CN101007801A - Pyrrole substituted 2-dihydromolindone derivative, its preparation method and medical uses - Google Patents

Pyrrole substituted 2-dihydromolindone derivative, its preparation method and medical uses Download PDF

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CN101007801A
CN101007801A CNA2006100650024A CN200610065002A CN101007801A CN 101007801 A CN101007801 A CN 101007801A CN A2006100650024 A CNA2006100650024 A CN A2006100650024A CN 200610065002 A CN200610065002 A CN 200610065002A CN 101007801 A CN101007801 A CN 101007801A
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methyl
trifluoromethyl
pyrroles
hydrogen
carboxylic acid
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邓炳初
别平彦
刘卫利
杨式波
张蕾
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Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to PCT/CN2007/000323 priority patent/WO2007085205A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/14—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 three or more hetero rings

Abstract

The invention relates to 2- dihydroindole-ones derivatives or its salt demonstrated in general formula (I), and the substituent group in formula is demonstrated in instruction manual. The invention also relates to the compound comprising said derivatives, method for preparing the same, and the application for preventing and treating cell dysfunction of pulmonary ventilation relevant to protein kinase.

Description

The 2-indolinone derivative that the pyrroles replaces, its method for making and purposes pharmaceutically
Technical field
The present invention relates to the 2-indolinone derivative that a kind of pyrroles replaces, 3-(3-trifluoromethyl-4-amidopyrrol-2-methylene)-2-indolinone derivative particularly, its preparation method and this derivative purposes in the preparation kinases inhibitor.
Background technology
(Protein kinases PKs) has important effect to protein kinase in the signal conductive process.It can be transferred to γ-phosphate of ATP on the particular amino acid residue of functional protein, causes a series of biological respinses.According in the phosphorylation process as the amino acid classification of substrate, protein kinase can be divided into serine-threonine kinase (STKs) and Tyrosylprotein kinase (PTKs).
Nearly 100 kinds of protein tyrosine kinases (protein tyrosine kinases) have been determined aminoacid sequence (Hanks and Hunter, 1995, FASEB J.9:576-596), and appreciable amt may reach 1000 kinds.
Tyrosine phosphorylation mechanism is prevalent in the signal conductive process, regulating and control such as various kinds of cell functions such as mitotic division, cell cycle progression and differentiation (Hanks and Hunter, 1995, FASEB is J.9:576-596; Cadena and Gill, 1992, FASEB is J.6:2332-2337; Schlessinger and Ullrich, 1992, Neuron9:383-391; Vandergeer et al., 1994, Annu.Rev.Cell Biol.10:251-337).When protein tyrosine kinase is expressed under variation, situation out of control, or when under abnormal high level, expressing, normal cell can be changed into tumour phenotype (neoplastic phenotype) (Chiao et al., 1994, Cancer Metast.Rev.9:63-80; Hunter, 1991, Cell 64:249-270).
The most cells growth factor receptors contains the peptide chain-ordering of Tyrosylprotein kinase, the overexpression of visible different tyrosine kinase receptors or excessive activation in many tumours, as the overexpression of common EGFR family in the epithelial cell tumour, the overexpression of the growth factor receptors (PDGFR) in common thrombocyte source etc. in the glioma.Similarity and some other structural characteristics according to the peptide chain-ordering, these acceptors are divided into some families: be the receptor family of representative with EGF-R ELISA (EGFR) 1), comprise EGFR, HER2, HER3 and HER4 etc., the high expression level of this receptoroid is common in the epithelial cell tumour; 2) Insulin Receptor Family comprises insulin receptor, IGF-1 (IGF-R) and Regular Insulin associated receptor (IRR) etc., the high expression level of common this receptoroid in leukemia; 3) platelet-derived growth factor receptors (PDGFR) family comprises PDGFR α, PDGFR β, clone's stimulating factor (CSF-1R), c-Kit etc., this receptoroid is common high expression level in cerebral tumor and leukemia; 4) bfgf receptor (FGFR) includes FGFR1, FGFR2, and FGFR3, FGFR4 and keratinocyte growth factor acceptor etc., this receptoroid plays an important role aspect vasculogenesis; 5) vascular endothelial growth factor receptor (VEGFR) is the important positivity regulatory factor of vasculogenesis; In addition, also have hepatocyte growth factor receptor (HGFR) class, Fibronectin III receptor class and the tame same clan of nerve growth factor acceptor (NGFR).Tyrosine kinase receptor overexpression in different types of tumors respectively causes the interior abnormal signal of its cell to activate, and causes cell transformation, constantly breeds, and promotes generation, the development of tumour, resists apoptosis, upsets the growth balance of cell.Therefore, target tyrosine kinase signal approach is good antitumor strategy.
Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) be the somatomedin of main vasoactive endotheliocyte, have the endothelial cell proliferation of promotion, increase multiple function (Hanks and Hunter such as microvascular permeability, induction of vascular generation, 1995, FASEB J.9:576-596).VEGF be at present known to the most effective, direct acting angiopoietin-like 4 protein (angiogenic protein), be a kind of diffusible endothelial cell specific mitogen and angiogenesis factor (Ferrara N et al., EndocrRev.1997,18,4-25; Tofimura T et al., Hum Pharthol.1998,29,986-991).VEGF family comprises that 6 member: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placenta generate the factor (PDF) at present, be dimer glycoprotein form, and the sterie configuration that all contains 8 regular cystine residues, the tool specificity is considered to " cystine knot " (cysteine knot).Li Ling etc. (Li Ling etc. Acta Biochimica et Biophysica Sinica, 2002,34 (1), 21-27) find malignant cell high level expression VEGF, and find also high level expression Flk-1 of tumour cell, the prompting tumor by local exists VEGF autocrine and paracrine path.The expression of VEGF and the microvessel density of some solid tumors have dependency, and the concentration of VEGF is relevant with the prognosis of some solid tumor in the tissue, as mammary cancer, lung cancer, prostate cancer and colorectal carcinoma.Known anoxic is the important factor that stimulates VEGF to produce, and the not raising of only genetic transcription rate of hypoxia inducible VEGF genetic expression in tumour cell also has the enhancing of VEGF mRNA stability.Clearly there are 3 kinds of VEGFR-1/Fit-1, VEGFR-2/Flk-1/KDR and VEGFR-4/FIt-4 in VEGFR family, and VEGFR-1 and VEGFR-2 are the cell surface tyrosine kinase receptor, mainly are positioned at the tumor vascular endothelial cell surface.Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and vascular endothelial growth factor receptor (vascularendothe-lial growth factor receptor, VEGFR) in the tumor neogenetic blood vessels forming process, play an important role, and become the important target spot that anti-tumor biological is treated.
Be that the oncotherapy of target spot mainly contains following five kinds with VEGF and VEGFR at present: 1. (EllisLM et al.J Biol Chem 1998,273,1052-1057): VEGF and VEGFR play positive control for neonate tumour blood vessel in gene therapy.By gene therapy, make VEGF and VEGFR expression decreased, or block its signal transduction pathway, thereby suppress the two performance biologic activity.2。Anti-VEGF/VEGFR monoclonal antibody (Gordon Met al.Proc Am Soc Clin Oneol, I998, I7,2IIa): the monoclonal antibody of using VEGF and VEGFR, can seal excretory VEGF and VEGFR, the endothelium signal transduction that stops VEGF to bring out suppresses the formation of blood vessel.3 small molecules inhibitions: by the su series compound of sugen company development.4。Soluble VEGFR: solvable VEGFR only has the binding ability with VEGF, but no signal transduction function.5。Two principal recipient Fit-1 of targeted therapy: VEGF and Flk-1/KDR overexpression in tumor vascular endothelial cell, and VEGFR almost can not detect in adjacent healthy tissues blood vessel endothelium.Therefore, VEGF and VEGFR provide specificity higher target spot for the targeted therapy of tumour, VEGF can with couplings such as other antitumor drugs, toxin, radionuclide, be used for the targeted therapy of tumour.
In the prior art, for example at WO9850356, WO0202551, WO02055517, WO0164681 discloses indole ketone compound among WO0160814 and the WO02096361 etc., and has announced that they are of value to the propagation of controlling improper cell by the inhibition Tyrosylprotein kinase.The su series compound of sugen company exploitation particularly, can be used as KDR/FIk-1, pdgf receptor and FGF acceptor is the inhibitor of RTK widely of target spot, plays a role by a plurality of target spots.
Summary of the invention
One object of the present invention is to provide a kind of 2-indolinone derivative, particularly 3-(3-trifluoromethyl-4-amidopyrrol-2-methylene)-2-indolinone derivative of pyrroles's replacement.
Therefore, the present invention relates to the 2-indolinone derivative that the pyrroles shown in the general formula (I) replaces, and their tautomer, enantiomorph, diastereomer, raceme and physiologically acceptable salt, wherein said tautomer comprises Z configuration and E configuration.
Figure A20061006500200071
Wherein:
R 1, R 2, R 3And R 4Be selected from respectively hydrogen atom, halogen, alkyl, haloalkyl, halogenated alkoxy, cycloalkyl, thiazolinyl, alkynyl, aryl, heteroaryl, Heterocyclylalkyl, hydroxyl ,-OR 8,-O[CH 2CH 2O] rR 11,-SR 8,-NR 10R 11,-SOR 8,-SO 2R 8,-NSO 2R 8,-SO 2NR 8R 9,-(CH 2) nCOOR 8,-(CH 2) nCONR 8R 9,-C (=S) NR 8R 9,-COR 8,-NR 8COR 9,-NHC (=O) OR 9,-OCOOR 9,-OCONR 8R 9,-CN or-NO 2, wherein aryl, heteroaryl, Heterocyclylalkyl functional group can further be replaced by alkyl or halogen;
R 5And R 6Have at least one to be trifluoromethyl; R 5And R 6Be selected from hydrogen atom, alkyl, aryl or trifluoromethyl respectively;
R 7Be selected from hydrogen atom, alkyl or-(CO) R 10
R 8And R 9Be selected from hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl respectively, wherein alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl can further be replaced by one or more alkyl, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R 8And R 9Can form 4～8 yuan of heterocyclic radicals; Wherein can further contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters, halogen or-NR 8R 9Replace;
R 10Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R 11) (CH 2) mR 12,-NR 11[CH 2CH 2O] rR 11,-NR 8R 9Perhaps-NR 11(CH 2) m[CH (OH) CH 2] pZ, wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 8R 9,-COOR 11Or CONR 8R 9
R 11Be selected from hydrogen atom or alkyl;
R 12Be selected from-NR 8R 9, hydroxyl, aryl, heteroaryl, alkoxyl group ,-O[CH 2CH 2O] rR 11,-N +(O -) R 8R 9,-N (OH) R 8,-NHC (O) R 13Or-COR 13, R wherein 13Be unsubstituted alkyl, haloalkyl or aralkyl;
N is 0～4;
R is 1～6;
M is 1～6;
P is 1～2.
In the described compound or its salt of general formula of the present invention (I), R preferably 5It is trifluoromethyl;
Typical compound of the present invention includes, but are not limited to:
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(6-ethanamide-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide; With
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide.
Another object of the present invention is to provide a kind of pharmaceutical composition, it comprises 2-indolinone derivative or its salt and the pharmaceutically acceptable carrier as the described pyrroles's replacement of general formula of the present invention (I) of medicine effective dose.
Another object of the present invention is to provide the preparation method of the 2-indolinone derivative that a kind of pyrroles replaces, may further comprise the steps:
Trifluoromethyl compound a cyclization is generated trifluoromethyl compound c;
Figure A20061006500200091
Described trifluoromethyl compound c is become compound d by the mineral alkali selective hydrolysis;
Trifluoromethyl compound e is oxidized to compound f by PCC.
Figure A20061006500200093
The purposes of the 2-indolinone derivative compound or its salt that the pyrroles that a further object of the present invention is to provide shown in the present replaces in the preparation kinases inhibitor.Derivative of the present invention can be regulated the activity of protein kinase, therefore can be used for the prevention and the treatment of protein kinase dependency cell dysfunction.Thereby as seen, compound of the present invention can also be used for the treatment of and relate to the active dysfunction of unusual PK.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
In order to prepare compound of the present invention, mainly finish with following general synthetic method:
Figure A20061006500200101
Raw material a is obtained compound b with the Sodium Nitrite reaction in the presence of acetic acid; The cyclization under the zinc powder effect of compound b and 3-carbonyl-butyric acid-tert-butyl ester obtains compound c; Make solvent with tetrahydrofuran (THF), first alcohol and water, the ester hydrolysis takes place and obtains compound d in compound c under the potassium hydroxide effect; Compound d obtains Verbindung through borane reduction; Verbindung is oxidized to aldehyde cpd f through PCC; Further, compound f obtains compound g after sloughing the tertiary butyl under the effect of trifluoroacetic acid; Next, compound g obtains amide compound h with the reaction of different amine; At last, compound h just makes the compound shown in the general formula (I) with the indolone condensation of different replacements.
Wherein, in general formula (I) molecule two keys be configured as Z configuration (cis), this point can be inferred by nuclear magnetic data.Usually the chemical shift at NH on the pyrrole ring is about 9ppm, and in the compound that obtains the NH on the pyrrole ring about 14ppm, major cause is that the oxygen of NH and the indolone carbonyl that closes on the pyrrole ring has the intramolecular hydrogen bond effect, causes the chemical shift of NH to shift to low.This point also is described in patent WO0160814 (Su-11248).
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment are not limiting scope of the present invention.
Embodiment
The structure of all derivative compounds that the present invention relates to is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is to use the BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterochloroform (CDCl 3), deuterated dimethyl sulfoxide (DMSO-D 6), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph.
The mensuration of the average inhibiting rate of kinases VEGFR is used HTScan microplate reader (Cell Signaling company).
The mensuration of the average inhibiting rate of kinases EGFR/HER-2 is with NovoStar microplate reader (German BMG company).
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
DMSO-D 6: deuterated dimethyl sulfoxide;
CDCl 3: deuterochloroform;
PCC: pyridine chromium trioxide hydrochloride
Preparation embodiment:
Embodiment 1
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200111
Figure A20061006500200121
The first step
4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates
Under the condition of ice bath, with 4,4,4-three fluoro-3-carbonyl-ethyl butyrate 1a (3.822 g, 20.75mmol) and Glacial acetic acid (6ml) join in the round-bottomed flask of 100ml, stir the aqueous solution (14.2g that dropwise drips Sodium Nitrite down, 20.75mmol be dissolved in the 4ml water), control reaction temperature is 0～5 ℃ in whole process, after dropping finishes, add water (1ml) again, in ice-water bath, react half an hour, remove ice-water bath, at room temperature continue about 3 hours of reaction, the point plate tracks to raw material and disappears, reaction finishes, and obtains title product 4,4, the solution of 4-three fluoro-2-oximido 3-carbonyl-ethyl butyrate 1b is directly cast single step reaction.
Second step
5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the 4 dicarboxylic acid-4-tert-butyl ester-2-ethyl ester
Get one and be furnished with thermometer, the three-necked flask of the 100ml of dropping funnel takes by weighing the 3-carbonyl-butyric acid-tert-butyl ester (3.28g, 20.75mmol), Glacial acetic acid (9.3ml) is warming up to 65 ℃ under stirring in three-necked bottle, weighing zinc powder (2.7g, 41.5mmol), drip the reaction solution 1b that the first step is reacted with dropping funnel, add zinc powder several times, water-bath hierarchy of control temperature remains on about 75 ℃, reacted 2 hours, and reduced the temperature to 40～45 ℃ then, reaction is spent the night.The point plate is followed the tracks of reaction and is finished, and adds entry (30ml) and ethyl acetate (50ml) in reaction solution, stirs after 15 minutes, with ethyl acetate (50ml * 3) extractive reaction liquid.Merge organic phase, water (50ml * 2), saturated sodium bicarbonate aqueous solution (50ml * 2), saturated sodium-chloride water solution (50ml * 2) washing successively, the ethyl acetate layer anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, resistates obtains title product 5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4 dicarboxylic acid-4-tert-butyl ester-2-ethyl ester 1c (3.66g with toluene-normal hexane recrystallization, the cotton-shaped solid of white), productive rate: 55%.
MS?m/z(ESI)：320(M-1)。
1H?NMR(400MHz，CDCl 3-d)9.94(brs，1H，N H)，4.37(q，J＝7.2Hz，2H，C H 2CH 3)，2.45(s，3H，C H 3)，1.56(s，9H，3×CC H 3)，1.37(t，J＝7.2Hz，3H，CH 2C H 3)。
The 3rd step
5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the 4 dicarboxylic acid-4-tert-butyl ester
In the round-bottomed flask of 1000ml, add 5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2 respectively, 4 dicarboxylic acid-4-the tert-butyl ester-2-ethyl ester 1c (19.0g, 59.2mmol), tetrahydrofuran (THF) (150ml), methyl alcohol (150ml), water (200ml) and potassium hydroxide (4.04g, 59.2mmol), be heated to 30 ℃, stirring is spent the night, next day, reaction solution is boiled off partial solvent to white solid occurring, add ethyl acetate (500ml) and saturated sodium bicarbonate solution (150ml) extractive reaction liquid, organic phase is used saturated sodium bicarbonate solution (150ml * 2) washing again, combining water layer, and it is 1 that water is regulated pH with concentrated hydrochloric acid, with ethyl acetate (200ml * 2) aqueous layer extracted, merge organic phase, the ethyl acetate layer anhydrous magnesium sulfate drying filters, filtrate decompression concentrate title product 5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4 dicarboxylic acid-4-tert-butyl ester 1d (9.8g, white solid), productive rate 56%.
The 4th step
5-methylol-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester
Under the nitrogen atmosphere, in the 250ml round-bottomed flask, with 5-methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4 dicarboxylic acid-4-tert-butyl ester 1d (9.8g, 33.4mmol) stir down and be dissolved in the anhydrous tetrahydro furan (20ml) tetrahydrofuran solution (67ml, the 1mol/L of dropping borine in reaction solution, 67mmol), stirring at room is 4 hours.The point plate tracks to raw material and disappears, and (2ml 50%v/v) with the cancellation reaction, adds ethyl acetate (200ml), again with saturated sodium bicarbonate solution abstraction reaction liquid (100ml * 3) slowly to drip dilute acetic acid in reaction solution.Merge organic phase, the ethyl acetate layer anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates (ethyl acetate/normal hexane=1: 4), obtain title product 5-methylol-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester 1e (5.0g, white solid), productive rate 55%.
MS?m/z(ESI)：278(M-1)。
1H?NMR(400MHz，CDCl 3-d)8.05(brs，1H，N H)，4.80(s，2H，C H 2OH)，2.47(s，3H，C H 3)，1.55(s，9H，3×CC H 3)。
The 5th step
5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester
With pyridine chromium trioxide hydrochloride (4.3g, 19.99mmol), sodium-acetate (1.0g, 12.36mmol) and methylene dichloride (50ml) add in the 250ml round-bottomed flask, stir the methylene dichloride suspension solution (5.0g of slow Dropwise 5-methylol-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester 1e down, 80ml), room temperature reaction 5 hours, some plate are followed the tracks of raw material and are disappeared substantially.Reaction solution is through diatomite filtration; concentrating under reduced pressure with silica gel column chromatography purifying gained resistates (ethyl acetate/normal hexane=1: 8), obtains title product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester 1f (3.51g; white solid), productive rate 70%.
MS?m/z(ESI)：276(M-1)。
1H?NMR(400MHz，CDCl 3-d)9.83(s，1H，C HO)，9.57(brs，1H，N H)，2.57(s，3H，C H 3)，1.57(s，9H，3×CC H 3)。
The 6th step
5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid
In the there-necked flask of 100ml; with 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-4-tert-butyl ester 1f (3.5g; 12.67mmol) be dissolved in the methylene dichloride (35ml), adding trifluoracetic acid under stirring (9.4ml, 126.7mmol); room temperature reaction 5 hours; the point plate is followed the tracks of raw material and is disappeared substantially, and the reaction solution concentrating under reduced pressure is spin-dried for solvent, obtains title product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid 1g (2.95g; white solid), productive rate 100%.Be directly used in next step reaction.
MS?m/z(ESI)：220(M-1)。
The 7th step
5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Under the nitrogen atmosphere; in the there-necked flask of a 250ml; with 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid 1g (2.95g; 12.67mmol) be dissolved in the N ' dinethylformamide (40ml); stir and add N-ethyl-N '-(dimethylamino-propyl)-carbodiimide hydrochloride (3.64g down successively; 19.00mmol); I-hydroxybenzotriazole (2.57g; 19.00mmol); triethylamine (3.2g; 31.68mmol) and diethylin ethamine (2.20g; 19.00mmol); stirring at room 8 hours; the point plate tracks to raw material and disappears substantially; add methylene dichloride (200ml) in the stirring downhill reaction liquid, with saturated sodium bicarbonate solution (80ml * 3) cleaning mixture, combining water layer methylene dichloride (80ml * 1) Hui Cui.Merge organic phase; the dichloromethane layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates title product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-acid amides 1h (5.1g; oily matter), directly carry out next step reaction.
MS?m/z(ESI)：320(M+1)。
The 8th step
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Directly be not dissolved in the ethanol (10ml) previous step product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h (5.1g) is purified; stir and add 5-fluoro-1 down; 3-dihydro-indol-2-one (1.53g; 10.14mmol) and hexahydropyridine (85mg; 1.01mmol); reflux 8 hours; the point plate tracks to raw material and disappears substantially; reaction solution naturally cools to room temperature; there is yellow solid to produce; filter, solid washs with cold ethanol (2ml * 2), vacuum-drying; obtain title product 5-(5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-and 2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1 (3.4g, yellow solid), productive rate 55%.
MS?m/z(ESI)：453(M+1)。
1H?NMR(400MHz，DMSO-d6)7.61(d，J＝8.4Hz，1H，Ar H)，7.57(s，1H，C H)，7.07(m，1H，Ar H)，，6.92(m，1H，Ar H)，3.28(t，J＝6.8Hz，2H，NCH 2CH 2NEt 2)，2.51(m，6H，2×NC H 2CH 3?and?C H 2NEt 2)，2.39(s，3H，C H 3)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 2
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200151
Repeat the embodiment of the invention reaction in seven steps of 1 the first step to the; different be to use that resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h makes raw material in above-mentioned the 7th step; make this raw material and 5-chloro-1 according to described same way as of the embodiment of the invention 1 the 8th step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-chloro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 2 (98mg; yellow solid), productive rate: 35.4%.
MS?m/z(ESI)：469(M+1)。
1H?NMR(400MHz，DMSO-d6)7.83(s，1H，Ar H)，7.62(s，1H，C H)，7.27(d，J＝8.4Hz，1H，Ar H)，6.94(d，J＝8.4Hz，1H，Ar H)，3.28(t，J＝6.8Hz，2H，NC H 2CH 2NEt 2)，2.51(m，6H，2×NC H 2CH 3?and?C H 2NEt 2)，2.39(s，3H，C H 3)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 3
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200152
Repeat the embodiment of the invention reaction in seven steps of 1 the first step to the; different be to use that resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h makes raw material in above-mentioned the 7th step; make this raw material and 5-chloro-1 according to described same way as of the embodiment of the invention 1 the 8th step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-bromo-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 3 (124mg; yellow solid), productive rate: 38%.
MS?m/z(ESI)：513(M)。
1H?NMR(400MHz，DMSO-d6)7.94(s，1H，Ar H)，7.61(s，1H，C H)，7.39(d，J＝8.4Hz，1H，Ar H)，6.89(d，J＝8.0Hz，1H，Ar H)，3.28(t，J＝6.8Hz，2H，NC H 2CH 2NEt 2)，2.51(m，6H，2×NC H 2CH 3?and?C H 2NEt 2)，2.39(s，3H，C H 3)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 4
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200161
Repeat the embodiment of the invention reaction in seven steps of 1 the first step to the; resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h makes raw material in above-mentioned the 7th step of different uses; make this raw material and 5-Toluidrin-1 according to described same way as of the embodiment of the invention 1 the 8th step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-Toluidrin-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 4 (50mg; yellow solid), productive rate: 15%.
MS?m/z(ESI)：528(M+1)。
1H?NMR(400MHz，DMSO-d6).14.14(s，1H，N H)，12.23(s，1H，N H)，9.40(s，1H，N H)，8.03(s，1H，N H)，7.46(s，1H，Ar H)，7.44(d，J＝8.4Hz，1H，Ar H)，7.16(d，J＝8.4Hz，1H，Ar H)，6.93(d，J＝8.0Hz，1H，Ar H)，3.28(t，J＝6.8Hz，2H，NC H 2CH 2NEt 2)，2.95(s，3H，C H 3SO 2)，2.51(m，6H，2×NC H 2CH 3?and?C H 2NEt 2)，2.40(s，3H，C H 3)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 5
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200171
Repeat the embodiment of the invention reaction in seven steps of 1 the first step to the; different be to use that resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h makes raw material in above-mentioned the 7th step; make this raw material and 5-ethanamide-1 according to described same way as of the embodiment of the invention 1 the 8th step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-ethanamide-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 5 (120mg; yellow solid), productive rate: 38.7%.
MS?m/z(ESI)：492(M+1)。
1H?NMR(400?MHz，DMSO-d6)7.79(s，1H，Ar H)，7.44(d，J＝8.4Hz，1H，Ar H)，7.39(s，1H，C H)，6.88(d，J＝8.0Hz，1H，Ar H)，3.28(t，J＝6.8Hz，2H，NC H 2CH 2NEt 2)，2.51(m，6H，2×NC H 2CH 3?and?C H 2NEt 2)，2.38(s，3H，C H 3)，2.04(s，3H，C H 3CO)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 6
5-(6-ethanamide-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide
Figure A20061006500200172
Compound 6-ethanamide-5-fluoro-1, the 3-dihydro-indol-2-one is by 6-amino-5-fluoro-1, and the excess acetyl chloride of 3-dihydro-indol-2-one and equivalent is prepared from.
Repeat the embodiment of the invention reaction in seven steps of 1 the first step to the; different be to use that resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 1h makes raw material in above-mentioned the 7th step; make this raw material and 6-ethanamide-5-fluoro-1 according to described same way as of the embodiment of the invention 1 the 8th step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(6-ethanamide-5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide 6 (84mg; yellow solid), productive rate: 26%.
MS?m/z(ESI)：510(M+1)。
1H?NMR(400MHz，DMSO-d6)7.71(s，1H，Ar H)，7.68(s，1H，Ar H)，7.46(s，1H，C H)，3.27(t，J＝6.8Hz，2H，NC H 2CH 2NEt 2)，2.51(m，6H，2×NC H 2CH 3?andC H 2NEt 2)，2.37(s，3H，C H 3)，2.12(s，3H，C H 3CO)，0.97(t，J＝6.8Hz，6H，2×NCH 2C H 3)。
Embodiment 7
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200181
The first step
5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
According to described same way as of the 7th step of the embodiment of the invention 1; under the nitrogen atmosphere; in the there-necked flask of a 250ml; with 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid 1g (0.605g; 2.73mmol) be dissolved in the N ' dinethylformamide (8.5ml); stir and add N-ethyl-N '-(dimethylamino-propyl)-carbodiimide hydrochloride (1.047g down successively; 5.46mmol); I-hydroxybenzotriazole (553mg; 2.73mmol); triethylamine (0.689g; 6.83mmol) and N-morphine quinoline-4-base-ethamine (532mg; 4.095mmol); stirring at room 8 hours, the some plate tracks to raw material and disappears substantially, stirs in the downhill reaction liquid to add methylene dichloride (200ml); with saturated sodium bicarbonate solution (80ml * 2) cleaning mixture, combining water layer methylene dichloride (50ml * 1) Hui Cui.Merge organic phase; the dichloromethane layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates title product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 7a (1.190g; oily matter), directly carry out next step reaction.
Second step
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
According to described same way as of the 8th step of the embodiment of the invention 1; with previous step product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 7a (137mg; 0.41mmol) not purified directly being dissolved in the ethanol (2ml); stir and add 5-fluoro-1 down; 3-dihydro-indol-2-one (59mg; 0.39mmol) and hexahydropyridine (4mg; 0.04mmol); reflux 8 hours, the some plate tracks to raw material and disappears substantially, and reaction naturally cools to room temperature; there is yellow solid to produce; filter, solid washs with cold ethanol (5ml), vacuum-drying; obtain title product 5-(5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-and 2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 7 (84mg, yellow solid), productive rate 44%.
MS?m/z(ESI)：467(M+1)。
1H?NMR(400?MHz，DMSO-d6)7.63(d，J＝8.4Hz，1H，Ar H)，7.58(s，1H，C H)，7.07(d，J＝8.0Hz，1H，Ar H)，6.93(m，1H，Ar H)，3.57(t，J＝6.8Hz，4H，2×NCH 2C H 2O)，3.35(t，J＝6.8Hz，2H，NC H 2CH 2N)，2.45(m，6H，2×NC H 2CH 2O?andNCH 2C H 2N)，2.34(s，3H，C H 3)。
Embodiment 8
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200191
Repeat the reaction of the embodiment of the invention 7 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-morphine quinoline-4-base-ethyl)-methane amide 7a that are to use make raw material; make this raw material and 5-chloro-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-chloro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 8 (98mg; orange/yellow solid), productive rate: 35.6%.
MS?m/z(ESI)：483(M+1)。
1H?NMR(400MHz，DMSO-d6)7.83(s，1H，Ar H)，7.62(s，1H，C H)，7.28(d，J＝8.0Hz，1H，Ar H)，6.95(d，J＝8.0Hz，1H，Ar H)，3.57(m，4H，2×NCH 2C H 2O)，3.38(t，J＝6.8Hz，2H，NC H 2CH 2N)，2.45(m，6H，2×NC H 2CH 2O?and?NCH 2C H 2N)，2.34(s，3H，C H 3)。
Embodiment 9
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200201
Repeat the reaction of the embodiment of the invention 7 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-morphine quinoline-4-base-ethyl)-methane amide 7a that are to use make raw material; make this raw material and 5-bromo-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-bromo-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 9 (77mg; yellow solid)
Productive rate: 37%.
MS?m/z(ESI)：527(M)。
1H?NMR(400MHz，DMSO-d6)7.98(s，1H，Ar H)，7.63(s，1H，C H)，7.40(d，J＝8.4Hz，1H，Ar H)，6.90(d，J＝8.0Hz，1H，Ar H)，3.57(t，J＝6.8Hz，4H，2×NCH 2C H 2O)，3.34(t，J＝6.8Hz，2H，NC H 2CH 2N)，2.43(m，6H，2×NC H 2CH 2O?andNCH 2C H 2N)，2.39(s，3H，C H 3)。
Embodiment 10
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200202
Repeat the reaction of the embodiment of the invention 7 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-morphine quinoline-4-base-ethyl)-methane amide 7a that are to use make raw material; make this raw material and 5-Toluidrin-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-Toluidrin-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 10 (35mg; yellow solid), productive rate: 16%.
MS?m/z(ESI)：542(M+1)。
1H?NMR(400MHz，DMSO-d6)7.46(s，1H，Ar H)，7.43(s，1H，C H)，7.15(d，J＝8.4Hz，1H，Ar H)，6.94(d，J＝8.0Hz，1H，Ar H)，3.66(t，J＝6.8Hz，4H，2×NCH 2C H 2O)，3.30(t，J＝6.8Hz，2H，NC H 2CH 2N)，2.98(s，3H，C H 3SO 2)，2.43(m，6H，2×NC H 2CH 2O?and?NCH 2C H 2N)，2.39(s，3H，C H 3)。
Embodiment 11
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200211
Repeat the reaction of the embodiment of the invention 7 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-morphine quinoline-4-base-ethyl)-methane amide 7a that are to use make raw material; carry out this raw material and 5-ethanamide-1 according to described same way as of 7 second step of the embodiment of the invention; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-ethanamide-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 11 (86mg; yellow solid), productive rate: 31.5%.
MS?m/z(ESI)：506(M)。
1H?NMR(400MHz，DMSO-d6)7.79(s，1H，Ar H)，7.44(d，J＝8.4Hz，1H，Ar H)，7.40(s，1H，C H)，6.88(d，J＝8.0Hz，1H，Ar H)，3.57(m，4H，2×NCH 2C H 2O)，3.34(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.44(m，6H，2×NC H 2CH 2O?and?NCH 2C H 2N)，2.40(s，3H，C H 3)，2.04(s，3H，C H 3CO)。
Embodiment 12
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide
Figure A20061006500200212
Repeat the reaction of the embodiment of the invention 7 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-morphine quinoline-4-base-ethyl)-methane amide 7a that are to use make raw material; make this raw material and 6-amino-5-fluoro-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(6-amino-5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide 12 (115mg; yellow solid), productive rate: 61%.
MS?m/z(ESI)：482(M+1)。
1H?NMR(400MHz，DMSO-d6)7.36(d，J＝10.8Hz，1H，Ar H)，7.16(s，1H，C H)，6.37(d，J＝7.6Hz，1H，Ar H)，3.58(m，4H，2×NCH 2C H 2O)，3.32(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.42(m，6H，2×NC H 2CH 2O?and?NCH 2C H 2N)，2.34(s，3H，C H 3)。
Embodiment 13
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
Figure A20061006500200221
The first step
5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
According to described same way as of the 7th step of the embodiment of the invention 1; under the nitrogen atmosphere; in the there-necked flask of a 250ml; with 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid 1g (0.605g; 2.73mmol) be dissolved in the N ' dinethylformamide (8ml); stir and add N-ethyl-N '-(dimethylamino-propyl)-carbodiimide hydrochloride (1.047g down successively; 5.46mmol); I-hydroxybenzotriazole (0.553g; 4.09mmol); triethylamine (0.689g; 6.82mmol) and N-piperidines-1-base-ethamine (0.525g; 4.09mmol); stirring at room 8 hours, the some plate tracks to raw material and disappears substantially, stirs in the downhill reaction liquid to add methylene dichloride (200ml); with saturated sodium bicarbonate solution (80ml * 2) cleaning mixture, combining water layer methylene dichloride (50ml * 1) Hui Cui.Merge organic phase; the dichloromethane layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates title product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 13a (1.188g; oily matter), directly carry out next step reaction.
Second step
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
According to described same way as of the 8th step of the embodiment of the invention 1; with previous step product 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 13a (121mg; 0.364mmol) not purified being dissolved in the ethanol (2ml); stir and add 5-fluoro-1 down; 3-dihydro-indol-2-one (52mg; 0.346mmol) and hexahydropyridine (3mg; 0.036mmol); reflux 8 hours, the some plate tracks to raw material and disappears substantially, and reaction naturally cools to room temperature; there is yellow solid to produce; filter, solid washs with cold ethanol (5ml), vacuum-drying; obtain title product 5-(5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-and 2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 7 (62mg, yellow solid), productive rate 37%.
MS?m/z(ESI)：465(M+1)。
1H?NMR(400MHz，DMSO-d6)7.63(d，J＝6.8Hz，1H，Ar H)，7.58(s，1H，C H)，7.06(m，1H，Ar H)，6.93(m，1H，Ar H)，3.32(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.45(s，3H，C H 3)，2.39(m，6H，2×CH 2NC H 2CH 2?and?NCH 2C H 2N)，1.50(m，4H，C H 2CH 2C H 2)，1.38(m，2H，CH 2C H 2CH 2)。
Embodiment 14
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
Figure A20061006500200231
Repeat the reaction of the embodiment of the invention 13 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-piperidines-1-base-ethyl)-methane amide 13a that are to use make raw material; make this raw material and 5-chloro-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-chloro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 14 (84mg; yellow solid), productive rate: 50%.
MS?m/z(ESI)：481(M+1)。
1H?NMR(400MHz，DMSO-d6)7.83(s，1H，Ar H)，7.62(s，1H，C H)，7.27(d，J＝8.4Hz，1H，Ar H)，6.95(d，J＝8.4Hz，1H，Ar H)，3.32(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.41(s，3H，C H 3)，2.38(m，6H，2×CH 2NC H 2CH 2?and?NCH 2C H 2N)，1.50(m，4H，C H 2CH 2C H 2)，1.38(m，2H，CH 2C H 2CH 2)。
Embodiment 15
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
Figure A20061006500200241
Repeat the reaction of the embodiment of the invention 13 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-piperidines-1-base-ethyl)-methane amide 13a that are to use make raw material; make this raw material and 5-bromo-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-bromo-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 15 (110mg; yellow solid), productive rate: 21%.
MS?m/z(ESI)：525(M)。
1H?NMR(400MHz，DMSO-d6)7.96(s，1H，Ar H)，7.62(s，1H，C H)，7.40(d，J＝8.4Hz，1H，Ar H)，6.90(d，J＝8.4Hz，1H，Ar H)，3.32(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.41(s，3H，C H 3)，2.37(m，6H，2×CH 2NC H 2CH 2?and?NCH 2C H 2N)，1.50(m，4H，C H 2CH 2C H 2)，1.38(m，2H，CH 2C H 2CH 2)。
Embodiment 16
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
Figure A20061006500200242
Repeat the reaction of the embodiment of the invention 13 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-piperidines-1-base-ethyl)-methane amide 13a that are to use make raw material; make this raw material and 5-ethanamide-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(5-ethanamide-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 16 (76mg; yellow solid), productive rate: 44%.
MS?m/z(ESI)：504(M+1)。
1H?NMR(400MHz，DMSO-d6)7.79(s，1H，Ar H)，7.44(d，J＝8.4Hz，1H，Ar H)，7.39(s，1H，C H)，6.88(d，J＝8.4Hz，1H，Ar H)，3.30(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.41(s，3H，C H 3)，2.38(m，6H，2×CH 2NC H 2CH 2?and?NCH 2C H 2N)，2.03(s，3H，C H 3CO)，1.50(m，4H，C H 2CH 2C H 2)，1.38(m，2H，CH 2C H 2CH 2)。
Embodiment 17
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide
Repeat the reaction of the embodiment of the invention 13 the first steps; different resulting compound 5-formyl radical-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid in the above-mentioned the first step-(2-piperidines-1-base-ethyl)-methane amide 13a that are to use make raw material; make this raw material and 6-amino-5-fluoro-1 according to described same way as of the embodiment of the invention 7 second step; the reaction of 3-dihydro-indol-2-one; then obtain title product 5-(6-amino-5-fluoro-2-oxo-1; 2-dihydro-indoles-3-subunit-methyl)-and 2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide 17 (130mg), productive rate: 78%.
MS?m/z(ESI)：480(M+1)。
1H?NMR(400MHz，DMSO-d6)7.35(d，J＝7.6Hz，1H，Ar H)，7.16(s，1H，C H)，6.37(d，J＝7.6Hz，1H，Ar H)，3.32(t，J＝6.4Hz，2H，NC H 2CH 2N)，2.39(m，6H，2×CH 2NC H 2CH 2?and?NCH 2C H 2N)，2.30(s，3H，C H 3)，1.49(m，4H，C H 2CH 2C H 2)，1.37(m，2H，CH 2C H 2CH 2)。
Test case:
The mensuration of kinase inhibiting activity
At target spot VEGFR, detection mode is that (Time-resolvedFluorescence TRF), uses the HTScan VEGF-R2 Kinase Assay Kit (Cat.No.7788) of Cell Signaling company to time-resolved fluoroimmunoassay, tests highly sensitive.Through groping of experiment condition repeatedly, determine that in 30 μ l reaction systems use reorganization VEGFR2 albumen 6U, concentration of substrate is 1.5 μ M, suppressing compound concentration is the basic parameters of 10 μ M as screening model, and testing compound is screened;
At target spot EGFR/HER-2, use the K-LISA of CALBIOCHEM company TM96 hole elisa plates of PTK ScreeningKit (Cat.No.539701) and EGFR/HER-2 effect E4Y substrate bag quilt, kinases (rat spleen extract) 0.25-1 μ g is used in the reaction of every hole, using the inhibition compound concentration simultaneously is the basic parameter of the experiment condition of 50 μ M as the screening platform, so that testing compound is screened.
The present invention records the EGFR/HER-2 of compound and the average kinase inhibition rate of VEGFR sees Table 1
The average kinase inhibition rate of table 1 EGFR/HER-2 and VEGFR
Figure A20061006500200261

Claims (6)

1. 2-indolinone derivative or its salt that replaces by the pyrroles of general formula (I) expression:
Wherein:
R 1, R 2, R 3And R 4Be selected from respectively hydrogen atom, halogen, alkyl, haloalkyl, halogenated alkoxy, cycloalkyl, thiazolinyl, alkynyl, aryl, heteroaryl, Heterocyclylalkyl, hydroxyl ,-OR 8,-O[CH 2CH 2O] rR 11,-SR 8,-NR 10R 11,-SOR 8,-SO 2R 8,-NSO 2R 8,-SO 2NR 8R 9,-(CH 2) nCOOR 8,-(CH 2) nCONR 8R 9,-C (=S) NR 8R 9,-COR 8,-NR 8COR 9,-NHC (=O) OR 9,-OCOOR 9,-OCONR 8R 9,-CN or-NO 2, wherein aryl, heteroaryl, Heterocyclylalkyl functional group can further be replaced by alkyl or halogen;
R 5And R 6Have at least one to be trifluoromethyl; R 5And R 6Be selected from hydrogen atom, alkyl, aryl or trifluoromethyl respectively;
R 7Be selected from hydrogen atom, alkyl or-(CO) R 10
R 8And R 9Be selected from hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl respectively, wherein alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl can further be replaced by one or more alkyl, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R 8And R 9Can form 4～8 yuan of heterocyclic radicals; Wherein can further contain one or more N, O, S atom in 5～8 yuan of heterocycles, and can be further on 4～8 yuan of heterocycles by one or more alkyl, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters, halogen or-NR 8R 9Replace;
R 10Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R 11) (CH 2) mR 12,-NR 11[CH 2CH 2O] rR 11,-NR 8R 9Perhaps-NR 11(CH 2) m[CH (OH) CH 2] pZ, wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 8R 9,-COOR 11Or CONR 8R 9
R 11Be selected from hydrogen atom or alkyl;
R 12Be selected from-NR 8R 9, hydroxyl, aryl, heteroaryl, alkoxyl group ,-O[CH 2CH 2O] rR 11,-N +(O -) R 8R 9,-N (OH) R 8,-NHC (O) R 13Or-COR 13, R wherein 13Be unsubstituted alkyl, haloalkyl or aralkyl;
N is 0～4;
R is 1～6;
M is 1～6;
P is 1～2.
2. 2-indolinone derivative or its salt, wherein R that pyrroles according to claim 1 replaces 5It is trifluoromethyl;
3. compound or its salt according to claim 1 and 2, comprising:
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(6-ethanamide-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-diethylin-ethyl)-methane amide;
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-Toluidrin-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-morphine quinoline-4-base-ethyl)-methane amide;
5-(5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-chloro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-bromo-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide;
5-(5-ethanamide-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide; With
5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indoles-3-subunit-methyl)-2-methyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-carboxylic acid-(2-piperidines-1-base-ethyl)-methane amide.
4. the preparation method of the 2-indolinone derivative that pyrroles according to claim 1 and 2 replaces may further comprise the steps:
Trifluoromethyl compound a is pressed the following formula cyclization generate trifluoromethyl compound c;
Figure A2006100650020004C1
Described trifluoromethyl compound c is become compound d by the mineral alkali selective hydrolysis;
Figure A2006100650020004C2
Trifluoromethyl compound e is oxidized to compound f by PCC.
Figure A2006100650020004C3
5. pharmaceutical composition, it comprises any one described pyrroles replaces in the claim 1～3 of medicine effective dose 2-indolinone derivative or its salt and pharmaceutically acceptable carrier.
6. according to the purposes of any one described compound or its salt in the claim 1～3 in the preparation kinases inhibitor.
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