CN114989178A - Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical chemistry, and particularly discloses spiro [ beta-lactam-3, 3' -oxindole]The like derivatives, and a preparation method and application thereof. The spiro [ beta-lactam-3, 3' -oxindole]The derivatives have a structure shown in a formula I; wherein R is ¹ Selected from hydrogen, alkyl, alkoxy, halogen or ester groups; r ² Selected from alkyl, alkenyl or benzyl; r is ³ Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring; r is ⁴ Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring. Research shows that the spiro [ beta-lactam-3, 3' -oxindoleIndole (A)]The derivative has a certain antiviral effect; in addition, the preparation method can carry out reaction under mild conditions, and has the advantages of simple and convenient operation, few steps, good functional group compatibility, high yield and high diastereoselectivity; therefore, the method has good application prospect in the production of the pharmaceutical industry.

Description

A kind of spiro[beta-lactam-3,3'-oxindole] derivatives and preparation method and application thereof

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a spiro[beta-lactam-3,3'-oxidole] derivative and a preparation method and application thereof.

Background technique

β-lactam and spiro-oxidated indole ring systems are the core structural units that constitute many natural products and biologically active molecules, because they contain highly electronegative heteroatoms such as oxygen and nitrogen, which are incompatible with many biological macromolecules. It has a strong intermolecular force and is a kind of active compound with a special structure, which is widely concerned as a "predominant structure" in drug design.

The marketed drugs penicillin and aztreonam both contain β-lactam structural units; Horsfiline is a chiral spiro compound with indole oxide and pyrrole units isolated from Myristaceae, which has analgesic effect; Coerulescine and Elacomine is a natural product isolated from Canary grass and Elaeagnus, and has good antibacterial activity; Spirotryprostatins A is also a spiro compound with oxyindole and pyrrole units, which is effective against mammalian TsFT210 cells. The G2/M division of G2/M can be completely inhibited. In recent years, the construction of chiral spirocyclic indole oxides has received increasing attention from medicinal chemists and synthetic chemists.

However, at present, there are few studies on the antiviral effect of the structure of spirocyclic indole oxides; therefore, a spirocyclic indole oxide compound with antiviral effect is provided, especially a spirocyclic oxide with excellent antiviral effect. Oxidole compounds have important application value.

SUMMARY OF THE INVENTION

In order to overcome at least one of the technical problems existing in the prior art, the present invention provides a new structure of spiro[β-lactam-3,3'-oxindole] derivatives; studies have shown that the The spiro[β-lactam-3,3'-oxindole] derivatives have antiviral effects and can be used to further develop drugs with antiviral effects.

The above-mentioned technical problems to be solved by the present invention are realized through the following technical solutions:

A spiro[beta-lactam-3,3'-oxindole] derivative, which has the structure shown in formula I:

wherein R ¹ is selected from hydrogen, alkyl, alkoxy, halogen or ester;

R ² is selected from alkyl, alkenyl or benzyl;

^R is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring;

R ⁴ is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.

2. The spiro[beta-lactam-3,3'-oxindole] derivatives according to claim 1, characterized in that,

wherein R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or C ₂ -C ₆ ester;

R ² is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or benzyl;

R ³ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring;

R ⁴ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.

Preferably, R ¹ is selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen or C ₂ -C ₃ ester.

Preferably, R ² is selected from C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl.

Preferably, R ³ is selected from phenyl, substituted phenyl, furan ring or thiophene ring.

Preferably, ^R4 is selected from phenyl or substituted phenyl.

Preferably, the spiro[β-lactam-3,3'-oxindole] derivatives are selected from compounds having the following structures:

The present invention also provides a preparation method of the above spiro[beta-lactam-3,3'-oxindole] derivatives, which uses propargyl amides and nitrones as raw materials, and then adds a monovalent The copper salt catalyst, ligand and base are reacted in an inert gas atmosphere, and after the reaction is completed, the target product is separated to obtain the spiro[beta-lactam-3,3'-oxidole] derivatives.

The invention provides a brand-new preparation method of spiro[beta-lactam-3,3'-oxidole] derivatives; the method innovatively catalyzes the continuous synthesis of propargyl amides and nitrones by monovalent copper Kinugasa reaction/intramolecular carbon-carbon coupling reaction, one-step efficient construction of spiro[β-lactam-3,3'-oxindole] compounds. In this method, propargyl amides and nitrones are used as substrates, and monovalent copper salts are used as catalysts. These compounds have the advantages of easy availability of raw materials, cheap and easily available catalysts, simple synthesis conditions, few steps, high diastereoselectivity, high yield and wide application range of substrates, etc., and are suitable for mass production and application in the pharmaceutical and chemical industries.

Preferably, the propargyl amide compound has the structure shown in formula II; the nitrone compound has the structure shown in formula III;

Wherein, R ¹ in formula II is selected from hydrogen, alkyl, alkoxy, halogen or ester group, R ² is selected from alkyl, alkenyl or benzyl; R ³ in formula III is selected from alkyl, phenyl , substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring, R ⁴ is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.

Further preferably, R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or C ₂ -C ₆ ester;

R ² is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or benzyl;

R ³ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring;

R ⁴ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.

Even more preferably, R ¹ is selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen or C ₂ -C ₃ ester.

Even more preferably, R ² is selected from C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl.

Even more preferably, R ³ is selected from phenyl, substituted phenyl, furan ring or thiophene ring.

Even more preferably, R ⁴ is selected from phenyl or substituted phenyl.

Preferably, the monovalent copper catalyst is cuprous chloride, cuprous bromide, cuprous iodide, tetraacetonitrile copper hexafluorophosphate, tetraacetonitrile copper tetrafluoroborate, cuprous cyanide or copper trifluoromethanesulfonate .

Preferably, the ligand is an amine ligand; the amine ligand is N,N'-dimethyl-1,2-diphenyl-1,2-ethylenediamine, 2,2'- Bipyridine or 1,10-phenanthroline.

Most preferably, the monovalent copper catalyst is selected from cuprous iodide, while the amine ligand is selected from 2,2'-bipyridine.

Studies have shown that cuprous iodide complexed with 2,2'-bipyridine has the best catalytic activity.

Preferably, the base is K ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ , NaOH, KOH, CSOH, CsF or tBuOLi.

Most preferably, the base is tBuOLi.

Most preferably, the inert gas environment is nitrogen or argon.

The cyclization reaction of the present invention is carried out under an inert gas atmosphere, which provides an oxygen-free environment, reduces side reactions, and thus effectively increases the yield.

Preferably, the molar ratio of the nitrogen ligand to the propargyl amide compound is 0.1-0.2:1.

More preferably, the molar ratio of the amine ligand to the amide compound is 0.1:1.

Preferably, the amount of the monovalent copper catalyst is 5-10% of the molar amount of the propargyl amide compound.

More preferably, the amount of the monovalent copper catalyst is 10% of the molar amount of the propargyl amide compound.

Preferably, the molar ratio of the base to the propargyl amide compound is 1.5-4.5:1.

More preferably, the molar ratio of the base to the propargyl amide compound is 2:1.

Preferably, the molar ratio of the propargyl amide compound to the nitrone is 1-2:1.

Preferably, the solvent is acetonitrile.

Preferably, the reaction temperature is 15-30°C.

Most preferably, the preparation method of spiro[β-lactam-3,3'-oxidole] derivatives is as follows: propargyl amide compounds and nitrone compounds are dissolved in an organic solvent, and a monovalent copper catalyst, nitrogen The ligand and base were reacted under an inert gas atmosphere for 8 hours, and the spiro[β-lactam-3,3'-indole oxide] compound 3 was obtained by column chromatography.

The present invention also provides the application of the above spiro[beta-lactam-3,3'-oxindole] derivatives in the preparation of medicines with antiviral effect.

Preferably, the virus is herpes simplex virus.

Beneficial effects:

(1) The present invention provides a new structure of spiro[beta-lactam-3,3'-oxidole] derivatives, and studies have shown that the spiro[beta-lactam-3,3'-oxidation Indole] derivatives have a certain anti-herpes simplex disease effect.

(2) The inventor found in research that in the core structure of the spiro[β-lactam-3,3'-oxindole] derivatives described in the present invention, R ¹ , R ² , R ³ , The compounds obtained after R ⁴ is substituted by different groups have huge differences in the anti-herpes simplex effect; the compounds obtained after R ¹ is substituted by alkyl, alkoxy, ester or halogen have better anti-herpes simplex effects. Compared with the compound whose R ¹ is not substituted, its anti-herpes simplex virus effect is obviously improved. The inventor surprisingly found in further research that the compound obtained after the R ³ group is substituted by a heterocyclic group has a very excellent anti-herpes simplex virus effect; The anti-herpes simplex virus effect has been greatly improved. To sum up, the spiro[beta-lactam-3,3'-oxindole] derivatives of the present invention are used to develop medicines with anti-herpes simplex virus, and have broad application prospects.

(3) In addition, the present invention also provides a brand-new, efficient and concise preparation method of spiro[β-lactam-3,3'-oxidole] compounds; it uses relatively cheap and easily available monovalent copper as The catalyst reacts under mild conditions, with simple operation, few steps, good functional group compatibility, high yield and high diastereoselectivity; therefore, the method has good application prospects in the production of pharmaceutical industry.

Description of drawings

Figure 1 is a schematic diagram of the synthetic route of the spiro[beta-lactam-3,3'-oxindole] derivatives of the present invention.

Detailed ways

The present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

Preparation of Example 1 Compounds 1 and 2

The raw material compound 1 of the present invention is a reported compound, which is synthesized by the method reported in the reference (Yan, J. etal. Org. Lett. 2012, 14, 1262), and is prepared by the condensation reaction of an aromatic amine compound and propynoic acid. The specific synthesis method is as follows: 25 mL of dry dichloromethane and dicyclohexylcarbodiimide (DCC) (5 mmol) were added to the reaction flask containing the aromatic amine compound (5 mmol) and propargylic acid (5 mmol) in turn. . The above reaction solution was stirred at 25°C for 24 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product formula (I) (the yield was 74-80%), and the synthesis reaction formula was as follows:

The raw material compound 2 of the present invention is a reported compound, which is synthesized by the method reported in the reference (Biswas, P.K. et al. Synth. Commun. 2011, 41, 1146), and is prepared by reacting hydroxylamine compounds with aldehydes. The specific synthesis method is as follows: 25 mL of methanol was added to the reaction flask containing the hydroxylamine compound (5 mmol) and the aldehyde (5 mmol) in turn. The above-mentioned reaction solution was stirred at 25 ° C for 4 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product formula (I) (the yield was 85-95%), and the synthesis reaction formula was as follows:

The synthesis of embodiment 2 compound 3aa

The synthetic reaction formula of compound 3aa is shown below:

Under nitrogen atmosphere, 2 mL of propargyl amide 1a (59.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product 3aa (54 mg, yield 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (d, J=7.2 Hz, 1H), 7.41-7.29 (m, 10H), 7.15 (m, 2H), 6.84 (d, J=8.0 Hz, 1H) , 5.50(s, 1H), 3.04(s, 3H). ¹³ C NMR(100MHz, CDCl ₃ )δ168.6,161.3,144.4,136.8,131.7,129.9,129.1,129.0,128.2,127.6,124.6,124.1,123.2, 122.9,117.7,108.6,68.4,65.6,26.4.HRMS calcd for C ₂₃ H ₁₉ N ₂ O ₂ ⁺ (M+H) ⁺ 355.1442,found355.1444.

Example 3 Synthesis of compound 3ba

The synthetic reaction formula of compound 3ba is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1b (62.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3ba as a white solid product (56 mg, yield 73%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.47-7.30 (m, 11H), 7.14 (q, J=7.2Hz, 2H), 6.82 (d, J=7.6Hz, 1H), 5.70-5.58 (m, 1H), 5.51(s, 1H), 5.13-4.95(m, 2H), 4.31-4.21(m, 1H), 4.06-4.00(m, 1H). ¹³ C NMR(100MHz, CDCl ₃ )δ168.4,161.2, _{143.5,136.9,131.7,130.7,129.8,129.2,128.9,128.2,127.4,124.6,124.1,123.3,122.9,117.6,117.2,109.4,68.5,65.7,42.3.HRMS calcd} for C ₂₅ H ₂₁ ^N (M+H) ⁺ 381.1598, found 351.1600.

Example 4 Synthesis of compound 3ca

The synthetic reaction formula of compound 3ca is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3ca (61 mg, yield 71%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.48-7.41 (m, 3H), 7.39-7.32 (m, 7H), 7.27-7.20 (m, 5H), 7.17 (t, J=7.2Hz, 1H), 7.13-7.07(m,1H),6.96-6.90(m,2H),6.71(d,J=7.6Hz,1H),5.52(s,1H),4.97(d,J=15.6Hz,1H),4.45 (d, J=15.6 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 161.2, 143.4, 136.9, 135.2, 131.7, 129.8, 129.2, 129.0, 128.6, 128.2, 127.5, 127.4, 127.1, 124.6, 124.1, 123.4, 123.0, 117.7, 109.5, 68.7, 65.9, 43.7. HRMS calcd for C ₂₉ H ₂₃ N ₂ O ₂ ⁺ (M+H) ⁺ 431.1755, found 431.1754.

Example 5 Synthesis of compound 3cb

The synthetic reaction formula of compound 3cb is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2b (43.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product 3cb (65 mg, yield 72%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.40 (m, 3H), 7.38-7.33 (m, 4H), 7.29-7.22 (m, 4H), 7.20-7.15 (m, 1H), 7.13-7.01 (m,3H),6.99-6.96(m,2H),6.73(d,J=8.0Hz,1H),5.50(s,1H),4.95(d,J=15.6Hz,1H),4.49(d, J=15.6 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 163.0 (d, J=247.0 Hz), 161.0, 143.4, 136.7, 135.2, 129.9, 129.4 (d, J=9.0 Hz), 129.2 calc d for C ₂₉ H ₂₂ FN ₂ O ₂ ⁺ (M+H) ⁺ 449.1660, found449.1663.

Example 6 Synthesis of compound 3cc

The synthetic reaction formula of compound 3cc is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2c (43.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flask. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3cc (65 mg, 70% yield) of a white solid product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.26 (m, 10H), 7.24-7.21 (m, 3H), 7.19-7.15 (m, 1H), 7.13-7.06 (m, 1H), 7.00-6.95 (m,2H),6.74(d,J=8.0Hz,1H),5.47(s,1H),4.95(d,J=15.6Hz,1H),4.49(d,J=15.6Hz,1H). ¹³ C NMR (100MHz, CDCl ₃ )δ168.9,160.9,143.4,136.7,135.2,134.9,130.3,13.0,129.3,128.9,128.6,128.5,127.7,127.2,124.8,123.8,123.4,123.1,68.017 65.2, 43.8. HRMS calcd for C ₂₉ H ₂₂ ClN ₂ O ₂ ⁺ (M+H) ⁺ 465.1365, found 465.1360.

Example 7 Synthesis of compound 3cd

The synthetic reaction formula of compound 3cd is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2d (55.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3cd (74 mg, yield 73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J=8.4 Hz, 2H), 7.43-7.39 (m, 3H), 7.38-7.32 (m, 2H), 7.29-7.21 (m, 6H), 7.19-7.15(m, 1H), 7.11-7.07(m, 1H), 6.97-6.90(m, 2H), 6.74(d, J=7.8Hz, 1H), 5.45(s, 1H), 4.95(d, J=15.6Hz, 1H), 4.48 (d, J=15.6Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 168.9, 160.9, 143.4, 136.7, 135.2, 131.5, 130.8, 130.0, 129.3, 129.2, 128.7 ,127.7,127.2,124.8,123.7,123.4,123.2,123.1,117.6,109.5,68.7,65.3,43.8.HRMS calcd for C ₂₉ H ₂₂ BrN ₂ O ₂ ⁺ (M+H) ⁺ 509.0860,found 509.0865.

Example 8 Synthesis of compound 3ce

The synthetic reaction formula of compound 3ce is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2e (45.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product 3ce (61 mg, yield 66%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.01 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.48-7.33 (m, 5H) ,7.29-7.25(m,1H),7.22-7.16(m,4H),7.11(td,J=7.6,0.8Hz,1H),6.956-6.93(m,2H),6.75(d,J=7.8Hz , 1H), 5.58(s, 1H), 4.91(d, J=15.6Hz, 1H), 4.48(d, J=15.6Hz, 1H). ¹³ C NMR(100MHz, CDCl ₃ )δ191.6,168.7,160.7, 143.4,138.6,136.6,136.5,135.0,130.1,129.6,129.3,128.7,128.1,127.7,127.1,125.0,123.5,123.4,123.2,117.5,109.7,68.7,65.0,43.8 HRMS N calc for C d ₃ H d _{23.HRMS 2} O ₃ ⁺ (M+H) ⁺ 459.1704,found459.1700.

Example 9 Synthesis of compound 3cf

The synthetic reaction formula of compound 3cf is shown below:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2f (42.2 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3cf (64 mg, yield 72%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (t, J=7.6 Hz, 3H), 7.35 (t, J=8.0 Hz, 2H), 7.28 (s, 1H), 7.26-7.13 (m, 8H) ,7.09(t,J＝7.6Hz,1H),6.98-6.95(m,2H),6.71(d,J＝7.8Hz,1H),5.50(s,1H),4.96(d,J＝15.6Hz, 1H), 4.49(d, J=15.6Hz, 1H), 2.37(s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 161.2, 143.4, 138.8, 137.0, 135.3, 129.7, 129.1, 128.2, 128.6 ,128.5,127.5,127.4,127.1,124.6,124.2,123.3,122.9,117.7,109.4,68.8,66.0,43.7,21.3.HRMS calcd for C ₃₀ H ₂₅ N ₂ O ₂ ⁺ (M+H) ⁺ 445.1911,found 445.1908.

Example 10 Synthesis of compound 3cg

The synthetic reaction formula of compound 3cg is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2 g (45.4 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flasks in sequence. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3 cg (68 mg, 74% yield) of a white solid product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.40 (m, 3H), 7.38-7.29 (m, 4H), 7.26-7.19 (m, 4H), 7.17-7.13 (m, 1H), 7.10 (td ,J=7.6,0.8Hz,1H),6.97-6.95(m,2H),6.89(d,J=8.8Hz,2H),6.70(d,J=8.0Hz,1H),5.47(s,1H) , 4.97 (d, J=15.6Hz, 1H), 4.48 (d, J=15.6Hz, 1H), 3.80 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 161.3, 160.1, 143.4, 137.0 _{, 135.3,129.7,129.1,128.9,128.61,127.5,127.1,124.6,124.2,123.4,123.3,123.0,117.7,113.6,109.4,68.9,65.9,55.2,43.7.HRMS _ _} ⁺ (M+H) ⁺ 461.1860,found 461.1862.

Example 11 Synthesis of compound 3ch

The synthetic reaction formula of compound 3ch is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2h (54.8 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flask in turn. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3ch (80 mg, 78% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.51 (m, 2H), 7.47-7.43 (m, 3H), 7.40-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.30-7.17 (m, 6H), 7.15-7.07(m, 3H), 6.72(d, J=8.0Hz, 1H), 5.83(s, 1H), 4.98(d, J=15.6Hz, 1H), 4.57(d, J=15.6Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.6, 161.2, 143.5, 136.7, 135.1, 132.5, 132.1, 130.3, 130.0, 129.6, 129.3, 128.5, 127.5, 127.2, 126.9, 124.78, ,123.0,123.9,121.9,117.6,109.5,68.1,64.2,43.9.HRMScalcd for C ₂₉ H ₂₂ BrN ₂ O ₂ ⁺ (M+H) ⁺ 509.0860,found 509.0863.

Example 12 Synthesis of compound 3ci

The synthetic reaction formula of compound 3ci is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2i (44.6 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3ci (68 mg, yield 74%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J=8.4, 1.0 Hz, 2H), 7.47-7.45 (m, 2H), 7.39-7.30 (m, 6H), 7.24-6.98 (m, 9H) ),6.84(d,J＝16.0Hz,1H),6.72(d,J＝8.0Hz,1H),5.08(d,J＝15.6Hz,1H),5.00(d,J＝9.2Hz,1H), 4.70(d, J=15.6Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.2, 160.6, 143.5, 137.6, 136.9, 135.5, 135.1, 129.8, 129.2, 128.7, 127.6, 127.1, 127.0, 124.7, 1238. ,123.8,123.4,123.1,117.4,109.5,69.2,64.4,43.9.HRMS calcd for C ₃₁ H ₂₅ N ₂ O ₂ ⁺ (M+H) ⁺ 457.1911,found 457.1910.

Example 13 Synthesis of compound 3cj

The synthetic reaction formula of compound 3cj is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2j (52.8 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product 3cj (72 mg, yield 72%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (d, J=8.0 Hz, 2H), 7.40-7.31 (m, 5H), 7.27-7.15 (m, 5H), 7.10 (t, J=7.6 Hz, 1H), 6.73(d, J＝7.6Hz, 1H), 6.59(d, J＝3.2Hz, 1H), 6.34(d, J＝3.2Hz, 1H), 5.49(s, 1H), 5.10(d, J=15.6Hz, 1H), 4.62 (d, J=15.6Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 168.5, 160.5, 147.7, 143.4, 136.2, 135.0, 130.1, 129.3, 128.9, 127.7, 127.0 ,125.0,123.3,123.2,123.1,122.3,117.6,114.3,112.9,109.8,68.0,58.7,43.9.HRMScalcd for C ₂₇ H ₂₀ BrN ₂ O ₃ ⁺ (M+H) ⁺ 499.0654,found 499.0650.

Example 14 Synthesis of compound 3ck

The synthetic reaction formula of compound 3ck is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2k (40.6 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flasks in sequence, respectively. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3ck (65.4 mg, yield 75%) as a white solid product.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.48-7.45 (m, 2H), 7.41-7.32 (m, 4H), 7.29-7.21 (m, 6H), 7.17 (t, J=7.6Hz, 1H), 7.12-7.01(m, 4H), 6.72(d, J=8.0Hz, 1H), 5.71(s, 1H), 5.00(d, J=15.6Hz, 1H), 4.58(d, J=15.6Hz, 1H) ). ¹³ C NMR(100MHz, CDCl ₃ )δ168.7,160.8,143.4,136.5,135.1,133.7,129.9,129.1,128.6,128.5,127.5,127.2,127.1,126.4,124.8,123.7,123.3,109.6. ,69.1,61.8,43.8.HRMS calcd for C ₂₇ H ₂₁ N ₂ O ₂ S ⁺ (M+H) ⁺ 437.1319,found 437.1316.

Example 15 Synthesis of compound 3cl

The synthetic reaction formula of compound 3cl is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2l (46.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flasks in sequence, respectively. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3cl (73 mg, yield 78%) as a white solid product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (d, J=7.2 Hz, 1H), 7.42-7.17 (m, 13H), 7.10 (t, J=7.6 Hz, 1H), 6.95-6.92 (m, 2H), 6.71(d, J=7.6Hz, 1H), 5.50(s, 1H), 4.96(d, J=15.6Hz, 1H), 4.44(d, J=15.6Hz, 1H). ¹³ C NMR( 100MHz, CDCl ₃ )δ168.8,161.1,143.4,135.4,135.1,131.2,129.9,129.8,129.3,129.1,128.6,128.3,127.5,127.4,127.1,123.8,123.4,123.0,3.09,6.9 .HRMS calcd for C ₂₉ H ₂₁ ClN ₂ O ₂ ⁺ (M+H) ⁺ 465.1365, found 465.1361.

Example 16 Synthesis of compound 3cm

The synthetic reaction formula of compound 3cm is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1c (72.0 mg, 0.2 mmol), nitrone 2m (45.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flasks in sequence. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain a white solid product 3cm (68 mg, yield 74%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (d, J=6.8 Hz, 1H), 7.42-7.33 (m, 7H), 7.27-7.17 (m, 4H), 7.11-1.07 (m, 1H), 6.96-6.93(m, 2H), 6.91-6.85(m, 2H), 6.70(d, J=7.6Hz, 1H), 5.49(s, 1H), 4.96(d, J=15.6Hz, 1H), 4.45 (d, J=15.6 Hz, 1H), 3.79 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.1, 160.6, 156.5, 143.4, 135.2, 131.8, 130.4, 129.7, 128.9, 128.6, 128.2, 127.5 ,127.1,124.1,123.4,123.0,119.0,114.4,109.4,68.7,65.9,55.4,43.6.HRMScalcd for C ₃₀ H ₂₅ N ₂ O ₃ ⁺ (M+H) ⁺ 461.1860,found 461.1858.

Example 17 Synthesis of compound 3da

The synthetic reaction formula of compound 3da is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1d (87.6 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flask Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3da (73 mg, yield 72%) as a white solid product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=1.2 Hz, 1H), 7.44-7.33 (m, 10H), 7.25-7.14 (m, 4H), 6.98-6.87 (m, 2H), 6.58 (d, J=8.4Hz, 1H), 5.51 (s, 1H), 4.94 (d, J=15.6Hz, 1H), 4.44 (d, J=15.6Hz, 1H). ¹³ C NMR (100MHz, CDCl) ₃ ) δ168.4, 160.3, 142.4, 136.7, 134.7, 132.6, 131.3, 129.2, 129.1, 128.7, 127.7, 127.5, 127.1, 126.6, 126.0, 124.9, 117.7, 115.6, 110.9, 68.5, 65 29H ₂₂ BrN ₂ O ₂ ⁺ (M+H) ⁺ _509.0860 , found 509.0862.

Example 18 Synthesis of compound 3ea

The synthetic reaction formula of compound 3ea is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1e (84.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flask. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3ea (74 mg, yield 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=1.2 Hz, 1H), 7.44-7.33 (m, 10H), 7.25-7.14 (m, 4H), 6.98-6.87 (m, 2H), 6.58 (d, J=8.4Hz, 1H), 5.51 (s, 1H), 4.94 (d, J=15.6Hz, 1H), 4.44 (d, J=15.6Hz, 1H). ¹³ C NMR (100MHz, CDCl) ₃ ) δ168.4, 160.3, 142.4, 136.7, 134.7, 132.6, 131.3, 129.2, 129.1, 128.7, 127.7, 127.5, 127.1, 126.6, 126.0, 124.9, 117.7, 115.6, 110.9, 68.5, 65 29H ₂₂ BrN ₂ O ₂ ⁺ (M+H) ⁺ _509.0860 , found 509.0862.

Example 19 Synthesis of compound 3fa

The synthetic reaction formula of compound 3fa is as follows:

Under nitrogen atmosphere, 2 mL of propargyl amide 1f (78.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were sequentially added to the reaction flasks. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25° C. for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain the white solid product 3fa (69 mg, yield 78%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (d, J=7.6 Hz, 2H), 7.40-7.31 (m, 7H), 7.25-7.14 (m, 4H), 7.05 (d, J=2.4 Hz, 1H), 6.95-6.93(m, 2H), 6.77(dd, J=8.4, 2.4Hz, 1H), 6.60(d, J=8.4Hz, 1H), 5.51(s, 1H), 4.94(d, J =15.6Hz,1H),4.42(d,J=15.6Hz,1H),3.77(s,3H). 13CNMR(100MHz, _CDCl3 ) ^{δ168.7,161.1,156.3,136.9,136.8,135.3,131.7,129.2} , 129.0,128.6,128.2,127.4,127.1,125.1,124.6,117.7,114.5,110.4,110.0,69.1,66.0,55.9,43.7.HRMS calcd for C ₃₀ H ₂₅ N ₂ O ₃ ⁺ (M+H) ⁺ 461.1860, found 461.1857.

Example 20 Synthesis of compound 3ga

The synthetic reaction formula of compound 3ga is as follows:

Under a nitrogen atmosphere, 2 mL of propargyl amide 1 g (65.0 mg, 0.2 mmol), nitrone 2a (40.0 mg, 0.2 mmol) and cuprous iodide (3.8 mg, 0.02 mmol) were added to the reaction flasks in sequence. Dry acetonitrile, lithium tert-butoxide (34 mg, 0.4 mmol) and 2,2'-bipyridine (3.1 mg, 0.02 mmol). The above reaction solution was stirred at 25°C for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain 3ga (60 mg, yield 68%) as a white solid product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (dd, J=8.4, 0.8 Hz, 2H), 7.39-7.32 (m, 7H), 7.21-7.12 (m, 5H), 6.92-6.85 (m, 3H) ), 6.55(d, J＝8.0Hz, 1H), 5.66(s, 1H), 5.01(d, J＝15.6Hz, 1H), 4.30(d, J＝15.6Hz, 1H), 2.36(s, 3H ). ¹³ C NMR (100MHz, CDCl ₃ )δ169.1,160.9,143.7,137.1,135.4,134.9,131.8,129.7,129.3,128.8,128.5,128.2,127.6,127.4,127.1,125.0,124.7,127.7. ,69.2,62.5,43.6,17.9.HRMS calcd for C ₃₀ H ₂₅ N ₂ O ₂ ⁺ (M+H) ⁺ 445.1911,found 445.1910.

Experimental Example 1 Antiviral activity test of the spiro[β-lactam-3,3'-oxidole] derivatives of the present invention

Take MDCK cells and put them into a 96-well cell culture plate. After the cells are covered with a monolayer, wash them with Eagle's solution; after washing, discard the supernatant, and then add 80 μL of 100 TCID ₅₀ I to each well of the 96-well cell culture plate. type herpes simplex virus solution (SM44 virus strain), and then add 80 μL of the compound to be tested double-diluted in MEM to each well _; and incubated for 48h under saturated humidity; after the incubation, discard the old solution in the 96-well plate, and then add 10 μL of CCK8 solution to each well; continue to incubate for 1h, and then use a microplate reader to test the absorbance at 450nm; and calculate the IC ₅₀ value ; The experiment set a virus control group and a cell control group at the same time; the test results are shown in Table 1.

Taking the drug concentration as the X-axis and the cell viability on the Y-axis, plotting in Origin, the drug concentration corresponding to 50% cell viability is obtained as IC ₅₀ ;

Cell survival rate=(OD value of drug addition hole-OD value of virus control group)/(OD value of cell control group-OD value of virus control group)×100%.

Table 1. Antiviral activity of spiro[β-lactam-3,3'-oxindole] derivatives

It can be seen from the experimental data in Table 1 that the spiro[beta-lactam-3,3'-oxidole] derivatives prepared in Examples 2 to 20 of the present invention all show anti-herpes simplex disease activity; it illustrates the present invention The spiro[beta-lactam-3,3'-oxindole] derivatives have a certain anti-herpes simplex effect.

In addition, it can also be seen from the experimental data in Table 1 that in the core structure of the spiro[β-lactam-3,3'-oxindole] derivatives according to the present invention, R ¹ , R ² , R ^3. The compound obtained after R ⁴ is substituted by different groups, the difference of its anti-herpes simplex effect is huge; wherein R ¹ is substituted by an alkyl group, an alkoxy group, an ester group or a halogen. The IC50 values of the compounds of 20 are all less than 10 μM, and have a good anti-herpes simplex virus effect; compared with the compounds prepared in Example 4 with unsubstituted R ¹ , their IC50 values have been significantly reduced. This shows that: in the core structure of the spiro[β-lactam-3,3'-oxindole] derivatives of the present invention, after R ¹ is substituted by an alkyl group, an alkoxy group, an ester group or a halogen The obtained compound has significantly improved anti-herpes simplex virus effect compared to the compound with unsubstituted R ¹ .

In addition, it can also be seen from the experimental data in Table 1 that R ³ prepared in Examples 13 and 14 is a compound substituted by a heterocyclyl group, and its IC50 values are all less than 1 μM, which is greatly lower than that of other compounds, and has very excellent Anti-herpes simplex virus effect. This shows that: in the core structure of the spiro[β-lactam-3,3'-oxindole] derivatives according to the present invention, the compound obtained after the R ³ group is substituted by a heterocyclic group is more The compound obtained after being substituted by other groups has greatly improved anti-herpes simplex virus effect, and has very excellent anti-herpes simplex virus effect. Especially when the R ³ group was substituted by a thiophene ring, the IC50 value of the compound reached 0.27 μM, which has the best anti-herpes simplex virus effect.

Claims (10)

1. A spiro[β-lactam-3,3'-oxidole] derivatives, characterized in that it has the structure shown in formula I:

wherein R ¹ is selected from hydrogen, alkyl, alkoxy, halogen or ester; R ² is selected from alkyl, alkenyl or benzyl; ^R is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring; R ⁴ is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring. 2. The spiro[beta-lactam-3,3'-oxindole] derivatives according to claim 1, characterized in that, R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen or C ₂ -C ₆ ester; R ² is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or benzyl; R ³ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring; R ⁴ is selected from C ₁ -C ₆ alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring. 3. The spiro[beta-lactam-3,3'-oxidole] derivatives according to claim 1, wherein R ¹ is selected from hydrogen, C ₁ -C ₃ alkyl, C ₁ - _C3alkoxy , halogen or C2 _{- C3ester} . 4. The spiro[β-lactam-3,3'-oxindole] derivatives according to claim 1, wherein R ² is selected from C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl. 5. The spiro[beta-lactam-3,3'-oxindole] derivative according to claim 1, wherein R ³ is selected from phenyl, substituted phenyl, furan ring or thiophene ring. 6. The spiro[beta-lactam-3,3'-oxindole] derivative according to claim 1, wherein R ⁴ is selected from phenyl or substituted phenyl. 7. The method for preparing spiro[beta-lactam-3,3'-oxindole] derivatives according to any one of claims 1 to 6, characterized in that: Using propargyl amide compounds and nitrone compounds as raw materials, then adding a monovalent copper salt catalyst, a ligand and a base, the reaction is carried out under an inert gas atmosphere, and after the reaction is completed, the target product is separated to obtain the spiro[β- Lactam-3,3'-oxindole] derivatives. 8. preparation method according to claim 8 is characterized in that, propargyl amide compounds have the structure shown in formula II; nitrones compounds have the structure shown in formula III;

Wherein, R ¹ in formula II is selected from hydrogen, alkyl, alkoxy, halogen or ester group, R ² is selected from alkyl, alkenyl or benzyl; R ³ in formula III is selected from alkyl, phenyl , substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring, R ⁴ is selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring. 9. Use of the spiro[beta-lactam-3,3'-oxindole] derivatives according to any one of claims 1 to 6 in the preparation of a medicament with antiviral effect. 10. application according to claim 9, is characterized in that, described virus is herpes simplex virus.

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