Rhododendron molle toxin VI derivative with analgesic activity as well as preparation method and application of rhododendron molle toxin VI derivative

Abstract

The invention belongs to the technical field of medicines, and discloses an application of a rhododendron molle toxin VI derivative in analgesia. Specifically, the invention discloses a derivative shown as a formula I or a pharmacodynamically acceptable salt thereof, a pharmaceutical composition containing the derivative or the pharmacodynamically acceptable salt thereof, an application of the compound in preparation of a medicine for preventing or treating pain and an acute toxicity research of the compound.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a VI derivative of *Rhododendron molle* toxin with analgesic activity, its preparation method, and its application. Background Technology

[0002] Analgesics are widely used in clinical practice, both prescription and over-the-counter, with very high usage. Currently, the traditional analgesics used clinically are mainly nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, acetaminophen, and ibuprofen, as well as opioids, such as morphine, meperidine, and fentanyl. However, NSAIDs have gastrointestinal side effects, while opioids have a high rate of addiction and can cause adverse reactions in the blood and cardiovascular systems, seriously affecting patient safety and greatly limiting their clinical use. Therefore, finding safe and effective analgesics has become a primary task in pain management.

[0003] Hesperidin-type diterpenoids possess diverse pharmacological activities and are a hot research area in natural product studies, with their significant analgesic activity attracting considerable attention. Studies have found that *Rhododendron molle* toxin VI exhibits good analgesic effects in various acute and chronic pain models, and that it does not act on opioid receptors, but may instead inhibit the interaction between N-ethylcis-butenedimide-sensitive fusion protein (NSF) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA2, thereby thereby affecting neuronal calcium receptors. 2+ The blockage of ion entry leads to a decrease in the excitability of nerve cells, thereby regulating analgesia. It has advantages such as high analgesic efficacy, non-addictiveness, and non-compulsiveness. However, its high toxicity and narrow safety margin limit the further development of rhododendron toxin VI into pharmaceuticals.

[0004] Therefore, developing Rhododendron VI toxin derivatives with low toxicity and high analgesic activity is a new direction for finding safe and effective analgesics. Summary of the Invention

[0005] One of the technical problems to be solved by the present invention is to provide a derivative of Rhodotorula oxytoxin VI with low toxicity and high analgesic activity, or a pharmaceutically acceptable salt, salt hydrate, or precursor compound thereof.

[0006] The second technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising compounds of various types as described in Formula I, or pharmaceutically acceptable salts thereof, hydrates of salts, prodrugs, and pharmaceutical carriers.

[0007] The third technical problem to be solved by the present invention is to provide the use of a low-toxicity and high-analgesic-activity apothecin VI derivative or its pharmaceutically acceptable salt, salt hydrate and precursor compound in the preparation of a medicament for the prevention or treatment of pain.

[0008] Furthermore, the median lethal dose (LD50) of the less toxic rhodopsin VI derivative is higher than that of rhodopsin VI.

[0009] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0010] According to the present invention, the general formula of the compound is as follows:

[0011] 1) Compounds represented by general formula I or pharmaceutically acceptable salts thereof:

[0012]

[0013] Where n is 0 or 1; R1, R2, and R3 are each independently selected from -H and -COR. A .

[0014] R A Selected from -CHR a R b -L1R c -CH=CHR d -NHR e R a R b Each is independently selected from -H, straight-chain or branched saturated C 1-8 alkyl;

[0015] L1 is selected from none or C. 1-5 Alkylene;

[0016] R c Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups;

[0017] R d Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0018] R eThe following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0019] In case one, the compound or a pharmaceutically acceptable salt thereof is represented by general formula IA:

[0020]

[0021] Where n is 0 or 1; R 1a Selected from -CHR a1 R b1 -L 1a R c1 -CH=CHR d1 -NHR e1 .

[0022] R a1 R b1 Each is independently selected from -H, straight-chain or branched saturated C 1-8 alkyl

[0023] L 1a Selected from none or C 1-5 Alkylene;

[0024] R c1 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups;

[0025] R d1 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0026] R e1 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0027] According to the present invention, the preferred R-based compounds represented by general formula IA are selected from:

[0028] n is 0 or 1; R 1a Selected from -CHR a1 R b1 -L 1a R c1 -CH=CHR d1 -NHR e1 R a1 R b1 Each is independently selected from -H, methyl, propyl, butyl, isopropyl, and isobutyl L. 1a Selected from none or C 1-2 Alkylene;

[0029] R c1 Selected from cyclopropyl, cyclopentyl, cyclohexyl, and phenyl;

[0030] R d1 Selected from phenyl, furan, and pyridine substituted with one or more substituents, wherein the substituents may be selected from -H, isopropyl, methoxy, -F, -CF3, and -CN;

[0031] R e1 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, thiazole, benzothiazole, indole, wherein the substituents may be selected from -H, methyl, methoxy, -F, -Cl, -Br, -COPh, -CF3, -SO2CH3, -NO. 2、 -COCH3、-N(CH3)2.

[0032] Scenario 2: The compound or a pharmaceutically acceptable salt thereof is represented by the general formula IB:

[0033]

[0034] Among them, R 2a Selected from -CHR a2 R b2 -L 2a R c2 -CH=CHR d2 -NHR e2 .

[0035] R a2 R b2 Each is independently selected from -H, straight-chain or branched saturated C 1-8 alkyl

[0036] L 2a Selected from none or C 1-5 Alkylene;

[0037] R c2 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups;

[0038] R d2 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0039] R e2 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0040] According to the present invention, the preferred R-based compounds represented by the general formula IB are selected from:

[0041] R 2a Selected from -CHR a2 R b2 -L 2a R c2 -CH=CHR d2 -NHR e2 .

[0042] R a2 R b2 Each is independently selected from -H, methyl, propyl, butyl, isopropyl, and isobutyl L. 2a Selected from none or C 1-2 Alkylene;

[0043] R c2 Selected from cyclopropyl, cyclopentyl, cyclohexyl, and phenyl;

[0044] R d2Selected from phenyl, furan, and pyridine substituted with one or more substituents, wherein the substituents may be selected from -H, isopropyl, methoxy, -F, -CF3, and -CN;

[0045] R e2 Selected from the following groups substituted with one or more substituents: phenyl, benzyl, wherein the substituents may be selected from -H, methyl, methoxy, -F, -Cl, -Br, -COPh, -CF3, -SO2CH3, -NO 2、 -COCH3、-N(CH3)2.

[0046] Scenario 3: The compound or a pharmaceutically acceptable salt thereof is represented by the general formula IC:

[0047]

[0048] Among them, R 3a Selected from -CHR a3 R b3 -L 3a R c3 -CH=CHR d3 -NHR e3 .

[0049] R a3 R b3 Each is independently selected from -H, straight-chain or branched saturated C 1-8 alkyl

[0050] L 3a Selected from none or C 1-5 Alkylene;

[0051] R c3 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups;

[0052] R d3 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0053] R e3 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

[0054] According to the present invention, the preferred R-based compounds represented by the general formula IC are selected from:

[0055] R 3a Selected from -CHR a3 R b3 -L 3a R c3 -CH=CHR d3 -NHR e3 .

[0056] R a3 R b3 Each is independently selected from -H, methyl, propyl, butyl, isopropyl, and isobutyl L. 3a Selected from none or C 1-2 Alkylene;

[0057] R c3 Selected from cyclopropyl, cyclopentyl, cyclohexyl, and phenyl;

[0058] R d3 Selected from phenyl groups substituted with one or more substituents, wherein the substituents may be selected from -H, isopropyl, methoxy, -F, -CF3, -CN;

[0059] R e3 The group is selected from the following groups substituted with one or more substituents: phenyl, benzyl, indole, wherein the substituents may be selected from -H, methyl, methoxy, -F, -Br, -COPh, -CF3, -SO2CH3, -COCH3.

[0060] According to the present invention, the method for synthesizing the compound is as follows:

[0061] In scenario one, the compound is a carboxylic acid ester derivative of peperomia toxin VI, synthesized via the following method:

[0062] Weigh out VI of *Rhododendron molle* toxin into a reaction flask, dissolve it in anhydrous N,N-dimethylformamide, then add the corresponding carboxylic acid, EDCI, DMAP, and triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography. After the reaction is complete, add water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by silica gel column chromatography or preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A ultraviolet detector, Shimadzu RID-10A differential refractive index detector; SilGreen-C18 column, 250×10mm, 5μm; flow rate 3mL / min) to obtain the compound.

[0063] In scenario two, the compound is a carbamate derivative of peperomia toxin VI, synthesized via the following method:

[0064] Weigh out VI of the herbicide and add it to ultra-dry N,N-dimethylformamide. Stir until completely dissolved, then add the corresponding isocyanate. React at room temperature. After the reaction is complete, add water to the reaction solution and extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Preliminary separation is performed by silica gel column chromatography, followed by further purification by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250×10mm, 5μm; flow rate 3mL / min) to obtain the compound.

[0065] Scenario 3: The compound is an ether derivative of peperomia toxin VI, synthesized by the following method:

[0066] NaH and ultra-dry N,N-dimethylformamide were added to a reaction flask. While stirring in an ice bath, *Anoectochilus luteum* toxin VI dissolved in ultra-dry N,N-dimethylformamide was slowly added dropwise, and the reaction was allowed to proceed for 30 min. Then, the corresponding 2-bromoacetamide dissolved in ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography to obtain the compound.

[0067] According to the present invention, preferred compounds include, but are not limited to, the following compounds:

[0068] 1) 6-O-pentanoyl rhodotorulatoxin VI

[0069] 2) 6-O-(3-methylbutyryl)rhoa toxin VI

[0070] 3) 6-O-(4-methylpentanoyl)rhodotorhinol VI

[0071] 4) 6-O-(3-cyclopropylpropionyl)rhodotorhinol VI

[0072] 5) 6-O-(3-cyclohexylpropionyl)rhodotorhinol VI

[0073] 6) 6-O-(3-phenylpropionyl)rhoa toxin VI

[0074] 7) 6-O-((E)-3-(4-fluorophenyl)acryloyl)rhodotorhinol VI

[0075] 8) 6-O-((E)-3-(4-(trifluoromethyl)phenyl)acryloyl)rhodotorhinol VI

[0076] 9) 6-O-((E)-3-(4-cyanophenyl)acryloyl)rhodotorhinol VI

[0077] 10) 6-O-((E)-3-(4-isopropylphenyl)acryloyl)rhodotorhinol VI

[0078] 11) 6-O-((E)-3-(4-methoxyphenyl)acryloyl)rhodotorhinol VI

[0079] 12) 2-O-(N-benzylcarbamoyl)rhoa toxin VI

[0080] 13) 2-O-(N-(4-fluorophenyl)carbamoyl)rhodotorhinol VI

[0081] 14)2-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI

[0082] 15) 2-O-(N-(4-bromophenyl)carbamoyl)rhodotorhinol VI

[0083] 16) 2-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI

[0084] 17) 2-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI

[0085] 18)2-O-(N-(4-fluorobenzyl)carbamoyl)rhodotorhinol VI

[0086] 19)2-O-(N-(4-methoxyphenyl)carbamoyl)rhodotorhinol VI

[0087] 20)2-O-(N-(4-benzoylphenyl)carbamoyl)rhodotorhinol VI

[0088] 21) 2-O-(N-(1-methyl-1H-indol-6-yl)carbamoyl) Rhodotorula oxytoxin VI

[0089] 22)3-O-(N-(4-fluorophenyl)carbamoyl)rhodotorhinol VI

[0090] 23) 3-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI

[0091] 24)3-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI

[0092] 25)3-O-(N-(4-bromophenyl)carbamoyl)rhodotorhinol VI

[0093] 26)3-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI

[0094] 27) 3-O-(N-(4-methoxyphenyl)carbamoyl)rhodotorhinol VI

[0095] 28) 3-O-(N-benzylcarbamoyl)rhoa toxin VI

[0096] 29)3-O-(N-(4-fluorobenzyl)carbamoyl)rhoa toxin VI

[0097] 30)6-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI

[0098] 31) 6-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI

[0099] 32)6-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI

[0100] 33)6-O-(N-(4-bromophenyl)carbamoyl)rhodotorhinol VI

[0101] 34) 6-O-(N-(4-fluorobenzyl)carbamoyl)rhoa toxin VI

[0102] 35)6-O-(N-(4-benzoylphenyl)carbamoyl)rhodotorhinol VI

[0103] 36) 2-O-(N-phenylcarbamoylmethyl)rhodotorhinol VI

[0104] 37)2-O-(N-(4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0105] 38)2-O-(N-(4-fluorobenzyl)carbamoylmethyl)rhodotorhinol VI

[0106] 39)2-O-(N-(4-fluorophenylethyl)carbamoylmethyl)rhodotorhinol VI

[0107] 40)2-O-(N-(3-fluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0108] 41) 2-O-(N-(2-fluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0109] 42)2-O-(N-(3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI

[0110] 43)2-O-(N-(4-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI

[0111] 44)2-O-(N-(4-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI

[0112] 45)2-O-(N-(3-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI

[0113] 46)2-O-(N-(4-nitrophenyl)carbamoylmethyl)rhodotorhinol VI

[0114] 47)2-O-(N-(4-methoxyphenyl)carbamoylmethyl)rhodotorhinol VI

[0115] 48)2-O-(N-(4-methylphenyl)carbamoylmethyl)rhodotorhinol VI

[0116] 49)2-O-(N-(4-acetylphenyl)carbamoylmethyl)rhodotorhinol VI

[0117] 50)2-O-(N-(4-(dimethylamino)phenyl)carbamoylmethyl)rhodotorhinol VI

[0118] 51)2-O-(N-(thiazolyl-2-yl)carbamoylmethyl)rhodotorhinol VI

[0119] 52)2-O-(N-(3,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0120] 53)2-O-(N-(2,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0121] 54)2-O-(N-(3,5-difluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0122] 55)2-O-(N-(4-fluoro-3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI

[0123] 56)2-O-(N-(4-fluoro-3-nitrophenyl)carbamoylmethyl)rhodotorhinol VI

[0124] 57)2-O-(N-(3-chloro-4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI

[0125] 58)2-O-(N-(4-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI

[0126] 59)2-O-(N-(3-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI

[0127] 60)2-O-(N-(4-phenoxyphenyl)carbamoylmethyl)rhodotorhinol VI

[0128] 61)2-O-(N-(2-methylbenzo[d]thiazolyl-5-yl)carbamoylmethyl)rhodotorhinol VI

[0129] This invention relates to a pharmaceutical composition containing a compound of effective dosage as described in general formula I and a pharmaceutically acceptable carrier thereof.

[0130] According to the present invention, the compounds of the present invention may exist in the form of isomers, and the compounds of the present invention generally include isomers of the compounds.

[0131] This invention relates to pharmaceutical compositions containing the compound of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants. Typically, the pharmaceutical compositions of the present invention also contain 0.1-95% by weight of the compound of the present invention, and in unit dosage forms, the general content of the pharmaceutical composition of the present invention is 0.1-100 mg, preferably 4-50 mg in unit dosage forms.

[0132] The pharmaceutical compositions of the present invention can be prepared according to methods known in the art. For this purpose, one or more compounds of the present invention can be combined in the form of solid or liquid excipients and adjuvants to prepare a suitable form of use or dosage form for human or veterinary use.

[0133] The compounds of this invention or pharmaceutical compositions containing the compounds of this invention can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum. The compounds of this invention and their pharmaceutical compositions can be administered by injection, including intravenous injection, intramuscular injection, subcutaneous injection, and acupoint injection.

[0134] Dosage polarity allows for either liquid or solid dosage forms. Liquid dosage forms can include solutions, colloids, microparticles, emulsions, suspensions, aerosols, and pellets. Solid dosage forms can include tablets, capsules, powders, granules, suppositories, and lyophilized powders.

[0135] By formulating unit-dose dosage forms into tablets, a wide range of carriers known in the art can be used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, and ethylcellulose; disintegration inhibitors such as sucrose, tristearate, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium salts and sodium dodecyl sulfate; and lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, and polyethylene glycol. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, and enteric-coated tablets.

[0136] For example, various carriers known in the art can be widely used to formulate the drug delivery unit into pills. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0137] For example, to formulate the drug delivery unit into a capsule, the active ingredient, the compound of the present invention, is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. Alternatively, the active ingredient, the compound of the present invention, can be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or filled into a hard capsule or formulated as an injectable preparation for use.

[0138] For example, the compounds of this invention can be formulated into injectable formulations, such as solutions, suspension solutions, emulsions, and lyophilized powders for injection. These formulations can be aqueous or non-aqueous and may contain one or more pharmacodynamically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. For example, diluents may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan esters, fatty acid esters, etc. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulation. In addition, conventional solubilizers, buffers, pH adjusters, etc., may also be added. These excipients are commonly used in the art.

[0139] In addition, colorants, preservatives, flavorings, tasters, sweeteners or other materials may be added to pharmaceutical preparations if necessary.

[0140] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0141] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the frequency of administration, and the therapeutic purpose. Therefore, the therapeutic dosage of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical components used in the present invention is well known to those skilled in the art. The actual amount of drug contained in the final formulation of the compound composition of the present invention can be appropriately adjusted to achieve the required therapeutic dose and fulfill the preventive or therapeutic purpose of the present invention. The suitable daily dosage range of the compounds of the present invention is: 0.001-100 mg / kg body weight, preferably 0.1-60 mg / kg body weight, more preferably 1-30 mg / kg body weight, and most preferably 2-15 mg / kg body weight. For adult patients, the daily dosage of the compounds of the present invention is 10-500 mg, preferably 20-100 mg, which can be taken once or divided into 2-3 doses; for children, the dosage is 5-30 mg / kg body weight, preferably 10-20 mg / kg body weight. The above dosage can be administered as a single dose or divided into several doses, such as two, three, or four doses, depending on the clinical experience of the attending physician and the dosing regimen of the treatment. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs.

[0142] The VI derivative of Rhododendron molle toxin disclosed in this invention has a good inhibitory effect on mouse acetic acid writhing test.

[0143] The acute toxicity of the rhodopsin VI derivative disclosed in this invention to mice is lower than that of the previously discovered rhodopsin VI.

[0144] This invention also relates to the use of the compounds of this invention in the preparation of medicaments for the prevention or treatment of pain, which is related to the central or peripheral nervous system.

[0145] Furthermore, the pain is selected from acute pain or chronic pain.

[0146] Furthermore, the pain is somatic pain, visceral pain, or neuropathic pain. Attached Figure Description

[0147] Figure 1 .Handicap dose curves of compounds 51 and 52

[0148] Terms and Abbreviations

[0149] HRESI-MS high-resolution electrospray mass spectrometry

[0150] NMR (Nuclear Magnetic Resonance)

[0151] ED 50 Half-effective dose

[0152] LD 50 Median lethal dose

[0153] TI Selectivity Index

[0154] EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0155] DMAP 4-Dimethylaminopyridine

[0156] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0157] NMI N-methylimidazole Detailed Implementation

[0158] The following embodiments further illustrate the present invention, but this does not imply any limitation on the present invention.

[0159] Example 1: Preparation of Compound 1 (6-O-pentanoyl peper ...

[0160]

[0161] Weigh 40.00 mg (0.10 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 1.0 mL of anhydrous N,N-dimethylformamide, then add 17.0 μL (0.15 mmol) of valeric acid, 32.59 mg (0.17 mmol) of EDCI, 2.44 mg (0.020 mmol) of DMAP and 24.0 μL (0.17 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 12 h of reaction, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, and purify by silica gel column chromatography (CH2Cl2 / MeOH = 25:1) to obtain compound 1 (4.8 mg, yield 9.9%).

[0162] Molecular formula C 25 H 42 O8, HRESI-MS m / z: [M+Na] + 493.2770.

[0163] 1 H NMR(600MHz,pyridine-d5)δ:7.06(d,J=3.0Hz,1H),6.81(d,J=6.6Hz,1H),6.73(d,J=5.4Hz,1H),6.17(s,1H),5.83(d d,J=10.8,4.2Hz,1H),5.55(s,1H),5.28(s,1H),5.14(d,J=6.6Hz,1H),5.13–5.09(m,1H),3.95(t,J=5.4Hz,1H),2.95( d,J=7.2Hz,1H),2.85(dd,J=13.2,4.2Hz,1H),2.68–2.61(m,1H),2.52(s,1H),2.45(dd,J=13.2,10.8Hz,1H),2.32–2.2 5(overlap,3H),2.19(d,J=7.2Hz,1H),2.16(d,J=15.0Hz,1H),2.09(dd,J=13.8,7.2Hz,1H),1.92(s,3H),1.75–1.69(m 1H),1.67–1.55(overlap,6H),1.53(s,3H),1.35(s,3H),1.28–1.20(overlap,2H),0.76(t,J=7.2Hz,3H). 13C NMR(150MHz,pyridine-d5)δ:172.6,86.1,82.7,79.7,79.6,78.8,78.0,77.8,60.2,58.8 ,56.5,55.1,52.3,49.2,40.2,34.6,29.4,27.2,27.0,25.0,23.7,22.5,22.1,20.6,13.8.

[0164] Example 2: Preparation of Compound 2 (6-O-(3-methylbutyryl)rhodotorhinol VI)

[0165]

[0166] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 1.0 mL of anhydrous N,N-dimethylformamide, then add 16.0 μL (0.16 mmol) of 3-methylbutyric acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 12 h of reaction, add 5 mL of water to the reaction solution. Extract three times with ethyl acetate. Wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A ultraviolet detector). RID-10A differential refractive index detector; SilGreen-C18 column, 250×10mm, 5μm; 35% acetonitrile as mobile phase; flow rate 3mL / min) purification, to give compound 2 (1.9mg, yield 5.2%).

[0167] Molecular formula C 25 H 42 O8, HRESI-MS m / z: [M+Na] + 493.2765.

[0168] 1H NMR(600MHz,pyridine-d5)δ:7.05(s,1H),6.81(d,J=6.6Hz,1H),6.74(d,J=4.2Hz,1H),6.18(s,1H),5.82(dd,J=10.8,4.8Hz,1H),5.55(s,1H) ,5.25(s,1H),5.14(d,J=6.6Hz,1H),5.11(dd,J=7.2,4.2Hz,1H),3.95(t,J=4.2Hz,1H),2.96(d,J=7.2Hz,1H),2.86(dd,J=13.2,4.8Hz,1H),2. 69–2.61(m,1H),2.52(s,1H),2.44(dd,J=13.2,10.8Hz,1H),2.28(d,J=14.4Hz,1H),2.21–2.13(overlap,5H),2.09(dd,J=14.4,6.6Hz,1H),1. 91(s,3H),1.72(dt,J=13.8,4.8Hz,1H),1.68–1.61(m,1H),1.60(s,3H) ,1.53(s,3H),1.35(s,3H),0.89(d,J=6.0Hz,3H),0.86(d,J=6.0Hz,3H). 13 C NMR(150MHz,pyridine-d5)δ:171.9,86.2,82.7,79.7,79.6,78.7,78.0,77.8,60.3,58.9 ,56.5,55.2,52.3,49.2,43.9,40.2,29.4,27.0,25.7,24.9,23.7,22.5,22.4,22.1,20.6.

[0169] Example 3 Preparation of compound 3 (6-O-(4-methylpentanoyl)rhodotorhinol VI)

[0170]

[0171] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 1.0 mL of anhydrous N,N-dimethylformamide, then add 19.5 μL (0.16 mmol) of 4-methylvaleric acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 12 h of reaction, add 5 mL of water to the reaction solution. Extract three times with ethyl acetate. Wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A ultraviolet detector). RID-10A differential refractive index detector; SilGreen-C18 column, 250×10mm, 5μm; 40% acetonitrile as mobile phase; flow rate 3mL / min) purification, to give compound 3 (1.3mg, yield 3.5%).

[0172] Molecular formula C 26 H 44 O8, HRESI-MS m / z: [M+Na] + 507.2921.

[0173] 1H NMR(600MHz,pyridine-d5)δ:7.08(s,1H),6.82(d,J=6.6Hz,1H),6.74(d,J=5.4Hz,1H),6.18(s,1H),5.83(dd,J=10.8,4.2H z,1H),5.56(s,1H),5.31(s,1H),5.15(d,J=6.6Hz,1H),5.11(t,J=6.0Hz,1H),3.96(t,J=5.4Hz,1H),2.96(d,J=7.2Hz,1H),2 .86(dd,J=13.2,4.2Hz,1H),2.68–2.60(m,1H),2.52(s,1H),2.46(t,J=13.2Hz,1H),2.34–2.26(overlap,3H),2.20(d,J=7. 2Hz,1H),2.17(d,J=14.4Hz,1H),2.13–2.06(dd,J=14.4,6.0Hz,1H),1.92(s,3H),1.72(dt,J=13.2,5.4Hz,1H),1.68–1.62(m 1H),1.61(s,3H),1.59–1.52(overlap,5H),1.51–1.45(m,1H),1.36(s,3H),0.77(d,J=3.0Hz,3H),0.75(d,J=3.0Hz,3H). 13 CNMR(150MHz,pyridine-d5)δ:172.7,86.1,82.6,79.6,79.6,78.8,78.0,77.8,60.2,58.8,5 6.5,55.1,52.3,49.2,40.2,33.9,33.0,29.4,27.8,27.0,25.0,23.7,22.3,22.1,22.1,20.6.

[0174] Example 4: Preparation of compound 4 (6-O-(3-cyclopropylpropionyl)rhodotorhinol VI)

[0175]

[0176] Weigh 40.00 mg (0.10 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 1.0 mL of anhydrous N,N-dimethylformamide, then add 16.0 μL (0.15 mmol) of 3-cyclopropylpropionic acid, 32.59 mg (0.17 mmol) of EDCI, 2.44 mg (0.020 mmol) of DMAP and 24.0 μL (0.17 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 12 h of reaction, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, and purify by silica gel column chromatography (CH2Cl2 / MeOH = 10:1) to obtain compound 4 (2.0 mg, yield 4.0%).

[0177] Molecular formula C 26 H 42 O8, HRESI-MS m / z: [M+Na] + 505.2773.

[0178] 1 H NMR(600MHz,pyridine-d5)δ:7.07(d,J=3.6Hz,1H),6.82(d,J=6.6Hz,1H),6.7 2(d,J=5.4Hz,1H),6.16(s,1H),5.83(dd,J=10.8,4.2Hz,1H),5.55(s,1H),5.3 0(s,1H),5.14(d,J=6.6Hz,1H),5.11(dt,J=7.2,3.6Hz,1H),3.95(t,J=5.4Hz, 1H),2.96(d,J=7.2Hz,1H),2.87(dd,J=13.2,4.2Hz,1H),2.68–2.62(m,1H),2. 52(s,1H),2.48–2.41(overlap,3H),2.28(d,J=14.4Hz,1H),2.19(d,J=7.2Hz, 1H),2.17(d,J=14.4Hz,1H),2.10(dd,J=13.8,6.0Hz,1H),1.92(s,3H),1.72(d t,J=13.2,4.8Hz,1H),1.68–1.58(overlap,5H),1.55–1.49(overlap,4H),1.3 6(s,3H),0.72–0.66(m,1H),0.33(dd,J=8.4,1.8Hz,2H),-0.00–-0.03(m,2H). 13C NMR(150MHz,pyridine-d5)δ:172.5,86.1,82.6,79.6,79.6,78.8,78.0,77.8,60.2,58.8,5 6.5,55.1,52.3,49.2,40.2,35.0,30.1,29.4,27.0,24.9,23.7,22.1,20.6,10.9,4.9,4.6.

[0179] Example 5: Preparation of compound 5 (6-O-(3-cyclohexylpropionyl)rhodotorhinol VI)

[0180]

[0181] Weigh 40.00 mg (0.10 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 1.0 mL of anhydrous N,N-dimethylformamide, then add 27.0 μL (0.15 mmol) of 3-cyclohexylpropionic acid, 32.59 mg (0.17 mmol) of EDCI, 2.44 mg (0.020 mmol) of DMAP and 24.0 μL (0.17 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after reacting for 15 h, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, and purify by silica gel column chromatography (CH2Cl2 / MeOH = 25:1) to obtain compound 5 (3.0 mg, yield 5.5%).

[0182] Molecular formula C 29 H 48 O8,HRESI-MS m / z:[M+HCOO] – 569.3342.

[0183] 1H NMR(600MHz,pyridine-d5)δ:7.07(s,1H),6.82(d,J=6.6Hz,1H),6.75(d,J=4.8Hz,1H),6.19(s,1H),5.84(dd,J=10.8,4.2Hz,1H),5.56(s,1H),5.30 (s,1H),5.15(d,J=6.6Hz,1H),5.12(t,J=4.8Hz,1H),3.97(t,J=4.8Hz,1H) ,2.97(d,J=6.6Hz,1H),2.87(dd,J=13.2,4.2Hz,1H),2.68–2.61(m,1H),2. 52(s,1H),2.50–2.43(t,J=13.2,1H),2.37–2.32(m,2H),2.29(d,J=14.4H z,1H),2.22–2.15(overlap,2H),2.10(dd,J=13.8,6.0Hz,1H),1.92(s,3H) ,1.75–1.70(m,1H),1.66–1.61(overlap,4H),1.60–1.49(overlap,9H),1.37(s,3H),1.19–1.12(m,1H),1.12–0.98(overlap,4H),0.78–0.70(m,2H). 13 C NMR(150MHz,pyridine-d5)δ:172.9,86.2,82.7,79.7,79.6,78.8,78.0,77.8,60.3,58.9,56.5,55.1 ,52.3,49.2,40.2,37.3,33.1,33.0,32.5,32.5,29.4,27.0,26.7,26.4,26.4,25.0,23.7,22.1,20.6.

[0184] Example 6 Preparation of compound 6 (6-O-(3-phenylpropionyl)rhodotorhinol VI)

[0185]

[0186] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, dissolve it in 0.5 mL of anhydrous N,N-dimethylformamide, then add 24.03 mg (0.16 mmol) of 3-phenylpropionic acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 12 h of reaction, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, which is then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph). An SPD-20A UV detector was used; a SilGreen-C18 column (250×10 mm, 5 μm) was used; 40% acetonitrile was used as the mobile phase; and the flow rate was 3 mL / min. Compound 6 (2.5 mg, yield 6.2%) was obtained.

[0187] Molecular formula C 29 H 42 O8, HRESI-MS m / z: [M+Na] + 541.2763.

[0188] 1 H NMR(600MHz,pyridine-d5)δ:7.29(td,J=7.2,1.8Hz,2H),7.25–7.22(m,2H),7.19(overlap,1H),7.05(s,1H),6.82(d,J=6.6Hz,1H),6.72(s,1 H),6.19(s,1H),5.81(dd,J=10.8,4.2Hz,1H),5.55(s,1H),5.24(s,1H) ,5.13(d,J=6.6Hz,1H),5.11–5.08(m,1H),3.93(s,1H),3.05–2.98(m,2H ),2.93(dd,J=7.2,1.8Hz,1H),2.82(dd,J=13.8,4.2Hz,1H),2.71–2.59(overlap,3H),2.52(s,1H),2.40(t,J=13.8Hz,1H),2.26(d,J=14.4Hz,1 H),2.19–2.12(overlap,2H),2.09(dd,J=14.4,7.2Hz,1H),1.90(s,3H),1.75–1.71(m,1H),1.66–1.60(m,1H),1.53(overlap,6H),1.26(s,3H). 13C NMR(150MHz,pyridine-d5)δ:171.8,141.2,128.8,128.8,128.8,128.8,126.5,86.2,82.6,79.6,79.6,7 8.8,78.1,78.0,60.1,58.8,56.5,55.2,52.3,49.2,40.1,36.6,31.1,29.4,27.0,24.9,23.7,22.1,20.6.

[0189] Example 7 Preparation of compound 7 (6-O-((E)-3-(4-fluorophenyl)acryloyl)rhodotoxin VI)

[0190]

[0191] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, add 0.5 mL of anhydrous N,N-dimethylformamide, then add 26.58 mg (0.16 mmol) of (E)-3-(4-fluorophenyl)acrylic acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after 20 h of reaction, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, which is then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph). An SPD-20A UV detector was used; a SilGreen-C18 column (250×10 mm, 5 μm) was used; 40% acetonitrile was used as the mobile phase; and the flow rate was 3 mL / min. Compound 7 (4.3 mg, yield 10.4%) was obtained.

[0192] Molecular formula C 29 H 39 O8F,HRESI-MS m / z:[M+HCOO] – 579.2612.

[0193] 1H NMR(600MHz,pyridine-d5)δ:7.89(d,J=16.2Hz,1H),7.44(dd,J=8.4,5.4Hz,2H),7.13(s,1H),7.10(t,J=8.4Hz,2H),6.89(d,J=6.6Hz,1H),6.83(d, J=4.8Hz,1H),6.58(d,J=16.2Hz,1H),6.21(s,1H),6.00(dd,J=10.8,4.2H z,1H),5.60(s,1H),5.35(s,1H),5.19(d,J=6.6Hz,1H),5.14(s,1H),3.97( t,J=4.8Hz,1H),3.01(d,J=7.2Hz,1H),2.97(dd,J=13.2,4.2Hz,1H),2.71 –2.64(m,1H),2.59–2.52(m,2H),2.31(d,J=14.4Hz,1H),2.22(d,J=6.6Hz, 1H),2.18(d,J=14.4Hz,1H),2.11(dd,J=13.8,6.6Hz,1H),1.94(s,3H),1. 77–1.70(m,1H),1.70–1.65(m,1H),1.64(s,3H),1.53(s,3H),1.40(s,3H). 13 CNMR(150MHz,pyridine-d5)δ:165.9,164.1,143.5,131.3,130.5,130.5,119.5,116.2,116.2,86.1,82.7,79 .6,79.6,78.8,78.2,78.0,60.2,58.8,56.5,55.2,52.3,49.3,45.3,40.3,29.5,27.0,25.0,23.7,22.1,20.7.

[0194] Example 8 Preparation of compound 8 (6-O-((E)-3-(4-(trifluoromethyl)phenyl)acryloyl)rhodotoxin VI)

[0195]

[0196] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, add 0.5 mL of anhydrous N,N-dimethylformamide, then add 34.58 mg (0.16 mmol) of (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP, and 27.0 μL (0.20 mmol) of triethylamine. React in an ice bath for 30 min, then bring to room temperature and continue stirring for 12 h. The reaction progress is monitored by thin-layer chromatography. After 20 h of reaction, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate to obtain the crude product, and purify by preparative liquid chromatography (Shimadzu LC-6AD type liquid chromatograph). An SPD-20A UV detector was used; a SilGreen-C18 column (250×10 mm, 5 μm) was used; 43% acetonitrile was used as the mobile phase; and the flow rate was 3 mL / min. Compound 8 (4.0 mg, yield 8.8%) was obtained.

[0197] Molecular formula C 30 H 39 O8F3,HRESI-MS m / z:[M+HCOO] – 629.2578.

[0198] 1H NMR(600MHz,pyridine-d5)δ:7.94(d,J=15.6Hz,1H),7.66(d,J=7.8Hz,2H),7.58(overlap,2H),7.12(s,1H),6.91(d,J=6.6Hz,1H),6.89(s,1H),6. 76(d,J=15.6Hz,1H),6.26(s,1H),6.02(dd,J=10.8,4.8Hz,1H),5.61(s,1 H),5.35(s,1H),5.19(d,J=6.6Hz,1H),5.15(dd,J=7.2,4.2Hz,1H),3.99(t ,J=4.2Hz,1H),3.03(d,J=7.2Hz,1H),2.97(dd,J=13.2,4.2Hz,1H),2.71–2.63(m,1H),2.59–2.53(overlap,2H),2.31(d,J=14.4Hz,1H),2.23(d,J=7 .2Hz,1H),2.19(d,J=14.4Hz,1H),2.14–2.09(m,1H),1.94(s,3H),1.74(d t,J=14.4,4.8Hz,1H),1.68–1.61(overlap,4H),1.54(s,3H),1.41(s,3H). 13 CNMR(150MHz,pyridine-d5)δ:165.5,142.9,138.6,131.0,128.8,126.0,126.0,124.5,122.4,122.4,86.2,82 .8,79.6,79.6,78.8,78.5,78.0,60.1,58.9,56.5,55.2,52.3,49.3,40.3,29.4,27.0,25.0,23.7,22.1,20.8.

[0199] Example 9 Preparation of compound 9 (6-O-((E)-3-(4-cyanophenyl)acryloyl)rhodotorhinol VI)

[0200]

[0201] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, add 0.4 mL of anhydrous N,N-dimethylformamide and 0.3 mL of anhydrous dichloromethane to dissolve it, then add 27.71 mg (0.16 mmol) of (E)-3-(4-cyanophenyl)acrylic acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after reacting for 13 h, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, and purify by silica gel column chromatography (CH2Cl2 / MeOH = 30:1) to obtain compound 9 (5.3 mg, yield 12.6%).

[0202] Molecular formula C 30 H 39 O8N, HRESI-MS m / z: [M+Na] + 564.2569.

[0203] 1 H NMR(600MHz,pyridine-d5)δ:7.85(d,J=16.2Hz,1H),7.64(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),7.11(s,1H),6.92–6.87(overlap,2H),6.74(d,J =16.2Hz,1H),6.23(s,1H),6.02(dd,J=10.8,4.2Hz,1H),5.60(s,1H),5.3 0(s,1H),5.19(d,J=7.2Hz,1H),5.14(t,J=5.4Hz,1H),3.98(t,J=4.8Hz,1 H),3.02(d,J=7.2Hz,1H),2.97(dd,J=13.2,4.2Hz,1H),2.71–2.64(m,1H),2.60–2.53(overlap,2H),2.31(d,J=14.4Hz,1H),2.23(d,J=7.2Hz,1H), 2.19(d,J=14.4Hz,1H),2.11(dd,J=14.4,6.0Hz,1H),1.94(s,3H),1.74(d t,J=13.8,4.8Hz,1H),1.69–1.62(overlap,4H),1.54(s,3H),1.40(s,3H). 13CNMR(150MHz,pyridine-d5)δ:165.3,142.6,139.0,132.8,132.8,128.8,128.8,123.0,118.9,113.3,86.2,82 .8,79.6,79.6,78.8,78.5,78.0,60.1,59.0,56.5,55.2,52.3,49.3,40.2,29.4,27.0,24.9,23.7,22.1,20.8.

[0204] Example 10 Preparation of compound 10 (6-O-((E)-3-(4-isopropylphenyl)acryloyl)rhodotorhinol VI)

[0205]

[0206] Weigh 15.00 mg (0.039 mmol) of azadirachtin VI into a 5 mL reaction flask, add 0.3 mL of anhydrous N,N-dimethylformamide and 0.4 mL of anhydrous dichloromethane to dissolve it, then add 14.84 mg (0.078 mmol) of (E)-3-(4-isopropylphenyl)acrylic acid, 16.49 mg (0.086 mmol) of EDCI, 2.44 mg (0.020 mmol) of DMAP and 14.0 μL (0.098 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after reacting for 12 h, add 5 mL of water to the reaction solution, extract three times with dichloromethane, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, and purify by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu). An SPD-20A UV detector was used; a SilGreen-C18 column (250×10 mm, 5 μm) was used; 60% acetonitrile was used as the mobile phase; and the flow rate was 3 mL / min. Compound 10 (1.4 mg, yield 6.5%) was obtained.

[0207] Molecular formula C 32 H 46 O8, HRESI-MS m / z: [M+Na] + 581.3077.

[0208] 1H NMR(600MHz,pyridine-d5)δ:8.00(d,J=16.2Hz,1H),7.44(d,J=7.8Hz,2H),7.21(o verlap,2H),7.12(s,1H),6.88(d,J=6.6Hz,1H),6.79(d,J=5.4Hz,1H),6.66(d,J=16 .2Hz,1H),6.20(s,1H),6.00(dd,J=10.8,4.2Hz,1H),5.58(s,1H),5.39(s,1H),5.1 8(d,J=7.2Hz,1H),5.14(t,J=6.6Hz,1H),3.96(t,J=5.4Hz,1H),3.00(d,J=7.2Hz,1H ),2.96(dd,J=13.2,4.8Hz,1H),2.81–2.74(m,1H),2.70–2.63(m,1H),2.59–2.52(o verlap,2H),2.30(d,J=14.4Hz,1H),2.22(d,J=6.6Hz,1H),2.17(d,J=14.4Hz,1H),2 .11(dd,J=14.4,6.0Hz,1H),1.94(s,3H),1.73(dt,J=13.8,4.8Hz,1H),1.68–1.60(o verlap,4H),1.53(s,3H),1.41(s,3H),1.13(d,J=2.4Hz,3H),1.12(d,J=2.4Hz,3H). 13 C NMR(150MHz,pyridine-d5)δ:166.2,151.7,144.9,132.6,128.6,128.6,127.4,127.4,118.7,86.1,82.8,79.6,79. 6,78.8,78.1,78.0,60.1,58.7,56.5,55.3,52.3,49.3,40.3,34.2,29.5,27.0,25.1,23.7,23.7,23.7,22.1,20.7.

[0209] Example 11 Preparation of compound 11 (6-O-((E)-3-(4-methoxyphenyl)acryloyl)rhodotorhinol VI)

[0210]

[0211] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI into a 5 mL reaction flask, add 0.3 mL of anhydrous N,N-dimethylformamide and 0.4 mL of anhydrous dichloromethane to dissolve it, then add 28.51 mg (0.16 mmol) of (E)-3-(4-methoxyphenyl)acrylic acid, 32.59 mg (0.17 mmol) of EDCI, 4.76 mg (0.039 mmol) of DMAP and 27.0 μL (0.20 mmol) of triethylamine. Stir at room temperature, monitor the reaction progress by thin-layer chromatography, and after reacting for 12 h, add 5 mL of water to the reaction solution, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product, which is then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph). An SPD-20A UV detector was used; a SilGreen-C18 column (250×10 mm, 5 μm) was used; 45% acetonitrile was used as the mobile phase; and the flow rate was 3 mL / min. Compound 11 (3.3 mg, yield 7.8%) was obtained.

[0212] Molecular formula C 30 H 42 O9,HRESI-MS m / z:[M+H] + 547.2892.

[0213] 1H NMR(600MHz,pyridine-d5)δ:7.96(d,J=15.6Hz,1H),7.45(d,J=8.4Hz,2H),7 .15(s,1H),6.96(d,J=8.4Hz,2H),6.88(d,J=6.6Hz,1H),6.79(s,1H),6.55(d ,J=15.6Hz,1H),6.20(s,1H),5.99(dd,J=11.4,4.8Hz,1H),5.60(s,1H),5.40 (s,1H),5.19(d,J=6.6Hz,1H),5.13(dt,J=7.8,3.6Hz,1H),3.96(t,J=4.8Hz, 1H),3.65(s,3H),3.00(d,J=7.8Hz,1H),2.97(dd,J=13.8,4.8Hz,1H),2.71–2 .64(m,1H),2.59–2.52(overlap,2H),2.31(d,J=14.4Hz,1H),2.22(d,J=7.2H z,1H),2.18(d,J=14.4Hz,1H),2.11(dd,J=14.4,6.6Hz,1H),1.94(s,3H),1.7 4(dt,J=13.8,4.8Hz,1H),1.68–1.61(overlap,4H),1.53(s,3H),1.41(s,3H). 13 CNMR(150MHz,pyridine-d5)δ:166.3,161.8,144.7,130.1,130.1,127.5,117.0,114.8,114.8,86.1,82.7,79 .6,79.5,78.8,78.0,78.0,60.2,58.7,56.5,55.3,55.3,52.3,49.2,40.4,29.5,27.0,25.1,23.7,22.1,20.8.

[0214] Example 12 Preparation of compound 12 (2-O-(N-benzylcarbamoyl)azotoxin VI)

[0215]

[0216] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI and add it to 0.5 mL of ultra-dry N,N-dimethylformamide. Stir until completely dissolved, then add 42.0 μL (0.32 mmol) of benzyl isocyanate and 12.5 μL of LdBU (0.082 mmol). React in an ice bath for 20 min, then bring to room temperature and continue stirring. Monitor the reaction progress by thin-layer chromatography. After 16 h of reaction, add 5 mL of water to the reaction solution and extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, and purify by silica gel column chromatography (CH2Cl2 / MeOH = 25:1) to obtain compound 12 (3.5 mg, yield 8.7%).

[0217] Molecular formula C 28 H 41 O8N, HRESI-MS m / z: [M+Na] + 542.2719.

[0218] 1 H NMR(600MHz,pyridine-d5)δ:8.82(t,J=6.6Hz,1H),7.44(d,J=7.8Hz,2H),7.28(t ,J=7.8Hz,2H),7.22(overlap,1H),7.07(d,J=4.8Hz,1H),6.48(s,1H),6.28(d,J=7 .8Hz,1H),6.16(d,J=3.6Hz,1H),5.58(s,1H),5.47(s,1H),5.05(overlap,1H),4. 69(s,1H),4.68–4.63(m,1H),4.61(dd,J=15.0,6.6Hz,1H),4.50(dd,J=15.0,5.4Hz ,1H),4.12(d,J=4.8Hz,1H),3.29(d,J=3.6Hz,1H),2.91(dd,J=13.8,4.2Hz,1H),2 .70-2.62(m,1H),2.54(dd,J=13.8,10.8Hz,1H),2.51(brs,1H),2.28(d,J=14.4Hz, 1H),2.19(d,J=7.2Hz,1H),2.13(d,J=14.4Hz,1H),2.05(dd,J=13.8,6.0Hz,1H),1 .92(s,3H),1.72-1.66(overlap,4H),1.65–1.58(m,1H),1.53(s,3H),1.39(s,3H). 13C NMR(150MHz,pyridine-d5)δ:158.3,140.2,128.8,128.8,127.8,127.8,127.3,85.7,85.6,84.2,79.9 ,79.4,77.3,74.0,61.1,60.1,56.4,54.7,52.5,50.5,45.2,44.4,29.4,26.9,24.1,22.5,22.4,20.3.

[0219] Example 13 Preparation of compound 13 (2-O-(N-(4-fluorophenyl)carbamoyl)rhodotoxin VI)

[0220]

[0221] 30.00 mg (0.078 mmol) of azadirachtin VI was weighed and added to 0.5 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 18.0 μL (0.16 mmol) of 4-fluorophenyl isocyanate and 1.5 μL of NMI (0.016 mmol) were added dropwise. The mixture was stirred at room temperature, and the reaction progress was monitored by thin-layer chromatography. After 22 h of reaction, 5 mL of water was added to the reaction solution, and the crude product was concentrated under reduced pressure. The crude product was then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 45% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 13 (2.6 mg, yield 6.4%).

[0222] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2470.

[0223] 1H NMR(600MHz,pyridine-d5)δ:10.96(s,1H),7.86–7.79(m,2H),7.15–7.08(overlap,3H),6.58(s,1H),6.21(d,J=3.0Hz,1H),6.15(d ,J=8.4Hz,1H),5.63–5.56(overlap,2H),5.05(overlap,1H),4.71(s,1H),4.63–4.56(m,1H),4.10(d,J=5.4,1H),3.30(d,J=3.0Hz, 1H),2.90(dd,J=13.2,3.6Hz,1H),2.68-2.61(m,1H),2.57–2.53(overlap,2H),2.29(d,J=14.4Hz,1H),2.20(d,J=7.2Hz,1H),2.13( d,J=14.4Hz,1H),2.04(dd,J=13.8,5.4Hz,1H),1.95(s,3H),1.71-1.66(overlap,4H),1.66-1.61(m,1H),1.54(s,3H),1.24(s,3H). 13 C NMR(150MHz,pyridine-d5)δ:158.6,155.0,136.9,120.4,120.4,115.7,115.7,85.5,85.5,84.4,8 0.0,79.6,77.5,73.9,60.3,60.0,56.3,54.8,52.6,50.5,44.4,29.3,26.9,24.2,22.4,22.3,20.3.

[0224] Example 14 Preparation of compound 14 (2-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotoxin VI)

[0225]

[0226] Weigh 30.00 mg (0.078 mmol) of azadirachtin VI and add it to 0.5 mL of ultra-dry N,N-dimethylformamide. Stir until completely dissolved, then add 22.5 μL (0.16 mmol) of 4-(trifluoromethyl)phenyl isocyanate and 1.5 μL of NMI (0.016 mmol). Stir at room temperature and monitor the reaction progress by thin-layer chromatography. After reacting for 12 h, add 5 mL of water to the reaction solution and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (CH2Cl2 / MeOH = 30:1) to obtain compound 14 (2.3 mg, yield 5.2%).

[0227] Molecular formula C 28 H 38 O8NF3, HRESI-MS m / z: [M+Na] + 596.2443.

[0228] 1 H NMR (600MHz, pyridine-d5) δ: 11.32 (s, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.62 (d, J = 8.4Hz, 2H), 7.12 (d, J = 4.8Hz, 1H), 6.60 (s, 1H), 6.23 (d, J=3.6Hz,1H),6.09(d,J=8.4Hz,1H),5.67(s,1H),5.59(s,1H),5.05(d,J=8.4Hz,1H),4.72(s,1H),4.60–4.55(m,1H),4.10(d,J=4.8Hz ,1H),3.30(d,J=3.6Hz,1H),2.90(dd,J=13.8,4.2Hz,1H),2.69–2.62(m,1H),2.58–2.50(overlap,2H),2.29(d,J=14.4Hz,1H),2.21(d ,J=6.6Hz,1H),2.14(d,J=14.4Hz,1H),2.04(dd,J=13.8,6.0Hz,1H),1.96(s,3H),1.73–1.62(overlap,5H),1.55(s,3H),1.21(s,3H). 13 CNMR(150MHz,pyridine-d5)δ:154.6,144.2,126.4,126.4,125.2,123.5,118.5,118.5,85.4,85.3,84. 8,80.0,79.6,77.6,73.8,60.0,60.0,56.3,54.8,52.7,50.4,44.4,29.2,26.9,24.2,22.4,22.2,20.2.

[0229] Example 15 Preparation of compound 15 (2-O-(N-(4-bromophenyl)carbamoyl)azotoxin VI)

[0230]

[0231] 50.00 mg (0.13 mmol) of azadirachtin VI was weighed and added to 1.0 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 31.68 mg (0.16 mmol) of 4-bromophenyl isocyanate was added. The mixture was stirred at room temperature, and the reaction progress was monitored by thin-layer chromatography. After 12 h of reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 35% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 15 (4.4 mg, yield 5.8%).

[0232] Molecular formula C 27 H 38 O8NBr, HRESI-MS m / z: [M+Na] + 606.1674.

[0233] 1 H NMR(500MHz,pyridine-d5)δ:11.09(s,1H),7.78(d,J=8.5Hz,2H),7.49(d,J=8.5Hz,2H),7.17(d,J=5.0Hz,1H),6.62(s,1H),6.21(d,J=3 .5Hz,1H),6.15(d,J=8.0Hz,1H),5.69(s,1H),5.65(d,J=6.0Hz,1H),5.04(overlap,1H),4.73(s,1H),4.62–4.54(m,1H),4.09(d,J=5.0Hz ,1H),3.29(d,J=3.5Hz,1H),2.90(dd,J=13.5,4.0Hz,1H),2.70–2.61(m,1H),2.58–2.51(overlap,2H),2.28(d,J=14.5Hz,1H),2.20(d,J =6.5Hz,1H),2.12(d,J=14.5Hz,1H),2.07–2.00(dd,J=13.5,5.5Hz,1H),1.95(s,3H),1.73–1.59(overlap,5H),1.54(s,3H),1.21(s,3H). 13C NMR(125MHz,pyridine-d5)δ:154.7,140.0,132.1,132.1,120.6,120.6,114.8,85.4,85.3,84.6,8 0.0,79.5,77.5,73.9,60.1,60.0,56.3,54.8,52.6,50.4,44.4,29.2,26.9,24.2,22.4,22.2,20.3.

[0234] Example 16 Preparation of compound 16 (2-O-(N-(3-fluorophenyl)carbamoyl)rhodotoxin VI)

[0235]

[0236] 40.00 mg (0.10 mmol) of azadirachtin VI was weighed and added to 0.5 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 13.5 μL (0.12 mmol) of 3-fluorophenyl isocyanate was added dropwise. The mixture was stirred at room temperature, and the reaction progress was monitored by thin-layer chromatography. After 13 h of reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 33% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 16 (2.7 mg, yield 5.0%).

[0237] Molecular formula C 27 H 38 O8FN,HRESI-MS m / z:[M+Na] + 546.2460.

[0238] 1H NMR(600MHz,pyridine-d5)δ:11.17(s,1H),7.94(d,J=11.4Hz,1H),7.48(d,J=7.2Hz,1H),7.26(d,J=7.2Hz,1H),7.12(d,J=4.2Hz,1H),6.85–6.7 9(m,1H),6.57(s,1H),6.21(d,J=3.0Hz,1H),6.11(d,J=7.2Hz,1H),5.62 (s,1H),5.56(s,1H),5.04(overlap,1H),4.69(s,1H),4.60–4.54(m,1H), 4.08(d,J=4.2Hz,1H),3.28(d,J=3.0Hz,1H),2.89(dd,J=14.4,4.2Hz,1H),2.69–2.60(m,1H),2.59–2.49(overlap,2H),2.28(d,J=14.4Hz,1H),2 .20(d,J=6.0Hz,1H),2.13(d,J=14.4Hz,1H),2.07–2.01(dd,J=14.4,6.0Hz,1H),1.95(s,3H),1.74–1.61(overlap,5H),1.54(s,3H),1.20(s,3H). 13 C NMR(150MHz,pyridine-d5)δ:163.6,154.7,142.6,130.5,114.4,109.0,105.9,85.4,85.4,84.6,8 0.0,79.6,77.5,73.8,60.1,60.0,56.3,54.8,52.6,50.4,44.4,29.2,26.9,24.2,22.4,22.2,20.2.

[0239] Example 17 Preparation of compound 17 (2-O-(N-(2-fluorophenyl)carbamoyl)rhodotoxin VI)

[0240]

[0241] 40.00 mg (0.10 mmol) of azadirachtin VI was weighed and added to 0.5 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 17.0 μL (0.12 mmol) of 2-fluorophenyl isocyanate was added dropwise. The mixture was stirred at room temperature, and the reaction progress was monitored by thin-layer chromatography. After 13 h of reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 25:1) to obtain compound 17 (4.6 mg, yield 8.5%).

[0242] Molecular formula C 27 H 38 O8FN,HRESI-MS m / z:[M+Na] + 546.2469.

[0243] 1 H NMR(600MHz,pyridine-d5)δ:10.97(s,1H),8.36(t,J=7.8Hz,1H),7.17–7.08(overlap,3H),7.00–6.95(m,1H),6.53(s,1H),6.26(d, J=3.6Hz,1H),6.20(d,J=7.8Hz,1H),5.64(s,1H),5.58(s,1H),5.07(d,J=7.8Hz,1H),4.72(s,1H),4.61–4.57(m,1H),4.13(d,J=5.4Hz ,1H),3.35(d,J=3.6Hz,1H),2.90(dd,J=13.2,3.6Hz,1H),2.69–2.63(m,1H),2.57–2.51(overlap,2H),2.29(d,J=14.4Hz,1H),2.21(d ,J=6.6Hz,1H),2.14(d,J=14.4Hz,1H),2.05(dd,J=13.8,6.0Hz,1H),1.96(s,3H),1.73–1.61(overlap,5H),1.54(s,3H),1.24(s,3H). 13 C NMR(150MHz,pyridine-d5)δ:155.2,153.8,128.2,124.6,123.9,123.0,115.6,85.5,85.4,85.0,7 9.9,79.5,77.6,73.8,60.1,60.0,56.3,54.8,52.6,50.4,44.4,29.3,26.9,24.1,22.4,22.2,20.2.

[0244] Example 18 Preparation of compound 18 (2-O-(N-(4-fluorobenzyl)carbamoyl)azotoxin VI)

[0245]

[0246] 40.00 mg (0.10 mmol) of azadirachtin VI was weighed and added to 0.5 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 20.0 μL (0.15 mmol) of 1-fluoro-4-(isocyanomethyl)benzene was added dropwise. The mixture was stirred at 45 °C, and the reaction progress was monitored by thin-layer chromatography. After 16 h of reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 25:1) to obtain compound 18 (2.6 mg, yield 4.7%).

[0247] Molecular formula C 28 H 40 O8FN,HRESI-MS m / z:[M+Na] + 560.2625.

[0248] 1H NMR(600MHz,pyridine-d5)δ:8.82(t,J=6.0Hz,1H),7.44–7.36(dd,J=7.8,6.0Hz,2H),7.07–6.96(overlap,3H),6.49(s,1H),6.26(d,J=7.8Hz,1H),6.16 (d,J=3.0Hz,1H),5.59(s,1H),5.46(s,1H),5.04(d,J=7.8Hz,1H),4.70(s,1H ),4.67–4.61(m,1H),4.53(dd,J=15.0,6.0Hz,1H),4.47(dd,J=15.0,6.0Hz,1 H),4.11(d,J=4.8Hz,1H),3.28(d,J=3.0Hz,1H),2.91(dd,J=13.8,4.2Hz,1H ),2.68–2.60(m,1H),2.57–2.49(overlap,2H),2.28(d,J=14.4Hz,1H),2.18( d,J=6.6Hz,1H),2.12(d,J=14.4Hz,1H),2.05(dd,J=13.8,6.0Hz,1H),1.92(s ,3H),1.73–1.66(overlap,4H),1.65–1.57(m,1H),1.53(s,3H),1.38(s,3H). 13 C NMR(150MHz,pyridine-d5)δ:162.2,158.2,136.3,129.6,129.6,115.4,115.4,85.7,85.6,84.3,80.0 ,79.5,77.4,74.0,61.1,60.1,56.4,54.8,52.6,50.5,44.4,44.4,29.4,26.9,24.1,22.5,22.4,20.3.

[0249] Example 19 Preparation of compound 19 (2-O-(N-(4-methoxyphenyl)carbamoyl)rhodotoxin VI)

[0250]

[0251] 30.00 mg (0.078 mmol) of azadirachtin VI was weighed and added to 0.5 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 13.0 μL (0.094 mmol) of 4-methoxyphenyl isocyanate and 1.5 μL of NMI (0.016 mmol) were added dropwise. The mixture was stirred at room temperature, and the reaction progress was monitored by thin-layer chromatography. After 24 h of reaction, 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, and purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 50% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 19 (2.7 mg, yield 6.5%).

[0252] Molecular formula C 28 H 41 O9N, HRESI-MS m / z: [M+Na] + 558.2672.

[0253] 1 H NMR(600MHz,pyridine-d5)δ:10.76(s,1H),7.82(d,J=8.4Hz,2H),7.10(s,1H),6.99(d,J=8.4Hz,2H),6.55(s,1H),6.22(d,J=3.6Hz,1H) ,6.17(s,1H),5.61–5.55(overlap,2H),5.07(overlap,1H),4.72(s,1H),4.63–4.58(m,1H),4.12(d,J=4.8Hz,1H),3.64(s,3H),3.31(d, J=3.6Hz,1H),2.91(dd,J=13.2,4.2Hz,1H),2.69–2.62(m,1H),2.57–2.51(overlap,2H),2.29(d,J=14.4Hz,1H),2.20(d,J=6.6Hz,1H),2 .13(d,J=14.4Hz,1H),2.05(dd,J=14.4,6.0Hz,1H),1.95(s,3H),1.72–1.66(overlap,4H),1.66–1.60(m,1H),1.54(s,3H),1.27(s,3H). 13CNMR(150MHz,pyridine-d5)δ:155.7,155.2,133.7,120.6,120.6,114.5,114.5,85.5,85.5,84.3,80. 0,79.5,77.5,73.9,60.5,60.1,56.3,55.3,54.8,52.6,50.4,44.4,29.3,26.9,24.2,22.4,22.3,20.3.

[0254] Example 20 Preparation of compound 20 (2-O-(N-(4-benzoylphenyl)carbamoyl)rhodotorhinol VI)

[0255]

[0256] 40.00 mg (0.10 mmol) of azadirachtin VI was weighed and added to 1.0 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 26.79 mg (0.12 mmol) of (4-isocyanophenyl)(phenyl)methyl ketone was added. The mixture was reacted at room temperature for 18 h. 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was initially separated by silica gel column chromatography (CH2Cl2 / MeOH = 20:1), and then further purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 38% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 20 (2.1 mg, yield 3.3%).

[0257] Molecular formula C 34 H 43 O9N, HRESI-MS m / z: [M+Na] + 632.2823.

[0258] 1H NMR(500MHz,pyridine-d5)δ:11.40(s,1H),8.00(d,J=9.0Hz,2H),7.95(d,J=9.0Hz,2H),7.88(dd,J=8.0,1.5Hz,2H),7.55–7.53(m,1H),7.52–7.42(m,2 H),7.15(d,J=5.0Hz,1H),6.61(s,1H),6.26(d,J=3.5Hz,1H),6.12(d,J=8.5 Hz,1H),5.70(s,1H),5.60(d,J=6.5Hz,1H),5.07(overlap,1H),4.72(s,1H) ,4.61–4.54(m,1H),4.11(d,J=5.0Hz,1H),3.32(d,J=4.0Hz,1H),2.91(dd,J =13.5,4.0Hz,1H),2.71–2.63(m,1H),2.59–2.50(overlap,2H),2.29(d,J=1 4.5Hz,1H),2.21(d,J=7.0Hz,1H),2.14(d,J=14.5Hz,1H),2.05(dd,J=13.0, 5.0Hz,1H),1.97(s,3H),1.73–1.61(overlap,5H),1.55(s,3H),1.22(s,3H). 13 C NMR(125MHz,pyridine-d5)δ:195.2,154.6,145.0,138.8,132.2,132.0,132.0,131.5,130.0,130.0,128.6,128.6,117.9,1 17.9,85.4,85.3,84.8,80.0,79.6,77.6,73.9,60.0,60.0,56.3,54.9,52.7,50.5,44.4,29.2,26.9,24.2,22.4,22.2,20.2.

[0259] Example 21 Preparation of compound 21 (2-O-(N-(1-methyl-1H-indol-6-yl)carbamoyl) peperomia toxin VI)

[0260]

[0261] 40.00 mg (0.10 mmol) of azadirachtin VI was weighed and added to 0.6 mL of ultra-dry N,N-dimethylformamide. The mixture was stirred until completely dissolved, and then 21.38 mg (0.12 mmol) of 6-isocyano-1-methyl-1H-indole was added. The mixture was reacted at room temperature for 12 h. 5 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was initially separated by silica gel column chromatography (CH2Cl2 / MeOH = 20:1), and then further purified by preparative liquid chromatography (Shimadzu LC-6AD liquid chromatograph, Shimadzu SPD-20A UV detector; SilGreen-C18 column, 250 × 10 mm, 5 μm; 35% acetonitrile as mobile phase; flow rate 3 mL / min) to obtain compound 21 (0.61 mg, yield 1.1%).

[0262] Molecular formula C 30 H 42 O8N2, HRESI-MS m / z: [M+Na] + 581.2835.

[0263] 1 H NMR(600MHz,pyridine-d5)δ:10.88(s,1H),8.17(s,1H),7.70(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.10(d,J=3.0Hz,1H),7.07–7.04(m,1H),6.56 (d,J=3.0Hz,1H),6.27(d,J=3.6Hz,1H),6.22(s,1H),5.64(s,1H),5.57(s ,1H),4.76(s,1H),5.08(overlap,1H),4.76(s,1H),4.62(d,J=8.4Hz,1H), 4.15(d,J=4.2Hz,1H),3.52(s,3H),3.34(d,J=3.6Hz,1H),2.92(dd,J=13. 8,4.2Hz,1H),2.68–2.61(m,1H),2.58–2.51(overlap,2H),2.29(d,J=14.4 Hz,1H),2.21(d,J=6.6Hz,1H),2.14(d,J=14.4Hz,1H),2.06(dd,J=13.8,6. 0Hz,1H),1.97(s,3H),1.72–1.60(overlap,5H),1.54(s,3H),1.28(s,3H). 13C NMR(150MHz,pyridine-d5)δ:155.4,137.7,135.2,129.0,125.0,121.2,113.0,101.2,100.3,85.7,85.6,84. 3,80.0,79.6,77.5,73.9,60.6,60.1,56.3,54.8,52.6,50.5,44.4,32.4,29.4,26.9,24.1,22.4,22.4,20.3.

[0264] Example 22 Preparation of compound 22 (3-O-(N-(4-fluorophenyl)carbamoyl)rhodotoxin VI)

[0265]

[0266] Compound 22 (2.0 mg, yield 4.9%) was obtained in the same manner as in Example 13.

[0267] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2466.

[0268] 1 H NMR(600MHz,pyridine-d5)δ:10.88(s,1H),7.85(dd,J=9.0,4.8Hz,2H),7.77(s,1H),7.16(t,J=9.0Hz,2H),6.72(s,1H),6.58(d,J= 7.2Hz,1H),6.37(s,1H),5.38(d,J=4.8Hz,1H),5.27–5.23(m,1H),5.12(overlap,2H),4.72(s,1H),4.67–4.62(m,1H),2.98(d,J=10. 2Hz,1H),2.89(dd,J=14.4,2.4Hz,1H),2.60–2.49(overlap,3H),2.41(d,J=14.4Hz,1H),2.35(d,J=14.4Hz,1H),2.31(d,J=7.2Hz,1H ), 2.14(dd,J=13.8,6.0Hz,1H),1.88(s,3H),1.73(dt,J=14.4,4.2Hz,1H),1.69–1.61(m,1H),1.57(s,3H),1.51(s,3H),1.37(s,3H). 13 C NMR(150MHz,pyridine-d5)δ:158.6(d,J C-F=238.5Hz),155.2,136.8,120.4,120.4,115.8(d,J C-F =21.0Hz), 115.8(d,J C-F =21.0Hz),89.0,82.3,80.6,80.6,78.9,78.3,70.3,61.3,55.7,55.2,53.6,52.2,48.6,44.4,29.0,27.1,24.0,21.7,21.7,18.7.

[0269] Example 23 Preparation of compound 23 (3-O-(N-(3-fluorophenyl)carbamoyl)rhodotoxin VI)

[0270]

[0271] Compound 23 (2.2 mg, yield 4.1%) was obtained in the same manner as in Example 16.

[0272] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2463.

[0273] 1 H NMR(600MHz,pyridine-d5)δ:11.07(s,1H),7.95(dt,J=12.0,1.8Hz,1H),7.74(s,1H),7.53–7.50(m,1H),7.31(q,J=8.4Hz,1H),6.85(td,J=8.4, 2.4Hz,1H),6.72(s,1H),6.56(d,J=7.2Hz,1H),6.34(s,1H),5.36(d,J=4 .8Hz,1H),5.26–5.20(m,1H),5.12(d,J=7.2Hz,1H),5.09(s,1H),4.71(s, 1H),4.63(s,1H),2.98(d,J=10.2Hz,1H),2.91–2.86(dd,J=14.4,1.8Hz,1H),2.59–2.48(overlap,3H),2.41(d,J=14.4Hz,1H),2.35(d,J=14.4Hz, 1H),2.31(d,J=7.2Hz,1H),2.14(dd,J=13.8,6.0Hz,1H),1.87(s,3H),1. 76–1.70(m,1H),1.701.61(m,1H),1.57(s,3H),1.49(s,3H),1.34(s,3H).13 C NMR(150MHz,pyridine-d5)δ:163.7,154.9,142.5,130.6,114.4,109.1,105.9,89.2,82.3,80.6,8 0.6,78.8,78.3,70.1,61.4,55.7,55.2,53.5,52.2,48.6,44.4,29.0,27.1,27.1,24.0,21.7,18.7.

[0274] Example 24 Preparation of compound 24 (3-O-(N-(2-fluorophenyl)carbamoyl)rhodotoxin VI)

[0275]

[0276] Compound 24 (6.7 mg, yield 12.4%) was obtained in the same manner as in Example 17.

[0277] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2465.

[0278] 1 H NMR(600MHz,pyridine-d5)δ:10.81(s,1H),8.40(t,J=7.8Hz,1H),7.92(s,1H),7.18(overlap,1H),7.13(t,J=7.8Hz,1H),7.04–6.97(m,1H),6. 76(s,1H),6.56(d,J=6.6Hz,1H),6.35(s,1H),5.41(d,J=5.4Hz,1H),5.30(d,J=10.2Hz,1H),5.15–5.10(overlap,2H),4.80(s,1H),4.64(d,J=8. 4Hz,1H),2.98(d,J=10.8Hz,1H),2.89(dd,J=14.4,1.8Hz,1H),2.63–2.47(overlap,3H),2.42(d,J=14.4Hz,1H),2.37(d,J=14.4Hz,1H),2.33(d, J=6.6Hz,1H),2.15(dd,J=14.4,6.0Hz,1H),1.89(s,3H),1.74(dt,J=13. 8,5.4Hz,1H),1.69–1.63(m,1H),1.58(s,3H),1.51(s,3H),1.39(s,3H). 13C NMR(150MHz,pyridine-d5)δ:155.3,153.7,128.2,124.7,123.8,122.7,115.5,89.6,82.2,80.7,8 0.6,78.7,78.3,70.0,61.4,55.6,54.8,53.5,52.2,48.6,44.4,29.0,27.2,27.1,24.0,21.7,18.6.

[0279] Example 25 Preparation of compound 25 (3-O-(N-(4-bromophenyl)carbamoyl)rhodotoxin VI)

[0280]

[0281] Compound 25 (3.2 mg, yield 4.2%) was obtained in the same manner as in Example 15.

[0282] Molecular formula C 27 H 38 O8NBr, HRESI-MS m / z: [M+Na] + 606.1675.

[0283] 1 H NMR(600MHz,pyridine-d5)δ:10.96(s,1H),7.79(d,J=9.0Hz,2H),7.75(s,1H),7.53(d,J=9.0Hz,2H),6.73(s,1H),6.55(d,J=7.2Hz,1 H),6.34(s,1H),5.36(d,J=4.8Hz,1H),5.25–5.21(m,1H),5.12(d,J=7.2Hz,1H),5.10(s,1H),4.70(s,1H),4.65–4.61(m,1H),2.97(d,J =10.2Hz,1H),2.89(dd,J=14.4,2.4Hz,1H),2.60–2.49(overlap,3H),2.41(d,J=14.4Hz,1H),2.36(d,J=14.4Hz,1H),2.32(d,J=7.2Hz, 1H),2.14(dd,J=13.8,6.0Hz,1H),1.87(s,3H),1.73(dt,J=13.8,3.6Hz,1H),1.70–1.62(m,1H),1.57(s,3H),1.49(s,3H),1.34(s,3H). 13CNMR(150MHz,pyridine-d5)δ:154.9,139.9,132.2,132.2,120.7,120.7,114.9,89.1,82.2,80.6,8 0.6,78.9,78.3,70.1,61.4,55.7,55.1,53.6,52.2,48.6,44.4,29.0,27.1,27.1,24.0,21.7,18.7.

[0284] Example 26 Preparation of compound 26 (3-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotoxin VI)

[0285]

[0286] Compound 26 (1.3 mg, yield 2.9%) was obtained in the same manner as in Example 14.

[0287] Molecular formula C 28 H 38 O8NF3, HRESI-MS m / z: [M+Na] + 596.2443.

[0288] 1 H NMR(600MHz,pyridine-d5)δ:11.23(s,1H),7.98(d,J=8.4Hz,2H),7.76(s,1H),7.66(d,J=8.4Hz,2H),6.76(s,1H),6.55(d,J=6.6Hz,1H ),6.35(s,1H),5.38(d,J=4.8Hz,1H),5.25(dt,J=10.2,4.8Hz,1H),5.15–5.09(overlap,2H),4.75(s,1H),4.66–4.61(m,1H),2.99(d,J =10.2Hz,1H),2.89(dd,J=14.4,2.4Hz,1H),2.60–2.49(overlap,3H),2.42(d,J=14.4Hz,1H),2.37(d,J=14.4Hz,1H),2.33(d,J=7.2Hz, 1H),2.15(dd,J=13.8,6.0Hz,1H),1.88(s,3H),1.74(dt,J=14.4,4.8Hz,1H),1.70–1.63(m,1H),1.58(s,3H),1.50(s,3H),1.35(s,3H). 13CNMR(150MHz,pyridine-d5)δ:154.9,144.1,126.5,126.5,124.2,123.6,118.5,118.5,89.4,82.3,80. 6,80.6,78.9,78.3,70.1,61.4,55.7,55.2,53.5,52.2,48.6,44.4,29.0,27.1,27.0,24.0,21.7,18.6.

[0289] Example 27 Preparation of compound 27 (3-O-(N-(4-methoxyphenyl)carbamoyl)rhodotoxin VI)

[0290]

[0291] Compound 27 (2.3 mg, yield 5.5%) was obtained in the same manner as in Example 19.

[0292] Molecular formula C 28 H 41 O9N, HRESI-MS m / z: [M+Na] + 558.2673.

[0293] 1 H NMR(600MHz,pyridine-d5)δ:10.68(s,1H),7.85(d,J=8.4Hz,2H),7.79(s,1H),7.02(d,J=8.4Hz,2H),6.70(s,1H),6.59(d,J=6.6Hz,1H), 6.36(s,1H),5.39(d,J=4.8Hz,1H),5.27(dd,J=10.2,4.8Hz,1H),5.16–5.11(overlap,2H),4.67(s,1H),4.64(d,J=9.0Hz,1H),3.66(s,3H) ,2.99(d,J=10.8Hz,1H),2.89(dd,J=14.4,2.4Hz,1H),2.61–2.47(overlap,3H),2.41(d,J=14.4Hz,1H),2.35(d,J=14.4Hz,1H),2.31(d,J =7.2Hz,1H),2.18–2.09(dd,J=15.0,6.6Hz,1H),1.88(s,3H),1.76–1.70(m,1H),1.69–1.61(m,1H),1.57(s,3H),1.51(s,3H),1.38(s,3H). 13C NMR(150MHz,pyridine-d5)δ:155.7,155.3,133.7,120.5,120.5,114.6,114.6,88.8,82.3,80.6,80.5 ,78.9,78.3,70.2,61.3,55.7,55.3,55.2,53.6,52.2,48.6,44.4,29.0,27.1,27.1,23.9,21.7,18.7.

[0294] Example 28 Preparation of compound 28 (3-O-(N-benzylcarbamoyl)rhodotoxin VI)

[0295]

[0296] Compound 28 (2.8 mg, yield 6.9%) was obtained in the same manner as in Example 12.

[0297] Molecular formula C 28 H 41 O8N, HRESI-MS m / z: [M+Na] + 542.2717.

[0298] 1 H NMR(600MHz,pyridine-d5)δ:7.75(s,1H),7.45(d,J=7.8Hz,2H),7.29(t,J=7.8Hz,2H),7.24(d,J=7.8Hz,1H),6.69–6.55(overlap,2H),6.30( s,1H),5.35(d,J=5.4Hz,1H),5.26(dd,J=10.2,4.8Hz,1H),5.13(overlap,2H),4.67–4.62(overlap,2H),4.60(dd,J=12.6,6.0Hz,2H),2.97(d ,J=10.2Hz,1H),2.88(dd,J=14.4,3.0Hz,1H),2.58–2.52(overlap,2H),2.50(s,1H),2.39(d,J=14.4Hz,1H),2.33(d,J=14.4Hz,1H),2.28(d,J =7.2Hz,1H),2.13(dd,J=14.4,6.0Hz,1H),1.87(s,3H),1.72(dt,J=13. 84.8Hz,1H),1.66–1.59(m,1H),1.56(s,3H),1.52(s,3H),1.43(s,3H). 13C NMR(150MHz,pyridine-d5)δ:158.2,140.5,128.8,128.8,127.8,127.8,127.3,88.8,82.3,80.6,80.5 ,78.9,78.2,70.5,61.3,55.7,55.3,53.7,52.2,48.7,45.2,44.4,29.1,27.1,27.1,23.9,21.7,18.9.

[0299] Example 29 Preparation of compound 29 (3-O-(N-(4-fluorobenzyl)carbamoyl)azotoxin VI)

[0300]

[0301] Compound 29 (1.0 mg, yield 1.8%) was obtained in the same manner as in Example 18.

[0302] Molecular formula C 28 H 40 O8NF,HRESI-MS m / z:[M+Na] + 560.2625.

[0303] 1 H NMR(600MHz,pyridine-d5)δ:8.75(t,J=4.8Hz,1H),7.71(s,1H),7.43–7.37(m,2H),7.05(td,J=9.0,1.8Hz,2H),6.69–6.56(overlap ,2H),6.36(s,1H),5.34(d,J=3.6Hz,1H),5.26(dd,J=9.6,4.8Hz,1H),5.14(overlap,2H),4.68–4.62(overlap,2H),4.56–4.51(m,2H ),2.97(d,J=10.2Hz,1H),2.88(d,J=13.8Hz,1H),2.59–2.48(overlap,3H),2.39(d,J=14.4Hz,1H),2.32(d,J=14.4Hz,1H),2.28(d,J =6.0Hz,1H),2.13(dd,J=14.4,6.0Hz,1H),1.87(s,3H),1.74–1.69(m,1H),1.67–1.59(m,1H),1.56(s,3H),1.52(s,3H),1.42(s,3H). 13C NMR(150MHz,pyridine-d5)δ:162.2,158.2,136.6,129.6,129.6,115.4,115.4,88.9,82.3,80.6,8 0.4,78.9,78.3,70.6,61.2,55.8,55.4,53.8,52.2,48.7,44.4,44.4,29.1,27.1,23.9,21.7,18.9.

[0304] Example 30 Preparation of compound 30 (6-O-(N-(3-fluorophenyl)carbamoyl)rhodotoxin VI)

[0305]

[0306] Compound 30 (4.2 mg, yield 7.8%) was obtained in the same manner as in Example 16.

[0307] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2466.

[0308] 1 H NMR(600MHz,pyridine-d5)δ:11.07(s,1H),8.04(d,J=12.0Hz,1H),7.58(overlap,1H),7.30(q,J=7.8Hz,1H),7.09(d,J=3.6Hz,1H),6.86–6.7 9(overlap,2H),6.73(s,1H),6.20(s,1H),5.91(dd,J=10.2,4.2Hz,1H),5.36(s,1H),5.15–5.11(overlap,2H),4.30(s,1H),4.02(s,1H),3.11( d,J=6.0Hz,1H),2.96(dd,J=13.8,4.2Hz,1H),2.62–2.52(overlap,2H),2.50(s,1H),2.29(d,J=14.4Hz,1H),2.17(d,J=7.2Hz,1H),2.14(d,J= 14.4Hz, 1H), 2.03 (dd, J=14.4, 6.0Hz, 1H), 1.88 (s, 3H), 1.70 (dt, J=12. 6,5.4Hz,1H),1.58–1.51(m,1H),1.50(s,3H),1.48(s,3H),1.47(s,3H). 13C NMR(150MHz,pyridine-d5)δ:163.7,154.1,142.6,130.5,114.5,109.1,106.1,86.7,83.8,80.5,7 9.8,79.1,78.0,77.4,60.5,60.3,56.2,54.7,52.2,49.7,40.4,29.2,26.9,24.5,23.7,22.0,20.3.

[0309] Example 31 Preparation of compound 31 (6-O-(N-(2-fluorophenyl)carbamoyl)azotoxin VI)

[0310]

[0311] Compound 31 (5.8 mg, yield 10.7%) was obtained in the same manner as in Example 17.

[0312] Molecular formula C 27 H 38 O8NF,HRESI-MS m / z:[M+Na] + 546.2468

[0313] 1 H NMR(600MHz,pyridine-d5)δ:10.54(s,1H),8.45(t,J=7.8Hz,1H),7.17(ddd,J=11.4,7.8,1.2Hz,1H),7.13(t,J=7.8Hz,1H),7.07(s,1H),7.03–6. 96(m,1H),6.84(d,J=5.4Hz,1H),6.80(s,1H),6.19(s,1H),5.95(dd,J=10 .8,4.2Hz,1H),5.42(s,1H),5.19–5.10(overlap,2H),4.45(s,1H),4.01( s,1H),3.09(d,J=6.0Hz,1H),2.99(dd,J=13.2,4.2Hz,1H),2.64–2.56(overlap,2H),2.51(s,1H),2.30(d,J=14.4Hz,1H),2.19(d,J=6.6Hz,1H),2 .15(d,J=14.4Hz,1H),2.05(dd,J=14.4,6.0Hz,1H),1.89(s,3H),1.71(dt,J=13.2,5.4Hz,1H),1.62–1.55(m,1H),1.52(s,3H),1.51(overlap,6H). 13C NMR(150MHz,pyridine-d5)δ:154.3,153.8,128.2,124.7,123.9,123.1,115.5,86.6,83.7,80.3,7 9.7,79.0,78.0,78.0,60.2,60.2,56.3,54.9,52.2,49.7,40.4,29.3,27.0,24.6,23.7,22.0,20.4.

[0314] Example 32 Preparation of compound 32 (6-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotoxin VI)

[0315]

[0316] Compound 32 (4.0 mg, yield 9.0%) was obtained in the same manner as in Example 14.

[0317] Molecular formula C 28 H 38 O8NF3, HRESI-MS m / z: [M+Na] + 596.2443.

[0318] 1 H NMR (600MHz, pyridine-d5) δ: 11.25 (s, 1H), 8.06 (d, J = 8.4Hz, 2H), 7.66 (d, J = 8.4Hz, 2H), 7.13 (d, J = 4.2Hz, 1H), 6.83 (d, J = 6.6Hz, 1H), 6.7 3(s,1H),6.21(s,1H),5.94(dd,J=10.2,4.2Hz,1H),5.37(s,1H),5.17–5.11(overlap,2H),4.32(s,1H),4.05–4.01(m,1H),3.13(d,J=6.0H z,1H),2.98(dd,J=13.8,4.2Hz,1H),2.63–2.55(overlap,2H),2.51(s,1H),2.30(d,J=14.4Hz,1H),2.19(d,J=7.2Hz,1H),2.16(d,J=14.4 Hz,1H),2.04(dd,J=14.4,6.0Hz,1H),1.89(s,3H),1.70(dt,J=13.8,4.8Hz,1H),1.60–1.52(m,1H),1.50(s,3H),1.49(s,3H),1.48(s,3H). 13C NMR(150MHz,pyridine-d5)δ:154.0,144.3,126.5,126.5,125.2,118.7,118.7,86.7,83.8,80.5,7 9.8,79.1,78.0,77.6,60.6,60.3,56.2,54.7,52.2,49.8,40.4,29.2,26.9,24.5,23.7,22.0,20.3.

[0319] Example 33 Preparation of compound 33 (6-O-(N-(4-bromophenyl)carbamoyl)rhodotorhinol VI)

[0320]

[0321] Compound 33 (18.0 mg, yield 23.8%) was obtained in the same manner as in Example 15.

[0322] Molecular formula C 27 H 38 O8NBr, HRESI-MS m / z: [M+Na] + 606.1674.

[0323] 1 H NMR (500MHz, pyridine-d5) δ: 11.03 (s, 1H), 7.87 (d, J = 9.0Hz, 2H), 7.53 (d, J = 9.0Hz, 2H), 7.15 (d, J = 4.0Hz, 1H), 6.87 (d, J = 6.5Hz, 1H), 6.80 (d, J=3.5Hz,1H),6.21(s,1H),5.91(dd,J=10.5,4.0Hz,1H),5.42(s,1H),5.17–5.11(overlap,2H),4.34(s,1H),4.01(dd,J=4.0,3.0Hz,1H),3.12( d,J=6.0Hz,1H),2.97(dd,J=13.5,4.0Hz,1H),2.64–2.53(overlap,2H),2.51(s,1H),2.29(d,J=14.5Hz,1H),2.17(d,J=7.0Hz,1H),2.14(d,J= 14.5Hz, 1H), 2.03 (dd, J=14.5, 6.0Hz, 1H), 1.88 (s, 3H), 1.70 (dt, J=13. 0,5.0Hz,1H),1.59–1.51(m,1H),1.49(s,3H),1.48(s,3H),1.46(s,3H). 13C NMR(125MHz,pyridine-d5)δ:154.1,140.0,132.1,132.1,120.8,120.8,114.8,86.7,83.8,80.5,7 9.7,79.1,77.9,77.4,60.5,60.2,56.2,54.7,52.2,49.7,40.4,29.2,26.9,24.5,23.7,22.0,20.4.

[0324] Example 34 Preparation of compound 34 (6-O-(N-(4-fluorobenzyl)carbamoyl)rhodotoxin VI)

[0325]

[0326] Compound 34 (5.2 mg, yield 9.4%) was obtained in the same manner as in Example 18.

[0327] Molecular formula C 28 H 40 O8NF,HRESI-MS m / z:[M+Na] + 560.2622.

[0328] 1 H NMR(600MHz,pyridine-d5)δ:8.58(t,J=6.0Hz,1H),7.44(dd,J=7.8,6.0Hz,2H),7.06(t,J=7.8Hz,2H),6.96–6.84(overlap,2H),6.73(d, J=4.8Hz,1H),6.12(s,1H),5.77(dd,J=10.8,3.6Hz,1H),5.42(s,1H),5.16–5.11(overlap,2H),4.72(s,1H),4.65–4.52(m,2H),4.01(s,1 H),3.04(d,J=6.6Hz,1H),2.95(dd,J=13.8,3.6Hz,1H),2.63–2.56(overlap,2H),2.50(s,1H),2.28(d,J=14.4Hz,1H),2.17(d,J=7.2Hz,1 H),2.14(d,J=14.4Hz,1H),2.06(dd,J=14.4,6.0Hz,1H),1.88(s,3H),1.70(dt,J=13.2,4.8Hz,1H),1.61–1.53(overlap,4H),1.49(s,6H). 13C NMR(150MHz,pyridine-d5)δ:162.2,157.3,136.6,129.6,129.6,115.5,115.5,86.6,83.5,80.4,79.7 ,79.2,78.0,77.6,60.4,59.8,56.1,55.0,52.2,49.6,44.4,40.5,29.4,26.9,24.9,23.7,21.9,20.4.

[0329] Example 35 Preparation of compound 35 (6-O-(N-(4-benzoylphenyl)carbamoyl)rhodotoxin VI)

[0330]

[0331] Compound 35 (1.8 mg, yield 2.9%) was obtained in the same manner as in Example 20.

[0332] Molecular formula C 34 H 43 O9N, HRESI-MS m / z: [M+Na] + 632.2830.

[0333] 1 H NMR(500MHz,pyridine-d5)δ:11.34(s,1H),8.10(d,J=9.0Hz,2H),7.99(d,J=9.0Hz,2H),7.90(dd,J=8.5,1.5Hz,2H),7.56–7.52(m,1H),7.49–7.45(m, 2H),7.15(s,1H),6.87(d,J=7.0Hz,1H),6.75(s,1H),6.23(s,1H),5.96(dd ,J=11.0,4.0Hz,1H),5.39(s,1H),5.17–5.13(overlap,2H),4.35(s,1H),4. 04(s,1H),3.14(d,J=6.0Hz,1H),2.99(dd,J=13.5,4.0Hz,1H),2.64–2.55( overlap,2H),2.51(s,1H),2.31(d,J=15.0Hz,1H),2.20(d,J=7.0Hz,1H),2. 16(d,J=15.0Hz,1H),2.04(dd,J=14.0,6.0Hz,1H),1.90(s,3H),1.70(dt,J= 13.0,4.0Hz,1H),1.60–1.53(m,1H),1.53–1.50(overlap,6H),1.50(s,3H).13 C NMR(125MHz,pyridine-d5)δ:195.2,154.0,145.0,138.8,132.2,132.0,132.0,131.6,130.0,130.0,128.6,128.6,118.1,1 18.1,86.7,83.8,80.5,79.8,79.1,78.0,77.6,60.6,60.3,56.2,54.7,52.2,49.8,40.4,29.2,26.9,24.5,23.7,22.0,20.4.

[0334] Example 36 Preparation of compound 36 (2-O-(N-phenylcarbamoylmethyl)rhodotorhinol VI)

[0335]

[0336] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 13.27 mg (0.062 mmol) of 2-bromo-N-phenylacetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 2 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 36 (14.6 mg, yield 54.3%).

[0337] Molecular formula C 28 H 41 NO8, HRESI-MS m / z: [M+Na] + 542.2717.

[0338] 1H-NMR(600MHz,pyridine-d5)δ:10.29(s,1H),7.92(d,J=7.8Hz,2H),7.23(t,J=7.8Hz,2H),7.00(t,J=7.2Hz,1H),6.79(s,1H),6.34–6.26(m,1 H),6.08(s,1H),5.15(s,1H),5.04(s,1H),4.80(s,1H),4.78(d,J=4.2H z,1H),4.69(dd,J=10.8,4.2Hz,1H),4.52(d,J=16.2Hz,1H),4.44(d,J=1 6.2Hz,1H),3.96(s,1H),3.23(d,J=4.2Hz,1H),2.94(dd,J=13.2,4.2Hz,1H),2.73–2.65(m,1H),2.59–2.50(overlap,2H),2.33(d,J=15.0Hz,1 H),2.23–2.15(overlap,2H),2.08(dd,J=14.4,6.0Hz,1H),1.90(s,3H),1.85–1.78(m,1H),1.74–1.66(overlap,4H),1.56(s,3H),1.46(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.7,139.0,128.9,128.9,123.9,120.2,120.2,92.2,85.3,83.4,79. 7,79.3,78.5,73.5,69.8,60.7,60.5,56.5,54.7,52.3,50.7,44.4,29.1,26.9,23.9,22.8,22.2,20.3.

[0339] Example 37 Preparation of compound 37 (2-O-(N-(4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0340]

[0341] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 14.39 mg (0.062 mmol) of 2-bromo-N-(4-fluorophenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 37 (13.0 mg, yield 46.7%).

[0342] Molecular formula C 28 H 40 FNO8, HRESI-MS m / z: [M+Na] + 560.2619.

[0343] 1 H-NMR(600MHz,pyridine-d5)δ:10.30(s,1H),7.85–7.80(dd,J=8.4,4.8Hz,2H),6.99(t,J=8.4Hz,2H),6.74(d,J=7.2Hz,1H),6.35(s,1H),6.27(s,1H), 6.12(s,1H),5.78(s,1H),5.12(d,J=7.2Hz,1H),4.82(s,1H),4.78(d,J=3.6 Hz,1H),4.70(dd,J=10.8,3.6Hz,1H),4.52(d,J=16.2Hz,1H),4.45(d,J=16. 2Hz,1H),3.97(d,J=4.8Hz,1H),3.22(d,J=3.6Hz,1H),2.94(dd,J=13.2,3.6 Hz,1H),2.70–2.62(m,1H),2.60–2.49(overlap,2H),2.33(d,J=15.0Hz,1H) ,2.22–2.15(overlap,2H),2.08(dd,J=14.4,6.0Hz,1H),1.90(s,3H),1.83(dt,J=13.2,4.8Hz,1H),1.73-1.67(overlap,4H),1.57(s,3H),1.47(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:169.6,159.1,135.2,121.8,121.8,115.3,115.3,92.2,85.3,83.4,79. 7,79.3,78.7,73.6,69.7,60.6,60.4,56.5,54.7,52.4,50.7,44.4,29.1,27.0,23.9,22.8,22.2,20.4.

[0344] Example 38 Preparation of compound 38 (2-O-(N-(4-fluorobenzyl)carbamoylmethyl)rhodotorhinol VI)

[0345]

[0346] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-fluorobenzyl)acetamide (15.26 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 12 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 38 (8.8 mg, yield 30.8%).

[0347] Molecular formula C 29 H 42 FNO8, HRESI-MS m / z: [M+Na] + 574.2778.

[0348] 1H-NMR(600MHz,pyridine-d5)δ:9.12(t,J=6.0Hz,1H),7.27–7.22(m,2H),7.00(t,J=8.4Hz,2H),6.67(d,J=7.2Hz,1H),6.30(s,1H),6.26(d,J=3.6H z,1H),5.75(s,1H),5.66(s,1H),5.03(overlap,1H),4.79(s,1H),4.77(d,J=3.6Hz,1H),4.67–4.62(overlap,2H),4.53(d,J=16.2Hz,1H),4.45(d,J =16.2Hz,1H),4.18(dd,J=15.0,4.2Hz,1H),3.97(d,J=6.0Hz,1H),3.18(d,J=3.6Hz,1H),2.90(dd,J=13.8,3.6Hz,1H),2.54–2.42(overlap,3H),2.2 9(d,J=14.4Hz,1H),2.18–2.11(overlap,2H),1.95(dd,J=14.4,6.0Hz,1H),1.86(s,3H),1.68(overlap,4H),1.61(m,1H),1.51(s,3H),1.42(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:171.1,162.1,135.7,129.6,129.6,115.3,115.3,91.3,85.3,83.3,79.7, 79.2,78.5,73.4,69.2,60.6,60.3,56.3,54.6,52.3,50.6,44.3,41.9,29.2,26.8,23.8,22.8,22.1,20.3.

[0349] Example 39 Preparation of compound 39 (2-O-(N-(4-fluorophenylethyl)carbamoylmethyl)azotoxin VI)

[0350]

[0351] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 16.13 mg (0.062 mmol) of 2-bromo-N-(4-fluorophenylethyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 39 (6.0 mg, yield 20.5%).

[0352] Molecular formula C 30 H 44 FNO8, HRESI-MS m / z: [M+Na] + 588.2934

[0353] 1 H-NMR(600MHz,pyridine-d5)δ:8.63(t,J=4.8Hz,1H),7.09–7.06(m,2H),7.06–6.99(t,J=8.4Hz 2H),5.76(s,1H),5.08(overlap,1H),4.79(s,1H),4.74(d,J=4.2Hz,1H),4.66(dd,J=10.8,3.6Hz,1H),4.45(d,J=16.2Hz,1H ),4.40(d,J=16.2Hz,1H),3.94(s,1H),3.68-3.61(m,1H),3.31-3.24(m,1H),3.19(d,J=4.2Hz,1H),2.91(dd,J=13.8,3.6Hz,1 H),2.78–2.68(m,2H),2.60(m,1H),2.56–2.49(overlap,2H),2.31(d,J=14.4Hz,1H),2.19(d,J=6.6Hz,1H),2.16(d,J=14.4Hz ,1H),2.04(dd,J=14.4,6.0Hz,1H),1.89(s,3H),1.78–1.71(m,1H),1.68(s,3H),1.66-1.61(m,1H),1.53(s,3H),1.40(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:171.1,161.8,135.7,130.6,130.6,115.4,115.4,91.1,85.3,83.3,79.8,79. 3,78.4,73.4,69.0,60.6,60.4,56.3,54.6,52.4,50.6,44.4,40.5,35.1,29.3,27.0,23.9,22.8,22.1,20.3.

[0354] Example 40 Preparation of compound 40 (2-O-(N-(3-fluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0355]

[0356] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 14.39 mg (0.062 mmol) of 2-bromo-N-(3-fluorophenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 2 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 40 (7.7 mg, yield 27.7%).

[0357] Molecular formula C 28 H 40 FNO8, HRESI-MS m / z: [M+Na] + 560.2618.

[0358] 1H-NMR(600MHz,pyridine-d5)δ:10.37(s,1H),7.89(dt,J=11.4,1.8Hz,1H),7.57–7 .55(overlap,1H),7.18–7.11(m,1H),6.78–6.72(overlap,2H),6.33(s,1H),6.27(d ,J=6.6Hz,1H),6.18(s,1H),5.79(s,1H),5.13(d,J=6.6Hz,1H),4.83(s,1H),4.77(d ,J=3.6Hz,1H),4.73-4.67(m,1H),4.51(d,J=16.2Hz,1H),4.43(d,J=16.2Hz,1H),3. 96(d,J=6.6Hz,1H),3.21(d,J=3.6Hz,1H),2.94(dd,J=13.2,4.2Hz,1H),2.73-2.66 (m,1H),2.59(s,1H),2.54(dd,J=13.2,11.4Hz,1H),2.33(d,J=14.4Hz,1H),2.20(d, J=7.2Hz,1H),2.18(d,J=14.4Hz,1H),2.08(dd,J=14.4,6.0Hz,1H),1.90(s,3H),1.8 9-1.83(dt,J=13.8,4.8Hz,1H),1.75-1.67(overlap,4H),1.57(s,3H),1.47(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.9,163.0,140.6,130.2,115.7,110.3,107.2,92.4,85.3,83.5,79. 7,79.3,78.7,73.6,69.8,60.6,60.4,56.5,54.8,52.3,50.7,44.4,29.0,26.9,23.9,22.8,22.2,20.4.

[0359] Example 41 Preparation of compound 41 (2-O-(N-(2-fluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0360]

[0361] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 14.39 mg (0.062 mmol) of 2-bromo-N-(2-fluorophenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 2 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 41 (8.1 mg, yield 29.1%).

[0362] Molecular formula C 28 H 40 FNO8, HRESI-MS m / z: [M+Na] + 560.2621.

[0363] 1 H-NMR(600MHz,pyridine-d5)δ:10.10(s,1H),8.34(t,J=7.2Hz,1H),7.03–6.96(m,2H),6.95–6.90(m,1H),6.83(d,J=6.6Hz,1H),6.29(overlap ,2H),5.91(s,1H),5.72(s,1H),5.18(d,J=6.6Hz,1H),4.80(s,1H),4.78 (d,J=3.6Hz,1H),4.70(dd,J=10.2,4.2Hz,1H),4.55(s,2H),3.99(d,J=6 .0Hz,1H),3.24(d,J=3.6Hz,1H),2.94(dd,J=13.2,3.6Hz,1H),2.73–2.66(m,1H),2.57(s,1H),2.53(dd,J=13.2,11.4Hz,1H),2.32(d,J=14.4Hz, 1H),2.20–2.13(overlap,2H),2.01(dd,J=14.4,6.0Hz,1H),1.90(s,3H),1.75–1.70(overlap,4H),1.68–1.63(m,1H),1.54(s,3H),1.46(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:169.9,153.8,153.0,126.6,125.1,124.4,123.7,115.4,92.0,85.3,83.7, 79.7,79.2,78.0,73.7,69.6,60.7,60.4,56.6,54.8,52.4,50.7,44.5,29.1,26.7,23.8,22.8,22.2,20.4.

[0364] Example 42 Preparation of compound 42 (2-O-(N-(3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI)

[0365]

[0366] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(3-(trifluoromethyl)phenyl)acetamide (17.49 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 42 (6.7 mg, yield 22.0%).

[0367] Molecular formula C 29 H 40 F3NO8, HRESI-MS m / z: [M+Na] + 610.2582.

[0368] 1H-NMR (600MHz, pyridine-d5) δ: 10.41 (s, 1H), 8.13 (d, J = 8.4Hz, 1H), 8.09 (s, 1H) ,7.27(t,J=8.4Hz,1H),7.22(overlap,1H),6.76(d,J=7.2Hz,1H),6.35(s,1H),6 .29(s,1H),6.27(d,J=6.0Hz,1H),5.81(s,1H),5.12(d,J=7.2Hz,1H),4.86(s,1H ),4.77(d,J=3.6Hz,1H),4.75–4.68(m,1H),4.54(d,J=16.2Hz,1H),4.46(d,J=16. 2Hz,1H),3.98(d,J=6.0Hz,1H),3.22(d,J=3.6Hz,1H),2.95(dd,J=13.2,4.2Hz,1 H),2.73–2.66(m,1H),2.63(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.34(d,J=14.4 Hz,1H),2.21(d,J=7.2Hz,1H),2.18(d,J=14.4Hz,1H),2.07(dd,J=14.4,6.0Hz,1 H),1.93–1.88(overlap,4H),1.77–1.68(overlap,4H),1.59(s,3H),1.51(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.1,139.5,130.4,129.7,125.6,123.3,120.1,116.6,92.7,85.3,83.5, 79.7,79.3,78.9,73.6,70.0,60.6,60.4,56.5,54.8,52.3,50.8,44.4,28.9,26.9,23.9,22.8,22.2,20.4.

[0369] Example 43 Preparation of compound 43 (2-O-(N-(4-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI)

[0370]

[0371] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (17.49 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 43 (11.6 mg, yield 38.2%).

[0372] Molecular formula C 29 H 40 F3NO8, HRESI-MS m / z: [M+Na] + 610.2588.

[0373] 1 H-NMR(600MHz,pyridine-d5)δ:10.43(s,1H),7.94(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),6.73(s,1H),6.37(s,1H),6.25(s,1H),6.20(s,1H), 5.13(s,1H),4.86(s,1H),4.78(d,J=3.6Hz,1H),4.71(dd,J=10.8,4.2H z,1H),4.53(d,J=16.2Hz,1H),4.46(d,J=16.2Hz,1H),3.98(s,1H),3.22 (d,J=3.6Hz,1H),2.95(dd,J=13.2,4.2Hz,1H),2.71–2.63(m,1H),2.62(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.34(d,J=15.0Hz,1H),2.21(d,J =7.2Hz,1H),2.18(d,J=15.0Hz,1H),2.09(dd,J=14.4,6.0Hz,1H),1.93–1.85(overlap,4H),1.76–1.68(overlap,4H),1.59(s,3H),1.49(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:170.2,142.1,126.0,126.0,124.9,124.7,119.9,119.9,92.4,85.3,83.4, 79.7,79.3,78.9,73.6,69.8,60.6,60.3,56.5,54.8,52.4,50.8,44.4,29.0,27.0,23.9,22.8,22.1,20.4.

[0374] Example 44 Preparation of compound 44 (2-O-(N-(4-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI)

[0375]

[0376] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-(methanesulfonyl)phenyl)acetamide (18.11 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 44 (7.3 mg, yield 23.6%).

[0377] Molecular formula C 29 H 43 NO 10 S,HRESI-MS m / z:[M+Na] + 620.2494.

[0378] 1H-NMR (600MHz, pyridine-d5) δ: 10.52 (s, 1H), 7.99 (d, J = 8.4Hz, 2H), 7.94 (d ,J=8.4Hz,2H),6.69(d,J=6.6Hz,1H),6.39(s,1H),6.26(s,1H),6.24(s,1H), 5.11(d,J=6.6Hz,1H),4.88(s,1H),4.78(d,J=3.6Hz,1H),4.71(dd,J=10.8, 4.2Hz,1H),4.54(d,J=16.2Hz,1H),4.48(d,J=16.2Hz,1H),3.98(s,1H),3.22 (d,J=3.6Hz,1H),3.19(s,3H),2.95(dd,J=13.2,4.2Hz,1H),2.67–2.62(m,1 H),2.60(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.33(d,J=15.0Hz,1H),2.20( d,J=6.6Hz,1H),2.17(d,J=15.0Hz,1H),2.07(dd,J=14.4,5.4Hz,1H),1.90(s ,3H),1.86–1.81(m,1H),1.75–1.67(overlap,4H),1.59(s,3H),1.49(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.4,143.3,135.7,128.5,128.5,120.0,120.0,92.5,85.3,83.4,79.7, 79.3,78.9,73.6,69.8,60.5,60.3,56.4,54.8,52.4,50.8,44.4,44.4,28.9,27.0,23.9,22.8,22.1,20.4.

[0379] Example 45 Preparation of compound 45 (2-O-(N-(3-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI)

[0380]

[0381] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(3-(methanesulfonyl)phenyl)acetamide (22.79 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 45 (11.5 mg, yield 29.8%).

[0382] Molecular formula C 29 H 43 NO 10 S,HRESI-MS m / z:[M+Na] + 620.2487.

[0383] 1H-NMR (600MHz, pyridine-d5) δ: 10.50 (s, 1H), 8.57 (s, 1H), 8.09 (d, J = 7.8Hz, 1H), 7. 67(d,J=7.8Hz,1H),7.32(t,J=7.8Hz,1H),6.70(d,J=7.2Hz,1H),6.37(s,1H),6.30(d ,J=6.0Hz,1H),6.25(s,1H),5.81(s,1H),5.13(d,J=7.2Hz,1H),4.86(s,1H),4.79(d, J=3.6Hz,1H),4.74–4.69(m,1H),4.54(d,J=16.2Hz,1H),4.48(d,J=16.2Hz,1H),3.99 (d,J=6.0Hz,1H),3.23(d,J=3.6Hz,1H),3.15(s,3H),2.95(dd,J=13.2,3.6Hz,1H),2 .79–2.72(m,1H),2.68(s,1H),2.55(dd,J=13.2,11.4Hz,1H),2.33(d,J=14.4Hz,1H), 2.21(d,J=6.6Hz,1H),2.18(d,J=14.4Hz,1H),2.10(dd,J=14.4,6.0Hz,1H),1.94(dt, J=13.2,5.4Hz,1H),1.89(s,3H),1.77–1.67(overlap,4H),1.58(s,3H),1.51(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.2,141.9,139.7,129.9,124.7,122.3,118.6,92.5,85.3,83.5,79.7, 79.4,79.0,73.6,69.8,60.6,60.4,56.4,54.8,52.4,50.8,44.4,44.1,28.9,27.1,23.9,22.8,22.2,20.4.

[0384] Example 46 Preparation of compound 46 (2-O-(N-(4-nitrophenyl)carbamoylmethyl)rhodotorhinol VI)

[0385]

[0386] 1.40 mg (0.058 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 15.00 mg (0.039 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 12.18 mg (0.047 mmol) of 2-bromo-N-(4-nitrophenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After reacting for 1 h, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 46 (3.1 mg, yield 13.6%).

[0387] Molecular formula C 28 H 40 N2O 10 HRESI-MS m / z: [M+Na] + 587.2564.

[0388] 1 H-NMR (600MHz, pyridine-d5) δ: 10.57 (s, 1H), 8.10 (d, J = 9.0Hz, 2H), 7.93 (d, J=9.0Hz,2H),6.67(d,J=7.2Hz,1H),6.40(s,1H),6.25(d,J=4.8Hz,1H),6.18( s,1H),5.83(s,1H),5.11(d,J=7.2Hz,1H),4.89(s,1H),4.77(d,J=3.6Hz,1H) ,4.71(dd,J=10.8,3.6Hz,1H),4.55(d,J=16.2Hz,1H),4.48(d,J=16.2Hz,1H), 3.98(d,J=4.8Hz,1H),3.21(d,J=3.6Hz,1H),2.95(dd,J=13.2,3.6Hz,1H),2. 68–2.60(overlap,2H),2.54(dd,J=13.2,10.8Hz,1H),2.34(d,J=14.4Hz,1H), 2.21(d,J=7.2Hz,1H),2.18(d,J=14.4,Hz,1H),2.09(dd,J=14.4,6.0Hz,1H), 1.92–1.86(overlap,4H),1.76–1.70(overlap,4H),1.60(s,3H),1.50(s,3H).13 C-NMR(150MHz,pyridine-d5)δ:170.6,144.6,143.3,124.8,124.8,119.6,119.6,92.4,85.3,83.4,79. 7,79.3,78.9,73.6,69.8,60.5,60.3,56.4,54.7,52.4,50.8,44.4,28.9,27.0,24.0,22.8,22.1,20.4.

[0389] Example 47 Preparation of compound 47 (2-O-(N-(4-methoxyphenyl)carbamoylmethyl)rhodotorhinol VI)

[0390]

[0391] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-methoxyphenyl)acetamide (15.13 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 1 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 47 (10.6 mg, yield 37.3%).

[0392] Molecular formula C 29 H 43 NO9, HRESI-MS m / z: [M+Na] + 572.2821.

[0393] 1H-NMR(600MHz,pyridine-d5)δ:10.23(s,1H),7.83(d,J=9.0Hz,2H),6.86(d,J=9.0Hz,2H),6.77(s,1H),6.29(s,1H),6.09(s,1H),5.15(s ,1H),4.81–4.78(overlap,2H),4.70(dd,J=10.8,4.2Hz,1H),4.52(d,J=16.2Hz,1H),4.45(d,J=16.2Hz,1H),3.97(s,1H),3.61(s,3H),3. 24(d,J=3.6Hz,1H),2.94(dd,J=13.8,4.2Hz,1H),2.73–2.65(m,1H),2.60–2.49(overlap,2H),2.33(d,J=15.0Hz,1H),2.22–2.16(overla p,2H),2.10(dd,J=14.4,6.0Hz,1H),1.91(s,3H),1.85–1.78(dt,J=13.2,5.4Hz,1H),1.74–1.65(overlap,4H),1.56(s,3H),1.46(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.2,156.3,132.3,121.7,121.7,114.2,114.2,92.1,85.3,83.4,79.7, 79.3,78.6,73.5,69.7,60.6,60.5,56.5,55.2,54.8,52.4,50.7,44.4,29.1,27.0,23.9,22.8,22.2,20.4.

[0394] Example 48 Preparation of compound 48 (2-O-(N-(4-methylphenyl)carbamoylmethyl)rhodotoxin VI)

[0395]

[0396] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 14.14 mg (0.062 mmol) of 2-bromo-N-(4-methylphenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 2 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 48 (5.2 mg, yield 18.8%).

[0397] Molecular formula C 29 H 43 NO8, HRESI-MS m / z: [M+Na] + 556.2877.

[0398] 1 H-NMR (600MHz, pyridine-d5) δ: 10.23 (s, 1H), 7.81 (d, J = 8.4Hz, 2H), 7.00 (d, J=8.4Hz,2H),6.80(d,J=6.6Hz,1H),6.32(s,1H),6.27(d,J=6.0Hz,1H),6.07( s,1H),5.76(s,1H),5.16(d,J=6.6Hz,1H),4.79(s,1H),4.78(d,J=3.6Hz,1H), 4.69(dd,J=10.8,4.2Hz,1H),4.51(d,J=16.2Hz,1H),4.43(d,J=16.2Hz,1H),3 .96(d,J=6.0Hz,1H),3.23(d,J=3.6Hz,1H),2.95(dd,J=13.2,4.2Hz,1H),2.75 –2.67(m,1H),2.59(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.34(d,J=15.0Hz,1 H),2.23–2.16(overlap,2H),2.12(s,3H),2.10(dd,J=14.4,6.0Hz,1H),1.90( s,3H),1.87–1.81(m,1H),1.74-1.66(overlap,4H),1.57(s,3H),1.46(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:169.4,136.5,133.1,129.4,129.4,120.2,120.2,92.2,85.3,83.4,79.7, 79.3,78.5,73.5,69.8,60.7,60.5,56.5,54.8,52.3,50.7,44.4,29.1,26.9,23.9,22.8,22.2,20.6,20.4.

[0399] Example 49 Preparation of compound 49 (2-O-(N-(4-acetylphenyl)carbamoylmethyl)rhodotorhinol VI)

[0400]

[0401] 3.88 mg (0.097 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 25.00 mg (0.065 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 19.97 mg (0.078 mmol) of 2-bromo-N-(4-acetylphenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 8 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 49 (12.9 mg, yield 35.5%).

[0402] Molecular formula C 30 H 43 NO9, HRESI-MS m / z: [M+Na] + 584.2823.

[0403] 1H-NMR(400MHz,pyridine-d5)δ:10.45(s,1H),7.99–7.93(m,4H),6.72(d,J=6.8Hz,1H),6.35(s,1H),6.25(d,J=6.0Hz,1H),6.13(s,1H),5.77(s,1H) ,5.13(d,J=6.8Hz,1H),4.83(s,1H),4.78(d,J=3.6Hz,1H),4.70(dd,J=10 .8,3.6Hz,1H),4.54(d,J=16.4Hz,1H),4.46(d,J=16.4Hz,1H),3.98(d,J=6 .0Hz,1H),3.22(d,J=3.6Hz,1H),2.94(dd,J=13.2,3.6Hz,1H),2.74–2.63 (m,1H),2.60(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.48(s,3H),2.34(d,J =14.4Hz,1H),2.24–2.14(overlap,2H),2.09(dd,J=13.6,5.6Hz,1H),1.93–1.82(overlap,4H),1.78–1.66(overlap,4H),1.59(s,3H),1.48(s,3H). 13 C-NMR(100MHz,pyridine-d5)δ:196.4,170.2,143.0,132.8,129.6,129.6,119.4,119.4,92.4,85.3,83.5,79 .7,79.3,78.8,73.5,69.9,60.6,60.4,56.4,54.8,52.4,50.7,44.4,29.0,27.0,26.3,23.9,22.8,22.1,20.4.

[0404] Example 50 Preparation of compound 50 (2-O-(N-(4-(dimethylamino)phenyl)carbamoylmethyl)rhodotorhinol VI)

[0405]

[0406] Steps: Preparation of 2-O-(N-(4-(dimethylamino)phenyl)carbamoylmethyl)rhodotorhinol VI

[0407] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-(dimethylamino)phenyl)acetamide (15.94 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 2 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 50 (5.4 mg, yield 18.5%).

[0408] Molecular formula C 30 H 46 N₂O₈, HRESI-MS m / z: [M+Na] + 585.3141.

[0409] 1 H-NMR(600MHz,pyridine-d5)δ:10.16(s,1H),7.80(d,J=9.0Hz,2H),6.80(d,J=7.2Hz,1H),6.66(d,J=9.0Hz,2H),6.31(overlap,2H),6.05(s,1H),5.75(s ,1H),5.17(d,J=7.2Hz,1H),4.81(d,J=3.6Hz,1H),4.77(s,1H),4.70(dd,J=1 0.8,4.2Hz,1H),4.52(d,J=16.2Hz,1H),4.45(d,J=16.2Hz,1H),3.97(d,J=6. 0Hz,1H),3.25(d,J=3.6Hz,1H),2.95(dd,J=13.8,4.2Hz,1H),2.70(overlap,7H),2.58–2.51(overlap,2H),2.33(d,J=14.4Hz,1H),2.21(d,J=7.2Hz,1H), 2.18(d,J=14.4Hz,1H),2.11(dd,J=14.4,6.0Hz,1H),1.91(s,3H),1.84–1.77 (dt,J=13.2,5.4Hz,1H),1.73–1.64(overlap,4H),1.55(s,3H),1.46(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:168.9,147.9,129.1,121.7,121.7,113.1,113.1,92.0,85.3,83.4,79.7,79. 3,78.5,73.5,69.7,60.7,60.5,56.5,54.8,52.4,50.7,44.4,40.6,40.6,29.2,27.0,23.8,22.8,22.2,20.4.

[0410] Example 51 Preparation of compound 51 (2-O-(N-(thiazolyl)carbamoylmethyl)rhodotorhinol VI)

[0411]

[0412] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 13.71 mg (0.062 mmol) of 2-bromo-N-(thiazolyl-2-yl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After reacting for 4 h, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 51 (5.9 mg, yield 21.7%).

[0413] Molecular formula C 25 H 38 N₂O₈S, HRESI-MS m / z: [M+H] + 527.2431.

[0414] 1H-NMR(600MHz,pyridine-d5)δ:12.81(s,1H),7.55(d,J=3.6Hz,1H),7.07(d,J=3.6Hz,1H),6.72(s,1H),6.35(s,1H),6.30(s,1H),5.52(s ,1H),5.13(s,1H),4.81–4.79(overlap,2H),4.76(d,J=16.2Hz,1H),4.68(dd,J=10.2,3.6Hz,1H),4.59(d,J=16.2Hz,1H),4.02(s,1H),3. 24(d,J=4.2Hz,1H),2.92(dd,J=13.8,3.6Hz,1H),2.77–2.70(m,1H),2.56–2.50(overlap,2H),2.32(d,J=15.0Hz,1H),2.21–2.14(overla p,2H),2.01(dd,J=14.4,6.0Hz,1H),1.88(s,3H),1.76–1.71(dt,J=13.8,5.4Hz,1H),1.70–1.63(overlap,4H),1.53(s,3H),1.43(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.1,158.5,138.2,113.7,91.7,85.2,83.7,79.8,79.3,78 .5,73.3,68.9,60.7,60.1,56.4,54.5,52.3,50.6,44.4,29.2,26.8,23.8,22.9,22.2,20.2.

[0415] Example 52 Preparation of compound 52 (2-O-(N-(3,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0416]

[0417] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(3,4-difluorophenyl)acetamide (15.50 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 1 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 52 (11.8 mg, yield 41.0%).

[0418] C 28 H 39 F2NO8, HRESI-MS m / z: [M+Na] + 578.2530.

[0419] 1 H-NMR(600MHz,pyridine-d5)δ:10.34(s,1H),7.93(ddd,J=13.2,7.8,2.4Hz,1H),7.44(d,J=9.0Hz,1H),7.06(q,J=9.6Hz,1H),6.71(s,1H),6.28(s,1H ),6.21(s,1H),5.11(s,1H),4.85(s,1H),4.76(d,J=3.6Hz,1H),4.70(dd,J =10.8,4.2Hz,1H),4.51(d,J=16.2Hz,1H),4.44(d,J=16.2Hz,1H),3.97(s,1 H),3.21(d,J=3.6Hz,1H),2.94(dd,J=13.8,4.2Hz,1H),2.69–2.62(m,1H), 2.59(s,1H),2.54(dd,J=13.8,10.8Hz,1H),2.33(d,J=15.0Hz,1H),2.20(d, J=7.2Hz,1H),2.17(d,J=15.0Hz,1H),2.08(dd,J=15.0,6.0Hz,1H),1.89(s, 3H),1.88–1.84(m,1H),1.74–1.68(overlap,4H),1.57(s,3H),1.49(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:169.8,149.8,146.4,135.7,117.1,116.1,109.4,92.3,85.3,83.4,79. 7,79.3,78.9,73.6,69.7,60.6,60.4,56.4,54.8,52.4,50.8,44.4,29.0,27.0,23.9,22.8,22.1,20.4.

[0420] Example 53 Preparation of compound 53 (2-O-(N-(2,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0421]

[0422] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(2,4-difluorophenyl)acetamide (19.50 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 53 (8.6 mg, yield 23.9%).

[0423] Molecular formula C 28 H 39 F2NO8, HRESI-MS m / z: [M+Na] + 578.2525.

[0424] 1H-NMR (600MHz, pyridine-d5) δ: 10.14 (s, 1H), 8.16 (q, J = 8.4Hz, 1H), 6.93–6.86 (m, 1H), 6.82–6.74 (overlap, 2H), 6.32 (s, 1H), 6.29–6.25 (m, 1H) ),6.00(s,1H),5.74(s,1H),5.17(d,J=6.6Hz,1H),4.82(s,1H),4.78(d ,J=3.6Hz,1H),4.70(dd,J=10.8,4.2Hz,1H),4.54(s,2H),3.99(d,J=5.4 Hz,1H),3.24(d,J=3.6Hz,1H),2.94(dd,J=13.2,4.2Hz,1H),2.71–2.64(m,1H),2.57(s,1H),2.52(dd,J=13.2,10.8Hz,1H),2.32(d,J=14.4Hz,1 H),2.19–2.12(overlap,2H),1.99(dd,J=14.4,6.0Hz,1H),1.90(s,3H),1.77–1.70(overlap,4H),1.69–1.61(m,1H),1.54(s,3H),1.46(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.9,159.1,154.1,125.0,122.9,110.8,104.0,92.0,85.3,83.5,79. 7,79.2,78.2,73.7,69.5,60.6,60.2,56.6,54.7,52.4,50.7,44.5,29.1,26.7,23.8,22.7,22.2,20.4.

[0425] Example 54 Preparation of compound 54 (2-O-(N-(3,5-difluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0426]

[0427] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(3,5-difluorophenyl)acetamide (19.50 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 54 (16.5 mg, yield 45.8%).

[0428] Molecular formula C 28 H 39 F2NO8, HRESI-MS m / z: [M+Na] + 578.2525.

[0429] 1 H-NMR(600MHz,pyridine-d5)δ:10.42(s,1H),7.54(dd,J=9.0,1.8Hz,2H),6.64–6.57(tt,J=9.0,1.8Hz,1H),6.29(s,1H),5.11(s,1H),4. 87(s,1H),4.76(d,J=3.6Hz,1H),4.71(dd,J=10.8,4.2Hz,1H),4.51(d,J=16.2Hz,1H),4.43(d,J=16.2Hz,1H),3.96(s,1H),3.20(d,J=3.6H z,1H),2.94(dd,J=13.2,4.2Hz,1H),2.73–2.66(m,1H),2.61(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.33(d,J=14.4Hz,1H),2.21(d,J=7.2H z,1H),2.17(d,J=14.4Hz,1H),2.08(dd,J=14.6,6.0Hz,1H),1.93–1.88(overlap,4H),1.76–1.68(overlap,4H),1.57(s,3H),1.49(s,3H). 13C-NMR(150MHz,pyridine-d5)δ:170.2,163.1,141.2,103.0,98.7,92.6,85.3,83.5,79.7,79.3 ,78.9,73.6,69.9,60.6,60.4,56.4,54.8,52.3,50.8,44.4,28.9,26.9,23.9,22.8,22.1,20.4.

[0430] Example 55 Preparation of compound 55 (2-O-(N-(4-fluoro-3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI)

[0431]

[0432] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)acetamide (23.40 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 55 (13.6 mg, yield 34.6%).

[0433] Molecular formula C 29 H 39 F4NO8, HRESI-MS m / z: [M+Na] + 628.2496.

[0434] 1H-NMR(600MHz,pyridine-d5)δ:10.41(s,1H),8.14–8.08(m,1H),7.95(d,J=6.0Hz,1H),7.09(t,J=9.6Hz,1H),6.70(s,1H),6.30(s,1H),5.1 0(s,1H),4.88(s,1H),4.78(d,J=3.6Hz,1H),4.72(dd,J=10.8,3.6Hz,1H),4.54(d,J=16.2Hz,1H),4.49(d,J=16.2Hz,1H),3.99(s,1H),3.22( d,J=3.6Hz,1H),2.95(dd,J=13.8,3.6Hz,1H),2.68–2.58(overlap,2H),2.54(dd,J=13.8,10.8Hz,1H),2.34(d,J=14.4Hz,1H),2.20(d,J=7. 2Hz,1H),2.18(d,J=14.4Hz,1H),2.06(dd,J=14.4,6.0Hz,1H),1.94–1.87(overlap,4H),1.77–1.69(overlap,4H),1.59(s,3H),1.52(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.0,155.4,135.3,125.5,123.1,118.4,117.5,117.2,92.5,85.3,83.5, 79.7,79.3,79.1,73.6,69.8,60.5,60.3,56.4,54.8,52.3,50.8,44.4,28.9,26.9,23.9,22.8,22.1,20.4.

[0435] Example 56 Preparation of compound 56 (2-O-(N-(4-fluoro-3-nitrophenyl)carbamoylmethyl)rhodotorhinol VI)

[0436]

[0437] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(4-fluoro-3-nitrophenyl)acetamide (21.61 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 56 (16.7 mg, yield 44.4%).

[0438] Molecular formula C 28 H 39 FN2O 10 HRESI-MS m / z: [M+Na] + 605.2467.

[0439] 1H-NMR (600MHz, pyridine-d5) δ: 10.48 (s, 1H), 8.46 (dd, J = 6.0, 2.4Hz, 1H), 8.12 ( dt,J=9.0,3.0Hz,1H),7.15(dd,J=10.2,9.0Hz,1H),6.66(d,J=7.2Hz,1H),6.41( s,1H),6.31–6.24(overlap,2H),5.11(d,J=7.2Hz,1H),4.91(s,1H),4.77(d,J=3 .6Hz,1H),4.72(dd,J=10.8,4.2Hz,1H),4.54(d,J=16.2Hz,1H),4.48(d,J=16.2H z,1H),3.99(d,J=4.8Hz,1H),3.22(d,J=3.6Hz,1H),2.95(dd,J=13.2,4.2Hz,1H) ,2.74–2.65(overlap,2H),2.54(dd,J=13.2,10.8Hz,1H),2.33(d,J=14.4Hz,1H) ,2.21(d,J=6.6Hz,1H),2.17(d,J=14.4Hz,1H),2.08(dd,J=14.4,6.0Hz,1H),1.9 8–1.92(m,1H),1.89(s,3H),1.78–1.68(overlap,4H),1.59(s,3H),1.52(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:170.2,151.2,136.8,135.4,126.9,118.4,117.0,92.4,85.3,83.4,79. 7,79.3,79.2,73.6,69.7,60.5,60.3,56.4,54.8,52.4,50.8,44.4,28.8,27.0,23.9,22.8,22.1,20.4.

[0440] Example 57 Preparation of compound 57 (2-O-(N-(3-chloro-4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI)

[0441]

[0442] Add 3.88 mg (0.097 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 25.00 mg (0.065 mmol) of azoospermum erythrorhizon toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(3-chloro-4-fluorophenyl)acetamide (20.79 mg, 0.078 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 8 h, the mixture was cooled to room temperature, and 10 mL of water was added to the reaction solution. The mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 57 (12.3 mg, yield 33.2%).

[0443] Molecular formula C 28 H 39 ClFNO8, HRESI-MS m / z: [M+Na] + 594.2222.

[0444] 1H-NMR (600MHz, pyridine-d5) δ: 10.30 (s, 1H), 7.89 (dd, J = 6.6, 2.4Hz, 1H), 7.73 (dd d,J=9.0,4.2,2.4Hz,1H),7.02(t,J=9.0Hz,1H),6.75(d,J=7.2Hz,1H),6.37(s,1H) ,6.29(s,1H),6.26(d,J=6.0Hz,1H),5.80(s,1H),5.12(d,J=7.2Hz,1H),4.86(s,1H ),4.75(d,J=3.6Hz,1H),4.71(dd,J=10.8,4.2Hz,1H),4.51(d,J=16.8Hz,1H),4.44( d,J=16.8Hz,1H),3.97(d,J=6.0Hz,1H),3.21(d,J=3.6Hz,1H),2.95(dd,J=13.2,4. 2Hz,1H),2.72–2.65(m,1H),2.63(s,1H),2.54(dd,J=13.2,10.8Hz,1H),2.34(d,J= 14.4Hz,1H),2.20(d,J=7.2Hz,1H),2.18(d,J=14.4Hz,1H),2.07(dd,J=15.0,6.0Hz ,1H),1.95–1.88(overlap,4H),1.77–1.68(overlap,4H),1.59(s,3H),1.50(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.7,154.2,135.9,122.0,120.2,119.8,116.5,92.5,85.3,83.5,79. 7,79.3,78.9,73.7,69.9,60.6,60.4,56.5,54.8,52.3,50.8,44.4,28.9,27.0,23.9,22.8,22.2,20.4.

[0445] Example 58 Preparation of compound 58 (2-O-(N-(4-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI)

[0446]

[0447] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, N-(4-benzoylphenyl)-2-bromoacetamide (19.73 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 4 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 58 (11.0 mg, yield 34.1%).

[0448] Molecular formula C 35 H 45 NO9, HRESI-MS m / z: [M+Na] + 646.2983.

[0449] 1H-NMR(600MHz,pyridine-d5)δ:10.53(s,1H),8.00(d,J=7.8Hz,2H),7.82(d,J=7.2Hz ,2H),7.81(d,J=7.8Hz,2H),7.55(t,J=7.2Hz,1H),7.47(t,J=7.2Hz,2H),6.73(d,J=7. 2Hz,1H),6.37(s,1H),6.28(d,J=6.0Hz,1H),6.19(s,1H),5.82(s,1H),5.14(d,J=7.2 Hz,1H),4.86(s,1H),4.81(d,J=3.6Hz,1H),4.74–4.69(m,1H),4.57(d,J=16.2Hz,1H), 4.50(d,J=16.2Hz,1H),3.99(d,J=6.0Hz,1H),3.24(d,J=3.6Hz,1H),2.95(dd,J=13.2 ,3.6Hz,1H),2.72–2.64(m,1H),2.59(s,1H),2.55(dd,J=13.2,11.4Hz,1H),2.33(d,J= 14.4Hz,1H),2.21(d,J=7.2Hz,1H),2.18(d,J=14.4Hz,1H),2.09(dd,J=14.4,6.0Hz,1H ),1.91(s,3H),1.86–1.81(m,1H),1.75–1.67(overlap,4H),1.57(s,3H),1.49(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:195.1,170.3,142.8,138.5,132.7,132.4,131.4,131.4,130.0,130.0,128.7,128.7,119.4,119 .4,92.4,85.3,83.5,79.7,79.3,78.8,73.6,69.8,60.6,60.4,56.4,54.8,52.4,50.8,44.4,29.0,26.9,23.9,22.8,22.2,20.4.

[0450] Example 59 Preparation of compound 59 (2-O-(N-(3-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI)

[0451]

[0452] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, N-(3-benzoylphenyl)-2-bromoacetamide (19.72 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 6 h, the mixture was cooled to room temperature, and 10 mL of water was added to the reaction solution. The mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 59 (13.0 mg, yield 40.3%).

[0453] Molecular formula C 35 H 45 NO9, HRESI-MS m / z: [M+Na] + 646.2971.

[0454] 1H-NMR(500MHz,pyridine-d5)δ:10.45(s,1H),8.30–8.26(overlap,2H),7.86(dd,J= 8.5,1.5Hz,2H),7.56–7.52(tt,J=8.5,1.5Hz,1H),7.47–7.41(overlap,3H),7.31(t, J=9.0Hz,1H),6.71(d,J=7.0Hz,1H),6.31(s,1H),6.26(d,J=5.5Hz,1H),6.19(s,1H) ,5.09(d,J=7.0Hz,1H),4.81(s,1H),4.79(d,J=4.0Hz,1H),4.70(dd,J=10.5,4.0Hz,1 H),4.53(d,J=16.5Hz,1H),4.46(d,J=16.5Hz,1H),3.97(d,J=5.5Hz,1H),3.21(d,J= 4.0Hz,1H),2.93(dd,J=14.0,4.0Hz,1H),2.65–2.56(m,1H),2.56–2.49(overlap,2H) ,2.32(d,J=14.0Hz,1H),2.19–2.13(overlap,2H),2.02(dd,J=14.5,6.0Hz,1H),1.88 (s,3H),1.81–1.75(m,1H),1.72(s,3H),1.70–1.63(m,1H),1.55(s,3H),1.48(s,3H). 13 C-NMR(125MHz,pyridine-d5)δ:195.8,170.0,139.1,138.4,137.9,132.8,130.3,130.3,128.9,128.7,128.7,125.4,123.9,121 .4,92.3,85.3,83.4,79.7,79.3,78.8,73.6,69.8,60.6,60.3,56.4,54.8,52.3,50.7,44.4,29.0,26.9,23.9,22.8,22.1,20.4.

[0455] Example 60 Preparation of compound 60 (2-O-(N-(4-phenoxyphenyl)carbamoylmethyl)rhodotorhinol VI)

[0456]

[0457] 3.10 mg (0.078 mmol) of NaH and 0.3 mL of ultra-dry N,N-dimethylformamide were added to a 10 mL reaction flask. While stirring in an ice bath, 20.00 mg (0.052 mmol) of azolla toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was slowly added dropwise. The reaction was allowed to proceed for 30 min. Then, 18.98 mg (0.062 mmol) of 2-bromo-N-(4-phenoxyphenyl)acetamide dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was slowly raised to 60 °C. The reaction progress was monitored by thin-layer chromatography. After 6 h of reaction, the mixture was cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to give compound 60 (6.3 mg, yield 19.9%).

[0458] Molecular formula C 34 H 45 NO9, HRESI-MS m / z: [M+Na] + 634.2976.

[0459] 1H-NMR(600MHz,pyridine-d5)δ:10.34(s,1H),7.90(d,J=9.0Hz,2H),7.35(t,J=7.8H z,2H),7.10(t,J=7.8Hz,1H),7.01(d,J=7.8Hz,2H),6.97(d,J=9.0Hz,2H),6.75(d,J= 7.2Hz,1H),6.33(s,1H),6.27(d,J=5.4Hz,1H),6.17(s,1H),5.78(s,1H),5.14(d,J=7 .2Hz,1H),4.82(s,1H),4.81(d,J=3.6Hz,1H),4.70(dd,J=10.8,4.2Hz,1H),4.55(d,J =16.2Hz,1H),4.47(d,J=16.2Hz,1H),3.98(d,J=5.4Hz,1H),3.24(d,J=3.6Hz,1H),2 .94(dd,J=13.8,4.2Hz,1H),2.70–2.63(m,1H),2.58–2.50(m,2H),2.33(d,J=15.0Hz, 1H),2.20(d,J=7.2Hz,1H),2.17(d,J=15.0Hz,1H),2.08(dd,J=14.4,6.0Hz,1H),1.90 (s,3H),1.83–1.77(m,1H),1.72(s,3H),1.71–1.65(m,1H),1.56(s,3H),1.48(s,3H). 13 C-NMR(150MHz,pyridine-d5)δ:169.5,158.3,152.9,134.9,130.2,130.2,123.3,121.8,121.8,119.7,119.7,118.5,118.5, 92.2,85.3,83.4,79.7,79.3,78.7,73.5,69.8,60.6,60.4,56.4,54.7,52.4,50.7,44.4,29.1,26.9,23.9,22.8,22.2,20.4.

[0460] Example 61 Preparation of compound 61 (2-O-(N-(2-methylbenzo[d]thiazolyl)carbamoylmethyl)azotoxin VI)

[0461]

[0462] Add 3.10 mg (0.078 mmol) NaH and 0.3 mL of ultra-dry N,N-dimethylformamide to a 10 mL reaction flask. Under ice bath stirring, slowly add 20.00 mg (0.052 mmol) of azoospermum jasminoides toxin VI dissolved in 0.3 mL of ultra-dry N,N-dimethylformamide to the reaction flask and react for 30 min. Then, 2-bromo-N-(2-methylbenzo[d]thiazo-5-yl)acetamide (17.68 mg, 0.062 mmol) dissolved in ultradry N,N-dimethylformamide (0.3 mL) was added dropwise to the reaction flask. After the addition was complete, the temperature was slowly raised to 60 °C, and the reaction progress was monitored by thin-layer chromatography. After reacting for 3 h, the mixture was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (CH2Cl2 / MeOH = 20:1) to obtain compound 61 (9.6 mg, yield 31.4%).

[0463] Molecular formula C 30 H 42 N₂O₈S, HRESI-MS m / z: [M+H] + 591.2731.

[0464] 1H-NMR(600MHz,pyridine-d5)δ:10.45(s,1H),8.68(d,J=1.8Hz,1H),7.89(dd,J=8 .4,1.8Hz,1H),7.68(d,J=8.4Hz,1H),6.79(d,J=7.2Hz,1H),6.33(s,1H),6.31(d,J =6.0Hz,1H),6.21(s,1H),5.77(s,1H),5.18(d,J=7.2Hz,1H),4.83–4.79(overlap, 2H),4.71(d,J=9.6Hz,1H),4.54(d,J=16.2Hz,1H),4.47(d,J=16.2Hz,1H),3.99(d, J=6.0Hz,1H),3.26(d,J=3.6Hz,1H),2.95(dd,J=13.2,4.2Hz,1H),2.81–2.73(m,1H ),2.66(s,3H),2.61(s,1H),2.54(dd,J=13.2,11.4Hz,1H),2.33(d,J=15.0Hz,1H), 2.21(d,J=7.2Hz,1H),2.18(d,J=15.0Hz,1H),2.11(dd,J=14.4,6.0Hz,1H),1.91(s ,3H),1.90–1.85(m,1H),1.72(s,3H),1.71–1.65(m,1H),1.56(s,3H),1.49(s,3H). 13 C-NMR (150MHz, pyridine-d5) δ: 169.7, 167.7, 154.5, 137.4, 131.0, 121.5, 118.2, 113.8, 92.2, 85.3, 83.4, 79.7, 79.3, 78.7, 73.6, 69.8, 60.7, 60.4, 56.5, 54.8, 52.3, 50.8, 44.4, 29.0, 27.0, 23.9, 22.8, 22.2, 20.4, 19.8. Pharmacological experiments

[0465] Example 1: Screening of in vivo analgesic activity of compound 1-61 (mouse acetic acid writhing model)

[0466] (I) Materials and Methods

[0467] Material:

[0468] 1) Male Kunming mice, 18-22g (SPF grade, Beijing Spaford Laboratory Animal Technology Co., Ltd.);

[0469] 2) The test compound was prepared into a dose of 2 mg / kg using physiological saline and Tween 80;

[0470] 3) Positive control drugs: Rhododendron VI toxin was prepared with physiological saline and Tween 80 to a dose of 0.1 mg / kg, and ibuprofen was prepared with physiological saline and Tween 80 to a dose of 20 mg / kg.

[0471] 4) Acetic acid solution, prepared with glacial acetic acid and physiological saline;

[0472] method:

[0473] 1) Before the experiment, the mice were acclimatized for 3 days. During the experiment, the mice were randomly divided into a blank group, a positive control ibuprofen (20 mg / kg) group, a positive control styrax toxin VI (0.1 mg / kg) group, and a test compound (2 mg / kg) group, with 10 mice in each group.

[0474] 2) After weighing, administer the drug intraperitoneally according to the mouse's body weight, with a dosage of 0.1 mL / 10 g. -1 The control group received the same volume of physiological saline.

[0475] 3) Each group received an intraperitoneal injection of a 1.2% (0.1 mL / 10 g) acetic acid solution, a chemical irritant, 15 minutes after administration. -1 After acetic acid injection, the number of writhing movements in mice was recorded within 20 minutes. The inhibition rate of the drug on the writhing response was calculated using the following formula to evaluate the analgesic effect of the drug: Inhibition rate % = [(mean number of writhing movements in the blank group - mean number of writhing movements in the experimental group) /

[0476] [Number of twisted bodies in blank group] × 100%;

[0477] (II) Experimental Results

[0478] As can be seen from Table 1, several compounds of the present invention exhibit good analgesic activity. Among them, compounds 30, 31, 33, 35, 51, and 52 showed good analgesic activity in mice at a dose of 2 mg / kg, indicating normal mice condition and no toxicity. They are worthy of further research. However, subsequent experiments revealed that compounds 30, 31, 33, and 35 caused severe toxicity and death in mice when the dose was increased to 10 mg / kg. Therefore, compounds 51 and 52 were the main focus of the study.

[0479] Table 1. Twisting inhibition rate of test compounds 1-61.

[0480]

[0481]

[0482] aMild toxicity was observed in mice. Note: Writhing inhibition rate is expressed as Mean±SEM. Compared with the control group, *P<0.05; **P<0.01; ***P<0.001. Experimental Example 2: Study of the half-maximal effective dose of compounds 51 and 52 (mouse acetic acid writhing model).

[0483] (I) Materials and Methods

[0484] Material:

[0485] 1) Male Kunming mice, 18-22g (SPF grade, Beijing Spaford Laboratory Animal Technology Co., Ltd.);

[0486] 2) Compounds 51 and 52 were prepared with physiological saline and Tween 80 to obtain doses of 0.05 mg / kg, 0.1 mg / kg, and 0.5 mg / kg, respectively.

[0487] Dosage at mg / kg, 1 mg / kg, and 5 mg / kg

[0488] 3) Positive control drugs: Rhododendron VI toxin was prepared with physiological saline and Tween 80 to a dose of 0.1 mg / kg, and ibuprofen was prepared with physiological saline and Tween 80 to a dose of 20 mg / kg.

[0489] 4) Acetic acid solution, prepared with glacial acetic acid and physiological saline;

[0490] method:

[0491] 1) Mice were acclimatized for 3 days before the experiment. During the experiment, mice were randomly divided into a blank group, a positive control ibuprofen (20 mg / kg) group, a positive control styrax toxin VI (0.1 mg / kg) group, and a test compound group, with 10 mice in each group.

[0492] 2) After weighing, administer the drug intraperitoneally according to the mouse's body weight, with a dosage of 0.1 mL / 10 g. -1 The control group received the same volume of physiological saline.

[0493] 3) Each group received an intraperitoneal injection of a 1.2% (0.1 mL / 10 g) acetic acid solution, a chemical irritant, 15 minutes after administration. -1 After acetic acid injection, the number of writhing movements in mice was recorded within 20 minutes. The inhibition rate of the drug on the writhing response was calculated using the following formula to evaluate the analgesic effect of the drug: Inhibition rate % = [(mean number of writhing movements in the blank group - mean number of writhing movements in the experimental group) /

[0494] [Number of twisted bodies in the blank group] × 100%;

[0495] 4) Input the obtained data into Graphpad (version 8.0) to calculate the drug's efficacy. 50 ;

[0496] (II) Experimental Results

[0497] As can be seen from Table 2, compounds 51 and 52 of the present invention still possess good analgesic activity, ED 50 The values ​​were 0.72 mg / kg (95% CI: 0.41-1.41 mg / kg) and 0.32 mg / kg (95% CI: 0.17-0.62 mg / kg), respectively. (See the dose-torsion inhibition rate curve for details.) Figure 1 ).

[0498] Table 2. Torsional inhibition rates of test compounds 51 and 52.

[0499]

[0500] Note: Wry neck inhibition rate is expressed as Mean±SEM. Compared with the blank group, *P<0.05; **P<0.01; ***P<0.001. Example 3: Acute toxicity test of compounds 51 and 52.

[0501] (I) Materials and Methods

[0502] Material:

[0503] 1) Male Kunming mice, 18-22g (SPF grade, Beijing Spaford Laboratory Animal Technology Co., Ltd.);

[0504] 2) Compound 51 was prepared with physiological saline and Tween 80 to doses of 100 mg / kg, 126 mg / kg, 159 mg / kg and 200 mg / kg (the concentrations were determined through preliminary experiments); Compound 52 was prepared with physiological saline and Tween 80 to dose of 200 mg / kg.

[0505] method:

[0506] Based on the "Technical Guidelines for Acute Toxicity Testing of Chemical Drugs" and the results of preliminary experiments, the initial dose was designed to be 126 mg / kg, with a dose-order factor of 1.26 and concentration gradients of 100, 126, 159, and 200 mg / kg, at a dose of 0.1 mL·10 g. -1 Administer via intraperitoneal injection. The first animal was given a dose lower than the estimated LD50. 50 One dose (126 mg / kg) was administered to the animal. If the animal survived, the next animal was given a higher dose (159 mg / kg). If the first animal died or was near death within 24 hours, the next animal was given a lower dose (100 mg / kg). The animals were observed for one week, and the survival / death status was recorded.

[0507] An experiment shall be terminated when one of the following criteria is met: 1. Three consecutive animals survive; 2. Five out of any six consecutive experimental animals undergo a survival / death transition; 3. At least four animals enter the experiment after the first animal undergoes a survival / death transition, and their LD (Leadership Level) is within the range of 5. 50 The estimated values ​​exceeded the critical value by 2.5 times. During administration, animals were observed for signs of poisoning and mortality, and the onset and disappearance of symptoms and the circumstances of death were recorded. Animals that lost 20% of their body weight were euthanized and their deaths were recorded as poisoning-related deaths. The dosage and mortality data for each trial were entered into AOT425StatPgm (developed by the US EPA), and the program automatically determined the endpoint dose. Administration was stopped when one of the termination criteria was met, and the LD50 was calculated based on the condition of all animals at termination. 50 And 95% CI.

[0508] (II) Experimental Results

[0509] As shown in Table 3, compound 51, with concentrations between 159 mg / kg and 200 mg / kg, met the criterion of 5 out of 6 consecutive animals experiencing a survival / death transition, therefore the experiment was terminated. The LD50 of compound 51 was estimated using AOT425StatPgm software. 50 The LD50 value was 186.8 mg / kg (95% CI: 159-200 mg / kg). Due to solubility limitations, compound 52 has a maximum solubility of 200 mg / kg. In the experiment, eight mice injected intraperitoneally with 200 mg / kg of compound 52 showed normal activity and no abnormalities. Therefore, the LD50 of compound 52 is... 50 >200 mg / kg. As can be seen from Table 4, compounds 51 and 52 of the present invention have significantly reduced toxicity compared with the parent compound, Rhodotorula toxicum VI, with selectivity indices of 10 times and greater than 25 times that of Rhodotorula toxicum VI, respectively.

[0510] Table 3. Acute toxicity results of compound 51 administered intraperitoneally to mice.

[0511]

[0512] Table 4. Efficacy of compounds 51 and 52 50 ,LD 50 Summary of TI results

[0513]

Claims

1. A compound represented by general formula I or a pharmaceutically acceptable salt thereof: in, n is 0 or 1; R1, R2, and R3 are each independently selected from -H and -COR. A . R A Selected from -CHR a R b -L1R c -CH=CHR d -NHR e R a R b Each is independently selected from -H, straight-chain or branched saturated C 1-8 alkyl; L1 is selected from none or C. 1-5 Alkylene; R c Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups; R d Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2. R e The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound represented by general formula IA or a pharmaceutically acceptable salt thereof: Where n is 0 or 1; R 1a Selected from -CHR a1 R b1 -L 1a R c1 -CH=CHR d1 -NHR e1 . R a1 R b1 Each is independently selected from -H, straight-chain or branched saturated C 1-8 Alkyl L 1a Selected from none or C 1-5 Alkylene; R c1 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups; R d1 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2. R e1 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound represented by general formula IB or a pharmaceutically acceptable salt thereof: Among them, R 2a Selected from -CHR a2 R b2 -L 2a R c2 -CH=CHR d2 -NHR e2 . R a2 R b2 Each is independently selected from -H, straight-chain or branched saturated C 1-8 Alkyl L 2a Selected from none or C 1-5 Alkylene; R c2 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups; R d2 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2. R e2 The substituents are selected from the following groups substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, and thiazole, wherein the substituents may be selected from -H, straight-chain, or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound represented by general formula IC or a pharmaceutically acceptable salt thereof: Among them, R 3a Selected from -CHR a3 R b3 -L 3a R c3 -CH=CHR d3 -NHR e3 . R a3 R b3 Each is independently selected from -H, straight-chain or branched saturated C 1-8 Alkyl L 3a Selected from none or C 1-5 Alkylene; R c3 Selected from 3-8 membered saturated cycloalkyl groups and phenyl groups; R d3 Selected from the following groups substituted with one or more substituents: phenyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2. R e3 The following groups are selected from those substituted with one or more substituents: phenyl, benzyl, phenethyl, five- or six-membered saturated or unsaturated heterocycles containing 1-3 heteroatoms, indole, benzothiazole, wherein the substituents may be selected from -H, straight-chain or branched C. 1-6 Alkyl, straight-chain or branched C 1-6 Alkoxy, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, -COCH3, -COPh, -OPh, -SO2CH3, -NH2, -N(CH3)2.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The compounds are selected from the following group: 1) 6-O-pentanoyl rhodotorulatoxin VI 2) 6-O-(3-methylbutyryl)rhoa toxin VI 3) 6-O-(4-methylpentanoyl)rhodotorhinol VI 4) 6-O-(3-cyclopropylpropionyl)rhodotorhinol VI 5) 6-O-(3-cyclohexylpropionyl)rhodotorhinol VI 6) 6-O-(3-phenylpropionyl)rhoa toxin VI 7) 6-O-((E)-3-(4-fluorophenyl)acryloyl)rhodotorhinol VI 8) 6-O-((E)-3-(4-(trifluoromethyl)phenyl)acryloyl)rhodotorhinol VI 9) 6-O-((E)-3-(4-cyanophenyl)acryloyl)rhodotorhinol VI 10) 6-O-((E)-3-(4-isopropylphenyl)acryloyl)rhodotorhinol VI 11) 6-O-((E)-3-(4-methoxyphenyl)acryloyl)rhodotorhinol VI 12) 2-O-(N-benzylcarbamoyl)rhoa toxin VI 13) 2-O-(N-(4-fluorophenyl)carbamoyl)rhodotorhinol VI 14)2-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI 15) 2-O-(N-(4-bromophenyl)carbamoyl)rhoa toxin VI 16) 2-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI 17) 2-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI 18)2-O-(N-(4-fluorobenzyl)carbamoyl)rhodotorhinol VI 19)2-O-(N-(4-methoxyphenyl)carbamoyl)rhodotorhinol VI 20)2-O-(N-(4-benzoylphenyl)carbamoyl)rhodotorhinol VI 21)2-O-(N-(1-methyl-1H-indol-6-yl)carbamoyl)rhodotorhinol VI 22)3-O-(N-(4-fluorophenyl)carbamoyl)rhodotorhinol VI 23) 3-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI 24)3-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI 25)3-O-(N-(4-bromophenyl)carbamoyl)rhodotorhinol VI 26)3-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI 27) 3-O-(N-(4-methoxyphenyl)carbamoyl)rhodotorhinol VI 28) 3-O-(N-benzylcarbamoyl)rhoa toxin VI 29)3-O-(N-(4-fluorobenzyl)carbamoyl)rhoa toxin VI 30)6-O-(N-(3-fluorophenyl)carbamoyl)rhodotorhinol VI 31) 6-O-(N-(2-fluorophenyl)carbamoyl)rhodotorhinol VI 32)6-O-(N-(4-(trifluoromethyl)phenyl)carbamoyl)rhodotorhinol VI 33)6-O-(N-(4-bromophenyl)carbamoyl)rhoa toxin VI 34) 6-O-(N-(4-fluorobenzyl)carbamoyl)rhoa toxin VI 35)6-O-(N-(4-benzoylphenyl)carbamoyl)rhodotorhinol VI 36) 2-O-(N-phenylcarbamoylmethyl)rhodotorhinol VI 37)2-O-(N-(4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI 38)2-O-(N-(4-fluorobenzyl)carbamoylmethyl)rhodotorhinol VI 39)2-O-(N-(4-fluorophenylethyl)carbamoylmethyl)rhodotorhinol VI 40)2-O-(N-(3-fluorophenyl)carbamoylmethyl)rhodotorhinol VI 41) 2-O-(N-(2-fluorophenyl)carbamoylmethyl)rhodotorhinol VI 42)2-O-(N-(3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI 43)2-O-(N-(4-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI 44)2-O-(N-(4-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI 45)2-O-(N-(3-methanesulfonylphenyl)carbamoylmethyl)rhodotorhinol VI 46)2-O-(N-(4-nitrophenyl)carbamoylmethyl)rhodotorhinol VI 47)2-O-(N-(4-methoxyphenyl)carbamoylmethyl)rhodotorhinol VI 48)2-O-(N-(4-methylphenyl)carbamoylmethyl)rhodotorhinol VI 49)2-O-(N-(4-acetylphenyl)carbamoylmethyl)rhodotorhinol VI 50)2-O-(N-(4-(dimethylamino)phenyl)carbamoylmethyl)rhodotorhinol VI 51)2-O-(N-(thiazolyl-2-yl)carbamoylmethyl)rhodotorhinol VI 52)2-O-(N-(3,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI 53)2-O-(N-(2,4-difluorophenyl)carbamoylmethyl)rhodotorhinol VI 54)2-O-(N-(3,5-difluorophenyl)carbamoylmethyl)rhodotorhinol VI 55)2-O-(N-(4-fluoro-3-(trifluoromethyl)phenyl)carbamoylmethyl)rhodotorhinol VI 56)2-O-(N-(4-fluoro-3-nitrophenyl)carbamoylmethyl)rhodotorhinol VI 57)2-O-(N-(3-chloro-4-fluorophenyl)carbamoylmethyl)rhodotorhinol VI 58)2-O-(N-(4-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI 59)2-O-(N-(3-benzoylphenyl)carbamoylmethyl)rhodotorhinol VI 60)2-O-(N-(4-phenoxyphenyl)carbamoylmethyl)rhodotorhinol VI 61)2-O-(N-(2-methylbenzo[d]thiazolyl)carbamoylmethyl) peperomia toxin VI.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release formulations, controlled-release formulations, and various microparticle delivery systems.

8. The use of any compound of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of pain.

9. The application according to claim 8, characterized in that, The pain described is related to the central or peripheral nervous system.

10. The application according to claim 9, characterized in that, The pain described is selected from acute pain or chronic pain.

11. The application according to claim 10, characterized in that, The pain described is somatic pain, visceral pain, or neuropathic pain.

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