A benzothiazole-containing flavonol derivative, and a preparation method and use thereof

Abstract

The application discloses a benzothiazole-containing flavonol derivative, characterized by a structural formula as shown in the formula L, wherein when R1 is not a hydrogen atom, R1 is a methyl group, a methoxy group, a tert-butyl group or a halogen atom at an ortho position, a para position or a meta position, and R2 is a methyl group, a methoxy group or a halogen atom. The benzothiazole-containing flavonol derivative is subjected to an anti-virus activity test, and it is proved that the benzothiazole-containing flavonol derivative has good anti-virus activity and can be applied to the preparation of a plant virus inhibiting agent.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pesticide synthesis, in particular to a preparation method of a benzothiazole-containing flavonol derivative and application thereof in antiviral aspect. BACKGROUND

[0002] Natural products and their biomimetic pesticides have the characteristics of environmental friendliness, unique action site and high selectivity, and play an increasingly important role in the prevention and control of plant diseases. Flavonols are a special class of flavonoids, also known as 3-hydroxyflavones, which are widely present in the plant kingdom, with about 2000 species, accounting for about 1 / 3 of the total number of flavonoids. The most common ones are kaempferol, myricetin and quercetin, etc. Flavonols have many important pharmacological effects and biological activities, and generally have strong antioxidant, antibacterial, antiviral, anticancer and other effects. Therefore, it is extremely possible to obtain organic active molecules with excellent antiviral activity by taking such compounds as a lead and modifying their structures. This also shows that flavonol compounds have further research and application value.

[0003] In 2017, Huang et al. (Huang M G, Nguyen X H, Zhang J P, Li Q, Wang Y H, Chen L J, Zhang C, Li P, Xue W. Org. Chem. 2017, 37(08): 2145-2152.) reported the synthesis of a series of flavonol derivatives containing phosphate groups. The biological assay results showed that the target compounds had good inhibitory activity against Xanthomonas campestris and Xanthomonas oryzae.

[0004] In 2015, Han et al. (Han, Y.; Ding, Y.; Xie, D. D.; Hu, D. Y.; Li, P.; Li, X. T.; Xue, W.; Jin, L. H.; Song, B. A. Eur. J. Med. Chem. 2015, 92: 732-737.) reported the synthesis of a series of flavonol compounds containing 1,4-pentadien-3-one groups, and evaluated their antiviral activity. The biological activity assay showed that most of the compounds had strong antiviral activity against cucumber mosaic virus.

[0005] In 2023, Gong et al. (Gong C. Y; Meng K. N; Sun Z. L; Zeng W; An Y. S; Zhou H. Q; Qiu Y. J; Liu D; Xue W. Chem. Biodivers. 2023, 21(2): e202301737) designed and synthesized a series of flavonol derivatives containing quinazolinone, and the antiviral biological activity test results showed that compound K5 showed significant therapeutic activity against TMV, with an EC 50The concentration was 139.6 μg / mL, which is better than the commercial drug ningnanmycin at 296.0 μg / mL.

[0006] Flavonols are derived from natural products. To date, there have been no reports on flavonol derivatives containing benzothiazole and their applications in pesticides, nor have there been any reports on their activity against tobacco mosaic virus. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing and applying benzothiazole-containing flavonol derivatives. By introducing active benzothiazole into the structure of flavonols, a series of benzothiazole-containing flavonol derivatives with anti-plant virus properties are synthesized.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] A flavonol derivative containing benzothiazole has the following general structural formula:

[0010]

[0011] When R1 is not a hydrogen atom, R1 contains a methyl, methoxy, tert-butyl, or halogen atom in the ortho, para, or meta position, and R2 is a methyl, methoxy, or halogen atom, with the halogen atom being fluorine, chlorine, or bromine.

[0012] A method for preparing a flavonol derivative containing benzothiazole, the synthetic route of which is as follows:

[0013] (1) The aldol condensation reaction of o-hydroxyacetophenone with substituted benzaldehyde yields (E)-1-(2-hydroxyphenyl)-3-(substituted phenyl)prop-2-en-1-one (intermediate 1);

[0014]

[0015] (2) 3-hydroxy-2-(substituted phenyl)-3-(substituted phenyl)prop-2-en-1-one, sodium hydroxide, and hydrogen peroxide were used as solvents in ethanol to prepare 3-hydroxy-2-(substituted phenyl)-4H-chromen-4-one (intermediate 2) at room temperature.

[0016]

[0017] (3) 2-aminobenzothiazole and chloroacetyl chloride were reacted with dichloromethane as solvent and potassium carbonate as acid binder at room temperature to give 2-chloro-N-(substituted benzo[d]thiazole-2-yl)acetamide (intermediate 3);

[0018]

[0019] (4) 2-chloro-N-(substituted benzo[d]thiazol-2-yl)acetamide and 3-hydroxy-2-(substituted phenyl)-4H-chromen-4-one were refluxed at 100 °C with N,N-dimethylformamide as solvent and potassium carbonate as acid binder to obtain a flavonol derivative (L) containing benzothiazol.

[0020]

[0021] Application of flavonol derivatives containing benzothiazole in antiviral treatment of plants.

[0022] The plant virus mentioned is tobacco mosaic virus.

[0023] The beneficial technical effects of this invention are as follows: This application introduces a 2-aminobenzothiazole group with excellent activity into the structure of flavonols, that is, a 2-chloro-N-(substituted benzo[d]thiazole-2-yl)acetamide structure is attached to the 3-position hydroxyl group of the flavonol. A series of benzothiazole-containing flavonol derivatives were synthesized. Through antiviral activity tests on the synthesized benzothiazole-containing flavonol derivatives, it was found that the compounds of this invention have excellent anti-plant virus activity and can be used to prepare anti-plant virus agents.

[0024] Specifically, compounds L17, L20, and L24 showed therapeutic activities against TMV of 67.5%, 71.8%, and 66.4%, respectively, which were superior to ningnanmycin (60.1%). Compounds L20 and L21 showed protective activities against TMV of 64.9% and 63.9%, respectively, which were also superior to ningnanmycin (61.2%). Based on the initial screening results, EC50 tests were performed on some compounds to assess their antiviral activity. The test results showed that L17, L20, and L24 had the highest EC50 values. 50 The values ​​were 223.2, 90.5, and 146.9 μg / mL, respectively, which were superior to ningnanmycin (252.0 μg / mL); the EC values ​​of L20 and L21 were... 50 The protective activities were 202.2 and 162.6 μg / mL, respectively, which were superior to those of ningnanmycin (204.2 μg / mL). Detailed Implementation

[0025] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0026] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included within this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0027] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0028] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0029] Example 1

[0030] The preparation method of N-(5-bromobenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L1) includes the following steps:

[0031] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (intermediate 1):

[0032] 3.5 g (25.7 mmol) of o-hydroxyacetophenone and 3.1 g (77.4 mmol) of sodium hydroxide were dissolved in 50 mL of ethanol and reacted at room temperature for 30 min. Then, 2.7 g (25.7 mmol) of benzaldehyde was slowly added. The reaction system was stirred at room temperature for 10–12 h, and the reaction was monitored by thin-layer chromatography (petroleum ether:ethyl acetate = 4:1, v / v). After the reaction was complete, the system was poured into ice water. The pH of the system was adjusted to approximately 5–6 with 10% dilute hydrochloric acid solution. After standing, a large amount of solid precipitated out. The solid was then filtered to obtain a yellow solid, which was dried for later use. The yield was 80%.

[0033] (2) Preparation of 3-hydroxy-2-phenyl-4H-chromen-4-one (intermediate 2):

[0034] 3.0 g of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one was dissolved in 50 mL of methanol and reacted at room temperature. After intermediate 1 was completely dissolved, 2.1 g (53.5 mmol) of sodium hydroxide (prepared as a 20% sodium hydroxide solution) was added. After 10 min, 2.7 g (80.3 mmol) of 30% hydrogen peroxide solution was slowly added. The mixture was stirred at room temperature for 8-10 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 4:1, volume ratio). After the reaction was complete, the system was poured into ice water and the pH was adjusted to 5-6. The mixture was allowed to stand until a large amount of solid precipitated. The solid was filtered and the filter cake was dried for later use. The yield was 73%.

[0035] (3) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0036] 2.0 g (8.7 mmol) of 5-bromobenzo[d]thiazol-2-amine and 2.4 g (17.5 mmol) of K₂CO₃ were dissolved in 50 mL of dichloromethane. After stirring at room temperature for 30 min, 2.1 mL (26.2 mmol) of chloroacetyl chloride was slowly added. The reaction mixture was stirred at room temperature for 2–3 h, and the reaction was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1, v / v). After the reaction was complete, the mixture was filtered, and the filter cake was washed with water to obtain a large amount of white solid, which was dried for later use. The yield was 82%.

[0037] (4) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L1):

[0038] 0.5 g (2.1 mmol) of 3-hydroxy-2-phenyl-4H-chromen-4-one and 0.9 g (6.3 mmol) of K₂CO₃ were dissolved in 25 mL of DMF and refluxed at 100 °C for 30 min. Then, 0.8 g (2.5 mmol) of N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide was added and refluxed at 100 °C for 3–4 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 3:1, v / v). After the reaction was complete, the system was poured into ice water and allowed to stand to precipitate a solid. The solid was obtained by filtration and then purified by column chromatography (petroleum ether:ethyl acetate 6:1, v / v) to obtain a white solid L1, with a yield of 43%.

[0039] Example 2

[0040] The preparation method of N-(5-bromobenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L2) includes the following steps:

[0041] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one (intermediate 1):

[0042] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-methylbenzaldehyde.

[0043] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one (intermediate 2):

[0044] As in step (2) of Example 1.

[0045] (3) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0046] As in step (3) of Example 1.

[0047] (4) Preparation of N-(5-bromobenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L2):

[0048] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one, yield: 39%.

[0049] Example 3

[0050] The preparation method of N-(5-bromobenzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L3) includes the following steps:

[0051] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0052] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of m-methoxybenzaldehyde.

[0053] (2) Preparation of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0054] As in step (2) of Example 1.

[0055] (3) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0056] As in step (3) of Example 1.

[0057] (4) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L3):

[0058] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced with an equimolar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromene-4-one, yield: 49%.

[0059] Example 4

[0060] The preparation method of N-(5-bromobenzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L4) includes the following steps:

[0061] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (intermediate 1):

[0062] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-fluorobenzaldehyde.

[0063] (2) Preparation of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one (intermediate 2):

[0064] As in step (2) of Example 1.

[0065] (3) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0066] As in step (3) of Example 1.

[0067] (4) Preparation of N-(5-bromobenzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L4):

[0068] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-fluorophenyl)-4H-chromene-4-one, yield: 50%.

[0069] Example 5

[0070] The preparation method of N-(5-bromobenzo[d]thiazo-2-yl)-2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L5) includes the following steps:

[0071] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tert-butylphenyl)prop-2-en-1-one (intermediate 1):

[0072] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-tert-butylbenzaldehyde.

[0073] (2) Preparation of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one (intermediate 2):

[0074] As in step (2) of Example 1.

[0075] (3) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0076] As in step (3) of Example 1.

[0077] (4) Preparation of N-(5-bromobenzo[d]thiazolyl)-2-((2-(4-(tert-butylphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L5):

[0078] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one, yield: 45%.

[0079] Example 6

[0080] The preparation method of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L6) includes the following steps:

[0081] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (intermediate 1):

[0082] As in step (1) of Example 1.

[0083] (2) Preparation of 3-hydroxy-2-phenyl-4H-chromen-4-one (intermediate 2):

[0084] As in step (2) of Example 1.

[0085] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0086] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazole-2-amine.

[0087] (4) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L6):

[0088] As in step (4) of Example 1, except that p-5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazol-2-amine, yield: 51%.

[0089] Example 7

[0090] The preparation method of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L7) includes the following steps:

[0091] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one (intermediate 1):

[0092] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-methylbenzaldehyde.

[0093] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one (intermediate 2):

[0094] As in step (2) of Example 1.

[0095] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0096] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazole-2-amine.

[0097] (4) Preparation of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L7):

[0098] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 37%.

[0099] Example 8

[0100] The preparation method of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L8) includes the following steps:

[0101] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0102] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of m-methoxybenzaldehyde.

[0103] (2) Preparation of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0104] As in step (2) of Example 1.

[0105] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0106] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazole-2-amine.

[0107] (4) Preparation of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L8):

[0108] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-methoxyphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 39%.

[0109] Example 9

[0110] The preparation method of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L9) includes the following steps:

[0111] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (intermediate 1):

[0112] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-fluorobenzaldehyde.

[0113] (2) Preparation of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one (intermediate 2):

[0114] As in step (2) of Example 1.

[0115] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0116] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazole-2-amine.

[0117] (4) Preparation of 3N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L9):

[0118] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 42%.

[0119] Example 10

[0120] The preparation method of 2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(6-chlorobenzo[d]thiazo-2-yl)acetamide (target compound L10) includes the following steps:

[0121] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tert-butylphenyl)prop-2-en-1-one (intermediate 1):

[0122] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-tert-butylbenzaldehyde.

[0123] (2) Preparation of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one (intermediate 2):

[0124] As in step (2) of Example 1.

[0125] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0126] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazole-2-amine.

[0127] (4) Preparation of 2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(6-chlorobenzo[d]thiazo-2-yl)acetamide (target compound L10):

[0128] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 40%.

[0129] Example 11

[0130] The preparation method of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L11) includes the following steps:

[0131] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0132] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of o-methoxybenzaldehyde.

[0133] (2) Preparation of 3-hydroxy-2-(2-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0134] As in step (2) of Example 1.

[0135] (3) Preparation of N-(6-chlorobenzo[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0136] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 6-chlorobenzo[d]thiazol-2-amine.

[0137] (4) Preparation of N-(6-chlorobenzo[d]thiazo-2-yl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L11):

[0138] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(2-methoxyphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 44%.

[0139] Example 12

[0140] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L12) includes the following steps:

[0141] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (intermediate 1):

[0142] As in step (1) of Example 1.

[0143] (2) Preparation of 3-hydroxy-2-phenyl-4H-chromen-4-one (intermediate 2):

[0144] As in step (2) of Example 1.

[0145] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0146] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0147] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamone (target compound L12):

[0148] As in step (4) of Example 1, except that N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide was replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 46%.

[0149] Example 13

[0150] The preparation method of N-(benzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L13) includes the following steps:

[0151] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one (intermediate 1):

[0152] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-methylbenzaldehyde.

[0153] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one (intermediate 2):

[0154] As in step (2) of Example 1.

[0155] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0156] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0157] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L13):

[0158] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 45%.

[0159] Example 14

[0160] The preparation method of N-(benzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L14) includes the following steps:

[0161] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0162] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of m-methoxybenzaldehyde.

[0163] (2) Preparation of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0164] As in step (2) of Example 1.

[0165] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0166] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0167] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L14):

[0168] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 36%.

[0169] Example 15

[0170] The preparation method of N-(benzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L15) includes the following steps:

[0171] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (intermediate 1):

[0172] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-fluorobenzaldehyde.

[0173] (2) Preparation of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one (intermediate 2):

[0174] As in step (2) of Example 1.

[0175] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0176] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0177] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L15):

[0178] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 37%.

[0179] Example 16

[0180] The preparation method of N-(benzo[d]thiazo-2-yl)-2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L16) includes the following steps:

[0181] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tert-butylphenyl)prop-2-en-1-one (intermediate 1):

[0182] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-tert-butylbenzaldehyde.

[0183] (2) Preparation of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one (intermediate 2):

[0184] As in step (2) of Example 1.

[0185] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0186] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0187] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L16):

[0188] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 32%.

[0189] Example 17

[0190] The preparation method of N-(benzo[d]thiazo-2-yl)-2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L17) includes the following steps:

[0191] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one (intermediate 1):

[0192] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-chlorobenzaldehyde.

[0193] (2) Preparation of 3-hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one (intermediate 2):

[0194] As in step (2) of Example 1.

[0195] (3) Preparation of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (intermediate 3):

[0196] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0197] (4) Preparation of N-(benzo[d]thiazo-2-yl)-2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L17):

[0198] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide, yield: 38%.

[0199] Example 18

[0200] The preparation method of N-(4-methylbenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L18) includes the following steps:

[0201] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (intermediate 1):

[0202] As in step (1) of Example 1.

[0203] (2) Preparation of 3-hydroxy-2-phenyl-4H-chromen-4-one (intermediate 2):

[0204] As in step (2) of Example 1.

[0205] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0206] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0207] (4) Preparation of N-(4-methylbenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L18):

[0208] As in step (4) of Example 1, the difference is that N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 40%.

[0209] Example 19

[0210] The preparation method of N-(4-methylbenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L19) includes the following steps:

[0211] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one (intermediate 1):

[0212] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-methylbenzaldehyde.

[0213] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one (intermediate 2):

[0214] As in step (2) of Example 1.

[0215] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0216] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0217] (4) Preparation of N-(4-methylbenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxo)acetamide (target compound L19):

[0218] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 44%.

[0219] Example 20

[0220] The preparation method of 2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L20) includes the following steps:

[0221] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0222] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of m-methoxybenzaldehyde.

[0223] (2) Preparation of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0224] As in step (2) of Example 1.

[0225] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0226] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0227] (4) Preparation of 2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L20):

[0228] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 42%.

[0229] Example 21

[0230] The preparation method of 2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L21) includes the following steps:

[0231] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (intermediate 1):

[0232] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-fluorobenzaldehyde.

[0233] (2) Preparation of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one (intermediate 2):

[0234] As in step (2) of Example 1.

[0235] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0236] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0237] (4) Preparation of 2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L21):

[0238] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 51%.

[0239] Example 22

[0240] The preparation method of 2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L22) includes the following steps:

[0241] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tert-butylphenyl)prop-2-en-1-one (intermediate 1):

[0242] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-tert-butylbenzaldehyde.

[0243] (2) Preparation of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one (intermediate 2):

[0244] As in step (2) of Example 1.

[0245] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0246] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0247] (4) Preparation of 2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L22):

[0248] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 46%.

[0249] Example 23

[0250] The preparation method of 2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L23) includes the following steps:

[0251] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-chlorophenyl)prop-2-en-1-one (intermediate 1):

[0252] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-chlorobenzaldehyde.

[0253] (2) Preparation of 3-hydroxy-2-(p-chlorophenyl)-4H-chromen-4-one (intermediate 2):

[0254] As in step (2) of Example 1.

[0255] (3) Preparation of N-(4-methyl[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0256] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 4-methylbenzo[d]thiazole-2-amine.

[0257] (4) Preparation of 2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazo-2-yl)acetamide (target compound L23):

[0258] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-chlorophenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide, yield: 53%.

[0259] Example 24

[0260] The preparation method of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L24) includes the following steps:

[0261] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (intermediate 1):

[0262] As in step (1) of Example 1.

[0263] (2) Preparation of 3-hydroxy-2-phenyl-4H-chromen-4-one (intermediate 2):

[0264] As in step (2) of Example 1.

[0265] (3) Preparation of N-(6-methoxy[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0266] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-methoxybenzo[d]thiazole-2-amine.

[0267] (4) Preparation of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L24):

[0268] As in step (4) of Example 1, except that N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide was replaced with an equimolar amount of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide, yield: 49%.

[0269] Example 25

[0270] The preparation method of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxy)acetamide (target compound L25) includes the following steps:

[0271] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(p-tolyl)prop-2-en-1-one (intermediate 1):

[0272] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of p-methylbenzaldehyde.

[0273] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one (intermediate 2):

[0274] As in step (2) of Example 1.

[0275] (3) Preparation of N-(6-methoxy[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0276] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-methoxybenzo[d]thiazole-2-amine.

[0277] (4) Preparation of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxy)acetamide (target compound L25):

[0278] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(p-tolyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide, yield: 37%.

[0279] Example 26

[0280] The preparation method of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L26) includes the following steps:

[0281] (1) Preparation of (E)-1-(2-hydroxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (intermediate 1):

[0282] As in step (1) of Example 1, the difference is that benzaldehyde is replaced with an equimolar amount of m-methoxybenzaldehyde.

[0283] (2) Preparation of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one (intermediate 2):

[0284] As in step (2) of Example 1.

[0285] (3) Preparation of N-(6-methoxy[d]thiazolyl)-2-chloroacetamide (intermediate 3):

[0286] As in step (3) of Example 1, the difference is that p-5-bromobenzo[d]thiazole-2-amine is replaced with an equimolar amount of 6-methoxybenzo[d]thiazole-2-amine.

[0287] (4) Preparation of N-(6-methoxybenzo[d]thiazo-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L26):

[0288] As in step (4) of Example 1, the difference is that 3-hydroxy-2-phenyl-4H-chromen-4-one is replaced with an equimolar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromen-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced with an equimolar amount of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide, yield: 36%.

[0289] The physicochemical properties of the benzothiazole-containing flavonol derivatives prepared in Examples 1-26 are shown in Table 1, and their nuclear magnetic resonance (NMR) spectra are as follows: 1 H NMR, carbon spectrum 13 C NMR and fluorine spectrum 19 F NMR data are shown in Table 2.

[0290] Table 1. Physicochemical properties of the target compounds obtained in Examples 1-22

[0291]

[0292]

[0293] Table 2. Nuclear magnetic resonance spectral data of benzothiazole-containing flavonol derivatives prepared in Examples 1-26

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Experimental Example 1

[0302] Anti-plant virus activity test:

[0303] 1. Extraction of TMV

[0304] The method of Luo Chaopeng (Luo Chaopeng et al., Tobacco Science and Technology, 2012, 10:77-80.) was adopted. Upper leaves of *Nicotiana tabacum* L. plants inoculated for more than 3 weeks were selected. The TMV system was used to infect the leaves, homogenize them in phosphate buffer, filter through double-layer gauze, centrifuge at 8000 r / min, treat twice with polyethylene glycol, centrifuge again, and resuspend the precipitate in phosphate buffer to obtain the purified TMV extract. The entire experiment was conducted at 4℃.

[0305] 2. Preparation for TMV activity assay

[0306] (1) Seedling cultivation: The tobacco variety used in the activity assay experiment was Tobacco denudata. The seedling cultivation operation followed the cultivation method of Tobacco denudata in 3.3.1. After the Tobacco denudata was placed in an artificial climate chamber for about 25 days, the Tobacco denudata with good growth and uniform leaf size was selected. The tender leaves at the top and the old leaves at the base were removed, and 4-6 leaves were retained to carry out the antiviral experiment.

[0307] (2) Preparation of the drug: Weigh 2 mg of the compound, dissolve it in 15 μL of DMSO, and then add 2 mL of 1% Tween water (1 mL of Tween 80 is added to 99 mL of secondary water and mixed well) to obtain a prepared drug solution with a concentration of 500 μg / mL.

[0308] 3. Therapeutic activity

[0309] Evenly sprinkle carborundum on tobacco leaves. Use a brush to evenly apply a 500-fold diluted virus solution to both sides of the tobacco leaves. After 30 minutes of infection, rinse off the carborundum from the leaf surface with water, then wipe the surface of the tobacco leaves dry with filter paper. Finally, use a brush to apply a 500 μg / mL solution to the right side of the tobacco leaf (leaf tip facing the experimenter). Incubate the leaves in an artificial climate chamber (28℃) for 2-3 days. When spots appear on the leaves, count the number of spots on both sides and calculate the inhibition rate. Repeat the experiment three times for each drug.

[0310] 4. Protective activity

[0311] First, apply the drug solution to the right side of the tobacco leaf with a brush. After 24 hours, sprinkle with carborundum. Then, use a flat brush to apply a 500-fold diluted virus solution to both sides of the tobacco leaf. After 30 minutes, rinse off the carborundum and incubate in an artificial climate chamber for 2-3 days. Count the spots on both sides of the tobacco leaf and calculate the inhibition rate. Repeat the experiment three times for each drug.

[0312] 5. Passivation activity

[0313] First, a 250-fold diluted virus solution was mixed with an equal volume of the target compound solution and allowed to incubate for 0.5 hours. Then, a whole tobacco leaf was sprinkled with carborundum (emery), and the mixed solution was inoculated onto the right half of the leaf using a brush. A 500-fold diluted virus solution was inoculated onto the left side of the leaf. After 30 minutes of infection, the carborundum on the leaf surface was rinsed off with clean water, and the leaves were placed in an artificial climate chamber for incubation. After 2-3 days of infection, the number of lesions on both sides of the leaf was counted, and the inhibition rate was calculated. Each drug was tested three times.

[0314] 6. Data Processing

[0315]

[0316] I: Inhibition rate;

[0317] L: Number of spots on the left leaf of the blank control group;

[0318] R: Number of spots on the right leaf after compound treatment;

[0319] The results of the bioactivity test for inhibiting plant fungi are shown in Table 3.

[0320] Table 3. Protective, therapeutic, and inactivating activities of the target compounds against tobacco mosaic virus (500 μg / mL) a

[0321]

[0322]

[0323] a An average of three repetitions; b Commercial drug Ningnanmycin.

[0324] Table 4 shows the EC50 activity of some target compounds against tobacco mosaic virus (Tobacco Mosaic Virus). 50 value a

[0325]

[0326] a An average of three repetitions; b Commercial drug Ningnanmycin.

[0327] Table 3 shows that some compounds exhibit good antiviral activity. Compounds L17, L20, and L24 showed therapeutic activities against TMV of 67.5%, 71.8%, and 66.4%, respectively, which were superior to ningnanmycin (60.1%). Compounds L20 and L21 showed protective activities against TMV of 64.9% and 63.9%, respectively, which were also superior to ningnanmycin (61.2%). Based on the initial screening results in Table 3, ECMO tests were performed on some compounds to assess their antiviral activity. 50 The test results are shown in Table 4. The test results indicate that the EC values ​​of L17, L20, and L24 are... 50 The values ​​were 223.2, 90.5, and 146.9 μg / mL, respectively, which were superior to ningnanmycin (252.0 μg / mL); the EC values ​​of L20 and L21 were... 50 The protective activities were 202.2 and 162.6 μg / mL, respectively, which were superior to ningnanmycin (204.2 μg / mL). These experimental activity data indicate that flavonol derivatives containing benzothiazole have a certain inhibitory effect on tobacco mosaic virus, and some of the target compounds exhibit excellent inhibitory activity against tobacco mosaic virus, suggesting they may serve as potential antiviral drugs with good application prospects.

[0328] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A flavonol derivative containing benzothiazole, characterized in that: The structural formula is shown in formula L: ， Where R1 and R2 are shown below: 。 2. A method for preparing a benzothiazole-containing flavonol derivative as described in claim 1, characterized in that: The specific steps include: (1) The aldol condensation reaction of o-hydroxyacetophenone with substituted benzaldehyde yields ( E )-1-(2-hydroxyphenyl)-3-(substituted phenyl)prop-2-en-1-one; ； (2) E 3-hydroxy-2-(substituted phenyl)-4-prop-2-en-1-one, sodium hydroxide, and hydrogen peroxide were used to prepare 3-hydroxy-2-(substituted phenyl)-4-propane at room temperature using ethanol as a solvent. H -chromone-4-one; ； (3) A substitution reaction was carried out between substituted 2-aminobenzothiazole and chloroacetyl chloride, with dichloromethane as solvent and potassium carbonate as acid-binding agent, at room temperature to give 2-chloro- N -(substituted benzo[ d 1,2-thiazolyl)acetamide; ； (4) 2-Chloro- N -(substituted benzo[ d ]Thiazol-2-yl)acetamide and 3-hydroxy-2-(substituted phenyl)-4 H -chromone-4-one, N , N Using dimethylformamide as a solvent and potassium carbonate as an acid-binding agent, reflux yields 2-((2-(substituted phenyl)-4-oxo-4-) H -chromene-3-yl)oxy)- N -(substituted benzo[ d 1,2-thiazolyl)acetamide; 。 3. The application of a benzothiazole-containing flavonol derivative in the preparation of an anti-tobacco mosaic virus drug, wherein the derivative has the structural formula shown in Formula L: ,in: When R1 is not a hydrogen atom, R1 is a methyl, methoxy, tert-butyl, or halogen atom, and R2 is a methyl, methoxy, or halogen atom; when R1 is a hydrogen atom, R2 is a 5-bromine, 6-chloro, hydrogen, 4-methyl, or 6-methoxy atom.

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