CN113292476A

CN113292476A - Sulfaindole derivative and preparation method and application thereof

Info

Publication number: CN113292476A
Application number: CN202110537707.6A
Authority: CN
Inventors: 扈圆圆; 张嘉恒; 潘光兴; 孙航; 于聪伟; 李铁军; 胡春芳; 胡顺友
Original assignee: Harbin Institute of Technology Shenzhen
Current assignee: Harbin Institute of Technology Shenzhen
Priority date: 2021-05-18
Filing date: 2021-05-18
Publication date: 2021-08-24
Anticipated expiration: 2041-05-18
Also published as: CN113292476B

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a sulfaindole derivative, and a preparation method and application thereof. A sulfaindole derivative represented by general formula I or a pharmaceutically acceptable salt thereof:

wherein R is¹，R²Each independently represents hydrogen, alkyl or an alkyl derivative, alkenyl or an alkenyl derivative, alkynyl or an alkynyl derivative, aryl, cyano, acyl, ester group or carboxyl; r³Represents hydrogen or acetyl. The compound or pharmaceutically acceptable salt thereof has good inhibitory activity effect on gram-positive bacteria and gram-negative bacteria, especially has good antibacterial effect on Staphylococcus aureus, is not easy to generate drug resistance, has low cytotoxicity, and can inhibit Staphylococcus aureusThe bacterial membrane of staphylococcus has osmosis effect and rapid bactericidal effect; the compound or the pharmaceutically acceptable salt thereof has the advantages of simple raw materials, low price, easy obtainment and short synthetic route, and has important significance in the application of resisting infection.

Description

Sulfaindole derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a sulfaindole derivative, and a preparation method and application thereof.

Background

The dramatic increase in the variety of drug-resistant pathogenic bacteria due to overuse and abuse of antibacterial drugs (e.g., antibiotics) has become a major challenge in global public health today. Therefore, the design and synthesis of novel antibacterial agents with drug-resistant strains is becoming extremely urgent, and the research and development of antibacterial agent molecules with high efficiency, low toxicity and low possibility of causing drug resistance of germs are currently important research subjects.

The high morbidity and mortality caused by pathogenic infections has posed a serious threat to human health and survival. Sulfonamides are the first type of artificially synthesized antibacterial drugs, and further development thereof has attracted a high degree of attention in the fields of biology and medicine. To date, a large number of sulfonamides and sulfonamides having various pharmacological activities have been widely used in clinical applications, such as amprenavir and tipranavir for antiviral, methamphetamine for antiparasitic, acetazolamide and methazolamide for carbonic anhydrase inhibitors, glibenclamide and chlorpropamide tablets for lowering blood glucose, and the like. In particular, in the antibacterial aspect, many sulfadiazine antibacterial drugs, such as sulfamylone, sulfadimethoxine, sulfapyridine, sulfathiazole, sulfamethoxazole, sulfamethazine, etc., have played an important role in the treatment of infectious diseases. However, pathogen resistance and drug side effects from abuse of antibacterial drugs limit their clinical use. Therefore, research on novel sulfonamides having low toxicity and high activity and being less likely to cause drug resistance against pathogenic bacteria has been the focus of research.

Indole alkaloid is a signal molecule between bacterial cells, has the unique characteristic of mediating various biological processes, can interact with active targets in biological cells through various non-covalent bonds such as coordination bonds, hydrogen bonds, pi-pi accumulation and the like, and improves the physicochemical and pharmacokinetic properties of drug molecules, thereby improving the bioavailability and the drug selectivity. In addition, the indole scaffold can also play a potential biological activity by groove combination or insertion of DNA, has wide application prospects in various fields of chemistry, pharmacy, biology, material science and the like, shows great development values, and particularly has attracted great attention for benign promotion of antibacterial activity.

Therefore, it is necessary to provide an antibacterial compound or a drug which has low toxicity and high activity and is less likely to cause drug resistance against germs.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above.

To this end, it is an object of the present invention to provide a sulfaindole derivative or a pharmaceutically acceptable salt thereof.

The invention also aims to provide a preparation method of the sulfaindole derivative or the pharmaceutically acceptable salt thereof.

The invention also aims to provide a medicament containing the sulfaindole derivative or the pharmaceutically acceptable salt thereof.

The invention also aims to provide the application of the sulfaindole derivative or the pharmaceutically acceptable salt thereof in preparing antibacterial drugs.

In order to achieve the purpose, the invention provides the following technical scheme:

according to one of its objects, the present invention provides a sulfaindole derivative represented by the general formula I:

wherein R is¹，R²Each independently represents hydrogen, alkyl or an alkyl derivative, alkenyl or an alkenyl derivative, alkynyl or an alkynyl derivative, aryl, cyano, acyl, ester group or carboxyl; r³Represents hydrogen or acetyl.

Preferably, the carbon number of the alkyl group is 1 to 12; more preferably, the carbon number of the alkyl group is 1 to 9; more preferably, the number of carbons of the alkyl group is 1, 3, 5, 7, 9.

Preferably, the alkyl derivative comprises methoxy, ethoxy, propoxy or hydroxyethyl.

Preferably, the carbon number of the alkenyl group is 3 to 11; more preferably, the carbon number of the alkenyl group is 3 to 9; more preferably, the number of carbons of the alkenyl group is 3, 4, or 5.

Preferably, the carbon number of the alkynyl is 3 to 11; more preferably, the carbon number of the alkynyl group is 3 to 9; more preferably, the carbon number of the alkynyl group is 3, 4 or 5.

Preferably, the aryl group comprises benzyl or halobenzyl; further preferably, the halobenzyl group is a benzyl group containing F or Cl.

Preferably, the pharmaceutically acceptable salt of the sulfaindole derivative shown in the general formula I is hydrochloride, nitrate, acetate or sulfate.

Further preferably, the structural formula of the sulfaindole derivative is any one of the following formulas:

wherein, the compounds represented by the numbers I-1 to I-17 and II-1 to II-17 are sulfaindole derivatives represented by the general formula I, the compound represented by the formula I-1 can be converted into the compound represented by the formula II-1 through hydrolysis reaction, and the compounds represented by the formulas I-2 to I-17 and II-2 to II-17 can also be converted through hydrolysis reaction.

According to a second object of the present invention, there is provided a process for preparing the above-mentioned sulfaindole derivative or a pharmaceutically acceptable salt thereof, comprising the steps of:

adding the intermediate III, the intermediate IV and an acid catalyst into a solvent, and reacting to obtain the sulfaindole derivative shown in the general formula I; the structural formulas of the intermediate III and the intermediate IV are shown as follows:

wherein R is²Represents hydrogen, alkyl or alkyl derivatives, alkenyl or alkenyl derivatives, alkynyl or alkynyl derivatives, aryl, cyano, acyl, ester groups or carboxyl groups.

Preferably, said intermediate III is prepared according to the process reference "B.Wang, Z.C.Yan, L.Y.Liu et al.TBN-mediated regio-and stereoselective sulfonation&oximation(oximosulfonylation)of alkynes with sulfonyl hydrazines in EtOH/H₂O.Green chem.2019,21,205-212. "the preparation method disclosed.

Preferably, the preparation method of the intermediate III comprises the following steps: acetanilide is used as an initial raw material to perform sulfonation reaction with chlorosulfonic acid to obtain p-acetamino benzene sulfonyl chloride, and the product is prepared through amination reaction; further preferably, the temperature of the sulfonation reaction is 0-60 ℃; the solvent used in the amination reaction is tetrahydrofuran.

Preferably, the intermediate IV is prepared by the method disclosed in references "z.z.li, v.k.r.tangadanchhu, n.battini et al, oil-nitro-imidazole conjugates as effective microorganisms to the production of the genes expression of methicillin-resistant Staphylococcus aureus.

Preferably, containing different substituents (R)²) The preparation method of the intermediate IV comprises the following steps: indole is taken as a starting material, and reacts with phosphorus oxychloride at 0 ℃ in a dimethylformamide solution to obtain indole aldehyde, and then the indole aldehyde is subjected to substitution reaction with a substance containing halogenated alkyl, alkenyl, alkynyl or halobenzyl at 45-80 ℃ in an acetonitrile solution to obtain the indole aldehyde; further preferably, the molar ratio of the compound indole aldehyde to the substance containing halogenated alkyl, alkenyl, alkynyl or halogenated benzyl is 1 (0.5-2); more preferably, the molar ratio is 1: 1.

Preferably, the solvent is an alcohol; further preferably, the solvent is ethanol.

Preferably, the acid catalyst is an organic acid; further preferably, the organic acid is acetic acid, formic acid or propionic acid; more preferably, the organic acid is acetic acid.

Preferably, the molar ratio of the intermediate III to the intermediate IV is 1 (0.5-2); further preferably, the molar ratio of the intermediate III to the intermediate IV is 1: 1.

Preferably, the amount of the acid catalyst used is small, and for example, the mass of the acid catalyst may be 0.05% or more of the mass of the intermediate III.

Preferably, the reaction temperature is 70-90 ℃, and the reaction time is 5-12 hours; further preferably, the reaction temperature is 80-85 ℃, and the reaction time is 6-10 hours.

Preferably, the conversion process between the compounds of numbers I-1 to I-17 and II-1 to II-17 is:

and (3) carrying out hydrolysis reaction on the sulfaindole derivatives shown in the numbers I-1 to I-17 to prepare the sulfaindole derivatives shown in the numbers II-1 to II-17.

Preferably, the temperature of the hydrolysis reaction is 75-85 ℃; further preferably, the temperature of the hydrolysis reaction is 80 ℃.

Further preferably, the hydrolysis reaction is carried out under the conditions of hydrochloric acid as a catalyst and ethanol reflux.

Preferably, the preparation method of the pharmaceutically acceptable salt of the sulfaindole derivative shown in the general formula I comprises the following steps:

dissolving the sulfaindole derivative shown in the general formula I in an organic solvent, and adding a pharmaceutically acceptable acid for reaction to obtain the pharmaceutically acceptable salt of the sulfaindole derivative shown in the general formula I.

Preferably, the organic solvent is at least one of chloroform, acetone, acetonitrile, diethyl ether or tetrahydrofuran.

Preferably, the pharmaceutically acceptable acid is hydrochloric acid, nitric acid, acetic acid or sulfuric acid.

According to a third object of the invention, the invention provides a medicament, which comprises the sulfaindole derivative shown in the general formula I or pharmaceutically acceptable salt thereof and an auxiliary material.

Preferably, the auxiliary materials are pharmaceutically acceptable auxiliary materials; further preferably, the auxiliary material is selected from at least one of a filler, a lubricant, a disintegrant, a binder or a glidant.

Preferably, the filler comprises lactose, sucrose, starch, microcrystalline cellulose or powdered cellulose.

Preferably, the lubricant comprises stearic acid, magnesium stearate, calcium stearate or zinc stearate.

Preferably, the disintegrant comprises sodium starch glycolate, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose.

Preferably, the binder comprises hydroxypropylmethylcellulose or polyethylene glycol.

Preferably, the glidant comprises talcum powder, anhydrous colloidal silicon dioxide or micropowder silica gel.

Preferably, the dosage form of the medicament is any dosage form; preferably, the medicament is in the form of one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments, aerosols, powders, dropping pills, solutions, suspensions, emulsions, gels, films, transdermal patches, controlled release preparations or nano preparations.

According to the fourth purpose of the invention, the invention provides the application of the sulfaindole derivative or the pharmaceutically acceptable salt thereof in preparing antibacterial drugs. The antibacterial drug has good inhibitory activity effect on various gram-positive bacteria and gram-negative bacteria.

Preferably, the gram-positive bacteria include, but are not limited to, methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, or staphylococcus aureus ATCC 29213.

Preferably, the bacterium is staphylococcus. More preferably, the bacterium is staphylococcus aureus.

The compound I-8 has a good antibacterial effect on staphylococcus aureus, and the compound I-8 is used for performing an anti-staphylococcus aureus test to find that the staphylococcus aureus is not easy to generate drug resistance, and the antibacterial effect is superior to that of drugs norfloxacin and sulfathiazole on the staphylococcus aureus.

Preferably, the gram-negative bacteria include, but are not limited to, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922, or acinetobacter baumannii.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention utilizes the drug design split principle, indole derivatives containing different substituents are bridged on a sulfonamide structure through Schiff base, a series of sulfonamide indole derivatives with novel structures are designed and synthesized, and the compounds are found to have good inhibitory activity effects on gram-positive bacteria and gram-negative bacteria through in vitro antimicrobial activity detection, so that the compounds or pharmaceutically acceptable salts thereof can be used for preparing antibacterial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial therapy, and being beneficial to solving the clinical treatment problems of increasingly serious drug resistance, stubborn germs, newly appeared harmful microorganisms and the like.

(2) The compound or the pharmaceutically acceptable salt thereof has the advantages of simple raw material preparation, low price, easy obtainment and short synthetic route, and has important significance in the application of resisting infection.

Drawings

FIG. 1 is a graph comparing the resistance of compound I-8 to the reference drugs norfloxacin and sulfathiazole against Staphylococcus aureus.

FIG. 2 is a graph of the cytotoxicity of Compound I-8 against normal mammalian cells (RAW 264.7).

FIG. 3 is a graph of the bacterial membrane permeability experiment of Compound I-8 against Staphylococcus aureus.

FIG. 4 is a graph of the bactericidal kinetics of Compound I-8 against Staphylococcus aureus.

Detailed Description

In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.

The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.

Example 1: preparation of intermediate III

Preparation of intermediate III references B.Wang, Z.C.Yan, L.Y.Liu et al.TBN-mediated regio-and stereoselective sulfonation&oximation(oximosulfonylation)of alkynes with sulfonyl hydrazines in EtOH/H₂O.Green chem.2019,21,205-212. "the preparation method disclosed.

Example 2: preparation of intermediate IV

Preparation of intermediate IV is described in the methods disclosed in "Z.Z.Li, V.K.R.Tangdanchu, N.Battini et al, oil-nitro-imidazole conjugates as effective microorganisms to the production of the genes expression of methicillin-resistant Staphylococcus aureus. Eur.J.Med.chem.2019,179, 723-735".

Example 3: preparation of Compound I-1

Intermediate III (1.15g, 5.00mmol), indole aldehyde (0.73g, 5.00mmol) (i.e. R)²Intermediate IV) as hydrogen, 5 drops of acetic acid and 25mL of ethanol as solvent are added into a 50mL round-bottom flask and reacted at 80 ℃ and stirred for 6 h. After the completion of the reaction by thin layer chromatography, the reaction mixture was cooled to room temperature, ethanol was evaporated under reduced pressure and then subjected to silica gel column chromatography, followed by drying to obtain compound I-1(1.48g) in 80.8% yield.

The compound I-1 is light yellow solid, and the melting point is 98-100 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:11.50(s,1H,Indo-NH),10.79(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.08(s,1H,NCH),7.98(d,J＝7.7Hz,1H,Indo-NHCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.71(d,J＝2.7Hz,1H,Indo-4-H),7.40(d,J＝7.9Hz,1H,Indo-7-H),7.15(m,J＝14.6,7.0Hz,2H,Indo-5,6-H),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.5,143.6,137.4,133.1,130.9,129.1,124.5,123.0,122.1,121.0,118.8,112.3,111.6,24.6ppm。

example 4: preparation of Compound II-1

Compound I-1(0.36g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and reflux at 80 ℃ for 8 h. And (3) tracking by using the thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-1(0.19g), wherein the yield is 60.6%.

The compound II-1 is yellow solid, and the melting point is 94-96 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:11.51(s,1H,Indo-NH),10.49(s,1H,SO₂NH),8.06(s,1H,NCH),8.02(d,J＝7.7Hz,1H,Indo-NHCH),7.69(d,J＝2.7Hz,1H,Indo-4-H),7.57(d,J＝8.7Hz,2H,Ph-2,6-H),7.40(d,J＝7.9Hz,1H,Indo-7-H),7.19–7.15(m,1H,Indo-5-H),7.12(t,J＝7.1Hz,1H,Indo-6-H),6.62(d,J＝8.7Hz,2H,Ph-3,5-H)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.0,144.7,137.4,130.5,129.8,124.9,124.5,123.0,122.2,120.8,113.2,112.2,111.8ppm。

example 5: preparation of Compound I-2

Intermediate III (1.15g, 5.00mmol), methyl indole aldehyde (0.80g, 5.00mmol) (i.e. R)²Intermediate IV) which is methyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask for reaction at 80 ℃, the mixture is stirred for 6 hours, thin layer chromatography is carried out until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated by silica gel column chromatography and dried, and the compound I-2(1.45g) is obtained, and the yield is 78.2%.

The compound I-2 is a white solid, and the melting point is 160-162 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.79(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.06(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.69(s,1H,Indo-4-H),7.45(d,J＝8.1Hz,1H,Indo-7-H),7.24(t,J＝7.3Hz,1H,Indo-5-H),7.17(t,J＝7.4Hz,1H,Indo-6-H),3.77(s,3H,Indo-CH₃),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.0,143.6,137.9,134.4,133.1,129.1,124.9,123.1,122.2,121.2,118.8,110.6,33.2,24.6ppm。

example 6: preparation of Compound II-2

Compound I-2(0.37g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-2(0.22g), wherein the yield is 66.8%.

The compound II-2 is a yellow solid with a melting point of 136-138 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.55(s,1H,SO₂NH),8.04(s,1H,NCH),8.01(d,J＝7.9Hz,1H,Indo-NCH),7.67(s,1H,Indo-4-H),7.60(d,J＝8.6Hz,2H,Ph-2,6-H),7.45(d,J＝8.2Hz,1H,Indo-7-H),7.26–7.21(m,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),6.70(d,J＝8.7Hz,2H,Ph-3,5-H),3.77(s,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:144.3,137.9,134.1,129.8,124.9,124.0,123.1,122.2,121.4,121.1,114.1,111.4,110.7,33.2ppm。

example 7: preparation of Compound I-3

Intermediate III (1.15g, 5.00mmol), propyl indole aldehyde (0.94g, 5.00mmol) (i.e. R)²Intermediate IV) which is propyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask for reaction at 80 ℃, the mixture is stirred for 6 hours, thin layer chromatography is used for tracking till the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated and dried by silica gel column chromatography, and the compound I-3(1.56g) is obtained, and the yield is 78.1%.

The compound I-3 is a white solid with a melting point of 100-102 ℃; hydrogen spectrum of nuclear magnetic resonanceAnd the characterization results of the carbon spectrum are:¹H NMR(600MHz,DMSO-d₆)δ:10.81(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.06(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.78–7.72(m,3H,Ph-3,5-H,Indo-4-H),7.50(d,J＝8.1Hz,1H,Indo-7-H),7.22(t,J＝7.6Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),4.11(t,J＝6.9Hz,2H,Indo-NCH₂),2.05(s,3H,COCH₃),1.75(m,J＝7.2Hz,2H,Indo-NCH₂CH₂),0.81(t,J＝7.4Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.0,143.6,137.3,133.6,133.1,129.1,124.9,123.1,122.3,121.1,118.8,110.7,47.7,24.6,23.3,11.5ppm。

example 8: preparation of Compound II-3

Adding the compound I-3(0.40g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-3(0.22g), wherein the yield is 60.1%.

The compound II-3 is yellow solid, and the melting point is 92-94 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.53(s,1H,SO₂NH),8.04(s,1H,NCH),8.02(d,J＝7.9Hz,1H,Indo-NCH),7.72(s,1H,Indo-4-H),7.58(d,J＝8.7Hz,2H,Ph-2,6-H),7.50(d,J＝8.1Hz,1H,Indo-7-H),7.22(t,J＝7.6Hz,1H,Indo-5-H),7.14(t,J＝7.4Hz,1H,Indo-6-H),6.66(d,J＝8.7Hz,2H,Ph-3,5-H),4.12(t,J＝6.9Hz,2H,Indo-NCH₂),1.76(m,J＝14.3,7.2Hz,2H,Indo-NCH₂CH₂),0.82(t,J＝7.3Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:144.3,137.3,133.3,129.8,125.5,125.0,122.9,122.4,121.0,113.7,110.8,47.7,23.4,11.5ppm。

example 9: preparation of Compound I-4

Intermediate III (1.15g, 5.00mmol), pentylindole aldehyde (1.10g, 5.00mmol) (i.e., R)²Pentyl intermediate IV), 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round bottom flask at 80 ℃, reacted, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and subjected to silica gel column chromatography, and dried to obtain compound I-4(1.63g) with a yield of 76.4%.

The compound I-4 is a white solid, and the melting point is 96-98 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.81(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.06(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.78–7.74(m,3H,Ph-3,5-H,Indo-4-H),7.49(d,J＝8.2Hz,1H,Indo-7-H),7.22(t,J＝7.3Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),4.14(t,J＝6.9Hz,2H,Indo-NCH₂),2.05(s,3H,COCH₃),1.77–1.69(m,2H,Indo-NCH₂CH₂),1.27(m,J＝14.1,7.0Hz,2H,Indo-NCH₂CH₂CH₂),1.22–1.14(m,2H,Indo-NCH₂CH₂CH₂CH₂),0.81(t,J＝7.2Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.0,143.6,137.2,133.6,133.1,129.0,124.9,123.1,122.3,121.1,118.8,110.7,46.1,29.7,28.8,24.6,22.2,14.3ppm。

example 10: preparation of Compound II-4

Compound I-4(0.43g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-4(0.24g), wherein the yield is 62.2%.

The compound II-4 is brown solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.49(s,1H,SO₂NH),8.03(s,1H,NCH),8.00(d,J＝8.6Hz,1H,Indo-NCH),7.72(s,1H,Indo-4-H),7.55(d,J＝8.7Hz,2H,Ph-2,6-H),7.49(d,J＝8.1Hz,1H,Indo-7-H),7.22(d,J＝7.0Hz,1H,Indo-5-H),7.13(d,J＝7.0Hz,1H,Indo-6-H),6.60(d,J＝8.6Hz,2H,Ph-3,5-H),4.14(t,J＝6.9Hz,2H,Indo-NCH₂),1.76–1.71(m,2H,Indo-NCH₂CH₂),1.23–1.17(m,4H,Indo-NCH₂CH₂(CH₂)₂),0.81(d,J＝7.3Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.3,144.2,137.2,133.2,129.8,125.0,124.5,124.0,123.0,122.4,121.0,112.9,110.9,46.4,29.7,28.8,22.2,14.3ppm。

example 11: preparation of Compound I-5

Intermediate III (1.15g, 5.00mmol), heptylindolal aldehyde (1.20g, 5.00mmol) (i.e., R)²Intermediate IV) as a heptyl group, 5 drops of acetic acid and 25mL of ethanol as solvents were added into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure, separated by silica gel column chromatography, and dried to obtain compound I-5(1.84g) with a yield of 78.9%.

The compound I-5 is light yellow solid, and the melting point is 80-82 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.80(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.05(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.78–7.74(m,3H,Ph-3,5-H,Indo-4-H),7.49(d,J＝8.2Hz,1H,Indo-7-H),7.22(t,J＝7.5Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),4.14(t,J＝6.9Hz,2H,Indo-NCH₂),2.05(s,3H,COCH₃),1.77–1.68(m,2H,Indo-NCH₂CH₂),1.20(m,J＝9.3,4.2Hz,8H,Indo-NCH₂CH₂(CH₂)₄),0.82(t,J＝6.8Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.4,145.0,143.6,137.2,133.6,133.1,129.0,124.9,123.1,122.3,121.1,118.8,110.7,46.2,31.6,30.0,28.7,26.6,24.6,22.5,14.4ppm。

example 12: preparation of Compound II-5

Compound I-5(0.45g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl followed by reflux at 80 ℃ for 8h, TLC followed to completion of the reaction, heating was stopped, and cooling to room temperature was allowed to occur. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-5(0.25g), wherein the yield is 60.8%.

The compound II-5 is brown liquid; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:7.94(s,1H,NCH),7.93(s,1H,Indo-NCH),7.60(s,1H,Indo-4-H),7.45(d,J＝8.6Hz,2H,Ph-2,6-H),7.39(d,J＝7.9Hz,1H,Indo-7-H),7.06–7.02(m,2H,Indo-5,6-H),6.50(d,J＝8.7Hz,2H,Ph-3,5-H),5.84(s,2H,NH₂),4.04(t,J＝6.9Hz,2H,Indo-NCH₂),1.69(d,J＝6.6Hz,2H,Indo-NCH₂CH₂),1.13(d,J＝3.7Hz,8H,Indo-NCH₂CH₂(CH₂)₄),0.73(s,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.2,143.9,137.5,137.2,134.9,133.0,129.8,125.0,123.0,120.9,112.9,111.0,110.7,46.1,31.6,30.0,28.7,26.6,22.5,14.4ppm。

example 13: preparation of Compound I-6

Intermediate III (1.15g, 5.00mmol), nonyl indole aldehyde (1.40g, 5.00mmol) (i.e. R)²Nonyl intermediate IV), 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottom flask at 80 ℃, reacted, stirred for 6h, followed by thin layer chromatography until the reaction was complete, cooled to room temperature, evaporated under reduced pressure and chromatographed on a silica gel column, oven dried to give compound I-6(1.95g) in 77.6% yield.

The compound I-6 is light yellow solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.81(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.05(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.78–7.73(m,3H,Ph-3,5-H,Indo-4-H),7.49(d,J＝8.1Hz,1H,Indo-7-H),7.22(t,J＝7.5Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),4.14(t,J＝6.9Hz,2H,Indo-NCH₂),2.05(s,3H,COCH₃),1.73(m,J＝13.7,6.8Hz,2H,Indo-NCH₂CH₂),1.20(d,J＝10.7Hz,12H,Indo-NCH₂CH₂(CH₂)₆),0.83(t,J＝6.8Hz,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.4,145.0,143.6,137.2,133.6,133.1,129.0,124.9,123.0,122.3,121.1,118.8,110.7,46.2,31.7,30.0,29.3,29.0,26.6,24.6,22.5,14.4ppm。

example 14: preparation of Compound II-6

Adding the compound I-6(0.48g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-6(0.24g), wherein the yield is 55.3%.

The compound II-6 is brown liquid; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:8.09(d,J＝7.8Hz,1H,NCH),7.90(s,1H,Indo-NCH),7.50(s,1H,Indo-4-H),7.47(d,J＝5.4Hz,2H,Ph-2,6-H),7.41(d,J＝8.1Hz,1H,Indo-7-H),7.28–7.25(m,1H,Indo-5-H),7.06(t,J＝6.1Hz,1H,Indo-6-H),6.53(d,J＝8.6Hz,2H,Ph-3,5-H),5.58(s,2H,NH₂),4.10(t,J＝7.0Hz,2H,Indo-NCH₂),1.74–1.70(m,2H,Indo-NCH₂CH₂),1.20(s,12H,Indo-NCH₂CH₂(CH₂)₆)),0.84(s,3H,Indo-CH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:151.5,137.5,137.1,129.1,128.6,127.1,125.9,125.4,122.4,121.5,120.0,113.2,112.7,110.2,45.9,31.7,30.1,29.4,29.1,26.6,22.5,14.4ppm。

example 15: preparation of Compound I-7

Intermediate III (1.15g, 5.00mmol), allylindole aldehyde (0.93g, 5.00mmol) (i.e. R)²Intermediate IV) which is allyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, the reaction is tracked by thin layer chromatography until the reaction is finished, the mixture is cooled to room temperature, and after ethanol is evaporated under reduced pressure, the mixture is separated by silica gel column chromatography and dried to obtain compound I-7(1.26g) with the yield of 61.2%.

The compound I-7 is a white solid with a melting point of 110-112 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.84(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.07(s,1H,NCH),7.99(d,J＝7.7Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.72(s,1H,Indo-4-H),7.45(d,J＝8.1Hz,1H,Indo-7-H),7.22(m,J＝11.2,4.0Hz,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),5.98(m,J＝15.7,10.5,5.4Hz,1H,Indo-NCH₂CHCH₂),5.18–5.13(m,1H,Indo-NCH₂CHCH₂),5.03(m,J＝17.1,1.3Hz,1H,Indo-NCH₂CHCH₂),4.81(d,J＝5.3Hz,2H,Indo-NCH₂CHCH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.9,143.6,137.2,134.3,133.6,133.1,129.1,125.0,123.2,122.3,121.3,118.8,117.6,111.0,48.7,24.6ppm。

example 16: preparation of Compound II-7

Adding the compound I-7(0.40g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-7(0.21g), wherein the yield is 58.2%.

The compound II-7 is a yellow solid, and the melting point is 68-70 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.50(s,1H,SO₂NH),8.04(s,1H,NCH),8.02(s,1H,Indo-NCH),7.70(s,1H,Indo-4-H),7.55(d,J＝8.7Hz,2H,Ph-2,6-H),7.45(d,J＝8.1Hz,1H,Indo-7-H),7.22(t,J＝7.2Hz,1H,Indo-5-H),7.15(t,J＝7.3Hz,1H,Indo-6-H),6.60(d,J＝8.7Hz,2H,Ph-3,5-H),6.05–5.97(m,1H,Indo-NCH₂CHCH₂),5.95(s,2H,NH₂),5.18–5.13(m,1H,Indo-NCH₂CHCH₂),5.04(m,J＝17.1,1.3Hz,1H,Indo-NCH₂CHCH₂),4.82(d,J＝5.3Hz,2H,Indo-NCH₂CHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.4,144.1,137.2,134.3,133.2,129.8,125.1,124.5,123.1,122.4,121.1,117.6,112.9,111.3,111.0,48.7ppm。

example 17: preparation of Compound I-8

Intermediate III (1.15g, 5.00mmol), Etenbutylindolealdehyde (1.00g, 5.00mmol) (i.e. R²Intermediate IV) of an alkene butyl, 5 drops of acetic acid and 25mL of ethanol are added into a 50mL round-bottom flask as a solvent, the mixture is reacted for 6 hours under stirring, the reaction is tracked by thin layer chromatography until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated by silica gel column chromatography and dried, and the compound I-8(1.24g) is obtained, and the yield is 60.2%.

The compound I-8 is a white solid with a melting point of 120-122 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.81(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.05(s,1H,NCH),7.97(d,J＝7.8Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.79–7.73(m,3H,Ph-3,5-H,Indo-4-H),7.52(d,J＝8.2Hz,1H,Indo-7-H),7.23(t,J＝7.5Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),5.81–5.71(m,1H,Indo-NCH₂CH₂CHCH₂),4.97(m,J＝13.6,12.5Hz,2H,Indo-NCH₂CH₂CHCH₂),4.23(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CHCH₂),2.51–2.48(m,2H,Indo-NCH₂CH₂CHCH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.0,143.6,137.2,135.4,133.5,133.1,129.1,124.9,123.1,122.3,121.2,118.8,117.9,110.7,45.5,34.3,24.6ppm。

example 18: preparation of Compound II-8

Adding the compound I-8(0.41g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-8(0.22g) with the yield of 59.0%.

The compound II-8 is a yellow solid,the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.54(s,1H,SO₂NH),8.01(d,J＝7.5Hz,2H,NCH,Indo-NCH),7.71(s,1H,Indo-4-H),7.55(d,J＝8.7Hz,2H,Ph-2,6-H),7.52(d,J＝8.2Hz,1H,Indo-7-H),7.22(t,J＝7.1Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),6.60(d,J＝8.7Hz,2H,Ph-3,5-H),5.95(s,2H,NH₂),5.81–5.74(m,1H,Indo-NCH₂CH₂CHCH₂),4.96(d,J＝10.4Hz,2H,Indo-NCH₂CH₂CHCH₂),4.23(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CHCH₂),2.51(s,2H,Indo-NCH₂CH₂CHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.3,144.1,137.2,135.4,133.1,129.8,125.0,124.5,123.0,122.4,121.0,117.9,112.9,110.9,110.7,45.5,34.3ppm。

example 19: preparation of Compound I-9

Intermediate III (1.15g, 5.00mmol), alkenylpentylindole aldehyde (1.10g, 5.00mmol) (i.e., R²Intermediate IV) in the form of an alkenyl group, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ to react, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and subjected to silica gel column chromatography to separate and dry the product, thereby obtaining compound I-9(1.18g) in 55.6% yield.

The compound I-9 is a white solid, and the melting point is 82-84 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.82(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.06(s,1H,NCH),7.98(d,J＝7.8Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.76(d,J＝10.2Hz,3H,Ph-3,5-H,Indo-4-H),7.50(d,J＝8.2Hz,1H,Indo-7-H),7.23(t,J＝7.5Hz,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),5.80(m,J＝16.8,10.2,6.5Hz,1H,Indo-NCH₂CH₂CH₂CHCH₂),5.00(m,J＝24.1,6.2Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),4.16(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),2.05(s,3H,COCH₃),1.98(m,J＝14.2,6.9Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),1.87–1.79(m,2H,Indo-NCH₂CH₂CH₂CHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,145.0,143.6,138.1,137.2,133.6,133.1,129.0,124.9,123.1,122.3,121.2,118.8,115.9,110.8,45.6,30.7,29.1,24.6ppm。

example 20: preparation of Compound II-9

Compound I-9(0.42g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, precipitating a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-9(0.21g), wherein the yield is 53.7%.

The compound II-9 is yellow solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.50(s,1H,SO₂NH),8.03(d,J＝8.9Hz,2H,NCH,Indo-NCH),7.72(s,1H,Indo-4-H),7.55(d,J＝8.7Hz,2H,Ph-2,6-H),7.49(d,J＝8.2Hz,1H,Indo-7-H),7.22(t,J＝7.5Hz,1H,Indo-5-H),7.15(t,J＝7.4Hz,1H,Indo-6-H),6.60(d,J＝8.7Hz,2H,Ph-3,5-H),5.84–5.76(m,1H,Indo-NCH₂CH₂CH₂CHCH₂),4.97(d,J＝10.7Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),4.16(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),1.98(m,J＝14.5,7.2Hz,2H,Indo-NCH₂CH₂CH₂CHCH₂),1.86–1.80(m,2H,Indo-NCH₂CH₂CH₂CHCH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.3,144.1,138.1,137.2,133.2,129.8,125.0,124.5,123.0,122.4,121.0,115.9,112.9,111.0,110.7,45.6,30.7,29.1ppm。

example 21: preparation of Compound I-10

Intermediate III (1.15g, 5.00mmol), propargyl indole aldehyde (0.92g, 5.00mmol) (i.e., R)²Intermediate IV) which is propargyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask at 80 ℃, the mixture is stirred for 6 hours, thin layer chromatography is carried out until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated and dried by silica gel column chromatography to obtain compound I-10(0.99g) with the yield of 50.2 percent.

The compound I-10 is light yellow solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.87(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.08(s,1H,NCH),8.00(d,J＝7.8Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.76(d,J＝9.6Hz,3H,Ph-3,5-H,Indo-4-H),7.54(d,J＝8.2Hz,1H,Indo-7-H),7.27(t,J＝7.5Hz,1H,Indo-5-H),7.20(t,J＝7.4Hz,1H,Indo-6-H),5.10(d,J＝2.3Hz,2H,Indo-NCH₂CCH),3.45(t,J＝2.4Hz,1H,Indo-NCH₂CCH),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.7,143.6,136.9,133.0,129.1,125.1,123.4,122.4,121.6,118.8,111.5,111.0,79.1,76.6,35.9,24.6ppm。

example 22: preparation of Compound II-10

Compound I-10(0.39g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl followed by reflux at 80 ℃ for 8h, TLC followed to completion of the reaction, heating was stopped, and cooling to room temperature was allowed to occur. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-10(0.18g), wherein the yield is 51.2%.

The compound II-10 is yellow solid, and the melting point is 88-90 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.66(s,1H,SO₂NH),8.06(s,1H,NCH),8.03(d,J＝7.8Hz,1H,Indo-NCH),7.76(s,1H,Indo-4-H),7.62(d,J＝8.7Hz,2H,Ph-2,6-H),7.54(d,J＝8.2Hz,1H,Indo-7-H),7.27(t,J＝7.4Hz,1H,Indo-5-H),7.19(t,J＝7.5Hz,1H,Indo-6-H),6.74(d,J＝8.7Hz,2H,Ph-3,5-H),5.10(d,J＝2.3Hz,2H,Indo-NCH₂CCH),3.45(t,J＝2.3Hz,1H,Indo-NCH₂CCH)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:151.0,144.1,136.9,132.7,129.8,126.5,125.2,123.4,122.5,121.5,114.6,111.7,110.9,79.1,76.5,35.9ppm。

example 23: preparation of Compound I-11

Intermediate III (1.15g, 5.00mmol), acetylenic butyl indole aldehyde (0.99g, 5.00mmol) (i.e. R)²Intermediate IV) of acetylenic butyl, 5 drops of acetic acid and 25mL of ethanol were added as solvents to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6h, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and then chromatographed on silica gel column, and dried to obtain compound I-11(0.76g) with a yield of 37.2%.

The compound I-11 is a white solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.82(s,1H,SO₂NH),10.28(s,1H,NHCOCH₃),8.05(s,1H,NCH),7.98(d,J＝7.7Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.78–7.73(m,3H,Ph-3,5-H,Indo-4-H),7.55(d,J＝8.1Hz,1H,Indo-7-H),7.23(t,J＝7.2Hz,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),4.31(t,J＝6.6Hz,2H,Indo-NCH₂CH₂CCH),2.84(t,J＝2.5Hz,1H,NCH₂CH₂CCH),2.67(m,J＝6.5,2.4Hz,2H,NCH₂CH₂CCH),2.04(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.9,143.6,137.1,133.7,133.0,129.0,125.0,123.2,122.3,121.3,118.8,110.8,81.8,73.8,44.9,24.6,19.9ppm。

example 24: preparation of Compound II-11

Adding the compound I-11(0.41g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-11(0.20g), wherein the yield is 54.3%.

The compound II-11 is light yellow solid, and the melting point is 76-78 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.53(s,1H,SO₂NH),8.07(d,J＝5.5Hz,2H,NCH,Indo-NCH),7.79(s,1H,Indo-4-H),7.61–7.58(m,3H,Ph-2,6-H,Indo-7-H),7.27(t,J＝7.3Hz,1H,Indo-5-H),7.21(t,J＝7.4Hz,1H,Indo-6-H),6.64(d,J＝8.7Hz,2H,Ph-3,5-H),5.99(s,2H,NH₂),4.36(t,J＝6.6Hz,2H,Indo-NCH₂CH₂CCH),2.89(t,J＝2.5Hz,1H,NCH₂CH₂CCH),2.72(m,J＝6.6,2.4Hz,2H,NCH₂CH₂CCH)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.3,144.0,137.1,133.3,129.8,125.1,124.5,123.1,122.4,121.2,112.9,111.1,110.7,81.8,73.8,44.9,19.9ppm。

example 25: preparation of Compound I-12

Intermediate III (1.15g, 5.00mmol), propargyl indole aldehyde (1.10g, 5.00mmol) (i.e., R²Is alkynylpentylThe intermediate IV) of (1), 5 drops of acetic acid and 25mL of ethanol are added into a 50mL round-bottom flask as a solvent, the mixture is reacted for 6 hours, the mixture is stirred and tracked by thin layer chromatography until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure, and then the mixture is separated by silica gel column chromatography and dried to obtain the compound I-12(1.02g) with the yield of 48.3%.

The compound I-12 is a white solid, and the melting point is 70-72 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.83(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.06(s,1H,NCH),7.99(d,J＝7.8Hz,1H,Indo-NCH),7.85(d,J＝8.8Hz,2H,Ph-2,6-H),7.79–7.72(m,3H,Ph-3,5-H,Indo-4-H),7.51(d,J＝8.2Hz,1H,Indo-7-H),7.24(t,J＝7.3Hz,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),4.23(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CH₂CCH),2.87(t,J＝2.5Hz,1H,Indo-NCH₂CH₂CH₂CCH),2.12(m,J＝6.9,2.4Hz,2H,Indo-NCH₂CH₂CH₂CCH),2.05(s,3H,COCH₃),1.92(m,J＝7.0Hz,2H,Indo-NCH₂CH₂CH₂CCH)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.9,143.6,137.2,133.5,133.1,129.0,124.9,123.2,122.4,121.3,118.8,110.9,110.6,83.8,72.5,45.0,28.9,24.6,15.6ppm。

example 26: preparation of Compound II-12

Adding the compound I-12(0.42g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-12(0.22g) with the yield of 57.8%.

The compound II-12 is a yellow solid, and the melting point is 68-70 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.52(s,1H,SO₂NH),8.03(d,J＝7.0Hz,2H,NCH,Indo-NCH),7.71(s,1H,Indo-4-H),7.56(d,J＝8.7Hz,2H,Ph-2,6-H),7.51(d,J＝8.2Hz,1H,Indo-7-H),7.23(t,J＝7.6Hz,1H,Indo-5-H),7.16(t,J＝7.4Hz,1H,Indo-6-H),6.62(d,J＝8.7Hz,2H,Ph-3,5-H),4.23(t,J＝6.9Hz,2H,Indo-NCH₂CH₂CH₂CCH),2.88(t,J＝2.5Hz,1H,Indo-NCH₂CH₂CH₂CCH),2.12(m,J＝6.9,2.4Hz,2H,Indo-NCH₂CH₂CH₂CCH),1.95–1.90(m,2H,Indo-NCH₂CH₂CH₂CCH)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:153.1,144.1,137.2,133.1,129.8,125.0,124.7,123.1,122.5,121.1,113.1,111.2,110.6,83.8,72.5,45.0,28.9,15.6ppm。

example 27: preparation of Compound I-13

Intermediate III (1.15g, 5.00mmol), 2-fluorobenzyl indole aldehyde (1.27g, 5.00mmol) (i.e. R)²Intermediate IV) of 2-fluorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and then chromatographed on a silica gel column, and dried to obtain compound I-13(1.82g) with a yield of 78.4%.

The compound I-13 is a white solid, and the melting point is 78-80 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.88(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.08(s,1H,NCH),7.99(d,J＝7.6Hz,1H,Indo-NCH),7.88–7.82(m,3H,Indo-4-H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.49(d,J＝8.0Hz,1H,Indo-7-H),7.33(m,J＝8.6,3.8Hz,1H,Indo-5-H),7.21(m,J＝15.2,6.8Hz,3H,Indo-6-H,Indo-CH₂Ph-3,4-H),7.10(m,J＝6.1,3.5Hz,2H,Indo-CH₂Ph-5,6-H),5.48(s,2H,Indo-CH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,161.6,159.2,144.8,143.6,137.2,133.8,133.1,130.4,130.1,129.1,125.3,124.7,123.4,122.4,121.5,118.8,116.1,115.9,111.4,110.9,43.9,24.6ppm。

example 28: preparation of Compound II-13

Adding the compound I-13(0.46g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-13(0.31g), wherein the yield is 73.6%.

The compound II-13 is a yellow solid, and the melting point is 166-168 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.62(s,1H,SO₂NH),8.06(s,1H,NCH),8.03(d,J＝7.8Hz,1H,Indo-NCH),7.81(s,1H,Indo-4-H),7.60(d,J＝8.7Hz,2H,Ph-2,6-H),7.49(d,J＝8.0Hz,1H,Indo-7-H),7.29(d,J＝9.6Hz,2H,Indo-5,6-H),7.18(d,J＝6.3Hz,2H,Indo-CH₂Ph-3,4-H),7.11(d,J＝5.7Hz,2H,Indo-CH₂Ph-5,6-H),6.69(d,J＝8.7Hz,2H,Ph-3,5-H),5.48(s,2H,Indo-CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:161.6,159.2,144.0,137.2,133.5,130.4,130.1,129.8,125.2,124.2,123.3,123.1,122.5,121.6,121.3,115.9,114.0,111.6,110.8,43.8ppm。

example 29: preparation of Compound I-14

Intermediate III (1.15g, 5.00mmol), 4-fluorobenzylindolal (1.27g, 5.00mmol) (i.e. R)²Intermediate IV) of 4-fluorobenzyl, adding 5 drops of acetic acid and 25mL of ethanol as solvent into a 50mL round-bottom flask, reacting at 80 ℃, stirring for 6h, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, and evaporating under reduced pressureAfter separation by silica gel column chromatography using ethanol, drying was carried out to give compound I-14(1.87g) in 80.5% yield.

Compound I-14 is a white solid with a melting point of 72-74 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.87(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.08(s,1H,NCH),7.99(d,J＝7.4Hz,1H,Indo-NCH),7.89–7.84(m,3H,Indo-4-H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.49(d,J＝7.9Hz,1H,Indo-7-H),7.27(m,J＝8.4,5.6Hz,2H,Indo-5,6-H),7.19–7.10(m,4H,Indo-CH₂Ph-2,3,5,6-H),5.40(s,2H,Indo-CH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,163.2,160.8,144.8,143.6,137.1,134.2,133.7,133.1,129.7,129.0,125.1,123.3,122.4,121.4,118.8,116.0,115.8,111.3,111.1,49.0,24.6ppm。

example 30: preparation of Compound II-14

Compound I-14(0.46g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-14(0.31g), wherein the yield is 72.8%.

The compound II-14 is yellow solid with a melting point of 110-112 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.59(s,1H,SO₂NH),8.06(s,1H,NCH),8.02(d,J＝7.5Hz,1H,Indo-NCH),7.87(s,1H,Indo-4-H),7.57(d,J＝8.7Hz,2H,Ph-2,6-H),7.48(d,J＝7.9Hz,1H,Indo-7-H),7.39(m,J＝8.5,5.5Hz,1H,Indo-5-H),7.29(d,J＝5.5Hz,1H,Indo-6-H),7.14(m,J＝15.9,7.3Hz,4H,Indo-CH₂Ph-2,3,5,6-H),6.65(d,J＝8.7Hz,2H,Ph-3,5-H),5.40(s,2H,Indo-CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:152.5,144.0,137.1,134.2,133.4,129.7,125.2,123.3,122.5,121.3,116.0,115.8,113.5,111.9,111.5,111.1,49.0ppm。

example 31: preparation of Compound I-15

Intermediate III (1.15g, 5.00mmol), 2-chlorobenzyl indole aldehyde (1.35g, 5.00mmol) (i.e. R)²Intermediate IV) of 2-chlorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvents are added into a 50mL round-bottom flask at 80 ℃ for reaction, stirred for 6 hours, followed by thin layer chromatography until the reaction is finished, cooled to room temperature, and subjected to separation by silica gel column chromatography after ethanol is evaporated under reduced pressure and dried to obtain compound I-15(1.92g) with the yield of 79.8%.

The compound I-15 is a yellow solid, and the melting point is 68-70 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.89(s,1H,SO₂NH),10.30(s,1H,NHCOCH₃),8.08(s,1H,NCH),8.02(m,J＝6.4,2.3Hz,1H,Indo-NCH),7.87(d,J＝8.8Hz,2H,Ph-2,6-H),7.81–7.76(m,3H,Ph-3,5-H,Indo-4-H),7.50(d,J＝7.9Hz,1H,Indo-7-H),7.43–7.39(m,1H,Indo-5-H),7.31(m,J＝10.9,4.4Hz,1H,Indo-6-H),7.25–7.16(m,3H,Indo-CH₂Ph-3,4,5-H),6.76(d,J＝6.9Hz,1H,Indo-CH₂Ph-6-H),5.51(s,2H,Indo-CH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.7,143.6,137.4,135.1,134.0,133.1,132.4,130.0,129.1,128.1,125.0,123.5,122.5,121.5,118.9,111.5,110.9,47.6,24.6ppm。

example 32: preparation of Compound II-15

Compound I-15(0.48g, 1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-15(0.32g), wherein the yield is 74.0%.

The compound II-15 is yellow solid, and the melting point is 190-192 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.65(s,1H,SO₂NH),8.07–8.04(m,2H,NCH,Indo-NCH),7.79(s,1H,Indo-4-H),7.62(d,J＝8.7Hz,2H,Ph-2,6-H),7.55(d,J＝7.4Hz,1H,Indo-7-H),7.51(d,J＝8.0Hz,1H,Indo-5-H),7.40(d,J＝7.1Hz,1H,Indo-6-H),7.29(d,J＝3.1Hz,2H,Indo-CH₂Ph-3,4-H),7.18(m,J＝5.1,2.6Hz,2H,Indo-CH₂Ph-5,6-H),6.72(d,J＝8.6Hz,2H,Ph-3,5-H),5.51(s,2H,Indo-CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:151.6,144.0,141.7,137.4,135.1,133.7,132.3,130.3,130.0,129.8,129.1,128.1,125.1,124.3,123.2,121.7,118.1,114.2,111.7,110.9,47.6ppm。

example 33: preparation of Compound I-16

Intermediate III (1.15g, 5.00mmol), 4-chlorobenzyl indole aldehyde (1.35g, 5.00mmol) (i.e. R)²Intermediate IV) of 4-chlorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and then subjected to silica gel column chromatography for separation and drying to obtain compound I-16(1.95g) with a yield of 81.1%.

The compound I-16 is light yellow solid, and the melting point is 116-118 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹HNMR(600MHz,DMSO-d₆)δ:10.88(s,1H,SO₂NH),10.29(s,1H,NHCOCH₃),8.08(s,1H,NCH),7.99(d,J＝7.1Hz,1H,Indo-NCH),7.89–7.84(m,3H,Indo-4-H,Ph-2,6-H),7.76(d,J＝8.8Hz,2H,Ph-3,5-H),7.45(d,J＝7.7Hz,1H,Indo-7-H),7.36(d,J＝8.4Hz,2H,Indo-5,6-H),7.23–7.14(m,4H,Indo-CH₂Ph-2,3,5,6-H),5.42(s,2H,Indo-CH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.7,143.6,137.1,133.8,133.1,132.6,129.4,129.1,125.1,123.4,122.4,121.4,118.9,111.4,111.1,49.0,24.6ppm。

example 34: preparation of Compound II-16

Adding the compound I-16(0.48g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-16(0.32g) with the yield of 73.7%.

The compound II-16 is yellow solid with a melting point of 134-136 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.67(s,1H,SO₂NH),8.07–8.04(m,2H,NCH,Indo-NCH),7.78(s,1H,Indo-4-H),7.68(d,J＝2.1Hz,1H,Indo-7-H),7.62(d,J＝8.7Hz,2H,Ph-2,6-H),7.42–7.38(m,2H,Indo-5,6-H),7.32–7.27(m,2H,Indo-CH₂Ph-2,3-H),7.21–7.17(m,2H,Indo-CH₂Ph-5,6-H),6.74–6.71(m,2H,Ph-3,5-H),5.50(s,2H,Indo-CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:151.5,143.9,137.3,134.4,133.6,133.3,130.3,130.0,129.5,128.3,125.1,124.4,123.5,122.6,121.7,118.2,114.2,111.9,110.9,47.2ppm。

example 35: preparation of Compound I-17

Intermediate III (1.15g, 5.00mmol), 2, 4-dichlorobenzyl aldehyde (1.52g, 5.00mmol) (i.e., R)²Intermediate IV) of 2, 4-dichlorobenzyl), 5 drops of acetic acid and 25mL of ethanol as solvent were added to 50mL of a round-bottomed flaskReacting at 80 ℃ in a bottle, stirring for 6h, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, evaporating ethanol under reduced pressure, separating by silica gel column chromatography, and oven drying to obtain compound I-17(2.04g) with yield of 79.2%.

The compound I-17 is a light yellow solid, and the melting point is 100-102 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.90(s,1H,SO₂NH),10.30(s,1H,NHCOCH₃),8.07(s,1H,NCH),8.02(m,J＝6.4,2.2Hz,1H,Indo-NCH),7.86(d,J＝8.8Hz,2H,Ph-2,6-H),7.80–7.76(m,3H,Ph-3,5-H,Indo-4-H),7.68(d,J＝2.1Hz,1H,Indo-7-H),7.42–7.39(m,1H,Indo-5-H),7.32(m,J＝8.4,2.1Hz,1H,Indo-6-H),7.23–7.16(m,2H,Indo-CH₂Ph-3,5-H),6.74(d,J＝8.4Hz,1H,Indo-CH₂Ph-6-H),5.49(s,2H,Indo-CH₂),2.05(s,3H,COCH₃)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:169.5,144.7,143.6,137.3,134.3,133.9,133.4,133.1,130.4,129.5,129.1,128.3,125.0,123.6,122.5,121.6,118.9,111.7,110.9,47.2,24.6ppm。

example 36: preparation of Compound II-17

Adding the compound I-17(0.52g, 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-17(0.35g), wherein the yield is 74.8%.

The compound II-17 is a yellow solid with a melting point of 120-122 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows:¹H NMR(600MHz,DMSO-d₆)δ:10.63(s,1H,SO₂NH),8.07(s,1H,NCH),8.03(d,J＝7.2Hz,1H,Indo-NCH),7.87(s,1H,Indo-4-H),7.61(d,J＝8.6Hz,2H,Ph-2,6-H),7.44(m,J＝8.3,5.0Hz,2H,Indo-7,5-H),7.36(d,J＝8.5Hz,2H,Indo-6-H,Indo-CH₂Ph-3-H),7.22(d,J＝8.4Hz,2H,Indo-CH₂Ph-5,6-H),6.71(d,J＝8.6Hz,2H,Ph-3,5-H),5.42(s,2H,Indo-CH₂)ppm；¹³C NMR(150MHz,DMSO-d₆)δ:151.6,144.0,141.5,137.1,133.5,132.6,129.8,129.4,129.1,125.2,124.2,123.3,122.5,121.6,118.0,114.1,111.6,111.0,49.0ppm。

example 37: preparation of tablets containing Compound I-8

Taking compound I-810 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and a proper amount of ethanol solution with the volume percentage concentration of 70%, and preparing into 1000 tablets.

The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-8 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.

Example 38: preparation of capsules containing Compound I-5

Taking compound I-525 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and preparing into 1000 capsules.

The preparation method comprises the following steps: micronizing compound I-5 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each capsule has a weight of 50mg and an active ingredient content of 25 mg.

Example 39: preparation of granules containing Compound II-5

Taking compound II-526 g, dextrin 120g and sucrose 280 g.

The preparation method comprises the following steps: mixing compound II-5, dextrin and sucrose, granulating by wet method, drying at 60 deg.C, and packaging to obtain granule.

Example 40: preparation of injection containing Compound I-6

1000mL of an injection was prepared from 610 g of Compound I, 500mL of propylene glycol, and 500mL of water for injection.

The preparation method comprises the following steps: weighing the compound I-6, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule bottle, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the injection.

Example 41: preparation of powder injection containing compound I-7

The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-7 under the sterile condition to obtain the compound I-7.

Example 42: preparation of eye drops containing Compound I-8

1000mL of compound I-83.78 g, 0.9g of sodium chloride, 3g of phenethyl alcohol, a proper amount of boric acid buffer solution and distilled water are added.

The preparation method comprises the following steps: weighing the compound I-8 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr to obtain eye drop.

Example 43: preparation of Liniment containing Compound II-13

Adding compound II-134 g, potassium soap 7.5g, camphor 5g and distilled water to 100 mL.

The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound II-13, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full amount to obtain liniment.

Example 44: preparation of suppository containing compound II-15

Adding compound II-154 g, gelatin 14g, glycerol 70g and distilled water to 100 mL.

The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound II-15, stirring, pouring into vaginal suppository mold when it is nearly solidified, cooling and solidifying to obtain suppository.

Example 45: preparation of an ointment containing Compound II-2

Taking 20.5-2 g of compound II, 6-8g of hexadecanol, 8-10g of white vaseline, 8-19g of liquid paraffin, 2-5g of monoglyceride, 2-5g of polyoxyethylene (40) stearate, 5-10g of glycerol, 0.1g of ethylparaben and distilled water to 100 g.

The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely melt, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound II-2, stirring, and cooling to obtain ointment.

Example 46: preparation of compound powder injection containing compound II-3 and metronidazole

Taking compound II-350 g, metronidazole 50g and sodium benzoate 1g, and preparing into 100 bottles.

The preparation method comprises the following steps: taking the compound II-3, metronidazole and sodium benzoate according to the prescription amount, uniformly mixing under a sterile state, and subpackaging 100 bottles to obtain the compound powder injection.

Example 47: preparation of Aerosol containing Compound II-4

Taking compound II-42.5 g, Span20 (sorbitan monolaurate) 3g, talcum powder (100 meshes) 4g and trichlorofluoromethane to add to appropriate amount.

The preparation method comprises the following steps: respectively drying the compound II-4, the Span20 and the talcum powder in a vacuum drying oven for several hours, cooling in a drier to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the aerosol.

Product effectiveness testing

1. In vitro antimicrobial Activity of Sulfaindole derivatives prepared in examples 3-36

The sulfaindole derivatives prepared in examples 3 to 36 were tested for the Minimal Inhibitory Concentration (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus (MRSA), enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213) and gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards (CLSI) set by the national Committee of America, and MIC was measured at 490nm after the culture plates were sufficiently shaken on an oscillator after the test compounds were dissolved in a small amount of dimethyl sulfoxide and diluted with water to a solution having a concentration of 1.28mg/mL, diluted to 128. mu.g/mL with a culture solution and cultured at 35 ℃ for 24 to 72 hours, the control groups were intermediate III, Norfloxacin (Norfloxacin) and Sulfathiazole (Sulfathiazole), respectively, and the results are shown in tables 1-2.

Table 1: in vitro gram-positive activity data (MIC, μ g/mL) of sulfaindole derivatives prepared in examples 3-36

As can be seen from Table 1, the compounds prepared in examples 3 to 36 of the present invention exhibited certain inhibitory effects on the tested bacteria, and in particular, the heptyl-, alkenyl-, and alkynyl-pentyl-substituted sulfaindole derivatives I-5, II-5, and I-8 exhibited high antibacterial activity against Staphylococcus aureus, and the MIC values were 2 to 4. mu.g/mL. The antibacterial activity of part of compounds can be compared with that of the sulfathiazole and norfloxacin serving as reference medicaments, and is even stronger. In addition, Compound I-8(Compound I-8) was tested against the reference drugs norfloxacin and sulfathiazole for resistance to Staphylococcus aureus (Staphylococcus aureus), the results of which are shown in FIG. 1. As can be seen from FIG. 1, compared with the reference drugs Norfloxacin (Norfloxacin) and Sulfathiazole (Sulfathiazole), the inhibitory activity of Compound I-8(Compound I-8) against Staphylococcus aureus was substantially unchanged, and the Staphylococcus aureus was less resistant after subculture. The cytotoxicity test shows that the Compound I-8(Compound I-8) does not generate obvious cytotoxicity to normal mammalian cells (RAW 264.7), and the result is shown in FIG. 2 (wherein Control is a blank Control group). Cell membrane permeability experiments show that the Compound I-8(Compound I-8) has obvious destructive effect on bacterial membranes of staphylococcus aureus, so that the strong activity of the Compound against staphylococcus aureus is reflected, and the result is shown in figure 3 (wherein Control is a blank Control group). The bactericidal kinetics experiment shows that the addition of the Compound I-8(Compound I-8) has rapid bactericidal performance on Staphylococcus aureus, and the result is shown in FIG. 4 (wherein Control is a blank Control group).

Table 2: in vitro gram-negative activity data (MIC, μ g/mL) of sulfaindole derivatives prepared in examples 3-36

As can be seen from Table 2, the compounds prepared in examples 3 to 36 of the present invention exhibited certain inhibitory effects on the tested bacteria, and in particular, the heptyl and o-chlorobenzyl substituted sulfaindole derivatives II-5 and II-15 exhibited high antibacterial activity against Pseudomonas aeruginosa, and the MIC values were all 8. mu.g/mL. In addition, the propargyl substituted sulfaindole derivative II-12 has higher antibacterial activity to Acinetobacter baumannii, and the MIC value is 8 mu g/mL. The antibacterial activity of part of compounds can be compared with that of the sulfathiazole and norfloxacin serving as reference medicaments, and is even stronger.

2. Pharmaceutical use of sulfaindole derivatives

According to the antimicrobial activity detection result, the sulfaindole derivative has good antibacterial activity, and can be prepared into antibacterial drugs for clinical use. The medicines can be single preparations, for example, prepared by sulfanilamide indole derivatives with a structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, prepared by sulfaindole derivatives with one structure, existing antibacterial active ingredients (such as sulfamethoxazole, sulfathiazole and the like) and pharmaceutically acceptable auxiliary materials, or prepared by a plurality of sulfaindole derivatives with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. A sulfaindole derivative represented by general formula I or a pharmaceutically acceptable salt thereof:

2. The sulfaindole derivative or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the alkyl group has a carbon number of 1-12; the carbon number of the alkenyl is 3-11; the carbon number of the alkynyl is 3-11.

3. The sulfaindole derivative or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the alkyl derivative comprises methoxy, ethoxy, propoxy or hydroxyethyl; the aryl group includes benzyl or halobenzyl.

4. The sulfaindole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the sulfaindole derivative shown in the general formula I is hydrochloride, nitrate, acetate or sulfate.

5. A sulfaindole derivative or a pharmaceutically acceptable salt thereof, characterized in that it is selected from one of the following compounds:

6. a process for the preparation of a sulfaindole derivative or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, comprising the steps of:

7. The production method according to claim 6, wherein the acid catalyst is an organic acid; preferably, the organic acid is acetic acid, formic acid or propionic acid.

8. The preparation method according to claim 6, wherein the molar ratio of the intermediate III to the intermediate IV is 1 (0.5-2).

9. The method according to claim 6, wherein the reaction temperature is 70 to 90 ℃ and the reaction time is 5 to 12 hours.

10. The process according to claim 6, wherein the process for the preparation of the pharmaceutically acceptable salt of the sulfaindole derivative of formula I comprises the following steps:

dissolving the sulfaindole derivative shown in the general formula I in an organic solvent, and adding a pharmaceutically acceptable acid for reaction to obtain a pharmaceutically acceptable salt of the sulfaindole derivative shown in the general formula I; preferably, the pharmaceutically acceptable acid is hydrochloric acid, nitric acid, acetic acid or sulfuric acid.

11. A medicament comprising the sulfaindole derivative represented by the general formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and an auxiliary material.

12. The medicament of claim 11, wherein the excipient is a pharmaceutically acceptable excipient; preferably, the auxiliary material is selected from at least one of a filler, a lubricant, a disintegrant, a binder or a glidant.

13. The medicament of claim 11, wherein the dosage form of the medicament is any dosage form; preferably, the dosage form of the medicine is any one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments, aerosols, powders, dropping pills, emulsions, gels, films, transdermal patches, controlled release preparations or nano preparations.

14. Use of the sulfaindole derivative of the general formula I or a pharmaceutically acceptable salt thereof as claimed in any of claims 1 to 5 for the preparation of an antibacterial medicament.

15. The use of claim 14, wherein the bacteria is of the genus staphylococcus.