An indigo derivative, and a preparation method and application thereof

Abstract

The application discloses an indigo red derivative, a preparation method of the indigo red derivative, and application of the indigo red derivative in preparation of an anti-cerebral ischemia neuroprotective drug or a drug component. The indigo red derivative has good anti-cerebral ischemia neuroprotective activity, can overcome defects of existing active ingredients, such as easy bleeding, difficulty in penetrating a blood-brain barrier, poor oral bioavailability, low selectivity, and high neurobehavioral toxicity, and can be used as a cerebral neuroprotective active ingredient for treatment of ischemic cerebral stroke. According to an animal experiment of cerebral neuroprotective activity screening, it can be seen that after the compound is given preventively, the survival time of acute cerebral ischemia mice can be obviously prolonged, and the compound has good anti-cerebral ischemia neuroprotective effect.

Description

TECHNICAL FIELD

[0001] The present application relates to an indigo derivative, and also relates to a preparation method of the indigo derivative and application of the indigo derivative in preparation of an anti-cerebral ischemia neuroprotective drug or a drug component. BACKGROUND

[0002] Stroke is one of the diseases with the highest mortality and disability rate at present, and nearly 80% of the stroke is ischemic stroke. The survival or death of brain cells after the occurrence of stroke depends on the degree of damage to the neuron cells, that is, the degree of reduction of cerebral blood flow for providing oxygen and nutrients for the cells. When ischemic stroke occurs, the cerebral blood flow in the ischemic core is severely reduced, and the brain tissue is irreversibly damaged after 60-90 min of ischemia; while the local ischemic penumbra outside the core, the cerebral blood flow is relatively reduced, but the cell metabolism is abnormally increased, and within a few hours after the occurrence of ischemia, abnormal electrical activity and metabolic disorder in the ischemic area form a chain reaction, which is called "ischemic cascade", and the outcome of the cascade effect is the continuous expansion of the ischemic core and the gradual disappearance of the penumbra, and this process is the time window for the treatment of stroke.

[0003] Since the 1990s, the neuroprotective treatment of ischemic stroke has been proposed abroad, and has developed rapidly in the following decade. The goal of neuroprotection is to intervene in the pathological and biochemical cascade reaction of the ischemic penumbra, to save the brain tissue with vitality, and to prevent or delay cell death. At present, there are various types and mechanisms of neuroprotective agents, such as voltage-dependent calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers and nitric oxide synthase inhibitors, which have become a research hotspot in the treatment of stroke. SUMMARY

[0004] The purpose of the present application is to provide an indigo derivative with good anti-cerebral ischemia neuroprotective activity; and another purpose of the present application is to provide a preparation method of the indigo derivative and application of the indigo derivative in preparation of an anti-cerebral ischemia neuroprotective drug or a drug component.

[0005] The technical scheme of the present application is as follows: the indigo derivative provided by the present application has the following general structure:

[0006]

[0007] In the formula, R1 is H, halogen, a hydrocarbon group, an alkoxy group, an aralkyloxy group, a heterocyclic alkoxy group, an aryl group, a substituted heterocyclic group or a substituted aryl group; and R2 is a bridging group, specifically any one of -O-CH2-CO-, -CH=CH-CO- or -O-CH2-CH2-.

[0008] In the formula, the aryl group in the aryl group or aralkyloxy group represented by R1 is benzene, biphenyl or naphthalene, or F, Cl, Br, I, C1～10 alkyl, C 1～10 alkoxy, nitro or amino substituted benzene, biphenyl or naphthalene.

[0009] wherein the hydrocarbon group represented by R1 means a straight chain or branched alkyl group having 1 to 10 carbon atoms, or a straight chain or branched alkenyl group having 2 to 10 carbon atoms, or a straight chain or branched cycloalkyl group having 3 to 10 carbon atoms; the alkyl group in the alkoxyl, aralkyloxyl or heterocycloalkyloxyl means a straight chain or branched alkyl group having 1 to 10 carbon atoms; the above-mentioned alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a pentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group or a decyl group; the above-mentioned alkenyl group is a vinyl group, a propenyl group, an allyl group, a butenyl group, an isobutenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group or a decenyl group; and the above-mentioned cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group or a cyclodecyl group.

[0010] wherein the heterocyclic group in the substituted heterocyclic ring or heterocycloalkyloxyl represented by R1 means a saturated heterocyclic ring or an aromatic heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms.

[0011] wherein the halogen represented by R1 is F, Cl, Br or I.

[0012] wherein the substituent of the substituted aryl group in R1 is a halogen.

[0013] wherein when R2 is -O-CH2-CO-, the structural general formula of the compound is shown in formula (II):

[0014]

[0015] A method for preparing the compound of formula (II) is provided, comprising the following steps:

[0016] (1) mixing a substituted aromatic phenol, ethyl chloroacetate, acetonitrile and potassium carbonate, heating to reflux temperature, after reaction, filtering while hot, and rotary evaporation of the filtrate; if the residue is oily, it is distilled under reduced pressure; if a solid is obtained by concentration, it is recrystallized with anhydrous ethanol to obtain the corresponding substituted aryloxyacetic acid ethyl ester (V);

[0017] (2) mixing the substituted aryloxyacetic acid ethyl ester and anhydrous piperazine (diethylene diamine), passing N2, heating to not less than 110°C, after reflux, standing and cooling, dissolving the residue in chloroform, washing with saturated NaHCO3 solution, then washing with water, and concentrating the organic phase to obtain a white solid, which is the substituted aryloxyacetyl piperazine (VI);

[0018] (3) Under ice-water bath, slowly add chlorosulfonic acid to indigo, after the addition is completed, stir and warm to react, monitor the reaction progress by TLC, after the reaction is completed, cool to room temperature; slowly add the reaction solution into crushed ice, stir until solid precipitates, add ethyl acetate, stir, dissolve, separate, the ethyl acetate layer is washed with water and saturated sodium chloride solution, after washing, dry with anhydrous sodium sulfate overnight; the next day, filter, evaporate the solvent under reduced pressure, obtain brown viscous material, separate by column chromatography to obtain 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) and 2,3-dioxoindoline-5-sulfonyl chloride (VIII);

[0019] (4) Mix substituted aryloxyacetyl piperazine (VI) and N-ethyldiisopropylamine, under ice-water bath, add tetrahydrofuran to stir and dissolve, obtain reaction solution; dissolve 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran, slowly add it into the reaction solution; after the addition is completed, warm to room temperature, stir overnight; the next day, filter, evaporate the solvent under reduced pressure, obtain yellow viscous material, gradient elution with ethyl acetate and petroleum ether mixture as eluent, separate by column chromatography to obtain compound of general formula (II);

[0020] The synthesis route of the above method is as follows:

[0021]

[0022] When R2 is -CH=CH-CO-, the structural general formula of the compound is shown in formula (III):

[0023]

[0024] The preparation method of the compound of formula (III) is as follows:

[0025] (1) Mix substituted benzaldehyde, malonic acid and piperidine, add pyridine to stir and dissolve, warm to not less than 120°C to stir and react, monitor the reaction progress by TLC, after the reaction is completed, evaporate the solvent under reduced pressure, add concentrated hydrochloric acid / ice mixture, stir vigorously, a large amount of white solid precipitates, suction filter, recrystallize the crude product with anhydrous ethanol to obtain substituted phenylacrylic acid (IX);

[0026] (2) Mix N-Boc-piperazine and triethylamine, add dichloromethane to stir and dissolve under ice bath to obtain mixture; dissolve 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) or 2,3-dioxoindoline-5-sulfonyl chloride (VIII) in dichloromethane, slowly add it into the mixture, after the addition is completed, warm to room temperature, monitor the reaction progress by TLC, after the reaction is completed, separate by column chromatography to obtain 4-(3,3-dichloro-2-oxoindole-5-sulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X);

[0027] (3) Put 4-(3,3-dichloro-2-oxoindol-5-ylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester (X) into a reaction flask, mix trifluoroacetic acid and dichloromethane into a 25% mass fraction trifluoroacetic acid solution, add the trifluoroacetic acid solution directly into the reaction flask, stir at room temperature, monitor the reaction progress by TLC, after the reaction is completed, remove the solvent under reduced pressure to obtain 3,3-dichloro-5-(piperazin-1-ylsulfonyl)indol-2-one trifluoroacetate (XI);

[0028] (4) Put 3,3-dichloro-5-(piperazin-1-ylsulfonyl)indol-2-one trifluoroacetate (XI) into a reaction flask, add aqueous acetic acid (acetic acid / water = 50 mL / 50 mL) into the reaction flask, react at a temperature not lower than 100°C, monitor the reaction progress by TLC, after the reaction is completed, remove the solvent under reduced pressure to obtain 5-(piperazin-1-ylsulfonyl)indoline-2,3-dione trifluoroacetate (XII);

[0029] (5) Mix 5-(piperazin-1-ylsulfonyl)indoline-2,3-dione trifluoroacetate (XII), N-ethyldiisopropylamine (dipea) and tetrahydrofuran, and stir to dissolve under ice water bath condition to obtain a reaction solution; put substituted phenylpropenoic acid (IX), anhydrous dichloromethane and DMF into a reaction flask, add oxalyl chloride dropwise into the reaction flask under ice bath condition, after the dropwise addition is completed, warm to room temperature, stir to react, and then concentrate the reaction solution to obtain substituted phenylpropenoyl chloride; dissolve the substituted phenylpropenoyl chloride in tetrahydrofuran, and then slowly drop into the above reaction solution, after the dropwise addition is completed, warm to room temperature, and stir overnight; the next day, monitor the reaction progress by TLC, after the reaction is completed, concentrate under reduced pressure to obtain a yellow oily solution, use a mixture of ethyl acetate and petroleum ether as an eluent, perform gradient elution, and perform column chromatography to separate to obtain a compound of general formula (III);

[0030] The synthesis route of the above method is as follows:

[0031]

[0032]

[0033] When R2 is -O-CH2-CH2-, the structural general formula of the compound is shown in formula (IV):

[0034]

[0035] The preparation method of the compound of formula (IV) has the following steps:

[0036] (1) mixed substituted phenol, 1,2-dibromoethane and water, stirred and heated to 95°C, added dropwise sodium hydroxide solution, after dropwise addition, heated to 100°C, stirred and reacted, monitored by TLC, after reaction, cooled to room temperature, extracted with dichloromethane, combined dichloromethane layers, washed with sodium hydroxide solution and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain substituted phenoxyethyl bromide (XIII);

[0037] (2) mixed substituted phenoxyethyl bromide, methanol and piperazine, heated to 70°C, monitored by TLC, after reaction, removed solvent under reduced pressure, added dichloromethane and saturated sodium carbonate solution, dissolved, separated, washed with saturated sodium bicarbonate solution and water, washed organic phase with hydrochloric acid, adjusted pH>10 with sodium hydroxide solution, precipitated solid, extracted with dichloromethane, combined organic phase, dried with anhydrous sodium sulfate overnight, filtered, and concentrated under reduced pressure to obtain substituted phenoxyethyl piperazine (XIV);

[0038] (3) placed substituted phenoxyethyl piperazine in a reaction bottle, added tetrahydrofuran under ice water bath, stirred and dissolved, added N-ethyl diisopropylamine, stirred, obtained reaction solution, dissolved 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2,3-dioxoindoline-5-sulfonyl chloride in tetrahydrofuran, slowly added dropwise into reaction solution, heated to room temperature after dropwise addition, stirred overnight, monitored by TLC, after reaction, removed solvent under reduced pressure to obtain substituted 3,3-dichloro-5-(4-(2-phenoxyethyl) piperazine-1-ylsulfonyl) indole-2-one (XV);

[0039] (4) placed 3,3-dichloro-5-(4-(2-phenoxyethyl) piperazine-1-ylsulfonyl) indole-2-one in a reaction bottle, added acetic acid aqueous solution (volume ratio of acetic acid to water was 1:1), heated to 96°C, stirred and reacted, monitored by TLC, after reaction, cooled to room temperature, added dropwise sodium hydroxide solution to pH=7, added dropwise saturated sodium bicarbonate solution until no bubbles were generated, extracted with ethyl acetate, combined organic phase, washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate overnight, filtered, and concentrated under reduced pressure to obtain yellow oil, gradient eluted with ethyl acetate and petroleum ether mixture as eluent, column chromatography to obtain compound of general formula (IV);

[0040] The synthesis route of the above method is as follows:

[0041]

[0042] The isatin derivative is used for preparing an anti-cerebral ischemia neuroprotective drug or a drug component. In the application test, the free base and hydrochloride of the compound are used.

[0043] Advantages: Compared with the prior art, the present application has the following remarkable advantages: the isatin derivative has good anti-cerebral ischemia neuroprotective activity, can overcome the defects of the prior active ingredients, such as easy to induce hemorrhage, difficult to penetrate the blood-brain barrier, poor oral bioavailability, low selectivity and high neurobehavioral toxicity, and can be used as a cerebral neuroprotective active ingredient for the treatment of ischemic stroke; through the animal experiment of cerebral neuroprotective activity screening, it can be seen that the survival time of acute cerebral ischemia mice can be obviously prolonged after the prophylactic administration of the compound, and the compound has good anti-cerebral ischemia neuroprotective effect. DETAILED DESCRIPTION

[0044] Example 1

[0045] The preparation method of the compound of general formula (II) {5-((4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A1)} is as follows:

[0046]

[0047] Specifically includes the following steps:

[0048] (1) Put p-chlorophenol (31.2 mmol) in a 250 mL gourd-shaped bottle, add ethyl chloroacetate (4.6 g, 37.4 mmol), potassium carbonate (4.4 g, 31.2 mmol) and acetonitrile 60 mL, stir and heat to reflux for 5 hours, monitor the reaction progress by TLC, filter hot after the reaction is completed, and concentrate the filtrate under reduced pressure to obtain a yellowish viscous liquid, which is p-chlorophenoxyacetic acid ethyl ester. The crude product does not need to be purified and can be directly used in the next reaction;

[0049] (2) Put ethyl p-chlorophenoxyacetate (16.1 mmol) and piperazine (5.5 g, 64.4 mmol) in a 100 mL vial, purge with N2, heat to 110 °C and reflux for 4 h, monitor the reaction progress by TLC, after the reaction is completed, cool to room temperature, add dichloromethane 40 mL and saturated sodium carbonate solution 30 mL to separate, wash the organic phase with saturated sodium bicarbonate solution 30 mL twice, wash with water 30 mL once, extract the organic phase with 15 mL of 10% hydrochloric acid, make the water layer pH < 3, keep the water layer; adjust the pH > 10 with 10 mL of 20% sodium hydroxide solution, precipitate the solid, extract with dichloromethane 30 mL for 3 times, combine the organic phase, dry with anhydrous sodium sulfate overnight; the next day, filter, filter the filtrate under reduced pressure to obtain a yellowish viscous liquid, which is 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone, the crude product does not need to be purified, and is directly used in the next step reaction;

[0050] (3) Put isatin (8.22 g, 55.9 mmol) in a 250 mL vial, ice water bath, slowly add chlorosulfonic acid (37 mL, 559 mmol), after the addition is completed, heat to 70 °C, continue to stir for 3 h, monitor the reaction progress by TLC, after the reaction is completed, cool to room temperature, slowly add the reaction solution into 250 g of clean crushed ice, stir vigorously until the solid precipitates, add ethyl acetate 150 mL to stir, dissolve, separate, wash the ethyl acetate layer with water 100 mL twice, wash with saturated sodium chloride solution 50 mL once, dry with anhydrous sodium sulfate overnight; the next day, filter, filter the filtrate under reduced pressure to obtain a brown viscous substance, column chromatography is used to separate 2,3-dioxoindoline-5-sulfonyl chloride, white powder, 9.8 g, yield 58.3%; 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride, yellow powder, 1.26 g, yield 9.2%;

[0051] (4) Put 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (1.1 g, 4.0 mmol) and dipea (0.5 mL, 4.0 mmol) in a 100 mL vial, ice water bath, add tetrahydrofuran 30 mL to stir and dissolve; dissolve 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride (0.8 g, 3.3 mmol) in tetrahydrofuran 20 mL, slowly add it into the vial, after the addition is completed, heat to room temperature, stir overnight; TLC shows impurities, use a mixture of ethyl acetate and petroleum ether as the eluent, gradient elution, column chromatography to obtain yellow solid 0.75 g, yield 49.0%, m.p. 271.5-274.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 20 H 17 ClN3O6S[M-H] - 462.0527, found 462.0534. 1H NMR (DMSO-d6, 300 MHz) δ: 2.73~2.94 (m, 4H, SO2N(CH2)2), 3.55 (s, 4H, CON(CH2)2), 3.65 (s, 3H, OCH3), 4.67 (s, 2H, COCH20), 6.76~7.91 (m, 7H, ArH), 11.49 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.55, 43.55, 45.80, 45.80, 55.26, 66.57, 112.76, 114.34, 114.34, 115.42, 115.42, 118.09, 123.33, 128.55, 137.06, 151.71, 153.55, 153.87, 159.32, 166.18, 182.80.

[0052] Example 2

[0053] On the basis of Example 1, R1 is replaced with 4-methoxy instead of 4-chloro, and other reaction conditions are the same, to obtain compound {5-((4-(2-(4-methoxyphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A2)}

[0054]

[0055] Yellow solid, yield 61.3%, m.p. 259.5-261.2 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 20 N3O7S[M-H] - 458.1022, found 458.1029. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.73~2.94 (m, 4H, SO2N(CH2)2), 3.55 (s, 4H, CON(CH2)2), 3.65 (s, 3H, OCH3), 4.67 (s, 2H, COCH20), 6.76~7.91 (m, 7H, ArH), 11.49 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.55, 43.55, 45.80, 45.80, 55.26, 66.57, 112.76, 114.34, 114.34, 115.42, 115.42, 118.09, 123.33, 128.55, 137.06, 151.71, 153.55, 153.87, 159.32, 166.18, 182.80.

[0056] Example 3

[0057] On the basis of Example 1, R1 was replaced with 4-methyl instead of 4-chloro, and other reaction conditions were the same, to obtain compound {5-((4-(2-(4-methylphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A3)}

[0058]

[0059] Yellow solid, yield 88.2%, m.p. 278.8-280.0 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 20 N3O6S[M-H] - 442.1073, found 442.1083. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.19 (s, 3H, PhCH3), 2.88-2.97 (m, 4H, SO2N(CH2)2), 3.54 (s, 4H, CON(CH2)2), 4.70 (s, 2H, COCH2O), 6.72-7.93 (m, 7H, ArH), 11.50 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 19.90, 43.50, 43.50, 45.63, 45.79, 65.91, 112.76, 114.31, 114.31, 118.07, 123.35, 128.63, 129.52, 129.52, 129.52, 137.03, 153.84, 155.64, 159.29, 166.06, 182.77.

[0060] Example 4

[0061] On the basis of Example 1, R1 was replaced with 4-methyl instead of 4-chloro, and other reaction conditions were the same, to obtain compound {5-((4-(2-(4-methylphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A3)}

[0062]

[0063] Yellow solid, yield 39.0%, m.p. 278.2-279.5 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 20 N3O7S[M-H] - 458.1022, found 458.1033. 1H NMR (DMSO-d6, 300 MHz) δ: 2.90~2.96 (m, 4H, SO2N(CH2)2), 3.56 (s, 4H, CON(CH2)2), 3.72 (s, 3H, OCH3), 4.71 (s, 2H, COCH2O), 6.78~7.92 (m, 7H, ArH), 11.49 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.71, 43.71, 45.69, 45.84, 55.49, 66.88, 112.32, 112.80, 113.84, 118.14, 120.41, 121.44, 123.31, 128.63, 137.03, 147.19, 148.95, 153.88, 159.32, 165.98, 182.79.

[0064] Example 5

[0065] On the basis of Example 1, R1 is replaced with 2-methyl instead of 4-chloro, and other reaction conditions are the same, to obtain compound {5-((4-(2-(2-methylphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A5)}

[0066]

[0067] Yellow solid, yield 77.6%, m.p. 304.9-306.5℃. HRMS (ESI-MS, m / z): Calcd. for C 21 H 20 N3O6S[M-H] - 442.1073, found 442.1079. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.112 (s, 3H, PhCH3), 2.89~2.95 (m, 4H, SO2N(CH2)2), 3.56 (s, 4H, CON(CH2)2), 4.76 (s, 2H, COCH2O), 6.76~7.91 (m, 7H, ArH), 11.40 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 15.84, 43.59, 43.59, 45.73, 45.73, 66.10, 111.34, 112.81, 118.05, 120.44, 123.33, 125.61, 126.61, 128.57, 130.34, 137.05, 153.89, 155.81, 159.30, 166.08, 182.81.

[0068] Example 6

[0069] On the basis of Example 1, R1 is replaced by 4-bromophenyl instead of 4-chlorophenyl, and other reaction conditions are the same, the compound {5-((4-(2-(4-bromophenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A6)} is obtained

[0070]

[0071] Yellow solid, yield 38.9%, m.p. 276.7-278.5°C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 17 N3O6SBr[M-H] - 506.0021, found 506.0026. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.90~2.98 (m, 4H, SO2N(CH2)2), 3.53 (s, 4H, CON(CH2)2), 4.79 (s, 2H, COCH2O), 6.82~7.93 (m, 7H, ArH), 11.47 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.36, 43.36, 45.60, 45.66, 65.77, 112.16, 112.79, 116.84, 116.84, 118.07, 123.35, 128.72, 131.80, 131.80, 137.04, 153.87, 157.15, 159.28, 165.61, 182.79.

[0072] Example 7

[0073] On the basis of Example 1, R1 is replaced by 2-naphthyl instead of 4-chlorophenyl, and other reaction conditions are the same, the compound {5-((4-(2-(2-naphthoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A7)} is obtained

[0074]

[0075] Yellow solid, yield 48.5%, m.p. 299.4-301.5°C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 20 N3O6S[M-H] - 478.1073, found 478.1082. 1H NMR(DMSO-d6,300MHz)δ:2.90~3.01(m,4H,SO2N(CH2)2),3.60(s,4H,CON(CH2)2),4.90(s,2H,COCH2O),7.11-7.93(m,10H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d6,75MHz)δ:43.54,43.54,45.66,45.82,65.82,107.25,112.78,118.05,118.29,123.36,123.62 ,126.31,126.46,127.38,128.52,128.65,129.14,133.87,137.05,153.85,155.63,159.29,165.79,182.77.

[0076] Example 8

[0077] Based on Example 1, R1 was replaced by 3-methyl group, and other reaction conditions remained unchanged to obtain compound {5-((4-(2-(3-methylphenoxy)acetyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-A8)}

[0078]

[0079] Yellow solid, yield 46.1%, mp 273.0-275.1 ° C. HRMS (ESI-MS, m / z): Calcd.forC 21 H 20 N3O6S[MH] - 442.1073, found 442.1081. 1 H NMR(DMSO-d6,300MHz)δ:2.22(s,3H,PhCH3),2.90~2.96(m,4H,SO2N(CH2)2),3.55 (s,4H,CON(CH2)2),4.72(s,2H,COCH2O),6.63-7.92(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d6,75MHz)δ:21.01,43.55,43.55,45.72,45.88,65.74,111.53,112.83,115.13,118 .15,121.60,123.40,128.62,129.02,137.09,138.79,153.90,157.82,159.37,166.05,182.82.

[0080] Example 9

[0081] On the basis of Example 1, R1 is replaced with 4-tert-pentyl instead of 4-chloro, other reaction conditions are the same, the compound {5-((4-(2-(4-tert-pentylphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A9)} is obtained

[0082]

[0083] Yellow solid, yield 53.4%, m.p. 135.7-137.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 25 H 28 N3O6S[M-H] - 498.1699, found 498.1675. 1 H NMR (DMSO-d6, 300 MHz) δ: 0.56 (t, 3H, J = 7.5 Hz, C(CH3)2CH2CH3), 1.18 (s, 6H, C(CH3)2CH2CH3), 1.51 (q, 2H, J = 7.5 Hz, C(CH3)2CH2CH3), 2.90 ~ 2.99 (m, 4H, SO2N(CH2)2), 3.55 (s, 4H, CON(CH2)2), 4.72 (s, 2H, COCH2O), 6.76 ~ 7.94 (m, 7H, ArH), 11.50 (s, 1H, NH). 13 CNMR (DMSO-d6, 75 MHz) δ: 8.89, 28.28, 28.28, 36.08, 36.78, 43.53, 43.53, 45.76, 45.76, 65.84, 112.77, 113.96, 113.96, 118.09, 123.35, 126.43, 126.43, 128.77, 137.04, 141.26, 153.85, 155.43, 159.28, 166.08, 182.77.

[0084] Example 10

[0085] On the basis of Example 1, R1 is replaced with 2-chloro instead of 4-chloro, other reaction conditions are the same, the compound {5-((4-(2-(2-chlorophenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A10)} is obtained

[0086]

[0087] Yellow solid, yield 64.7%, m.p. 299.9-302.7 °C. HRMS (ESI-MS, m / z): Calcd. for C 20 H 17 N3O6SCl[M-H] - 462.0527, found 462.0537. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.96 (s, 4H, SO2N(CH2)2), 3.61 (s, 4H, CON(CH2)2), 4.97 (s, 2H, COCH2O), 6.85-8.14 (m, 10H, ArH), 11.50 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.52, 43.52, 45.67, 45.81, 66.30, 112.80, 113.85, 118.08, 121.01, 121.62, 123.37, 127.90, 128.61, 129.79, 137.06, 153.15, 153.88, 159.30, 165.37, 182.78.

[0088] Example 11

[0089] On the basis of Example 1, R1 was replaced with 1-naphthyl instead of 4-chlorophenyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(1-naphthoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A11)}

[0090]

[0091] Yellow solid, yield 66.0%, m.p. 296.0-298.4 °C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 20 N3O6S[M-H] - 478.1073, found 478.1081. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.96 (s, 4H, SO2N(CH2)2), 3.61 (s, 4H, CON(CH2)2), 4.97 (s, 2H, COCH2O), 6.85-8.14 (m, 10H, ArH), 11.50 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ: 43.56, 43.56, 45.79, 45.79, 66.16, 105.51, 112.75, 118.04, 120.22, 121.37, 123.30, 124.69, 125.22, 125.80, 126.32, 127.29, 128.59, 133.88, 136.95, 153.14, 153.81, 159.30, 165.78, 182.76.

[0092] Example 12

[0093] On the basis of Example 1, R1 was replaced with 4-tert-butyl instead of 4-chloro, and other reaction conditions were the same, to obtain compound {5-((4-(2-(4-tert-butylphenoxy)acetyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-A12)}

[0094]

[0095] Yellow solid, yield 72.1%, m.p. 229.4-230.8 °C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 26 N3O6S[M-H] - 484.1542, found 484.1556. 1 H NMR (DMSO-d6, 300 MHz) δ: 1.223 (s, 9H, C(CH3)3), 2.91 ~ 2.99 (m, 4H, SO2N(CH2)2), 3.55 (s, 4H, CON(CH2)2), 4.72 (s, 2H, COCH2O), 6.76 ~ 7.94 (m, 7H, ArH), 11.50 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 43.56, 43.56, 45.79, 45.79, 66.16, 105.51, 112.75, 118.04, 120.22, 121.37, 123.30, 124.69, 125.22, 125.80, 126.32, 127.29, 128.59, 133.88, 136.95, 153.14, 153.81, 159.30, 165.78, 182.76.

[0096] Example 13

[0097] The preparation method of the compound of general formula (III) {(E)-5-((4-(3-(benzo[d][1,3]dioxol-5-yl)acryloyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B1)} has the following synthesis route:

[0098]

[0099] Specifically includes the following steps:

[0100] (1) Put piperonal (41.6 mmol), malonic acid 6.4 g (62.4 mmol) and piperidine 1 mL (10.4 mmol) into a 250 mL tomato bottle, add pyridine 40 mL to dissolve and stir, warm to 120°C and stir for 5 hours, monitor the reaction progress by TLC, after the reaction is completed, remove the solvent under reduced pressure, add a mixture of concentrated hydrochloric acid / ice (mix 26 mL of concentrated hydrochloric acid with 52 g of ice) 26 mL / 52 g, and stir vigorously, a large amount of white solid is precipitated, filter, and recrystallize the crude product with anhydrous ethanol to obtain white powdery crystals (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylic acid, yield 87.8%;

[0101] (2) Put N-Boc-piperazine 9.3 g (49.9 mmol) and triethylamine (7 mL, 49.9 mmol) into a 250 mL tomato bottle, add dichloromethane 50 mL, and stir to dissolve in an ice bath. Separately dissolve 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2,3-dioxoindoline-5-sulfonyl chloride (41.6 mmol) in dichloromethane 30 mL, and slowly drop into the tomato bottle. After the drop is completed, warm to room temperature, stir for 5 hours, monitor the reaction progress by TLC, after the reaction is completed, concentrate under reduced pressure to obtain a light yellow oil, and column chromatography to obtain 4-(3,3-dichloro-2-oxoindole-5-ylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester, white powder, yield 91.8%;

[0102] (3) Put 4-(3,3-dichloro-2-oxoindole-5-ylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester (27.15 g, 33.3 mmol) into a 250 mL tomato bottle, mix trifluoroacetic acid 25 mL and dichloromethane 100 mL to form a 25% trifluoroacetic acid solution, and directly add into the tomato bottle, stir at room temperature for 2 hours, monitor the reaction progress by TLC, after the reaction is completed, remove the solvent under reduced pressure to obtain white solid 3,3-dichloro-5-(piperazin-1-ylsulfonyl)indolin-2-one trifluoroacetate, the crude product is directly used in the next step without purification;

[0103] (4) 3,3-dichloro-5-(piperazin-l-ylsulfonyl)indolin-2-one trifluoroacetate 10 g was placed in a 250 mL flask, 100 mL of aqueous acetic acid (acetic acid / water = 50 mL / 50 mL) was added, and the mixture was stirred at 100 °C for 24 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure to give 5-(piperazin-l-ylsulfonyl)indoline-2,3-dione trifluoroacetate as a yellow solid. The crude product was used directly in the next step without purification;

[0104] (5) (E)-3-(benzo[d][l,3]dioxol-5-yl)acrylic acid (0.58 g, 3 mmol) and dry dichloromethane (25 mL) were placed in a 250 mL flask, and the mixture was stirred. N,N-dimethylformamide (2 drops) was added dropwise. Oxalyl chloride (0.6 mL, 6 mmol) and dry dichloromethane (2 mL) were mixed and added slowly dropwise to the flask. After the addition was completed, the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was completed, the dichloromethane was removed under reduced pressure at low temperature to give (E)-3-(benzo[d][l,3]dioxol-5-yl)acryloyl chloride as a yellow oily liquid. The crude product was used directly in the next step without purification;

[0105] (6) 5-(piperazin-l-ylsulfonyl)indoline-2,3-dione (1.67 g, 3.6 mmol), dipea (1.3 mL, 7.5 mmol), and tetrahydrofuran (20 mL) were placed in a 100 mL flask, and the mixture was stirred with an ice-water bath. (E)-3-(benzo[d][l,3]dioxol-5-yl)acryloyl chloride was dissolved in tetrahydrofuran (10 mL) and added slowly dropwise to the flask. After the addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the product was not pure, and the product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether as the eluent to give 0.54 g of a yellow solid in a yield of 38.3%. m.p. 202.3-204.7 °C. HRMS (ESI-MS, m / z): Calcd. for C 22 H 18 N3O7S[M-H] - 468.0865, found 468.0873. 1 H NMR (CDC13, 300 MHz) δ: 3.71 (s, 8H, SO2N(CH2)4NCO), 6.00 (s, 2H, OCH2O), 6.63 (d, 1H, J = 15.3 Hz, COCH=), 6.79-8.07 (m, 6H, ArH), 7.59 (d, 1H, J = 15.3 Hz, PhCH=), 11.05 (s, 1H, NH). 13C NMR (CDC13, 75 MHz) δ: 42.15, 44.81, 45.24, 101.46, 106.36, 108.52, 114.11, 120.34, 123.97, 125.54, 126.82, 129.33, 132.24, 141.28, 143.57, 148.28, 149.26, 165.39, 165.78, 184.65.

[0106] Example 14

[0107] On the basis of Example 13, R1 was replaced with 4-chlorophenyl instead of 5-piperonyl, and other reaction conditions were the same, to obtain compound {(E)-5-((4-(3-(4-chlorophenyl)acryloyl)piperazin-l-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B2)

[0108]

[0109] Yellow solid, yield 29.0%, m.p. 322.7-324.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 17 N3O5SCl[M-H] - 458.0577, found 458.0588. 1 H NMR (CDC13, 300 MHz) δ: 2.94 (s, 4H, SO2N(CH2)2), 3.67 (bs, 4H, CON(CH2)2), 7.09 ~ 7.72 (m, 7H, ArH), 7.19 (d, 1H, J = 15.3 Hz, COCH=), 7.40 (d, 1H, J = 15.3 Hz, PhCH=), 11.45 (s, 1H, NH). 13 C NMR (CDC13, 75 MHz) δ: 44.72, 46.34, 46.84, 113.25, 118.71, 119.08, 123.83, 128.98, 129.15, 129.15, 130.15, 130.15, 134.37, 134.51, 137.46, 141.00, 154.36, 159.84, 164.69, 183.26.

[0110] Example 15

[0111] On the basis of Example 13, R1 was replaced with 4-methylphenyl instead of 5-piperonyl, and other reaction conditions were the same, to obtain compound {(E)-5-((4-(3-(4-methylphenyl)acryloyl)piperazin-l-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B3)

[0112]

[0113] Yellow solid, yield 45.5%, m.p. 308.8-310.5 °C. HRMS (ESI-MS, m / z): Calcd. for C 22 H 20 N3O5S[M-H] - 438.1124, found 438.1130. 1 H NMR (CDC13, 300 MHz) δ: 2.31 (s, 3H, PhCH3), 2.93 (s, 4H, SO2N(CH2)2), 3.66 (bs, 4H, CON(CH2)2), 7.08 ~ 7.92 (m, 7H, ArH), 7.15 (d, 1H, J = 15.3 Hz, COCH=), 7.37 (d, 1H, J = 15.3 Hz, PhCH=), 11.46 (s, 1H, NH). 13 C NMR (CDC13, 75 MHz) δ: 20.85, 44.13, 44.33, 45.89, 46.34, 112.75, 116.49, 118.24, 123.29, 127.93, 127.93, 128.33, 129.24, 129.24, 132.14, 136.94, 139.36, 141.97, 154.03, 159.44, 164.48, 182.85.

[0114] Example 16

[0115] On the basis of Example 13, R1 was replaced with 4-methoxyphenyl instead of 5-piperonyl, and other reaction conditions were the same, to obtain compound {(E)-5-((4-(3-(4-methoxyphenyl)acryloyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B4)

[0116]

[0117] Yellow solid, yield 32.2%, m.p. 312.1-314.8 °C. HRMS (ESI-MS, m / z): Calcd. for C 22 H 20 N3O6S[M-H] - 454.1073, found 454.1079. 1H NMR (CDC13, 300 MHz) δ: 2.94 (s, 4H, SO2N(CH2)2), 3.78 (s, 3H, PhOCH3), 3.78 (bs, 4H, CON(CH2)2), 6.93 ~ 7.93 (m, 7H, ArH), 7.01 (d, 1H, J = 15.3 Hz, COCH=), 7.38 (d, 1H, J = 15.3 Hz, PhCH=), 11.45 (s, 1H, NH). 13 C NMR (CDC13, 75 MHz) δ: 44.19, 46.28, 55.18, 112.72, 114.09, 114.93, 118.22, 123.30, 127.50, 128.40, 129.61, 136.94, 141.81, 153.84, 159.34, 160.43, 164.63, 182.73.

[0118] Example 17

[0119] On the basis of Example 13, R1 was replaced with 2-methoxyphenyl instead of 5-piperonyl, and other reaction conditions were the same, to obtain compound {(E)-5-((4-(3-(2-methoxyphenyl)acryloyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B5)

[0120]

[0121] Yellow solid, yield 30.8%, m.p. 267.8-269.9 °C. HRMS (ESI-MS, m / z): Calcd. for C 22 H 20 N3O6S[M-H] - 454.1073, found 454.1081. 1 H NMR (CDC13, 300 MHz) δ: 2.94 (s, 4H, SO2N(CH2)2), 3.78 (s, 3H, PhOCH3), 3.78 (bs, 4H, CON(CH2)2), 6.93 ~ 7.93 (m, 7H, ArH), 7.01 (d, 1H, J = 15.3 Hz, COCH=), 7.38 (d, 1H, J = 15.3 Hz, PhCH=), 11.45 (s, 1H, NH). 13C NMR(CDCl3,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123 .21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77.

[0122] Example 18

[0123] Based on Example 13, R1 was replaced with 4-fluorophenyl for 5-piperidinyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(4-fluorophenyl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B6)}

[0124]

[0125] Yellow solid, yield 64.8%, mp 289.8-299.1 ° C. HRMS (ESI-MS, m / z): Calcd.forC 21 H 17 N3O5FS[MH] - 442.0873, found 442.0883. 1 H NMR(CDCl3,300MHz)δ:2.93(s,4H,SO2N(CH2)2),3.66(bs,4H,CON(CH2)2),7.03~7.93(m, 7H, ArH), 7.13 (d, 1H, J = 15.6Hz, COCH =), 7.41 (d, 1H, J = 15.6Hz, PhCH =), 11.47 (s, 1H, NH). 13 C NMR(CDCl3,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123 .21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77.

[0126] Example 19

[0127] Based on Example 13, R1 was replaced with 2-chlorophenyl for 5-piperidinyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(2-chlorophenyl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B7)}

[0128]

[0129] Yellow solid, yield 51.4%, mp 297.2-299.2 ° C. HRMS (ESI-MS, m / z): Calcd.for C 21 H 17 N3O5SCl[MH] - 458.0577, found 458.0588. 1 H NMR(CDCl3,300MHz)δ:2.95(s,4H,SO2N(CH2)2),3.68(bs,4H,CON(CH2)2),7.10~7.98(m, 7H, ArH), 7.23 (d, 1H, J = 15.3Hz, COCH =), 7.73 (d, 1H, J = 15.3Hz, PhCH =), 11.47 (s, 1H, NH). 13 C NMR(CDCl3,75MHz)δ:44.24,45.77,46.32,112.74,118.22,120.81,123.31,127.40,128.11 ,128.47,129.73,131.01,132.56,133.29,136.82,136.97,153.85,159.34,163.89,182.75.

[0130] Example 20

[0131] Based on Example 13, R1 was replaced with 3-chlorophenyl for 5-piperidinyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(3-chlorophenyl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B8)}

[0132]

[0133] Yellow solid, yield 58.1%, mp302.7-304.6℃. HRMS (ESI-MS, m / z): Calcd.forC 21 H 17 N3O5SCl[MH] - 458.0577, found 458.0568. 1H NMR(CDCl3,300MHz)δ:2.94(s,4H,SO2N(CH2)2),3.67(bs,4H,CON(CH2)2),7.10~7.94(m, 7H, ArH), 7.26 (d, 1H, J = 15.3Hz, COCH =), 7.39 (d, 1H, J = 15.3Hz, PhCH =), 11.47 (s, 1H, NH). 13 C NMR(CDCl3,75MHz)δ:44.21,45.77,46.33,112.73,118.19,119.48,123.29,127.00,128 .49,129.11,130.40,133.55,136.93,137.15,140.24,153.84,159.30,164.06,182.73.

[0134] Example 21

[0135] Based on Example 13, R1 was replaced with 2,4-dichlorophenyl for 5-piperonyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(2,4-dichlorophenyl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B9)}

[0136]

[0137] Yellow solid, yield 40.5%, mp340.5-342.9℃. HRMS (ESI-MS, m / z): Calcd.forC 21 H 16 N3O5SCl2[MH] - 492.0188, found 492.0196. 1 H NMR(CDCl3,300MHz)δ:2.95(s,4H,SO2N(CH2)2),3.67(bs,4H,CON(CH2)2),7.09~8.02(m, 6H, ArH), 7.27 (d, 1H, J = 15.3Hz, COCH =), 7.73 (d, 1H, J = 15.3Hz, PhCH =), 11.47 (s, 1H, NH). 13C NMR(CDCl3,75MHz)δ:44.25,45.70,46.28,112.77,118.17,121.47,123.32,127.63,128.54 ,129.16,129.34,131.64,134.06,134.59,135.61,136.97,153.88,159.30,163.72,182.77.

[0138] Example 22

[0139] Based on Example 13, R1 was replaced with 3-bromophenyl for 5-piperidinyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(3-bromophenyl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B10)}

[0140]

[0141] Yellow solid, yield 46.5%, mp 299.9-302.8 ° C. HRMS (ESI-MS, m / z): Calcd.for C 21 H 17 N3O5SBr[MH] - 502.0072,found 502.0065. 1 H NMR(CDCl3,300MHz)δ:2.94(s,4H,SO2N(CH2)2),3.66(bs,4H,CON(CH2)2),7.09~8.00(m, 7H, ArH), 7.25 (d, 1H, J = 15.3Hz, COCH =), 7.37 (d, 1H, J = 15.3Hz, PhCH =), 11.46 (s, 1H, NH). 13 C NMR(CDCl3,75MHz)δ:44.21,45.83,46.40,112.76,118.26,119.45,122.19,123.23,127.49 ,128.40,129.87,130.72,132.08,136.97,137.44,140.26,153.87,159.37,164.07,182.76.

[0142] Example 23

[0143] Based on Example 13, R1 was replaced by 2-furyl, and other reaction conditions remained unchanged to obtain compound {(E)-5-((4-(3-(furan-2-yl)acryloyl)piperazin-1-yl)sulfonyl)indoline-2,3-dione (ZJG-B11)}

[0144]

[0145] Yellow solid, yield 48.1%, m.p. 278.4-279.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 19 H 16 N3O6S[M-H] - 414.0760, found 414.0768. 1 H NMR (CDC13, 300 MHz) δ: 2.93 (s, 4H, SO2N(CH2)2), 3.68 (bs, 4H, CON(CH2)2), 6.57 ~ 7.92 (m, 6H, ArH & funan), 6.81 (d, 1H, J = 15.0 Hz, COCH=), 7.25 (d, 1H, J = 15.0 Hz, PhCH=), 11.45 (s, 1H, NH). 13 C NMR (CDC13, 75 MHz) δ: 44.23, 46.03, 112.40, 112.73, 114.06, 114.47, 118.19, 123.30, 128.49, 129.14, 136.93, 144.83, 150.97, 153.83, 159.33, 164.01, 182.74.

[0146] Example 24

[0147] On the basis of Example 13, R1 was replaced with 3,4-dimethoxyphenyl instead of 5-piperonyl, and other reaction conditions were the same, to obtain compound {(E)-5-((4-(3-(3,4-dimethoxyphenyl)acryloyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-B12)

[0148]

[0149] Yellow solid, yield 57.6%, m.p. 285.2-286.8 °C. HRMS (ESI-MS, m / z): Calcd. for C 23 H 22 N3O7S[M-H] - 484.1178, found 484.1186. 1H NMR (CDC13, 300 MHz) δ: 2.94 (s, 4H, SO2N(CH2)2), 3.70 (bs, 4H, CON(CH2)2), 3.78 (bs, 6H, Ph(OCH3)2), 6.93-7.93 (m, 7H, ArH), 7.02 (d, 1H, J = 15.0 Hz, COCH=), 7.37 (d, 1H, J = 15.0 Hz, PhCH=), 11.46 (s, 1H, NH). 13 C NMR (CDC13, 75 MHz) δ: 44.14, 45.97, 46.24, 55.48, 55.65, 110.39, 111.47, 112.74, 114.90, 118.24, 122.38, 123.34, 127.72, 128.39, 136.97, 142.39, 148.86, 150.35, 153.87, 159.36, 164.68, 182.76.

[0150] Example 25

[0151] The preparation method of the compound of general formula (IV) {5-((4-(2-(2-methylphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C1)} is as follows:

[0152]

[0153] Specifically includes the following steps:

[0154] (1) Put o-methylphenol (40.3 mmol), 1,2-dibromoethane 11.3 g (60.4 mmol) and water 25 mL in a 250 mL flask, stir and heat to 95°C, add 7.2 mL of 25% sodium hydroxide solution dropwise, continue to heat to 100°C and stir for 12 hours after dropwise addition is completed, monitor the reaction progress by TLC, cool to room temperature after the reaction is completed, extract with dichloromethane 30 mL for 3 times, take the dichloromethane layer, wash with 15 mL of 5% sodium hydroxide solution twice and 15 mL of saturated sodium chloride solution once, dry over anhydrous magnesium sulfate for 5 hours, filter, and evaporate the solvent under reduced pressure to obtain a colorless liquid, which is 1-(2-bromooxy)-2-methylbenzene, the crude product does not need to be purified and can be directly used in the next step reaction;

[0155] (2) 1-(2-bromooxy)-2-methylbenzene (25.3 mmol), methanol 50 mL and piperazine 8.7 g (101.1 mmol) were placed in a 100 mL flask, warmed to 70 °C and stirred for 3 hours, TLC monitoring reaction progress, reaction was completed, the solvent was removed under reduced pressure. Added dichloromethane 60 mL and saturated sodium carbonate solution 30 mL dissolved, separated; dichloromethane layer was washed with saturated sodium bicarbonate solution 30 mL twice, water 30 mL once, with mass fraction of 10% hydrochloric acid 15 mL to extract the organic phase, the water layer pH <3, keep the water layer; with mass fraction of 20% sodium hydroxide solution 10 mL to adjust pH >10, precipitate solid, extracted with dichloromethane 30 mL three times, combined organic phase, anhydrous sodium sulfate drying overnight; the next day, filtered, concentrated under reduced pressure, to get a colorless viscous liquid 1-(2-(2-methylphenoxy)ethyl)piperazine, crude without purification, directly used in the next step reaction;

[0156] (3) 1-(2-(2-methylphenoxy)ethyl)piperazine (1.94 g, 8.8 mmol) was placed in a 100 mL flask, ice water bath, added tetrahydrofuran 30 mL stirring dissolved, added dipea (3.4 mL, 11 mmol) continue to stir 5 min; with tetrahydrofuran 10 mL dissolved 3,3-dichloro-2-oxoindole-5-sulfonyl chloride (2.2 g, 7.3 mmol), slowly drop into the flask, dropwise addition was completed, warmed to room temperature, stirring overnight, TLC monitoring reaction progress, reaction was completed, the solvent was removed under reduced pressure, 3,3-dichloro-5-(4-(2-(2-methylphenoxy)ethyl)piperazin-1-yl)sulfonyl)indol-2-one was obtained without purification, directly used in the next step reaction;

[0157] (4) The above 3,3-dichloro-5-(4-(2-(2-methylphenoxy)ethyl)piperazin-1-yl)sulfonyl)indol-2-one was placed in a 100 mL flask, added water and acetic acid mixture 40 mL (V water:V acetic acid = 1:1), warmed to 96 °C and stirred for 30 hours, TLC monitoring reaction progress, reaction was completed, cooled to room temperature, dropwise 10% sodium hydroxide solution to pH = 7, dropwise saturated sodium bicarbonate solution until no bubbles were generated; ethyl acetate extraction twice (40 mL x 2), combined organic phase, the solvent was removed under reduced pressure to get a brown viscous liquid, TLC showed impurity, with ethyl acetate and petroleum ether mixture as eluent, gradient elution, column chromatography to get yellow solid 1.62 g, yield 42.9%, m.p. 208.5-210.4 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 22 N3O5S[M-H] - 428.1280, found 428.1273. 1H NMR (DMSO-d6, 300 MHz) δ: 2.10 (s, 3H, PhCH3), 2.60 (bs, 4H, SO2N(CH2)2), 2.71 (t, 2H, J = 5.4 Hz, NCH2-), 2.91 (bs, 4H, CN(CH2)2), 3.80 (t, 2H, J = 5.4 Hz, OCH2-), 6.78 ~ 7.92 (m, 7H, ArH), 11.46 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 15.91, 45.90, 51.85, 55.98, 65.87, 111.21, 112.66, 118.12, 120.14, 123.31, 125.61, 126.81, 128.60, 130.27, 136.98, 153.75, 156.39, 159.37, 182.82.

[0158] Example 26

[0159] On the basis of Example 25, 2-methyl in o-methylphenol was replaced by 3-methyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(3-methylphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C2)

[0160]

[0161] Yellow solid, yield 58.2%, m.p. 208.1-210.0 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 22 N3O5S[M-H] - 428.1280, found 428.1272. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.10 (s, 3H, PhCH3), 2.60 (bs, 4H, SO2N(CH2)2), 2.71 (t, 2H, J = 5.4 Hz, NCH2-), 2.91 (bs, 4H, CN(CH2)2), 3.80 (t, 2H, J = 5.4 Hz, OCH2-), 6.78 ~ 7.92 (m, 7H, ArH), 11.46 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ: 20.97, 45.87, 51.74, 55.89, 65.19, 111.34, 112.64, 115.04, 118.12, 121.19, 123.30, 128.49, 129.06, 136.98, 138.81, 153.76, 158.29, 159.36, 182.80.

[0162] Example 27

[0163] On the basis of Example 25, substituting 2-methyl in o-methyl phenol with 4- chloro, and other reaction conditions are the same, the compound {5-((4-(2-(4-chlorophenoxy) ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C3) is obtained

[0164]

[0165] Yellow solid, yield 47.5%, m.p. 198.9-200.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 20 H 19 N3O5SCl[M-H] - 448.0734, found 448.0742. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.56 (bs, 4H, SO2N(CH2)2), 2.66 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.98 (t, 2H, J = 5.4 Hz, OCH2-), 6.89 ~ 7.92 (m, 7H, ArH), 11.45 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 45.82, 51.70, 55.73, 65.73, 112.64, 116.15, 118.08, 123.29, 124.14, 128.55, 129.05, 136.96, 153.75, 157.14, 159.34, 182.79.

[0166] Example 28

[0167] On the basis of Example 25, substituting 2-methyl in o-methyl phenol with 4- chloro, and other reaction conditions are the same, the compound {5-((4-(2-(4-chlorophenoxy) ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C3) is obtained

[0168]

[0169] Yellow solid, yield 48.0%, m.p. 202.1-203.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 22 N3O6S[M-H] - 444.1229, found 444.1236. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.56 (bs, 4H, SO2N(CH2)2), 2.64 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.67 (s, 3H, PhOCH3), 3.91 (t, 2H, J = 5.4 Hz, OCH2-), 6.81 ~ 7.92 (m, 7H, ArH), 11.45 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 45.85, 51.75, 55.26, 55.95, 65.89, 112.63, 114.48, 115.31, 118.11, 123.29, 128.49, 136.97, 152.30, 153.29, 153.75, 159.36, 182.79.

[0170] Example 29

[0171] On the basis of Example 25, 2-methyl in o-methylphenol was replaced by 4-methyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(4-methylphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C5)}

[0172]

[0173] Yellow solid, yield 61.4%, m.p. 212.6-213.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 22 N3O5S[M-H] - 428.1280, found 428.1276. 1H NMR (DMSO-d6, 300 MHz) δ: 2.20 (s, 3H, PhCH3), 2.56 (bs, 4H, SO2N(CH2)2), 2.65 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.93 (t, 2H, J = 5.4 Hz, OCH2-), 6.75 ~ 7.92 (m, 7H, ArH), 11.45 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 19.95, 45.85, 51.76, 55.90, 65.35, 112.65, 114.23, 118.12, 123.31, 128.53, 129.09, 129.67, 136.98, 153.76, 156.17, 159.36, 182.81.

[0174] Example 30

[0175] On the basis of Example 25, R1in o-methylphenol was replaced by 4-bromo-2-methyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(4-bromophenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C6)}

[0176]

[0177] Yellow solid, yield 50.6%, m.p. 207.5-208.7 °C. HRMS (ESI-MS, m / z): Calcd. for C 20 H 19 N3O5SBr[M-H] - 492.0229, found 492.0236. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.56 (bs, 4H, SO2N(CH2)2), 2.67 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.98 (t, 2H, J = 5.4 Hz, OCH2-), 6.85 ~ 7.92 (m, 7H, ArH), 11.47 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 45.82, 51.70, 55.71, 65.66, 111.83, 112.65, 116.70, 118.09, 123.30, 128.52, 131.96, 136.97, 153.75, 157.59, 159.34, 182.80.

[0178] Example 31

[0179] On the basis of example 25, replace R1 in o-methyl phenol with 2-methoxy, and other reaction conditions remain unchanged, to obtain compound {5-((4-(2-(2-methoxyphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C8)}

[0180]

[0181] Yellow solid, yield 49.8%, m.p. 205.6-207.7°C. HRMS (ESI-MS, m / z): Calcd. for C 20 H 19 N3O6S [M-H] - 444.1229, found 444.1236. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.56 (bs, 4H, SO2N(CH2)2), 2.74 (t, 2H, J = 5.4 Hz, NCH2-), 2.91 (bs, 4H, CN(CH2)2), 4.08 (t, 2H, J = 5.4 Hz, OCH2-), 6.90 ~ 7.93 (m, 7H, ArH), 11.47 (s, 1H, NH). 13 CNMR (DMSO-d6, 75 MHz) δ: 45.84, 51.80, 55.64, 66.92, 112.64, 113.83, 118.06, 121.29, 121.41, 123.31, 128.13, 128.57, 129.74, 136.97, 153.69, 153.74, 159.33, 182.80.

[0182] Example 31

[0183] On the basis of example 25, replace R1 in o-methyl phenol with 2-methoxy, and other reaction conditions remain unchanged, to obtain compound {5-((4-(2-(2-methoxyphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C8)}

[0184]

[0185] Yellow solid, yield 49.8%, m.p. 205.6-207.7°C. HRMS (ESI-MS, m / z): Calcd. for C 21 H 22 N3O6S [M-H] - 444.1229, found 444.1236.1 H NMR (DMSO-d6, 300 MHz) δ: 2.58 (bs, 4H, SO2N(CH2)2), 2.67 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.71 (s, 3H, PhOCH3), 3.96 (t, 2H, J = 5.4 Hz, OCH2-), 6.83 ~ 7.92 (m, 7H, ArH), 11.46 (s, 1H, NH). 13 C NMR (DMSO-d6, 75 MHz) δ: 45.86, 51.80, 55.46, 55.94, 66.44, 112.29, 112.65, 113.68, 118.12, 120.62, 121.03, 123.32, 128.51, 136.99, 147.90, 149.12, 153.77, 159.37, 182.82.

[0186] Example 33

[0187] On the basis of Example 25, 2-methyl of o-methylphenol was replaced by 4-tert-pentyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(4-tert-pentylphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C9)}

[0188]

[0189] Yellow solid, yield 73.1%, m.p. 219.8-221.6 °C. HRMS (ESI-MS, m / z): Calcd. for C 25 H 30 N3O5S[M-H] - 484.1906, found 484.1916. 1 H NMR (DMSO-d6, 300 MHz) δ: 0.57 (t, 3H, J = 7.5 Hz, C(CH3)2CH2CH3), 1.19 (s, 6H, C(CH3)2CH2CH3), 1.51 (q, 2H, J = 7.5 Hz, C(CH3)2CH2CH3), 2.57 (bs, 4H, SO2N(CH2)2), 2.66 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (bs, 4H, CN(CH2)2), 3.95 (t, 2H, J = 5.4 Hz, OCH2-), 6.78 ~ 7.92 (m, 7H, ArH), 11.45 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz) δ: 8.9, 28.32, 36.13, 36.76, 45.85, 51.76, 55.92, 65.26, 112.64, 113.77, 118.09, 123.30, 126.53, 128.51, 136.98, 140.76, 153.75, 155.93, 159.34, 182.79.

[0190] Example 34

[0191] On the basis of Example 25, R1in o-methyl phenol was replaced by 4-tert-butyl instead of 2-methyl phenyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(4-tert-butylphenoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C10)}

[0192]

[0193] Yellow solid, yield 64.6%, m.p. 236.2-238.1 °C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 28 N3O5S[M-H] - 471.1750, found 471.1745. 1 H NMR (DMSO-d6, 300 MHz) δ: 1.23 (s, 9H, C(CH3)3), 2.56 (s, 4H, SO2N(CH2)2), 2.66 (t, 2H, J = 5.4 Hz, NCH2-), 2.90 (s, 4H, CN(CH2)2), 3.95 (t, 2H, J = 5.4 Hz, OCH2-), 6.78 ~ 7.92 (m, 7H, ArH), 11.46 (s, 1H, NH. 13 C NMR (DMSO-d6, 75 MHz) δ: 31.25, 33.63, 45.87, 51.77, 55.92, 65.34, 112.67, 113.85, 118.12, 123.32, 125.91, 128.55, 137.00, 142.64, 153.78, 156.04, 159.36, 182.82.

[0194] Example 35

[0195] On the basis of Example 25, R1was replaced by 2-naphthyl instead of 2-methyl phenyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(2-naphthoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C11)}

[0196]

[0197] Yellow solid, yield 61.1%, m.p. 260.1-262.5 °C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 22 N3O5S[M-H] - 464.1280, found 464.1286. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.60 (s, 4H, SO2N(CH2)2), 2.75 (t, 2H, J = 5.4 Hz, NCH2-), 2.91 (s, 4H, CN(CH2)2), 4.12 (t, 2H, J = 5.4 Hz, OCH2-), 7.09 ~ 7.92 (m, 10H, ArH), 11.46 (s, 1H, NH. 13 CNMR (DMSO-d6, 75 MHz) δ: 45.86, 51.77, 55.84, 65.44, 106.73, 112.64, 118.08, 118.55, 123.31, 123.43, 126.24, 126.52, 127.36, 128.37, 128.51, 129.13, 134.14, 136.97, 153.75, 156.19, 159.34, 182.80.

[0198] Example 36

[0199] On the basis of Example 25, R1 was replaced with 1-naphthyl instead of 2-methylphenyl, and other reaction conditions were unchanged, to obtain compound {5-((4-(2-(1-naphthoxy)ethyl)piperazin-1-yl)sulfonyl)dihydroindole-2,3-dione (ZJG-C12)}

[0200]

[0201] Yellow solid, yield 64.0%, m.p. 219.4-220.4 °C. HRMS (ESI-MS, m / z): Calcd. for C 24 H 22 N3O5S[M-H] - 464.1280, found 464.1286. 1H NMR (DMSO-d6, 300 MHz) δ: 2.66 (s, 4H, SO2N(CH2)2), 2.85 (t, 2H, J = 5.4 Hz, NCH2-), 2.91 (s, 4H, CN(CH2)2), 4.18 (t, 2H, J = 5.4 Hz, OCH2-), 6.91 ~ 8.11 (m, 10H, ArH), 11.46 (s, 1H, NH. 13 CNMR (DMSO-d6, 75 MHz) δ: 45.90, 51.81, 55.93, 66.09, 105.20, 112.64, 118.08, 119.87, 121.42, 123.30, 124.85, 125.16, 126.06, 126.28, 127.32, 128.55, 133.91, 136.97, 153.74, 153.83, 159.34, 182.79.

[0202] The effect of the compounds prepared in Examples 1-36 on the survival time of acute cerebral ischemia mice.

[0203] The target compounds and the positive control drug nimodipine were suspended in 0.5% wt sodium carboxymethyl cellulose to the desired concentration just before use; the test animals were ICR mice, weighing 19-25 g, all male. The mice were randomly divided into groups of 10; each group was given 0.2 mL / 10 g of the test drug by gavage, the blank control group was given an equal volume of NS, and the positive control group was given an equal volume of nimodipine 80 mg / Kg. One hour after administration, the mice were anesthetized with ether, the neck was cut in the middle, the bilateral common carotid arteries and vagus nerves were isolated and ligated, and the survival time of the mice (when the number of breaths per minute was less than or equal to 5, the mouse was considered dead) was recorded. The results are shown in Table 1.

[0204] Table 1: Effect of the compounds prepared in Examples 1-36 on the survival time of acute cerebral ischemia mice (min)

[0205]

[0206]

[0207]

[0208] * P < 0.05, ** P < 0.01 compared with the NS group, # P < 0.05, ## P < 0.01 compared with the nimodipine group.

[0209] The above test results show that the compounds of the present application all have the effect of resisting cerebral ischemia, and the compounds ZJG-A1, ZJG-A2, ZJG-A4, ZJG-A5, ZJG-A8, ZJG-A11, ZJG-A12, ZJG-B1, ZJG-B2, ZJG-B3, ZJG-B4, ZJG-B6, ZJG-B11, ZJG-B12, ZJG-C4, ZJG-C7, ZJG-C8, ZJG-C10 can all significantly prolong the survival time of acute cerebral ischemic mice in each dose group, and have good neuroprotective activity on acute cerebral ischemic mice. The compounds ZJG-A6, ZJG-A7, ZJG-A10, ZJG-C2, ZJG-C3, ZJG-C5, ZJG-C11 can significantly prolong the death time of acute cerebral ischemic mice in the high-dose group (200 mg / Kg), but have no obvious effect in the medium-dose and low-dose groups.

[0210] The compounds of the present application can also resist oxidation, improve the survival rate of cells, and have a protective effect.

[0211] Effects of the compounds prepared in Examples 1-36 on the survival rate of PC-12 cells induced by H2O2.

[0212] PC-12 cells were cultured in 1.0×10 4The density of 1 cell / hole was inoculated in 96-well plates, and after 24 h of culture in an incubator, the cell fusion degree was observed under a microscope. When the cell fusion degree reached about 60%, the cell drug administration operation was performed. The 96-well plates were set with a blank control group, an H2O2 group, a drug group, and a drug-H2O2 group, each with 5 replicate wells. The blank control group was only given 100 μL of 2% BSA DMEM medium, the H2O2 group was only given 100 μL of 450 μmol H2O2 containing 2% BSA DMEM medium, the drug group was given 100 μL of different concentration gradient drugs (0.5 μmol, 2.5 μmol, 5.0 μmol) containing 2% BSA DMEM medium, and the drug / H2O2 group was first given 100 μL of different concentration gradient drugs (0.5 μmol, 2.5 μmol, 5.0 μmol) containing 2% BSA DMEM medium for 6 h, and then given 100 μL of different concentration gradient drugs, 450 μmol H2O2, and 2% BSA DMEM medium for 24 h. The drug group and the drug / H2O2 group were simultaneously given different concentration gradient drugs for 6 h in an incubator at this time, and the H2O2 group was given 100 μL of 2% BSA DMEM medium; after 6 h, the drug group was continuously incubated for 24 h, the H2O2 group was given a culture solution containing a corresponding concentration of H2O2 for incubation for 24 h, and the drug / H2O2 group was given a mixed culture solution of different concentrations of drugs and corresponding H2O2 concentrations for incubation for 24 h. After 24 h of incubation, the culture medium was aspirated, 100 μL of 1.0 mg / mL MTS serum-free culture solution was added to each well, and the incubation was stopped after 1 h of incubation in an incubator. The absorbance of each well was measured on an enzyme marker at a wavelength of 490 nm. The cell survival rate (%) was calculated according to the following formula:

[0213] Cell survival rate (%) = (Z-B) / (G-B) x 100%

[0214] In the formula, Z, B, and G represent the average values of the absorbance of the drug-H2O2 group, the blank control group, and the H2O2 group, respectively. The results are shown in Table 2.

[0215] Table 2 shows the effect of the compounds prepared in Examples 1-36 on the survival rate of PC-12 cells induced by H2O2 (%).

[0216]

[0217]

[0218]

[0219] * P<0.05 compared with the H2O2 group.

[0220] The above test results show that the compounds of the present application all have antioxidant activity, and the compounds ZJG-A1, ZJG-A2, ZJG-A7, ZJG-A9, ZJG-B3, ZJG-B4, ZJG-B5, ZJG-B9, ZJG-B11, ZJG-B12, ZJG-C3, ZJG-C4, ZJG-C6, ZJG-C7, ZJG-C8, ZJG-C10 can significantly improve the survival rate of PC-12 cells induced by H2O2 in each dose group, and are better than the positive control drug melatonin (MLT) at the same concentration, showing good antioxidant activity.

Claims

1. An isatin derivative, characterized in that The general structural formula is shown below: ； Wherein, R1 is halogen, hydrocarbon or alkoxy; R2 is any one of -O-CH2-CO-, -CH=CH-CO- or -O-CH2-CH2-; The hydrocarbon group represented by R1 refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms; the alkyl group in the alkoxy group refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms; the halogen represented by R1 is F or Br; When R2 is -O-CH2-CO-, the general structural formula is shown in formula (II): (II); When R2 is -CH=CH-CO-, the general structural formula is shown in formula (III): (III); When R2 is -O-CH2-CH2-, the general structural formula is shown in formula (IV): (IV)。 2. The method for preparing the isatin derivative according to claim 1, wherein The preparation method of the compound of formula (III) comprises the following steps: (1) Mix substituted benzaldehyde, malonic acid, and piperidine, add pyridine, and stir to dissolve. Heat to not less than 120°C and stir to react. Monitor the reaction progress by TLC. After the reaction is complete, remove the solvent under reduced pressure, add a concentrated hydrochloric acid / ice mixture, and stir vigorously. A large amount of white solid precipitates. Filter with suction, and recrystallize the crude product from anhydrous ethanol to obtain substituted phenylacrylic acid (IX). (2) N-Boc-piperazine and triethylamine were mixed, dichloromethane was added thereto, and the mixture was stirred and dissolved in an ice-water bath to obtain a mixed solution; 3,3-dichloro-2-oxoindole-5-sulfonyl chloride (VII) was dissolved in dichloromethane and slowly added dropwise to the mixed solution. After the addition was complete, the mixture was heated to room temperature and the reaction progress was monitored by TLC. After the reaction was complete, 4-(3,3-dichloro-2-oxoindole-5-ylsulfonyl)piperazine-1-carboxylic acid tert-butyl ester (X) was obtained by column chromatography; (3) tert-Butyl 4-(3,3-dichloro-2-oxoindole-5-ylsulfonyl)piperazine-1-carboxylate (X) was placed in a reaction flask, trifluoroacetic acid and dichloromethane were mixed to form a trifluoroacetic acid solution with a mass fraction of 25%, and the trifluoroacetic acid solution was directly added to the reaction flask. The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain 3,3-dichloro-5-(piperazin-1-ylsulfonyl)indole-2-one trifluoroacetate (XI); (4) 3,3-dichloro-5-(piperazin-1-ylsulfonyl)indole-2-one trifluoroacetate (XI) was placed in a reaction flask, and an acetic acid aqueous solution was added to the reaction flask. The temperature was raised to not less than 100°C for reaction. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain 5-(piperazin-1-ylsulfonyl)indole-2,3-dione trifluoroacetate (XII); (5) 5-(piperazine-1-ylsulfonyl)indoline-2,3-dione trifluoroacetate (XII), N-ethyldiisopropylamine and tetrahydrofuran were mixed and stirred in an ice-water bath to dissolve to obtain a reaction solution; substituted phenylacrylic acid (IX), anhydrous dichloromethane and DMF were placed in a reaction flask, oxalyl chloride was added dropwise to the reaction flask in an ice bath, the temperature was raised to room temperature after the addition was complete, the reaction solution was stirred for reaction, and the reaction solution was concentrated to obtain substituted phenylacrylic acid chloride; substituted phenylacrylic acid chloride was dissolved in tetrahydrofuran and slowly added dropwise to the above reaction solution, the temperature was raised to room temperature after the addition was complete, and the reaction solution was stirred overnight; the next day, the reaction progress was monitored by TLC, and after the reaction was completed, the solution was concentrated under reduced pressure to obtain a yellow oily liquid, which was separated by column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent and gradient eluted to obtain a compound of general formula (III); The synthetic route of the above method is: 。 3. The method for preparing the isatin derivative according to claim 1, wherein The preparation method of the compound of formula (IV) comprises the following steps: (1) A substituted phenol, 1,2-dibromoethane and water are mixed, stirred and heated to not less than 95°C, and a sodium hydroxide aqueous solution is added dropwise thereto. After the addition is complete, the temperature is continued to be raised to 100°C and stirred for reaction. The reaction progress is monitored by TLC. After the reaction is complete, the mixture is cooled to room temperature and extracted with dichloromethane. The dichloromethane layers are combined, washed with a sodium hydroxide aqueous solution and a saturated sodium chloride solution in sequence, and then dried over anhydrous magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain a substituted phenoxyethyl bromide (XIII). (2) Mix substituted phenoxyethyl bromide, methanol and piperazine, raise the temperature to not less than 70°C for reaction, monitor the reaction progress by TLC, and remove the solvent under reduced pressure after the reaction is completed; then add a mixture of dichloromethane and saturated sodium carbonate solution to dissolve the mixture, separate the layers, wash the dichloromethane layer with saturated sodium bicarbonate solution and water in sequence, and then wash the organic phase with hydrochloric acid; adjust the pH of the aqueous layer to >10 with sodium hydroxide solution, precipitate a solid, extract it with dichloromethane, combine the organic phases, and dry it over anhydrous sodium sulfate overnight; the next day, filter and concentrate under reduced pressure to obtain substituted phenoxyethyl piperazine (XIV); (3) Place the substituted phenoxyethylpiperazine in a reaction flask, add tetrahydrofuran to the flask under ice-water bath and stir to dissolve, then add N-ethyldiisopropylamine and continue stirring to obtain a reaction solution; dissolve 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran and slowly dropwise add the chloride to the reaction solution; after the addition is complete, warm the solution to room temperature and stir overnight; monitor the reaction progress by TLC; after the reaction is complete, remove the solvent by evaporation under reduced pressure to obtain substituted 3,3-dichloro-5-(4-(2-phenoxyethyl)piperazin-1-ylsulfonyl)indole-2-one (XV); (4) 3,3-dichloro-5-(4-(2-phenoxyethyl)piperazin-1-ylsulfonyl)indole-2-one was placed in a reaction flask, an aqueous solution of acetic acid was added, the temperature was raised to not less than 96°C and stirred for reaction, the reaction progress was monitored by TLC, and after the reaction was completed, the mixture was cooled to room temperature, sodium hydroxide solution was first added dropwise to adjust the pH to 7, and then a saturated sodium bicarbonate solution was added dropwise until no bubbles were generated; ethyl acetate was used for extraction, the organic phases were combined, washed with a saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate overnight; the next day, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily liquid, which was separated by column chromatography using a mixture of ethyl acetate and petroleum ether as the eluent, gradient elution, and gradient elution to obtain a compound of formula (IV); The synthetic route of the above method is: 。 4. Use of the isatin derivative according to claim 1 in the preparation of anti-cerebral ischemia neuroprotective drugs or drug components.

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