CN107522659B - 3-nitroquinoline derivative and preparation method and application thereof - Google Patents

3-nitroquinoline derivative and preparation method and application thereof Download PDF

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CN107522659B
CN107522659B CN201710701746.9A CN201710701746A CN107522659B CN 107522659 B CN107522659 B CN 107522659B CN 201710701746 A CN201710701746 A CN 201710701746A CN 107522659 B CN107522659 B CN 107522659B
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hydrogen atom
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nitroquinoline
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严胜骄
王保取
林军
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Yunnan University YNU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The invention relates to a preparation method and application of 3-nitroquinoline derivatives, belonging to the technical field of organic synthesis and pharmaceutical chemistry. The structural general formula of the compound is shown as a formula (I),
Figure DEST_PATH_IMAGE002
formula (I). The method synthesizes the 3-nitroquinoline derivative with the anti-tumor activity by reacting the isatin compound shown in the formula (II) and the 1, 1-enediamine compound shown in the formula (III) which are simple and easily obtained raw materials in an aprotic solvent. The invention has the characteristics of short synthetic route, simple and efficient process, simple and convenient operation, no water condition, no need of metal catalysis, high yield, low production cost and the like, and is very favorable for industrial production. The 3-nitroquinoline derivative has good anti-tumor activity and a remarkable application prospect.

Description

3-nitroquinoline derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry, and particularly relates to a 3-nitroquinoline derivative and a preparation method and application thereof.
Background
Cancer is an important disease in the world today that is seriously threatening to human life and health, and is increasingly devastating to more lives. The treatment and prevention of cancer has become a problem of great concern throughout society. The world health organization issued the world cancer report 2014 that cancer has become the most lethal cause for mankind worldwide.
Whereas colorectal cancer is generally less sensitive or difficult to treat with currently available chemotherapy, the only effective agent for this type of cancer is 5-fluorouracil. There is currently no alternative treatment to 5-fluorouracil-based complex chemotherapy. Therefore, the new medicine with better curative effect on the cancer has important practical significance for relieving the pain of patients.
Quinoline derivatives are nitrogen-containing heterocyclic compounds which have wide biological activity and are widely concerned by chemists and pharmacologists. Various methods have been developed for synthesizing quinolines, and Skraup, Doebner-von Miller, Friedlander, etc. are the classical synthetic methods. The classical synthesis methods are usually long in reaction time, low in synthesis yield, and require metal catalysts, high temperature and other conditions, and in pharmaceutical research, the synthesis methods have certain limitations. The research and development of the simple and efficient quinoline amide synthesis method has important significance.
Quinolinyl derivatives have a broad spectrum of biological activity including antimalarial, anti-HIV, anti-tumor (Vyas, v.; Variya, b.; Ghate, m.eur.j.med.chem.2014,82,385; Pathuri, g.; Li, q.; Mohammed, a.; Gali, h.; Pento, t.bioorg.med.chem.lett.2014,24,1380; Chen, h.; Yang, z.; Ding, c.; Chu l.; Zhang, y.; Terry, k.; Liu, h.; she, q.; Zhou, j.eur.j.med.m.2013, med 62,498; Manera, c.; maltan o, a.; parkka, t.; lucesi v.; sarc., s.2015 s.s., pacif s., pacif g., p., s., p., pacif g., c., pacific, c. Many patents of quinoline compounds have been reported at home and abroad.
WO2013000269 (periplaneta) discloses camptothecin derivatives having anti-lung cancer and anti-colon cancer activities.
CN201610077368.7 (Zhoujinjun) discloses a quinoline multi-target kinase inhibitor with anti-tumor activity and a preparation method thereof.
US9493419(Johnny Cheuk-on Tang) discloses a quinoline compound with anti-tumor activity.
US4826850(Masatoshi Yamato) discloses a class of quinoline-based antitumor drugs.
US5112817(Nobuyuki Fukazawa) discloses a quinoline compound having an antitumor activity.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method and application of a 3-nitroquinoline derivative, and the compound has good antitumor activity and extremely wide application prospect.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the structure of the 3-nitroquinoline derivative is shown as the formula (I):
Figure BDA0001380504680000021
in the formula (I), n is 0,1 or 2;
m is 0,1 or 2;
R1is a halogen atom, a hydrogen atom or an alkyl group;
R2is a halogen atom, a hydrogen atom or an alkyl group;
r is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl.
R' is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl.
The invention also provides a preparation method of the 3-nitroquinoline derivative, which comprises the following steps:
performing addition cyclization and rearrangement reaction on an isatin compound shown as a formula (II) and a 1, 1-enediamine compound shown as a formula (III) in an aprotic solvent under the catalysis of organic acid, tracking by TLC (thin layer chromatography), and after the reaction is completed, purifying and drying reactants to obtain the 3-nitroquinoline derivative with the structure shown as the formula (I); the specific reaction formula is as follows:
Figure BDA0001380504680000031
in the formula (II), R1Is a halogen atom, a hydrogen atom or an alkyl group; r2Is a halogen atom, a hydrogen atom or an alkyl group;
in the formula (III), n is 0,1 or 2; m is 0,1 or 2; r is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl; r' is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl.
Further, the mol ratio of the isatin-based compound shown in the formula (II) to the 1, 1-enediamine compound shown in the formula (III) is preferably 1: 1-2: 1; the volume ratio of the mol of the isatin compound shown in the formula (II) to the aprotic solvent is 1 mmol: 15-25 mL.
Further, the reaction temperature is preferably 25 ℃ to 120 ℃ and the reaction time is preferably 2 to 16 hours.
Further, it is preferable that the organic acid is acetic acid, trifluoroacetic acid, trichloroacetic acid or p-toluenesulfonic acid; the molar ratio of the organic acid to the isatin compound shown in the formula (II) is 4: 1-1: 1.
Further, it is preferable that the aprotic solvent is toluene, xylene, acetonitrile or 1, 4-dioxane.
Further, preferably, the drying is vacuum drying, natural drying or drying under an infrared lamp.
Further, it is preferable that the purification method is a method of extracting the reaction solution with an organic solvent and a saturated saline solution, and the organic phase is extracted with anhydrous Na2SO4Or anhydrous MgSO4Drying, concentrating the dried organic phase under reduced pressure to dryness, and separating by column chromatography to obtain pure 3-nitroquinoline derivatives shown in formula (I). Wherein, the concentrate can adopt dry method for sample loading through column chromatography separation, but is not limited to, for example, a proper amount of 100-200 mesh silica gel and a proper amount of dichloromethane or acetone are added into the concentrate, the mixture is fully and uniformly mixed, and then the mixture is decompressed and dried in a spinning way, and then sample loading is carried out.
Further, preferably, the organic solvent for extraction is ethyl acetate or dichloromethane;
the eluent adopted by the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1-2: 1;
the invention also provides the application of the 3-nitroquinoline derivative in preparing anti-tumor active medicaments.
Compared with the prior art, the invention has the beneficial effects that:
the invention utilizes simple and easily obtained raw materials: performing addition cyclization and rearrangement reaction on the isatin compound shown in the formula (II) and the 1, 1-enediamine compound shown in the formula (III) in an aprotic solvent at the temperature of 25-120 ℃, tracking by TLC (thin layer chromatography), purifying a reactant after the reaction is completed, and drying to obtain a target compound with antitumor activity, namely the 3-nitroquinoline derivative shown in the formula (I). The method has the characteristics of short synthetic route (only one-step reaction), simple and convenient operation, mild reaction conditions, no need of anhydrous conditions, no need of metal catalysis, high yield (75-95%), low production cost and the like, and is very favorable for industrial production. The 3-nitroquinoline derivative has good anti-tumor activity and a remarkable application prospect.
The compound has better anti-tumor activity on human colon cancer (HCT116) and human colon cancer (HT 29). Experimental studies showed that IC's of compounds 5, 6, 30 and 39 on HCT116 cell line50(mu mol/L) is respectively 5.02, 8.13, 6.05 and 6.25 which are all smaller than the IC of the cis-platinum50(mu mol/L) ═ 8.74, and both were less than 10 mu mol/L, showing superior anticancer activity relative to cisplatin. The 4 compounds also show excellent anticancer activity and IC on HCT116 (human colorectal cancer) cell line50Respectively is 7.15 mu mol/L, 9.56 mu mol/L, 9.20 mu mol/L and 8.36 mu mol/L, and is less than the IC of positive control medicament cisplatin5012.78 mu mol/L, and all are less than 10.0 mu mol/L.
Drawings
FIG. 1 is a single crystal diagram of Compound 16.
FIG. 2 is a hydrogen spectrum of Compound 21.
Fig. 3 is a carbon spectrum of compound 21.
Detailed Description
The present invention will be described in further detail with reference to examples.
It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents, instruments and the like used are not indicated by manufacturers, and are all conventional products which can be obtained by purchasing.
The starting materials of the present invention can be prepared by methods well known in the art or obtained as commercially available products.
The general method for synthesizing the 3-nitroquinoline derivative of the present invention is further explained below, but the method for producing the 3-nitroquinoline derivative of the present invention is not limited thereto.
The method for synthesizing the 3-nitroquinoline derivative comprises the following steps:
performing addition cyclization and rearrangement reaction on an isatin compound shown as a formula (II) and a 1, 1-enediamine compound shown as a formula (III) in an aprotic solvent under the catalysis of organic acid, tracking by TLC (thin layer chromatography), and after the reaction is completed, purifying and drying reactants to obtain the 3-nitroquinoline derivative with the structure shown as the formula (I); the specific reaction formula is as follows:
Figure BDA0001380504680000051
in the formula (II), R1Is a halogen atom, a hydrogen atom or an alkyl group; r2Is a halogen atom, a hydrogen atom or an alkyl group;
in the formula (III), n is 0,1 or 2; m is 0,1 or 2; r is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl; r' is phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, trifluoromethyl substituted phenyl, furyl or n-butyl.
The mol ratio of the isatin compound shown in the formula (II) to the 1, 1-enediamine compound shown in the formula (III) is 1: 1-2: 1; the volume ratio of the mol of the isatin compound shown in the formula (II) to the aprotic solvent is 1 mmol: 15-25 mL.
The reaction temperature is 25-120 ℃, and the reaction time is 2-16 hours.
The organic acid is acetic acid, trifluoroacetic acid, trichloroacetic acid or p-toluenesulfonic acid; the molar ratio of the organic acid to the isatin compound shown in the formula (II) is 4: 1-1: 1.
The aprotic solvent is not particularly limited, but toluene, xylene, acetonitrile or 1, 4-dioxane is preferred, and the molar ratio of the isatin-based compound represented by the formula (II) to the aprotic solvent is preferably 1 mmo: 15-25 mL.
The drying can adopt vacuum drying, natural drying, infrared lamp drying and other drying methods.
The purification method comprises the steps of firstly, extracting reaction liquid by adopting an organic solvent and saturated salt water, and using anhydrous Na as an organic phase2SO4Or anhydrous MgSO4Drying, concentrating the dried organic phase under reduced pressure to dryness, and separating by column chromatography to obtain pure 3-nitroquinoline derivatives shown in formula (I). Wherein, the concentrate can adopt dry method for sample loading through column chromatography separation, but is not limited to, for example, a proper amount of 100-200 mesh silica gel and a proper amount of dichloromethane or acetone are added into the concentrate, the mixture is fully and uniformly mixed, and then the mixture is decompressed and dried in a spinning way, and then sample loading is carried out.
The organic solvent for extraction is ethyl acetate or dichloromethane;
the eluent adopted by the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1-2: 1;
the compound represented by the formula (II) is known according to a known method, and the compound represented by the formula (III) is commercially available or can be prepared according to a known method.
Human tumor cell line experiments were performed on the compounds of the invention: HCT116 (human colon carcinoma), HT29 (colon carcinoma). The cell test compounds were incubated for 144 hours and then cytotoxicity was measured using the MTT assay (Mossman, t.j.immunol.methods 1983, 65, 55 "rapid colorimetric assay for cell viability; application of cytotoxicity and growth inhibitory lymphokine quantification". Green, l.m.j.immunol.methods 1984, 70, 257 "rapid colorimetric assay for cell viability; application of cytotoxicity and growth inhibitory lymphokine quantification").
The data obtained demonstrate that the compounds of the invention have significant activity against solid tumors, in particular colon-colorectal and colon cancers.
The daily dose of the compound of the present invention is 0.01mg to 10 mg/kg. A preferred daily dose is from about 0.2mg to 2mg per kg of body weight, with a single dose of from about 14mg to about 140mg of active substance being administered in a 24 hour period for a patient weighing about 70 kg. This dosage range can be adjusted to achieve better therapeutic results. The active compounds of the present invention can be administered orally, intravenously, intramuscularly, subcutaneously, and the like.
The compounds of the present invention may be administered in combination with other agents used to cause tumor regression, to synergistically increase the antitumor effect of the compounds. The compounds of the present invention can be used with different anti-cancer drugs, such as: cisplatin, thaliplatin, 5-fluorouracil, adriamycin, gemcitabine, taxol, vincristine, hydroxycamptothecin, topotecan and irinotecan are administered in combination (the combination administration ratio is 1: 10-10: 1).
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the invention in admixture with a pharmaceutically acceptable carrier.
Oral compositions comprise capsules, tablets, pills, suspensions or syrups suitable for oral administration.
To prepare pharmaceutical compositions for parenteral administration, the active ingredient may be incorporated into a solution or suspension.
The invention is described in detail below with reference to some specific embodiments. These examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The preparation schemes in the examples are only preferred schemes, but the present invention is not limited to the preferred preparation schemes.
First part Synthesis example
Example 1: synthesis of 6-fluoro-3-nitro-N- (4- (trifluoromethyl) benzyl) -2- (4- (trifluoromethyl) benzylamino) quinoline-4-carboxamide (Compound 1)
2-Nitro-N, N' -bis (4- (trifluoro) benzene was charged into a 25mL round bottom flaskMethyl) benzyl) ethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (1.1 mmol), toluene (15 ml) and acetic acid (4 mmol) were added and the mixture was heated to reflux under magnetic stirring, and the reaction was refluxed for 16 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, loading, separating by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1, and drying in vacuum to obtain a yellow solid product, namely 6-fluoro-3-nitro-N- (4- (trifluoromethyl) benzyl) -2- (4- (trifluoromethyl) benzylamino) quinoline-4-formamide (compound 1) with the yield of 80%. Melting point: 193-194 ℃.
Nuclear magnetic resonance hydrogen spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): 4.64(d, J ═ 4.7Hz,2H, NCH2),4.82(d,J＝5.2Hz,2H,NCH2),7.24(d,J＝9.1Hz,1H,ArH),7.61–7.68(m,8H,ArH),7.76(d,J＝8.0Hz,2H,ArH),8.33(t,J＝5.2Hz,1H,NH),9.52(t,J＝5.3Hz,1H,CONH)。
Nuclear magnetic resonance carbon spectrum (deutero dimethyl sulfoxide, Bruker AM 600 instrument): 43.0,44.3,110.2(d, J ═ 22.5Hz),118.7(d, J ═ 10.5Hz),123.5(d, J ═ 24.0Hz),123.9(d, J ═ 9.0Hz),125.5(d, J ═ 4.5Hz),127.5,127.8,128.0,128.3,128.5,128.6,129.0,129.3(d, J ═ 9.0Hz),130.7,140.8(d, J ═ 4.5Hz),144.4(d, J ═ 228.0Hz),146.8(d, J ═ 208.5Hz),158.5(d, J ═ 241.5Hz), 163.3.
High resolution mass spectrum C26H17F7N4O3Theoretical value 567.1262; found 567.1262.
Example 2: synthesis of 6-fluoro-N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -3-nitroquinoline-4-carboxamide (Compound 2)
After N, N' -bis (4-fluorobenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (20 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. The reaction was monitored by TLC until the starting material spot was completeAfter the reaction solution disappeared, 50 ml of ethyl acetate and 50 ml of saturated aqueous sodium chloride solution were added to extract the mixture, and the organic layer was extracted with anhydrous Na2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 5ml of acetone and 5 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, loading, separating by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1, and naturally drying to obtain a yellow solid product 6-fluoro-N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -3-nitroquinoline-4-formamide (compound 2) with the yield of 90%. Melting point: 193.0 to 193.2 ℃.
Nuclear magnetic resonance hydrogen spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 4.51(d, J ═ 5.5Hz,2H, NCH)2),4.70(d,J＝6.0Hz,2H,NCH2),7.10(t,J＝8.5Hz,2H,ArH),7.19–7.23(m,3H,ArH),7.40(q,J＝5.5Hz,2H,ArH),7.46(q,J＝6.0Hz,2H,ArH),7.65(t,J＝2.5Hz,2H,ArH),8.19(br,1H,NH),9.40(br,1H,CONH)。
Nuclear magnetic resonance carbon spectrum (deutero dimethyl sulfoxide, Bruker AM 500 instrument): 42.6,43.9,110.2(d, J ═ 23.8Hz),115.4(q, J ═ 21.3Hz),118.7(d, J ═ 10.0Hz),123.6(d, J ═ 26.3Hz),129.3(d, J ═ 8.8Hz),130.0(d, J ═ 8.8Hz),130.3(d, J ═ 8.8Hz),130.7,135.0(d, J ═ 2.5Hz),136.2(d, J ═ 2.5Hz),140.9(d, J ═ 5.0Hz),146.1,147.5,158.4(d, J ═ 241.3Hz),161.6(d, J ═ 240.0Hz),160.9(d, J ═ 3.163, 163.1.241 Hz).
High resolution mass spectrum C24H17F3N4O3[(M+H)-]Theoretical value 465.1175; found 465.1180.
Example 3: synthesis of N-benzyl-2- (benzylamino) -6-fluoro-3-nitroquinoline-4-carboxamide (Compound 3)
After N, N' -dibenzyl-2-nitroethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, xylene (15 ml) and acetic acid (2 mmol) were added, and the mixture was magnetically stirred and heated to 120 ℃ for 2 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying the organic matterConcentrating the phases under reduced pressure to dryness, adding 2 ml of acetone and 2 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a yellow solid product, namely N-benzyl-2- (benzylamino) -6-fluoro-3-nitroquinoline-4-formamide (a compound 3), wherein the yield is 80%. Melting point: 183.0-183.2 ℃.
Nuclear magnetic resonance hydrogen spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 4.54(d, J ═ 5.5Hz,2H, NCH)2),4.74(d,J＝6.0Hz,2H,NCH2),7.23–7.45(m,11H,ArH),7.63(t,J＝5.5Hz,2H,ArH),8.16(br,1H,NH),9.46(br,1H,CONH)。
Nuclear magnetic resonance carbon spectrum (deutero dimethyl sulfoxide, Bruker AM 500 instrument): 43.3,44.6,110.2(d, J ═ 23.8Hz),118.7(d, J ═ 8.8Hz),120.6,123.4(d, J ═ 25.0Hz),127.2,127.7,128.0(d, J ═ 25.0Hz),128.7,128.9,129.3(d, J ═ 8.8Hz),130.8,138.8,140.0,140.9(d, J ═ 5.0Hz),146.2,147.6,158.3(d, J ═ 241.3Hz), 163.1.
High resolution mass spectrum C24H19FN4O3[(M+H)+]Theoretical value 431.1514; found 431.1514.
Example 4: synthesis of 6-fluoro-N- (4-methoxybenzyl) -2- ((4-methoxybenzyl) amino) -3-nitroquinoline-4-carboxamide (Compound 4)
After N, N' -bis (4-methoxybenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, 1, 4-dioxane (15 ml) and acetic acid (2 mmol) were added and the mixture was magnetically stirred and heated to 100 ℃ for 16 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, loading, separating with petroleum ether/ethyl acetate (7: 1) eluent silica gel column, and drying under an infrared lamp to obtain a yellow solid product, namely 6-fluoro-N- (4-methoxybenzyl) -2- ((4-methoxybenzyl) amino) -3-nitroquinoline-4-formamide(Compound 4) in 85% yield. Melting point: 190.7-190.9 ℃.
High resolution mass spectrum C26H23FN4O5[(M+H)-]Theoretical value 489.1574; found 489.1582.
Example 5: synthesis of N- (2, 4-difluorobenzyl) -2- (2, 4-difluorobenzylamino) -6-fluoro-3-nitroquinoline-4-carboxamide (Compound 5)
After N, N' -bis (2, 4-difluorobenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (2.0 mmol) were added to a 25-ml round-bottom flask, acetonitrile (25 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 25 ℃ for 16 hours, 50 ml of ethyl acetate and 50 ml of a saturated aqueous sodium chloride solution were added to the reaction mixture to extract the mixture, and the organic layer was extracted with anhydrous Na2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 5ml of acetone and 5 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a yellow solid product N- (2, 4-difluorobenzyl) -2- (2, 4-difluorobenzylamino) -6-fluoro-3-nitroquinoline-4-formamide (compound 5) with the yield of 85%. Melting point: 186.0-186.2 ℃.
Nuclear magnetic resonance fluorine spectrum (deutero dimethyl sulfoxide, Bruker AM 500 instrument): 116.8, -114.3(d, J ═ 4.8Hz), -113.8(d, J ═ 4.8Hz), -112.4(d, J ═ 4.8Hz), -111.2(d, J ═ 9.5 Hz).
Nuclear magnetic resonance hydrogen spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 4.55(d, J ═ 5.0Hz,2H, NCH2),4.73(d,J＝5.0Hz,2H,NCH2),7.00(d,J＝1.5Hz,1H,ArH),7.13(d,J＝1.5Hz,1H,ArH),7.20–7.24(t,2H,ArH),7.28(s,1H,ArH),7.50–7.54(q,2H,ArH),7.64(d,J＝7.0Hz,2H,ArH),8.18(br,1H,NH),9.40(br,1H,CONH)。
Nuclear magnetic resonance carbon spectroscopy (deuterated dimethylsulfoxide, Bruker AM 500 instrument): 36.9(d, J, 3.8Hz),38.2,103.8(d, J, 26.3Hz),104.1(t, J, 13.8Hz),104.5,110.2(d, J, 23.8Hz),111.5(d, J, 2.5Hz),111.6(d, J, 3.8Hz),111.7(d, J, 2.5Hz),111.9(d, J, 2.5Hz),118.8(d, J, 10.0Hz),122.4(d, J, 187.5Hz),123.5,123.7,129.3(d, J, 8.8Hz),130.6,131.2(d, J, 6.3Hz),131.3(q, J, 6.3Hz),132.2(d, J, 6.3), 132.3(d, J, 6.3), 6.3 (d, J, 6.3Hz),163.2 (d, J, 7, 16.3, 163, 16.7, 163, 16.5 Hz), 163.7 (d, J, 16.3, 16.7, 16 Hz),159 (d, J, 16.5 Hz),163, 16.7, 16.5 Hz),163, 16.7 (d, J, 16.7, 16, h).
High resolution mass spectrum C24H15F5N4O3[(M+H)+]Theoretical value 503.1137; found 503.1136.
Example 6: synthesis of (N- (3, 4-difluorobenzyl) -2- (3, 4-difluorobenzylamino) -6-fluoro-3-nitroquinoline-4-carboxamide (Compound 6)
After N, N' -bis (3, 4-difluorobenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of dichloromethane and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure, loading, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a yellow solid product (N- (3, 4-difluorobenzyl) -2- (3, 4-difluorobenzylamino) -6-fluoro-3-nitroquinoline-4-formamide (compound 6) with the yield of 90% and the melting point of 187.2-187.4 ℃.
Nuclear magnetic resonance fluorine spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 141.7(d, J23.8 Hz), 141.0(d, J23.8 Hz), 139.2(d, J19.0 Hz), 138.9(d, J38.0 Hz) and 116.8.
Nuclear magnetic resonance hydrogen spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 4.54(d, J ═ 5.0Hz,2H, NCH2),4.70(d,J＝5.5Hz,2H,NCH2),7.25–7.29(q,3H,ArH),7.34–7.43(m,1H,ArH),7.44–7.48(t,3H,ArH),7.66(m,J＝4.5Hz,2H,ArH),8.25(d,J＝5.5Hz,1H,NH),9.44(d,J＝5.5Hz,1H,CONH)。
Nuclear magnetic resonance carbon spectroscopy (deuterated dimethylsulfoxide, Bruker AM 500 instrument): 42.3,43.7,110.2(d, J ═ 23.8Hz),117.0,117.1(d, J ═ 16.3Hz),117.5(d, J ═ 16.3Hz),117.8(d, J ═ 17.5Hz),118.7(d, J ═ 10.0Hz),123.5(d, J ═ 26.3Hz),124.7(q, J ═ 2.5Hz),125.0(q, J ═ 2.5Hz),129.3(d, J ═ 8.8Hz),130.7,136.6(t, J ═ 5.0Hz),138.0(t, J ═ 3.8Hz),140.8(d, J ═ 5.0Hz),146.1,147.4,147.8(d, J ═ 12.5, 149 ═ 1.149 (149), 149.1(d, J ═ 2.5Hz), 146.1,147.4,147.8(d, J ═ 2.5Hz), 27.5 (d, J ═ 2.5Hz), 27.5 Hz, J ═ 2.5Hz, 27 (d, J ═ 2.5 Hz).
High resolution mass spectrum C24H15F5N4O3[(M+H)+]Theoretical value 503.1137; found 503.1135.
Example 7: synthesis of 6-fluoro-N- (4-fluorophenethyl) -2- (4-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (Compound 7)
The reaction was carried out using N, N '-bis (4-fluorophenethyl) -2-nitroethylene-1, 1-diamine instead of 2-nitro-N, N' -bis (4- (trifluoromethyl) benzyl) ethylene-1, 1-diamine in example 1 to give 6-fluoro-N- (4-fluorophenethyl) -2- (4-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (Compound 7) as a yellow solid in 85% yield. Melting point: 181.1-181.3 ℃.
High resolution mass spectrum C26H21F3N4O3[(M+H)-]Theoretical value 495.1639; found 495.1636.
Example 8: synthesis of 6-fluoro-3-nitro-N-phenethyl-2- (phenethylamino) quinoline-4-carboxamide (Compound 8)
The 2-nitro-N, N '-stilbene-1, 1-diamine was used in place of the 2-nitro-N, N' -bis (4- (trifluoromethyl) benzylidene-1, 1-diamine in example 1 to give 6-fluoro-3-nitro-N-phenethyl-2- (phenethylamino) quinoline-4-carboxamide (compound 8) as a red solid in 80% yield and 158.5-158.8 ℃ melting point.
High resolution mass spectrum C26H23FN4O3[(M+H)+]Theoretical value 459.1827; found 495.1826.
Example 9: synthesis of 6-fluoro-N- (2-fluorophenethyl) -2- (2-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (Compound 9)
By substituting N, N '-bis (2-fluorophenethyl) -2-nitroethylene-1, 1-diamine for 2-nitro-N, N' -bis (4- (trifluoromethyl) benzyl) ethylene-1, 1-diamine in example 1, 6-fluoro-N- (2-fluorophenethyl) -2- (2-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (compound 9) was obtained as a yellow solid in 85% yield. Melting point: 160.1-160.4 ℃.
High resolution mass spectrum C26H21F3N4O3[(M+H)+]Theoretical value 495.1639; found 495.1634.
Example 10: synthesis of 6-fluoro-3-nitro-N- ((tetrahydrofuran-2-yl) methyl) -2- ((tetrahydrofuran-2-yl) methylamino (quinoline-4-carboxamide (Compound 10)
The reaction was carried out using 2-nitro-N, N '-bis ((tetrahydrofuran-2-yl) methyl) ethylene-1, 1-diamine instead of 2-nitro-N, N' -bis (4- (trifluoromethyl) benzyl) ethylene-1, 1-diamine as in example 1 to give 6-fluoro-3-nitro-N- ((tetrahydrofuran-2-yl) methyl) -2- ((tetrahydrofuran-2-yl) methylamino (quinoline-4-carboxamide (compound 10) as a yellow solid in 80% yield, melting point: 136.5 to 136.7 ℃.
High resolution mass spectrum C20H23FN4O3[(M+H)+]Theoretical value 419.1725; found 419.1728.
Example 11: synthesis of N-butyl-2- (butylamino) -6-fluoro-3-nitroquinoline-4-carboxamide (Compound 11)
The reaction was carried out using N, N '-dibutyl-2-nitroethylene-1, 1-diamine instead of 2-nitro-N, N' -bis (4- (trifluoromethyl) benzyl) ethylene-1, 1-diamine in example 1 to give N-butyl-2- (butylamino) -6-fluoro-3-nitroquinoline-4-carboxamide (compound 11) as a red solid in a yield of 95%. Melting point: 126.0 to 126.3 ℃.
High resolution mass spectrum C18H23FN4O3[(M+H)+]Theoretical value 363.1827; found 363.1830.
Example 12: synthesis of N-benzyl-2- (benzylamino) -6-bromo-3-nitroquinoline-4-carboxamide (Compound 12)
Into a 25ml round bottom flask were added N, N' -dibenzyl-2-nitroethylene-1, 1-diamine (1 mmol) and 5-bromoindoline-2, 3After-diketone (1.1 mmol), acetonitrile (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 75 ℃ for 16 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of dichloromethane and 3 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a red solid product, namely N-benzyl-2- (benzylamino) -6-bromo-3-nitroquinoline-4-formamide (a compound 12), with the yield of 80%. Melting point: 201.5-201.7 ℃.
High resolution mass spectrum C24H19BrN4O3[(M+H)-]Theoretical value 489.0564; found 489.0562.
Example 13: synthesis of 6-bromo-N-butyl-2- (butylamino) -3-nitroquinoline-4-carboxamide (Compound 13)
The reaction was carried out using N, N '-dibutyl-2-nitroethylene-1, 1-diamine instead of N, N' -dibenzyl-2-nitroethylene-1, 1-diamine in example 12 to give 6-bromo-N-butyl-2- (butylamino) -3-nitroquinoline-4-carboxamide (Compound 13) as a yellow solid in 90% yield. Melting point: 161.4-161.6 ℃.
High resolution mass spectrum C18H23BrN4O3[(M+H)-]Theoretical value 421.0875; found 421.0880.
Example 14: synthesis of (4- (trifluoromethyl) benzyl) -2- (4- (trifluoromethyl) benzylamino) quinoline-4-carboxamide (Compound 14)
The reaction was carried out using indoline-2, 3-dione instead of 5-fluoroindoline-2, 3-dione in example 1 to give (4- (trifluoromethyl) benzyl) -2- (4- (trifluoromethyl) benzylamino) quinoline-4-carboxamide (compound 14) as a yellow solid in 80% yield. Melting point: 219.7-219.9 ℃.
High resolution mass spectrum C26H18F6N4O3[(M+H)+]Theoretical value 549.1356; found 549.1355.
Example 15: synthesis of N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -3-nitroquinoline-4-carboxamide (Compound 15)
The reaction was carried out using indoline-2, 3-dione instead of 5-fluoroindoline-2, 3-dione in example 2 to give N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -3-nitroquinoline-4-carboxamide (compound 15) as a yellow solid in 90% yield. Melting point: 183.3-183.5 ℃.
High resolution mass spectrum C24H18F2N4O3[(M+H)+]Theoretical value 449.1420; found 449.1419.
Example 16: synthesis of N-benzyl-2- (benzylamino) -3-nitroquinoline-4-carboxamide (Compound 16)
The reaction was carried out using indoline-2, 3-dione instead of 5-fluoroindoline-2, 3-dione in example 3 to give N-benzyl-2- (benzylamino) -3-nitroquinoline-4-carboxamide (compound 16) as a yellow solid in 80% yield. Melting point: 195.2-195.5 ℃. The single crystal is shown in FIG. 1.
High resolution mass spectrum C24H20N4O3[(M+H)-]Theoretical value 411.1457; found 411.1465.
Example 17: synthesis of N- (4-methylbenzyl) -2- (4-methylbenzylamino) -3-nitroquinoline-4-carboxamide (Compound 17)
After N, N' -bis (4-methylbenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and indoline-2, 3-dione (1.1 mmol) were charged in a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added, and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 5ml of dichloromethane and 5 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure, sampling, separating and drying by using an eluent silica gel column of petroleum ether/ethyl acetate 7:1 to obtain a red solid product N- (4-methylbenzyl) -2- (4-methylbenzylamino)-3-nitroquinoline-4-carboxamide (compound 17) in 85% yield. Melting point: 208.6 to 208.8 ℃.
High resolution mass spectrum C26H24N4O3[(M+H)+]Theoretical value 441.1921; found 441.1920.
Example 18: synthesis of N- (4-methoxybenzyl) -2- (4-methoxybenzylamino) -3-nitroquinoline-4-carboxamide (Compound 18)
The reaction was carried out using indoline-2, 3-dione instead of 5-fluoroindoline-2, 3-dione in example 4 to give N- (4-methoxybenzyl) -2- (4-methoxybenzylamino) -3-nitroquinoline-4-carboxamide (compound 18) as a red solid in 80% yield. Melting point: 214.4 to 214.6 ℃.
High resolution mass spectrum C26H24N4O5[(M+H)-]Theoretical value 471.1675; found 411.1675.
Example 19: synthesis of N- (2, 4-difluorobenzyl) -2- (2, 4-difluorobenzylamino) -3-nitroquinoline-4-carboxamide (Compound 19)
The reaction was carried out using indoline-2, 3-dione instead of 5-fluoroindoline-2, 3-dione in example 5 to give N- (2, 4-difluorobenzyl) -2- (2, 4-difluorobenzylamino) -3-nitroquinoline-4-carboxamide (Compound 19) as a yellow solid in 90% yield. Melting point: 214.4 to 214.6 ℃.
High resolution mass spectrum C24H16F4N4O3[(M+H)-]Theoretical value 483.1086; found 483.1081.
Example 20: synthesis of N- (3, 4-difluorobenzyl) -2- (3, 4-difluorobenzylamino) -3-nitroquinoline-4-carboxamide (Compound 20)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 6, N- (3, 4-difluorobenzyl) -2- (3, 4-difluorobenzylamino) -3-nitroquinoline-4-carboxamide (compound 20) was obtained as a yellow solid in 90% yield. Melting point: 185.0 to 185.2 ℃.
High resolution mass spectrum C24H16F4N4O3[(M+H)-]Theoretical value 483.1086; found 483.1084.
Example 21: synthesis of N- (4-fluorophenethyl) -2- (4-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (Compound 21)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 7, N- (4-fluorophenethyl) -2- (4-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (compound 21) was obtained as a red solid in 85% yield. Melting point: 155.5 to 155.7 ℃. The nuclear magnetic hydrogen spectrum is shown in FIG. 2 and the nuclear magnetic carbon spectrum is shown in FIG. 3.
High resolution mass spectrum C26H22F2N4O3[(M+H)+]Theoretical value 477.1733; found 477.1735.
Example 22: synthesis of 3-nitro-N-phenethyl-2- (phenethylamino) quinoline-4-carboxamide (Compound 22)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 8, 3-nitro-N-phenethyl-2- (phenethylamino) quinoline-4-carboxamide (compound 22) was obtained as a yellow solid in 80% yield. Melting point: 155.5-155.6 ℃.
High resolution mass spectrum C26H24N4O3[(M+H)-]Theoretical 439.1770 found, 439.1776.
Example 23: synthesis of N- (2-fluorophenethyl) -2- (2-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (Compound 23)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 9, N- (2-fluorophenethyl) -2- (2-fluorophenethylamino) -3-nitroquinoline-4-carboxamide (compound 23) was obtained as a yellow solid in 85% yield. Melting point: 152.3 to 152.5 ℃.
High resolution mass spectrum C26H22F2N4O3[(M+H)+]Theoretical value 477.1733; found 477.1726.
Example 24: synthesis of 3-nitro-N- ((tetrahydrofuran-2-yl) methyl) -2- ((tetrahydrofuran-2-yl) methylamino) quinoline-4-carboxamide (Compound 24)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 10, 3-nitro-N- ((tetrahydrofuran-2-yl) methyl) -2- ((tetrahydrofuran-2-yl) methylamino) quinoline-4-carboxamide (compound 24) was obtained as a red solid in 80% yield. Melting point: 147.7-147.9 ℃.
High resolution mass spectrum C20H24N4O5[(M+H)+]Theoretical value 401.1819; found 401.1817.
Example 25: synthesis of N-butyl-2- (butylamino) -3-nitroquinoline-4-carboxamide (Compound 25)
By substituting indoline-2, 3-dione for 5-fluoroindoline-2, 3-dione in example 11, N-butyl-2- (butylamino) -3-nitroquinoline-4-carboxamide (compound 25) was obtained as a red solid in 90% yield. Melting point: 128.0-128.3 ℃.
High resolution mass spectrum C18H24N4O3[(M+H)+]Theoretical value 345.1921; found 345.1919.
Example 26: synthesis of N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -6-methyl-3-nitroquinoline-4-carboxamide (Compound 26)
After N, N' -bis (4-fluorobenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-methyldihydroindole-2, 3-dione (1.1 mmol) were charged in a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 5:1 to obtain a red solid product N- (4-fluorobenzyl) -2- (4-fluorobenzylamino) -6-methyl-3-nitroquinoline-4-formamide (a compound 26) with the yield of 85%. Melting point: 237.2-237.5 ℃.
High resolution mass spectrum C25H20F2N4O3[(M+H)-]Theoretical value 461.1425; found 461.1429.
Example 27: synthesis of N- (4-fluorophenethyl) -2- (4-fluorophenethylamino) -6-methyl-3-nitroquinoline-4-carboxamide (Compound 27)
After N, N' -bis (4-fluorophenethyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-methylindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a red solid product N- (4-fluorophenethyl) -2- (4-fluorophenethyl amino) -6-methyl-3-nitroquinoline-4-formamide (a compound 27) with the yield of 85%. Melting point: 151.7-151.9 ℃.
High resolution mass spectrum C27H24F2N4O3[(M+H)-]Theoretical value 491.1889; found 491.1888.
Example 28: synthesis of N- (2-fluorophenethyl) -2- (2-fluorophenethylamino) -6-methyl-3-nitroquinoline-4-carboxamide (Compound 28)
After N, N' -bis (2-fluorophenethyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 5-methylindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column of petroleum ether/ethyl acetate (7: 1) to obtain a yellow solid product N- (2-fluorine) productPhenethyl) -2- (2-fluorophenethylamino) -6-methyl-3-nitroquinoline-4-carboxamide (Compound 28) in 80% yield. Melting point: 143.2 to 143.5 ℃.
High resolution mass spectrum C27H24F2N4O3[(M+H)+]Theoretical value 491.1889; found 491.1885.
Example 29: synthesis of N-butyl-2- (butylamino) -6-methyl-3-nitroquinoline-4-carboxamide (Compound 29)
After N, N' -dibutyl-2-nitroethylene-1, 1-diamine (1 mmol) and 5-methyldihydroindole-2, 3-dione (1.1 mmol) were charged in a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added, and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a red solid product N-butyl-2- (butylamino) -6-methyl-3-nitroquinoline-4-formamide (a compound 29), wherein the yield is 90%. Melting point: 135.0 to 135.3 ℃.
High resolution mass spectrum C19H26N4O3[(M+H)+]Theoretical value 359.2078; found 359.2078.
Example 30: synthesis of N- (4-chlorobenzyl) -2- (4-chlorobenzylamino) -7-fluoro-3-nitroquinoline-4-carboxamide (Compound 30)
After (E) -N-4-chlorobenzyl) -N- (4-methylbenzyl) -2-nitroethylene-1, 1-diamine (1 mmol) and 7-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottomed flask, toluene (15 mL) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. The reaction was monitored by TLC, and after the starting material spot had disappeared completely, 50 ml of ethyl acetate and 50 ml of saturated aqueous sodium chloride solution were added to the reaction solution to conduct extraction, and the organic layer was extracted with anhydrous MgSO4Is dried byThe eluent of petroleum ether/ethyl acetate 7:1 is separated and dried by a silica gel column to obtain a yellow solid product N- (4-chlorobenzyl) -2- (4-chlorobenzylamino) -7-fluoro-3-nitroquinoline-4-formamide (compound 30) with the yield of 75 percent. Melting point: 214.5 to 214.7 ℃.
High resolution mass spectrum C24H17Cl2FN4O3[(M+H)-]Theoretical value 497.0583; found 497.0588.
Example 31: synthesis of N-benzyl-2- (benzylamino) -7-fluoro-3-nitroquinoline-4-carboxamide (Compound 31)
After N, N' -dibenzyl-2-nitroethylene-1, 1-diamine (1 mmol) and 7-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added, and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a yellow solid product N-benzyl-2- (benzylamino) -7-fluoro-3-nitroquinoline-4-formamide (a compound 31) with the yield of 80%. Melting point: 182.5 to 182.7 ℃.
High resolution mass spectrum C24H20FN4O3[(M+H)-]Theoretical value 429.1363; found 429.1370.
Example 32: synthesis of N-butyl-2- (butylamino) -7-fluoro-3-nitroquinoline-4-carboxamide (Compound 32)
After N, N' -dibutyl-2-nitroethylene-1, 1-diamine (1 mmol) and 7-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added, and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using the organic layerAnhydrous Na2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a red solid product N-butyl-2- (butylamino) -7-fluoro-3-nitroquinoline-4-formamide (a compound 32) with the yield of 90%. Melting point: 122.5 to 122.7 ℃.
High resolution mass spectrum C18H23FN4O3[(M+H)-]Theoretical value 361.1676; found 361.1684.
Example 33: synthesis of N- (4-fluorobenzyl) -3-nitro-2- (phenylamino) quinoline-4-carboxamide (Compound 33)
After (E) -N- (4-fluorobenzyl) -2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and indoline-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottomed flask, toluene (15 mL) and acetic acid (1 mmol) were added and the mixture was heated to 110 ℃ with magnetic stirring and reacted for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 5:1 to obtain a red solid product N- (4-fluorobenzyl) -3-nitro-2- (phenylamino) quinoline-4-formamide (compound 33), wherein the yield is 58%. Melting point: 147.2-148.5 ℃.
Nuclear magnetic resonance hydrogen spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 4.47(d, J ═ 6.0Hz,2H, NCH)2),7.03(s,1H,ArH),7.14(t,J＝8.5Hz,2H,ArH),7.29–7.32(m,2H,ArH),7.36–7.39(m,3H,ArH),7.60–7.66(m,2H,ArH),7.72–7.74(m,2H,ArH),9.21(s,1H,NH),9.43(s,1H,CONH)；
Nuclear magnetic resonance carbon spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 42.6,115.5(d, J ═ 21.3Hz),119.5,121.6,123.7,125.6,127.1(d, J ═ 11.3Hz),129.1,130.2(d, J ═ 7.5Hz),131.1,133.7,135.0,139.9,141.4,145.2,147.9,160.9(d, J ═ 245.0Hz),163.2.
High resolution mass spectrum C23H17FN4O3[(M+H)+]Theoretical value 417.1357; found 417.1360.
Example 34: synthesis of N- (4-fluorobenzyl) -3-nitro-2- (p-tolylamino) quinoline-4-carboxamide (Compound 34)
After (E) -N- (4-fluorobenzyl) -2-nitro-N- (p-tolyl) ethylene-1, 1-diamine (1 mmol) and indoline-2, 3-dione (1.1 mmol) were charged in a 25-ml round-bottom flask, toluene (15 ml) and acetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 5:1 to obtain a red solid product N- (4-fluorobenzyl) -3-nitro-2- (p-tolylamino) quinoline-4-formamide (compound 34) with the yield of 62%. Melting point: 175.2-176.5 ℃.
Nuclear magnetic resonance hydrogen spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 2.23(s,3H, CH)3),4.47(d,J＝5.5Hz,2H,NCH2),7.10–7.17(m,4H,ArH),7.34–7.39(m,3H,ArH),7.58–7.61(m,4H,ArH),7.68–7.71(m,1H,ArH),9.13(s,1H,NH),9.40(t,J＝6.0Hz,1H,CONH)；
Nuclear magnetic resonance carbon spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 21.0,42.6,115.6(d, J ═ 21.3Hz),119.6,121.9,125.3,127.1,129.5,130.2(d, J ═ 7.5Hz),131.0,132.8,133.7,135.1,137.3,141.4,145.4,148.1,161.0(d, J ═ 241.3Hz),163.3.
High resolution mass spectrum C24H19FN4O3[(M+H)+]Theoretical value 431.1514; found 431.1519.
Example 35: synthesis of N-benzyl-6-methyl-3-nitro-2- (phenylamino) quinoline-4-carboxamide (Compound 35)
After (E) -N-benzyl-2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and 5-methyldihydroindole-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottom flask, toluene (15 mL) and acetic acid (1 mmol) were added and the mixture was heated to 110 ℃ with magnetic stirring and reacted for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 5:1 to obtain a red solid product, namely N-benzyl-6-methyl-3-nitro-2- (phenylamino) quinoline-4-formamide (compound 35), with the yield of 52%. Melting point: 208.0-208.5 ℃.
Nuclear magnetic resonance hydrogen spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 2.30(s,3H, CH)3),4.70(t,J＝5.5Hz,2H,NCH2),7.08–7.26(m,2H,ArH),7.31–7.40(m,2H,ArH),7.48–7.50(m,5H,ArH),7.51–7.53(m,2H,ArH),7.60–7.61(m,2H,ArH),8.18(t,J＝6.0Hz,1H,NH),10.80(s,1H,CONH)；
Carbon nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 21.3,44.6,118.4,120.2,124.8,125.5,126.7,127.2,128.1,128.7,129.3,129.5,134.0,136.3,138.9,140.2,141.2,147.8,148.1,162.3.
High resolution mass spectrum C24H20N4O3[(M+H)+]Theoretical value 413.1608; found 413.1607.
Example 36: synthesis of 2- (benzylamino) -6-methyl-3-nitro-N-phenylquinoline-4-carboxamide (Compound 36)
After (E) -N-benzyl-2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and 5-methyldihydroindole-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottom flask, toluene (15 mL) and acetic acid (1 mmol) were added and the mixture was heated to 110 ℃ with magnetic stirring and reacted for 14 hours. The reaction was monitored by TLC, and after the starting material spot had disappeared completely, 50 ml of ethyl acetate and 50 ml of saturated aqueous sodium chloride solution were added to the reaction solution to conduct extractionCollecting organic layer with anhydrous Na2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 10:1 to obtain a red solid product, namely N-benzyl-6-methyl-3-nitro-2- (phenylamino) quinoline-4-formamide (compound 36), with the yield of 40%. Melting point: 188.2-189.5 ℃.
Nuclear magnetic resonance hydrogen spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 2.28(s,3H, CH)3),4.49(d,J＝5.0Hz,2H,NCH2),7.0(s,1H,ArH),7.25–7.37(m,8H,ArH),7.55(d,J＝2.0Hz,2H,ArH),7.72(d,J＝7.5Hz,2H,ArH),9.14(br,1H,NH),9.42(s,1H,CONH)；
Carbon nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): 21.3,43.3,119.5,121.3,123.4,125.7,127.0,127.7,128.3,128.6,128.9,129.0,131.1,134.9,135.7,139.0,140.1,140.9,144.8,146.4,163.3.
High resolution mass spectrum C24H20N4O3[(M+H)+]Theoretical value 413.1608; found 413.1606.
Example 37: synthesis of N- (4-fluorobenzyl) -6-methyl-3-nitro-2- (phenylamino) quinoline-4-carboxamide (Compound 37)
After (E) -N- (4-fluorobenzyl) -2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and 5-methylindoline-2, 3-dione (1.1 mmol) were charged in a 25-mL round-bottomed flask, toluene (15 mL) and p-toluenesulfonic acid (1 mmol) were added and the mixture was heated to 110 ℃ with magnetic stirring and refluxed for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na as organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and evaporated dry matter, uniformly stirring, evaporating to dryness under reduced pressure, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 5:1 to obtain a red solid product N- (4-fluorobenzyl) -6-methyl-3-nitro-2- (phenylamino) quinoline-4-formamide (compound formula I)Material 37), yield 50%. Melting point: 235.2-236.5 ℃.
High resolution mass spectrum C24H19FN4O3[(M+H)+]Theoretical value 431.1514; found 431.1512.
Example 38: synthesis of 2- ((4-fluorobenzyl) amino) -6-methyl-3-nitro-N-phenylquinoline-4-carboxamide (Compound 38)
After (E) -N- (4-fluorobenzyl) -2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and 5-methylindoline-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottomed flask, toluene (15 mL) and acetic acid (1 mmol) were added and the mixture was heated to 110 ℃ under magnetic stirring and refluxed for 14 hours. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 2:1 to obtain a red solid product N- (4-fluorobenzyl) -6-methyl-3-nitro-2- (phenylamino) quinoline-4-formamide (a compound 38) with the yield of 30%. Melting point: 191.2 to 192.5 ℃.
High resolution mass spectrum C24H19FN4O3[(M+H)+]Theoretical value 431.1514; found 431.1511.
Example 39: synthesis of N-benzyl-8-fluoro-3-nitro-2- (phenylamino) quinoline-4-carboxamide (Compound 39)
After (E) -N-benzyl-2-nitro-N-phenylethene-1, 1-diamine (1 mmol) and 7-fluoroindoline-2, 3-dione (1.1 mmol) were added to a 25-mL round-bottomed flask, toluene (15 mL) and trichloroacetic acid (1 mmol) were added and the mixture was heated to 110 ℃ under magnetic stirring and refluxed for 14 hours. The reaction was monitored by TLC, after the starting material spot had disappeared completely, 50 ml of methylene chloride and 50 ml of saturated aqueous sodium chloride solution were added to the reaction solution to conduct extraction, and the organic layer was extracted with anhydrous Na2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, and concentratingAnd adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the condensed and evaporated product, uniformly stirring, performing reduced pressure evaporation, sampling, separating and drying by using an eluent silica gel column with the ratio of petroleum ether to ethyl acetate being 7:1 to obtain a red solid product, namely N-benzyl-8-fluoro-3-nitro-2- (phenylamino) quinoline-4-formamide (a compound 39), with the yield being 70%. Melting point: 218.2-219.5 ℃.
High resolution mass spectrum C23H17FN4O3[(M+H)+]Theoretical value 417.1357; found 417.1362.
Example 40: synthesis of N-benzyl-8-fluoro-3-nitro-2- (p-tolylamino) quinoline-4-carboxamide (Compound 40)
After (E) -N-benzyl-2-nitro-N- (p-tolyl) ethylene-1, 1-diamine (1 mmol) and 7-fluoroindoline-2, 3-dione (1 mmol) were charged in a 25-ml round-bottom flask, toluene (15 ml) and trifluoroacetic acid (1 mmol) were added and the mixture was magnetically stirred and heated to 110 ℃ for 14 hours under reflux. TLC monitoring reaction, after the material point completely disappeared, adding 50 ml ethyl acetate and 50 ml saturated sodium chloride water solution into the reaction liquid for extraction, and using anhydrous Na for organic layer2SO4Drying, concentrating the dried organic phase under reduced pressure to dryness, adding 3 ml of acetone and 4 g of 100-200 mesh silica gel into the concentrated and dried product, uniformly stirring, drying by reduced pressure to dryness, sampling, separating and drying by using an eluent silica gel column with petroleum ether/ethyl acetate ratio of 7:1 to obtain a red solid product, namely N-benzyl-8-fluoro-3-nitro-2- (p-tolylamino) quinoline-4-formamide (a compound 40), with the yield of 65%. Melting point: 220.2-221.5 ℃.
High resolution mass spectrum C24H19FN4O3[(M+H)+]Theoretical value 431.1514; found 431.1520.
The structure of the 3-nitroquinoline derivative synthesized in the method is shown in the table 1:
TABLE 13 structural formula of nitroquinoline derivatives
Figure BDA0001380504680000211
Figure BDA0001380504680000221
Figure BDA0001380504680000231
Figure BDA0001380504680000241
The second part of the antitumor activity of the compounds of the present invention:
application example
The 6 compounds of the invention were randomly selected for three human tumor cell line experiments: HCT116 (human colorectal cancer), HT29 (colon cancer). The cell test compounds were incubated for 144 hours and then the cytotoxicity was measured using the MTT assay (Mossman, t.j.immunol.methods 1983, 65, 55 "rapid colorimetric assay for cell viability; application of cytotoxicity and growth inhibitory lymphokine quantification". Green, l.m.j.immunol.methods 1984, 70, 257 "rapid colorimetric assay for cell viability; application of cytotoxicity and growth inhibitory lymphokine quantification"), the results of which are shown in table 2.
The obtained data prove that the compound has better anti-tumor activity on human colon cancer (HCT116) and human colon cancer (HT 29). Experimental studies showed that IC's of compounds 5, 6, 30 and 39 on HCT116 cell line50(mu mol/L) is respectively 5.02, 8.13, 6.05 and 6.25 which are all smaller than the IC of the cis-platinum50(mu mol/L) ═ 8.74, and both were less than 10 mu mol/L, showing superior anticancer activity relative to cisplatin. The 4 compounds also show excellent anticancer activity and IC on HCT116 (human colorectal cancer) cell line50Respectively is 7.15 mu mol/L, 9.56 mu mol/L, 9.20 mu mol/L and 8.36 mu mol/L, and is less than the IC of positive control medicament cisplatin5012.78 mu mol/L, and all are less than 10.0 mu mol/L.
TABLE 2 cytotoxic Activity of the Compounds of the invention against human tumor cell lines
Figure BDA0001380504680000242
Figure BDA0001380504680000251
Note: IC in watch50The values are given in μmol/L.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (12)

  1. The 3-nitroquinoline derivative is characterized in that the structure of the compound is shown as the formula (I):
    Figure DEST_PATH_IMAGE001
    formula (I);
    in the formula (I), n is 0,1 or 2;
    m is 0,1 or 2;
    R1is a halogen atom or a hydrogen atom
    R2Is a halogen atom or a hydrogen atom;
    r is phenyl, halogenated phenyl or trifluoromethyl substituted phenyl;
    r' is phenyl, halogenated phenyl or trifluoromethyl substituted phenyl.
  2. The 3-nitroquinoline derivative is characterized in that the structure of the compound is shown as the formula (I):
    Figure 654080DEST_PATH_IMAGE002
    formula (I);
    in the formula (I), n is 1, m is 1,R1is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a 4-fluorophenyl group;
    n is 2, m is 2, R1Is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a 4-fluorophenyl group;
    n is 2, m is 2, R1Is methyl, R2Is a hydrogen atom, R is a 2-fluorophenyl group, R' is a 2-fluorophenyl group;
    n is 3, m is 3, R1Is methyl, R2Is a hydrogen atom, R is a methyl group, R' is a methyl group;
    n is 1, m is 0, R1Is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a phenyl group;
    n is 0, m is 1, R1Is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a phenyl group;
    n is 1, m is 0, R1Is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a phenyl group;
    n is 0, m is 1, R1Is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a 4-fluorophenyl group;
    n is 1, m is 1, R1Is a fluorine atom, R2Is hydrogen atom, R is 4-methoxy substituted phenyl, R' is 4-methoxy substituted phenyl;
    n is 1, m is 1, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-methoxy substituted phenyl, R' is 4-methoxy substituted phenyl;
    n is 1, m is 0, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-fluorophenyl, R' is 4-methyl substituted phenyl;
    n is 1, m is 0, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-phenyl, R' is 4-methyl substituted phenyl.
  3. 3. The method for preparing 3-nitroquinoline derivatives according to claim 1, comprising the steps of:
    performing addition cyclization and rearrangement reaction on an isatin compound shown as a formula (II) and a 1, 1-enediamine compound shown as a formula (III) in an aprotic solvent under the catalysis of organic acid, tracking by TLC (thin layer chromatography), and after the reaction is completed, purifying and drying reactants to obtain the 3-nitroquinoline derivative with the structure shown as the formula (I); the specific reaction formula is as follows:
    Figure DEST_PATH_IMAGE003
    in the formula (II), R1Is a halogen atom or a hydrogen atom; r2Is a halogen atom or a hydrogen atom;
    in the formula (III), n is 0,1 or 2; m is 0,1 or 2; r is phenyl, halogenated phenyl or trifluoromethyl substituted phenyl; r' is phenyl, halogenated phenyl or trifluoromethyl substituted phenyl.
  4. 4. The method for preparing 3-nitroquinoline derivatives according to claim 2, comprising the steps of:
    performing addition cyclization and rearrangement reaction on an isatin compound shown as a formula (II) and a 1, 1-enediamine compound shown as a formula (III) in an aprotic solvent under the catalysis of organic acid, tracking by TLC (thin layer chromatography), and after the reaction is completed, purifying and drying reactants to obtain the 3-nitroquinoline derivative with the structure shown as the formula (I); the specific reaction formula is as follows:
    Figure 367958DEST_PATH_IMAGE004
    wherein n is 1, m is 1, R1Is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a 4-fluorophenyl group;
    n is 2, m is 2, R1Is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a 4-fluorophenyl group;
    n is 2, m is 2, R1Is methyl, R2Is a hydrogen atom, R is a 2-fluorophenyl group, R' is a 2-fluorophenyl group;
    n is 3, m is 3, R1Is methyl, R2Is a hydrogen atom, R is a methyl group, R' is a methyl group;
    n is 1, m is 0,R1is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a phenyl group;
    n is 0, m is 1, R1Is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a phenyl group;
    n is 1, m is 0, R1Is methyl, R2Is a hydrogen atom, R is a 4-fluorophenyl group, R' is a phenyl group;
    n is 0, m is 1, R1Is methyl, R2Is a hydrogen atom, R is a phenyl group, R' is a 4-fluorophenyl group;
    n is 1, m is 1, R1Is a fluorine atom, R2Is hydrogen atom, R is 4-methoxy substituted phenyl, R' is 4-methoxy substituted phenyl;
    n is 1, m is 1, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-methoxy substituted phenyl, R' is 4-methoxy substituted phenyl;
    n is 1, m is 0, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-fluorophenyl, R' is 4-methyl substituted phenyl;
    n is 1, m is 0, R1Is a hydrogen atom, R2Is hydrogen atom, R is 4-phenyl, R' is 4-methyl substituted phenyl.
  5. 5. The method for preparing a 3-nitroquinoline derivative according to claim 3 or 4, wherein the molar ratio of the isatin-based compound represented by formula (II) to the 1, 1-enediamine-based compound represented by formula (III) is 1:1 to 2: 1; the volume ratio of the mol of the isatin compound shown in the formula (II) to the aprotic solvent is 1 mmol: 15-25 mL.
  6. 6. The preparation method of 3-nitroquinoline derivatives according to claim 3 or 4, wherein the reaction temperature is 25 ℃ to 120 ℃ and the reaction time is 2 to 16 hours.
  7. 7. The method for preparing 3-nitroquinoline derivatives according to claim 3 or 4, wherein the organic acid is acetic acid, trifluoroacetic acid, trichloroacetic acid or p-toluenesulfonic acid; the molar ratio of the organic acid to the isatin compound shown in the formula (II) is 4: 1-1: 1.
  8. 8. The method for preparing 3-nitroquinoline derivatives according to claim 3 or 4, wherein the aprotic solvent is toluene, xylene, acetonitrile or 1, 4-dioxane.
  9. 9. The method for preparing 3-nitroquinoline derivatives according to claim 3 or 4, wherein the drying is vacuum drying, natural drying or drying under an infrared lamp.
  10. 10. The process for preparing 3-nitroquinoline derivatives according to claim 3 or 4, wherein the purification step comprises extracting the reaction mixture with an organic solvent and a saturated saline solution, and the organic phase is treated with anhydrous Na2SO4Or anhydrous MgSO4Drying, concentrating the dried organic phase under reduced pressure to dryness, and separating by column chromatography to obtain pure 3-nitroquinoline derivatives shown in formula (I).
  11. 11. The method of claim 10, wherein the organic solvent used for extraction is ethyl acetate or dichloromethane;
    the eluent adopted by the column chromatography separation is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1-2: 1.
  12. 12. Use of 3-nitroquinoline derivatives according to claim 1 or 2 for the preparation of a medicament with antitumor activity.
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