Benzothiazole-containing flavonol derivative as well as preparation method and application thereof

Abstract

The invention discloses a flavonol derivative containing benzothiazole, which is characterized in that the structural formula is as shown in formula L: # imgabs0 #, when R1 is not a hydrogen atom, R1 contains one methyl, methoxyl, tertiary butyl or halogen atom at ortho-position, para-position or meta-position, and R2 is methyl, methoxyl or halogen atom. An antiviral activity test on the flavonol derivative containing benzothiazole proves that the flavonol derivative containing benzothiazole disclosed by the invention has very good antiviral activity and can be applied to preparation of a medicament for inhibiting plant viruses.

Description

Technical Field

[0001] The invention relates to the technical field of pesticide synthesis, and in particular to a preparation method of a flavonol derivative containing benzothiazole and its application in antiviral treatment. Background Art

[0002] Natural products and their biomimetic pesticides are environmentally friendly, have unique action sites and high selectivity, and play an increasingly important role in preventing and controlling plant diseases. Flavonols are a special type of flavonoid compound, also known as 3-hydroxyflavone, which is widely found in the plant kingdom. There are about 2,000 species, accounting for about 1 / 3 of the total number of flavonoid compounds. The most common ones are kaempferol, myricetin and quercetin. Flavonols have many important pharmacological effects and biological activities. They generally have strong antioxidant, antibacterial, antiviral and anticancer effects. Therefore, taking this type of compound as a guide and modifying its structure, it is very likely to obtain organic active molecules with excellent anti-plant virus activity. This also shows that flavonol compounds have further research and application value.

[0003] In 2017, Huang et al. (Huang Minguo, Ruan Xianghui, Zhang Juping, Li Qin, Wang Yihui, Chen Lijuan, Zhang Cheng, Li Pu, Xue Wei. Organic Chemistry, 2017, 37(08): 2145-2152.) reported the synthesis of a series of flavonol derivatives containing phosphate groups. The results of bioassays showed that the target compounds had good inhibitory activity against citrus canker pathogen and rice bacterial blight pathogen.

[0004] In 2015, Han et al. (Han, Y.; Ding, Y.; Xie, DD; Hu, DY; Li, P.; Li, XT; Xue, W.; Jin, LH; Song, BA 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 CY; Meng KN; Sun ZL; Zeng W; An YS; Zhou HQ; Qiu Y.J; Liu D; Xue W.Chem.Biodivers.2023,21(2):e202301737) designed and synthesized a series of flavonol derivatives containing quinazolinone. The antiviral bioactivity test results showed that compound K5 exhibited significant therapeutic activity against TMV, and its 50% effective concentration (EC 50) value was 139.6μg / mL, which was better than the commercial drug Ningnanmycin 296.0μg / mL.

[0006] Flavonols are derived from natural products. So far, there have been no reports on flavonol derivatives containing benzothiazole and their application in pesticides, and there have been no reports on their activity tests against tobacco mosaic virus. Summary of the invention

[0007] The purpose of the present invention is to provide a preparation method and application of benzothiazole-containing flavonol derivatives. By introducing active benzothiazole into the structure of flavonol, a series of benzothiazole-containing flavonol derivatives with resistance to plant viruses are synthesized.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A flavonol derivative containing benzothiazole, the general structural formula of which is shown below:

[0010]

[0011] Wherein, when R1 is not a hydrogen atom, R1 contains a methyl group, methoxy group, tert-butyl group or halogen atom at the ortho, para or meta position, and R2 is a methyl group, methoxy group or halogen atom, and the halogen atom is fluorine, chlorine or bromine.

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

[0013] (1) conducting an aldol condensation reaction of o-hydroxyacetophenone and substituted benzaldehyde to obtain (E)-1-(2-hydroxyphenyl)-3-(substituted phenyl)prop-2-en-1-one (intermediate 1);

[0014]

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

[0016]

[0017] (3) Substitution reaction of 2-aminobenzothiazole with chloroacetyl chloride, dichloromethane as solvent and potassium carbonate as acid binding agent at room temperature to obtain 2-chloro-N-(substituted benzo[d]thiazol-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 reacted with N,N-dimethylformamide as solvent and potassium carbonate as acid binding agent at 100°C to obtain a benzothiazole-containing flavonol derivative (L)

[0020]

[0021] Application of benzothiazole-containing flavonol derivatives in resisting plant viruses.

[0022] The plant virus is tobacco mosaic virus.

[0023] The beneficial technical effects of the present invention are as follows: the present invention introduces a 2-aminobenzothiazole group with excellent activity into the structure of flavonol, that is, a 2-chloro-N-(substituted benzo[d]thiazol-2-yl)acetamide structure is connected to the 3-hydroxyl group of flavonol. A series of benzothiazole-containing flavonol derivatives are synthesized, and through the antiviral activity test of the synthesized benzothiazole-containing flavonol derivatives, it is found that the compounds of the present invention have excellent anti-plant virus activity and can be used to prepare anti-plant virus agents.

[0024] Specifically, the therapeutic activities of compounds L17, L20 and L24 against TMV were 67.5, 71.8 and 66.4%, respectively, which were better than Ningnanmycin (60.1%); the protective activities of compounds L20 and L21 against TMV were 64.9 and 63.9%, respectively, which were better than Ningnanmycin (61.2%). According to the preliminary screening results, the EC50 test of antiviral activity was carried out on some compounds. The test results show that the EC50 of L17, L20, L24 is 50 The values ​​were 223.2, 90.5, and 146.9 μg / mL, respectively, which were better than 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 better than Ningnanmycin (204.2 μg / mL). DETAILED DESCRIPTION

[0025] Now, various exemplary embodiments of the present invention are described in detail, which should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing specific embodiments and are not used to limit the present invention.

[0026] In addition, for the numerical range in the present invention, it is understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0027] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention.

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

[0029] Example 1

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

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

[0032] Dissolve 3.5g (25.7mmol) of o-hydroxyacetophenone and 3.1g (77.4mmol) of sodium hydroxide in 50mL of ethanol, react for 30min at room temperature, and then slowly add 2.7g (25.7mmol) of benzaldehyde. Stir the reaction system at room temperature for 10-12h and monitor by thin layer chromatography (petroleum ether: ethyl acetate = 4:1, volume ratio). After the reaction is completed, pour the system into ice water. Use 10% dilute hydrochloric acid solution to adjust the pH of the system to about 5-6. After standing with a large amount of solid precipitated, filter to obtain a yellow solid, dry it for use, and the yield is 80%

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

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

[0035] (3) Preparation of N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

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

[0039] Example 2

[0040] The preparation method of N-(5-bromobenzo[d]thiazol-2-yl)-2-((4-oxo-2-(p-methylphenyl)-4H-chromen-3-yl)oxy)acetamide (target compound L2) comprises 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, except that benzaldehyde is replaced by an equal molar amount of p-tolualdehyde.

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

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

[0045] (3) Preparation of N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

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

[0049] Example 3

[0050] The preparation method of N-(5-bromobenzo[d]thiazol-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L3) comprises 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, except that benzaldehyde is replaced by 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]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0058] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar 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]thiazol-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L4) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

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

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

[0065] (3) Preparation of N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0067] (4) Preparation of N-(5-bromobenzo[d]thiazol-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 by 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]thiazol-2-yl)-2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L5) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-tert-butylbenzaldehyde.

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

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

[0075] (3) Preparation of N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

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

[0079] Example 6

[0080] The preparation method of N-(6-chlorobenzo[d]thiazol-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L6) comprises 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-chromene-4-one (Intermediate 2):

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

[0085] (3) Preparation of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

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

[0089] Example 7

[0090] The preparation method of N-(6-chlorobenzo[d]thiazol-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxy)acetamide (target compound L7) comprises 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, except that benzaldehyde is replaced by an equal molar amount of p-tolualdehyde.

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

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

[0095] (3) Preparation of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0098] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tolyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar 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]thiazol-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L8) comprises 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, except that benzaldehyde is replaced by 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]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0107] (4) Preparation of N-(6-chlorobenzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-methoxyphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar 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]thiazol-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L9) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

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

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

[0115] (3) Preparation of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0117] (4) Preparation of 3N-(6-chlorobenzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar 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]thiazol-2-yl)acetamide (target compound L10) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-tert-butylbenzaldehyde.

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

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

[0125] (3) Preparation of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0128] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 40%.

[0129] Embodiment 11

[0130] The preparation method of N-(6-chlorobenzo[d]thiazol-2-yl)-2-((2-(2-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L11) comprises 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, except that benzaldehyde is replaced by an equimolar amount of o-anisaldehyde.

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

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

[0135] (3) Preparation of N-(6-chlorobenzo[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

[0136] As in step (3) of Example 1, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equal molar amount of 6-chlorobenzo[d]thiazol-2-amine

[0137] (4) Preparation of N-(6-chlorobenzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(2-methoxyphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar 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) comprises 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-chromene-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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0147] (4) Preparation of N-(Benzo[d]thiazol-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide ketone (target compound L12):

[0148] As in step (4) of Example 1, except that 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: 46%.

[0149] Example 13

[0150] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((4-oxo-2-(p-tolyl)-4H-chromen-3-yl)oxy)acetamide (target compound L13) comprises 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, except that benzaldehyde is replaced by an equal molar amount of p-tolualdehyde.

[0153] (2) Preparation of 3-hydroxy-2-(p-tolyl)-4H-chromene-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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

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

[0158] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tolyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 45%.

[0159] Embodiment 14

[0160] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L14) comprises 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, except that benzaldehyde is replaced by 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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0167] (4) Preparation of N-(Benzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 36%.

[0169] Embodiment 15

[0170] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L15) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

[0173] (2) Preparation of 3-hydroxy-2-(4-fluorophenyl)-4H-chromene-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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0177] (4) Preparation of N-(Benzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 37%.

[0179] Example 16

[0180] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L16) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-tert-butylbenzaldehyde.

[0183] (2) Preparation of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromene-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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0187] (4) Preparation of N-(Benzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 32%.

[0189] Embodiment 17

[0190] The preparation method of N-(benzo[d]thiazol-2-yl)-2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L17) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-chlorobenzaldehyde.

[0193] (2) Preparation of 3-hydroxy-2-(4-chlorophenyl)-4H-chromene-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, except that 5-bromobenzo[d]thiazol-2-amine is replaced with an equimolar amount of 2-aminobenzothiazole.

[0197] (4) Preparation of N-(Benzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(4-chlorophenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(benzo[d]thiazol-2-yl)-2-chloroacetamide. Yield: 38%.

[0199] Embodiment 18

[0200] The preparation method of N-(4-methylbenzo[d]thiazol-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L18) comprises 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-chromene-4-one (Intermediate 2):

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

[0205] (3) Preparation of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0208] As in step (4) of Example 1, except 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] Embodiment 19

[0210] The preparation method of N-(4-methylbenzo[d]thiazol-2-yl)-2-((4-oxo-2-(p-methylphenyl)-4H-chromene-3-yl)oxy)acetamide (target compound L19) comprises 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, except that benzaldehyde is replaced by an equal molar amount of p-tolualdehyde.

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

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

[0215] (3) Preparation of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0218] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tolyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide. Yield: 44%.

[0219] Embodiment 20

[0220] The preparation method of 2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazol-2-yl)acetamide (target compound L20) comprises 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, except that benzaldehyde is replaced by 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]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0228] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide. Yield: 42%.

[0229] Embodiment 21

[0230] The preparation method of 2-((2-(4-fluorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazol-2-yl)acetamide (target compound L21) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-fluorobenzaldehyde.

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

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

[0235] (3) Preparation of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0238] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(4-fluorophenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide. Yield: 51%.

[0239] Embodiment 22

[0240] The preparation method of 2-((2-(4-(tert-butyl)phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazol-2-yl)acetamide (target compound L22) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-tert-butylbenzaldehyde.

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

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

[0245] (3) Preparation of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0248] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tert-butylphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide. Yield: 46%.

[0249] Embodiment 23

[0250] The preparation method of 2-((2-(4-chlorophenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(4-methylbenzo[d]thiazol-2-yl)acetamide (target compound L23) comprises 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, except that benzaldehyde is replaced by an equimolar amount of p-chlorobenzaldehyde.

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

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

[0255] (3) Preparation of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

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

[0258] As in step (4) of Example 1, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-chlorophenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(4-methyl[d]thiazol-2-yl)-2-chloroacetamide. Yield: 53%.

[0259] Embodiment 24

[0260] The preparation method of N-(6-methoxybenzo[d]thiazol-2-yl)-2-((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)acetamide (target compound L24) comprises 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-chromene-4-one (Intermediate 2):

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

[0265] (3) Preparation of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0267] (4) Preparation of N-(6-methoxybenzo[d]thiazol-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 is replaced by an equimolar amount of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide, yield: 49%.

[0269] Embodiment 25

[0270] The preparation method of N-(6-methoxybenzo[d]thiazol-2-yl)-2-((4-oxo-2-(p-methylphenyl)-4H-chromen-3-yl)oxy)acetamide (target compound L25) comprises 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, except that benzaldehyde is replaced by an equal molar amount of p-tolualdehyde.

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

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

[0275] (3) Preparation of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0277] (4) Preparation of N-(6-methoxybenzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(p-tolyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar amount of N-(6-methoxy[d]thiazol-2-yl)-2-chloroacetamide. Yield: 37%.

[0279] Embodiment 26

[0280] The preparation method of N-(6-methoxybenzo[d]thiazol-2-yl)-2-((2-(3-methoxyphenyl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (target compound L26) comprises 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, except that benzaldehyde is replaced by 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]thiazol-2-yl)-2-chloroacetamide (Intermediate 3):

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

[0287] (4) Preparation of N-(6-methoxybenzo[d]thiazol-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, except that 3-hydroxy-2-phenyl-4H-chromene-4-one is replaced by an equal molar amount of 3-hydroxy-2-(3-methoxyphenyl)-4H-chromene-4-one, and N-(5-bromobenzo[d]thiazol-2-yl)-2-chloroacetamide is replaced by an equal molar 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 to 26 are shown in Table 1. The H NMR spectra ( 1 H NMR), carbon spectrum ( 13 C NMR) and fluorine spectra ( 19 F NMR) data are shown in Table 2.

[0290] Table 1 Physical and chemical properties of target compounds obtained in Examples 1-22

[0291]

[0292]

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

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Test Example 1

[0302] Anti-plant virus activity test:

[0303] 1. Extraction of TMV

[0304] The Luo Chaopeng method (Luo Chaopeng et al., Tobacco Science and Technology, 2012, 10: 77-80.) was used to select the upper leaves of Nicotiana tabacum.L plants that had been inoculated for more than 3 weeks and infected by TMV system. The leaves were homogenized in phosphate buffer, filtered through double gauze, centrifuged at 8000r / min, treated with polyethylene glycol twice, centrifuged again, and the precipitate was suspended in phosphate buffer to obtain the TMV extract. The entire experiment was carried out at 4°C.

[0305] 2. TMV Activity Assay Preparation

[0306] (1) Seedling cultivation: The tobacco variety used in the activity test experiment was heart-leaf tobacco, and the tobacco seedling cultivation operation was based on the cultivation method of medium-sized tobacco in 3.3.1. After the heart-leaf tobacco was cultured in an artificial climate chamber for about 25 days, heart-leaf tobacco with good growth and uniform leaf size was selected, and the top tender leaves and the base old leaves were removed, leaving 4-6 leaves for antiviral experiments.

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

[0308] 3. Therapeutic activity

[0309] Sprinkle corundum evenly on the tobacco leaves, and use a brush to evenly brush the 500-fold diluted virus solution on the left and right sides of the tobacco leaves. After 30 minutes of infection, rinse the corundum on the surface of the leaves with water, and then wipe the residual moisture on the surface of the tobacco leaves with filter paper. Finally, use a brush to dip 500μg / mL of the drug solution and apply it to the right side of the tobacco leaves (the tip of the tobacco leaf faces the experimenter), and culture it in an artificial climate chamber (28°C) for 2-3 days. When spots appear on the leaves, count the number of spots on the left and right sides, and calculate the inhibition rate. Repeat the experiment three times for each drug.

[0310] 4. Protective activity

[0311] First, use a brush to dip the drug solution and apply it to the right side of the tobacco leaf. After 24 hours, sprinkle corundum on it and use a brush to brush the left and right sides of the tobacco leaf with 500 times diluted virus solution. After 30 minutes, rinse off the corundum and place it in an artificial climate chamber for 2-3 days. Count the spots on the left and right 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 for 0.5 h, and the entire tobacco leaf was sprinkled with corundum. The mixed solution was then inoculated on the right half of the tobacco leaf with a brush, and a 500-fold diluted virus solution was inoculated on the left side of the tobacco leaf. After infection for 30 minutes, the corundum on the surface of the leaf was finally rinsed with clean water and placed in an artificial climate chamber for cultivation. After infection for 2-3 days, the number of lesions on the leaves on the left and right sides was counted, and the inhibition rate was calculated. The experiment was repeated three times for each drug.

[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 on inhibiting plant fungi are shown in Table 3.

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

[0321]

[0322]

[0323] a Three replicates were averaged; b Commercial pharmaceutical Ningnanmycin.

[0324] Table 4 EC values ​​of some target compounds for therapeutic and protective activities against tobacco mosaic virus 50 value a

[0325]

[0326] a Three replicates were averaged; b Commercial pharmaceutical Ningnanmycin.

[0327] As shown in Table 3, some compounds have good antiviral activity. The therapeutic activities of compounds L17, L20 and L24 against TMV are 67.5, 71.8 and 66.4%, respectively, which are better than Ningnanmycin (60.1%); the protective activities of compounds L20 and L21 against TMV are 64.9 and 63.9%, respectively, which are better than Ningnanmycin (61.2%). According to the preliminary screening results in Table 3, EC tests for antiviral activity were performed on some compounds. 50 The test results are shown in Table 4. From the test results, it can be seen that the EC of L17, L20, and L24 50 The values ​​were 223.2, 90.5, and 146.9 μg / mL, respectively, which were better than 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 better than Ningnanmycin (204.2 μg / mL). The above experimental activity data showed that flavonol derivatives containing benzothiazole had a certain inhibitory effect on tobacco mosaic virus, and some of the target compounds showed excellent inhibitory activity against tobacco mosaic virus, which can be used as potential antiviral drugs with good application prospects.

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

Claims

1. A flavonol derivative containing benzothiazole, characterized in that: The structural formula is shown in formula L: Wherein: when R1 is not a hydrogen atom, R1 contains a methyl group, methoxy group, tert-butyl group or halogen atom at the ortho, para or meta position, and R2 is a methyl group, methoxy group or halogen atom.

2. The flavonol derivative containing a benzothiazole structure according to claim 1, characterized in that: The halogen atom is fluorine, chlorine or bromine.

3. A method for preparing a benzothiazole-containing flavonol derivative as claimed in claim 1, characterized in that: The specific steps include: (1) conducting an aldol condensation reaction of o-hydroxyacetophenone and substituted benzaldehyde to obtain (E)-1-(2-hydroxyphenyl)-3-(substituted phenyl)prop-2-en-1-one; (2) (E)-1-(2-hydroxyphenyl)-3-(substituted phenyl)prop-2-en-1-one and sodium hydroxide and hydrogen peroxide are used to prepare 3-hydroxy-2-(substituted phenyl)-4H-chromen-4-one at room temperature using ethanol as solvent; (3) Substitution reaction of substituted 2-aminobenzothiazole with chloroacetyl chloride, using dichloromethane as solvent and potassium carbonate as acid binding agent, at room temperature to obtain 2-chloro-N-(substituted benzo[d]thiazol-2-yl)acetamide; (4) 2-chloro-N-(substituted benzo[d]thiazol-2-yl)acetamide and 3-hydroxy-2-(substituted phenyl)-4H-chromen-4-one are refluxed with N,N-dimethylformamide as solvent and potassium carbonate as acid binding agent to obtain 2-((2-(substituted phenyl)-4-oxo-4H-chromen-3-yl)oxy)-N-(substituted benzo[d]thiazol-2-yl)acetamide; 4. Use of the benzothiazole-containing flavonol derivative according to claim 1 or 2 in the preparation of anti-plant virus drugs.

5. The use according to claim 4, characterized in that: The plant virus is tobacco mosaic virus.

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