Polysubstituted furoic acid derivative, bactericidal composition and application

Abstract

The invention provides a polysubstituted furancarboxylic acid derivative, a bactericidal composition and application. The structural formula of the polysubstituted furoic acid derivative is as shown in (I): # imgabs0. According to the invention, a natural polysubstituted furoic acid skeleton is subjected to structural modification, and a molecular design strategy combining bioinformatics and pharmacophore hybridization is adopted; a series of polysubstituted furan formate compounds, polysubstituted furan amide compounds and furan dihydrazide compounds are designed and synthesized; results show that part of the compounds show obvious bactericidal activity on crop pathogenic bacteria such as sclerotinia rot of colza, grape gray mold, wheat glume wilt, rice sheath blight disease, pear black spot and the like, can be used as a primer for development of novel bactericides, and can also be used as a bactericide or an effective component thereof for green prevention and control of agricultural pathogenic fungal diseases.

Description

Technical Field

[0001] The invention relates to the technical field of bio-organic and medicinal chemistry, and in particular to a polysubstituted furancarboxylic acid derivative and a bactericidal composition and application thereof. Background Art

[0002] Fungal diseases are common diseases widely distributed in agricultural production, occurring in rice, wheat, vegetables, fruit trees or many other crops, and multiple fungal diseases can infect the same plant at the same time. In the five major crops of rice, wheat, corn, soybeans and potatoes, the annual losses caused by fungal infections are enough to feed hundreds of millions of people.

[0003] Fungal diseases have posed a serious threat to food production and security, affecting plant growth, health and yield. For example, Sclerotinia sclerotiorum is a common plant pathogen that can affect many crops, infect rapeseed, causing rapeseed seed production to decrease, and can also spread through the soil to affect other crops; peanuts, soybeans, etc. are very susceptible to Sclerotinia sclerotiorum, resulting in a decrease in yield. Large-scale infection of plants with fungal diseases not only causes huge losses to agricultural products, but also affects the development of agriculture. Not only does Sclerotinia sclerotiorum affect crop growth, but gray mold is also an obstacle to healthy growth in flowers and fruits. Gray mold is an invasive Botrytis fungus that infects plants such as tomatoes, lilies, and grapes through stomata, leading to the occurrence of diseases. Some fungal species can produce toxic substances in some areas, which pose a potential threat to human health. With the development of science and technology, great progress has been made in the prevention and control of plant diseases, especially the rational use of fungicides has alleviated the current pressure of agricultural fungi infecting crops, protecting plants from fungal invasion, and improving the yield and quality of crops. However, the long-term use of a single variety of drugs is likely to aggravate the development of fungal resistance. Therefore, the continuous search for safe and efficient green control drugs targeting plant pathogenic fungi is one of the key issues that need to be addressed urgently. Summary of the invention

[0004] In view of the above problems existing in the prior art, the object of the present invention is to provide a polysubstituted furancarboxylic acid derivative and a fungicide composition and application.

[0005] The technical solution adopted by the present invention is as follows:

[0006] In a first aspect, the present invention provides a polysubstituted furancarboxylic acid derivative, wherein the polysubstituted furancarboxylic acid derivative has a structural formula as shown in (I):

[0007]

[0008] Among them, the R 1 Any one of ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and methylthio;

[0009] The R2 is methyl, ethyl, n-propyl, isopropyl;

[0010] The R is a substituent containing an aromatic ring, and the R is connected with the formic acid in formula (I) to form an ester compound with a structure shown in the following formula (II):

[0011] The R 3 It is a fluorine-containing aromatic group;

[0012] Or, the R is a substituent containing an amino group, and the R is connected with the amino group in formula (I) to form an amide compound having a structure as shown in the following formula (III):

[0013] The R 4 is a substituted aryl group;

[0014] Or, the R is a substituent containing an amino group, and the R is connected with the amino group in formula (I) to form a dihydrazide compound having a structure as shown in the following formula (IV):

[0015] The R 5 It is a nitrogen-methyl heterocyclic pyrazole;

[0016] Or, the R is a substituent containing an amino acid unit, and the R is connected with the amino group in formula (I) to form an amide compound having a structure as shown in the following formula (V):

[0017] The R 6 is any one of benzyl and isopropyl; said R 7 It is any of benzyl and 4-hydroxybenzyl.

[0018] In a second aspect, the present invention also provides a fungicide composition comprising the poly-substituted furancarboxylic acid derivative.

[0019] In a third aspect, the present invention also provides a use of the polysubstituted furancarboxylic acid derivative or the fungicide composition in the preparation of drugs for killing plant diseases.

[0020] The polysubstituted furanic acid derivatives, fungicidal compositions and applications provided by the present invention have the following beneficial effects compared to the prior art:

[0021] The present invention designs and synthesizes a series of polysubstituted furancarboxylic acid ester compounds, polysubstituted furanamide compounds, and furan dihydrazide compounds by structurally modifying the natural polysubstituted furancarboxylic acid skeleton and adopting a molecular design strategy combining bioinformatics and pharmacophore hybridization. Screening finds that the compounds have good fungicidal activity against a variety of pathogens, providing more candidate molecules for the development of new biogenic fungicides. The new structure polysubstituted furancarboxylic acid derivatives of the present invention are structurally confirmed by nuclear magnetic resonance hydrogen and carbon spectra, and the fungicidal activity of the obtained 48 target compounds is tested, and the results show that some of the compounds exhibit obvious fungicidal activity against crop pathogens such as rapeseed sclerotinia rot, grape gray mold, wheat glumen blight, rice sheath blight, and pear black spot, and can be used as leads for the development of new fungicides, and can also be used as fungicides or their active ingredients for green prevention and control of agricultural pathogenic fungal diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0023] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 5g;

[0024] Figure 2 The treatment effects of compound 5a, compound 5g, compound 6a, compound 6e, compound 6f, compound 10b, compound 10e and the control group on four pathogenic fungi, namely, Sclerotinia sclerotiorum of rape, Botrytis cinerea, Sheath blight of rice and Black spot of pear;

[0025] Figure 3 The graph shows the inhibitory effects of compound 5g and compound 6a on Sclerotinia sclerotiorum at different concentrations;

[0026] Figure 4 The inhibition rates of compound 5g and compound 6a on Sclerotinia sclerotiorum at different concentrations;

[0027] Figure 5 This is the in vivo antibacterial test result of compound 5g. DETAILED DESCRIPTION

[0028] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] The present invention provides a multi-substituted furancarboxylic acid derivative, the structural formula of which is shown as (I):

[0030]

[0031] Among them, R 1 Any one of ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and methylthio;

[0032] R 2 is methyl, ethyl, n-propyl, isopropyl;

[0033] R is a substituent containing an aromatic ring, and R is connected with the formic acid in formula (I) to form an ester compound with a structure shown in the following formula (II):

[0034] R 3 It is a fluorine-containing aromatic group.

[0035] In some embodiments, R is a substituent containing an amino group, and R is connected to the amino group in formula (I) to form an amide compound having a structure shown in the following formula (III):

[0036] R 4 is a substituted aryl group.

[0037] In some embodiments, R is a substituent containing an amino group, and R is connected to the amino group in formula (I) to form a structure as follows:

[0038] The bishydrazide compounds shown are:

[0039] R 5 It is a nitrogen-methyl heterocyclic pyrazole.

[0040] In some embodiments, R is a substituent containing an amino acid unit, and R is connected to the amino group in formula (I) to form an amide compound having a structure shown in the following formula (V): R 6 Benzyl Isopropyl Any of;

[0041] R 7 Benzyl 4-Hydroxybenzyl Any of .

[0042] In some embodiments, R 3 for Any of .

[0043] In some embodiments, R 4 for Any of .

[0044] In some embodiments, R 5 for Any of .

[0045] In some embodiments, the polysubstituted furancarboxylic acid derivative is selected from any one of compounds 1 to 48 in Table 1 below;

[0046] Table 1 - Structural formula of compounds 1 to 48

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054] The present invention designs and synthesizes a series of polysubstituted furancarboxylic acid ester compounds, polysubstituted furanamide compounds, and furan dihydrazide compounds by structurally modifying the natural polysubstituted furancarboxylic acid skeleton and adopting a molecular design strategy combining bioinformatics and pharmacophore hybridization. Screening finds that the compounds have good fungicidal activity against a variety of pathogens, providing more candidate molecules for the development of new biogenic fungicides. The new structure polysubstituted furancarboxylic acid derivatives of the present invention are structurally confirmed by nuclear magnetic resonance hydrogen and carbon spectra, and the fungicidal activity of the obtained 48 target compounds is tested, and the results show that some of the compounds exhibit obvious fungicidal activity against crop pathogens such as rapeseed sclerotinia rot, grape gray mold, wheat glumen blight, rice sheath blight, and pear black spot, and can be used as leads for the development of new fungicides, and can also be used as fungicides or their active ingredients for green prevention and control of agricultural pathogenic fungal diseases.

[0055] Based on the same inventive concept, the present invention also provides a fungicide composition comprising the multi-substituted furancarboxylic acid derivative.

[0056] Based on the same inventive concept, the present invention also provides an application of the above-mentioned multi-substituted furancarboxylic acid derivative or the above-mentioned fungicide composition in the preparation of drugs for killing plant diseases.

[0057] In some embodiments, the plant diseases include at least one of rapeseed sclerotinia, grape gray mold, wheat head blight, wheat glumebodesis, cotton verticillium wilt, rice sheath blight, rice blast, and pear black spot.

[0058] The following further illustrates the polysubstituted furan carboxylic acid derivatives and applications of the present application with specific examples. This section further illustrates the content of the present invention in conjunction with specific examples, but should not be construed as limiting the present invention. Unless otherwise specified, the technical means used in the examples are conventional means known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0059] Example 1

[0060] The synthesis of the compound intermediate 2-methyl-5-hexylfurancarboxylic acid, the specific chemical reaction formula is:

[0061]

[0062] The specific synthesis method comprises the following steps:

[0063] S1. Add 20 mmol (2.0018 g) of 1-octanal and 20 ml of acetonitrile to an eggplant-shaped flask, then add 1 mmol (0.133 g) of anhydrous AlCl3 and 20 mmol (3.5596 g) of NBS (N-bromosuccinimide), add a magnetic particle and place the eggplant-shaped flask in a constant temperature oil bath with stirring. The reaction temperature is 80° C. and the temperature is kept constant for 12 hours. The reaction is monitored by TCL. When the reaction is complete, the solid is removed by suction filtration, and then water is added to quench the reaction. The organic phase is extracted with ethyl acetate, and the organic phase is separated by column chromatography (the eluent is a mixture of petroleum ether and ethyl acetate, and the ratio of petroleum ether to ethyl acetate is 20:1). Purification gives compound 2-methyl-5-hexylfurancarboxylic acid ethyl ester (i.e., compound 2a);

[0064] S2. Dissolve the ethyl 2-methyl-5-hexylfuranate purified in S1 in 40 ml of methanol in a 100 ml eggplant-shaped flask, weigh 30 mmol (1.20 g) of NaOH, dissolve it in 10 ml of water to obtain a NaOH solution, load the NaOH solution into a constant pressure dropping funnel, then place it on the eggplant-shaped flask, slowly drop the NaOH solution, and after the dropwise addition is completed, place the flask in a constant temperature oil bath for reaction at a reaction temperature of 50° C., stir at the constant temperature for 6 hours, and monitor the reaction by TCL. After the reaction is completed, spin-dry the methanol, add 20 ml of water, place it in an ice-water bath, slowly drop hydrochloric acid until the pH value of the solution is between 1 and 2, and stir continuously. After the dropwise addition is completed, continue stirring for 10 minutes, filter, rinse the solid with a small amount of water, and place it in a fume hood to dry to obtain 2-methyl-5-hexylfurancarboxylic acid (i.e., compound 3a).

[0065] Example 2

[0066] This embodiment provides a method for synthesizing a polysubstituted furanic acid derivative, specifically the synthesis of compounds 4a to 4w in Table 1. Taking the target compound 4c as an example, the specific chemical reaction formula is:

[0067]

[0068] The synthesis method of compound 4c comprises the following steps:

[0069] S1. First weigh 1 mmol (219.27 mg) of 2-methyl-5-hexylfurancarboxylic acid into a flask, add 5 ml of acetonitrile to dissolve, then add 1.2 mmol (172 mg) of K2CO3 and 1 mmol (207.02 mg) of 2,3-difluorobenzyl bromide (i.e., 2,3-difluorobenzyl bromide), react at room temperature (25°C) for 6 hours, and after the reaction is completed by TCL monitoring, add water to quench the reaction solution, extract with ethyl acetate three times, combine the organic phases and separate them by column chromatography (the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 15:1), and 117 mg of compound 4c is obtained by purification, with an isolation yield of 52.61%.

[0070] The obtained spectral data of compound 4c are as follows: 1 HNMR (600MHz, Chloroform-d): δ7.22-7.17(m,1H),7.17-7.12(m,1H),7.10-7.05(m,1H),6.22(s,1H),5. 33(s,2H),2.56-2.53(m,2H),2.52(s,3H),1.63-1.56(m,2H),1.35-1.26(m,6H),0.88(t,J=13.6Hz,3H). 13C NMR (151MHz, Chloroform-d): δ163.86,158.19,154.67,151.36,149.89,148.23,126.04,1 25.09,124.15,117.30,113.15,105.30,59.14,33.71,28.30,27.65,22.54,14.57,13.81.

[0071] Example 3

[0072] This embodiment provides a method for synthesizing a polysubstituted furanic acid derivative, specifically the synthesis of compounds 5a to 5i in Table 1. Taking the target compound 5g as an example, the specific chemical reaction formula is:

[0073]

[0074] The synthesis method of compound 5g comprises the following steps:

[0075] S1. First weigh 1 mmol (219.27 mg) of 2-methyl-5-hexyl-3-furancarboxylic acid into a flask, add 6 ml of acetonitrile to dissolve, add 1.5 mmol (118.65 mg) of pyridine, and then add a stirrer. Place the flask in an ice bath, slowly drop methylsulfonyl chloride, stir for 30 min, add 2-phenoxyaniline, remove the ice bath, react at room temperature, monitor the reaction by TCL, quench the reaction solution with water after the reaction is completed, extract three times with ethyl acetate, combine the organic phases and separate by column chromatography (the eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 10:1), and purify to obtain 216.5 mg of compound 5g with an isolation yield of 95%.

[0076] The H NMR spectrum of compound 5g is as follows Figure 1 As shown, the spectral data of compound 5g are as follows: 1 H NMR (600MHz, Chloroform-d): δ7.65 (d, J=8.1Hz, 1H), 7.45-6.80 (m, 9H), 6.24 (s, 1H), 3 .00(s,2H),2.65-2.46(m,3H),1.69-1.48(m,2H),1.42-1.15(m,6H),0.95-0.79(m,3H). 13C NMR (151MHz, Chloroform-d): δ170.85,159.39,155.95,154.27,146.96,130.16,128.19,1 26.45,124.35,121.18,118.62,118.30,105.50,39.48,31.53,29.85,27.64,22.55,14.74.

[0077] Example 4

[0078] This embodiment provides a method for synthesizing a polysubstituted furanic acid derivative, specifically the synthesis of compounds 6a to 6h in Table 1. Taking the target compound 6a as an example, the specific chemical reaction formula is:

[0079]

[0080] The synthesis method of compound 6a comprises the following steps:

[0081] S1. First weigh 1 mmol (211.2 mg) of 2-methyl-5-hexylfurancarboxylic acid into a flask, add 1 mmol (200.8 mg) of 1-methyl-3-(trifluoromethyl)-pyrazole-4-carboxylic acid hydrazide, dissolve in 10 ml of dichloromethane (DCM), then add 1.5 mmol (491 mg) of TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate) and 3 mmol (303.47 mg) of triethylamine (TEA), react at room temperature for 6 h, monitor the reaction by TCL, quench the reaction solution with water after the reaction is completed, extract three times with ethyl acetate, combine the organic phases, and separate by column chromatography (the eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 10:1), and purify to obtain 143 mg of compound 6a, with an isolation yield of 35.73%.

[0082] The spectral data of the obtained compound 6a are as follows: 1 H NMR (400MHz, Chloroform-d): δ9.99(s,1H),9.07(s,1H),8.19(s,1H),6.23(s,1H),3.85(s,3 H),2.85-2.75(m,2H),2.49(s,3H),1.57-1.51(m,2H),1.33-1.23(m,6H),0.90-0.82(m,3H). 13C NMR (101MHz, CDCl3): δ164.48,160.16,157.12,155.22,134.00,121.94,119.26, 113.16,113.04,103.04,39.81,31.61,28.90,27.83,27.77,22.64,14.16,13.04.

[0083] Example 5

[0084] This embodiment provides a method for synthesizing a polysubstituted furancarboxylic acid derivative, specifically the synthesis of compounds 10a to 10h in Table 1. Taking the target compound 10e as an example, the specific chemical reaction formula is:

[0085]

[0086]

[0087] The synthesis method of compound 10e comprises the following steps:

[0088] S1, first weigh 3mmol (630.39mg) of 2-methyl-5-hexylfurancarboxylic acid and put it into a 50mL eggplant-shaped flask, add 25ml of dichloromethane to dissolve, then add 3.6mmol (710mg) of EDCI (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride), 3.6mmol (486.4mg) of HOBt (1-hydroxybenzotriazole) and 6mmol (607.14mg) of TEA (TEA) in sequence, add a stirrer, and finally add 3.3mmol (711.74mg) of phenylalanine methyl ester hydrochloride to react for 4h. TCL detection reaction is complete, the reaction is poured into a separatory funnel, washed three times with water, washed once with saturated sodium carbonate solution, washed once with water, and then spin-dried to obtain intermediate compound 7a;

[0089] S2. Dissolve 2.8mmol (371.21mg) of intermediate compound 7a in a 50ml eggplant flask, dissolve it with 20ml of methanol, and add a stirrer; then weigh 4.1mmol (175mg) of lithium hydroxide monohydrate in a beaker, and dissolve the lithium hydroxide monohydrate with 5ml of water. Add the dissolved lithium hydroxide solution drop by drop into the eggplant flask under stirring. After the addition is complete, react for 2h and monitor the reaction by TCL. After the reaction is complete, concentrate part of the solvent, and then adjust the pH to about 2-3 with dilute hydrochloric acid to obtain the intermediate compound 8a;

[0090] S3, weigh 1.4mmol (499.8mg) of intermediate compound 8a and place it in an eggplant-shaped flask, dissolve it with 25ml of dichloromethane, then add 1.68mmol (322.056mg) of EDCI, 1.68mmol (227.00mg) of HOBt and 2.8mmol (283.136mg) of TEA in sequence, add a stirrer, and finally add 1.54mmol (332.15mg) of tyrosine methyl ester hydrochloride to react for 4h. TCL detection reaction is complete, pour the reaction into a separatory funnel, wash three times with water, add saturated sodium carbonate solution to wash once, wash again with water, spin dry to obtain intermediate compound 9e;

[0091] S4, weigh 0.76mmol (396mg) of intermediate 9e into an eggplant flask, dissolve it with 20ml of methanol, and add a stirrer; then weigh 0.7mmol (32mg) of lithium hydroxide monohydrate in a beaker and dissolve it with 5ml of water. Add the dissolved lithium hydroxide solution drop by drop into the eggplant flask under stirring. After the addition is complete, react for 2h and monitor the reaction by TCL. After the reaction is complete, concentrate to remove part of the solvent, then adjust the pH to about 2-3 with dilute hydrochloric acid, and a light yellow solid precipitates. Filter and obtain 200mg of the target compound 10e, 54.92%.

[0092] The obtained spectral data of compound 10e are as follows: 1 HNMR (400MHz, Chloroform-d): δ7.32-7.11(m,5H),6.88-6.54(m,4H),6.04(d,J=9.5Hz,1H),5.00-.93(m,1H),4.83- 4.66(m,1H),3.16-2.74(m,4H),2.56-2.32(m,5H),1.62-1.52(m,2H),1.38-1.22(m,6H),0.90(q,J=7.0,6.0Hz,3H). 13 C NMR (101MHz, CDCl3): δ173.84,171.67,170.87,164.75,164.32,155.91,155.20,154.89,154.80,136.11,130.54,129.45,1 29.32,128.71,128.59,127.19,127.01,115.63,115.13,114.97,103.34,31.56,29.76,28.86,27.81,22.60,14.13,13.66.

[0093] Referring to the above synthesis method, other compounds in the general formula (I) of the present invention can be prepared by selecting different basic chemical starting materials. All the reaction raw materials disclosed in the present invention can be purchased commercially, and the purity is preferably analytical grade. The prepared compounds can be used as precursor molecules or key intermediates for further preparation or construction of new bactericidal drug molecular building blocks. The spectral analysis data of some representative compounds are as follows:

[0094] Compound 4a: 1 H NMR(600MHz,Chloroform-d)δ6.18(s,1H),5.37(s,2H),4.59(s,2H),3.41(s, 3H),2.54(t,J=7.6Hz,2H),2.50(s,3H),1.62-1.52(m,2H),1.39-1.31(m,2H). 13 C NMR(151MHz,Chloroform-d)δ163.52,158.45,154.72,146.07,145.97,144.43,144.3 0,116.87,115.06,112.84,105.32,61.46,58.60,53.28,29.86,27.33,22.17,13.78.

[0095] Compound 4b: 1 H NMR(600MHz,Chloroform-d)δ7.21-7.17(m,1H),7.17-7.12(m,1H),7.10–7.05(m,1H),6.21(s,1H),5.33(s,2H),3.7 5-3.67(m,1H),2.56(t,J=8.1Hz,2H),1.63-1.56(m,2H),1.40-1.32(m,2H),1.26-1.22(m,7H),0.92(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ166.33,163.74,154.77,151.36,149.63,148.13,126.09,1 25.06,124.13,117.26,111.57,105.13,59.08,30.38,27.34,27.21,22.20,20.77,13.79.

[0096] Compound 4c: 11H NMR (600 MHz, Chloroform-d) δ 7.22 - 7.17 (m, 1H), 7.17 - 7.12 (m, 1H), 7.10 - 7.05 (m, 1H), 6.22 (s, 1H), 5.33 (s, 2H), 2.56 - 2.53 (m, 2H), 2.52 (s, 3H), 1.63 - 1.56 (m, 2H), 1.35 - 1.26 (m, 6H), 0.88 (t, J = 13.6 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 163.86, 158.19, 154.67, 151.36, 149.89, 148.23, 126.04, 125.09, 124.15, 117.30, 113.15, 105.30, 59.14, 33.71, 28.30, 27.65, 22.54, 14.57, 13.81.

[0097] Compound 4d: 1 1H NMR (600 MHz, Chloroform-d) δ 7.22 - 7.17 (m, 1H), 7.17 - 7.13 (m, 1H), 7.11 - 7.07 (m, 1H), 6.44 (s, 1H), 5.34 (s, 2H), 3.60 (s, 2H), 2.56 (s, 3H), 2.08 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 163.45, 159.60, 151.37, 149.54, 148.18, 125.83, 125.12, 124.19, 117.31, 113.51, 109.44, 60.54, 30.07, 16.35, 13.94.

[0098] Compound 4e: 1 1H NMR (600 MHz, Chloroform-d) δ 7.22 - 7.17 (m, 1H), 7.17 - 7.11 (m, 1H), 7.11 - 7.05 (m, 1H), 6.23 (s, 1H), 5.33 (s, 2H), 2.54 (t, J = 8.1 Hz, 2H), 2.52 (s, 3H), 1.63 - 1.54 (m, 2H), 1.40 - 1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR(151MHz,Chloroform-d)δ163.85,158.21,155.81,151.28,149.64,147.73,12 5.97,125.09,124.15,117.19,113.16,105.33,59.14,29.87,27.95,22.20,14.39.

[0099] Compound 4f: 1 H NMR(600MHz,Chloroform-d)δ6.17(s,1H),5.36(s,2H),4.58(s,2H),3.41(s,3H),2.51(t ,J=7.2Hz,2H),2.50(s,3H),1.62-1.55(m,2H),1.35-1.25(m,8H),0.87(t,J=7.0Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ163.64,158.53,154.85,146.15,146.02,144.48,144.36,116.83, 115.15,112.92,105.39,61.57,58.70,53.36,31.63,28.86,27.81,27.75,22.65,14.16,13.89.

[0100] Compound 4g: 1 HNMR(600MHz,Chloroform-d)δ7.12-7.06(m,1H),6.18(s,1H),5.37(s,2H),2.59- 2.51(m,2H),2.50(s,3H),1.62-1.56(m,2H),1.35-1.26(m,6H),0.91-0.83(m,3H). 13 C NMR(151MHz,Chloroform-d)δ163.65,158.97,155.24,147.31,144.51,115.69,1 12.96,106.76,105.41,53.81,31.65,28.88,27.84,27.77,22.67,14.64,13.89.

[0101] Compound 4h: 1HNMR(600MHz, Chloroform-d) δ 6.18 (s, 1H), 5.34 (s, 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.50 (s, 3H), 2.31 - 2.26 (m, 3H), 1.62 - 1.54 (m, 2H), 1.34 - 1.24 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H). 13 C NMR(151MHz, Chloroform-d) δ 163.61, 158.28, 154.66, 145.96, 144.35, 117.09, 112.93, 111.84, 105.30, 53.81, 32.02, 28.73, 28.06, 27.63, 22.52, 14.69, 13.75, 8.17.

[0102] Compound 4i: 1 H NMR(600MHz, Chloroform-d) δ 7.14 - 7.01 (m, 1H), 6.16 (s, 1H), 5.36 (s, 2H), 3.69–3.64 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 1.61 - 1.55 (m, 2H), 1.37 - 1.33 (m, 2H), 1.23 (d, J = 7.0 Hz, 6H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR(151MHz, Chloroform-d) δ 166.58, 163.46, 154.47, 146.63, 146.09, 144.99, 144.40, 119.44, 115.60, 110.79, 106.63, 105.89, 105.12, 53.30, 53.01, 29.79, 27.34, 27.24, 22.20, 20.74, 13.79.

[0103] Compound 4j: 1 H NMR(600MHz, Chloroform-d) δ 6.16 (s, 1H), 5.34 (s, 2H), 3.72 - 3.64 (m, 1H), 2.55 (t, J = 7.1 Hz, 2H), 2.29 (t, J = 2.1 Hz, 3H), 1.61 - 1.55 (m, 2H), 1.41 - 1.31 (m, 2H), 1.23 (d, J = 7.0 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR(151MHz,Chloroform-d)δ166.40,163.48,154.36,146.00,145.59,144.35,143.97, 117.04,111.88,110.88,105.12,53.21,29.76,27.30,27.19,22.17,20.71,13.75,7.23.

[0104] Compound 4k: 1 H NMR(600MHz,Chloroform-d)δ6.15(s,1H),5.35(s,2H),4.59(s,2H),3.72-3.61(m,1H),3.41(s,3H), 2.58-2.52(m,2H),1.59-1.56(m,2H),1.38-1.34(m,2H),1.23(d,J=7.0Hz,6H),0.92(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ166.54,163.40,155.38,146.39,140.98,118.22, 111.33,105.08,61.44,59.02,53.19,29.74,27.31,27.19,23.17,20.74,13.78.

[0105] Compound 4l: 1 H NMR(600MHz,Chloroform-d)δ7.14-7.06(m,1H),6.19(s,1H),5.37(s,2H),2.54(t,J= 7.6Hz,2H),2.51(s,3H),1.61-1.55(m,2H),1.39-1.32(m,2H),0.91(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ163.51,158.42,154.68,146.61,146.05,144.96,144.39 ,115.53,112.80,106.78,106.63,106.48,105.28,53.26,29.83,26.89,22.14,13.76.

[0106] Compound 4m: 1H NMR(600MHz,Chloroform-d)δ6.18(s,1H),5.34(s,2H),2.53(t,J=7.6Hz,2H),2.50(s ,3H),2.30-2.27(m,3H),1.62-1.55(m,2H),1.38-1.32(m,2H),0.91(t,J=7.3Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ163.74,158.43,154.75,146.10,143.91,117.79,1 14.28,111.96,111.85,105.44,54.53,29.97,29.85,27.44,22.28,13.89,8.93.

[0107] Compound 4n: 1 HNMR(600MHz,Chloroform-d)δ7.14-7.05(m,1H),6.39(s,1H),5.37(s,2H),3.58(s,2H),2.53(s,3H),2.06(s,3H). 13 C NMR(151MHz,Chloroform-d)δ163.10,159.80,149.62,146.61,146.04,144.99 ,144.41,115.37,113.16,108.07,106.72,53.40,41.64,30.04,15.32,13.88.

[0108] Compound 4o: 1 H NMR (600MHz, Chloroform-d) δ6.39(s,1H),5.34(s,2H),3.58(s,2H),2.53(s,3H),2.28(s,3H),2.06(s,3H). 13 C NMR(151MHz,Chloroform-d)δ173.12,163.33,160.20,149.64,147.01,144. 41,117.35,114.28,108.73,52.27,41.82,30.18,16.59,15.45,14.02,8.53.

[0109] Compound 4p: 11H NMR (600 MHz, Chloroform-d) δ 6.40 (s, 1H), 5.38 (s, 2H), 4.60 (s, 2H), 3.59 (s, 2H), 3.41 (d, J = 2.9 Hz, 3H), 2.54 (s, 3H), 2.07 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 172.30, 163.23, 159.95, 149.70, 146.03, 144.44, 117.05, 113.27, 108.22, 61.56, 58.74, 53.01, 38.82, 30.17, 17.60, 15.45, 14.04.

[0110] Compound 4q: 1 1H NMR (600 MHz, Chloroform-d) δ 7.06 - 6.99 (m, 2H), 6.22 (s, 1H), 5.17 (s, 2H), 2.57 - 2.54 (m, 2H), 2.53 (s, 3H), 1.64 - 1.58 (m, 2H), 1.37 - 1.26 (m, 6H), 0.88 (t, J = 12.0 Hz 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 163.72, 158.42, 154.84, 152.11, 152.02, 150.45, 150.36, 140.28, 138.61, 132.70, 112.94, 112.00, 111.97, 111.89, 111.86, 105.15, 63.91, 31.52, 28.76, 27.72, 27.66, 22.54, 14.06, 13.85.

[0111] Compound 4r: 1 1H NMR (600 MHz, Chloroform-d) δ 7.46 - 7.39 (m, 1H), 6.90 - 6.81 (m, 2H), 6.21 (s, 1H), 5.27 (s, 2H), 2.53 (t, J = 7.7 Hz, 2H), 2.51 (s, 3H), 1.63 - 1.56 (m, 2H), 1.37 - 1.24 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR(151MHz,Chloroform-d)δ164.10,162.28,160.61,158.21,154.75,131.91,119.82,1 13.79,110.98,106.28,104.13,59.94,31.65,28.88,27.86,27.78,22.67,14.58,13.91.

[0112] Compound 4s: 1 H NMR(600MHz,Chloroform-d)δ7.45-7.38(m,1H),6.91-6.81(m,2H),6.22(s,1H),5.27(s, 2H),2.54(t,J=7.6Hz,2H),2.51(s,3H),1.58(m,2H),1.35(m,2H),0.91(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ164.08,163.91,162.26,160.61,158.21,154.70,13 1.91,120.56,113.38,111.35,105.45,104.12,59.93,29.99,28.15,22.28,13.89.

[0113] Compound 4t: 1 H NMR(600MHz,Chloroform-d)δ7.45-7.38(m,1H),6.91-6.80(m,2H),6.20(s,1H),5.26(s,2H),3.69( m,1H),2.55(t,J=8.1Hz,2H),1.59(m,2H),1.36(m,2H),1.23(d,J=7.0Hz,6H),0.92(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ166.33,164.52,162.32,160.61,154.47,131.90,119.7 3,111.49,111.36,105.27,104.11,59.18,29.92,27.47,27.34,22.78,20.89,13.91.

[0114] Compound 4u: 11H NMR (600 MHz, Chloroform-d) δ 7.06 - 6.99 (m, 2H), 6.23 (s, 1H), 5.17 (s, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.54 (s, 3H), 1.63 - 1.57 (m, 2H), 1.40 - 1.33 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 163.72, 158.45, 154.81, 152.04, 150.38, 140.30, 138.73, 132.27, 112.96, 111.99, 111.86, 105.19, 64.41, 29.88, 27.75, 22.46, 13.84.

[0115] Compound 4v: 1 1H NMR (600 MHz, Chloroform-d) δ 7.06 - 6.99 (m, 2H), 6.21 (s, 1H), 5.16 (s, 2H), 3.74–3.64 (m, 1H), 2.57 (t, J = 7.6 Hz, 2H), 1.63 - 1.56 (m, 2H), 1.41 - 1.34 (m, 2H), 1.26 - 1.22 (m, 6H), 0.93 (t, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 166.59, 163.62, 154.58, 152.09, 152.05, 150.43, 150.39, 140.27, 138.60, 132.80, 111.99, 111.96, 111.88, 111.85, 110.91, 104.99, 63.88, 29.80, 27.35, 27.25, 22.21, 20.77, 13.79.

[0116] Compound 4w: 1 1H NMR (600 MHz, Chloroform-d) δ 7.21 - 7.15 (m, 1H), 6.97 - 6.86 (m, 2H), 6.35 (s, 1H), 3.77 - 3.71 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 1.67 - 1.61 (m, 2H), 1.44 - 1.37 (m, 2H), 1.29 (d, J = 7.0 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR(151MHz,Chloroform-d)δ167.87,161.42,159.20,154.81,153.48,134.46,12 4.56,111.23,110.10,105.28,105.02,29.77,27.42,27.35,22.21,20.69,13.79.

[0117] Compound 5a: 1 H NMR(600MHz,Chloroform-d)δ8.53-8.48(m,1H),7.53-7.49(m,2H),7.45-7.36(m,5H),7.27-7.24(m,1H),7.18-7.12(m,1H),5.54( s,1H),3.69-3.61(m,1H),2.50(t,J=7.6Hz,2H),1.55-1.49(m,2H),1.37-1.31(m,2H),1.20(d,J=7.0Hz,6H),0.92(t,J=7.4Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ163.76,161.96,154.40,138.24,135.25,131.69,130.48,129.81,129.47,129.1 8,128.83,128.56,128.08,127.22,123.77,120.63,114.49,102.63,29.66,27.33,27.08,22.15,20.97,13.82.

[0118] Compound 5b: 1 H NMR(600MHz,Chloroform-d)δ8.56(d,J=8.2Hz,1H),7.97(s,1H),7.40-6.85(m,9H),5. 94(s,1H),2.55-2.51(m,3H),1.62-1.50(m,2H),1.39-1.32(m,2H),0.98-0.84(m,3H). 13C NMR(151MHz,Chloroform-d)δ162.17,156.57,155.67,154.70,145.25,130.18,130.05,129.79,124.33,123.88,123.70, 123.26,120.68,118.34,118.10,116.55,103.20,31.53,31.46,30.20,30.15,29.93,29.73,27.43,22.20,13.80,13.61.

[0119] Compound 5c: 1 H NMR(600MHz,Chloroform-d)δ8.57(dd,J=1.8,1.6Hz,1H),7.99(s,1H),7.39-6.84(m,9H),5.90(s,1H),3.74(s ,1H),2.55(t,J=8.1Hz,2H),1.61-1.54(m,2H),1.40-1.32(m,2H),1.25(d,J=7.0Hz,6H),0.92(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3) δ163.69,162.16,156.59,154.52,145.13,130.28,130.01,124.34,123.80,123.63, 120.61,118.23,118.15,114.69,102.99,31.43,30.18,29.81,29.70,27.41,27.11,22.20,20.98,13.79.

[0120] Compound 5d: 1 H NMR(600MHz,Chloroform-d)δ8.47(d,J=8.3Hz,1H),7.53-7.38(m,6H),7.29-7.2 6(m,1H),7.20-7.16(m,1H),5.82(s,1H),3.54(s,2H),2.46(s,3H),2.05(s,3H). 13 CNMR(151MHz,Chloroform-d)δ161.47,156.88,149.63,138.12,134.99,131.76,129.83 ,129.42,129.21,128.60,128.17,123.98,120.69,116.79,105.55,30.09,15.41,13.58.

[0121] Compound 5e: 1 H NMR(600MHz,Chloroform-d)δ8.53-8.47(m,1H),7.55-7.49(m,3H),7.47-7.37(m,5H),7.30-7.25(m,1H),7.21-7.15 (m,1H),5.59(s,1H),2.49(t,J=7.6Hz,2H),2.47(s,3H),1.58-1.51(m,2H),1.34-1.27(m,6H),0.91(t,J=6.7Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ161.96,155.60,154.59,138.20,135.18,131.69,129.79,129.50,12 9.17,128.57,128.09,123.80,120.65,116.37,102.81,31.53,28.70,27.61,22.56,14.10,13.46.

[0122] Compound 5f: 1 H NMR(400MHz,Chloroform-d)δ7.41-7.31(m,1H),7.15(t,J=6.9Hz,2H),7.07-6.95 (m,2H),6.89(d,J=9.6Hz,2H),6.18(s,1H),3.59(s,1H),2.58(s,3H),2.08(s,3H). 13 CNMR(101MHz,CDCl3)δ162.37,157.05,156.51,149.79,145.37,130.95,124 .35,124.00,123.93,120.74,118.42,118.08,106.72,30.16,16.51,14.28.

[0123] Compound 5g: 1 H NMR(600MHz,Chloroform-d)δ7.65(d,J=8.1Hz,1H),7.45-6.80(m,9H),6.24(s,1H),3. 00(s,2H),2.65-2.46(m,3H),1.69-1.48(m,2H),1.42-1.15(m,6H),0.95-0.79(m,3H). 13C NMR(151MHz,Chloroform-d)δ170.85,159.39,155.95,154.27,146.96,130.16,128.19,12 6.45,124.35,121.18,118.62,118.30,105.50,39.48,31.53,29.85,27.64,22.55,14.74.

[0124] Compound 5h: 1 HNMR(600MHz,Chloroform-d)δ6.18(s,1H),5.37(s,2H),4.59(s,2H),3.41(s, 3H),2.54(t,J=7.6Hz,2H),2.50(s,3H),1.62-1.52(m,2H),1.39-1.31(m,2H). 13 CNMR(151MHz,Chloroform-d)δ163.52,158.45,154.72,146.07,145.97,144.43,144. 30,116.87,115.06,112.84,105.32,61.46,58.60,53.28,29.86,27.33,22.17,13.78.

[0125] Compound 5i: 1 H NMR(600MHz,Chloroform-d)δ7.40-7.35(m,1H),6.86-6.77(m,2H),6.12-6.08(m,1H),5.96(s,1H),4.54(d,J=6.0Hz,2H),3 .79-3.73(m,1H),2.54(t,J=7.8Hz,2H),1.61-1.56(m,2H),1.41-1.32(m,2H),1.24(d,J=7.0Hz,6H),0.92(t,J=7.4Hz,3H). 13 CNMR(151MHz,Chloroform-d)δ164.12,163.57,161.56,160.16,154.37,131.31,121. 70,113.45,111.43,103.79,102.82,36.77,29.85,27.41,26.93,22.19,20.97,13.77.

[0126] Compound 6a: 1HNMR(400MHz,Chloroform-d)δ9.99(s,1H),9.07(s,1H),8.19(s,1H),6.23(s,1H),3.85(s,3 H),2.85-2.75(m,2H),2.49(s,3H),1.57-1.51(m,2H),1.33-1.23(m,6H),0.90-0.82(m,3H). 13 C NMR (101MHz, CDCl3) δ164.48,160.16,157.12,155.22,134.00,121.94,119.26,1 13.16,113.04,103.04,39.81,31.61,28.90,27.83,27.77,22.64,14.16,13.04.

[0127] Compound 6b: 1 HNMR(400MHz,Chloroform-d)δ10.07(s,1H),8.96(s,1H),8.20(s,1H),6.22(s,1H),3.85(s,3H),3.67(p,J=7.2H z,1H),2.52(t,J=7.6Hz,2H),1.59-1.49(m,2H),1.37-1.25(m,2H),1.19(d,J=7.2Hz,6H),0.90(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.18,164.10,159.74,154.88,133.58,121.89,119.7 6,113.25,111.66,102.83,39.73,29.77,27.38,27.26,22.19,20.77,13.78.

[0128] Compound 6c: 1 HNMR(400MHz,Chloroform-d)δ9.96(s,1H),8.91(s,1H),8.18(s,1H),6.21(s,1H),3.87( s,3H),2.57-2.46(m,5H),1.55(p,J=7.6Hz,2H),1.39-1.20(m,2H),0.90(t,J=7.3Hz,3H). 13C NMR (101MHz, CDCl3) δ164.09,160.63,156.97,155.51,133.97,121.84,11 9.65,113.75,112.32,102.93,39.73,29.79,27.85,22.12,13.73,13.67.

[0129] Compound 6d: 1 HNMR(400MHz,Chloroform-d)δ9.82(s,1H),9.16(s,1H),8.18(s,1H),6.48(s,1 H),3.93(s,3H),3.60(s,1H),3.17-3.14(m,1H),2.56(s,3H),2.09-2.03(m,3H). 13 C NMR (101MHz, CDCl3) δ163.41,159.67,158.37,150.17,134.06,132.52,121.85,113.29,105.62,39.82,30.04,15.38,13.83.

[0130] Compound 6e: 1 H NMR(400MHz,Chloroform-d)δ7.32-7.11(m,5H),6.88-6.54(m,4H),6.04(d,J=9.5Hz,1H),5.00-4.93(m,1H),4.83- 4.66(m,1H),3.16-2.74(m,4H),2.56-2.32(m,5H),1.62-1.52(m,2H),1.38-1.22(m,6H),0.90(q,J=7.0,6.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.84,171.67,170.87,164.75,164.32,155.91,155.20,154.89,154.80,136.11,130.54,129.45,1 29.32,128.71,128.59,127.19,127.01,115.63,115.13,114.97,103.34,31.56,29.76,28.86,27.81,22.60,14.13,13.66.

[0131] Compound 6f: 11H NMR (400 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.86 (s, 1H), 8.07 (s, 1H), 6.18 (s, 1H), 3.87 (s, 3H), 2.54 - 2.46 (m, 4H), 1.60 - 1.50 (m, 2H), 1.34 - 1.24 (m, 6H), 0.92 - 0.84 (m, 3H). 13 13C NMR (101 MHz, CDCl3) δ 163.88, 160.77, 156.88, 155.07, 133.24, 113.00, 112.86, 109.92, 107.58, 102.79, 39.55, 31.45, 28.72, 27.66, 27.60, 22.48, 14.00, 13.63.

[0132] Compound 10e: 1 1H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.11 (m, 5H), 6.88 - 6.54 (m, 4H), 6.04 (d, J = 9.5 Hz, 1H), 5.00 - 4.93 (m, 1H), 4.83 - 4.66 (m, 1H), 3.16 - 2.74 (m, 4H), 2.56 - 2.32 (m, 5H), 1.62 - 1.52 (m, 2H), 1.38 - 1.22 (m, 6H), 0.90 (q, J = 7.0, 6.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 173.84, 171.67, 170.87, 164.75, 164.32, 155.91, 155.20, 154.89, 154.80, 136.11, 130.54, 129.45, 129.32, 128.71, 128.59, 127.19, 127.01, 115.63, 115.13, 114.97, 103.34, 31.56, 29.76, 28.86, 27.81, 22.60, 14.13, 13.66.

[0133] Compound 10f: 1 1H NMR (400 MHz, Chloroform-d) δ 7.29 - 6.97 (m, 10H), 5.98 (s, 1H), 4.94 (d, J = 7.5 Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H), 3.23 - 2.92 (m, 4H), 2.56 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H), 1.68 - 1.57 (m, 2H), 1.43 - 1.21 (m, 6H), 0.97 - 0.83 (m, 3H).13 C NMR (101MHz, CDCl3) δ171.11,164.37,155.82,154.73,136.42,135.74,129.41,128.63,128.42,127.02 ,126.89,115.14,103.30,53.84,37.86,37.58,31.59,29.77,28.86,27.86,27.78,22.62,14.14,13.64.

[0134] Compound 10g: 1 HNMR(400MHz,Chloroform-d)δ7.25-7.04(m,5H),6.10-6.05(m,1H),4.90-4.79(m,1H),4.54-4.30(m,1H),3.26-3.12(m ,2H),3.06-2.89(m,2H),2.68-2.42(m,5H),2.20-1.86(m,2H),1.68-1.51(m,2H),1.36-1.23(m,6H),0.94-0.76(m,9H). 13 C NMR (101MHz, CDCl3) δ173.63,171.50,164.50,155.89,154.78,136.00,129.51,129.43,128.55,128.40,126.92,1 15.21,103.34,58.40,53.99,37.07,32.39,30.92,28.88,27.89,27.82,21.58,19.16,18.48,16.90,14.13,13.75.

[0135] Compound 10h: 1 HNMR(400MHz,Chloroform-d)δ6.98(d,J=8.0Hz,1H),6.91-6.84(m,1H),6.70(d,J=7.8Hz,1H),6.56(d,J=7.8Hz,1H),6.22(s,1H),6.16-6.08(m,1H ),4.80(s,1H),4.53-4.40(m,1H),3.15-2.83(m,2H),2.57-2.39(m,5H),2 .10-1.87(m,1H),1.65-1.49(m,2H),1.38-1.18(m,8H),0.91-0.67(m,9H). 13C NMR (101MHz, CDCl3) δ173.81,171.90,171.72,165.12,164.92,155.97,155.22,154.91,154.81,130.54,127.00 ,115.63,115.15,103.38,53.63,31.57,31.12,28.89,27.83,22.58,19.30,19.11,18.44,18.02,14.11,13.77.

[0136] Example 6

[0137] This example provides a test for the fungicidal activity of some of the polysubstituted furanoic acid derivatives in Table 1.

[0138] Specific test targets: Fusarium graminearum, Verticillium dahliae, Rhizoctonia solani, Botrytis cinerea, Sclerotinia sclerotiorum, Alternaria alternata, Septorian odorum, Pyricularia oryzae.

[0139] Test treatment: Each test compound was dissolved in DMSO to form a 1% EC stock solution for later use. The mycelium growth rate inhibition method was used to evaluate the indoor fungicidal activity of the test compound at a dose of 100 μg / mL against the test target, with DMSO as the blank control (CK).

[0140] Test method: Weigh a certain mass of the compound to be tested, dissolve it with 500 μL of dimethyl sulfoxide (DMSO), then prepare the calculated amount of the drug solution with PDA medium to a test concentration of 100 μg / mL at a final concentration, prepare the medium into a plate in a 9 cm culture dish, cut off the hyphae on the fungal block with a diameter of 2 mm and place it in the culture medium, and after inoculation, culture it in a culture room with the optimal growth temperature for the pathogen. When the colony diameter in the blank control culture dish is 7.5-8 cm, the colony diameter of each treatment and control is measured by the cross method, and the inhibition rate is calculated, with 3 replicates per group.

[0141] Mycelial growth inhibition rate (%) = [blank colony growth diameter (mm) - colony growth diameter on drug-containing medium (mm)] / control colony growth diameter (mm) × 100%. When testing the inhibition rate of the compound on pathogens at different concentrations, the test compound and PDA medium were prepared to a final concentration of 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL, 6.25 μg / mL, and 3.13 μg / mL, respectively, and then the inhibition rate of the compound on pathogens at different concentrations was tested.

[0142] The results of the activity evaluation of the prepared partially polysubstituted furanoic acid derivatives against the tested pathogens at a concentration of 100 μg / mL are shown in Table 2 below:

[0143] Table 2 - Inhibition rate of some polysubstituted furancarboxylic acid derivatives on different fungi (%)

[0144]

[0145]

[0146]

[0147] As can be seen from Table 2, the compounds in the table have different degrees of inhibition on the plant pathogenic fungi in the table. The inhibition rates of the compounds on Botrytis cinerea and Sclerotinia sclerotiorum are generally high, especially compounds 5g and 6a, which have inhibition rates of 84.23% and 78.37% on Sclerotinia sclerotiorum, respectively. These compounds have obvious inhibitory effects on Botrytis cinerea, Sclerotinia sclerotiorum, and Rhizoctonia solani listed in the table, and have the potential to become new agricultural antifungal agents.

[0148] Figure 2 The graph shows the treatment effects of compound 5a, compound 5g, compound 6a, compound 6e, compound 6f, compound 10a, and compound 10e at a concentration of 100 μg / mL and DMSO as the blank control (CK) group on four pathogenic fungi, namely, rice sheath blight, Botrytis cinerea, rapeseed sclerotinia, and pear black spot.

[0149] from Figure 2 It can be seen that the six compounds have different degrees of inhibition on the four pathogens, among which compound 5g, compound 6a and compound 10e have significant inhibitory effects on rapeseed sclerotinia, and these three compounds have a good inhibitory effect and have the potential to become a new fungicide.

[0150] Figure 3The graph shows the inhibitory effect of compound 5g and compound 6a on Sclerotinia sclerotiorum at different concentrations (3.13 μg / ml, 6.25 μg / ml, 12.5 μg / ml, 25 μg / ml, 50 μg / ml, and 100 μg / ml, respectively). Figure 3 It can be seen that compound 5g and compound 6a have inhibitory effects on the growth of Sclerotinia sclerotiorum at different concentrations, and the inhibitory effect gradually increases with the increase of concentration.

[0151] Figure 4 Compound 5g (i.e. Figure 4 Compound 5g), compound 6a (i.e. Figure 4 The inhibition rate (%) of compound 6a) on Sclerotinia sclerotiorum of rape at different concentrations (concentrations are 3.13ppm, 6.25ppm, 12.5ppm, 25ppm, 50ppm, 100ppm, 1ppm=1μg / ml). It can be seen from the in vitro activity test results that the polysubstituted furancarboxylic acid derivatives of the present application have different degrees of inhibition on the tested plant pathogenic fungi, among which the inhibition rate of compound 5g on Sclerotinia sclerotiorum of rape is more than 80%, and the inhibition rate on Botrytis cinerea is close to 80%. At low concentrations, compounds 5g and 6a also show antifungal activity against Sclerotinia sclerotiorum of rape.

[0152] Figure 5 The live infection of rapeseed leaves and cherry tomatoes by compound 5g at different concentrations against rapeseed sclerotinia and grape gray mold; Figure 5 CK is a blank control without any drug added; Figure 5 It can be seen that under the test concentrations of 50μg / ml, 100μg / ml, 200μg / ml and 400μg / ml, the rapeseed leaves infected by rapeseed sclerotinia rot are basically not diseased, which is equivalent to the control boscalid (Bos); under the test concentrations of 100μg / ml, 250μg / ml and 500μg / ml, the in vivo antibacterial effect of compound 5g on gray mold of cherry tomatoes is also very significant.

[0153] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A polysubstituted furanic acid derivative, characterized in that: The structural formula of the polysubstituted furancarboxylic acid derivative is shown in (I): Among them, the R 1 Any one of ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and methylthio; The R 2 is methyl, ethyl, n-propyl, isopropyl; The R is a substituent containing an aromatic ring, and the R is connected with the formic acid in formula (I) to form an ester compound with a structure shown in the following formula (II): The R 3 It is a fluorine-containing aromatic group; Or, the R is a substituent containing an amino group, and the R is connected with the amino group in formula (I) to form an amide compound having a structure as shown in the following formula (III): The R 4 is a substituted aryl group; Or, the R is a substituent containing an amino group, and the R is connected with the amino group in formula (I) to form a dihydrazide compound having a structure as shown in the following formula (IV): The R 5 It is a nitrogen-methyl heterocyclic pyrazole; Or, the R is a substituent containing an amino acid unit, and the R is connected with the amino group in formula (I) to form an amide compound having a structure as shown in the following formula (V): The R 6 is any one of benzyl and isopropyl; said R 7 It is any of benzyl and 4-hydroxybenzyl.

2. The polysubstituted furanoic acid derivative according to claim 1, characterized in that The R 3 for Any of .

3. The polysubstituted furanoic acid derivative according to claim 1, characterized in that The R 4 for Any of .

4. The polysubstituted furanoic acid derivative according to claim 1, characterized in that The R 5 for Any of .

5. The polysubstituted furanoic acid derivative according to claim 1, characterized in that The polysubstituted furancarboxylic acid derivative is selected from any one of the following compounds; 6. A bactericidal composition, characterized in that: It includes the multi-substituted furancarboxylic acid derivatives described in any one of claims 1 to 5.

7. Use of the polysubstituted furancarboxylic acid derivative according to any one of claims 1 to 5 or the fungicide composition according to claim 6 in the preparation of a drug for killing plant diseases.

8. The use according to claim 7, wherein the plant diseases include at least one of rapeseed sclerotinia, grape gray mold, wheat head blight, wheat glumes blight, cotton verticillium wilt, rice sheath blight, rice blast, and pear black spot.

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