Kounis a derivative, synthetic method and application in antitumor and pharmaceutical composition

Abstract

The application discloses a series of derivatives based on natural product gelsemium methyl, pharmaceutically acceptable salts and preparation methods thereof. Bioactivity tests show that the compounds have the effect of inhibiting the proliferation of various tumor cells. The compounds can be used for the treatment of various cancers (including but not limited to gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer and skin cancer) as active pharmaceutical ingredients.

Description

Technical Field

[0001] This invention relates to various gelseminine derivatives and their preparation methods, as well as pharmaceutical components for treating various malignant tumors. Background Technology

[0002] Gelsemium elegans is the whole herb of Gelsemium elegans, a plant in the Loganiaceae family. It is divided into two types: Chinese Gelsemium and North American Gelsemium. The history of its application is quite long. In 1887, H. Gerrad et al. prepared it into a preparation called Gelsemium elegans, which was included in the pharmacopoeias of several countries. It is also recorded in the American Drug Index and the Japanese book "World Folk Medicines." The history of research on Gelsemium elegans in my country is even longer. The "Shennong's Classic of Materia Medica" and "Compendium of Materia Medica" record that it "when inserted into the abdomen of humans and animals, adheres to the intestines, and within half a day it turns black and rotten; it is also known as 'rotten intestine grass'"; and that it "treats wounds, mastitis, stroke, cough, shortness of breath, and treats poisoning by ghosts and insects." Liu Hao et al. reported that the main active ingredient in Gelsemium elegans is gelseminine alkaloids (Journal of Fujian Medical University, 2008, 42(5): 469-471). Currently, gelseminine alkaloids are found to be indole alkaloids, including more than 40 monomers such as gelseminine A, Gelsemium elegans, Gelsemium elegans, Gelsemium elegans, Gelsemium elegans A, and 1-methoxygelseminine. Their structures are similar, but their toxicity and pharmacological activities are not the same.

[0003] Gelsemium elegans, as the main indole alkaloid and active compound in Gelsemium elegans, possesses a wide range of biological activities, including neurobiological activity, immunosuppression, and antitumor effects. It has traditionally been used to treat pain, neuralgia, anxiety, insomnia, asthma, respiratory diseases, and cancer (Fitoterapia, 2015, 100, 35-43). Studies have found that gelsemium elegans and its metabolites, including the 4-N-demethylated derivative and the 21-position oxidized gelsemium elegans, exhibit significant inhibitory effects on HepG2 and HeLa tumor cells at high concentrations (Journal of Asian Natural Products Research, 2010, 12(9), 731-739). Despite these potential applications, the anticancer activity of gelsemium elegans and its natural derivatives is generally low, with effective and toxic doses being close, thus limiting its potential for new drug development. Improving drug-likeness through structural optimization is a common method in medicinal chemistry; however, to date, no reports have been published on its derivatization and modification. Through structural analysis, we believe that gelsemium elegans possesses several easily modifiable chemical groups, allowing for diverse structural derivatization. Therefore, in this invention, we report a variety of novel structural derivatives of gelseminine A and their synthetic methods, and find that the anticancer activity of most of these derivatives is significantly enhanced, thus laying a better foundation for the development of new antitumor drugs. Summary of the Invention

[0004] One of the objectives of this invention is to provide a variety of gelsemin A derivatives through a semi-synthetic method to enhance their antitumor proliferative activity (including but not limited to gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, and skin cancer), thereby improving their drug potential.

[0005] To achieve the above objectives, the present invention proposes a series of gelseminine derivatives, the general formula (I) of which is as follows:

[0006]

[0007] in,

[0008] R 1 It is any one of vinyl, ethyl, or 1-bromoethyl groups;

[0009] R 2 For H, C 1-20 Alkyl, benzyl, substituted or unsubstituted C 1-20 Fatty acyl group, substituted or unsubstituted aromatic acyl group, substituted or unsubstituted sulfonyl group, R 2’ R 2” One or more of NCO-, wherein R 2’ and R 2” Each independently represents H and C. 1-3 Alkyl, or R 2’ R 2” It forms a 4-6 membered cyclic amino group with N;

[0010] R 3 The H, halogen, substituted or unsubstituted aromatic group, substituted or unsubstituted styryl group, or C are substituted at any position on the phenyl group of gelsemin A. 2-5 alkynyl group, C 2-5 alkenyl, -NO2, or R 3’ R 3” Any two or more groups in N-, wherein R 3’ and R 3” Each independently represents H and C. 1-20 Alkyl, substituted or unsubstituted aromatic acyl, substituted or unsubstituted C 1-20 One or more of fatty acyl groups, substituted or unsubstituted sulfonyl groups;

[0011] n represents the R substituted on the toluene group of gelsemin. 3 The number of them can be 1, 2, 3 or 4.

[0012] R 4 H, substituted or unsubstituted C 1-20 Alkyl, R 4’COCH2-, one or more of substituted or unsubstituted aromatic groups, wherein R 4’ For H2N-, (CH3)2N-, HO-, CH3(CH2) n’ O-, CH3(CH2) n’ One or more of NH-, where n' is an integer between 0 and 19.

[0013] In some embodiments, R 1 It is any group selected from vinyl, ethyl, and 1-bromoethyl; preferably R 1 It can be vinyl or ethyl.

[0014] In some embodiments, R 2 For H, C 1-20 Alkyl, benzyl; or R 2 For substituted or unsubstituted C 1-20 Fatty acyl group, wherein the substituent is one or more of (CH3)2N- and CH3CH2OCO- with arbitrary substitution; or R 2 The substituted or unsubstituted aromatic acyl group, or the substituted or unsubstituted benzenesulfonyl group, wherein the substituent is one or more of the following: methyl, ethyl, propyl, F, Cl, CF3, CH3CO-, HO-, CH3O-, CH3CH2O-; or R 2 For R 2’ R 2” NCO-, where R 2’ and R 2” Each can be independently H, methyl, ethyl, propyl, or R. 2’ R 2” It can form one or more of cyclobutanylamino, cyclopentanylamino, and cyclohexylamino with N;

[0015] Preferred, R 2 It is one or more of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, pentadecyl, (CH3)2CH-, (CH3)2CHCH2-, allyl, propyneyl, benzyl, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pentadecanoyl, trifluoroacetyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-ethylbenzoyl, p-propylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, furan-2-carboxyl, naphthyl, thiophene-2-carboxyl, benzenesulfonyl, p-toluenesulfonyl, or R 2 For R 2’ R 2” NCO-, where R 2’ and R2” Each is independently one or more of H, CH3-, CH3CH2-, or R 2’ R 2” Composed of N One or more of the following;

[0016] More preferably, R 2 The following are not part of the given name: H, CH3-, CH3CH2-, CH3CH2CH2-, heptyl, pentadecyl, benzyl, formyl, acetyl, propionyl, heptyl, pentadecylyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, 2-naphthoyl, furan-2-ylformyl, thiophene-2-ylformyl, benzenesulfonyl, p-toluenesulfonyl, NH2CO-, (CH3)2NCO-, CH3NHCO-, CH3CH2NHCO-, (CH3CH2)2NCO-. One or more of the following;

[0017] Further preferred, R 2 The following are not part of the given name: H, CH3-, CH3CH2-, CH3CH2CH2-, heptyl, pentadecyl, benzyl, formyl, acetyl, heptyl, pentadecylyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, 2-naphthoyl, furan-2-ylformyl, benzenesulfonyl, p-toluenesulfonyl, NH2CO-, (CH3)2NCO-, CH3NHCO-, CH3CH2NHCO-. One or more of them.

[0018] In some embodiments, R 3 The substituted H, Cl, Br, -NO2, substituted or unsubstituted aromatic group, substituted or unsubstituted styryl group, or -NR group are present at any position on the phenyl group of gelsemium methyl. 3’ R 3” One or more groups in, wherein R 3’ and R 3” Each independently represents H and C. 1-20 Alkyl, C 1-20The aliphatic acyl group, substituted or unsubstituted aromatic acyl group, and substituted or unsubstituted benzenesulfonyl group are selected as one or more groups, wherein the aromatic group refers to any one of the following groups: phenyl, furanyl, thiophene, naphthyl, pyridyl, benzofuranyl, benzothiophene, and thiopheno[3,2-b]thiophene; and the substituent refers to F, Cl, Br, -CN, -OH, -NH2, -CF3, methyl, F2HC-, ethyl, propyl, (CH3)2CH-, butyl, (CH3)3C-, pentyl, hexyl, heptyl, CH3O-, CF3O-, CH3CH2O-, CH3CH2CH2O-, (CH3)2CHO-, (CH3)2N-, phenyl, acetyl, NH2CO-, ethylenedioxy,

[0019] Furthermore, R 3 The substituents are H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiophene[3,2-b]thiophene, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene-2-yl, substituted or unsubstituted thiophene-3-yl, wherein the substituents are F, Cl, -CN, -OH, -CF3, CH3-, F2HC-, ethyl, propyl, (CH3)2CH-, (CH3)3C-, butyl, pentyl, CH3O-, CF3O-, CH3CH2O-, (CH3)2CHO-, (CH3)2N-, phenyl, acetyl, NH2CO-, ethylenedioxy, etc., at any position on the phenyl group of gelsemium methyl. Or R 3 For -NR 3’ R 3” , where R 3’ and R 3” Each is independently H, methyl, ethyl, C 1-20 One or more of fatty acyl, naphthalene-1-formyl, naphthalene-2-formyl, substituted or unsubstituted benzoyl, wherein the substituent refers to F, Cl, Br, -OH, CH3-, CH3CH2-, CH3O-, CH3CH2O-, (CH3)2N-;

[0020] Preferred, R 3The following are arbitrary substitutions on the phenyl group of gelsemium methyl: H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiophene[3,2-b]thiophene, phenyl, p-fluorophenyl, m-fluorophenyl, p-cyanophenyl, m-cyanophenyl, p-isopropylphenyl, m-isopropylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-isopropoxyphenyl, m-isopropoxyphenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-difluoromethylphenyl, m-difluoromethylphenyl, p-tert-butylphenyl, p-n-butylphenyl, p-n-pentylphenyl. One or more of 5-methylthiophen-2-yl, 5-cyanothiophen-2-yl, 5-acetylthiophen-2-yl, 5-phenylthiophen-2-yl, and 5-chlorothiophen-2-yl, or R 3 For -NR 3’ R 3” , where R 3’ and R 3” Each is independently H, methyl, ethyl, C 1-20 One or more of the following: fatty acyl, naphthalene-1-formyl, naphthalene-2-formyl, benzoyl, p-methoxybenzoyl, m-methoxybenzoyl, p-fluorobenzoyl, m-fluorobenzoyl, and p-toluyl;

[0021] More preferably, R 3 For any position of H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiopheno[3,2-b]thiophene, phenyl, p-fluorophenyl, m-fluorophenyl, p-cyanophenyl, p-isopropylphenyl, m-isopropylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-isopropoxyphenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-difluoromethylphenyl, p-tert-butylphenyl, p-n-butylphenyl, p-n-pentylphenyl, One or more of the following: 5-methyl-thiophen-2-yl, 5-cyano-thiophen-2-yl, 5-acetyl-thiophen-2-yl, 5-phenyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, -NH2, acetamido, propionamido, butamido, pentamido, hexamido, heptaamido, octamido, nonamido, decamido, undecanoamide, dodecanoamide, tridecanoamide, tetradecanoamide, pentadecanoamide, hexadecanoamide, heptanoamide, octadecanoamide, nonadecanoamide, eicosamide, benzamide, p-methoxybenzamide, and naphth-2-carboxamide.

[0022] n represents the R substituted on the toluene group of gelsemin. 3 The number of elements is an integer between 1 and 4; preferably, n is 1 or 2.

[0023] In some embodiments, R 4 H, substituted or unsubstituted C 1-20 Alkyl, wherein the substituent is phenyl, alkynyl, alkenyl, or R 4 For R 4’ One or more of COCH2-, wherein R 4’ For H2N-, (CH3)2N-, CH3NH-, CH3PhN-, HO-, CH3(CH2) n’ O-, CH3(CH2) n’ One or more of NH-, where n' is an integer between 0 and 19, or R 4 The aryl group may be substituted or unsubstituted, and here the aryl group is one or more of phenyl, pyridyl, quinolinyl, thiophenyl, indole, and N-methylindole, wherein the substituent is one or more of F, Cl, Br, -CN, -CF3, methoxy, and ethoxy.

[0024] Furthermore, R 4 The following are the possible values: H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, decyl, tridecyl, pentadecyl, heptadecanyl, eicosyl, benzyl, propargyl, allyl, H2NCOCH2-, (CH3)2NCOCH2-, CH3NHCOCH2-, CH3PhNCOCH2-. HOCOCH2-, CH3OCOCH2-, CH3(CH2) 1-19OCOCH2-, phenyl, p-methoxyphenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-cyanophenyl, o-methoxyphenyl, p-trifluoromethylphenyl, quinoline-6-yl, N-methylindol-6-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, thiophen-2-yl, thiophen-3-yl;

[0025] Preferably, R 4 The following are not part of the given name: H, methyl, ethyl, butyl, heptyl, decyl, tridecyl, pentadecyl, heptadecanyl, eicosyl, benzyl, propargyl, (CH3)2NCOCH2-, CH3PhNCOCH2-. HOCOCH2-, CH3CH2OCOCH2-, CH3(CH2)5OCOCH2-, CH3(CH2) 10 OCOCH2-, CH3(CH2) 12 OCOCH2-, CH3(CH2) 16 One or more of the following: OCOCH2-, phenyl, p-methoxyphenyl, o-fluorophenyl, p-cyanophenyl, o-methoxyphenyl, p-trifluoromethylphenyl, quinoline-6-yl, N-methylindol-6-yl, pyridin-3-yl, and thiophene-2-yl.

[0026] In some embodiments, R in gelseminine derivatives 1 -R 4 The functional groups do not affect each other and can be combined in any pair.

[0027] In some embodiments, the gelseminine derivative or its pharmaceutically acceptable salt comprises one or more of the following structures:

[0028]

[0029]

[0030]

[0031] In some embodiments, compound I can form a salt with a pharmaceutically acceptable acid, the general formula of which is shown in II, wherein the acid is any one or more of HCl, HBr, citric acid, fumaric acid, succinic acid, tartaric acid, citric acid, sulfuric acid, methanesulfonic acid, formic acid, and acetic acid, wherein X - The acid radical ion corresponding to the acid;

[0032]

[0033] In some embodiments, gelseminine derivatives are reacted with haloalkanes (R... 5 The quaternary ammonium salt generated by X) is shown in general formula III, where R5 X is any one or more of methyl, ethyl, propyl, and benzyl. - For Br - Cl - One or two of them;

[0034] In some embodiments, the gelseminine derivative can be one or more of the following: salt, hydrate, solvate, or crystal.

[0035] In some embodiments, one or more of gelsemin A derivatives or pharmaceutically acceptable salts thereof are used as active ingredients in the preparation of drugs for treating tumors, including but not limited to one or more of gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, and skin cancer.

[0036] In some embodiments, a pharmaceutical composition is formed by one or more of gelsemin A derivatives or pharmaceutically acceptable salts thereof, together with one or more of any pharmaceutically acceptable excipients, carriers, diluents and / or other active compounds.

[0037] The compounds described above comprise free bases, salts formed with pharmaceutically acceptable acids, hydrates, solvates, and various crystals. When the compounds are in diastereomeric form, they comprise a mixture of diastereomers and individual diastereomeric monomers; when the compounds are in enantiomeric form, they comprise a mixture of enantiomers and individual enantiomeric monomers.

[0038] In the compounds according to the invention, the term "alkyl" preferably represents a straight-chain or branched hydrocarbon group having a defined number of carbon atoms.

[0039] The term "phenyl" represents -C6H5, where the benzene ring may have one or more substituents.

[0040] The term "alkoxy" means -OR, where R is an alkyl group as defined above.

[0041] The term "alkoxyformyl" means -OCOR, where R is an alkyl group as defined above.

[0042] Another object of the present invention is to provide a composition comprising the compounds of the present invention with pharmaceutically acceptable excipients or other active compounds.

[0043] The present invention also relates to pharmaceutical compositions comprising one or more of the above-described gelsemin A derivatives. In other words, the compounds according to the present invention can be used as pharmaceutically active substances, particularly for tumor treatment.

[0044] They can be used to prepare pharmaceutical formulations containing at least one of the compounds described in this invention.

[0045] The free base of the compound according to the invention, or the salt formed with a pharmaceutically acceptable acid, can be formulated into suitable galen dosage forms, such as oral, injectable, or spray-administered compositions, according to acceptable pharmaceutical procedures. Pharmaceutical compositions according to the invention comprise an effective amount of the compound of the invention, and a suitable pharmaceutically acceptable carrier or diluent, which is well known in the art. The carrier can be any inert raw material, organic or inorganic, suitable for enteral, transdermal, or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline starch, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc. The composition may also contain other pharmaceutically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc.

[0046] The compositions according to the invention can be formulated into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, and syrups; into sterile solutions, suspensions, or emulsions for parenteral administration; and into dry powder formulations, sterile solutions, suspensions, or emulsions for spray administration.

[0047] Another object of the present invention is to provide the application of the compounds of the present invention in the treatment of various types of tumors (including but not limited to gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, and skin cancer). The dosage of the specific compound will vary depending on its potency, route of administration, patient age and weight, and the severity of the treated condition. Detailed Implementation

[0048] The following will describe the implementation of the present invention in detail with reference to the embodiments, so that the process of how the present invention uses technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly.

[0049] It should be understood that, when used in this specification and the appended claims, the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components and / or collections thereof.

[0050] It should also be understood that the terminology used in this specification of embodiments of the invention is for the purpose of describing particular embodiments only and is not intended to limit the embodiments of the invention. As used in this specification of embodiments of the invention and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0051] This invention also reports a method for preparing the aforementioned gelsemin A derivative I. Experienced researchers can easily select appropriate reaction conditions for the chemical reaction by referring to similar literature reports or the specific examples shown below. The raw materials required for this type of reaction are commercially available or can be prepared by conventional methods.

[0052] According to the conditions disclosed in this invention, the following methods are provided:

[0053] Synthesis Method 1

[0054]

[0055] Scheme 1. In the reaction formula, R 1 Same as the definition above

[0056] Reaction a:

[0057] I-A0 (i.e., gelsemium methyl ether, 1 mmol, 1.0 molar equivalent) was dissolved in 15 mL of dry methanol, and 10% Pd / C (Pd content 10% wt) of I-A0 was added. After vacuuming and purging with hydrogen three times, the reaction was carried out for 12 hours under a hydrogen balloon atmosphere. After the reaction was complete, palladium on carbon was removed by diatomaceous earth filtration, and the solvent was removed by vacuum evaporation of the filtrate to obtain the target product I-A1.

[0058] Reaction b:

[0059] I-A0 (1 mmol, 1.0 molar equivalent) was dissolved in dry acetonitrile (15 mL), and 69% hydrobromic acid (6 mL) was added. The mixture was then heated to reflux and reacted at this temperature for 24 hours. After the reaction was complete, sodium hydroxide solution (1 M) was added to adjust the pH to 10. Dichloromethane (15 mL) was added for extraction three times, and the product was purified by silica gel column chromatography to obtain the target product I-A2.

[0060] Synthesis Method 2

[0061]

[0062] Scheme 2. In the reaction formula, R 1 R 2 Same as the definition above.

[0063] Reaction c:

[0064] In a dry, sealed tube, substrate IA (1 mmol, 1.0 molar equivalent) was dissolved in dry dichloromethane (15 mL). Potassium bicarbonate (10 mmol relative to I-A0 or IA) and 1-chloroethyl chloroformate (5 mmol relative to gelsemin A or IA) were added sequentially. After sealing, the reaction was carried out at 45 °C for 2 hours. After the reaction was confirmed to be complete by LC-MS, the dichloromethane was removed under reduced pressure. Tetrahydrofuran and water (2:1, 15 mL, v / v) were added, and the mixture was stirred at room temperature for 12 hours. The organic phase was separated and extracted three times with ethyl acetate (1 mmol gelsemin A or IA each time with 15 mL of ethyl acetate). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography to obtain the target product I-B1.

[0065] Reaction d:

[0066] When using acyl chlorides (benzoyl chloride, furan-2-carboxyl chloride, 4-piperidinylpiperidin-1-carboxyl chloride, p-methylbenzenesulfonyl chloride, 4-fluorobenzoyl chloride, 4-methoxycarboxyl chloride, 2-naphthoyl chloride, or oxaloyl chloride monoethyl ester) as acylation reagents: In a dry round-bottom flask, dissolve I-B1 (1 mmol, 1.0 molar equivalent) in dry dichloromethane (15 mL), add triethylamine (2 molar equivalent), and then add substituted or unsubstituted aromatic compounds at 0 °C. Carboxyl chloride, naphthoyl chloride, carbamoyl chloride, ethoxyformyl chloride, or substituted or unsubstituted benzenesulfonyl chloride (1.5 molar equivalents) were reacted at 25°C for 12 hours, quenched with water (15 mL), and extracted three times with ethyl acetate (20 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The target product I-Bn was obtained by silica gel column chromatography or preparative plate purification (where n is the compound number, greater than or equal to 2).

[0067] When using an acid in the presence of a condensing agent: In a dry round-bottom flask, I-B1 (1 mmol, 1.0 mol equivalent) is dissolved in dry N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (2 mol equivalent) is added, followed by a carboxylic acid reagent (1.5 mol equivalent of an aromatic carboxylic acid corresponding to the R2 definition range). Then, at 0 °C, HATU (1.5 mol equivalent) is added as an amide condensing agent, and the reaction is carried out at 25 °C for 12 hours. The mixture is then quenched with water (20 mL), extracted three times with ethyl acetate (20 mL each time), and the organic phases are combined. After drying with anhydrous sodium sulfate, the solvent is removed by vacuum distillation, and the product is purified by silica gel column chromatography or preparative plate chromatography to obtain the target product I-Bn (where n is the compound number, greater than or equal to 2).

[0068] When R 2As an alkyl group, in a dry round-bottom flask, I-B1 (1 mmol, 1.0 molar equivalent) was dissolved in 10 mL of dry N,N-dimethylformamide, potassium carbonate (2 molar equivalent) was added, followed by the addition of an alkyl halide or halide-like compound (haloalkyl R). 2 -X, Methanesulfonate R 2 -OMs or p-toluenesulfonate R 2 -OTs)(1.5 molar equivalent), then react at 65℃, quench with water (5-50 mL), extract three times with ethyl acetate (20 mL ethyl acetate each time for 1 mmol I-B1), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by silica gel column chromatography or preparative plate to obtain the corresponding target product I-Bn (n greater than or equal to 2).

[0069] Synthesis Method 3

[0070]

[0071] In Scheme 3, R... 1 -R 3 Same as the definition above.

[0072] Reaction e:

[0073] Add acetic anhydride (15 mL I-A0 or IA) to the reaction flask, add nitric acid (0.5 mL per mole of I-A0 or IA), stir at room temperature for 5 min, then add I-A0 or IA (1 mmol, 1.0 molar equivalent), stir at room temperature for 4 hours, and check the reaction is complete by LC-MS. Add 20 mL of water, adjust the pH to 10-12 with sodium hydroxide, extract three times with ethyl acetate (1 mmol of I-A0 or IA with 20 mL of ethyl acetate each time), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by silica gel column chromatography or preparative plate to obtain the corresponding target product IC.

[0074] Reaction f:

[0075] Add IC (1 molar equivalent) to the reaction flask, dissolve in 20 mL of ethanol by stirring, then add ammonium chloride (10 molar equivalent), zinc powder (5 molar equivalent), and 4 mL of water. Heat to 85°C and stir for 4 hours. LC-MS confirms complete reaction. Filter, concentrate the filtrate to obtain the target product ID, and proceed directly to the next reaction without further purification.

[0076] Reaction g:

[0077] Add ID (1 molar equivalent, 0.1 mmol) dissolved in dry dichloromethane (10 mL) to a reaction flask, then add triethylamine (2 molar equivalent, 0.2 mmol), and add acyl chloride (1.5 molar equivalent, 0.15 mmol) at 0 °C. React at 25 °C for 12 hours, quench the reaction with 10 mL of water, and then extract three times with dichloromethane (10 mL each time). After drying with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by silica gel column chromatography or preparative plate to obtain the target product IE.

[0078] Reaction h:

[0079] IA (1 molar equivalent, 0.1 mmol) was dissolved in acetonitrile (10 mL) and reacted at 0 °C with N-bromosuccinimide (1.05 molar equivalent). The reaction was continued at this temperature for 0.5 h. 10 mL of water was added to quench the reaction. The mixture was then extracted three times with ethyl acetate (10 mL each time). After drying with anhydrous sodium sulfate, the solvent was removed by vacuum distillation. The product IF was purified by silica gel column chromatography or preparative plate chromatography. Reaction i:

[0080] Under nitrogen protection, IF (1 molar equivalent, 0.1 mmol), boric acid or borate ester (equivalent to R) 3 The defined aryl or heteroaryl boric acid or borate ester (2 molar equivalents, 0.2 mmol) and potassium carbonate (4 molar equivalents, 0.4 mmol) were suspended in a mixed solution of 1,4-dioxane and water (5 mL, volume ratio 4:1). Then, Pd(PPh3)2Cl2 (5% molar equivalent, 0.005 mmol) was added, and the mixture was sealed and reacted at 85 °C for 12 hours. The reaction was quenched by adding 10 mL of water, followed by three applications of ethyl acetate (10 mL each time). After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the product IG was purified by silica gel column chromatography or preparative plate chromatography.

[0081] Synthesis Method 4

[0082]

[0083] Scheme 4. In the reaction formula, R 1 -R 4 Same as the definition above.

[0084] When R 4 It is a 1-5 carbon straight-chain or branched alkyl or substituted alkyl group, using reaction j:

[0085] Dissolve IA, IB, IC, IF, or IG (1.0 mol equivalent, 0.1 mmol) in dry tetrahydrofuran (5 mL per mmol substrate), then add NaH (2 mol equivalent, 0.2 mmol) at 0 °C, and continue the reaction at 0 °C for 15 min. Then add C.1-20 The reaction is carried out with substituted or unsubstituted alkyl chlorides, bromines, iodides, or halogen-like compounds (iodomethane, benzyl bromide, propargyl bromide, ethyl bromoacetate, bromoacetylmethylphenylamine, bromoacetylcyclohexylamine, hexyl bromoacetate, decyl bromoacetate, 12-alkyl bromoacetate, or 16-alkyl bromoacetate, 1.0-2 molar equivalents), followed by a reaction time of 12 hours. The reaction is quenched by the addition of 10 mL of water, then extracted three times with ethyl acetate (10 mL each time). After drying with anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the product is purified by silica gel column chromatography or preparative plate chromatography to obtain the target product IH.

[0086] When R 4 It is a substituted or unsubstituted phenyl, naphthyl, or substituted or unsubstituted aromatic heterocycle, using reaction k:

[0087] Substrate IA, IB, IC, IF, or IG (1.0 mol equivalent, 0.1 mmol) was dissolved in dry acetonitrile (3 mL per millimole of starting material). Under nitrogen protection, potassium carbonate (2.2 mol equivalent), iodo- or bromo-substituted or unsubstituted phenyl, naphthyl, or substituted or unsubstituted aromatic heterocyclic compounds (iodobenzene, bromobenzene, 2-fluoroiodobenzene, 2-methoxyiodobenzene, 4-methoxyiodobenzene, 4-trifluoromethyliodobenzene, 3-iodopyridine, 6-iodoquinoline, 2-iodothiophene, or 6-iodo-1-methylindole, 1.5 mol equivalent), cuprous iodide (0.1 mol equivalent), and N,N'-dimethylvinyldiamine (0.2 mol equivalent) were added sequentially. After sealing the tube, the reaction was carried out at 82 °C for 16 hours. The reaction was quenched by adding 5 mL of water. The mixture was then extracted three times with ethyl acetate (10 mL each time). After drying with anhydrous sodium sulfate, the solvent was removed by vacuum distillation. The product IH was then purified by silica gel column chromatography or preparative plate chromatography.

[0088] Synthesis Method Five

[0089]

[0090] In Scheme 5, R... 1 -R 4 X is defined the same as above.

[0091] Reaction l:

[0092] Substrate I (I containing a basic group, 1 mmol, 1.0 molar equivalent) is dissolved in organic solvents such as ethyl acetate, tetrahydrofuran, dichloromethane, and methanol (5-50 ml per 1 mmol I). Then, an acid (any pharmaceutically acceptable acid as defined in claim 9, 1.0-5.0 molar equivalent relative to I) is slowly added. The mixture is then stirred at room temperature for 1-5 hours. After removing the solvent under reduced pressure and drying, the target product II can be obtained.

[0093] Synthesis Method Six

[0094]

[0095] In Scheme 6, R... 1 -R 5 X is defined the same as above.

[0096] IA, IC, ID, IE, IF, or IG (1 molar equivalent) are dissolved in dry N,N-dimethylformamide (4 mL, 0.1 mmol), potassium carbonate (4 molar equivalent), and alkyl halide (iodomethane or benzyl bromide, 3 molar equivalent). The reaction solution is reacted at 50 °C for 12 hours. The solvent is removed by vacuum distillation, and the product is purified by silica gel column chromatography or preparative plate chromatography to obtain the target product III.

[0097] Among them, R 1 R 2 R 3 R 4 R 5 X and n are as defined above.

[0098] According to the present invention, the compound represented by general formula I, or its salt formed with a physiologically acceptable acid, can be formulated into suitable galen dosage forms, such as for oral administration, injection, nasal spray, etc., according to acceptable pharmaceutical procedures. The pharmaceutical compositions according to the present invention comprise the compound represented by general formula I, and compatible pharmaceutically acceptable carrier materials or diluents, which are well known in the art. The carrier can be any inert material, organic or inorganic, suitable for enteral, transdermal, or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline cellulose starch, starch, sodium glycolate starch, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc. The composition may also contain other pharmaceutically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc.

[0099] The compositions according to the invention can be formulated into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, syrups, elixirs, etc., and into sterile solutions, suspensions or emulsions for parenteral administration.

[0100] The compounds and pharmaceutical compositions according to the present invention can be used to prepare applications for the treatment of various types of tumors (including but not limited to colorectal cancer, breast cancer, liver cancer, cervical cancer, thyroid cancer, and gastric cancer). The dosage of a specific compound will vary depending on its potency, route of administration, patient age and weight, and the severity of the treated condition.

[0101] The following non-limiting examples and pharmacological experiments will further illustrate the invention.

[0102] Experimental Section

[0103] General methods

[0104] All compounds 1 ¹H-NMR spectra were acquired on a Brucker AVANCE III 400MHz instrument, with tetraethylsilane (TMS) as an internal standard. Liquid chromatography-mass spectrometry (LC-MS) analysis was performed on a Waters Alliance e2695-ZQ2000 system, and m / z values ​​are reported. Unless otherwise stated, all solvents were used directly, all solvent ratios are v / v, and all temperatures are in degrees Celsius. o C).

[0105] The following non-limiting examples and pharmacological experiments will further illustrate the invention.

[0106] Example 1 (I-A1)

[0107] Using the synthetic method under reaction conditions a, with gelseminale A (0.1 g, 0.3 mmol) as the starting material, 0.095 g of a white solid I-A1 product was obtained, with a yield of 95%. MS (m / z): 325.23 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.46 (dd, J=7.8, 1.2Hz, 1H), 7.21 (td, J=7.7, 1.2Hz, 1H), 6.99 (td, J=7.7, 1.2H z,1H),6.86(dd,J=7.8,1.1Hz,1H),4.15(dd,J=10.9,2.3Hz,1H),3.95(dd,J=11.0,2.1Hz,1H),3.82 –3.73(m,1H),3.52(d,J=1.4Hz,1H),2.86(d,J=10.1Hz,1H),2.73(dd,J=13.9,3.2Hz,1H),2.54–2.4 5(m,1H),2.20–2.00(m,4H),1.90(dt,J=14.2,7.3Hz,1H),1.85–1.80(m,1H),0.88(t,J=7.4Hz,3H).

[0108] Example 2 (I-A2)

[0109] Using reaction b of method one, with gelseminale A (0.32 g, 1.0 mmol, 1.0 mmol) and hydrobromic acid as raw materials, 240 mg of product I-A2, a white solid, was obtained, with a yield of 60%. MS (m / z): 402.93, 405.05 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.44(d,J=7.7Hz,1H),7.20(td,J=7.7,1.2Hz,1H),6.98(td,J=7.6,1.2Hz,1H),6. 85(d,J=7.7Hz,1H),5.93(q,J=7.0Hz,1H),4.13(dd,J=11.1,2.3Hz,1H),3.92(dd,J=11.1,2.1Hz,1H),3. 78(d,J=3.2Hz,1H),3.50(d,J=1.4Hz,1H),3.28(s,1H),2.63(dd,J=14.8,3.1Hz,1H),2.57(d,J=8.4Hz, 1H), 2.31 (t, J = 7.0Hz, 1H), 2.27 (d, J = 3.0Hz, 3H), 2.24 (s, 1H), 2.13–2.02 (m, 2H), 1.57 (d, J = 7.0Hz, 3H).

[0110] Example 3 (I-B1)

[0111] Using reaction condition c of synthesis method two, with gelseminale A (32 mg, 0.1 mmol) and 1-chloroethyl chloroformate (72 mg, 0.5 mmol) as starting materials, a white solid product I-B1 was obtained in 70% yield. MS (m / z): 309.19 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.44(d,J=7.6Hz,1H),7.19(t,J=7.7Hz,1H),6.99(t,J=7.6Hz,1H),6.79(d,J=7.7Hz,1H),6. 20(dd,J=17.8,11.0Hz,1H),5.09(d,J=11.0Hz,1H),4.95(d,J=17.8Hz,1H),4.02(dd,J=11.1,2.1Hz,1H),3.95(dd ,J=11.1,2.1Hz,1H),3.87(s,1H),3.79(d,J=3.3Hz,1H),2.99(d,J=11.2Hz,1H),2.83(dd,J=14.4,3.0Hz,1H),2.7 0(d,J=11.2Hz,1H),2.42(t,J=7.0Hz,1H),2.33(d,J=8.4Hz,1H),2.00(ddd,J=14.4,5.7,2.9Hz,1H),1.75(s,1H).

[0112] Example 4 (I-B2)

[0113] Using reaction d of synthetic method two, with I-B1 (20 mg, 0.065 mmol) and benzoyl chloride as starting materials, 18 mg of white solid product I-B1 was obtained, with a yield of 67%. MS (m / z): 413.27 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.22(dd,J=39.9,5.8Hz,1H),7.64-7.42(m,2H),7.42-7.30(m,3H),7.20(dt,J=1 5.7,7.8Hz,1H),7.07(t,J=8.1Hz,1H),6.85(dd,J=27.8,7.7Hz,1H),6.30(ddd,J=59.3,17.8,11.0Hz, 1H),5.30-5.13(m,1H),5.14-5.07(m,1H),5.06-4.42(m,1H),4.22-3.83(m,2H),3.83-3.69(m,1H),3. 53-3.08(m,2H),2.90(td,J=14.6,3.0Hz,1H),2.52(ddd,J=34.7,12.9,7.5Hz,2H),2.14-1.95(m,2H).

[0114] Example 5 (I-B3)

[0115] Using reaction d of synthetic method two, with I-B1 (20 mg) and furan-2-formyl chloride as raw materials, 20 mg of white solid product I-B3 was obtained, with a yield of 76%. MS (m / z): 403.18 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.19(d,J=38.8Hz,1H),7.62–7.49(m,1H),7.45(d,J=8.4Hz,1H),7.21(q,J=7.3Hz,1H),7 .10–6.99(m,2H),6.83(dd,J=13.1,7.7Hz,1H),6.54–6.42(m,1H),6.34(td,J=18.0,11.0Hz,1H),5.44–5.14(m, 2H),5.10(dd,J=17.8,9.3Hz,1H),4.17–3.99(m,2H),3.94–3.63(m,2H),3.56–3.19(m,1H),2.92(ddd,J=14.1,1 0.1, 3.0Hz, 1H), 2.58 (q, J = 6.9Hz, 1H), 2.45 (t, J = 10.0Hz, 1H), 2.08 (ddd, J = 14.5, 5.9, 2.8Hz, 1H), 1.99 (s, 1H).

[0116] Example 6 (I-B4)

[0117] Using reaction d of synthesis method two, with I-B1 (20 mg) and piperidinylpiperidineformyl chloride hydrochloride (21 mg) as raw materials, 30 mg of white solid I-B4 was obtained in 92% yield. MS (m / z): 420.34 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.21(d,J=27.9Hz,1H),7.48(d,J=7.6Hz,1H),7.17(dd,J=8.4,7.0Hz,1H),7.00(td,J=7.6,1.3Hz,1H),6.77(d, J=7.7Hz,1H),6.23(dd,J=17.8,11.0Hz,1H),5.15(d,J=11.0Hz,1H),5.01(dd,J=17.8,1.1Hz,1H),4.50(d,J=1.5Hz,1H),3.80(dq,J=1 0.6,3.6,3.0Hz,3H),3.33(d,J=10.1Hz,1H),2.97(d,J=10.1Hz,1H),2.84(dd,J=14.3,3.0Hz,1H),2.67(tdd,J=12.7,4.9,2.4Hz,2H), 2.58(d,J=5.9Hz,2H), 2.02(ddd,J=14.4,5.1,2.8Hz,1H), 1.85(d,J=11.9Hz,3H), 1.67(t,J=5.9Hz,2H), 1.46(td,J=12.1,4.2Hz,3H).

[0118] Example 7 (I-B5)

[0119] Using reaction d of synthetic method two, with I-B1 and dimethylglycine as raw materials, a white solid product I-B5 was obtained in 87% yield. MS (m / z): 394.29 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.46(d,J=18.7Hz,1H),7.65–7.50(m,3H),7.43(dd,J=17.1,7.6Hz,1H),7.35(td,J=7.6,1.2Hz,1H),7.25–7.10(m,2H) ,6.99(dtd,J=22.1,7.7,1.1Hz,1H),6.79(dd,J=36.2,7.7Hz,1H),6.32(ddd,J=17.8,14.2,11.0Hz,1H),5.25–5.11(m,1H),5.11–4.93(m,3H) ,4.86(dd,J=9.7,1.4Hz,1H),4.82–4.62(m,4H),4.31–3.92(m,4H),3.88–3.57(m,3H),3.52(t,J=11.7Hz,1H),3.28–3.02(m,5H),2.98–2.90 (m,2H),2.84(dq,J=7.8,3.7,3.3Hz,4H),2.70–2.55(m,6H),2.43–2.2 7(m,6H),2.24(d,J=14.3Hz,6H),2.11–1.99(m,1H),1.94–1.78(m,3H).

[0120] Example 8 (I-B6)

[0121] Using reaction d of synthetic method two, with I-B1 and p-methylbenzenesulfonyl chloride as raw materials, a white solid product I-B6 was obtained in 78% yield. MS (m / z): 463.18 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.46–7.39 (m, 1H), 7.36–7.32 (m, 2H), 7.32–7.27 (m, 1H), 7.11 (td, J = 7.6, 1.1Hz, 1H), 6. 87(d,J=8.0Hz,2H),6.78(dd,J=7.7,1.0Hz,1H),5.96(dd,J=17.8,11.0Hz,1H),5.10(d,J=11.0Hz,1H),4.94(dd,J=17.8,1 .0Hz,1H),4.36(d,J=1.5Hz,1H),3.98(t,J=2.2Hz,2H),3.74(d,J=3.0Hz,1H),3.15(d,J=11.3Hz,1H),3.07(d,J=11.2Hz,1 H),2.72(dd,J=14.6,3.0Hz,1H),2.52(d,J=8.4Hz,1H),2.48–2.39(m,1H),2.27(s,3H),1.97(ddd,J=14.6,5.7,2.8Hz,1H).

[0122] Example 9 (I-B7)

[0123] Using reaction d of synthetic method two, with I-B1 and p-fluorobenzoyl chloride as raw materials, a white solid product I-B7 was obtained in 66% yield. MS (m / z): 431.22 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.52(dd,J=45.4,9.3Hz,1H),7.56(d,J=7.6Hz,1H),7.47(dd,J=8.6,5.4Hz,1H),7.40– 7.30(m,1H),7.20(q,J=7.1Hz,1H),7.13–7.00(m,3H),6.81(dd,J=7.6,2.1Hz,1H),6.30(ddd,J=53.6,17.8, 11.0Hz,1H),5.29–4.44(m,3H),4.08–3.99(m,1H),3.87–3.67(m,2H),3.32(dd,J=65.5,11.5Hz,1H),3.19–2 .82(m,2H),2.63–2.51(m,1H),2.51–2.40(m,1H),2.08(ddd,J=9.0,5.8,2.9Hz,1H),1.98(d,J=11.1Hz,1H).

[0124] Example 10 (I-B8)

[0125] Using reaction d of synthetic method two, with I-B1 and p-methoxybenzoyl chloride as raw materials, a white solid I-B8 was obtained in 57% yield. MS (m / z): 443.25 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.88(d,J=46.1Hz,1H),7.55(d,J=7.6Hz,1H),7.45(d,J=8.4Hz,1H),7.31(d,J=8.3Hz,1H),7. 17(t,J=7.7Hz,1H),7.14–6.96(m,1H),6.94–6.81(m,2H),6.79(t,J=6.7Hz,1H),6.30(ddd,J=50.7,17.8,11.0Hz,1H ),5.27–4.56(m,3H),4.17–3.75(m,6H),3.59(dd,J=104.0,11.5Hz,1H),3.19(dd,J=28.6,11.5Hz,1H),2.98–2.81(m ,1H),2.54(dd,J=9.1,5.8Hz,1H),2.47(t,J=9.8Hz,1H),2.05(ddd,J=14.4,5.3,2.6Hz,1H),1.97(d,J=11.2Hz,1H).

[0126] Example 11 (I-B9)

[0127] Using reaction d of synthetic method two, with I-B1 and 2-naphthoyl chloride as raw materials, white solid I-B9 was obtained in 77% yield. MS (m / z): 463.25 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.61 (dd, J=51.5, 10.6Hz, 1H), 8.01–7.70 (m, 4H), 7.6 5–7.41(m,3H),7.26–6.71(m,4H),6.31(ddd,J=69.3,17.8,11.0Hz,1H),5.3 4–4.65(m,3H),4.26–4.05(m,1H),4.03–3.40(m,3H),3.25(dd,J=61.1,11.5 Hz,1H),2.91(td,J=14.7,3.0Hz,1H),2.66–2.39(m,2H),2.16–1.95(m,2H).

[0128] Example 12 (I-B10)

[0129] Using reaction d of synthetic method two, with I-B1 and oxaloyl chloride as raw materials, white solid B10 was obtained in 66% yield. MS (m / z): 409.27 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.60 (dd, J=51.5, 10.6Hz, 1H), 8.03–7.71 (m, 4H), 7.65–7.42 (m, 3H ),7.20(dt,J=12.6,7.7Hz,1H),7.12–6.96(m,1H),6.88–6.75(m,1H),6.31(ddd,J=69.3, 17.8,11.0Hz,1H),5.32–4.66(m,3H),4.24–4.03(m,1H),4.03–3.42(m,3H),3.25(dd,J=6 1.1,11.5Hz,1H),2.90(td,J=14.7,3.0Hz,1H),2.65–2.43(m,2H),2.05(d,J=6.9Hz,2H).

[0130] Example 13 (I-B11)

[0131] Using reaction d of synthetic method two, with I-B1 n-heptanoyl chloride as the starting material, white solid B11 was obtained in 73% yield. MS (m / z): 421.5 [M+H] + . 1H NMR(600MHz, CDCl3)δ8.08(d,J=72.9Hz,1H),7.47(dd,J=46.5,7.6Hz,1H),7.26–7.1 7(m,1H),7.04(dt,J=20.8,7.6Hz,1H),6.83(dd,J=35.2,7.7Hz,1H),6.31(dd,J=17. 8,11.0Hz,1H),5.19(dd,J=11.1,7.7Hz,1H),5.06(dd,J=17.8,8.3Hz,1H),4.72(d,J =327.0Hz,1H),4.11–4.03(m,1H),3.99(ddd,J=10.7,7.9,2.2Hz,1H),3.89–3.79(m,1 H),3.48(dd,J=57.7,11.2Hz,1H),3.10(dd,J=17.3,11.2Hz,1H),2.89(ddd,J=18.0, 14.4,3.0Hz,1H),2.52(dt,J=13.2,6.9Hz,1H),2.31(dd,J=19.9,8.4Hz,1H),2.23(d dd,J=10.4,8.7,6.3Hz,1H),2.07(dtd,J=12.9,6.8,3.1Hz,3H),1.88(d,J=3.6Hz,1H ),1.77(s,2H),1.55(p,J=6.8Hz,3H),1.40–1.26(m,7H),0.86(td,J=6.7,3.5Hz,4H).

[0132] Example 14 (I-B12)

[0133] Using reaction d of synthesis method two, with I-B1 and pentadecanoyl chloride (26 mg) as raw materials, white solid B12 can be obtained with a yield of 64%. 1H NMR (600MHz, CDCl3) δ7.98 (d, J=66.4Hz, 1H), 7.47 (dd, J=47.6, 7.7Hz, 1H), 7. 26–7.15(m,1H),7.04(dt,J=18.1,7.6Hz,1H),6.82(dd,J=34.2,7.7Hz,1H),6 .31(dd,J=17.8,11.0Hz,1H),5.19(dd,J=11.1,7.1Hz,1H),5.06(dd,J=17.8, 8.9Hz,1H),4.71(d,J=327.7Hz,1H),4.03(dd,J=41.4,10.7Hz,2H),3.84(d,J =28.9Hz,1H),3.47(dd,J=57.9,11.2Hz,1H),3.09(dd,J=16.8,11.2Hz,1H),2 .89(ddd,J=18.0,14.5,3.0Hz,1H),2.52(dt,J=12.6,6.7Hz,1H),2.31(dd,J= 19.4,8.2Hz,1H),2.27–2.15(m,1H),2.07(tt,J=10.6,5.2Hz,2H),1.88(s,1H ), 1.74 (s, 2H), 1.56 (q, J = 7.5Hz, 2H), 1.36–1.18 (m, 24H), 0.93–0.84 (m, 3H).

[0134] Example 15 (I-B13)

[0135] Using reaction d of synthetic method two, with I-B1 and 1-bromo-n-heptane as raw materials, white solid B13 was obtained in 56% yield. MS (m / z): 407.5 [M+H] + . 1H NMR (600MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.28–7.24(m,1H),7.03(t,J=7.5Hz,1H),6.80(d,J=7.7Hz,1H),6.25(dd,J=1 7.7,10.9Hz,1H),5.13(d,J=11.0Hz,1H),5.00–4.91(m,1H),4.12(dd,J=11.1,2.2Hz,1H),3.92(dd,J=11.1,2.0Hz,1H),3. 80–3.72(m,2H),3.65(t,J=6.7Hz,1H),3.58(p,J=7.1Hz,2H),2.93–2.82(m,2H),2.53–2.19(m,5H),2.00(ddd,J=14.3,5.8 ,2.8Hz,1H),1.89(s,1H),1.64(dq,J=14.7,6.1Hz,3H),1.58(dd,J=7.9,6.4Hz,1H),1.34(ddd,J=36.5,12.9,7.2Hz,23H).

[0136] Example 16 (I-B14)

[0137] Using reaction d of synthesis method two, with I-B1 and 1-bromopentadecane as raw materials, a white solid I-B14 can be obtained in a yield of 68%. 1 H NMR (600MHz, CDCl3) δ7.42(d,J=7.6Hz,1H),7.31(s,1H),7.19(t,J=7.7Hz,1H),7.01(t,J=7.6Hz,1H),6.79(d,J=7.6Hz,1H),6.24(dd, J=17.8,11.0Hz,1H),5.09(dd,J=11.0,1.3Hz,1H),4.94(dd,J=17.8,1.4Hz,1H),4.10(dd,J=11.1,2.3Hz,1H),3.89(dd,J=11.1,2.0Hz ,1H),3.82(d,J=3.2Hz,1H),3.52(s,1H),2.89–2.78(m,2H),2.43(d,J=8.5Hz,1H),2.39–2.32(m,1H),2.32–2.27(m,2H),2.25–2.19(m ,1H),2.04–1.94(m,2H),1.37(s,2H),1.34(d,J=9.1Hz,3H),1.28(s,4H),1.24(dt,J=18.0,6.4Hz,13H),0.87(dt,J=13.9,7.0Hz,5H).

[0138] Example 17 (IC)

[0139] Using the three-reaction synthesis method e, with gelsemin A and nitric acid as raw materials, a white solid product IC was obtained in 63% yield. MS (m / z): 409.27 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.27(d,J=2.4Hz,1H),8.22(dd,J=8.6,2.3Hz,1H),7.01(d,J=8.6Hz,1H),6.21(d d,J=17.8,11.0Hz,1H),5.06(dd,J=11.1,1.3Hz,1H),4.98(dd,J=17.8,1.4Hz,1H),4.16(dd,J=11.2,2 .2Hz,1H),3.99(dd,J=11.2,2.1Hz,1H),3.77(d,J=3.1Hz,1H),3.50(d,J=1.4Hz,1H),2.85–2.71(m,2H ),2.54(d,J=8.5Hz,1H),2.40(t,J=7.1Hz,1H),2.34(d,J=10.5Hz,1H),2.29(s,3H),2.12–1.98(m,2H).

[0140] Example 18 (ID)

[0141] Using the three-reaction synthesis method e, with IC and zinc powder as raw materials, a yellow solid product ID was obtained in 100.0% yield. MS (m / z): 338.01 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.16 (d, J=2.3Hz, 1H), 6.83 (dd, J=8.2, 2.2Hz, 1H), 6.74 (d, J=8. 2Hz,1H),6.26(dd,J=17.8,11.1Hz,1H),5.21(d,J=11.1Hz,1H),5.13(d,J=17.8Hz,1H ),4.49(s,1H),4.13(d,J=1.9Hz,2H),3.78(d,J=3.1Hz,1H),3.18(s,1H),2.86(d,J=9 .4Hz, 4H), 2.68 (q, J=8.2, 7.6Hz, 2H), 2.41 (s, 1H), 2.10 (ddd, J=14.6, 5.5, 2.9Hz, 1H).

[0142] Example 19 (I-E1)

[0143] Using the three-reaction synthesis method g, with ID and benzoyl chloride as raw materials, a yellow solid product I-E1 was obtained in 36.4% yield. MS (m / z): 442.05 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.99–7.91(m,2H),7.88(d,J=2.2Hz,1H),7.62–7.49(m,4H),6.87(d, J=8.3Hz, 1H), 6.26 (dd, J=17.8, 11.0Hz, 1H), 5.06 (dd, J=11.0, 1.3Hz, 1H), 4.98 (dd, J=17. 8,1.4Hz,1H),4.17–4.08(m,1H),4.00(dd,J=11.2,2.1Hz,1H),3.79–3.69(m,2H),2.90–2. 78(m,2H),2.51(d,J=8.4Hz,1H),2.47–2.36(m,2H),2.34(s,3H),2.05(s,1H),2.01(s,1H).

[0144] Example 20 (I-E2)

[0145] Using the three-reaction synthesis method g, with ID and p-methoxybenzoyl chloride as starting materials, a yellow solid product I-E2 was obtained in 59.5% yield. MS (m / z): 442.05 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.99–7.91(m,2H),7.87(d,J=2.1Hz,1H),7.47(dd,J=8.3,2.1Hz,1H),7.09–7.00(m,2H),6 .88(d,J=8.3Hz,1H),6.27(dd,J=17.8,11.1Hz,1H),5.14(dd,J=11.1,1.1Hz,1H),5.06(dd,J=17.9,1.2Hz,1H),4 .14(dd,J=11.3,2.1Hz,1H),4.04(d,J=11.2Hz,2H),3.88(s,3H),3.79(d,J=3.3Hz,1H),3.00(d,J=11.3Hz,1H), 2.90–2.78(m,2H),2.58(d,J=8.0Hz,4H),2.53(t,J=6.8Hz,1H),2.24(s,1H),2.08(ddd,J=14.5,5.6,2.8Hz,1H).

[0146] Example 21 (I-E3)

[0147] Using a three-reaction synthetic method (g) with ID and p-2-naphthoyl chloride as starting materials, the product I-E3, a yellow solid, was obtained in 71% yield. MS (m / z): 491.25 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.52(s,1H),8.07–8.03(m,2H),8.01(d,J=1.2Hz,2H),7.99–7.93(m,2H),7.63(dddd,J=13.8,11. 3,6.2,1.9Hz,4H),6.90(d,J=8.4Hz,1H),6.28(dd,J=17.9,10.9Hz,1H),5.06(dd,J=10.9,1.4Hz,1H),4.98(dd,J=17.9, 1.6Hz,1H),4.15(dt,J=11.1,2.2Hz,1H),4.07–4.01(m,1H),3.75(d,J=23.7Hz,2H),2.86(dt,J=14.3,4.0Hz,1H),2.82– 2.74(m,1H),2.50(t,J=8.7Hz,1H),2.42–2.38(m,1H),2.35(d,J=10.5Hz,2H),2.30(d,J=8.2Hz,5H),2.12–1.99(m,3H).

[0148] Example 22 (I-E4)

[0149] Using the three-reaction synthesis method g, with ID and hexanoyl chloride as raw materials, a white solid product I-E4 was obtained in 40% yield. MS (m / z): 436.27 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.07(s,1H),7.57(s,1H),7.53(d,J=2.2Hz,1H),7.46(dd,J=8.4,2.1Hz,1H),6.69( d,J=8.3Hz,1H),6.23(dd,J=17.7,11.0Hz,1H),5.13(d,J=11.0Hz,1H),4.97(d,J=17.8Hz,1H),4.08(dd, J=11.3,2.2Hz,1H),3.99(dd,J=11.2,2.1Hz,1H),3.87–3.75(m,2H),2.90–2.76(m,2H),2.60(t,J=10.9H z,2H),2.46–2.30(m,6H),2.11–1.94(m,2H),1.82–1.67(m,2H),1.36(q,J=3.6Hz,4H),0.96–0.89(m,3H).

[0150] Example 23 (I-E5)

[0151] Using the three-reaction synthesis method g, with ID and octanoic acid as raw materials, a white solid product I-E5 was obtained in 55% yield. MS (m / z): 436.27 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.63(s,1H),7.55(d,J=2.2Hz,1H),7.47(dd,J=8.4,2.1Hz,1H),7.41(s,1H),6.72(d,J =8.3Hz,1H),6.23(dd,J=17.8,11.0Hz,1H),5.13(d,J=11.0Hz,1H),4.96(d,J=17.8Hz,1H),4.09(dd,J=11.3, 2.2Hz,1H),3.99(dd,J=11.1,2.1Hz,1H),3.82(d,J=3.2Hz,1H),3.73(s,1H),2.88–2.75(m,2H),2.56(s,2H) ,2.35(q,J=7.4,6.0Hz,7H),2.09–1.96(m,3H),1.73(p,J=7.3Hz,2H),1.44–1.18(m,14H),0.94–0.83(m,4H).

[0152] Example 24 (I-E6)

[0153] Using the three-reaction synthesis method g, with ID and undecanoic acid as raw materials, a white solid product I-E6 was obtained in 36% yield. MS (m / z): 506.38 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ8.49(s,1H),7.62–7.46(m,2H),7.38(dd,J=8.4,2.1Hz,1H),6.60(d,J=8.3Hz,1H),6.21( dd,J=17.8,11.0Hz,1H),5.08(d,J=11.0Hz,1H),4.93(d,J=17.8Hz,1H),4.07(dd,J=11.2,2.2Hz,1H),3.95(dd, J=11.2,2.1Hz,1H),3.77(d,J=3.1Hz,1H),3.58(s,1H),2.84–2.77(m,2H),2.46(d,J=8.5Hz,1H),2.42–2.31(m, 4H), 2.28 (s, 3H), 1.99 (d, J = 14.0Hz, 2H), 1.71 (p, J = 7.5Hz, 2H), 1.27 (d, J = 12.4Hz, 17H), 0.87 (t, J = 6.7Hz, 3H).

[0154] Example 25 (I-E7)

[0155] Using the three-reaction synthesis method g, with ID and tetradecanoic acid as raw materials, a white solid product I-E7 was obtained in 45% yield. MS (m / z): 548.40 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.56(s,1H),8.16(s,1H),7.60(d,J=2.1Hz,1H),7.56–7.46(m,1H),6.66(d,J=8.3Hz,1H),6.23 (dd,J=17.8,11.0Hz,1H),5.12(d,J=11.1Hz,1H),4.96(d,J=17.8Hz,1H),4.14–3.95(m,3H),3.77(d,J=3.1Hz,1H),3 .04(q,J=7.3Hz,1H),2.89(d,J=11.2Hz,1H),2.80(dd,J=14.5,3.0Hz,1H),2.67(dt,J=14.7,7.2Hz,2H),2.49–2.31( m,7H),2.09(s,1H),2.00(ddd,J=14.6,5.9,2.9Hz,1H),1.77–1.58(m,3H),1.38–1.25(m,20H),0.87(t,J=6.7Hz,6H).

[0156] Example 26 (I-E8)

[0157] Using the three-reaction synthesis method g, with ID and hexadecanoic acid as raw materials, a white solid product I-E8 was obtained in 87% yield. MS (m / z): 576.36 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),7.98(s,1H),7.72(d,J=8.4Hz,1H),7.40(s,1H),6.70(d,J=8.4Hz,1H),6.22( dd,J=17.8,11.0Hz,1H),5.18(d,J=11.0Hz,1H),5.00(d,J=17.7Hz,1H),4.22(s,1H),4.05(q,J=11.3Hz,2H),3. 80(s,1H),2.95(s,1H),2.88–2.76(m,2H),2.72(d,J=8.2Hz,1H),2.48(d,J=11.1Hz,4H),2.36(t,J=7.6Hz,2H), 2.26–2.14(m,1H),2.08–1.95(m,2H),1.70(p,J=7.9,6.8Hz,2H),1.26(d,J=11.3Hz,33H),0.87(t,J=6.6Hz,4H).

[0158] Example 27 (I-E9)

[0159] Using the three-reaction synthesis method g, with ID and octadecanoic acid as raw materials, a white solid I-E9 can be obtained in 87% yield. MS (m / z): 604.52 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.75(s,1H),7.61(dd,J=8.4,2.0Hz,1H),7.52(d,J=2.1Hz,1H),6.73(d,J=8.3Hz, 1H),6.26(dd,J=17.8,11.1Hz,1H),5.10(d,J=11.1Hz,1H),5.03(d,J=17.9Hz,1H),4.04(s,1H),4.02–3.96(m,1H),3.90 (d,J=10.9Hz,1H),3.65(d,J=3.2Hz,1H),3.06(q,J=7.3Hz,4H),2.83(d,J=8.2Hz,1H),2.62(d,J=13.6Hz,4H),2.50(p,J =1.9Hz,5H),2.27(t,J=7.5Hz,2H),2.00–1.89(m,1H),1.58(t,J=7.2Hz,2H),1.32–1.23(m,21H),0.85(t,J=6.7Hz,4H).

[0160] Example 28 (I-E10)

[0161] Using the three-reaction synthesis method g, with ID and n-eicosanoic acid as raw materials, a white solid I-E10 is obtained in 40% yield. MS (m / z): 632.54 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.75(s,1H),7.61(dd,J=8.4,2.0Hz,1H),7.52(d,J=2.1Hz,1H),6.73(d,J=8.3Hz, 1H),6.26(dd,J=17.8,11.1Hz,1H),5.10(d,J=11.1Hz,1H),5.03(d,J=17.9Hz,1H),4.04(s,1H),4.02–3.96(m,1H),3.90 (d,J=10.9Hz,1H),3.65(d,J=3.2Hz,1H),3.06(q,J=7.3Hz,4H),2.83(d,J=8.2Hz,1H),2.62(d,J=13.6Hz,4H),2.50(p,J =1.9Hz,5H),2.27(t,J=7.5Hz,2H),2.00–1.89(m,1H),1.58(t,J=7.2Hz,2H),1.32–1.23(m,23H),0.85(t,J=6.7Hz,4H).

[0162] Example 29 (I-E11)

[0163] Using a three-reaction synthetic method (g), with ID and 3-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)propionic acid as starting materials, brown solid I-E11 was obtained in 76% yield. MS (m / z): 572.2 [M+H] + . 1 H NMR (600MHz, MeOD) δ8.52(d,J=8.2Hz,2H),7.78(s,1H),7.27(d,J=8.2Hz,1H),6.83(d,J=8.1Hz,1H ),6.45(d,J=8.5Hz,1H),6.25(dd,J=17.7,10.8Hz,1H),5.21(d,J=10.8Hz,1H),5.11(d,J=17.6Hz,1 H),4.20(s,1H),4.12(d,J=10.6Hz,1H),3.96(s,3H),3.78(s,1H),3.18(d,J=18.7Hz,2H),2.85(d, J=13.0Hz,3H),2.79(s,3H),2.65(s,2H),2.39(s,1H),2.23–1.97(m,3H),1.60(s,1H),1.32(s,5H).

[0164] Example 30 (I-E12)

[0165] Using a three-reaction synthetic method (g), with ID and 16-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexadecanoic acid as starting materials, brown solid I-E12 was obtained in 62% yield. MS (m / z): 754.4 [M+H] + . 1H NMR (600MHz, CD3OD) δ8.58–8.36(m,2H),7.80(d,J=2.1Hz,1H),7.26(dd,J=8.3,2.0Hz,1H),6.83(d,J=8.3Hz,1H),6.34(d,J=8.9Hz,1H), 6.26(dd,J=17.9,11.0Hz,1H),5.20(d,J=11.0Hz,1H),5.11(d,J=17.8Hz,1H),4.21(s,1H),4.14(d,J=11.1Hz,1H),4.03(d,J=11.3Hz,1H ),3.79(d,J=2.8Hz,1H),3.52(s,2H),3.18(d,J=17.2Hz,2H),2.86(dd,J=14.5,2.9Hz,1H),2.80(s,3H),2.65(d,J=6.9Hz,2H),2.37(dd, J=13.3,5.7Hz,3H),2.10(dt,J=13.9,4.0Hz,1H),1.77(p,J=7.3Hz,2H),1.70(p,J=7.4Hz,2H),1.46(p,J=7.1Hz,2H),1.42–1.23(m,24H).

[0166] Example 31 (I-F1)

[0167] Using a three-reaction synthesis method with ID and bromine as raw materials, a yellow solid I-F1 was obtained in 94% yield. MS (m / z): 403.15, 405.15 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.04 (s, 1H), 7.50 (d, J = 2.1Hz, 1H), 7.31-7.27 (m, 1H), 6.36 (d ,J=8.1Hz,1H),4.17-4.06(m,2H),3.94-3.83(m,2H),3.37(s,1H),2.99(d,J=9.9Hz ,1H),2.68(dd,J=13.9,3.1Hz,1H),2.49(d,J=7.7Hz,1H),2.28(s,3H),2.13-1.93( m,6H),1.89-1.80(m,1H),1.78(s,1H),1.25(t,J=7.1Hz,2H),0.81(t,J=7.3Hz,3H). 13C NMR (101MHz, CDCl3) δ179.60,139.74,134.69,131.28,131.09,114.53,110.41,71.48,69.39,63 .49,61.77,60.54,55.01,52.47,50.07,38.75,37.39,35.59,22.69,21.80,21.19,14.33,9.82.

[0168] Example 32 (I-F2)

[0169] Using a three-reaction synthesis method with ID and bromine as raw materials, a yellow solid I-F2 was obtained in 98% yield. MS (m / z): 481.03, 483.03, 484.94 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.66(s,1H),7.49(d,J=1.7Hz,1H),7.43(d,J=1.8Hz,1H ),4.10(dd,J=11.1,2.2Hz,1H),3.91–3.82(m,2H),3.30(s,1H),2.93(d,J=9.9 Hz,1H),2.66(dd,J=14.1,3.0Hz,1H),2.44(d,J=8.1Hz,1H),2.26(s,3H),2.09 (d,J=9.8Hz,1H),2.06–1.92(m,4H),1.90–1.77(m,2H),0.82(t,J=7.4Hz,3H).

[0170] Example 33 (I-G1)

[0171] Using reaction i of synthetic method three, with I-F1 and 4-isopropylphenylboronic acid as starting materials, a white solid product I-G1 was obtained in 56% yield. MS (m / z): 443.30 [M+H] + . 1H NMR(400MHz, CDCl3) δ8.89(d,J=66.1Hz,1H),7.62(d,J=1.9Hz,1H),7.49–7.42(m,2H),7.30(dd,J=9 .0,2.8Hz,3H),6.70–6.57(m,1H),4.14(dd,J=11.1,2.2Hz,1H),3.98–3.85(m,2H),3.50(s,1H),2.96 (p,J=6.7Hz,2H),2.73(dd,J=13.8,3.1Hz,1H),2.51(d,J=7.5Hz,1H),2.28(s,3H),2.25–2.13(m,1H) ,2.05(tdd,J=12.2,9.6,6.8Hz,3H),1.94–1.84(m,2H),1.30(d,J=6.9Hz,7H),0.85(t,J=7.3Hz,3H).

[0172] Example 34 (I-G2)

[0173] Using the third reaction of synthetic method i, with I-F2 and 4-isopropylphenylboronic acid as raw materials, a white solid product I-G2 was obtained in 57% yield. MS (m / z): 561.45 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.56 (d, J=1.8Hz, 1H), 7.49–7.42 (m, 2H), 7.40–7.29 (m, 5H), 7. 29–7.21(m,2H),4.10(dd,J=11.2,2.2Hz,1H),3.90–3.77(m,2H),3.54(s,1H),2.93(d q,J=16.0,6.9Hz,2H),2.87–2.80(m,1H),2.73–2.62(m,1H),2.43(d,J=7.4Hz,1H),2 .24(s,3H),2.15(d,J=10.1Hz,1H),2.08–1.96(m,3H),1.93(s,1H),1.83(dt,J=14.2,

[0174] Example 35 (I-G3)

[0175] Using the third reaction of synthetic method i, with I-F1 and 3-pyridineboronic acid as raw materials, a white solid product I-G3 was obtained in 70% yield. MS (m / z): 402.32 [M+H] + . 1H NMR (400MHz, CDCl3) δ9.21–9.04(m,1H),8.78(d,J=2.4Hz,1H),8.58–8.51(m,1H),7.79(dt,J=8.0,2 .0Hz,1H),7.59(d,J=1.9Hz,1H),7.39–7.29(m,2H),6.75(d,J=8.0Hz,1H),4.19–4.06(m,2H),3.95– 3.85(m,2H),3.46(s,1H),2.93(d,J=10.0Hz,1H),2.76–2.64(m,1H),2.50(d,J=7.4Hz,1H),2.29(s, 3H), 2.17 (d, J = 10.0Hz, 1H), 2.02 (h, J = 7.1Hz, 4H), 1.89 (q, J = 7.4, 7.0Hz, 2H), 0.83 (t, J = 7.3Hz, 4H).

[0176] Example 36 (I-G4)

[0177] Using the third reaction of synthetic method i, with I-F1 and 4-cyanobenzonic acid as raw materials, a white solid product I-G4 was obtained in 63% yield. MS (m / z): 426.27 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),7.70(d,J=8.5Hz,2H),7.60(d,J=8.4Hz,2H),7 .57(d,J=1.8Hz,1H),7.40(dd,J=8.1,1.8Hz,1H),6.86(d,J=8.1Hz,1H),4.17–4. 07(m,1H),3.95–3.83(m,2H),3.52(s,1H),2.90(d,J=10.4Hz,1H),2.77–2.65(m, 1H),2.58(d,J=7.5Hz,1H),2.35(s,4H),2.11–1.91(m,5H),0.83(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ179.31,145.95,140.99,133.33,132.90,132.81,131.07,127.70,127.56,127.45,119.1 2,110.50,109.84,72.03,69.37,63.68,61.61,54.56,52.40,49.26,39.84,36.63,29.81,22.61,21.72,9.85.

[0178] Example 37 (I-G5)

[0179] Using the third reaction of synthetic method i, with I-F1 and 3-fluorophenylboronic acid as raw materials, a white solid product I-G5 was obtained in 75% yield. MS (m / z): 419.28 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.20(s,1H),7.60(d,J=1.9Hz,1H),7.39(td,J=8.0,6.0Hz,1H),7.29(dt,J=7.8,1. 3Hz,1H),7.26–7.15(m,2H),7.01(td,J=8.4,2.6Hz,1H),6.60(d,J=8.0Hz,1H),4.15(dd,J=11.2,2.2Hz, 1H),3.99–3.85(m,2H),3.47(s,1H),2.97(d,J=9.9Hz,1H),2.73(dt,J=13.4,3.3Hz,1H),2.52(d,J=7.5H z,1H),2.29(s,3H),2.18(d,J=10.1Hz,1H),2.14–1.97(m,3H),1.96–1.79(m,2H),0.85(t,J=7.3Hz,3H). 19 F NMR (376MHz, CDCl3) δ-112.99.

[0180] Example 38 (I-G6)

[0181] Using the third reaction of synthetic method i, with I-F1 and 3-methoxyphenylboronic acid as starting materials, a white solid product I-G6 was obtained in 61% yield. MS (m / z): 431.23 [M+H] + . 1H NMR (400MHz, CDCl3) δ9.12(s,1H),7.63(d,J=1.8Hz,1H),7.35(t,J=7.9Hz,1H),7.27(d,J=7.5Hz,1H),7.12(dt,J=7. 8,1.2Hz,1H),7.05(t,J=2.1Hz,1H),6.87(ddd,J=8.3,2.6,0.9Hz,1H),6.57(d,J=8.0Hz,1H),4.15(dd,J=11.2,2.2H z,1H),3.91(dt,J=8.2,2.0Hz,2H),3.84(s,3H),3.48(s,1H),2.98(d,J=9.9Hz,1H),2.73(dd,J=13.8,3.1Hz,1H),2. 50(d,J=7.6Hz,1H),2.27(s,3H),2.16(d,J=9.8Hz,1H),2.13–1.97(m,3H),1.94–1.81(m,2H),0.85(t,J=7.3Hz,3H).

[0182] Example 39 (I-G7)

[0183] Using the third reaction of synthetic method i, with I-F1 and 3-carbamoylphenylboronic acid as raw materials, a white solid product I-G7 was obtained in 58% yield. MS (m / z): 444.23 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.44(s,1H),7.97(t,J=1.9Hz,1H),7.73(d,J=7.7Hz,1H),7.69–7.62(m,1H),7.60(d,J=1.8Hz, 1H),7.44(t,J=7.7Hz,1H),7.24(d,J=9.2Hz,1H),6.98(d,J=9.7Hz,1H),6.46(d,J=7.9Hz,1H),6.34(s,1H),4.20–4. 07(m,1H),3.97–3.89(m,1H),3.86(s,1H),3.51(s,1H),3.00(d,J=9.9Hz,1H),2.69(dd,J=13.5,3.4Hz,1H),2.49(d, J=7.5Hz,1H),2.27(s,3H),2.11(d,J=10.6Hz,1H),2.05–1.94(m,3H),1.85(d,J=13.8Hz,2H),0.82(t,J=7.3Hz,3H).

[0184] Example 40 (I-G8)

[0185] Using the third reaction of synthetic method i, with I-F1 and furan-3-boronic acid as raw materials, a white solid product I-G8 was obtained in 80% yield. MS (m / z): 391.24 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.94(s,1H),7.69(s,1H),7.52–7.39(m,2H),7.34–7.21(m,1H),6 .77(d,J=8.0Hz,1H),6.65(d,J=1.9Hz,1H),4.19–4.07(m,2H),4.00(dd,J=11.4,2.1Hz ,1H),3.87(d,J=3.2Hz,1H),3.80(s,1H),2.98–2.78(m,3H),2.71(dd,J=14.7,3.0Hz,1 H), 2.50 (s, 3H), 2.23–2.14 (m, 1H), 2.05 (q, J = 10.5, 8.8Hz, 5H), 0.86 (t, J = 7.4Hz, 4H).

[0186] Example 41 (I-G9)

[0187] Using reaction i of synthetic method three, with I-F1 and 3-dimethylaminophenylboronic acid as raw materials, a white solid product I-G9 was obtained in 48% yield. MS (m / z): 444.28 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),7.63(d,J=1.8Hz,1H),7.33(dd,J=6.6,1.4Hz,1H),7.32–7.28(m,1H),6.89(dt ,J=7.8,1.1Hz,1H),6.85(t,J=2.1Hz,1H),6.72(ddd,J=8.3,2.6,0.9Hz,1H),6.64(d,J=8.0Hz,1H),4.14(dd,J=1 1.1,2.2Hz,1H),3.95–3.86(m,2H),3.50(s,1H),2.99(s,6H),2.95(d,J=9.9Hz,1H),2.73(dd,J=13.9,3.1Hz,1H) ,2.50(s,1H),2.27(s,3H),2.18(d,J=9.5Hz,1H),2.11–1.98(m,3H),1.90(d,J=7.0Hz,2H),0.86(t,J=7.3Hz,3H).

[0188] Example 42 (I-G10)

[0189] Using reaction i of synthetic method three, with I-F1 and 2-furanboric acid as raw materials, a white solid product I-G10 was obtained in 70% yield. MS (m / z): 391.20 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.40(s,1H),7.70(d,J=1.8Hz,1H),7.46(d,J=1.8Hz,1H),7.30(dd,J=8.1,1.7Hz,1H) ,6.52(d,J=3.3Hz,1H),6.49–6.41(m,2H),4.15(dd,J=11.1,2.2Hz,1H),3.96(dd,J=11.1,2.0Hz,1H),3.88 (q,J=2.0Hz,1H),3.56–3.46(m,1H),2.96(d,J=10.0Hz,1H),2.71(dd,J=13.7,3.1Hz,1H),2.51(d,J=7.5Hz ,1H),2.27(s,3H),2.17(d,J=10.2Hz,1H),2.09–1.96(m,4H),1.84(d,J=6.7Hz,2H),0.83(t,J=7.4Hz,4H).

[0190] Example 43 (I-G11)

[0191] Using the third reaction of synthetic method i, with I-F1 and 4-pyridineboronic acid as starting materials, a white solid product I-G11 was obtained in 43% yield. MS (m / z): 402.28 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.59–8.47(m,2H),7.76(d,J=1.9Hz,1H),7.67(d,J=1.7Hz,1H),7.66(d,J=1.7Hz,1H) ,7.63(dd,J=8.1,1.9Hz,1H),6.99(d,J=8.1Hz,1H),4.17(dd,J=11.1,2.2Hz,1H),4.00(dd,J=11.0,2.1Hz, 1H),3.82(q,J=1.8Hz,1H),3.53(d,J=1.4Hz,1H),2.88(d,J=10.1Hz,1H),2.72(dd,J=14.0,3.2Hz,1H),2.5 4–2.44(m,1H),2.27(s,3H),2.24–2.15(m,1H),2.15–2.00(m,3H),1.93–1.83(m,2H),0.86(t,J=7.4Hz,3H).

[0192] Example 44 (I-G12)

[0193] Using the third reaction of synthetic method i, with I-F1 and 2-thiopheneboronic acid as raw materials, a white solid product I-G12 was obtained in 84% yield. MS (m / z): 407.26 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.00(s,1H),7.66(d,J=1.9Hz,1H),7.24(dd,J=5.1,1.1Hz,1H),7.23–7 .16(m,2H),7.09(dd,J=5.1,3.6Hz,1H),6.24(d,J=8.1Hz,1H),4.17(dd,J=11.2,2.2Hz,1H),3 .99–3.84(m,2H),3.45(d,J=1.3Hz,1H),3.06(d,J=9.9Hz,1H),2.72(dd,J=13.9,3.1Hz,1H),2 .50(d,J=7.6Hz,1H),2.25(s,3H),2.14–1.94(m,4H),1.86–1.74(m,2H),0.83(t,J=7.3Hz,3H).

[0194] Example 45 (I-G13)

[0195] Using the third reaction of synthetic method i, with I-F1 and benzirphen-2-boronic acid as raw materials, a white solid product I-G13 was obtained in 82% yield. MS (m / z): 457.22 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.80–7.71 (m, 2H), 7.44–7.28 ( m,4H),6.36(d,J=7.9Hz,1H),4.18(d,J=11.1Hz,1H),4.00(d,J=11.1Hz,1H),3.92(s,1H) ,3.53(s,1H),3.04(d,J=10.0Hz,1H),2.80–2.67(m,1H),2.59(d,J=7.4Hz,1H),2.30(s, 3H), 2.20 (d, J = 10.0Hz, 1H), 2.15–1.98 (m, 4H), 1.91–1.76 (m, 2H), 0.84 (t, J = 7.2Hz, 3H).

[0196] Example 46 (I-G14)

[0197] Using the third reaction of synthetic method i, with I-F1 and 2-methoxyphenylboronic acid as starting materials, a white solid product I-G14 was obtained in 74% yield. MS (m / z): 431.28 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.05(s,1H),7.63(d,J=1.8Hz,1H),7.29(dd,J=8.9,6.6Hz,2H),7.22(dd,J=8.0,1.7Hz,1H),7.01(td,J=7.4,1. 1Hz,1H),6.97(d,J=8.1Hz,1H),6.60(d,J=8.0Hz,1H),4.10(dd,J=11.0,2.3Hz,1H),3.91(q,J=2.0Hz,1H),3.84(dd,J=11.1,2.0Hz,1H ),3.79(s,3H),3.68(q,J=7.0Hz,1H),3.52(d,J=1.4Hz,1H),3.43(s,2H),2.93(d,J=9.9Hz,1H),2.71(dd,J=13.8,3.2Hz,1H),2.44(d, J=7.8Hz,1H),2.27(s,4H),2.16(d,J=10.0Hz,1H),2.10–1.95(m,4H),1.94–1.83(m,2H),1.21(t,J=7.0Hz,2H),0.85(t,J=7.4Hz,4H).

[0198] Example 47 (I-G15)

[0199] Using the third reaction of synthetic method i, with I-F1 and 3-hydroxyphenylboronic acid as starting materials, a white solid product I-G15 was obtained in 65% yield. MS (m / z): 417.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.61(d,J=1.9Hz,1H),7.42(dd,J=8.1,1.8Hz,1H),7.22(t,J=7.9Hz,1H),7.01(dt,J=7.7,1.3Hz ,1H),6.98(t,J=2.1Hz,1H),6.90(d,J=8.0Hz,1H),6.73(ddd,J=8.1,2.5,1.0Hz,1H),4.15(dd,J=11.1,2.2Hz,1H),3.9 4(dd,J=11.1,2.0Hz,1H),3.81(q,J=1.9Hz,1H),3.53(d,J=1.3Hz,1H),2.88(d,J=10.1Hz,1H),2.72(dd,J=13.8,3.2H z,1H),2.54–2.43(m,1H),2.26(s,3H),2.23–2.13(m,1H),2.13–1.99(m,3H),1.96–1.80(m,2H),0.86(t,J=7.4Hz,3H).

[0200] Example 48 (I-G16)

[0201] Using the third reaction of synthetic method i, with I-F1 and 2-naphthoboric acid as raw materials, a white solid product I-G16 was obtained in 54% yield. MS (m / z): 451.31 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.99(d,J=1.8Hz,1H),7.90(dd,J=8.0,4.4Hz,2H),7.85(dd,J=7.6,1.8Hz,1H),7.76(d,J=1.9Hz,1H) ,7.71(dd,J=8.5,1.9Hz,1H),7.58(dd,J=8.1,1.8Hz,1H),7.52–7.39(m,2H),6.97(d,J=8.1Hz,1H),4.15(dd,J=11.1,2.3Hz ,1H),3.97(dd,J=11.1,2.1Hz,1H),3.88–3.81(m,1H),3.57(d,J=1.4Hz,1H),2.87(d,J=10.2Hz,1H),2.72(dd,J=14.2,3.1H z,1H),2.51–2.41(m,1H),2.25(s,3H),2.16(d,J=10.2Hz,1H),2.13–1.96(m,3H),1.95–1.83(m,2H),0.86(t,J=7.4Hz,3H).

[0202] Example 49 (I-G17)

[0203] Using the third reaction of synthetic method i, with I-F1 and 1-naphthoboric acid as raw materials, a white solid product I-G17 was obtained in 82% yield. MS (m / z): 451.32 [M+H] + . 1 H NMR(400MHz, CDCl3)δ10.49(s,1H),7.99(dd,J=8.2,1.4Hz,1H),7.95–7.85(m,2H),7.60–7.50(m,2H),7.49–7 .44(m,1H),7.44–7.40(m,2H),7.30(dd,J=7.9,1.7Hz,1H),6.94(d,J=7.9Hz,1H),3.91(dd,J=10.9,2.1Hz,1H ),3.74(s,1H),3.59–3.52(m,1H),3.26–3.20(m,1H),2.75(d,J=9.3Hz,1H),2.53(dd,J=13.6,3.1Hz,1H),2.4 9(p,J=1.9Hz,3H),2.26(d,J=7.6Hz,1H),2.11(s,3H),2.02–1.78(m,5H),1.74(s,1H),0.78(t,J=7.3Hz,3H).

[0204] Example 50 (I-G18)

[0205] Using the third reaction of synthetic method i, with I-F1 and 4-n-n-pentylphenylboronic acid as raw materials, a white solid product I-G18 was obtained in 88% yield. MS (m / z): 471.40 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.62(d,J=1.9Hz,1H),7.44(dd,J=7.8,1.5Hz,2H),7.42–7.39(m,1H),7.27–7.17(m,2H),6.89(d,J =8.0Hz,1H),4.14(dd,J=11.1,2.3Hz,1H),3.93(dd,J=11.1,2.1Hz,1H),3.80(d,J=2.9Hz,1H),3.52(d,J=1.3Hz,1H),2.8 6(d,J=10.1Hz,1H),2.71(dd,J=13.9,3.2Hz,1H),2.69–2.57(m,2H),2.52–2.40(m,1H),2.23(s,3H),2.14(d,J=10.1Hz,1 H),2.12–1.96(m,3H),1.94–1.80(m,2H),1.69–1.58(m,2H),1.44–1.25(m,5H),0.95–0.88(m,3H),0.86(t,J=7.4Hz,3H).

[0206] Example 51 (I-G19)

[0207] Using the third reaction of synthetic method i, with I-F1 and 3-isopropylphenylboronic acid as raw materials, a white solid product I-G19 was obtained in 49% yield. MS (m / z): 443.37 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.61(d,J=1.9Hz,1H),7.44(dd,J=8.0,1.8Hz,1H),7.38(t,J=1.8Hz,1H),7.36–7.30(m,2H),7.21 –7.15(m,1H),6.93(d,J=8.1Hz,1H),4.18(dd,J=11.1,2.3Hz,1H),3.93(dd,J=11.1,2.1Hz,1H),3.83(q,J=1.9Hz,1H), 3.53(d,J=1.4Hz,1H),2.96(p,J=6.9Hz,1H),2.88(d,J=10.2Hz,1H),2.73(dd,J=13.9,3.1Hz,1H),2.53–2.45(m,1H),2 .26(s,3H),2.18(d,J=10.2Hz,1H),2.15–2.00(m,3H),1.96–1.84(m,2H),1.29(d,J=6.9Hz,7H),0.87(t,J=7.4Hz,3H).

[0208] Example 52 (I-G20)

[0209] Using the third reaction of synthetic method i, with I-F1 and 4-isopropoxyphenylboronic acid as starting materials, a white solid product I-G20 was obtained in 57% yield. MS (m / z): 459.34 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.61(d,J=1.8Hz,1H),7.43(dd,J=8.1,1.8Hz,1H),7.30(t,J=7.9Hz,1H),7.09(dt,J=7.8,1.2Hz,1H),7.04(t, J=2.1Hz,1H),6.91(d,J=8.1Hz,1H),6.85(ddd,J=8.3,2.5,0.9Hz,1H),4.64(p,J=6.0Hz,1H),4.16(dd,J=11.1,2.3Hz,1H),3.93(dd ,J=11.1,2.1Hz,1H),3.82(q,J=1.9Hz,1H),3.52(d,J=1.3Hz,1H),2.88(d,J=10.2Hz,1H),2.72(dd,J=13.8,3.1Hz,1H),2.52–2.42( m,1H),2.26(s,3H),2.17(d,J=10.1Hz,1H),2.14–1.98(m,4H),1.95–1.83(m,2H),1.34(dd,J=6.0,1.7Hz,7H),0.86(t,J=7.4Hz,3H).

[0210] Example 53 (I-G21)

[0211] Using the third reaction of synthetic method i, with I-F1 and 4-trifluoromethoxyphenylboronic acid as raw materials, a white solid product I-G21 was obtained in 91% yield. MS (m / z): 485.28 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.69–7.58(m,3H),7.47(dd,J=8.1,1.9Hz,1H),7.39–7.26(m,2H),6.94(d, J=8.1Hz,1H),4.16(dd,J=11.1,2.2Hz,1H),3.96(dd,J=11.1,2.1Hz,1H),3.82(q,J=1.9Hz,1H), 3.55(d,J=1.3Hz,1H),2.89(d,J=10.2Hz,1H),2.73(dd,J=13.8,3.1Hz,1H),2.54–2.43(m,1H),2 .28(s,3H),2.19(d,J=10.2Hz,1H),2.16–2.00(m,3H),1.96–1.81(m,2H),0.87(t,J=7.4Hz,3H).

[0212] Example 54 (I-G22)

[0213] Using the third reaction of synthetic method i, with I-F1 benzo-1,4-dioxane-6-boric acid as the starting material, a white solid product I-G22 was obtained in 74% yield. MS (m / z): 459.38 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.55(d,J=1.9Hz,1H),7.36(dd,J=8.1,1.9Hz,1H),7.00(dq,J=4.9,2.2Hz,2H),6. 87(dd,J=8.5,3.8Hz,2H),4.25(s,4H),4.15(dd,J=11.1,2.3Hz,1H),3.93(dd,J=11.0,2.1Hz,1H),3.80( q,J=1.9Hz,1H),3.51(d,J=1.4Hz,1H),2.87(d,J=10.1Hz,1H),2.72(dd,J=13.8,3.2Hz,1H),2.52–2.43( m,1H),2.25(s,3H),2.16(d,J=10.1Hz,1H),2.13–1.97(m,3H),1.95–1.81(m,2H),0.86(t,J=7.4Hz,3H). 13C NMR (101MHz, CD3OD) δ181.34,145.21,144.30,141.52,136.30,135.68,134.04,127.90,127.68,120.64,118.56,116. 28,110.56,72.98,70.99,65.70,65.68,64.46,62.57,56.16,53.46,50.61,39.36,38.42,37.52,23.48,22.81,10.05.

[0214] Example 55 (I-G23)

[0215] Using the third reaction of synthetic method i, with I-F1 and 4-trifluoromethylphenylboronic acid as raw materials, a white solid product I-G23 was obtained in 58% yield. MS (m / z): 469.29 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.81–7.65(m,5H),7.54(dd,J=8.1,1.9Hz,1H),6.98(d,J=8.1Hz,1 H),4.17(dd,J=11.1,2.2Hz,1H),3.99(dd,J=11.1,2.1Hz,1H),3.84(q,J=1.8Hz,1H),3.6 5(d,J=1.3Hz,1H),2.96(d,J=10.4Hz,1H),2.81–2.68(m,1H),2.58–2.48(m,1H),2.35(s, 3H), 2.32 (d, J = 10.5Hz, 1H), 2.17–2.03 (m, 3H), 1.99–1.86 (m, 2H), 0.88 (t, J = 7.4Hz, 3H).

[0216] Example 56 (I-G24)

[0217] Using the third reaction of synthetic method i, with I-F1 and 5-methyl-2-thiopheneboronic acid as starting materials, a white solid product I-G24 was obtained in 55% yield. MS (m / z): 421.30 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.59 (d, J=1.8Hz, 1H), 7.40 (dd, J=8.1, 1.9Hz, 1H), 7.03 (d, J=3.5Hz, 1H), 6.84 (d, J= 8.1Hz,1H),6.71(dd,J=3.6,1.4Hz,1H),4.16(dd,J=11.1,2.3Hz,1H),3.94(dd,J=11.1,2.1Hz,1H),3.79( q,J=2.0Hz,1H),3.45(d,J=1.3Hz,1H),2.85(d,J=10.1Hz,1H),2.70(dd,J=13.9,3.2Hz,1H),2.47(d,J=1. 1Hz, 4H), 2.24 (s, 3H), 2.13 (d, J = 10.1Hz, 1H), 2.11–1.98 (m, 3H), 1.93–1.81 (m, 2H), 0.85 (t, J = 7.4Hz, 3H).

[0218] Example 57 (I-G25)

[0219] Using the third reaction i of synthetic method, with I-F1 and 5-acetyl-2-thiopheneboronic acid as starting materials, a yellow solid product I-G25 was obtained in 30% yield. MS (m / z): 449.23 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.82(d,J=4.0Hz,1H),7.73(d,J=1.9Hz,1H),7.61(dd,J=8.1,1.9Hz,1H),7.39( d,J=4.0Hz,1H),6.93(d,J=8.1Hz,1H),4.19(dd,J=11.2,2.2Hz,1H),4.00(dd,J=11.2,2.1Hz,1H),3. 82(d,J=3.0Hz,1H),3.55(d,J=1.3Hz,1H),2.92(d,J=10.3Hz,1H),2.79–2.67(m,1H),2.58–2.50(m,3 H), 2.33 (s, 3H), 2.27 (d, J = 10.3Hz, 1H), 2.15–2.02 (m, 3H), 1.96–1.85 (m, 2H), 0.87 (t, J = 7.4Hz, 3H).

[0220] Example 58 (I-G26)

[0221] Using the third reaction of synthetic method i, with I-F1 and 3-thiopheneboronic acid as raw materials, a yellow solid product I-G26 was obtained in 70% yield. MS (m / z): 407.27 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.73(dd,J=2.9,1.4Hz,1H),7.61(dd,J=5.0,2.9Hz,1H),7.58(d,J=1.9Hz, 1H),7.52(dd,J=8.0,1.8Hz,1H),7.47(dd,J=5.0,1.4Hz,1H),6.82(d,J=8.0Hz,1H),4.01(dd,J=10.9,2.2Hz,1H), 3.94(dd,J=10.7,2.0Hz,1H),3.69(q,J=1.9Hz,1H),3.40(s,1H),2.79(d,J=9.4Hz,1H),2.59–2.51(m,1H),2.38( d,J=7.6Hz,1H),2.18(s,3H),2.08–1.86(m,4H),1.81(dt,J=14.5,7.4Hz,1H),1.67(s,1H),0.77(t,J=7.3Hz,3H).

[0222] Example 59 (I-G27)

[0223] Using the third reaction of synthetic method i, with I-F2 and 2-thiopheneboronic acid as raw materials, a white solid product I-G27 was obtained in 86% yield. MS (m / z): 489.24 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.63(dd,J=5.1,1.1Hz,1H),7.57(d,J=1.9Hz,1H),7.52–7.47(m,2H),7.45(dd,J= 3.6,1.2Hz,1H),7.36(dd,J=3.6,1.1Hz,1H),7.17(dd,J=5.1,3.5Hz,1H),7.13(dd,J=5.1,3.6Hz,1H),4.05(dd,J=11.1,2 .3Hz,1H),3.89(dd,J=10.9,1.9Hz,1H),3.78(d,J=2.0Hz,1H),3.27(s,1H),2.78(d,J=9.3Hz,1H),2.55(dd,J=13.6,3.2 Hz,1H),2.39(d,J=7.7Hz,1H),2.14(s,3H),2.01–1.88(m,4H),1.84(p,J=7.2Hz,1H),1.72(s,1H),0.79(t,J=7.3Hz,3H).

[0224] Example 60 (I-G28)

[0225] Using the third reaction of synthetic method i, with I-F1 and 5-phenyl-2-thiopheneboronic acid as raw materials, a red solid product I-G28 was obtained in 57% yield. MS (m / z): 483.27 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.69(d,J=1.9Hz,1H),7.67–7.61(m,2H),7.51(dd,J=8.1,1.9Hz,1H),7.43–7.32( m,3H),7.32–7.22(m,2H),6.89(d,J=8.1Hz,1H),4.18(dd,J=11.1,2.3Hz,1H),3.99(dd,J=11.1,2.1Hz,1 H),3.82(q,J=1.9Hz,1H),3.54(d,J=1.3Hz,1H),2.89(d,J=10.2Hz,1H),2.77–2.66(m,1H),2.59–2.45( m,1H),2.29(s,3H),2.21(d,J=10.3Hz,1H),2.14–2.00(m,3H),1.96–1.83(m,2H),0.86(t,J=7.4Hz,3H).

[0226] Example 61 (I-G29)

[0227] Using the third reaction of synthetic method i, with I-F1 and 5-chloro-2-thiopheneboronic acid as raw materials, a red solid product I-G29 was obtained in 95% yield. MS (m / z): 441.25 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.56(d,J=1.9Hz,1H),7.39(dd,J=8.1,1.9Hz,1H),7.07(d,J=3.9Hz,1H),6.92(d, J=3.9Hz,1H),6.85(d,J=8.1Hz,1H),4.15(dd,J=11.1,2.3Hz,1H),3.94(dd,J=11.1,2.1Hz,1H),3.79(q ,J=1.8Hz,1H),3.45(d,J=1.4Hz,1H),2.86(d,J=10.1Hz,1H),2.69(dd,J=13.9,3.2Hz,1H),2.52–2.42( m,1H),2.26(s,3H),2.14(d,J=10.1Hz,1H),2.11–1.97(m,3H),1.92–1.81(m,2H),0.85(t,J=7.4Hz,3H).

[0228] Example 62 (I-G30)

[0229] Using the third reaction of synthetic method i, with I-F1 and (4-(1-cyanocyclopropyl)phenyl)boronic acid as raw materials, a red solid product I-G30 was obtained in 66% yield. MS (m / z): 466.32 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.70–7.53(m,3H),7.48(d,J=8.2Hz,1H),7.40(d,J=7.9Hz,2H),6.95(d,J =8.2Hz,1H),4.17(d,J=11.2Hz,1H),3.98(d,J=11.2Hz,1H),3.84(s,1H),3.67(s,1H),2.96(d,J =10.5Hz,1H),2.74(d,J=13.9Hz,1H),2.58–2.49(m,1H),2.46–2.31(m,4H),2.10(q,J=6.6Hz,3H ),1.96(s,3H),1.80–1.67(m,2H),1.58–1.45(m,2H),1.31(t,J=13.9Hz,5H),0.95–0.83(m,4H).

[0230] Example 63 (I-G31)

[0231] Using the third reaction of synthetic method i, with I-F1 4-(trans-4-propylcyclohexyl)phenylboronic acid as the starting material, a red solid product I-G31 was obtained in 52% yield. MS (m / z): 525.40 [M+H] + .1 H NMR (400MHz, CD3OD) δ7.61(d,J=1.8Hz,1H),7.49–7.39(m,3H),7.31–7.19(m,2H),6.91(d,J=8.1Hz,1H),4.16(dd,J= 11.1,2.3Hz,1H),3.95(dd,J=11.1,2.1Hz,1H),3.82(d,J=2.4Hz,1H),3.56(d,J=1.3Hz,1H),2.89(d,J=10.2Hz,1H),2 .74(dt,J=13.0,3.2Hz,1H),2.56–2.44(m,2H),2.28(s,3H),2.22(d,J=10.2Hz,1H),2.14–2.02(m,3H),1.98–1.84(m, 6H), 1.51 (qd, J=12.4, 3.0Hz, 2H), 1.44–1.21 (m, 8H), 1.17–1.03 (m, 2H), 0.93 (t, J=7.3Hz, 3H), 0.87 (t, J=7.3Hz, 3H).

[0232] Example 64 (I-G32)

[0233] Using the third reaction of synthetic method i, with I-F1 and 4-tert-butylphenylboronic acid as raw materials, a red solid product I-G32 was obtained in 44% yield. MS (m / z): 457.37 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.62(d,J=1.8Hz,1H),7.52–7.41(m,5H),6.92(d,J=8.0Hz,1H),4.17(dd ,J=11.1,2.2Hz,1H),3.95(dd,J=11.1,2.1Hz,1H),3.82(q,J=2.0Hz,1H),3.55(d,J=1.3Hz,1H ),2.89(d,J=10.2Hz,1H),2.73(dd,J=13.7,3.0Hz,1H),2.48(d,J=7.5Hz,1H),2.27(s,3H),2. 20(d,J=10.2Hz,1H),2.17–1.99(m,4H),1.97–1.83(m,2H),1.35(s,9H),0.87(t,J=7.3Hz,3H).

[0234] Example 65 (I-H1)

[0235] The four-reaction synthesis method was employed, using gelsemin A and iodomethane as raw materials. A white solid product, I-H1, was obtained in 80% yield. MS (m / z): 336.21 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.35(d,J=7.6Hz,1H),7.22–7.15(m,1H),6.97(t,J=7.6Hz,1H),6.72(d,J=7.8Hz,1H),6.19( dd,J=17.8,11.0Hz,1H),5.06(d,J=11.0Hz,1H),4.87(d,J=17.8Hz,1H),4.03(dd,J=11.2,2.2Hz,1H),3.86(dd,J=1 1.1,2.0Hz,1H),3.66(d,J=3.4Hz,1H),3.46(s,1H),3.18(s,1H),3.10(s,3H),2.79(dd,J=14.3,3.0Hz,1H),2.66( d,J=10.6Hz,1H),2.41(dd,J=17.7,9.5Hz,2H),2.29(d,J=6.7Hz,1H),2.21(s,3H),2.01–1.90(m,1H),1.87(s,1H).

[0236] Example 66 (I-H2)

[0237] Using reaction fourj of synthetic method, with gelsemin A and ethyl bromoacetate as raw materials, a white solid product I-H2 was obtained in 51% yield. MS (m / z): 409.28 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.45(dd,J=7.6,1.3Hz,1H),7.27–7.22(m,1H),7.05(td,J=7.6,1.1Hz,1H),6.68(dd,J=7.9,1.1Hz,1H),6.18(dd,J= 17.8,11.0Hz,1H),5.11(dd,J=11.0,1.3Hz,1H),4.93(dd,J=17.8,1.3Hz,1H),4.50(d,J=17.4Hz,1H),4.32(d,J=17.5Hz,1H),4.18(qd,J= 7.1,1.6Hz,2H),4.13–4.07(m,1H),3.93(dd,J=11.1,2.1Hz,1H),3.79(tt,J=2.9,1.2Hz,1H),3.51(d,J=1.5Hz,1H),2.84(dd,J=14.4,3.0 Hz,1H),2.70(d,J=10.6Hz,1H),2.47(dd,J=17.6,9.5Hz,2H),2.36(t,J=7.1Hz,1H),2.28(s,3H),2.05–1.96(m,2H),1.23(t,J=7.1Hz,3H).

[0238] Example 67 (I-H3)

[0239] Using reaction fourj of synthetic method, with gelsemin A and 2-chloro-N,N-dimethylacetamide as raw materials, a white solid I-H3 was obtained in 85% yield. MS (m / z): 408.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.41(dd,J=7.6,1.2Hz,1H),7.22(td,J=7.7,1.2Hz,1H),7.02(td,J=7.6,1.1Hz,1H),6.74(dd,J=7.9,1.1Hz,1H),6.18(dd . 1,2.3Hz,1H),3.93(dd,J=11.2,2.1Hz,1H),3.79(dt,J=2.9,1.7Hz,1H),3.56(d,J=1.4Hz,1H),3.06(s,3H),2.94(s,3H),2.82(dd,J=14.4,3.0Hz ,1H),2.68(d,J=10.8Hz,1H),2.59–2.52(m,2H),2.36(dd,J=8.4,5.7Hz, 1H), 2.30 (s, 3H), 2.12–2.06 (m, 1H), 1.98 (ddd, J = 14.4, 5.8, 2.8Hz, 1H).

[0240] Example 68 (I-H4)

[0241] Using reaction fourj of synthetic method, with gelsemin A and 2-chloro-N-methyl-N-phenylacetamide as raw materials, a white solid I-H4 was obtained in 43% yield. MS (m / z): 470.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.70 (dd, J=5.7, 3.3Hz, 1H), 7.56–7.45 (m, 3H), 7.45–7.38 (m, 2H), 7.38–7.32 (m, 2H), 7.26–7.21 (m, 1H), 7.03 (d, J= 1.1Hz,1H),6.57(d,J=7.8Hz,1H),6.26–6.13(m,1H),5.15(dd,J=11.0,1.2Hz,1H),4.96(dd,J=17.8,1.2Hz,1H),4.31(d,J=17.0Hz,1H),4 .27–4.17(m,3H),4.11–4.02(m,2H),4.02–3.93(m,1H),3.77(d,J=3.0Hz,1H),3.67(s,1H),3.29(s,3H),2.85–2.79(m,2H),2.74(s,1H),2 .68(d,J=11.1Hz,1H),2.44(d,J=6.8Hz,1H),2.41(s,3H),2.17–2.08(m,1H),2.04–1.94(m,1H),1.67(h,J=6.2Hz,2H),1.49–1.37(m,3H).

[0242] Example 69 (I-H5)

[0243] Using reaction fourj of synthetic method, with gelsemin A and 2-chloro-1-piperidin-1-ylethyl ketone as raw materials, a white solid I-H5 was obtained in 78% yield. MS (m / z): 448.32 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.43(dd,J=7.6,1.2Hz,1H),7.23(td,J=7.7,1.2Hz,1H),7.03(td,J=7.6,1.1Hz,1H),6.80(dd,J=7.8,1.1Hz,1H),6.20(dd,J= 17.8,11.0Hz,1H),5.10(dd,J=11.0,1.3Hz,1H),4.93(dd,J=17.8,1.3Hz, 1H),4.61(d,J=16.0Hz,1H),4.30(d,J=16.0Hz,1H),4.09(dd,J=11.2,2.3H z,1H),3.94(dd,J=11.1,2.1Hz,1H),3.79(dt,J=3.2,1.8Hz,1H),3.55(d, J=1.4Hz,1H),3.45–3.39(m,2H),2.83(dd,J=14.4,3.0Hz,1H),2.69(d,J=1 0.7Hz,1H),2.51(d,J=10.1Hz,2H),2.36(t,J=7.1Hz,1H),2.29(s,3H),2. 05(t,J=1.5Hz,1H),1.99(ddd,J=14.4,5.7,2.8Hz,1H),1.70–1.48(m,7H).

[0244] Example 70 (I-H6)

[0245] Using reaction fourj of synthetic method, with gelsemin A and benzyl bromide as raw materials, a white solid I-H6 was obtained in 69% yield. MS (m / z): 413.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.43(dd,J=7.7,1.3Hz,1H),7.34–7.27(m,2H),7.27–7.20(m,3H),7.16(td,J=7.8,1.2Hz,1H),7.00(td,J=7.6,1.1Hz,1H), 6.68(dd,J=7.8,1.1Hz,1H),6.26(dd,J=17.8,11.0Hz,1H),5.15(dd,J=1 1.0,1.2Hz,1H),5.04–4.99(m,1H),4.99–4.93(m,1H),4.76(d,J=15.8Hz, 1H),4.13(dd,J=11.1,2.3Hz,1H),3.94(dd,J=11.1,2.1Hz,1H),3.83(tt,J=2.8,1.1Hz,1H),3.58(d,J=1.4Hz,1H),2.92(dd,J=14.4,3.0Hz,1H),2 .82(d,J=10.6Hz,1H),2.56(d,J=8.5Hz,1H),2.47(d,J=10.7Hz,1H),2.3 8(t,J=7.1Hz,1H),2.32(s,3H),2.10–2.02(m,1H),2.01(t,J=1.5Hz,1H).

[0246] Example 71 (I-H7)

[0247] Using reaction fourj of synthetic method, with gelsemin A and propargyl bromide as raw materials, a white solid I-H7 was obtained in 28% yield. MS (m / z): 361.26 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.44(dd,J=7.6,1.2Hz,1H),7.30(td,J=7.8,1.2Hz,1H),7.07(td,J=7.6,1.1Hz,1H),7.00(dd,J=7.9,1.1Hz,1H),6.21(dd,J =17.8,11.0Hz,1H),5.13(dd,J=11.0,1.2Hz,1H),4.94(dd,J=17.8,1.3Hz,1H),4.53(dd,J=17.6,2.6Hz,1H),4.37(dd,J=17.6,2.5Hz,1H),4.11–4 .06(m,1H),3.93(dd,J=11.2,2.1Hz,1H),3.75(tt,J=2.8,1.2Hz,1H),3. 53(d,J=1.4Hz,1H),2.84(dd,J=14.4,3.0Hz,1H),2.73(d,J=10.6Hz,1H), 2.53(d,J=8.4Hz,1H),2.47(d,J=10.6Hz,1H),2.41–2.33(m,1H),2.29(s, 3H), 2.20 (t, J=2.5Hz, 1H), 2.03–1.98 (m, 1H), 1.96 (q, J=2.2, 1.4Hz, 1H). 13 C NMR (101MHz, CDCl3) δ175.94,141.34,138.25,130.97,128.29,128.21,122.62,112.66,108.7 5,72.45,72.16,69.55,66.10,61.57,54.17,53.81,50.33,41.18,38.65,35.46,29.29,22.88.

[0248] Example 72 (I-H8)

[0249] Using reaction fourj of synthetic method, with gelsemin A and n-hexyl chloroacetate as raw materials, a white solid I-H8 was obtained in 25% yield. MS (m / z): 465.35 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.44(dd,J=7.6,1.2Hz,1H),7.25(td,J=7.7,1.2Hz,1H),7.06(td,J=7.6,1.1Hz,1H),6.68(dd,J=7.9,1.0Hz,1H),6.18 (dd,J=17.8,11.0Hz,1H),5.13(dd,J=10.9,1.2Hz,1H),4.95(dd,J=17.8,1.2Hz,1H),4.49(d,J=17.5Hz,1H),4.33(d,J=17.4Hz,1H),4.16–4 .06(m,3H),3.95(dd,J=11.2,2.1Hz,1H),3.79(tt,J=2.8,1.1Hz,1H),3.62–3.55(m,1H),2.84(dd,J=14.4,3.0Hz,1H),2.71(d,J=10.8Hz,1H ), 2.62 (d, J = 7.1Hz, 2H), 2.40 (t, J = 7.0Hz, 1H), 2.33 (s, 3H), 2.08–1.97 (m, 2H), 1.57 (p, J = 6.8Hz, 2H), 1.35–1.16 (m, 8H), 0.89–0.82 (m, 3H).

[0250] Example 73 (I-H9)

[0251] Using reaction fourj of synthetic method, with gelsemin A and n-decyl chloroacetate as raw materials, a white solid I-H9 was obtained in 35% yield. MS (m / z): 521.39 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.44(dd,J=7.6,1.2Hz,1H),7.29–7.24(m,1H),7.07(td,J=7.6,1.1Hz,1H),6.69(dd,J=7.9,1.0Hz,1H),6.18(dd,J= 17.8,11.0Hz,1H),5.15(dd,J=10.9,1.1Hz,1H),4.97(dd,J=17.8,1.2Hz,1H),4.50(d,J=17.5Hz,1H),4.33(d,J=17.5Hz,1H),4.15–4.07( m,3H),3.96(dd,J=11.2,2.1Hz,1H),3.83–3.78(m,1H),3.68–3.60(m,1H),2.85(dd,J=14.5,3.0Hz,1H),2.72(d,J=8.9Hz,3H),2.43(t,J= 7.2Hz,1H),2.37(s,3H),2.07(s,1H),2.02(ddd,J=14.4,5.8,2.8Hz,1H),1.58(p,J=7.3Hz,3H),1.36–1.17(m,19H),0.88(t,J=6.9Hz,4H).

[0252] Example 74 (I-H10)

[0253] Using reaction fourj of synthetic method, with gelsemin A and n-dodecyl chloroacetate as raw materials, a white solid I-H10 was obtained in 29% yield. MS (m / z): 549.42 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.25(t,J=7.6Hz,1H),7.06(t,J=7.6Hz,1H),6.68(d,J=7.7Hz,1H),6.18(dd,J=17. 8,11.0Hz,1H),5.13(d,J=11.0Hz,1H),4.95(d,J=17.8Hz,1H),4.50(d,J=17.5Hz,1H),4.33(d,J=17.5Hz,1H),4.16–4.06(m,3H) ,3.95(dd,J=11.1,2.0Hz,1H),3.79(d,J=3.0Hz,1H),3.68–3.55(m,2H),2.85(dd,J=14.4,3.0Hz,1H),2.71(d,J=10.7Hz,1H),2 .59(s,2H),2.39(t,J=7.0Hz,1H),2.33(s,3H),2.10–1.97(m,2H),1.57(p,J=6.9Hz,2H),1.34–1.17(m,22H),0.92–0.84(m,3H).

[0254] Example 75 (I-H11)

[0255] Using reaction fourj of synthetic method, with gelsemin A and n-hexadecyl chloroacetate as raw materials, a white solid I-H11 was obtained in 29% yield. MS (m / z): 605.47 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.43(dd,J=7.6,1.2Hz,1H),7.25(td,J=7.7,1.2Hz,1H),7.06(td,J=7.7,1.1Hz,1H),6.68(dd,J=7.8,1.0Hz,1H),6.16(dd,J =17.8,11.0Hz,1H),5.14(dd,J=11.0,1.1Hz,1H),4.96(dd,J=17.8,1.2H z,1H),4.49(d,J=17.5Hz,1H),4.32(d,J=17.5Hz,1H),4.15–4.04(m,3H), 3.96(dd,J=11.2,2.1Hz,1H),3.78(d,J=2.8Hz,1H),3.72–3.60(m,1H),3 .44(s,4H),2.84(dd,J=14.5,3.0Hz,1H),2.68(d,J=17.1Hz,4H),2.47–2. 39(m,1H),2.37(s,3H),2.07(t,J=1.5Hz,1H),2.01(ddd,J=14.5,5.8,2.8 Hz, 1H), 1.57 (t, J = 6.7Hz, 2H), 1.24 (d, J = 5.0Hz, 30H), 0.92–0.82 (m, 4H).

[0256] Example 76 (I-H12)

[0257] Using reaction fourj of synthetic method, with gelsemin A and 1-bromobutane as raw materials, a white solid I-H12 is obtained in 78% yield. MS (m / z): 379.5 [M+H] + . 1H NMR (600MHz, CDCl3) δ7.43(d,J=7.5Hz,1H),7.24(d,J=7.7Hz,1H),7.02(t,J=7.6Hz,1H),6.79(d,J=7.8Hz,1H),6.23(dd,J=17.8,10.9Hz ,1H),5.30(s,1H),5.12(d,J=10.9Hz,1H),4.93(d,J=17.8Hz,1H),4.11(dd,J=11.1,2.3Hz,1H),3.92(dd,J=11.2,2.1Hz,1H),3.77–3.69( m,2H),3.60(dt,J=14.1,7.1Hz,1H),3.48(s,1H),2.87(dd,J=14.3,3.0Hz,1H),2.76(d,J=10.3Hz,1H),2.47(s,1H),2.33(t,J=7.3Hz,2H) ,2.27(s,3H),1.99(ddd,J=14.4,5.8,2.8Hz,1H),1.62(dhept,J=13.6,6.7Hz,4H),1.42–1.31(m,3H),1.25(s,1H),0.93(t,J=7.4Hz,3H).

[0258] Example 77 (I-H13)

[0259] Using reaction fourj of synthetic method, with gelsemin A and 1-bromoheptane as raw materials, 36 mg of a white solid was obtained in 86% yield. MS (m / z): 421.5 [M+H] + . 1H NMR (600MHz, CDCl3) δ7.42(d,J=7.6Hz,1H),7.23(d,J=15.4Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.8Hz,1H),6.22(dd,J =17.7,10.9Hz,1H),5.10(d,J=10.9Hz,1H),4.92(d,J=17.8Hz,1H),4.09(d,J=11.1Hz,1H),3.90(d,J=11.1Hz,1H),3.71(d, J=14.3Hz,2H),3.56(dt,J=14.2,7.1Hz,1H),3.46(s,1H),2.89–2.83(m,1H),2.74(d,J=10.4Hz,1H),2.44(d,J=8.3Hz,1H), 2.37–2.28(m,2H),2.24(s,3H),2.02–1.93(m,1H),1.60(dt,J=16.0,8.0Hz,3H),1.39–1.13(m,11H),0.85(t,J=7.0Hz,3H).

[0260] Example 78 (I-H14)

[0261] Using reaction j of synthetic method four, with gelsemin A and 1-bromodecane as raw materials, 31 mg of a colorless oil was obtained, with a yield of 66%. MS (m / z): 463.6 [M+H] + . 1H NMR (600MHz, CDCl3) δ7.43(d,J=7.5Hz,1H),7.24(t,J=7.7Hz,1H),7.00(t,J=7.6Hz,1H),6.78(d,J=7.8Hz,1H),6.22(dd,J=17.7,10.9H z,1H),5.10(d,J=10.9Hz,1H),4.92(d,J=17.8Hz,1H),4.10(dd,J=11.1,2.3Hz,1H),3.90(dd,J=11.1,2.1Hz,1H),3.76–3.68(m,2H),3.5 7(dt,J=14.0,7.0Hz,1H),3.46(s,1H),2.86(dd,J=14.3,3.0Hz,1H),2.75(d,J=10.4Hz,1H),2.44(d,J=8.4Hz,1H),2.35–2.28(m,2H),2 .25(s,3H),1.98(ddd,J=14.4,5.8,2.8Hz,1H),1.88(s,1H),1.61(td,J=7.3,3.6Hz,2H),1.27(d,J=37.8Hz,16H),0.86(t,J=7.0Hz,3H).

[0262] Example 79 (I-H15)

[0263] Using the four-reaction synthesis method (j), with gelseminine A and 1-bromotridecane as raw materials, 37 mg of a colorless oily substance can be obtained, with a yield of 74%. 1H NMR (600MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.25(t,J=7.7Hz,1H),7.02(t,J=7.6Hz,1H),6.80(d,J=7.7Hz,1H),6.24(dd,J=17.8,11.0Hz ,1H),5.12(d,J=10.9Hz,1H),4.94(d,J=17.8Hz,1H),4.12(dd,J=11.1,2.3Hz,1H),3.92(dd,J=11.1,2.1Hz,1H),3.79–3.70(m,2H),3.59( dt,J=14.1,7.0Hz,1H),3.47(s,1H),2.88(dd,J=14.4,3.0Hz,1H),2.77(d,J=10.3Hz,1H),2.45(d,J=8.4Hz,1H),2.33(dd,J=9.2,5.7Hz, 2H),2.26(s,3H),2.00(ddd,J=14.3,5.8,2.8Hz,1H),1.90(s,1H),1.63(td,J=7.1,3.5Hz,2H),1.41–1.19(m,22H),0.89(t,J=6.9Hz,3H).

[0264] Example 80 (I-H16)

[0265] Using the four-reaction synthesis method (j), with gelseminine A and 1-bromopentadecane as raw materials, 46 mg of a colorless oily substance can be obtained, with a yield of 87%. 1H NMR (600MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.26(d,J=15.5Hz,1H),7.02(t,J=7.6Hz,1H),6.80(d,J=7.8Hz,1H),6.24(dd,J=17 .8,10.9Hz,1H),5.12(d,J=10.9Hz,1H),4.94(d,J=17.8Hz,1H),4.12(d,J=11.1Hz,1H),3.93(d,J=11.1Hz,1H),3.74(d,J=14.6H z,2H),3.59(dt,J=14.0,7.1Hz,1H),3.48(s,1H),2.91–2.86(m,1H),2.77(d,J=10.4Hz,1H),2.46(d,J=8.4Hz,1H),2.34(d,J=1 0.1Hz,2H),2.26(s,3H),2.03–1.97(m,1H),1.64(dd,J=14.6,7.6Hz,2H),1.29(dd,J=30.8,12.2Hz,29H),0.89(t,J=6.9Hz,3H).

[0266] Example 81 (I-H17)

[0267] Using the four-reaction synthesis method (j), with gelseminine methyl 1-bromoheptadecane as the raw material, 43 mg of a colorless oily substance was obtained, with a yield of 77%. 1HNMR (600MHz, CDCl3) δ7.45(d,J=7.5Hz,1H),7.25(t,J=7.7Hz,1H),7.02(t,J=7.6Hz,1H),6.80(d,J=7.7Hz,1H),6.24(dd,J=17.8,10.9Hz,1H), 5.12(dd,J=10.9,1.3Hz,1H),4.94(dd,J=17.7,1.3Hz,1H),4.11(dd,J=11.1,2.2Hz,1H),3.92(dd,J=11.1,2.0Hz,1H),3.78–3.68(m,2H),3.58(d t,J=14.0,7.0Hz,1H),3.47(s,1H),2.88(dd,J=14.2,3.0Hz,1H),2.77(d,J=10.3Hz,1H),2.45(d,J=8.4Hz,1H),2.32(dd,J=9.2,5.1Hz,2H),2.26 (s,3H),2.00(ddd,J=14.4,5.8,2.8Hz,1H),1.90(d,J=2.3Hz,1H),1.63(ddt,J=10.3,7.3,3.5Hz,2H),1.39–1.22(m,30H),0.89(t,J=7.0Hz,3H).

[0268] Example 82 (I-H18)

[0269] Using the four-reaction synthesis method (j), with gelseminine A and 1-bromoeicosane as raw materials, 52 mg of a colorless oily substance can be obtained, with a yield of 87%. 1H NMR (600MHz, CDCl3) δ7.40(d,J=7.6Hz,1H),7.28(d,J=7.8Hz,1H),7.03(t,J=7.6Hz,1H),6.81(d,J=7.8Hz,1H),6.23( dd,J=17.8,11.0Hz,1H),5.18(d,J=10.8Hz,1H),4.98(d,J=17.8Hz,1H),4.10(dd,J=11.3,2.3Hz,1H),3.98(d,J=11.5H z,1H),3.74(d,J=3.1Hz,1H),3.70(dt,J=14.6,7.4Hz,1H),3.61(dt,J=14.2,7.1Hz,1H),2.87(dd,J=14.4,3.0Hz,1H) ,2.74(s,1H),2.44(s,4H),2.08–1.93(m,2H),1.62(dd,J=10.2,4.7Hz,3H),1.37–1.20(m,39H),0.88(t,J=7.0Hz,3H).

[0270] Example 83 (I-H19)

[0271] Synthetically, using reaction j (method four), gelsemin A and N-(3-bromopropyl)-7-nitrobenzo[c][1,2,5]oxadiazole-4-amine as starting materials, 41 mg of a brown solid was obtained in 75% yield. MS (m / z): 543.3 [M+H] + . 1H NMR (600MHz, CDCl3) δ8.47(d,J=8.6Hz,1H),7.50(d,J=7.5Hz,1H),7.38(d,J=6.6Hz,1H),7.29(t,J=7.7Hz,1H),7.09(t,J=7.6Hz,1H),6.82(d ,J=7.8Hz,1H),6.25(dd,J=17.7,11.0Hz,1H),6.16(d,J=8.6Hz,1H),5.09(d,J=10.9Hz,1H),4.98(d,J=17.7Hz,1H),4.14(dd,J=11.1,2.2Hz, 1H),3.97(ddd,J=13.8,8.6,4.5Hz,1H),3.92(dd,J=11.1,2.0Hz,1H),3.78(td,J=10.7,5.7Hz,2H),3.56(t,J=6.0Hz,1H),3.48(s,1H),3.47– 3.40(m,1H),2.97–2.88(m,1H),2.85(d,J=10.3Hz,1H),2.47(d,J=8.3H z,1H),2.35–2.30(m,1H),2.26(s,4H),2.14–2.01(m,3H),1.90(s,1H).

[0272] Example 84 (I-H2O)

[0273] Synthetically, reaction j, using gelsemin A and N-(12-bromododecyl)-7-nitrobenzo[c][1,2,5]oxadiazole-4-amine as starting materials, yielded 38 mg of a brown solid in 56% yield. MS (m / z): 669.4 [M+H] + . 1H NMR (600MHz, CDCl3) δ8.50(d,J=8.6Hz,1H),7.37(d,J=7.5Hz,1H),7.30(s,1H),7.05(s,1H),6.82(d,J=7.8Hz,1H),6.24 (dd,J=17.8,11.0Hz,2H),6.17(d,J=8.6Hz,1H),5.23(s,1H),5.02(d,J=17.9Hz,1H),4.11(dd,J=14.7,9.0Hz,1H),4.00 (s,1H),3.76(s,1H),3.67(dd,J=15.4,8.0Hz,2H),3.48(q,J=6.7Hz,2H),2.88(d,J=14.5Hz,1H),2.80–2.40(m,5H),2.1 0–1.98(m,2H),1.79(q,J=7.4Hz,3H),1.70–1.51(m,10H),1.51–1.41(m,3H),1.36(p,J=7.0Hz,3H),1.33–1.20(m,17H).

[0274] Example 85 (I-H21)

[0275] Synthetic method four-reaction k, using gelseminale methyl and iodobenzene as starting materials, yielded 34 mg of a white solid in 85% yield. Using bromobenzene as a starting material, 15 mg of product was obtained in 38% yield. MS (m / z): 399.29 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.56–7.46(m,3H),7.39(d,J=7.4Hz,1H),7.37–7.31(m,2H),7.23–7.13(m,1H),7.06(t,J= 7.5Hz,1H),6.73(d,J=7.8Hz,1H),6.23(dd,J=17.7,11.0Hz,1H),5.14–5.03(m,1H),5.00–4.86(m,1H),4.13(dd ,J=11.0,2.2Hz,1H),4.02–3.94(m,1H),3.92(q,J=4.1,3.2Hz,1H),3.55(s,1H),2.89(dd,J=14.4,3.0Hz,1H),2 .79(d,J=10.4Hz,1H),2.49(d,J=8.5Hz,1H),2.44–2.25(m,5H),2.10(s,1H),2.02(ddd,J=14.4,5.8,2.8Hz,1H).

[0276] Example 86 (I-H22)

[0277] Synthetically, using reaction k (four-step reaction) with gelsemin A and 4-methoxyiodobenzene as raw materials, 43 mg of a white solid was obtained in 98% yield. MS (m / z): 429.25 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.49(dd,J=7.6,1.3Hz,1H),7.29–7.22(m,2H),7.18(td,J=7.7,1.3Hz,1H),7.09–7.03(m,1H),7.03–6.98(m,2H),6.68(dd,J =7.9,1.1Hz,1H),6.23(dd,J=17.8,11.0Hz,1H),5.06(dd,J=11.0,1.3Hz,1H),4.92(dd,J=17.7,1.4Hz,1H),4.13(dd,J=11.1,2.3Hz,1H),3.96(dd ,J=11.0,2.1Hz,1H),3.91(tt,J=2.9,1.2Hz,1H),3.84(s,3H),3.54(d,J =1.4Hz,1H),2.88(dd,J=14.4,3.0Hz,1H),2.78(d,J=10.5Hz,1H),2.63(s ,1H),2.49(d,J=8.3Hz,1H),2.39(d,J=10.5Hz,1H),2.34(t,J=7.0Hz,1H ), 2.30 (s, 3H), 2.08 (p, J = 1.4Hz, 1H), 2.02 (ddd, J = 14.4, 5.8, 2.8Hz, 1H).

[0278] Example 87 (I-H23)

[0279] Synthetically, using reaction k (four-reaction method) with gelsemin A and 3-iodopyridine as raw materials, 39 mg of a white solid was obtained in 98% yield. MS (m / z): 400.24 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.66 (dd, J=2.5, 0.8Hz, 1H), 8.62 (dd, J=4.8, 1.5Hz, 1H), 7 .73(ddd,J=8.1,2.5,1.5Hz,1H),7.52(ddd,J=7.7,1.3Hz,1H),7.45(ddd,J=8.2, 4.9,0.8Hz,1H),7.20(td,J=7.7,1.3Hz,1H),7.09(td,J=7.6,1.2Hz,1H),6.73( dd,J=7.9,1.1Hz,1H),6.16(dd,J=17.7,11.0Hz,1H),5.07(dd,J=11.0,1.3Hz,1 H),4.93(dd,J=17.7,1.3Hz,1H),4.12(dd,J=11.1,2.3Hz,1H),3.94(dd,J=11.1 ,2.1Hz,1H),3.91(tt,J=2.9,1.1Hz,1H),3.52(d,J=1.4Hz,1H),2.85(dd,J=14. 5,3.0Hz,1H),2.77(d,J=10.5Hz,1H),2.68(s,2H),2.52–2.45(m,1H),2.40–2.3 1(m,2H),2.27(s,3H),2.08(t,J=1.5Hz,1H),2.02(ddd,J=14.5,5.8,2.8Hz,1H).

[0280] Example 88 (I-H24)

[0281] Synthetically, using reaction k (four-reaction method) with gelsemin A and 6-iodoquinoline as starting materials, 45 mg of a white solid was obtained in 100% yield. MS (m / z): 450.26 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.95 (dd, J=4.3, 1.7Hz, 1H), 8.23 ​​(d, J=8.9Hz, 1H), 8.17 ( dd,J=8.2,1.7Hz,1H),7.87(d,J=2.3Hz,1H),7.70(dd,J=8.9,2.3Hz,1H),7.54 (dd,J=7.6,1.3Hz,1H),7.44(dd,J=8.3,4.2Hz,1H),7.20(td,J=7.7,1.3Hz,1H ),7.09(td,J=7.6,1.2Hz,1H),6.80(dd,J=7.9,1.1Hz,1H),6.21(dd,J=17.7,1 1.0Hz,1H),5.06(dd,J=10.9,1.3Hz,1H),4.93(dd,J=17.7,1.3Hz,1H),4.14(d d,J=11.1,2.3Hz,1H),4.01–3.91(m,2H),3.55(d,J=1.4Hz,1H),2.89(dd,J=14 .5,3.1Hz,2H),2.79(d,J=10.5Hz,1H),2.53–2.45(m,1H),2.36(dd,J=9.2,4.5 Hz,2H),2.29(s,3H),2.13(q,J=1.5Hz,1H),2.04(ddd,J=14.4,5.7,2.8Hz,1H).

[0282] Example 89 (I-H25)

[0283] Using the four-reaction synthesis method K, with gelsemin A and 2-iodothiophene as raw materials, 40 mg of a white solid was obtained in 98% yield. MS (m / z): 405.26 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.43(d,J=7.6Hz,1H),7.26–7.21(m,1H),7.17(t,J=8.0Hz,1H),7.07–6.94(m,3H),6.85(d,J =7.9Hz,1H),6.12(dd,J=17.7,10.9Hz,1H),5.03(d,J=10.9Hz,1H),4.87(d,J=17.7Hz,1H),4.10–4.01(m,1H),3.88 (d,J=11.1Hz,1H),3.83(s,1H),3.48(s,1H),2.81(dd,J=14.4,3.0Hz,1H),2.70(d,J=10.5Hz,1H),2.44(d,J=8.4H z,1H),2.37(d,J=10.5Hz,1H),2.29(d,J=6.7Hz,1H),2.24(s,3H),2.01(s,1H),1.96(ddd,J=14.6,5.9,2.9Hz,1H).

[0284] Example 90 (I-H26)

[0285] Synthetically, using reaction k (four-step reaction) with gelsemin A and 4-trifluoromethyliodobenzene as raw materials, 47 mg of a white solid was obtained in 99% yield. MS (m / z): 467.29 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.3Hz,2H),7.58–7.49(m,3H),7.21(td,J=7.7,1.3Hz,1H),7.10(td,J=7.6,1.2Hz,1H),6.79(dd,J =7.9,1.1Hz,1H),6.18(dd,J=17.7,11.0Hz,1H),5.08(dd,J=11.0,1.3Hz,1H),4.94(dd,J=17.7,1.3Hz,1H),4.14(dd,J=11.0,2.2Hz ,1H),3.95(dd,J=11.1,2.0Hz,1H),3.92(dt,J=3.2,1.9Hz,1H),3.53(d,J=1.3Hz,1H),2.87(dd,J=14.5,3.0Hz,1H),2.79(d,J=10. 4Hz, 1H), 2.49 (d, J = 8.4Hz, 1H), 2.35 (dd, J = 9.3, 6.1Hz, 2H), 2.29 (s, 3H), 2.09 (t, J = 1.5Hz, 1H), 2.03 (ddd, J = 14.4, 5.7, 2.8Hz, 1H). 19F NMR (376MHz, CDCl3) δ -62.58.

[0286] Example 91 (I-H27)

[0287] Synthetically, using reaction k (four-step reaction) with gelsemin A and 1-methyl-6-bromoindole as starting materials, 22 mg of a white solid was obtained in 48% yield. MS (m / z): 466.35 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.71 (dd, J=8.3, 0.6Hz, 1H), 7.51 (dd, J=7.6, 1.3Hz, 1H), 7 .30(dt,J=1.6,0.7Hz,1H),7.17(td,J=7.7,1.3Hz,1H),7.12(d,J=3.1Hz,1H),7 .06(td,J=7.6,1.2Hz,1H),7.02(dd,J=8.3,1.8Hz,1H),6.70(dd,J=7.9,1.1Hz, 1H),6.53(dd,J=3.1,0.9Hz,1H),6.26(dd,J=17.8,11.0Hz,1H),5.06(dd,J=11.0 ,1.3Hz,1H),4.93(dd,J=17.7,1.3Hz,1H),4.15(dd,J=11.1,2.3Hz,1H),4.03–3 .96(m,2H),3.79(s,3H),3.62(d,J=1.4Hz,1H),2.92(dd,J=14.4,3.0Hz,1H),2.8 0(d,J=10.7Hz,1H),2.56(d,J=8.4Hz,1H),2.50(d,J=10.7Hz,1H),2.39(d,J=6. 6Hz, 1H), 2.35 (s, 3H), 2.16 (t, J=1.4Hz, 1H), 2.05 (ddd, J=14.5, 5.8, 2.8Hz, 1H).

[0288] Example 92 (I-H28)

[0289] Synthetically, using reaction k (four-step reaction) with gelsemin A and 4-cyanoiodobenzene as raw materials, 30 mg of a white solid was obtained in 71% yield. MS (m / z): 424.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.83–7.75(m,2H),7.58–7.51(m,3H),7.22(td,J=7.8,1.3Hz,1H),7.12(td,J=7.6,1.2Hz,1H),6.82(dd,J=7 .9,1.2Hz,1H),6.15(dd,J=17.8,11.0Hz,1H),5.08(dd,J=11.0,1.2Hz,1H),4.94(dd,J=17.8,1.3Hz,1H),4.13(dd,J=11.1,2.2Hz ,1H),3.95(dd,J=11.1,2.1Hz,1H),3.90(tt,J=2.9,1.1Hz,1H),3.52(d,J=1.5Hz,1H),2.84(dd,J=14.5,3.0Hz,1H),2.79(d,J=10 .4Hz,1H),2.49(d,J=8.5Hz,1H),2.35(dd,J=8.2,4.8Hz,3H),2.28(s,3H),2.09–2.06(m,1H),2.03(ddd,J=12.7,5.7,2.9Hz,1H).

[0290] Example 93 (I-H29)

[0291] Synthesizing method four-reaction k, using gelsemin A and 2-fluoroiodobenzene as raw materials, yielded 7 mg of a white solid in 17% yield. MS (m / z): 417.30 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.56–7.47(m,1H),7.39(dddd,J=17.0,9.0,7.5,3.4Hz,2H),7.34–7.27(m,1H),7.26–7.16(m,2H),7.08(td,J=7.6,1 .2Hz,1H),6.65–6.51(m,1H),6.20(dt,J=17.7,11.2Hz,1H),5.07(ddd,J=11.0,5.3,1.3Hz,1H),4.93(dt,J=17.8,1.5Hz,1H),4.69(s,1H) ,4.14(dt,J=11.1,2.5Hz,1H),4.00–3.88(m,2H),3.65(dd,J=3.3,1.6Hz,1H),3.55(dd,J=23.5,1.4Hz,1H),2.88(ddd,J=14.0,7.2,2.9Hz ,1H),2.78(dd,J=10.5,5.7Hz,1H),2.53–2.47(m,1H),2.43–2.33(m,2H),2.30(d,J=7.2Hz,3H),2.12(q,J=1.5Hz,1H),2.07–1.99(m,2H).

[0292] Example 94 (I-H30)

[0293] Synthetically, using reaction k (four-step reaction) with gelsemin A and 2-methoxyiodobenzene as raw materials, 17 mg of a white solid was obtained, with a yield of 39%. MS (m / z): 429.27 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.48(ddd,J=10.8,7.6,1.3Hz,1H),7.39(tdd,J=7.9,4.4,1.7Hz,1H),7.25(td,J=7.9,3.8Hz,1H),7.14(tdd,J=7.6,3.7,1.3H z,1H),7.10–6.98(m,3H),6.44(ddd,J=29.3,7.8,1.1Hz,1H),6.25(ddd,J =17.8,11.0,5.6Hz,1H),5.05(dd,J=10.9,1.3Hz,1H),4.91(dt,J=17.8,1. 6Hz,1H),4.14(ddd,J=11.1,5.9,2.3Hz,1H),4.00–3.89(m,2H),3.73(d,J =52.5Hz,3H),3.56(dd,J=26.3,1.4Hz,1H),2.89(ddd,J=14.5,7.0,3.0Hz, 1H), 2.80 (dd, J=22.3, 10.5Hz, 1H), 2.48 (dd, J=28.1, 9.5Hz, 2H), 2.40–2. 27(m,5H),2.15(dt,J=3.8,1.7Hz,1H),2.01(dtd,J=13.9,5.4,2.8Hz,1H).

[0294] Example 95 (I-H31)

[0295] Using the four-reaction synthesis method (k) with I-G18 and iodobenzene as raw materials, 33 mg of a white solid was obtained in 89% yield. MS (m / z): 547.37 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.71(d,J=1.9Hz,1H),7.58–7.50(m,2H),7.49–7.44(m,2H),7.44–7.39(m,1H),7.37(dt,J=8.1,1.7Hz,3H),7.26(d,J =8.1Hz,2H),6.76(d,J=8.1Hz,1H),4.18(dd,J=11.1,2.3Hz,1H),4.07–4.02(m,1H),3.96(dd,J=11.0,2.1Hz,1H),3.54(s,1H),2.92(d,J=9 .9Hz,1H),2.80(dd,J=14.1,3.1Hz,1H),2.65(dd,J=8.8,6.8Hz,2H),2.51(d,J=8.1Hz,1H),2.31(s,3H),2.26–2.20(m,1H),2.14–1.99(m,4 H),1.89(dq,J=14.6,7.3Hz,1H),1.73–1.61(m,2H),1.37(h,J=3.5Hz,4H),1.26(d,J=5.6Hz,3H),0.97–0.90(m,3H),0.86(t,J=7.3Hz,3H).

[0296] Example 96 (I-H32)

[0297] Using the four-reaction synthesis method (k) with I-G31 and 2-iodothiophene as starting materials, 37 mg of a white solid was obtained in 92% yield. MS (m / z): 607.38 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.71(d,J=1.8Hz,1H),7.50–7.45(m,2H),7.42(dd,J=8.2,1.8Hz,1H),7.32(dd,J=5.1,1.9Hz,1H),7.31–7.27(m,2H) ,7.12–7.06(m,2H),6.96(d,J=8.2Hz,1H),4.17(dd,J=11.1,2.3Hz,1H),4.03(td,J=2.9,1.5Hz,1H),3.94(dd,J=11.1,2.0Hz,1H),3.49(d, J=1.4Hz,1H),2.91(d,J=9.9Hz,1H),2.80(dd,J=14.4,3.1Hz,1H),2.52(ddt,J=12.1,9.6,3.2Hz,2H),2.29(s,3H),2.26–2.14(m,1H),2.14 –1.76(m,10H),1.50(qd,J=12.7,3.0Hz,2H),1.43–1.18(m,8H),1.08(qd,J=12.7,2.9Hz,2H),0.92(t,J=7.2Hz,3H),0.84(t,J=7.3Hz,3H).

[0298] Example 97 (III-1)

[0299] Using reaction m of method six, with gelsemin methyl iodoform as a starting material, 0.044 g of a white solid was obtained, with a yield of 93%. MS (m / z): 352.47 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.43–7.31(m,2H),7.10–6.98(m,2H),6.23(dd,J=1 8.0,11.0Hz,1H),5.13(d,J=11.4Hz,1H),5.01(d,J=17.9Hz,1H),4.58(s,1 H),4.01(s,2H),3.61(s,1H),3.30(d,J=7.3Hz,4H),3.17(d,J=5.2Hz,1H), 3.10(d,J=11.7Hz,7H),2.90(s,1H),2.74–2.61(m,2H),2.04–1.94(m,1H).

[0300] Example 98 (III-2)

[0301] Using reaction m of method six, gelseminalein methylbenzyl bromide as a starting material, 0.047 g of a white solid was obtained, with a yield of 81.0%. MS (m / z): 503.26 [M+H]+ . 1 H NMR (400MHz, CD3OD) δ7.63–7.54(m,3H),7.51–7.45(m,1H),7.41(td,J=7.7,1.2Hz,1H),7.35(t,J=3.4Hz,5H),7.32–7.26(m,3H),7.15(td,J=7 .7,1.1Hz,1H),7.01(td,J=8.3,1.2Hz,3H),6.38(dd,J=17.9,11.1Hz,1H),5.33(d,J=11.1Hz,1H),5.22(d,J=17.9Hz,1H),5.12(d,J=15.7Hz,1H ), 4.65(s,1H), 4.49(d,J=13.5Hz,1H), 4.28(s,1H), 4.15(dd,J=11.7,2.8Hz,1H), 4.01(dd,J=11.6,1.9Hz,1H), 3.83(d,J=2.9Hz,1H), 3.72(d,J=12.5Hz,1H), 3.53(d,J=12.5Hz,1H), 3.07(d,J=8.5Hz,1H), 3.02–2.92(m,3H), 2.85(d,J=7.4Hz,1H), 2.18(ddd,J=14.6,5.9,2.7Hz,1H). Activity test:

[0302] Appendix Explanation

[0303] Table 1: Half-inhibitory concentration (IC50) of gelseminine derivatives against HT-29 colon cancer cells 50 surface

[0304] Table 2: Half-inhibitory concentrations (IC50) of representative gelseminine derivatives against various tumor cell types 50 surface

[0305] Tumor cells including HT-29, Hela, HepG2, A549, HCT-15, and HGC-27 were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). DMEM, RPMI 1640, and Mcoy'5A culture media (brand: Gibco) were purchased from Ingenic Semiconductor (Shanghai) Trading Co., Ltd. Fetal bovine serum (FBS) was purchased from Suzhou Qianshe Biotechnology Co., Ltd. (brand: PAN). Phosphate-buffered saline (PBS) was purchased from Sangon Biotech (Shanghai) Co., Ltd. (brand: Sangon). Dimethyl sulfoxide (DMSO) and EDTA-free trypsin were purchased from Beyotime Biotechnology Co., Ltd. (brand: Beyotime). The cell viability and fluorescence intensity assay platform was the Ensight multi-plate reader from PE Corporation.

[0306] Cell culture: HT-29 cells were cultured in McCoy'5A medium containing 10% FBS; HCT-15, A549, and HGC-27 cells were cultured in RPMI 1640 medium containing 10% FBS; and HeLa and HepG2 cells were cultured in DMEM medium containing 10% FBS. Cells were cultured at 37°C in a cell culture incubator with 5% CO2 atmosphere. Cells were used in various assays when they were in the logarithmic growth phase.

[0307] Preparation of drug solution: Prepare a 50 mM solution of gelsemin A derivative with DMSO and store at -20℃.

[0308] Example 1: In vitro antitumor activity experiment

[0309] Test method:

[0310] a) Take the cell suspension in the logarithmic growth phase and seed it into a 96-well cell culture plate, 100 μL per well, 4,000 cells per well, and incubate in an incubator at 37°C with a CO2 concentration of 5% by volume.

[0311] b) After 24 h of cell culture, the experimental group was given 100 μl of fresh culture medium containing the tested gelseminine derivative (the concentrations for single-point activity detection were 100 μM and 10 μM, respectively, and the IC50 was measured). 50 The drug concentration at the time of administration was 50 μM (diluted 2-fold to 8 concentration gradients). 100 μl of 10 μM 5-fluorouracil was added to the control group, and 100 μl of 0.1% DMSO was added to the blank group. The mixture was then incubated at 37°C in an incubator with 5% CO2 air content for 72 h.

[0312] c) After removing the old culture medium from each well, add 100 μl of fresh culture medium containing 10% CCK8 assay reagent (the kit was purchased from Meilun Biotechnology Co., Ltd.), and place it in an incubator at 37°C with 5% CO2 air content for 0.5-1 h (the incubation time varies depending on the cell line; approximately 40 min for HT-29, HCT-15, HepG2, and HGC-27 cells, and approximately 30 min for HeLa and A549 cells).

[0313] d) The OD values ​​of each group of wells were detected at a wavelength of 450 nM using an Ensight microplate reader. The values ​​were then calculated according to the formula (OD...). 实验 -OD 空白 ) / (OD 对照 -OD 空白 Calculate the survival rate of each Gelsemium derivative after treatment (see Tables 1 and 2 below).

[0314] Table 1 lists the inhibition rates of gelseminaline A and its derivatives against HT-29 colorectal cancer cells at concentrations of 100 μM and 10 μM. Compared to gelseminaline A I-A0, the IA series products, after the double bond is reduced (I-A1) or after the addition of hydrogen bromide (I-A2), showed a slight increase in antitumor activity. The IB series products, with long-chain alkyl or acyl groups introduced onto the piperidine ring, generally exhibited moderate antitumor activity, with only I-B5 and I-B9 showing some improvement. When nitro (IC), amino (ID), and aromatic amide groups (I-E1 to I-E3) are introduced onto the toluene ring of gelseminale, the antitumor activity is significantly improved, except for the decrease in the activity of electron-donating aromatic amides (I-E2). The introduction of chain amide groups shows a certain pattern in the increase in activity. With the introduction of short (I-E4 and I-E5), medium (I-E6 and I-E7), and long (I-E8 to I-E10) straight-chain amides, the antitumor activity gradually increases and then decreases with the length of the chain. Among them, the introduction of hexadecamide (I-E8) has the highest activity, which can completely inhibit the growth of tumor cells at a concentration of 10 μM. Bromination on the benzene ring improves the activity, and the monobrominated product I-F1 has better activity than the dibrominated product I-F2. The introduction of substituted aromatic groups such as phenyl, pyridine, and thiophene enhances their antitumor activity, regardless of whether they are substituted with electron-rich groups (I-G1, I-G2, I-G9, I-G14, I-G18, and I-G20) or electron-deficient groups (I-G4, I-G21, and I-G23). The activity is particularly enhanced when alkyl groups are substituted (I-G1, I-G2, I-G18, I-G19, and I-G30-I-G32), completely inhibiting tumor cell proliferation at a concentration of 10 μM. However, the introduction of different aromatic heterocycles has varying effects on activity. For example, pyridine-substituted I-G3 and I-G11 at different positions exhibit weaker antitumor activity than those substituted with benzene rings (I-G4 and I-G5); those substituted with 2-thiophene (I-G27-I-G29) show better antitumor activity. Alkylation (I-H1-I-H18) or arylation (I-H19-I-H30) of gelseminine formamide on nitrogen can also enhance its antitumor proliferative activity.

[0315] Table 1. Inhibition rate of gelsemin A derivatives on HT-29 colon cancer cells

[0316]

[0317]

[0318]

[0319] Table 2 further examines the antiproliferative activity (IC50) of some of the more active compounds against various other tumor cell types. 50The results showed that most of the selected compounds exhibited good inhibitory effects on colorectal cancer HCT-15, cervical cancer HeLa, lung cancer A549, liver cancer HepG2, and gastric cancer HGC-27 cell lines. However, some compounds showed weaker activity against certain cell lines (IC50). 50 These compounds (>20 μM) showed some selectivity. However, overall, they were more sensitive to the HT-29 colorectal cancer cell line, with some showing IC50 values. 50 Values ​​can reach the nanomolar level (such as I-E8, I-G2 and I-H2).

[0320] Table 2. IC50 of some highly active gelseminine derivatives on various tumor cells. 50 value

[0321]

[0322] Bioactivity tests showed that the compounds of this invention have the effect of inhibiting the proliferation of various tumor cells. The compounds of this invention can be used as active pharmaceutical ingredients for the treatment of various cancers (including but not limited to gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal carcinoma, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, and skin cancer).

Claims

1. A gelseminine derivative, the structure of which is shown in general formula I below. in, R 1 It is any one or more groups selected from vinyl, ethyl, and 1-bromoethyl; R 2 For H, C 1-20 Alkyl, benzyl, substituted or unsubstituted C 1-20 Fatty acyl group, substituted or unsubstituted aromatic acyl group, substituted or unsubstituted sulfonyl group, R 2’ R 2” One or more of N-CO-, wherein R 2’ and R 2” Each independently represents H and C. 1-3 Alkyl, or R 2’ R 2” It forms a 4-6 membered cyclic amino group with N; R 3 The H, halogen, substituted or unsubstituted aromatic group, substituted or unsubstituted styryl group, or C are substituted at any position on the phenyl group of gelsemin A. 2-5 alkynyl group, C 2-5 alkenyl, -NO2, or R 3’ R 3” Any one or more groups in N-, wherein R 3’ and R 3” Each independently represents H and C. 1-20 Alkyl, substituted or unsubstituted aromatic acyl, substituted or unsubstituted C 1-20 One or more of fatty acyl groups, substituted or unsubstituted sulfonyl groups; n represents the R substituted on the toluene group of gelsemin. 3 The number of them can be 1, 2, 3 or 4; R 4 H, substituted or unsubstituted C 1-20 Alkyl, R 4’ COCH2-, one or more of substituted or unsubstituted aromatic groups, wherein R 4’ For H2N-, (CH3)2N-, HO-, CH3(CH2) n’ O-, CH3(CH2) n’ One or more of NH-, where n' is an integer between 0 and 19.

2. The gelseminine derivative according to claim 1, characterized in that, R 1 It is any group selected from vinyl, ethyl, and 1-bromoethyl; preferably, R 1 It can be vinyl or ethyl.

3. The gelseminine derivative according to claim 1, characterized in that, R 2 For H, C 1-20 Alkyl, benzyl; or R 2 For substituted or unsubstituted C 1-20 Fatty acyl group, substituted C 1-20 The substituent in the fatty acyl group is one or more of (CH3)2N- and CH3CH2OCO-, which are substituted at any position; or R 2 The substituted or unsubstituted aromatic acyl group, or the substituted or unsubstituted benzenesulfonyl group, wherein the substituent in the substituted aromatic acyl group or the substituted sulfonyl group is one or more of the following: methyl, ethyl, propyl, F, Cl, CF3, CH3CO-, HO-, CH3O-, CH3CH2O-; or R 2 For R 2’ R 2” NCO-, where R 2’ and R 2” Each can be independently H, methyl, ethyl, propyl, or R. 2’ R 2” It can form one or more of cyclobutanylamino, cyclopentanylamino, and cyclohexylamino with N; Furthermore, R 2 It is one or more of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, (CH3)2CH-, (CH3)2CHCH2-, allyl, propyneyl, benzyl, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, pentadecanoyl, trifluoroacetyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-ethylbenzoyl, p-propylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, furan-2-carboxyl, naphthioyl, thiophene-2-carboxyl, benzenesulfonyl, p-toluenesulfonyl, or R 2 For R 2’ R 2” NCO-, where R 2’ and R 2” Each is independently one or more of H, CH3-, CH3CH2-, or R 2’ R 2” Composed of N One or more of the following; Furthermore, R 2 The following are the possible values ​​for the radicals: H, methyl, ethyl, propyl, benzyl, heptyl, pentadecyl, formyl, acetyl, propionyl, heptyl, pentadecanoyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, 2-naphthoyl, furan-2-ylformyl, thiophene-2-ylformyl, benzenesulfonyl, p-toluenesulfonyl, NH2CO-, (CH3)2NCO-, CH3NHCO-, CH3CH2NHCO-, (CH3CH2)2NCO-. One or more of the following; Preferred, R 2 The following are not part of the given name: H, methyl, ethyl, propyl, benzyl, heptyl, pentadecyl, formyl, acetyl, heptyl, pentadecanoyl, (CH3)2NCH2CO-, CH3CH2OCOCO-, benzoyl, p-methylbenzoyl, p-fluorobenzoyl, p-methoxybenzoyl, 2-naphthoyl, furan-2-ylformyl, benzenesulfonyl, p-toluenesulfonyl, NH2CO-, (CH3)2NCO-, CH3NHCO-, CH3CH2NHCO-. One or more of them.

4. The gelseminine derivative according to claim 1, characterized in that, R 3 The substituted H, Cl, Br, -NO2, substituted or unsubstituted aromatic group, substituted or unsubstituted styryl group, or -NR group are present at any position on the phenyl group of gelsemium methyl. 3’ R 3” One or more groups in, wherein R 3’ and R 3” Each independently represents H and C. 1-20 Alkyl, C 1-20 The group comprises one or more of the following: fatty acyl, substituted or unsubstituted aromatic acyl, and substituted or unsubstituted benzenesulfonyl. The aromatic group refers to any one or more of the following: phenyl, furanyl, thiophene, naphthyl, pyridyl, benzofuranyl, benzothiophene, and thiopheno[3,2-b]thiophene. The substituent refers to F, Cl, Br, -CN, -OH, -NH2, -CF3, methyl, ethyl, propyl, F2HC-, (CH3)2CH-, butyl, (CH3)3C-, pentyl, hexyl, heptyl, CH3O-, CF3O-, CH3CH2O-, CH3CH2CH2O-, (CH3)2CHO-, (CH3)2N-, phenyl, acetyl, NH2CO-, ethylenedioxy, ... Furthermore, R 3 The substituents are H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiophene[3,2-b]thiophene, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene-2-yl, substituted or unsubstituted thiophene-3-yl, wherein the substituents are F, Cl, -CN, -OH, -CF3, methyl, F2HC-, ethyl, propyl, (CH3)2CH-, (CH3)3C-, butyl, pentyl, CH3O-, CF3O-, CH3CH2O-, (CH3)2CHO-, (CH3)2N-, phenyl, acetyl, NH2CO-, ethylenedioxy, etc., which can be found at any position on the phenyl group of gelseminine A. Or R 3 For -NR 3’ R 3” , where R 3’ and R 3” Each is independently H, methyl, ethyl, C 1-20 One or more of fatty acyl, naphthalene-1-formyl, naphthalene-2-formyl, substituted or unsubstituted benzoyl, wherein the substituent refers to F, Cl, Br, -OH, CH3-, CH3CH2-, CH3O-, CH3CH2O-, (CH3)2N-; Furthermore, R 3 The following are arbitrary substitutions on the phenyl group of gelsemium methyl: H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiophene[3,2-b]thiophene, phenyl, p-fluorophenyl, m-fluorophenyl, p-cyanophenyl, m-cyanophenyl, p-isopropylphenyl, m-isopropylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-isopropoxyphenyl, m-isopropoxyphenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-difluoromethylphenyl, m-difluoromethylphenyl, p-tert-butylphenyl, p-n-butylphenyl, p-n-pentylphenyl. One or more of 5-methylthiophen-2-yl, 5-cyanothiophen-2-yl, 5-acetylthiophen-2-yl, 5-phenylthiophen-2-yl, and 5-chlorothiophen-2-yl, or R 3 For -NR 3’ R 3” , where R 3’ and R 3” Each is independently H, methyl, ethyl, C 1-20 One or more of the following: fatty acyl, naphthalene-1-formyl, naphthalene-2-formyl, benzoyl, p-methoxybenzoyl, m-methoxybenzoyl, p-fluorobenzoyl, m-fluorobenzoyl, and p-toluyl; Preferably, R 3 For any position of H, Cl, Br, -NO2, styryl, furan-2-yl, furan-3-yl, pyridin-3-yl, pyridin-4-yl, thiophene-2-yl, thiophene-3-yl, naphthio-1-yl, naphthio-2-yl, benzothiophene-2-yl, thiopheno[3,2-b]thiophene, phenyl, p-fluorophenyl, m-fluorophenyl, p-cyanophenyl, p-isopropylphenyl, m-isopropylphenyl, p-methoxyphenyl, m-methoxyphenyl, o-methoxyphenyl, p-isopropoxyphenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-difluoromethylphenyl, p-tert-butylphenyl, p-n-butylphenyl, p-n-pentylphenyl, One or more of the following: 5-methyl-thiophen-2-yl, 5-cyano-thiophen-2-yl, 5-acetyl-thiophen-2-yl, 5-phenyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, -NH2, acetamido, propionamido, butamido, pentamido, hexamido, heptaamido, octamido, nonamido, decamido, undecanoamide, dodecanoamide, tridecanoamide, tetradecanoamide, pentadecanoamide, hexadecanoamide, heptanoamide, octadecanoamide, nonadecanoamide, eicosamide, benzamide, p-methoxybenzamide, and naphth-2-carboxamide. n represents the R substituted on the phenyl group of gelsemium methyl methionine. 3 The number of elements is an integer between 1 and 4; preferably, n is 1 or 2.

5. The gelseminine derivative according to claim 1, characterized in that, R 4 H, substituted or unsubstituted C 1-20 Alkyl, wherein the substituent is phenyl, alkynyl, alkenyl, or R 4 For R 4’ One or more of COCH2-, wherein R 4’ For H2N-, (CH3)2N-, CH3NH-, CH3PhN-, HO-, CH3(CH2) n’ O-, CH3(CH2) n’ One or more of NH-, where n' is an integer between 0 and 19, or R 4 The aryl group may be substituted or unsubstituted, and here the aryl group is one or more of phenyl, pyridyl, quinolinyl, thiophenyl, indole, and N-methylindole, wherein the substituent is one or more of F, Cl, Br, -CN, -CF3, methoxy, and ethoxy. Furthermore, R 4 The following are the possible values: H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, decyl, tridecyl, pentadecyl, heptadecanyl, eicosyl, benzyl, propargyl, allyl, H2NCOCH2-, (CH3)2NCOCH2-, CH3NHCOCH2-, CH3PhNCOCH2-. HOCOCH2-, CH3OCOCH2-, CH3(CH2) 1-19 OCOCH2-, phenyl, p-methoxyphenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-cyanophenyl, o-methoxyphenyl, p-trifluoromethylphenyl, quinoline-6-yl, N-methylindol-6-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, thiophen-2-yl, thiophen-3-yl; Preferred, R 4 The following are not part of the given name: H, methyl, ethyl, butyl, heptyl, decyl, tridecyl, pentadecyl, heptadecanyl, eicosyl, benzyl, propargyl, (CH3)2NCOCH2-, CH3PhNCOCH2-. HOCOCH2-, CH3CH2OCOCH2-, CH3(CH2)5OCOCH2-, CH3(CH2) 10 OCOCH2-, CH3(CH2) 12 OCOCH2-, CH3(CH2) 16 One or more of the following: OCOCH2-, phenyl, p-methoxyphenyl, o-fluorophenyl, p-cyanophenyl, o-methoxyphenyl, p-trifluoromethylphenyl, quinoline-6-yl, N-methylindol-6-yl, pyridin-3-yl, and thiophene-2-yl.

6. The gelseminine derivative according to claims 1-5, wherein R is defined as follows: 1 -R 4 They are independent of each other and can be combined arbitrarily.

7. The gelseminine derivative according to claims 1-6, wherein the structure comprises one or more of the following structures:

8. The gelseminine derivative according to claims 1-7, which can form a salt with a pharmaceutically acceptable acid, having the general formula shown in II, wherein the acid is any one or more of HCl, HBr, citric acid, fumaric acid, succinic acid, tartaric acid, citric acid, sulfuric acid, methanesulfonic acid, formic acid, and acetic acid, wherein X - The acid radical ion corresponding to the acid; Alternatively, the gelseminine derivative according to any one of claims 1-7 and a haloalkane (R 5 The quaternary ammonium salt generated by X) is shown in general formula III, where R 5 X is any one or more of methyl, ethyl, propyl, and benzyl. - For Br - Cl - One or two of them; 9. The gelseminine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, characterized in that, The derivative or its salt includes one or more of the corresponding hydrate, solvate or crystal.

10. The use of one or more of the gelseminalis derivatives or pharmaceutically acceptable salts thereof as active ingredients in the preparation of a medicament for treating tumors, wherein the tumors include, but are not limited to, gastric cancer, liver cancer, lung cancer, esophageal cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, nasopharyngeal cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, and skin cancer.

11. A pharmaceutical composition comprising one or more of the gelseminalis derivatives or pharmaceutically acceptable salts thereof as described in any one of claims 1-10, and one or more of any pharmaceutically acceptable excipients, carriers, diluents and / or other active compounds.

12. A method for synthesizing a gelseminaline A derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, characterized in that, One of the following methods can be used to synthesize general formula I: Synthesis Method 1 Scheme 1. With respect to R in claim 1, 2 or 7 1 The relevant synthesis methods, Reaction a: Dissolve I-A0 (i.e., gelseminale A, 1 mmol, 1.0 molar equivalent) in one or more of the following solvents (5-100 ml per 1 mmol gelseminale A): dry tetrahydrofuran, methanol, ethanol, ethyl acetate or dichloromethane. Add 5%-10% Pd / C (Pd content 5%-30% wt) of I-A0 by mass. After evacuation and hydrogen purging, react under a hydrogen atmosphere (greater than or equal to 1 atmosphere, preferably 1-4 atmospheres) for 5-24 hours. After the reaction is complete, remove Pd / C and solvent to obtain the target product I-A1. Or, reaction b: Dissolve I-A0 (1 mmol, 1.0 molar equivalent) in dry acetonitrile (5-100 mL per 1 mmol gelsminoid A), add hydrobromic acid (6-12 mL per 1 mmol I-A0), then heat to reflux temperature and react at this temperature for 24-72 hours. After the reaction is complete, add sodium hydroxide solution (0.5-2 M) to adjust the pH to 9-12, add dichloromethane (5-20 mL per mmol I-A0) and extract 1-5 times. Purify by silica gel column chromatography to obtain the target product I-A2. Synthesis Method 2 Scheme 2. Similar to R in claims 1, 3, and 7 2 The relevant synthesis methods, Reaction c: In a dry, sealed tube, dissolve substrate I-A0 or I-A1 (1 mmol, 1.0 molar equivalent) in dry dichloromethane or 1,2-dichloroethane (5-50 mL), then add potassium bicarbonate (10-15 molar equivalents relative to I-A0 or I-A1) and 1-chloroethyl chloroformate (5-10 molar equivalents relative to I-A0 or I-A1). After sealing, react at 40-60 °C for 24-48 hours. Remove dichloromethane, add tetrahydrofuran and water (2:1-10:1, 5-50 mL), and stir at room temperature for 12-24 hours. Separate the organic phase, extract 1-5 times with ethyl acetate (1 mmol I-A0 or I-A1 each time with 10-100 mL ethyl acetate). Combine the organic phases, dry to anhydrous sodium sulfate, remove the solvent, and purify by silica gel column chromatography to obtain the target product I-B1; or, reaction d: When using acyl chlorides as acylation reagents: In a dry round-bottom flask, dissolve I-B1 (1 mmol, 1.0 molar equivalent) in a dry solvent (one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or dichloroethane, 5-50 mL), add triethylamine, N,N-diisopropylethylamine, pyridine, or 4-dimethylaminopyridine (2-5 molar equivalents relative to I-B1), and then add the acyl chloride reagent (corresponding to aromatic formyl chloride, amino formyl chloride, etc. within the R2 definition range) at -10°C to 0°C. One or more of formyl chloride, ethoxyformyl formyl chloride, or substituted or unsubstituted benzenesulfonyl chloride (1-5 molar equivalents) are reacted at 0°C to 30°C for 2-24 hours, quenched with water (5-50 mL), and extracted 1-5 times with ethyl acetate (10-100 mL of ethyl acetate or one or two of dichloromethane for each 1 mmol I-B1). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography or preparative column chromatography after removing the solvent to obtain the corresponding target product I-Bn (here, n is the compound number, greater than or equal to 2). When using an acid in the presence of a condensing agent: In a dry round-bottom flask, dissolve I-B1 (1 mmol, 1.0 molar equivalent) in a dry solvent (one or more of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or dichloroethane, 5-50 mL), add one or more of triethylamine, N,N-diisopropylethylamine, pyridine, or 4-dimethylaminopyridine (2-5 molar equivalents), and add a carboxylic acid reagent (corresponding to R...). 2 Aromatic carboxylic acids within the defined range (1-5 molar equivalents) are then added at -10°C to 0°C, with BOP, PyBOP, or HATU (1-5 molar equivalents) as amide condensing agents. The reaction is carried out at 0°C to 30°C for 5-48 hours, quenched with water (5-50 mL), and extracted 1-5 times with ethyl acetate (10-100 mL of ethyl acetate or one or more of dichloromethane for each 1 mmol I-B1). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography or preparative column chromatography after solvent removal to obtain the corresponding target product I-Bn (n greater than or equal to 2). When R 2 When the alkyl group is alkyl: In a dry round-bottom flask, dissolve I-B1 (1 mmol, 1.0 molar equivalent) in a dry solvent (one or more of N,N-dimethylformamide, tetrahydrofuran, or acetone, 5-50 mL), add one or two of potassium carbonate or cesium carbonate (2-5 molar equivalents), and add the alkylating agent (haloalkyl R). 2 -X, Methanesulfonate R 2 -OMs or p-toluenesulfonate R 2 One or more of the following OTs (1-5 molar equivalents) are used, and the reaction is carried out at 25°C to 100°C. The reaction is quenched with water (5-50 mL), and extracted with ethyl acetate 1-5 times (1 mmol I-B1 is extracted with 10-100 mL of ethyl acetate or one or two of dichloromethane each time). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography after removing the solvent to obtain the corresponding target product I-Bn (n is greater than or equal to 2). Synthesis Method 3 Scheme 3. Similar to R in claims 1, 4, and 7 3 Related synthesis methods, Reaction e: Add acetic anhydride (10-30 mL per mole of I-A0 or I-A1) to the reaction flask, add nitric acid (0.2-1 mL per mole of I-A0 or I-A1), stir at room temperature for 5-20 min, then add I-A0 or I-A1 (1 mmol, 1.0 molar equivalent), stir at room temperature for 1-5 hours, add 20-100 mL of water, adjust the pH to 10-12 with sodium hydroxide, extract with ethyl acetate 1-5 times (1 mmol IA each time with 10-100 mL of ethyl acetate or dichloromethane), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent, and purify by silica gel column chromatography to obtain the corresponding target product IC; Reaction f: Add IC (1 molar equivalent) to the reaction flask, stir to dissolve with 10-100 mL of ethanol, then add ammonium chloride (5-20 molar equivalent), zinc powder (5-20 molar equivalent) and 2-10 mL of water. Heat to 60-90℃ and stir for 2-10 hours. Filter and concentrate the filtrate to obtain the target product ID. Alternatively, it can be directly added to the next reaction without further purification. Reaction g: Add ID (1 molar equivalent) dissolved in a dry solvent (5-20 mL, one or more of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, or N,N-dimethylformamide) to the reaction flask, then add triethylamine, pyridine, or N,N-diisopropylethylamine (1-5 molar equivalents), and add acyl chloride (1.1-5 molar equivalents, corresponding to R) at -10 to 0 °C. 3 The acyl chloride corresponding to the acyl group within the defined range is reacted at 10-50℃ for 1-24 hours, 5-20mL of water is added to quench the reaction, and then one or two of ethyl acetate or dichloromethane are extracted 1-5 times (5-20mL each time). After drying with anhydrous sodium sulfate, the solvent is removed, and the product is purified by silica gel column chromatography or preparative plate to obtain the corresponding target product IE. Reaction h: Gelsemium elegans A or I-A0 or I-A1 (1 molar equivalent) is dissolved in acetonitrile (5-20 mL), and N-bromosuccinimide or dibromohydantoin (1.0-3.0 molar equivalent) is added at -10-0℃. The reaction is then continued at this temperature for 0.2-2 hours. 5-20 mL of water is added to quench the reaction. The product is then extracted 1-5 times (5-20 mL each time) with one or two of ethyl acetate or dichloromethane. After drying with anhydrous sodium sulfate, the solvent is removed by vacuum distillation. The product is purified by silica gel column chromatography or preparative plate chromatography to obtain the corresponding target product IF. Reaction i: Under nitrogen protection, IF (0.1 mmol, 1 molar equivalent), substituted or unsubstituted aryl or heteroaryl borate or borate esters (1.2-3 molar equivalents, corresponding to R) 3 Boric acid or boronic acid esters within the defined range, and base (1.5-5 molar equivalents, potassium carbonate, cesium carbonate or sodium carbonate) are suspended in a mixed solution of 1,4-dioxane and water (2-10 mL, volume ratio 1:1 to 5:1). Then, palladium catalyst (1%-10% molar equivalents, Pd(PPh3)2Cl2, Pd(dppf)Cl2 or Pd(PPh3)4) is added. After sealing the tube, the reaction is carried out at 80-100℃ for 6-48 hours. The reaction is quenched by adding 5-20 mL of water. Then, the product is extracted 1-5 times (5-20 mL each time) with one or two of ethyl acetate or dichloromethane. After drying with anhydrous sodium sulfate, the solvent is removed, and the product is purified by silica gel column chromatography or preparative plate to obtain the corresponding target product IG. Synthesis Method 4 Scheme 4. Similar to R in claims 1, 5, and 7 4 Related synthesis methods, When R 4 It is C 1-20 When substituted or unsubstituted alkyl groups are used, reaction j is employed: Dissolve IA, IB, IC, IF, or IG (1.0 mol equivalent) in one or two of dry tetrahydrofuran or N,N-dimethylformamide (5-10 mL per mmol substrate), then add one or more of NaH, KH, potassium tert-butoxide, sodium tert-butoxide, butyllithium, LiHMDS, or LDA (1.0-2 mol equivalent) at -78°C to 0°C, and continue the reaction at -78°C to 0°C for 5 to 30 minutes, then add C. 1-20 One or more of substituted or unsubstituted alkyl chlorides, bromines, iodines, or halogen-like compounds (1.0-2 molar equivalents, corresponding to R...). 4 The reaction is carried out on alkyl halides or halide-like compounds within the defined range, and then the reaction is continued for 1-24 hours. 5-20 mL of water is added to quench the reaction, and then the product is extracted 1-5 times (5-20 mL each time) with one or two of ethyl acetate or dichloromethane. After drying with anhydrous sodium sulfate, the solvent is removed, and the product is purified by silica gel column chromatography or preparative plate to obtain the corresponding target product IH. When R 4 Whether the aryl group is substituted or unsubstituted, reaction k is used: Dissolve substrate IA, IB, IC, IF, or IG (1.0 mol equivalent) in one or more of dry acetonitrile, tetrahydrofuran, or dioxane (5-20 mL per millimole of raw material). Under nitrogen protection, add a base (potassium carbonate, cesium carbonate, or sodium carbonate, 2-5 mol equivalent) sequentially, followed by the iodinated or unsubstituted aryl derivative (1.2-3 mol equivalent, corresponding to R). 4 The target product IH can be obtained by reacting substituted or unsubstituted phenyl or heteroaryl iodides or bromides within the defined range, cuprous iodide (0.05-0.5 molar equivalents), and N,N′-dimethylvinyldiamine (0.1-1 molar equivalents) in a sealed tube at 75-100℃ for 4-24 hours. The reaction is quenched by adding 5-20 mL of water. Then, the product is extracted 1-5 times (5-20 mL each time) with one or two of ethyl acetate or dichloromethane. After drying with anhydrous sodium sulfate, the solvent is removed, and the product is purified by silica gel column chromatography or preparative plate chromatography. Synthesis Method Five Scheme 5. Similar to X and R in claims 1-8 1 -R 4 Related synthesis methods, Reaction l: Substrate I (I containing a basic group, 1 mmol, 1.0 molar equivalent) is dissolved in one or more organic solvents such as ethyl acetate, tetrahydrofuran, dichloromethane, and methanol (5-50 ml per 1 mmol of substrate), then an acid (any pharmaceutically acceptable acid as defined in claim 9, 1.0-5.0 molar equivalent relative to the substrate) is added, and the mixture is stirred at room temperature for 1-5 hours. After removing the solvent under reduced pressure and drying, the corresponding target product II can be obtained. Synthesis Method Six Scheme 6. Similar to X and R in claims 1-8 1 -R 5 Related synthesis methods, Reaction m: IA, IC, IE, IF, or IG (1 molar equivalent) dissolved in one or more of dry acetone, N,N-dimethylformamide, tetrahydrofuran, or acetonitrile (5-20 mL per millimole of raw material), a base (one or more of potassium carbonate, cesium carbonate, triethylamine, or N,N-isopropylethylamine, 2-5 molar equivalents), and an alkyl halide (one or more of chlorine, bromine, or iodine, 2-5 molar equivalents, corresponding to R). 5 Iodinated or brominated derivatives within the defined range are reacted at 20°C to 50°C for 2-12 hours. After the reaction is complete as detected by LC-MS, the corresponding target product III can be obtained by silica gel column chromatography or preparative column purification after removing the solvent.

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