CN105503837A - Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof - Google Patents

Substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof Download PDF

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CN105503837A
CN105503837A CN201511033604.7A CN201511033604A CN105503837A CN 105503837 A CN105503837 A CN 105503837A CN 201511033604 A CN201511033604 A CN 201511033604A CN 105503837 A CN105503837 A CN 105503837A
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compound
base
acceptable salt
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CN105503837B (en
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鲁桂
彭伟
涂正超
龙亮
罗羽
刘强
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Sun Yat Sen University
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Sun Yat Sen University
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    • 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
    • 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
    • C07D403/14—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

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Abstract

The invention discloses a substitute quinazolines derivative with Aurora kinase inhibitory activity and application thereof. The substitute quinazolines derivative is a compound as shown in a formula (I) and a formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug. A medicine composition includes one or more of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug. The application of the substitute quinazolines derivative with the Aurora kinase inhibitory activity comprises application of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for inhibiting Aurora kinase; or application of the compound as shown in the formula (I) and the formula (II), or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for treating and/or preventing and/or relieving and/or conducting auxiliary treating and/or treating proliferative diseases; or application of the compound as shown in the formula (I) and the formula (II),or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance,tautomer or prodrug to preparation of medicine for resisting to tumor. The series compound has good inhibitory activity on Aurora kinase.

Description

There is substituted quinazoline analog derivative and the application thereof of Aurora kinase inhibitory activity
Technical field
The present invention relates to the substituted quinazoline analog derivative and application thereof with Aurora kinase inhibitory activity.
Background technology
The feature of cancer and other hyperproliferative disease is uncontrolled cell proliferation.The forfeiture of cell proliferation normal regulating normally occurs because the gene regulating and controlling the cell passage that the whole cell cycle carries out sustains damage.Research shows, in eukaryotic cell, the orderly cascade Mach-Zehnder interferometer of protein phosphorylation the cell cycle.Identify the proteolytic enzyme of several families in this cascade with vital role at present.Compared with healthy tissues, many above-mentioned kinase whose activity obviously increase in people's tumour.This may be because protein expression level improves or assisted activation albumen or resist the expression of albumen and change and caused.The serine-threonine protein kinase enzyme of Aurora A coding and regulating cell cycle is (see TrendsinCellBiology, 2001,11,49-54, Adams etc.) participate in regulating spindle body formation, centrosome maturation, karyomit(e) differentiation and division of cytoplasm process, to the genomic stability of maintenance, there is keying action.Research finds, the overexpression of Aurora A easily causes cell mitogen abnormal, closely related with the formation of tumour.Aurora A overexpression in many cancer cells (as lung cancer, mammary cancer, the rectum cancer, thyroid carcinoma, carcinoma of the pancreas), suppresses the activity of Aurora A can cause the gathering of tumour cell polyploid, promotes apoptosis, blocks cell proliferation.Be that the research and development that target spot carries out antitumor drug are also more and more subject to people's attention with Aurora A.Aurora A is just expressed and activates in mitotic division, and they are invalid for the cell of non-proliferative, and in human body most of Normocellular rate of propagation unhappy.Therefore Aurora A inhibitor belongs to anti-tumor drugs targeting, compared with other non-specific cell cytotoxic drug, will have larger advantage.
The Aurora A inhibitor mainly competitive kinase inhibitor of ATP of current research, mainly through being combined with ATP pocket, suppresses Aurora A active competitively.ATP pocket mainly comprises three regions: the hydrophobic region being in kinases inside, be in the hinge area in the middle of kinases and be in outside solvent can and district.And the Aurora A inhibitor studied at present also mainly comprises three parts: fatty contents, hydrogen bonded part, water-soluble portion.They are combined with ATP pocket respective regions above respectively.
The high reactivity Aurora A inhibitor of existing report is mainly divided into full Aurora A inhibitor, selectivity AuroraA kinase inhibitor and selectivity AuroraB kinase inhibitor, and following several structure is the Aurora A inhibitor structure entering clinical study:
U.S.'s Vertex Standard (Vertex) drugmaker is AuroraA kinases and quinazoline compound N-(3-cyclopropyl-1H-pyrazoles-5-base)-2-phenylquinazoline-4-amine compound crystalline structure reported first in 2003.Compound structure involved in its patent (US7361492B2, WO2003092607A2) patent is as follows.Three atom N on this mixture pyrazoles side chain can form hydrogen bond action with kinase whose hinge area residue, in kinase whose Loop region, there is pi-pi accumulation effect between kinases and the phenyl ring of this mixture.
Vertex company and Merck (Merck) company have developed jointly first Aurora A inhibitor VX-680 (having another name called MK-0457) (WO2004000833A1).This molecular structure is Y shape, and the pyrimidine ring at center is positioned at kinase whose hydrophobic region, and has hydrophobic interaction between kinase amino acid residue; Stretch into kinase whose hinge area containing amino pyrazoles side chain, have crucial hydrogen bond action with its amino-acid residue; Side chain containing phenyl stretches into kinases hydrophobic region; Piperazine sidechain then by the active region of enzyme be stretched over enzyme solvent can and district.Research finds, VX-680 has good restraining effect to AuroraA, B and C, IC 50value is respectively 0.6,18 and 4.6nM, can suppress the propagation of numerous tumour cells such as colorectal carcinoma, mammary cancer, prostate cancer, carcinoma of the pancreas, melanoma, tumor colli, leukemia.2006, VX-680 entered clinical II phase research, is mainly used in treating obstinate chronic lymphocytic leukemia and kemia.Research finds the QTc of patient can be caused to extend risk by this medicine, and (QTc is the time difference between T ripple and Q ripple that electrocardiogram(ECG corrects, QTc prolongation easily causes irregular pulse), in November, 2007, Merck terminated the II clinical trial phase (ExpertOpin.InvestingDrugs.2009 of VX-680,18,379).
When the pyrimidine 2-bit substituent of VX-680 is become styryl by CASI drugmaker (original name EntreMed), the compd E NMD981693 obtained demonstrates good cytoactive, and can optionally suppress AuroraA kinases, it is made into L-TARTARIC ACID salt (ENMD-2076).ENMD-2076 is a kind of efficient AuroraA inhibitor that can be oral, to the inhibit activities IC of AuroraA 50value is the inhibit activities IC of 14nM, AuroraB 50be about 350nM, be also vasculogenesis kinase inhibitor simultaneously, act on the target spots such as VEGFR, Flt-3 and FGFR3.The antitumor test of ENMD-2076 is carried out to 67 routine ovarian cancers, colorectal cancer patients, this inhibitor shows good antitumor action, and the content comprising antineoplastic important target spot VEGFR2 (VEGF R2) in blood plasma obviously declines.The researchists such as Diamond find in the research of ENMD-2076 to three negative breast cancer (TNBC) hypotype and human epidermal growth factor receptor 2 (HER2) positive subgroup, and ENMD-2076 is to shortage estrogen receptor expression or do not have the breast cancer cell of HER-2 overexpression to have potent restraining effect.II clinical trial phase carried out now mainly comprises advanced metastatic three negative breast cancer TNBC (NCT01639248), clear cell carcinoma of ovary (NCT01914510) and late period or transitivity soft tissue sarcoma (NCT01719744), the research for the treatment of liver fibrolamellar cancer (FLC) is about to enter III clinical trial phase.
In addition, also have some patents (WO2002000649A1, WO2003055491A1, WO2004058781A1, WO2004113324A1, CN104098551A, US7951820B2) to report quinazoline derivative to can be used for suppressing Aurora A:
Develop the new compound with Aurora kinase inhibitory activity, in present stage, be significant.
Summary of the invention
The object of the present invention is to provide the substituted quinazoline analog derivative and application thereof with Aurora kinase inhibitory activity.
The technical solution used in the present invention is:
Lead to formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug,
Wherein:
R 1be selected from H ,-N (R) 2,-OR ,-SR, one in halogen; To R 1definition in, the R related to is selected from the one in H, unsubstituted low alkyl group ,-C (O) H ,-OH;
R 2be selected from H, replacement or do not have replace aryl or heterocyclic aryl, wherein substituting group is selected from halogen ,-NO 2,-CN ,-CF 3,-CF 2r ,-C (R)=CR ' 2,-C (R)=C (R ') (R ") ,-C ≡ C-R ,-OR ,-SR ,-S (O) R ,-SO 2r ,-SO 2n (R) 2,-N (R) 2,-OCO 2r ,-OC (O) NR 2,-OC (O) R ,-CO 2r ,-C (O) R ,-C (O) NR 2,-C (=NR)-NR ' 2,-C (=NR)-OR ' ,-NRC (=NR ')-NR " 2,-NRSO 2r ' ,-NRSO 2nR ' 2,-P (O) R 2,-P (O) (OR) 2in one; To R 2definition in, described R, R ' and R " be selected from H, unsubstituted low alkyl group, phenyl or substituted-phenyl independently of one another;
R 3be selected from heterocyclic aryl or Non-aromatic heterocyclic, the C of 4-6 ring 1-C 6aliphatic group, Alkoxyalkylamino, alkoxyalkyl, amino, alkyl or dialkyl amido, alkyl or dialkylaminoalkoxy groups, kharophen, alkoxy carbonyl, alkyl or dialkyl amino carbonyl or substituted-phenyl;
R 4and R 4 'be selected from hydrogen, C independently of one another 1-C 4aliphatic group, alkoxy carbonyl, substituted or unsubstituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarboxyl, monoalkyl or two alkyl aminocarboxyl, aminoalkyl group, alkylaminoalkyl group, dialkyl aminoalkyl, phenyl amino carbonyl, (N-heterocycle) carbonyl; Or, R 4and R 4 'the structure of dicyclo is formed with pyrazoles in logical formula I or (II);
X is carbon atom or nitrogen-atoms.
Described R 1nH 2; Described R 2be selected from the one in substituted-phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; Wherein on phenyl, substituting group is selected from 3-COOH, 3-COOMe, 3-COOEt, 3-COOiPr, 3-OMe, 4-OMe, 2-OMe, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 3-Cl-4-COOMe, 3-OMe-4-COOMe, 2-Cl-2-OMe, 2-CONH 2-3-F, 3-CONH 2, 2-CH 2oH, 4-CONHMe, 2,4-diOMe, 2,5-diOMe, 2-Me-4-OMe, 2,4-diCl, 3,4-diCl, 2-morpholinyl, morpholinyl, 4-morpholinyl, 3,4-methylene-dioxies, 4-CH 2cOOEt, 4-NO 2, 3-NO 2, 2-NO 2, 2-CN, 3-CN, 2-CF 3or 3-CF 3in one.
R 3be selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrryl, piperidyl, morpholinyl, carboxyl, azetidine base, hydroxy piperidine base, N-(4-hydroxy piperidine base), O-(4-piperidyl), piperazinyl, alkylpiperazinyl, 4-methylpiperazine base, N-acetylpiperazinyl, N-alkyl carboxyl amide piperazidine base, N-mesylpiperazinyl, N-(4-nitrophenyl) sulfonyl piperazinium base, N-trifyl piperazinyl, N-p-toluenesulfonyl piperazinyl, N-is to tnBuoromethyl-benzenesulfonyl piperazinyl, thiophene, furans, tetrahydrofuran (THF), ring [2.2.2] heptenyl, methyl, ethyl, cyclopropyl, sec.-propyl, the tertiary butyl, methoxyethylamino, methoxymethyl, methoxy ethyl ethylamino, dimethylamino, dimethylamino propoxy, halogenophenyl, carboxyl phenyl, carboxyanilino, hydroxypyrrolyl, carboxy pyrrole alkyl, formamido-pyrrolidyl, azanol acyl pyrroline alkyl, sulfoamido pyrrolidyl, tetrazole base pyrrolidyl, hydroxy piperidine base, carboxypiperidin base, formamido-piperidyl, azanol acylpiperidine base, sulfoamido piperidyl, tetrazole phenylpiperidines base, carboxypiperazinyl, formamido-piperazinyl, azanol acyl piperazine base, sulfoamido piperazinyl, one in tetrazole base piperazinyl, or, in logical formula I or (II):
Wherein, A is selected from the bioisostere of carboxyl, amide group, ester group or carboxyl;
Y is-(CH 2) m-,-O-,-S-,-S (O) n-or-N (R 5)-;
B is-(CH 2) p-;
C is-(CH 2) t-;
R 5be selected from H or C 1-C 4alkyl, hydroxyl, amino, C 1-C 4alkoxyl group, C 1-C 4alkylamino, C 1-C 4alkyl-OC (O) NH-or C 1-C 4alkyl-C (O) O-;
A and R 5the chiral configuration of the carbon atom that group connects is R configuration independently of one another, or S configuration;
M, n, p, t are respectively 0,1,2,3,4.
Described R 3in containing time amino, amino nitrogen-atoms is free alkali form or pharmacy acceptable salt or quaternary ammonium salt.
R 4and R 4 'be selected from the one in following groups independently of one another: methyl, cyclopropyl, ethyl, sec.-propyl, propyl group, the tertiary butyl, cyclopentyl, phenyl, COOH, CO 2me, CH 2oH, CH 2oMe, CH 2cH 2cH 2oH, CH 2cH 2cH 2oMe, CH 2cH 2cH 2oCH 2ph, CH 2cH 2cH 2nH 2, CH 2cH 2cH 2nHCOOtBu, CONHiPr, CONHCH 2cH=CH 2, CONHCH 2cH 2oMe, CONHCH 2ph, CONH (cyclohexyl), CON (Et) 2, CON (Me) (CH 2ph), CONH (nPr), CON (Et) (nPr), CONHCH 2cH (CH 3) 2, CON (nPr) 2, CO (3-methoxymethyl 1-pyrryl), CONH (3-tolyl), CONH (4-tolyl), CONHMe, CO (1-morpholinyl), CO (4-methyl 1-piperazinyl), CONHCH 2cH 2oH, CONH 2, CO (piperidino); Or R 4and R 4 'the twin nuclei formed with pyrazoles in logical formula I or (II) is one of following:
Described compound is specifically selected from any one in following structural:
A kind of pharmaceutical composition, comprises at least one in following material: a) prodrug of compound, b) this compound pharmaceutically tautomer, g) this compound of polymorphic form, f) this compound of solvate, e) this compound of hydrate, d) this compound of acceptable salt, c) this compound; Wherein, described compound is the compound shown in logical formula I or (II).
Pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug suppress the application in the medicine of Aurora A in preparation to lead to formula I or the compound shown in (II) or its.
Logical formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug preparation treat and/or prevent and/or delay and/or assisting therapy and/or process proliferative disease medicine in application.
Logical formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug are preparing the application in antitumor drug.
The invention has the beneficial effects as follows:
Pass through in 2,4,7-positions of quinazoline ring in the present invention, introduce different pharmacophores, provide a kind of quinazoline derivative of new synthesis, the quinazoline derivative of this new synthesis demonstrates good inhibit activities to Aurora A.
Series compound of the present invention, preparation treat and/or prevent and/or delay and/or assisting therapy and/or process proliferative disease medicine in, there is good prospect.
Embodiment
Lead to formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug,
Wherein:
R 1h ,-N (R) 2,-OR ,-SR, halogen etc., R 1in R be H, unsubstituted low alkyl group ,-C (O) H ,-OH; R 2be H, replace or do not have aryl or the heterocyclic aryl of replacement, wherein substituting group is halogen ,-NO 2,-CN ,-CF 3,-CF 2r ,-C (R)=CR ' 2,-C (R)=C (R ') (and R ") ,-C ≡ C-R ,-OR ,-SR ,-S (O) R ,-SO 2r ,-SO 2n (R) 2,-N (R) 2,-OCO 2r ,-OC (O) NR 2,-OC (O) R ,-CO 2r ,-C (O) R ,-C (O) NR 2,-C (=NR)-NR ' 2,-C (=NR)-OR ' ,-NRC (=NR ')-NR " 2,-NRSO 2r ' ,-NRSO 2nR ' 2, or-P (O) R 2,-P (O) (OR) 2; R 2middle R, R ' and R " be H, unsubstituted low alkyl group, phenyl or substituted-phenyl;
R 3heterocyclic aryl or the Non-aromatic heterocyclic of 4-6 ring, C 1-C 6aliphatic group, Alkoxyalkylamino, alkoxyalkyl, amino, alkyl or dialkyl amido, alkyl or dialkylaminoalkoxy groups, kharophen, alkoxy carbonyl, alkyl and dialkyl amino carbonyl, or substituted-phenyl;
R 4and R 4 'be hydrogen independently of one another, C 1-C 4aliphatic group, alkoxy carbonyl, substituted or unsubstituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarboxyl, the aminocarboxyl of monoalkyl or two alkyl, aminoalkyl group, alkylaminoalkyl group, dialkyl aminoalkyl, phenyl amino carbonyl, or (N-heterocycle) carbonyl; Or R 4and R 4 'the structure of dicyclo is formed with pyrazoles in logical formula I or (II);
X is carbon atom or nitrogen-atoms.
Preferably, described R 1nH 2.
Preferably, described R 2substituted-phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, wherein on phenyl, substituting group is 3-COOH, 3-COOMe, 3-COOEt, 3-COOiPr, 3-OMe, 4-OMe, 2-OMe, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 3-Cl-4-COOMe, 3-OMe-4-COOMe, 2-Cl-2-OMe, 2-CONH 2-3-F, 3-CONH 2, 2-CH 2oH, 4-CONHMe, 2,4-diOMe, 2,5-diOMe, 2-Me-4-OMe, 2,4-diCl, 3,4-diCl, 2-morpholinyl, morpholinyl, 4-morpholinyl, 3,4-methylene-dioxy, 4-CH 2cOOEt, 4-NO 2, 3-NO 2, 2-NO 2, 2-CN, 3-CN, 2-CF 3or 3-CF 3.
Preferably, R 3it is 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrryl, piperidyl, morpholinyl, carboxyl, azetidine base, hydroxy piperidine base, N-(4-hydroxy piperidine base), O-(4-piperidyl), piperazinyl, alkylpiperazinyl, 4-methylpiperazine base, N-acetylpiperazinyl, N-alkyl carboxyl amide piperazidine base, N-mesylpiperazinyl, N-(4-nitrophenyl) sulfonyl piperazinium base, N-trifyl piperazinyl, N-p-toluenesulfonyl piperazinyl, N-is to tnBuoromethyl-benzenesulfonyl piperazinyl, thiophene, furans, tetrahydrofuran (THF), ring [2.2.2] heptenyl, methyl, ethyl, cyclopropyl, sec.-propyl, the tertiary butyl, methoxyethylamino, methoxymethyl, methoxy ethyl ethylamino, dimethylamino, dimethylamino propoxy, halogenophenyl, carboxyl phenyl, carboxyanilino, hydroxypyrrolyl, carboxy pyrrole alkyl, formamido-pyrrolidyl, azanol acyl pyrroline alkyl, sulfoamido pyrrolidyl, tetrazole base pyrrolidyl, hydroxy piperidine base, carboxypiperidin base, formamido-piperidyl, azanol acylpiperidine base, sulfoamido piperidyl, tetrazole phenylpiperidines base, carboxypiperazinyl, formamido-piperazinyl, azanol acyl piperazine base, sulfoamido piperazinyl, tetrazole base piperazinyl,
Or R 3structure be:
Namely in logical formula I or (II),
Wherein, A is carboxyl, amide group, ester group or the bioisostere for carboxyl, as sulfoamido, and hydroximic acid base, tetrazole base, sulfonic acid amides base, sulphur urea groups, trifluoroethanol base, trifluoroethanone base etc.;
Y is-(CH 2) m-,-O-,-S-,-S (O) n-or-N (R 5)-;
B is-(CH 2) p-;
C is-(CH 2) t-;
R 5for H or C 1-C 4alkyl, hydroxyl, amino, C 1-C 4alkoxyl group, C 1-C 4alkylamino, C 1-C 4alkyl-OC (O) NH-or C 1-C 4alkyl-C (O) O-;
A and R 5the chiral configuration of the carbon atom that group connects can be R configuration respectively, or S configuration;
M, n, p, t are respectively 0,1,2,3,4.
Preferred further, described R 3in containing time amino, amino nitrogen-atoms is free alkali form or pharmacy acceptable salt or quaternary ammonium salt.
Preferably, R 4and R 4 'be selected from the one in following groups independently of one another: methyl, cyclopropyl, ethyl, sec.-propyl, propyl group, the tertiary butyl, cyclopentyl, phenyl, COOH, CO 2me, CH 2oH, CH 2oMe, CH 2cH 2cH 2oH, CH 2cH 2cH 2oMe, CH 2cH 2cH 2oCH 2ph, CH 2cH 2cH 2nH 2, CH 2cH 2cH 2nHCOOtBu, CONHiPr, CONHCH 2cH=CH 2, CONHCH 2cH 2oMe, CONHCH 2ph, CONH (cyclohexyl), CON (Et) 2, CON (Me) (CH 2ph), CONH (nPr), CON (Et) (nPr), CONHCH 2cH (CH 3) 2, CON (nPr) 2, CO (3-methoxymethyl 1-pyrryl), CONH (3-tolyl), CONH (4-tolyl), CONHMe, CO (1-morpholinyl), CO (4-methyl 1-piperazinyl), CONHCH 2cH 2oH, CONH 2or CO (piperidino); Or R 4and R 4 'the twin nuclei formed with pyrazoles in logical formula I or (II) is one of following:
Further preferred, described compound is specifically selected from any one in following structural:
A kind of pharmaceutical composition, comprises logical formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug.
Preferably, pharmaceutically acceptable auxiliary material is also comprised.
Preferred further, described auxiliary material comprises at least one in following material: solvent, propellent, solubilizing agent, stablizer, glidant, correctives, sanitas, suspending agent, coating material, perfume compound, anti-tamanori, integrated agent, penetration enhancer, pH value regulator, buffer reagent, softening agent, solubility promoter, emulsifying agent, tinting material, tamanori, disintegrating agent, weighting agent, lubricant, wetting agent, osmotic pressure regulator, tensio-active agent, whipping agent, defoamer, thickening material, inclusion agents, wetting Agent for Printing Inks, absorption agent, thinner, flocculation agent and defloculating agent, flocculating aids, release retarding agent.
Pharmaceutical composition of the present invention can be made into various formulation: classify according to the dispersion system of formulation: specifically, can make following formulation: solution-type, colloidal solution type, emulsion-type, suspension type, gas dispersion type, microdispersed form, solid dispersing; According to typoiogical classification, specifically, following formulation can be made: liquid dosage form (as aromatic water, solution, injection, mixture, lotion, liniment etc.), gas formulation (as aerosol, sprays etc.), solid dosage (as powder, pill, tablet, film etc.), semisolid dosage form (as ointment, suppository, paste etc.); Classify according to route of administration: specifically, following formulation can be made: the formulation through gastrointestinal administration, the formulation without gastrointestinal administration.
Above-mentioned pharmaceutical composition suppresses the application in the medicine of Aurora A in preparation.
Pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug suppress the application in the medicine of Aurora A in preparation to lead to formula I or the compound shown in (II) or its.
Preferably, described Aurora A is the one in AuroraA kinases, AuroraB kinases.
Logical formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug preparation treat and/or prevent and/or delay and/or assisting therapy and/or process proliferative disease medicine in application.
Preferably, described proliferative disease is cancer of the stomach, colorectal cancer, lung cancer, mammary cancer, liver cancer, prostate cancer, thyroid carcinoma, carcinoma of the pancreas, bladder cancer, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis, leukemia, pulmonary fibrosis, lymphatic cancer, rheumatism, chronic inflammatory diseases, non-lymphoreticular system tumour, cryoglobulinemia, papular mucinosis, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, monocytic leukemia, half molecular disease, primary macroglobulinaemia, primary macroglobulinaemia purpura, Secondary cases benign monoclonal gammopathy, osteolytic lesion, acute lymphoblastic leukemia, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndrome, infectious monocytosis, acute histocytic increase disease, hairy cell leukemia, Hodgkin lymphoma, colorectal carcinoma, the rectum cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumour, islet cell tumor, medullary thyroid carcinoma, melanoma, uterus carcinoma, chronic hepatitis, liver cirrhosis, ovarian cancer, retinoblastoma, cholecystitis, G. cephalantha, malignant tumor of digestive tract, nonsmall-cell lung cancer, cervical cancer, tumor of testis, bladder cancer, at least one in myelomatosis.
Especially, logical formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug are preparing the application in antitumor drug;
Preferably, at least one in following compounds or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug are preparing the application in antitumor drug.
As used herein, if for providing concrete restriction, term of the present invention has following implication.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" alkyl " refers to the stable hydrocarbon group of straight or branched, as C 1-C 20alkyl, is preferably C 1-C 12alkyl, is more preferably C 1-C 6alkyl, then be preferably C 1-C 4alkyl, in particular, for example methyl (Me), ethyl (Et), propyl group (such as, n-propyl and sec.-propyl), butyl (such as, normal-butyl, isobutyl-, the tertiary butyl), amyl group is (such as, n-pentyl, isopentyl, neo-pentyl), n-hexyl etc.Wherein, in the group that each substituted alkyl or alkyl replace, alkyl definition is the same.
" low alkyl group " refers to C 1-C 4alkyl.
" treatment significant quantity " refers to when giving the Mammals needing such treatment, is enough to the amount of the general formula compound of effectively treatment.Treatment significant quantity changes depending on the given activity of healing potion used, age of patient, physiological situation, the existence of Other diseases state and nutritional status.In addition, the other medicines treatment that patient may just accept will affect the determination of the treatment significant quantity of the healing potion that will give.
" treatment " means any treatment for disease in mammalian body, comprising:
(I) prevent disease, namely cause the clinical symptom of disease not develop;
(II) suppress disease, namely stop the development of clinical symptom; And/or
(III) palliate a disease, namely cause disappearing of clinical symptom.
In many cases, compound of the present invention can form acid and/or basic salt due to the existence of amino and/or carboxylic group, acid group or similar group.
Compound of the present invention also comprises tautomeric forms.Tautomeric forms derive from a singly-bound and adjacent double bond exchange and together with the migration of a proton.
Pharmacy acceptable salt refers to the form the basic group conversion salify in parent compound.Pharmacy acceptable salt include but not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.Pharmacy acceptable salt of the present invention can be synthesized by parent compound, and the acid of the basic group namely in parent compound and 1-4 equivalent is reacted in a solvent systems.Suitable salt is set forth in Remington ' sPharmaceuticalSciences, 17thed., MackPublishingCompany, Easton, Pa., and 1985,1418 and JournalofPharmaceuticalScience, 66,2, in 1977.
Pharmaceutically acceptable acid salt can be prepared by inorganic and organic acid.Hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. are comprised by the mineral acid of derived acids additive salt.Acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment, Phenylsulfonic acid etc. are comprised by the organic acid of derived acids additive salt.The mineral acid of derived acids additive salt and organic acid are especially selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, Hydrogen bromide, acetic acid, phenylformic acid and tosic acid.
Said composition is preferably formulated into unit dosage.Term " unit dosage " refers to the physical discrete unit being suitable for use as and giving human experimenter and other mammiferous single doses, and per unit contains the predetermined amount and relevant suitable pharmaceutical excipient (as tablet, capsule, ampoule) that calculate to produce the effective active substance of required treatment.The compound of logical formula I or (II) is effective and usually gives active drug amount in dosage range widely.Preferably, for oral administration, each dose unit comprises logical formula I or (II) compound of 10mg to 2g, be more preferably 10 to 700mg, and for administered parenterally, be preferably logical formula I or (II) compound of 10 to 700mg, more preferably from about 50 to 200mg.But, should understand, the amount of the actual logical formula I that gives or (II) compound is determined by doctor according to relevant situation, comprise the illness that will treat, the route of administration selected, the pragmatize compound given and its relative reactivity, age of each patient, body weight and reaction, the seriousness etc. of patients symptomatic.
In order to prepare solids composition as tablet, main active ingredient carried out mixing to form solid preformulation composition with drug excipient (or carrier), it comprises the uniform mixture of compound of the present invention.In time claiming these preformulation composition to be uniform, it refers to that active ingredient is dispersed in whole composition, so that composition easily can be subdivided into identical effective unit dosage as tablet, pill and capsule.
Tablet of the present invention or pill applied or otherwise can be had to provide a kind of the formulation extending effect beneficial by compound, or protection tablet or pill are from the effect of acidic conditions in stomach.Such as, tablet or pill can comprise interior dosage and external dose composition, and the latter has the form of the crust on the former.Can separate two kinds of compositions with enteric layer, wherein enteric layer is used for stoping disintegration under one's belt and composition is complete in allowing enters duodenum or be delayed by release.Various material may be used for such enteric layer or coating, and above-mentioned materials comprises many polymer acids and polymer acid and such material as the mixture of shellac, cetyl alcohol and cellulose acetate.
Solution in pharmaceutically acceptable water-containing solvent or organic solvent or its mixture and suspension is included in for the composition of inhalation or insufflation, and powder.Liquid or solid composition can comprise suitable pharmaceutical excipient as described above.Preferably, these compositions are given to obtain local or systemic effect by oral or nasal respiratory route.The composition in the acceptable solvent of preferred pharmacy can be atomized by using rare gas element.Directly can suck atomized soln from atomisation unit, or atomisation unit can be connected to face shield account shape thing or intermittent positive pressure breathing machine.Can by the device sending formulation in a suitable manner, preferred oral or nose approach, give solution, suspensoid or powder composite.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form of solvate or hydrate is equal to form that is non-solvated or non-hydrated, and contains within the scope of the invention.Likely there is polycrystal or unbodied form in some compound in the present invention.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
The present invention also comprises the prodrug of described compound.Prodrug is a pharmacological agents (medicine), is derived by parent drug.Once enter in body, prodrug is just become parent drug by metabolic transformation.Prodrug is prepared by replacing one or more functional groups of parent drug, and its substituted radical will be degraded and discharge parent compound in vivo.Preparation and the use of prodrug can at T.HiguchiandV.Stella, " Pro-drugsasNovelDeliverySystems; " Vol.14oftheA.C.S.SymposiumSeries and BioreversibleCarriersinDrugDesign, ed.EdwardB.Roche, AmericanPharmaceuticalAssociationandPergamonPress, finds in 1987.
The present invention also provides the pharmaceutical composition comprising general formula (I) or (II) compound or its pharmacologically acceptable salts or its prodrug and the pharmaceutically acceptable carrier of at least one.Pharmaceutical composition of the present invention can be oral, and injection is injected, and spraying sucks, skin external application, rectum use, nasal cavity use, vagina use, abdominal cavity use, or use by implanting the approach such as reservoir or transdermal patch.
In yet another aspect, of the present invention have the compound that represented by logical formula I or (II) or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer or prodrug, or comprise the application of pharmaceutical composition in the medicine suppressing Aurora A of the compound represented by logical formula I or (II), especially suppress the application in the kinase whose medicine of AuroraA.
In yet another aspect, the invention provides the method suppressing Aurora A with logical formula I or (II) compound.Comprise the above-mentioned compound represented by logical formula I or (II) of significant quantity, or its pharmaceutically acceptable salt, solvate, polymorphic form, tautomer, prodrug, or the pharmaceutical composition comprising the compound represented by logical formula I or (II) is for suppressing Aurora A.
" suppress Aurora A active " term herein means, Aurora A is once the quinazoline derivative replaced with 2,4,7-positions of the present invention contacts, and its activity declines to some extent relative to when contacting with this compound.Therefore, the invention provides a kind of quinazoline derivative that 2,4,7-position replaces and contact the method suppressing Aurora A activity with Aurora A.The compound with logical formula I or (II) of the present invention is mainly in order to suppress AuroraA kinase activity.The compound with logical formula I or (II) of the present invention can be used for inhibition tumor cell growth.
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is as shown in formula I or (II).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
If no special instructions, the unit " degree " of the temperature of reaction that the present invention relates to means " DEG C "; Concentration unit " M " means " mol/L ".
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable blocking group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compound of the present invention admittedly.
Process description below prepares the universal method of the compounds of this invention.
Reaction scheme I
Compound 5 is prepared by reaction scheme 1, wherein R 1, R 2, R 3, R 4and R 4 'have and define as described herein.Raw material 1 and the synthon such as carboxylic acid or acyl chlorides react and generate amido linkage and obtain compound 2.Close ring afterwards and generate Quinazol derivative 3.Compound 3 generates compound 4 with amine generation carbon nitrogen coupling reaction again.There is direct ammoxidation and obtain compound 5 in compound 4 and pyrazole derivatives.
Reaction scheme II
Compound 5 also can be prepared by scheme II, wherein R 1, R 2, R 3, R 4and R 4 'have and define as described herein.Compound 9 reduces and obtains compound 10 under palladium carbon and hydrogen atmosphere, and the amino reduced afterwards further amidation occurs again, substitution reaction, and reduction amination etc. are obtained by reacting compound 5.
Reaction scheme III
Compound 15 also can be prepared by scheme III, wherein R 1, R 2, R 3, R 4and R 4 'have and define as described herein.Compound 12 is generated by nucleophilic substitution reagent reacts such as compound 11 and corresponding amine.Compound 12 reductive hydrolysis under palladium carbon and hydrazine hydrate condition generates compound 13.Compound 13 is through amidation, and ring closure reaction generates Quinazol derivative 14.There is direct ammoxidation and obtain compound 15 in compound 14 and pyrazole derivatives.
Reaction scheme IV
Compound 5 also can be prepared by scheme IV, wherein R 1, R 2, R 3, R 4and R 4 'have and define as described herein.Compound 3 and pyrazole derivatives are obtained by reacting compound 16, and pyrazolyl THP protects and obtains compound 17 afterwards.Halogen Cl in compound 17 and corresponding amine generation carbon nitrogen coupling obtain compound 18.Compound 18 in acid condition Deprotection obtains compound 5.
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
Below in conjunction with specific embodiment, the present invention is described further:
One, representative compound in table 1 is prepared as follows
Embodiment 1
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-4-amino-2-styroyl quinazoline
The chloro-2-of step 1:4-(3-hydrocinnamamide base) phenylformic acid
By 2-amino-4-chloro-benzoic acid (10.3g, 60mmol), salt of wormwood (24.9g, 180mmol) joins in the acetonitrile of 200mL, the phenylpropyl alcohol acyl chlorides (72mmol) that slow instillation is now made, dropwise rear temperature of reaction system and be raised to 80 degree, reflux 5 hours, reaction system generates a large amount of precipitation, the hydrochloric acid soln adjust ph adding 1N is 2, add about 100mL methylene dichloride, after vigorous stirring, suction filtration obtains amide intermediate (12.4g, 68%). 1HNMR(400MHz,DMSO-d 6)δ:13.89(s,1H),11.24(s,1H),8.59(s,1H),7.96(d,J＝8.5Hz,1H),7.31-7.13(m,6H),2.93(t,J＝7.4Hz,2H),2.73(t,J＝7.4Hz,2H). 13CNMR(100MHz,DMSO-d 6)δ:170.9,168.7,141.8,140.5,138.4,132.8,128.3,128.2,126.0,122.4,119.1,114.9,38.9,30.4.
Step 2:7-chloro-2-styroyl quinazoline-4 (3H)-one
15mL diacetyl oxide is added, 140 degree of backflow 3h by the round-bottomed flask that the chloro-2-of 4-(3-phenylpropionic acid acid amides) phenylformic acid (2.43g, 8mmol) is housed, after some plate detection raw material reaction is complete, decompression removing residual acetic acid acid anhydride, adds anhydrous acetic acid ammonium, reacts and spend the night under 170 degree.Add water after being cooled to room temperature, have a large amount of Precipitation, after adding 20mL methylene dichloride vigorous stirring, suction filtration obtains target product (1.51g, 66%). 1HNMR(400MHz,DMSO-d 6)δ:12.42(s,1H),8.07(d,J＝8.5Hz,1H),7.67(d,J＝1.8Hz,1H),7.50(dd,J＝8.5,1.9Hz,1H),7.39-7.13(m,5H),3.05(dd,J＝9.5,6.3Hz,2H),2.90(dd,J＝9.5,6.3Hz,2H). 13CNMR(100MHz,DMSO-d 6)δ:161.6,158.8,150.4,141.1,139.4,128.9,128.8,128.3,126.8,126.6,126.4,120.1,36.8,32.9.
Step 3:N-(5-methyl isophthalic acid-(tetrahydrochysene-2H-furans-2-base)-1H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-4-amino-2-styroyl quinazoline
By chloro-for 7-2-styroyl quinazoline-4 (3H)-one (854mg, 3mmol), PyBrop (1.8g, 3.9mmol) be dissolved in 5mL acetonitrile, after stirred at ambient temperature 30min with DBU (1.3mL, 9mmol), add 3-amino-5-methylpyrazole (728mg, 7.5mmol) react 24 hours under 70 degree, have a large amount of yellow mercury oxide to separate out, suction filtration obtains intermediate.Intermediate is suspended in 10mL acetonitrile, add 3,4-dihydro-2H-pyrans (821 μ L, 9mmol), trifluoroacetic acid (222 μ L, 3mmol) post-heating to 75 spends stirring 3 hours, after decompression removing organic solvent, adds saturated sodium carbonate solution quaternization system, with dichloromethane extraction, organic phase anhydrous sodium sulfate drying, after concentrating under reduced pressure, crude by column chromatography purifying (MeOH:CH 2cl 2=2:98) obtain light green solid (642mg, 48%).Owing to there is chiral centre in the tautomerism of pyrazoles and tetrahydrochysene-2H-furans 2-base, the spectrogram obtained is comparatively complicated.MS(ESI+APCI)m/z448.2[M+H] +。
Step 4:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-4-amino-2-styroyl quinazoline
Toward N-(5-methyl isophthalic acid-(tetrahydrochysene-2H-furans-2-base)-1H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-4-amino-2-styroyl quinazoline (224mg, 0.5mmol), Pd 2(dba) 3(9mg; 0.01mmol); Xphos (12mg, 0.025mmol), sodium tert-butoxide (144mg; 1.5mmol); N methyl piperazine (111 μ L, 1.0mmol) adds dry dioxane (5mL) under anhydrous and oxygen-free condition, reacts 11 hours under 90 degree; after decompression removing organic solvent, obtain the midbody product of THP protection through column chromatography purification.Intermediate is dissolved in trifluoroacetic acid: stirred at ambient temperature 12 hours in methylene dichloride (1:1) mixed solvent, after removal of solvent under reduced pressure, with saturated sodium carbonate solution regulation system pH to alkalescence, add methylene dichloride: methyl alcohol (10:1) solvent, be separated organic phase, through column chromatography (CH after concentrated 2cl 2: MeOH=1:9) purifying obtains target product (67mg, 31%).
Embodiment 2
2-(1-amino-2-styroyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl) quinazoline-4-amine
Step 1:2-amino-4-(4-methylpiperazine-1-yl) benzamide
By chloro-for 4-2 nitrobenzonitrile (5.5g, 30mmol), methylpiperazine (7.4mL, 66mmol) be dissolved in 50mL dioxane, 110 degree of reaction backflows 16 hours, dichloromethane extraction is added after decompression removing dioxane, organic phase anhydrous sodium sulfate drying, the concentrated intermediate obtained is dissolved in 100mL ethanol, add wet Pd/C (300mg) and hydrazine hydrate (5.8mL, 120mmol), reaction system is spent the night 80 degree of reactions, after decompression removing organic solvent, add MeOH:CH 2cl 2(1:10) solvent is about 150mL lysate, crosses siliceous earth column, MeOH:CH 2cl 2(1:10) solvent wash, a small amount of washed with dichloromethane of the solid obtained after organic phase concentrates, obtains target product (6.4g, 91%). 1HNMR(400MHz,DMSO-d 6)δ:7.41(d,J＝8.8Hz,1H),6.57(s,2H),6.13(dd,J＝8.9,2.2Hz,1H),6.09(d,J＝2.1Hz,1H),3.24-2.96(m,4H),2.45-2.27(m,4H),2.20(s,3H). 13CNMR(100MHz,DMSO-d 6)δ:171.6,153.9,152.3,130.4,105.2,103.4,100.6,54.9,47.4,46.2.MS(ESI+APCI)m/z235.2[M+H] +.
Step 2:(1-(7-(4-methylpiperazine-1-yl)-4-oxa--3,4-dihydroquinazoline-2-base)-2-styroyl) t-butyl carbamate
By N-tertbutyloxycarbonyl phenylalanine (796mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) at room temperature stir after 1 hour, add 2-amino-4-(4-methylpiperazine-1-yl) benzamide (703mg, 3mmol), react under 50 degree and spend the night, after reaction shrend is gone out, add dichloromethane extraction, anhydrous sodium sulfate drying, be dissolved in 20mL ethanol after concentrated, 10MNaOH solution (1.2mL) is added after being cooled to 0 degree, stirred at ambient temperature is after 30 minutes, with concentrated hydrochloric acid adjust pH to neutral, after decompression removing ethanol, with dichloromethane extraction, anhydrous sodium sulfate drying, after concentrated, column chromatography obtains Light brown solid (1.2g, 86%). 1HNMR(400MHz,DMSO-d 6)δ:11.93(s,1H),7.89(d,J＝8.9Hz,1H),7.43-7.09(m,7H),6.89(s,1H),4.63(d,J＝4.0Hz,1H),3.36(s,4H),3.16-2.97(m,1H),2.97-2.78(m,1H),2.47(s,4H),2.24(s,3H),1.30(s,9H). 13CNMR(100MHz,DMSO-d 6)δ:161.6,158.1,155.6,155.5,150.8,138.1,129.8,128.6,127.3,126.9,115.1,112.1,109.0,78.8,55.7,54.7,47.1,46.1,39.2,28.6.MS(ESI+APCI)m/z464.3[M+H] +.
Step 3:2-(1-amino-2-styroyl)-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl) quinazoline-4-amine
By (1-(7-(4-methylpiperazine-1-yl)-4-oxa--3, 4-dihydroquinazoline-2-base)-2-styroyl) t-butyl carbamate (232mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 3 days, after decompression removing acetonitrile, directly column chromatography obtains Boc and protects product, be dissolved in trifluoroacetic acid afterwards: stirred at ambient temperature 2 hours in methylene dichloride (1:1) solvent, after decompression removing organic solvent, with in saturated sodium carbonate solution and system, add methylene dichloride: methyl alcohol (10:1) solvent, be separated organic phase, through column chromatography (CH after concentrated 2cl 2: MeOH=1:9) purifying obtains target product (45mg, 20%).
Embodiment 3
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-phenylethane base quinazoline-4-amine
Step 1:2-phenylethane base quinazoline-4 (3H)-one
By 2-aminobenzamide (8.2g, 60mmol), salt of wormwood (2equiv.) is suspended in dry acetonitrile, add phenylpropyl alcohol acyl chlorides (9.8mL gradually, 66mmol), after dropwising, system rises to 80 degree, reflux 5 hours, add 100mL water, suction filtration obtains intermediate, intermediate is dissolved in 100mL ethanol, 10MNaOH (4equiv.) solution is dripped under 0 degree, stirred at ambient temperature is after 30 minutes, under 0 degree with in concentrated hydrochloric acid and, separate out a large amount of solid, after decompression removing ethanol in proper amount, add 100mL water, suction filtration obtains target product (13.2g, 88%).
Step 2:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-phenylethane base quinazoline-4-amine
By 2-phenylethane base quinazoline-4 (3H)-one (125mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 1 day, and after decompression removing acetonitrile, directly column chromatography obtains target product (82mg, 50%).
Embodiment 4
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-phenylethane yl pyridines also [3,2-d] pyrimidine-4-amine
Step 1:3-(3-phenylpropionic acid acid amides)-2-pyridine carboxylic acid
By 3-amino-2-pyridine carboxylic acid (4.4g, 30mmol) be dissolved in 80mL pyridine, slow dropping phenylpropyl alcohol acyl chlorides (4.9mL, 33mmol), at room temperature stir after 6 hours, removal of solvent under reduced pressure, residue is through column chromatography purification, obtain target product (6.2g, 76%).
Step 2:2-phenylethane yl pyridines is [3,2-d] pyrimidine-4 (3H)-one also
By 3-(3-phenylpropionic acid acid amides)-2-pyridine carboxylic acid (1.4g, 5mmol) be heated in diacetyl oxide 140 degree stir 3 hours after, removal of solvent under reduced pressure, residue is heated to 185 degree and stirs 9 hours in dry methane amide (50mL).Add 150mL water, with chloroform extraction, the organic phase saturated common salt water washing of separation, after removal of solvent under reduced pressure, column chromatographic isolation and purification obtains target product (460mg, 36%).
Step 3:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-phenylethane yl pyridines also [3,2-d] pyrimidine-4-amine
By 2-phenylethane yl pyridines also [3,2-d] pyrimidine-4 (3H)-one (125mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) be dissolved in stirred at ambient temperature in acetonitrile and, after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 degree reaction 1 day, after decompression removing acetonitrile, directly column chromatography obtains target product (71mg, 43%).
Embodiment 5
2-(1-chloro-2-phenylethane base)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) quinazoline-4-amine
Step 1:2-(1-chloro-2-phenylethane base)-N-(5-methyl isophthalic acid H-pyrazole-3-yl) quinazoline-4-amine
By 2-(1-chloro-2-phenylethane base) quinazoline-4 (3H)-one (142mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 1 day, and after decompression removing acetonitrile, directly column chromatography obtains target product (63mg, 35%).
Embodiment 6
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-nitro-2-phenylethane base quinazoline-4-amine
Step 1:7-nitro-2-phenylethane base quinazoline-4 (3H)-one
By 2-amino-4-nitrobenzamide (1.8g, 10mmol), salt of wormwood (2equiv.) is suspended in dry acetonitrile, add phenylpropyl alcohol acyl chlorides (1.6mL gradually, 11mmol), after dropwising, system rises to 80 degree, heat faint backflow 5 hours, add 20mL water, suction filtration obtains intermediate, intermediate is dissolved in 20mL ethanol, 10MNaOH (4equiv.) solution is dripped under 0 degree, stirred at ambient temperature is after 30 minutes, under 0 degree with in concentrated hydrochloric acid and, separate out a large amount of solid, after decompression removing ethanol in proper amount, add 20mL water, suction filtration obtains target product (2.6g, 88%).
Step 2:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-nitro-2-phenylethane base quinazoline-4-amine
By 7-nitro-2-phenylethane base quinazoline-4 (3H)-one (148mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 1 day, and after decompression removing acetonitrile, directly column chromatography obtains target product (159mg, 85%).
Embodiment 7
N 4-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-phenylquinazoline-4,7-diamines
Example compound 6 (200mg, 0.58mmol) is dissolved in 10mL ethanol, adds Pd/C and is about 10mg, after air in nitrogen replacement reaction flask, pass into hydrogen, at room temperature stir 12 hours, point plate finds that its primitive reaction is complete, column chromatography purification (CH 2cl 2: MeOH=1:1) obtain target product (75mg, 38%)
Embodiment 8
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-morpholine-2-phenylethane base quinazoline-4-amine
Toward N-(5-methyl isophthalic acid-(tetrahydrochysene-2H-furans-2-base)-1H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-4-amino-2-styroyl quinazoline (224mg, 0.5mmol), Pd 2(dba) 3(9mg; 0.01mmol); Xphos (12mg, 0.025mmol), sodium tert-butoxide (144mg; 1.5mmol); morpholine (87 μ L, 1.0mmol) adds dry dioxane (5mL) under anhydrous and oxygen-free condition, reacts 11 hours under 90 degree; after decompression removing organic solvent, obtain the midbody product of THP protection through column chromatography purification.Intermediate is dissolved in trifluoroacetic acid: stirred at ambient temperature 12 hours in methylene dichloride (1:1) mixed solvent, after removal of solvent under reduced pressure, by saturated sodium carbonate solution regulation system pH value alkalescence, add methylene dichloride: methyl alcohol (10:1) solvent, be separated organic phase, through column chromatography (CH after concentrated 2cl 2: MeOH=1:9) purifying obtains target product (80mg, 39%).
Embodiment 9
The synthesis of operation steps and embodiment 8 is similar.Productive rate is 55%.
Embodiment 10
The synthesis of operation steps and embodiment 8 is similar.Productive rate is 39%.
Embodiment 11
The synthesis of operation steps and embodiment 8 is similar.Productive rate is 55%.
Embodiment 12
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-2-(3-nitrophenethyl) quinazoline-4-amine
Step 1:7-(4-methylpiperazine-1-yl)-2-(3-nitrophenethyl) quinazoline-4 (3H)-one
By 3-oil of mirbane propionic acid (796mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) at room temperature stir after 1 hour, add 2-amino-4-(4-methylpiperazine-1-yl) benzamide (703mg, 5mmol), react under 50 degree and spend the night, after reaction shrend is gone out, add dichloromethane extraction, anhydrous sodium sulfate drying, be dissolved in 20mL ethanol after concentrated, 10MNaOH solution (1.2mL) is added after being cooled to 0 degree, stirred at ambient temperature is after 30 minutes, with concentrated hydrochloric acid adjust pH to neutral, after decompression removing ethanol, with dichloromethane extraction, anhydrous sodium sulfate drying, after concentrated, column chromatography obtains Light brown solid (1.1g, 93%).
Step 2:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-2-(3-nitrophenethyl) quinazoline-4-amine
By 7-(4-methylpiperazine-1-yl)-2-(3-nitrophenethyl) quinazoline-4 (3H)-one (393mg, 1.0mmol), PyBrop (606mg, 1.3mmol), DBU (224 μ L, 1.5mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (194mg, 2.0mmol) post-heating to 70 spends reaction 3 days, after decompression removing acetonitrile, directly column chromatography purification obtains target product (176mg, 37%).
Embodiment 13
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-2-(3-(trifluoromethyl) styroyl) quinazoline-4-amine
The synthesis of operation steps and embodiment 12 is similar.Productive rate is 29%.
Embodiment 14
N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-(1-(methylamino-)-2-styroyl)-7-(4-methylpiperazine-1-yl) quinazoline-4-amine
Step 1:N-methyl (1-(7-(4-methylpiperazine-1-yl)-quinazolinone-2-base)-2-styroyl) the formyl tert-butyl ester
By N-tertbutyloxycarbonyl-N-methylphenylalanine (837mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) at room temperature stir after 1 hour, add 2-amino-4-(4-methylpiperazine-1-yl) benzamide (703mg, 3mmol), react under 50 degree and spend the night, after reaction shrend is gone out, add dichloromethane extraction, anhydrous sodium sulfate drying, be dissolved in 20mL ethanol after concentrated, 10MNaOH solution (1.2mL) is added after being cooled to 0 degree, stirred at ambient temperature is after 30 minutes, with concentrated hydrochloric acid adjust pH to neutral, after decompression removing ethanol, with dichloromethane extraction, anhydrous sodium sulfate drying, after concentrated, column chromatography obtains Light brown solid (1.1g, 77%). 1HNMR(400MHz,DMSO-d 6)δ:12.10-11.76(m,1H),7.90(d,J＝8.8Hz,1H),7.37-7.09(m,6H),6.94(s,1H),5.46-5.03(m,1H),3.46-3.27(m,5H),3.16-3.03(m,1H),2.87-2.71(d,3H),2.51-2.35(m,4H),2.23(s,3H),1.41-1.09(m,9H).
Step 2:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-(1-(methylamino-)-2-styroyl)-7-(4-methylpiperazine-1-yl) quinazoline-4-amine
By N-methyl (1-(7-(4-methylpiperazine-1-yl)-quinazolinone-2-base)-2-styroyl) the formyl tert-butyl ester (239mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 3 days, after decompression removing acetonitrile, directly column chromatography obtains Boc and protects product, be dissolved in trifluoroacetic acid afterwards: stirred at ambient temperature 2 hours in methylene dichloride (1:1) solvent, after decompression removing organic solvent, with in saturated sodium carbonate solution and system, add methylene dichloride: methyl alcohol (10:1) solvent, be separated organic phase, through column chromatography (CH after concentrated 2cl 2: MeOH=1:9) purifying obtains target product (166mg, 73%).
Embodiment 15
(E)-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-2-styryl quinazoline-4-amine
Step 1:(E)-7-(4 methylpiperazine-1-yl)-2-styryl quinazoline-4 (3H)-one
By styracin (444mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) at room temperature stir after 1 hour, add 2-amino-4-(4-methylpiperazine-1-yl) benzamide (703mg, 3mmol), react under 50 degree and spend the night, after reaction shrend is gone out, add dichloromethane extraction, anhydrous sodium sulfate drying, be dissolved in 20mL ethanol after concentrated, 10MNaOH solution (1.2mL) is added after being cooled to 0 degree, stirred at ambient temperature is after 30 minutes, with concentrated hydrochloric acid adjust pH to neutral, after decompression removing ethanol, with dichloromethane extraction, anhydrous sodium sulfate drying, after concentrated, column chromatography obtains Light brown solid (910mg, 88%).
Step 2:(E)-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-7-(4-methylpiperazine-1-yl)-2-styryl quinazoline-4-amine
By (E)-7-(4 methylpiperazine-1-yl)-2-styryl quinazoline-4 (3H)-one (173mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) to be dissolved in acetonitrile stirred at ambient temperature after 30 minutes, add 3-amino-5-methylpyrazole (97mg, 1.0mmol) post-heating to 70 spends reaction 3 days, after decompression removing acetonitrile, directly column chromatography obtains Boc and protects product, be dissolved in trifluoroacetic acid afterwards: stirred at ambient temperature 2 hours in methylene dichloride (1:1) solvent, after decompression removing organic solvent, with in saturated sodium carbonate solution and system, add methylene dichloride: methyl alcohol (10:1) solvent, be separated organic phase, through column chromatography (CH after concentrated 2cl 2: MeOH=1:9) purifying obtains target product (77mg, 36%).
Also prepared in the present invention as other compound in following table 1, the synthetic method of these compounds is with reference to aforesaid method simultaneously.The characterization data of these compounds, comprises nuclear magnetic data and high resolution mass spectrum data are as shown in table 1.
Table 1
Compound synthesized by the present invention is to Aurora A Inhibition test
Aurora A active testing is measured by CaliperMobilityShiftAssay method.By compound three times of dilutions successively from 10 μMs, altogether obtain 10 concentration, and add Aurora A, FAM labeling polypeptide and ATP, 25 degree of lower reactions add stop buffer termination reaction after 60 minutes; Finally adopt Caliper reading and converting rate data, calculated by Xlfit statistical software after being converted into inhibiting rate data and obtain IC 50data.Not add the solvent blank of medicine as negative control, take SNS314 as positive control.In above-mentioned table 1, each compound all has Aurora A restraining effect, and test result is as shown in table 2.
Aurora kinase inhibitory activity (the IC of table 2 embodiment compound 50, nM)
acompound 18T is L-(+)-tartrate of compound 18.
The activity experiment of the compound on tumor cell strain synthesized by the present invention
Tumor cell line comprises: human tissue cell lymphoma cell strain U937, human cervical carcinoma cell lines Hela, human chronic polymorpho nuclear leukemia cells strain K562, people's breast adenocarcinoma cell strain SK-BR-3, MCF-7 cell strainHJ2mm, Human carcinoma of prostate cell line DU145, people's acute lymphoblastic leukemia cell strain Molt-4.
Experimental technique: cell strain is growth survival in the DMEM/RPMI substratum of 10%FBS and 1% penicillin/Streptomycin sulphate.All cells strain all deposits in Thermo/FormaScientificCO 2grow in cell culture incubator, condition: containing 5%CO 2air, temperature is 37 DEG C.Cell activation assay is measured by CCK8 (DojinDo) method.Be inoculated in 384 well culture plates with the cell density in 400-800/ hole, add the compound of different concns, after 72 hours hatch, add CCK8 reagent, light absorption value under 450nM wavelength is measured with the multi-functional micropore analyser (PerkinElmer) of Envision2104, Prism (Version5, GraphPadsoftware) is finally used to go out anti-tumour cell proliferative IC by dose-effect curve calculation 50value..
Test with taxol (Taxol) for positive control, the IC of embodiment compound and contrast 50be worth as shown in the table.
Anti-tumour cell proliferative activity (the IC of table 3 the compounds of this invention 50, μM)
aembodiment compound 18T is L-(+)-tartrate of embodiment compound 18.
These are only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (10)

1. lead to formula I or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug,
Wherein:
R 1be selected from H ,-N (R) 2,-OR ,-SR, one in halogen; To R 1definition in, the R related to is selected from the one in H, unsubstituted low alkyl group ,-C (O) H ,-OH;
R 2be selected from H, replacement or do not have replace aryl or heterocyclic aryl, wherein substituting group is selected from halogen ,-NO 2,-CN ,-CF 3,-CF 2r ,-C (R)=CR ' 2,-C (R)=C (R ') (R ") ,-C ≡ C-R ,-OR ,-SR ,-S (O) R ,-SO 2r ,-SO 2n (R) 2,-N (R) 2,-OCO 2r ,-OC (O) NR 2,-OC (O) R ,-CO 2r ,-C (O) R ,-C (O) NR 2,-C (=NR)-NR ' 2,-C (=NR)-OR ' ,-NRC (=NR ')-NR " 2,-NRSO 2r ' ,-NRSO 2nR ' 2,-P (O) R 2,-P (O) (OR) 2in one; To R 2definition in, described R, R ' and R " be selected from H, unsubstituted low alkyl group, phenyl or substituted-phenyl independently of one another;
R 3be selected from heterocyclic aryl or Non-aromatic heterocyclic, the C of 4-6 ring 1-C 6aliphatic group, Alkoxyalkylamino, alkoxyalkyl, amino, alkyl or dialkyl amido, alkyl or dialkylaminoalkoxy groups, kharophen, alkoxy carbonyl, alkyl or dialkyl amino carbonyl or substituted-phenyl;
R 4and R 4 'be selected from hydrogen, C independently of one another 1-C 4aliphatic group, alkoxy carbonyl, substituted or unsubstituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarboxyl, monoalkyl or two alkyl aminocarboxyl, aminoalkyl group, alkylaminoalkyl group, dialkyl aminoalkyl, phenyl amino carbonyl, (N-heterocycle) carbonyl; Or, R 4and R 4 'the structure of dicyclo is formed with pyrazoles in logical formula I or (II);
X is carbon atom or nitrogen-atoms.
2. logical formula I according to claim 1 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug, is characterized in that: described R 1nH 2; Described R 2be selected from the one in substituted-phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl; Wherein on phenyl, substituting group is selected from 3-COOH, 3-COOMe, 3-COOEt, 3-COOiPr, 3-OMe, 4-OMe, 2-OMe, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 3-Cl-4-COOMe, 3-OMe-4-COOMe, 2-Cl-2-OMe, 2-CONH 2-3-F, 3-CONH 2, 2-CH 2oH, 4-CONHMe, 2,4-diOMe, 2,5-diOMe, 2-Me-4-OMe, 2,4-diCl, 3,4-diCl, 2-morpholinyl, morpholinyl, 4-morpholinyl, 3,4-methylene-dioxies, 4-CH 2cOOEt, 4-NO 2, 3-NO 2, 2-NO 2, 2-CN, 3-CN, 2-CF 3or 3-CF 3in one.
3. logical formula I according to claim 2 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug, is characterized in that: R 3be selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrryl, piperidyl, morpholinyl, carboxyl, azetidine base, hydroxy piperidine base, N-(4-hydroxy piperidine base), O-(4-piperidyl), piperazinyl, alkylpiperazinyl, 4-methylpiperazine base, N-acetylpiperazinyl, N-alkyl carboxyl amide piperazidine base, N-mesylpiperazinyl, N-(4-nitrophenyl) sulfonyl piperazinium base, N-trifyl piperazinyl, N-p-toluenesulfonyl piperazinyl, N-is to tnBuoromethyl-benzenesulfonyl piperazinyl, thiophene, furans, tetrahydrofuran (THF), ring [2.2.2] heptenyl, methyl, ethyl, cyclopropyl, sec.-propyl, the tertiary butyl, methoxyethylamino, methoxymethyl, methoxy ethyl ethylamino, dimethylamino, dimethylamino propoxy, halogenophenyl, carboxyl phenyl, carboxyanilino, hydroxypyrrolyl, carboxy pyrrole alkyl, formamido-pyrrolidyl, azanol acyl pyrroline alkyl, sulfoamido pyrrolidyl, tetrazole base pyrrolidyl, hydroxy piperidine base, carboxypiperidin base, formamido-piperidyl, azanol acylpiperidine base, sulfoamido piperidyl, tetrazole phenylpiperidines base, carboxypiperazinyl, formamido-piperazinyl, azanol acyl piperazine base, sulfoamido piperazinyl, one in tetrazole base piperazinyl, or, in logical formula I or (II):
Wherein, A is selected from the bioisostere of carboxyl, amide group, ester group or carboxyl;
Y is-(CH 2) m-,-O-,-S-,-S (O) n-or-N (R 5)-;
B is-(CH 2) p-;
C is-(CH 2) t-;
R 5be selected from H or C 1-C 4alkyl, hydroxyl, amino, C 1-C 4alkoxyl group, C 1-C 4alkylamino, C 1-C 4alkyl-OC (O) NH-or C 1-C 4alkyl-C (O) O-;
A and R 5the chiral configuration of the carbon atom that group connects is R configuration independently of one another, or S configuration;
M, n, p, t are respectively 0,1,2,3,4.
4. logical formula I according to claim 3 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug, is characterized in that: described R 3in containing time amino, amino nitrogen-atoms is free alkali form or pharmacy acceptable salt or quaternary ammonium salt.
5. logical formula I according to claim 4 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug, is characterized in that: R 4and R 4 'be selected from the one in following groups independently of one another: methyl, cyclopropyl, ethyl, sec.-propyl, propyl group, the tertiary butyl, cyclopentyl, phenyl, COOH, CO 2me, CH 2oH, CH 2oMe, CH 2cH 2cH 2oH, CH 2cH 2cH 2oMe, CH 2cH 2cH 2oCH 2ph, CH 2cH 2cH 2nH 2, CH 2cH 2cH 2nHCOOtBu, CONHiPr, CONHCH 2cH=CH 2, CONHCH 2cH 2oMe, CONHCH 2ph, CONH (cyclohexyl), CON (Et) 2, CON (Me) (CH 2ph), CONH (nPr), CON (Et) (nPr), CONHCH 2cH (CH 3) 2, CON (nPr) 2, CO (3-methoxymethyl 1-pyrryl), CONH (3-tolyl), CONH (4-tolyl), CONHMe, CO (1-morpholinyl), CO (4-methyl 1-piperazinyl), CONHCH 2cH 2oH, CONH 2, CO (piperidino); Or R 4and R 4 'the twin nuclei formed with pyrazoles in logical formula I or (II) is one of following:
6. logical formula I according to claim 5 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug, is characterized in that: described compound is specifically selected from any one in following structural:
7. a pharmaceutical composition, is characterized in that: comprise at least one in following material: a) prodrug of compound, b) this compound pharmaceutically tautomer, g) this compound of polymorphic form, f) this compound of solvate, e) this compound of hydrate, d) this compound of acceptable salt, c) this compound; Wherein, the logical formula I of described compound according to any one of claim 1-6 or the compound shown in (II).
8. the logical formula I according to any one of claim 1-6 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug suppress the application in the medicine of Aurora A in preparation.
9. the logical formula I according to any one of claim 1-6 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug preparation treat and/or prevent and/or delay and/or assisting therapy and/or process proliferative disease medicine in application.
10. the logical formula I according to any one of claim 1-6 or the compound shown in (II) or its pharmaceutically acceptable salt, hydrate, solvate, polymorphic form, tautomer or prodrug are preparing the application in antitumor drug.
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CN106957303A (en) * 2017-02-28 2017-07-18 中山大学 Quinazoline derivant of selective AuroraA kinase inhibiting activities and preparation method thereof and application
CN106957303B (en) * 2017-02-28 2019-06-04 中山大学 Quinazoline derivant of selective Aurora A kinase inhibiting activity and preparation method thereof and application
CN108078991A (en) * 2017-12-29 2018-05-29 中山大学附属第三医院 Application of the Aurora A inhibitor in terms of inhibition tumor microenvironment drug is prepared
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