CN104774193A - Indolone compounds as well as preparation method and medical application thereof - Google Patents

Indolone compounds as well as preparation method and medical application thereof Download PDF

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CN104774193A
CN104774193A CN201510200771.XA CN201510200771A CN104774193A CN 104774193 A CN104774193 A CN 104774193A CN 201510200771 A CN201510200771 A CN 201510200771A CN 104774193 A CN104774193 A CN 104774193A
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dimethyl
indolone
alkyl
subunit
pyrrole
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赖宜生
卢冲
庄健
王辉
张姗
张奕华
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention belongs to the field of medicines and in particular relates to indolone compounds with a structure shown in a formula (I) in the specification, stereoisomers or pharmaceutically acceptable salts of the indolone compounds, a preparation method of the indolone compounds and an application of the indolone compounds to preparation of antitumor medicines. Experimental results show that the compounds have regulating effects on the activity of protein kinase, can be used for inhibiting the activities of various protein tyrosine kinase and have inhibiting effects on proliferation of various tumor cells.

Description

Indole ketone compound, its preparation method and medicinal use
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of indole ketone compound, its steric isomer or its pharmacy acceptable salt with and preparation method thereof and medicinal use, particularly preparing the application in antitumor drug.
Background technology
Vital effect is played in the generation being created on tumour of blood vessel, development and transfer process.Just propose tumor-blood-vessel growth theory as far back as Folkman in 1971, think that the growth of tumour and transfer depend on the formation (Folkman J.New Engl J Med, 1971,285 (7): 404-405) of new vessel.Research subsequently also demonstrate that obvious growth (Folkman J.Semin Cancer Biol, 1992,3 (2): 65-71 affecting tumour of the formation of neovascularity; Folkman J.SeminOncol, 2002,29 (6 Suppl 16): 15-8).Blood vessel be generated as tumor tissue with nutrients matter and oxygen, excretion metabolism thing, blood vessel be again tumour occur transfer main path.Tumor vascular generation and Angiogenesis Stimulators in Human closely related.
Vascular endothelial growth factor (VEGF) is a kind of important Angiogenesis related factors, have and promote endothelial cell proliferation, several functions such as raising vascular permeability, induction of vascular generation etc., it is the native ligand of vascular endothelial growth factor receptor (VEGFR), and its function mainly realizes by being combined with VEGFR.
VEGFR is the important protein tyrosine kinase family of a class, comprises 3 hypotypes such as VEGFR-1, VEGFR-2 and VEGFR-3.VEGFR-1 is mainly distributed in vascular endothelial cell, hemopoietic stem cell and scavenger cell etc., main relevant with the growth regulating of hemopoietic stem cell; VEGFR-2 mainly expresses at vascular endothelial cell and lymphatic endothelium, relevant with vascular endothelial cell proliferation, vascular permeability and new vascular generation; VEGFR-3 is then mainly distributed in lymphatic endothelium, relates to the adjusting and controlling growth of lymphatic endothelium.These three kinds of acceptors mediate different physiological functions in different histoorgans, and their overexpression can cause pathologic blood vessel or lymphatic vessel to generate.The change of much endotheliocyte physiology caused by VEGF or pathology is mainly mediated by VEGFR-2.The avidity of VEGFR-1 and VEGF is higher than VEGFR-2 10 times, but it regulates activity (the Holmes K more much lower than VEGFR-2 of endotheliocyte, et al.Cell signal, 2007,19 (10): 2003-2012) signal transduction pathway that, therefore VEGFR-2 mediates is the critical path of modulating vascular new life.
VEGFR is primarily of three part compositions such as tyrosine kinase domains in the ectodomain of immunoglobulin-like, single pass transmembrane structural domain and born of the same parents.VEGFR is combined with part VEGF by ectodomain, induction VEGFR conformation changes, and causes kinases receptors dimerization, and makes the tyrosine residues generation autophosphorylation in kinase domain, thus activate downstream signal transduction path, and then the generation of induction of vascular.The dysfunction of VEGF/VEGFR and the growth of tumour and shift closely related (Rapisarda A, et al.Adv Cancer Res, 2012,114:237-267).
Sutent (Sunitinib) is the indole ketone anti-tumor angiogenesis drug of first listing, obvious restraining effect is all had to VEGFR-2, PDGFR α and β, c-Kit, Flt-3, CSF-1R and GFR, the clinical gastrointestinal stromal tumor (GIST) being used for the treatment of renal cell carcinoma (RCC) and imatinib-resistant, the survival rate of RCC patient can be improved and extend life (Faivre S imatinib having been produced to the GIST some patients of resistance, et al.Nat Rev Drug Discov, 2007,6 (9): 734-745).Nintedanib is the indole ketone kinases inhibitor that another has gone on the market, it can suppress VEGFR1/2/3, FGFR1/2/3, PDGFR α/β, Flt-3 and Src etc. effectively, to tumours such as nonsmall-cell lung cancer, ovarian cancer, idiopathic pulmonary fibrosis, there is good curative effect (Roth GJ, et al.J Med Chem, 2015,58 (3): 1053-1063).In addition, a series of indole ketone compound is also had to have Mutiple Targets protein kinase restraining effect (Prakash CR, et al.Pharmacology & Pharmacy, 2012,3,62-71).
Summary of the invention
The present invention relates to one there is the indole ketone compound shown in formula (I), its steric isomer or its pharmacy acceptable salt and preparation method thereof and preparing the application in antitumor drug.Experimental result shows, this compounds can suppress the activity of multiple protein Tyrosylprotein kinase, and inhibited to the propagation of kinds of tumor cells.
The present invention open indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt:
Wherein:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 2-C 10thiazolinyl, C 6-C 10aryl or C 5-C 10aromatic heterocyclic, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, nitro, trifluoromethyl, cyano group, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl, C 5-C 10aromatic heterocyclic or NR 5r 6, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, nitro, cyano group, trifluoromethyl, C 1-C 8alkyl, C 1-C 8alkoxyl group or C (O) OR 7;
R 2represent C 1-C 8alkyl, C 1-C 8alkoxyl group, C 3-C 6cycloalkyl or NR 5r 6, wherein said alkyl, alkoxyl group or cycloalkyl are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 3and R 4can be identical or not identical, certainly optional: hydrogen, halogen, hydroxyl, nitro, cyano group, amino, C 1-C 8alkyl or C 3-C 6cycloalkyl;
R 5and R 6can be identical or not identical, certainly optional: hydrogen, C 1-C 8alkyl or R 5and R 6form 5-7 unit heterocyclic radical together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic radical is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group comprises: halogen, hydroxyl, nitro, cyano group, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 7represent hydrogen or C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl.
Further, there is the indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt, it is characterized in that:
R 1represent C 1-C 8alkyl or C 2-C 6thiazolinyl, wherein said alkyl or alkenyl is optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: cyano group, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl, C 5-C 10aromatic heterocyclic or NR 5r 6, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: trifluoromethyl, C 1-C 8alkyl, C 1-C 8alkoxyl group or C (O) OR 7;
R 2represent NR 5r 6;
R 3and R 4can be identical or not identical, certainly optional: hydrogen or C 1-C 8alkyl;
R 5and R 6can be identical or not identical, optionally from hydrogen, C 1-C 8alkyl or R 3and R 4form 5-7 unit heterocyclic radical base together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is C 1-C 8alkyl;
R 7represent C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl.
Again further, there is the indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt, it is characterized in that:
R 1certainly optional:
R 2represent NR 5r 6;
R 3and R 4can be identical or not identical, certainly optional: hydrogen or C 1-C 8alkyl;
R 5and R 6can be identical or not identical, optionally from hydrogen, C 1-C 8alkyl or R 3and R 4form 5-7 unit heterocyclic radical base together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl;
R 10represent hydrogen, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl or C 5-C 10aromatic heterocyclic, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, trifluoromethyl, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 1-C 8alkoxyl group or C (O) O (C 1-C 8) alkyl.
Further, there is the indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt, it is characterized in that:
R 1certainly optional:
R 2certainly optional:
R 3and R 4for C 1-C 8alkyl.
Specifically, the indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt are preferably from following compounds:
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-(5-acrylamide-2-indolone-3-subunit) methyl-pyrrol-3-methane amide (LL-1);
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-2);
N-[(dimethylamino) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-3);
N-[3-(diethylin) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-4);
N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base] acrylamide (LL-5);
N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base] acrylamide (LL-6);
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-7);
(LL-8) of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-9);
N-[3-(dimethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-10);
N-[3-(diethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-11);
N-[3-[[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide (LL-12);
N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide (LL-13);
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-14);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-15);
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-16);
N-[2-(dimethylamino) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-17);
N-[2-(diethylin) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-18);
N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide (LL-19);
N-[3-[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide (LL-20);
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-20);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-22);
5-ethyl-[2-cyano group-3-[3-[[4-[[2-(diethylamino) ethyl) formamyl]-3,5-Dimethyl-pyrrol-2-base] methylene radical]-2-indolone-5-base] amino]-3-oxo third-1-alkene-1-base]-2,4-Dimethyl-pyrrol-3-carboxylic acid, ethyl esters (LL-23);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[(5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-24);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(1H-pyrroles-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-25);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-26);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] base]-pyrrole-3-carboxamide (LL-27);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(imidazoles-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-28);
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-29);
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-30);
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-31);
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido] 2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-32);
The compound numbers related in pharmacological evaluation is below equal to the compound herein corresponding to code name.
Another object of the present invention is to the preparation method that compound shown in general formula (I) is provided, it is characterized in that:
A) R is worked as 1during for vinyl, shown in general formula (I), the preparation method of compound is: 5-aldehyde radical pyrroles-3-carboxylic acid 1 and aminated compounds react obtained intermediate 2,5-amido indol-2-one and acrylate chloride react obtained intermediate 3,3 and 2 condensations obtain the compound shown in general formula (I), and its synthetic route is as follows:
Wherein, R 2, R 3and R 4definition as claimed in claim 1;
B) R is worked as 1for time, shown in general formula (I), the preparation method of compound is: intermediate 3 and piperidines or morpholine react obtained 4a-b, 4a-b and 2 condensations obtain the compound shown in general formula (I), and its synthetic route is as follows:
Wherein, R 2, R 3and R 4definition as claimed in claim 1;
C) R is worked as 1for time, shown in general formula (I), the preparation method of compound is: 5-nitroindoline-2-ketone and intermediate 2 react obtained intermediate 5,5 obtain intermediate 6 through reduction, 6 obtain intermediate 7 with cyanoacetic acid condensation, 7 obtain the compound shown in general formula (I) with aldehyde compound condensation, and its synthetic route is as follows:
Wherein, R 2, R 3, R 4and R 10definition as claimed in claim 1.
A further object of the present invention is to provide a kind of pharmaceutical composition, and its indole ketone compound, its steric isomer or its pharmacy acceptable salt according to any one of the claim 1-5 treating upper significant quantity and pharmaceutically acceptable carrier or auxiliary material form.
Another object of the present invention is to provide compound, its steric isomer or its pharmacy acceptable salt with general formula (I) and is preparing the application in antitumor drug, and wherein said tumour is lung cancer, liver cancer, colorectal carcinoma, cancer of the stomach, carcinoma of the pancreas, mammary cancer, bladder cancer, cervical cancer or kidney.
Embodiment
In order to illustrate the present invention further, provide a series of embodiment below, these embodiments are illustrative completely, and they are only used for specifically describing the present invention, not should be understood to limitation of the present invention.
Embodiment 1
The preparation of N-(2-diethylin ethyl)-2,4-dimethyl-5-formyl radical-1H-pyrrole-3-carboxamide (2a)
By 2; 4-dimethyl-5-formyl radical-1H-pyrroles-3-formic acid (0.50g; 2.99mmol), EDCIHCl (0.86g; 4.48mmol), DMAP (0.44g; 3.59mmol) with triethylamine (0.83mL; 5.98mmol) be dissolved in 30mL DMF, stirring at room temperature 1 hour, adds N; N-diethyl ethylenediamine (0.85mL; 5.98mmol), continue reaction 9h, pour in 200mL frozen water; extraction into ethyl acetate; column chromatography obtains light yellow solid 0.30g, yield 40.0%, mp 159-161 DEG C.
The preparation of N-[3-(1H-pyrroles-2-base) methylene radical]-2-indolone-5-base-acrylamide (3)
5-amino indole ketone (261mg, 1.76mmol) be dissolved in anhydrous tetrahydro furan, ice bath cools, and drips acrylate chloride (191mg.2.11mmol), remove ice bath, room temperature reaction 1h, filters, is spin-dried for filtrate, re-crystallizing in ethyl acetate, drying obtains white solid 147mg, yield 41%, mp 177-179 DEG C.ESI-MS：201.1[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：3.48(s，2H)，5.7(d，1H)，6.2(d，1H)，6.4(t，1H，J＝10Hz)，6.75(d，1H)，7.4(d，1H)，7.6(s，1H)，10(s，1H)，8.59(s，1H)，8.79(s，1H)，9.87(s，1H)，13.3(s，1H).
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-(5-acrylamide-2-indolone-3-subunit) methyl-pyrrol-3-methane amide (LL-1)
3 (0.28g, 0.854mmol) and 2a (0.142g, 0.535mmol) are dissolved in 10mL acetonitrile, under stirring, add 3 triethylamines, backflow 6h, ice bath cools, and filters, cold acetonitrile wash, drying, obtains orange/yellow solid 0.128g, yield 53.2%, mp 243-245 DEG C.ESI-MS：450.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.93(t，6H，J＝8.0Hz)，1.23(q，4H，J＝8.2Hz)，1.45(t，2H，J＝7.1Hz)，2.08～2.12(m，2H)，2.44(s，3H)，2.48(s，3H)，5.50(d，1H)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.38(d，1H)，7.47(s，1H)，7.49(s，1H)，8.0(s，1H)，10.22(s，1H)，10.9(s，1H).
Embodiment 2
The preparation of N-(2-dimethylamino ethyl)-2,4-dimethyl-5-formyl radical-1H-pyrrole-3-carboxamide (2b)
With reference to the preparation method of 2a, be obtained by reacting white solid by 1 and N, N-dimethyl-ethylenediamine, yield is 52%, mp142-144 DEG C. 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.01(t，6H)，2.30(s，3H)，2.40(s，3H)，2.41～2.43(m，4H)，2.53(t，2H)，3.36(t，2H，J＝8.0Hz)，7.35(t，1H)，9.53(s，1H)，11.81(s，1H).
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-2)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2b, yield is 39%, mp 251-253 DEG C.ESI-MS：420.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.94(t，6H，J＝8.0Hz)，1.45(t，2H，J＝7.1Hz)，2.09～2.11(m，4H)，2.3(s，6H)，2.44(s，3H，)，2.48(s，3H)，5.7(d，1H)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.38(d，1H)，7.47(s，1H)，7.49(s，1H)，10.2(s，1H)，11(s，1H)，13.8(s，1H).
Embodiment 3
The synthesis of N-(2-dimethylamino-propyl)-2,4-dimethyl-5-formyl radical-1H-pyrrole-3-carboxamide (2c)
With reference to the preparation method of 2a, be obtained by reacting white solid by 1 and N, N-dimethyl-1,3-propylene diamine, yield is 28%, mp 161-163 DEG C.ESI-MS：250.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.69～1.71(m，2H)，2.30(s，6H)，2.40(t，2H)，3.18(t，2H)，7.56(t，1H)，9.53(s，1H)，11.81(s，1H).
The preparation of N-[(dimethylamino) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-3)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2c, yield is 34%, mp 239-241 DEG C.ESI-MS：434.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.92(m，2H)，2.3(s，6H)，2.65(t，2H，J＝7.5Hz)，2.7(m，2H)，3.0(s，3H，)，3.1(s，3H)，5.50(d，1H)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.38(d，1H)，7.47(s，1H)，7.49(s，1H)，10.2(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 4
The synthesis of N-(2-diethylin propyl group)-2,4-dimethyl-5-formyl radical-1H-pyrrole-3-carboxamide (2d)
With reference to the preparation method of 2a, by 1 and N, N dimethylamine base-1,3-propylene diamine is obtained by reacting white solid, and yield is 32%, mp 155-157 DEG C.ESI-MS：278.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.02(t，6H)，1.60(m，2h)，2.46(t，2H)，2.40(q，4H，J＝8.0Hz)，3.18(t，2H)，7.56(t，1H)，9.63(s，1H)，11.84(s，1H).
The preparation of N-[3-(diethylin) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (LL-4)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2d, yield is 37%, mp 235-237 DEG C.ESI-MS：464.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.96(t，6H，J＝7.6Hz)，2.3(m，2H)，2.65(t，2H，J＝7.5Hz)，2.7(m，2H)，2.8(q，4H，J＝7.45Hz)，3.2(s，3H)，3.4(s，3H)，5.50(d，1H)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.68(d，1H)，7.77(s，1H)，7.89(s，1H)，10.2(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 5
The synthesis of 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-aldehyde (2e)
With reference to the preparation method of 2a, be obtained by reacting white solid by 1 and N methyl piperazine, yield is 31%, mp 115-117 DEG C. 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.27(t，4H，J＝7.1Hz)，2.32(t，4H，J＝7.1Hz)，9.63(s，1H)，11.90(s，1H).
The preparation of N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base] acrylamide (LL-5)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2e, yield is 31%, mp 175-177 DEG C.ESI-MS：434.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.31(t，2H，J＝7.5Hz)，2.4(s，3H)，2.45(s，3H，)，2.54(t，4H，J＝7.5Hz)，5.70(d，1H，J＝7.5Hz)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.68(d，1H)，7.77(s，1H)，7.89(s，1H)，10.2(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 6
The synthesis of 3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-aldehyde (2f)
With reference to the preparation method of 2a, be obtained by reacting white solid by 1 and morpholine, yield is 48%, mp 102-104 DEG C.ESI-MS：235.1[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.16(t，3H，J＝7.1Hz)，2.21(t，3H，J＝7.1Hz)，3.56(t，4H，J＝7.1Hz)，3.63(t，4H，J＝7.1Hz)，9.63(s，1H)，11.93(s，1H).
The preparation of N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base] acrylamide (LL-6)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2f, yield is 47%, mp 140-142 DEG C.ESI-MS：419.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.31(s，3H)，3.45(t，4H，J＝7.3Hz)，3.55(t，4H，J＝7.3Hz)，5.70(d，1H，J＝7.5Hz)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.68(d，1H)，7.77(s，1H)，7.89(s，1H)，10.2(s，1H)，10.92(s，1H)，13.6(s，1H).
Embodiment 7
N-[2-(dimethylamino) ethyl]-5-formyl radical-N, the synthesis of 2,4-trimethylammonium-1H-pyrrole-3-carboxamide (2g)
With reference to the preparation method of 2a, obtain white solid by 1 and N ', N, N-trimethylammonium reacting ethylenediamine, yield is 89%, mp104-106 DEG C.ESI-MS：250.2[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.16(s，6H)，2.17(s，3H)，2.36(t，2H，J＝7.1Hz)，2.37(s，3H)，3.46(t，2H，J＝7.1Hz)，3.63(s，3H)，9.63(s，1H)，11.93(s，1H).
The preparation of 5-[(5-acrylamide-2-indolone-3-subunit) methyl]-N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-pyrrole-3-carboxamide (LL-7)
With reference to the preparation method of LL-1, be obtained by reacting yellow solid by 3 and 2g, yield is 42%, mp 177-179 DEG C.ESI-MS：436.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.24(t，6H，J＝7.92Hz)，2.05(t，2H，J＝7.92Hz)，2.3(s，6H)，2.4(s，3H)，2.94(s，3H)，3.68(s，3H)，5.7(d，1H)，6.25(d，1H)，6.5(t，1H)，6.52(s，1H)，6.9(d，1H)，7.38(d，1H)，7.47(s，1H)，7.49(s，1H)，10.2(s，1H)，10.89(s，1H)，13.6(s，1H).
Embodiment 8
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-8)
3 (0.28g, 1.385mmol) and 2a (0.142g, 0.535mmol) are dissolved in 15mL acetonitrile, piperidines (59 μ L are added under stirring, 0.60mmol), backflow 4h, cooling crystallization, filter, recrystallized from acetonitrile, dry, obtain orange/yellow solid 0.286g, yield 89.0%, mp 269-271 DEG C.ESI-MS：535.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.98(t，6H，J＝7.6Hz)，1.23(m，2H)，1.45(t，2H，J＝7.35Hz)，1.6(m，4H)，2.25(s，3H)，2.34(q，4H，J＝7.5Hz)，2.36(t，2H，J＝7.45Hz)，2.40(t，4H，J＝7.21Hz)，2.45(s，3H)，2.5(t，4H，J＝7.45Hz)，3.60(m，2H)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.2(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 9
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-9)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2b, yield is 85%, mp 262-264 DEG C.ESI-MS：505.4[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.31(m，2H)，1.53(m，4H)，2.15(s，6H)，2.25(s，3H)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.47(t，4H，J＝7.42Hz)，2.48(t，2H，J＝7.41Hz)，2.60(m，2H)，3.34(t，2H，J＝7.41Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.1(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 10
The preparation of N-[3-(dimethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-10)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2c, yield is 85%, mp 270-272 DEG C.ESI-MS：521.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.31(m，2H)，1.60(m，2H)，2.13(m，4H)，2.15(s，6H)，2.25(s，3H)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.47(t，4H，J＝7.42Hz)，2.48(t，2H，J＝7.41Hz)，3.26(m，2H)，3.54(t，2H，J＝7.41Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.00(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 11
The preparation of N-[3-(diethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-11)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2d, yield is 82%, mp 294-296 DEG C.ESI-MS：549.5[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.45(t，6H，J＝7.37Hz)，1.51(m，2H)，1.60(m，2H)，2.13(m，4H)，2.25(s，3H)，2.35(q，4H，J＝7.37Hz)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.47(t，4H，J＝7.42Hz)，2.48(t，2H，J＝7.41Hz)，2.56(m，2H)，3.24(t，2H，J＝7.41Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.00(s，1H)，10.82(s，1H)，13.64(s，1H).
Embodiment 12
The preparation of N-[3-[[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide (LL-12)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2e, yield is 81%, mp 131-133 DEG C.ESI-MS：519.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.31(m，2H)，1.65(m，4H)，1.75(s，3H)，2.25(t，4H，J＝7.17Hz)，2.31(t，4H，J＝7.35Hz)，2.35(s，3H)，2.68(s，3H)，2.70(t，2H，J＝7.42Hz)，3.26(t，4H，J＝7.35Hz)，3.64(t，2H，J＝7.42Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，8.90(s，1H)，11.2(s，1H)，13.34(s，1H).
Embodiment 13
The preparation of N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide (LL-13)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2f, yield is 89%, mp 145-147 DEG C.ESI-MS：506.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.31(m，2H)，1.45(m，4H)，2.21(s，3H)，2.25(t，4H，J＝7.17Hz)，2.31(t，4H，J＝7.35Hz)，2.33(s，3H)，2.65(t，2H，J＝7.42Hz)，3.66(t，4H，J＝7.35Hz)，3.67(t，2H，J＝7.42Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.97(s，1H)，10.06(s，1H)，10.82(s，1H)，13.74(s，1H).
Embodiment 14
N-[2-(dimethylamino) ethyl]-N, the preparation of 2,4-trimethylammonium-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide (LL-14)
With reference to the preparation method of LL-8, be obtained by reacting yellow solid by 3 with piperidines, 2g, yield is 82%, mp 307-309 DEG C.ESI-MS：521.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.31(m，2H)，1.53(m，4H)，2.15(s，6H)，2.25(s，3H)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.47(t，4H，J＝7.42Hz)，2.48(t，2H，J＝7.41Hz)，2.60(t，2H，J＝7.35Hz)，3.34(t，2H，J＝7.41Hz)，3.40(s，3H)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.1(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 15
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-15)
Compound 3 (0.28g, 1.385mmol) is dissolved in 10mL acetonitrile, drips morpholine (52 μ L, 0.60mmol), backflow 5h, adds 2a (0.142g, 0.535mmol), continue backflow 4h, ice bath cools, filtration under diminished pressure, recrystallized from acetonitrile, dry, obtain yellow solid 0.25g, yield 85%, mp 260-262 DEG C.ESI-MS：537.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.98(t，6H，J＝7.21Hz)，2.22(t，2H，J＝7.35Hz)，2.24(t，4H，J＝7.33Hz)，2.25(s，3H)，2.34(q，4H，J＝7.21Hz)，2.36(t，2H，J＝7.45Hz)，2.45(s，3H)，2.5(m，2H)，3.3(t，2H，J＝7.35Hz)，3.64(t，4H，J＝7.33Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，9.92(s，1H)，10.92(s，1H)，13.64(s，1H).
Embodiment 16
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-16)
With reference to the preparation method of LL-15, be obtained by reacting yellow solid by 3 and morpholine and 2b, yield is 88%, mp 255-257 DEG C.ESI-MS：509.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.20(s，6H)，2.25(t，2H，J＝7.35Hz)，2.36(t，4H，J＝7.33Hz)，2.49(s，3H)，2.52(t，2H，J＝7.45Hz)，2.55(s，3H)，2.57(m，2H)，3.3(t，2H，J＝7.35Hz)，3.64(t，4H，J＝7.33Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，9.88(s，1H)，10.85(s，1H)，13.63(s，1H).
Embodiment 17
The preparation of N-[2-(dimethylamino) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-17)
With reference to the preparation method of LL-15, be obtained by reacting yellow solid by 3 and morpholine and 2c, yield is 81%, mp 265-267 DEG C.ESI-MS：523.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.60(m，2H)，2.13(t，4H，J＝7.42Hz)，2.15(s，6H)，2.25(s，3H)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.48(t，2H，J＝7.41Hz)，3.07(t，4H，J＝7.42Hz)，3.26(m，2H)，3.54(t，2H，J＝7.41Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.00(s，1H)，10.92(s，1H)，13.62(s，1H).
Embodiment 18
The preparation of N-[2-(diethylin) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-18)
With reference to the preparation method of LL-15, react obtained yellow solid by 3 and morpholine and 2d, yield is 80%, mp 267-269 DEG C.ESI-MS：551.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.45(t，6H，J＝7.37Hz)，1.60(m，2H)，2.25(s，3H)，2.35(q，4H，J＝7.37Hz)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.47(t，4H，J＝7.42Hz)，2.48(t，2H，J＝7.41Hz)，2.56(m，2H)，3.17(t，4H，J＝7.42Hz)，3.24(t，2H，J＝7.41Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.00(s，1H)，10.82(s，1H)，13.64(s，1H)。
Embodiment 19
The preparation of N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide (LL-19)
With reference to the preparation method of LL-15, react obtained yellow solid by 3 and morpholine and 2e, yield is 75%, mp 174-176 DEG C.ESI-MS：521.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.20(s，3H)，2.25(t，4H，J＝7.17Hz)，2.31(t，4H，J＝7.35Hz)，2.35(s，3H)，2.56(t，4H，J＝7.17Hz)，2.68(s，3H)，2.70(t，2H，J＝7.42Hz)，3.62(t，4H，J＝7.35Hz)，3.65(t，2H，J＝7.42Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，8.90(s，1H)，10.82(s，1H)，13.69(s，1H).
Embodiment 20
The preparation of N-[3-[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide (LL-20)
With reference to the preparation method of LL-15, react obtained yellow solid by 3 and morpholine and 2f, yield is 85%, mp 162-164 DEG C.ESI-MS：506.3[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.20(t，4H，J＝7.17Hz)，2.21(s，3H)，2.31(t，4H，J＝7.35Hz)，2.33(s，3H)，2.65(t，2H，J＝7.42Hz)，3.65(t，4H，J＝7.17Hz)，3.66(t，4H，J＝7.35Hz)，3.67(t，2H，J＝7.42Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.97(s，1H)，10.06(s，1H)，10.82(s，1H)，13.74(s，1H).
Embodiment 21
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide; (LL-21) preparation
With reference to the preparation method of LL-15, be obtained by reacting yellow solid by 3 and morpholine and 2g, yield is 81%, mp 134-136 DEG C.ESI-MS：521.3[M-H] -；H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.13(t，4H，J＝7.42Hz)，2.15(s，6H)，2.25(s，3H)，2.36(t，2H，J＝7.35Hz)，2.40(s，3H)，2.48(t，2H，J＝7.41Hz)，2.60(t，2H，J＝7.35Hz)，3.34(t，2H，J＝7.41Hz)，3.40(s，3H)，3.47(t，4H，J＝7.42Hz)，6.8(d，1H)，7.22(d，1H)，7.45(s，1H)，7.47(s，1H)，7.87(s，1H)，10.1(s，1H)，10.92(s，1H)，13.7(s，1H).
Embodiment 22
(Z) preparation of-N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[(5-nitro-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (5a)
5-nitroindoline ketone (1.78g, 10mmol) and 2a (2.65g, 10mmol) are dissolved in 50ml ethanol, add 5 μ L piperidines, backflow 3h, cooling, suction filtration, ethyl alcohol recrystallization, dry yellow solid 3.8g, yield is 89%, mp 263-265 DEG C.ESI-MS：426.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.95(t，6H，J＝7.32Hz)，2.47(s，3H)，2.51(q，4H，J＝7.32Hz)，2.60(s，3H)，2.62(t，2H，J＝7.35Hz)，3.37(m，2H)，7.0(d，1H)，7.52(d，1H)，8.15(s，1H)，8.87(s，1H)，11.47(s，1H)，13.7(s，1H).
(Z) preparation of-N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[(5-amino-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide (6a)
By 5a (4.25g, 10mmol) be dissolved in 100ml ethanol, add iron powder (1.29g, 23.4mmol), slowly add 4mL concentrated hydrochloric acid, backflow 4h, saturated sodium bicarbonate solution adjusts pH 8, extraction into ethyl acetate, dry faint yellow solid 2.4g, yield 60%, mp 254-256 DEG C.
(Z) preparation of-5-[[5-(2-Cyanoacetyl)-2-indolone-3-subunit] methyl]-N-[2-(diethylin) ethyl]-2,4-Dimethyl-pyrrol-3-methane amide (7a)
Itrile group acetic acid (0.5g, 5.95mmol) is dissolved in 20mLDMF, adds EDCHCl (2.4g successively, 12.5mmol), DIPEA (3.3mL, 18.8mmol) with 6a (1.22g, 3.1mmol), room temperature reaction 10h, pour in 50mL water, stir 10min, suction filtration, dry orange/yellow solid 0.81g, yield 56%, mp 247-249 DEG C.ESI-MS：463.2[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.96(t，6H，J＝7.32Hz)，2.38(s，3H)，2.51(q，4H，J＝7.32Hz)，2.60(s，3H)，2.62(t，2H，J＝7.35Hz)，3.37(m，2H)，3.60(s，2H)，7.0(d，1H)，7.52(d，1H)，8.15(s，1H)，8.87(s，1H)，11.47(s，1H)，13.7(s，1H).
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido]-2-indolone-3-subunit] methyl] preparation of-pyrrole-3-carboxamide (LL-22)
By 7a (46mg, 0.10mmol) be dissolved in 5mL acetonitrile, drip 2-trifluoromethylated benzaldehyde (0.12mmol), add catalytic amount Piperidineacetic acid, room temperature reaction 4h, suction filtration, use acetonitrile and washed with diethylether successively, dry yellow solid 39mg, yield 64%, mp 213-215 DEG C.ESI-MS：619.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.94(t，6H，J＝7.11Hz)，2.33(q，4H，J＝7.11Hz)，2.35(t，2H，J＝7.1Hz)，2.40(s，3H，)，2.45(m，2H)，3.28(s，3H)，6.90(d，1H)，7.25(d，1H)，7.5(t，1H)，7.52(s，1H)，7.9(d，1H)，8.08(d，1H)，8.18(d，1H)，8.20(d，1H)，8.47(s，1H)，8.37(m，1H)，8.49(s，1H)，10.51(s，1H)，11.07(s，1H)，13.81(s，1H).
Embodiment 23
5-ethyl-[2-cyano group-3-[3-[[4-[[2-(diethylamino) ethyl) formamyl]-3; 5-Dimethyl-pyrrol-2-base] methylene radical]-2-indolone-5-base] amino]-3-oxo third-1-alkene-1-base] preparation of-2,4-Dimethyl-pyrrol-3-carboxylic acid, ethyl esters (LL-23)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7a and 2,4-dimethyl-5-Formyl-pyrrol-3-carboxylic acid, ethyl ester, yield is 61%, mp 280-282 DEG C.ESI-MS：640.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.91(t，3H，J＝7.34Hz)，2.33(t，6H，J＝7.11Hz)，2.34(q，4H，J＝7.11Hz)，2.35(t，2H，J＝7.1Hz)，2.37(s，3H)，2.40(s，3H)，2.45(m，2H)，2.60(s，3H)，3.28(s，3H)，4.21(q，2H，J＝7.34Hz)，6.90(d，1H)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.6(s，1H)，8.08(d，1H)，10.03(s，1H)，11.04(s，1H)，11.07(s，1H)，13.71(s，1H)。
Embodiment 24
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[(5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl] preparation of-pyrrole-3-carboxamide (LL-24)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7a and special valeral, yield is 66%, mp 237-239 DEG C.ESI-MS：531.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.99(t，6H，J＝7.11Hz)，1.25(s，9H)，1.63(q，4H，J＝7.11Hz)，1.95(t，2H，J＝7.21Hz)，2.30(s，3H)，2.41(s，3H)，2.9(m，2H)，6.89(d，1H)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.9(d，1H)，10.11(s，1H)，10.92(s，1H)，13.63(s，1H).
Embodiment 25
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(1H-ratio coughs up-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-25)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7a and pyrrole-2-aldehyde, yield is 61%, mp279-281 DEG C.ESI-MS：540.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.33(t，6H，J＝7.11Hz)，2.34(q，4H，J＝7.11Hz)，2.35(t，2H，J＝7.1Hz)，2.40(s，3H)，2.45(m，2H)，3.28(s，3H)，6.90(d，1H)，7.12(t，1H，J＝7.41Hz)，7.21(t，1H，J＝7.53Hz)，7.25(d，1H)，7.35(d，1H)，7.5(s，1H)，7.52(s，1H)，7.6(s，1H)，8.08(d，1H)，10.03(s，1H)，11.04(s，1H)，11.07(s，1H)，13.71(s，1H).
Embodiment 26
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-26)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7a and cyclopropyl carboxaldehyde, yield is 68%, mp231-233 DEG C.ESI-MS：515.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：0.97(t，6H，J＝7.12Hz)，1.27(m，1H)，1.83(q，4H，J＝7.12Hz)，1.85(m，4H)，1.95(t，2H，J＝7.21Hz)，2.40(s，3H)，2.41(s，3H)，2.43(m，2H)，6.89(d，1H)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.9(d，1H)，9.99(s，1H)，10.94(s，1H)，13.63(s，1H).
Embodiment 27
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] base]-pyrrole-3-carboxamide (LL-27)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7a and Benzaldehyde,2-methoxy, yield is 63%, mp270-272 DEG C.ESI-MS：581.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.33(t，6H，J＝7.11Hz)，2.34(q，4H，J＝7.11Hz)，2.35(t，2H，J＝7.1Hz)，2.40(s，3H)，2.45(m，2H)，3.28(s，3H)，3.68(s，3H)，6.90(d，1H)，6.93(d，1H)，7.12(t，1H，J＝7.41Hz)，7.21(t，1H，J＝7.53Hz)，7.25(d，1H)，7.35(d，1H)，7.46(s，1H)，7.52(s，1H)，7.6(s，1H)，8.08(d，1H)，10.03(s，1H)，11.07(s，1H)，13.71(s，1H).
Embodiment 28
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(imidazoles-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-28)
With reference to the preparation method of LL-22, obtain yellow solid by 7a and imidazoles-2-formaldehyde reaction, yield is 58%, mp255-257 DEG C.ESI-MS：541.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.32(t，6H，J＝7.11Hz)，2.34(q，4H，J＝7.11Hz)，2.35(t，2H，J＝7.1Hz)，2.40(s，3H)，2.45(m，2H)，3.28(s，3H)，6.90(d，1H)，7.12(t，1H，J＝7.41Hz)，7.21(t，1H，J＝7.53Hz)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.6(s，1H)，8.08(d，1H)，10.03(s，1H)，11.04(s，1H)，13.07(s，1H)，13.73(s，1H).
Embodiment 29
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-29)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7b and cyclopropyl carboxaldehyde, obtain yellow solid, yield is 64%, mp 281-283 DEG C.ESI-MS：485.3[M-H] -； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.27(m，4H)，1.85(m，1H)，1.95(t，2H，J＝7.21Hz)，2.40(s，3H)，2.41(s，3H)，2.43(m，2H)，2.47(s，6H)，6.89(d，1H)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.9(d，1H)，9.99(s，1H)，10.94(s，1H)，13.63(s，1H).
Embodiment 30
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-30)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7b and Benzaldehyde,2-methoxy, yield is 65%, mp264-266 DEG C.ESI-MS：553.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.35(t，2H，J＝7.1Hz)，2.40(s，3H)，2.45(m，2H)，2.63(s，6H)，3.28(s，3H)，3.68(s，3H)，6.90(d，1H)，6.93(d，1H)，7.12(t，1H，J＝7.41Hz)，7.21(t，1H，J＝7.53Hz)，7.25(d，1H)，7.35(d，1H)，7.46(s，1H)，7.52(s，1H)，7.6(s，1H)，8.08(d，1H)，10.03(s，1H)，11.07(s，1H)，13.71(s，1H).
Embodiment 31
The preparation of N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-31)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7b and special valeral, yield is 66%, mp 293-295 DEG C.ESI-MS：503.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.25(s，9H)，1.95(t，2H，J＝7.21Hz)，2.30(s，3H)，2.41(s，3H)，2.63(s，6H)，2.9(m，2H)，6.89(d，1H)，7.25(d，1H)，7.5(s，1H)，7.52(s，1H)，7.9(d，1H)，10.11(s，1H)，10.92(s，1H)，13.63(s，1H).
Embodiment 32
The preparation of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido] 2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide (LL-32)
With reference to the preparation method of LL-22, be obtained by reacting yellow solid by 7b and p-trifluoromethyl benzaldehyde, yield is 66%, mp 270-272 DEG C.ESI-MS：591.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.35(t，2H，J＝7.1Hz)，2.40(s，3H)，2.43(s，6H)，2.45(m，2H)，3.28(s，3H)，6.90(d，1H)，7.25(d，1H)，7.5(t，1H)，7.52(s，1H)，7.9(d，1H)，8.08(d，1H)，8.18(d，1H)，8.20(d，1H)，8.47(s，1H)，8.37(m，1H)，8.49(s，1H)，10.51(s，1H)，11.07(s，1H)，13.81(s，1H)。
Embodiment 33
Protein tyrosine kinase inhibit activities is tested
Experimental technique: adopt Z-Lyte FRET (fluorescence resonance energy transfer) method to carry out the test of VEGFR1/2/3, FGFR-1 and PDGFR-β inhibit activities, positive control drug is Sutent.
Experiment material: protein kinase VEGFR, FGFR-1 and PDGFR-β and corresponding substrate reagent box (Lifetechnologies, USA) thereof; Positive drug Sutent (synthesizing from this laboratory); The multi-functional microplate reader (PerkinElmer, USA) of Envision Multilabel Reader; Echo520 ultrasonic wave micro liquid transfer system (Labcyte, USA).
Experimental procedure:
1) in 384 microwell plates, add the mixed solution of the appropriate protein kinase of 5 μ L and the corresponding substrate of 5 μ L (reacting final concentration is 2 μMs), then the compound of a series of gradient dilution is added by Echo520 ultrasonic wave micro liquid transfer system, finally add the ATP of respective concentration, after vibration mixing 5min, be placed in reaction 1.5h in 29 DEG C of thermostat containers;
2) add the detection liquid of 5 μ L respective concentration, vibration mixing 5min, be placed in reaction 1h in 29 DEG C of thermostat containers;
3) add 5 μ L stop buffers, detect by the multi-functional microplate reader of Envision Multilabel Reader after vibration mixing, excitation wavelength is 400nm, and wavelength of transmitted light is respectively 445nm and 520nm;
4) according to fluorescence ratio computerized compound to the inhibiting rate of enzyme reaction;
Emission Ratio ( % ) = Coumarin Emission ( 445 nm ) Fluorescein Emission ( 520 nm )
% Phosphorylation = ( Emission Ratio × F 100 % ) - C 100 % ( C 0 % - C 100 % ) + [ Emission Ratio × ( F 100 % - F 0 % ) ]
5) according to primary dcreening operation result, select the target compound that inhibiting rate is greater than 50%, gradient dilution 10 concentration diplopores sieve again.The IC of each compound of GraphPad Prism 5.0 computed in software 50value.Experimental result is as shown in table 1.
Table 1 the compounds of this invention is to the inhibit activities (IC of protein tyrosine kinase 50: μM)
Experimental result shows, the compounds of this invention has inhibit activities in various degree to VEGFR, FGFR-1 and PDGFR-beta kinase, and wherein the activity of part of compounds is better than or is equivalent to positive drug Sutent.
Embodiment 34
The compounds of this invention cell inhibitory effect active testing
The blue colorimetry (MTT) of tetramethyl-nitrogen azoles is adopted to evaluate the inhibit activities of part of compounds on cell proliferation of the present invention.Mtt assay has been widely used in large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy sensitivity and has measured.
Humanized cell strain: huve cell HUVEC, hepatoma Hep G 2 cells; Colon cancer cell line HT-29, lung cancer NCI-H460 cell, kidney A498 cell, gastrointestinal stromal tumor GIST882 cell.
Experimental technique: the cell in vegetative period of taking the logarithm is made into 4.5 × 10 5/ mL cell suspension, is seeded in 96 well culture plates, every hole 180 μ L, and often group establishes 5 parallel holes, adds each 20 μ L of different concns tested material respectively.Be placed in constant temperature CO 2cultivate 48 hours in incubator, tetramethyl-nitrogen azoles indigo plant is added in 96 orifice plates, every hole 20 μ L, continue cultivation 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, jolting 5 minutes on plate shaker.Be the optical density in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, each repetition of above experiment 3 times.Calculate cell proliferation inhibition rate by following formula, set up linear regression equation according to inhibiting rate and try to achieve half-inhibition concentration IC 50value.The results are shown in Table 2.
Table 2 part of compounds of the present invention is to the inhibit activities (IC of tumor cell proliferation 50: μM)
Experimental result shows, the compounds of this invention breeds the restraining effect had in various degree to kinds of tumor cells, wherein the activity of part of compounds is better than or is equivalent to positive drug Sutent.

Claims (9)

1. the indole ketone compound shown in general formula (I), its steric isomer or its pharmacy acceptable salt:
Wherein:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 2-C 10thiazolinyl, C 6-C 10aryl or C 5-C 10aromatic heterocyclic, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, thiazolinyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, nitro, trifluoromethyl, cyano group, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl, C 5-C 10aromatic heterocyclic or NR 5r 6, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, nitro, cyano group, trifluoromethyl, C 1-C 8alkyl, C 1-C 8alkoxyl group or C (O) OR 7;
R 2represent C 1-C 8alkyl, C 1-C 8alkoxyl group, C 3-C 6cycloalkyl or NR 5r 6, wherein said alkyl, alkoxyl group or cycloalkyl are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 3and R 4can be identical or not identical, certainly optional: hydrogen, halogen, hydroxyl, nitro, cyano group, amino, C 1-C 8alkyl or C 3-C 6cycloalkyl;
R 5and R 6can be identical or not identical, certainly optional: hydrogen, C 1-C 8alkyl or R 5and R 6form 5-7 unit heterocyclic radical together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic radical is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group comprises: halogen, hydroxyl, nitro, cyano group, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 7represent hydrogen or C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl.
2. indole ketone compound according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1represent C 1-C 8alkyl or C 2-C 6thiazolinyl, wherein said alkyl or alkenyl is optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: cyano group, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl, C 5-C 10aromatic heterocyclic or NR 5r 6, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: trifluoromethyl, C 1-C 8alkyl, C 1-C 8alkoxyl group or C (O) OR 7;
R 2represent NR 5r 6;
R 3and R 4can be identical or not identical, certainly optional: hydrogen or C 1-C 8alkyl;
R 5and R 6can be identical or not identical, optionally from hydrogen, C 1-C 8alkyl or R 3and R 4form 5-7 unit heterocyclic radical base together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is C 1-C 8alkyl;
R 7represent C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl.
3. indole ketone compound according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1certainly optional:
or
R 2represent NR 5r 6;
R 3and R 4can be identical or not identical, certainly optional: hydrogen or C 1-C 8alkyl;
R 5and R 6can be identical or not identical, optionally from hydrogen, C 1-C 8alkyl or R 3and R 4form 5-7 unit heterocyclic radical base together with the nitrogen be connected with them, wherein said alkyl is optionally by C 1-C 8alkoxyl group or NR 8r 9replace, described heterocyclic radical optionally comprises one or more other heteroatoms being selected from O or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is C 1-C 8alkyl;
R 8and R 9can be identical or not identical, optionally from hydrogen or C 1-C 8alkyl;
R 10represent hydrogen, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 6-C 10aryl or C 5-C 10aromatic heterocyclic, wherein said aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl, trifluoromethyl, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 1-C 8alkoxyl group or C (O) O (C 1-C 8) alkyl.
4. indole ketone compound according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that: R 1certainly optional:
or
R 2certainly optional:
or
R 3and R 4for C 1-C 8alkyl.
5. indole ketone compound according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that described compound is preferentially selected from:
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-(5-acrylamide-2-indolone-3-subunit) methyl-pyrrol-3-methane amide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide;
N-[(dimethylamino) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide;
N-[3-(diethylin) propyl group]-2,4-dimethyl-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide;
N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base] acrylamide;
N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base] acrylamide;
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[(5-acrylamide-2-indolone-3-subunit) methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[3-(dimethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[3-(diethylamino) propyl group]-2,4-dimethyl-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[3-[[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide;
N-[3-[[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical]-2-indolone-5-base]-3-(piperidin-1-yl) propionic acid amide;
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[[2-oxo-5-[3-(piperidin-1-yl) propionamido] indoline-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) propyl group]-2,4-dimethyl-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[3-[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide;
N-[3-[3,5-dimethyl-4-(morpholine-4-carbonyl)-pyrroles-2-base] methylene radical-2-indolone-5-base]-3-morpholine propionic acid amide;
N-[2-(dimethylamino) ethyl]-N, 2,4-trimethylammonium-5-[[5-(3-morpholine propionic acid amide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
5-ethyl-[2-cyano group-3-[3-[[4-[[2-(diethylamino) ethyl) formamyl]-3,5-Dimethyl-pyrrol-2-base] methylene radical]-2-indolone-5-base] amino]-3-oxo third-1-alkene-1-base]-2,4-Dimethyl-pyrrol-3-carboxylic acid, ethyl esters;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[(5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(1H-pyrroles-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] base]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(imidazoles-2-base) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-3-cyclopropyl acrylamide)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[[5-[2-cyano group-3-(2-p-methoxy-phenyl) acrylamido]-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[[5-(2-cyano group-4,4-dimethyl-penten-2-alkene acid amides)-2-indolone-3-subunit] methyl]-pyrrole-3-carboxamide;
5-[[5-[2-cyano group-3-[2-(trifluoromethyl) phenyl] acrylamido] 2-indolone-3-subunit] methyl]-N-[2-(dimethylamino) ethyl]-2,4-Dimethyl-pyrrol-3-methane amide.
6. the preparation method of indole ketone compound according to claim 1, is characterized in that:
A) R is worked as 1during for vinyl, shown in general formula (I), the preparation method of compound is: 5-aldehyde radical pyrroles-3-carboxylic acid 1 and aminated compounds react obtained intermediate 2,5-amido indol-2-one and acrylate chloride react obtained intermediate 3,3 and 2 condensations obtain the compound shown in general formula (I), and its synthetic route is as follows:
Wherein, R 2, R 3and R 4definition as claimed in claim 1;
B) R is worked as 1for or time, shown in general formula (I), the preparation method of compound is: intermediate 3 and piperidines or morpholine react obtained 4a-b, 4a-b and 2 condensations obtain the compound shown in general formula (I), and its synthetic route is as follows:
Wherein, R 2, R 3and R 4definition as claimed in claim 1;
C) R is worked as 1for time, shown in general formula (I), the preparation method of compound is: 5-nitroindoline-2-ketone and intermediate 2 react obtained intermediate 5,5 obtain intermediate 6 through reduction, 6 obtain intermediate 7 with cyanoacetic acid condensation, 7 obtain the compound shown in general formula (I) with aldehyde compound condensation, and its synthetic route is as follows:
Wherein, R 2, R 3, R 4and R 10definition as claimed in claim 1.
7. treat a pharmaceutical composition for tumour, its indole ketone compound, its steric isomer or its pharmacy acceptable salt according to any one of the claim 1-5 treating upper significant quantity and pharmaceutically acceptable carrier or auxiliary material form.
8. the compound according to any one of claim 1-5, its steric isomer, its pharmacy acceptable salt or composition according to claim 7 are preparing the application in antitumor drug.
9. application according to claim 8, wherein said tumour is lung cancer, liver cancer, colorectal carcinoma, cancer of the stomach, carcinoma of the pancreas, mammary cancer, bladder cancer, cervical cancer or kidney.
CN201510200771.XA 2015-04-22 2015-04-22 Indolone compounds as well as preparation method and medical application thereof Pending CN104774193A (en)

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