Five-membered sulfur-containing heterocyclic nucleoside lead compound and application thereof in anti-HIV (Human Immunodeficiency Virus) active medicine

Abstract

The invention discloses a five-membered sulfur-containing heterocyclic nucleoside derivative and application thereof in an anti-human immunodeficiency virus (HIV) active medicine, and belongs to the technical field of medicinal chemistry. A series of five-membered sulfur-containing heterocyclic ring nucleoside compounds are synthesized through a Sulfa-Michael / Aldol cascade reaction. The result shows that in an anti-HIV virus test, the five-membered sulfur-containing heterocyclic nucleoside lead compound 42a has the optimal anti-HIV-1 virus activity, and a new structural unit is provided for antiviral candidate drug molecules.

Description

Technical Field

[0001] The invention relates to a five-membered sulfur-containing heterocyclic nucleoside lead compound and application thereof in an anti-HIV active drug, belonging to the field of pharmaceutical chemistry. Background Art

[0002] Viruses seriously threaten human life and health and are one of the main causes of human death. The research and development of antiviral drugs has always been one of the important directions in drug development. Artificially synthesized nucleoside compounds are similar in structure to natural nucleoside compounds. After entering the human body, they can inhibit the replication of viruses or tumor cells, achieving the purpose of antiviral or anti-tumor.

[0003] People pay more and more attention to the research and development of nucleoside anti-tumor and antiviral drugs. Five-membered sulfur heterocyclic nucleoside compounds are a unique class of compounds among nucleoside compounds, with unique physical and chemical properties, and have become the focus of nucleoside drug research and development.

[0004] Currently, five-membered sulfur heterocyclic nucleoside compounds are an important class of antiviral drugs on the market, but there are relatively few studies on the antiviral activity of five-membered sulfur heterocyclic nucleoside compounds. Innovative research on five-membered sulfur heterocyclic nucleoside antiviral drugs has important scientific significance and potential application prospects. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention provides nucleoside lead compounds with more functional structures, and discloses a five-membered sulfur heterocyclic nucleoside lead compound with anti-HIV activity. Synthesis method: A series of five-membered sulfur heterocyclic nucleoside compounds are synthesized by Sulfa-Michael / Aldol tandem reaction and other reactions.

[0006] The present invention discloses a five-membered sulfur heterocyclic nucleoside lead compound, including its racemate and chiral compound, wherein: the chiral compound has an ee value of 0-100%, and is a single enantiomerically pure compound or a mixture of two enantiomers in different proportions. Its general structural formula is as follows:

[0007]

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

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

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

[0011] Further, under the most preferred conditions, the structure of the five-membered sulfur heterocyclic nucleoside lead compound is

[0012]

[0013] The present invention also provides a method for synthesizing a five-membered sulfur heterocyclic nucleoside lead compound, comprising the following steps:

[0014]

[0015] Compound 1-42A reacts in the presence of triphenylphosphine, sodium acetate, acetic acid and propiolate to obtain compound 1-42B; compound 1-42B then reacts with 1,4-dithiane-2,5-diol in the presence of triethylamine to obtain 1a-42a and 1b-42b; and then the corresponding chiral compounds are obtained after separation by a chiral separation column.

[0016] Furthermore, in the above technical solution, the first step reaction solvent is toluene, and the reaction temperature is 110°C.

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

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

[0019] The present invention also provides the use of the five-membered sulfur heterocyclic nucleoside lead compound in the preparation of antiviral drugs.

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

[0021] The present invention also provides the use of the five-membered sulfur heterocyclic nucleoside lead compound in the preparation of drugs for treating AIDS.

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

[0023] Beneficial effects of the invention:

[0024] 1. The raw materials used are simple and easy to obtain, and have broad application prospects.

[0025] 2. The product was tested for antiviral activity, and it was found that compound 42a (LZ-42a) had good anti-HIV-1 activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a graph showing the anti-HIV-1 activity of 42a (LZ-42a);

[0027] Figure 2 This is a graph showing the anti-HIV-1 viral activity of 11a (LZ-11a). DETAILED DESCRIPTION

[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 operation of the first step: 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 propiolate (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, and dichloromethane was added to extract the reaction mixture 3 times. 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] Typical operation of the second step: α-heterocyclic acrylate B (0.05 mmol) and 1,4-disulfane 2,5-diol (0.03 mmol) were added to a round-bottom flask. Then, 20 mmol% triethylamine was added and stirred at room temperature for 4 hours. The reaction product was detected by thin layer chromatography, and the solvent was 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] The compounds were separated by chiral separation column using CHIRALPAK IF (IF00CE-RL 017, 0.46cm IDx 25cmL) chromatographic column (injection volume 10μL / mobile phase MeOH / DCM-95 / 5 (V / V), flow rate 1.0mL / min, wavelength UV254nm, column temperature 35℃, HPLC: Shimadzu LC-20AD CP-HPLC-08). After separation, the chiral compounds were all greater than 98% ee.

[0116] Example 2

[0117] 2.1 Experimental Materials

[0118] 1. Plasmids and viruses

[0119] Plasmid pLAI-Δenv-Luc2, plasmid pJRFL / env. pLAI-Δenv-Luc contains the HIV-1 backbone gene sequence, but the env and vpr genes are deleted, and the Luciferase reporter gene is inserted into the nef gene site; pJRFL contains the CCR5-tropic HIV-1env gene. The two plasmids were co-transfected into HEK293T to obtain HIV-1 pseudovirus 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 Hut / CCR5, culture conditions RPMI1640+10% FBS+1% Pen-Strep, containing G418 (50 mg / mL), 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] 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); (tetramethylthiazolium 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 inoculated in a 96-well plate, and 50 μL of the compound with good initial screening effect was added, with the final concentration of the compound being 5 μM, 1 μM, 0.2 μM, and 0.04 μM; then 50 μL of the infected virus HIV-luc / JRFL was added; FNC (azithromycin) was used as a compound control;

[0135] Incubate at 37°C for 4 h, wash away free viruses, resuspend in culture medium, and add corresponding concentrations of compounds;

[0136] After culturing at 37°C for 3 days, the cells were lysed and the supernatant was collected to detect luciferase activity;

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

[0138] 2. MTT colorimetric assay for cytotoxicity

[0139] 5x 10 4 Hut / CCR5 cells were inoculated in 96-well cell culture plates. 100 μL (culture medium: RPMI-1640 / 10% FBS / 1% Pen / Strep) was added with 100 μL compound solution; the final concentration of the compound was 625 μM, 125 μM, 25 μM, 5 μM, and 1 μM; 3 replicates were performed for each concentration; a control without compound was also set up; after 72 hours of cell culture, 100 μL supernatant was discarded, 20 μL MTT (5 mg / mL) was added, and cultured at 37°C for 4 hours; centrifuged, 100 μL supernatant was discarded, 100 μL DMSO was added, and the mixture was kept at room temperature and away from light, and shaken for 15 minutes until the blue formazen dissolved; OD595 and OD630 were detected by an ELISA instrument as reference wavelengths. Cell survival rate was calculated.

[0140] 2.3 Test results: concentration-dependent anti-HIV-1 activity

[0141]

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

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

[0144] The antiviral activity experiment found that the compound 42a (LZ-42a) of the present invention has good anti-HIV-1 activity and has good prospects 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 by the above embodiments, and the above embodiments and the description only illustrate the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and any structural changes of the five-membered sulfur heterocyclic nucleoside, these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A five-membered sulfur heterocyclic nucleoside lead compound, including its racemate and chiral compound, characterized in that: The general structure is as follows: Where: R 1 is selected from hydrogen, halogen, amino, C1-C20 alkyl, C1-C20 alkoxy; R 2 is selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, C1-20 alkylthio, C2-C20 alkynylthio, halogenated C1-C20 alkylthio, benzylthio, phenylthio, substituted phenylthio, di(C1-C8 alkyl)amine, X = CH2, O, S, NH, N-(C1-C4)alkyl; n = 0-5; R 3 =C1-C8 alkyl, halogen, trifluoromethyl, benzyl, substituted phenylmethyl, morpholinyl; wherein the substituent in the substituted phenyl is halogen or C1-C8 alkyl; R is selected from hydrogen, C1-C20 alkyl.

2. The five-membered sulfur heterocyclic nucleoside lead compound according to claim 1, characterized in that: R 1 is selected from hydrogen, halogen, amino; R 2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-6 alkylthio, C2-C4 alkynylthio, halogenated C1-C4 alkylthio, benzylthio, phenylthio, substituted phenylthio, di(C1-C2 alkyl)amine, X = CH2, O, S, NH, N-(C1-C4)alkyl; n = 1-3; R 3 =C1-C4 alkyl, halogen, trifluoromethyl, benzyl, substituted phenylmethyl, morpholinyl; wherein the substituent in the substituted phenyl is halogen or C1-C4 alkyl.

3. The five-membered sulfur heterocyclic nucleoside lead compound according to claim 2, characterized in that: R is selected from ethyl.

4. The five-membered sulfur heterocyclic nucleoside lead compound according to claim 3, characterized in that: The structure of the five-membered sulfur heterocyclic nucleoside lead compound is 5. A method for synthesizing a five-membered sulfur heterocyclic nucleoside lead compound, characterized in that: The steps include: Compound 1-42A reacts in the presence of triphenylphosphine, sodium acetate, acetic acid and propiolate to obtain compound 1-42B; compound 1-42B then reacts with 1,4-dithiane-2,5-diol in the presence of triethylamine to obtain 1a-42a and 1b-42b; finally, the corresponding chiral compound is obtained after separation by a chiral separation column.

6. The method for synthesizing the five-membered sulfur heterocyclic nucleoside lead compound according to claim 5, characterized in that: The first step reaction solvent is toluene, and the reaction temperature is 110°C; the second step reaction solvent is dichloromethane, and the reaction temperature is 0-30°C; the third step chiral separation column separation is performed using a CHI RALPAK IF (IF00CE-RL017, 0.46cm IDx 25cm L) chromatographic column.

7. Use of the five-membered sulfur heterocyclic nucleoside lead compound according to any one of claims 1 to 4 in the preparation of antiviral drugs.

8. The use of the five-membered sulfur heterocyclic nucleoside lead compound in the preparation of antiviral drugs according to claim 7, characterized in that: Antiviral is against HIV-1 virus.

9. Use of the five-membered sulfur heterocyclic nucleoside lead compound according to any one of claims 1 to 4 in the preparation of drugs for treating AIDS.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

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