CN106565682A - Substituted indolinone derivative and application thereof - Google Patents

Substituted indolinone derivative and application thereof Download PDF

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CN106565682A
CN106565682A CN201610988209.2A CN201610988209A CN106565682A CN 106565682 A CN106565682 A CN 106565682A CN 201610988209 A CN201610988209 A CN 201610988209A CN 106565682 A CN106565682 A CN 106565682A
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methyl
bases
pyrroles
alkyl
anilino
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CN106565682B (en
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秦铭泽
宫平
章浩天
赵燕芳
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 a substituted indolinone derivative represented as the general formula (I) and used as a tyrosine kinase inhibitor, and medicinal acceptable salts or isomers thereof, wherein the R1, R2, R3, R4, R5, R6, R7, n and the ring A are defined as the specifications. The invention also relates to a preparation method of the compound, and an application of the compound in preparation of medicines for prevention or therapy of fibrosis diseases and excess hyperplasia diseases.

Description

Full ketone derivatives of substituted indole and application thereof
Technical field：
The present invention relates to the new dihydroindole ketone derivate as tyrosine kinase inhibitor, and its it is pharmaceutically acceptable Salt or isomers.The invention further relates to the preparation method of the compound, and the compound is in preparation prevention or treats fine Purposes in the medicine of dimension degenerative disease and excessively proliferative disease.
Background technology：
Angiogenesiss are to form the process of new blood vessel from vein development after existing capillary or capillary, just Under normal physiological condition, observe only during wound healing, embryonic development etc..New vessels generate be promote vascularization because The complex process of son and inhibiting factor coordinative role, under normal circumstances the two is in poised state, once break will for this balance Activation Angiogenesiss system, makes Angiogenesiss excessively, causes proliferative related disorders.Have conclusive evidence at present to show, blood vessel It is the neoplastic crucial sexual stage of swelling to generate excessive, particularly endothelial cell proliferation and the new vascular generation of association, newly-generated Blood vessel can be provided necessary " nutrition " for the growth of tumour.
New vessels generate to be regulated and controled by various growth factors (Musumeci et al., J Med Chem, 2012, 55,10797-10822).VEGF (Vascular endothelial growth factor, VEGF) is most For crucial Angiogenesiss stimulating factor, after it is combined with the acceptor VEGFR on endothelial cell, directly stimulate vascular endothelial cell Propagation, play central regulating and controlling effect (Ferrara et al., Nat Rev Drug Discovery, 2016,15,385- 403).In vivo and in vitro shows that platelet derived growth factor (Platelet-derived growth factor, PDGF) can Tumor Angiongesis, pericyte are stimulated to play important in tumor vessel development, ripe, stabilization process by raising pericyte Effect (Abramsson et al., Clin Invest, 2003,112:1142-1151).After PDGF signals weaken, can be obvious It was observed that the disappearance of tumor vessel pericyte and tumor vascular degeneration (Kitadai et al., Am J Pathol, 2006, 169:2054-2065).Additionally, fibroblast growth factor (Fibroblast growth factor, FGF) is also blood vessel The stimulating factor of generation, when VEGFR is persistently suppressed, the alternative activation of FGF mediations is had been found to as tumor cell proliferation One of mechanism, it is related to the generation of VEGFR inhibitor drug resistances (Casanovas et al., Cancer Cell, 2005,8, 299-309).The receptor tyrosine kinase activities such as targeted inhibition VEGFR, PDGFR, FGFR become suppression tumor neogenetic blood vessels life Into and tumor cell proliferation effective means, inhibitor Sorafenib, the Sutent of VEGFR and PDGFR is in succession by FDA Ratify treatment (Wilhelm et al., Nat Rev Drug Discovery, the 2006,5,835-844 for solid tumor； Roskoski et al.,Biochem Biophys Res Commun,2007,356,323-328)。
Additionally, recent studies indicate that VEGF, PDGF and FGF growth factor family is induced and lasting with fibrotic It is related.Repair procedure can be started when tissue suffers damage or inflammation is attacked so as to recover to initial state.However, abnormal Uncontrolled tissue repair can cause fibrotic formation.The fibrotic mistake for being characterised by extracellular matrix components Degree deposition and fibroblastic undue growth, the pathology is sexually revised and mostly occurred in the histoorgans such as skin, lung, liver, kidney, and Serious function damage, or even threat to life can be caused.
Research shows that suppression PDGF can effectively weaken hepatic fibrosis and pnemnofibrosis, point out different tissues Fibre modification may have similar mechanism, and it is directly related with the expression of PDGF (Borkham-Kamphorst et al., Biochem Biophys Res Commun,2015,457,307-313；Chaudhary et al.,Eur Respir J, 2007,29,976-985).Similar, the FGF related to interstitial scarring is expressed in people's renal interstitial fibre modification and experimental lung Present in fibrosis model and raise, reconfirm that the fibre modification in different tissues has common basis (Strutz et al.,Kidney Intl,2000,57,1521-1538；Barrios et al.,Am J Physiol,1997,273(2Pt1), L451-8).The expression of VEGF increases related to a large amount of microvascular formation and pulmonary fibrosis, and in the research to asthmatic patient It is observed that vegf expression rising (Kanazawa et al., Am J Respir CritCare Med, 2004,169, 1125-1130)；What the mouse that FGF is not enough also showed hepatic fibrosis after Long Term Contact carbon tetrachloride significantly reduces (Yu et al.,Am J Pathol,2003,163,1653-1662)。
Above-mentioned evidence shows that the growth factor such as VEGFR, PDGF and FGF and its acceptor are in hyperproliferative disease and fibre The adjustment effect of key is played in dimension degenerative process, the important plan that tyrosine kinase inhibitor is medicament research and development is targetedly developed Slightly.Idiopathic pulmonary fibrosis is a kind of lethal lung disease serious to mankind's harm, and middle position of the patient after diagnosis is given birth to The phase of depositing is only 2-3, and effective treatment means are clinically still lacked at present, and only pirfenidone, Nintedanib can alleviate disease Progress (structure sees below formula).Pirfenidone plays anti-fibrosis effect by suppressing TGF signal betas path, and Nintedanib can suppress EGFR-TK VEGFR, PDGFR and FGFR are active, for tumour and Fibrotic treatment (Roth et al., J Med Chem,2015,58,1053-1063)。
The present invention relates to the full ketone derivatives of the novel 6- substituted indoles of a class formation, to junket such as VEGFR, PDGFR and FGFR Histidine kinase shows prominent inhibitory activity, and can effectively suppress the propagation of vascular endothelial cell, tumour cell, part chemical combination Thing effect is suitable with Nintedanib or more excellent.
The content of the invention
The present invention relates to the dihydroindole ketone derivate and its pharmaceutically acceptable salt or isomers shown in formula I,
Wherein,
R1Represent hydrogen atom or prodrug base C1-C4Alkyl-carbonyl, preferably hydrogen atom or acetyl group；
R2Represent straight or branched C1-C4Alkoxy carbonyl, amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkane Base)-amino carbonyl；
R3Represent unsubstituted or by 1-3 R8The first aryl of substituted 5-6 or 5-6 unit's heteroaryls, the heteroaryl contains 1- 3 N atoms；
R8Represent halogen, hydroxyl, carboxyl, nitro, amino, cyano group, C1-C3Alkyl, C1-C3Alkoxyl；
R4Represent hydrogen atom or C1-C3Alkyl；
Ring A represents unsubstituted or by 1-3 R9The first aryl of substituted 5-6 or 5-6 unit's heteroaryls, the heteroaryl contains 1-3 N atom；
R9Represent halogen, C1-C3Alkyl, C1-C3Alkoxyl；
R5Represent C1-C3Alkyl amino, two-(C1-C3Alkyl)-amino, two-(C1-C3Alkyl) amino-(C1-C3Alkyl)- N-(C1-C3Alkyl)-amino, two-(C1-C3Alkyl) amino-(C1-C3Alkyl)-N- (C1-C3Alkyl-carbonyl)-amino, C1-C3Alkane Epoxide-(C1-C3Alkyl)-N- (C1-C3Alkyl)-amino, C1-C3Alkoxyl-(C1-C3Alkyl)-N- (C1-C3Alkyl-carbonyl)-ammonia Base；Replace or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical contains the 1-3 hetero atom selected from N, O or S, institute The substituent stated is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3Alkyl-carbonyl, C1-C3Alkyl sulphonyl, Amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkyl) amino carbonyl；
R6、R7Each represent hydrogen, halogen, C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3The C of alkyl, halo1-C3Alkane Base；
N represents 0 or 1.
Present invention is preferably related to the dihydroindole ketone derivate and its pharmaceutically acceptable salt or isomers shown in formula I,
Wherein,
R1Represent hydrogen atom or prodrug base acetyl group；
R2Represent straight or branched C1-C4Alkoxy carbonyl, amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkane Base)-amino carbonyl；
R3Represent unsubstituted or by 1-3 R8Substituted phenyl or pyridine radicals；
R4Represent hydrogen atom or C1-C3Alkyl；
Ring A represents unsubstituted or by 1-3 R9Substituted phenyl, pyridine radicals, pyrimidine radicals；
R8、R9Each represent halogen, C1-C3Alkyl, C1-C3Alkoxyl；
R5Represent two-(C1-C3Alkyl)-amino；Replace or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical Containing the 1-3 hetero atom selected from N, O or S, described substituent is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3Alkyl-carbonyl, C1-C3Alkyl sulphonyl, amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkyl) amino carbonyl；
R6、R7Each represent hydrogen, halogen, C1-C3Alkyl；
N represents 0 or 1.
Present invention is preferably related to the dihydroindole ketone derivate and its pharmaceutically acceptable salt or isomers shown in formula I,
Wherein,
R1、R4Each represent hydrogen atom；
R2Representation methoxy carbonyl, amino carbonyl, amino-carbonyl, dimethyl-aminocarbonyl, N- ethyl-N-methyls-amino Carbonyl；
R3Represent unsubstituted or by 1-3 R8Substituted phenyl；
R8Represent halogen；
Ring A represents unsubstituted or by 1-3 R9Substituted phenyl or pyridine radicals；
R9Represent halogen or C1-C3Alkyl；
R5Represent two-(C1-C3Alkyl)-amino；Replace or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical Containing the 1-3 hetero atom selected from N, O or S, described substituent is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3Alkyl-carbonyl；
R6、R7Each represent hydrogen or C1-C3Alkyl；
N represents 0 or 1.
Dihydroindole ketone derivate and its pharmaceutically acceptable salt or the isomery being related to shown in formula I specifically preferred according to the invention Body,
Wherein,
R1、R4Respectively represent hydrogen atom；
R2Representation methoxy carbonyl, amino carbonyl, amino-carbonyl；
R3Represent phenyl；
Ring A represents phenyl that is unsubstituted or being replaced by 1-3 fluorine atom or pyridine radicals；
R5Represent dimethylamino, N- methyl-N-ethylaminos, morpholine -4- bases, thiomorpholine -4- bases, pyrrolidines -1- Base, piperazine -1- bases, piperidin-1-yl, 4- methylpiperazine-1-yls, 4- Acetylpiperazine -1- bases, 4- Nmethanesulphonylpiperazine -1- bases, 4- methyl piperidine -1- bases, 4- (amino carbonyl) piperazine -1- bases；
R6、R7Each represent hydrogen or methyl；
N represents 0 or 1.
The present invention is more preferably related to dihydroindole ketone derivate and its pharmaceutically acceptable salt or isomery shown in formula I Body,
Wherein,
R1、R4Respectively represent hydrogen atom；
R2Representation methoxy carbonyl；
R3Represent phenyl；
Ring A represents phenyl；
R5Represent dimethylamino, N- methyl-N-ethylaminos, morpholine -4- bases, pyrrolidin-1-yl, 4- methyl piperazines - 1- bases, 4- Acetylpiperazine -1- bases；
R6、R7Each represent hydrogen or methyl；
N represents 0 or 1.
The present invention is more preferably related to dihydroindole ketone derivate and its pharmaceutically acceptable salt or isomery shown in formula I Body,
Wherein,
R1、R4Respectively represent hydrogen atom；
R2Representation methoxy carbonyl；
R3Represent phenyl；
Ring A represents phenyl；
R5Represent dimethylamino or 4- methylpiperazine-1-yls；
R6Represent methyl；
R7Represent hydrogen；
N represents 0.
Compound of Formula I of the present invention and its pharmaceutically acceptable salt or isomers preferably following compound, but these changes Compound is not meant to any limitation of the invention：
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- (pyridin-4-yl)-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- - oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (lignocaine-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- - oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] - 2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (thiomorpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (pyrrolidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (piperazine -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] - 2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (piperidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] - 2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- Acetylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- Nmethanesulphonylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methyl piperidines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- Phenyi-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -4- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- Phenyi-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -1- Acetyl group -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- - oxindole quinoline -6- formamides；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- formamides；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes]-N- Methyl -2--oxindole quinoline -6- formamides；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl]-N- methyl -2--oxindole quinoline -6- formamides；
(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) amino) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (the fluoro- 4- of 3- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (the fluoro- 4- of 2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- Ethyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- - oxindole quinoline -6- Ethyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- Phenyi-methylene] -2--oxindole quinoline -6- Ethyl formates；
(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) amino) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridin-3-yl) amino) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridin-3-yl) Amino) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyrimidine -5- bases) amino) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates.
And, according to some usual methods of the art, formula of I dihydroindole ketone derivates of the present invention can be with Pharmaceutically acceptable salt is generated with acid.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, with following sour addition Salt is particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, the sulphur of naphthalene two Acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine；" alkyl " refers to straight chain or props up The alkyl of chain, the moieties of described " dialkyl group " substituent may be the same or different；" heterocyclic radical " is referred to containing one or many The individual ring-type system heteroatomic monocyclic or polycyclic selected from N, O, S.
The present invention can the dihydroindole ketone derivate containing formula I above and its pharmaceutically acceptable salt or isomers as work Sexual element, with pharmaceutically acceptable carrier or excipient composition is prepared by mixing into, and is prepared into clinically acceptable dose Type.Above-mentioned excipient refers to diluent, binder, lubricant, disintegrant, cosolvent, stabilizer for can be used for pharmaceutical field etc. And some medicinal substrates.Above-mentioned formulation refers to clinically conventional injection, tablet, capsule etc..Above-mentioned carrier is medicine Feature pharmaceutic adjuvant is obtained in field, including：Surfactant, suspending agent, emulsifying agent and some novel medicinal high scores Sub- material, such as cyclodextrin, shitosan, PLA (PLA), polyglycolic acid copolymer of poly lactic acid (PLGA), hyaluronic acid.Medicine Preparation can by oral administration or parenteral (such as vein, subcutaneous, intraperitoneal or local) administration, if some drugses are in stomach Under the conditions of be unstable, enteric coated tablets can be prepared into.
By kinase activity test discovery, compound of Formula I of the present invention and its pharmaceutically acceptable salt or isomers pair Various EGFR-TKs related to Angiogenesiss such as VEGFR2, PDGFR β, FGFR1 has significant inhibitory activity.Additionally, right Endothelial cell HUVEC, fibroblast 3t3 proliferation inhibiting effect substantially, while also having stronger suppression to the propagation of tumour cell Make and use.Therefore, the compounds of this invention can be used for the medicine for preparing prevention or treatment hyperplasia and fibrotic conditions.Wherein The hyperproliferative disease is included but are not limited to：It is lung cancer, colorectal cancer, liver cancer, breast cancer, oophoroma, melanoma, front Row gland cancer, cervical carcinoma, cancer of the stomach, cancer of pancreas, thyroid cancer；The fibrotic conditions are included but are not limited to：Pnemnofibrosis With the lung disease with fibrotic component, hepatic fibrosis and the liver disease with fibrotic component, kidney fibre modification and have The kidney diaseases of fibrotic component, the disease of skin with fibrotic component.Described pnemnofibrosis and with fibrotic component Lung disease, including idiopathic pulmonary fibrosis denaturation, cystic fibrosis, drug-induced pnemnofibrosis, big and small matrix Property pneumonia, silicosis, COPD；The hepatic fibrosis and the liver disease with fibrotic component, including disease The cirrhosis that poison causes；The kidney fibre modification and the kidney diaseases with fibrotic component, including postangioplasty restenosis, The kidney fibre modification that CGN, drug-induced kidney fibre modification, hypertension are caused；It is described with fibrotic component Disease of skin, including chorionitis, sarcoidosis, systemic lupus erythematosus.
Compound according to the present invention or its pharmaceutically acceptable salt or isomers can be used as unique prevention or treatments Hyperproliferative disease medicine is used alone, or can be with the Drug combination for having listed, and therapeutic alliance can pass through will Each therapeutic component simultaneously, order or separate administration realizing.The marketed drug for use in conjunction includes but not only limits In：Platinum medicine, such as cis-platinum, carboplatin；Antibody drug, such as Trastuzumab, bevacizumab；Growth factor receptor inhibitors, Buddhist nun of such as relaxing For Buddhist nun, Sorafenib etc.；Mitotic inhibitor, such as taxol, docetaxel；Alkylating agent medicine, such as endoxan, card are not Department spit of fland etc..
The preparation of formula I derivatives of the present invention is summarized and described to following synthetic routes, and all of raw material is all by this Mode described in a little flow processs, prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or it is commercially available.This The all final derivative of invention is prepared by the method described in these flow processs or by similar method, this A little methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these flow processs as describe or such as Definition in claim.
Specific embodiment：
Below in an example, the method for preparing the part compound is depicted.It will be appreciated that following methods and affiliated Additive method goes for the preparation of compound of the present invention known to the those of ordinary skill in field.Embodiment is intended to Illustrate rather than limit the scope of the present invention.The proton nmr spectra of compound is determined with Bruker ARX-400 or ARX-600, Mass spectrum is determined with Agilent 1100LC/MSD；It is pure or chemical pure that agents useful for same is analysis.
Embodiment 1:(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- (pyridine - 4- yls)-methylene] -2--oxindole quinoline -6- methyl formates
(1) 1- (4- nitrobenzophenones) -1H- pyrroles
Under room temperature, sodium acetate (16.6g, 0.20mol) is dissolved in water (50mL), the lower addition 4- nitroanilines of stirring (5g, 36mmol), glacial acetic acid (50mL) is added, reactant liquor is warming up to into 75 DEG C, react 10min, be then slowly added dropwise 2,5- diformazans Epoxide tetrahydrofuran (5.27g, 36mmol), continues to react 3h, is cooled to room temperature, and reactant liquor is poured into water, and separates out product, takes out Micro-yellow powder 5.6g is filtered to obtain, yield is 82.4%.
(2) N, N- dimethyl -1- [1- (4- nitrobenzophenones) -1H- pyrroles's -2- bases] methylamine
By 1- (4- nitrobenzophenones) -1H- pyrroles (2g, 11mmol), paraformaldehyde (0.64g, 22mmol) and dimethylamine 40% aqueous solution (2.4g, 22mmol) is added into glacial acetic acid (20mL), and maintenance is stirred at room temperature reaction 5h.Pour reactant liquor into water In, NaOH solution adjusts pH value of solution to 10, separates out light yellow solid, and suction filtration is washed filter cake, is dried.Solid is placed in flask, Ethanol 15mL is added, 3h is stirred, is filtered and dry white solid 2.2g, yield is 84.6%.
(3) 4- [2- ((dimethylamino) methyl) -1H- pyrroles's -1- bases] aniline
Under room temperature, by N, N- dimethyl -1- [1- (4- nitrobenzophenones) -1H- pyrroles's -2- bases] methylamine (3g, 12.2mmol) It is placed in ethanol (20mL) with 10% palladium charcoal (0.3g), hydrogenation 2h.Diatomite removes insoluble matter, removes solvent under reduced pressure.To Ether 15mL is added in residue, 3h is stirred, is filtered and dry yellow solid 2.2g, yield is 83.6%.
(4) 1- (2- chloracetyls) -2--oxindole quinoline -6- methyl formates
Under room temperature, 6- methoxycarbonyls -2--oxindole quinolines (50g, 0.26mol) is added in toluene (150mL), slowly Add chloroacetic anhydride (67.5g, 0.39mol).Backflow, and stirring reaction 2.5h are heated the mixture to, 80 DEG C are then cooled to, And hexamethylene (100mL) is added in system, resulting solution is cooled to into room temperature.Filter, solid washed with toluene, and be dried, White solid 65.8g is obtained, yield is 94.2%.
(5) (E) -1- (2- chloracetyls) -3- [1- ethyoxyl -1- (pyridin-4-yl)-methylene] -2--oxindole quinolines - 6- methyl formates
By 1- (2- chloracetyls) -2--oxindole quinolines -6- methyl formates (2.67g, 10mmol) and DMAP (2.44g, 20mmol) add in DMF (25mL), in ice-water bath, be slowly added dropwise the DMF (6mL) of pyridine -4- formyl chlorides (2.12g, 15mmol) Solution, completion of dropping reacts 2h, and in pouring frozen water (60mL) into, it is 2-3 to adjust pH value of solution with concentrated hydrochloric acid under stirring, continues to stir 2h, Suction filtration, obtains brown solid.Gained solid and sodium carbonate (0.86g, 8mmol) are added in DMF (20mL), is slowly added dropwise under room temperature Iodoethane (1.87g, 12mmol), completion of dropping reaction 1h, reactant liquor is poured in frozen water (40mL), and suction filtration, filtration cakes torrefaction is obtained slightly Product, with re-crystallizing in ethyl acetate yellow solid 1.86g is obtained, and yield is 46.5%.
(6) (E) -3- [1- ethyoxyl -1- (pyridin-4-yl)-methylene] -2--oxindole quinoline -6- methyl formates
By (E) -1- (2- chloracetyls) -3- [1- ethyoxyl -1- (pyridin-4-yl)-methylene] -2--oxindole quinolines - 6- methyl formates (2g, 5mmol) are added in methyl alcohol (10mL), and KOH (0.093g, 1.67mmol) is added under room temperature, stir 1h, instead Liquid is answered to be cooled to 0 DEG C, crystallization.Filter, dry yellow solid 1.19g, yield is 73.2%.
(7) (Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- (pyridin-4-yl) - Methylene] -2--oxindole quinolines -6- methyl formates (embodiment 1)
Under room temperature, by (E) -3- [1- ethyoxyl -1- (pyridin-4-yl)-methylene] -2--oxindole quinoline -6- formic acid first Ester (0.26g, 0.8mmol), 4- [2- (dimethylamino-methyl) -1H- pyrroles's -1- bases] aniline (0.17g, 0.8mmol) are added In absolute methanol, back flow reaction 5h is warming up to, reactant liquor is cooled to room temperature, crystallization.Solid is filtered, filter cake is with cold methanol washing Yellow solid 0.21g is obtained, yield is 52.1%.
ESI-MS m/z:494.1[M+H]+.
Embodiment 2：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates
(1) (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates
By 2--oxindole quinolines -6- methyl formates (5g, 0.026mol), acetic anhydride (20mL) and original acid triethyl (29.1g, 0.13mol) is added in reaction bulb, 130 DEG C of reaction 6h.Reaction is finished, and reactant liquor is cooled to into room temperature, suction filtration, filter cake With petroleum ether, it is dried, obtains pale red solid 7.1g, yield is 75%.
(2) (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates
By (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (8.4g, 23mmol) and KOH (0.43g, 7.7mmol) are added in absolute methanol, room temperature reaction 1h.Reactant liquor is cooled to into 0 DEG C, And maintain to stir 2h.Filter, filter cake is washed with cold methanol, obtains yellow solid 4.17g, and yield is 56.1%.
(3) (Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinolines -6- methyl formates (embodiment 2)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (0.3g, 0.93mmol), 4- [2- ((dimethylamino) methyl) -1H- pyrroles's -1- bases] aniline (0.2g, 0.93mmol) is added to methyl alcohol (7mL) in, back flow reaction 7h is warming up to, reactant liquor is cooled to 0 DEG C, and maintains to stir 2h.Solid is filtered, methyl alcohol washing filter Cake, is dried, and obtains yellow solid 0.29g, and yield is 62.3%.
ESI-MS m/z:492.6[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.02(s,1H), 7.69-7.59 (m, 3H), 7.59-7.51 (m, 2H), 7.44 (d, 1H), 7.34-7.17 (m, 3H), 7.00 (d, J=8.8Hz, 3H), 6.58 (s, 1H), 6.27 (t, J=3.0Hz, 1H), 5.87 (d, J=8.2Hz, 1H), 4.13 (s, 2H), 3.78 (s, 3H), 2.41(s,6H).
According to the preparation method of embodiment 2, with 1- (4- nitrobenzophenones) -1H- pyrroles as raw material, from formaldehyde, different secondary Amine Jing Mannich reactions, again Jing catalytic hydrogenations are obtained corresponding 4- (2- replace -1H- pyrroles's -1- bases) aniline, then with (E) -3- The reaction of (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates prepares the chemical combination of embodiment 3-12 Thing.
Embodiment 3：(Z) -3- [1- (4- (2- (lignocaine-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:521.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),11.01(s,1H), 7.62-7.56 (m, 3H), 7.54-7.51 (m, 2H), 7.43 (d, J=1.1Hz, 1H), 7.38 (d, J=8.4Hz, 2H), 7.20 (dd, J=8.3,1.3Hz, 1H), 6.94 (d, J=8.5Hz, 2H), 6.85 (s, 1H), 6.09 (s, 2H), 5.84 (d, J= 8.2Hz, 1H), 3.77 (s, 3H), 3.27 (s, 2H), 2.32 (d, J=6.8Hz, 4H), 0.76 (t, J=6.9Hz, 6H).
Embodiment 4：(Z) -3- [1- (4- (2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:535.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.00(s,1H), 7.65-7.56 (m, 3H), 7.53 (d, J=6.8Hz, 2H), 7.43 (s, 1H), 7.37 (d, J=8.6Hz, 2H), 7.21 (d, J= 8.2Hz, 1H), 6.94 (d, J=8.7Hz, 2H), 6.87 (s, 1H), 6.09 (d, J=2.0Hz, 2H), 5.86 (d, J=8.2Hz, 1H),3.77(s,3H),3.45(s,4H),3.17(s,2H),2.20(s,4H).
Embodiment 5：(Z) -3- [1- (4- (2- (thiomorpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:551.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.00(s,1H), 7.60 (td, J=8.6,4.4Hz, 3H), 7.53 (d, J=6.5Hz, 2H), 7.43 (d, J=1.1Hz, 1H), 7.34 (d, J= 8.7Hz, 2H), 7.21 (dd, J=8.2,1.4Hz, 1H), 6.93 (d, J=8.7Hz, 2H), 6.88-6.84 (m, 1H), 6.08 (d, J=2.5Hz, 2H), 5.87 (d, J=8.2Hz, 1H), 3.78 (s, 3H), 3.18 (s, 2H), 2.44 (br, 8H).
Embodiment 6：(Z) -3- [1- (4- (2- (pyrrolidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:519.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.99(s,1H), 7.66-7.56 (m, 3H), 7.53 (dd, J=7.8,1.5Hz, 2H), 7.43 (d, J=1.4Hz, 1H), 7.36 (d, J=8.7Hz, 2H), 7.26-7.16 (m, 1H), 6.96 (s, 2H), 6.86 (s, 1H), 6.09 (d, J=2.2Hz, 2H), 5.86 (d, J= 8.2Hz,1H),3.78(s,3H),2.33(br,4H),1.63(br,4H).
Embodiment 7：(Z) -3- [1- (4- (2- (piperazine -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:534.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),11.01(s,1H), 7.67-7.56 (m, 3H), 7.53 (dd, J=7.8,1.4Hz, 2H), 7.43 (d, J=1.2Hz, 1H), 7.38 (d, J=8.7Hz, 2H), 7.21 (dd, J=8.2,1.5Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.90-6.85 (m, 1H), 6.09 (dd, J= 7.4,4.0Hz, 2H), 5.87 (d, J=8.2Hz, 1H), 3.78 (s, 3H), 3.14 (s, 2H), 2.65 (m, 4H), 2.21 (m, 4H),1.23(s,1H).
Embodiment 8：(Z) -3- [1- (4- (2- (piperidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates:
ESI-MS m/z:533.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.01(s,1H), 7.60 (dd, J=14.8,7.3Hz, 3H), 7.53 (d, J=6.6Hz, 2H), 7.43 (s, 1H), 7.38 (d, J=8.3Hz, 2H), 7.21 (dd, J=8.1,0.8Hz, 1H), 6.93 (d, J=8.5Hz, 2H), 6.87 (s, 1H), 6.09 (s, 2H), 5.86 (d, J= 8.2Hz,1H),3.77(s,3H),3.12(s,2H),2.20(br,4H),1.38(br,6H).
Embodiment 9：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- Phenyi-methylene] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:548.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),10.99(s,1H), 7.60 (dd, J=14.6,7.0Hz, 3H), 7.53 (d, J=6.5Hz, 2H), 7.43 (d, J=1.5Hz, 1H), 7.38 (d, J= 8.7Hz, 2H), 7.21 (dd, J=8.2,1.5Hz, 1H), 6.92 (d, J=8.7Hz, 2H), 6.88-6.86 (m, 1H), 6.08 (dd, J=5.6,2.5Hz, 2H), 5.87 (d, J=8.3Hz, 1H), 3.78 (s, 3H), 3.14 (s, 2H), 2.23 (m, 4H), 2.14(s,3H).
Embodiment 10：(Z) -3- [1- (4- (2- (4- Acetylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) aniline Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:576.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.00(s,1H), 7.66-7.56 (m, 3H), 7.56-7.50 (m, 2H), 7.43 (d, J=1.1Hz, 1H), 7.36 (d, J=8.7Hz, 2H), 7.21 (dd, J=8.3,1.3Hz, 1H), 6.95 (d, J=8.7Hz, 2H), 6.90-6.84 (m, 1H), 6.09 (s, 2H), 5.86 (d, J =8.2Hz, 1H), 3.78 (s, 3H), 3.28 (m, 4H), 3.21 (s, 2H), 2.21 (m, 2H), 2.13 (m, 2H), 1.97 (s, 3H).
Embodiment 11：(Z) -3- [1- (4- (2- (4- Nmethanesulphonylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) aniline Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:612.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),11.00(s,1H), 7.65-7.56 (m, 3H), 7.53 (dd, J=7.6,1.2Hz, 2H), 7.43 (d, J=1.1Hz, 1H), 7.35 (d, J=8.7Hz, 2H), 7.21 (dd, J=8.2,1.4Hz, 1H), 6.94 (d, J=8.7Hz, 2H), 6.88 (t, J=2.2Hz, 1H), 6.11 (d, J =1.8Hz, 2H), 5.86 (d, J=8.2Hz, 1H), 3.78 (s, 3H), 3.23 (s, 2H), 3.00 (m, 4H), 2.86 (s, 3H), 2.32(m,4H).
Embodiment 12：(Z) -3- [1- (4- (2- (4- methyl piperidines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:547.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),10.99(s,1H), 7.66-7.56 (m, 3H), 7.53 (d, J=6.4Hz, 2H), 7.43 (d, J=1.2Hz, 1H), 7.39 (d, J=8.7Hz, 2H), (7.21 dd, J=8.2,1.4Hz, 1H), 6.92 (d, J=8.7Hz, 2H), 6.89-6.83 (m, 1H), 6.07 (dd, J=7.6, 4.7Hz, 2H), 5.87 (d, J=8.3Hz, 1H), 3.78 (s, 3H), 3.11 (s, 2H), 2.63 (d, J=11.0Hz, 2H), 2.50 (d, J=1.4Hz, 2H), 1.78 (t, J=10.1Hz, 2H), 1.51 (d, J=12.2Hz, 2H), 1.23 (m, 1H), 0.87 (d, J =6.5Hz, 3H).
Embodiment 13：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
(1) 2- methyl isophthalic acids-(4- nitrobenzophenones) -1H- pyrroles
Under room temperature, by 4- fluoronitrobenzenes (14.1g, 0.1mol), 2- methylpyrroles (8.1g, 0.1mol) and potassium carbonate (41.5g, 0.3mol) is added in DMF (100mL), is warming up to 130 DEG C of reaction 7h.Reactant liquor is poured in substantial amounts of frozen water, after Continuous stirring 0.5h, filters, and filter cake is placed in into recrystallization in ethyl acetate (150mL), obtains yellow solid 8.7g, and yield is 43.2%.
(2) N, N- dimethyl -1- [5- methyl isophthalic acids-(4- nitrobenzophenones) -1H- pyrroles's -2- bases] methylamine
By 2- methyl isophthalic acids-(4- nitrobenzophenones) -1H- pyrroles (2g, 10mmol), paraformaldehyde (0.59g, 20mmol) and two The aqueous solution of methylamine 40% (2.7g, 20mmol) is added into glacial acetic acid, and maintenance is stirred at room temperature reaction 5h and finishes, and reactant liquor is poured into In water, NaOH solution adjusts pH value of solution to 9, separates out light yellow solid, and suction filtration is washed filter cake, is dried.In being placed on flask, Ethanol 15mL is added, 3h is stirred, is filtered and dry white solid 2.03g, yield is 79.3%.
(3) 4- [2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases] aniline
Under room temperature, by N, N- dimethyl -1- [5- methyl isophthalic acids-(4- nitrobenzophenones) -1H- pyrroles's -2- bases] methylamine (3g, 11.6mmol) it is placed in ethanol (20mL) with 10% palladium charcoal (0.3g), hydrogenation 2h.Diatomite removes insoluble matter, and filtrate is dense Contracting removes solvent.Ether 15mL is added in residue, 3h is stirred, is filtered and dry yellow solid 2.1g, yield is 79.2%.
(4) (Z) -3- [1- (4- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinolines -6- methyl formates (embodiment 13)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (0.32g, 1mmol) Add to methyl alcohol (10mL) with 4- [2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases] aniline (0.23g, 1mmol) In, back flow reaction 8h is warming up to, reactant liquor is cooled to room temperature, and maintains to stir 2h.Solid is filtered, methyl alcohol washing filter cake is done It is dry, yellow solid 0.23g is obtained, yield is 45%.
ESI-MS m/z:507.2[M+H]+.
According to the preparation method of embodiment 13, with 2- methyl isophthalic acids-(4- nitrobenzophenones) -1H- pyrroles as raw material, with formaldehyde, 4- methyl piperazine Jing Mannich reactions, again Jing catalytic hydrogenations are obtained 4- [2- methyl -5- (4- methylpiperazine-1-yls-methyl) -1H- Pyrroles's -1- bases] aniline, then react with (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates Prepare the compound of embodiment 14.
Embodiment 14：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) benzene Amido) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:562.2[M+H]+.1H NMR(600MHz,DMSO-d6)δ12.25(s,1H),10.98(s,1H), 7.60 (dt, J=2.7,2.0Hz, 1H), 7.56 (dd, J=11.4,4.4Hz, 2H), 7.52 (dd, J=8.0,1.3Hz, 2H), 7.43 (d, J=1.4Hz, 1H), 7.21 (dd, J=8.2,1.6Hz, 1H), 7.13 (d, J=8.7Hz, 2H), 6.95 (d, J= 8.7Hz,2H),5.88(m,2H),5.80–5.78(m,1H),3.78(s,3H),2.94(s,2H),2.18–2.11(br,11H), 1.91(s,3H).
According to the method for embodiment 13, with 4- fluoronitrobenzenes and 3- methylpyrroles as raw material be obtained intermediate 3- methyl isophthalic acids- (4- nitrobenzophenones) -1H- pyrroles, itself and formaldehyde, 4- methyl piperazine Jing Mannich reactions, again Jing catalytic hydrogenations 4- [4- first is obtained Base -2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline, then with (E) -3- (1- ethyoxyl -1- phenyl-meths Base) reaction of -2--oxindole quinoline -6- methyl formates prepares the compound of embodiment 15.
Embodiment 15：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -4- methyl isophthalic acid H- pyrroles's -1- bases) benzene Amido) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:562.1[M+H]+.
Embodiment 16：(Z) -3- [1- (4- ((2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- Phenyi-methylene] -2--oxindole quinoline -6- methyl formates
(1) 1- (4- nitrobenzyls) -1H- pyrroles
Under room temperature, sodium acetate (18g, 0.22mol) is dissolved in water (60mL), the lower addition 4- nitro-benzylamines of stirring (6g, 39mmol), glacial acetic acid (60mL) is added, reactant liquor is warming up to into 75 DEG C, react 10min, be then slowly added dropwise 2,5- diformazans Epoxide tetrahydrofuran (5.21g, 39mmol), continues to react 3h, is cooled to room temperature, and reactant liquor is poured into water, and separates out product, takes out Filter to obtain micro-yellow powder 6.8g, yield 85%.
(2) N, N- dimethyl -1- [1- (4- nitrobenzyls) -1H- pyrroles's -2- bases] methylamine
By 1- (4- nitrobenzyls) -1H- pyrroles (2g, 10mmol), paraformaldehyde (0.59g, 20mmol) and dimethylamine 40% aqueous solution (2.7g, 20mmol) is added into glacial acetic acid, and maintenance is stirred at room temperature reaction 5h and finishes, and pours reactant liquor into water In, NaOH solution adjusts pH to 10, separates out light yellow solid, and suction filtration is washed filter cake, is dried.Solid is placed in flask, is added Ethanol 15mL, stirs 3h, filters and dry white solid 2.16g, and yield is 84.4%.
(3) 4- [(2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl] aniline
Under room temperature, by N, N- dimethyl -1- [1- (4- nitrobenzyls) -1H- pyrroles's -2- bases] methylamines (1g, 3.9mmol) and 10% palladium charcoal (0.1g) is placed in ethanol (20mL), maintains room temperature hydrogenation 2h.Diatomite removes insoluble matter, and filtrate concentration is removed Remove solvent.Ether 15mL is added in residue, 3h is stirred, is filtered and dry yellow solid 0.73g, yield is 83%.
(4) (Z) -3- [1- (4- ((2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyl - Methylene] -2--oxindole quinolines -6- methyl formates (embodiment 16)
By (E) -3- [1- ethyoxyl -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates (0.32g, 1mmol) Add to methyl alcohol (15mL) with 4- [(2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl] aniline (0.23g, 1mmol) In, back flow reaction 5h is warming up to, reactant liquor is cooled to 25 DEG C, continues to stir 1h.Solid is filtered, methyl alcohol washing filter cake is dried, Yellow solid 0.19g is obtained, yield is 37.6%.
ESI-MS m/z:507.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),10.96(s,1H), 7.61-7.52 (m, 3H), 7.49-7.44 (m, 2H), 7.41 (d, J=1.2Hz, 1H), 7.18 (dd, J=8.3,1.3Hz, 1H), 6.88-6.79 (m, 4H), 6.72-6.68 (m, 1H), 5.91 (t, J=3.0Hz, 1H), 5.88 (s, 1H), 5.80 (d, J= 8.2Hz,1H),5.05(s,2H),3.77(s,3H),3.07(s,2H),2.01(s,6H).
According to the preparation method of embodiment 16, with 1- (4- nitrobenzyls) -1H- pyrroles as raw material, with formaldehyde, morpholine or 4- Methyl piperazine Jing Mannich reactions, then Jing catalytic hydrogenations are obtained corresponding 4- [(2- replace -1H- pyrroles's -1- bases) methyl] aniline, Again (reaction of 1- ethyoxyl -1- phenyi-methylene -2--oxindole quinoline -6- methyl formates prepares embodiment 17 with (E) -3- Compound with 18.
Embodiment 17：(Z) -3- [1- (4- ((2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) - 1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:549.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),10.97(s,1H), 7.56 (dd, J=15.9,8.2Hz, 3H), 7.46 (d, J=6.9Hz, 2H), 7.41 (s, 1H), 7.18 (d, J=8.2Hz, 1H), 6.84 (dd, J=20.2,8.4Hz, 4H), 6.75 (s, 1H), 5.93 (s, 2H), 5.80 (d, J=8.1Hz, 1H), 5.07 (s, 2H),3.77(s,3H),3.41(br,4H),3.18(s,2H),2.18(br,4H).
Embodiment 18：(Z) -3- [1- (4- ((2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) methyl) benzene Amido) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:562.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.96(s,1H), 7.62-7.52 (m, 3H), 7.46 (d, J=6.7Hz, 2H), 7.41 (d, J=1.2Hz, 1H), 7.27 (dd, J=17.2, 8.7Hz, 1H), 7.18 (dd, J=8.3,1.4Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 6.79 (d, J=8.5Hz, 2H), 6.72-6.70 (m, 1H), 5.90 (t, J=3.0Hz, 1H), 5.88-5.86 (m, 1H), 5.80 (d, J=8.2Hz, 1H), 5.04 (s,2H),3.76(s,3H),3.14(s,2H),2.19(br,4H),2.11(s,3H).
Embodiment 19：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -1- acetyl group -2--oxindole quinoline -6- methyl formates
Under room temperature, by (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formic acid Methyl esters (0.55g, 1.5mmol) and 4- [2- (dimethylamino-methyl) -1H- pyrroles's -1- bases] aniline (0.32g, 1.5mmol) Add into methyl alcohol (15mL), be warming up to back flow reaction 5h.Reactant liquor is cooled to into room temperature, hexamethylene (10mL) is added, is continued Stirring 0.5h.Suction filtration, washs filter cake with methyl alcohol, dry yellow solid 0.26g, and yield is 32.6%.
ESI-MS m/z:535.2[M+H]+.
Embodiment 20：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- formamides；
(1) (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides
With 2--oxindole quinoline -6- formamides as raw material, according to (E) -1- acetyl group -3- in embodiment 2 (1- ethyoxyls - 1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates preparation method be obtained.
(2) (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides
With (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides as former Material, according to the preparation of (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates in embodiment 2 Method is obtained.
(3) embodiment 20：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene] -2--oxindole quinoline -6- formamides
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides (0.2g, 0.65mmol), 4- [2- (dimethylamino-methyl) -1H- pyrroles's -1- bases] aniline (0.14g, 0.65mmol) is added to methyl alcohol (5mL) in, back flow reaction 3h is warming up to, reactant liquor is cooled to 35 DEG C, stirs 0.5h.Solid is filtered, methyl alcohol washing filter cake is done It is dry, yellow solid 0.15g is obtained, yield is 47.5%.
ESI-MS m/z:478.2[M+H]+.
Embodiment 21：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) - 1- phenyi-methylenes] -2--oxindole quinoline -6- formamides；
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides and 4- [2- (4- methyl Piperazine -1- bases-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 20 preparation method be obtained.
ESI-MS m/z:533.3[M+H]+.
Embodiment 22：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene]-N- methyl -2--oxindole quinoline -6- formamides；
(1) (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes)-N- methyl -2--oxindole quinoline -6- formyls Amine
With N- methyl -2--oxindole quinoline -6- formamides as raw material, according to (E) -1- acetyl group -3- (1- in embodiment 20 Ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides preparation method be obtained.
(2) (E) -3- (1- ethyoxyl -1- phenyi-methylenes)-N- methyl -2--oxindole quinoline -6- formamides
With (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes)-N- methyl -2--oxindole quinoline -6- formyls Amine is raw material, according to (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides in embodiment 20 Preparation method is obtained.
(3) embodiment 22：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- benzene Base-methylene]-N- methyl -2--oxindole quinoline -6- formamides；
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes)-N- methyl -2--oxindole quinoline -6- formamides and 4- [2- (dimethylamino-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 20 preparation method be obtained.
ESI-MS m/z:492.2[M+H]+.
Embodiment 23：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) - 1- phenyi-methylenes]-N- methyl -2--oxindole quinoline -6- formamides
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes)-N- methyl -2--oxindole quinoline -6- formamides and 4- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 20 preparation method be obtained.
ESI-MS m/z:547.3[M+H]+.
Embodiment 24：(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyridine -3- Base) amino) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
(1) 5- nitros -2- (1H- pyrroles's -1- bases) pyridine
Under room temperature, by the fluoro- 5- nitropyridines (21.3g, 0.15mol) of 2-, pyrroles (10.1g, 0.15mol) and cesium carbonate (97.7g, 0.3mol) is added in DMF (200mL), is warming up to 80 DEG C of reaction 10h.Reactant liquor is poured in substantial amounts of frozen water, after Continuous stirring 0.5h, filters, and filter cake is placed in into recrystallization in ethanol (150mL), obtains yellow solid 18.5g, and yield is 65.1%.
(2) 1- methyl -4- [(1- (5- nitropyridine -2- bases) -1H- pyrroles's -2- bases) methyl] piperazine
By 5- nitro -2- (1H- pyrroles's -1- bases) pyridine (2.08g, 11mmol), paraformaldehyde (0.64g, 22mmol) and N methyl piperazine (1.5g, 15mmol) is added into glacial acetic acid (15mL), and 5h is reacted at room temperature.Reaction is finished, by reactant liquor In pouring frozen water into, NaOH solution adjusts pH to 8.5, separates out light yellow solid, and suction filtration is washed filter cake, is dried.Column chromatography obtains white Solid 1.5g, yield is 45.9%.
(3) 6- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] pyridine -3- amine
Under room temperature, by 1- methyl -4- [(1- (5- nitropyridine -2- bases) -1H- pyrroles's -2- bases) methyl] piperazine (3g, 10mmol) it is placed in ethanol (15mL) with 10% palladium charcoal (0.3g), is passed through hydrogen room temperature reaction 4h.Insoluble matter is filtered to remove, is subtracted Pressure is evaporated off solvent.Column chromatography obtains yellow solid 2.1g, and yield is 76.6%.
(4) (Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) ammonia Base) -1- phenyi-methylenes] -2--oxindole quinolines -6- methyl formates (embodiment 24)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (0.2g, 0.62mmol), 6- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] pyridine -3- amine (0.17g, 0.62mmol) Add into methyl alcohol (10mL), back flow reaction 5h, reactant liquor is cooled to -5 DEG C, continue to stir 1.5h.Solid is filtered, methyl alcohol is washed Filter cake is washed, is dried, obtain yellow solid 0.17g, yield is 50.2%.
ESI-MS m/z:549.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.03(s,1H), 7.96 (d, J=7.5Hz, 1H), 7.86 (m, 1H), 7.80 (d, J=1.4Hz, 1H), 7.68 (m, 2H), 7.58-7.47 (m, 4H), 7.56 (dd, J=7.7,1.4Hz, 1H), 7.20 (m, 2H), 6.15 (t, J=7.4Hz, 1H), 6.08 (dd, J=7.5, 1.4Hz, 1H), 3.97 (s, 3H), 3.62 (s, 2H), 2.77 (t, J=6.1Hz, 2H), 2.55 (m, 4H), 2.36 (t, J= 5.9Hz,2H),2.31(s,3H).
Embodiment 25：(Z) -3- [1- (the fluoro- 4- of 3- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) aniline Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
(1) 1- (the fluoro- 4- nitrobenzophenones of 2-) -1H- pyrroles
Under room temperature, by the fluoro- 4- nitrobenzene (15.9g, 0.1mol) of 1,2- bis-, pyrroles (7.4g, 0.11mol) and potassium carbonate (27.6g, 0.2mol) is added in DMSO (100mL), is warming up to 90 DEG C of reaction 10h.Reactant liquor is poured in substantial amounts of frozen water, after Continuous stirring 0.5h, filters, and washing filter cake obtains yellow solid 15.5g, and yield is 75.1%.
(2) 1- [(1- (the fluoro- 4- nitrobenzophenones of 2-) -1H- pyrroles's -2- bases) methyl] -4- methyl piperazines
By 1- (the fluoro- 4- nitrobenzophenones of 2-) -1H- pyrroles (2.4g, 15mmol), paraformaldehyde (0.73g, 25mmol) and N- Methyl piperazine (2.5g, 25mmol) is added into glacial acetic acid (20mL), and at 30 DEG C 7h is reacted.Reaction is finished, and reactant liquor is fallen In entering frozen water, light yellow solid is separated out, suction filtration washes filter cake, filter cake added and is stirred overnight in ether (30mL), and suction filtration is obtained White solid 2.5g, yield is 52.3%.
(3) the fluoro- 4- of 3- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline
Under room temperature, by 1- [(1- (the fluoro- 4- nitrobenzophenones of 2-) -1H- pyrroles's -2- bases) methyl] -4- methyl piperazines (4.8g, 15mmol) it is placed in methyl alcohol (15mL) with 10% palladium charcoal (0.5g), hydrogenation 4h.Insoluble matter is filtered to remove, is removed under reduced pressure molten Agent, residue Jing column chromatographies purify to obtain yellow solid 2.8g, and yield is 63.7%.
(4) (Z) -3- [1- (the fluoro- 4- of 3- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- Phenyi-methylene] -2--oxindole quinolines -6- methyl formates (embodiment 25)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (0.32g, 1mmol), the fluoro- 4- of 3- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline (0.29g, 1mmol) add to In methyl alcohol (15mL), back flow reaction 7h, reactant liquor is cooled to 30 DEG C, stands 1.5h, separates out solid.Suction filtration, filter is washed with methyl alcohol Cake, is dried, and obtains yellow solid 0.21g, and yield is 37.8%.
ESI-MS m/z:566.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.92(s,1H), 7.93 (d, J=2.2Hz, 1H), 7.87 (m, 2H), 7.55 (m, 3H), 7.51 (m, 2H), 7.32 (d, J=8.1Hz, 1H), 7.05 (m, 1H), 6.86 (dd, J=8.5,2.3Hz, 1H), 6.62 (dd, J=8.7,2.2Hz, 1H), 6.32 (m, 2H), 3.82 (s, 3H),3.66(s,2H),2.78(m,2H),2.55(m,4H),2.38(m,2H),2.03(s,3H).
According to the preparation method of embodiment 25, with 2,4- difluoro nitrobenzenes for raw material, (3- is fluoro- to obtain 1- with pyrroles's reaction 4- nitrobenzophenones) -1H- pyrroles, then with formaldehyde, N methyl piperazine Jing Mannich reactions, again Jing catalytic hydrogenations 2- fluoro- 4- are obtained [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline, then with (E) -3- (1- ethyoxyl -1- phenyl-meths Base) reaction of -2--oxindole quinoline -6- methyl formates prepares the compound of embodiment 26.
Embodiment 26：(Z) -3- [1- (the fluoro- 4- of 2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) aniline Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
ESI-MS m/z:566.2[M+H]+.
Embodiment 27：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) - 1- phenyi-methylenes] -2--oxindole quinoline -6- Ethyl formates
(1) (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Ethyl formates
With 2--oxindole quinoline -6- Ethyl formates as raw material, according to (E) -1- acetyl group -3- (1- ethoxies in embodiment 2 Base -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates preparation method be obtained.
(2) (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Ethyl formates
With (E) -1- acetyl group -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Ethyl formates as former Material, according to the preparation of (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates in embodiment 2 Method is obtained.
(3) (Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinolines -6- Ethyl formates (embodiment 27)
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Ethyl formates and 4- [2- (4- first Base piperazine -1- bases-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 2 preparation method be obtained.
ESI-MS m/z:562.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),11.03(s,1H), 7.87 (m, 3H), 7.62 (d, J=6.6Hz, 2H), 7.41 (d, J=1.7Hz, 1H), 7.38 (d, J=8.7Hz, 2H), 7.25 (m, 1H), 7.05 (d, J=8.6Hz, 2H), 6.87 (m, 1H), 6.11 (dd, J=5.8,2.2Hz, 2H), 5.86 (d, J= 8.2Hz, 1H), 4.17 (m, 2H), 3.16 (s, 2H), 2.36 (br, 8H), 2.05 (s, 3H), 1.26 (m, 3H)
Embodiment 28：(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- Ethyl formates
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinolines -6- formic acid second and 4- [2- (dimethyl Amino-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 2 preparation method be obtained.
ESI-MS m/z:507.2[M+H]+.
Embodiment 29：(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) benzene Amido) -1- phenyi-methylenes] -2--oxindole quinoline -6- Ethyl formates
With (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Ethyl formates and 4- [2- methyl - 5- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] aniline be raw material, according to embodiment 13 preparation method be obtained.
ESI-MS m/z:576.3[M+H]+.
Embodiment 30：(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) ammonia Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
According to embodiment 24 preparation method, with 5- nitro -2- (1H- pyrroles's -1- bases) pyridine as raw material, with formaldehyde, two Methylamine Jing Mannich reactions, again Jing catalytic hydrogenations are obtained 6- [2- (dimethylamino-methyl) -1H- pyrroles's -1- bases] pyridine -3- amine, Prepare reality with the reaction of (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates again with again Apply the compound of example 30.
ESI-MS m/z:494.2[M+H]+.
Embodiment 31：(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridine -3- Base) amino) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
(1) 2- (2- methyl isophthalic acid H- pyrroles's -1- bases) -5- nitropyridines
Under room temperature, by the fluoro- 5- nitropyridines (21.3g, 0.15mol) of 2-, 2- methylpyrroles (14.6g, 0.18mol) and carbon Sour caesium (81.5g, 0.25mol) is added in DMF (150mL), is warming up to 80 DEG C of reaction 7h.Pour reactant liquor into substantial amounts of frozen water In, continue to stir 0.5h, filter.Crude product column chromatography obtains yellow solid 16.2g, and yield is 53.3%.
(2) N, N- dimethyl -1- [5- methyl isophthalic acids-(5- nitropyridine -2- bases) -1H- pyrroles's -2- bases] methylamine
By 2- (2- methyl isophthalic acid H- pyrroles's -1- bases) -5- nitropyridines (1.5g, 7.4mmol), paraformaldehyde (0.27g, 9mmol) add into glacial acetic acid (10mL) with the aqueous solution of dimethylamine 40% (1g, 9mmol), in 40 DEG C 7h is reacted.Part is evaporated off Solvent, NaOH solution adjusts reactant liquor pH to 9, separates out light yellow solid, and suction filtration is washed filter cake, is dried.Solid is placed in into flask In, ether 15mL is added, 2h is stirred, filter and dry white solid 1.2g, yield is 62.0%.
(3) 6- [2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases] pyridine -3- amine
By N, N- dimethyl -1- [5- methyl isophthalic acids-(5- nitropyridine -2- bases) -1H- pyrroles's -2- bases] methylamine (2.5g, 9.6mmol) it is placed in ethanol (15mL) with 10% palladium charcoal (0.3g), at room temperature hydrogenation 3h.Diatomite removes insoluble matter, Remove solvent under reduced pressure.Column chromatography obtains yellow solid 1.47g, and yield is 66.7%.
(4) (Z) -3- [1- ((6- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridin-3-yl) ammonia Base) -1- phenyi-methylenes] -2--oxindole quinolines -6- methyl formates (embodiment 31)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- methyl formates (0.32g, 1mmol) Add to methyl alcohol with 6- [2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases] pyridine -3- amine (0.23g, 1mmol) (10mL) in, back flow reaction 5h is warming up to, reactant liquor is cooled to 40 DEG C, hexamethylene (5mL) is added in system, continue to stir 2h.Solid is filtered, filter cake is washed with methyl alcohol, be dried, obtain yellow solid 0.19g, yield is 37.8%.
ESI-MS m/z:508.2[M+H]+.
Embodiment 32：(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) Pyridin-3-yl) amino) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
According to the preparation method of embodiment 31, with 2- (2- methyl isophthalic acid H- pyrroles's -1- bases) -5- nitropyridines as raw material, with Formaldehyde, again N methyl piperazine Jing Mannich reactions, prepared 6- [2- (4- methylpiperazine-1-yls-the methyl) -5- first of Jing catalytic hydrogenations Base -1H- pyrroles's -1- bases] pyridine -3- amine, then with (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- Methyl formate reaction prepares the compound of embodiment 32.
ESI-MS m/z:563.3[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),11.06(s,1H), 8.02 (m, 2H), 7.69 (dd, J=8.2,2.2Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.56 (m, 2H), 7.38 (m, 2H), 7.22 (dd, J=8.5,2.1Hz, 1H), 6.96 (d, J=8.2Hz, 1H), 5.72 (s, 2H), 4.03 (s, 2H), 3.88 (s,3H),2.62-2.46(br,8H),2.21(s,3H),1.91(s,3H).
Embodiment 33：(Z) -3- [1- ((2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyrimidine -5- Base) amino) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates
(1) 5- nitros -2- (1H- pyrroles's -1- bases) pyrimidine
Under room temperature, by the fluoro- 5- nitro-pyrimidines (20g, 0.14mol) of 2-, pyrroles (10g, 0.15mol) and potassium carbonate (29g, 0.21mol) add in DMF (150mL), be warming up to 50 DEG C of reaction 5h.Reactant liquor is poured in substantial amounts of frozen water, continues to stir 0.5h, filters, ether washing filter cake, obtains yellow solid 16.6g, and yield is 62.5%.
(2) 2- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] -5- nitro-pyrimidines
By 5- nitro -2- (1H- pyrroles's -1- bases) pyrimidine (1.3g, 6.8mmol), paraformaldehyde (0.31g, 10.2mmol) Add into glacial acetic acid (10mL) with N methyl piperazine (10.2g, 10.2mmol), in 35 DEG C 5h is reacted.Partial solvent is evaporated off, NaOH solution adjusts reactant liquor pH to 10, separates out light yellow solid, and suction filtration is washed filter cake, is dried.Jing column chromatographies obtain yellow solid 0.81g, yield is 39.6%.
(3) 2- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] pyrimidine -5- amine
By 2- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] -5- nitro-pyrimidines (1g, 3.3mmol) and 10% palladium charcoal (0.1g) is placed in methyl alcohol (8mL), at room temperature hydrogenation 2h.Diatomite removes insoluble matter, removes under reduced pressure molten Agent.Column chromatography obtains light yellow solid 0.56g, and yield is 62.5%.
(4) (Z) -3- [1- ((2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyrimidine -5- bases) ammonia Base) -1- phenyi-methylenes] -2--oxindole quinolines -6- methyl formates (embodiment 33)
By (E) -3- (1- ethyoxyl -1- phenyi-methylenes) -2--oxindole quinoline -6- formamides (0.5g, 1.5mmol), 2- [2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases] pyrimidine -5- amine (0.42g, 1.5mmol) is added to methyl alcohol (10mL) in, back flow reaction 7h is warming up to, reactant liquor is cooled to 25 DEG C, stirs 1.5h.Solid is filtered, is tied again with absolute methanol Crystalline substance, suction filtration obtains yellow solid 0.52g, and yield is 63.7%.
ESI-MS m/z:550.2[M+H]+.
The biological activity research of the compounds of this invention
1st, the external zymetology inhibitory activity research of the compounds of this invention
External suppression vascular endothelial cell growth factor R-2 (VEGFR2), blood platelet have been carried out to the compounds of this invention The kinase activity screening of derived growth factor receptor β (PDGFR β) and fibroblast growth factor acceptor 1 (FGFR1).
Experimental technique：
(1) with 50mM HEPES (pH 7.5), 0.0015%Brij-35,10mM MgCl21 times is prepared with 2mM DTT to swash Enzyme basis buffer；With 100mM HEPES (pH 7.5), 0.015%Brij-35,0.2%Coating Reagent, 50mM EDTA is prepared and is stopped buffer solution.
(2) test kinase is added in enzyme basis buffer and is configured to 2.5 times of enzyme solutions；The peptide and ATP that FAM is marked adds Enter 2.5 times of peptide solutions of preparation in enzyme basis buffer.
(3) test compound is configured to the solution of 0.5mM concentration with DMSO, and the dilute of gradient is carried out according to test concentrations Release；5 μ L test compounds are added in test board, 10 μ L, 2.5 times of enzyme solutions are added, and shakes 10min, be subsequently added 10 μ L 2.5 times of peptide solutions, reaction system and 28 DEG C of cultivation 1h；Add the stopping buffer solution stopped reaction of 25 μ L.
(4) inhibition concentration curve is drawn, calculates IC50Value.
The external zymetology inhibitory activity of the embodiment of the present invention compound of table 1
From table 1, the compounds of this invention has efficient inhibitory action to VEGFR2 and PDGFR beta kinase activity, right FGFR1 also has obvious inhibitory action.Wherein embodiment 2,5,6,8,9,12,13,15-21,24-26,30-33 is sharp for test The inhibitory activity of enzyme is suitable with Nintedanib even more excellent on the whole.
2nd, the compounds of this invention cell in vitro inhibitory activity research
The compounds of this invention has been carried out it is external suppression Human umbilical vein endothelial cells (HUVEC), mouse embryo fibroblast it is thin The screening active ingredients of born of the same parents (3T3)；Meanwhile, external suppression colon cancer cell HT-29, ovarian cancer cell SK-OV- have been carried out to derivative 3 screening active ingredients.
HUVEC, 3T3 cytoactive method of testing：
(1) with the medium culture HUVEC cell containing 10% heat-inactivated fetal bovine serum, concentration is 7.5 × 104/mL；With containing The medium culture 3T3 cell of 10% hyclone, concentration is 5 × 104/mL.Respectively cell liquid is added into 96 orifice plates, per hole 100 μ L, night incubation.
(2) diluted chemical compound is separately added into into the VEGF165 (HUVEC cells) and 10ng/ of 10ng/mL into variable concentrations The PDGF-BB (3T3 cells) of mL, is incubated 1h.
(3) the μ L of solution 100 containing compound and growth factor are added to into corresponding Tissue Culture Plate, compound is dense eventually Spend for 1,0.333,0.111,0.037,0.0123,0.0041,0.00137,0.00046 μM.72h is incubated respectively.Add per hole The Promega Substrate of 20 μ L, 37 DEG C of incubation 10h, are put into reading 490nm light absorption values in ELIASA, obtain medicine IC50 Value.
HT-29, SK-OV-3 cytoactive method of testing：
(1) cell recovery and pass on 2-3 time it is stable after, make it disappear from blake bottle bottom with trypsin solution (0.25%) Change is got off.After cell dissociation buffer is poured in centrifuge tube, nutrient solution is added to terminate digestion afterwards.By centrifuge tube in 800r/min Lower centrifugation 10min, adds 5mL nutrient solutions, piping and druming to mix cell after abandoning supernatant, draw 10 μ L cell suspensions and add cell Count in tally, adjustment cell concentration is 104Individual/hole.Except blank well is not added with extracellular in 96 orifice plates, remaining all adds 100 μ L cell suspensions.96 orifice plates are put in incubator and cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, appropriate nutrient solution is subsequently adding, makes sample be dissolved into 2mg/mL Liquid, is then diluted sample by concentration gradient in 24 orifice plates.Each concentration adds 3 holes, wherein the surrounding row cell of two row two Growing way is affected by environment larger, uses only and for blanc cell hole.96 orifice plates are put in incubator and cultivate 72h.
(3) band medicine nutrient solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole 100 μ L of middle addition MTT (0.5mg/mL) are put in incubator after 4h, discard MTT solution, add the μ L of dimethyl sulfoxide (DMSO) 100.In magnetic Vibration on forced oscillation device makes survivaling cell fully dissolve with MTT product, is put into measurement result in ELIASA.By Bliss Method can obtain medicine IC50Value.
The cell in vitro inhibitory activity of the embodiment of the present invention compound of table 2
From table 2, the compounds of this invention has significant inhibitory action to the propagation of HUVEC and 3T3 cells, and effectively presses down The propagation of HT-29, SK-OV-3 tumor cell line processed.
Embodiment 34：Tablet
With containing compound (by taking the embodiment 2 as an example) 10g in claim 1, add according to the general pressed disc method of pharmacy auxiliary After material 20g is mixed, 100 are pressed into, the weight 300mg per piece.
Embodiment 35：Capsule
With containing compound (by taking the compound of the embodiment 2 as an example) 10g in claim 1, according to pharmacy capsule After requiring to mix auxiliary material 20g, load Capsules, each capsule weight 300mg.
Embodiment 36：Injection
With containing compound (by taking the compound of the embodiment 14 as an example) 10g in claim 1, according to pharmacy routine side Method, carries out charcoal absorption, Jing after 0.65 μm of filtering with microporous membrane, inserts nitrogen pot and makes hydro-acupuncture preparation, per 2mL is only filled, altogether Filling 100 bottles.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field Will be apparent from for technical staff, and they are included within the scope of the invention.

Claims (11)

1. compounds of formula I and its pharmaceutically acceptable salt or isomers,
Wherein,
R1Represent hydrogen atom or prodrug base C1-C4Alkyl-carbonyl, preferably hydrogen atom or acetyl group；
R2Represent straight or branched C1-C4Alkoxy carbonyl, amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkyl)-ammonia Base carbonyl；
R3Represent unsubstituted or by 1-3 R8The first aryl of substituted 5-6 or 5-6 unit's heteroaryls, the heteroaryl contains 1-3 N Atom；
R8Represent halogen, hydroxyl, carboxyl, nitro, amino, cyano group, C1-C3Alkyl, C1-C3Alkoxyl；
R4Represent hydrogen atom or C1-C3Alkyl；
Ring A represents unsubstituted or by 1-3 R9The first aryl of substituted 5-6 or 5-6 unit's heteroaryls, the heteroaryl contains 1-3 N atoms；
R9Represent halogen, C1-C3Alkyl, C1-C3Alkoxyl；
R5Represent C1-C3Alkyl amino, two-(C1-C3Alkyl)-amino, two-(C1-C3Alkyl) amino-(C1-C3Alkyl)-N- (C1- C3Alkyl)-amino, two-(C1-C3Alkyl) amino-(C1-C3Alkyl)-N- (C1-C3Alkyl-carbonyl)-amino, C1-C3Alkoxyl- (C1-C3Alkyl)-N- (C1-C3Alkyl)-amino, C1-C3Alkoxyl-(C1-C3Alkyl)-N- (C1-C3Alkyl-carbonyl)-amino；Take Generation or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical contains the 1-3 hetero atom selected from N, O or S, described Substituent is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3Alkyl-carbonyl, C1-C3Alkyl sulphonyl, amino Carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkyl) amino carbonyl；
R6、R7Each represent hydrogen, halogen, C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3The C of alkyl, halo1-C3Alkyl；
N represents 0 or 1.
2. compound as claimed in claim 1 and its pharmaceutically acceptable salt or isomers, wherein,
R3Represent unsubstituted or by 1-3 R8Substituted phenyl or pyridine radicals.
3. its pharmaceutically acceptable salt of compound as claimed in claim 1 or 2 or isomers, wherein,
Ring A represents unsubstituted or by 1-3 R9Substituted phenyl, pyridine radicals or pyrimidine radicals.
4. the compound and its pharmaceutically acceptable salt or isomers as described in claim 1-3 any one, wherein,
R5Represent two-(C1-C3Alkyl)-amino；Replace or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical contains The 1-3 hetero atom selected from N, O or S, described substituent is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3 Alkyl-carbonyl, C1-C3Alkyl sulphonyl, amino carbonyl, C1-C3Alkyl amino-carbonyl, two-(C1-C3Alkyl) amino carbonyl.
5. the compound and its pharmaceutically acceptable salt or isomers as described in claim 1-4, wherein,
R1、R4Each represent hydrogen atom；
R2Representation methoxy carbonyl, amino carbonyl, amino-carbonyl, dimethyl-aminocarbonyl, N- ethyl-N-methyls-amino carbonyl；
R3Represent unsubstituted or by 1-3 R8Substituted phenyl；
R8Represent halogen；
Ring A represents unsubstituted or by 1-3 R9Substituted phenyl or pyridine radicals；
R9Represent halogen or C1-C3Alkyl；
R5Represent two-(C1-C3Alkyl)-amino；Replace or unsubstituted 5-7 units saturated heterocyclyl, described heterocyclic radical contains The 1-3 hetero atom selected from N, O or S, described substituent is C1-C3Alkyl, C1-C3Alkoxyl, hydroxyl-C1-C3Alkyl, C1-C3 Alkyl-carbonyl；
R6、R7Each represent hydrogen or C1-C3Alkyl.
6. following compounds and its pharmaceutically acceptable salt or isomers：
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- (pyridin-4-yl)-methylene Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxos Indoline -6- methyl formates；
(Z) -3- [1- (4- (2- (lignocaine-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxos Indoline -6- methyl formates；
(Z) -3- [1- (4- (2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxygen For indoline -6- methyl formates；
(Z) -3- [1- (4- (2- (thiomorpholine -4- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] - 2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (pyrrolidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- - oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (piperazine -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxygen For indoline -6- methyl formates；
(Z) -3- [1- (4- (2- (piperidin-1-yl-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxygen For indoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- Acetylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- Nmethanesulphonylpiperazines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methyl piperidines -1- bases-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -4- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyi-methylenes] - 2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (morpholine -4- bases-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- ((2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) methyl) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -1- acetyl Base -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxos Indoline -6- formamides；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- formamides；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes]-N- first Base -2--oxindole quinoline -6- formamides；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base]-N- methyl -2--oxindole quinoline -6- formamides；
(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) amino) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (the fluoro- 4- of 3- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (the fluoro- 4- of 2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-Asia Methyl] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyl-meths Base] -2--oxindole quinoline -6- Ethyl formates；
(Z) -3- [1- (4- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) anilino-) -1- phenyi-methylenes] -2- oxos Indoline -6- Ethyl formates；
(Z) -3- [1- (4- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) anilino-) -1- phenyl - Methylene] -2--oxindole quinoline -6- Ethyl formates；
(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -1H- pyrroles's -1- bases) pyridin-3-yl) amino) -1- phenyl-meths Base] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((6- (2- (dimethylamino-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridin-3-yl) amino) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((6- (2- (4- methylpiperazine-1-yls-methyl) -5- methyl isophthalic acid H- pyrroles's -1- bases) pyridin-3-yl) ammonia Base) -1- phenyi-methylenes] -2--oxindole quinoline -6- methyl formates；
(Z) -3- [1- ((2- (2- (4- methylpiperazine-1-yls-methyl) -1H- pyrroles's -1- bases) pyrimidine -5- bases) amino) -1- benzene Base-methylene] -2--oxindole quinoline -6- methyl formates.
7. a kind of Pharmaceutical composition, the compound comprising any one in claim 1-6 and its pharmaceutically acceptable salt or Isomers is used as active component and pharmaceutically acceptable excipient.
8. the compound and its pharmaceutically acceptable salt or isomers of any one or claim 7 institute in claim 1-6 Application of the composition stated in prevention or treatment fibrotic conditions medicine is prepared.
9. the compound and its pharmaceutically acceptable salt or isomers of any one or claim 7 institute in claim 1-6 The composition stated is preparing prevention or the application in treating cancer medicine.
10. application according to claim 8, it is characterised in that described fibrotic conditions include pnemnofibrosis and Lung disease with fibrotic component, hepatic fibrosis and the liver disease with fibrotic component, kidney fibre modification and with fibre Kidney diaseases, the disease of skin with fibrotic component of dimension chemical conversion point；Described pnemnofibrosis and with fibrotic component Lung disease, including idiopathic pulmonary fibrosis, cystic fibrosis, drug-induced pnemnofibrosis, giant cell interstitial lung Inflammation, silicosis, COPD；The hepatic fibrosis and the liver disease with fibrotic component, including virus draws The cirrhosis for rising；The kidney fibre modification and the kidney diaseases with fibrotic component, including it is postangioplasty restenosis, chronic The kidney fibre modification that glomerulonephritis, drug-induced kidney fibre modification, hypertension are caused；The skin with fibrotic component Skin disease, including chorionitis, sarcoidosis, systemic lupus erythematosus.
11. applications according to claim 9, it is characterised in that described cancer includes lung cancer, colorectal cancer, liver cancer, breast Gland cancer, oophoroma, melanoma, prostate cancer, cervical carcinoma, cancer of the stomach, cancer of pancreas, thyroid cancer.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115703758A (en) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 Compound used as kinase inhibitor and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043254A (en) * 1998-04-03 2000-03-28 Boehringer Ingelheim Pharma Kg Indolinones having kinase-inhibiting activity
CN103848814A (en) * 2012-12-06 2014-06-11 山东亨利医药科技有限责任公司 Substituted indole ketone derivative as tyrosine kinase inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043254A (en) * 1998-04-03 2000-03-28 Boehringer Ingelheim Pharma Kg Indolinones having kinase-inhibiting activity
CN103848814A (en) * 2012-12-06 2014-06-11 山东亨利医药科技有限责任公司 Substituted indole ketone derivative as tyrosine kinase inhibitor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115703758A (en) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 Compound used as kinase inhibitor and preparation method and application thereof
CN115703758B (en) * 2021-08-12 2024-03-26 中国医学科学院药物研究所 Compounds used as kinase inhibitors, preparation method and application thereof

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