CN111937892A - Application of Aza-type isoalburnine derivative in prevention and treatment of agricultural plant diseases - Google Patents
Application of Aza-type isoalburnine derivative in prevention and treatment of agricultural plant diseases Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses application of any compound of Aza-type isofraxinine derivatives A0-A-38 in prevention and treatment or agricultural plant disease resistance. The antibacterial activity test result shows that the compound of the invention has certain inhibitory activity on 6 plant diseases of corn leaf mold, sclerotinia sclerotiorum, rhizoctonia solani, tomato gray mold, rice blast and cotton wilt, and the inhibitory activity of part of the compound on germs is superior to that of azoxystrobin, so that the compound can be developed as a bactericide.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and discloses a new application of an Aza-type isoalbophylline derivative, in particular to an application of a derivative A-0-A-38 in preventing and treating plant diseases caused by corn leaf spot mildew, sclerotinia rot of colza, gray mold of tomato, rhizoctonia solani, rice blast and cotton fusarium wilt.
Background
At present, chemical agents are mostly adopted to control plant fungal diseases in agricultural production, but the resistance growth speed is astonishing in the long-term single use process of the medicine. Benzimidazole, triazole and methoxy acrylate antibacterial agents which are honored as three milestones in the field of agricultural antibacterial agents face severe resistance problems at present. However, the demand of agricultural production for antibacterial drugs is increasing day by day, so the development of novel pesticides with high efficiency, low toxicity and low residue is one of the important tasks of pesticide creation at present. Plant-derived pesticides have become an important field of pesticide research and development gradually due to their advantages of low toxicity, no residue, high selectivity, easy decomposition, difficult generation of drug resistance and the like. Almost 50% or more of the pesticide chemical entities that are currently commercialized are derived from the inspiration conferred on natural products by random screening, biomimetic synthesis, bio-rational design or natural products. According to the statistical data published by Agranova2018 in 9 months, the proportion of natural products and bionic medicines derived from the natural products is close to 60% in the market composition of bactericide commodity medicines in 2016. Therefore, searching and screening potential antibacterial active ingredients from natural resources, especially plant resources, and performing optimization design by taking the potential antibacterial active ingredients as a lead structure are becoming one of the main research directions for creating novel bactericides. Fungal diseases account for more than about 70% of plant diseases. According to statistics, the fungal diseases cause the yield reduction of main crops around 10 percent in the world every year, the economic loss reaches hundreds of billions of dollars, and the main food and economic crops in China, such as rice, cotton and the like, also have serious fungal diseases. Therefore, we selected representative fungal diseases of rice blast and cotton wilt in these two crops as our disease test subjects. In addition, 4 important fungal disease strains of sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea and corn leaf mold are selected for screening.
Isochrysin is a natural alkaloid separated from western non-traditional medicinal plant red blood leucocyte (Cryptolepis sanguinolentis), known biological activities are mainly expressed in antimalaria and hypertension treatment, other activities such as anti-tumor and the like are weak ((1) Tetrahedron Letters,2010,51(31): 4137-. Preliminary studies (CN109090123A) have found the potential activity of new cryptolepine derivatives in the control of rice blast, sclerotinia rot of colza and gray mold of tomato. Therefore, the invention designs and synthesizes a series of novel Aza-type iso-cryptolepine molecules by taking iso-cryptolepine of the same family as a lead model, finds that partially synthesized compounds have better bacteriostatic effects on corn phyllosticta, sclerotinia rot of colza, gray mold of tomato, rhizoctonia solani, rice blast and cotton fusarium wilt, and can be developed as a novel bactericide.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a new application of an Aza-type iso-cryptolepine derivative for agricultural production, namely the application of the Aza-type iso-cryptolepine derivative as a biological pesticide in preventing and treating maize phyllosticta, sclerotinia rot of colza, gray mold of tomatoes, rhizoctonia solani, rice blast and cotton fusarium wilt.
In order to achieve the purpose, the invention provides the following technical method: a medicine for resisting corn leaf spot fungus, rape sclerotinia rot, tomato gray mold, rhizoctonia solani, rice blast and cotton wilt disease contains isoalbugine derivative represented by any compound of A-0-A-38 with effective treatment amount, and the structure of the compound is shown in chemical formula 1.
Chemical formula 1
The invention relates to an Aza-type isoalburnine derivative A-0-A-38, which is prepared by three methods as introduced in chemical formulas 2 to 4:
chemical formula 2
Chemical formula 3
Chemical formula 4
The synthesis method of the azalide derivative is shown in the embodiment, a pure product is obtained by separation of conventional methods such as silica gel column chromatography for many times, and the azalide derivative A-0-A-38 of the claim is determined by spectrum techniques such as mass spectrum and nuclear magnetic resonance. The indoor biological activity test result shows that the Aza-type isoalbugine derivative has a strong inhibiting effect on corn leaf mold, sclerotinia rot of colza, gray mold of tomato, rhizoctonia solani, rice blast and cotton wilt, and can be used for preparing a bactericide.
Detailed Description
The foregoing and other aspects of the present invention will become more apparent from the following detailed description, given by way of example only, for purposes of illustrating the invention. This is not to be construed as limiting the invention. The experimental procedures described in the following examples are conventional unless otherwise specified.
Example 1 Synthesis of target Compound A-0
The synthesis method of the compound A-0 is carried out according to the following reaction formula:
synthesis of target Compound A-0: adding 2- (2 bromophenyl) benzimidazole (1mmol), sodium azide (2mmol), cuprous iodide (0.2mmol), p-toluenesulfonic acid (2mmol) and tert-butyl hydroperoxide (1mmol) into a 50mL round-bottom flask, then adding a proper amount of N, N-Dimethylacetamide (DMA), refluxing at 130 ℃ for 10h under the protection of nitrogen, cooling to room temperature after reaction, adding 50mL of dichloromethane, extracting for multiple times by using saline water and water, taking an organic layer, spin-drying, and purifying by column chromatography to obtain the compound (the synthetic method is shown in the following documents: Eur.J.Org.chem.,2017, 514-522).
Yield: 67.5 percent; a pale yellow powdery solid; m.p.: 228.3-230.6 ℃;1H NMR(400MHz, Chloroform-d6)9.15(s,1H),8.68(dd,J＝7.9,1.6Hz,1H),8.02(d,J＝8.3Hz,1H), 7.98(d,J＝7.5Hz,2H),7.80(td,J＝7.8,1.6Hz,1H),7.71(td,J＝7.6,1.3Hz,1H), 7.63–7.55(m,1H),7.53–7.46(m,1H).13C NMR(101MHz,Chloroform-d6) 144.20,143.11,140.82,137.68,134.77,132.40,130.11,128.20,124.43,124.14, 122.83,120.66,119.22,110.84.MS-ESI m/z:C14H9N3：220.37[M+H]+.
example 2 Synthesis of target Compound A-1
The synthesis method of the compound A-1 is carried out according to the following reaction formula:
synthesis of target Compound A-1: separately, 2- (2-bromophenyl) benzimidazole derivative (2mmol), guanidine hydrochloride (3mmol), cuprous iodide (5 mol%) and potassium phosphate (6mmol) were placed in a 50mL round-bottomed flask, and 7mL DMAF was added thereto, nitrogen was purged 3 times, air was purged, and the mixture was refluxed at 100 ℃ for 16 hours to monitor the reaction by TLC. After the reaction is finished, cooling to room temperature, dissolving with 50mL of dichloromethane, respectively adding 150mL of saturated sodium chloride solution for extraction for 3 times, then washing an organic phase with water, collecting an organic layer, decompressing and evaporating to dryness, and purifying by silica gel column chromatography with a petroleum ether-ethyl acetate system to obtain the compound. (see literature: Chemical Communications,2011,47(19):5596)
Yield: 67.5 percent; an orange-yellow powdery solid; m.p.: 264.5 to 267.0 ℃;1H NMR(400MHz, DMSO-d6)7.83(dd,J＝6.2,2.7Hz,3H),7.73-7.63(m,2H),7.60–7.51(m,2H), 7.43(t,J＝7.6Hz,1H).13C NMR(101MHz,DMSO-d6)169.26,159.08,158.70, 149.33,137.57,133.38,132.74,131.16,127.55,125.91,125.23,117.10,114.58, 114.23.MS-ESI m/z:C14H10N4：234.26[M+H]+.
example 3 Synthesis of target Compound A-2
The synthesis was the same as in example 2, except that guanidine hydrochloride was replaced by amidine hydrochloride.
Yield: 48.0 percent; a pale yellow powdery solid; m.p.: 200.0-202.3 ℃;1H NMR(400MHz, DMSO-d6)8.40(dd,J＝7.9,1.6Hz,1H),7.92(d,J＝8.0Hz,1H),7.66(ddd,J＝ 8.5,7.0,1.7Hz,1H),7.58–7.51(m,2H),7.46(s,2H),7.40-7.35(m,1H),3.18(s, 3H).13C NMR(101MHz,DMSO-d6)148.90,146.96,145.11,144.31,132.27, 128.63,125.52,124.82,124.24,123.63,122.80,119.52,115.12,114.79,19.12. MS-ESI m/z:C15H11N3：234.14[M+H]+.
example 4 Synthesis of target Compound A-3
The synthesis method of the compound A-3 is carried out according to the following reaction formula:
synthesis of target Compound A-3: respectively taking 2- (2-bromophenyl) benzimidazole (2mmol), copper powder (10 mol%), L-proline (20 mol%) and Cs2CO3(2mmol) was placed in a 50mL round bottom flask, nitrogen was bubbled through 3 times, air was evacuated, 6mL dry DMF was added, stirring slowly at ambient temperature (about 500r/min), and the different substituted aldehydes (2.4mmol) were added. After stirring for 15min, NaN was carefully added thereto3Powder (4mmol) and the flask neck was flushed with 1mL of dry DMF, purged again with nitrogen, purged of air and reacted at 80 ℃ for 12h, monitored by TLC. After the reaction is finished, cooling to room temperature, dissolving with 50mL of dichloromethane, respectively adding 150mL of saturated sodium chloride solution for extraction for 3 times, then washing an organic phase with water, collecting an organic layer, filtering with diatomite, evaporating to dryness under reduced pressure, and purifying by silica gel column chromatography with a petroleum ether-ethyl acetate system to obtain the product. (see the literature: RSCA Advances,2015,5:85915-
Yield: 68.2 percent; a light pink powdery solid; m.p.: 239.0-240.2 ℃;1H NMR(400MHz, Chloroform-d6)8.71(d,J＝7.8Hz,1H),7.95(d,J＝8.0Hz,2H),7.76(d,J＝8.2 Hz,1H),7.68(t,J＝7.2Hz,1H),7.64(d,J＝1.6Hz,2H),7.56-7.50(m,3H),7.44(t, J＝7.6Hz,1H),7.13(t,J＝7.6Hz,1H),6.64(d,J＝8.3Hz,1H)；13C NMR(101 MHz,Chloroform-d6)148.82,148.21,144.58,142.60,134.43,132.02,131.11, 129.70,129.33,128.56,128.37,128.35,125.77,124.31,122.82,120.14,118.50, 114.52.MS-ESI m/z:C20H13N3：296.21[M+H]+.
example 5 Synthesis of target Compound A-4
The synthesis was performed as in example 4, except that 2- (5-fluoro-2-bromophenyl) benzimidazole was used instead of 2- (2-bromophenyl) benzimidazole.
Yield: 77.5 percent; an orange-yellow powdery solid; m.p.: 214.6-217.0 ℃;1H NMR(400MHz, Chloroform-d6)8.31(dd,J＝8.5,2.9Hz,1H),7.99–7.86(m,2H),7.69-7.64(m, 3H),7.62(d,J＝6.7Hz,1H),7.59(d,J＝6.8Hz,1H),7.43(dt,J＝16.3,8.3Hz,2H), 7.06(t,J＝7.8Hz,1H),6.56(d,J＝8.5Hz,1H).13C NMR(101MHz,Chloroform-d6) 163.04,160.22,146.31,144.06,143.21,142.30,135.11,131.21,130.92,129.26, 129.26,127.58,127.58,124.52,123.34,122.92,119.89,118.75,115.14,113.85. MS-ESI m/z:C20H12FN3：314.45[M+H]+.
example 6 Synthesis of target Compound A-5
The synthesis was performed as in example 3, except that 2- (5-fluoro-2-bromophenyl) benzimidazole was used instead of 2- (2-bromophenyl) benzimidazole.
Yield: 68.4 percent; yellow microcrystals; m.p.: 200.0-200.1 ℃;1H NMR(400MHz, Chloroform-d6)8.30(dd,J＝8.5,2.9Hz,1H),8.05(dd,J＝11.8,8.2Hz,2H),7.88 (dd,J＝9.0,5.0Hz,1H),7.62–7.56(m,1H),7.51–7.42(m,2H),3.20(s,3H).13C NMR(101MHz,Chloroform-d6)160.08,146.99,144.29,138.90,129.80,129.72, 129.43,125.80,123.45,120.43,120.28,120.05,114.12,109.30(d,J＝12.5Hz), 24.02.MS-ESI m/z:C15H10FN3：252.44[M+H]+.
example 7 Synthesis of target Compound A-6
The synthesis method is the same as example 5, and only furfural is used to replace benzaldehyde.
Yield: 71.4 percent; a yellow powdered solid; m.p.: 200.4-201.8 ℃;1H NMR(400MHz, Chloroform-d6)8.35(dd,J＝8.5,2.9Hz,1H),7.99(dt,J＝9.0,2.8Hz,2H),7.78(d, J＝1.8Hz,1H),7.60–7.45(m,2H),7.34–7.24(m,1H),7.19(d,J＝3.4Hz,1H), 6.95(d,J＝8.4Hz,1H),6.79(dd,J＝3.5,1.8Hz,1H).13C NMR(101MHz, Chloroform-d6)163.23,160.73,146.01,144.26,144.12,138.66(d,J＝2.1Hz), 130.85(d,J＝9.0Hz),128.99,125.98,123.28,120.46,120.22,120.16,114.10, 113.86,112.27,109.68,109.43.MS-ESI m/z:C18H10FN3O：304.08[M+H]+.
example 8 Synthesis of target Compound A-7
The synthesis was carried out in the same manner as in example 5 except that 4-chlorobenzaldehyde was used instead of benzaldehyde.
Yield: 55.5 percent; a yellow powdered solid; m.p.: 222.9-223.6 ℃;1H NMR(400MHz, Chloroform-d6)8.36(dd,J＝8.5,2.9Hz,1H),8.03–7.92(m,2H),7.74–7.69(m, 2H),7.68–7.62(m,2H),7.50(td,J＝8.5,2.9Hz,2H),7.18(ddd,J＝8.4,7.2,1.2Hz, 1H),6.75(d,J＝8.5Hz,1H).13C NMR(101MHz,Chloroform-d6)163.04,160.55, 147.25(d,J＝4.3Hz),144.30,138.87(d,J＝2.2Hz),137.36,132.47,130.64(d,J＝ 8.8Hz),129.96,129.63,129.03,125.95,123.07,120.49,120.34,120.25,119.87, 119.77,114.23,109.49(d,J＝24.7Hz).MS-ESI m/z:C20H11FClN3：348.66[M+H]+.
example 9 Synthesis of target Compound A-8
The synthesis was performed as in example 5, except that 4-fluorobenzaldehyde was used instead of benzaldehyde.
Yield: 68.6 percent; orange powderA powdery crystallite; m.p.: 229.4-231.4 ℃;1H NMR(400MHz, Chloroform-d6)8.35(dd,J＝8.5,2.9Hz,1H),8.06–7.92(m,2H),7.81–7.70(m, 2H),7.49(ddd,J＝12.9,6.9,3.1Hz,2H),7.37(t,J＝8.5Hz,2H),7.16(t,J＝7.9Hz, 1H),6.69(d,J＝8.5Hz,1H).13C NMR(101MHz,Chloroform-d6)165.49,162.99, 160.51,147.28(d,J＝4.1Hz),146.86,144.30,138.89(d,J＝2.1Hz),130.73(d,J＝ 8.7Hz),130.60(d,J＝8.9Hz),130.25(d,J＝3.5Hz),129.12,125.90,123.01, 120.46,120.31,120.22,119.80(d,J＝10.1Hz),116.58(d,J＝22.0Hz),114.21, 109.47(d,J＝24.6Hz).MS-ESI m/z:calcd for C20H11F2N3：332.46[M+H]+.
example 10 Synthesis of target Compound A-9
The synthesis was the same as in example 5, except that benzaldehyde was replaced with 2-fluorobenzaldehyde.
Yield: 72.4 percent; a pale yellow powdery solid; m.p.: 216.4-217.8 deg.C;1H NMR(400MHz, Chloroform-d6)8.40(dd,J＝8.5,2.9Hz,1H),8.06–7.97(m,2H),7.73(td,J＝7.6, 5.7Hz,2H),7.58–7.46(m,3H),7.37(t,J＝8.9Hz,1H),7.18(t,J＝7.8Hz,1H), 6.63(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6)163.17,160.68, 158.95,146.93(d,J＝4.3Hz),144.20,143.06,138.86(d,J＝2.2Hz),133.15(d,J＝ 8.0Hz),130.78(d,J＝8.9Hz),130.54(d,J＝2.3Hz),129.08,125.95,125.38(d,J＝ 3.7Hz),123.42,120.44,120.29,120.20,116.69(d,J＝20.2Hz),113.10,109.52(d,J ＝24.6Hz).MS-ESI m/z:C20H11F2N3：332.28[M+H]+.
example 11 Synthesis of target Compound A-10
The synthesis was performed as in example 5, except that 3-fluorobenzaldehyde was used instead of benzaldehyde.
Yield: 70.1 percent; a yellow powdered solid; m.p.: 219.1-220.9 ℃;1H NMR(400MHz, Chloroform-d6)8.36(dd,J＝8.5,2.9Hz,1H),7.98(dt,J＝9.1,2.8Hz,2H),7.66 (td,J＝8.0,5.5Hz,1H),7.54(d,J＝7.7Hz,1H),7.52–7.47(m,3H),7.42(td,J＝ 8.5,2.6Hz,1H),7.17(t,J＝7.8Hz,1H),6.68(d,J＝8.4Hz,1H).13C NMR(101 MHz,Chloroform-d6)164.18,161.70,160.60,147.16(d,J＝4.1Hz),146.30, 144.28,138.78(d,J＝2.2Hz),135.85(d,J＝7.8Hz),131.22(d,J＝8.1Hz),130.69 (d,J＝8.8Hz),128.97,125.96,124.27(d,J＝3.3Hz),120.50,120.31,120.26, 118.25(d,J＝21.0Hz),115.94(d,J＝23.1Hz),114.15,109.51(d,J＝24.6Hz). MS-ESI m/z:C20H11F2N3：332.42[M+H]+.
example 12 Synthesis of target Compound A-11
The synthesis was carried out in the same manner as in example 5 except that 4-methoxybenzaldehyde was used instead of benzaldehyde.
Yield: 68.9 percent; a pink powdery solid; m.p.: 237.1-241.7 ℃;1H NMR(400MHz, Chloroform-d6)8.34(dd,J＝8.4,2.9Hz,1H),8.01–7.88(m,2H),7.67(d,J＝8.0 Hz,2H),7.47(dd,J＝8.7,6.7Hz,4H),7.16(t,J＝7.8Hz,1H),6.84(d,J＝8.4Hz, 1H),2.61(s,3H).13C NMR(101MHz,Chloroform-d)162.88,160.40,147.42(dd, J＝11.4,3.4Hz),144.28,143.01,139.03(d,J＝2.1Hz),130.56(d,J＝8.8Hz), 130.18,129.19,128.81,128.81,126.13,126.13,125.80,122.91,120.36,120.16, 120.13,114.55,109.41(d,J＝24.6Hz),15.22.MS-ESI m/z:C21H14FN3O： 344.58[M+H]+.
example 13 Synthesis of target Compound A-12
The synthesis was the same as in example 5, except that benzaldehyde was replaced by 4-nitrobenzaldehyde.
Yield: 51.5 percent; a yellow powdered solid; m.p.: 247.0-251.3 ℃;1H NMR(400MHz, Chloroform-d6)8.57–8.50(m,2H),8.34(dd,J＝8.4,2.9Hz,1H),8.05–7.91(m, 4H),7.50(qd,J＝7.7,6.9,3.2Hz,2H),7.21–7.13(m,1H),6.66(d,J＝8.4Hz,1H). 13C NMR(101MHz,Chloroform-d6)163.26,160.77,149.33,147.02(d,J＝4.1Hz), 145.41(d,J＝2.6Hz),144.28,139.78,138.60(d,J＝2.1Hz),130.80(d,J＝8.9Hz), 130.00,130.00,128.63,126.17,124.47,124.47,123.31,120.59,120.53(d,J＝24.1 Hz),113.76,109.58(d,J＝24.7Hz).MS-ESI m/z:C20H11FN4O2：359.67[M+H]+.
example 14 Synthesis of target Compound A-13
The synthesis was carried out in the same manner as in example 5, except that benzaldehyde was replaced by thiophene-2-carbaldehyde.
Yield: 67.5 percent; an orange-yellow powdery solid; m.p.: 239.0-240.4 ℃;1H NMR(400MHz, Chloroform-d6)8.35(dd,J＝8.5,2.9Hz,1H),7.99(dt,J＝9.0,2.8Hz,2H),7.78(d, J＝1.8Hz,1H),7.60–7.45(m,2H),7.34–7.24(m,1H),7.19(d,J＝3.4Hz,1H), 6.95(d,J＝8.4Hz,1H),6.79(dd,J＝3.5,1.8Hz,1H).13C NMR(101MHz, Chloroform-d6)163.23,160.73,146.01,144.26,144.12,138.66(d,J＝2.1Hz), 130.85(d,J＝9.0Hz),128.99,125.98,123.28,120.46,120.22,120.16,114.10, 113.86,112.27,109.68,109.43.MS-ESI m/z:C18H10FN3S：320.26[M+H]+.
example 15 Synthesis of target Compound A-14
The synthesis was carried out in the same manner as in example 5, except that the benzaldehyde was replaced by thiazole-2-carbaldehyde.
Yield: 77.5 percent; a yellow powdered solid; m.p.: 200.0-200.5 ℃;1H NMR(400MHz, Chloroform-d6)8.37(dd,J＝8.5,2.9Hz,1H),8.18(d,J＝3.1Hz,1H),8.03–7.94 (m,3H),7.78(d,J＝3.1Hz,1H),7.58–7.46(m,2H),7.34(ddd,J＝8.4,7.1,1.3Hz, 1H).13C NMR(101MHz,Chloroform-d6)163.44,161.20,147.25(d,J＝4.3Hz), 144.23,143.68,140.99(d,J＝2.9Hz),138.09(d,J＝2.1Hz),130.71(d,J＝8.9Hz), 129.33,126.23,124.03,123.14,120.41(d,J＝10.4Hz),120.37(d,J＝24.2Hz), 116.26,109.71(d,J＝24.9Hz).MS-ESI m/z:C17H9FN4S：321.55[M+H]+.
example 16 Synthesis of target Compound A-15
The synthesis was carried out as in example 5, except that pyridine-2-carbaldehyde was used instead of benzaldehyde.
Yield: 79.6 percent; a white powdery solid; m.p.: 217.0-218.5 ℃;1H NMR(400MHz, Chloroform-d6)8.87(d,J＝4.9Hz,1H),8.37(dd,J＝8.5,2.9Hz,1H),8.07(td,J＝ 7.7,1.8Hz,1H),7.98(td,J＝10.8,9.5,6.5Hz,3H),7.65(dd,J＝7.7,4.9Hz,1H), 7.53–7.41(m,2H),7.16(t,J＝7.8Hz,1H),6.59(d,J＝8.4Hz,1H).13C NMR(101 MHz,Chloroform-d6)161.92(d,J＝250.5Hz),152.37,149.73,147.15(d,J＝4.2 Hz),145.97(d,J＝2.6Hz),144.28,138.69(d,J＝2.1Hz),137.96,130.92,130.74(d, J＝8.9Hz),128.99,125.84(d,J＝1.8Hz),124.51,122.97,120.36,120.17,120.12, 114.49,109.56(d,J＝24.7Hz).MS-ESI m/z:C19H11FN4：315.62[M+H]+.
example 17 Synthesis of target Compound A-16
The synthesis was performed as in example 5, except that benzaldehyde was replaced with 2-amino-5-fluorobenzaldehyde.
Yield: 84.5 percent; white to light brown gray powdery solid, the crystal is brown microcrystal; m.p.: 271.5-273.3 ℃;1H NMR(400MHz,DMSO-d6)8.31(dd,J＝8.6,3.0Hz,1H),8.04 (dd,J＝8.9,5.1Hz,1H),7.94(d,J＝8.1Hz,1H),7.75(dt,J＝9.0,5.1Hz,1H),7.49 (t,J＝7.7Hz,1H),7.33–7.19(m,3H),6.95–6.84(m,1H),6.74(d,J＝8.4Hz,1H). 13C NMR(101MHz,DMSO-d6)162.52,160.07,155.18,152.87,147.48(d,J＝4.0 Hz),146.05,144.07(d,J＝19.6Hz),139.81,131.24(d,J＝9.2Hz),129.33,124.61 (d,J＝242.5Hz),120.53(d,J＝10.3Hz),120.30(d,J＝23.9Hz),119.89,118.97(d, J＝22.1Hz),118.24(d,J＝7.6Hz),116.96(d,J＝7.4Hz),116.08(d,J＝23.7Hz), 114.27,109.02(d,J＝24.2Hz).MS-ESI m/z:C20H12F2N4：347.88[M+H]+.
EXAMPLE 18 Synthesis of the object Compound A-17
The synthesis method is the same as example 5, and only cyclopropane formaldehyde is used for replacing benzaldehyde.
Yield: 75.5 percent; white powdery microcrystals; m.p.: 200.0-200.1 ℃;1H NMR(400MHz, Chloroform-d6)8.31(d,J＝8.3Hz,1H),8.26(dd,J＝8.6,2.9Hz,1H),8.01(d,J＝ 8.2Hz,1H),7.81(dd,J＝8.9,5.0Hz,1H),7.57(t,J＝7.7Hz,1H),7.50–7.37(m, 2H),2.70(tt,J＝8.2,5.0Hz,1H),1.49(dt,J＝6.4,3.4Hz,2H),1.35(dq,J＝7.3,4.2 Hz,2H).13C NMR(101MHz,Chloroform-d6)162.40,159.94,150.23(d,J＝2.4 Hz),147.18(d,J＝4.3Hz),144.33,138.87,129.88(d,J＝8.8Hz),129.34,125.61, 123.18,120.14(d,J＝20.9Hz),114.66,109.33,109.09,15.98,7.85.MS-ESI m/z: C17H12FN3：347.64[M+H]+.
EXAMPLE 19 Synthesis of the object Compound A-18
The synthesis was carried out in the same manner as in example 5 except that 4-thiomethylbenzaldehyde was used instead of benzaldehyde.
Yield: 70.5 percent; a yellow powdered solid; m.p.: 240.7-242.8 ℃;1H NMR(400MHz, Chloroform-d6)8.34(dd,J＝8.4,2.9Hz,1H),8.01–7.88(m,2H),7.67(d,J＝8.0 Hz,2H),7.47(dd,J＝8.7,6.7Hz,4H),7.16(t,J＝7.8Hz,1H),6.84(d,J＝8.4Hz, 1H),2.61(s,3H).13C NMR(101MHz,Chloroform-d6)162.88,160.40,147.42(dd, J＝11.4,3.4Hz),144.28,143.01,139.03(d,J＝2.1Hz),130.56(d,J＝8.8Hz), 130.18,129.19,128.81,128.81,126.13,126.13,125.80,122.91,120.36,120.16, 120.13,114.55,109.41(d,J＝24.6Hz),15.22.MS-ESI m/z:C21H14FN3S： 360.65[M+H]+.
EXAMPLE 20 Synthesis of target Compound A-19
The synthesis was carried out in the same manner as in example 5 except that 3, 4-dichlorobenzaldehyde was used instead of benzaldehyde.
Yield: 67.5 percent; a yellow powdered solid; m.p.: 220.1-223.7 ℃;1H NMR(400MHz, Chloroform-d6)8.33(dd,J＝8.4,2.9Hz,1H),8.03–7.88(m,3H),7.75(d,J＝8.2 Hz,1H),7.61(dd,J＝8.2,2.0Hz,1H),7.49(td,J＝8.7,2.4Hz,2H),7.21(t,J＝7.9 Hz,1H),6.81(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6)163.15, 160.66,147.11(d,J＝4.2Hz),145.32(d,J＝2.6Hz),144.28,138.68(d,J＝2.1Hz), 135.72,133.81(d,J＝21.5Hz),131.27,130.73,130.64,128.80,127.77,126.06, 123.25,120.56,120.46,120.32,114.01,109.54(d,J＝24.7Hz).MS-ESI m/z:calcd for C20H10Cl2FN3：383.41[M+H]+.
EXAMPLE 21 Synthesis of the object Compound A-20
The synthesis method is the same as example 5, and only 3, 4, 5-trimethoxybenzaldehyde is used for replacing benzaldehyde.
Yield: 62.5 percent; yellow powdery microcrystals; m.p.: 255.2-257.3 ℃;1H NMR(400MHz, Chloroform-d6)8.36(dd,J＝8.5,2.9Hz,1H),7.99(dd,J＝8.7,5.4Hz,2H),7.50(t, J＝7.5Hz,2H),7.20(t,J＝7.8Hz,1H),6.96(s,2H),6.80(d,J＝8.4Hz,1H),4.00 (s,3H),3.89(s,6H).13C NMR(101MHz,Chloroform-d6)162.94,160.45,154.08, 154.08,144.26,140.19,138.88(d,J＝2.1Hz),130.89,130.56(d,J＝8.9Hz),129.14 (d,J＝3.1Hz),128.83,125.89,123.09,120.40,120.15,120.15,114.63,109.45(d,J ＝24.6Hz),105.48,105.48,61.16,56.39,56.39.MS-ESI m/z:C23H18FN3O3： 383.45[M+H]+.
EXAMPLE 22 Synthesis of the object Compound A-21
The synthesis was carried out in the same manner as in example 5 except that 3-trifluoromethylbenzaldehyde was used instead of benzaldehyde.
Yield: 58.8 percent; a yellow powdered solid; m.p.: 253.2 to 255.7 ℃;1H NMR(400MHz, Chloroform-d6)8.38(d,J＝8.4Hz,1H),8.08(s,1H),8.00(d,J＝9.3Hz,4H),7.82 (t,J＝7.9Hz,1H),7.51(q,J＝8.0,7.5Hz,2H),7.20–7.11(m,1H),6.63(d,J＝8.4 Hz,1H).13C NMR(101MHz,Chloroform-d6)163.17,160.68,147.22,146.14, 144.33,138.77,134.81,131.91,130.72(d,J＝8.8Hz),129.88,128.90,127.80, 126.06,125.78,123.19,120.60,120.48,120.36,113.87,109.57(d,J＝24.8 Hz).MS-ESI m/z:C21H11F4N3：382.48[M+H]+.
EXAMPLE 23 Synthesis of the object Compound A-22
The synthesis was carried out in the same manner as in example 5 except that 4-trifluoromethoxybenzaldehyde was used instead of benzaldehyde.
Yield: 66.7 percent; a yellow powdered solid; m.p.: 229.1-231.1 ℃;1H NMR(400MHz, Chloroform-d6)8.33(d,J＝7.5Hz,1H),7.97(t,J＝7.2Hz,2H),7.84(t,J＝7.2Hz, 2H),7.54(d,J＝6.9Hz,2H),7.48(d,J＝6.8Hz,2H),7.17(d,J＝7.4Hz,1H),6.70 (t,J＝7.3Hz,1H).13C NMR(101MHz,Chloroform-d6)163.05,160.56,151.13, 147.20,146.43,144.27,138.80,132.56,130.62(d,J＝8.9Hz),130.43,130.43, 128.96,125.96,123.09,121.56,121.56,120.37(t,J＝12.0Hz),120.35,119.80(d,J＝ 10.1Hz),114.04,109.47(d,J＝24.6Hz).MS-ESI m/z:C21H11F4N3O：398.46[M+H]+.
EXAMPLE 24 Synthesis of the object Compound A-23
The synthesis was carried out in the same manner as in example 5 except that 2-chlorobenzaldehyde was used instead of benzaldehyde.
Yield: 77.5 percent; a yellow powdered solid; m.p.: 231.1-234.3 ℃;1H NMR(400MHz, Chloroform-d6)8.40(dd,J＝8.5,2.9Hz,1H),8.07–7.96(m,2H),7.68(d,J＝5.7 Hz,3H),7.63–7.57(m,1H),7.55–7.44(m,2H),7.15(ddd,J＝8.4,7.1,1.2Hz, 1H),6.40(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6)163.18,160.69, 146.74(d,J＝4.2Hz),145.16(d,J＝2.8Hz),144.19,138.82(d,J＝2.0Hz),133.45 (d,J＝4.0Hz),132.26,130.81(d,J＝8.9Hz),130.33(d,J＝3.2Hz),128.90,127.99, 125.94,123.55,120.42,120.23,120.18,120.07(d,J＝10.2Hz),113.02,109.52(d,J ＝24.7Hz).MS-ESI m/z:C20H11ClFN3：348.56[M+H]+.
EXAMPLE 25 Synthesis of target Compound A-24
The synthesis was carried out in the same manner as in example 5 except that 4-trifluoromethylbenzaldehyde was used instead of benzaldehyde.
Yield: 84.1 percent; light yellow powdery microcrystals; m.p.: 245.0-246.4 ℃;1H NMR(400MHz, Chloroform-d6)8.36(dd,J＝8.5,2.8Hz,1H),8.07–7.91(m,6H),7.50(dt,J＝9.4, 6.6Hz,2H),7.17(t,J＝7.8Hz,1H),6.66(d,J＝8.4Hz,1H).13C NMR(101MHz, Chloroform-d6)163.15,160.66,147.14(d,J＝4.1Hz),146.25(d,J＝2.6Hz), 144.31,138.76(d,J＝2.1Hz),137.47,130.72(d,J＝9.0Hz),129.15,129.15,128.86, 126.37(d,J＝3.8Hz),126.30(d,J＝3.9Hz),126.05,123.21,120.56,120.45,120.32, 113.97,109.54(d,J＝24.7Hz).MS-ESI m/z:C20H11ClFN3：348.68[M+H]+.
EXAMPLE 26 Synthesis of the object Compound A-25
The synthesis was carried out in the same manner as in example 5, except that 5-chlorothiophene-2-carbaldehyde was used instead of benzaldehyde.
Yield: 72.3 percent; a pink powdery solid; m.p.: 216.9-219.7 ℃;1H NMR(400MHz, Chloroform-d6)8.31(dd,J＝8.4,2.9Hz,1H),7.98(d,J＝8.2Hz,1H),7.93(dd,J ＝9.0,5.0Hz,1H),7.50(ddt,J＝14.9,8.8,3.8Hz,2H),7.43(d,J＝3.9Hz,1H),7.36 –7.21(m,2H),7.12(d,J＝3.9Hz,1H).13C NMR(101MHz,Chloroform-d6) 163.15,160.65,147.29(d,J＝4.1Hz),144.28,140.85(d,J＝2.6Hz),138.62(d,J＝ 2.1Hz),134.67,132.90,130.66(d,J＝8.9Hz),129.48,128.93,126.31(d,J＝48.1 Hz),123.09,120.51,120.39,120.27,114.24,109.51(d,J＝24.7Hz).MS-ESI m/z: C18H9ClFN3S：354.67[M+H]+.
EXAMPLE 27 Synthesis of the object Compound A-26
The synthesis was carried out in the same manner as in example 5 except that 3, 4-dimethylbenzaldehyde was used instead of benzaldehyde.
Yield: 57.8 percent; light yellow powdery microcrystals; m.p.: 225.2-227.0 ℃;1H NMR(400MHz, Chloroform-d6)8.33(dd,J＝8.6,2.9Hz,1H),7.99–7.91(m,2H),7.53–7.49(m, 1H),7.45(ddt,J＝10.9,7.5,4.0Hz,3H),7.39(d,J＝7.7Hz,1H),7.12(t,J＝7.8Hz, 1H),6.74(d,J＝8.4Hz,1H),2.45(s,3H),2.39(s,3H).13C NMR(101MHz, Chloroform-d)162.81,160.33,148.20(d,J＝2.7Hz),147.35(d,J＝4.1Hz), 144.27,139.96,139.11(d,J＝2.1Hz),137.91,131.56,130.55(d,J＝8.9Hz),130.32, 129.36,129.28,125.67,122.77,120.27,120.03,119.70(d,J＝10.1Hz),114.68, 109.36(d,J＝24.5Hz),20.02,19.88.MS-ESI m/z:C22H16ClFN3：343.45[M+H]+.
EXAMPLE 28 Synthesis of the object Compound A-27
The synthesis was the same as in example 9, except that 2- (2-bromo-5-fluorophenyl) -5-fluorobenzoimidazole was used instead of 2- (2-bromo-5-fluorophenyl) benzimidazole.
Yield: 66.5 percent; an orange-yellow powdery solid; m.p.: 227.4-229.6 ℃;1H NMR(400MHz, Chloroform-d6)8.29(td,J＝7.7,7.0,2.9Hz,1H),7.96(dt,J＝9.8,5.0Hz,1H), 7.76(ddd,J＝8.3,5.2,2.7Hz,2H),7.59(dd,J＝8.9,2.6Hz,1H),7.49(qd,J＝8.2, 2.9Hz,1H),7.40–7.34(m,2H),6.90(td,J＝9.1,2.6Hz,1H),6.62(dd,J＝9.2,4.7 Hz,1H).13C NMR(101MHz,Chloroform-d6)165.54,163.02,162.16,148.67, 146.43,145.29(d,J＝13.2Hz),138.94(d,J＝2.2Hz),130.71(d,J＝9.1Hz), 130.67(d,J＝8.1Hz),129.95(d,J＝3.4Hz),125.69,120.66(d,J＝24.2Hz),119.43 (d,J＝10.3Hz),116.72(dd,J＝22.0,2.5Hz),114.87(d,J＝10.1Hz),111.42(d,J＝25.9Hz),109.45(d,J＝25.3Hz),109.32(d,J＝25.3Hz),105.90(d,J＝24.2Hz), 101.30(d,J＝29.7Hz).MS-ESI m/z:C20H10F3N3：350.54[M+H]+.
EXAMPLE 29 Synthesis of the object Compound A-28
The synthesis method is the same as example 28, and only furfural is used to replace 4-fluorobenzaldehyde.
Yield: 71.0 percent; a yellow powdered solid; m.p.: 200.0-200.4 ℃;1H NMR(400MHz, Chloroform-d6)8.29(d,J＝8.4Hz,1H),7.99(dt,J＝9.6,5.2Hz,1H),7.79(d,J＝ 8.5Hz,1H),7.50(d,J＝8.8Hz,1H),7.28(d,J＝10.9Hz,1H),7.20(d,J＝3.4Hz, 1H),7.11–6.86(m,1H),6.80(s,1H),6.66(d,J＝9.5Hz,1H).13C NMR(101MHz, Chloroform-d6)163.31,160.82,159.87,157.96,145.74(d,J＝18.7Hz),144.38, 144.31,140.52,138.45,130.96(d,J＝8.1Hz),130.91(d,J＝8.1Hz),120.83(d,J＝ 8.9Hz),114.45,112.44(d,J＝6.5Hz),109.56(d,J＝25.3Hz),109.43(d,J＝25.3 Hz),105.74(d,J＝24.6Hz),101.07(d,J＝29.8Hz).MS-ESI m/z:C18H9F2N3O： 322.43[M+H]+.
EXAMPLE 30 Synthesis of the object Compound A-29
The synthesis was carried out in the same manner as in example 28 except that pyridine-2-carbaldehyde was used in place of 4-fluorobenzaldehyde.
Yield: 65.3 percent; a pale yellow powdery solid; m.p.: 214.7-217.4 ℃;1H NMR(400MHz, Chloroform-d6)8.88(d,J＝4.8Hz,1H),8.33(dd,J＝8.5,2.9Hz,1H),8.09(td,J＝ 7.7,1.8Hz,1H),7.98(dd,J＝8.6,4.6Hz,2H),7.91(dd,J＝8.9,5.0Hz,1H),7.67 (dd,J＝7.8,4.8Hz,1H),7.49(td,J＝8.5,2.9Hz,1H),7.24(td,J＝9.0,2.5Hz,1H), 6.36(dd,J＝9.4,2.5Hz,1H).13C NMR(101MHz,Chloroform-d6)163.26,160.77, 159.95,157.56,151.94,149.62,140.70,138.09,130.83(d,J＝8.9Hz),126.09, 124.67,120.82(d,J＝9.9Hz),120.38,120.32,120.22,120.14,114.42(d,J＝25.2 Hz),109.45(d,J＝24.9Hz),101.87(d,J＝29.7Hz).MS-ESI m/z:C19H10F2N4： 333.56[M+H]+.
EXAMPLE 31 Synthesis of the object Compound A-30
The synthesis was carried out in the same manner as in example 5 except that 3-chlorobenzaldehyde was used in place of benzaldehyde.
Yield: 60.5 percent; a pale yellow powdery solid; m.p.: 241.4-243.6 ℃;1H NMR(400MHz, Chloroform-d6)8.40(dd,J＝8.5,2.9Hz,1H),8.07–7.96(m,2H),7.68(d,J＝5.7 Hz,3H),7.63–7.57(m,1H),7.55–7.44(m,2H),7.15(ddd,J＝8.4,7.1,1.2Hz, 1H),6.40(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6)163.18,160.69, 146.74(d,J＝4.2Hz),145.16(d,J＝2.8Hz),144.19,138.82(d,J＝2.0Hz),133.45 (d,J＝4.0Hz),132.26,130.81(d,J＝8.9Hz),130.33(d,J＝3.2Hz),128.90,127.99, 125.94,123.55,120.42,120.23,120.18,120.07(d,J＝10.2Hz),113.02,109.52(d,J ＝24.7Hz).MS-ESI m/z:C20H11ClFN3：348.58[M+H]+.
example 32 Synthesis of the object Compound A-31
The synthesis was the same as in example 5, except that piperonal was used instead of benzaldehyde.
Yield: 61.7 percent; pale yellow powderA solid in the form of a powder; m.p.: 238.4-240.7 ℃;1H NMR(400MHz, Chloroform-d6)8.38(d,J＝9.6Hz,1H),8.01(d,J＝8.1Hz,2H),7.52(t,J＝7.9Hz, 2H),7.34–7.27(m,1H),7.24(s,2H),7.10(d,J＝7.9Hz,1H),6.94(d,J＝8.5Hz, 1H),6.20(d,J＝19.1Hz,2H).13C NMR(101MHz,Chloroform-d6)171.16,165.42, 147.36,146.88,146.52,142.32,139.67,136.52,132.72,130.58,125.44,125.22, 123.62,122.86,122.04,119.22,115.80,114.34,110.24,108.66,102.81.MS-ESI m/z: C21H12FN3O2：358.46[M+H]+.
EXAMPLE 33 Synthesis of the object Compound A-32
The synthesis was carried out in the same manner as in example 28, except that thiazole-2-carbaldehyde was used instead of 4-fluorobenzaldehyde.
Yield: 54.6 percent; a yellow powdered solid; m.p.: 200.0-200.7 ℃;1H NMR(400MHz, Chloroform-d6)8.22(td,J＝8.4,7.8,2.9Hz,1H),8.11(ddt,J＝12.1,8.8,4.0Hz, 1H),8.00(dd,J＝10.3,2.5Hz,1H),7.88(dt,J＝9.3,5.4Hz,1H),7.82(dd,J＝8.9, 5.1Hz,1H),7.68(d,J＝3.3Hz,1H),7.41(dtd,J＝11.4,8.6,4.2Hz,1H),7.26– 7.16(m,1H).13C NMR(101MHz,Chloroform-d6)167.73,161.49,159.99,157.60, 143.73,143.66,140.62,130.91,130.71(d,J＝9.1Hz),128.84,124.40(d,J＝5.3Hz), 120.80,120.59,120.24,114.82(d,J＝25.4Hz),109.62(dd,J＝24.8,13.3Hz), 104.09(d,J＝31.0Hz).MS-ESI m/z:C17H8F2N4S：339.82[M+H]+.
EXAMPLE 34 Synthesis of the object Compound A-33
The synthesis was the same as in example 9, except that 2- (2-bromo-5-fluorophenyl) benzimidazole was replaced with 2- (2-bromo-3-fluorophenyl) benzimidazole.
Yield: 58.3 percent; orange powdery microcrystals; m.p.: 226.8-229.0 ℃;1H NMR(400MHz, Chloroform-d6)8.33(dd,J＝8.5,2.9Hz,1H),7.95(dd,J＝8.8,4.7Hz,2H),7.80– 7.66(m,2H),7.47(dtd,J＝8.1,5.4,4.8,2.1Hz,2H),7.36(t,J＝8.5Hz,2H),7.15(t, J＝7.9Hz,1H),6.68(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6) 165.49,162.97(d,J＝2.0Hz),160.47,147.24(d,J＝4.1Hz),146.82(d,J＝2.6Hz), 144.27,138.87(d,J＝2.1Hz),130.74(d,J＝8.7Hz),130.57(d,J＝8.9Hz),130.25 (d,J＝3.6Hz),129.09,125.87,122.98,120.29(d,J＝24.2Hz),120.27,116.56(d,J＝ 22.0Hz),114.19,109.44(d,J＝24.6Hz).MS-ESI m/z:C20H11F2N3：331.33[M+H]+.
EXAMPLE 35 Synthesis of the object Compound A-34
The synthesis method is the same as example 34, and only furfural is used to replace 4-fluorobenzaldehyde.
Yield: 52.7 percent; a yellow powdered solid; m.p.: 200.1-200.2 ℃;1H NMR(400MHz, Chloroform-d6)8.34(dd,J＝8.5,2.9Hz,1H),8.08–7.88(m,2H),7.77(d,J＝1.7 Hz,1H),7.58–7.47(m,2H),7.30(t,J＝7.8Hz,1H),7.19(d,J＝3.4Hz,1H),6.95 (d,J＝8.4Hz,1H),6.78(dd,J＝3.4,1.8Hz,1H).13C NMR(101MHz, Chloroform-d6)163.22,160.73,151.36,146.03,144.24,144.13,138.66(d,J＝2.1 Hz),130.84(d,J＝9.0Hz),128.99,125.97,123.27,120.43,120.17(d,J＝3.3Hz), 113.97(d,J＝23.8Hz),112.26,109.54(d,J＝24.6Hz),106.47,98.64.MS-ESI m/z: C18H10FN3O：303.30[M+H]+.
EXAMPLE 36 Synthesis of the object Compound A-35
The synthesis was carried out in the same manner as in example 34, except that thiophene-2-carbaldehyde was used in place of 4-fluorobenzaldehyde.
Yield: 74.7 percent; yellow flocculent microcrystals; m.p.: 200.0-200.1 ℃;1H NMR(400MHz, Chloroform-d6)8.34(dd,J＝8.5,2.9Hz,1H),8.17(d,J＝3.3Hz,1H),7.99(s,1H), 7.96(q,J＝4.6Hz,2H),7.76(d,J＝3.2Hz,1H),7.57–7.50(m,1H),7.47(td,J＝8.5,2.9Hz,1H),7.32(dd,J＝9.0,7.2Hz,1H).13C NMR(101MHz,Chloroform-d6) 163.40,161.21,160.90,147.21(d,J＝4.2Hz),144.19,143.66,140.96(d,J＝2.8 Hz),138.05(d,J＝2.1Hz),130.67(d,J＝9.0Hz),129.31,126.20,124.03,123.11, 120.45,120.33(d,J＝24.2Hz),118.14(d,J＝373.1Hz),109.68(d,J＝24.8 Hz).MS-ESI m/z:C17H9FN4S：320.35[M+H]+.
EXAMPLE 37 Synthesis of the object Compound A-36
The synthesis was the same as in example 9, except that 2- (2-bromo-4, 5-difluorophenyl) benzimidazole was used instead of 2- (2-bromo-5-fluorophenyl) benzimidazole.
Yield: 52.9 percent; an orange powdery solid; m.p.: 215.5 to 217.3 ℃;1H NMR(400MHz, Chloroform-d6)8.44(dd,J＝10.0,8.2Hz,1H),7.95(d,J＝8.1Hz,1H),7.75(ddd, J＝13.4,9.7,6.3Hz,3H),7.48(t,J＝7.7Hz,1H),7.37(t,J＝8.6Hz,2H),7.23– 7.11(m,1H),6.70(d,J＝8.4Hz,1H).13C NMR(101MHz,Chloroform-d6)165.59, 163.08,154.30(d,J＝14.5Hz),151.87(d,J＝7.7Hz),151.72(d,J＝7.8Hz),149.32 (d,J＝14.3Hz),148.16(d,J＝2.6Hz),146.72(d,J＝3.6Hz),144.27,139.51(dd,J ＝10.4,2.7Hz),130.69(d,J＝8.6Hz),129.95(d,J＝3.6Hz),129.02,126.07,123.01, 120.24,116.62(d,J＝22.1Hz),116.19(d,J＝18.0Hz),114.20,111.68(d,J＝20.1 Hz).MS-ESI m/z:C20H10F3N3：349.32[M+H]+.
EXAMPLE 38 Synthesis of the object Compound A-37
The synthesis method is the same as example 4, only 4-fluorobenzaldehyde is used to replace benzaldehyde.
Yield: 74.7 percent; orange powdery microcrystals; m.p.: 221.3-223.0 ℃;1H NMR(400MHz, Chloroform-d6)8.73(dd,J＝8.0,1.5Hz,1H),7.97(dd,J＝8.5,2.5Hz,2H),7.77 (ddq,J＝8.1,5.4,3.0,2.3Hz,3H),7.69(td,J＝7.8,1.3Hz,1H),7.46(t,J＝7.7Hz, 1H),7.36(t,J＝8.6Hz,2H),7.13(td,J＝7.8,7.1,1.2Hz,1H),6.67(d,J＝8.4Hz, 1H).13C NMR(101MHz,Chloroform-d6)165.45,162.95,148.02,147.49,144.41, 142.26,131.90,130.73(d,J＝8.6Hz),129.15,128.28(d,J＝23.2Hz),128.28(d,J＝ 23.2Hz),125.70,124.20,124.20,122.63,120.13,118.40,116.53(d,J＝22.0Hz), 116.53(d,J＝22.0Hz),114.12.MS-ESI m/z:C20H12FN3：314.48[M+H]+.
EXAMPLE 39 Synthesis of the object Compound A-38
The synthesis method is the same as example 4, and only furfural is used to replace benzaldehyde.
Yield: 61.7 percent; a pale yellow powdery solid; m.p.: 200.0-201.1 ℃;1H NMR(400MHz, Chloroform-d6)8.71(d,J＝7.9Hz,1H),7.99(d,J＝8.2Hz,2H),7.81–7.73(m, 2H),7.68(t,J＝7.6Hz,1H),7.50(t,J＝7.7Hz,1H),7.27(t,J＝7.8Hz,1H),7.19(d, J＝3.4Hz,1H),6.93(d,J＝8.4Hz,1H),6.83–6.72(m,1H).13C NMR(101MHz, Chloroform-d6)147.82,146.21,144.24,144.17,142.02,139.16,131.82,129.01, 128.72,128.39,125.77,124.22,122.88,119.98,118.70,114.03,113.75, 112.21.MS-ESI m/z:C18H11N3O：286.58[M+H]+.
EXAMPLE 40 test method and results of anti-phytopathogenic fungi Activity of Compound A-0-A-38
The antibacterial activity assay of the present invention was performed using a potato dextrose agar medium (PDA medium). The preparation method comprises the following steps: firstly, cleaning and peeling potatoes, weighing 200g of potatoes, cutting the potatoes into small pieces, adding water, boiling the potatoes thoroughly (boiling for 20-30 minutes, the potato pieces can be punctured by a glass rod), filtering the potatoes by eight layers of gauze, heating the potatoes, adding 15g of agar, continuously heating, stirring the mixture evenly, adding glucose after the agar is dissolved, stirring the mixture evenly, slightly cooling the mixture, then supplementing the water to 1000 ml, subpackaging the mixture in conical bottles, plugging and binding the conical bottles, and sterilizing the mixture for 2 hours at 115 ℃ for later use. Respectively dissolving the compounds L01-43 by DMSO, adding into a culture medium, uniformly mixing to make the concentration of the compounds in the culture medium respectively 50 μ g/mL, taking DMSO with equal concentration as a blank control, and taking the above-mentioned azoxystrobin as a positive control. And (3) pouring the plates, cooling, inoculating bacteria respectively, culturing in an incubator at 23 ℃, and determining the bacteriostasis rate of each compound by taking blank control hypha to overgrow the culture dish as a limit. All experiments were performed in triplicate or in triplicate. The calculation of the bacteriostasis rate is carried out according to the following calculation formula:
the results of the activity test of the compounds A-0 to A-38 against phytopathogens are shown in Table 1.
TABLE 1 test data for anti-phytopathogen activity of target compounds A-0-A-38
As shown in the results of the antibacterial activity determination in Table 1, the azacitine derivatives A-0 to A-38 prepared by the invention show good inhibitory activity to 6 plant pathogenic bacteria at a concentration of 100 ppm and 50ppm, wherein the antibacterial activity of the compounds A-0, A-1, A-2 and A-5 to the pathogenic bacteria is superior to that of azoxystrobin. The Aza-type isoalburnine derivative has simple structure, easy synthesis and further research and development value, and is expected to be developed into a novel bactericide, so that the compound can be used for preparing the bactericide.
Claims (8)
1. The invention relates to application of an Aza-type isoalburnine derivative in preparation of a medicine for preventing and treating or resisting agricultural diseases, and relates to new application of the Aza-type isoalburnine derivative.
2. The azaine-type isoalburnine derivatives A-0 to A-38 as claimed in claim 1, have the following molecular structural features:
3. the use of any one of the compounds of the "Aza" type isoalburnine derivative A-0-A-38 according to claim 1 in the preparation of a medicament for preventing or treating diseases caused by M.
4. The use of any one of the compounds of claim 1, wherein the compound is selected from the group consisting of a-0-a-38, and derivatives thereof.
5. The use of any one of the compounds of claim 1, wherein the compounds are derivatives A-0 to A-38 of Aza-type cryptolepine in the preparation of a medicament for the prevention or treatment of tomato gray mold.
6. The use of any one of the compounds of claim 1 as "Aza" type cryptolepine derivatives A-0 to A-38 in the preparation of a medicament for the prevention or treatment of diseases caused by Rhizoctonia solani.
7. The use of any one of the compounds of "Aza" type cryptolepine derivative A-0 to A-38 according to claim 1 in the preparation of a medicament for controlling or resisting rice blast.
8. The use of any one of the compounds of claim 1, wherein the compound is selected from the group consisting of a-0 to a-38 for the prevention or treatment of cotton wilt.
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| WO2011079236A1 (en) * | 2009-12-22 | 2011-06-30 | The Ohio State University Research Foundation | Compositions and methods for cancer detection and treatment |
| CN106349244A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | Benzo imidazo quinazoline dimethyl oxygen benzene oxygen acetyl-AA-OBzl, as well as synthesis, activity and application thereof |
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