CN106565585A - N-substituted benzal pyrrolidinedione and preparation method and application thereof - Google Patents

N-substituted benzal pyrrolidinedione and preparation method and application thereof Download PDF

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CN106565585A
CN106565585A CN201610893312.9A CN201610893312A CN106565585A CN 106565585 A CN106565585 A CN 106565585A CN 201610893312 A CN201610893312 A CN 201610893312A CN 106565585 A CN106565585 A CN 106565585A
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arh
benzal
replaces
pyrrolidine
compound
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金毅
林军
张继虹
肖传凡
蒋昆明
朱黎
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Yunnan University YNU
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/04—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups one >CH- group, e.g. cyanines, isocyanines, pseudocyanines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses an N-substituted benzal pyrrolidinedione compound and a preparation method and application thereof. The N-substituted benzal pyrrolidinedione compound has very high tumor cell growth inhibition activity and particularly has a remarkable inhibition effect on growth of vascular endothelial growth factor receptor subtype 2 (VEGFR-2) high-expression human colon cancer cells (HCT116), the IC50 value of the N-substituted benzal pyrrolidinedione compound can reach 5.93 micromoles, and the N-substituted benzal pyrrolidinedione compound has an obvious inhibition effect on new vessel generation of chick embryos.

Description

A kind of N- replaces benzal pyrrolidine-diones and its production and use
Technical field
The present invention relates to drug world, and in particular to N- replaces benzal pyrrolidine-diones class compound, synthesis and its presses down The purposes of vascular endothelial growth factor receptor (VEGFR-2) processed.
Background technology
Tumor be body in the presence of various carcinogenic factor, some cell of local organization is on gene level Lose its normal regulation to growth itself, the abnormality that result in its clonal abnormality hypertrophy and formed.Malignant tumor Become the big killer for threatening human health, the mortality rate for causing is only second to cardiovascular and cerebrovascular disease.
Cancer of late stage tumor cell can be shifted, and this is the one of the main reasons of Cancer death.It is now recognized that tumor is thin Dysuria with lower abdominal colic is moved mainly from following three kinds of forms：First, tumor cell immersion blood vessel forms metastasis；Second, followed by lymph Loop systems, and then form metastasis into lympho-hematological blood circulation；3rd, directly come off from tumor parent, into peripheral group Knit.
The growth of tumor is divided into two periods, and one is avascular slow trophophase, and two is the fast breeding phase for having blood vessel, Generating for blood vessel can provide sufficient nutrient supply for the growth of tumor, if the generation without blood vessel, parent tumor is general Less than 1-2mm, once tumor cell generates blood vessel, will there is the transfer of tumor cell.That is the growth of tumor is not from The stimulation and release of the newborn and various somatomedin of blood vessel are opened, thus suppresses tumor neogenetic blood vessels to be likely to become treatment tumor A kind of effective ways.VEGF (VEGF) and its receptor vascular endothelial growth factor receptor (VEGFR) are in tumor Blood vessel plays an important role with generation hypertrophy in lymphatic vessel.And VEGFR-2 is to cause mitosiss, angiogenesis and VEGF permeate Property increase topmost transmitter.The high expression of VEGF and the formation of entity tumor and its close phase of transfer Close, VEGF with the specific receptor on endothelial cellular membrane by being combined come activation signal conduction.Research has confirmed VEGFR-2 has high expression in tumor vascular endothelial cell, and in health into the very low not even table of expression in the person Reach, vascular endothelial cell proliferation, migration can be promoted and increase capillary permeability.The mitosiss of tumor vascular endothelial cell Mainly occur by the interaction of VEGF and VEGFR-2 with the permeability of tumor-microvessel.Therefore, VEGF with The downstream signaling pathway of VEGFR and its correlation can be used as the target spot of antitumor drug effect.
Nearly ten years, the exploitation of this series antineoplastic medicament has become a focus of new drug development, therein to represent medicine Bevacizumab (bevacizumab, trade name：Avastin) obtained U.S. FDA in 2004 to ratify, for transitivity colon cancer The first-line treatment of patient.At present, in the suppression for having more than 40 compound, finding novel chemical structure of research of clinical phase The lead compound of VEGFR-2-TKI is the heat subject of current world Ge great drugmakers and scientific research institutions, especially with The research of pyrrolidine-diones class compound is the most deep.We are calculated by molecular model, and design has synthesized N- and replaced Asia Benzyl-pyrrole alkane diketone, by optimizing substituent structure, it would be desirable to by the specific life for disturbing or directly acting on tumor cell Thing process finds selectivity relatively strong, the anti-tumor small molecular medicine of high-efficiency low-toxicity.
The content of the invention
For the deficiencies in the prior art, the technical scheme is that one class of offer has and suppress VEGF The N- of receptor signal conduction replaces benzal pyrrolidine-diones noval chemical compound as well as preparation method and application thereof.
To realize object above, the present invention is achieved by the following technical programs：
Class N- that the present invention is provided replaces benzal pyrrolidine-diones compound, with following structure I：
Preferably, the R1For C1-C6Straight chained alkyl, C3-C7Cycloalkyl, C1-C6Alkylthio group, C1-C6Alkoxyl, halogen, C6-C10Aryl, C4-C10Heteroaryl, substituted C6-C10Aryl replaces C4-C8Heteroaryl；Described C6-C10Aryl or C4-C10 Heteroaryl is by one or more following substituent groups：Straight chained alkyl, halogen ,-CN ,-CF3、-NO2、-CO2R1、-C(O)NR1R1’、- OR1、-SR1, wherein, R1And R1' be：H、C6-C14The C of aryl or at most perhalogeno1-C10Alkyl.
Preferably, the R2For C1-C6Straight chained alkyl, C3-C7Cycloalkyl, C1-C6Alkylthio group, C1-C6It is alkoxyl, halogen, each Plant aminoacid, C6-C10Aryl, C4-C10Heteroaryl, substituted C6-C10Aryl replaces C4-C8Heteroaryl；Described C6-C10Virtue Base or C4-C10Heteroaryl is by one or more following substituent groups：Straight chained alkyl, halogen ,-CN ,-CF3、CHF2、-NO2、- CO2R1、-C(O)NR1R1’、-OR1、-SR1, wherein, R1And R1' be：H、C6-C14The C of aryl or at most perhalogeno1-C10Alkyl.
Preferably, it is the one kind in following 77 that the N- replaces benzal pyrrolidine-diones compound.
A kind of N- replaces the preparation method of benzal pyrrolidine-diones, comprises the following steps:
(1) maleic anhydride is dissolved in organic solvent 1, is stirred under ice bath, after maleic anhydride is completely dissolved, Primary amine is dissolved in organic solvent 1, in being slowly added to reaction, yellow solid is separated out, continues to stir 1h, ice bath cooling is filtered, washed Only, N- substituted-phenyl maleamic acids are obtained；
(2) maleamic acid is dissolved in acetic anhydride, adds triethylamine, 55-65 DEG C of oil bath heating to stir 1h, cool down, plus Enter equal-volume deionized water, stand overnight, separate out yellow solid, filter, clean, obtain N- substituted-phenyl maleimides；
(3) by N- substituted maleimides amine solvent in organic solvent 2, stirring treats that N- substituted maleimide amine is completely molten Xie Hou, adds additive, reacts 4-5 minutes, is rapidly added 3- carboxyl benzaldehydes, and stirring at normal temperature 6h separates out white solid, mistake Filter, washing, obtains product Intermediate 5；
(4) intermediate and condensing agent are dissolved in organic solvent 3, add DIEA, stir 30min, be slowly added to amine or The DCM solution of amino-acid ester, is stirred at room temperature 4～10 hours, uses dilute hydrochloric acid, aqueous slkali washing reaction liquid after reaction completely successively, Anhydrous sodium sulfate drying, column chromatography for separation or recrystallization is used to obtain target product again.
Preferably, in the step (1) organic solvent 1 be methanol, ethyl acetate, acetic anhydride, acetone, dichloromethane, N, The mixing of dinethylformamide or dimethyl sulfoxide and its both the above or multi-solvents.
Preferably, in the step (3) organic solvent 2 be methanol, ethanol, dichloromethane, chloroform, N, N- dimethyl formyls The mixing of amine, dimethyl sulfoxide or multi-solvents.
Preferably, additive is the one kind in triphenylphosphine, sodium acetate, potassium acetate in the step (3).
Preferably, organic solvent 3 is methanol, ethanol, ethyl acetate, acetonitrile, ether, tetrahydrochysene in the step (4) In furan, acetone, benzene, toluene, dichloromethane, chloroform, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide One or more mixture.
Preferably, the alkali is triethylamine, DIPEA, ethylenediamine, sodium hydroxide, Lithium hydrate, ethanol One or more mixture in sodium, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium tert-butoxide or sodium tert-butoxide.
The present invention also provides the purposes that a kind of N- replaces benzal pyrrolidine-diones as the inhibitor of VEGFR-2, especially It is that tumor described in its purposes in antitumor drug is prepared is included but is not limited to：Colon cancer, duodenal carcinoma, prostate Cancer, breast carcinoma, melanoma, duct carcinoma, hepatocarcinoma, cancer of pancreas, renal carcinoma, carcinoma of endometrium, gastric cancer, nonsmall-cell lung cancer, nerve are disliked Property tumor and hematologic malignancies.
Beneficial effects of the present invention：It is very high that the N- that the present invention is provided replaces benzal pyrrolidine-diones compound to show Suppress tumor cell growth activity, with the effect for significantly suppressing VEGFR-2 and anti-tumor activity.
Description of the drawings
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing The accompanying drawing to be used needed for having technology description is briefly described, it should be apparent that, drawings in the following description are only this Some embodiments of invention, for those of ordinary skill in the art, on the premise of not paying creative work, can be with Other accompanying drawings are obtained according to these accompanying drawings.
Fig. 1：Embryo Gallus domesticus the selection result figure, wherein a is physiological saline group；B is Sutent；C is compound 6；D is compound 7；E is compound 11；F is compound 12；G is compound 15；H is compound 19；I is compound 22；J is compound 28；K is Compound 31；L is compound 32；M is compound 33；N is compound 35；O is compound 41；P is compound 43；Q is chemical combination Thing 44；R is compound 46；S is compound 51.
Specific embodiment
To make purpose, technical scheme and the advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention, Technical scheme in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is the present invention one Divide embodiment, rather than the embodiment of whole.Based on the embodiment in the present invention, those of ordinary skill in the art are not making The every other embodiment obtained under the premise of creative work, belongs to the scope of protection of the invention.
Shown in the following reaction equation of synthesis of formula I：
Embodiment 1
(1) maleic anhydride 0.05mol is dissolved in 0.2mol ethyl acetate, is stirred under ice bath, treat maleic acid After acid anhydride is completely dissolved, 0.05mol substituted anilines are dissolved in into 0.2mol ethyl acetate solutions, in being slowly added to reaction, separate out yellow Solid, continues to stir 1h, and ice bath cooling is filtered, cleaned, and obtains N- substituted-phenyl maleamic acids；
(2) 0.05mol maleamic acids are dissolved in 0.2mol acetic anhydrides, add 0.025mol triethylamines, 55-65 DEG C of oil bath Heated and stirred 1h, cooling adds equal-volume deionized water, stands overnight, and separates out yellow solid, filters, and cleans, and obtains N- replacements Phenyl maleimide；
(3) by 0.014molN- substituted maleimides amine solvent in 40mL dehydrated alcohol, stirring treats that N- replaces maleoyl After imines is completely dissolved, 0.012mol triphenylphosphines are added, react 4-5 minutes, be rapidly added the 3- carboxyl benzene for adding 0.01mol Formaldehyde, stirring at normal temperature 6h separates out white solid, filters, and washing obtains product Intermediate；
(4) 0.5mmol intermediate and 0.6mmol TBTU, 0.6mmol EDCI are dissolved in 2mL DCM mixed solvents, 0.75mmol DIEA are added, 30min is stirred, DCM (8mL) solution of 0.5mmol amine or amino acid methyl ester, room is slowly added to Temperature 4～10h of stirring, TLC monitoring reaction, uses successively dilute hydrochloric acid, saturated sodium bicarbonate solution washing reaction liquid after reaction completely, then With anhydrous sodium sulfate drying, column chromatography for separation or recrystallization obtain compound 1.
Yellow solid；M.p.235-236℃；1H NMR(500MHz,DMSO-d6):δ=3.97-3.97 (d, J=1.6, 2H,CH2), 7.21-7.24 (t, J=8.8,2H, ArH), 7.39-7.40 (d, J=7.7,2H, ArH), 7.44-7.47 (t, J= 7.3,1H, ArH), 7.52-7.56 (t, J=12.3,2H, ArH), 7.65-7.69 (q, J=5.1, J=7.9,2H, ArH), 7.82-7.85 (q, J=5.1, J=5.05,2H, ArH), 7.93-7.94 (d, J=7.65,1H, ArH), 8.02-8.03 (d, J =7.7,1H, ArH), 8.22 (s, 1H ,=CH-),10.43(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ= 34.44,115.52,115.69,122.68,122.74,126.77,127.47,128.64,129.19,129.34,129.62, 129.69,132.23,133.29,134.63,135.76,135.99,157.85,159.76,165.32,170.17,173.72； HRMS(TOF ES+):m/z calcd for C24H17FN2O3[(M+Na)+],423.1115；found,423.1115.
1st, anticancer experiment in vitro：
The positive reference compound for adopting is for cisplatin.
Experimental procedure：
(1) cell is inoculated in 96 orifice plates, and overnight incubation adds sample (T), while being not added with sample controls (C) and dosing Front control (T0), (T is compareed before dosing0) cell add TCA be fixed, indwelling is stand-by；Add sample (T) and be not added with sample The cell of control (C) continues to be fixed again after cultivating 48 hours；
(2) all cells for fixing are with the dyeing of SRB dye liquors, then wash away free dyestuff with acetum, are air-dried 490nM determines OD values after adding Tris alkali, vibration dissolving to mix afterwards.
It is positive reference chemical combination that thing is adopted for cisplatin.
If T >=T0, rate of growth=(T-T0)/(C-T0) × 100%；
If T is ＜ T0, rate of growth=(T-T0)/T0×100。
Each sample list concentration sets duplicate hole during primary dcreening operation, is repeated twice, sample determination of the growth inhibition ratio more than 50% IC50 values, each sample gradient dilutes five concentration during measure, and each concentration sets duplicate hole.
Anti- HCT116, A549 cytotoxic activity (IC50) of the cell in vitro level of table 1
Pharmacological Results show that it is the highly active tumour growth suppression of a class that this kind of N- replaces benzal pyrrolidine-diones compound Preparation, the activity with very strong suppression HCT116, A549 growth of tumour cell, especially shows non-to HCT116 tumor cells Often high selectivity.
2nd, chick embryo method screening anti-angiogenic compounds
Experimental procedure:
(1) hatching egg incubation：Egg support is placed in 1 in ultraviolet lower sterilization 30min, hatching egg warm water cleaning:1000 bromo geramines are molten Liquid soaking disinfection 30min, dries and is put into egg support.Incubator is powered and is preheated, keep the temperature at 37.8 ± 5 DEG C, hatching egg is incubated Educate in incubator, humidity is 40%～60% in holding case.Hatching egg blunt end is upwards in 45 ° of inclinations, early, middle and late each unpacking door Turning egg(s), prevents embryo's adhesion.
(2) Embryo Gallus domesticus inspection：It is incubated and removes within the 3rd day clear egg, does not develop egg and dead germ, yolk rupture embryo.
(3) suppression of the inhibitor to Embryo Gallus domesticus angiogenesis：0.45 μm of cellulose acetate membrane is made with card punch a diameter of The sequin of 0.3mm, sterilizing-drying after distilled water immersion.The Embryo Gallus domesticus of hatching 3d are placed in into observation under egg candler and determine embryo position Put, and mark.Egg is sterilized, and opening aperture is scratched at 0.5～1.0cm below embryo head, and cellulose acetate film is placed in into Embryo Gallus domesticus It is other.
(4) successively by normal saline, 10nmol/L Sorafenib solution, 10nmol/L Sutent solution, 10nmol/ LVEGFR-2 kinase inhibition agent solution and the compounds of this invention distinguish Deca on cellulose acetate film, use adhesive tape sealing label, Continue to hatch, after dosing 4d, tear adhesive tape, digital camera film recording result, as a result such as Fig. 1.
Control experiment：Using normal saline as negative control, its anti-blood is tested and recorded to Sutent as positive control Pipe generates activity.
From result figure, the compounds of this invention has and preferably suppress angiogenic activity.
Embryo Gallus domesticus experiment shows that generation of these compounds to the new vesselses of Embryo Gallus domesticus has obvious inhibition, this kind of N- Replace the tumor growth inhibitors that benzal pyrrolidine-diones compound is the highly active new construction of a class.
Embodiment 2
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- benzene carbon amides (compound 2)
Yellow solid；M.p.231-232℃；1H NMR(500MHz,DMSO-d6):δ=3.97-3.98 (d, J=1.6, 2H,CH2), 7.13-7.15 (t, J=7.3,1H, ArH), 7.38-7.40 (t, J=8.25,4H, ArH), 7.44-7.47 (t, J =7.5,1H, ArH), 7.52-7.56 (t, J=7.85,2H, ArH), 7.66-7.69 (t, J=8,2H, ArH), 7.82-7.83 (d, J=7.75,2H, ArH), 7.93-7.94 (d, J=7.75,1H, ArH), 8.02-8.04 (d, J=7.7,1H, ArH), 8.23 (s, 1H ,=CH-),10.38(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=34.45,120.83, 124.23,126.76,127.50,128.66,129.05,129.21,129.40,129.62,129.75,132.24,132.95, 133.28,134.61,136.16,139.42,165.41,170.22,173.76；HRMS(TOF ES+):m/z calcd for C24H18N2O3[(M+Na)+],405.1209；found,405.1211.
Embodiment 3
N- normal-butyl -3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl) Benzoylamide (compound 3)
Yellow solid；M.p.169-170℃；1H NMR(500MHz,DMSO-d6):δ=0.91-0.92 (d, J=7.35, 2H,CH3), 1.34-1.37 (q, J=7.3, J=7.4,2H, CH2), 1.52-1.56 (q, J=6.55, J=6.65,2H, CH2), 3.94(s,2H,CH2), 7.38-7.40 (d, J=7.7,2H, ArH), 7.44-7.47 (t, J=7.35,1H, ArH), 7.52- 7.55 (t, J=7.6,1H, ArH), 7.58-7.61 (t, J=7.7,2H, ArH), 7.84-7.86 (d, J=7.65,1H, ArH), 7.91-7.92 (d, J=7.7,1H, ArH), 8.09 (s, 1H ,=CH-),8.56(s,1H,NH)；13C NMR(125MHz,DMSO- d6):δ=14.11,20.07,31.62,34.44,39.72,126.53,127.48,128.64,128.9 8,129.19, 129.49,132.31,132.95,134.47,135.82,165.89,170.21,173.78；HRMS(TOF ES+):m/z calcd for C22H22N2O3[(M+Na)+],385.1522；found,385.1522.
Embodiment 4
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N-p- toluene yl-benzamides (compound 4)
Yellow solid；M.p.231-232℃；1H NMR(500MHz,DMSO-d6):δ=2.30 (s, 3H ,-CH3),3.97- 3.98 (d, J=1.7,2H, CH2), 7.18-7.20 (d, J=8.25,2H, ArH), 7.39-7.40 (J=7.5,2H, ArH), 7.44-7.47 (t, J=7.3,1H, ArH), 7.52-7.56 (t, J=7.65,2H, ArH), 7.66-7.70 (t, J=8.65, 4H, ArH), 7.91-7.93 (d, J=7.75,1H, ArH), 8.01-8.02 (d, J=7.7,1H, ArH), 8.21 (s, 1H ,= CH-),10.29(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=20.89,34.44,120.85,126.72, 127.49,128.66,129.21,129.36,129.60,129.68,132.24,132.94,133.21,134.57,136.20, 136.87,165.17,170.22,173.77；HRMS(TOF ES+):m/z calcd for C25H20N2O3[(M+Na)+], 419.1366；found,419.1366.
Embodiment 5
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (4- methoxyphenyls) Benzoylamide (chemical combination Thing 5)
Yellow solid；M.p.231-232℃；1H NMR(500MHz,DMSO-d6):δ=3.68 (s, 3H ,-OCH3),
3.88(s,2H,CH2), 6.87-6.89 (d, J=8.8,2H, ArH), 7.30-7.32 (d, J=8.8,2H, ArH), 7.37-7.38 (d, J=7.05,1H, ArH), 7.44-7.46 (t, J=7.55,2H, ArH), 7.56 (s, 2H, ArH), 7.62- 7.64 (d, J=8.7,2H, ArH), 7.82-7.84 (d, J=7.6,1H, ArH), 7.93-7.94 (d, J=7.6,1H, ArH), 8.13 (s, 1H ,=CH-),10.16(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=24.96,34.95,56.06, 114.66,122.96,127.18,127.99,129.18,129.70,129.81,130.09,132.76,132.94,133.44, 133.65,135.07,136.69,156.56,165.43,170.71,174.27；HRMS(TOF ES+):m/z calcd for C25H20N2O4[(M+Na)+],435.1315；found,435.1317.
Embodiment 6
N- benzyl -3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl) Benzoylamide (compound 10)
Yellow solid；M.p.231-232℃；1H NMR(500MHz,DMSO-d6):δ=3.95-3.96 (d, J=2,2H, CH2), 4.56-4.56 (d, J=5.9,2H, CH2), 7.25-7.40 (m, 8H, ArH), 7.43-7.46 (t, J=7.3,1H, ), ArH 7.52-7.55 (t, J=7.85,2H, ArH), 7.59-7.64 (t, J=8.15,2H, ArH), 7.88-7.89 (d, J= 7.8,1H, ArH), 7.99-8.00 (d, J=7.7,1H, ArH), 8.17 (s, 1H ,=CH-), 9.18-9.21 (t, J=5.9, 1H,NH)；13C NMR(125MHz,DMSO-d6):δ=34.46,43.12,126.65,127.18,127.49,127.61, 128.70,129.00,129.13,129.61,132.27,132.95,133.28,134.59,135.47,139.89,166.07, 170.20,173.78；HRMS(TOF ES+):m/z calcd for C25H20N2O3[(M+Na)+],419.1366；found, 419.1363.
Embodiment 7
N- (4- chlorphenyls) -3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl) Benzoylamide (compound 12)
Yellow solid；M.p.233-234℃；1H NMR(500MHz,DMSO-d6):δ=3.7-3.98 (d, J=1.95, 2H,CH2), 7.39-7.40 (d, J=7.55,2H, ArH), 7.50-7.45 (t, J=7.5,3H, ArH), 7.52-7.55 (t, J =7.85,2H, ArH), 7.66-7.69 (m, 2H, ArH), 7.84-7.86 (m, 2H, ArH), 7.93-7.94 (d, J=7.75, 1H, ArH), 8.01-8.02 (d, J=7.5,1H, ArH), 8.21 (s, 1H ,=CH-),10.49(s,1H,NH)；13C NMR (125MHz,DMSO-d6):δ=34.44,122.31,126.82,127.48,127.85,128.66,128.96,129.21, 129.39,129.65,129.77,132.16,132.94,133.39,134.64,135.89,138.39,165.52,170.19, 173.74；HRMS(TOF ES+):m/z calcd for C24H17ClN2O3[(M+Na)+],439.0819；found, 439.0817.
Embodiment 8
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (3- fluorophenyls) Benzoylamide (compound 13)
Yellow solid；M.p.224-225℃；1H NMR(500MHz,DMSO-d6):δ=3.89 (s, 2H, CH2),6.86- 6.89 (m, 2H, ArH), 7.30-7.61 (m, 9H, ArH), 7.71-7.74 (d, J=11.7,1H, ArH), 7.85-7.86 (d, J =7.65,1H, ArH), 7.93-7.95 (d, J=7.7,1H, ArH), 8.14 (s, 1H ,=CH-),10.51(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=34.44,107.34,107.55,110.55,110.72,116.45,126.83, 127.48,128.65,129.20,129.41,129.64,129.81,130.60,130.67,132.16,132.94,133.46, 134.64,135.81,141.18,141.26,161.50,163.42,165.70,170.18,173.73；HRMS(TOF ES+): m/z calcd for C24H17FN2O3[(M+Na)+],423.1115；found,423.1116.
Embodiment 9
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N-m- toluene yl-benzamides (compound 14)
Yellow solid；M.p.225-226℃；1H NMR(500MHz,DMSO-d6):δ=2.34 (s, 3H, CH3),3.98 (s,2H,CH2), 6.95-6.97 (d, J=7.45,1H, ArH), 7.25-7.68 (m, 10H, ArH), 7.92-7.93 (d, J= 7.7,1H, ArH), 8.02-8.03 (d, J=7.75,1H, ArH), 8.22 (s, 1H ,=CH-),10.29(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=21.58,34.44,118.02,121.37,124.93,126.73,127.49,128.88, 129.21,129.37,129.61,129.69,132.24,132.95,133.26,134.59,136.16,138.21,139.33, 165.31,170.21,173.75；HRMS(TOF ES+):m/z calcd for C25H20N2O3[(M+Na)+],419.1366； found,419.1364.
Embodiment 10
N- (3,4- 3,5-dimethylphenyls) -3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl) Benzoylamide (is changed Compound 15)
Yellow solid；M.p.224-225℃；1H NMR(500MHz,DMSO-d6):δ=2.21 (s, 3H, CH3),2.24 (s,3H,CH3),3.97(s,2H,CH2), 7.13-7.14 (d, J=5.9,1H, ArH), 7.39-7.68 (m, 9H, ArH), 7.91- 7.92 (d, J=7.6,1H, ArH), 8.01-8.03 (d, J=7.75,1H, ArH), 8.21 (s, 1H ,=CH-),10.21(s, 1H,NH)；13C NMR(125MHz,DMSO-d6):δ=19.21,20.01,34.43,118.40,122.09,126.68, 127.48,128.65,129.20,129.34,129.58,129.64,132.02,132.27,132.95,133.17,134.56, 136.19,136.60,137.09,165.05,170.20,173.75；HRMS(TOF ES+):m/z calcd for C26H22N2O3[(M+Na)+],433.1522；found,433.1520.
Embodiment 11
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (4- ethoxybenzenes) Benzoylamide (compound 16)
Yellow solid；M.p.195-196℃；1H NMR(500MHz,DMSO-d6):δ=1.32-1.35 (t, J=7,3H, CH3),3.97(s,2H,CH2), 4.01-4.06 (q, J=6.85J=7,2H, CH2), 6.94-6.95 (d, J=8.9,2H, ArH), 7.39-7.71 (m, 9H, ArH), 7.91-7.92 (d, J=7.7,1H, ArH), 8.01-8.02 (d, J=7.7,1H, ), ArH 8.21 (s, 1H ,=CH-),10.24(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=15.07,34.44, 63.49,114.68,122.46,126.68,127.49,128.65,129.20,129.30,129.60,132.28,132.33, 132.94,133.15,134.57,136.22,155.34,164.93,170.21,173.77；HRMS(TOF ES+):m/z calcd for C26H22N2O4[(M+Na)+],449.1471；found,449.1474.
Embodiment 12
(N- (4- (difluoro-methoxy) phenyl) -3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl) benzoyl Amine (compound 20)
Yellow solid；M.p.213-214℃；1H NMR(500MHz,DMSO-d6):δ=3.97 (s, 2H, CH2),7.21- 7.69(m,11H,-CHF2, ArH), 7.84-7.86 (d, J=8.85,2H, ArH), 7.93-7.95 (d, J=7.7,1H, ArH), 8.02-8.04 (d, J=7.75,1H, ArH), 8.22 (s, 1H ,=CH-),10.45(s,1H,NH)；13C NMR(125MHz, DMSO-d6):δ=34.44,114.82,116.87,118.92,119.75,122.26,126.80,127.49,1 28.67, 128.84,129.21,129.36,129.65,129.74,132.19,133.34,134.64,135.94,136.68,147.14, 165.38,170.20,173.76；HRMS(TOF ES+):m/z calcd for C25H18F2N2O4[(M+Na)+],471.1126； found,471.1124.
Embodiment 13
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (4- methoxyl group -2- aminomethyl phenyls) benzoyl Amine (compound 21)
Yellow solid；M.p.238-239℃；1H NMR(500MHz,DMSO-d6):δ=2.25 (s, 3H, CH3),3.77 (s,3H,-OCH3),3.98(s,2H,CH2), 6.80-6.82 (m, 1H, ArH), 6.88 (s, 1H, ArH), 7.24-7.26 (d, J= 8.65,1H, ArH), 7.38-7.67 (m, 7H, ArH), 7.91-7.92 (d, J=9.7,1H, ArH), 8.03-8.05 (d, J= 7.7,1H, ArH), 8.23 (s, 1H ,=CH-),9.92(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=18.50, 34.47,55.54,111.69,115.6,126.73,127.51,128.42,128.66,129.21,129.42,129.67, 132.25,132.95,133.52,134.65,135.74,135.93,157.80,165.25,170.24,173.82；HRMS (TOF ES+):m/z calcd for C26H22N2O4[(M+Na)+],449.1471；found,449.1467.
Embodiment 14
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (4- ethylphenyls) Benzoylamide (compound 22)
Yellow solid；M.p.212-213℃；1H NMR(500MHz,DMSO-d6):δ=1.17-1.21 (t, J=7.4, 3H,CH3), 2.58-2.62 (q, J=7.55, J=7.6,2H, CH2),3.97(s,2H,CH2), 7.21-7.23 (d, J=8.3, 2H, ArH), 7.39-7.72 (m, 9H, ArH), 7.92-7.93 (d, J=7.85,1H, ArH), 8.01-8.03 (d, J=7.8, 1H, ArH), 8.23 (s, 1H ,=CH-),10.30(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=16.06, 28.04,34.44,120.94,126.72,127.48,128.23,128.65,129.20,129.35,129.69,132.26, 132.94,133.18,134.58,136.19,137.07,139.69,165.18,170.20,173.75；HRMS(TOF ES+): m/z calcd for C26H22N2O3[(M+Na)+],433.1522；found,433.1518.
Embodiment 15
3- ((2,5- dioxy -1- phenylpyrrole quinoline -3- subunits) methyl)-N- (3- ethylphenyls) Benzoylamide (compound 24)
Yellow solid；M.p.201-202℃；1H NMR(500MHz,DMSO-d6):δ=1.17-1.27 (m, 3H, CH3), 2.60-2.64(m,2H,CH2),3.97(s,2H,CH2), 6.98-6.70 (d, J=6.5,1H, ArH), 7.23-7.68 (m, 10H, ArH), 7.91-7.93 (d, J=7.75,1H, ArH), 8.01-8.03 (d, J=7.75,1H, ArH), 8.22 (s, 1H ,= CH-),10.30(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=15.94,28.70,34.45,118.27, 120.19,123.75,126.73,127.50,128.66,12.94,129.21,129.38,129.61,129.71,132.24, 132.94,133.27,134.58,136.17,139.41,144.60,165.30,170.22,173.78；HRMS(TOF ES+): m/z calcd for C26H22N2O3[(M+Na)+],433.1522；found,433.1519.
Embodiment 16
N- normal-butyl -3- ((1- (3- fluorophenyls) -2,5- dioxypyrrole quinoline -3- subunits) methyl) Benzoylamide (compound 25)
Yellow solid；M.p.161-162℃；1H NMR(500MHz,DMSO-d6):δ=0.90-0.93 (t, J=7.35, 3H,CH3),1.31-1.39(m,2H,CH2),1.50-1.57(m,2H,CH2),3.27-3.32(m,2H,CH2),3.93(s,2H, CH2), 7.26-7.33 (m, 4H, ArH), 7.55-7.61 (m, 4H, ArH), 7.84-7.86 (d, J=7.65,1H, ArH), 7.90-7.92 (d, J=7.65,1H, ArH), 8.08 (s, 1H ,=CH-), 8.55-5.58 (t, J=5.4,1H, NH)；13C NMR (125MHz,DMSO-d6):δ=14.11,20.08,31.63,34.46,39.73,114.62,114.81,115.50, 115.60,123.69,126.28,129.03,129.07,129.51,130.79,130.85,132.61,133.02,134.38, 135.84,161.16,163.09,165.87,169.90,173.50；HRMS(TOF ES+):m/z calcd for C22H21FN2O3[(M+Na)+],403.1428；found,403.1429.
Embodiment 17
3- ((1- benzyl -2,5- dioxypyrrole quinoline -3- subunits) methyl)-N- (3- ethylphenyls) Benzoylamide (compound 28)
Yellow solid；M.p.178-179℃；1HNMR(500MHz,DMSO-d6):δ=1.15-1.22 (m, 3H, CH3), 2.59-2.64 (q, J=7.5, J=7.55,2H, CH2),3.90(s,2H,CH2),4.71(s,2H,CH2),6.96-6.98(d,J =7.45,1H, ArH), 7.25-7.36 (m, 6H, ArH), 7.59-7.66 (m, 4H, ArH), 7.86-7.88 (d, J=7.7,1H, ), ArH 7.99-8.01 (d, J=7.5,1H, ArH), 8.18 (s, 1H ,=CH-),10.27(s,1H,NH)；13CNMR(125MHz, DMSO-d6):δ=15.92,28.69,34.14,41.96,118.25,120.17,123.73,126.60,127. 83, 127.93,128.89,129.32,129.53,132.02,133.18,134.54,136.11,136.63,139.40,144.58, 165.27,170.75,174.48；HRMS(TOF ES+):m/z calcd for C27H24N2O3[(M+Na)+],447.1679, found,403.47.1680.
Embodiment 18
3- ((1- butyl -2,5- dioxypyrrole quinoline -3- subunits) methyl)-N- (3- ethylphenyls) Benzoylamide (compound 29)
Yellow solid；M.p.168-169℃；1H NMR(500MHz,DMSO-d6):δ=0.87-0.90 (t, J=7.3, 3H,CH3), 1.18-1.22 (t, J=9.55,3H, CH3),1.24-1.32(m,2H,CH2),1.49-1.56(m,2H,CH2), 2.59-2.64 (q, J=7.6, J=7.6,2H, CH2), 3.48-3.52 (t, J=7.15,2H, CH2),3.81(s,2H,CH2), 6.96-6.98 (d, J=7.5,1H, ArH), 7.25-7.28 (t, J=7.05,1H, ArH), 7.55 (s, 1H, ArH), 7.61- 7.65 (m, 3H, ArH), 7.84-7.86 (d, J=7.75,1H, ArH), 7.97-7.99 (d, J=7.75,1H, ArH), 8.16 (s, 1H ,=CH-),10.25(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=13.87,15.91,19.89, 28.68,29.74,33.99,38.19,118.22,120.14,123.70,126.71,128.90,129.22,129.50, 129.57,131.47,133.14,134.58,136.06,139.40,144.56,165.26,170.92,174.60；HRMS (TOF ES+):m/z calcd for C24H26N2O3[(M+Na)+],413.1835；found,413.1842.
Embodiment 19
3- ((1- butyl -2,5- dioxypyrrole quinoline -3- subunits) methyl)-N- (4- chlorphenyls) Benzoylamide (compound 31)
Yellow solid；M.p.233-234℃；1H NMR(500MHz,DMSO-d6):δ=0.87-0.90 (t, J=7.3, 3H,CH3),1.23-1.31(m,2H,CH2),1.49-1.55(m,2H,CH2), 3.48-3.51 (t, J=7.15,2H, CH2), 3.80(s,2H,CH2), 7.41-7.43 (d, J=8.75,2H, ArH), 7.54 (s, 1H, ArH), 7.61-7.64 (t, J= 7.75,1H, ArH), 7.81-7.87 (m, 3H, ArH), 7.96-7.98 (d, J=7.75,1H, ArH), 8.14 (s, 1H ,= CH-),10.45(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=13.87,19.88,29.74,33.99,38.20, 122.24,126.79,127.80,128.93,129.23,129.55,129.66,131.39,133.28,134.63,135.80, 138.39,165.48,170.91,174.59；HRMS(TOF ES+):m/z calcd for C25H19ClN2O3[(M+K)+], 469.0715；found,469.0715.
Embodiment 20
3- ((2,5- dioxy -1-p- tolyl pyrrolin -3- subunits) methyl)-N- (3- fluorophenyls) Benzoylamide (chemical combination Thing 33)
Yellow solid；M.p.214-215℃；1H NMR(500MHz,DMSO-d6):δ=2.36 (s, 3H, CH3),3.95 (s,2H,CH2), 7.24-7.34 (m, 7H, ArH), 7.64-7.68 (m, 3H, ArH), 7.92-7.94 (d, J=7.6,1H, ), ArH 8.03-8.05 (d, J=7.5,1H, ArH), 8.23 (s, 1H ,=CH-),10.26(s,1H,NH)；13C NMR (125MHz,DMSO-d6):δ=21.13,34.41,116.16,116.32,124.72,125.92,126.01,126.89, 127.25,127.54,129.51,129.68,130.32,132.01,133.78,134.70,135.07,138.17,155.18, 157.14,165.31,157.14,170.28,173.84；HRMS(TOF ES+):m/z calcd for C22H21ClN2O3[(M+ Na)+],419.1132；found,419.1133.
Embodiment 21
N- (4- chlorphenyls) -3- ((2,5- dioxy -1-p- tolyl pyrrolin -3- subunits) methyl) Benzoylamide (chemical combination Thing 34)
Yellow solid；M.p.236-237℃；1H NMR(500MHz,DMSO-d6):δ=2.37 (s, 3H, CH3),3.95 (s,2H,CH2), 7.24-7.26 (d, J=8.15,2H, ArH), 7.31-7.33 (d, J=8.15,2H, ArH), 7.43-7.44 (d, J=8.8,2H, ArH), 7.63-7.67 (m, 2H, ArH), 7.91-7.93 (d, J=7.65,1H, ArH), 7.99-8.01 (d, J=7.75,1H, ArH), 8.20 (s, 1H ,=CH-),10.50(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ= 21.14,34.40,122.28,126.86,127.24,127.82,128.96,129.36,130.31,132.03,133.39, 134.65,135.88,138.17,138.40,165.52,170.26,173.81；HRMS(TOF ES+):m/z calcd for C23H24N2O3[(M+Na)+],399.1679；found,399.1676.
Embodiment 22
3- ((2,5- dioxy -1-p- tolyl pyrrolin -3- subunits) methyl)-N- (4- ethoxyl phenenyls) Benzoylamide (compound 35)
Yellow solid；M.p.238-239℃；1H NMR(500MHz,DMSO-d6):δ=1.31-1.37 (q, J=6.9, J =6.9,3H, CH3),3.94(s,2H,CH2), 3.98-4.03 (q, J=6.75, J=7.1,2H, CH2),6.92-6.94(d,J =8.65,2H, ArH), 7.24-7.26 (d, J=7.85,2H, ArH), 7.31-7.33 (d, J=8,2H, ArH), 7.63-7.69 (m, 4H, ArH), 7.89-7.90 (d, J=7.65,1H, ArH), 7.99-8.01 (d, J=7.65,1H, ArH), 8.20 (s, 1H, =CH-),10.25(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=15.08,21.14,34.41,39.39, 63.47,114.66,122.43,126.72,127.24,129.29,129.59,129.67,130.32,132.15,132.35, 133.15,134.58,136.21,138.16,155.32,164.92,170.29,173.84；HRMS(TOF ES+):m/z calcd for C25H19FN2O3[(M+Na)+],437.1271；found,437.1271.
Embodiment 23
3- ((2,5- dioxy -1-p- tolyl pyrrolin -3- subunits) methyl)-N- (3- ethylphenyls) Benzoylamide (is changed Compound 36)
Yellow solid；M.p.204-205℃；1H NMR(500MHz,DMSO-d6):δ=1.19-122 (t, J=7.45, 3H,CH3),2.37(s,3H,CH3), 2.59-2.64 (q, J=7.6, J=7.55,2H, CH2),3.95(s,2H,CH2),6.97- 6.99 (d, J=7.5,2H, ArH), 7.24-7.33 (m, 5H, ArH), 7.61-7.67 (m, 4H, ArH), 7.90-7.92 (d, J= 7.7,2H, ArH), 8.00-8.02 (d, J=7.7,1H, ArH), 8.20 (s, 1H ,=CH-),10.29(s,1H,NH)；13C NMR (125MHz,DMSO-d6):δ=15.93,21.14,28.68,34.41,118.26,120.18,123.75,126.79, 127.25,128.93,129.33,129.67,130.31,132.11,133.25,134.60,136.16,138.17,139.38, 144.59,165.30,170.29,173.83；HRMS(TOF ES+):m/z calcd for C25H19ClN2O3[(M+Na)+], 469.0715；found,469.0710.
Embodiment 24
3- ((1- (3,4- 3,5-dimethylphenyls) -2,5- dioxypyrrole quinoline -3- subunits) methyl)-N- (3- (methyl mercapto) phenyl) Benzoylamide (compound 61)
Yellow solid；M.p.201-202℃；1H NMR(500MHz,DMSO-d6):δ=2.26-2.27 (d, J=5.1, 6H,CH3),2.49(s,3H,-SCH3),3.94(s,2H,CH2), 7.01-7.03 (d, J=7.75,1H, ArH), 7.06-7.08 (d, J=7.9,1H, ArH), 7.13 (s, 1H, ArH), 7.26-7.33 (m, 2H, ArH), 7.59-7.68 (m, 3H, ArH), 7.78 (s, 1H, ArH), 7.91-7.93 (d, J=7.65,2H, ArH), 8.00-8.02 (d, J=7.65,1H, ArH), 8.20 (s, 1H, =CH-),10.38(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ=15.04,19.48,19.73,34.40, 117.18,117.77,121.54,124.78,126.83,128.20,129.34,129.58,129.76,130.09,130.49, 132.02,133.36,134.64,135.98,136.99,137.25,138.92,139.98,165.49,170.32,173.86； HRMS(TOF ES+):m/z calcd for C27H24N2O3S[(M+Na)+],479.1399；found,479.1399.
Embodiment 25
N- (3- ethylphenyls) -3- ((1- (4- iodophenyls) -2,5- dioxypyrrole quinoline -3- subunits) methyl) Benzoylamide (compound 65)
Yellow solid；M.p.201-202℃；1H NMR(500MHz,DMSO-d6):δ=1.15-1.22 (m, 3H, CH3), 2.59-2.64 (q, J=7.55, J=7.65,2H, CH2),3.95(s,2H,CH2), 6.96-6.98 (d, J=7.5,1H, ArH), 7.20-7.29 (m, 3H, ArH), 7.61-7.67 (m, 4H, ArH), 7.88-7.92 (t, J=8.5,3H, ArH), 8.00-8.02 (d, J=7.75,1H, ArH), 8.21 (s, 1H ,=CH-),10.31(s,1H,NH)；13C NMR(125MHz,DMSO-d6):δ= 15.95,28.69,34.49,94.71,118.26,120.19,123.75,126.60,128.94,129.44,129.56, 129.72,132.38,132.67,133.30,134.52,136.17,138.09,139.39,144.58,165.28,169.94, 173.53；HRMS(TOF ES+):m/z calcd for C26H21IN2O3[(M+Na)+],559.0489；found,559.0482.
Embodiment 26
3- ((1- (3,4- 3,5-dimethylphenyls) -2,5- dioxypyrrole quinoline -3- subunits) methyl)-N- (3- ethylphenyls) benzene first Amide (compound 76)
Yellow solid；M.p.179-180℃；1H NMR(500MHz,DMSO-d6):δ=1.17-1.22 (q, J=9.55, J =7.45,3H, CH3), 2.25-2.27 (d, J=5.4,6H, CH3), 2.59-2.64 (q, J=7.55, J=7.6,2H, CH2), 3.95(s,2H,CH2), 6.97-6.99 (d, J=7.55,1H, ArH), 7.06-7.08 (m, 1H, ArH), 7.12 (s, 1H, ArH), 7.26-7.29 (t, J=8.1,2H, ArH), 7.63-7.67 (m, 4H, ArH), 7.90-7.92 (d, J=7.8,2H, ), ArH 8.00-8.02 (d, J=7.7,1H, ArH), 8.20 (s, 1H ,=CH-),10.32(s,1H,NH)；13C NMR (125MHz,DMSO-d6):δ=15.96,19.49,19.73,28.69,34.39,118.24,120.16,123.75, 124.79,126.79,128.21,128.94,129.35,129.60,129.69,130.09,130.50,132.06,133.29, 134.60,136.15,137.00,137.24,139.41,144.59,165.31,170.34,173.89；HRMS(TOF ES+): m/z calcd for C27H24N2O4[(M+Na)+],463.1418；found,463.1630.
It should be noted that herein, such as first and second or the like relational terms are used merely to a reality Body or operation make a distinction with another entity or operation, and not necessarily require or imply these entities or deposit between operating In any this actual relation or order.And, term " including ", "comprising" or its any other variant are intended to Nonexcludability is included, so that a series of process, method, article or equipment including key elements not only will including those Element, but also including other key elements being not expressly set out, or also include for this process, method, article or equipment Intrinsic key element.In the absence of more restrictions, the key element for being limited by sentence "including a ...", it is not excluded that Also there is other identical element in process, method, article or equipment including the key element.
Above example only to illustrate technical scheme, rather than a limitation；Although with reference to the foregoing embodiments The present invention has been described in detail, it will be understood by those within the art that：It still can be to aforementioned each enforcement Technical scheme described in example is modified, or carries out equivalent to which part technical characteristic；And these modification or Replace, do not make the spirit and scope of the essence disengaging various embodiments of the present invention technical scheme of appropriate technical solution.

Claims (10)

1. a kind of N- replaces benzal pyrrolidine-diones compound, it is characterised in that with following structure I：
2. N- as claimed in claim 1 replaces benzal pyrrolidine-diones compound, it is characterised in that the R1For C1-C6Directly Alkyl group, C3-C7Cycloalkyl, C1-C6Alkylthio group, C1-C6Alkoxyl, halogen, C6-C10Aryl, C4-C10Heteroaryl, substituted C6- C10Aryl replaces C4-C8Heteroaryl；
The R2For C1-C6Straight chained alkyl, C3-C7Cycloalkyl, C1-C6Alkylthio group, C1-C6Alkoxyl, halogen, various aminoacid, C6- C10Aryl, C4-C10Heteroaryl, substituted C6-C10Aryl replaces C4-C8Heteroaryl；
Described C6-C10Aryl or C4-C10Heteroaryl is by one or more following substituent groups：Straight chained alkyl, halogen ,-CN ,- CF3、-NO2、-CO2R1、-C(O)NR1R1’、-OR1、-SR1, wherein, R1And R1' be：H、C6-C14The C of aryl or at most perhalogeno1- C10Alkyl.
3. N- as claimed in claim 2 replaces benzal pyrrolidine-diones compound, it is characterised in that the N- replaces benzal Base pyrrolidine-diones compound is the one kind in following 77.
4. a kind of N- as described in claims 1 to 3 is arbitrary replaces the preparation method of benzal pyrrolidine-diones, its feature to exist In comprising the following steps:
(1) maleic anhydride is dissolved in organic solvent 1, is stirred under ice bath, after maleic anhydride is completely dissolved, by primary Amine is dissolved in organic solvent 1, in being slowly added to reaction, separates out yellow solid, continues to stir 1h, and ice bath cooling is filtered, cleaned, Obtain N- substituted-phenyl maleamic acids；
(2) maleamic acid is dissolved in acetic anhydride, adds triethylamine, 55-65 DEG C of oil bath heating to stir 1h, cooling, addition etc. Volumes of deionized water, stands overnight, and separates out yellow solid, filters, and cleans, and obtains N- substituted-phenyl maleimides；
(3) by N- substituted maleimides amine solvent in organic solvent 2, stirring, after N- substituted maleimide amine is completely dissolved, Additive is added, 4-5min is reacted, 3- carboxyl benzaldehydes are rapidly added, stirring at normal temperature 6h separates out white solid, filters, washing, Obtain product Intermediate 5；
(4) intermediate is dissolved in organic solvent 3 with condensing agent, adds DIEA, stirs 30min, is slowly added to amine or amino The DCM solution of acid esters, is stirred at room temperature 4～10h, uses dilute hydrochloric acid, aqueous slkali washing reaction liquid after reaction completely successively, then with anhydrous Sodium sulfate is dried, and column chromatography for separation or recrystallization obtain target product.
5. N- as claimed in claim 4 replaces the preparation method of benzal pyrrolidine-diones, it is characterised in that the step (1) organic solvent 1 is that methanol, ethyl acetate, acetic anhydride, acetone, dichloromethane, N,N-dimethylformamide or dimethyl are sub- in The mixing of sulfone and its both the above or multi-solvents.
6. N- as claimed in claim 5 replaces the preparation method of benzal pyrrolidine-diones, it is characterised in that the step (3) organic solvent 2 is methanol, ethanol, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or multi-solvents in Mixing.
7. N- as claimed in claim 6 replaces the preparation method of benzal pyrrolidine-diones, it is characterised in that the step (3) additive is the one kind in triphenylphosphine, sodium acetate, potassium acetate in.
8. N- as claimed in claim 7 replaces the preparation method of benzal pyrrolidine-diones, it is characterised in that the step Suddenly organic solvent 3 is methanol, ethanol, ethyl acetate, acetonitrile, ether, tetrahydrofuran, acetone, benzene, toluene, dichloromethane in (4) One or more mixture in alkane, chloroform, 1,4- dioxane, N,N-dimethylformamide, dimethyl sulfoxide.
9. N- as claimed in claim 8 replaces the preparation method of benzal pyrrolidine-diones, it is characterised in that the alkali is three Ethamine, DIPEA, ethylenediamine, sodium hydroxide, Lithium hydrate, Sodium ethylate, potassium carbonate, cesium carbonate, sodium bicarbonate, One or more mixture in potassium tert-butoxide or sodium tert-butoxide.
10. the present invention also provides a kind of N- replacement benzal pyrrolidine-diones conducts as described in claims 1 to 3 is arbitrary The purposes of the inhibitor of VEGFR-2, the particularly tumor described in its purposes in antitumor drug is prepared are included but is not limited to： Colon cancer, duodenal carcinoma, carcinoma of prostate, breast carcinoma, melanoma, duct carcinoma, hepatocarcinoma, cancer of pancreas, renal carcinoma, carcinoma of endometrium, Gastric cancer, nonsmall-cell lung cancer, neurological malignancies and hematologic malignancies.
CN201610893312.9A 2016-10-13 2016-10-13 N-substituted benzal pyrrolidinedione and preparation method and application thereof Pending CN106565585A (en)

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