Cytosine nucleoside compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of compound synthesis, in particular to cytosine nucleoside compounds as well as a preparation method and application thereof. The structural general formula of the cytosine nucleoside compound is as shown in formula I in the specification. On the basis of a cytosine nucleoside structure, a saturated six-membered nitrogen heterocyclic structure with biological activity is introduced into the cytosine nucleoside structure, a series of novel cytosine nucleoside compounds are synthesized, and the compounds have a good inhibition effect on plant viruses and can be used for preparing plant viruses. The compound has a good inhibition effect on plant virus diseases such as tobacco mosaic virus (TMV) and the like.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a class of cytosine nucleoside compounds, their preparation methods, and applications. Background Technology

[0002] Plant viral diseases are the second largest category of diseases in agricultural production after fungal diseases, causing approximately 30% to 40% of global crop yield losses annually. Among the many plant viruses, Tobacco Mosaic Virus (TMV), Tomato Spotted Wilt Virus (TSWV), Tomato Yellow Leaf Curl Virus (TYLCV), Cucumber Mosaic Virus (CMV), and Potato Virus Y (PVY) are considered the most threatening due to their significant economic impact. Tobacco Mosaic Virus (TMV), as one of the most destructive plant viruses, causes direct economic losses exceeding US$100 million annually.

[0003] Currently, chemical control remains the most rapid and effective strategy for controlling TMV. However, field application data show that existing mainstream antiviral agents such as ningnanmycin (500 μg / mL) and ribavirin (500 μg / mL) have a control efficacy of only about 50%, which is insufficient to meet the stringent requirements of modern agriculture for viral disease control. Therefore, developing new, highly efficient, and environmentally friendly antiviral agents is of great significance.

[0004] Cytosine nucleoside derivatives have become a research hotspot due to their broad range of biological activities in antibacterial, antiviral, and anticancer properties. Meanwhile, compounds containing saturated six-membered nitrogen heterocycles also exhibit diverse biological activities in the pharmaceutical and pesticide fields. Therefore, there is a need to find new compounds with highly efficient antiviral activity. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a class of cytosine nucleoside compounds, their preparation methods, and applications. Based on the cytosine nucleoside structure, this invention introduces saturated six-membered nitrogen heterocyclic units that may enhance biological activity into the molecular system, designs and synthesizes a series of cytosine nucleoside derivatives, and systematically evaluates their biological activities, aiming to provide important scientific basis for the research and development and creation of new pesticides. These derivatives have novel molecular skeletons and exhibit good antiviral activity against tobacco mosaic virus.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] This invention provides a class of cytosine nucleoside compounds, the general structural formula of which is shown in Formula I:

[0008]

[0009] Where n is 4 or 10, and X is nitrogen, oxygen or sulfur;

[0010] R 1 Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenated C3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl.

[0011] Preferably, the cytosine nucleoside compound is any one of the following compounds:

[0012]

[0013]

[0014]

[0015] This invention also provides a method for preparing the cytosine nucleoside compound described in the above technical solution, comprising the following steps:

[0016] 1) Compound 1 was reacted with a mixture of 2,2,6,6-tetramethylpiperidine-1-oxy radical, iodophenylacetic acid, sodium bicarbonate and acetonitrile solution. The precipitate was collected and washed with diethyl ether and acetone until it was colorless to obtain compound 2.

[0017] The structure of compound 1 is as follows:

[0018]

[0019] The structure of compound 2 is as follows:

[0020]

[0021] 2) Compound 2 from step 1) was mixed with thiomorpholine, N,N-dimethylformamide, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and reacted, and then purified to obtain compound 3;

[0022] The structure of compound 3 is as follows:

[0023]

[0024] R 1 Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenatedC3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl;

[0025] 3) The compound 3 obtained in step 2) is mixed with formic acid solution and reacted. After purification, compound 4 is obtained.

[0026] The structure of compound 4 is as follows:

[0027]

[0028] 4) The compound 4 obtained in step 3) is mixed with an acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and reacted. After purification, a cytosine nucleoside compound is obtained; the acid is hexanoic acid or lauric acid.

[0029] Preferably, the mass ratio of compound 1 in step 1) to the mass of 2,2,6,6-tetramethylpiperidine-1-oxy radical, the mass of iodophenyldiacetic acid, the mass of sodium bicarbonate, and the volume of acetonitrile solution is 5 g: 0.552 g: 12.5 g: 2.97 g: 35 mL;

[0030] The reaction conditions include stirring at 0°C for 2 hours.

[0031] Preferably, the mass ratio of compound 2 in step 2) to the mass of thiomorpholine, the volume of N,N-dimethylformamide, the mass of 1-hydroxybenzotriazole, and the mass of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1 g: 836.55 mg: 10 mL: 1 g: 1.15 g;

[0032] The reaction conditions include: stirring the reaction at a temperature of 20–25°C for 4 hours;

[0033] The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:1.

[0034] Preferably, in step 3), the mass ratio of compound 3 to the volume ratio of formic acid solution is 500 mg: 10 mL; the mass percentage of formic acid solution is 50%.

[0035] The reaction conditions include: a temperature of 70°C and a time of 4 hours;

[0036] The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:1.

[0037] Preferably, the mass ratio of compound 4 in step 4) to lauric acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 400:368.34:364.41:418.67;

[0038] The reaction conditions include: stirring the reaction at 26°C for 4 hours;

[0039] The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 150:1 to 20:1.

[0040] This invention also provides the application of the cytosine nucleoside compounds described in the above-mentioned technical solutions in the prevention and control of plant viruses.

[0041] Preferably, the plant virus includes tobacco mosaic virus.

[0042] Preferably, the amount of the cytosine nucleoside compound used is 500 μg / mL.

[0043] The beneficial effects of this invention are:

[0044] These derivatives possess novel molecular skeletons and exhibit triple biological activity against tobacco mosaic virus, including therapeutic, protective, and inactivating effects. Specifically, compounds A3, A4, A10, A11, A21, and A22 in the examples showed excellent therapeutic effects against tobacco mosaic virus; compounds A1, A6, A11, A19, A22, and A35 showed excellent protective effects; and compounds A1, A4, A21, A22, A26, and A35 exhibited outstanding inactivating effects. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0046] Figure 1 To synthesize target compound A from 2',3'-O-isopropylcytidine as the starting material, a four-step reaction was performed: First, intermediate 2 was prepared by a free radical-mediated oxidation reaction; then, intermediate 3 was obtained by condensation with a saturated six-membered nitrogen heterocyclic derivative; intermediate 4 was obtained by hydrolysis with formic acid; finally, intermediate 4 was obtained by condensation with fatty acids of different chain lengths (hexanoic acid / lauric acid) to obtain a series of target products. Detailed Implementation

[0047] This invention provides a class of cytosine nucleoside compounds, the general structural formula of which is shown in Formula I:

[0048]

[0049] Where n is 4 or 10, and X is nitrogen, oxygen or sulfur;

[0050] R 1Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenated C3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl.

[0051] This invention also provides a method for preparing the cytosine nucleoside compound described in the above technical solution, comprising the following steps:

[0052] 1) Compound 1 was reacted with 2,2,6,6-tetramethylpiperidine-1-oxygen radical (TEMPO), iodophenyl diacetic acid (PhI(OAc)2), sodium bicarbonate and acetonitrile solution. The precipitate was collected and washed with diethyl ether and acetone until colorless to obtain compound 2.

[0053] The structure of compound 1 is as follows:

[0054]

[0055] The structure of compound 2 is as follows:

[0056]

[0057] 2) Compound 2 from step 1) was mixed with thiomorpholine, N,N-dimethylformamide, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and reacted, and then purified to obtain compound 3;

[0058] The structure of compound 3 is as follows:

[0059]

[0060] R 1 Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenatedC3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl;

[0061] 3) The compound 3 obtained in step 2) is mixed with formic acid solution and reacted. After purification, compound 4 is obtained.

[0062] The structure of compound 4 is as follows:

[0063]

[0064] 4) The compound 4 obtained in step 3) is mixed with an acid, 1-hydroxybenzotriazole (HOBt), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and reacted. After purification, a cytosine nucleoside compound is obtained; the acid is hexanoic acid or lauric acid.

[0065] In this invention, the preferred mass ratio of compound 1 in step 1) to the mass of 2,2,6,6-tetramethylpiperidine-1-oxygen radical (TEMPO), the mass of iodophenyl diacetic acid (PhI(OAc)2), the mass of sodium bicarbonate, and the volume of acetonitrile solution is 5 g: 0.552 g: 12.5 g: 2.97 g: 35 mL; the reaction conditions include stirring at 0 °C for 2 h.

[0066] In this invention, R1 is preferably any of the following:

[0067]

[0068] In this invention, the preferred mass ratio of compound 2 in step 2) to the mass of thiomorpholine, the volume of N,N-dimethylformamide, the mass of 1-hydroxybenzotriazole, and the mass of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1 g:836.55 mg:10 mL:1 g:1.15 g. In this invention, the preferred reaction conditions include stirring at 20–25°C for 4 h. In this invention, the preferred purification conditions include purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:1.

[0069] In this invention, the preferred mass ratio of compound 3 to formic acid solution in step 3) is 500 mg:10 mL; the formic acid solution has a mass percentage of 50%. In this invention, the preferred reaction conditions include a temperature of 70°C and a time of 4 hours. In this invention, the preferred purification conditions include purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:1.

[0070] In this invention, the preferred mass ratio of compound 4 in step 4) to lauric acid, 1-hydroxybenzotriazole (HOBt), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) is 400:368.34:364.41:418.67. In this invention, the preferred reaction conditions include stirring at 26°C for 4 hours. In this invention, the preferred purification conditions include purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 150:1 to 20:1.

[0071] This invention also provides the application of the cytosine nucleoside compounds described in the above-described technical solutions in the control of plant viruses. In this invention, the plant virus preferably includes tobacco mosaic virus. In this invention, the preferred dosage of the cytosine nucleoside compound is 500 μg / mL.

[0072] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0073] Example 1

[0074] This embodiment illustrates the preparation method of the cytosine nucleoside derivative containing a saturated six-membered nitrogen heterocycle according to the present invention. The synthetic route is as follows: Figure 1 As shown.

[0075] The preparation methods for representative compounds include the following steps:

[0076] (1) Synthesis of compound 2:

[0077]

[0078] Compound 1 (17.7 mmol, 5.00 g) was mixed with 2,2,6,6-tetramethylpiperidine-1-oxygen radical (TEMPO) (3.53 mmol, 0.552 g), iodophenyl diacetic acid (PhI(OAc)2) (38.8 mmol, 12.5 g), and sodium bicarbonate (35.3 mmol, 2.97 g), and dissolved in acetonitrile / water (35 ml). The reaction mixture was kept in an ice-water bath at 0°C and stirred for 2 hours. After complete conversion of the starting material, the precipitate was collected by vacuum filtration and washed successively with pre-cooled (0°C) diethyl ether and acetone until colorless, finally yielding compound 2.

[0079] (2) Synthesis of compound 3:

[0080]

[0081] Compound 2 (3.36 mmol, 1.00 g) and thiomorpholine (4.04 mmol, 836.55 mg) were dissolved in N,N-dimethylformamide (DMF, 10 ml), followed by the sequential addition of 1-hydroxybenzotriazole (HOBt, 7.40 mmol, 1.00 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 7.40 mmol, 1.15 g). The mixture was stirred at room temperature for 4 hours. After the reaction was confirmed by thin-layer chromatography (TLC), the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1 to 10:1) to obtain compound 3.

[0082] (3) Synthesis of compound 4:

[0083]

[0084] Compound 3 (1.31 mmol, 500.00 mg) was deprotected by treatment with 10 ml of 50% formic acid solution at 70°C for 4 hours. After confirmation of complete reaction by thin-layer chromatography (TLC), the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1 to 10:1, v / v) to obtain compound 4.

[0085] (4) Synthesis of compound 5:

[0086]

[0087] Compound 4 (1.23 mmol, 400.00 mg) was mixed with lauric acid (1.84 mmol, 368.34 mg), 1-hydroxybenzotriazole (HOBt) (2.70 mmol, 364.41 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.70 mmol, 418.67 mg) and stirred at 26 °C for 4 hours. After the reaction was confirmed by thin-layer chromatography, the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 150:1 to 20:1, v / v) to obtain the target compound A35.

[0088] The structural formula, molecular formula, physicochemical properties, and nuclear magnetic resonance hydrogen spectrum, carbon spectrum, and fluorine spectrum data of the target compound A35 obtained in Example 1 of this invention are shown in the table below. Compound A35 can be obtained through the above synthesis steps (1)-(5).

[0089] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(4-methoxyphenyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A1)

[0090] Red solid,yield 48%,mp115.9-116.3℃; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),6.91(d,J=9.1Hz,2H),6.82(d,J=9.1Hz,2H),5.98(d,J=4.1Hz,1H),5.71(s,2H),4.95(d,J=4.9Hz,1H),4.12(t,J=4.8Hz,1H),4.03(t,J=4.3Hz,1H),3.74-3.68(m,7H),3.07-2.97(m,4H),2.39(t,J=7.4Hz,2H),1.58-1.50(m,2H),1.31-1.21(m,4H),0.85(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.0,168.2,162.5,154.9,153.4,145.8,145.1,118.1,114.3,95.6,90.3,79.0,75.0,72.9,55.2,50.3,49.8,44.9,41.8,36.4,30.7,24.2,21.9,13.9.HRMS(ESI)[M+H] + calcd for C 26 H 36 N5O7 + :530.2609,found:530.2612.N-(1-((2R,3S,4R,5R)-5-(4-benzoylpiperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2dihy dropyrimidin-4-yl)hexanamide(A2)

[0091] Yellow oil,yield 44%, 1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.95(d,J=7.6Hz,1H),7.46(d,J=5.9Hz,3H),7.42(d,J=6.5Hz,2H),7.26(d,J=7.4Hz,1H),5.95(s,1H),5.81(s,1H),5.04-4.84(m,1H),4.10(d,J=5.1Hz,1H),4.02(t,J=4.5Hz,1H),3.66-3.61(d,J=34.9Hz,4H),3.39-3.34(m,4H),2.38(t,J=7.4Hz,2H),1.55-1.51(m,2H),1.26-1.20(m,4H),0.85-0.82(m,3H). 13 C NMR(151MHz,DMSO-d6)δ174.1,169.4,168.6,162.6,155.0,145.9,135.7,129.9,128.6,127.2,95.7,90.4,79.1,74.9,72.9,36.5,30.8,24.3,22.0,14.0.HRMS(ESI)[M+Na] + calcd for C 26 H 33 N5O7Na + :550.2272,found:550.2274.

[0092] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(4-nitrophenyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A3)

[0093] Yellow solid,yield 39%,m.p.150.5-152.3℃; 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.94(d,J=7.5Hz,1H),8.07(d,J=9.1Hz,2H),7.25(d,J=7.5Hz,1H),7.02(d,J=9.2Hz,2H),5.97(d,J=4.0Hz,1H),5.72-5.65(m,2H),4.96(d,J=5.0Hz,1H),4.15-4.12(m,1H),4.05-4.02(m,1H),3.75-3.70(m,4H),3.58-3.52(m,4H),3.34(s,2H),2.38(t,J=7.4Hz,2H),1.58-1.50(m,2H),1.31-1.21(m,4H),0.85(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,169.0,162.9,155.3,154.8,146.2,137.5,126.2,113.1,96.0,90.8,79.5,75.3,73.2,46.6,46.1,44.4,41.6,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na]+calcd for C 25 H 32 N6O8Na + :567.2174,found:567.2180.

[0094] N-(1-((2R,3S,4R,5R)-5-(4-(4-cyanophenyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A4)

[0095] White solid,yield 30%,m.p.131.1-132.4℃; 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.95(d,J=7.5Hz,1H),7.57(d,J=8.7Hz,2H),7.26(d,J=7.5Hz,1H),7.10-6.91(m,2H),5.97(d,J=4.0Hz,1H),5.73-5.69(m,2H),4.96(d,J=5.1Hz,1H),4.15-4.12(m,1H),4.06-4.03(m,1H),3.75-3.61(m,4H),3.42-3.37(m,4H),2.37(t,J=7.4Hz,2H),1.56-1.49(m,2H),1.26-1.18(m,4H),0.85-0.81(m,3H). 13 CNMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,155.4,153.2,146.2,133.8,120.4,114.6,99.0,96.1,90.8,79.4,75.3,73.3,46.9,46.4,44.5,41.7,36.8,31.1,24.6,22.3,14.2.HRMS(ESI)[M+Na] + calcd for C 26 H 32 N6O6Na + :547.2276,found:547.2280.N-(1-((2R,3S,4R,5R)-5-(4-(4-fluorophenyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A5)

[0096] Colorless oil,yield 57%, 1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.98(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),7.06(t,J=8.9Hz,2H),6.99-6.97(m,2H),5.96(d,J=4.1Hz,1H),5.82-5.71(m,2H),4.96(d,J=5.1Hz,1H),4.11(t,J=4.7Hz,1H),4.01(t,J=4.3Hz,1H),3.70-3.66(m,4H),3.12-3.06(m,4H),2.38(t,J=7.5Hz,2H),1.56-1.51(m,2H),1.28-1.23(m,4H),0.85(t,J=7.0Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ174.5,168.6,162.9,155.3,148.1,146.3,118.2(d,J=7.9Hz),115.9,115.8,96.0,90.7,79.4,75.3,73.3,50.0,49.5,45.2,42.0,36.8,31.2,24.6,22.3,14.3. 19 F NMR(377MHz,DMSO-d6)δ-124.81.HRMS(ESI)[M+Na] + calcd forC 25 H 32 FN5O6Na + :540.2229,found:540.2223.

[0097] N-(1-((2R,3S,4R,5R)-5-(4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A6)

[0098] White solid,yield 44%,m.p.134.3-135.7℃; 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.94(d,J=7.5Hz,1H),8.48(d,J=2.4Hz,1H),7.85(dd,J=9.0,2.4Hz,1H),7.25(d,J=7.5Hz,1H),6.93(d,J=9.1Hz,1H),5.96(d,J=4.0Hz,1H),5.73-5.68(m,2H),4.96(d,J=5.1Hz,1H),4.15-4.12(m,1H),4.05-4.02(m,1H),3.74-3.63(m,8H),2.37(t,J=7.4Hz,2H),1.56-1.49(m,2H),1.20-1.27(m,4H),0.84(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,169.0,162.9,159.4,155.4,152.9,146.2,140.5,119.1,107.1,96.1,90.9,79.5,75.3,73.3,44.6,44.5,44.0,41.8,36.8,31.2,24.6,22.3,14.3.HRMS(ESI)[M+Na]+calcd for C 25 H 31 N7O6Na + :548.2228,found:548.2229.

[0099] N-(1-((2R,3S,4R,5R)-5-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A7)

[0100] White oil,yield 37%; 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.93(d,J=7.5Hz,1H),7.42-7.29(m,4H),7.25(d,J=7.5Hz,1H),5.96(d,J=4.2Hz,1H),5.66(s,2H),4.89(d,J=4.8Hz,1H),4.07(t,J=4.7Hz,1H),4.00(t,J=4.4Hz,1H),3.55(d,J=5.2Hz,2H),3.49(s,2H),3.06(q,J=7.3Hz,2H),2.45-2.32(m,6H),1.58-1.50(m,2H),1.27-1.23(m,3H),0.85(t,J=6.8Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ174.4,168.5,162.9,155.3,146.2,137.2,132.1,131.2,128.7,96.0,90.6,79.4,75.3,73.3,61.2,53.1,52.5,45.2,42.1,31.2,24.6,22.3,14.3,8.9.HRMS(ESI)[M+H] + calcdfor C 26 H 34 ClN5O6 + :548.2270,found:548.2276.

[0101] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-phenylpiperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A8)

[0102] Colorless oil,yield 52%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.98(d,J=7.5Hz,1H),7.30-7.17(m,3H),6.94(d,J=8.2Hz,2H),6.80(t,J=7.2Hz,1H),5.98(d,J=4.0Hz,1H),5.83-5.64(m,2H),4.97(d,J=5.1Hz,1H),4.13(t,J=4.8Hz,1H),4.04(t,J=4.3Hz,1H),3.72-3.65(m,4H),3.19-3.11(m,4H),2.39(t,J=7.4Hz,2H),1.50-1.58(m,2H),1.30-1.21(m,4H),0.84(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.6,162.9,155.4,151.1,146.2,129.5,119.8,116.3,96.0,90.8,79.4,75.4,73.3,49.2,48.7,45.1,42.0,36.8,31.2,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd for C 25 H 33 N5O6Na + :522.2323,found:522.2326.

[0103] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(pyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A9)

[0104] Colorless oil,yield 49%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.97(d,J=7.5Hz,1H),8.12(dd,J=5.0,1.9Hz,1H),7.56-7.52(m,1H),7.26(d,J=7.5Hz,1H),6.84(d,J=8.6Hz,1H),6.67-6.64(m,1H),5.97(d,J=4.0Hz,1H),4.97(d,J=5.0Hz,1H),4.13(t,J=4.8Hz,1H),4.03(t,J=4.3Hz,1H),3.67-3.64(m,3H),3.57(d,J=4.6Hz,1H),3.51-3.50(m,1H),3.46-3.40(m,4H),3.17(s,1H),2.38(t,J=7.4Hz,2H),1.57-1.50(m,2H),1.28-1.21(m,4H),0.84(t,J=6.8Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,159.1,155.4,148.0,146.2,138.1,113.8,107.8,96.0,90.8,79.5,75.4,73.3,49.1,45.3,44.9,44.8,41.9,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd for C 24 H 32 N6O6Na + :501.2456,found:501.2455.

[0105] N-(1-((2R,3S,4R,5R)-5-(4-(furan-2-carbonyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A10)

[0106] Colorless oil,yield 61%, 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.93(d,J=7.5Hz,1H),7.86(d,J=1.7Hz,1H),7.26(d,J=7.5Hz,1H),7.04(d,J=3.4Hz,1H),6.64(dd,J=3.5,1.8Hz,1H),5.96(d,J=4.1Hz,1H),5.72(d,J=5.5Hz,1H),5.67(d,J=5.9Hz,1H),4.94(d,J=5.0Hz,1H),4.12-4.09(m,1H),4.02-4.01(m,1H),3.62-3.56(m,9H),2.39(t,J=7.4Hz,2H),1.56-1.51(m,2H),1.29-1.23(m,4H),0.86(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,158.9,155.3,147.2,146.2,145.4,116.5,111.9,96.0,90.8,79.5,75.2,73.2,45.1,42.2,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd for C 24 H 31 N5O8Na + :540.2065,found:540.2062.Benzyl 4-((2R,3R,4S,5R)-5-(4-hexanamido-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-carbonyl)piperazine-1-carboxylate(A11)

[0107] Yellow oil,yield 53%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.92(d,J=7.5Hz,1H),7.36(d,J=4.4Hz,4H),7.34-7.29(m,1H),7.26(d,J=7.5Hz,1H),5.95(d,J=4.1Hz,1H),5.74-5.70(m,1H),5.69-5.62(m,1H),5.10(s,2H),4.91(d,J=5.0Hz,1H),4.13-4.08(m,1H),4.03(q,J=4.2Hz,1H),3.57-3.53(m,4H),3.47(s,4H),2.38(t,J=7.4Hz,2H),1.57-1.50(p,J=7.3Hz,2H),1.27-1.23(m,4H),0.84(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.6,169.1,163.1,155.5,155.1,146.4,137.4,129.1,128.6,128.3,96.6,91.0,79.7,75.5,73.4,67.1,45.2,42.2,37.0,31.4,24.8,22.5,14.5.HRMS(ESI)[M+Na] + calcd for C 27 H 35 N5O8Na + :580.2378,found:580.2375.

[0108] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(methylsulfonyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A12)

[0109] Yellow oil yield 33%, 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.89(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),5.95(d,J=4.1Hz,1H),5.83-5.62(m,2H),4.92(d,J=5.1Hz,1H),4.12(t,J=4.8Hz,1H),4.02(t,J=4.3Hz,1H),3.65(t,J=5.0Hz,4H),3.14(p,J=6.2,5.5Hz,4H),2.88(s,3H),2.38(t,J=7.4Hz,2H),1.57-1.50(m,2H),1.27-1.21(m,4H),0.85(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,168.8,162.9,155.3,146.2,96.1,90.8,79.4,75.2,73.2,46.0,45.6,44.9,41.7,36.8,34.7,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd forC 20 H 32 N5O8S+Na + :524.1785,found:524.1789.

[0110] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(5-nitropyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A13)

[0111] Yellow solid,yield 47%,m.p.149.1-151.3℃; 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.12-8.77(m,2H),8.24(dd,J=9.5,2.8Hz,1H),7.25(d,J=7.5Hz,1H),6.94(d,J=9.6Hz,1H),5.96(d,J=4.0Hz,1H),5.75-5.70(m,2H),4.96(d,J=5.1Hz,1H),4.13(t,J=4.8Hz,1H),4.05-4.02(m,1H),3.88-3.77(m,4H),3.72-3.65(m,4H),2.38(t,J=7.4Hz,2H),1.57-1.50(m,2H),1.28-1.21(m,4H),0.84(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,169.0,162.9,160.5,155.3,146.4,146.2,135.0,133.4,106.3,96.0,90.8,79.5,75.3,73.3,44.9,44.5,44.3,41.8,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd for C 24 H 31 N7O8Na + :568.2126,found:568.2133.

[0112] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A14)

[0113] White solid,yield 54%,m.p.124.3-126.1℃; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.5Hz,1H),8.42(d,J=2.5Hz,1H),7.81(dd,J=9.1,2.6Hz,1H),7.26(d,J=7.5Hz,1H),6.97(d,J=9.1Hz,1H),5.97(d,J=4.0Hz,1H),5.76-5.68(m,2H),4.96(d,J=5.1Hz,1H),4.15-4.12(m,1H),4.05-4.02(m,1H),3.72-3.61(m,8H),2.40-2.36(m,2H),1.57-1.50(m,2H),1.22-1.28(m,4H),0.84(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9(d,J=8.1Hz),160.4,155.3,146.2,145.7(d,J=4.0Hz),135.1(d,J=3.0Hz),125.3(q,J=814.1Hz),114.1(d,J=32.3Hz),106.9,96.0,90.8,79.5,75.3,73.3,44.7,44.2,41.8,36.8,36.2,31.1,24.6,22.3,14.2.19FNMR(377MHz,DMSO-d6)δ-59.42.HRMS(ESI)[M+Na] + calcd for C 25 H 31 F3N6O6Na + :591.2149,found:591.2149.N-(1-((2R,3S,4R,5R)-5-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A15)

[0114] White oil,yield 41%; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.93(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),6.91-6.79(m,2H),6.74(dd,J=7.9,1.6Hz,1H),5.98(s,2H),5.96(d,J=4.2Hz,1H),5.86-5.59(m,1H),4.88(d,J=4.9Hz,1H),4.07(t,J=4.7Hz,1H),4.00(t,J=4.3Hz,1H),3.58-3.45(m,3H),3.39(s,4H),2.41-2.27(m,6H),1.57-1.50(m,2H),1.26-1.21(m,4H),0.85(t,J=6.8Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ174.4,168.5,155.3,147.7,146.7,146.2,132.0,122.5,109.6,108.3,101.3,96.0,90.6,79.5,75.4,73.3,61.9,53.1,52.4,45.3,42.2,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+H] + calcdfor C 27 H 35 N5O8 + :558.2558,found:558.2562.N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(2-methoxyethyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A16)

[0115] White oil yield 41%; 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.95(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),5.97(d,J=4.2Hz,1H),5.68(s,2H),4.89(d,J=4.8Hz,1H),4.08(t,J=4.7Hz,1H),4.00(t,J=4.4Hz,1H),3.51(d,J=5.7Hz,2H),3.40(s,4H),3.23(s,3H),2.51(dd,J=3.6,1.7Hz,2H),2.48(d,J=5.7Hz,1H),2.40(t,J=7.3Hz,4H),1.59-1.52(m,2H),1.29-1.23(m,4H),0.86(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.6,168.6,163.0,155.5,146.3,96.2,90.7,79.6,75.5,73.4,70.5,58.6,57.4,53.9,53.3,45.5,42.3,37.0,31.3,24.7,22.4,14.4.HRMS(ESI)[M+Na] + calcd for C 27 H 35 N5O7 + :504.2429,found:504.2428.

[0116] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(4-methoxyphenyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A17)

[0117] Red solid,yield 44%,m.p.121.3-122.6℃; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),6.95-6.88(m,2H),6.87-6.79(m,2H),5.97(d,J=4.1Hz,1H),5.75-5.63(m,2H),4.95(d,J=4.9Hz,1H),4.11(t,J=4.5Hz,1H),4.02(q,J=4.2Hz,1H),3.68(s,7H),3.05-2.98(m,4H),2.38(t,J=7.4Hz,2H),1.53(t,J=7.2Hz,2H),1.24(d,J=5.6Hz,16H),0.92-0.80(m,3H). 13 C NMR(101MHz,DMSO-d6)δ173.0,167.1,161.4,153.8,152.4,144.7,144.0,117.1,113.3,94.5,89.3,78.0,73.9,71.8,54.2,49.3,48.7,43.9,40.7,35.4,30.3,28.0,27.9,27.7,27.4,23.4,21.1,12.9.HRMS(ESI)[M+H] + calcd for C 32 H 48 N5O7 + :614.3548,found:614.3558.

[0118] N-(1-((2R,3S,4R,5R)-5-(4-benzoylpiperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A18)

[0119] Yellow oil,yield 42%, 1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.95(d,J=7.5Hz,1H),7.46(d,J=6.8Hz,3H),7.42(d,J=7.6Hz,2H),7.26(d,J=7.5Hz,1H),5.94(s,1H),5.79(s,1H),5.05-4.82(m,1H),4.10(t,J=4.9Hz,1H),4.01(t,J=4.5Hz,1H),3.59(s,1H),3.46(s,8H),2.38(t,J=7.4Hz,2H),1.52(t,J=7.2Hz,2H),1.22(d,J=9.1Hz,16H),0.83(t,J=6.9Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ174.1,169.4,168.6,162.5,155.0,145.8,135.7,129.8,128.6,127.1,95.7,90.4,79.1,74.9,72.9,36.5,31.4,29.1,29.0,28.8,28.6,24.4,22.2,14.1.HRMS(ESI)[M+Na] + calcdfor C 32 H 45 N5O7Na + :634.3211,found:634.3228.

[0120] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(4-nitrophenyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A19)

[0121] Yellow solid,yield 42%,m.p.113.7-114.1℃; 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.18-8.81(m,1H),8.07(d,J=9.4Hz,2H),7.25(s,1H),7.02(d,J=9.7Hz,2H),6.01-5.90(m,1H),5.70(s,2H),4.96(s,1H),4.08(d,J=39.2Hz,2H),3.71(s,3H),3.54(s,3H),3.16(d,J=8.6Hz,2H),2.47-2.19(m,2H),1.52(s,2H),1.22(s,16H),0.98-0.69(m,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,155.3,154.8,146.1,137.5,126.2,113.0,96.0,90.8,79.4,75.3,73.2,49.0,46.6,46.1,44.4,41.6,36.8,31.7,29.4,29.3,29.2,28.9,24.9,22.5,14.4.HRMS(ESI)[M+Na] + calcdfor C 31 H 44 N6O8Na + :651.3113,found:651.3116.

[0122] N-(1-((2R,3S,4R,5R)-5-(4-(4-cyanophenyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A20)

[0123] Yellow oil,yield 37%, 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.96(d,J=7.5Hz,1H),7.56(d,J=8.7Hz,2H),7.25(d,J=7.5Hz,1H),7.00(d,J=8.8Hz,2H),5.96(d,J=3.9Hz,1H),5.68-5.73(m,2H),4.96(d,J=5.1Hz,1H),4.14-4.11(m,1H),4.05-4.02(m,1H),3.76-3.64(m,4H),3.44(s,4H),2.37(t,J=7.3Hz,2H),1.55-1.48(m,2H),1.20(d,J=6.1Hz,16H),0.81(t,J=6.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,155.4,153.2,146.2,133.8,120.4,114.6,99.1,96.1,90.9,79.4,75.4,73.3,46.9,46.4,44.6,41.7,36.9,31.8,29.5,29.4,29.2,29.0,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd for C 32 H 44 N6O6Na + :631.3215,found:631.3211.N-(1-((2R,3S,4R,5R)-5-(4-(4-fluorophenyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A21)

[0124] Yellow oil,yield 64%, 1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.98(d,J=7.6Hz,1H),7.60(d,J=8.8Hz,2H),7.26(d,J=7.6Hz,1H),7.03(d,J=8.9Hz,2H),5.95(d,J=4.0Hz,1H),4.96(d,J=5.0Hz,1H),4.11(t,J=4.8Hz,1H),4.01(t,J=4.2Hz,1H),3.70-3.63(m,4H),3.41(d,J=15.5Hz,4H),2.37(t,J=7.3Hz,2H),1.54-1.50(m,2H),1.22(d,J=9.3Hz,16H),0.83(t,J=6.8Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ174.5,168.9,162.9,154.3(d,J=314.1Hz),146.2,133.9,120.5,114.6,99.0,96.0,90.8,79.4,75.3,73.3,46.9,46.4,44.6,41.7,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4. 19 F NMR(377MHz,DMSO-d6)δ-124.82.HRMS(ESI)[M+Na] + calcdforC 31 H 44 FN5O6Na + :624.3168,found:624.3167.

[0125] N-(1-((2R,3S,4R,5R)-5-(4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A22)

[0126] White solid,yield 46%,m.p.120.7-121.3℃; 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.95(d,J=7.5Hz,1H),8.47(d,J=2.3Hz,1H),7.84(dd,J=9.0,2.4Hz,1H),7.25(d,J=7.4Hz,1H),6.92(d,J=9.2Hz,1H),5.95(d,J=3.8Hz,1H),5.78-5.65(m,2H),4.96(d,J=5.2Hz,1H),4.12(d,J=5.0Hz,1H),4.04(d,J=4.8Hz,1H),3.74-3.61(m,8H),2.37(t,J=7.3Hz,2H),1.53-1.48(m,2H),1.20(d,J=6.6Hz,16H),0.81(t,J=6.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,169.0,162.9,159.4,155.4,152.9,146.2,140.5,119.1,107.1,96.1,91.0,79.5,75.4,73.3,44.6,44.5,43.9,41.8,36.9,31.8,29.5,29.4,29.2,29.0,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcdfor C 31 H 43 N7O6Na + :632.3167,found:632.3168.

[0127] N-(1-((2R,3S,4R,5R)-5-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamid(A23)

[0128] White solid yield 49%,m.p.124.1-126.3℃; 1H NMR(600MHz,DMSO-d6)δ10.87(s,1H),8.96(d,J=7.5Hz,1H),7.39-7.30(m,4H),7.25(d,J=7.5Hz,1H),5.95(d,J=4.2Hz,1H),5.72(d,J=5.5Hz,1H),5.63(d,J=5.8Hz,1H),4.88(d,J=4.8Hz,1H),4.06(q,J=5.2Hz,1H),3.99(q,J=4.7Hz,1H),3.47(s,2H),3.39(s,4H),2.42-2.30(m,6H),1.52(p,J=8.1,7.6Hz,2H),1.22(d,J=11.3Hz,16H),0.83(t,J=6.9Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ174.4,168.5,162.9,155.3,146.2,137.3,132.0,131.1,128.6,96.0,90.6,79.3,75.3,73.3,61.2,53.2,52.5,45.3,42.1,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcd forC 32 H 46 ClN5O6 + :632.3209,found:632.3211.

[0129] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-phenylpiperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A24)

[0130] Colorless oil,yield 57%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.97(d,J=7.5Hz,1H),7.28-7.19(m,3H),6.95(d,J=8.1Hz,2H),6.80(t,J=7.3Hz,1H),5.97(d,J=4.0Hz,1H),4.96(d,J=5.1Hz,1H),4.12(t,J=4.8Hz,1H),4.03(t,J=4.2Hz,1H),3.74-3.65(m,5H),3.18-3.13(m,4H),2.38(t,J=7.4Hz,2H),1.53(t,J=7.1Hz,2H),1.23(d,J=7.1Hz,16H),0.84(t,J=6.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.6,162.9,155.3,151.2,146.2,129.5,119.8,116.3,96.0,90.8,79.4,75.4,73.349.2,48.7,45.1,42.0,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd for C 31 H 45 N5O6Na + :606.3262,found:606.3262.

[0131] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(pyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A25)

[0132] White solid,yield 55%,m.p.126.8-127.3℃; 1HNMR(400MHz,DMSO-d6)δ10.82(s,1H),8.98(d,J=7.5Hz,1H),8.12(dd,J=5.0,1.9Hz,1H),7.62-7.45(m,1H),7.26(d,J=7.5Hz,1H),6.84(d,J=8.6Hz,1H),6.67-6.64(m,1H),5.97(d,J=3.9Hz,1H),5.73-5.68(m,2H),4.96(d,J=5.0Hz,1H),4.12(d,J=5.8Hz,1H),4.04-4.02(m,1H),3.69-3.61(m,4H),3.58-3.50(m,4H),2.38(t,J=7.3Hz,2H),1.56-1.49(m,2H),1.22(d,J=7.3Hz,16H),0.83(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,159.1,155.3,148.0,146.2,138.1,113.8,107.8,96.0,90.8,79.4,75.4,73.3,45.3,44.9,44.8,41.9,36.8,31.8,29.5,29.3,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcd for C 30 H 45 N6O6 + :585.3395,found:585.3397.

[0133] N-(1-((2R,3S,4R,5R)-5-(4-(furan-2-carbonyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A26)

[0134] Colorless oil,yield 57%, 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.94(d,J=7.4Hz,1H),7.84(d,J=1.9Hz,1H),7.26(d,J=7.4Hz,1H),7.03(d,J=3.4Hz,1H),6.63(dd,J=3.5,1.8Hz,1H),5.95(d,J=4.0Hz,1H),5.72(d,J=5.5Hz,1H),5.67(d,J=5.9Hz,1H),4.94(d,J=5.0Hz,1H),4.14-4.11(m,1H),4.01-4.04(m,1H),3.75-3.57(m,8H),2.38(t,J=7.3Hz,2H),1.54-1.49(m,2H),1.23(d,J=6.9Hz,16H),0.94-0.71(m,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,159.0,155.3,147.2,146.2,145.4,116.5,111.9,96.0,90.8,79.5,75.3,73.2,45.2,42.2,36.8,31.8,29.5,29.3,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd for C 30 H 43 N5O8Na + :624.3004,found:624.3001.

[0135] Benzyl 4-((2R,3R,4S,5R)-5-(4-dodecanamido-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-carbonyl)piperazine-1-carboxylate(A27)

[0136] Colorless oil,yield 53%, 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.93(d,J=7.5Hz,1H),7.36(d,J=4.4Hz,4H),7.26(d,J=7.5Hz,1H),5.95(d,J=4.0Hz,1H),5.72(d,J=5.4Hz,1H),5.65(d,J=5.9Hz,1H),5.09(s,2H),4.92(d,J=5.1Hz,1H),4.13-4.09(m,1H),4.04-4.01(m,1H),3.58-3.52(m,5H),3.45(s,4H),2.38(t,J=7.3Hz,2H),1.56-1.49(m,2H),1.21(s,16H),0.90-0.77(m,3H). 13 CNMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,155.3,154.9,146.2,137.2,128.9,128.3,128.1,96.0,90.9,79.4,75.3,73.2,66.9,45.0,41.9,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd for C 33 H 47 N5O8Na + :664.3317,found:664.3316.N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(methylsulfonyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A28)

[0137] Yellow oil,yield 36%, 1H NMR(400MHz,DMSO-d6)δ10.92-10.59(m,1H),8.91(d,J=7.4Hz,1H),7.90(d,J=8.3Hz,1H),7.61(d,J=8.2Hz,1H),7.26(d,J=7.4Hz,1H),5.95(d,J=4.0Hz,1H),4.92(d,J=5.1Hz,1H),4.12(t,J=4.8Hz,1H),4.03(t,J=4.2Hz,1H),3.73-3.52(m,4H),3.15(p,J=6.7,5.9Hz,4H),2.89(s,3H),2.38(t,J=7.3Hz,2H),1.53(t,J=7.1Hz,2H),1.23(d,J=8.7Hz,16H),0.83(t,J=6.7Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,155.3,146.1,96.0,90.9,79.4,75.2,73.2,54.0,46.0,45.6,44.9,41.7,36.8,34.7,31.8,29.5,29.4,29.2,29.0,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd forC 26 H 43 N5O8SNa + :608.2725,found:608.2726.

[0138] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(5-nitropyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A29)

[0139] Yellow solid,yield 52%,m.p.129.7-130.1℃; 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.99-8.88(m,2H),8.23(dd,J=9.5,2.9Hz,1H),7.25(d,J=7.5Hz,1H),6.94(d,J=9.6Hz,1H),5.95(d,J=4.0Hz,1H),5.80-5.66(m,2H),4.96(d,J=5.2Hz,1H),4.14(t,J=5.0Hz,1H),4.05-4.02(m,1H),3.84-3.78(m,4H),3.72-3.67(m,4H),2.37(t,J=7.3Hz,2H),1.52(t,J=7.1Hz,2H),1.22(d,J=7.4Hz,16H),0.83(t,J=6.7Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.6,169.2,163.1,160.7,155.5,146.6,146.4,135.2,133.6,106.5,96.2,91.1,79.7,75.5,73.5,45.1,44.8,44.5,42.0,37.0,32.0,29.7,29.6,29.4,29.1,25.1,22.8,14.6.HRMS(ESI)[M+Na] + calcdforC 30 H 43 N7O8Na + :652.3065,found:652.3064.

[0140] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A30)

[0141] Colorless oil,yield 61%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.96(d,J=7.5Hz,1H),8.42(d,J=2.6Hz,1H),7.81(dd,J=9.1,2.6Hz,1H),7.26(d,J=7.5Hz,1H),6.98(d,J=9.1Hz,1H),5.96(d,J=4.0Hz,1H),5.74(s,2H),4.96(d,J=5.0Hz,1H),4.13(t,J=4.9Hz,1H),4.03(t,J=4.3Hz,1H),3.72-3.64(m,8H),2.38(t,J=7.3Hz,2H),1.54-1.51(m,2H),1.23(d,J=6.4Hz,16H),0.83(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.9,162.9,162.8,160.4,155.3,146.2,145.7,130.5-20.5(m),115.5-112.5(m),106.9,96.0,90.9,79.5,75.3,73.3,44.7(d,J=3.8Hz),44.2,41.8,36.8,36.2,31.8,31.2,29.5,29.3,29.2,28.9,24.9,22.6,14.4. 19 F NMR(377MHz,DMSO-d6)δ-59.41.HRMS(ESI)[M+Na] + calcd for C 31 H 43 F3N6O6Na + :675.3088,found:675.3103.N-(1-((2R,3S,4R,5R)-5-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbonyl)-3,4-dihydroxytetrahydrof

[0142] uran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A31)

[0143]

[0144] Yellow solid yield 44%,m.p.103.5-106.3℃; 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.93(d,J=7.5Hz,1H),7.24(d,J=7.5Hz,1H),6.89-6.78(m,2H),6.74(d,J=7.9Hz,1H),5.97(s,2H),5.95(d,J=4.0Hz,1H),4.88(d,J=4.9Hz,1H),4.07(t,J=4.6Hz,1H),3.99(t,J=4.3Hz,1H),3.74(s,1H),3.58-3.47(m,3H),3.42-3.35(m,4H),2.40-2.32(m,6H),1.54-1.51(m,2H),1.23(d,J=6.8Hz,16H),0.83(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.5,162.9,155.3,147.7,146.7,146.2,132.0,122.5,109.6,108.3,101.3,96.0,90.7,79.5,75.4,73.3,61.9,53.1,52.4,45.3,42.2,36.8,31.8,29.5,29.3,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcd for C 33 H 48 N5O8 + :642.3497,found:642.3495.

[0145] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(2-methoxyethyl)piperazine-1-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A32)

[0146] Yellow solid yield 57%,m.p.107.3-108.8℃; 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.97(d,J=7.4Hz,1H),7.27(d,J=7.5Hz,1H),5.98(d,J=4.1Hz,1H),5.68(s,2H),4.90(d,J=4.8Hz,1H),4.09(t,J=4.7Hz,1H),4.02(t,J=4.3Hz,1H),3.58-3.50(m,3H),3.48-3.40(m,6H),2.56-2.48(m,2H),2.45-2.38(m,6H),1.58-1.51(m,2H),1.25(d,J=6.8Hz,16H),0.85(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.3,168.4,162.8,155.3,146.1,96.0,90.6,79.4,75.3,73.2,70.3,58.4,57.2,53.7,53.1,45.6,42.1,36.8,31.7,29.4,29.3,29.1,28.9,24.8,22.5,14.3.HRMS(ESI)[M+H] + calcd for C 28 H 48 N5O7 + :566.3548,found:566.3555.

[0147] N-(1-((3aS,4R,6R,6aR)-2,2-dimethyl-6-(thiomorpholine-4-carbonyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A33)

[0148] White solid yield 51%,m.p.128.7-129.3℃; 1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.24(d,J=7.5Hz,1H),7.19(d,J=7.5Hz,1H),5.98(s,1H),5.23(dd,J=6.1,2.9Hz,1H),5.02(dd,J=9.4,4.6Hz,2H),3.83-3.77(m,4H),3.72-3.62(m,4H),2.37(t,J=7.3Hz,2H),2.15(t,J=7.4Hz,2H),1.51(s,3H),1.31(s,3H),1.22(s,16H),0.83(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,167.4,163.3,155.0,147.3,113.3,95.7,94.2,84.8,84.5,82.6,48.3,44.9,36.8,34.3,31.8,29.5,29.2,27.1,25.5,25.0,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcd for C 28 H 45 N4O6S + :565.3054,found:565.3059.

[0149] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(thiomorpholine-4-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A34)

[0150] Colorless oil,yield 51%, 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.87(d,J=7.5Hz,1H),7.25(d,J=7.4Hz,1H),5.94(d,J=4.1Hz,1H),5.65(dd,J=18.8,5.7Hz,2H),4.87(d,J=4.9Hz,1H),4.10-4.09(m,1H),4.03-4.00(m,1H),3.76-3.79(m,3H),3.17(d,J=5.2Hz,1H),2.69-2.56(m,4H),2.39(t,J=7.4Hz,2H),1.58-1.51(m,2H),1.32-1.19(m,4H),0.86(t,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.0,168.2,162.5,154.8,145.8,95.6,90.3,79.1,74.8,72.7,47.7,44.4,36.4,30.7,27.2,26.6,24.2,21.9,13.8.HRMS(ESI)[M+Na] + calcd for C 19 H 28 N4O6SNa + :463.1622,found:463.1624.

[0151] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(thiomorpholine-4-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A35)

[0152] White solid,yield 49%,m.p.132.3-134.7℃; 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.88(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),5.94(d,J=4.1Hz,1H),5.67(d,J=5.5Hz,1H),5.62(d,J=5.9Hz,1H),4.87(d,J=5.0Hz,1H),4.12-4.08(m,1H),4.03-3.99(m,1H),3.80-3.76(m,4H),2.66-2.58(m,4H),2.38(t,J=7.3Hz,2H),1.57-1.50(m,2H),1.24(d,J=5.1Hz,16H),0.84(t,J=6.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.0,168.2,162.4,154.8,145.7,95.5,90.4,79.0,74.8,72.7,47.7,44.4,36.4,31.3,29.0,28.9,28.7,28.5,27.2,26.6,24.4,22.1,14.0.HRMS(ESI)[M+Na] + calcdfor C 25 H 40 N4O6SNa + :547.2561,found:547.2561.

[0153] N-(1-((2R,3S,4R,5R)-5-(1,1-dioxidothiomorpholine-4-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)hexanamide(A36)

[0154] Yellow oil,yield 42%, 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.82(d,J=7.6Hz,1H),7.25(d,J=7.5Hz,1H),5.90(d,J=4.2Hz,1H),4.96(d,J=4.9Hz,1H),4.18(t,J=4.6Hz,1H),4.07(t,J=4.3Hz,1H),3.90-3.85(m,2H),3.66-3.39(m,4H),3.30-3.10(m,4H),2.38(t,J=7.4Hz,2H),1.57-1.50(m,2H),1.27-1.21(m,4H),0.84(t,J=6.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,169.1,162.94155.3,146.5,96.1,91.3,79.7,74.8,73.0,51.7,51.4,43.9,36.8,31.1,24.6,22.3,14.3.HRMS(ESI)[M+Na] + calcd for C 19 H 28 N4O8SNa + :495.1520,found:495.1528.N-(1-((2R,3S,4R,5R)-5-(1,1-dioxidothiomorpholine-4-carbonyl)-3,4-dihydroxytetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A37)

[0155] Yellow oil,yield 51%, 1 H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.82(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),5.90(d,J=4.2Hz,1H),5.68(t,J=5.9Hz,2H),4.95(d,J=4.8Hz,1H),4.19-4.15(m,1H),4.08-4.05(m,1H),4.02-3.81(m,4H),3.28-3.13(m,4H),2.38(t,J=7.4Hz,2H),1.55-1.51(m,2H),1.24(d,J=5.1Hz,16H),0.84(t,J=6.6Hz,3H).13 C NMR(101MHz,DMSO-d6)δ174.4,169.0,162.9,155.2,146.4,95.9,91.2,79.6,74.8,73.0,51.7,51.3,43.8,36.8,31.7,29.4,29.3,29.1,28.9,24.8,22.5,14.3.HRMS(ESI)[M+Na]+calcd for C 25 H 40 N4O8SNa + :579.2459,found:579.2465.

[0156] 4-amino-1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(thiomorpholine-4-carbonyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one(A38)

[0157] White solid,yield 67%,m.p.149.7-151.3℃; 1 H NMR(400MHz,DMSO-d6)δ8.22(d,J=7.4Hz,1H),7.18(d,J=26.6Hz,2H),5.96(d,J=5.2Hz,1H),5.76(d,J=7.4Hz,1H),5.54(d,J=21.2Hz,2H),4.76(d,J=3.9Hz,1H),4.08(t,J=4.3Hz,1H),3.93(t,J=5.0Hz,1H),3.85-3.66(m,4H),2.60(d,J=17.0Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ168.6,166.0,155.9,141.9,94.6,89.3,79.5,74.6,73.0,48.0,44.7,27.6,26.9.HRMS(ESI)[M+Na] + calcd for C 13 H 18 N4O5SNa + :365.0890,found:365.0888.

[0158] (E)-N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(thiomorpholine-4-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)-2-methylbut-2-enamide(A39)

[0159] White solid,yield 46%,m.p.155.3-156.1℃; 1 HNMR(400MHz,DMSO-d6)δ10.72(s,1H),8.91(d,J=7.5Hz,1H),7.28(d,J=7.5Hz,1H),5.94(d,J=4.0Hz,1H),5.75-5.60(m,3H),4.88(d,J=5.0Hz,1H),4.12-4.10(m,1H),4.03(t,J=4.4Hz,1H),3.80-3.77(m,4H),2.65-2.59(m,4H),1.89-1.83(m,3H),1.70-1.67(m,3H). 13 C NMR(101MHz,DMSO-d6)δ170.8,168.7,163.1,155.3,146.2,132.8,129.2,96.4,90.9,79.5,75.2,73.2,48.2,44.9,27.7,27.0,20.5,15.4.HRMS(ESI)[M+Na] + calcd forC 18 H 24 N4O6SNa + :447.1309,found:447.1298.

[0160] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(morpholine-4-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A40)

[0161] White solid,yield 41%,m.p.141.3-141.7℃; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.95(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),5.95(d,J=4.0Hz,1H),5.75-5.62(m,2H),4.89(d,J=5.1Hz,1H),4.08(d,J=5.0Hz,1H),4.02-3.99(m,1H),3.59-3.54(m,8H),2.38(t,J=7.3Hz,2H),1.55-1.49(m,2H),1.23(d,J=5.8Hz,16H),0.84(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,155.3,146.2,96.0,90.7,79.3,75.3,73.2,66.6,66.5,45.9,42.6,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+Na] + calcd forC 25 H 40 N4O7Na + :509.2970,found:509.2970.

[0162] N-(1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(thiazolidine-3-carbonyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)dodecanamide(A41)

[0163] White solid,yield 47%,m.p.135.7-136.1℃; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.98(d,J=7.5Hz,1H),7.25(d,J=7.5Hz,1H),5.94(t,J=4.0Hz,1H),4.81(dd,J=17.8,5.3Hz,1H),4.75-4.63(m,1H),4.59-4.47(m,1H),4.10(t,J=4.9Hz,1H),4.02(t,J=4.1Hz,1H),3.90-3.80(m,1H),3.76-3.69(m,1H),3.50-3.39(m,3H),3.10(t,J=6.3Hz,1H),3.03-2.99(m,1H),2.38(t,J=7.3Hz,2H),1.56-1.49(m,2H),1.23(d,J=6.3Hz,16H),0.83(t,J=6.5Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.4,168.8,162.9,155.3,146.1,96.0,90.8,81.0,75.3,73.5,49.5,48.8,48.0,36.8,31.8,29.5,29.4,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcd for C 24 H 39 N4O6S + :511.2585,found:511.2588.

[0164] (2R,3R,4S,5R)-N-(2-(dimethylamino)ethyl)-5-(4-dodecanamido-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxy-N-methyltetrahydrofuran-2-carboxamide(A42)

[0165] White solid,yield 33%,m.p.140.1-140.9℃; 1HNMR (400MHz, DMSO-d6) δ10.81(s,1H),8.94(dd,J=17.0,7.5Hz,1H),7.24(dd,J=7.5,3. 0Hz,1H),5.95(dd,J=17.2,4.1Hz,1H),4.84(dd,J=11.0,4.7Hz,1H),4.08-4.05(m,1H), 4.03(dd,J=7.4,3.6Hz,1H),3.98(t,J=4.4Hz,1H),3.50-3.47(m,6H),2.42-2.36(m,4H) ,2.17(d,J=2.2Hz,6H),1.55-1.49(m,2H),1.23(d,J=5.6Hz,16H),0.83(t,J=6.6Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ174.5,170.0,162.9,155.4,146.2,96.1,90.7,90.3,79.9,79.3,75.5,73.4,57 .8,56.3,46.0,45.7,36.9,35.4,34.5,31.8,29.5,29.3,29.2,28.9,24.9,22.6,14.4.HRMS(ESI)[M+H] + calcdforC 26 H 46 N5O6 + :524.3443,found:524.3444.

[0166] Example 2

[0167] This embodiment tests the antiviral activity of the target compound prepared in Example 1. The test results are shown in Table 2.

[0168] The antiviral activity of tobacco mosaic virus (Tobacco Mosaic Virus) was determined using the half-leaf necrosis method (extracted using the method described in the reference: "Design, Synthesis, and Antiviral Activity and Mechanism of Sulfonamide-Substituted Purine Nucleoside Derivatives"). Common broad-spectrum antiviral agents, ningnanmycin and ribavirin, were used as positive controls. A high-concentration stock solution was prepared by dissolving the target compound in DMSO, and then diluted to the desired concentration with 0.1% Tween-80 water to obtain an inhibitor emulsion.

[0169] Therapeutic activity: Tobacco leaves were sprinkled with 500-mesh carborundum, then dipped in TMV suspension (prepared with 0.01 mg / mL PBS) and rubbed in. After 30 min, the leaves were rinsed and air-dried. The compound was dissolved in DMSO and diluted to 500 μg / mL with 2.0% Tween 80 aqueous solution. Half-leaf treatment was used: the right half of the leaf was sprayed with the solution, and the left half was sprayed with an equal amount of blank control (containing an equal amount of DMSO and 2.0% Tween 80). After incubation at 25℃ for 48-72 h, the number of necrotic spots was counted. Each treatment was repeated three times.

[0170] Protective activity: The right half of the leaf was smeared with the target compound solution (500 μg / mL), and the left half of the leaf was treated with a 2% Tween 80 aqueous solution as a negative control. After 24 h of treatment, 500-mesh carborundum was sprinkled on the leaf surface, and the leaves were then inoculated by rubbing with a TMV suspension (prepared with 0.01 mg / mL PBS), followed by rinsing after 30 min. The tobacco plants were then incubated at 25℃ and 70% humidity in an artificial climate chamber, and the number of necrotic spots was counted after 48-72 h. Each treatment was repeated three times.

[0171] Passivation activity: 500-mesh carborundum was sprinkled on tobacco leaves. The agent (500 μg / mL) (DMSO + 2.0% Tween 80 aqueous solution) was mixed with TMV suspension at a 1:1 ratio and incubated at 0℃ on ice for 30 min. The right half of the leaves was inoculated with the agent-virus mixture (treatment group), and the left half with the solvent-virus mixture (control group), using a gentle brush for inoculation. After 30 min, the leaves were rinsed and incubated in a 25℃, 70% humidity incubator. The number of necrotic spots was counted after 48-72 h, with each treatment repeated three times. Results are shown in Table 1.

[0172] Table 1. Antiviral activity of cytosine nucleoside derivatives containing saturated six-membered nitrogen heterocycles

[0173]

[0174]

[0175] Table 3 shows that the target compounds exhibited good inhibitory activity against plant viral diseases (such as tobacco mosaic virus). Among them, compounds A4, A10, A11, A21, A22, and A35 showed excellent therapeutic effects against tobacco mosaic virus, with inhibition rates of 65.08%, 57.03%, 54.91%, 57.67%, 60.64%, and 67.68%, respectively. Compounds A1, A6, A11, A19, A22, and A35 showed good protective effects against the virus. The inhibitory effects were 59.03%, 54.18%, 61.53%, 60.15%, 59.79%, and 69.63%, respectively; while compounds A1, A4, A21, A22, A26, and A35 showed good passivation effects, with inhibition rates of 67.06%, 66.12%, 67.87%, 66.71%, 64.88%, and 75.86%, respectively. This indicates that these compounds have good research prospects in the resistance to plant viral diseases.

[0176] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A class of cytosine nucleoside compounds, characterized in that, The general structural formula of the cytosine nucleoside compounds is shown in Formula I: Where n is 4 or 10, and X is nitrogen, oxygen or sulfur; R 1 Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenated C3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl.

2. The cytosine nucleoside compound according to claim 1, characterized in that, The cytosine nucleoside compound is any one of the following compounds:

3. A method for preparing the cytosine nucleoside compound according to claim 1, characterized in that, Includes the following steps: 1) Compound 1 was reacted with 2,2,6,6-tetramethylpiperidine-1-oxy radical, iodophenyl diacetic acid, sodium bicarbonate and acetonitrile solution, the precipitate was collected and washed with diethyl ether and acetone until colorless to obtain compound 2; The structure of compound 1 is as follows: The structure of compound 2 is as follows: 2) The compound 2 obtained in step 1) was reacted with a saturated six-membered nitrogen heterocyclic derivative, N,N-dimethylformamide, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the mixture was purified to obtain compound 3. The structure of compound 3 is as follows: R 1 Selected from phenyl, pyridyl, 4-methoxyphenyl, 4-nitrophenyl, 4-cyanophenyl, 4-fluorophenyl, pyridyl, 2-cyanopyridyl, 2-nitropyridyl, 2-trifluoromethylpyridyl, methyl benzoate, 2-furanacetyl, methanesulfonyl, 4-chlorobenzyl, piperyl, 3-methoxypropyl, phenyl-C1-C4 alkoxy, 5-6 membered heterocyclic-C1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 alkenyl, C3-C6 haloalkenyl, C3-C6 alkyne, C3-C6 haloalkyne, C1-C6 alkylcarbonyl, phenyl-C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenoxycarbonyl, phenyl-C1-C6 alkoxycarbonyl, cyano-C1-C6 alkyl, C1-C6 alkylsulfinyl The following are all of the following: alkyl-C1-C6 alkyl, C1-C6 alkylsulfonyl-C1-C6 alkyl, C1-C6 alkylcarbonyl-C1-C6 alkyl, C1-C6 alkylcarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyloxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C3-C6 alkenyl, C1-C6 alkoxycarbonyl-halogenatedC3-C6 alkenyl, C1-C6 haloalkoxycarbonyl-C1-C6 alkyl, C3-C6 alkenoxycarbonyl-C1-C6 alkyl, C3-C6 alkynoxycarbonyl-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkylaminocarbonyl-C1-C6 alkyl, and C3-C6 cycloalkyl-C1-C6 alkyl; 3) The compound 3 obtained in step 2) is mixed with formic acid solution and reacted. After purification, compound 4 is obtained. The structure of compound 4 is as follows: 4) The compound 4 obtained in step 3) is mixed with an acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and reacted. After purification, a cytosine nucleoside compound is obtained; the acid is hexanoic acid or lauric acid.

4. The preparation method according to claim 3, characterized in that, The mass ratio of compound 1 in step 1) to the mass of 2,2,6,6-tetramethylpiperidine-1-oxy radical, the mass of iodophenyldiacetic acid, the mass of sodium bicarbonate, and the volume of acetonitrile solution is 5 g: 0.552 g: 12.5 g: 2.97 g: 35 mL. The reaction conditions include stirring at 0°C for 2 hours.

5. The preparation method according to claim 3, characterized in that, Step 2) The mass ratio of compound 2 to the mass of thiomorpholine, the volume of N,N-dimethylformamide, the mass of 1-hydroxybenzotriazole, and the mass of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1 g: 836.55 mg: 10 mL: 1 g: 1.15 g; The reaction conditions include: stirring the reaction at a temperature of 20–25°C for 4 hours; The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:

1.

6. The preparation method according to claim 3, characterized in that, Step 3) The mass ratio of compound 3 to the volume of formic acid solution is 500 mg: 10 mL; the mass percentage of formic acid solution is 50%. The reaction conditions include: a temperature of 70°C and a time of 4 hours; The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 100:1 to 10:

1.

7. The preparation method according to claim 3, characterized in that, Step 4) The mass ratio of compound 4 to hexanoic acid / lauric acid, 1-hydroxybenzotriazole, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 400:368.34:364.41:418.67; The reaction conditions include: stirring the reaction at 26°C for 4 hours; The purification conditions include: purification by silica gel column chromatography, with an eluent of dichloromethane / methanol at a volume ratio of 150:1 to 20:

1.

8. The application of the cytosine nucleoside compound according to claim 1 or 2 in the prevention and control of plant viruses.

9. The application according to claim 8, characterized in that, The plant viruses mentioned include tobacco mosaic virus.

10. The application according to claim 8, characterized in that, The amount of the cytosine nucleoside compound used is 500 μg / mL.

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