Application of spinosad derivative as insecticide

Abstract

The invention discloses application of spinosad derivatives or salts, stereoisomers and tautomers thereof in preparation of insecticides for preventing and removing plant diseases and insect pests, wherein the structure of the spinosad derivatives is shown in the specification. The spinosad derivatives of the present invention exhibit comparable or higher activity to noctuidae, snout moth insects, arachnids and / or nematodes than natural products of the spinosad class, and are useful in the agricultural and animal health markets. # imgabs0 #

Description

[0001] This application is a divisional application of the invention entitled “Spinosad derivatives as insecticides, preparation methods and applications thereof” filed on December 19, 2022, with application number 2022116301732. Technical Field

[0002] The present invention relates to spinosad derivatives and preparation methods and applications thereof. Background Art

[0003] Spinosyn is a macrolide compound extracted from the fermentation broth of Saccharopolyspora spinosa, originally isolated from an abandoned winery in the Caribbean. The main components are spinosyn A and spinosyn D, with a ratio of about 5:1. The molecular formula of spinosyn A is C 41 H 65 NO 10 , whose structure was determined by NMR, MS and X-ray analysis, contains a tetracyclic polyketide aglycone with a neutral sugar substituent (2,3,4-tri-methoxy-α-L-rhamnose) attached to the C-9 hydroxyl group and an amino sugar moiety (β-D-forosaminyl) attached to the C-17 hydroxyl group. The researchers found that this unique spinosad tetracyclic system consisting of a cis-anti-trans-5,6,5-tricyclic moiety fused to a 12-membered lactone has very high insecticidal activity. As a class of highly efficient and safe biological insecticides, it has rapid and efficient insecticidal activity against target pests and is safe against non-target organisms. The main degradation modes are photolysis and microbial degradation, and it eventually decomposes into carbon, nitrogen, oxygen, etc. It plays an important role in the prevention and control of agricultural pests, stored grain pests, sanitary pests, and animal parasites. At present, this type of product has been successfully registered in more than 80 countries and can be used to prevent and control more than 200 pests. The spinosad products on the market in my country include the "Cui Sha" (spinosad 48%) suspension concentrate for cotton and the "Cai Xi" (spinosad 2.5%) suspension concentrate for fruits and vegetables.

[0004] Spinosad is considered to be an agonist of nicotinic acid acetylcholine receptors. Its mechanism of action is to continuously activate the target insect acetylcholine nicotinic receptors, but its binding site is different from nicotine and imidacloprid. Spinosad can also affect GABA (γ-aminobutyric acid) receptors, but the mechanism of action has not yet been clarified. Spinosad can quickly paralyze and paralyze pests, and finally lead to death. Its insecticidal effect is significant, and compared with many other insecticides, spinosad usually shows greater selectivity for target insects, and has high safety. It has no obvious toxicity to beneficial insects and mammals. The original drug has an acute oral LD50 of >5000 mg / kg for female rats. It is suitable for the production and application of pollution-free vegetables and fruits. It is a new type of low-toxic, high-efficiency, and low-residue biological insecticide.

[0005] The unique nucleus structure and excellent insecticidal activity of spinosad make it a potential agricultural chemical, which also provides opportunities and challenges for its synthesis. In addition, with the use of traditional pesticides, insect resistance has increased, and there is an urgent need to discover diversified, highly effective and low-toxic spinosad compounds. Developing new pesticides with low toxicity, low residue and no pollution to the ecological environment, and developing biopesticides are the main ways to enhance the international competitiveness of agricultural products and develop green industries. Screening compounds with new structures can solve the current problems of narrow insecticide spectrum and few product types, and is also an important method for field resistance management. Summary of the invention

[0006] The purpose of the present invention is to provide a class of spinosyn derivatives, which are spinosyn derivatives in which the C5-C6 double bond of spinosyn A is hydrogenated and C9, C17 are substituted or functionalized; the spinosyn derivatives have insecticidal activity against insects such as Noctuidae and Pyralidae, and show activity comparable to or higher than that of natural spinosyn products against insects, arachnids and nematodes, and have an improved resistance spectrum compared to natural products; the spinosyn derivatives of the present invention may be used in the agricultural and animal health markets.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] The spinosyn derivative or its salt, stereoisomer, tautomer is shown in formula I:

[0009]

[0010] in, represents a single bond or a double bond;

[0011] X is selected from O, S, and N;

[0012] Y is selected from O, S, and N;

[0013] A is selected from a covalent bond, hydrogen, substituted alkyl, substituted or unsubstituted heterocycloalkyl, alkoxy, substituted carbonyl, substituted benzoyl, substituted aromatic heteroformyl, substituted phenylacetyl, and the like;

[0014] B is selected from hydrogen, substituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted carbonyl, substituted benzoyl, substituted aromatic heteroformyl, substituted phenylacetyl, and the like.

[0015] Specifically, the substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted oxygen-containing six-membered ring group.

[0016] Preferably, X is selected from O and N; Y is selected from O;

[0017] When X is selected from O, A is selected from a covalent bond, Z and W are independently selected from CH and N, but Z and W cannot be selected from N at the same time; R1 is selected from H, halogen, methoxy, and dimethylamino; R2 is selected from halogen and acetyl; R3 is selected from H and methyl; R4 and R5 are independently selected from H, methyl, and ethyl; R6 is selected from hydrogen and methoxymethyl; R7 is selected from hydrogen, methyl, and hydroxymethyl;

[0019] When X is selected from N, A is selected from methoxy;

[0020] B is selected from quilt (3-pyridyl), (2-thienyl)substituted carbonyl.

[0021] When X is selected from O and N, the C9 position is an R-configuration chiral carbon atom, and the C17 position is an S-configuration chiral carbon atom.

[0022] Variations of the spinosyn derivatives shown in Formula I include addition, subtraction or movement of the various components as described for each compound. Similarly, when one or more chiral centers are present in the molecule, all possible chiral variants are included.

[0023] Specifically, the spinosad derivative is selected from the following compounds:

[0024]

[0025]

[0026]

[0027] The spinosyn derivative or its salt, stereoisomer, tautomer is as described in Formula II:

[0028]

[0029] Among them, A1 is selected from Z1 and W1 are independently selected from CH and N, but Z1 and W1 cannot be selected from CH or N at the same time; R'1 is selected from halogen; R'3 is selected from H and methyl; R'4 and R'5 are independently selected from H, methyl and ethyl;

[0030] B1 is selected from

[0031] The halogen is selected from F, Cl, Br, and I.

[0032] Another object of the present invention is to provide a method for preparing a spinosad derivative, the synthetic route of which is as follows:

[0033]

[0034] The method comprises reacting the C-5,6 double bond of spinosyn A to form the spinosyn compound of the present invention, wherein the spinosyn compound is formed via an α-haloketone intermediate.

[0035] The spinosyn derivatives of the present invention can be prepared in several ways. At least some of these methods are known in the field of organic chemical synthesis. The spinosyn derivatives herein are prepared from simple and readily available raw materials, and the optimal reaction conditions may vary depending on the specific conditions used, and these conditions can be determined by a person skilled in the art of organic synthesis through conventional optimization procedures.

[0036] In addition, compound synthesis may involve the protection and deprotection of various chemical groups. The use of protection and deprotection and the selection of appropriate protecting groups can be determined by those skilled in the art.

[0037] The spinosyn derivatives described in the present invention can be prepared using spinosyn precursors, spinosyn or spinosyn analog starting materials. As used herein, the spinosyn precursors, spinosyn or spinosyn analog starting materials used in the synthesis method include any tetracyclic spinosyn molecule containing a tetracyclic macrolide having a polyketide structure to which two sugars are attached.

[0038] The process for preparing the spinosyn derivatives of the present invention may comprise one to five chemical steps of subjecting spinosyn to treatment, generally without purification of the intermediates thus formed.

[0039] In the synthetic method shown in Scheme 1 above, the C17 position of spinosad A can be hydrolyzed using sulfuric acid (H2SO4) under alkaline or acidic conditions in the presence of water. The hydrolyzed intermediate can be oxidized using Dess-Martin periodinane or Swern conditions, followed by treatment of the intermediate with thioamide or thiourea.

[0040] The spinosyn derivatives of the present invention show comparable or higher activity to natural spinosyn products against Noctuidae, Pyralidae insects, arachnids and / or nematodes, and can be used in the agricultural and animal health markets.

[0041] Another object of the present invention is to provide the use of the spinosad derivatives in the preparation of pesticides for controlling plant diseases and insect pests.

[0042] The plant pests are rice stem borer, beet armyworm, citrus red spider and southern root-knot nematode.

[0043] The insecticide is a contact-acting insecticide.

[0044] Another object of the present invention is to provide a composition comprising the spinosyn derivatives of the present invention and an acceptable carrier. DETAILED DESCRIPTION

[0045] The synthesis of the compounds of the invention is described below in the examples. In general, the methods generally include several steps of reaction steps (semi-synthesis) of spinosyn or its precursors. The compounds of the invention can be prepared using spinosyn precursors, spinosyn or spinosyn analog starting materials, such as the spinosyn precursors, spinosyn or spinosyn analog starting materials used in the synthesis method of the invention include any tetracyclic spinosyn molecule containing a tetracyclic macrolide having a polyketide structure with two sugars attached.

[0046] The reaction to form the compounds of the invention may be carried out in a solvent, which may be selected by a person skilled in the art of organic synthesis. The solvent is non-reactive with the reaction components, i.e., the starting materials (reactants), intermediates, or products, at the temperature and pressure at which the reaction is carried out. The reaction may be carried out in a single solvent or in a mixture of multiple solvents. The formation of products or intermediates may be monitored by any suitable method known in the art. For example, the formation of products or intermediates may be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry (MS), or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0047] Example 1

[0048] Intermediate 1 (i.e., compound 13): (2R, 3aS, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-9-ethyl-13-hydroxy-14-methyl-2-(((2R, 3R, 4R, 5S, 6S)-3, 4, 5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2, 3, 3a, 5a, 5b, 6, 9, 10, 12, 13, 16a, 16b-tetrahydro-1H-as-indolo[3, 2-d][1]oxocyclododecane-7, 15-dione

[0049]

[0050] To an aqueous solution of spinosad (5.0 g, 6.8 mmol) was added dilute sulfuric acid (670 mg, 6.8 mmol), the mixture was stirred at 95 °C for 6 h, filtered, the filter cake was washed three times with dilute sulfuric acid, dried, ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (150 mL) were added, the organic layer was washed three times with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, separated by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to give a white solid (Intermediate 1, 4.0 g, 97.1%).

[0051] 1H NMR (500MHz, CDCl3) δ4.81 (d, J=12.0Hz, 1H), 4.22 (p, J=6.0Hz, 1H), 3.83-3.79 (m,1H),3.55(d,J=3.0Hz,3H),3.52(dd,J=6.0,3.5Hz,1H),3.50-3.47(m,7H), 3.44(dd,J=9.0,3.5Hz,1H),3.10(t,J=9.5Hz,1H),2.92-2.87(m,1H),2.74(p, J=7.0Hz,1H),2.57(dt,J=15.0,3.0Hz,2H),2.28(dd,J=9.5,6.5Hz,1H),2.22( dt,J=13.5,7.0Hz,1H),2.12(td,J=12.5,7.0Hz,1H),1.98(dt,J=11.5,5.5Hz, 1H),1.82-1.76(m,4H),1.71-1.63(m,5H),1.59-1.52(m,5H),1.46-1.39(m,1H ),1.35-1.31(m,2H),1.27(d,J=6.5Hz,3H),1.24-1.21(m,1H),1.17(d,J=7.0H z,3H),1.06(dd,J=12.5,5.0Hz,1H),1.01-0.96(m,1H),0.85(d,J=7.5Hz,3H).

[0052] Intermediate 2 (i.e., compound 20): (2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,9,11,12,16a,16b-dodecahydro-1H-indolo[3,2-d][1]oxocyclododecane-7,13,15(14H)-trione

[0053] At 0°C, Dess-Martin periodinane (144 mg, 0.34 mmol) was added in batches to a solution of intermediate 1 (2 g, 3.4 mmol) in dichloromethane (20 mL), and stirred under reflux for 6 hours; after the reaction, the reaction solution was diluted with dichloromethane (80 mL), and then washed with saturated sodium bicarbonate (30 mL), saturated Na2SO3 (20 mL) and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain an oil, which was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 to 15: 1 V / V) to obtain intermediate 2 (1.94 g, 97.0%) as a white solid.

[0054] 1 H NMR (500MHz, CDCl3) δ6.87 (s, 1H), 5.82 (d, J = 10.0Hz, 1H), 5.74-5.70 (m, 1H), 4.76- 4.74(m,1H),4.24(q,J=7.0Hz,1H),4.18(q,J=7.0Hz,1H),3.51-3.47(m,4H),3.46- 3.42(m,8H),3.39(dd,J=9.5,3.0Hz,1H),3.17(dd,J=13.5,4.0Hz,1H),3.02-2.98( m,1H),2.94-2.92(m,1H),2.80-2.76(m,1H),2.54(ddd,J=18.0,10.0,4.0Hz,1H),2 .37-2.29(m,2H),2.22(dt,J=13.5,7.0Hz,1H),2.10(q,J=10.5Hz,1H),1.86(dd,J= 13.5,7.0Hz,1H),1.72-1.68(m,1H),1.59-1.55(m,1H),1.52(dd,J=8.0,4.5Hz,1H) ,1.46(td,J=14.0,5.0Hz,2H),1.36(td,J=13.5,6.5Hz,2H),1.32-1.27(m,2H),1.2 5(d,J=7.0Hz,3H),1.22(d,J=6.0Hz,3H),0.89-0.81(m,1H),0.75(t,J=7.5Hz,3H).

[0055] Intermediate 3: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-13-(((6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-ethyl-2-hydroxy-14-methyl-2,3,3a,5a,5b,6,9,11,12,13,16a,16b-tetradecahydro-1H-as-indolo[3,2-d][1]oxocyclododecane-7,15-dione

[0056]

[0057] At -30 ° C, boron tribromide (12 ml, 134 mmol) was added dropwise to a dichloromethane solution (50 ml) of spinosad (5.0 g, 6.8 mmol), and the mixture was stirred at -30 ° C for 6 h. The reaction was quenched, and dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (150 mL) were added. The organic layer was washed three times with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and separated by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 1 to 4: 1 V / V) to give intermediate 3 (400 mg, 10.8%) as a white solid.

[0058] Intermediate 4: (2R,3R,5aR,bS,9S,14R,16aS,16bR)-9-ethyl-13-hydroxy-14-methyl-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)octahydro-1H-asindolo[3,2-d][1]oxocyclododecane-7,15-dione

[0059]

[0060] Pd / C (10%, 500 mg) was added to a solution of intermediate 1 (5 g, 8.46 mmol) in anhydrous dichloromethane (30 mL). The mixture was reacted at room temperature for 10 hours in a hydrogen atmosphere. After the reaction stopped, the mixture was filtered under reduced pressure. The filtrate was evaporated to dryness under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain intermediate 4 (4.95 g, 100%) as a white solid.

[0061] Intermediate 5: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-2,13-dihydroxy-14-methyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-1H-asindolo[3,2-d][1]oxocyclododecane-7,15-dione

[0062] To a dichloromethane solution (50 ml) of spinosad (5.0 g, 6.8 mmol) was added boron tribromide (12 ml, 134 mmol) dropwise at -30°C, and the mixture was stirred at -30°C for 6 h. The reaction was quenched, and dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (150 mL) were added. The organic layer was washed three times with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Intermediate 5 (600 mg, 22.0%) was isolated by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1 to 4:1) as a white solid.

[0063] Example 2: (2R, 3S, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-9-ethyl-14-methyl-7, 15-dioxo-2-(((2R, 3R, 4R, 5S, 6S)-3, 4, 5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2, 3, 3a, 5a, 5b, 6, 7, 9, 11, 12, 13, 14, 15, 16a, 16b-hexahydro-1H-indolo[3, 2-d][1]oxocyclododecane-13-isonicotinate (Compound 1)

[0064]

[0065] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (DCM, 10 mL) were added isonicotinoyl chloride (141 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (DMAP, 122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 1 (223 mg, 94.5%) as a white solid.

[0066] 1H NMR (500MHz, CDCl3) δ8.73-8.70 (m, 2H), 7.79 (t, J = 3.5Hz, 2H), 6.76 (s, 1H), 5.83 ( d,J=10.0Hz,1H),5.75-5.73(m,1H),5.23(dt,J=9.5,4.5Hz,1H),4.79(s,1H),4.66 -4.63(m,1H),4.25(t,J=6.5Hz,1H),3.53-3.50(m,1H),3.49(d,J=2.0Hz,3H),3.4 7(d,J=6.5Hz,1H),3.45-3.42(m,7H),3.44-3.39(m,1H),3.11-3.03(m,2H),3.00(d ,J=8.5Hz,1H),2.85-2.80(m,1H),2.39(dd,J=13.5,3.5Hz,1H),2.20(dt,J=13.0, 7.0Hz,1H),2.14-2.08(m,1H),1.87(dd,J=13.5,7.0Hz,1H),1.70-1.67(m,3H),1.5 0-1.36(m,5H),1.28(dt,J=13.0,8.0Hz,3H),1.21(dd,J=6.5,2.0Hz,3H),1.12(d,J =6.5Hz,3H),0.89(td,J=7.5,2.0Hz,1H),0.84(d,J=2.0Hz,1H),0.77-0.74(m,3H).

[0067] Example 3: (2R, 3S, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-9-ethyl-14-methyl-7, 15-dioxo-2-(((2R, 3R, 4R, 5S, 6S)-3, 4, 5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2, 3, 3a, 5a, 5b, 6, 7, 9, 11, 12, 13, 14, 15, 16a, 16b-hexahydro-1H-indolo[3, 2-d][1]oxocyclododec-13-ylnicotinate (Compound 2)

[0068]

[0069] Nicotinoyl chloride (140 mg, 0.96 mmol) and N,N-dimethylpyridin-4-amine (122 mg 1.0 mmol) were added to a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 2 (236 mg, 99.5%) as a white solid.

[0070] 1 H NMR(500MHz, CDCl3)δ9.18(s,1H),8.73(dd,J=4.5,2.0Hz,1H),8.28-8.26(m,1H),7.37(ddd,J=7.5,5.0,2.5Hz,1H),6.77(s,1H),5.83(d,J=10.0Hz, 1H),5.74(d,J=9.5Hz,1H),5.25(dd,J=10.0,5.0Hz,1H),4.79(s,1H),4.6 7-4.64(m,1H),4.25(p,J=6.5Hz,1H),3.54-3.44(m,5H),3.43-3.38(m,9H) ,3.11-3.05(m,2H),3.00(d,J=8.0Hz,1H),2.41-2.37(m,1H),2.20(dd,J= 13.0,6.5Hz,1H),2.11(d,J=9.5Hz,1H),1.87(dd,J=13.5,7.0Hz,1H),1.70 -1.67(m,3H),1.50-1.38(m,5H),1.34-1.25(m,3H),1.22-1.17(m,4H),1. 14-1.09(m,3H),0.88(td,J=11.0,4.5Hz,1H),0.76(td,J=7.5,2.0Hz,3H).

[0071] Example 4: (2R, 3S, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-9-ethyl-14-methyl-7, 15-dioxo-2-(((2R, 3R, 4R, 5S, 6S)-3, 4, 5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2, 3, 3a, 5a, 5b, 6, 7, 9, 11, 12, 13, 14, 15, 16a, 16b-hexahydro-1H-indolo[3, 2-d][1]oxocyclododec-13-yl 2-fluoronicotinate (Compound 3)

[0072]

[0073] 2-Fluoronicotinoyl chloride (159 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol) were added to a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 3 (236 mg, 99.5%) as a white solid.

[0074] 1 H NMR (500MHz, CDCl3) δ8.35-8.32 (m, 2H), 7.26 (ddd, J = 7.0, 5.0, 1.5Hz, 1H), 6.7 8(q,J=3.0Hz,1H),5.84-5.81(m,1H),5.74(dt,J=10.0,3.0Hz,1H),5.26-5.22 (m,1H),4.79(d,J=2.0Hz,1H),4.67-4.62(m,1H),4.25(p,J=7.0Hz,1H),4.06( t,J=7.0Hz,1H),3.53-3.47(m,5H),3.45-3.38(m,10H),3.08-3.06(m,1H),3.04 (d,J=9.5Hz,1H),3.02-2.95(m,1H),2.84(ddt,J=11.0,8.5,2.5Hz,1H),2.38( dd,J=13.5,3.5Hz,1H),2.22(dt,J=13.5,7.0Hz,1H),2.15-2.08(m,1H),1.97( s,2H),1.87(dd,J=13.5,7.0Hz,1H),1.60-1.55(m,1H),1.52-1.24(m,7H),1.2 2-1.17(m,6H),1.15(d,J=7.0Hz,3H),0.91-0.84(m,1H),0.76(t,J=7.5Hz,3H).

[0075] Example 5: (2R,3S,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-4-(dimethylamino)benzoate (Compound 4)

[0076]

[0077] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added 4-(dimethylamino)benzoyl chloride (183 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 4 (236 mg, 99.5%) as a white solid.

[0078] 1H NMR(500MHz,CDCl3)δ7.87-7.85(m,2H),6.75(s,1H),6.63(d,J=8.5Hz,2H),5.83-5.81(m,1H),5.74(dd,J=10.0,3.0Hz,1H),5.15(dt,J=9.5,4.0Hz,1H),4.79(d,J=2.0Hz,1H),4.64(t,J=8.0Hz,1H),4.26-4.22(m,1H),4.07-4.02(m,2H),3.49(d,J=2.0Hz,4H),3.47(d,J=7.5Hz,1H),3.47-3.42(m,8H),3.40(dd,J=9.0,3.0Hz,1H),3.11-3.07(m,1H),3.04(d,J=9.5Hz,1H),2.98(d,J=2.0Hz,6H),2.95(s,1H),2.84-2.80(m,1H),2.37(dd,J=13.5,3.0Hz,1H),2.21(dt,J=13.0,7.0Hz,1H),2.12-2.10(m,1H),1.97(d,J=2.0Hz,3H),1.86(dd,J=13.5,7.0Hz,1H),1.55-1.50(m,2H),1.47(dd,J=15.0,7.5Hz,2H),1.44-1.38(m,2H),1.31-1.24(m,2H),1.22-1.19(m,4H),1.17-1.15(m,3H),1.11(dd,J=7.0,2.5Hz,3H),0.79(d,J=7.0Hz,1H),0.75(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.6,171.6,165.4,152.2,146.3,143.2,130.3,128.3,127.9,109.9,94.5,81.3,80.1,80.0,76.7,73.7,66.9,60.0,58.0,56.7,48.5,46.7,45.1,44.9,40.5,40.1,39.2,36.4,35.3,33.2,31.7,29.2,27.2,20.2,16.8,15.4,8.40.

[0079] Example 6: (2R,3S,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,11,12,14,15,16a,16b-hexahydro-1H-as-indolo[3,2-d][1]oxocyclododec-13-ylcinnamate (Compound 5)

[0080]

[0081] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added cinnamoyl chloride (166 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain the title compound 5 (200 mg, 81.6%) as a white solid.

[0082] 1H NMR(500MHz,CDCl3)δ7.64(d,J=16.0Hz,1H),7.47(dt,J=6.0,4.0Hz,2H),7.36-7.32(m,4H),6.73(s,1H),6.38(d,J=16.0Hz,1H),5.82(d,J=10.0Hz,1H),5.76-5.73(m,1H),5.09(dt,J=9.5,4.5Hz,1H),4.79(d,J=2.0Hz,1H),4.65-4.63(m,1H),4.24(dd,J=8.5,4.5Hz,1H),4.05(q,J=7.0Hz,2H),3.49(s,3H),3.47(d,J=6.0Hz,1H),3.43-3.38(m,10H),3.11-3.03(m,2H),2.99(d,J=8.0Hz,1H),2.82(dd,J=11.5,8.5Hz,1H),2.37(dd,J=13.5,3.5Hz,1H),2.21(dt,J=13.0,7.0Hz,1H),2.11-2.05(m,1H),1.97(s,3H),1.86(dd,J=13.5,7.0Hz,1H),1.62(d,J=7.5Hz,2H),1.48-1.40(m,5H),1.31-1.24(m,2H),1.21(d,J=2.0Hz,3H),1.18(d,J=7.0Hz,3H),1.10(d,J=6.5Hz,3H),0.76(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.3,171.6,165.5,146.3,144.0,143.2,142.3,133.4,129.3,128.4,128.0,127.9,127.8,127.7,127.4,127.1,117.1,94.5,81.3,80.1,76.7,74.2,66.9,60.0,59.4,58.0,56.7,48.5,46.7,45.1,44.6,40.5,40.2,36.4,35.3,33.1,31.5,29.2,27.2,16.8,15.3,13.2,8.39.

[0083] Example 7: (2R,3S,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-arsen-indolo[3,2-d][1]oxocyclododec-13-yl-2-(4-methoxyphenyl)acetate (Compound 6)

[0084]

[0085] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added 2-(4-methoxyphenyl)acetyl chloride (184 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 6 (240 mg, 97.5%) as a white solid.

[0086] 1H NMR(500MHz,CDCl3)δ7.14(t,J=7.5Hz,1H),6.97(d,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H),6.84-6.82(m,1H),6.77(d,J=8.2Hz,1H),6.67(s,1H),5.81(d,J=10.0Hz,1H),5.73-5.69(m,1H),4.99-4.91(m,1H),4.78(d,J=7.0Hz,1H),4.58(d,J=11.5Hz,1H),4.24(q,J=7.5Hz,1H),3.75-3.70(m,5H),3.64-3.56(m,2H),3.49-3.47(m,3H),3.47(s,1H),3.44-3.38(m,8H),3.23(t,J=11.5Hz,1H),3.07-3.01(m,2H),2.94(d,J=9.0Hz,1H),2.78(d,J=11.0Hz,1H),2.34(d,J=13.0Hz,1H),2.21-2.15(m,1H),2.14-2.02(m,1H),1.86(dd,J=14.0,7.0Hz,1H),1.49-1.42(m,4H),1.35-1.27(m,3H),1.22(d,J=6.0Hz,3H),1.14-1.02(m,1H),0.97-0.91(m,3H),0.85-0.79(m,1H),0.73(tq,J=5.5,2.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.9,171.5,167.2,157.8,146.4,143.0,131.4,129.6,129.0,127.8,124.4,113.3,113.4,112.8,94.5,81.3,80.1,76.7,75.2,67.0,61.9,60.0,58.0,56.7,54.3,54.2,48.5,46.6,45.1,40.5,40.1,36.4,35.3,33.2,29.2,27.1,19.7,16.8,15.5,8.37.

[0087] Example 8: (2R,3aS,5aR,5bS,9S,14R,16aS,16bR,E)-9-ethyl-13-(methoxyimino)-14-methyl-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,10,11,13,14,16a,16b-tetradecahydro-1H-as-indolo[3,2-d][1]oxocyclododecane-7,15-dione (Compound 7)

[0088] To a solution of intermediate 2 (200 mg, 0.34 mmol) in anhydrous ethanol (EtOH, 10 mL) was added O-methylhydroxylamine (94 mg, 2.0 mmol), followed by stirring at room temperature for 12 hours under nitrogen protection; after the reaction stopped, the solvent was removed under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 7 (212 mg, 98.6%) as a white solid.

[0089] 1 H NMR(500MHz, CDCl3)δ7.10(d,J=7.0Hz,1H),5.89(d,J=9.5Hz,1H),5.82-5.78 (m,1H),4.75(d,J=7.0Hz,1H),4.32(q,J=7.0Hz,1H),4.06(q,J=7.0Hz,1H),3 .86(s,3H),3.50(d,J=1.5Hz,9H),3.48-3.45(m,1H),3.44-3.40(m,1H),3.30 -3.25(m,1H),3.12(td,J=9.5,2.5Hz,1H),2.99-2.95(m,1H),2.88(dd,J=11.5 ,9.0Hz,1H),2.45(dd,J=14.0,3.0Hz,1H),2.33-2.27(m,1H),2.26-2.10(m,4 H),1.93(dd,J=13.5,7.0Hz,1H),1.65(t,J=5.5Hz,1H),1.55(dq,J=14.5,7.0 Hz,2H),1.49-1.42(m,3H),1.39-1.33(m,4H),1.29(d,J=6.5Hz,3H),1.27(d, J=7.0Hz,3H),1.15(d,J=7.0Hz,1H),0.97-0.88(m,1H),0.83(d,J=7.5Hz,3H); 13C NMR (151MHz, CDCl3) δ197.0,171.6,158.1,148.9,141.7,128.5,127.8,94.6,81.4,80.2,76.8,75.2,72.8,67.1,60.5, 60.0,58.1,56.8,48.6,47.3,47.1,45.0,41.2,40.4,36.5,35.5,33.2,30.9,26.0,25.6,18.6,16.9,13.9,11.3,8.92.

[0090] Example 9: (2R, 3aS, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-13-(((6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-ethyl-14-methyl-7,15-dioxo-2,3,3a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-2-ylnicotinate (Compound 9)

[0091]

[0092] Nicotinoyl chloride (141 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol) were added to a solution of intermediate 3 (200 mg, 0.37 mmol) in anhydrous dichloromethane (10 mL), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 9 (219 mg, 91.2%) as a white solid.

[0093] 1H NMR (500MHz, CDCl3) δ9.15 (s, 1H), 8.71 (d, J = 5.0Hz, 1H), 8.23-8.20 (m, 1H) ,7.34-7.32(m,1H),6.75-6.71(m,1H),5.85(d,J=10.0Hz,1H),5.77(d,J=1 1.0Hz,1H),5.39(t,J=6.5Hz,1H),4.67-4.55(m,1H),3.80(d,J=11.0Hz,1H ),3.48-3.39(m,2H),3.29-3.20(m,1H),3.05-3.00(m,2H),2.87(q,J=12.0H z,1H),2.50(dt,J=14.5,7.5Hz,1H),2.37(dd,J=15.5,11.5Hz,1H),2.25-2 .19(m,8H),2.10(dd,J=13.5,6.0Hz,1H),1.72-1.65(m,3H),1.63-1.59(m,3 H),1.52-1.46(m,4H),1.44-1.39(m,4H),1.23(d,J=7.0Hz,3H),1.19(d,J= 6.0Hz,3H),1.12(d,J=7.0Hz,2H),1.05-0.97(m,1H),0.75(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3) δ201.6,171.5,164.0,152.4,149.9,145.6,143.0,136.0,128.6,127.7,125.3,122.3,102.5,90.8,79.7,76 .2,75.4,75.0,74.2,64.4,63.9,52.4,48.6,46.6,45.8,45.3,40.5,39.6,36.2,33.7,29.9,29.4,26.9,18.8,18.0,17.3,8.40.

[0094] Example 10: (2R, 3aS, 5aR, 5bS, 9S, 13S, 14R, 16aS, 16bR)-13-(((6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-9-ethyl-14-methyl-7,15-dicarbonyl-2,3,3a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-as-indolo[3,2-d][1]oxocyclododec-2-ylcinnamate (Compound 11)

[0095]

[0096] To a solution of intermediate 3 (200 mg, 0.37 mmol) in anhydrous dichloromethane (10 mL) were added cinnamoyl chloride (166 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 11 (174 mg, 69.6%) as a white solid.

[0097] 1 H NMR (500MHz, CDCl3) δ7.62(t,J=16.0Hz,1H),7.47-7.44(m,2H),7.34-7.32(m,2H),7.27(t,J=6.0Hz,1H),7.19(s,1H),6.75-6.71( m,1H),6.39-6.34(m,1H),5.84(d,J=10.5Hz,1H),5.75(d,J=10.0Hz,1H),4.65-4.60(m,1H),3.82-3.79(m,1H),3.47-3.41(m,2H),3 .29-3.20(m,1H),3.11-3.01(m,2H),2.87-2.82(m,1H),2.43(q,J=7.0Hz,1H),2.39-2.33(m,1H),2.20-2.18(m,8H),2.03-1.99(m, 1H),1.74-1.59(m,5H),1.53-1.35(m,8H),1.24-1.17(m,6H),1.11(dd,J=9.0,6.5Hz,2H),1.00-0.94(m,1H),0.75(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3) δ201.7,171.5,165.7,145.8,143.7,142.9,133.4,129.3,127.9,127.1,117.4,102.5,90.8,79.7,76.2,75 .0,74.2,74.1,64.4,63.9,59.4,48.6,45.8,45.3,40.5,39.7,39.6,36.2,33.7,29.9,29.4,26.9,18.0,17.2,13.9,13.2,8.39.

[0098] Example 11: Tetrahydrospinosad A

[0099]

[0100] Pd / C (10%, 136 mg) was added to a solution of spinosad A (1 g, 1.36 mmol) in anhydrous dichloromethane (30 mL), and then the mixture was reacted at room temperature for 5 hours in a hydrogen atmosphere. After the reaction stopped, the mixture was filtered under reduced pressure, and the filtrate was evaporated to dryness under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 12 (993 mg, 100%) as a white solid.

[0101] 1 H NMR (500MHz, CDCl3) δ4.77 (dd, J=12.0, 2.0Hz, 1H), 4.72 (dd, J=11.5, 6.0Hz, 1H), 4.3 2(d,J=9.0Hz,1H),4.13(d,J=6.5Hz,1H),3.59(s,1H),3.48(d,J=5.5Hz,3H),3.43-3 .40(m,9H),3.37(dd,J=9.0,3.0Hz,1H),3.03(q,J=9.5Hz,1H),2.81-2.76(m,2H),2. 56(d,J=12.0Hz,1H),2.44(dd,J=14.0,5.0Hz,1H),2.20-2.13(m,8H),2.09(dt,J=12 .5,7.0Hz,1H),1.99(dd,J=12.0,6.0Hz,1H),1.88(d,J=10.0Hz,1H),1.80(d,J=7.5H z,2H),1.75-1.69(m,3H),1.65-1.57(m,5H),1.52-1.42(m,3H),1.40(t,J=5.0Hz,2H ),1.34-1.30(m,2H),1.27-1.24(m,3H),1.21-1.19(m,6H),1.10(d,J=7.0Hz,1H),1. 07(d,J=7.0Hz,3H),0.97-0.92(m,1H),0.83(t,J=5.0Hz,1H),0.78(t,J=7.5Hz,3H); 13CNMR(151MHz, CDCl3)δ216.2,172.6,103.9,95.5,82.4,81.1,81.1,77.8,77.2,75.6,73.7,67.8,64.9,60.9,58.9,57.6,56.5,51.0 ,45.1,44.8,44.0,42.6,40.7,38.7,38.3,37.1,36.6,35.1,33.0,31.1,31.0,28.2,26.4,24.8,20.8,19.0,18.5,17.8,16.0,9.52.

[0102] Example 12: (2R,3R,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)icosa-1H-indolo[3,2-d][1]oxocyclododec-13-yl isonicotinate (Compound 14)

[0103]

[0104] To a solution of intermediate 4 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added isonicotinoyl chloride (141 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 14 (233 mg, 98.7%) as a white solid.

[0105] 1H NMR (500MHz, CDCl3) δ4.81 (d, J=12.0Hz, 1H), 4.22 (p, J=6.0Hz, 1H), 3.83-3.79 (m,1H),3.55(d,J=3.0Hz,3H),3.52(dd,J=6.0,3.5Hz,1H),3.50-3.47(m,7H), 3.44(dd,J=9.0,3.5Hz,1H),3.10(t,J=9.5Hz,1H),2.92-2.87(m,1H),2.74(p, J=7.0Hz,1H),2.57(dt,J=15.0,3.0Hz,2H),2.28(dd,J=9.5,6.5Hz,1H),2.22( dt,J=13.5,7.0Hz,1H),2.12(td,J=12.5,7.0Hz,1H),1.98(dt,J=11.5,5.5Hz, 1H),1.82-1.76(m,4H),1.71-1.63(m,5H),1.59-1.52(m,5H),1.46-1.39(m,1H ),1.35-1.31(m,2H),1.27(d,J=6.5Hz,3H),1.24-1.21(m,1H),1.17(d,J=7.0H z,3H),1.06(dd,J=12.5,5.0Hz,1H),1.01-0.96(m,1H),0.85(d,J=7.5Hz,3H); 13 C NMR (151MHz, CDCl3) δ216.8,172.8,95.4,82.4,81.1,81.1,77.9,75.5,72.2,67.8,60.9,58.9,57.7,56.5,50 .5,45.2,45.1,44.9,42.6,38.7,38.3,38.2,38.0,35.1,32.6,31.1,28.1,26.4,24.9,20.3,17.8,14.7,9.63.

[0106] Example 13: (2R,3R,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)icosa-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-fluoronicotinate (Compound 16)

[0107]

[0108] 2-Fluoronicotinoyl chloride (159 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol) were added to a solution of intermediate 4 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 16 (237 mg, 100.1%) as a white solid.

[0109] 1 H NMR (500MHz, CDCl3) δ8.36-8.30(m,2H),7.26-7.23(m,1H),5.26(t,J=8.0Hz,1H),4.80(d,J=8.5Hz,1H),4.15(d,J=6.0Hz,1H),3.47(d,J=3.0H z,4H),3.41(d,J=3.5Hz,6H),3.37(dd,J=9.5,3.0Hz,1H),3.08(dt,J=10.0,7.0Hz,1H),3.02(t,J=9.5Hz,1H),2.91(p,J=6.0Hz,1H),2.57-2.4 9(m,2H),2.19-2.10(m,3H),1.97-1.94(m,1H),1.77-1.70(m,5H),1.64 (d,J=13.5Hz,3H),1.60-1.53(m,2H),1.52-1.44(m,3H),1.40-1.34(m, 3H),1.28(q,J=6.0Hz,3H),1.21-1.17(m,3H),1.10(d,J=7.0Hz,3H),1.01(dd,J=11.5,5.0Hz,2H),0.85(d,J=6.0Hz,1H),0.80(d,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3) δ214.2,171.9,161.7,150.7,150.5,142.3,120.5,113.1,112.9,94.5,81.4,80.1,80.0,76.8,75.2,74.5,66.8,59.9,5 9.4,57.9,56.6,55.2,48.7,44.0,44.0,43.9,41.6,37.8,37.7,37.3, 36.4,32.7,32.0,30.3,27.1,25.3,23.8,19.4,16.8,14.6,13.2,8.63.

[0110] Example 14: (2R,3R,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)icosahydro-1H-indolo[3,2-d][1]oxocyclododecyl-4-(dimethylamino)benzoate (Compound 17)

[0111]

[0112] To a solution of intermediate 4 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added 4-(dimethylamino)benzoyl chloride (183 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 17 (236 mg, 99.5%) as a white solid.

[0113] 1 H NMR (500MHz, CDCl3) δ7.86(t,J=8.5Hz,2H),6.65(t,J=9.5Hz,2H),5.16(t,J=8.5Hz,1H),4.78(d,J=9.0Hz,1H),4.14(d,J=6.0Hz,1H),3.47-3.4 4(m,4H),3.42-3.40(m,8H),3.36(dd,J=9.0,3.0Hz,1H),3.03(q,J=9.0 Hz,2H),2.98(s,6H),2.94-2.89(m,1H),2.60-2.56(m,1H),2.51(dd,J=1 3.5,5.0Hz,1H),2.21-2.08(m,3H),2.00(d,J=6.0Hz,1H),1.75-1.69(m ,4H),1.61-1.55(m,3H),1.51-1.43(m,3H),1.38-1.34(m,2H),1.28-1.2 5(m,3H),1.23-1.20(m,2H),1.18(d,J=6.0Hz,3H),1.07(d,J=7.0Hz,3H) ,1.00-0.98(m,1H),0.83(dd,J=13.0,6.0Hz,1H),0.79(d,J=7.5Hz,3H); 13C NMR (101MHz, CDCl3) δ214.3,171.9,165.0,130.3,110.4,94.3,81.4,80.0,76.8,75.5,74.5,73.5,66.8,59.9,57.9,55. 1,48.9,44.1,43.9,43.5,41.6,39.5,37.7,37.3,37.2,36.0,32.4,31.9,30.3,27.1,25.3,23.8,19.6,16.8,14.7,8.62.

[0114] Example 15: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododecyl(4-acetylphenyl)carbamate (Compound 21)

[0115]

[0116] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added (4-acetylphenyl)carbamoyl chloride (197 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 21 (233 mg, 93.2%) as a white solid.

[0117] 1H NMR(500MHz, CDCl3)δ7.98-7.96(m,2H),7.58-7.56(m,2H),6.66(dd,J=8.5, 2.5Hz,1H),5.89(d,J=10.0Hz,1H),5.84-5.81(m,1H),4.88(d,J=8.0Hz,1H) ,4.73(t,J=8.0Hz,1H),4.27(t,J=7.0Hz,1H),3.69-3.61(m,3H),3.55(d,J= 3.0Hz,3H),3.49(d,J=3.0Hz,6H),3.44-3.41(m,2H),3.15-3.08(m,3H),3.0 7-3.04(m,1H),2.60(d,J=2.5Hz,3H),2.54-2.50(m,2H),2.23-2.17(m,1H), 2.10(d,J=9.0Hz,1H),1.90(dd,J=14.0,7.0Hz,1H),1.69-1.63(m,3H),1.58 -1.50(m,4H),1.35(ddd,J=15.0,8.5,3.5Hz,2H),1.26(d,J=4.0Hz,3H),1.2 0-1.17(m,1H),1.12(d,J=5.5Hz,3H),0.93-0.89(m,1H),0.86-0.83(m,3H); 13 C NMR (101MHz, CDCl3) δ201.4,196.9,173.8,152.6,145.9,145.3,142.8,132.0,130.8,130.0,129.5,128.3,117.4,113.7,95.5,82.2,81.0,77 .7,77.6,76.3,76.0,67.9,60.9,59.0,57.7,49.18,47.7,45.6,44.7, 41.4,41.1,37.3,36.2,33.3,31.0,28.3,26.4,21.5,17.8,13.9,9.27.

[0118] Example 16: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-bromoacetate (Compound 22)

[0119]

[0120] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (DCM; 10 mL) were added bromoacetyl chloride (157 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol); then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 22 (233 mg, 98.3%) as a white solid.

[0121] 1 H NMR(500MHz, CDCl3)δ6.81(s,1H),5.89(d,J=10.0Hz,1H),5.80(dt,J=10.0,3.0Hz,1H),5.10-5.05(m,1H),4.72-4.64(m,1H),4.32(q,J=7.0 Hz,1H),3.87-3.82(m,2H),3.50(d,J=2.5Hz,6H),3.47(dd,J=9.5,3.5Hz,3H),3.41(s,3H),3.37(d,J=5.5Hz,2H),3.14-3.10(m,3H),3.07-3 .02(m,1H),2.92-2.86(m,1H),2.43(dd,J=13.5,3.0Hz,1H),2.27(dt,J=13.0,7.0Hz,1H),2.18(d,J=9.0Hz,1H),1.94(dd,J=13.5,7.0Hz,1H ),1.65-1.60(m,4H),1.55-1.46(m,4H),1.36(t,J=7.5Hz,2H),1.29(d,J=6.5Hz,3H),1.17(d,J=7.0Hz,3H),0.94-0.88(m,1H),0.82(s,3H); 13 C NMR (101MHz, CDCl3) δ200.9,172.5,166.8,147.7,144.0,129.4,128.7,103.1,95.5,82.3,81.1,77.7,68.0,61.0,59 .0,57.7,53.9,49.6,47.7,46.1,45.3,41.5,41.2,37.4,36.3,34.2,32.3,30.7,30.1,25.9,20.9,17.8,16.4,9.39.

[0122] Example 17: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododecyl(4-chlorophenyl)carbamate (Compound 23)

[0123]

[0124] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added (4-chlorophenyl)carbamoyl chloride (190 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 23 (233 mg, 98.3%) as a white solid.

[0125] 1H NMR(500MHz, CDCl3)δ7.41(s,2H),7.30-7.28(m,2H),6.60(s,1H),5.88(d, J=10.0Hz,1H),5.83-5.80(m,1H),4.72(dt,J=11.0,6.0Hz,1H),4.28(q,J=7 .0Hz,1H),3.68-3.60(m,3H),3.56(s,3H),3.49(d,J=3.0Hz,6H),3.46-3.4 2(m,2H),3.14-3.10(m,3H),3.04(d,J=9.5Hz,1H),2.61(t,J=10.0Hz,1H),2 .47(dd,J=14.5,3.0Hz,1H),2.19(dt,J=13.0,7.0Hz,1H),2.15-2.07(m,1H ),1.90(dd,J=13.5,7.0Hz,1H),1.79-1.74(m,1H),1.64-1.62(m,4H),1.57- 1.49(m,4H),1.34(td,J=13.0,7.5Hz,2H),1.27-1.25(m,3H),1.20(dt,J=12 .5,6.0Hz,2H),1.11(d,J=6.5Hz,3H),0.92-0.87(m,1H),0.85-0.82(m,3H); 13 C NMR (101MHz, CDCl3) δ201.5,173.8,152.9,145.8,145.3,136.9,136.4,129.5,129.1,128.4,128.1,122.1,119.4,95.5,82.3,81.0 ,77.7,76.1,76.0,67.9,60.9,59.0,57.7,49.2,47.8,45.6,44.7,41.5,41.1,37.3,36.2,33.4,31.1,28.3,21.5,17.8,14.2,9.29.

[0126] Example 18: 2-(((2R,3AS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-((((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3a,5a,5b,6,7,9,11,12,13,14,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododecyl)oxyacetaldehyde (Compound 24)

[0127]

[0128] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (10 mL) were added 2-bromoacetaldehyde (157 mg, 0.99 mmol) and potassium carbonate (K2CO3, 139 mg 1.0 mmol); then heated to 70°C under nitrogen protection for 8 hours; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, extracted with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 24 (189 mg, 89.6%) as a white solid.

[0129] 1 H NMR (500MHz, CDCl3) δ9.76(d,J=1.5Hz,1H),6.68(d,J=2.5Hz,1H),5.88(d,J=10.0Hz,1H),5.78(dt,J=10.0,3.0Hz,1H),4.82(p,J=6.0Hz,1H),4. 32(q,J=7.0Hz,1H),3.56(s,3H),3.54(d,J=7.5Hz,1H),3.51(d,J=4.0Hz ,6H),3.45(d,J=3.5Hz,1H),3.12(td,J=9.5,1.5Hz,1H),3.08-3.05(m,1 H),2.85-2.78(m,2H),2.77-2.62(m,5H),2.48-2.43(m,2H),2.30(dt,J= 13.0,7.0Hz,1H),2.19-2.10(m,1H),1.92(dd,J=13.5,7.0Hz,1H),1.68- 1.60(m,2H),1.56-1.52(m,6H),1.41-1.33(m,2H),1.29(d,J=6.5Hz,3H) ,1.08(d,J=7.5Hz,3H),0.97(qd,J=11.5,6.5Hz,1H),0.89-0.86(m,3H); 13 C NMR (101MHz, CDCl3) δ202.1,200.3,172.2,144.4,144.2,129.7,129.1,95.5,82.2,81.0,77.6,76.1,74.6,67.9, 60.9,59.0,57.6,49.4,46.7,45.9,44.9,43.5,41.0,37.4,37.0,36.3,32.8,32.2,26.8,17.8,17.7,9.55,8.16.

[0130] Example 19: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododecylisoxazole-5-carboxylate (Compound 25)

[0131]

[0132] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (10 mL) were added isoxazole-5-yl chloride (111 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 25 (193 mg, 84.6%) as a white solid.

[0133] 1H NMR(500MHz,CDCl3)δ8.40(d,J=2.0Hz,1H),7.01(d,J=2.0Hz,1H),6.86(t,J=2.5Hz,1H),5.90(d,J=9.5Hz,1H),5.83-5.80(m,1H),5.29(t,J=4.5Hz,1H),4.74-4.69(m,1H),4.33(q,J=7.0Hz,1H),3.61-3.58(m,1H),3.57(s,3H),3.51(s,3H),3.50(s,3H),3.47(dd,J=9.5,3.0Hz,2H),3.17-3.11(m,2H),3.08-3.05(m,1H),2.93-2.88(m,1H),2.46(dd,J=13.5,3.5Hz,1H),2.28(dt,J=13.0,7.0Hz,1H),2.19(q,J=10.5Hz,1H),1.95(dd,J=13.5,7.0Hz,1H),1.78-1.73(m,3H),1.67-1.62(m,1H),1.59-1.45(m,5H),1.35(td,J=12.5,6.0Hz,3H),1.29(d,J=6.5Hz,3H),1.26(d,J=7.0Hz,1H),1.21(d,J=6.5Hz,3H),0.93(td,J=11.5,6.5Hz,1H),0.84(d,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.7,172.5,160.0,156.2,150.7,147.9,143.9,129.5,128.7,109.0,95.6,82.3,81.1,77.8,77.7,76.4,76.2,68.0,61.0,59.0,57.7,49.6,47.7,46.1,45.4,41.5,41.2,37.4,36.3,34.2,32.5,30.1,28.2,20.9,17.8,16.5,9.39.

[0134] Example 20: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododecyl-13-((S)-2-methylmorpholinyl)acetate (Compound 29)

[0135]

[0136] To a solution of intermediate 1 (2200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added ((S)-2-methylmorpholinyl)acetyl chloride (177 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and the mixture was heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 29 (223 mg, 91.4%) as a white solid.

[0137] 1H NMR(500MHz,CDCl3)δ6.79(s,1H),5.89(d,J=10.0Hz,1H),5.80(dt,J=10.0,3.0Hz,1H),5.07(dt,J=9.5,4.5Hz,1H),4.69(p,J=6.0Hz,1H),4.32(q,J=7.0Hz,1H),3.88-3.85(m,1H),3.78(dd,J=11.5,2.5Hz,1H),3.76-3.71(m,1H),3.57(s,3H),3.56-3.53(m,1H),3.50(t,J=2.0Hz,8H),3.47(dt,J=9.0,2.5Hz,2H),3.44-3.38(m,1H),3.15-3.10(m,2H),3.03(t,J=6.0Hz,1H),2.91-2.86(m,1H),2.81(t,J=9.0Hz,2H),2.43(dd,J=13.5,3.0Hz,1H),2.35(td,J=11.5,3.0Hz,1H),2.27(dt,J=13.0,7.0Hz,1H),2.21-2.15(m,1H),2.06-2.02(m,2H),1.94(dd,J=13.5,7.0Hz,1H),1.60(dq,J=14.5,8.0Hz,3H),1.56-1.51(m,1H),1.50-1.42(m,3H),1.39-1.33(m,2H),1.29(d,J=6.5Hz,3H),1.26(d,J=5.5Hz,2H),1.15(d,J=6.5Hz,3H),1.13(d,J=6.5Hz,3H),0.97-0.88(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ201.0,172.5,147.5,144.1,129.4,128.7,95.5,82.3,81.1,77.7,76.3,76.2,75.7,71.6,68.0,66.5,61.0,59.6,59.3,59.0,57.7,52.5,49.5,47.6,46.1,45.4,41.6,41.2,37.4,36.3,34.2,32.6,30.1,28.2,21.2,19.0,17.8,16.4,9.39.

[0138] Example 21: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(4-methylpiperazin-1-yl)acetate (Compound 34)

[0139]

[0140] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(4-methylpiperazine-1-yl)acetyl chloride (178 mg, 1.0 mmol) and N,N-dimethylpyridin-4-amine (122 mg 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 34 (202 mg, 81.4%) as a white solid.

[0141] 1H NMR(500MHz,CDCl3)δ6.71(t,J=2.5Hz,1H),5.82(d,J=10.0Hz,1H),5.73(dt,J=10.0,3.0Hz,1H),4.99(dt,J=10.0,4.0Hz,1H),4.61(q,J=7.0Hz,1H),4.25(q,J=7.0Hz,1H),3.49-3.46(m,5H),3.43(t,J=3.0Hz,8H),3.40(dd,J=9.5,3.0Hz,2H),3.36-3.30(m,1H),3.15(d,J=2.5Hz,2H),3.07(d,J=4.5Hz,1H),3.05-3.03(m,1H),2.96(d,J=7.5Hz,1H),2.84-2.79(m,1H),2.57-2.47(m,6H),2.35(dd,J=13.5,3.0Hz,1H),2.25(s,3H),2.20(p,J=7.0Hz,1H),2.11(q,J=11.0Hz,1H),1.86(dd,J=13.5,7.0Hz,1H),1.55-1.51(m,4H),1.48-1.44(m,1H),1.43-1.36(m,3H),1.33-1.25(m,2H),1.22(d,J=6.5Hz,3H),1.20-1.16(m,1H),1.05(d,J=7.0Hz,3H),0.89-0.81(m,1H),0.75(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ201.0,172.4,169.7,147.4,144.0,129.3,128.7,95.5,82.2,81.0,77.6,76.3,76.1,75.5,67.9,60.9,59.3,59.0,57.6,54.7,52.8,49.5,47.6,46.0,45.8,45.4,41.5,41.1,37.4,36.3,34.1,32.5,30.0,28.1,21.1,17.8,16.3,9.31.

[0142] Example 22: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(pyrrolidin-1-yl))acetate (Compound 38)

[0143]

[0144] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(pyrrolidin-1-yl)acetyl chloride (147 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (146 mg, 0.99 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 38 (230 mg, 98.4%) as a white solid.

[0145] 1H NMR(500MHz,CDCl3)δ6.78(s,1H),5.89(d,J=10.0Hz,1H),5.80(dt,J=10.0,3.0Hz,1H),5.08(dt,J=10.0,4.5Hz,1H),4.69(p,J=6.5Hz,1H),4.32(q,J=7.0Hz,1H),3.58-3.53(m,4H),3.50(t,J=2.5Hz,7H),3.47(dt,J=9.0,3.0Hz,2H),3.42(q,J=3.5Hz,1H),3.38(d,J=13.5Hz,2H),3.15-3.10(m,2H),3.03(d,J=7.5Hz,1H),2.89(td,J=10.0,4.5Hz,1H),2.69(d,J=7.5Hz,4H),2.42(dd,J=13.5,3.5Hz,1H),2.27(dt,J=13.5,7.0Hz,1H),2.18(d,J=10.0Hz,1H),1.93(dd,J=13.4,7.0Hz,1H),1.85(q,J=3.5Hz,4H),1.62-1.57(m,3H),1.56-1.51(m,1H),1.47(dt,J=11.0,6.0Hz,3H),1.36(ddd,J=13.0,8.0,5.5Hz,2H),1.29(d,J=6.5Hz,3H),1.26(s,1H),1.13(d,J=6.5Hz,3H),0.92(qd,J=11.5,6.5Hz,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ201.1,172.5,170.1,147.4,144.0,129.3,128.7,95.5,82.2,81.0,77.6,76.3,76.1,75.4,67.9,60.9,59.0,57.6,56.7,53.9,49.5,47.6,46.0,45.4,41.5,41.1,37.4,36.3,34.1,32.5,30.0,28.2,23.8,21.1,17.8,16.3,9.33.

[0146] Example 23: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(N,N-diethyl)acetate (Compound 39)

[0147]

[0148] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(N,N-diethyl)acetyl chloride (147 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 0.98 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 39 (229 mg, 97.9%) as a white solid.

[0149] 1H NMR (500MHz, CDCl3) δ6.80 (t, J = 2.5 Hz, 1H), 5.89 (d, J = 10.0 Hz, 1H), 5.81 (dt, J = 10. 0,3.0Hz,1H),5.07(dt,J=9.5,4.0Hz,1H),4.69(q,J=7.5Hz,1H),4.33(q,J=6.0Hz, 1H),3.57-3.54(m,4H),3.51(t,J=3.0Hz,8H),3.47(dd,J=9.5,3.0Hz,2H),3.43-3. 39(m,1H),3.37(d,J=2.0Hz,2H),3.16-3.10(m,2H),2.91-2.86(m,1H),2.70(dd,J=1 0.5,4.5Hz,4H),2.43(dd,J=13.5,3.0Hz,1H),2.28(dt,J=13.5,7.0Hz,1H),2.19(t ,J=10.0Hz,1H),1.94(dd,J=13.5,7.0Hz,1H),1.63-1.58(m,3H),1.56-1.51(m,1H) ,1.50-1.43(m,3H),1.40-1.34(m,2H),1.29(d,J=6.5Hz,3H),1.28-1.23(m,2H),1. 13(d,J=7.0Hz,3H),1.09(t,J=7.0Hz,6H),0.98-0.87(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3) δ201.2,172.7,172.6,147.6,144.1,129.5,128.8,95.6,82.4,81.2,77.8,76.5,76.2,68.1,61.1, 59.1,57.8,49.6,47.8,47.7,46.2,45.5,41.6,41.3,37.5,36.4,34.3,32.8,30.2,28.3,21.3,17.9,16.5,12.3,9.48.

[0150] Example 24: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2,3a,5a,5b,6,7,9,10,11,12,14,15,16a,16b-hexahydro-1H-as-indolo[3,2-d][1]oxocyclododecane-2,13-bis(thiophene-2-carboxylate) (Compound 41)

[0151]

[0152] To a solution of intermediate 5 (200 mg, 0.5 mmol) in anhydrous dichloromethane (10 mL) were added nicotinophene-2-yl chloride (292 mg, 2.0 mmol) and N,N-dimethylpyridin-4-amine (244 mg, 2.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 41 (305 mg, 98.1%) as a white solid.

[0153] 1 H NMR (500MHz, CDCl3) δ7.85-7.82(m,1H),7.81-7.78(m,1H),7.61-7.53(m,2H) ,7.13-7.10(m,2H),6.86(s,1H),5.93(d,J=10.0Hz,1H),5.85(dt,J=10.0,3. 0Hz,1H),5.40(td,J=7.5,5.0Hz,1H),5.22(dt,J=9.5,4.5Hz,1H),4.74-4.69 (m,1H),3.54(dt,J=10.0,7.5Hz,2H),3.17(dd,J=13.5,5.0Hz,1H),3.10-3.0 8(m,1H),2.98-2.92(m,1H),2.54(dt,J=14.0,7.0Hz,1H),2.46(dd,J=13.5,3 .0Hz,1H),2.36-2.25(m,1H),2.15(dd,J=14.0,7.0Hz,1H),1.76-1.69(m,3H) ,1.66-1.60(m,2H),1.59-1.43(m,6H),1.31(p,J=7.0Hz,1H),1.26-1.23(m,1 H),1.21(d,J=7.0Hz,3H),1.07(qd,J=11.5,6.5Hz,1H),0.83(t,J=7.5Hz,3H); 13CNMR(101MHz, CDCl3)δ201.2,172.6,162.0,161.7,147.2,144.2,134.2,133.9,133.5,133.3,132.4,132.3,129.1,128.9,12 7.9,127.7,76.5,76.1,76.0,53.4,49.6,47.7,46.4,45.7,41.6,41.5,37.3,37.2,34.2,32.6,30.2,28.2,21.1,16.5,9.42.

[0154] Example 25: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(2,4-dioxo-3)4-dihydropyrimidin-1(2H)-yl)acetate (Compound 42)

[0155]

[0156] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(2,4-dioxo-3-(4-dihydropyrimidin-1(2H)-yl)acetyl chloride (187 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 0.98 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 42 (205 mg, 82.9%) as a white solid.

[0157] 1H NMR(500MHz,CDCl3)δ9.09(s,1H),7.15(d,J=8.0Hz,1H),6.81(s,1H),5.90(d,J=10.0Hz,1H),5.79(t,J=10.5Hz,2H),5.31(d,J=2.0Hz,1H),5.10(dt,J=9.5,4.5Hz,1H),4.69(s,1H),4.51-4.43(m,2H),4.32(q,J=6.5Hz,1H),3.58-3.54(m,4H),3.53-3.49(m,8H),3.49-3.45(m,2H),3.43-3.40(m,1H),3.15-3.13(m,1H),3.10(d,J=5.5Hz,1H),3.06-3.00(m,1H),2.95-2.87(m,1H),2.43(dd,J=13.5,3.5Hz,1H),2.27(dd,J=13.0,7.0Hz,1H),2.23-2.13(m,1H),1.94(dd,J=13.5,7.0Hz,1H),1.67-1.60(m,3H),1.56-1.44(m,4H),1.39-1.33(m,2H),1.29(d,J=6.0Hz,3H),1.27-1.25(m,1H),1.14(d,J=6.5Hz,3H),0.96-0.88(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.7,172.5,166.9,163.4,150.6,147.9,144.3,143.9,129.5,128.7,102.8,95.6,82.3,81.1,77.8,77.7,76.4,76.2,68.0,61.0,59.0,57.7,49.6,49.0,47.6,46.1,45.3,41.5,41.2,37.4,36.4,34.2,32.3,30.1,28.2,20.9,17.8,16.3,9.38.

[0158] Example 26: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxy-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-arsen-indeno[3,2d][1]oxocyclododecyl-2-(R)-2-(methoxymethyl)pyrrolidinyl acetate (Compound 44)

[0159]

[0160] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added ((R)-2-(methoxymethyl)pyrrolidinyl)acetyl chloride (239 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 1.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 44 (209 mg, 91.2%) as a white solid.

[0161] 1H NMR(500MHz,CDCl3)δ6.79(s,1H),5.89(d,J=10.0Hz,1H),5.80(dt,J=10.0,3.0Hz,1H),5.06(dt,J=10.0,4.5Hz,1H),4.69(dt,J=13.0,6.0Hz,1H),4.32(q,J=7.0Hz,1H),3.75(d,J=17.3Hz,1H),3.56-3.53(m,5H),3.50(t,J=2.0Hz,8H),3.48-3.45(m,2H),3.42-3.39(m,2H),3.36(q,J=5.5Hz,1H),3.33(s,3H),3.26-3.21(m,1H),3.17-3.14(m,1H),3.13-3.10(m,1H),3.03(d,J=8.0Hz,1H),3.00-2.93(m,1H),2.91-2.86(m,1H),2.58(q,J=8.5Hz,1H),2.42(dd,J=13.5,3.5Hz,1H),2.27(dt,J=13.5,7.0Hz,1H),2.18(q,J=10.5Hz,1H),1.96-1.91(m,2H),1.84-1.77(m,2H),1.62-1.57(m,3H),1.56-1.50(m,2H),1.49-1.44(m,3H),1.39-1.31(m,2H),1.29(d,J=6.5Hz,3H),1.27-1.24(m,1H),1.13(d,J=6.5Hz,3H),0.96-0.88(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ201.3,172.7,172.6,147.5,144.2,129.5,128.8,95.6,82.4,81.2,77.8,76.5,76.2,75.2,68.0,61.9,61.1,59.1,57.8,54.9,54.5,49.6,47.7,46.1,45.6,41.6,41.2,37.5,36.4,34.2,32.7,30.2,28.4,28.3,23.4,21.2,17.9,16.5,9.46.

[0162] Example 27: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxy-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,11,12,13,14,15,16a,16b-hexahydro-1H-arsen-indeno[3,2d][1]oxocyclododecyl-2-(S)-2-(methoxymethyl)pyrrolidinyl acetate (Compound 45)

[0163]

[0164] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added ((S)-2-(methoxymethyl)pyrrolidinyl)acetyl chloride (191 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 2.0 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 45 (209 mg, 91.2%) as a white solid.

[0165] 1H NMR(500MHz,CDCl3)δ6.79(s,1H),5.89(d,J=10.0Hz,1H),5.80(dt,J=10.0,3.0Hz,1H),5.05(dt,J=10.0,4.5Hz,1H),4.70-4.64(m,1H),4.32(q,J=6.5Hz,1H),3.71(d,J=17.5Hz,1H),3.56-3.53(m,5H),3.50(t,J=2.5Hz,8H),3.47(dd,J=9.0,3.0Hz,2H),3.40(q,J=8.0Hz,2H),3.36(d,J=4.5Hz,1H),3.33(s,3H),3.18(d,J=8.0Hz,1H),3.14(t,J=3.5Hz,1H),3.13-3.10(m,1H),3.04-2.97(m,2H),2.91-2.87(m,1H),2.61(q,J=8.5Hz,1H),2.43(dd,J=13.5,3.0Hz,1H),2.27(dt,J=13.0,7.0Hz,1H),2.18(q,J=10.5Hz,1H),1.94(dt,J=14.0,7.0Hz,2H),1.84-1.78(m,2H),1.62-1.58(m,3H),1.56-1.52(m,1H),1.50-1.43(m,3H),1.40-1.33(m,2H),1.29(d,J=6.5Hz,3H),1.25(d,J=7.0Hz,2H),1.13(d,J=6.5Hz,3H),0.96-0.88(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ201.1,172.5,172.4,147.4,144.0,129.3,128.7,95.5,82.2,81.0,77.6,76.5,76.3,76.1,75.1,67.9,61.8,60.9,59.0,57.6,54.6,54.2,49.5,47.6,46.0,45.4,41.5,41.1,37.4,36.3,34.1,32.6,30.1,28.4,28.1,23.3,21.1,17.8,16.4,14.1,9.34.

[0166] Example 28: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(2,4-dicarbonyl-5-methyl-3-4-dihydropyrimidin-1(2H)-yl)acetate (Compound 46)

[0167]

[0168] To a solution of intermediate 1 (2000 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(2,4-dicarbonyl-5-methyl-3)4-dihydropyrimidin-1(2H)-yl)acetyl chloride (207 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 0.98 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 46 (205 mg, 82.9%) as a white solid.

[0169] 1H NMR(500MHz,CDCl3)δ8.70(s,1H),6.96(s,1H),6.80(s,1H),5.89(d,J=10.0Hz,1H),5.80(d,J=10.0Hz,1H),5.09(dt,J=9.5,4.5Hz,1H),4.69(dd,J=10.5,6.0Hz,1H),4.43(s,2H),4.32(q,J=6.8Hz,1H),3.57-3.55(m,4H),3.52-3.49(m,8H),3.47(d,J=9.5Hz,2H),3.43(q,J=6.5Hz,1H),3.14(d,J=9.0Hz,1H),3.10(d,J=4.5Hz,1H),3.04(d,J=8.5Hz,1H),2.91(t,J=10.0Hz,1H),2.43(dd,J=14.0,3.5Hz,1H),2.28(dt,J=13.0,7.0Hz,1H),2.23-2.14(m,1H),1.95(s,3H),1.92(d,J=6.5Hz,1H),1.65-1.60(m,3H),1.54-1.45(m,3H),1.39-1.33(m,2H),1.29(d,J=6.0Hz,3H),1.25(d,J=6.5Hz,1H),1.14(d,J=6.5Hz,3H),0.96-0.88(m,1H),0.82(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ200.7,172.5,167.2,163.9,150.6,147.9,143.9,140.1,129.5,128.7,111.3,95.6,82.3,81.1,77.7,77.6,76.3,76.2,68.0,61.0,59.0,57.7,49.6,48.8,47.6,46.1,45.3,41.6,41.2,37.4,36.4,34.2,32.3,30.1,28.2,20.9,17.8,16.3,12.4,9.39.

[0170] Example 29: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexahydro-1H-indolo[3,2-d][1]oxocyclododec-13-yl-2-(2,4-dicarbonyl-5-hydroxymethyl-3-4-dihydropyrimidin-1(2H)-yl)acetate (Compound 47)

[0171]

[0172] To a solution of intermediate 1 (200 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added 2-(2,4-dicarbonyl-5-hydroxymethyl-3-(4-dihydropyrimidin-1(2H)-yl)acetyl chloride (217 mg, 0.99 mmol) and N,N-dimethylpyridin-4-amine (122 mg, 0.98 mmol), and then heated to reflux for 4 hours under nitrogen protection; after the reaction was completed, the reaction solution was cooled to room temperature, washed with saturated ammonium chloride solution 3 times, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 2:1 V / V) to obtain compound 47 (205 mg, 82.9%) as a white solid.

[0173] 11H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 5.90 (d, J = 10.0 Hz, 1H), 5.80 (dd, J = 7.5, 5.0 Hz, 1H), 5.08 (dt, J = 9.5, 4.5 Hz, 1H), 4.69 (d, J = 9.0 Hz, 1H), 4.48 (s, 2H), 4.44 (s, 2H), 4.32 (q, J = 6.5 Hz, 1H), 3.59 - 3.54 (m, 4H), 3.50 (d, J = 2.0 Hz, 8H), 3.49 - 3.46 (m, 2H), 3.46 - 3.41 (m, 1H), 3.15 - 3.10 (m, 2H), 3.03 (d, J = 8.5 Hz, 1H), 2.90 (d, J = 8.0 Hz, 1H), 2.43 (dd, J = 13.5, 3.5 Hz, 2H), 2.28 (dt, J = 13.5, 7.0 Hz, 1H), 2.23 - 2.13 (m, 1H), 1.94 (dd, J = 13.5, 7.0 Hz, 1H), 1.66 - 1.60 (m, 3H), 1.55 - 1.46 (m, 3H), 1.43 - 1.33 (m, 3H), 1.29 (t, J = 6.5 Hz, 3H), 1.27 - 1.23 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H), 0.98 - 0.87 (m, 1H), 0.82 (t, J = 7.5 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 200.8, 172.6, 167.1, 163.6, 150.6, 148.1, 144.0, 141.4, 129.6, 128.8, 114.3, 95.6, 82.4, 81.1, 77.8, 77.7, 76.5, 76.3, 68.0, 61.1, 59.1, 58.2, 57.8, 49.7, 49.2, 47.7, 46.1, 45.4, 41.6, 41.3, 37.5, 36.5, 34.2, 32.2, 30.3, 28.2, 21.0, 17.9, 16.3, 9.48.

[0174] Biological Example 1

[0175] The Chilo suppressalis belongs to the Pyralidae family of the Lepidoptera order, also known as the heart borer and stalk borer. It mainly harms rice, but also harms rice stems, corn and other gramineous crops. It is a major pest of rice. The Chilo suppressalis has a long occurrence time, is difficult to control, and causes large yield losses, which are the main obstacles to rice production. At present, rice farmers mainly rely on chemical pesticides to control the Chilo suppressalis, but due to the long-term improper use of chemical agents, the pest has developed a certain degree of drug resistance in some areas, resulting in a significant decrease in the field control effect or even ineffectiveness. Therefore, it is urgent to scientifically and rationally select and use pesticides to delay the resistance of the Chilo suppressalis and ensure the safe production of rice.

[0176] Test insect source: Chilo suppressalis (Walker), collected in Wuhu, Anhui by Jiangsu Academy of Agricultural Sciences in 2013, introduced to this laboratory from Jiangsu Academy of Agricultural Sciences in September 2018, and raised indoors on rice. The second-instar larvae were used for testing.

[0177] Test compounds: the 30 compounds synthesized above (compounds 1-7, 9, 11-14, 16-17, 20-25, 29, 34, 38-39, 41-42, 44-47); control agent: 92.5% spinosad original drug.

[0178] The indoor activity of the above 30 compounds against the stem borer was initially screened indoors in September 2021 by the rice seedling immersion method: 21-day-old rice seedlings (about 25 cm high) were cultivated in small plastic cups (7 cm in diameter and 5 cm in height), with about 30 plants per cup, and old and dead leaves were removed. The original drugs (30 compounds, spinosad original drug) were prepared into high-concentration mother solutions with methanol, and the mother solutions were diluted to the required concentration with clean water containing 0.1% Triton X-100. The rice seedlings were completely immersed in the solution for 10 seconds, and the rice seedlings were taken out and dried naturally for 1 hour. The clean water containing 0.1% Triton X-100 was used as a control. Place 4 filter papers of appropriate size in a 7cm diameter petri dish, add 3mL sterile water to keep it moist, cut the rice stems in the plastic cup at the root, remove the upper leaves, and leave about 6cm of stems; place them in the prepared petri dishes, 15 stems per dish; pick the 2nd instar larvae of the Chilo suppressalis with a brush, 10 per dish, cover the petri dish with a layer of black cotton cloth and cover it tightly to prevent the Chilo suppressalis larvae from escaping. Set up 4 replicates for each treatment, 10 per replicate, a total of 40. Place the treated Chilo suppressalis larvae in an incubator with a temperature of 27±1℃, a relative humidity of 50% to 70%, and a photoperiod of 16h:8h (L:D, i.e. light: dark) for cultivation. Check the death of the test insects 3 days after treatment, and the failure of coordinated movement of the insect body when touched with a brush is regarded as the standard of death. Record the total number of insects and the number of dead insects in each treatment.

[0179] The DPS data processing software was used to analyze the significant differences among the treatment groups (p=0.05).

[0180] Preliminary screening activity against Chilo suppressalis: At a treatment concentration of 2 mg / L, the mortality of early 2nd instar larvae of compounds 4-5, 7, 9, 11, 13, 17, 21-25, 38, 41, 44, 46-47 was in the range of 17.5%-30%; the mortality of compounds 6, 12, 14, 16, 20, 42, 45 was in the range of 32.5%-55%; the mortality of compounds 1-3, 29, 34, 39 was in the range of 77.5%-95.0%.

[0181] Table 1. Preliminary screening activity of compounds against Chilo suppressalis (preliminary screening concentration 2 mg / L)

[0182] Compound No. Average mortality rate % Compound No. Average mortality rate % 1 95 21 27.5 2 80 22 17.5 3 77.5 23 22.5 4 25 24 22.5 5 25 25 12.5 6 45 29 87.5 7 25 34 77.5 9 25 38 17.5 11 30 39 85 12 37.5 41 22.5 13 20 42 35 14 35 44 25 16 35 45 32.5 17 20 46 27.5 20 55 47 30 Spinosad 92.5

[0183] Biological Example 2

[0184] Spodoptera exigua (Hübner) belongs to the family Noctuidae of the order Lepidoptera. It has occurred in more than 20 provinces, municipalities and autonomous regions in my country. The areas prone to recurrence are mainly concentrated in South China, the Yangtze River Basin and the Huaihe River Basin. It has changed from intermittent outbreaks to perennial outbreaks. Chemical pesticides are often used to control beet armyworms, resulting in rapid development of resistance. When pests develop medium to high levels of resistance to insecticides, the pesticides will not be able to effectively control them at the recommended dosage.

[0185] Test insect source: Beet armyworm (Spodopteraexigua Hübner), provided by Wuhan Kono Biotechnology Co., Ltd. in May 2001, a sensitive strain that has been raised indoors without any exposure to any pesticides, and the early 3rd instar larvae were used for testing.

[0186] Test compounds: 30 compounds synthesized above. Control agent: 92.5% spinosad original drug.

[0187] The indoor activity of the above 30 compounds against Spodoptera exigua was initially screened indoors in September 2021 using the artificial feed mixing method: the original drug to be tested was first dissolved in methanol to prepare a high-concentration mother solution, then diluted with distilled water to the required concentration, mixed with artificial feed (the content of methanol in the feed did not exceed 1%), poured into a 24-well plate, and the early 3rd instar larvae were picked; 4 replicates were set for each treatment, 10 heads per replicate, and a total of 40 heads. Distilled water containing methanol (the methanol content was the same as that of the drug-containing treatment) was mixed with artificial feed as a blank control. The treated Spodoptera exigua larvae were placed in an incubator with a temperature of 27±1℃, a relative humidity of 70% to 80%, and a photoperiod of 16h:8h (L:D). After 3 days of treatment, the death of the test insects was checked. The inability to coordinate movement when the insect body was lightly touched with a brush was regarded as the standard of death. The total number of insects and the number of dead insects in each treatment were recorded.

[0188] The DPS data processing software was used to analyze the significant differences among the treatment groups (p=0.05).

[0189] Initial screening activity against Spodoptera exigua: At a treatment concentration of 6 mg / L, the mortality of compounds 4-7, 9, 11, 13-14, 16, 21-25, 38, 42, 44-47 against the early 3rd instar larvae of Spodoptera exigua was in the range of 15%-30%; the mortality of compounds 12, 17, 20, and 41 was in the range of 32.5%-45%; the mortality of compounds 1-3, 29, 34, and 39 was in the range of 75.0%-95.0%.

[0190] Table 2. Initial screening activity of compounds against Spodoptera exigua (initial screening concentration 6 mg / L)

[0191] Compound No. Average mortality rate % Compound No. Average mortality rate % 1 95 21 30 2 75 22 22.5 3 92.5 23 15 4 30 24 15 5 27.5 25 20 6 22.5 29 82.5 7 20 34 85 9 15 38 25 11 22.5 39 90 12 40 41 37.5 13 25 42 22.5 14 25 44 25 16 22.5 45 30 17 45 46 15 20 32.5 47 25 Spinosad 97.5

[0192] Biological Example 3

[0193] Panonychus citri (McGregor), also known as citrus red spider, is one of the main mites that harm citrus. It has a strong reproductive capacity and can produce 18 to 30 generations a year. It can occur all year round, seriously affecting the yield and quality of citrus in various production areas. At present, the main chemical agents for the prevention and control of citrus mites are mixed. Although most of them are regular products, their efficacy varies. Through screening and development of new compounds, we hope to find a control agent with better efficacy and higher cost-effectiveness, and provide precise technical support for citrus growers.

[0194] Test insect source: The indoor strain of citrus mites was collected from the citrus orchard of Huazhong Agricultural University in August 2020. It has been raised under indoor temperature of 25±1℃, relative humidity of 60±5%, and photoperiod of L:D=14:10 until now, and has not been exposed to any pesticides during this period.

[0195] Test compounds: Compounds 1 to 3, 29, 34, and 39. Control agent: 92.5% spinosad original drug.

[0196] The bioassay adopts the leaf disc immersion method: fresh sweet orange leaves that have not been sprayed with pesticides are collected, washed with ultrapure water, and dried, and then a circular leaf disc with a diameter of about 2 cm is made with a hole puncher. The leaf disc is placed with the back facing up on a cotton wool covered with filter paper, moistened with ultrapure water, and placed in a disposable culture dish. 30 female adult mites are picked up on the leaf disc with a small brush, and left to stand at room temperature for 2-3 hours. Then, the leaf disc is clamped with tweezers and slowly immersed in the drug solution (prepared with methanol), CK is methanol. After 5s (start timing after the leaves are completely immersed in the drug solution), take it out, cut the filter paper into thin strips, and carefully absorb the excess drug solution around the mite body and on the leaf disc. The treated leaf disc is placed in a temperature of 25±1℃, relative humidity of 60±5%, and light cycle L:D=14:10. After 24h of treatment, the death of mites is observed under a stereo microscope, and the mite body is gently touched with a small brush. If the mite can move normally, it is considered alive, otherwise it is considered dead. The experimental data were processed using DPS software.

[0197] Preliminary screening activity against Panonychus citri: Compounds 1-3, 29, 34, and 39 at concentrations of 50 mg / L and 100 mg / L can cause the death of female adult mites of Panonychus citri after treatment for 24 hours, with a mortality rate between 28.41% and 75.25%, and the toxicity is higher than that of spinosad.

[0198] Table 3. Preliminary toxicity of compounds to Panonychus citri

[0199]

[0200] Biological Example 4

[0201] Southern root-knot nematode is a common plant parasitic nematode that is widely distributed worldwide. Its hosts include more than 3,000 species of vegetables, food crops, fruit trees, and ornamental plants, which seriously endangers the world's agricultural production. For a long time, the use of chemical pesticides to control root-knot nematodes has achieved good results, but with the abuse of chemical pesticides, the pathogens have developed resistance to pesticides and the environmental pollution caused by pesticide residues has gradually worsened. There is an urgent need to find new and efficient alternative insecticides.

[0202] Source of test insects: Root-knot nematodes are propagated and maintained in the laboratory, and the host plant tomato is often used for cultivation.

[0203] Test compounds: Compounds 1 to 3, 29, 34, and 39. Control agent: 92.5% spinosad original drug.

[0204] Direct contact killing method was used. 1 mL of newly hatched second-instar larvae suspension of southern root-knot nematodes with a concentration of about 200 heads / mL was added to each high-temperature sterilized culture dish, and 1 mL of the test agent (prepared with acetone) with a concentration of 60 μg / mL was added. 1 mL of acetone was added to the control (CK), and 1 mL of 60 μg / mL of spinosad (prepared with acetone) was added to the positive control. Each treatment was repeated 3 times and placed in a constant temperature incubator at 25°C for culture. After 24 hours of treatment, the death of nematodes was checked under a microscope, the number of deaths was counted, and the mortality rate was calculated. The needle puncture method was used to identify the life and death of nematodes. The stiff nematodes were picked with a fine needle. The pseudo-dead nematodes would bend and start to move, while the dead nematodes would remain stiff and motionless.

[0205] For the initial screening activity against southern root-knot nematodes: the six spinosad derivatives were as effective as spinosad, with a mortality rate of 100% for all of them at a concentration of 30 ppm for 12 hours.

[0206] Table 4. Activity of spinosad derivatives against southern root-knot nematodes

[0207]

[0208] The above test results show that 3 days after application, compounds 1-3, 29, 34, and 39 all showed excellent insecticidal effects on Chilo suppressalis and Spodoptera exigua; at the same concentration, the insecticidal activities of the six spinosad derivatives on Panonychus citri were greater than that of the positive control spinosad; and as nematicides, the effects of the spinosad derivatives were comparable to those of spinosad, indicating that the spinosad derivatives of the present invention have great potential for application as insecticides in the future.

Claims

1. The use of spinosad derivatives or their salts, stereoisomers, and tautomers having the following structures in the preparation of pesticides for controlling plant diseases and insect pests:

2. The use according to claim 1, characterized in that: The plant pests are rice stem borer, beet armyworm, citrus red spider and southern root-knot nematode.

3. The use according to claim 1, characterized in that: The insecticide is a contact-acting insecticide.

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