A stilbene derivative of guaiacylamine and its preparation method and application

Abstract

The present invention provides a stilbene derivative of guaiazulene, which belongs to the technical field of medicinal chemistry. The present invention combines guaiazulene with a stilbene skeleton for pharmacophore combination to synthesize stilbene derivatives of guaiazulene. This structure contains guaiazulene functional units and stilbene skeleton functional units, which can give such compounds a wide range of anti-tumor and anti-influenza virus activities, laying the foundation for the development of stilbene derivatives of guaiazulene as anti-tumor and anti-influenza virus candidate drugs. The results of the examples show that the stilbene derivatives of guaiazulene provided by the present invention have certain inhibitory activity on human chronic myeloid leukemia cells K562, human breast cancer cells MDA-MB-231, and human pancreatic cancer cells ASPC-1; the stilbene derivatives of guaiazulene provided by the present invention have certain inhibitory activity on H1N1 virus, which is the first time that a compound with antiviral activity has been found from guaiazulene derivatives, broadening the direction of antiviral drug development.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a stilbene derivative of guaiacylamine, a preparation method thereof, and an application thereof. Background Art

[0002] Guaiazulene and its derivatives possess diverse biological activities and are promising candidates for low-toxicity drug scaffolds. Guaiazulene is widely found in terrestrial Asteraceae plants and marine gorgonians, serving as their primary active compound and a key source of candidate anti-tumor lead molecules. Liu Xiaoling et al. isolated a novel guaiacyl alkaloid backbone molecule, muriceidines A, from the gorgonian Muriceides collaris, originating from the South China Sea. Muriceidines A demonstrated pharmacological activity against human myeloid leukemia K562 cells at a half-maximal inhibitory concentration of 8.4 μM (Sci Rep, 2017, 7697). Wu Yu et al. further tested the activity of muriceidines A derivatives, identifying guaiacyl derivatives with enhanced inhibitory activity against human triple-negative breast cancer cells MDA-MB-231 (Antioxidants 2022, 11, 834). Despite the diverse medicinal potential of guaiacylene derivatives, their anti-infective properties have not been reported. Summary of the Invention

[0003] In view of this, the object of the present invention is to provide a stilbene derivative of guaiaczulene and a preparation method and application thereof. The stilbene derivative of guaiaczulene provided by the present invention has good anti-tumor and anti-infection pharmacological activities.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides a stilbene derivative of guaiazulene having a structure shown in Formula I or Formula II:

[0006]

[0007] In Formula I and Formula II, Ar is an aromatic group;

[0008] In formula II, R is aldehyde, hydrogen, acetyl, substituted acyl,

[0009] The substituted acetyl group is a chloroacetyl group, a nitrile acetyl group, a benzoyl group or a benzofuranacetyl group.

[0010] Preferably, the aromatic group is benzene, 2-methylbenzene, 3-methylbenzene, 4-methylbenzene, 3,5-dimethylbenzene, 4-ethylbenzene, 4-isopropylbenzene, 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5-trimethoxybenzene, Anisyl, 4-dimethylaminobenzene, 2-nitrobenzene, 4-nitrobenzene, 4-methylmercaptobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2,4-dichlorobenzene, 4-trifluoromethylbenzene, 2,6-dichlorobenzene, 2,6-difluorobenzene, 2-fluoro-6-chlorobenzene, naphthalene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3-indolyl, 2-furan, 2-thiophene, or 3-guaiazulene.

[0011] The present invention provides a method for preparing the stilbene derivatives of the above-mentioned guaiazulene, comprising the following steps:

[0012] (1) When the stilbene derivative of guaiacylamine has a structure shown in Formula I, the preparation method comprises the following steps:

[0013] Under the action of phosphorus oxychloride, guaiazulene and N,N-dimethylformamide undergo a formylation reaction to obtain guaiazulene aldehyde having a structure represented by Formula Ia;

[0014]

[0015] Guaiazulene aldehyde having a structure represented by Formula Ia is subjected to a reduction reaction with a reducing agent to obtain guaiazulenol having a structure represented by Formula Ib;

[0016]

[0017] Guaiazulene methanol having a structure represented by Formula Ib undergoes a substitution reaction with triphenylphosphine hydrobromide to obtain guaiazulene triphenylphosphine bromide having a structure represented by Formula Ic;

[0018]

[0019] Under the action of sodium ethoxide, a compound having a structure represented by Formula Ic undergoes a Wittig reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure represented by Formula I;

[0020] (2) When the stilbene derivative of guaiacylamine has a structure shown in Formula II, the preparation method comprises the following steps:

[0021] ① When R is an aldehyde group, under the catalysis of piperidine and acetic acid, guaiazulene aldehyde having a structure represented by Formula Ia undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure represented by Formula II-a;

[0022]

[0023] ② When R is hydrogen, guaiazulene undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure under the catalysis of potassium tert-butoxide to obtain a stilbene derivative of guaiazulene having a structure shown in Formula II-b;

[0024]

[0025] ③ When R is an acetyl group or a substituted acetyl group, a stilbene derivative of guaiazulene having a structure shown in formula II-b is subjected to a substitution reaction with an acetyl chloride compound under the catalysis of aluminum chloride to obtain a stilbene derivative of guaiazulene having a structure shown in formula II-c; the acetyl chloride compound is acetyl chloride, nitrile acetyl chloride, chloroacetyl chloride, benzoyl chloride or benzofuranacetyl chloride;

[0026] In formula II-c, R' is H, -CN, Cl,

[0027] ④When R is When, under the action of sodium triacetoxyborohydride, the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes a reductive amination reaction with amine to obtain R A stilbene derivative of guaiazulene; the amine is piperidine or pyrrolidine;

[0028] ⑤When R is When, under piperidine catalysis, the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes condensation reaction with an active methylene compound to obtain R The active methylene group is malononitrile, dimethyl malonate or diethyl malonate.

[0029] Preferably, in (1), the molar ratio of phosphorus oxychloride to guaiacylamine is 2 to 10:1; the temperature of the formylation reaction is -5 to 5°C, and the time is 1 to 2 hours;

[0030] The molar ratio of the reducing agent to guaiazulene aldehyde is 1 to 3:1; the temperature of the reduction reaction is room temperature, and the time is 1 to 2 hours.

[0031] Preferably, in (1), the molar ratio of triphenylphosphine hydrobromide to guaiazulene methanol is 1 to 3:1, the temperature of the substitution reaction is 50 to 70° C., and the time is 3 to 7 hours;

[0032] The molar ratio of the guaiazulene triphenylphosphine bromide to the aromatic aldehyde having the ArCHO structure is 1:0.33-1.5, and the molar ratio of the guaiazulene triphenylphosphine bromide to sodium ethoxide is 1:1-3; the temperature of the Wittig reaction is room temperature, and the time is 5-12 hours.

[0033] Preferably, in (2), when R is an aldehyde group, the molar ratio of the guaiazulene aldehyde to the aromatic aldehyde having the ArCHO structure is 1 to 3:1; the temperature of the condensation reaction is 50 to 80° C., and the time is 10 to 30 hours;

[0034] When R is hydrogen, the molar ratio of the guaiacylamine to the aromatic aldehyde having the ArCHO structure is 1 to 3:1; the temperature of the condensation reaction is 90 to 120° C., and the time is 1 to 3 hours.

[0035] Preferably, in (2), when R is an acetyl group or a substituted acetyl group, the molar ratio of the stilbene derivative of guaiazulene having the structure shown in formula II-b to the acetyl chloride compound is 1:1-3; the temperature of the substitution reaction is room temperature, and the time is 10-20 hours;

[0036] When R is When the molar ratio of the stilbene derivative of guaiazulene having the structure shown in formula II-a to the amine is 2:1 to 1:2; the temperature of the reductive amination reaction is room temperature, and the time is 1 to 3 hours.

[0037] When R is When the molar ratio of the stilbene derivative of guaiacylamine having the structure shown in formula II-a to the active methylene compound is 3:1 to 1:3; the temperature of the condensation reaction is 50 to 80°C, and the time is 1 to 3 hours.

[0038] The present invention provides the use of the stilbene derivatives of guaiazulene in the preparation of anti-tumor and / or antiviral drugs.

[0039] Preferably, the anti-tumor drug is one or more of an anti-human myeloid leukemia drug, an anti-triple-negative breast cancer drug, and an anti-pancreatic cancer drug;

[0040] The antiviral drug is an anti-influenza virus drug.

[0041] The present invention provides a stilbene derivative of guaiazulene having a structure shown in Formula I or Formula II. The diphenylethylene derivative has a wide range of biological activities and has good application effects in the fields of anti-tumor, anti-virus, and anti-inflammatory. The present invention combines guaiazulene with a diphenylethylene skeleton to form a pharmacophore to synthesize a stilbene derivative of guaiazulene. This structure contains a guaiazulene functional unit and a diphenylethylene skeleton functional unit, which can endow the compound with a wide range of anti-tumor and anti-influenza virus activities, laying the foundation for the development of stilbene derivatives of guaiazulene as candidate anti-tumor and anti-influenza virus drugs. The results of the examples show that the stilbene derivatives of guaiaczulene provided by the present invention have certain inhibitory activity against human chronic myeloid leukemia cells K562, human breast cancer cells MDA-MB-231, and human pancreatic cancer cells ASPC-1; the stilbene derivatives of guaiaczulene provided by the present invention have certain inhibitory activity against the H1N1 virus, which is the first time that compounds with antiviral activity have been discovered from guaiaczulene derivatives, broadening the direction of antiviral drug development. DETAILED DESCRIPTION

[0042] The present invention provides a stilbene derivative of guaiazulene having a structure shown in Formula I or Formula II:

[0043]

[0044] In Formula I and Formula II, Ar is an aromatic group;

[0045] In formula II, R is aldehyde, hydrogen, acetyl, substituted acyl,

[0046] The substituted acetyl group is a chloroacetyl group, a nitrile acetyl group, a furanbenzoyl group or a benzofuranacetyl group.

[0047] In the present invention, the aromatic group is preferably benzene, 2-methylbenzene, 3-methylbenzene, 4-methylbenzene, 3,5-dimethylbenzene, 4-ethylbenzene, 4-isopropylbenzene, 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5 -trimethoxybenzene, 4-dimethylaminobenzene, 2-nitrobenzene, 4-nitrobenzene, 4-methylmercaptobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2,4-dichlorobenzene, 4-trifluoromethylbenzene, 2,6-dichlorobenzene, 2,6-difluorobenzene, 2-fluoro-6-chlorobenzene, naphthalene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3-indolyl, 2-furan, 2-thiophene or 3-guaiazulene.

[0048] In the present invention, the stilbene derivative of guaiazulene preferably has a structure represented by any one of formulas I-1 to I-18 or a structure represented by any one of formulas II-1 to II-75:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] The present invention provides a method for preparing the stilbene derivatives of the above-mentioned guaiazulene, comprising the following steps:

[0056] (1) When the stilbene derivative of guaiacylamine has a structure shown in Formula I, the preparation method comprises the following steps:

[0057] Under the action of phosphorus oxychloride, guaiazulene and N,N-dimethylformamide undergo a formylation reaction to obtain guaiazulene aldehyde having a structure represented by Formula Ia;

[0058]

[0059] Guaiazulene aldehyde having a structure represented by Formula Ia is subjected to a reduction reaction with a reducing agent to obtain guaiazulenol having a structure represented by Formula Ib;

[0060]

[0061] Guaiazulene methanol having a structure represented by Formula Ib undergoes a substitution reaction with triphenylphosphine hydrobromide to obtain guaiazulene triphenylphosphine bromide having a structure represented by Formula Ic;

[0062]

[0063] Under the action of sodium ethoxide, a compound having a structure shown in Formula Ic undergoes a Wittig reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure shown in Formula I.

[0064] In the present invention, guaiazulene and N,N-dimethylformamide undergo a formylation reaction in the presence of phosphorus oxychloride to produce guaiazulene aldehyde having the structure represented by Formula Ia. In the present invention, the N,N-dimethylformamide serves as both a reaction raw material and a reaction solvent. The molar ratio of phosphorus oxychloride to guaiazulene is preferably 2 to 10:1, more preferably 5 to 8:1. The formylation reaction is preferably carried out at a temperature of -5 to 5°C, more preferably -2 to 2°C, and for a time of 1 to 2 hours, more preferably 1.5 hours.

[0065] In the present invention, guaiazulene aldehyde having a structure represented by formula Ia is subjected to a reduction reaction with a reducing agent to obtain guaiazulene methanol having a structure represented by formula Ib. In the present invention, the reducing agent is preferably sodium borohydride; the molar ratio of the reducing agent to guaiazulene aldehyde is preferably 1 to 3:1, more preferably 2:1.

[0066] In the present invention, the solvent used in the reduction reaction is preferably ethanol. In the present invention, the temperature of the reduction reaction is preferably room temperature, and the time is preferably 1 to 2 hours, more preferably 1.5 hours.

[0067] In the present invention, guaiazulene methanol having a structure represented by Formula Ib undergoes a substitution reaction with triphenylphosphine hydrobromide to obtain guaiazulene triphenylphosphine bromide having a structure represented by Formula Ic. In the present invention, the molar ratio of triphenylphosphine hydrobromide to guaiazulene methanol is preferably 1 to 3:1, more preferably 2:1.

[0068] In the present invention, the organic solvent used in the substitution reaction is preferably chloroform; the temperature of the substitution reaction is preferably 50-70° C., more preferably 60° C.; and the time is preferably 3-7 h, more preferably 4-6 h.

[0069] In the present invention, a compound having a structure represented by Formula Ic and an aromatic aldehyde having an ArCHO structure undergo a Wittig reaction in the presence of sodium ethoxide to obtain a stilbene derivative of guaiazulene having a structure represented by Formula I. In the present invention, the molar ratio of the guaiazulene triphenylphosphine bromide to the aromatic aldehyde having an ArCHO structure is preferably 3:1 to 1:1.5, and the molar ratio of the guaiazulene triphenylphosphine bromide to sodium ethoxide is preferably 1:1 to 3, more preferably 1:2.

[0070] In the present invention, the organic solvent used in the Wittig reaction is preferably ethanol; in the present invention, the temperature of the Wittig reaction is preferably room temperature, and the reaction time is preferably 5 to 12 hours, more preferably 6 to 10 hours.

[0071] In the present invention, when the stilbene derivatives of guaiaczulene have a structure shown in Formula I, Ar is preferably benzene, 4-ethylbenzene, 4-isopropylbenzene, 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 3,4,5-trimethoxybenzene, 2-nitrobenzene, 4-nitrobenzene, 4-methylmercaptobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2,4-dichlorobenzene, 4-trifluoromethylbenzene, 2-pyridyl, 2-furan or 2-thiophene. In the present invention, the synthetic route of the stilbene derivatives of guaiaczulene having a structure shown in Formula I is shown in Formula A:

[0072]

[0073] (2) When the stilbene derivative of guaiacylamine has a structure shown in Formula II, the preparation method comprises the following steps:

[0074] ① When R is an aldehyde group, under the catalysis of piperidine and acetic acid, guaiazulene aldehyde having a structure represented by Formula Ia undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure represented by Formula II-a;

[0075]

[0076] ② When R is hydrogen, guaiazulene undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure under the catalysis of potassium tert-butoxide to obtain a stilbene derivative of guaiazulene having a structure shown in Formula II-b;

[0077]

[0078] ③ When R is an acetyl group or a substituted acetyl group, a stilbene derivative of guaiazulene having a structure shown in formula II-b is subjected to a substitution reaction with an acetyl chloride compound under the catalysis of aluminum chloride to obtain a stilbene derivative of guaiazulene having a structure shown in formula II-c; the acetyl chloride compound is acetyl chloride, nitrile acetyl chloride, chloroacetyl chloride, benzoyl chloride or benzofuranacetyl chloride;

[0079] In formula II-c, R' is H, -CN, Cl,

[0080] ④When R is When the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes an aldehyde-amine condensation reaction with a reducing amine to obtain R The stilbene derivatives of guaiazulene; the reducing amine is piperidine or pyrrolidine;

[0081] ⑤When R is When, under piperidine catalysis, the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes condensation reaction with an active methylene compound to obtain R The active methylene group is malononitrile, dimethyl malonate or diethyl malonate.

[0082] In the present invention, when R is an aldehyde group, guaiazulene aldehyde having the structure represented by Formula Ia undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure under the catalysis of piperidine and acetic acid to obtain a stilbene derivative of guaiazulene having the structure represented by Formula II-a. In the present invention, the molar ratio of piperidine to acetic acid is preferably 3:1 to 1:3, more preferably 1:1; the molar ratio of the total molar amount of piperidine and acetic acid to guaiazulene aldehyde is 1:5 to 20, more preferably 1:10 to 15. In the present invention, the molar ratio of guaiazulene aldehyde to the aromatic aldehyde having an ArCHO structure is preferably 1 to 3:1, more preferably 2:1.

[0083] In the present invention, the organic solvent used in the condensation reaction is preferably toluene. In the present invention, the temperature of the condensation reaction is preferably 50 to 80°C, more preferably 60 to 70°C; and the time is preferably 10 to 30 hours, more preferably 15 to 25 hours.

[0084] In the present invention, when R is an aldehyde group, Ar is preferably benzene, 2-methylbenzene, 3-methylbenzene, 4-methylbenzene, 3,5-dimethylbenzene, 4-ethylbenzene, 4-isopropylbenzene, 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4, 5-trimethoxybenzene, 4-dimethylaminobenzene, 2-nitrobenzene, 4-nitrobenzene, 4-methylmercaptobenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2,4-dichlorobenzene, 4-trifluoromethylbenzene, 2,6-dichlorobenzene, 2,6-difluorobenzene, 2-fluoro-6-chlorobenzene, naphthalene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3-indolyl, 2-furan, 2-thiophene or 3-guaiazulene. In the present invention, the synthetic route of the stilbene derivative of guaiazulene having the structure shown in Formula II-a is as shown in Formula B:

[0085]

[0086] In the present invention, when R is hydrogen, guaiazulene undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure under the catalysis of potassium tert-butoxide to obtain a stilbene derivative of guaiazulene having the structure represented by Formula II-b. In the present invention, the molar ratio of guaiazulene to the aromatic aldehyde having an ArCHO structure is preferably 1 to 3:1, more preferably 2:1; and the molar ratio of potassium tert-butoxide to guaiazulene is preferably 1:2 to 5, more preferably 1:3 to 4.

[0087] In the present invention, the organic solvent used in the condensation reaction is preferably tert-amyl alcohol. In the present invention, the temperature of the condensation reaction is preferably 90-120° C., more preferably 100-110° C.; the time of the condensation reaction is preferably 1-3 hours, more preferably 2 hours.

[0088] In the present invention, when R is hydrogen, Ar is preferably 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5-trimethoxybenzene, 4-dimethylaminobenzene, 4-methylmercaptobenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl. In the present invention, the synthetic route of the stilbene derivative of guaiazulene having the structure shown in Formula II-b is shown in Formula C:

[0089]

[0090] In the present invention, when R is an acetyl group or a substituted acetyl group, a stilbene derivative of guaiazulene having a structure shown in formula II-b undergoes a substitution reaction with an acetyl chloride compound under the catalysis of aluminum chloride to obtain a stilbene derivative of guaiazulene having a structure shown in formula II-c; the acetyl chloride compound is acetyl chloride, nitrile acetyl chloride, chloroacetyl chloride, benzoyl chloride or benzofuranacetyl chloride. In the present invention, the molar ratio of the stilbene derivative of guaiazulene having a structure shown in formula II-b to the acetyl chloride compound is preferably 1:1 to 3, more preferably 1:2. In the present invention, the molar ratio of the aluminum chloride to the stilbene derivative of guaiazulene having a structure shown in formula II-b is preferably 1:2 to 5, more preferably 1:3 to 4.

[0091] In the present invention, the organic solvent used in the substitution reaction is preferably dichloromethane. In the present invention, the temperature of the substitution reaction is preferably room temperature, and the time is preferably 10 to 20 hours, more preferably 15 hours.

[0092] In the present invention, when R is an acetyl group or a substituted acetyl group, Ar is preferably 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5-trimethoxybenzene, 4-dimethylaminobenzene, 4-methylmercaptobenzene, 2-pyridyl, 3-pyridyl, or 4-pyridyl. In the present invention, the synthetic route of the stilbene derivative of guaiazulene having the structure shown in Formula II-c is shown in Formula D:

[0093]

[0094] In the present invention, when R is When, under the action of sodium triacetoxyborohydride, the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes a reductive amination reaction with amine to obtain R wherein the stilbene derivative of guaiazulene having the structure of Formula II-a is selected from the group consisting of piperidine and pyrrolidine. In the present invention, the molar ratio of the stilbene derivative of guaiazulene having the structure of Formula II-a to the amine is preferably 2:1 to 1:2, more preferably 1:1.

[0095] In the present invention, the organic solvent used in the reductive amination reaction is preferably dichloromethane. In the present invention, the temperature of the reductive amination reaction is preferably room temperature, and the time is preferably 1 to 3 hours, more preferably 2 hours.

[0096] In the present invention, when R is When Ar is preferably 3,4,5-trimethoxybenzene.

[0097] In the present invention, when R is When, under piperidine catalysis, the stilbene derivative of guaiazulene having the structure shown in formula II-a undergoes condensation reaction with an active methylene compound to obtain R The active methylene group is malononitrile, dimethyl malonate or diethyl malonate. In the present invention, the molar ratio of the stilbene derivative of guaiazulene having the structure represented by formula II-a to the active methylene compound is preferably 3:1 to 1:3, more preferably 1:1; the molar ratio of the piperidine to the stilbene derivative of guaiazulene having the structure represented by formula II-a is preferably 1:5 to 20, more preferably 1:10 to 15.

[0098] In the present invention, the organic solvent used in the condensation reaction is preferably toluene. In the present invention, the temperature of the condensation reaction is preferably 50 to 80° C., more preferably 60 to 70° C., and the time is preferably 1 to 3 hours, more preferably 2 hours.

[0099] The present invention provides the use of the stilbene derivatives of guaiazulene in the preparation of anti-tumor and / or antiviral drugs.

[0100] In the present invention, the anti-tumor drug is preferably one or more of an anti-human myeloid leukemia drug, an anti-triple-negative breast cancer drug, and an anti-pancreatic cancer drug; and the anti-viral drug is preferably an anti-influenza virus drug.

[0101] The stilbene derivatives of guaiazulene provided by the present invention, as well as their preparation methods and applications, are described in detail below with reference to the following examples. However, these examples should not be construed as limiting the scope of protection of the present invention.

[0102] Example 1: Synthesis of Compound I-1: (E)-Guaiazulene-3-phenylvinyl

[0103] To a dry 50mL three-necked round-bottom flask, add 3.0g of guaiacylamine and 15mL of dry DMF. Add 3.0ml of phosphorus oxychloride slowly (20min) via a constant pressure dropping funnel in an ice bath at 0°C. Stir the reaction for 1h, then add 3.0g of sodium hydroxide in water. Stir until no gas is generated, then transfer to a 90°C oil bath and stir for 1h to expel dimethylamine gas. Pour the reaction solution into plenty of ice water and stir until uniform. Extract with dichloromethane (50mL x 3), wash with DMF, combine the organic extracts, and elute with a 4:1 ratio of petroleum ether / acetone (v / v). Combine the eluates containing azulene aldehyde, and the yield reaches 90.0%.

[0104] 2 g of guaiazulene aldehyde and 670 mg of sodium borohydride were added to a 50 ml round-bottom flask and dissolved in 20 ml of ethanol. After stirring at 25 °C for 2 h, the reaction of the raw materials was monitored for completion. Water was added to stop the reaction, and the organic phase was extracted with dichloromethane. The target product was obtained by silica gel column chromatography with a yield of 80.0%.

[0105] Take the reduction product guaiazulene methanol from the previous step, add 1.30 g of triphenylphosphine hydrobromide, use chloroform as solvent, reflux at 65 ° C under nitrogen protection for 5 hours, then stop the reaction, concentrate, evaporate to dryness, seal and set aside.

[0106] The guaiazulene triphenylphosphonium bromide prepared in the previous step was dissolved in anhydrous ethanol, 720 mg of sodium ethoxide was added under nitrogen protection, and the mixture was stirred at room temperature for 30 minutes under nitrogen protection. 1.1 g of benzaldehyde was added, and the mixture was stirred at room temperature under nitrogen protection overnight. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined and column chromatography was performed, and eluted with n-hexane to obtain compound I-1 (E) -guaiazulene-3-phenylvinyl with a yield of 23.8%.

[0107] 1H NMR (400MHz, CDCl3): δ8.02 (d, J = 15.60, 1H), 7.99 (d, 1H, J = 3.0Hz), 7.91 (s, 1H), 7.50 (d, 2H, J = 7.3Hz), 7.35 (t, 1H, J = 7.0Hz, 15. 4Hz), 7.21 (m, 2H), 6.91 (d, 1H, J = 15.4Hz), 6.85 (d, 1H, J = 10.4Hz), 3.04 (s, 3H), 2.99 (m, 1H), 2.62 (s, 3H), 1.34 (d, 6H, J = 7.0Hz). 13 C NMR (100MHz, CDCl3) δ145.98,141.02,140.48,138.87,135.77,134.92,133.72,132.66 ,128.66,127.42,126.65,126.52,126.16,125.90,37.71,29.72,28.50,24.45,13.01.

[0108] Example 2: Synthesis of Compound I-2: (E)-Guaiazulene-3-(4'-ethyl)phenylvinyl

[0109] The product was prepared according to the steps of Example 1 using 4-ethylbenzaldehyde as raw material, with a yield of 12.4%.

[0110] 1 H NMR (400MHz, CDCl3): δ7.97 (m, 2H), 7.90 (s, 1H), 7.43 (d, 2H, J = 7.3Hz), 7.21 (dd, 1H, J = 10.4Hz, 3.2Hz), 7.18 (d, 2H, J = 8.8Hz), 6.90 (d, 1H, J = 1 5.4Hz),6.82(d,1H,J=10.4Hz),3.03(s,3H),2.99(m,1H),2.65(q,J=7.5Hz,2H),2.61(s,3H),1.33(d,6H,J=7.0Hz),1.25(t,J=7.4Hz,3H).13C NMR (100MHz, CDCl3) δ146.01,142.81,140.83,140.42,136.38,135.79,134.88,133.66,132.47,12 8.20,127.25,126.73,126.42,126.08,125.91,125.37,37.71,28.66,28.49,24.46,15.67,13.02.

[0111] Example 3: Synthesis of Compound I-3: (E)-Guaiazulene-3-(4'-isopropyl)phenylvinyl

[0112] The product was prepared according to the steps of Example 1 using 4-ethylbenzaldehyde as raw material, with a yield of 11.8%.

[0113] 1 HNMR (400MHz, CDCl3): δ7.98 (d, 1H, J = 16.8Hz), 7.97 (d, 1H, J = 2.4Hz), 7.89 (s, 1H), 7.44 (d, 2H, J = 7.3Hz), 7.21 (d, 1H, J = 8.8 Hz),7.18(d,2H,J=8.8Hz),6.89(d,1H,J=15.4Hz),6.82(d,1H,J=10.4Hz),3.02(s,3H),2.98(m,1H),2.91(m,1H),2.61(s,3H ),1.33(d,6H,J=7.0Hz),1.27(d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ147.43,146.01,140.83,140.41,136.54,135.80,1 34.88,133.66,132.46,127.24,126.74,126.71,126.43,126.07,125.90,125.41,37.71,33.89,28.48,24.46,24.02,13.01.

[0114] Example 4: Synthesis of Compound I-4: (E)-Guaiazulene-3-(2'-methoxy)phenylvinyl

[0115] The product was prepared according to the steps of Example 1 using 2-methoxybenzaldehyde as raw material, with a yield of 27.4%.

[0116] 1H NMR (400MHz, CDCl3): δ8.08(d,1H,J=16.8Hz),7.97(m,2H),7.58(dd,2H,J=1.8Hz,7.3Hz),7.26-7.17(m,3H),6.97(td,1H,J=2.4Hz,8.0H z),6.90(dd,1H,J=1.2Hz,8.2Hz),6.81(d,1H,J=10.8Hz),3.90(s,3H),3.03(s,3H),2.99(m,1H),2.62(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ156.61,145.98,140.77,140.49,135.99,134.76,133.56,132.49,128.00,127.45 ,127.19,127.01,126.80,126.10,125.97,121.39,120.80,110.99,55.59,37.70,28.50,24.45,13.01.

[0117] Example 5: Synthesis of Compound I-5: (E)-Guaiazulene-3-(3'-methoxy)phenylvinyl

[0118] The product was prepared according to the steps of Example 1 using 3-methoxyformaldehyde as raw material, with a yield of 7.7%.

[0119] 1H NMR (400MHz, CDCl3): δ8.02(d,1H,J=16.8Hz),7.99(s,1H),7.90(s,1H),7.23(d ,1H,J=7.8Hz),7.23(dd,2H,J=1.8Hz,7.3Hz),7.11(m,1H),7.04(t,1H,J=2.0Hz ),6.88(d,1H,J=16.2Hz),6.85(d,1H,J=10.8Hz),6.85(dd,1H,J=8.6Hz,2.8Hz) ,3.85(s,3H),3.04(s,3H),3.00(m,1H),2.61(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ159.92,145.99,141.09,140.53,140.39,135.79,134.95,133.74,132.74,129.59,12 7.50,126.53,126.47,126.18,126.05,118.65,111.88,111.48,55.26,37.72,29.73,28.52,24.46,13.02.

[0120] Example 6 Compound I-6: Synthesis of (E)-guaiazulene-3-(4'-methoxy)phenylvinyl

[0121] The product was prepared according to the steps of Example 1 using 4-methoxybenzaldehyde as raw material, with a yield of 19.3%.

[0122] 1H NMR (400MHz, CDCl3): δ7.97 (d, 1H, J = 2.0Hz), 7.89 (d, 1H, J = 4.4Hz), 7.86 (d, 1H, J = 11.4Hz), 7.44 (d, 2H, J = 7.8Hz), 7.20 (dd, 2H, J = 1.8Hz, 7.3Hz), 6 .90(d,2H,J=7.8Hz),6.87(d,1H,J=16.2Hz),6.80(d,1H,J=10.8Hz),3.83 (s,3H),3.02(s,3H),2.99(m,1H),2.61(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ158.57,145.98,140.69,140.33,135.70,134.84,133.61,132.26,131.80,12 7.09,127.02,126.50,126.33,126.03,124.33,114.16,55.37,37.69,29.73,28.46,24.45,13.01.

[0123] Example 7 Compound I-7: Synthesis of (E)-guaiazulene-3-(3',4'5'-trimethoxy)phenylvinyl

[0124] The product was prepared according to the steps of Example 1 using 3,4,5-trimethoxybenzaldehyde as raw material with a yield of 37.7%.

[0125] 1 H NMR (400MHz, CDCl3): δ8.00 (d, 1H, J = 2.0Hz), 7.90 (d, 1H, J = 11.4Hz), 7.88 (s, 1H), 7.23 (dd, 2H, J = 1.8Hz, 7.3Hz), 6.86 (s, 1H), 6 .83(d,1H,J=6.84Hz),6.73(s,2H),3.92(s,6H),3.87(s,3H),3.03(s,3H),3.00(m,1H),2.61(s,3H),1.34(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ153.44,145.88,141.06,140.47,137.28,135.81,134.97,134.74,133.75,13 2.66,127.42,126.63,126.13,126.01,125.90,103.04,61.02,56.16,37.72,28.44,24.45,13.01.

[0126] Example 8 Compound I-8: Synthesis of (E)-guaiazulene-3-(2'-nitro)phenylvinyl

[0127] The product was prepared according to the steps of Example 1 using 2-nitrobenzaldehyde as raw material, with a yield of 37.7%.

[0128] 1 H NMR (400MHz, CDCl3): δ8.30 (t, 1H, J = 2.6Hz), 8.14 (d, 1H, J = 16.0Hz), 8.04 (d, 1H,J=3.0Hz),8.01(dd,1H,J=2.0Hz,8.0Hz),7.91(s,1H),7.75(d,1H,J=7.6H z),7.47(t,1H,J=7.6Hz),7.29(dd,2H,J=1.8Hz,7.3Hz),6.93(dd,1H,J=2.4H z,13.0Hz),3.07(s,3H),3.06(m,1H),3.03(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (101MHz, CDCl3) δ147.60,145.74,142.13,141.18,136.15,135.14,134.31,134.03,133.73,132.78,131.1 4,128.37,127.14,126.77,126.46,125.49,124.91,120.12,77.35,77.04,76.72,37.77,28.66,24.45,12.98.

[0129] Example 9 Compound I-9: Synthesis of (E)-guaiazulene-3-(4'-nitro)phenylvinyl

[0130] The product was prepared according to the steps of Example 1 using 4-nitrobenzaldehyde as raw material, with a yield of 19.1%.

[0131] 1H NMR(400M Hz, CDCl3): δ8.16 (d, 1H, J = 16.0Hz), 8.12 (d, 2H, J = 8.6Hz), 7.98 (d, 1H, J = 3.0Hz), 7.88 (s, 1H), 7.49 (d, 2H, J = 8.6Hz), 7.25 (dd, 2H ,J=1.8Hz,7.3Hz),6.91(d,1H,J=2.4Hz),6.88(d,1H,J=7.4Hz),3.01(s,3H),2.96(m,1H),2.55(s,3H),1.28(d,6H,J=7.0Hz).13C NMR (101MHz, CDCl3) δ146.01,145.65,135.46,135.42,134.17,130.42,12 8.87,127.00,125.79,124.30,123.46,37.79,29.71,28.73,24.43,13.05.

[0132] Example 10: Synthesis of Compound I-10: (E)-Guaiazulene-3-(4'-fluoro)phenylvinyl

[0133] The product was prepared according to the steps of Example 1 using 4-fluorobenzaldehyde as raw material, with a yield of 15.1%.

[0134] 1 HNMR (400MHz, CDCl3): δ8.00 (d, 1H, J = 3.0Hz), 7.92 (d, 1H, J = 16.0Hz), 7.88 (s, 1H), 7.44 (dd, 2H, J = 10.0Hz, 6.0Hz), 7.23 (dd, 2H, J = 1.8Hz, 7. 3Hz),7.03(t,2H,J=10.2Hz),6.87(d,1H,J=7.4Hz),6.83(d,1H,J=2.4Hz),3.03(s,3H),3.00(m,1H),2.61(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (101MHz, CDCl3) δ145.91,141.06,140.46,135.68,135.08,135.05,134.97,133.77,132.65,127 .45,127.25,127.18,126.15,125.97,125.95,125.42,115.64,115.43,37.72,28.50,24.45,13.01.

[0135] Example 11: Synthesis of Compound I-11: (E)-Guaiazulene-3-(4'-chloro)phenylvinyl

[0136] The product was prepared according to the steps of Example 1 using 4-chlorobenzaldehyde as raw material, with a yield of 15.1%.

[0137] 1 H NMR(400M Hz, CDCl3): δ8.00 (s, 1H), 7.98 (d, 1H, J = 16.0Hz), 7.89 (s, 1H), 7.41 (d, 2H, J = 8.2Hz), 7.30 (d, 2H, J = 8.2Hz), 7.24 (dd, 1H, J = 1 0.0Hz,2.6Hz),6.87(d,1H,J=7.4Hz),6.84(d,1H,J=2.4Hz),3.03(s,3H),3.00(m,1H),2.61(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ145.92,141.30,140.63,137.41,135.64,135.03,133.82,132.86,131 .83,128.77,127.67,126.98,126.68,126.28,125.79,125.15,37.73,28.54,24.45,13.02.

[0138] Example 12: Synthesis of Compound I-12: (E)-Guaiazulene-3-(4'-bromo)phenylvinyl

[0139] The product was prepared according to the steps of Example 1 using 4-bromobenzaldehyde as raw material, with a yield of 12.9%.

[0140] 1HNMR(400M Hz, CDCl3): δ8.00 (d, 1H, J = 2.6Hz), 7.99 (d, 1H, J = 16.0Hz), 7.89 (s, 1H), 7.45 (d, 2H, J = 8.2Hz), 7.35 (d, 2H, J = 8.2Hz), 7.24 (dd, 1H ,J=10.0Hz,2.6Hz),6.87(d,1H,J=7.4Hz),6.84(d,1H,J=2.4Hz),3.03(s,3H),3.00(m,1H),2.62(s,3H),1.34(d,6H,J=7.0Hz).13C NMR (101MHz, CDCl3) δ145.93,141.35,140.66,137.85,135.62,135.04,133.84,132.89,131.69,127.7 0,127.32,126.78,126.31,125.76,125.15,119.88,77.35,77.03,76.71,37.73,28.54,24.44,13.01.

[0141] Example 13: Synthesis of Compound I-13: (E)-Guaiazulene-3-(2'-bromo)phenylvinyl

[0142] The product was prepared according to the steps of Example 1 using 2-bromobenzaldehyde as raw material, with a yield of 16.3%.

[0143] 1 HNMR(400M Hz, CDCl3): δ8.02-7.96 (m, 3H), 7.99 (d, 1H, J = 16.0Hz), 7.66 (dd, 1H, J = 8.0Hz, 2.0Hz), 7.58 (dd, 1H, J = 8.0Hz, 2.0Hz), 7.31-7.22 (m,3H),7.05(dt,1H,J=2.0Hz,8.0Hz),6.88(d,1H,J=10.6Hz),3.04(s,3H),3.01(m,1H),2.63(s,3H),1.34(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ145.89,141.45,140.78,138.44,136.09,135.01,133.85,133.12,128 .66,127.80,127.61,127.48,126.38,125.96,125.00,123.67,37.74,28.60,24.45,13.01.

[0144] Example 14: Synthesis of Compound I-14: (E)-Guaiazulene-3-(2',4'-dichloro)phenylvinyl

[0145] The product was prepared according to the steps of Example 1 using 2,4-dichlorobenzaldehyde as raw material, with a yield of 14.5%.

[0146] 1 H NMR(400M Hz, CDCl3): δ8.02(s,1H),8.00(d,1H,J=2.6Hz),7.94(s,1H),7.58(d,1H,J=8.2Hz),7.39(d,2H ,J=2.4Hz),7.28-7.18(m,4H),3.03(s,3H),3.00(m,1H),2.61(s,3H),1.34(d,6H,J=7.0Hz).13C NMR(100M Hz, CDCl3)δ145.84,141.72,140.92,135.93,135.42,135.09,133.94,133.29,133.11,131.93, 129.53,128.87,128.03,127.19,126.51,126.37,125.67,120.99,37.75,28.62,24.45,13.01.

[0147] Example 15: Synthesis of Compound I-15: (E)-Guaiazulene-3-(4'-trifluoromethyl)phenylvinyl

[0148] The product was prepared according to the steps of Example 1 using 4-trifluoromethylbenzaldehyde as raw material, with a yield of 13.9%.

[0149] 1 HNMR(400M Hz, CDCl3): δ8.11 (d, 1H, J = 15.8Hz), 8.00 (d, 1H, J = 2.6Hz), 7.92 (s, 1H), 7.56 (s, 4H), 7.27 (dd, 1H, J = 10.6Hz,2.4Hz),6.94-6.89(m,2H),3.05(s,3H),3.01(m,1H),2.62(s,3H),1.35(d,6H,J=7.0Hz).13C NMR(100M Hz, CDCl3) δ145.92,141.74,140.88,135.62,135.15,133.95,133.32,128.42,128 .08,126.47,125.78,125.60,125.57,125.45,124.68,37.75,28.59,24.44,13.02.

[0150] Example 16: Synthesis of Compound I-16: (E)-Guaiazulene-3-(2'-furan)vinyl

[0151] The product was prepared according to the steps of Example 1 using 2-furancarboxaldehyde as raw material, with a yield of 17.2%.

[0152] 1 H NMR (400MHz, CDCl3): δ7.95 (s, 1H), 7.94 (d, 1H, J = 15.8Hz), 7.84 (s, 1H), 7.38 (s, 1H), 7.21 (dd, 1H, J = 10.6Hz, 2.4Hz), 6.82 (d, 1H, J = 10.0Hz), 6.73(d,1H,J=15.2Hz),6.42(dd,1H,J=3.8Hz,2.0Hz),6.26(d,1H,J=3.0Hz),3.03(s,3H),2.98(m,1H),2.60(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ154.75,146.26,141.24,141.11,140.74,135.16,134.99,133.69,132 .57,127.51,126.31,125.81,124.61,114.37,111.63,106.54,37.69,28.50,24.43,13.03.

[0153] Example 17 Compound I-17: Synthesis of (E)-guaiazulene-3-(2'-thiophene)vinyl

[0154] The product was prepared according to the steps of Example 1 using 2-thiophenecarboxaldehyde as raw material, with a yield of 18.1%.

[0155] 1HNMR (400MHz, CDCl3): δ7.96 (d, 1H, J = 2.4Hz), 7.95 (s, 1H), 7.94 (d, 1H, J = 15.8Hz), 7.20 (dd, 1H, J = 10.6Hz, 2.4Hz), 7.10 (dd, 1H, J = 3.8H z,2.0Hz),7.04(d,1H,J=15.8Hz),6.98(m,2H),6.82(d,1H,J=10.8Hz),3.00(s,3H),2.97(m,1H),2.59(s,3H),1.32(d,6H,J=7.0Hz).13C NMR(100M Hz, CDCl3)δ146.13,144.85,141.17,140.66,135.40,135.03,133.75,132.58,127.66, 127.59,126.33,126.13,125.69,124.25,122.73,119.61,37.73,28.45,24.46,13.05.

[0156] Example 18: Synthesis of Compound I-18: (E)-Guaiazulene-3-(2'-pyridyl)vinyl

[0157] The product was prepared according to the steps of Example 1 using 2-pyridinecarboxaldehyde as raw material, with a yield of 12.6%.

[0158] 1 H NMR (400MHz, CDCl3): δ8.48 (td, 1H, J = 1.2Hz, 4.8Hz), 7.96 (d, 1H, J = 2.4Hz), 7. 46(d,1H,J=12.4Hz),7.23-7.18(m,3H),7.06(td,1H,J=1.2Hz,8.0Hz),7.04(d, 1H,J=15.8Hz),6.93(dd,1H,J=4.4Hz,1.6Hz),6.84(d,1H,J=10.8Hz),6.59(d,1 H,J=13.0Hz),2.95(m,1H),2.94(s,3H),2.43(s,3H),1.28(d,6H,J=7.0Hz).13C NMR(100M Hz, CDCl3) δ157.08,149.10,146.37,140.67,138.89,135.41,135.06,133.51,132 .99,127.56,126.89,125.23,123.87,123.69,121.17,37.86,27.52,24.55,12.78.

[0159] Example 19: Synthesis of Compound II-1: (E)-1-Formylguaiazulene-8-phenylvinyl

[0160] To a 50 mL round-bottom flask, add 400 mg of guaiazulene aldehyde solid, 250 μl of benzaldehyde, and dissolve it in 30 mL of dry toluene. Add 24 μl of piperidine and 15 μl of glacial acetic acid, and heat in an oil bath at 60°C with stirring. Monitor the reaction progress by TLC until the starting material is completely reacted (after 24 hours). After completion of the reaction, evaporate the reaction solution to dryness, dissolve the resulting solid in 30 mL of distilled water, and add an appropriate amount of sodium bicarbonate to neutralize the acetic acid in the reaction system until no more bubbles are released. Extract with dichloromethane (30 mL x 3), combine the organic layers, and evaporate to dryness. Mix 300-400 mesh silica gel with petroleum ether:ethyl acetate 20:1 (v:v) and wet-pack the column. Mix the crude product with 100-200 mesh silica gel and dry-load it. The product was eluted with a mobile phase of petroleum ether:ethyl acetate 20:1 (v:v), and the purple fraction eluates were combined to obtain (E)-1-formylguaiazulene-8-phenylvinyl with a yield of 71.2%.

[0161] 1 H NMR (400MHz, CDCl3): δ10.61 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.09 (dd, J = 16.0Hz, 2.0Hz, 1H), 7. 81-7.65(m,4H),7.50-7.31(m,4H),3.24(p,J=16.0Hz,1H),2.67(s,3H),1.48(d,J=7.2Hz,6H).13C NMR (400MHz, CDCl3): δ186.13,147.59,145.38,144.19,139.59,138.23,136.57,136.25,135.51,134.86,133.01, 129.11,129.11,129.00,128.83,127.44,127.33,127.33,126.82,38.50,29.86,24.63,24.63,13.12.HRMS:calcd forC23H23O[M+H]+:315.1743; found:315.1752.

[0162] Example 20: Synthesis of Compound II-2: (E)-1-formylguaiazulene-8-(2'-methyl)phenylvinyl was prepared according to the steps of Example 19 using 2-methylbenzaldehyde as raw material with a yield of 55%.

[0163] 1H NMR (400MHz, CDCl3): δ10.52(s,1H),8.34(s,1H),8.25(s,1H),7.94(d,J=16.0Hz,1H),7.79-7.71(m,3H),7.52( d,J=8.0Hz,1H),7.33-7.25(m,3H),3.23(p,J=16.0Hz,1H),2.65(s,3H),2.51(s,3H),1.47(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3): δ186.20,147.58,145.70,144.23,139.30,138.33,136.53,136.24,135.61,135.51,134. 21,132.51,130.83,129.21,128.86,127.50,126.88,126.76,125.87,38.53,24.66,20.07,13.13.HRMS:calcd for C24H25O[M+H]+:329.1900; found:329.1909.

[0164] Example 21: Synthesis of Compound II-3: (E)-1-formylguaiazulene-8-(3'-methyl)phenylvinyl. The compound was prepared according to the steps of Example 19 using 3-methylbenzaldehyde as the starting material with a yield of 54%.

[0165] 1 H NMR (400MHz, CDCl3): δ10.42(s,1H),8.15(s,1H),8.07(s,1H),7.85(d,J=16.0Hz,1H),7.59(d,J=12.0Hz,1H),7.52(dd ,J=12.0Hz,4.0Hz,1H),7.27-7.02(m,5H),3.04(p,J=16.0Hz,1H),2.47(s,3H),2.27(s,3H),1.28(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3): δ186.21,147.55,145.52,144.18,139.37,138.71,138.31,136.50,136.22,135.50,135.07, 132.78,129.89,129.02,128.91,127.91,127.45,126.87,124.61,38.51,24.64,24.64,21.62,13.13.HRMS:calcd for C24H25O[M+H]+:329.1900; found:329.1910.

[0166] Example 22: Synthesis of Compound II-4: (E)-1-formylguaiazulene-8-(4'-methyl)phenylvinyl. The compound was prepared according to the steps of Example 19 using 4-methylbenzaldehyde as the starting material with a yield of 51%.

[0167] 1 H NMR (400MHz, CDCl3): δ10.55(s,1H),8.27(s,1H),8.19(s,1H),7.97(d,J=16.0Hz,1H),7.73(d,J=12.0Hz,1H),7.64(dd,J=10.8Hz ,2.0Hz,2H),7.49(d,J=8.0Hz,2H),7.22-7.19(m,3H),3.16(p,J=16.0Hz,1H),2.60(s,3H),2.39(s,3H),1.41(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3): δ186.15,147.42,145.63,144.09,139.41,139.14,138.26,136.19,135.41,134.89,133.85, 132.02,129.82,129.82,128.77,127.36,127.29,127.29,126.83,38.47,24.62,24.62,21.53,13.11.HRMS:calcd for C24H25O[M+H]+:329.1900; found:329.1909.

[0168] Example 23 Compound II-5: Synthesis of (E)-1-formylguaiazulene-8-(3',5'-dimethyl)phenylvinyl

[0169] The product was prepared according to the steps of Example 19 using 3,5-dimethylbenzaldehyde as raw material, with a yield of 56%.

[0170] 1H NMR (400MHz, CDCl3): δ10.57(s,1H),8.29(d,J=2.0Hz,1H),8.21(s,1H),7.96(d,J=16.0,1H),7.72(d,J=11.0Hz,1H),7.66(dd,J=10 .4Hz,2.0Hz,1H),7.19(m,3H),7.00(s,1H),5.29(s,1H),3.17(p,J=16.0Hz,1H),2.61(s,3H),2.37(s,6H),1.42(d,J=3.2Hz,6H).13C NMR (100MHz, CDCl3) δ186.25,147.49,145.62,144.14,139.15,138.60,138.60,138.35,136.45,136.19,135.49,135 .25,132.57,130.90,128.97,127.44,126.91,125.22,125.22,38.51,24.64,24.64,21.48,21.48,13.13.HRMS:calcd for C25H27O[M+H]+:343.2066; found:343.2066.

[0171] Example 24: Synthesis of Compound II-6: (E)-1-formylguaiazulene-8-(4'-ethyl)phenylvinyl was prepared according to the steps of Example 19 using 4-ethylbenzaldehyde as raw material with a yield of 54%.

[0172] 1H NMR (400MHz, CDCl3): δ10.55(s,1H),8.28(d,J=2.2Hz,1H),8.20(s,1H),7.99(d,J=16.0Hz,1H),7.74(d,J=12.0,1H),7.66(dd,J=12.0Hz,4.0Hz,1H), 7.55(d,J=8.0Hz,1H),7.29-7.21(m,3H),3.18(p,J=16.0Hz,1H),2.95(p,J =12.0Hz,2H),2.61(s,3H),1.42(d,J=8.0Hz,6H),1.29(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.25,150.20,147.45,145.70,144.13,139.41,138.32,136.23,135.48,134.91,134.28,1 32.23,128.82,127.43,127.43,127.43,127.26,127.26,126.90,38.54,34.20,24.67,24.67,24.07,24.07,13.15.

[0173] Example 25 Compound II-7: Synthesis of (E)-1-formylguaiazulene-8-(4'-isopropyl)phenylvinyl was prepared according to the steps of Example 19 using 4-isopropylbenzaldehyde as raw material with a yield of 56%.

[0174] 1H NMR (400MHz, CDCl3): δ10.57 (s, 1H), 8.29 (d, J = 4.0Hz, 1H), 8.21 (s, 1H), 8.00 (d,J=16.0Hz,1H),7.75(d,J=12.0,1H),7.67(dd,J=8.0Hz,2.0Hz,1H),7.54( d,J=8.0,2H),7.28-7.26(m,2H),7.22(s,1H),3.19(p,J=16.0Hz,1H),2.71(q ,J=8.0Hz,1H),2.62(s,3H),1.43(d,J=8.0Hz,6H),1.29(t,J=4.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.19,147.45,145.66,145.55,144.11,139.39,138.30,136.21,135.44,134.91,134.0 9,132.11,128.80,128.66,128.66,127.40,127.40,127.40,126.84,38.49,28.91,24.63,24.63,15.69,13.12.

[0175] Example 26 Compound II-8: Synthesis of (E)-1-Formylguaiazulene-8-naphthylvinyl

[0176] The product was prepared according to the steps of Example 19 using naphthaldehyde as raw material with a yield of 54%.

[0177] 1H NMR (400MHz, CDCl3): δ10.59(s,1H),8.29(s,1H),8.21(s,1H),8.16(d,J=16.0Hz,1H),7.91(s,1H),7.86-7.76(m,5H),7.66(dd ,J=12.0Hz,2.0Hz,1H),7.52-7.40(m,2H),7.38(d,J=16.0Hz,1H),3.16(p,J=16.0Hz,1H),2.61(s,3H),1.42(d,J=3.2Hz,6H).1 3CNMR (100MHz, CDCl3) δ186.10,147.58,145.41,144.21,139.77,138.23,136.25,135.47,135.03,134.12,133.71,133.69,133 .28,128.91,128.76,128.43,128.16,127.95,127.44,126.81,126.69,126.69,123.66,38.50,24.63,24.63,13.14.HRMS:calcd forC27H25O[M+H]+:365.1900; found:365.1910.

[0178] Example 27 Compound II-9: Synthesis of (E)-1-formylguaiazulene-8-(2'-methoxy)phenylvinyl was prepared according to the steps of Example 19 using 2-methoxybenzaldehyde as raw material with a yield of 52%.

[0179] 1H NMR (400MHz, CDCl3): δ10.63 (s, 1H), 8.27 (d, J = 4.0Hz, 1H), 8.19 (s, 1H), 8.1 0(d,J=16.0Hz,1H),7.78(d,J=4.0,1H),7.76-7.57(m,3H),7.31(td,J=8.0Hz ,4.0Hz,1H),7.01(td,J=8.0Hz,4.0Hz,1H),6.94(dd,J=8.0Hz,1H),3.92(s, 3H),3.16(p,J=16.0Hz,1H),2.60(d,J=4.0Hz,3H),1.41(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3)186.45,157.66,147.29,146.15,144.07,138.97,138.40,136.15,135.37,133.68,130.13,130. 08,128.98,127.85,127.27,126.86,125.54,121.13,111.23,55.71,53.60,38.48,24.63,24.63,13.11.HRMS:calcd for C24H25O2[M+H]+:345.1849; found:345.1859.

[0180] Example 28: Synthesis of Compound II-10: (E)-1-Formylguaiazulene-8-(3'-methoxy)phenylvinyl

[0181] The product was prepared according to the steps of Example 19 using 3-methoxybenzaldehyde as raw material with a yield of 56%.

[0182] 1H NMR (400MHz, CDCl3): δ10.52 (s, 1H), 8.27 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 8.0 3(d,J=16.0Hz,1H),7.70(d,J=4.0,1H),7.64(dd,J=14.8Hz,2.0Hz,1H),7.31 (t,J=16.0Hz,1H),7.19-7.12(m,3H),6.89(dd,J=8.0Hz,2.2Hz,1H),3.86(s, 3H),3.15(p,J=16.0Hz,1H),2.59(d,J=4.0Hz,3H),1.41(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.02,160.15,147.55,145.24,144.14,139.74,138.11,137.99,136.22,135.44,134.72, 133.31,130.04,128.73,127.36,126.75,119.87,114.63,112.58,55.42,38.44,24.57,24.57,13.07.HRMS:calcd for C24H25O2[M+H]+:345.1849; found:345.1857.

[0183] Example 29 Compound II-11: Synthesis of (E)-1-formylguaiazulene-8-(4'-methoxy)phenylvinyl

[0184] The product was prepared according to the steps of Example 19 using 4-methoxybenzaldehyde as raw material with a yield of 62%.

[0185] 1H NMR (400MHz, CDCl3): δ10.53 (s, 1H), 8.24 (d, J = 4.0Hz, 1H), 8.15 (s, 1H), 7. 99(d,J=16.0Hz,1H),7.71(d,J=4.0,1H),7.61(dd,J=14.8Hz,2.0Hz.1H),7. 52(d,J=8.0Hz,2H),7.18(d,J=16.0Hz,1H),6.93(d,J=8.0Hz,2H),3.84(s,3 H),3.15(p,J=16.0Hz,1H),2.59(d,J=4.0Hz,3H),1.39(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.07,160.41,147.24,145.81,143.97,139.47,138.20,136.16,135.27,134.53,130.87, 129.43,128.76,128.76,128.59,127.25,126.74,114.52,114.52,55.49,38.42,24.58,24.58,13.09.HRMS:calcd for C24H25O2[M+H]+:345.1849; found:345.1859.

[0186] Example 30: Synthesis of Compound II-12: (E)-1-Formylguaiazulene-8-(2',3'-dimethoxy)phenylvinyl

[0187] The product was prepared according to the steps of Example 19 using 2,3-dimethoxybenzaldehyde as raw material, with a yield of 58%. 1H NMR (400MHz, CDCl3): δ10.55 (s, 1H), 8.29 (d, 1H, J = 2.0Hz), 8.19 (s, 1H), 8.04 (d, 1H, J = 16.0Hz), 7.7 9(d,J=11.8Hz,1H),7.70(dd,1H,J=11.2Hz,2.4Hz),7.62(d,1H,J=16.0Hz),7.33(dd,J=1.2Hz,8.0Hz 1H),7.12(t,J=8.0Hz,16.0Hz,1H),6.92(dd,J=1.6Hz,8.0Hz,1H),3.90(d,6H,J=5.4Hz),3.19(m,1H),2.61(s,3H),1.42(d,6H,J=6.8Hz).13C NMR (100MHz, CDCl3) δ185.94,153.11,147.61,147.50,145.64,144.22,139.22,138.33,136.18,135.43,134.00,130.59 ,129.10,129.07,127.38,126.63,124.53,118.27,112.61,61.43,55.90,53.47,38.42,24.52,19.19,13.00.HRMS:calcd forC25H27O3[M+H]+:375.1955; found:375.1951.

[0188] Example 31: Synthesis of Compound II-13: (E)-1-Formylguaiazulene-8-(2',4'-dimethoxy)phenylvinyl

[0189] The product was prepared according to the steps of Example 19 using 2,4-dimethoxybenzaldehyde as raw material, with a yield of 54%.

[0190] 1H NMR (400MHz, CDCl3): δ10.61 (s, 1H), 8.24 (d, 1H, J = 2.0Hz), 8.17 (s, 1H), 8.00 ( d,1H,J=16.0Hz),7.79(d,J=11.8Hz,1H),7.63(dd,1H,J=11.2Hz,2.4Hz),7.57( d,1H,J=16.0Hz),7.52(s,1H),6.55(dd,J=1.6Hz,8.0Hz,1H),6.50(d,1H,J=2.4 Hz),3.88(d,6H,J=5.4Hz),3.15(m,1H),2.59(s,3H),1.39(d,6H,J=6.8Hz).13C NMR (100MHz, CDCl3) δ186.29,161.56,158.84,146.94,146.56,143.83,138.65,138.39,135.98,135.09,131.33, 129.97,128.86,128.72,127.08,126.65,118.68,105.29,98.62,55.61,55.51,38.35,24.51,13.01.HRMS:calcd for C25H27O3[M+H]+:375.1955; found:375.1954.

[0191] Example 32 Compound II-14: Synthesis of (E)-1-formylguaiazulene-8-(2',5'-dimethoxy)phenylvinyl.

[0192] 1H NMR (400MHz, CDCl3): δ10.58(s,1H),8.27(d,1H,J=2.0Hz),8.18(s,1H),8.12(d,1H,J=16.0Hz),7.78(d,J=11.8Hz,1H),7.65(dd,1H,J=1 1.2Hz, 2.4Hz), 7.56 (d, 1H, J = 16.0Hz), 7.20, 2H), 6.87 (s, 1H), 3.85 (d, 6H, J = 5.4Hz), 3.16 (m, 1H), 2.60 (s, 3H), 1.40 (d, 6H, J = 6.8Hz). 13C NMR (100MHz, CDCl3) δ186.21,153.81,152.05,147.30,145.88,144.05,139.19,138.28,136.07,135.28,133.86,129 .85,128.88,127.19,126.65,126.11,115.28,112.63,112.39,56.23,55.85,53.48,38.38,24.51,13.00.HRMS:calcd forC25H27O3[M+H]+:375.1955; found:375.1950.

[0193] Example 33 Compound II-15: Synthesis of (E)-1-formylguaiazulene-8-(2',6'-dimethoxy)phenylvinyl

[0194] The product was prepared according to the steps of Example 19 using 2,6-dimethoxybenzaldehyde as raw material, with a yield of 36%.

[0195] 1H NMR (400MHz, CDCl3): δ10.84 (s, 1H), 8.48 (d, 1H, J = 16.6Hz), 8.24 (d, 1H, J = 2.0Hz), 8.19 (s, 1H), 7.81 (d, 1H, J = 13.0Hz), 7.67(d,J=16.0Hz,1H),6.59(d,1H,J=8.8Hz),3.85(d,6H,J=5.4Hz),3.16(m,1H),2.60(s,3H),1.40(d,6H,J=6.8Hz).13C NMR (100MHz, CDCl3) δ187.32,159.09,147.35,146.72,143.72,138.58,137.57,136.43,135.93,135. 11,129.64,128.87,126.94,126.86,126.24,114.01,103.88,55.94,38.34,24.54,13.02.HRMS:calcd for C25H27O3[M+H]+:375.1955; found:375.1951.

[0196] Example 34: Synthesis of Compound II-16: (E)-1-Formylguaiazulene-8-(3',4'-dimethoxy)phenylvinyl

[0197] The product was prepared according to the steps of Example 19 using 3,4-dimethoxybenzaldehyde as raw material, with a yield of 13%.

[0198] 1H NMR (400MHz, CDCl3): δ10.54 (s, 1H), 8.27 (d, 1H, J = 2.0Hz), 8.17 (s, 1H), 8.01 (d, 1H, J = 17.8Hz), 7.76 (d, 1H, J = 13.0Hz), 7.65 (dd, 1H, J = 11.0Hz, 2.2Hz),7.22(d,1H,J=16.2Hz),7.16(m,2H),6.91(d,1H,J=8.8Hz),3.9 5(d,6H,J=16.4Hz),3.18(m,1H),2.60(s,3H),1.41(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ186.00,149.98,149.33,147.27,145.69,144.01,139.89,136.12,135.25,134.77, 131.13,129.71,128.49,127.24,120.95,111.28,109.35,56.03,56.00,38.38,24.51,13.02.HRMS:calcd for C25H27O3[M+H]+:375.1955; found:375.1954.

[0199] Example 35 Compound II-17: Synthesis of (E)-1-formylguaiazulene-8-(3',5'-dimethoxy)phenylvinyl

[0200] The product was prepared according to the steps of Example 19 using 3,5-dimethoxybenzaldehyde as raw material, with a yield of 17%.

[0201] 1H NMR (400MHz, CDCl3): δ10.52(s,1H),8.29(d,1H,J=2.0Hz),8.19(s,1H),8.06(d,1H,J=17.8Hz),7.70(m,1H),7.16(d ,1H,J=16.6Hz),6.76(d,2H,J=2.8Hz),6.47(m,1H),3.85(s,6H),3.18(m,1H),2.61(s,3H),1.41(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ185.95,161.16,147.52,145.12,144.14,139.80,138.44,138.08,136.13,135. 41,134.78,133.45,128.71,127.35,126.66,105.23,101.14,55.48,38.40,24.51,12.99.HRMS:calcd for C25H27O3[M+H]+:375.1955; found:375.1953.

[0202] Example 36 Compound II-18: Synthesis of (E)-1-formylguaiazulene-8-(3'4',5'-dimethoxy)phenylvinyl

[0203] The product was prepared according to the steps of Example 19 using 3,4,5-dimethoxybenzaldehyde as raw material with a yield of 75%.

[0204] 1H NMR (400MHz, CDCl3): δ10.49(s,1H),8.25(s,1H),8.14(s,1H),8.07(d,J=16.0Hz,1H),7.72(d,J=4.0Hz,1H),7.63(dt,J=12.0Hz,4. 0Hz.1H),7.16(d,J=16.0Hz,1H),6.85(s,1H),3.91(d,J=12.0Hz,9H),3.14(p,J=16.0Hz,1H),2.58(s,3H),1.39(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.00,153.65,153.65,147.46,145.35,144.11,140.42,139.06,138.04,136.25,135.34,134.86 ,132.69,132.45,128.46,127.28,126.59,104.47,104.47,61.08,56.30,56.30,38.42,24.55,24.55,13.05.HRMS:calcd forC26H29O4[M+H]+:405.2060; found:405.2067.

[0205] Example 37 Compound II-19: Synthesis of (E)-1-formylguaiazulene-8-(4'-fluoro)phenylvinyl was prepared according to the steps of Example 19 using 4-fluorobenzaldehyde as raw material with a yield of 85%.

[0206] 1H NMR (400MHz, CDCl3): δ10.48(s,1H),8.27(s,1H),8.16(s,1H),7.97(d,J=16.0Hz,1H),7.71-7.53(m,4H),7.16( dd,J=20.0Hz,4.0Hz.1H),7.07(t,J=12.0Hz,2H),3.16(p,J=16.0Hz,1H),2.59(s,3H),1.41(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.01,164.38,161.90,147.67,145.23,144.23,140.06,138.13,136.31,135.51,133. 55,132.84,129.02,128.94,128.70,127.45,126.67,116.21,115.99,38.49,24.61,24.61,13.10.HRMS:calcd for C23H22OF[M+H]+:333.1649; found:333.1659.

[0207] Example 38: Synthesis of Compound II-20: (E)-1-formylguaiazulene-8-(4'-chloro)phenylvinyl was prepared according to the steps of Example 19 using 4-chlorobenzaldehyde as raw material with a yield of 87%.

[0208] 1 H NMR (400MHz, CDCl3): δ10.46(s,1H),8.27(s,1H),8.16(s,1H),8.04(d,J=16.0Hz,1H),7.71-7.63(m,2H),7.49(d,J=8, 0Hz,2H),7.34(d,J=8,0Hz,2H),7.14(d,J=16.0Hz,1H),3.17(p,J=16.0Hz,1H),2.59(s,3H),1.41(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ185.93,147.76,145.00,144.28,140.27,138.06,136.32,135.55,135.14,134.63,133. 65,133.43,131.02,129.58,129.26,128.66,128.48,127.48,126.65,38.50,24.61,24.61,13.11.HRMS:calcd for C23H22OCl[M+H]+:349.1354; found:333.1364.

[0209] Example 39 Compound II-21: Synthesis of (E)-1-formylguaiazulene-8-(4'-bromo)phenylvinyl was prepared according to the steps of Example 19 using 4-bromobenzaldehyde as raw material with a yield of 84%.

[0210] 1 H NMR (400MHz, CDCl3): δ10.46(s,1H),8.27(s,1H),8.17(s,1H),8.07(d,J=16.0Hz,1H),7.73-7.64(m,4H),7.50(d, J=8,0Hz,2H),7.43(d,J=8,0Hz,2H),7.13(d,J=16.0Hz,1H),3.17(p,J=16.0Hz,1H),2.59(s,3H),1.41(d,J=8.0Hz ,6H).13CNMR(400MHz,CDCl3)δ185.95,147.78,145.01,144.31,140.32,138.04,136.33,135.59,133.78,133.52, 132.58,132.24,131.12,129.93,128.77,128.66,127.51,126.68,122.92,38.53,24.64,24.64,13.13.HRMS:calcd for C23H22OBr[M+H]+:393.0849; found:393.0859.

[0211] Example 40 Compound II-22: Synthesis of (E)-1-formylguaiazulene-8-(2',6'-difluoro)phenylvinyl

[0212] The product was prepared according to the steps of Example 19 using 2,6-difluorobenzaldehyde as raw material, with a yield of 47%.

[0213] 1H NMR (400MHz, CDCl3): δ10.63(s,1H),8.30(m,2H),8.22(s,1H),7.70(s,1H),7 .26(m,2H),6.96(m,2H),3.19(m,1H),2.61(s,3H),1.41(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ186.20,147.71,145.06,144.30,139.18,138.71,138.00,136.07,135 .65,128.92,127.48,126.80,121.26,112.01,111.75,38.44,24.53,12.98.HRMS:calcdfor C23H21OF2[M+H]+:351.1555; found:351.1554.

[0214] Example 41: Synthesis of Compound II-23: (E)-1-Formylguaiazulene-8-(2'-fluoro-6'-chloro)phenylvinyl

[0215] The product was prepared according to the steps of Example 19 using 2-fluoro-6-chlorobenzaldehyde as raw material, with a yield of 23%.

[0216] 1 H NMR(400M Hz, CDCl3): δ10.56 (s, 1H), 8.25 (d, 1H, J = 2.6Hz), 8.17 (m, 2H), 7.66 (s, 1H), 7.31 (d, 1H, J =16.4Hz),7.17(m,2H),7.02(m,1H),3.12(m,1H),2.54(s,3H),1.35(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ185.24,146.71,143.31,139.15,139.02,137.66,135.03,134.64,128.36,128.08, 126.48,125.75,124.85,124.39,114.14,113.91,76.32,76.00,75.68,37.41,23.48,11.94.HRMS:calcd for C23H21OFCl[M+H]+:367.1259; found:367.1258.

[0217] Example 42: Synthesis of Compound II-24: (E)-1-Formylguaiazulene-8-(2'-bromo)phenylvinyl

[0218] The product was prepared according to the steps of Example 19 using 2-bromo-benzaldehyde as raw material with a yield of 66%.

[0219] 1 H NMR (400MHz, CDCl3): δ10.48(s,1H),8.28(s,1H),8.17(s,1H),7.98(dd,J=16.0Hz,2.4Hz,1H),7.77(td,J=8.0Hz,1.2Hz,2H),7.69 (dd,J=12.0Hz,2.0Hz,2H),7.60(td,J=8.0Hz,1.2Hz,2H),7.36(t,J=8.0Hz,1H),7.17(td,J=8.0Hz,2.0Hz,1H),3.17(p,J=16.0Hz,1 H),2.59(s,3H),1.41(d,J=8.0Hz,6H).13CNMR(100MHz,CDCl3)δ185.87,147.88,144.83,144.37,140.12,138.05,136.36,136.31, 135.64,135.62,133.34,133.14,129.99,129.15,128.08,127.48,127.39,126.62,124.71,38.50,24.59,24.59,13.09.HRMS:calcd for C23H22OBr[M+H]+:393.0849; found:393.0859.

[0220] Example 43 Compound II-25: Synthesis of (E)-1-formylguaiazulene-8-(4'-trifluoromethyl)phenylvinyl

[0221] The product was prepared according to the steps of Example 19 using 4-trifluoromethylbenzaldehyde as raw material, with a yield of 79%.

[0222] 1H NMR(400M Hz, CDCl3): δ10.52(s,1H),8.36(d,J=1.2Hz,1H),8.29(s,1H),8.25(s,1H),7.80-7.69(m, 5H),7.30(d,J=4.0Hz,2H),3.24(p,J=16.0Hz,1H),2.67(s,3H),1.47(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ185.96,148.07,144.67,144.50,140.78,140.11,138.03,136.43,135.77,135.66,133. 14,130.11,128.74,127.66,127.50,127.50,126.71,126.12,126.07,38.60,24.66,24.66,13.14.HRMS:calcd for C24H22OF3[M+H]+:38.1617; found:383.1624.

[0223] Example 44: Synthesis of Compound II-26: (E)-1-Formylguaiazulene-8-(4'-methylmercapto)phenylvinyl

[0224] The product was prepared according to the steps of Example 19 using 4-methylmercaptobenzaldehyde as raw material with a yield of 47%.

[0225] 1H NMR(400M Hz, CDCl3): δ10.51 (s, 1H), 8.26 (d, 1H, J = 2.6Hz), 8.17 (s, 1H), 8.01 (d, 1H, J = 16.8Hz), 7.74 (d, 1H, J = 12.4Hz), 7.65 (dd, 1H, J = 10.5Hz ,2.0Hz),7.51(d,1H,J=8.6Hz),7.27(m,2H),7.19(d,1H,J=16.8Hz),3.17(m,1H),2.60(s,3H),2.52(s,3H),1.40(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ185.89,147.42,145.36,144.06,139.82,139.66,138.10,136.10,135.32,134. 21,133.28,132.18,128.57,127.59,127.30,126.60,126.58,38.38,24.51,15.60,13.00.HRMS:calcd for C24H25OS[M+H]+:361.1621; found:361.1618.

[0226] Example 45 Compound II-27: Synthesis of (E)-1-formylguaiazulene-8-(2'-nitro)phenylvinyl was prepared according to the steps of Example 19 using 2-nitrobenzaldehyde as raw material with a yield of 17%.

[0227] 1H NMR (400MHz, CDCl3): δ10.49(s,1H),8.32(d,J=2.2Hz,1H),8.18(s,1H),8.11(d,J=16.0Hz,1H),8.04(dd,J=8.0Hz,1.2Hz,1H),7. 98(dd,J=8.0Hz,1.2Hz.1H),7.82(d,J=8.0Hz,1H),7.75-7.68(m,3H),7.49(ddd,J=3.2Hz,1.2Hz,1H),3.14(p,J=16.0Hz,1H),2.6 1(s,3H),1.43(d,J=8.0Hz,6H).13CNMR(100MHz,CDCl3): δ185.83,148.39,148.32,144.74,144.53,141.23,137.98,137.80,136. 73,135.86,133.90,132.59,129.54,129.40,129.14,128.98,127.61,126.45,125.14,38.63,24.66,24.66,13.15.HRMS:calcdfor C23H22O3N[M+H]+:360.1594; found:360.1605.

[0228] Example 46 Compound II-28: Synthesis of (E)-1-formylguaiazulene-8-(4'-dimethylamino)phenylvinyl

[0229] The product was prepared according to the steps of Example 19 using 4-dimethylaminobenzaldehyde as raw material, with a yield of 55%.

[0230] 1H NMR (400MHz, CDCl3): δ10.58(s,1H),8.23(d,1H,J=2.4Hz),8.16(s,1H),7.87(d,1H,J=14.4Hz),7.77(d,1H,J=14.4Hz),7.61(dd,1H ,J=11.8Hz,3.2Hz),7.52(d,2H,J=8.4Hz),7.25(d,1H,J=16.4Hz),3.16(m,1H),3.04(s,3H),2.59(s,3H),1.40(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ186.08,146.70,138.18,135.90,134.97,128.70,128.30,127.02,126.65,56.21,56.04,38.32,24.50,13.02.HRMS:calcd for C25H28ON[M+H]+:358.2165; found:358.2162.

[0231] Example 47 Compound II-29: Synthesis of (E)-1-Formylguaiazulene-8-2'-pyridinylvinyl

[0232] The product was prepared according to the steps of Example 19 using 2-pyridinecarboxaldehyde as raw material with a yield of 47%.

[0233] 1 H NMR (400MHz, CDCl3): δ10.60(s,1H),8.69(d,J=4.4Hz,1H),8.58(d,J=16.0,1H),8.34(s,1H),8.26(s,1H),7.78-7.68(m,3 H),7.54(d,J=8.0,1H),7.31(d,J=2.3Hz,1H),7.25(m,1H),3.22(p,J=16.0Hz,1H),2.64(s,3H),1.45(d,J=3.2Hz,6H).13C NMR (400MHz, CDCl3) δ186.41,154.80,150.15,147.83,144.77,144.27,139.63,138.15,137.03,136.84,1 36.25,135.62,133.99,128.84,127.54,126.92,123.09,122.68,38.52,24.60,24.60,13.09.HRMS:calcd for C22H22ON[M+H]+:316.1696; found:316.1705.

[0234] Example 48: Synthesis of Compound II-30: (E)-1-Formylguaiazulene-8-3'-pyridinylvinyl

[0235] The product was prepared according to the steps of Example 19 using 3-pyridinecarboxaldehyde as raw material with a yield of 12%.

[0236] 1 H NMR (400MHz, CDCl3): δ10.42(s,1H),8.75(s,1H),8.56(d,1H,J=4.8Hz),8.29(s,1H),8.18(m,2H),8.00(d,1H,J=7.6Hz) ,7.70(m,2H),7.35(dd,1H,J=4.8Hz,7.6Hz),7.18(d,1H,J=16.8Hz),3.18(m,1H),2.59(s,3H),1.42(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ185.66,149.54,149.28,147.88,144.45,144.31,140.70,137.76,136.30,135.5 4,135.13,133.07,132.30,130.72,128.53,127.42,126.40,123.90,38.38,24.47,12.97.HRMS:calcd for C22H22ON[M+H]+:316.1696; found:316.1695.

[0237] Example 49 Compound II-31: Synthesis of (E)-1-Formylguaiazulene-8-4'-pyridinylvinyl

[0238] The product was prepared according to the steps of Example 19 using 4-pyridinecarboxaldehyde as raw material, with a yield of 24%.

[0239] 1H NMR (400MHz, CDCl3): δ10.35(s,1H),8.60(m,2H),8.30(m,2H),8.13(s,1H),7.68(s,2H),7.41 (d,2H,J=5.2Hz),7.06(d,1H,J=14.0Hz),3.17(m,1H),2.57(s,3H),1.41(d,6H,J=7.6Hz).13C NMR (100MHz, CDCl3) δ185.50,150.34,150.17,148.14,144.37,143.83,143.72,141.04,137.57,137.3 6,136.32,135.62,131.66,128.49,127.46,126.29,121.27,121.05,38.35,24.44,12.94.HRMS:calcd for C22H22ON[M+H]+:316.1696; found:316.1693.

[0240] Example 50: Synthesis of Compound II-32: (E)-1-Formylguaiazulene-8-2'-pyrrolevinyl

[0241] The product was prepared according to the steps of Example 19 using 2-pyrrolecarboxaldehyde as raw material, with a yield of 24%.

[0242] 1 H NMR (400MHz, CDCl3): δ10.35(s,1H),9.96(s,1H),8.24(d,1H,J=16.0Hz,),8.1 2(d,1H,J=2.0Hz,),8.00(s,1H),7.81(d,1H,J=12.0Hz),7.59(dd,2H,J=12.0H z,2.0Hz),7.27(d,1H,J=16.0Hz),6.99,(d,1H,J=6.0Hz),6.47(d,1H,J=6.0Hz ),6.30(q,1H),3.12(p,J=16.0Hz,1H),2.50(s,3H),1.39(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ186.30,147.02,146.62,144.09,142.92,137.87,136.33,134.55,131.13,12 7.25,126.96,125.65,125.40,122.08,113.02,110.33,77.37,77.06,76.74,38.27,24.41,12.95.

[0243] Example 51: Synthesis of Compound II-33: (E)-1-Formylguaiazulene-8-3'-indolevinyl

[0244] The product was prepared according to the steps of Example 19 using 3-indolecarboxaldehyde as raw material with a yield of 26%.

[0245] 1 H NMR (400MHz, CDCl3): δ10.66(s,1H),9.06(s,1H),8.25(d,1H,J=2.0Hz),8.18(s,1H),8.00(d,1H,J=16.0Hz),7.95(m,1H),7.83(d,1H,J=11. 2Hz),7.64(dd,1H,J=11.2Hz,2.4Hz),7.53(d,1H,J=16.0Hz),7.39(m,2H),7.22(m,2H),3.17(m,1H),2.61(s,3H),1.42(d,6H,J=6.8Hz).13C NMR (100MHz, CDCl3) δ186.24,147.18,146.91,143.91,138.94,138.42,137.15,136.16,135.09,129.13,128.80,128.6 1,127.18,126.59,126.05,125.65,123.08,121.18,119.85,115.28,112.00,77.48,77.16,76.84,38.44,24.61,13.15.

[0246] Example 52: Synthesis of Compound II-34: (E)-1-Formylguaiazulene-8-2'-furylvinyl

[0247] The product was prepared according to the steps of Example 19 using 2-furancarboxaldehyde as raw material, with a yield of 37%.

[0248] 1HNMR (400MHz, CDCl3): δ10.61(s,1H),8.27(t,J=8.0Hz,1H),8.21(s,1H),7.92(d,J=16.0Hz,1H),7.65(dd,J=16.0,8.0,2H),7.48(s, 1H),7.06(d,J=16.0,1H),6.53(d,J=3.2Hz,1H),6.48(t,J=4.0Hz,1H),3.16(p,J=16.0Hz,1H),2.60(s,3H),1.41(d,J=3.2Hz,6H).13C NMR (400MHz, CDCl3) δ186.36,152.66,147.46,144.94,144.10,143.81,139.21,138.31,136.12,135.50, 131.23,128.30,127.52,127.00,122.32,112.21,111.39,38.57,29.90,24.67,24.67,13.16.HRMS:calcd for C21H21O2[M+H]+:305.1536; found:305.1545.

[0249] Example 53: Synthesis of Compound II-35: (E)-1-Formylguaiazulene-8-2'-thienylvinyl

[0250] The product was prepared according to the steps of Example 19 using 2-thiophenecarboxaldehyde as raw material with a yield of 34%.

[0251] 1H NMR(400M Hz, CDCl3): δ10.54 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.85 (d, J = 16.0Hz, 1H), 7.71 (d, J = 8.0Hz, 1H), 7.65 (d, J = 12.0Hz, 1H), 7.39 (d, J = 12. 0Hz,1H),7.32(d,J=18.0,1H),7.22(d,J=3.6Hz,1H),7.07(t,J=4.0Hz,1H),3.17(p,J=16.0Hz,1H),2.60(s,3H),1.41(d,J=3.2Hz,6H).13C NMR (400MHz, CDCl3) δ186.10,147.54,144.84,144.18,142.15,139.78,138.12,136.19,135.52,132. 44,128.41,128.18,128.06,127.82,127.51,126.91,126.67,38.57,24.67,24.67,13.16.HRMS:calcd for C21H21OS[M+H]+:321.1308; found:321.1316.

[0252] Example 54: Synthesis of Compound II-36: (E)-1-Formylguaiazulene-8-3'-guaiazulene vinyl

[0253] The product was prepared according to the steps of Example 19 using 3-guaiazulene carboxaldehyde as raw material, with a yield of 34%.

[0254] 1 HNMR (500MHz, CDCl3): δ10.66(s,1H),8.30(d,J=15.4Hz,1H),8.21(s,1H),8.15(s,1H),8.05 (d,J=15.3Hz,2H),7.88(d,J=15.4Hz,1H),7.80(d,J=11.1Hz,1H),7.61(d,J=11.2Hz,1H),7. 31(d,J=10.5Hz,1H),6.97(d,J=10.6Hz,1H),3.14(dt,J=13.8,6.9Hz,1H),3.09(s,3H),3.04 (dt,J=13.7,6.9Hz,1H),2.61(d,J=17.5Hz,6H),1.41(d,J=6.9Hz,6H),1.36(d,J=6.9Hz,6H).

[0255] Example 55 Compound II-37: Synthesis of (E)-guaiazulene-4-vinyl (3'4'5'-trimethoxy)benzene

[0256] To 300 mg of t-BuOK was added 10 ml of tert-amyl alcohol, and the mixture was refluxed at 105°C with stirring for 30 minutes. 600 mg of 3,4,5-trimethoxybenzaldehyde was added, and a solution of 200 mg of guaiacyl azulene in tert-amyl alcohol was added dropwise. The mixture was refluxed at 105°C with stirring for 24 hours. The reaction solution was evaporated to dryness, and the residue was extracted with n-hexane. The mixture was purified by column chromatography using petroleum ether / ethyl acetate as the eluent. The yield was 20%.

[0257] 1 HNMR (400MHz, CDCl3): δ8.19 (d, 1H, J = 2.0Hz), 7.89 (d, 1H, J = 15.4Hz), 7.67 (s, 1H), 7.51-7.42 (m, 3H), 7.31 ( d,1H,J=16.8Hz),6.54(s,2H),3.93(s,6H),3.90(s,3H),3.09(m,1H),2.68(s,3H),1.38(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ153.56,141.78,140.21,138.66,136.80,136.78,136.51,134.98,133.99,133.2 0,133.09,129.11,125.99,120.39,111.93,104.21,61.08,56.25,56.12,53.54,38.38,24.81,13.14.

[0258] Example 56: Synthesis of Compound II-38: (E)-guaiazulene-4-vinyl(2'-methoxy)benzene

[0259] The product was prepared according to the procedure of Example 55 using 2-methoxybenzaldehyde as raw material with a yield of 46%.

[0260] 1H NMR (400MHz, CDCl3): δ8.15 (d, 1H, J = 2.0Hz), 8.03 (d, 1H, J = 15.4Hz), 7.78-7.63 (m, 3H), 7.52-7.43 (m, 3H), 7.22 (td, 1H, J = 8.0Hz ,2.0Hz),6.96(t,J=6.8Hz,1H),6.83(dd,J=8.0Hz,1.0Hz,1H),3.81(s,3H),3.04(m,1H),2.66(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ157.50,142.66,140.06,137.07,136.82,136.53,135.07,133.17,130.04,129.67,129.0 7,127.23,126.54,125.87,121.02,120.65,112.13,111.21,77.61,77.29,76.97,55.68,38.49,24.96,13.30.

[0261] Example 57: Synthesis of Compound II-39: (E)-Guaiazulene-4-vinyl(3'-methoxy)benzene

[0262] The product was prepared according to the procedure of Example 55 using 3-methoxybenzaldehyde as raw material with a yield of 32%.

[0263] 1 H NMR (400MHz, CDCl3): δ8.17 (d, 1H, J = 2.0Hz), 7.97 (d, 1H, J = 15.4Hz), 7.65 (s, 1H), 7.47-7.11 (m, 4H ),6.83(dd,J=8.0Hz,1.0Hz,1H),3.81(s,3H),3.04(m,1H),2.66(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ160.10,141.83,140.29,138.86,137.00,136.96,136.62,135.04,133.91,133 .25,130.04,129.92,126.00,120.45,119.90,114.05,112.50,112.10,55.41,38.45,24.89,13.21.

[0264] Example 58: Synthesis of Compound II-40: (E)-guaiazulene-4-vinyl(4'-methoxy)benzene

[0265] The product was prepared according to the procedure of Example 55 using 4-methoxybenzaldehyde as raw material with a yield of 28%.

[0266] 1 H NMR (400MHz, CDCl3): δ8.16 (d, 1H, J = 2.0Hz), 7.86 (d, 1H, J = 15.4Hz), 7.64 (d, J = 4.0Hz, 1H), 7.52 (d, J = 9.2Hz, 2H), 7.46 (d, J = 2.8Hz ,2H),7.43(s,2H),7.31(d,J=15.6Hz,1H),6.88(d,J=9.2Hz,2H),3.75(s,3H),3.05(m,1H),2.66(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ160.05,142.33,139.95,136.85,136.68,136.40,135.02,133.65,133.13 ,130.23,128.55,127.46,125.92,120.31,114.39,114.01,112.02,55.45,38.43,24.91,13.25.

[0267] Example 59: Synthesis of Compound II-41: (E)-guaiazulene-4-vinyl(2',3'-dimethoxy)benzene

[0268] The product was prepared according to the steps of Example 55 using 2,3-dimethoxybenzaldehyde as raw material, with a yield of 30%.

[0269] 1H NMR (400MHz, CDCl3): δ8.18 (d, 1H, J = 2.0Hz), 8.05 (d, 1H, J = 15.4Hz), 7.74 (d, 1H, J = 15.4Hz), 7.65 (d, J = 4.0Hz, 1H), 7.54-7.46 (m, 3H), 7.35 (dd, J = 8. 0Hz, 2.0Hz, 1H), 7.06 (t, J=9.0Hz, 1H), 6.81 (dd, J=7.2Hz, 2.0Hz, 1H), 3.8 5(s,3H),3.81(s,3H),3.06(m,1H),2.66(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ153.31,147.56,142.29,140.27,137.06,136.97,136.63,135.10,133.26,131.65 ,130.98,128.43,125.95,124.45,120.63,118.58,112.23,112.10,61.35,55.96,38.49,24.93,13.25.

[0270] Example 60: Synthesis of Compound II-42: (E)-guaiazulene-4-vinyl(2',4'-dimethoxy)benzene

[0271] The product was prepared according to the procedure of Example 55 using 2,4-dimethoxybenzaldehyde as raw material, with a yield of 13%.

[0272] 1 H NMR (400MHz, CDCl3): δ8.16 (d, 1H, J = 2.0Hz), 7.94 (d, 1H, J = 15.4Hz), 7.72-7.63 (m, 3H), 7.55-7.47 (m, 3H), 6.55 (dd, J = 8.0Hz,2.0Hz,1H),6.48(d,J=2.8Hz,1H),3.87(s,3H),3.82(s,3H),3.08(m,1H),2.67(s,3H),1.36(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ161.26,158.62,142.96,139.66,136.75,136.33,136.16,134.92,132.96,128.77,1 28.07,127.66,125.66,120.37,119.60,111.84,105.22,98.58,55.63,55.51,55.32,38.34,24.83,13.16.

[0273] Example 61: Synthesis of Compound II-43: (E)-guaiazulene-4-vinyl(2',5'-dimethoxy)benzene

[0274] The product was prepared according to the procedure of Example 55 using 2,5-dimethoxybenzaldehyde as raw material, with a yield of 41%.

[0275] 1 H NMR (400MHz, CDCl3): δ8.17 (d, 1H, J = 2.0Hz), 8.02 (d, 1H, J = 15.4Hz), 7.74 (d, J = 16.4Hz, 1H), 7.65 (d, J = 4.0Hz, 1H), 7. 53-7.44(m,3H),7.28(s,1H),6.78(d,J=2.8Hz,1H),3.78(s,6H),3.05(m,1H),2.67(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ153.92,153.90,152.03,142.40,140.10,137.03,136.83,136.53,135.03,133.15,13 0.26,128.81,127.29,125.87,120.60,114.56,112.47,112.46,112.05,56.34,55.92,38.45,24.91,13.24.

[0276] Example 62: Synthesis of Compound II-44: (E)-guaiazulene-4-vinyl(2',6'-dimethoxy)benzene

[0277] The product was prepared according to the procedure of Example 55 using 2,6-dimethoxybenzaldehyde as raw material, with a yield of 24%.

[0278] 1H NMR (400MHz, CDCl3): δ8.53 (d, 1H, J = 15.4Hz), 8.17 (d, 1H, J = 2.0Hz), 7.76 (d, 1H, J = 15.4Hz), 7.63 (d, J = 4.0Hz, 1H), 7.58-7.46 (m, 3H) ,7.17(m,1H),6.58(d,J=7.6Hz,2H),6.47(td,J=9.4Hz,4.0Hz,1H),3.89(s,6H),3.07(m,1H),2.67(s,3H),1.35(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ159.10,144.29,139.61,136.92,136.31,136.26,134.99,133.27,132.95 ,129.03,125.49,125.23,120.45,114.96,112.17,106.24,104.12,55.99,38.39,24.88,13.19.

[0279] Example 63: Synthesis of Compound II-45: (E)-guaiazulene-4-vinyl (3', 4'-dimethoxy)benzene

[0280] The product was prepared according to the procedure of Example 55 using 3,4-dimethoxybenzaldehyde as raw material, with a yield of 19%.

[0281] 1 H NMR (400MHz, CDCl3): δ8.18 (d, 1H, J = 2.0Hz), 7.87 (d, 1H, J = 15.4Hz), 7.65 (d, J = 4.0Hz, 1H), 7.50-7.46 (m, 3H), 7.32 (d,J=16.0Hz,1H),7.17-7.13(m,2H),6.86(d,J=7.0Hz,1H),3.95(s,3H),3.88(s,3H),3.08(m,1H),2.67(s,3H),1. 37(d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ149.65,149.28,142.14,139.98,136.74,136.61,136.37,134.96,133 .86,133.11,130.48,127.65,125.89,120.76,120.29,111.90,111.30,109.30,56.02,56.00,38.36,24.82,13.15.

[0282] Example 64: Synthesis of Compound II-46: (E)-guaiazulene-4-vinyl(3',5'-dimethoxy)benzene

[0283] The product was prepared according to the procedure of Example 55 using 3,5-dimethoxybenzaldehyde as raw material, with a yield of 24%.

[0284] 1 H NMR (400MHz, CDCl3): δ8.17 (d, 1H, J = 2.0Hz), 7.97 (d, 1H, J = 15.4Hz), 7.66 (d, J = 4.0Hz, 1H), 7.48-7.40 (m, 3H), 7.28 (d, J = 16.8 Hz,1H),6.77(d,J=2.0Hz,2H),6.44(dd,J=2.2Hz,4.4Hz,1H),3.80(s,6H),3.06(m,1H),2.67(s,3H),1.37(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ161.17,141.71,140.29,139.40,136.97,136.91,136.60,135.00,133 .97,133.22,130.20,125.98,120.45,112.05,105.24,100.66,55.50,38.42,24.85,13.16.

[0285] Example 65: Synthesis of Compound II-47: (E)-Guaiazulene-4-vinyl (4'-methylmercapto)benzene

[0286] The product was prepared according to the steps of Example 55 using 4-methylmercaptobenzaldehyde as raw material with a yield of 12%.

[0287] 1H NMR (400MHz, CDCl3): δ8.18 (d, 1H, J = 2.0Hz), 7.96 (d, 1H, J = 15.4Hz), 7.53 (d, J = 8.6Hz, 2H), 7.48-7.43 (m, 3H), 7.32(d,J=16.8Hz,1H),7.26(d,J=8.6Hz,2H),3.09(m,1H),2.67(s,3H),2.50(s,3H),1.37(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ141.85,140.13,139.04,136.78,136.43,134.94,134.18,133.31 ,133.16,128.88,127.49,126.60,125.94,120.24,111.90,38.37,24.80,15.72,13.13.

[0288] Example 66: Synthesis of Compound II-48: (E)-Guaiazulene-4-vinyl (4'-dimethylamino)benzene

[0289] The product was prepared according to the procedure of Example 55 using 4-dimethylaminobenzaldehyde as raw material, with a yield of 21%.

[0290] 1 HNMR (400MHz, CDCl3): δ8.15 (d, 1H, J = 2.0Hz), 7.83 (d, 1H, J = 15.4Hz), 7.62 (s, 1H), 7.55-7.43 (m, 4H), 7. 34(d,J=16.8Hz,1H),6.69(d,J=8.6Hz,2H),3.05(m,1H),2.94(s,6H),2.66(s,3H),1.36(d,6H,J=7.0Hz).

[0291] Example 67 Compound II-49: Synthesis of (E)-guaiazulene-4-vinyl-2'-pyridine

[0292] The product was prepared according to the steps of Example 55 using 2-pyridinecarboxaldehyde as raw material with a yield of 63%.

[0293] 1H NMR (400MHz, CDCl3): δ8.57(dd,J=5.2Hz,2.0Hz,1H),7.63(d,1H,J=4.0Hz),7.46(td,1H,J=7.4Hz,2.2Hz ),7.36(dd,J=3.2Hz,10.8Hz,2H),7.06-7.00(m,3H),3.03(m,1H),2.65(s,3H),1.33(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ161.44,149.53,148.07,140.06,137.12,136.70,136.47,136.28,13 5.39,133.43,125.36,124.76,123.06,121.37,112.45,39.94,38.58,38.38,24.92,13.14.

[0294] Example 68: Synthesis of Compound II-50: (E)-Guaiazulene-4-vinyl-3'-pyridine

[0295] The product was prepared according to the steps of Example 55 using 3-pyridinecarboxaldehyde as raw material, with a yield of 35%.

[0296] 1 H NMR (400MHz, CDCl3): δ8.78 (d, J=2.0Hz, 1H), 8.51 (dd, J=4.0Hz, 2.0Hz, 1H), 8. 18(d,1H,J=4.0Hz),8.00(d,1H,J=16.8Hz),7.85(d,1H,J=8.0Hz),7.67(d,1H,J =4.0Hz),7.48(dd,J=3.2Hz,10.8Hz,2H),7.43(d,1H,J=4.0Hz),7.38(d,1H,J=1 0.0Hz),7.28-7.24(m,2H),3.07(m,1H),2.66(s,3H),1.37(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ149.20,149.06,140.96,140.60,137.28,136.86,136.80,134.98,133 .35,133.14,132.97,131.73,130.00,126.16,123.70,120.24,112.00,38.41,24.81,13.14.

[0297] Example 69: Synthesis of Compound II-51: (E)-Guaiazulene-4-vinyl-4'-pyridine

[0298] The product was prepared according to the steps of Example 55 using 4-pyridinecarboxaldehyde as raw material with a yield of 38%.

[0299] 1 H NMR (400MHz, CDCl3): δ8.48(d,J=2.0Hz,1H),8.20(d,1H,J=4.0Hz),7.64(d,1H,J=4.0Hz),7.37(dd ,J=2.0Hz,12.0Hz,1H),7.27(d,1H,J=4.0Hz),7.09(d,2H,J=6.0Hz),6.89(d,1H,J=10.0Hz),3.02( m,1H),2.66(s,3H),1.37(d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ150.72,149.89,146.83,140.3 6,136.83,136.80,136.44,135.29,133.61,125.60,124.55,123.90,112.08,39.05,24.87,13.09.

[0300] Example 70: Synthesis of Compound II-52: (E)-3-acetylguaiazulene-4-vinyl(3',5'-dimethoxy-4'hydroxy)benzene

[0301] Compound II-37 was dissolved in dichloromethane, and 1.5 equivalents of acetyl chloride were added dropwise to the reaction mixture at room temperature. This was followed by 0.5 equivalents of anhydrous aluminum chloride and stirred for 20 hours. The mixture was concentrated under vacuum, extracted with dichloromethane (20 mL x 3), and evaporated in vacuo. The residue was purified by silica gel column chromatography with a yield of 21%.

[0302] 1HNMR (400MHz, CDCl3): δ8.20 (d, 1H, J = 2.0Hz), 7.92 (d, 1H, J = 15.4Hz), 7.68 (s, 1H), 7.51-7.42 (m, 3H), 7.31 ( d,1H,J=16.8Hz),6.87(s,2H),3.93(s,6H),3.10(m,1H),2.68(s,3H),2.35(s,3H),1.38(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ168.82,152.38,141.56,140.33,136.90,136.74,136.55,135.80,134.96,133.7 5,133.26,130.09,128.92,126.00,120.42,111.92,103.67,56.26,56.23,38.36,24.77,20.55,13.08.

[0303] Example 71: Synthesis of Compound II-53: (E)-3-acetylguaiazulene-4-vinyl(2'-methoxy)benzene

[0304] According to the steps of Example 70, II-38 was prepared as the starting material with a yield of 18%. 1 HNMR (400MHz, CDCl3): δ8.33 (d, 1H, J = 2.0Hz), 8.19 (d, 1H, J = 2.0Hz), 8.10 (d, 1H, J = 15.4Hz), 7.93 (dd, J = 8.0Hz, 3.2Hz, 1H), 7.72-7 .68(m,2H),7.54-7.48(m,3H),6.96(d,J=8.6Hz,1H),3.96(s,3H),3.11(m,1H),2.70(s,3H),2.64(s,3H),1.38(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ196.94,160.92,142.02,140.18,136.91,136.84,136.51,134.91,133.17,131.34,13 0.34,130.26,127.99,127.64,126.48,125.89,120.47,112.08,110.44,55.90,38.36,26.50,24.78,13.09.

[0305] Example 72 Compound II-54: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(3'-methoxy)benzene was prepared according to the steps of Example 70 using II-39 as raw material with a yield of 7%.

[0306] 1 HNMR (400MHz, CDCl3): δ8.19 (d, 1H, J = 2.0Hz), 8.10 (d, 1H, J = 15.4Hz), 7.83 (s, 1H), 7.80 (d, 1H, J = 8.0Hz), 7.67 (d, 1H, J = 2.4Hz), 7.59-7.52 (m, 2H), 7 .47(d,1H,J=2.4Hz),6.83(d,J=3.0Hz,1H),6.91(dd,J=3.0Hz,9.0Hz),3.9 5(s,3H),3.12(m,1H),2.71(s,3H),2.61(s,3H),1.37(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ162.35,141.81,140.33,136.80,136.55,135.13,133.95,133.19,13 2.45,132.07,125.73,120.92,113.56,112.71,111.71,55.59,38.36,29.23,24.75,13.06.

[0307] Example 73 Compound II-55: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(4'-methoxy)benzene

[0308] According to the steps of Example 70, II-40 was prepared as the starting material with a yield of 9%. 1 HNMR (400MHz, CDCl3): δ8.20 (d, 1H, J = 2.0Hz), 7.94 (s, 1H), 7.83 (d, 1H, J = 15.4Hz), 7.75 (d, J = 11.4Hz, 1H), 7.60 (d, J = 10.0Hz, 2.0Hz, 1H), 7. 52(d,J=9.4Hz,2H),7.23(d,J=15.6Hz,1H),6.93(d,J=9.2Hz,2H),3.83(s,3H),3.12(m,1H),2.65(s,3H),2.59(s,3H),1.38(d,6H,J=7.0Hz).

[0309] Example 74: Synthesis of Compound II-56: (E)-3-acetylguaiazulene-4-vinyl(2',3'-dimethoxy)benzene

[0310] According to the steps of Example 70, II-41 was used as the starting material to prepare the product with a yield of 22%.

[0311] 1HNMR (400MHz, CDCl3): δ8.23(d,1H,J=2.0Hz),7.95(s,1H),7.93(d,1H,J=15.4Hz),7.81(d,1H,J=10.6Hz),7.67-7.59(m,3H),7.37(dd,J=8.0Hz,2.0 Hz,1H),7.11(t,J=9.0Hz,1H),6.88(dd,J=7.2Hz,2.0Hz,1H),3.88(d,6H,J =7.0Hz),3.14(m,1H),2.66(s,3H),2.61(s,3H),1.40(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ152.96,147.36,145.48,144.92,141.77,140.67,136.04,135.04,134.51,134.33,13 1.50,127.56,126.85,126.75,124.49,124.43,118.52,112.15,61.39,55.85,38.18,30.95,24.53,12.96.

[0312] Example 75 Compound II-57: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(2',4'-dimethoxy)benzene

[0313] According to the steps of Example 70, II-42 was used as the starting material to prepare the product with a yield of 27%.

[0314] 1 H NMR (400MHz, CDCl3): δ12.86 (s, 1H), 8.19 (d, 1H, J = 2.0Hz), 8.06 (s, 1H), 7.94 (d, 1H, J = 15.4Hz), 7.67 (s, 1H), 7.58 (d ,1H,J=15.4Hz),7.53-7.46(m,3H),6.47(d,J=2.8Hz,1H),3.95(s,3H),3.11(m,1H),2.68(s,3H),2.67(s,3H),1.39( d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ202.92,165.27,163.78,142.27,140.05,136.70,136.59,136.40,134.93, 133.15,129.81,129.09,128.03,125.87,120.36,119.06,113.80,111.75,99.65,56.02,38.33,26.43,24.77,13.09.

[0315] Example 76 Compound II-58: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(2',5'-dimethoxy)benzene

[0316] According to the steps of Example 70, II-43 was used as the starting material to prepare the product with a yield of 7%.

[0317] 1 H NMR (400MHz, CDCl3): δ8.20 (d, 1H, J = 2.0Hz), 8.10 (d, 1H, J = 15.4Hz), 7.71 (d, J = 16.4Hz, 1H), 7.69 (d, J = 4.0Hz, 1H), 7 .53-7.47(m,3H),7.40(s,1H),7.30(s,1H),4.00(s,3H),3.91(s,3H),3.11(m,1H),2.69(s,3H),2.67(s,3H),1.39(d ,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ198.65,153.77,151.39,141.67,140.45,136.93,136.64,134.95,133.24,1 32.48,131.63,128.03,127.59,125.95,120.51,112.65,111.77,110.37,56.20,56.16,38.37,32.10,24.74,13.06.

[0318] Example 77 Compound II-59: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(2',6'-dimethoxy)benzene

[0319] According to the steps of Example 70, II-44 was used as the starting material to prepare the product with a yield of 2%.

[0320] 1H NMR (400MHz, CDCl3): δ13.54 (s, 1H), 8.64 (d, 1H, J = 15.4Hz), 8.17 (d, 1H, J = 2.0Hz), 7.72 (d, 1H, J = 7.6Hz), 7.69 (s, 1H ),7.65(s,1H),7.57-7.48(m,3H),6.55(d,J=7.6Hz,2H),4.02(s,3H),3.10(m,1H),2.68(s,3H),2.62(s,3H),1.38(d ,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ203.24,163.68,163.10,143.74,139.71,136.86,136.47,136.27,134.93,1 34.01,132.94,131.75,125.52,123.64,120.27,114.38,113.95,112.19,102.25,56.12,38.33,26.44,24.78,13.08.

[0321] Example 78: Synthesis of Compound II-60: (E)-3-acetylguaiazulene-4-vinyl(3',4'-dimethoxy)benzene

[0322] According to the steps of Example 70, II-45 was used as the starting material to prepare the product with a yield of 20.4%.

[0323] 1 H NMR (400MHz, CDCl3): δ8.19 (d, 1H, J = 2.0Hz), 8.00 (d, 1H, J = 15.4Hz), 7.76 (d, J = 4.0Hz, 1H), 7.67 (s, 1H), 7.55-7.4 6(m,3H),7.26(m,2H),4.05(s,3H),3.98(s,3H),3.11(m,1H),2.68(s,3H),2.62(s,3H),1.39(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ200.14,151.86,141.82,140.30,136.72,136.53,135.12,133.30,133.21,132.3 5,131.20,130.30,125.81,120.73,112.35,111.62,110.17,56.22,56.17,38.35,29.88,24.75,13.07.

[0324] Example 79 Compound II-61: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(3',5'-dimethoxy)benzene

[0325] According to the steps of Example 70, II-46 was used as the starting material to prepare the product with a yield of 15.1%.

[0326] 1 HNMR (400MHz, CDCl3): δ8.18 (d, 1H, J = 2.0Hz), 7.88 (d, 1H, J = 15.4Hz), 7.67 (s, 1H), 7.51 (dd, = 4.0Hz, 2.0Hz, 1H), 7.43-7.39 (m, 3H), 6. 92(d,J=2.0Hz,2H),6.47(d,J=2.2Hz,1H),3.93(s,3H),3.86(s,3H),3.10(m,1H),2.67(s,3H),2.53(s,3H),1.38(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ204.24,161.54,158.50,141.43,140.47,137.31,136.93,136.81,136.64,135.06,133.25,1 32.55,131.12,125.84,124.24,120.70,111.77,102.71,98.33,80.06,55.80,55.60,38.36,32.90,24.73,13.04.

[0327] Example 80 Compound II-62: Synthesis of (E)-3-acetylguaiazulene-4-vinyl(4'-methylmercapto)benzene was prepared according to the steps of Example 70 using II-47 as raw material with a yield of 18.6%.

[0328] 1H NMR (400MHz, CDCl3): δ8.21 (d, 1H, J = 2.0Hz), 8.02 (d, 1H, J = 15.4Hz), 8.01 (d, J = 8.6Hz, 1H), 7.77 (dd, J = 9.0Hz, 3.0Hz, 1H), 7.69 (d, J = 8.6Hz, 1 H),7.54-7.45(m,3H),7.39(d,J=5.8Hz,1H),7.36(d,J=2.0Hz,1H),3.12(m,1H),2.70(d,J=7.0Hz,6H),2.49(s,3H),1.40(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ198.88,142.86,141.36,140.39,136.94,136.73,136.55,134.95,134.52,133.28,13 2.79,132.24,130.02,129.99,129.71,126.09,125.31,120.21,111.82,38.36,28.28,24.76,16.05,13.09.

[0329] Example 81: Synthesis of Compound II-63: (E)-3-acetylguaiazulene-4-vinyl(4'-dimethylamino)benzene

[0330] According to the steps of Example 70, II-48 was prepared as the starting material with a yield of 11%. 1 HNMR (400MHz, CDCl3): δ8.16 (d, 1H, J = 2.0Hz), 7.889 (s, 1H), 7.76 (d, 1H, J = 10.0Hz), 7.72 (d, 1H, J = 15.4Hz), 7.55 (dd, J = 9.0Hz, 3.0Hz, 1H), 7.4 8(d,J=8.6Hz,2H),7.26(d,J=15.8Hz,1H),6.74(d,J=2.0Hz,1H),3.10( m,1H),3.00(s,3H),2.63(s,3H),2.59(s,3H),1.38(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ201.84,150.70,144.00,139.90,135.66,134.70,133.86,128.75,127.20,125.70,124.18,38.09,31.33,24.51,12.95.

[0331] Example 82: Synthesis of Compound II-64: (E)-3-acetylguaiazulene-4-vinyl-2'-pyridine

[0332] According to the steps of Example 70, II-49 was used as the starting material to prepare the product with a yield of 11.3%.

[0333] 1 H NMR (400MHz, CDCl3): δ8.53 (dd, J=5.2Hz, 2.0Hz, 1H), 8.24 (d, 1H, J=4.0Hz), 7.97 (s, 1H), 7.60-7.55 (m, 3H) ,7.45(d,10.2Hz,1H),7.24(t,J=1.2Hz,1H),7.11(dd,J=5.8Hz,2.0Hz,1H),3.11(m,1H),2.73(s,3H),2.60( s,3H),1.36(d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ196.34,161.44,152.46,148.86,144.62,141.48,141 .23,136.74,136.64,135.83,134.34,131.54,126.26,124.29,123.26,121.22,37.92,30.54,24.51,13.04.

[0334] Example 83: Synthesis of Compound II-65: (E)-3-acetylguaiazulene-4-vinyl-3'-pyridine

[0335] According to the steps of Example 70, II-50 was used as the starting material to prepare the product with a yield of 11.6%.

[0336] 1H NMR (400MHz, CDCl3): δ8.73 (d, J = 2.0Hz, 1H), 8.52 (dd, J = 4.0Hz, 2.0Hz, 1H), 8.26 (d, 1H, J = 4.0Hz), 8.06 (d, 1H, J = 16.8Hz), 8.01 (s, 1H), 7.98 (dt, 1H, J = 1.4Hz, 9.8Hz), 7.74 (d, J = 11.6Hz, 1H), 7.65 (dd, J = 3.2Hz, 10.8Hz, 2H), 7.33 (d, 1H, J = 4.0Hz), 7.16 (d, 1H, J = 16. 0Hz),3.15(m,1H),2.68(s,3H),2.62(s,3H),1.39(d,6H,J=7.0Hz).13CNMR(100MHz,CDCl3)δ196.18,149.20,149.00,145.47,144. 62,142.18,141.37,136.22,136.02,135.16,134.62,133.30,128.91,126.82,126.34,124.82,123.89,38.18,30.65,24.50,12.97.

[0337] Example 84: Synthesis of Compound II-66: (E)-3-acetylguaiazulene-4-vinyl-4'-pyridine

[0338] According to the steps of Example 70, II-51 was used as the starting material to prepare the product with a yield of 6.1%.

[0339] 1 H NMR (400MHz, CDCl3): δ8.46(d,J=6.8Hz,2H),8.26(d,1H,J=4.0Hz),8.00(s,1H),7.58(dd,J=2.0Hz,12.0Hz,1H),7.32( d,1H,J=11.8Hz),7.17(d,2H,J=6.8Hz),3.48(s,3H),3.13(m,1H),2.73(s,3H),2.61(s,3H),1.37(d,6H,J=7.0Hz).13C NMR (100MHz, CDCl3) δ196.16,151.32,148.84,144.95,141.72,141.64,136.71,13 5.68,134.64,131.35,126.15,124.64,124.18,53.44,37.93,30.49,24.50,13.03.

[0340] Example 85 Compound II-67: Synthesis of (E)-1-(guaiazulene-8'-(3",4",5"-trimethoxyphenyl)vinyl)cyanoacetyl

[0341] According to the steps of Example 70, II-37 and nitrile acetyl were used as raw materials to prepare the product with a yield of 18.9%.

[0342] 1 H NMR (400MHz, CDCl3): δ8.17(d,J=1.4Hz,1H),7.61(s,1H),7.43(dd,J=10.0Hz,4.0Hz,1H),6.89(d,J=7.0Hz,1H),6.41(s,2H),6.34( s,2H),3.71(s,3H),3.62(s,3H),3.60(d,2H,J=4.0Hz),3.07(p,J=16.0Hz,1H),2.57(s,3H),2.50(s,3H),1.33(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ168.81,156.98,153.07,146.87,145.75,142.99,136.61,135.09,1 31.44,126.42,118.86,118.25,104.25,60.73,56.02,38.18,24.49,24.43,20.99,12.79.

[0343] Example 86 Compound II-68: Synthesis of (E)-1-(guaiazulene-8'-(3",4",5"-trimethoxyphenyl)vinyl)benzoyl

[0344] According to the steps of Example 70, II-37 and benzoyl were used as raw materials to prepare the product with a yield of 15.6%.

[0345] 1HNMR (400MHz, CDCl3): δ8.28(s,1H),7.85(d,J=6.2Hz,2H),7.75(s,1H),7.61(s,2H),7.51-7.45(m,2H),7.35(t,J=7.6Hz,2H) ,7.04(d,J=17.0Hz,1H),6.84(s,2H),3.83(s,3H),3.72(s,6H),3.16(p,J=16.0Hz,1H),2.63(s,3H),1.42(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ213.01,179.29,160.68,153.19,144.10,141.06,140.68,140.43,138.45,136.03,135.91,134.37,133.44, 132.86,132.04,131.44,130.19,127.97,125.21,124.52,104.12,89.11,88.71,60.95,55.90,38.29,31.60,24.59,22.67,12.92.

[0346] Example 87 Compound II-69: (E)-1-(guaiazulene-8'-(3",4",5"-trimethoxyphenylvinyl)vinyl)chloroacetyl

[0347] According to the steps of Example 70, II-37 and chloroacetyl were used as raw materials to prepare the product with a yield of 18.3%.

[0348] 1H NMR (400MHz, CDCl3): δ8.24(d,J=1.4Hz,1H),7.91(s,1H),7.84(d,J=11.8Hz,1H),7.74(d,J=16.8Hz,1H),7.66(dd,J=10.0Hz,4.0Hz,1H), 7.24(d,J=7.0Hz,1H),6.86(s,2H),4.69(s,2H),3.94(s,3H),3.89(s,3H),3.16(p,J=16.0Hz,1H),2.60(s,3H),1.39(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ189.10,170.68,153.42,146.34,145.60,142.79,139.72,138.74,136.89,136.56,134.5 1,134.00,132.86,132.28,127.29,125.20,122.46,104.53,61.00,56.18,48.45,40.61,38.25,24.48,12.98.

[0349] Example 88 Compound II-70: (E)-1-(guaiazulene-8'-(3",4",5"-trimethoxyphenyl)vinyl)benzofuranacetyl

[0350] According to the steps of Example 70, II-37 and benzofuran acetyl were used as raw materials to prepare the product with a yield of 17.1%.

[0351] 1H NMR (400MHz, CDCl3): δ8.31(d,J=1.4Hz,1H),8.04(s,1H),7.63(d,J=1.8Hz,1H),7.62(s, 1H),7.56-7.54(m,2H),7.51(s,1H),7.46(d,J=8.2Hz,1H),7.39(td,J=7.0Hz,2.0Hz,1H), 7.24(dd,J=8.0Hz,2.0Hz,1H),7.23(d,J=1.4Hz,1H),6.94(d,J=15.6Hz,1H),6.45(s,2H) ,3.83(s,3H),3.75(s,6H),3.18(p,J=16.0Hz,1H),2.67(s,3H),1.43(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ182.55,155.71,154.95,153.14,144.98,140.57,136.18,134.75,133.71,132.46,127.56,127.51,12 6.25,125.09,124.78,123.52,122.91,121.09,115.49,114.67,112.27,103.88,60.90,55.90,38.33,31.61,24.58,12.97.

[0352] Example 89 Compound II-71: (E)-guaiazulenyl-1-nitromethylpyrrolidine-4-(3', 4', 5'-trimethoxy)phenylvinyl

[0353] A mixture of equal amounts of II-18, pyrrolidine, and two equivalents of sodium triacetoxyborohydride was dissolved in 10 mL of dichloromethane, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with water, and the organic layer was washed with saturated sodium chloride solution. The resulting solution was dried over magnesium sulfate and concentrated to dryness. The compound was obtained by column chromatography using petroleum ether and ethyl acetate as eluents in a 59% yield.

[0354] 1H NMR (400MHz, CDCl3): δ8.62(d,J=15.8Hz,1H),8.11(s,1H),7.57(s,1H),7.39(s,1H),7.20(d,J=10.4Hz,1H),6.98(d,J=16. 8Hz,1H),6.85(s,2H),3.93(s,6H),3.90(s,3H),3.06(q,J=7.0Hz,1H),2.62(m,7H),1.79(s,4H),1.36(d,J=6.4Hz,6H).13C NMR (100MHz, CDCl3) δ153.52,145.00,141.46,138.31,134.75,134.38,133.50,1 30.03,124.13,119.42,104.35,61.03,56.27,54.07,38.00,24.65,23.56,12.91.

[0355] Example 90 Compound II-72: (E)-guaiazulenyl-1-nitromethylpiperidin-4-(3', 4', 5'-trimethoxy)phenylvinyl

[0356] According to the procedure of Example 89, II-18 and piperidine were used as raw materials to prepare the product with a yield of 61%.

[0357] 1 H NMR (400MHz, CDCl3): δ8.62(d,J=15.8Hz,1H),8.11(s,1H),7.49(s,1H),7.39(d,J=11.4Hz,1H),7.19(d,J=10.4Hz,1H),6.94(d,J=16.8Hz ,1H),6.81(s,2H),3.91(s,6H),3.89(s,3H),3.77(s,2H),3.06(q,J=7.0Hz,1H),2.63(s,3H),1.58-1.42(m,6H),1.36(d,J=6.4Hz,6H).13C NMR (100MHz, CDCl3) δ153.54,145.57,142.46,139.81,138.59,138.45,134.78,134.55,133.97, 133.24,132.56,123.65,104.68,61.04,58.86,56.43,54.57,53.50,38.00,26.38,24.69,12.94.

[0358] Example 91 Compound II-73: (E)-2-(guaiazulene-8'-(3",4",5"-trimethoxyphenylvinyl)vinyl)malononitrile

[0359] According to the steps of Example 19, II-18 and malononitrile were used as raw materials to prepare the product with a yield of 71%.

[0360] 1 H NMR (400MHz, CDCl3): δ8.54(s,1H),8.45(s,1H),8.25(s,1H),7.76-7.68(m,2H),7.60(d,J=17.8Hz,1H),7.17(d,J= 17.8Hz,1H),6.80(s,2H),3.97(s,3H),3.91(s,3H),3.19(p,J=16.0Hz,1H),2.59(s,3H),1.42(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ153.83,150.57,150.33,146.48,145.53,140.36,139.59,137.50,136.76,136.13 ,135.63,131.57,131.32,130.45,120.72,117.08,116.35,104.18,61.07,56.31,38.49,24.38,13.13.

[0361] Example 92 Compound II-74: (E)-2-(guaiazulene-8'-(3",4",5"-trimethoxyphenylvinyl)vinyl)malonic acid dimethyl ester

[0362] According to the steps of Example 19, II-18 and dimethyl malonate were used as raw materials to prepare the product with a yield of 82%.

[0363] 1HNMR (400MHz, CDCl3): δ8.71(s,1H),8.12(d,J=2.0Hz,1H),7.82(d,J=16.0Hz,1H),7.62(s,1H),7.51(dd,J=10.4Hz,1.4Hz,1H),7.46(d,J= 10.6Hz.1H),7.09(d,J=16.0Hz,1H),6.86(s,2H),3.92(m,12H),3.61(s,3H),3.10(p,J=16.0Hz,1H),2.57(s,3H),1.37(d,J=8.0Hz,6H).13C NMR (100MHz, CDCl3) δ168.88,165.44,153.46,145.66,145.32,142.42,139.69,138.79,136.98,136.03,134.63,134.54,132.25,131.96,127.6 1,127.50,120.13,117.32,104.39,104.30,77.46,77.14,76.83,61.01 ,60.97,56.15,52.54,51.86,38.35,38.17,24.48,24.44,13.04,12.98.

[0364] Example 93 Compound II-75: (E)-2-(guaiazulene-8'-(3",4",5"-trimethoxyphenylvinyl)vinyl)malonic acid diethyl ester

[0365] According to the steps of Example 19, II-18 and diethyl malonate were used as raw materials to prepare the product with a yield of 76%.

[0366] 1H NMR (400MHz, CDCl3): δ8.64(s,1H),8.11(d,J=2.0Hz,1H),7.84(d,J=16.0Hz,1H),7.70(s,1H),7.49(dd,J=10.4Hz,1.4Hz,1H),7.44(d,J=10.6Hz.1H) ,7.09(d,J=16.0Hz,1H),6.85(s,2H),4.41(q,J=7.2Hz,2H),4.09(q,J=7.2 Hz,2H),3.92(m,12H),3.09(p,J=16.0Hz,1H),2.57(s,3H),1.37(m,9H).13C NMR (100MHz, CDCl3) δ168.44,165.09,153.58,153.49,145.55,144.96,142. 22,138.91,138.78,137.36,136.73,135.86,134.57,134.39,132.34,132.0 0,127.28,127.20,120.31,118.53,104.39,104.29,77.44,77.12,76.80,61.38,60.94,60.82,56.17,38.16,24.48,24.45,14.08,13.93,13.01,12.98.

[0367] Performance Test 1 Anti-tumor Activity Test

[0368] Experimental method: MTT assay

[0369] Cell lines: human chronic myeloid leukemia cells K562, human breast cancer cells MDA-MB-231, human pancreatic cancer cells ASPC-1

[0370] Tumor cells in the logarithmic phase were suspended at a concentration of 200,000 cells / mL, and 200 μL was added to each well of a 96-well cell culture plate. The cells were incubated in an incubator for 4 hours (37°C, 5% CO2). Five concentration gradients of the test sample were set (three replicates per concentration), along with negative and positive controls. 2 μL of blank solution or sample solution was added to each well and incubated for 72 hours. 10 μL of MTT solution was added to each well and incubated for another 4 hours. The incubation was terminated, and the cells were centrifuged for 8 minutes (37°C, 2000 rpm), and the culture medium was aspirated. 100 μL of DMSO was added to each well and the plates were shaken on a microplate oscillator for 15 minutes until the crystals were fully dissolved. The absorbance (OD) of each well was measured at 570 nm using a microplate reader. The average OD value of the three wells was taken, and the inhibition rate (IR%) of the cell proliferation was calculated using the formula IR% = (OD blank control - OD sample) / OD blank control × 100%. The Bliss method was then used to calculate the half-maximal inhibitory concentration (IC 50 The antitumor activities of some compounds of the present invention are shown in Table 1.

[0371] Table 1 Antitumor activity of guaiacyl stilbene derivatives

[0372]

[0373]

[0374]

[0375] The results showed that some of the compounds provided by the present invention had certain inhibitory activity against human chronic myeloid leukemia cells K562, human breast cancer cells MDA-MB-231, and human pancreatic cancer cells ASPC-1, and the compounds provided by the present invention have good prospects for development as anti-tumor drugs. Compounds II-1, II-2, II-4, II-6, II-10, II-11, II-13, II-14, II-15, II-18, II-22, II-23, II-24, II-26, II-28, II-29, II-30, II-31, II-32, II-33, II-35, II-49, II-51, II-52, II-64, and II-69 provided by the present invention had strong inhibitory activity against K562, with half inhibitory concentrations below 10 μM; The compounds II-4, II-7, II-11, II-12, II-13, II-14, II-18, and II-31 provided by the present invention have strong inhibitory activity against MDA-MB-231, with a half-inhibitory concentration of less than 10 μM; the compounds II-1, II-4, II-10, II-12, II-27, II-29, II-31, II-32, and II-35 provided by the present invention have strong inhibitory activity against ASPC-1, with a half-inhibitory concentration of less than 10 μM.

[0376] Test Example 2 Antiviral Activity Test

[0377] Experimental method: CPE detection method

[0378] MDCK cell monolayers were first incubated with influenza virus (A / Puerto Rico / 8 / 34(H1N1), PR / 8) at 37°C for 1 hour. The virus dilution was discarded, and the cells were maintained at 37°C in infection medium (RPMI1640, 4g / mL trypsin) containing various concentrations of the test drug. After incubation at 37°C for 48 hours, the MDCK cells were fixed with 100 μL of 4% paraformaldehyde for 20 minutes at room temperature. After removal of the formaldehyde, the MDCK cells were stained with 0.1% crystal violet for 30 minutes. The plates were washed and dried, and the intensity of the crystal violet staining in each well was measured at 570 nm using a microplate reader (Bio-Rad, USA). The IC50 value, defined as the compound concentration that inhibited CPE by 50% 48 hours after infection, was calculated. The anti-H1N1 activity of some compounds of the present invention is shown in Table 2.

[0379] Table 2: Anti-H1N1 activity of guaiacyl stilbene derivatives

[0380]

[0381]

[0382] The results showed that some of the compounds provided by the present invention had certain inhibitory activity against the H1N1 virus. This is the first discovery of compounds with antiviral activity from guaiacylamine derivatives, broadening the scope of antiviral drug development. Compounds II-20 and II-21 provided by the present invention achieved inhibition rates of 68.3% and 75.1% against H1N1 at 30 μM, respectively, demonstrating strong inhibitory effects. Their 50% inhibitory concentrations were 15.2 μM and 17.3 μM, respectively, indicating significant anti-H1N1 activity. Compound I-36 provided by the present invention achieved a 50% inhibitory concentration of 57.5 μM, demonstrating significant anti-H1N1 activity.

[0383] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A stilbene derivative of guaiazulene having a structure shown in Formula I or Formula II: Ar in Formula I is 4-ethylbenzene, 4-isopropylbenzene, 2-methoxybenzene, 3-methoxybenzene, 4-methoxybenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5-trimethoxybenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2-pyridyl, 3-pyridyl or 4-pyridyl; In formula II, R is an aldehyde group, hydrogen, an acetyl group or a substituted acyl group; the substituted acyl group is a chloroacetyl group; Ar in Formula II is benzene, 2-methylbenzene, 3-methylbenzene, 4-methylbenzene, 3,5-dimethylbenzene, 4-ethylbenzene, 4-isopropylbenzene, 2,3-dimethoxybenzene, 2,4-dimethoxybenzene, 2,5-dimethoxybenzene, 2,6-dimethoxybenzene, 3,4-dimethoxybenzene, 3,5-dimethoxybenzene, 3,4,5-trimethoxybenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 2-bromobenzene, 2,4-dichlorobenzene, 4-trifluoromethylbenzene, 2,6-dichlorobenzene, 2,6-difluorobenzene, 2-fluoro-6-chlorobenzene, 4-trifluoromethylbenzene, 2,6-dichlorobenzene, 2,6-difluorobenzene, 2-fluoro-6-chlorobenzene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 2-furan or 2-thiophene.

2. A stilbene derivative of guaiazulene, characterized in that: It has a structure represented by any one of formulas I-2 to I-18 or a structure represented by any one of formulas II-1 to II-69:

3. The method for preparing the stilbene derivative of guaiazulene according to any one of claims 1 to 2, comprising the following steps: (1) When the stilbene derivative of guaiacylamine has a structure shown in Formula I, the preparation method comprises the following steps: Under the action of phosphorus oxychloride, guaiazulene and N,N-dimethylformamide undergo a formylation reaction to obtain guaiazulene aldehyde having a structure represented by Formula Ia; Guaiazulene aldehyde having a structure represented by Formula Ia is subjected to a reduction reaction with a reducing agent to obtain guaiazulenol having a structure represented by Formula Ib; Guaiazulene methanol having a structure represented by Formula Ib undergoes a substitution reaction with triphenylphosphine hydrobromide to obtain guaiazulene triphenylphosphine bromide having a structure represented by Formula Ic; Under the action of sodium ethoxide, a compound having a structure represented by Formula Ic undergoes a Wittig reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure represented by Formula I; (2) When the stilbene derivative of guaiazulene has a structure shown in Formula II, the preparation method comprises the following steps: ① When R is an aldehyde group, under the catalysis of piperidine and acetic acid, guaiazulene aldehyde having a structure represented by Formula Ia undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure to obtain a stilbene derivative of guaiazulene having a structure represented by Formula II-a; ② When R is hydrogen, guaiazulene undergoes a condensation reaction with an aromatic aldehyde having an ArCHO structure under the catalysis of potassium tert-butoxide to obtain a stilbene derivative of guaiazulene having a structure shown in Formula II-b; ③ When R is an acetyl group or a substituted acetyl group, a stilbene derivative of guaiazulene having a structure shown in Formula II-b is subjected to a substitution reaction with an acetyl chloride compound under the catalysis of aluminum chloride to obtain a stilbene derivative of guaiazulene having a structure shown in Formula II-c; the acetyl chloride compound is acetyl chloride or chloroacetyl chloride; In formula II-c, R' is H or Cl.

4. The preparation method according to claim 3, characterized in that In (1), the molar ratio of phosphorus oxychloride to guaiacyl is 2 to 10:1; the temperature of the formylation reaction is -5 to 5°C, and the time is 1 to 2 hours; The molar ratio of the reducing agent to guaiazulene aldehyde is 1 to 3:1; the temperature of the reduction reaction is room temperature, and the time is 1 to 2 hours.

5. The preparation method according to claim 3, characterized in that In (1), the molar ratio of triphenylphosphine hydrobromide to guaiazulene methanol is 1 to 3:1, the temperature of the substitution reaction is 50 to 70° C., and the time is 3 to 7 hours; The molar ratio of the guaiazulene triphenylphosphine bromide to the aromatic aldehyde having the ArCHO structure is 1:0.33-1.5, and the molar ratio of the guaiazulene triphenylphosphine bromide to sodium ethoxide is 1:1-3; the temperature of the Wittig reaction is room temperature, and the time is 5-12 hours.

6. The preparation method according to claim 3, characterized in that In (2), when R is an aldehyde group, the molar ratio of the guaiazulene aldehyde to the aromatic aldehyde having an ArCHO structure is 1 to 3:1; the temperature of the condensation reaction is 50 to 80° C., and the time is 10 to 30 hours; When R is hydrogen, the molar ratio of the guaiacylamine to the aromatic aldehyde having the ArCHO structure is 1 to 3:1; the temperature of the condensation reaction is 90 to 120° C., and the time is 1 to 3 hours.

7. The preparation method according to claim 3, characterized in that In (2), when R is an acetyl group or a substituted acetyl group, the molar ratio of the stilbene derivative of guaiacylamine having the structure shown in formula II-b to the acetyl chloride compound is 1:1 to 3; the temperature of the substitution reaction is room temperature, and the time is 10 to 20 hours.

8. Use of the stilbene derivative of guaiaczulene according to any one of claims 1 to 2 or the stilbene derivative of guaiaczulene prepared by the preparation method according to any one of claims 3 to 7 in the preparation of anti-tumor and / or antiviral drugs; The anti-tumor drug is one or more of an anti-human myeloid leukemia drug, an anti-triple-negative breast cancer drug, and an anti-pancreatic cancer drug; The antiviral drug is an anti-H1N1 influenza virus drug.

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