3-DEOXY-2-KETOALDONIC ACID NITROGEN-CONTAINING DERIVATIVE, PREPARATION METHOD THEREOF, AND USE THEREOF

Abstract

The invention relates to a compound represented by general Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable hydrate thereof or pharmaceutically acceptable solvate thereof and the invention also relates to a pharmaceutical composition comprising the compound, and a preparation method for the compound and a use of the compound.

##STR00001##

Claims

1. A compound represented by general Formula I, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof, ##STR00046## wherein: R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, allyl, phenyl or benzyl; R.sub.2 and R.sub.3 are each independently azido, amino, amino substituted by one or two R.sup.a, 5-membered or 6-membered nitrogen-containing heterocyclyl or 5-membered or 6-membered nitrogen-containing heterocyclyl substituted by R.sup.b, wherein each R.sup.a is independently C.sub.1-C.sub.6 alkyl, allyl, phenyl, benzyl, formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tert-butoxyformyl or benzyloxyacyl, R.sup.b is C.sub.1-C.sub.6 alkyl, halogen or —(CH.sub.2).sub.mOH, wherein m is 0, 1, 2, 3 or 4; R.sub.4 and R.sub.5 are each independently hydroxyl, amino, guanidino, hydroxyl substituted by R.sup.c, amino substituted by R.sup.c, guanidino substituted by R.sup.c, 5-membered or 6-membered nitrogen-containing heterocyclyl or 5-membered or 6-membered nitrogen-containing heterocyclyl substituted by R.sup.b, wherein each R.sup.c is independently C.sub.1-C.sub.6 alkyl, allyl, phenyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tert-butoxyformyl or benzyloxyacyl, R.sup.b is C.sub.1-C.sub.6 alkyl, halogen or —(CH.sub.2).sub.mOH, wherein m is 0, 1, 2, 3 or 4; or, R.sub.4 and R.sub.5 together with the carbon atoms to which they connect form a 5-membered or 6-membered oxygen-containing or nitrogen-containing heterocyclic ring (e.g., 1,3-dioxolane, 1,3-dioxolan-2-one, dioxane, dioxanone, oxazolidine or oxazolidinone); R.sub.6 is hydrogen, C.sub.1-C.sub.6 alkyl, allyl, phenyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, or trifluoroacetyl; R.sub.7 is hydrogen, ##STR00047##  R.sub.6OCH.sub.2— or R.sub.6OCH.sub.2(R.sub.6O)CH—, wherein R.sub.6 is as defined above; n is 0, 1, 2 or 3.

2. The compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1, wherein: R.sub.1 is hydrogen or C.sub.1-C.sub.4 alkyl; R.sub.2 and R.sub.3 are each independently azido, amino or 5-membered or 6-membered nitrogen-containing heterocyclyl substituted by R.sup.b, wherein R.sup.b is —(CH.sub.2).sub.mOH, wherein m is 0, 1, 2, 3 or 4, the 5-membered or 6-membered nitrogen-containing heterocyclyl is triazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, piperidinyl, pyridyl, oxazolyl or imidazolyl; R.sub.4 and R.sub.5 are each independently hydroxyl, amino, hydroxyl substituted by R.sup.c, amino substituted by R.sup.c, wherein each R.sup.c is independently C.sub.1-C.sub.4 alkyl, allyl, phenyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, formyl, acetyl, benzoyl, trifluoroacetyl, methoxyformyl, tert-butoxyformyl or benzyloxyacyl; or R.sub.4 and R.sub.5 together with the carbon atoms to which they connect form a 5-membered oxygen-containing heterocyclic ring (e.g., 1,3-dioxolane, 1,3-dioxolan-2-one); R.sub.6 is formyl, acetyl, benzoyl or trifluoroacetyl; R.sub.7 is ##STR00048##  R.sub.6OCH.sub.2— or R.sub.6OCH.sub.2(R.sub.6O)CH—, wherein R.sub.6 is as defined above; n is 0, 1 or 2.

3. The compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1, wherein: R.sub.1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; R.sub.2 and R.sub.3 are each independently azido, amino or 5-membered nitrogen-containing heterocyclyl substituted by R.sup.b, wherein R.sup.b is —(CH.sub.2).sub.mOH, wherein m is 0, 1, 2 or 3, the 5-membered nitrogen-containing heteroaryl is triazolyl, tetrazolyl, pyrrolyl, tetrahydropyrrolyl, oxazolyl or imidazolyl; R.sub.4 and R.sub.5 are each independently hydroxyl, hydroxyl substituted by R.sup.c, amino substituted by R.sup.c, wherein each R.sup.c is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, formyl, acetyl, benzoyl, or trifluoroacetyl.

4. The compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvent thereof according to claim 1, wherein: R.sub.1 is hydrogen or methyl; R.sub.2 is azido or ##STR00049## R.sub.3 is azido, amino or ##STR00050## R.sub.4 is hydroxyl, tert-butyldimethylsilyloxy, benzoyloxy, acetylamino or acetyloxy; R.sub.5 is hydroxyl, trifluoroacetyloxy, acetylamino or acetyloxy; or R.sub.4 and R.sub.5 together with the carbon atoms to which they connect form 1,3-dioxolane or 1,3-dioxolan-2-one; R.sub.6 is acetyl or benzoyl; R.sub.7 is ##STR00051##  or R.sub.6OCH.sub.2, wherein R.sub.6 is as defined above; n is 0, 1 or 2.

5. The compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvent thereof according to claim 1, wherein the compound is selected from the group consisting of: ##STR00052## ##STR00053## ##STR00054##

6. A method for preparing the compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1, comprising: ##STR00055## a) in a solvent, a compound represented by Formula II, a hypervalent iodine reagent and azidotrimethylsilane reacting under light conditions to generate a bis-azide represented by Formula III; b) the bis-azide represented by Formula III generating the compound represented by the general Formula I through hydrolysis of the ester group, reduction of the azido group, removal of each protecting group on the hydroxyl or amino group, or formation of an azacycle, wherein: the definition of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 is as described in claim 1.

7. A pharmaceutical composition comprising at least one the compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1, and one or more pharmaceutically acceptable carriers or excipients.

8.-15. (canceled)

16. A method for preventing and/or treating a disease or infection caused by a virus in a mammal in need, comprising administering to the mammal in need a therapeutically and/or prophylactically effective amount of the compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1.

17. A method for inhibiting the replication or reproduction of a virus in a mammal in need, comprising administering to the mammal in need a therapeutically and/or prophylactically effective amount of the compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1.

18. A method for inhibiting the replication or reproduction of a virus in a cell, comprising contacting the cell with the compound, a stereoisomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester, a pharmaceutically acceptable hydrate or a pharmaceutically acceptable solvate thereof according to claim 1.

19. The method according to claim 16, wherein the mammal comprises bovine, equine, caprinae, suidae, canidae, feline, rodent, primate.

20. The method according to claim 6, wherein the hypervalent iodine reagent in step a) is selected from the group consisting of ##STR00056## the solvent in step a) is selected from the group consisting of dichloromethane, acetone, dimethyl sulfoxide, acetonitrile; the light source for the light conditions in step a) is natural light or LED light of various colors; the reaction in step a) is carried out at a temperature of 0-60° C.; the hydrolysis of the ester group in step b) is carried out in the presence of a base and a solvent, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, and the solvent is water or alcoholic solvents; the reduction of the azido in step b) is carried out in the presence of a reducing agent and a solvent, the reducing agent is selected from the group consisting of triphenylphosphine, trimethylphosphine, tributylphosphine, palladium carbon/hydrogen, palladium hydroxide/hydrogen, and Raney nickel/hydrogen, and the solvent is water, tetrahydrofuran or alcoholic solvents; the removal of the protecting group in step b) is carried out in the presence of an acid or a base and a solvent, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide, and the solvent is water, dichloromethane, tetrahydrofuran or alcohol solvents; the formation of azacycle in step b) is carried out in the presence of an alkyne, a copper catalyst and a solvent, the alkyne is selected from the group consisting of terminal alkynes or internal alkynes having various lengths with or without various functional groups, the copper catalyst is selected from the group consisting of cuprous chloride, cuprous bromide, cuprous iodide, and copper sulfate/sodium ascorbate, and the solvent is water, dichloromethane, tetrahydrofuran or alcoholic solvents.

21. The method according to claim 20, wherein the hypervalent iodine reagent in step a) is ##STR00057## the solvent in step a) is acetonitrile; the light source for the light conditions in step a) is blue LED light; the reaction in step a) is carried out under light conditions and at a temperature of 20-40° C.; the hydrolysis of the ester group in step b) is carried out in the presence of a base and a solvent, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, and the solvent is one or two selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol; the reduction of the azido in step b) is carried out in the presence of a reducing agent and a solvent, the reducing agent is selected from the group consisting of triphenylphosphine, trimethylphosphine, tributylphosphine, palladium carbon/hydrogen, palladium hydroxide/hydrogen, and Raney nickel/hydrogen, and the solvent is one or two selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol; the removal of the protecting group in step b) is carried out in the presence of an acid or a base and a solvent, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide, and the solvent is one or two selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol; the formation of azacycle in step b) is carried out in the presence of an alkyne, a copper catalyst and a solvent, the alkyne is selected from the group consisting of terminal alkynes or internal alkynes having various lengths with or without various functional groups, the copper catalyst is selected from the group consisting of cuprous chloride, cuprous bromide, cuprous iodide, and copper sulfate/sodium ascorbate, and the solvent is one or two selected from the group consisting of methanol, ethanol, isopropanol, and tert-butanol.

22. The method according to claim 16, wherein the virus is Zika virus or rhinovirus.

23. The method according to claim 17, wherein the virus is Zika virus or rhinovirus.

24. The method according to claim 18, wherein the virus is Zika virus or rhinovirus.

25. The method according to claim 19, wherein the mammal is a human, a cat, a dog or a pig.

26. The method according to claim 18, wherein the cell is a cell of mammal.

27. The method according to claim 26, wherein the mammal comprises bovine, equine, caprinae, suidae, canidae, feline, rodent, primate.

28. The method according to claim 26, wherein the mammal is a human, a cat, a dog or a pig.

Description

SPECIFIC MODELS FOR CARRYING OUT THE INVENTION

[0156] The present application can be further described by the following examples and test examples. However, the scope of the present application is not limited to the following examples or test examples. Those skilled in the art can understand that various changes and modifications can be made to the present application without departing from the spirit and scope of the present application. The present application provides a general and/or specific description of the materials and test methods used in the tests. Although many materials and operating methods used to achieve the purpose of the present application are well known in the art, the present application is still described herein as much detail as possible.

[0157] For all the following examples, standard operation and purification methods known to those skilled in the art can be used. All temperatures are expressed in ° C. (Celsius) unless otherwise stated.

[0158] In order to further describe the technical solution of the present application, some examples are given below, but the protection scope of the present application is not limited to the following description.

EXAMPLE 1: SYNTHESIS OF COMPOUND 4A AND 4B

[0159] ##STR00018##

[0160] The unsaturated glycal compound 3 (201 mg, 0.351 mmol, 1.0 eq.) and BI-OAc (215 mg, 0.702 mmol, 2.0 eq.) were placed in a dry round-bottomed flask, after replacement with argon by suction, onsite-dried MeCN (3.5 mL) was added for dissolution, and TMSN.sub.3 (138 μL, 1.05 mmol, 3.0 eq.) was added. The reaction was carried out under stirring and the illumination of 34 W blue LED light, and the temperature was controlled at 25-30° C. After 2 h of reaction, TLC detection showed that the raw materials disappeared completely. A saturated KHCO.sub.3 solution was added to the reaction solution to quench the reaction, then the reaction solution was diluted with EtOAc, and stirred vigorously at room temperature for 5 min, then extracted with EtOAc four times, the organic phases were combined and washed with water and saturated saline solution, respectively, dried with anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, the crude product was separated and purified by silica gel column chromatography (petroleum ether:EtOAc=12:1 to 8:1 v/v) to obtain white solid 4a (65.3 mg, 28%) and 4b (131 mg, 57%).

[0161] Compound 4a: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.26 (d, J=8.4 Hz, 1H), 4.41 (dd, J=10.8, 1.2 Hz, 1H), 4.14 (q, J=6.4 Hz, 1H), 4.07-3.86 (m, 3H), 3.92 (s, 3H), 3.85-3.75 (m, 1H), 3.70-3.55 (m, 2H), 1.98 (s, 3H), 1.39 (s, 3H), 1.29 (s, 3H), 0.89 (s, 18H), 0.17 (s, 3H), 0.13 (s, 6H), 0.06 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 169.6, 166.3, 108.6, 91.4, 76.0, 73.2, 71.5, 70.6, 66.4, 66.3, 53.9, 53.6, 26.6, 25.9, 25.6, 24.8, 23.9, 18.5, 18.0, −3.6, −4.0, −4.6, −4.6; [α]25 D=−16.0 (c 0.4, CHCl.sub.3); IR (neat): ν.sub.max=2955, 2930, 2858, 2112, 1757, 1666, 1253, 1120, 1069, 1023, 836, 777, 736; HRMS: calcd. for C.sub.27H.sub.51N.sub.7NaO.sub.8Si.sub.2 [M+Na].sup.+ m/z 680.3235; found m/z 680.3249.

[0162] Compound 4b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.29 (d, J=8.0 Hz, 1H), 4.73 (dd, J=10.0, 3.6 Hz, 1H), 4.59 (d, J=10.8 Hz, 1H), 4.24-4.16 (m, 1H), 4.07-4.01 (m, 2H), 3.97-3.83 (m, 2H), 3.85 (s, 3H), 3.67-3.55 (m, 1H), 1.96 (s, 3H), 1.40 (s, 3H), 1.29 (s, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.07 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 170.2, 165.4, 108.1, 91.0, 72.7, 70.6, 67.8, 65.7, 64.9, 53.2, 50.8, 29.7, 26.4, 25.9, 25.6, 24.7, 23.9, 18.5, 17.9, −3.4, −4.1, −4.4, −5.1; [α]25 D=−0.9 (c 0.4, CHCl.sub.3); IR (neat): ν.sub.max=2955, 2930, 2858, 2111, 1758, 1668, 1256, 1068, 1039, 837, 779, 734; HRMS calcd. for C.sub.27H.sub.51N.sub.7NaO.sub.8Si.sub.2 [M+Na].sup.+ m/z 680.3235; found m/z 680.3235.

EXAMPLE 2: SYNTHESIS OF COMPOUND 6A-D

[0163] ##STR00019##

[0164] The preparation method was the same as in Example 1. Compound 5 (2.03 g, 2.82 mmol, 1.0 eq.), BIOAc (1.72 g, 5.63 mmol, 2.0 eq.), TMSN.sub.3 (1.11 mL, 8.45 mmol, 3.0 eq.) were reacted in dry MeCN. The crude product was separated and purified by silica gel column (petroleum ether:acetone=4:1 v/v) to obtain white solid mixture 6 (1.92 g, 85%), which was separated by silica gel column (petroleum ether:EtOAc=4:1 to 2:1 v/v) to obtain 1.50 g of a mixture of Compounds 6a, 6b and 6c and pure Compound 6d (416 mg), and the mixture of the three was separated by analytical HPLC (Waters e2695, 2489 UV Detector, ZORBAX 300SB-C8, flow rate: 1 mL/min, temperature: 25° C., mobile phase was water:methanol=60:40.fwdarw.40:60.fwdarw.30:70.fwdarw.20:80) to obtain three isomers in a ratio of 6a:6b:6c=1:1:5.2, in combination with the mass ratio analysis obtained by silica gel column purification, it could be known that the ratios of the four isomers were: 6a:6b:6c:6d=1:1:5.2:2. The mixture of Compounds 6a, 6b and 6c could be separated by repeated silica gel column chromatography (petroleum ether:acetone=8:1 v/v and petroleum ether:EtOAc=5:1 v/v) and preparative silica gel plate separation (petroleum ether:EtOAc=1.5:1 v/v) to obtain pure Compounds 6a (52.3 mg), 6b (32.8 mg) and 6c (638 mg), and partial mixture, respectively.

[0165] Compound 6a: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.09-7.91 (m, 8H), 7.63-7.32 (m, 12H), 5.90 (dd, J=6.4, 1.6 Hz, 1H), 5.87-5.81 (m, 1H), 5.64 (d, J=9.6 Hz, 1H), 5.55 (t, J=2.0 Hz, 1H), 4.94 (dd, J=12.4, 3.2 Hz, 1H), 4.64 (dd, J=10.8, 2.0 Hz, 1H), 4.50-4.35 (m, 2H), 4.21 (d, J=10.0 Hz, 1H), 3.96 (s, 3H), 1.78 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.0, 166.6, 166.0, 165.6, 165.2, 165.2, 133.8, 133.5, 133.4, 133.1, 130.0, 129.9, 129.9, 129.7, 129.5, 129.4, 129.2, 128.6, 128.6, 128.5, 128.3, 91.6, 72.9, 71.5, 70.6, 68.4, 62.9, 62.8, 54.1, 49.8, 23.0; [α]25 D=+6.1 (c 0.8, CHCl.sub.3); IR (neat): ν.sub.max=2967, 2132, 2113, 1722, 1451, 1257, 1091, 1067, 1024, 800, 707, 686; HRMS calcd. for C.sub.40H.sub.35N.sub.7NaO.sub.12 [M+Na].sup.+ m/z 828.2241; found m/z 828.2232.

[0166] Compound 6b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.17-7.88 (m, 8H), 7.65-7.31 (m, 12H), 5.96-5.76 (m, 3H), 5.53 (d, J=9.6 Hz, 1H), 4.79 (dd, J=12.4, 2.8 Hz, 1H), 4.67 (dd, J=10.8, 2.0 Hz, 1H), 4.49-4.32 (m, 2H), 3.75 (d, J=10.0 Hz, 1H), 3.48 (s, 3H), 1.80 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.0, 166.5, 166.0, 165.6, 165.3, 164.8, 133.7, 133.5, 133.0, 130.0, 129.9, 129.9, 129.7, 129.6, 129.2, 129.2, 128.6, 128.6, 128.5, 128.3, 91.2, 73.8, 71.5, 69.3, 67.9, 65.7, 63.0, 53.3, 49.3, 23.0; [α]25 D=+29.5 (c 0.9, CHCl.sub.3); IR (neat): ν.sub.max=3364, 2963, 2932, 2114, 1726, 1249, 1093, 1068, 1026, 709; HRMS calcd. for C.sub.40H.sub.35N.sub.7NaO.sub.12 [M+Na].sup.+ m/z 828.2241; found 828.2235.

[0167] Compound 6c: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.18-8.13 (m, 2H), 8.05-7.98 (m, 4H), 7.98-7.92 (m, 2H), 7.64-7.45 (m, 6H), 7.45-7.31 (m, 6H), 5.94-5.86 (m, 2H), 5.84 (dd, J=10.4, 3.2 Hz, 1H), 5.69-5.94 (m, 1H), 5.11 (dd, J=12.4, 2.8 Hz, 1H), 4.68 (dd, J=10.8, 2.0 Hz, 1H), 4.59 (dd, J=12.4, 6.4 Hz, 1H), 4.49 (q, J=10.4 Hz, 1H), 4.36 (d, J=3.2 Hz, 1H), 3.96 (s, 3H), 1.81 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.1, 166.1, 166.0, 165.7, 165.6, 164.6, 133.8, 133.5, 133.3, 133.0, 130.1, 130.0, 129.9, 129.7, 129.7, 129.5, 129.2, 128.6, 128.6, 128.4, 128.4, 128.3, 91.2, 72.78, 71.5, 670.0, 69.0, 63.1, 62.5, 53.7, 45.9, 23.2; [α]25 D=−1.3 (c 0.7, CHCl.sub.3); IR (neat): ν.sub.max=3375, 2970, 2924, 2112, 1723, 1695, 1257, 1092, 1068, 1026, 803, 709; HRMS calcd. for C.sub.40H.sub.35N.sub.7NaO.sub.12 [M+Na].sup.+ m/z 828.2241; found m/z 828.2232.

[0168] Compound 6d: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.19-8.13 (m, 2H), 8.07-7.98 (m, 4H), 7.97-7.92 (m, 2H), 7.67-7.32 (m, 12H), 5.97-5.90 (m, 1H), 5.86 (dd, J=7.6, 1.6 Hz, 1H), 5.80 (dd, J=10.8, 3.2 Hz, 1H), 5.64-5.55 (m, 1H), 4.95 (dd, J=12.4, 3.2 Hz, 1H), 4.64 (dd, J=10.8, 1.6 Hz, 1H), 4.59-4.49 (m, 2H), 4.20-4.08 (m, 1H), 3.62 (s, 3H), 1.85 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.4, 166.0, 165.9, 165.9, 165.7, 165.3, 133.8, 133.7, 133.3, 133.0, 130.2, 123.0, 129.9, 129.7, 129.6, 129.0, 128.7, 128.6, 128.5, 128.3, 89.5, 73.0, 69.9, 69.4, 68.7, 63.1, 62.8, 53.7, 46.6, 23.3; [α]25 D=+41.2 (c 0.7, CHCl.sub.3); IR (neat): ν.sub.max=3375, 2963, 2111, 1724, 1255, 1106, 1094, 1069, 1026, 709; HRMS calcd. for C.sub.40H.sub.35N.sub.7NaO.sub.12 [M+Na].sup.+ m/z 828.2241; found m/z 828.2237.

EXAMPLE 3: SYNTHESIS OF COMPOUNDS 8A AND 8B

[0169] ##STR00020##

[0170] The preparation method was the same as in Example 1. Compound 7 (4.21 g, 5.91 mmol, 1.0 eq.), BIOAc (3.62 g, 11.8 mmol, 2.0 eq.) and TMSN.sub.3 (2.33 mL, 17.7 mmol, 3.0 eq.) were reacted in dry MeCN. The crude product was separated and purified by silica gel column (petroleum ether EtOAc=3:1 to 2:1 v/v) to obtain white solids 8a (1.27 g, 57%) and 8b (0.732 g, 32%).

[0171] Compound 8a: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.10-7.98 (m, 4H), 7.97-7.90 (m, 2H), 7.65-7.31 (m, 9H), 7.16-7.07 (m, 1H), 6.72 (d, J=8.8 Hz, 1H), 5.91-5.81 (m, 2H), 5.12 (dd, J=12.8, 2.4 Hz, 1H), 4.93 (d, J=10.8 Hz, 1H), 4.70-4.61 (m, 1H), 4.53 (dd, J=12.4, 5.6 Hz, 1H), 4.35-4.25 (m, 1H), 4.02 (d, J=3.6 Hz, 1H), 3.94 (s, 3H), 2.01 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 171.1, 166.1, 166.0, 165.3, 164.4, 158.4, 158.1, 157.7, 157.3, 133.8, 133.6, 133.1, 130.1, 129.9, 129.6, 129.5, 129.2, 128.8, 128.6, 128.6, 128.5, 128.3, 119.7, 116.9, 114.0, 111.1, 91.2, 71.4, 68.9, 68.5, 62.7, 61.1, 53.7, 49.8, 44.6, 23.2; [α]25 D=+63.1 (c 1.7, CHCl.sub.3); IR (Neat): ν.sub.max=2114, 1725, 1259, 1088, 1068, 735, 709; HRMS calcd. for C.sub.35H.sub.31F.sub.3N.sub.8NaO.sub.11[M+Na].sup.+ m/z 819.1962; found m/z 819.1954.

[0172] Compound 8b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.09-7.98 (m, 4H), 7.94 (d, J=7.6 Hz, 2H), 7.64-7.49 (m, 4H), 7.49-7.41 (m, 3H), 7.41-7.32 (m, 2H), 6.71-6.56 (m, 1H), 5.92-5.85 (m, 1H), 5.80 (dd, J=7.6, 1.6 Hz, 1H), 5.22 (d, J=11.2, Hz, 1H), 4.92 (dd, J=12.8, 2.8 Hz, 1H), 4.61 (d, J=7.2 Hz, 1H), 4.46 (dd, J=12.4, 4.8 Hz, 1H), 4.33-4.20 (m, 1H), 4.15 (q, J=6.8 Hz, 1H), 3.68 (s, 3H), 1.96 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 172.4, 166.4, 166.0, 165.6, 165.5, 159.2, 158.8, 158.4, 158.05, 134.0, 133.6, 133.1, 130.1, 129.8, 129.6, 129.4, 129.2, 128.7, 128.6, 128.3, 128.3, 119.8, 117.0, 114.1, 111.2, 89.6, 70.1, 69.9, 68.5, 62.5, 59.0, 53.6, 50.6, 46.0, 22.9; [α]25 D=+53.4 (c 1.0, CHCl.sub.3); IR (neat): ν.sub.max=2116, 1726, 1263, 1247, 1091, 1069, 734, 708; HRMS calcd. for C.sub.35H.sub.31F.sub.3N.sub.8NaO.sub.11 [M+Na].sup.+ m/z 819.1962; found m/z 819.1961.

EXAMPLE 4: SYNTHESIS OF COMPOUND 10A-D

[0173] ##STR00021##

[0174] The preparation method was the same as in Example 1. Compound 9 (1.01 g, 2.51 mmol, 1.0 eq.), BIOAc (1.54 g, 5.02 mmol, 2.0 eq.) and TMSN.sub.3 (0.991 mL, 7.53 mmol, 3.0 eq.) were reacted in dry MeCN. The crude product was purified by silica gel column (petroleum ether:acetone=8:1 v/v) to obtain 1.05 g of a mixed total product of four isomers (Compounds 10a, 10b, 10c, 10d), which were separated by analytical HPLC (Waters e2695, 2424 ELS Detector, ZORBAX 300SB-C8, flow rate: 1 mL/min, temperature: 20° C., mobile phase was water:methanol=60:40.fwdarw.50:50.fwdarw.40:60) to obtain four isomers in a ratio of 10a:10b:10c:10d=7:11:5:1. The total product was separated and purified by repeated silica gel column chromatography (petroleum ether:acetone=13:1 v/v, petroleum ether:EtOAc=7:1 v/v) to obtain white solid 10a (34.0 mg), 10b (163 mg), 10c (194 mg), 10d (41.3 mg), and partial mixture.

[0175] Compound 10a: .sup.1H NMR (600 MHz, CDCl.sub.3) δ: 5.48 (d, J=1.8 Hz, 1H), 5.21-5.16 (m, 2H), 4.47 (dd, J=12.6, 2.4 Hz, 1H), 4.43 (d, J=9.6 Hz, 1H), 4.23 (d, J=10.8 Hz, 1H), 4.09 (dd, J=12.6, 3 Hz, 1H), 3.97 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 170.6, 170.1, 169.6, 169.5, 165.3, 91.6, 69.8, 69.2, 66.8, 65.4, 61.8, 58.0, 56.2, 54.1, 20.7, 20.6, 20.6; [α]25 D=+64.5 (c 0.11, CHCl.sub.3); IR (neat): ν.sub.max=2927, 2118, 1752, 1437, 1370, 1226, 1076, 957, 750 cm.sup.−1; HRMS calcd. for C.sub.17H.sub.22N.sub.6NaO.sub.11 [M+Na].sup.+ m/z 509.1244; found m/z 509.1253.

[0176] Compound 10b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.48 (d, J=9.2 Hz, 2H), 5.14 (d, J=9.2 Hz, 1H), 4.36 (t, J=8.8 Hz, 2H), 4.22 (dd, J=12, 2.8 Hz, 1H), 3.92 (s, 3H), 3.76 (d, J=10 Hz, 1H), 2.14 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 170.3, 170.1, 169.5, 169.5, 165.7, 91.2, 71.5, 69.4, 67.4, 65.1, 61.8, 61.3, 53.6, 20.7, 20.6, 20.6, 20.6; [α]25 D=+32.5 c 0.08, CHCl.sub.3); IR (neat): ν.sub.max=2926, 2118, 1752, 1437, 1372, 1228, 1080, 804, 735 cm.sup.−1; HRMS calcd. for C.sub.17H.sub.22N.sub.6NaO.sub.11 [M+Na].sup.+ m/z 509.1244; found m/z 509.1253.

[0177] Compound 10c: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.42 (d, J=2.4 Hz, 2H), 5.34 (d, J=10 Hz, 1H), 4.55 (dd, J=12.4, 2 Hz, 1H), 4.42 (d, J=9.6 Hz, 1H), 4.24 (dd, J=12.8, 2.8 Hz, 1H), 4.07 (t, J=2.0 Hz, 1H), 3.93 (s, 3H), 2.13 (s, 3H), 2.08 (s, 6H), 1.99 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 170.5, 170.5, 169.4, 169.2, 164.4, 91.5, 69.4, 67.3, 67.1, 63.3, 61.8, 58.5, 53.7, 20.7, 20.6, 20.6, 20.3; [α]25 D=+116.2 (c 0.32, CHCl.sub.3); IR (neat): ν.sub.max=2959, 2118, 1748, 1438, 1372, 1223, 1053, 924, 732 cm.sup.−1; HRMS calcd. for C.sub.17H.sub.22N.sub.6NaO.sub.11 [M+Na].sup.+ m/z 509.1244; found m/z 509.1231.

[0178] Compound 10d: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.34 (s, 1H), 5.30 (d, J=9.6 Hz, 1H), 5.15 (t, J=2.8 Hz, 1H), 4.46 (d, J=12.4 Hz, 1H), 4.29 (dd, J=12.4, 3.2 Hz, 1H), 4.22 (d, J=3.2 Hz, 1H), 3.97 (d, J=9.6 Hz, 1H), 3.92 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H), 1.98 (s, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3) δ: 170.5, 170.4, 169.3, 169.3, 165.8, 90.1, 71.9, 67.7, 67.3, 62.9, 61.7, 58.7, 53.9, 20.7, 20.6, 20.5, 20.4; [α]25 D=+101.8 (c 0.09, CHCl.sub.3); IR (neat): ν.sub.max=2918, 2115, 1747, 1436, 1372, 1225, 1045, 923, 733 cm.sup.−1; HRMS calcd. for C.sub.17H.sub.22N.sub.6NaO.sub.11 [M+Na].sup.+ m/z 509.1244; found m/z 509.1258.

EXAMPLE 5: SYNTHESIS OF COMPOUNDS 12A AND 12B

[0179] ##STR00022##

[0180] The preparation method was the same as in Example 1. Compound 11 (1.20 g, 4.00 mmol, 1.0 eq.), BIOAc (2.45 g, 8.00 mmol, 2.0 eq.) and TMSN.sub.3 (1.58 mL, 12.0 mmol, 3.0 eq.) were reacted in dry MeCN. The crude product was separated and purified by silica gel column (petroleum ether EtOAc=8:1 to 5:1 v/v) to obtain white solids 12a (537 mg, 35%) and 12b (845 mg, 55%).

[0181] Compound 12a: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 4.91 (dd, J=6.8, 2 Hz, 1H), 4.77 (t, J=6.8 Hz, 1H), 4.37-4.32 (m, 1H), 4.21 (d, J=6.8 Hz, 1H), 4.18-4.12 (m, 1H), 4.01 (d, J=2 Hz, 1H), 3.99-3.95 (m, 1H), 3.94 (s, 3H), 1.44 (s, 3H), 1.36 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 165.1, 152.5, 110.2, 90.0, 74.5, 73.3, 72.7, 71.2, 67.0, 60.1, 54.2, 26.8, 24.8; [α]25 D=+76.7 (c 0.68, CHCl.sub.3); IR (neat): ν.sub.max=2988, 2968, 2121, 1820, 1768, 1079, 846, 759 cm.sup.−1; HRMS calcd. for C.sub.13H.sub.16N.sub.6NaO.sub.8 [M+Na].sup.+ m/z 407.0927; found m/z 407.0932.

[0182] Compound 12b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 5.02 (dd, J=8.0, 5.2 Hz, 1H), 4.96 (dd, J=8.0, 1.6 Hz, 1H), 4.36-4.31 (m, 1H), 4.19-4.12 (m, 2H), 3.94 (s, 3H), 3.91 (d, J=4.8 Hz, 1H), 3.79 (dd, J=8.4, 1.6 Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 165.4, 152.7, 110.2, 89.3, 73.7, 72.8, 72.5, 72.4, 66.7, 61.2, 53.7, 26.9, 24.8; [α]25 D=+40.0 (c 0.08, CHCl.sub.3); IR (neat): ν.sub.max=2988, 2967, 2111, 1820, 1767, 1078, 846, 759 cm.sup.−1; HRMS calcd. for C.sub.13H.sub.16N.sub.6NaO.sub.8 [M+Na].sup.+ m/z 407.0927; found m/z 407.0915.

EXAMPLE 6: SYNTHESIS OF COMPOUND 13

[0183] ##STR00023##

[0184] Compound 6c (50.3 mg, 0.062 mmol, 1.0 eq.) and LiI (83.1 mg, 0.621 mmol, 10.0 eq.) were placed in a dry test tube, after replacement with Ar gas by suction, 1 mL of pyridine was added for dissolution, stirred in an oil bath at 90° C. overnight. The reaction solution was concentrated under reduced pressure, and purified by a silica gel column (CH.sub.2Cl.sub.2:MeOH=20:1 v/v) to obtain a white solid product 13 (42.5 mg, 86%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.17 (d, J=7.2 Hz, 2H), 8.05 (d, J=7.2 Hz, 2H), 8.00 (d, J=7.2 Hz, 2H), 7.94 (d, J=7.2 Hz, 2H), 7.69-7.34 (m, 12H), 6.05-5.93 (m, 2H), 5.54 (dd, J=10.4, 3.6 Hz, 1H), 5.08 (dd, J=12.4, 2.4 Hz, 1H), 4.68-4.47 (m, 4H), 4.44 (d, J=3.6 Hz, 1H), 1.80 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 173.3, 167.6, 167.1, 167.0, 166.8, 150.0, 134.7, 134.6, 134.6, 134.3, 131.3, 131.0, 131.0, 131.0, 130.9, 130.8, 130.7, 130.3, 129.7, 129.6, 129.6, 129.5, 73.3, 73.1, 71.6, 69.6, 64.9, 63.6, 46.0, 30.7, 22.7; [α]25 D=+21.4 (c 0.44, CHCl.sub.3. MeOH=4:1); IR (neat): ν.sub.max=3398, 2119, 1725, 1662, 1261, 1090, 1069, 1025, 707, 686; HRMS calcd. for C.sub.39H.sub.33N.sub.7NaO.sub.12 [M+Na].sup.+ m/z 814.2085; found m/z 814.2055.

EXAMPLE 7: SYNTHESIS OF COMPOUND 14

[0185] ##STR00024##

[0186] Compound 6c (140 mg, 0.174 mmol, 1.0 eq.) and Pd/C (14.0 mg) were placed in a round-bottomed flask, after replacement with H.sub.2 by suction, 10 mL of methanol was added for dissolution, stirred at room temperature for 4 h. The reaction solution was filtered through diatomite, concentrated under reduced pressure, and purified by silica gel column (petroleum ether:EtOAc=2:1 v/v) to obtain a white solid product 14 (110 mg, 81%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.21-8.14 (m, 2H), 8.03-7.97 (m, 4H), 7.96-7.90 (m, 2H), 7.64-7.45 (m, 6H), 7.45-7.30 (m, 6H), 5.98 (dd, J=10.8, 3.6 Hz, 1H), 5.95-5.80 (m, 1H), 5.84 (dd, J=5.6, 2.0 Hz, 1H), 5.58 (d, J=9.6 Hz, 1H), 5.19 (dd, J=12.4, 2.8 Hz, 1H), 4.81 (dd, J=10.4, 2.0 Hz, 1H), 4.56 (dd, J=12.0, 7.6 Hz, 1H), 4.44 (q, J=10.0 Hz, 1H), 4.32 (d, J=3.6 Hz, 1H), 3.88 (s, 3H), 2.13 (s, 2H), 1.81 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.3, 170.1, 166.4, 166.2, 165.9, 133.7, 133.4, 132.9, 130.2, 130.0, 129.8, 129.8, 129.6, 129.4, 129.4, 128.6, 128.5, 128.5, 128.5, 128.3, 86.3, 72.0, 71.2, 70.3, 69.5, 63.8, 63.7, 53.0, 46.5, 23.3; [α]25 D=+4.4 (c 0.50, CHCl.sub.3); IR (neat): ν.sub.max=3378, 2928, 2855, 2111, 1718, 1261, 1107, 1094, 1069, 1026, 708; HRMS calcd. for C.sub.40H.sub.37N.sub.5NaO.sub.12 [M+Na].sup.+ m/z 802.2336; found m/z 802.2325.

EXAMPLE 8: SYNTHESIS OF COMPOUND 15

[0187] ##STR00025##

[0188] The preparation method was the same as in Example 6. Compound 8a (100 mg, 0.126 mmol, 1.0 eq.) and LiI (168.1 mg, 1.26 mmol, 10.0 eq.) were reacted in 2 mL of pyridine. The crude product was purified by silica gel column (CH.sub.2Cl.sub.2:MeOH=20:1 to 15:1 v/v) to obtain a white solid product 15 (74.7 mg, 76%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.13 (d, J=7.6 Hz, 2H), 8.02 (d, J=7.2 Hz, 2H), 7.93 (d, J=7.2 Hz, 2H), 7.70-7.34 (m, 9H), 6.10-6.02 (m, 1H), 5.98 (dd, J=8.0, 2.0 Hz, 1H), 5.16 (dd, J=12.4, 2.0 Hz, 1H), 4.70 (dd, J=11.2, 1.6 Hz, 1H), 4.65-4.55 (m, 3H), 4.49 (dd, J=12.4, 4.8 Hz, 1H), 4.39 (dd, J=11.2, 4.4 Hz, 1H), 4.00 (d, J=3.2 Hz, 1H), 2.01 (s, 3H); .sup.13C NMR (150 MHz, CD.sub.3OD) δ: 171.4, 168.3, 165.6, 164.9, 164.7, 157.1, 156.8, 132.8, 132.6, 132.4, 129.2, 129.0, 128.9, 128.7, 128.6, 128.5, 128.5, 127.7, 127.6, 127.5, 127.5, 127.5, 127.5, 127.4, 116.1, 114.2, 91.7, 69.5, 67.9, 66.9, 61.5, 61.3, 48.3, 42.9, 20.9; [α]25 D=+45.0 (c 0.50, CHCl.sub.3); IR (neat): ν.sub.max=2117, 1718, 1654, 1452, 1259, 1177, 1091, 1068, 709; HRMS calcd. for C.sub.34H.sub.29F.sub.3N.sub.8NaO.sub.11 [M+Na].sup.+ m/z 805.1806; found m/z 805.1803.

EXAMPLE 9: PREPARATION OF COMPOUND 16

[0189] ##STR00026##

[0190] The preparation method was the same as in Example 7. Compound 8a (100 mg, 0.126 mmol) and Pd/C (10.2 mg) were placed in a round-bottomed flask, after replacement with H.sub.2 by suction, 5 mL of methanol was added for dissolution, stirred at room temperature for 3 h. The reaction solution was filtered through diatomite, concentrated under reduced pressure, and purified by silica gel column (petroleum ether:EtOAc=1.5:1 v/v) to obtain a white solid product 16 (58.9 mg, 63%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.15-8.07 (m, 2H), 8.06-7.99 (m, 2H), 7.98-7.89 (m, 2H), 7.72 (d, J=9.2 Hz, 1H), 7.64-7.32 (m, 9H), 6.76 (d, J=9.2 Hz, 1H), 5.91-5.85 (m, 1H), 5.75 (dd, J=4.8, 1.6 Hz, 1H), 5.31 (dd, J=12.4, 2.4 Hz, 1H), 4.78-4.69 (m, 2H), 4.46 (dd, J=12.4, 7.2 Hz, 1H), 4.43-4.35 (m, 1H), 3.89 (s, 3H), 3.84 (d, J=3.2 Hz, 1H), 2.02 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ: 170.6, 170.0, 166.4, 166.4, 165.3, 158.0, 157.5, 157.1, 156.8, 133.6, 133.5, 133.1, 130.1, 129.9, 129.6, 129.6, 129.2, 129.0, 128.6, 128.6, 128.4, 116.9, 114.0, 86.0, 72.4, 69.2, 67.6, 63.8, 62.7, 53.2, 49.8, 44.5, 23.5; [α]25 D=+124.8 (c 0.40, CHCl.sub.3); IR (neat): ν.sub.max=3377, 3287, 2115, 1718, 1259, 1250, 1089, 1068, 1025, 708; HRMS calcd. for C.sub.35H.sub.33F.sub.3N.sub.6NaO.sub.11 [M+Na].sup.+ m/z 793.2057; found m/z 793.2049.

EXAMPLE 10: PREPARATION OF COMPOUND 17

[0191] ##STR00027##

[0192] Compound 8a (150 mg, 0.188 mmol, 1.0 eq.) was dissolved in a mixed solvent of THF and H.sub.2O (14 mL, 1:1 v/v), and then pentynyl alcohol (38.6 μL, 0.414 mmol, 2.2 eq.), CuSO.sub.4.Math.5H.sub.2O (18.8 mg, 0.075 mmol, 0.4 eq.) and sodium ascorbate (149 mg, 0.754 mmol, 4.0 eq.) were added in sequence. The reaction was carried out under stirring at room temperature for 2 h, monitored by TLC until the completion of the reaction of the raw materials, and the reaction solution was directly concentrated under reduced pressure, first purified by a reverse-phase silica gel column (MeOH:H.sub.2O=1:4 to 1:1 v/v), and then purified by normal phase silica gel column purification (CH.sub.2Cl.sub.2:MeOH=15:1 v/v) to obtain a white solid product 17 (151 mg, 83%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.25-8.18 (m, 2H), 8.02 (s, 1H), 7.93-7.87 (m, 4H), 7.85 (s, 1H), 7.74-7.53 (m, 5H), 7.46 (t, J=8.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 2H), 6.95 (d, J=8.0 Hz, 1H), 5.95 (dd, J=8.0, 1.6 Hz, 1H), 5.78-5.71 (m, 1H), 5.17-5.06 (m, 2H), 5.02 (dd, J=10.8, 6.8 Hz, 1H), 4.63 (dd, J=10.8, 1.6 Hz, 1H), 4.60 (s, 1H), 4.39 (dd, J=12.8, 4.8 Hz, 1H), 3.62 (s, 3H), 3.57-3.50 (m, 4H), 2.74 (t, J=7.2 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H), 1.88-1.70 (m, 4H), 1.82 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 173.7, 167.5, 166.7, 166.6, 165.4, 160.0, 159.6, 159.3, 158.9, 150.8, 148.3, 135.1, 134.9, 134.5, 131.3, 130.8, 130.7, 130.7, 130.4, 130.2, 129.9, 129.8, 129.7, 129.6, 129.5, 126.2, 123.0, 118.6, 115.7, 92.6, 71.3, 70.8, 69.8, 63.1, 62.0, 61.8, 58.5, 54.8, 49.9, 47.2, 33.1, 32.5, 22.8, 22.5, 22.4; [α]25 D=+36.4 (c 0.52, CHCl.sub.3); IR (neat): ν.sub.max=3339, 2936, 1721, 1260, 1106, 1068, 708 cm.sup.−1; HRMS calcd. for C.sub.45H.sub.47F.sub.3N.sub.8NaO.sub.13 [M+Na].sup.+ m/z 987.3112; found m/z 987.3072.

EXAMPLE 11: PREPARATION OF COMPOUND 18

[0193] ##STR00028##

[0194] The preparation method was the same as in Example 6. Compound 8b (52.3 mg, 0.066 mmol, 1.0 eq.) and LiI (87.9 mg, 0.657 mmol, 10.0 eq.) were reacted in 1 mL of pyridine. The crude product was purified by silica gel column (CH.sub.2Cl.sub.2:MeOH=20:1 to 10:1 v/v) to obtain a white solid product 18 (42.6 mg, 83%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 8.11 (dd, J=8.0, 1.2 Hz, 2H), 7.96 (dd, J=8.0, 1.2 Hz, 2H), 7.90 (dd, J=8.4, 1.6 Hz, 2H); 7.68-7.30 (m, 9H), 5.98-5.85 (m, 2H), 5.10 (dd, J=12.4, 3.2 Hz, 1H), 4.78 (dd, J=10.4, 2.0 Hz, 1H), 4.70 (dd, J=12.4, 6.4 Hz, 1H), 4.61-4.50 (m, 1H), 4.44 (t, J=5.2 Hz, 1H), 4.21 (d, J=4.8 Hz, 1H), 1.95 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 173.8, 172.6, 167.6, 167.0, 166.7, 159.5, 159.2, 158.8, 158.4, 134.7, 134.4, 134.3, 134.1, 131.1, 131.1, 131.0, 130.9, 130.8, 130.7, 130.6, 130.5, 130.5, 129.7, 129.6, 129.5, 129.5, 129.4, 129.3, 121.5, 118.6, 115.8, 93.6, 72.6, 70.9, 63.8, 62.6, 50.2, 46.0, 22.9, 13.9; [α]25 D=+82.8 (c 0.40, CHCl.sub.3); IR (neat): ν.sub.max=3726, 3083, 2889, 2114, 1722, 1647, 1262, 1177, 1093, 1069, 707; HRMS calcd. for C.sub.34H.sub.29F.sub.3N.sub.8NaO.sub.11 [M+Na].sup.+ m/z 805.1806; found m/z 805.1811.

EXAMPLE 12: PREPARATION OF COMPOUND 19

[0195] ##STR00029##

[0196] Compound 12b (50.4 mg, 0.131 mmol, 1.0 eq.) was dissolved in MeOH (1 mL), 1M NaOH aqueous solution (0.131 mL) was added dropwise, after the dropping was completed, the reaction solution was stirred at room temperature for 1 h, and then H.sup.+ ion exchange resin was added to regulate pH to neutral, the reaction solution was filtered, concentrated under reduced pressure, and purified by a reverse-phase silica gel column (MeOH:H.sub.2O=1:9 v/v) to obtain a white solid product 19 (34.2 mg, 76%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ: 4.41 (dd, J=10.4, 3.6 Hz, 1H), 4.34-4.25 (m, 1H), 4.08 (dd, J=8.8, 6.0 Hz, 1H), 4.02-3.90 (m, 3H), 3.46 (d, J=10.4 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD) δ: 171.7, 110.4, 94.4, 77.7, 74.6, 71.0, 69.3, 68.3, 66.3, 27.0, 25.6; [α]25 D=+91.2 (c 0.17, CHCl.sub.3); IR (neat): ν.sub.max=3383, 2925, 2114, 1622, 1615, 1384, 1375, 1247, 1226, 1071, 1059, 842; HRMS calcd. for C.sub.11H.sub.16N.sub.6NaO.sub.7 [M+Na].sup.+ m/z 367.0978; found m/z 367.0961.

EXAMPLE 13: BIOLOGICAL ACTIVITY TEST

[0197] The nitrogen-containing derivatives of 3-deoxy-2-ketoaldonic acid obtained in the above examples were subjected to an antiviral test, and the results were shown in Table 1.

[0198] (1) Anti-Zika (ZIKV) Virus Activity Test

[0199] Test object: Zika virus-infected BHK cells

[0200] Testing Method: [0201] {circle around (1)} BBHK cells (preserved by the Academy of Military Medical Sciences) were inoculated into a 96-well plate at a concentration of 5×10.sup.3 cells/well, and the cell culture medium was DMEM medium (purchased from Gibco Company, Cat. No. 11995065) containing 10% FBS (purchased from Gibco, Cat. No. 16000044), the plate was placed in a CO.sub.2 incubator, and incubated at 37° C. for 24 hours. [0202] {circle around (2)} The original medium in the 96-well plate was discarded, 100 μL of DMEM medium (purchased from Gibco, Cat. No. 11995065) containing 2% FBS (purchased from Gibco, Cat. No. 16000044) was taken and added into the cells. Then, the stock solution of the compound to be tested was serially diluted with the above-mentioned DMEM medium to 800 μM, 266.67 μM, 88.89 μM, 29.63 μM, 9.88 μM, 3.29 μM, 1.10 μM, 0.37 μM, and 50 μL was added to the cell culture plate. The stock solution of positive compound NITD008 (purchased from MCE Company, Cat. No. HY-12957) was serially diluted with the above DMEM medium to 80 μM, 26.67 μM, 8.89 μM, 2.96 μM, 0.99 μM, 0.33 μM, 0.11 μM, 0.04 μM, and 50 μL was added to the cell culture plate. Finally, 50 μL of Zika virus SZ-SMGC-01 strain (preserved by the Academy of Military Medical Sciences) diluted in DMEM medium containing 2% FBS was added to the cells, each well contained 100 TCID.sub.50 of the virus. The final concentration of the compound to be tested was 0.25 times the pretreatment concentration, that was, the initial concentration was 200 μM, and dilution was carried out by 3-fold series, so that the final concentrations of the compound to be tested were: 200 μM, 66.67 μM, 22.22 μM, 7.41 μM, 2.47 μM, 0.82 μM, 0.27 μM, 0.09 μM. The final concentrations of the positive compound were: 20 μM, 6.67 μM, 2.22 μM, 0.74 μM, 0.25 μM, 0.082 μM, 0.027 μM, 0.009 μM. Negative control (to the cell well, DMSO and culture medium were added, without drug) and positive control (to the cell well, DMSO, culture medium and virus were added, without drug) were set. The cell culture plates were incubated at 37° C. for 9 days. [0203] {circle around (3)} The Buffer and the substrate of CellTiter-Glo® Chemiluminescent Cell Viability Assay (purchased from Promega, Cat. No. G7573) were mixed in the dark to prepare a working solution. The working solution was mixed with PBS (purchased from Gibco, Cat. No. 10010049) at a ratio of 4:6. After the medium in the cell culture plate was discarded, 100 μl of detection reagent was added to each well, and the 96-well plate was shaken for 5 min with an orbital shaker to induce cell lysis. After stabilizing the signal in the dark for 2 minutes, a microplate reader (purchased from Molecular Devices, model SpectraMax M5) was used to measure the chemiluminescent units, the plate reading program was the preset program of CellTiter-Glo, and the cell viability was calculated:

Cell viability (%)=(A.sub.(drug treatment group)−A.sub.(positive control))/(A.sub.(negative control)−A.sub.(positive control))×100%

[0204] wherein, A represented the reading of the microplate reader.

[0205] Result evaluation: origin8.0 software was used to carry out the S-type curve fitting on the inhibition rate-concentration, and the IC.sub.50 value of the compound to be tested was calculated.

[0206] (2) Anti-Rhinovirus (HRV-1059) Activity Test

[0207] Test object: Rhinovirus (HRV-1059)-infected H1 Hela cells

[0208] Testing method: [0209] {circle around (1)} H1 Hela cells (purchased from the National Experimental Cell Resource Sharing Platform, Cat. No. 3111C0001CCC000344) were inoculated into a 96-well plate at a concentration of 1.5×10.sup.4 cells/well, and the cell culture medium was DMEM medium (purchased from Gibco, Cat. No. 11995065) containing 10% FBS (purchased from Gibco, Cat. No. 16000044), the plate was placed in a CO.sub.2 incubator and incubated at 37° C. for 24 hours. [0210] {circle around (2)} The original medium in the 96-well plate was discarded, 100 μL of DMEM medium (purchased from Gibco, Cat. No. 11995065) containing 2% FBS (purchased from Gibco, Cat. No. 16000044) was taken and added into the cells. Then the stock solution of the compound to be tested was serially diluted with the above DMEM medium to 800 μM, 266.67 μM, 88.89 μM, 29.63 μM, 9.88 μM, 3.29 μM, 1.10 μM, 0.37 μM, 0.12 μM, 0.04 μM, and 50 μL was added to the cell culture plate. The stock solution of positive compound NITD008 (purchased from MCE Company, Cat. No. HY-12957) was serially diluted with the above DMEM medium to 80 μM, 26.67 μM, 8.89 μM, 2.96 μM, 0.99 μM, 0.33 μM, 0.11 μM, 0.04 μM, 0.012 μM, 0.004 μM, 50 μL was added to the cell culture plate. Finally, 50 μL of the rhinovirus HRV-1059 strain (purchased from ATCC, Cat. No. VR-482) diluted with DMEM medium containing 2% FBS was added to the cells, the amount of virus contained in each well was 100 TCID.sub.50. The final concentration of the compound to be tested was 0.25 times of the pretreatment concentration, that was, the initial concentration was 200 μM, the dilution was carried out by 3-fold series, the final concentrations of the compound to be tested were: 200 μM, 66.67 μM, 22.22 μM, 7.41 μM, 2.47 μM, 0.82 μM, 0.27 μM, 0.09 μM, 0.03 μM, 0.01 μM. The final concentrations of the positive compound were: 20 μM, 6.67 μM, 2.22 μM, 0.74 μM, 0.25 μM, 0.082 μM, 0.027 μM, 0.009 μM, 0.003 μM, 0.001 μM. Negative control (to the cell well, DMSO and medium were added, without drug) and positive control (to the cell well, DMSO, medium and virus were added, without drug) were set. The cell culture plates were incubated at 37° C. for 6 days. [0211] {circle around (3)} The Buffer and the substrate of CellTiter-Glo® Chemiluminescent Cell Viability Assay (purchased from Promega, Cat. No. G7573) was mixed in the dark to obtain a working solution. The working solution was mixed with PBS (purchased from Gibco, Cat. No. 10010049) at a ratio of 4:6. After the medium in the cell culture plate was discarded, 100 μl of detection reagent was added to each well, and the 96-well plate was shaken for 5 min with an orbital shaker to induce cell lysis. After stabilizing the signal in the dark for 2 minutes, a microplate reader (purchased from Molecular Devices, model SpectraMax M5) was used to measure the chemiluminescent units, the plate reading program was the preset program of CellTiter-Glo, and the cell viability was calculated:

Cell viability (%)=(A.sub.(drug treatment group)−A.sub.(positive control))/(A.sub.(negative control)−A.sub.(positive control))×1000%

[0212] wherein, A represented the reading of the microplate reader.

[0213] Result evaluation: origin8.0 software was used to carry out the S-type curve fitting on the inhibition rate-concentration, and the IC.sub.50 value of the compound to be tested was calculated.

TABLE-US-00001 TABLE 1 Antiviral activity results of representative nitrogen-containing derivatives of 3- deoxy-2-ketoaldonic acid IC.sub.50 (μM) Anti- Anti- Com- ZIKV HRV pound Structure Formula (BHK) (H1Hela) NITD008 1.00 0.05 4a [00030] 1.41 4.58 4b [00031] 2.49 18.89 6a [00032] 21.66 >200 6b [00033] 10.61 >200 6c [00034] 11.02 >200 6d [00035] 10.33 >200 8a [00036] 5.50 0.93 8b [00037] 7.30 2.05 10a  [00038] >200 10.77 13  [00039] 20.04 13.27 14  [00040] 14.60 >200 15  [00041] 86.90 12.53 16  [00042] 29.71 5.39 17  [00043] 20.04 >200 18  [00044] 22.73 1.87 19  [00045] >200 24.55

[0214] The above test results showed that the nitrogen-containing derivatives of 3-deoxy-2-ketoaldonic acid prepared in various examples of the present application showed moderate to strong antiviral activity against Zika virus (ZIKV) and rhinovirus (HRV).

[0215] Although the specific embodiments of the present application have been described in detail, those skilled in the art will understand that according to all the teachings disclosed, various modifications and substitutions can be made to those details, and these changes are all within the protection scope of the present application. The full scope of the present application is given by the appended claims and any equivalents thereof.