Benz[c][2,7]naphthyridine compounds, methods of making and agricultural uses thereof

Abstract

This invention is benzo[ c [2,7] Naphthidine compounds, their preparation methods and agricultural uses, wherein the benzo[ c [2,7] The general structural formulas of naphthidine compounds, their preparation methods, and uses are shown in Figure I. These compounds not only have short synthesis steps and low synthesis costs, but also exhibit excellent antiviral and bactericidal activities significantly superior to the control drug, achieving unexpected results and breakthroughs, and showing promising application prospects.

Description

Technical Field

[0001] This invention belongs to the field of fine chemicals technology, specifically relating to benzo[ c [2,7] Naphthidine compounds, their preparation and their application as biocides in agriculture. Background Technology

[0002] The unique extreme environment of the ocean, such as high salinity, high pressure, and low temperature, forces marine organisms to form marine natural products (MNPs) with unique structures and significant biological activities. These MNPs possess special skeletons that can interact with biomolecules and exhibit a wide range of biological activities, providing an advantage for their development into new drugs. Life Science. Technol. [2021, 3: 44-61.]. Benzonaphthidine compounds are widely found in marine natural products, especially those containing benzo[…]. c [2,7] Compounds with the naphthidine skeleton, such as veranamine, amphimedine, subarine, and perlolidine.

[0003]

[0004] Structural Formula 1 Currently benzo[ c The synthesis of the [2,7]naphthidine skeleton mainly involves the following strategies: ① Using pyridine derivatives as starting materials, a structural unit containing a benzene ring is first introduced, followed by the construction of benzo[ c [2,7] Naphthidine skeleton. As shown in structural formula 2, Nutaitis et al. reported the use of 5-bromonicotinic acid as a starting material [ J. Heterocyclic Chemistry ., 1992, 29(4): 971-973.], First, esterification is used to generate ethyl 5-bromonicotinate, which is then reduced to 5-bromopyridine triethanolate. After chlorination, it reacts with anilines of different substitutions to generate the important intermediate 3-bromo-5-(chloromethyl)pyridine. Finally, cyclization is performed under the action of lithium diisopropylamino (LDA) to obtain benzo[ c [2,7] Naphthidine compounds. This method involves the reaction of the intermediate 3-bromo-5-(chloromethyl)pyridine with an aromatic amine. N -The alkylation reaction requires the use of aromatic amines as solvents or in excess of more than 5 times, and the reaction time is 20 hours or more.

[0005]

[0006] Structural Form 2 ② Using quinoline derivatives as raw materials or important intermediates, benzo[…] is prepared by introducing specific functional groups at the 3 and 4 positions of quinoline and subsequent transformation.c [2,7] Naphthidine compounds. As shown in structural formula 3, Kim et al. reported benzo[ c [2,7] Synthesis of naphthidine derivatives and their use as PDK-1 inhibitors [Kyung-Hee Kim, et al.] Bioorg. Med. Chem. Lett. [, 2009, 19: 5225-5228.]. Using 4-chloro-3-cyanoquinoline as a starting material, it was first reacted with tert-butyl cyanoacetate to generate cyanoquinoline compounds, which were then thermally decarboxylated to yield dicyano compounds. These dicyano compounds were then reacted with various amines or imidazoles to prepare benzo[…]. c [2,7] Naphthidine compounds; the reaction with hydrogen chloride gas in ethanol-free chloroform also provides a chlorinated intermediate, which can then be reacted with aryl or heteroarylboronic acids to prepare benzo[ c [2,7] Naphthidine compounds. When the starting material is a 4-methyl-3-cyanoquinoline derivative, it is condensed with methyl carboxylate or imidazolinone compounds with different substitutions in the presence of lithium bis(trimethylsilylamine) (LiHMDS) to obtain an intermediate, which is then directly reacted with ammonium acetate under reflux in acetic acid to obtain benzo[ c [2,7] Naphthidine compounds. This synthetic method can achieve the synthesis of benzo[ c Substituents are introduced at positions 2, 8, 9, and 4 of the [2,7]naphthidine skeleton to form benzo[ c A new method has been provided for the synthesis of [2,7]naphthidine derivatives. Additionally, a new method has been developed using 4-methyl-3-cyanoquinoline as a starting material. Tetrahedron [, 2012, 68: 4693-4700.] Alternatively, the methyl group can be converted to an enamine using Bredereck's reagent, followed by cyclization with hydrogen bromide to obtain 4-bromobenzo[ c [2,7] Naphthylidine (Structure Formula 4).

[0007]

[0008] Structural Form Three

[0009] Structure Four ③ Using aniline derivatives as raw materials, specific functional groups are introduced at their ortho positions, followed by conversion to benzo[ c [2,7] Naphthidine compounds. Ling et al. [ J. Chem. Res.[2015, 39: 105-107] Using 2-bromoaniline as a starting material, an alkyne intermediate was prepared by coupling reaction with 2-methyl-3-yn-2-ol, followed by cyclization to give the intermediate 2,2-dimethyl-2,3-dihydroquinolin-4-one, which then underwent a heterodiels-Alder reaction with 3-methyl-1,2,4-triazine to give 4,5,5-trimethyl-5,6-dihydrobenzo[ c [2,7] Naphthidine and its isomers (Structural Formula 5). This method is simple, but the palladium catalyst and 3-methyl-1,2,3-triazine required are expensive, and the product is a mixture of two isomers, making separation and purification difficult. Therefore, further optimization is needed before it can be used for the synthesis of benzo[…]. c [2,7]A new method for naphthidine. Additionally, Liang Dawei [CN104447736B] (structural formula six) and Kochanowska-Karamyan [ J. Nat. Prod. , 2020, 83(4): 1092-1098.](Structural Formula 7) all reported the preparation of dihydrobenzo[ ] using aniline derivatives as raw materials through 5-6 steps of reaction conversion. c ][2,7]Naphthyridine compound veranamine.

[0010]

[0011] Structural Form Five

[0012] Structural Form Six

[0013] Structural Formula 7 To date, although benzo[ c [2,7] Naphthidine compounds have been found to have certain cytotoxic, anti-HIV and anti-cancer activities. Their applications are mainly in the pharmaceutical field. However, their application is greatly limited due to the difficulty of synthesis and high cost. Summary of the Invention

[0014] The technical problem to be solved by this invention is: to provide benzo[ c [2,7] Naphthidine compounds, their preparation methods, and agricultural uses (Structural Formula 8). The benzo[ c The synthesis of naphthidine compounds overcomes the problems of multiple synthesis steps, difficult preparation, and high cost associated with this class of compounds. The preparation method of this invention can rapidly prepare large quantities of benzo[ c [2,7] Naphthidine compounds, for in-depth research on benzo[ c The application of [2,7] naphthidine compounds provides methods for the preparation of starting materials. The provided benzo[ c[2,7] Naphthidine compounds, their preparation methods, and uses not only have short synthesis steps and low synthesis costs, but also exhibit excellent antiviral and bactericidal activities that are significantly better than control drugs, achieving unexpected results and breakthroughs, and have promising applications.

[0015]

[0016] Structural Formula Eight The benzo[ c [2,7] Naphthidine compounds I specifically include Ia-1 to Ia-3 and Ib-1 to Ib-16, where: R 1 ~R 4 These are the functional groups shown in the structures of compounds Ia-1 to Ia-3 and Ib-1 to Ib-16.

[0017] The compound of the present invention, benzo[ c [2,7] Naphthidine compounds Ia-1 to Ia-3 were synthesized according to the method described in Reaction Formula 1: First, compound 5-bromopyridine-3-carboxaldehyde reacted with aromatic amines of different substitutions in a dichloromethane solvent containing acetic acid at room temperature to generate an imine intermediate. After the starting material disappeared, sodium triacetoxyborohydride was added for reduction to obtain the compound. N -((5-bromopyridin-3-yl)methyl)aniline derivative; then, treated with a solution of lithium diisopropylamino (LDA) tetrahydrofuran. N Cyclization of 5-bromopyridin-3-yl)methyl)aniline derivatives yields compounds Ia-1 to Ia-3; compound 5-bromopyridin-3-carboxaldehyde reacts with aromatic amines of different substitutions in a dichloromethane solvent containing acetic acid at room temperature to form an imine. After the starting material disappears, sodium triacetoxyborohydride is added for reduction to obtain compound Ia-1 to Ia-3. N -((5-bromopyridin-3-yl)methyl)aniline derivatives; the crude product obtained after subsequent treatment with lithium diisopropylamino (LDA) tetrahydrofuran solution was dissolved in dichloromethane solution, and manganese dioxide was added to it to aromatize it to obtain compounds Ib-1 to Ib-16.

[0018]

[0019] Reaction 1 The compound of the present invention, benzo[ c [2,7] Naphthidine compounds Ib-1 to Ib-16 were synthesized according to the method described in reaction formula two:

[0020] Reaction 2 The benzo[ c[2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 as fungicides against plant pathogenic fungi, namely, *Fusarium wiltii* of cucumber, *Brachystomum chinense* of peanut, *Rhizoctonia solani* of apple, *Rhizoctonia solani* of wheat, *Phytophthora indicum* of tomato, *Blastomyces oryzae* of rice, *Phytophthora capsici*, and *Sclerotinia sclerotiorum*; among them, compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 exhibit broad-spectrum fungicidal activity, compounds Ib-1 and Ib-15 show significantly better inhibitory activity against *Rhizoctonia solani* than chlorothalonil, compound Ib-15 shows significantly better inhibitory activity against *Fusarium wiltii* of cucumber than chlorothalonil, compound Ib-1 shows significantly better inhibitory activity against *Phytophthora indicum* of tomato and *Phytophthora capsici* than chlorothalonil, and compounds Ia-2, Ib-1, Ib-2, and Ib-9 show significantly better inhibitory activity against *Sclerotinia sclerotiorum* than chlorothalonil.

[0021] The benzo[ c [2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 as antiviral agents for plants, wherein the plant viruses are tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit virus or maize dwarf mosaic virus; most of these compounds have significantly better inhibitory activity against tobacco mosaic virus than the control drug ribavirin.

[0022] Compared with the prior art, the present invention has the following outstanding substantive features and significant progress: (1) This invention is aimed at benzo[ c To address the difficulty in synthesizing the [2,7]naphthidine structural unit, a series of benzo[] compounds were synthesized using readily available and inexpensive 5-bromopyridine-3-carboxaldehyde and aromatic amines as raw materials, through condensation, reduction, and hydrazolysis, followed by reaction with isothiocyanates or aldehydes. c [2,7] Naphthidine compounds Ia-1~Ia-3 and Ib-1~Ib-16; this series of benzo[ c [2,7] The preparation of naphthidine compounds Ia-1~Ia-3 and Ib-1~Ib-16 involves short experimental steps and mild reaction conditions, requiring no harsh experimental conditions such as high temperature, high pressure, or metal catalyst catalysis, and can rapidly prepare large quantities of benzo[ c [2,7] Naphthidine compounds have good economic benefits and are easy to industrialize; (2) First discovery of benzo[ c [2,7] Naphthidine compounds exhibit excellent activity against plant pathogens. Under the same test conditions, benzo[ c[2,7] Naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 exhibited broad-spectrum fungicidal activity. Compounds Ib-1 and Ib-15 showed significantly better inhibitory activity against *Rhizoctonia solani* than chlorothalonil. Compound Ib-15 showed significantly better inhibitory activity against *Fusarium wilt* of cucumber than chlorothalonil. Compound Ib-1 showed significantly better inhibitory activity against *Early Pulmonaria tomato* and *Phytophthora capsici* than chlorothalonil. Compounds Ia-2, Ib-1, Ib-2, and Ib-9 showed significantly better inhibitory activity against *Sclerotinia sclerotiorum* than chlorothalonil.

[0023] (3) First discovery of benzo[ c [2,7] Naphthidine compounds exhibit excellent antiviral activity against plant viruses, and under the same testing conditions, most are superior to the commercially available virazole, thus expanding the scope of benzo[ c [2,7] The application scope of naphthidine compounds as biological pesticides.

[0024] This invention is the first to discover benzo[ c [2,7] Naphthidine compounds have broad-spectrum and highly efficient antimicrobial and antiviral activities against plant pathogens, achieving unexpected results and breakthroughs. Detailed Implementation

[0025] Example 1: Synthesis of compounds Ia-1 to Ia-3 First, 5-bromopyridine-3-carboxaldehyde (5.4 mmol) was dissolved in dichloromethane (50 mL), and 2-chloroaniline (6.0 mmol, 1.1 equiv.) and CH3COOH (1.0 mL) were added. The reaction was carried out at room temperature for 8 h. After the reaction was completed, sodium triacetoxyborohydride (16.2 mmol, 3.0 equiv.) was added to the reaction system. After the reaction was completed, the pH was adjusted to 8-9 with saturated NaHCO3 solution, and the mixture was extracted with water (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and then dissolved under vacuum. The crude product was purified by column chromatography to obtain a yellow solid 2-chloro- N -(pyridin-3-ylmethyl)aniline, yield 76%, melting point 45–47 °C. 1 H NMR (400 MHz, CDCl3) d 8.60 (s, 1H), 8.54 (s, 1H), 7.86 (s, 1H),7.31–7.25 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 6.52(d, J = 8.0 Hz, 1H), 4.45 (s, 3H);13 C NMR (100 MHz, CDCl3) d 149.9, 146.8, 143.0, 137.6, 136.5, 129.4, 128.0, 121.2, 119.5, 118.4, 111.5, 45.0. The second step is to take a 100 mL three-necked round-bottom flask and add 2-chloro- N 4.0 mmol of pyridin-3-ylmethyl)aniline was dissolved in anhydrous THF (30 mL), and 4.0 mol / L lithium diisopropylamino (LDA) solution was added at -78 °C. The mixture was stirred for 20 min, then transferred to room temperature to monitor the reaction progress. After the starting material disappeared, the solution was removed under vacuum. The residue was directly subjected to column chromatography to give a brown solid, 7-chloro-5,6-dihydrobenzo[...] c [2,7] Naphthidine Ia-1, the product containing other substituents was a mixture and proceeded directly to the next step without purification, with a yield of 42% and a melting point of 122–123 °C. 1 H NMR (400MHz, CDCl3) d 8.60–8.50 (m, 1H), 8.42 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.51(d, J = 5.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.9 Hz, 1H), 4.78(s, 1H), 4.56 (s, 1H); 13 C NMR (100 MHz, CDCl3) d 149.2, 147.3, 142.9, 139.0,130.9, 122.8, 120.1, 119.8, 118.7, 116.4, 115.5, 43.0; HR-MS (ESI): calcd forC 12 H7FN2 [M+H] + 217.0527, found (ESI + 217.0533. The synthesis steps for compounds Ia-2 to Ia-3 are the same as those for the synthesis of compound Ia-1 in Example 1.

[0026] 10-Chloro-5,6-dihydrobenzo[ c[2,7] Naphthidine (Ia-2): Brown solid, yield 23%, melting point 132–134 °C. 1 H NMR (400 MHz, CDCl3) d 8.54 (d, J = 5.3 Hz, 1H), 8.43 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.23 (s, 2H); 13 C NMR (100 MHz, CDCl3) d 149.5, 149.2, 147.3,142.8, 139.0, 131.4, 130.9, 127.8, 118.7, 116.4, 115.5, 43.0; HR-MS (ESI):calcd for C 12 H9ClN2 [M+H] + 217.0527, found (ESI + 217.0528. 8-(trifluoromethyl)-5,6-dihydrobenzo[ c [2,7] Naphthidine (Ia-3): Brown solid, yield 40%, melting point 121–123 °C. 1 H NMR (400 MHz, CDCl3) d 8.54 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 4.46 (s, 1H), 4.19 (s, 2H); 13 C NMR (100 MHz, CDCl3) d149.4, 148.8, 146.5, 137.9, 129.9, 129.1, 128.2, 127.9, 123.3, 120.2 (dq, J = 223.2, 6.1 Hz), 119.5, 118.6, 43.3; 19 F NMR (376 MHz, CDCl3) d –55.34; HR-MS(ESI): calcd for C 13 H9F3N2 [M+H] + 251.0791, found (ESI + 251.0799. Example 2 Synthesis of compounds Ib-1 to Ib-16 First, 5-bromopyridine-3-carboxaldehyde (5.4 mmol) was dissolved in dichloromethane (50 mL), along with aniline (6.0 mmol) and CH3COOH (1.0 mL). The reaction was carried out at room temperature for 8 h, and the reaction progress was monitored by TLC. After the reaction was completed, sodium triacetoxyborohydride (3.43 g, 16.2 mmol, 3.0 equiv.) was added to the reaction system. The reaction was continued until the starting material disappeared. The pH was adjusted to 8-9 with saturated NaHCO3 solution. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and then dissolved under vacuum. The crude product was purified to obtain a red solid. N -((5-bromopyridin-3-yl)methyl)aniline, yield 92%, melting point 41–42 °C. 1 H NMR (400 MHz, CDCl3) d 8.57 (d, J = 20.0 Hz, 2H), 7.86 (s,1H), 7.19 (t, J = 7.9 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 4.36 (s, 2H); 13 C NMR (100 MHz, CDCl3) d 149.8, 147.1, 137.7, 137.0, 129.5, 121.1, 118.6, 113.2, 45.4. The second step is to take a 100 mL three-necked round-bottom flask and... N4.0 mmol of 5-bromopyridin-3-yl)methyl)aniline was dissolved in anhydrous THF (30 mL), followed by the addition of 2 mol / L LDA solution (4.0 equiv.) and stirring for 20 min. The mixture was then transferred to room temperature, and after the reactants disappeared, the solvent was removed under vacuum. The residue was dissolved in dichloromethane (40 mL), and manganese dioxide (12.0 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere while monitoring the reaction progress. After the reactants disappeared, the mixture was filtered, and the organic phase was desolvated under vacuum. The residue was purified to obtain a yellow solid benzo[…]. c [2,7] Naphthidine (Ib-1), yield 53%, melting point 138–140 °C. 1 H NMR (400 MHz, CDCl3) d 9.41 (d, J = 9.0 Hz, 2H), 8.95(d, J = 5.4 Hz, 1H), 8.56 (d, J = 8.1 Hz, 3H), 8.37 (d, J = 5.5 Hz, 1H), 8.25(d, J = 8.2 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H); 13 CNMR (100 MHz, CDCl3) d 152.3, 152.1, 149.0, 145.8, 137.4, 131.1, 130.5,127.9, 122.9, 122.1, 121.4, 115.4; HR-MS (ESI): calcd for C 12 H8N2 [M+H] + 181.0766, found (ESI + 181.0763. The synthesis of compounds Ib-2 to Ib-16 is the same as that of Ib-1.

[0027] 7-Methylbenzo[ c [2,7] Naphthidine (Ib-2), brown solid, yield 66%, melting point 169–171 °C. 1 HNMR (400 MHz, CDCl3) d 9.42 (d, J= 3.5 Hz, 2H), 8.93 (d, J = 5.7 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 2.89 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 148.9,146.7, 144.9, 140.3, 132.4, 126.9, 122.6, 122.4, 118.6, 118.5, 116.5, 43.4,17.0; HR-MS (ESI): calcd for C 13 H 10 N2 [M+H] + 195.0922, found (ESI + 195.0912. 9-Methylbenzo[ c [2,7] Naphthidine (Ib-3), yellow solid, 54% yield, melting point 185–186 °C. 1 HNMR (400 MHz, CDCl3) d 9.38 (s, 1H), 9.31 (s, 1H), 8.91 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 6.0 Hz, 1H), 8.30 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 2.64 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6) d 152.8, 152.0, 149.2,144.1, 138.2, 136.8, 133.2, 130.0, 123.7, 122.0, 121.5, 116.3, 21.8; HR-MS(ESI): calcd for C 13 H 10 N2 [M+H]+ 195.0922, found (ESI + 195.0913. 7-Methoxybenzo[ c [2,7] Naphthidine (Ib-4), brown solid, yield 52%, melting point 109–111 °C. 1 HNMR (400 MHz, CDCl3) d 9.42 (d, J = 8.3 Hz, 2H), 8.93 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.14 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 156.1,152.4, 150.8, 148.8, 137.3, 136.7, 128.3, 123.3, 121.5, 115.9, 114.5, 110.5,56.3; HR-MS (ESI): calcd for C 13 H 10 N2O [M+H] + 211.0871, found (ESI + 211.0869. 8-Methoxybenzo[ c [2,7] Naphthidine (Ib-5), brown solid, yield 27%, melting point 132–134 °C. 1 HNMR (400 MHz, CDCl3) d 9.36 (s, 2H), 8.88 (d, J = 5.7 Hz, 1H), 8.44 (d, J =9.0 Hz, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.63 (s, 1H), 7.38 (dd, J = 9.0, 1.9Hz, 1H), 4.01 (s, 3H); 13C NMR (100 MHz, CDCl3) d 161.9, 152.7, 152.4, 148.8,147.8, 137.4, 124.1, 120.7, 118.9, 116.0, 114.9, 110.3, 55.8; HR-MS (ESI):calcd for C 13 H 10 N2O [M+H] + 211.0871, found (ESI + 211.0869. 9-Methoxybenzo[ c [2,7] Naphthidine (Ib-6), brown solid, yield 64%, melting point 142–144 °C. 1 H NMR (400 MHz, CDCl3) d 9.34 (d, J = 12.4 Hz, 2H), 9.15 (d, J = 6.0 Hz, 1H),8.91–8.85 (m, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.18(d, J = 7.9 Hz, 1H), 4.14 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 159.0, 153.0,151.8, 149.1, 147.7, 136.9, 130.6, 122.9, 121.6, 120.7, 112.9, 108.5, 55.9;HR-MS (ESI): calcd for C 13 H 10 N2O [M+H] + 211.0871, found (ESI + 211.0868. 10-Methoxybenzo[ c [2,7]Naphthidine (Ib-7), brown solid, 35% yield, melting point 154–155 °C. 1 H NMR (400 MHz, CDCl3) d 9.39 (s, 1H), 9.26 (s, 1H), 8.91 (d,J = 5.7 Hz,1H), 8.31–8.26 (m, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J =11.5 Hz, 1H), 4.03 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 159.0, 152.4, 149.6,148.5, 141.2, 136.8, 131.9, 123.3, 121.5, 121.0, 115.4, 103.4, 55.8; HR-MS(ESI): calcd for C 13 H 10 N2O [M+H] + 211.0871, found (ESI + 211.0863. 9-(benzyloxy)benzo[ c [2,7] Naphthidine (Ib-8), white solid, yield 43%, melting point 185–187 °C. 1 H NMR (400 MHz, CDCl3) d 9.27 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.95 (s,1H), 7.59–7.56 (m, 2H), 7.53 (d, J = 7.6 Hz, 3H), 7.44 (t, J = 7.5 Hz, 3H), 7.38 (t, J = 7.2 Hz, 1H), 7.26 (s, 1H), 5.30 (s, 2H); 13 C NMR (100 MHz, CDCl3) d 158.2, 152.3, 149.7, 148.5, 141.1, 136.9, 136.3, 131.9, 128.9, 128.4,127.6, 123.3, 121.5, 104.9, 100.0, 70.7; (ESI): calcd for C 19 H 14 N2O [M+H] + 287.1184, found (ESI+ 287.1181. 10-Fluorobenzo[ c [2,7] Naphthidine (Ib-9), brown solid, 54% yield, melting point 145–147 °C. 1 HNMR (400 MHz, CDCl3) d 9.45 (s, 1H), 9.39 (s, 1H), 8.98 (d, J = 5.7 Hz, 1H), 8.74 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.82 (q, J = 7.9 Hz, 1H),7.52–7.43 (m, 1H); 13 C NMR (100 MHz, CDCl3) d 161.0 (d, J = 256.8 Hz), 153.3,152.1, 149.9, 149.9, 147.4, 147.4, 135.2, 135.1, 130.6 (d, J = 10.5 Hz), 126.5 (d, J = 3.3 Hz), 121.5, 119.8 (d, J = 19.7 Hz), 114.1 (d, J = 22.7 Hz), 112.2 (d, J = 10.3 Hz); 19 F NMR (376 MHz, CDCl3) d –110.28; HR-MS (ESI): calcdfor C 12 H7FN2 [M+H] + 199.0672, found (ESI + 199.0662. 7-Chlorobenzo[ c [2,7] Naphthidine (Ib-10), brown solid, 44% yield, melting point 143–145 °C. 1 HNMR (400 MHz, CDCl3) d 9.41 (s, 1H), 9.39 (s, 1H), 8.94 (d, J= 5.6 Hz, 1H), 8.55 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 5.7 Hz, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) d 152.3, 152.2, 149.1,145.8, 137.4, 131.0, 130.5, 127.8, 122.9, 122.1, 121.3, 115.4; HR-MS (ESI):calcd for C 12 H7ClN2 [M+H] + 215.0371, found (ESI + 215.0379. 9-Chlorobenzo[ c [2,7] Naphthidine (Ib-11), yellow solid, 44% yield, melting point 165–167 °C. 1 HNMR (400 MHz, CDCl3) d 9.42 (d, J = 22.7 Hz, 2H), 8.98 (d, J = 4.5 Hz, 1H),8.51 (s, 1H), 8.36–8.25 (m, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.3Hz, 1H); 13 C NMR (100 MHz, CDCl3) d 152.4, 152.3, 149.4, 144.3, 136.5, 134.0,132.0, 131.6, 123.2, 122.5, 121.4, 115.3; HR-MS (ESI): calcd for C 12 H7ClN2 [M+H] + 215.0371, found (ESI + 215.0380. 10-Chlorobenzo[ c[2,7] Naphthidine (Ib-12), brown solid, 45% yield, melting point 161–163 °C. 1 HNMR (400 MHz, CDCl3) d 9.60 (d, J = 6.0 Hz, 1H), 9.44 (s, 1H), 9.37 (s, 1H), 8.98 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H); 13 C NMR (100 MHz, CDCl3) d 153.2, 152.4, 149.2,148.1, 136.8, 132.3, 131.3, 130.3, 130.2, 121.9, 120.0, 119.2; HR-MS (ESI):calcd for C 12 H7ClN2 [M+H] + 215.0371, found (ESI + 215.0376. 8-(trifluoromethyl)benzo[ c [2,7] Naphthidine (Ib-13), brown solid, yield 24%, melting point 156–158 °C. 1 H NMR (400 MHz, CDCl3) d 9.50 (s, 2H), 9.05 (d, J = 5.6 Hz, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.54 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) d 153.5, 152.5, 149.7, 145.3, 136.7, 132.8 (d, J = 33.0 Hz), 128.0 (d, J = 3.9 Hz), 124.8 (d,J = 63.6 Hz), 124.0, 123.8 (d, J = 3.3 Hz), 122.4, 121.7, 115.6; 19 F NMR (376 MHz, CDCl3) d –62.55; HR-MS(ESI): calcd for C 13 H7F3N2 [M+H] + 249.0634, found (ESI + 249.0639. 10-(trifluoromethyl)benzo[ c [2,7] Naphthidine (Ib-14), brown solid, yield 32%, melting point 145–147 °C. 1 H NMR (400 MHz, CDCl3) d 9.45 (d, J = 13.3 Hz, 2H), 8.97 (d, J = 5.6 Hz, 1H), 8.64 (d, J = 6.0 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) d 153.6, 152.8, 149.4,147.6, 136.0, 135.1, 129.4, 128.0 (q, J = 7.6 Hz), 125.0 (d, J = 301.0 Hz),126.2–126.1 (m), 123.5, 122.1, 120.4, 119.6 (q, J = 8.9 Hz); 19 F NMR (376 MHz, CDCl3) d –56.60; HR-MS (ESI): calcd for C 13 H7F3N2 [M+H] + 249.0634, found (ESI + 249.0639. 9-Methoxy-7-methylbenzo[ c [2,7] Naphthidine (Ib-15), brown solid, 48% yield, melting point 120–121 °C. 1 H NMR (400 MHz, CDCl3) d 9.39 (s, 1H), 9.26 (s, 1H), 8.88 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.35 (s, 1H), 4.01 (s, 23H), 2.85 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 158.4, 152.4, 148.2, 148.1, 140.1, 140.1, 137.0, 123.2,121.6, 121.3, 115.5, 100.9, 55.6, 18.7; HR-MS (ESI): calcd for C 14 H 12 N2O [M+H] + 225.1028, found (ESI + 225.1027. 8-Chloro-9-methoxybenzo[ c [2,7] Naphthidine (Ib-16), white solid, yield 36%, melting point 162–163 °C. 1 H NMR (400 MHz, CDCl3) d 9.38 (s, 1H), 9.25 (s, 1H), 8.92 (d, J = 5.8 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 2H), 7.79 (s, 1H), 4.12 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 154.5, 152.5, 150.6, 148.8, 141.0, 136.3, 131.6, 127.8, 121.7,121.2, 115.1, 102.6, 56.6; HR-MS (ESI): calcd for C 13 H9ClN2O [M+H] + 245.0476,found (ESI + 245.0470. Example 3 The above-mentioned benzo[ c [2,7] Antibacterial activity tests and in vitro bactericidal tests of individual compounds in naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 were performed according to the following procedure: The bacterial cell growth rate determination method, also known as the plate method, involves placing 3 mg of the above-mentioned benzo[ c [2,7] Individual compounds from naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 were dissolved in 0.03 mL of acetone, and then dissolved in a solution containing 200... m Dilute the Tween 80 aqueous solution at a concentration of g / mL to a test concentration of 50 mg / kg. Then, pipette 1 mL of the solution into the corresponding culture dish, add 9 mL of culture medium, and shake well to prepare a 50 mg / kg solution. m For each treatment, a plate containing g / mL of the drug was prepared, with a plate containing 1 mL of sterile purified water as a blank control. Mycelial discs were cut along the outer edge of the hyphae using a 4 mm diameter punch and transferred to the drug-prepared plate. Each treatment was repeated three times. The petri dishes were incubated in a constant temperature incubator at 24±1 ℃. After 48 h, the diameter of the mycelial discs in each treatment was investigated, the average value was calculated, and the relative inhibition rate was calculated by comparing it with the blank control.

[0028]

[0029] The above-mentioned benzo[ c [2,7] The results of the in vitro fungicidal activity of individual compounds in the naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 are shown in Table 1.

[0030] Table 1. Benzo[ c [2,7] Results of in vitro bactericidal activity tests of individual compounds in naphthidine compounds Ia-1~Ia-3 and Ib-1~Ib-16

[0031] As shown in Table 1, most compounds were tested at a concentration of 50 μmol / L. mAt the given concentration of g / mL, the compounds exhibited broad-spectrum fungicidal activity against eight common plant pathogens, with generally good fungicidal effects. Nine compounds (Ia-2, Ib-1, Ib-3, Ib-6~Ib-7, Ib-9, Ib-12, Ib-15~Ib-16) showed inhibition rates of 90% or higher against the pathogen causing cucumber wilt; nine compounds (Ia-1~Ia-2, Ib-1, Ib-3, Ib-6, Ib-9, Ib-12, Ib-15~Ib-16) showed inhibition rates of 80% or higher against the pathogen causing peanut brown spot. It exhibits higher activity than the commercially available fungicide chlorothalonil; seven compounds (Ib-1, Ib-3, Ib-6~Ib-7, Ib-9, Ib-15~Ib-16) show inhibition rates of 90% or higher against the pathogen causing apple ring rot; eleven compounds (Ia-1~Ia-2, Ib-1, Ib-3~Ib-4, Ib-6~Ib-7, Ib-9, Ib-12, Ib-15~Ib-16) show activity against the pathogen causing wheat sheath blight. The fungicidal activity of all compounds was higher than that of the commercial fungicide chlorothalonil, with an inhibition rate of 90% or more; two compounds (Ia-1~Ia-2) showed higher fungicidal activity against the pathogen of early blight of tomato than the commercial fungicide chlorothalonil, with an inhibition rate of 94%; and 15 compounds (Ia-1~Ia-3, Ib-1, Ib-3~Ib-4, Ib-6~Ib-7, Ib-9~Ib-10, Ib-12, Ib-14~Ib-16) showed antifungal activity against rice. The fungicidal activity against rice blast pathogens reached 100%, exhibiting activity comparable to the commercially available fungicide chlorothalonil; three compounds (Ia-3, Ib-1, and Ib-9) all achieved 100% fungicidal activity against pepper blight pathogens; and ten compounds (Ia-1~Ia-3, Ib-1, Ib-3~Ib-4, Ib-9, Ib-12, and Ib-14~Ib-15) all achieved 100% fungicidal activity against rapeseed sclerotinia stem rot pathogens.

[0032] Example 4 The above-mentioned benzo[ c [2,7] Antibacterial activity testing of individual compounds in naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16, with concentrations further reduced to 25%. m g / mL, 12.5 m g / mL, 6.25 m g / mL, 3.125 m g / mL or 1.5 m The in vitro sterilization test was performed at g / mL, and the relative inhibition rate was calculated according to the procedure in Example 3 above.

[0033] The above-mentioned benzo[ c[2,7] The results of the in vitro fungicidal activity of individual compounds in the naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 are shown in Table 2.

[0034] Table 2. In vitro EC of some compounds 50 value( m g / mL)

[0035] As shown in Table 2, the concentrations of some selected compounds were further reduced for testing, and their in vitro EC values ​​were calculated. 50 EC50 values ​​of compounds Ib-1 and Ib-15 against the pathogen of apple ring rot. 50 The values ​​are 6.23. m g / mL and 5.89 m g / mL, all lower than the positive control chlorothalonil (EC). 50 = 7.33 m (g / mL), exhibiting better bactericidal activity; compound Ib-9 showed better bactericidal activity against EC50 of the pathogen of apple ring rot. 50 The value is 8.95 m The concentration of the compound was g / mL, comparable to the positive control chlorothalonil. Compound Ib-15 exhibited excellent activity against wheat sheath blight pathogen (EC). 50 = 4.80 m g / mL), compared with the positive control chlorothalonil (EC). 50 = 4.26 m The concentration (g / mL) is close to that of compound Ib-15 (EC) for the pathogen of cucumber wilt. 50 = 3.95 m (g / mL) showed higher bactericidal activity than the positive control (EC). 50 = 5.63 m g / mL). Rice blast pathogen, compound Ia-2 (EC). 50 = 6.93 m g / mL) and compound Ib-9 (EC 50 = 6.81 m (g / mL) showed a difference compared to the positive control chlorothalonil (EC). 50 = 6.25 m Compound Ia-2 (EC) exhibits comparable biological activity (g / mL). 50 = 5.07 m g / mL), Ib-1 (EC) 50 = 5.45 m g / mL), Ib-2 (EC) 50 = 5.95 m g / mL), Ib-9 (EC)50 = 4.31 m Both (g / mL) showed better performance than the positive control chlorothalonil (EC). 50 = 6.46 m Compound Ib-1 (EC) showed higher activity against Sclerotinia sclerotinia rot pathogens in rapeseed (g / mL). For Phytophthora capsulatum pathogens in peppers, compound Ib-1 (EC) exhibited higher activity. 50 = 7.26 m (g / mL) showed better performance than the positive control chlorothalonil (EC) 50 = 7.57 m Higher bactericidal activity (g / mL). The bactericidal activity results showed that compounds Ib-1, Ib-9, and Ib-15 exhibited high biological activity against a variety of pathogens, which is of reference value for their further application in the field of bactericides.

[0036] Example 5 The above-mentioned benzo[ c The antiviral activity of individual compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 of the naphthidine class was determined using the following procedure: Step 1: Purification and concentration determination of tobacco mosaic virus: The purification and concentration determination of tobacco mosaic virus were carried out in accordance with the SOP (Standard Operating Procedure) for tobacco mosaic virus prepared by the Bioassay Laboratory of the Institute of Elementobiology, Nankai University. The crude virus extract was centrifuged twice with polyethylene glycol, and the concentration was determined to be 20%. m g / mL, refrigerate at 4 ℃ for later use; The second step is the above-mentioned benzo[ c [2,7] Preparation of pharmaceutical solutions for individual compounds of naphthidine Ia-1 to Ia-3 and Ib-1 to Ib-16: Weigh benzo[ c [2,7] 40 mg of each of the naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 was used as the technical grade, and then 0.4 mL of DMF was added to each technical grade to dissolve it, yielding 1×10⁻⁶ ppm. 5 m The stock solution was diluted with 1‰ Tween 80 aqueous solution to a test concentration of 500 g / mL. m g / mL or 100 m g / mL, thus preparing the above benzo[ c [2,7] Individual compound solutions of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 are shown. In addition, Ningnanmycin preparation is directly diluted with water as a comparative substance. Step 3, in vitro action: Prepare ten samples of 3-5 leaf stage Shanxi tobacco leaves for friction inoculation, rinse them with running water, and the virus concentration is 10. m g / mL, after drying, cut off, and split along the midrib. The left and right halves are respectively immersed in a 1‰ Tween 80 aqueous solution and the benzo[a] prepared in the second step. c [2,7] The individual compounds of naphthidine Ia-1~Ia-3 and Ib-1~Ib-16 were placed in the drug solution, and after 30 min, they were removed and cultured under moist conditions at room temperature and light. Each 3 leaves constituted one replicate, and the replicates were repeated 3 times. After 3 days, the number of lesions was recorded and the control efficacy was calculated. Inhibition rate (%) = [(Number of control necrotic spots - Number of treated necrotic spots) / Number of control necrotic spots] × 100% The above-mentioned benzo[ c The results of the determination of the anti-tobacco mosaic virus activity of individual compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 of the naphthidine class are shown in Table 3.

[0037] Table 3. Benzo[ c [2,7] Results of anti-TMV activity tests on individual compounds of naphthidine class Ia-1~Ia-3 and Ib-1~Ib-16:

[0038] According to the results in Table 3, benzo[ c [2,7] Naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 have good antiviral activity against plant viruses. Under the same test conditions, most of them are superior to the commercial variety Virazole and have development value.

[0039] All percentages in the above embodiments are mass percentages.

[0040] The raw materials and reagents involved in the above embodiments were all commercially available, and the chemical reaction process was mastered by those skilled in the art.

[0041] Matters not covered in this invention are common knowledge.

Claims

1. Benzo[ c [2,7] Naphthidine compound I, characterized in that Compound I specifically comprises Ia-1 to Ia-3 and Ib-1 to Ib-16. ， In the formula: R 1 ~R 4 These are the functional groups shown in the structures of compounds Ia-1 to Ia-3 and Ib-1 to Ib-16.

2. The benzo[] as described in claim 1 c [2,7] A method for preparing naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16, characterized in that: Compounds Ia-1 to Ia-3 were synthesized according to the method described in reaction formula one: ， First, compound 5-bromopyridine-3-carboxaldehyde reacts with aromatic amines of different substitutions in a dichloromethane solvent containing acetic acid at room temperature to form an imine intermediate. After the starting material disappears, sodium triacetoxyborohydride is added for reduction to obtain the compound. N -((5-bromopyridin-3-yl)methyl)aniline derivative; then, treated with a solution of lithium diisopropylamino (LDA) tetrahydrofuran. N cyclization of -((5-bromopyridin-3-yl)methyl)aniline derivatives yields compounds Ia-1 to Ia-3; Compounds Ib-1 to Ib-16 were synthesized according to the method described in reaction formula two: ， Compound 5-bromopyridine-3-carboxaldehyde reacts with aromatic amines of different substitutions in a dichloromethane solvent containing acetic acid at room temperature to form an imine. After the reactants disappear, sodium triacetoxyborohydride is added for reduction to obtain the compound. N -((5-bromopyridin-3-yl)methyl)aniline derivatives; the crude product obtained after subsequent treatment with lithium diisopropylamino (LDA) tetrahydrofuran solution was dissolved in dichloromethane solution, and manganese dioxide was added to it to aromatize it to obtain compounds Ib-1 to Ib-16.

3. The benzo[] as described in claim 1 c [2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16, characterized in that: Used to kill plant pathogenic fungi, the plant pathogens being *Fusarium wilt* of cucumber, *Bryophyte macrantha* of peanut, *Rhizoctonia solani* of apple, *Rhizoctonia solani* of wheat, *Early blight* of tomato, *Blastomyces oryzae* of rice, *Phytophthora capsici* of pepper, and *Sclerotinia sclerotiorum*.

4. The benzo[] as described in claim 1 c [2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16, characterized in that: Used as an antiviral agent against plant viruses, wherein the plant viruses are tobacco mosaic virus, pepper virus, rice virus, tomato virus, sweet potato virus, potato virus, cucurbit virus, or maize dwarf mosaic virus.

5. The benzo[a] as described in claims 1 and 3 c [2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 in inhibiting plant pathogens, characterized in that... Compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 exhibited broad-spectrum fungicidal activity. Compounds Ib-1 and Ib-15 showed significantly better inhibitory activity against *Rhizoctonia solani* than chlorothalonil. Compound Ib-15 showed significantly better inhibitory activity against *Fusarium wilt* of cucumber than chlorothalonil. Compound Ib-1 showed significantly better inhibitory activity against *Early Pulmonaria tomato* and *Phytophthora capsici* than chlorothalonil. Compounds Ia-2, Ib-1, Ib-2, and Ib-9 showed significantly better inhibitory activity against *Sclerotinia sclerotiorum* than chlorothalonil.

6. The benzo[a] as described in claims 1 and 3 c [2,7] The application of naphthidine compounds Ia-1 to Ia-3 and Ib-1 to Ib-16 in inhibiting plant viruses, characterized in that... Its inhibitory activity against tobacco mosaic virus is significantly better than that of ribavirin and ningnanmycin.

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