),5.60(s,2H),5.24(t.J=5.6 Hz,1H),4.23-4.15(m,2H),3.86(d,J=12Hz,1H),3.53(d,J=12 Hz,1H),3.20(q,J=6 Hz,1H),3.08-2.99(m,2H)2.95(q,J=5.6Hz,1H),2.42-2.33(m,1H),2.00(d,J=12.8 Hz,2H),1.69-1.56(m,2H),1.13(t.J=6.8Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.6,153.9,151.8,151.0,137.2,128.5,125.8,119.8,79.5,73.9,62.9,44.2,40.7(q,J C-F =27.4 Hz),35.8,35.1,24.7,14.0. 19 F NMR(376MHz,CDCl3)δ-73.90.ESI-HRMS(m / z)calcd C 18 H 22 F3N5O3SNa(M+Na) + ,446.1468;found,446.1468.HPLC purity:95.6%.13b:yellow solid,37.5%yield. 1H NMR(400 MHz,CDCl3)δ8.24(s,1H)8.03(s,1H),5.97(s,1H),5.63(s,2H),5.41(t.J=6.4 Hz,1H),4.22,(q,J=6.8 Hz,2H),3.75(d,J=12 Hz,1H),3.45(d,J=12 Hz,1H),3.23(dd,J=11.2 Hz,J=6Hz,1H),3.07(t,J=11.6Hz,2H),2.81(dd,J=10.8 Hz,J=7.2 Hz,1H),2.46-2.34(m,1H),2.03(d,J=12.8Hz,2H),1.72-1.61(m,2H),1.25-1.15(m,3H). 13 C NMR(100 MHz,CDCl3)δ168.6,154.0,151.9,151.0,138.1,119.8,73.9,63.1,40.8(d,J C-F =27.3),35.3,33.3,24.8,14.0. 19 F NMR(376MHz,CDCl3)δ-73.90.ESI-HRMS(m / z)calcd C 18 H 22 F3N5O3SNa(M+Na) + ,446.1468;found,446.1467.HPLC purity:96.7%.

[0060] 1.2.14.(±)-Ethyl-3-(6-(4-chloropiperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro thiophene-3-carboxylate(14a,14b)

[0061] 14a:light yellow solid,51.7%yield. 1H NMR(600 MHz,CDCl3)δ8.23(s,1H),8.02(s,1H),6.03(s,1H),5.40(t,J=6.6 Hz,1H),4.60(s,2H)4.38-4.35(m,1H),4.22(q,J=7.2 Hz,4H),3.74(d,J=12 Hz,1H),3.45(d,J=12 Hz,1H),3.23(dd,J=4.8 Hz,J=10.8 Hz,1H),2.80(dd,J=7.2 Hz,J=10.8 Hz,1H),2.22-2.19(m,2H),2.00-1.96(m,2H),1.19(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.5,154.0,151.8,150.9,137.9,119.8,73.8,63.1,57.0,35.4,35.2,33.4,14.0.ESI-HRMS(m / z)calcd C 17 H 23 ClN5O3S(M+H) + ,412.1205;found,412.1198.HPLC purity:96.1%.14b:light yellow solid,31.0%yield. 1 H NMR(400 MHz,CDCl3)δ8.27(s,1H),7.93(s,1H),6.50(s,1H),5.26(t,J=5.6 Hz,1H),4.62(s,2H),4.39-4.34(m,1H),4.27-4.16(m,4H),3.88(d,J=12.0 Hz,1H),3.54(d,J=12.0 Hz,1H),3.24(q,J=6 Hz,1H),2.93(dd,J=5.2 Hz,J=11.6 Hz,1H),2.25-2.17(m,2H),2.02-1.93(m,2H),1.15(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.7,154.0,151.9,151.1,137.2,119.9,79.6,74.0,63.0,57.0,35.9,35.4,35.2,14.1.ESI-HRMS(m / z)calcd C 17 H 23 ClN5O3S(M+H) +,412.1205;found,412.1203.HPLC purity:95.0%.1.2.15.(±)-Ethyl-4-hydroxy-3-(6-(4-morpholinopiperidin-1-yl)-9H-purin-9-yl)tetra hydrothiophene-3-carboxylate(15a,15b)

[0062] 15a:white solid,37.7%yield. 1 H NMR(600 MHz,CDCl3)δ8.22(s,1H),8.02(s,1H),5.50(s,1H),5.40(t,J=9.6 Hz,1H),4.22(q,J=10.8 Hz,2H),3.76(s,1H),3.72(t,J=6.6 Hz,4H),3.44(d,J=18 Hz,1H),3.22(dd,J=9 Hz,J=16.2 Hz,1H),3.13(s,2H),2.80(dd,J=11.4 Hz,J=16.2 Hz,1H),2.59-2.52(m,5H),2.01(d,J=19.2 Hz,2H),1.62-1.52(m,4H),1.19(t,J=10.8 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.6,154.0,150.8,137.8,119.8,73.8,67.4,63.1,62.2,49.9,35.3,33.3,28.6,14.0.ESI-HRMS(m / z)calcdC 21 H 31 N6O4S(M+H) + ,463.2111;found,463.2113.HPLC purity:97.9%.15b:white solid,38.6%yield. 1H NMR(600 MHz,CDCl3)δ8.25(s,1H),7.92(s,1H),6.55(s,1H)5.49(s,1H),5.25(t,J=8.4 Hz,1H),4.26-4.17(m,2H),3.88(d,J=18.6 Hz,1H),3.73(t,J=6.6 Hz,4H),3.53(d,J=18 Hz,1H),3.24(dd,J=9 Hz,J=16.8 Hz,1H),3.12(s,2H),2.93(q J=7.8 Hz,1H),2.60-2.53(s,5H),2.02(d,J=18 Hz,2H),1.63-1.52(m,4H),1.15(t,J=10.8Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.8,153.9,151.9,151.0,137.0,119.9,79.6,74.0,67.3,63.0,62.2,49.9,35.9,35.2,29.8,28.6,14.1.ESI-HRMS(m / z)calcd C 21 H 31 N6O4S(M+H) + ,463.2111;found,463.2120.HPLC purity:95.9%.

[0063] 1.2.16.(±)-Ethyl-3-(6-(4-benzylpiperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro thiophene-3-carboxylate(16a,16b)

[0064] 16a:white solid,32.4%yield. 1H NMR(600 MHz,CDCl3)δ8.18(s,1H),7.97(s,1H),7.28-7.11(m,5H),5.37(t,J=10.0 Hz.3H),4.22-4.16(m,2H),3.71(d,J=17.4Hz,1H),3.41(d,J=17.4 Hz,1H)3.21(dd,J=9.6 Hz,J=16.8 Hz,1H),2.99(s,2H),2.78(dd,J=10.8 Hz,J=16.2 Hz,1H)2.55(d,J=10.8 Hz,2H),1.90-1.78(m,4H),1.35-1.22(m,1H),1.16(t,J=10.8 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ168.6,154.0,151.9,150.7,140.2,137.6,129.3,128.4,126.1,119.7,73.8,63.0,43.3,38.5,35.3,33.3,32.4,14.0.ESI-HRMS(m / z)calcd C 24 H 29 N5O3SNa(M+Na) + ,490.1883;found,490.1886.HPLCpurity:97.9%.16b:white solid,31.8%yield. 1 H NMR(600 MHz,CDCl3)δ8.21(s,1H),7.87(s,1H),7.28-7.11(m,5H),5.43(s,2H),5.23(t,J=8.4 Hz,1H),4.23-4.14(m,2H),3.84(d,J=18 Hz,1H),3.50(d,J=18 Hz,1H),3.21(dd,J=9 Hz,J=16.8 Hz,1H),3.00(s,2H),2.91(dd,J=7.8 Hz,J=16.8Hz,1H),2.55(d,J=10.8 Hz,2H),1.90-1.78(m,4H),1.36-1.21(m,1H),1.13(t,J=10.8 Hz,3H). 13C NMR(150 MHz,CDCl3)δ169.8,154.0,151.9,150.9,140.2,136.8,129.3,128.4,126.1,119.8,79.7,74.0,62.9,43.3,38.5,35.9,35.1,32.4,14.1.ESI-HRMS(m / z)calcd C 24 H 30 N5O3S(M+H) + ,468.2064;found,468.2067.HPLC purity:99.7%.

[0065] 1.2.17.(±)-Ethyl-3-(6-(4-(2-fluorobenzyl)piperidin-1-yl)-9H-purin-9-yl)-4-hydroxy tetrahydrothiophene-3-carboxylate(17a,17b)

[0066] 17a:white solid,24.6%yield. 1 H NMR(600 MHz,CDCl3)δ8.24(s,1H),7.90(s,1H),7.20-7.12(m,2H),7.07-7.00(m,2H),6.63(s,1H),5.45(s,2H),5.25(t,J=6Hz,1H),4.26-4.18(m,1H),3.87(d,J=11.4 Hz,1H),3.53(d,J=12 Hz,1H),3.24(dd,J=6 Hz,J=10.8 Hz,1H),3.03(s,2H),2.94(q,J=4.8 Hz,1H),2.62(d,J=7.2Hz,2H),1.96-1.92(m,1H),1.82(d,J=12.6 Hz,2H),1.38-1.34(m,2H),1.15(t,J=7.2 Hz,3H). 13 C NMR(150MHz,CDCl3)δ169.8,162.2,160.6,154.0,151.9,136.8,131.7(Jc-F=5.0 Hz),128.0(Jc- F =7.7 Hz),127.1(Jc- F =11.4 Hz),123.9(Jc- F =3.9Hz),119.8,115.4,(Jc- F=22.1 Hz),79.7,73.9,62.9,37.4,36.1,35.9,35.1,32.4,14.1. 19 F NMR(376MHZ,CDCl3)δ-117.84.ESI-HRMS(m / z)calcd C 24 H 29 FN5O3S(M+H) + ,486.1970;found,486.1980.HPLCpurity:96.4%.17b:white solid,37.8%yield. 1 H NMR(400 MHz,CDCl3)δ8.24(s,1H),7.90,(s,1H),7.20-7.00(m,4H),5.47(s,2H),5.26(t,J=5.6 Hz,1H),4.26-4.17(m,2H),3.87(d,J=12.4 Hz,1H),3.53(d,J=12Hz,1H),3.24(dd,J=6.4 Hz,J=11.6 Hz,1H),3.03(s,2H),2.94(dd,J=11.2 Hz,J=5.2 Hz,1H),2.62(d,J=7.2 Hz,2H),1.95(s,2H),1.82(d,J=13.2 Hz,2H),1.64(s,1H),1.15(t,J=17.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.8,154.0,152.0,150.9,136.8,131.7,128.0(d,J C-F =7.9),127.1(d,J C-F =16.1 Hz),123.9,119.8,115.4(d,J C-F =21.7 Hz),79.7,74.0,63.0,37.4,36.2,35.2,32.3,29.8,14.1. 19 F NMR(376 MHZ,CDCl3)δ-117.86.ESI-HRMS(m / z)calcd C 24 H 29 FN5O3S(M+H) + ,486.1970;found,486.1978.HPLC purity:99.6%.

[0067] 1.2.18.(±)-Ethyl-4-hydroxy-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydro thiophene-3-carboxylate(18a,18b)

[0068] 18a:white solid,29.5%yield. 1 H NMR(600 MHz,CDCl3)δ8.23(s,1H),8.02(s,1H),5.40(t,J=6.6 Hz,1H),4.35(s,2H),4.24-4.20(m,2H),3.74(d,J=11.4 Hz,1H),3.44(d,J=11.4 Hz,1H),3.23(dd,J=6 Hz,J=10.8 Hz,1H),2.80(dd,J=7.2Hz,J=10.8Hz,1H),2.55(t,J=5.4 Hz,4H),2.35(s,3H)1.77(s,2H),1.19(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.6,154.1,151.9,150.9,137.9,119.8,73.8,63.1,55.2,46.2,35.3,33.4,14.0.ESI-HRMS(m / z)calcd C 17 H 24 ClN6O3SNa(M+Na) + ,393.1703;found,393.1701.HPLC purity:98.1%.18b:white solid,41.6%yield. 1 H NMR(600 MHz,CDCl3)δ8.26(s,1H),7.93(s,1H),5.26(t,J=6 Hz,1H),4.34(s,2H),4.25-4.18(m,2H),3.88(d,J=12 Hz,1H),3.54(d,J=12 Hz,1H),3.24(q,J=5.4 Hz,1H),2.93(q,J=5.4 Hz,1H),2.56(s,4H),2.36(s,3H),1.75(s,2H),1.15(t,J=7.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ169.8,154.1,151.9,151.0,137.1,119.9,79.6,74.0,63.0,55.2,46.3,35.9,35.2,14.1.ESI-HRMS(m / z)calcd C 17 H 24 ClN6O3SNa(M+Na) + ,393.1703;found,393.1699.HPLCpurity:95.6%.

[0069] 1.2.19.(±)-Ethyl-3-(6-(azepan-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(19a,19b)

[0070] 19a:white solid,31.8%yield. 1 H NMR(600 MHz,CDCl3)δ8.25(s,1H),7.88(s,1H),6.84(s,1H)5.30-5.24(m,1H),4.45(s,1H),4.28-4.20(m,3H),3.99(s,1H),3.88(d,J=17.4 Hz,2H),3.55(d,J=18 Hz,1H),3.27(dd,J=9.6 Hz,J=16.8 Hz,1H),2.98(q,J=7.8 Hz,1H),1.89(s,4H),1.62-1.57(m,4H),1.17(t,J=10.8 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.7,154.5,151.8,150.6,136.9,119.6,79.7,73.9,62.8,35.9,35.0,14.0.ESI-HRMS(m / z)calcd C 18 H 26 N5O3S(M+H) + ,392.1751;found,392.1744.HPLC purity:95.7%.19b:white solid,52.4%yield. 1H NMR(600MHz,CDCl3)δ8.22(s,1H),7.99(s,1H),6.42(s,1H),5.41(t,J=6.6 Hz,1H),4.44(s,1H)4.30-4.20(m,3H),3.97(s,1H),3.85(s,1H),3.75(d,J=11.4 Hz,1H),3.44(d,J=11.4 Hz,1H),3.22(dd,J=6 Hz,J=10.8 Hz,1H),2.83(t,J=7.2 Hz,1H),1.89(s,4H),1.60(s,1H),1.20(t,J=6.6 Hz,3H). 13 C NMR(100MHz,CDCl3)δ168.7,154.7,151.9,150.5,137.8,119.6,73.8,63.0,50.0,48.6,35.3,33.3,29.1,27.3,27.0,14.0.ESI-HRMS(m / z)calcd C 18 H 26 N5O3S(M+H) + ,392.1751;found,392.1758.HPLC purity:95.3%.

[0071] 1.2.20.(±)-Ethyl-4-hydroxy-3-(6-(pyrrolidin-1-yl)-9H-purin-9-yl)tetrahydrothiophen e-3-carboxylate(20a,20b)

[0072] 20a:white solid,26.5%yield. 1 H NMR(600 MHz,CDCl3)δ8.27(s,1H),7.87(s,1H),5.26(t,J=6.0 Hz,1H),4.26-4.16(m,4H),3.88(d,J=12.0 Hz,1H),3.76(s,2H),3.55(d,J=12.0 Hz,1H),3.27(dd,J=6.4 Hz,J=11.2 Hz,1H),2.96(dd,J=5.2 Hz,J=11.2 Hz,1H),2.04(d,J=26 Hz,4H),1.16(t,J=7.2 Hz,3H). 13C NMR(100 MHz,CDCl3)δ169.7,153.4,152.3,150.3,137.6,120.3,79.9,74.0,62.9,36.0,35.0,14.1.ESI-HRMS(m / z)calcd C 16 H 22 N5O3S(M+H) + ,364.1438;found,364.1437.HPLC purity:98.4%.20b:whitesolid,58.0%yield. 1 H NMR(600 MHz,CDCl3)δ8.22(s,1H),7.96(s,1H),6.43(s,1H),5.41(t,J=6.4 Hz,1H),4.30-4.15(m,4H),3.72(d,J=9.2 Hz,3H),3.47(d,J=11.6 Hz,1H),3.24(dd,J=6 Hz,J=10.8 Hz,1H),2.84(dd,J=6.8 Hz,J=10.8 Hz,1H),2.03(t,J=25.6 Hz,4H),1.18(t,J=6.8Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.7,153.3,152.3,150.0,138.3,120.1,74.0,63.0,49.1,47.7,35.2,33.5,26.4,24.4,14.0.ESI-HRMS(m / z)calcd C 16 H 22 N5O3S(M+H) + ,364.1438;found,364.1435.HPLC purity:95.3%.

[0073] 1.2.21.(±)-Ethyl-4-hydroxy-3-(6-(methylthio)-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(21a,21b)

[0074] 21a:yellowish solid,33.4%yield. 1H NMR(400 MHz,CDCl3)δ8.63(s,1H),8.22(s,1H),5.74(s,1H),5.30(t,J=5.2 Hz,1H),4.18-4.12(m,2H),3.91(d,J=12.4 Hz,1H),3.56(d,J=12.0 Hz,1H),3.15(dd,J=5.2 Hz,=11.6 Hz,1H),2.86(dd,J=4.8Hz,J=11.6 Hz,1H),2.68(s,3H),1.07(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.1,162.7,151.4,148.2,141.3,131.4,79.0,74.0,63.0,35.5,35.2,13.9,11.8.ESI-HRMS(m / z)calcd C 13 H 16 N4O3S2Na(M+Na) + ,363.0556;found,363.0546.HPLC purity:99.8%.21b:yellowish solid,40.5%yield. 1 H NMR(600 MHz,CDCl3)δ8.61(s,1H),8.28(s,1H),5.45(t,J=6.0 Hz,1H),5.04(s,1H),4.23-4.14(m,2H),3.69(dd,J=11.6 Hz,J=36.8 Hz,2H),3.30(q,J=6.0 Hz,1H),2.87(q,J=6.0 Hz,1H),2.67(s,3H),1.12(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.2,162.6,151.5,148.3,142.3,131.1,76.5,74.0,63.1,34.8,34.0,13.9,11.9.ESI-HRMS(m / z)calcd C 13 H 16 N4O3S2Na(M+Na) +,363.0556;found,363.0564.HPLC purity:99.6%.1.2.22.(±)-Ethyl-3-(6-(ethylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(22a,22b)

[0075] 22a:yellow solid,21.5%yield. 1 H NMR(600 MHz,CDCl3)δ8.58(s,1H),8.28(s,1H),5.44(q,J=6 Hz,1H),5.12(d,J=5.4 Hz,1H),4.18-4.13(m,2H),3.73(d,J=12 Hz,1H),3.65(d,J=11.4 Hz,1H),3.34-3.28(m,3H),2.86(q,J=5.4 Hz,1H),1.41(t,J=7.8Hz,3H),1.12(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ168.2,162.3,151.5,148.4,142.3,130.9,76.5,74.0,63.0,34.8,33.9,23.4,14.7,13.9.ESI-HRMS(m / z)calcdC 14 H 18 N4O3S2Na(M+Na) + ,377.0713;found,377.0697.HPLC purity:99.8%.22b:yellowsolid,22.6%yield. 1 H NMR(600 MHz,CDCl3)δ8.63(s,1H),8,28(s,1H),5.48(q,J=6 Hz,1H),4.81(d,J=5.4 Hz,1H),4.23-4.19(m,2H),3.77(d,J=12 Hz,1H),3.55(d,J=12 Hz,1H),3.38(q,J=7.2 Hz,2H),3.28(q,J=6 Hz,1H),2.85(dd,J=6.6 Hz,J=11.4 Hz,1H),1.45(t,J=7.2 Hz,3H),1.17(t,J=7.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ168.2,162.9,151.5,148.5,142.2,131.3,74.0,63.2,35.1,33.6,23.5,14.8,14.0.ESI-HRMS(m / z)calcdC 14 H 18 N4O3S2Na(M+Na) + ,377.0713;found,377.0704.HPLC purity:99.3%.

[0076] 1.2.23.(±)-Ethyl-4-hydroxy-3-(6-(isopropylthio)-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(23a,23b)

[0077] 23a:white solid,51.2%yield. 1 H NMR(600 MHz,CDCl3)δ8.63(s,1H),8.27(s,1H),5.48(s,1H),4.81(s,1H)4.37-4.33(m,1H),4.24-4.20(m,2H)3.78(d,J=12 Hz,1H),3.53(d,J=12 Hz,1H),3.28(q,J=6 Hz,1H),2.85(dd,J=6.6 Hz,J=10.8 Hz,1H),1.50(d,J=7.2 Hz,6H),1.18(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ168.3,163.2,151.5,148.5,142.1,131.2,74.0,63.3,35.1,34.7,33.6,23.4,23.3,14.0.ESI-HRMS(m / z)calcd C 15 H 20 N4O3S2Na(M+Na) + ,391.0869;found,391.0871.HPLC purity:99.8%.23b:whitesolid,22.4%yield. 1H NMR(600 MHz,CDCl3)δ8.61(s,1H),8.20(s,1H),5.76(s,1H),5.30(s,1H),4.34-4.29(m,1H),4.19-4.15(m,2H)3.91(d,J=12.6 Hz,1H),3.56(d,J=12.6Hz,1H),3.16(dd,J=4.8 Hz,J=11.4 Hz,1H),2.86(dd,J=5.4 Hz,J=12 Hz,1H),1.46(d,J=6.0 Hz,6H),1.09(t,J=6.6 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.2,162.8,151.4,148.4,141.2,131.2,74.0,63.1,35.5,35.2,34.6,23.3,23.2,13.9.ESI-HRMS(m / z)calcd C 15 H 20 N4O3S2Na(M+Na) + ,391.0869;found,391.0868.HPLC purity:95.1%.

[0078] 1.2.24.(±)-Ethyl-4-hydroxy-3-(6-(prop-2-yn-1-ylthio)-9H-purin-9-yl)tetrahydrothio phene-3-carboxylate(24a,24b)

[0079] 24a:white solid,41.2%yield. 1 H NMR(600 MHz,CDCl3)δ8.68(s,1H),8.32(s,1H),5.46(s,1H),4.65(s,1H),4.23-4.18(m,2H),4.16(d,J=2.4 Hz,2H),3.76(d,J=12Hz,1H),3.60(d,J=12 Hz,1H),3.29(q,J=6 Hz,1H),2.85(q,J=6 Hz,1H),2.22(t,J=2.4 Hz,1H),1.16(t,J=7.2 Hz,3H). 13C NMR(150 MHz,CDCl3)δ168.1,160.2,151.6,148.9,142.6,131.0,79.3,74.0,71.3,63.2,35.0,33.7,17.3,14.0.ESI-HRMS(m / z)calcdC 15 H 16 N4O3S2Na(M+Na) + ,387.0556;found,387.0550.HPLC purity:98.6%.24b:whitesolid,49.7%yield. 1 H NMR(600 MHz,CDCl3)δ8.71(s,1H),8.27(s,1H),5.54(s,1H),5.33(s,1H),4.23-4.19(m,4H),3.93(d,J=12.6 Hz,1H),3.57(d,J=12.6 Hz,1H),3.19(dd,J=4.8 Hz,J=12 Hz,1H),2.83(dd,J=4.8Hz,J=11.4 Hz,1H),2.23(t,J=2.4 Hz,1H),1.12(t,J=7.2 Hz,3H). 13 C NMR(150MHz,CDCl3)δ169.4,160.3,151.6,148.7,141.7,131.4,79.3,79.1,74.1,71.3,63.3,35.6,35.4,17.3,14.0.ESI-HRMS(m / z)calcdC 15 H 16 N4O3S2Na(M+Na) + ,387.0556;found,387.0566.HPLC purity:97.2%.

[0080] 1.2.25.(±)-Ethyl-3-(6-(butylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(25a,25b)

[0081] 25a:white solid,45.1%yield. 1H NMR(400 MHz,DMSO)δ8.72(s,1H),8.68(s,1H),5.93(d,J=5.2 Hz,1H),5.23-5.20(m,1H),4.17-4.07(m,2H),4.00(d,J=11.6Hz,1H),3.62(d,J=11.2 Hz,1H),3.41-3.30(m,3H),2.90(dd,J=3.6 Hz,J=11.2Hz,1H),1.73-1.66(m,2H),1.49-1.39(m,2H),1.04(t,J=7.2 Hz,3H),0.91(t,J=7.2 Hz,3H). 13 CNMR(100 MHz,DMSO)δ167.9,159.8,151.3,148.6,143.8,130.5,73.9,73.8,62.0,35.5,33.7,31.2,27.5,21.4,13.6,13.5.ESI-HRMS(m / z)calcd C 16 H 22 N4O3S2(M+Na) + ,405.1026;found,405.1020.HPLC purity:99.6%.25b:white solid,30.2%yield. 1 H NMR(400 MHz,CDCl3)δ8.62(s,1H),8.21(s,1H),5.74(s,1H),5.33-5.30(m,1H),4.22-4.15(m,2H),3.91(d,J=12 Hz,1H),3.56(d,J=12.4 Hz,1H),3.40-3.35(m,1H),3.18(q,J=4.8 Hz,1H),2.87(q=3.2,1H),1.80-1.72(m,2H),1.54-1.45(m,2H),1.10(t,J=7.2 Hz,3H),0.94(t,J=7.6 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.3,162.9,151.5,148.3,141.2,131.4,79.1,74.0,63.0,35.6,35.3,31.5,28.6,22.1,14.0,13.7.ESI-HRMS(m / z)calcd C 16 H 22 N4O3S2(M+Na) +,405.1026;found,405.1031.HPLC purity:98.6%.

[0082] 1.2.26.(±)-Ethyl-4-hydroxy-3-(6-(pentylthio)-9H-purin-9-yl)tetrahydrothiophene-3-carboxylate(26a,26b)

[0083] 26a:white solid,43.3%yield. 1 H NMR(400 MHz,CDCl3)δ8.62(s,1H),8.27(s,1H),5.48(q,J=6.0 Hz,1H),4.80(d,J=6.0 Hz,1H),4.21(q,J=7.2 Hz,2H),3.78(d,J=12 Hz,1H),3.54(d,J=12.0 Hz,1H),3.38(t.J=7.2 Hz,2H),3.28(q,J=6.0 Hz,1H),2.85(dd,J=6.4 Hz,J=11.2 Hz,1H),1.83-1.75(m,2H),1.51-1.33(m,4H),1.17(t,J=6.8 Hz,3H),0.91(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.3,163.1,151.5,148.4,142.2,131.3,74.0,63.2,35.1,33.6,31.1,29.2,29.0,22.4,14.1,14.0.ESI-HRMS(m / z)calcd C 17 H 25 N4O3S2(M+H) + ,397.1363;found,397.1354.HPLC purity:99.6%.26b:white solid,25.1%yield. 1H NMR(600 MHz,CDCl3)δ8.62(s,1H),8.21(s,1H),5.75(s,1H),5.32-5.30(m,1H),4.21-4.14(m,2H),3.91(d,J=12.0 Hz,1H),3.56(d,J=12.0 Hz,1H),3.39-3.32(m,2H),3.17(dd,J=4.8 Hz,J=11.4 Hz,1H),2.87(dd,J=4.8 Hz,J=11.4 Hz,1H),1.79-1.74(m,2H),1.47-1.42(m,2H),1.37-1.31(m,2H),1.09(t,J=7.2 Hz,3H),0.88(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.1,162.7,151.4,148.2,141.3,131.3,79.0,74.0,63.0,35.5,35.2,31.0,29.0,28.8,22.2,14.0,14.0.ESI-HRMS(m / z)calcd C 17 H 25 N4O3S2(M+H) + ,397.1363;found,397.1361.HPLC purity:95.3%.

[0084] 1.2.27.(±)-Ethy-3-(6-(benzylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(27a,27b)

[0085] 27a:white solid,43.2%yield. 1H NMR(400 MHz,DMSO)δ8.73(s,1H),8.68(s,1H),7.44(d,J=7.2 Hz,1H),7.31-7.20(m,3H),6.40(d,J=5.6 Hz,1H),5.43(dd,J=5.6Hz,J=9.6 Hz,1H),4.64(dd,J=13.6 Hz,J=16 Hz,2H),4.12-4.00(m,J=13.6 Hz 2H),3.90(d,J=12.4 Hz,1H),3.78(d,J=12.4 Hz,1H),3.26-3.22(m,1H),2.96(dd,J=4 Hz,J=12 Hz,1H),1.00(t,J=7.2 Hz,3H). 3 C NMR(100 MHz,DMSO)δ167.9,159.0,151.2,148.8,144.0,137.8,130.3,129.0,128.5,127.2,73.9,62.0,35.5,33.7,31.6,13.7.ESI-HRMS(m / z)calcd C 19 H 20 N4O3S2(M+Na) + ,439.0869;found,439.0872.HPLC purity:99.7%.27b:white solid,42.4%yield. 1 H NMR(400 MHz,DMSO)δ8.75(s,1H),8.74(s,1H),7.47(d,J=7.2 Hz,2H),7.34-7.22(m,3H),5.94(d,J=5.2 Hz,1H),5.24-5.21(m,1H),4.66(dd,J=13.6 Hz,J=18.4Hz,2H),4.15-4.07(m,2H),4.00(d,J=11.6 Hz,1H),3.62(d,J=11.2 Hz,1H),3.40-3.38(m,1H),2.90(dd,J=3.2 Hz,J=11.2 Hz,1H),1.04(t,J=6.8Hz,3H). 13 C NMR(100 MHz,DMSO)δ167.3,159.3,151.3,148.7,143.0,137.7,130.5,129.0,128.5,127.2,76.6,75.4,61.8,35.8,34.6,31.6,13.8.ESI-HRMS(m / z)calcd C 19 H20 N4O3S2(M+Na) + ,439.0869;found,439.0863.HPLC purity:98.3%.

[0086] 1.2.28.(±)-Ethyl-3-(6-((3-fluorophenyl)thio)-9H-purin-9-yl)-4-Hydroxytetrahydro thi ophene-3-carboxylate(28a,28b)

[0087] 28a:white solid,26.4%yield. 1 H NMR(600 MHz,CDCl3)δ8.21(s,1H),7.90(s,1H),6.48(s,1H),5.21(t,J=6 Hz,1H),4.93-4.84(m,1H),4.46(s,2H)4.19-4.13(m,4H),3.83(d,J=12 Hz,1H),3.50(d,J=12.6 Hz,1H),3.18(q,J=6 Hz,1H),2.89(dd,J=4.8Hz,J=11.4 Hz,1H),1.99-1.90(m,4H),1.10(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.5,153.8,151.8,150.9,137.0,119.7,88.6,87.5,79.4,73.9,62.8,42.3,35.7,35.0,31.4(Jc- F =19.7),13.9. 19 F NMR(376MHz,CDCl3)δ-111.38.ESI-HRMS(m / z)calcdC 18 H 17 FN4O3S2(M+Na) + ,443.0618;found,443.0613.HPLC purity:99.0%.28b:white solid,31.3%yield. 1H NMR(400 MHz,CDCl3)δ8.58(s,1H),8.31(s,1H),7.46-7.40(m,3H),7.21-7.16(m,1H),5.33(t,J=4.8 Hz,1H),4.24-4.18(m,2H),3.94(d,J=12.4 Hz,1H),3.58(d,J=12.4 Hz,1H)3.19(dd,J=4.8 Hz,J=11.6 Hz,1H),2.86(dd,J=4.8 Hz,J=11.6 Hz,1H),1.12(t,J=7.2Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.4,164.0,161.4(d,J C-F =38Hz),151.9,149.0,142.0,131.3(d,J C-F =3.4 Hz),130.9,130.7(d,J C-F =8.1 Hz),128.8(d,J C-F =8.0 Hz),122.8,122.6,117.2,117.0,79.1,74.1,63.3,35.6,35.4,14.0. 19 F NMR(376MHz,CDCl3)δ-111.35.ESI-HRMS(m / z)calcd C 18 H 18 FN4O3S2(M+H) + ,421.0799;found,421.0790.HPLC purity:95.7%.

[0088] 1.2.29.(±)-Ethyl-3-(6-((4-(tert-butyl)phenyl)thio)-9H-purin-9-yl)-4-hydroxytetra hyd rothiophene-3-carboxylate(29a,29b)

[0089] 29a:white solid,33.4%yield. 1H NMR(400 MHz,DMSO)δ8.80(s,1H),8.55(s,1H),7.57-7.51(m,4H),5.95(d,J=5.2 Hz,1H),5.24-5.20(m,1H),4.15-4.08(m,2H),4.01(d,J=11.2 Hz,1H),3.63(d,J=11.2 Hz,1H),3.38(dd,J=5.6 Hz,J=11.2 Hz,1H),2.91(dd,J=3.6 Hz,J=11.2 Hz,1H),1.33(s,9H),1.04(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,DMSO)δ167.9,159.2,152.3,151.5,149.0,144.4,135.3,129.8,126.4,123.1,73.9,62.0,35.5,34.5,33.7,31.0,13.6.ESI-HRMS(m / z)calcd C 22 H 27 N4O3S2(M+H) + ,459.1519;found,459.1515.HPLC purity:96.4%.29b:white solid,37.4%yield. 1 H NMR(400 MHz,DMSO)δ8.76(s,1H),8.56(s,1H),7.57-7.51(m,4H),6.42(d,J=5.2 Hz,1H),5.49-5.45(m,1H),4.13-4.03(m,2H),3.92(d,J=12.4 Hz,1H),3.80(d,J=12.0 Hz,1H),3.28(dd,J=5.2Hz,J=12 Hz,1H),2.99(dd,J=3.6 Hz,J=12.0 Hz,1H),1.32(s,10H),1.03(t,J=6.8Hz,3H). 13 C NMR(100 MHz,DMSO)δ167.3,159.5,152.3,151.5,148.9,143.3,135.3,130.0,126.4,123.0,76.6,75.5,61.8,35.8,34.6,34.5,31.0,13.8.ESI-HRMS(m / z)calcdC 22 H 27 N4O3S2(M+H) +,459.1519;found,459.1514.HPLC purity:96.3%.

[0090] 1.2.30.(±)-Ethyl-3-(6-((3-fluoropropyl)thio)-9H-purin-9-yl)-4-hydroxytetrahydro thi ophene-3-carboxylate(30a,30b)

[0091] 30a:white solid,31.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.63(s,1H),8.30(s,1H),5.47(t,J=6.4 Hz,1H),4.71(s,1H),4.67(t,J=6 Hz,1H),4.55(t,J=6.0 Hz,1H),4.21(q,J=6.8 Hz,2H)3.77(d,J=11.6 Hz,1H),3.56(d,J=11.6 Hz,1H),3.50(t,J=6.8Hz,2H),3.29(q,J=5.6 Hz,1H),2.84(dd,J=6.8 Hz,J=11.2 Hz,1H),2.27-2.14(m,2H),1.17(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.2,162.0,151.5.148.6142.4,131.4,83.3,81.6,74.0,63.2,35.1,33.6,30.6(d,J C-F =20Hz),24.8(d,J C-F =5.2 Hz),14.0. 19 F NMR(376MHz,CDCl3)δ20.41.ESI-HRMS(m / z)calcd C 15 H 19 FN4O3S2Na(M+Na) + ,409.0775;found,409.0774.HPLC purity:97.1%.30b:white solid,30.2%yield. 1H NMR(400 MHz,CDCl3)δ8.65(s,1H),8.24(s,1H),5.66(s,1H),5.32(t,J=4.8 Hz,1H),4.66(t,J=5.6 Hz,1H),4.54(t,J=6.0 Hz,1H),4.20(dd,J=6.4 Hz,J=13.6 Hz,2H),3.92(d,J=12.4 Hz,1H),3.56(d,J=12.0 Hz,1H),3.50(t,J=6.8 Hz,2H),3.18(dd,J=11.2 Hz,J=4.8 Hz,1H),2.86(dd,J=11.6 Hz,J=5.2 Hz,1H),2.26-2.14(m,2H),1.11(t,J=7.2Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.3,161.9,151.5,148.5,141.5,131.5,83.3,81.6,79.1,74.1,63.2,35.42(d,J C-F =25.4 Hz),30.6(d,J C-F =20.1 Hz),24.8(d,J C-F =5.1Hz),14.0. 19 F NMR(376MHz,CDCl3)δ-20.45.ESI-HRMS(m / z)calcd C 15 H 19 FN4O3S2Na(M+Na) + ,409.0775;found,409.0768.HPLC purity:97.7%.

[0092] 1.2.31.(±)-Ethyl-3-(6-((3-chloropropyl)thio)-9H-purin-9-yl)-4-hydroxytetrahydro thi ophene-3-carboxylate(31a,31b)

[0093] 31a:white solid,42.4%yield. 1H NMR(400 MHz,CDCl3)δ8.59(s,1H),8.31(s,1H),5.44(s,1H),5.01(s,1H),4.20-4.13(m,2H),3.75-3.63(m,4H),3.47(t,J=6.8Hz,2H),3.29(q,J=5.6 Hz,1H),2.85(dd,J=6.4 Hz,J=11.2 Hz,1H),2.26-2.20(m,2H),1.13(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.1,161.4,151.5,148.6,142.5,131.0,73.9,63.1,43.5,34.8,33.9,32.2,26.0,13.9.ESI-HRMS(m / z)calcdC 15 H 19 ClN4O3S2Na(M+Na) + ,425.0479;found,425.0470.HPLC purity:96.4%.31b:whitesolid,21.7%yield. 1 H NMR(400 MHz,CDCl3)δ8.62(s,1H),8.24(s,1H),5.67(s,1H),5.31(s,1H),4.176(q,J=7.2 Hz,2H),3.92(d,J=12 Hz,1H),3.68(t,J=6.4 Hz,2H),3.56(d,J=12.4 Hz,1H),3.50(t,J=6.8 Hz,2H),3.16(dd,J=5.2 Hz,J=11.6 Hz,1H),2.86(dd,J=4.8 Hz,J=11.6 Hz,1H),2.28-2.21(m,2H),1.094(t,J=7.2 Hz,3H). 13 C NMR(100MHz,CDCl3)δ169.2,161.7,151.4,148.4,141.5,131.4,79.0,74.1,63.1,43.5,35.5,35.3,32.2,26.0,13.9.ESI-HRMS(m / z)calcd C 15 H 19 ClN4O3S2Na(M+Na) + ,425.0479;found,425.0474.HPLC purity:95.2%.

[0094] 1.2.32.(±)-Ethyl-3-(2-amino-6-(piperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro t hiophene-3-carboxylate(32a,32b)

[0095] 32a:yellow solid,43.0%yield. 1 H NMR(600 MHz,CDCl3)δ7.60(s,1H),5.18(t,J=5.4 Hz,1H),4.60(s,2H),4.27-4.16(m,4H),3.80(d,J=12 Hz,1H),3.49(d,J=12 Hz,1H),3.24(dd,J=6.6 Hz,J=11.4 Hz,1H),2.97(q,J=5.4 Hz,1H),1.71-1.64(m,6H),1.18(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ169.9,152.8,134.5,114.7,79.5,73.6,62.7,58.6,36.0,34.9,29.8,26.3,24.9,18.6,14.1.ESI-HRMS(m / z)calcd C 17 H 25 N6O3S(M+H) + ,393.1703;found,393.1701.HPLC purity:99.0%.32b:yellow solid,32.6%yield. 1 HNMR(600 MHz,CDCl3)δ7.72(s,1H),5.34(t,J=6.6 Hz,1H),4.59(s,2H),4.26-4.11(m,4H),3.68(d,J=12 Hz,1H)3.37(d,J=12 Hz,1H),3.17(dd,J=6 Hz,J=10.8 Hz,1H),2.81(dd,J=7.2 Hz,J=10.8Hz,1H),1.72-1.65(m,6H),1.20(t,J=7.2 Hz,3H). 13 C NMR(150 MHz,CDCl3)δ168.8,158.5,154.5,152.4,135.1,114.7,73.5,62.8,35.2,33.4,26.3,24.9,14.1.ESI-HRMS(m / z)calcd C 17H 25 N6O3S(M+H) + ,393.1703;found,393.1701.HPLCpurity:98.2%.

[0096] 1.2.33.(±)-Ethyl-3-(2-fluoro-6-(piperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro thiophene-3-carboxylate(33a,33b)

[0097] 33a:yellow solid,36.4%yield. 1 H NMR(600 MHz,CDCl3)δ8.01(s,1H),5.44(s,1H),4.35(s,2H),4.23(q,J=7.2,2H),3.94-3.68(m,3H),3.47(d,J=11.6,1H),3.26(dd,J=6,J=11.2,1H),2.84(dd,J=6.4,J=11.2,1H),1.72(s,6H),1.21(t,J=7.6,3H) 13 C NMR(100 MHz,CDCl3)δ168.3,159.6,157.5,154.9(d,J C-F =19.6),152.4(d,J C-F =11.5),137.5(d,J C-F =2.9),117.8(d,J C-F =4.3),76.3,73.6,63.1,58.6,35.2,33.9,26.2,24.5,18.5,14.0. 19 F NMR(376MHz,CDCl3)δ-50.27.ESI-HRMS(m / z)calcd C 17 H 23 FN5O3S(M+H) + ,396.1500;found,396.1499.HPLC purity:99.4%.33b:yellow solid,43.6%yield. 1HNMR(600 MHz,CDCl3)δ7.96(s,1H),5.38(s,1H),5.26-5.24(m,1H),4.60-4.45(m,2H),4.29-4.19(m,2H),3.97(s,1H),3.86(d,J=12,2H),3.49(d,J=12.6,1H),3.13(dd,J=4.8,J=12,1H),3.8(dd,J=3.6,J=11.4,1H),1.16(t,J=7.2,3H). 13 C NMR(150 MHz,CDCl3)δ169.7,159.1,157.7,154.9(Jc- F =19.8),152.3(Jc- F =18.6),136.6(J c-F =3),118.0(J c-F =4.4),78.9,73.6,63.1,35.6(J c-F =6.5),24.7,14.0.. 19 F NMR(376MHz,CDCl3)δ-50.14.ESI-HRMS(m / z)calcd C 17 H 22 FN5O3S(M+Na) + ,418.1320;found,418.1322.HPLCpurity:96.6%.

[0098] 1.2.34.(±)-Ethyl-3-(2-chloro-6-(piperidin-1-yl)-9H-purin-9-yl)-4-hydroxytetrahydro thiophene-3-carboxylate(34a,34b)

[0099] 34a:white solid,17.6%yield. 1 H NMR(600 MHz,CDCl3)δ8.01(s,1H),5.41(t,J=6 Hz,1H),4.62(s,2H),4.29-4.20(m,4H),3.69(d,J=12 Hz,1H),3.45(d,J=11.4Hz,1H),3.25(q,J=5.4 Hz,1H),2.82(dd,J=7.2 Hz,J=11.4 Hz,1H),1.74-1.68(m,6H),1.22(t,J=7.2 Hz,3H). 13C NMR(100 MHz,CDCl3)δ168.4,154.0,153.7,152.1,137.6,118.4,73.6,63.2,35.3,33.7,29.8,26.3,24.7,14.0.ESI-HRMS(m / z)calcd C 17 H 23 ClN5O3S(M+H) + ,412.1205;found,412.1210.HPLC purity:96.1%.34b:white solid,21.6%yield 1 H NMR(400 MHz,CDCl3)δ7.93(s,1H),5.65(s,1H),5.24(t,J=4.8 Hz,1H),4.31-4.16(m,6H),3.86(d,J=12,6 Hz,1H),3.48(d,J=12Hz,1H),3.16(dd,J=4.8 Hz,J=11.4 Hz,1H),2.86(dd,J=4.8 Hz,J=11.4 Hz,1H),1.73-1.67(m,6H),1.18(t,J=7.2 Hz,3H). 13 CNMR(100 MHz,CDCl3)δ169.6,154.0,153.6,152.0,136.8,118.6,79.2,73.7,63.1,35.7,35.4,26.2,24.7,14.0.ESI-HRMS(m / z)calcd C 17 H 23 ClN5O3S(M+H) + ,412.1205;found,412.1206.HPLC purity:98.7%.

[0100] 1.2.35.(±)-Ethyl-3-(2-amino-6-(propylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothio phene-3-carboxylate(35a,35b)

[0101] 35a:white solid,41.3%yield. 1H NMR(400 MHz,CDCl3)δ7.90(s,1H),5.42(t,J=5.6 Hz,1H),4.96(s,2H),4.23-4.16(m,2H),3.71(d,J=11.6 Hz,1H),3.44(d,J=11.2Hz,1H),3.27-3.21(m,3H),2.86(dd,J=6.0 Hz,J=10.8 Hz,1H),1.82-1.73(m,2H),1.19(t,J=7.2 Hz,3H),1.05(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.5,163.8,158.3,150.0,139.3,125.5,76.7,73.8,63.0,35.1,33.7,30.7,23.0,14.0,13.6.ESI-HRMS(m / z)calcd C 15 H 22 N5O3S2(M+H) + ,384.1159;found,384.1150.HPLC purity:99.7%.35b:white solid,43.5%yield. 1 H NMR(400 MHz,CDCl3)δ7.84(s,1H),5.98(s,1H),5.24(t,J=5.2 Hz,1H),4.95(s,2H),4.27-4.14(m,2H),3.82(d,J=12 Hz,1H),3.50(d,J=12.0 Hz,1H),3.28-3.24(m,2H),3.17(q,J=5.6Hz,1H),2.90(dd,J=4.8 Hz,J=11.2 Hz,1H),1.82-1.73(m,2H),1.15(t,J=7.2 Hz,3H),1.05(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.7,163.4,158.2,150.3,138.4,125.6,79.0,73.6,63.0,35.6,35.1,30.6,23.0,14.0,13.6.ESI-HRMS(m / z)calcd C 15 H 22 N5O3S2(M+H) +,384.1159;found,384.1149.HPLC purity:98.4%.1.2.36.(±)-Ethyl-3-(2-fluoro-6-(propylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothio phene-3-carboxylate(36a,36b)

[0102] 36a:white solid,38.5%yield. 1 H NMR(400 MHz,CDCl3)δ8.31,(s,1H)5.44,(t,J=6 Hz,1H),4.24(q,J=13.6 Hz,2H),3.72(d,J=11.6 Hz,1H),3.61(d,J=11.6 Hz,1H),3.34-3.29(m,2H),2.85(dd,J=11.2,J=6 Hz,1H),1.86-1.77(m,2H),1.19(t,J=6.8 Hz,3H)1.08(t,J=7.6 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.3,166.0(d,J C-F =16.5 Hz),159.7,158.3,152.2(d,J C-F =17.6 Hz),145.2(d,J C-F =3.2 Hz),76.4,75.7,36.0,31.9,23.9,14.1,13.6. 19 F NMR(376MHz,CDCl3)δ-49.78.ESI-HRMS(m / z)calcd C 15 H 19 FN4O3S2Na(M+Na) + ,409.0775;found,409.0775.HPLC purity:99.4%.36b:white solid,41.5%yield. 1H NMR(600 MHz,CDCl3)δ8.27(s,1H),5.29(t,J=4.2 Hz,1H),4.25-4.19(m,2H)3.92(d,J=12.6 Hz,1H)3.54(d,J=12.6 Hz,1H),3.36-3.29(m,2H),3.11(dd,J=4.2 Hz,J=12 Hz,1H),3.81(dd,J=4.8 Hz,J=12 Hz,1H),1.84-1.78(m,2H),1.14(t,J=7.2 Hz,3H),1.07(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ169.1,166.1(Jc-F=16.5 Hz),157.6(d,Jc-F=215.0 Hz),150.1(Jc-F=17.3 Hz),141.4(Jc-F=3.2 Hz),129.8(Jc-F=4.2 Hz),78.5,73.8,63.4,35.4(Jc-F=45 Hz),31.3,22.7,14.0,13.5. 19 F NMR(376 MHz,CDCl3)δ-49.51.ESI-HRMS(m / z)calcd C 15 H 19 FN4O3S2Na(M+Na) + ,409.0775;found,409.0769.HPLC purity:99.4%.

[0103] 1.2.37.(±)-Ethyl-3-(2-chloro-6-(propylthio)-9H-purin-9-yl)-4-hydroxytetrahydrothio phene-3-carboxylate(37a,37b)

[0104] 37a:white solid,22.4%yield. 1H NMR(400 MHz,DMSO)δ7.57(s,1H),5.90(d,J=5 Hz,2H),5.17-5.14(m,1H),4.14(q,J=7.2 Hz,2H),3.92(J=11.2 Hz,1H),3.57(d,J=11.2 Hz,1H),3.37(q,J=5.6 Hz,1H),3.33-3.29(m,2H),2.88(dd,J=3.6 Hz,11.6,1H),1.78-1.69(m,2H),1.07(t,J=7.2 Hz,3H),1.00(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,DMSO)δ167.6,162.4,151.8,150.0,144.6,130.0,74.0,73.6,62.1,22.2,13.6,13.1.ESI-HRMS(m / z)calcd C 15 H 19 ClN4O3S2Na(M+Na) + ,425.0479;found,425.0471.HPLC purity:99.8%.37b:white solid,51.6%yield. 1 H NMR(400 MHz,CDCl3)δ8.25(s,1H),5.30-5.27(m,1H),5.12-5.11(m,1H),4.28-4.12(m,2H),3.91(d,J=12.4 Hz,1H),3.53(d,J=12.4Hz,1H),3.37-3.27(m,2H),3.12(dd,J=4.4 Hz,J=11.6 Hz,1H),2.85-2.80(m,1H),1.84-1.75(m,1H),1.13(q,J=7.2Hz,3H),1.05(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.9,164.7,153.3,149.6,141.5,130.2,78.6,73.9,63.3,35.4(J C-F =13.7 Hz),31.2,22.6,13.9,13.4.ESI-HRMS(m / z)calcd C 15 H 19 ClN4O3S2Na(M+Na) + ,425.0479;found,425.0478.HPLC purity:97.9%.

[0105] 1.2.38.(±)-Ethyl-3-(2-amino-6-chloro-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(38a,38b)

[0106] 38a:white solid,71.0%yield. 1 H NMR(600 MHz,MeOD)δ8.31(s,1H),5.35(t,J=5.4 Hz,1H),4.23-4.15(m,2H),4.02(d,J=12.6 Hz,1H),3.73(d,J=12.6 Hz,1H),3.33(s,1H),3.21(q,J=5.4 Hz,1H),3.10(dd,J=4.8 Hz,J=11.4 Hz,1H),1.13(t,J=6.6Hz,3H). 13 C NMR(150 MHz,CDCl3)δ69.5,158.5,153.4,152.3,140.4,125.3,78.4,73.5,63.1,35.5,35.3,13.9.ESI-HRMS(m / z)calcd C 12 H 14 ClN5O3SNa(M+Na) + ,366.0398;found,366.0399.HPLC purity:97.1%.38b:white solid,16.7%yield. 1 H NMR(600 MHz,MeOD)δ8.43(s,1H),5.33(t,J=5.4 Hz,1H),4.23-4.19(m,2H),4.01(d,J=11.4 Hz,1H),3.67(d,J=11.4 Hz,1H),3.43(q,J=6.0 Hz,1H),2.94(dd,J=4.2 Hz,J=10.8 Hz,1H),1.16(t,J=6.6 Hz,3H). 13 C NMR(100 MHz,DMSO)δ168.2,159.5,154.4,149.7,142.4,123.2,74.1,73.7,62.1,35.5,33.6,13.8.ESI-HRMS(m / z)calcd C 12 H 14 ClN5O3SNa(M+Na) +,366.0398;found,366.0398.HPLC purity:98.8%.

[0107] 1.2.39.(±)-Ethy-3-(6-chloro-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carboxylate(39a,39b)

[0108] 39a:brown solid,21.5%yield. 1 H NMR(600 MHz,CDCl3)δ8.61(s,1H),5.40(t,J=6.6 Hz,1H),4.28-4.21(m,2H),3.72(dd,J=12.0 Hz,J=29.4 Hz,2H),3.59(s,1H),3.32(q,J=6.0 Hz,1H),2.82(dd,J=11.4 Hz,J=6.6 Hz,1H),1.18(t,J=7.2 Hz,3H). 13 CNMR(100 MHz,CDCl3)δ167.6,145.2,76.6,73.8,63.6,53.6,34.7,33.7(dd,J=100.6),14.0. 19 F NMR(376 MHz,CDCl3)δ-48.89.ESI-HRMS(m / z)calcd C 12 H 12 ClFN4O3SNa(M+Na) + ,369.0195;found,369.0187.HPLC purity:97.5%.39b:brown solid,32.5%yield. 1 H NMR(400 MHz,CDCl3)δ8.51(s,1H),5.30(s,2H),4.55(s,1H),4.29-4.21(m,2H),3.97(d,J=12.8 Hz,1H),3.56(d,J=12.4 Hz,1H),3.12(dd,J=3.2 Hz,J=11.6 Hz,1H),2.78(dd,J=4.4 Hz,J=11.6 Hz,1H),1.14(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.7,158.0,155.8,153.8,144.2(d,J C-F=3.6),130.6,78.3,74.1,63.8,53.6,35.6,35.1,14.0. 19 F NMR(376 MHz,CDCl3)δ-48.89.ESI-HRMS(m / z)calcd C 12 H 12 ClFN4O3SNa(M+Na) + ,369.0195;found,366.0192.HPLC purity:99.0%.

[0109] 1.2.40.(±)-Ethyl-3-(2,6-dichloro-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-car boxylate(40a,40b)

[0110] 40a:white solid,22.6%yield. 1 H NMR(600 MHz,CDCl3)δ 1 H NMR(600 MHz,CDCl3)δ8.61(s,1H),5.40(q,J=6 Hz,1 H),4.25(q,J=7.2 Hz,2H),3.71(dd,J=12.0Hz,J=31.2 Hz,1H),3.58(d,J=4.8 Hz,1H),3.32(q,J=6.0 Hz,1H),2.81(q,J=6.6 Hz,J=11.4 Hz,1H),1.19(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ167.6,153.6,152.8,152.2,145.4,130.5,76.5,73.9,63.6,34.6,33.7,14.0.ESI-HRMS(m / z)calcdC 12 H 13 N4BrO3SNa(M+Na) + ,371.9892;found,351.0290.HPLC purity:99.0%.40b:whitesolid,35.6%yield. 1H NMR(600 MHz,CDCl3)δ8.51(s,1H),5.30(q,J=3.0 Hz,1H),4.65(q,J=1.8 Hz,1H),4.32-4.19(m,2H),3.96(d,J=12.6 Hz,1H),3.55(d,J=12.6 Hz,1H),3.13(dd,J=3.0,J=12.0 Hz,1H),2.78(dd,J=4.2 Hz,J=12.0 Hz,1H),1.15(t,J=7.2Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.6,163.1,151.6,148.3,141.2,131.5,79.3,74.1,53.7,35.7,35.2,30.9,22.9,13.6.ESI-HRMS(m / z)calcd C 12 H 13 N4BrO3SNa(M+Na) + ,371.9892;found,351.0290.HPLC purity:96.0%.

[0111] 1.2.41.(±)-Ethyl-3-(2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrothiophene-3-carbo xylate(41a,41b)

[0112] 41a:white solid,54.6%yield. 1 H NMR(600 MHz,CDCl3)δ8.96(s,1H),8.56(s,1H),5.44(t,J=6.0 Hz,1H),4.29-4.21(m,2H),3.71(dd,J=12.0 Hz,J=43.8 Hz,2H),3.33(q,J=6.0 Hz,1H),2.83(dd,J=6.6 Hz,J=11.4 Hz,1H),1.18(t,J=7.2Hz,3H). 13 CNMR(150 MHz,CDCl3)δ167.9,154.2,153.7,150.6,145.5,132.9,76.4,73.6,63.5,34.8,33.8,14.0;ESI-HRMS(m / z)calcd C 12 H 13 N4ClO3SNa(M+Na) +,351.0289;found,351.0295.HPLC purity:99.5%.41b:white solid,27.1%yield. 1 H NMR(600 MHz,CDCl3)δ8.99(s,1H),8.48(s,1H),5.34(t,J=4.4 Hz,1H),4.89(s,1H),4.31-4.14(m,2H),3.96(d,J=12.4 Hz,1H),3.56(d,J=12.4 Hz,1H),3.14(dd,J=3.6 Hz,J=11.6 Hz,1H),2.81(dd,J=4.8 Hz,J=11.6 Hz,Hz,1H),1.12(t,J=7.2 Hz,3H). 13 C NMR(100 MHz,CDCl3)δ168.9,154.3,153.2,150.8,144.5,133.3,78.4,73.9,63.5,35.6,35.2,13.9;ESI-HRMS(m / z)calcd C 12 H 13 N4ClO3SNa(M+Na) + ,351.0289;found,351.0290.HPLC purity:99.7%.

[0113] 1.2.42.(±)-Ethy-3-(2-chloro-6-morpholino-9H-purin-9-yl)-4-hydroxytetrahydrothio phene-3-carboxylate(42a,42b)

[0114] 42a:white solid,18.4%yield. 1 H NMR(400 MHz,CDCl3)δ8.06(s,1H),5.42(q,J=6 Hz,1H),4.33(d J=5.2 Hz,3H),4.34-4.19(m,6H),3.82(t,J=5.2 Hz,4H),3.70(d,J=12.0 Hz,1H),3.46(d,J=11.6 Hz,1H)3.26(dd,J=6.0 Hz,J=10.8 Hz,1H),2.81(dd,J=6.8 Hz,J=11.2 Hz,1H),1.23(t,J=6.8 Hz,3H). 13C NMR(100MHz, CDCl3)δ168.3,154.2,153.7,152.4,138.1,118.6,76.6,73.6,67.1,63.3,35.3,33.7,14.0.ESI-HRMS(m / z)calcd C 16 H 20 ClN5O4SNa(M+Na) + , 436.0817; found, 436.0824. HPLC purity: 97.6%. 42b: white solid, 53.2% yield. 1 H NMR (400 MHz, CDCl3) δ7.98 (s, 1H), 5.49 (s, 1H), 5.26 (t, J = 4.4 Hz, 1H), 4.32-4.17 (m, 6H), 3.88 (d, J = 12.4 Hz, 1H), 3.83 (t, J = 4.8 Hz, 4H), 3.49 (d, J = 12.4 Hz, 1H), 3.17 (dd, J = 4.8 Hz, J = 11.6 Hz, 1H), 2.85 (dd, J = 4.4 Hz, J = 11.6 Hz, 1H) 1.18 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ169.5,154.1,153.6,152.2,137.4,118.8,79.1,73.8,67.1,63.3,35.7,35.5,14.1.ESI-HRMS(m / z)calcd C 16 H 20 ClN5O4SNa(M+Na) + ,436.0817; found,436.0817.HPLC purity:96.9%.

[0115] Chiral separation of compounds was performed using a CHIRALPAK IF (IF00CE-RL 017, 0.46cm IDx 25cmL) column (injection volume 10μL / mobile phase MeOH / DCM-95 / 5 (V / V), flow rate 1.0mL / min, wavelength UV 254nm, column temperature 35℃, HPLC: Shimadzu LC-20AD CP-HPLC-08). The chiral compounds after separation were all greater than 98% ee.

[0116] Example 2

[0117] 2.1 Experimental Materials

[0118] 1. Plasmids and viruses

[0119] Plasmids pLAI-Δenv-Luc2 and pJRFL / env were used. pLAI-Δenv-Luc contains the HIV-1 backbone gene sequence but deletes the env and vpr genes and inserts the Luciferase reporter gene at the nef gene site; pJRFL contains the CCR5-tropic HIV-1 env gene. Both plasmids were co-transfected with HEK293T to obtain pseudotyped single-cycle infectious HIV-1 (HIV-luc / JRFL).

[0120] 2. Cells

[0121] HEK 293T, culture conditions: DMEM + 10% FBS + 1% Pen-Strep;

[0122] CD4+ T cells with Hut / CCR5, cultured under RPMI 1640 + 10% FBS + 1% Pen-Strep, containing G418 (50 mg / mL) and Puromycin (1 mg / mL).

[0123] 3. Main reagents

[0124] RPMI-1640 medium (GIBCO, cat: C11875500BT);

[0125] Fetal bovine serum FBS (Gibco, cat: 10099-141);

[0126] Bismuth subsalicylate Pen-Strep (10,000 U / mL) (Gibco, cat: 15140122);

[0127] G418 (Millipore, cat: 345810);

[0128] Puromycin Dihydrochloride (InvivoGen, cat: ant-pr-1);

[0129] Luciferase Cell Culture Lysis 5X Reagent (promega, cat: E1531);

[0130] Luciferase Assay Substrate (promega, cat: E1501);

[0131] MTT: (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); (Tetramethylazozolium salt) (MCE, cat: HY-15924)

[0132] 2.2 Research Methods

[0133] 1. Dose-dependent anti-HIV assay

[0134] 5x 10 4 Hut / CCR5 cells were seeded in 96-well plates, and 50 μL of compounds with good initial screening effects were added. The final concentrations of the compounds were 5 μM, 1 μM, 0.2 μM, and 0.04 μM. 50 μL of HIV-luc / JRFL was then added. FNC (Azvudine) was used as a compound control.

[0135] Incubate at 37°C for 4 hours to wash away free viruses; resuspend in culture medium and add appropriate concentrations of the compound.

[0136] Cells were cultured at 37°C for 3 days, and the supernatant was collected after cell lysis to detect luciferase activity.

[0137] The replication rate of the virus can be calculated, and the inhibition rate can be further calculated.

[0138] 2. MTT assay for cytotoxicity

[0139] 5x 10 4 Hut / CCR5 cells were seeded in 96-well cell culture plates. 100 μL of the compound solution was added to 100 μL of culture medium (RPMI-1640 / 10% FBS / 1% Pen / Strep); the final compound concentrations were 625 μM, 125 μM, 25 μM, 5 μM, and 1 μM; each concentration was repeated in triplicate. A control without the compound was also included. After 72 h of cell culture, 100 μL of supernatant was discarded, and 20 μL of MTT (5 mg / mL) was added. The cells were incubated at 37°C for 4 h. After centrifugation, 100 μL of supernatant was discarded, and 100 μL of DMSO was added. The cells were incubated at room temperature in the dark, and shaken for 15 minutes until the blue formazene dissolved. OD595 and OD630 were measured using a microplate reader as reference wavelengths. Cell viability was calculated.

[0140] 2.3 Detection Results: Concentration-dependent anti-HIV-1 activity

[0141]

[0142] from Figure 1 It can be seen that the (±)-42a(LZ-42a) compound EC50 =0.541μM,CC 50 =34.958μM. The selectivity coefficients for both are SI = CC. 50 / EC 50 =65.54.

[0143] from Figure 2 It can be seen that the (±)-11a(LZ-11a) compound EC 50 =6.372μM,CC 50 =42.034μM. The selectivity coefficients for both are SI = CC. 50 / EC 50 =6.60.

[0144] Antiviral activity experiments revealed that compound 42a (LZ-42a) of this invention exhibits good anti-HIV-1 activity and shows promising potential in the preparation of drugs for treating AIDS and related symptoms.

[0145] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the present invention without departing from its principles, including any structural changes to five-membered thioheterocyclic nucleosides. All such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A five-membered thioheterocyclic nucleoside lead compound, characterized in that, Its chemical structure is:

2. The use of the five-membered thioheterocyclic nucleoside lead compound as described in claim 1 in the preparation of antiviral drugs.

3. The application of the five-membered thioheterocyclic nucleoside lead compound according to claim 2 in the preparation of antiviral drugs, characterized in that: The antiviral agent is effective against HIV-1.

4. The use of the five-membered thioheterocyclic nucleoside lead compound as described in claim 1 in the preparation of drugs for treating AIDS.

5. A pharmaceutical composition comprising the compound of claim 1.

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