CN105503837B - Substituted quinazoline analog derivative and its application with Aurora kinase inhibitory activity - Google Patents

Substituted quinazoline analog derivative and its application with Aurora kinase inhibitory activity Download PDF

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CN105503837B
CN105503837B CN201511033604.7A CN201511033604A CN105503837B CN 105503837 B CN105503837 B CN 105503837B CN 201511033604 A CN201511033604 A CN 201511033604A CN 105503837 B CN105503837 B CN 105503837B
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compound
acid
aurora
acceptable salt
pharmaceutically acceptable
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CN105503837A (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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    • 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 the substituted quinazoline analog derivative with Aurora kinase inhibitory activity and its applications.General formula（Ⅰ）Or（Ⅱ）Compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug.

Description

Substituted quinazoline analog derivative and its application with Aurora kinase inhibitory activity
Technical field
The present invention relates to the substituted quinazoline analog derivative with Aurora kinase inhibitory activity and its applications.
Background technology
Cancer and other hyperproliferative diseases are characterized in uncontrolled cell Proliferation.Cell Proliferation normal regulating The gene for losing the cell passage for being often as entire cell cycle progress is damaged and occurs.Research shows that In eukaryocyte, the orderly cascade Mach-Zehnder interferometer of protein phosphorylation the cell cycle.Identified at present has weight in this cascade The protease of several families to be acted on.Compared with normal structure, the activity of many above-mentioned kinases significantly increases in human tumour. This may be caused by protein expression level improves or the expression of Assisted Activation albumen or resistance albumen changes. Aurora A coding adjust the cell cycle serine-threonine protein kinase enzyme (referring to Trends in CellBiology, 2001,11,49-54, Adams etc.) it participates in adjusting spindle formation, centrosome maturation, chromosome differentiation and cytokinesis process, There is key effect to the stability for maintaining genome.The study found that the overexpression of Aurora A easily leads to cell mitogenic Abnormal division, it is closely related with the formation of tumour.Aurora A is in many cancer cells (such as lung cancer, breast cancer, the carcinoma of the rectum, first Shape gland cancer, cancer of pancreas) in over-express, inhibit Aurora A activity can cause tumour cell polyploid aggregation, promote Into Apoptosis, block cell Proliferation.Using Aurora A as target spot carry out antitumor drug research and development also increasingly by To the attention of people.Aurora A is just expressed and activates in mitosis, they are invalid for non-proliferative cell, and The growth rate of most of normal cells and unhappy in human body.Therefore Aurora A inhibitor belongs to targeting anti-tumor medicine Object, compared with other non-specific cell cytotoxic drugs, by the advantage with bigger.
The Aurora A inhibitor studied at present is mainly ATP competitiveness kinase inhibitors, mainly by with ATP pockets With reference to competitively inhibition Aurora A is active.ATP pockets mainly include three regions：Hydrophobic region inside kinases, Hinge area among kinases and in external solvent can and area.And the Aurora A inhibitor studied at present is also main Including three parts：Fatty contents, Hydrogenbond part, water-soluble portion.They respectively with ATP pockets corresponding region knot above It closes.
The high activity Aurora A inhibitor of existing report is broadly divided into full Aurora A inhibitor, selectivity AuroraA kinase inhibitors and selectivity Aurora B kinase inhibitors, following several structures are into clinical research Aurora A inhibitor structure：
Vertex Standard (Vertex) drugmaker in the U.S.'s reported Aurora A kinases and quinazoline for the first time in 2003 Close object N- (3- cyclopropyl -1H- pyrazoles -5- bases) -2- phenylquinazoline -4- amine compound crystal structures.Its patent Involved compound structure is as follows in (US7361492B2, WO2003092607A2) patent.The compound pyrazoles side chain On three N atoms can form hydrogen bond action, in the Loop regions of kinases, kinases and the compound with the hinge area residue of kinases Phenyl ring between there are pi-pi accumulation effects.
Vertex companies and Merck (Merck) company have developed jointly first Aurora A inhibitor VX-680 (again Name MK-0457) (WO2004000833A1).The molecular structure is in Y shapes, and the pyrimidine ring at center is located at the hydrophobic region of kinases, with swashing There is hydrophobic effect between enzyme amino acid residue；Amino-containing pyrazoles side chain stretches into the hinge area of kinases, with its amino acid residue There is crucial hydrogen bond action；Side chain containing phenyl stretches into kinases hydrophobic region；Piperazine sidechain is then stretched over enzyme by the active region of enzyme Solvent can and area.The study found that VX-680 has good inhibiting effect, IC to AuroraA, B and C50Value respectively 0.6, 18 and 4.6nM can inhibit colorectal cancer, breast cancer, prostate cancer, cancer of pancreas, melanoma, tumor colli, leukaemia Etc. the proliferation of numerous tumour cells.2006, VX-680 entered clinical II phase research, is mainly used for the obstinate chronic bone for the treatment of Myelogenous leukemia and acute lymphatic leukemia.Research find the drug can cause patient QTc extend risk (QTc is electrocardio Time difference between the T waves and Q waves that are corrected on figure, QTc extensions are easy to cause arrhythmia cordis), in November, 2007, Merck terminated II clinical trial phase (Expert Opin.Investing Drugs.2009,18,379) of VX-680.
When the pyrimidine 2- bit substituents of VX-680 are become styryl by CASI drugmakers (original name EntreMed), obtain Compound ENMD 981693 show preferable cell activity, and can selectively inhibit Aurora A kinases, made Into L-TARTARIC ACID salt (ENMD-2076).ENMD-2076 is a kind of orally available efficient AuroraA inhibitor, to Aurora A's Inhibitory activity IC50It is worth for 14nM, the inhibitory activity IC of Aurora B50About 350nM, while be also angiogenesis kinase inhibition Agent acts on the target spots such as VEGFR, Flt-3 and FGFR3.67 oophoromas, colorectal cancer patients progress ENMD-2076 are resisted swollen Knurl is tested, which shows good antitumor action, (intravascular including important target spot VEGFR2 antitumor in blood plasma Skin growth factor receptor 2) content be decreased obviously.The researchers such as Diamond are in ENMD-2076 to triple negative breast cancer (TNBC) it is found in the research of hypotype and human epidermal growth factor receptor 2 (HER2) positive subgroup, ENMD-2076 is female sharp to lacking Plain expression of receptor or without HER-2 overexpressions breast cancer cell have potent inhibiting effect.II phase carried out now Clinical test mainly includes advanced metastatic triple negative breast cancer TNBC (NCT01639248), clear cell carcinoma of ovary (NCT01914510) it is ground with late period or metastatic soft tissue sarcoma (NCT01719744), treatment liver fibrolamellar cancer (FLC) III clinical trial phase will be entered by studying carefully.
In addition, there are also patent (WO2002000649A1, WO2003055491A1, WO2004058781A1, WO2004113324A1, CN104098551A, US7951820B2) quinazoline derivative is reported available for inhibiting Aurora Kinases：
The new compound with Aurora kinase inhibitory activity of exploitation, at this stage, is of great significance.
Invention content
The purpose of the present invention is to provide the substituted quinazoline analog derivative with Aurora kinase inhibitory activity and its answer With.
The technical solution used in the present invention is：
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline Type object, tautomer or prodrug,
Wherein：
R1Selected from H ,-N (R)2,-OR ,-SR, one kind in halogen；To R1Definition in, the R that is related to is selected from H, unsubstituted Low alkyl group, one kind in-C (O) H ,-OH；
R2Selected from H, substitution either without the aryl or heterocyclic aryl that replace, wherein substituent group is selected from halogen ,-NO2、- CN、-CF3、-CF2R ,-C (R)=CR '2,-C (R)=C (R ') (R ") ,-C ≡ C-R ,-OR ,-SR ,-S (O) R ,-SO2R、-SO2N (R)2、-N(R)2、-OCO2R、-OC(O)NR2、-OC(O)R、-CO2R、-C(O)R、-C(O)NR2,-C (=NR)-NR '2,-C (= NR)-OR ' ,-NRC (=NR ')-NR "2、-NRSO2R’、-NRSO2NR’2、-P(O)R2、-P(O)(OR)2In one kind；To R2's In definition, described R, R ' and R " be each independently selected from H, unsubstituted low alkyl group, phenyl or substituted-phenyl；
R3Heterocyclic aryl or Non-aromatic heterocyclic, C selected from 4-6 round ringss1-C6Aliphatic group, Alkoxyalkylamino, alcoxyl Base alkyl, amino, alkyl or dialkyl amido, alkyl or dialkylaminoalkoxy groups, acetylamino, alkoxy carbonyl, alkyl Or dialkyl amino carbonyl or substituted-phenyl；
R4And R4’It is each independently selected from hydrogen, C1-C4Aliphatic group, alkoxy carbonyl, substituted or unsubstituted phenyl, Hydroxy alkyl, alkoxyalkyl, amino carbonyl, the amino carbonyl of monoalkyl or double alkyl, aminoalkyl, alkylaminoalkyl group, Dialkyl aminoalkyl, phenyl amino carbonyl, (N- heterocycles) carbonyl；Alternatively, R4And R4’It is formed with pyrazoles in general formula (I) or (II) Bicyclic structure；
X is carbon atom or nitrogen-atoms.
The R1It is NH2；The R2One kind in substituted-phenyl, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups；Wherein Substituent group is selected from 3-COOH, 3-COOMe, 3-COOEt, 3-COOiPr, 3-OMe, 4-OMe, 2-OMe, 2-F, 3-F, 4- on phenyl F、2-Cl、3-Cl、4-Cl、3-Cl-4-COOMe、3-OMe-4-COOMe、2-Cl-2-OMe、2-CONH2-3-F、3-CONH2、2- CH2OH, 4-CONHMe, 2,4-diOMe, 2,5-diOMe, 2-Me-4-OMe, 2,4-diCl, 3,4-diCl, 2- morpholinyl, 3- Quinoline base, 4- morpholinyls, 3,4- methylene-dioxies, 4-CH2COOEt、4-NO2、3-NO2、2-NO2、2-CN、3-CN、2-CF3Or 3- CF3In one kind.
R3Selected from 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, pyrrole radicals, piperidyl, morpholinyl, carboxyl, azete piperidinyl, Hydroxy piperidine base, N- (4- hydroxy piperidines base), O- (4- piperidyls), piperazinyl, alkylpiperazinyl, 4- methyl piperazines base, N- second Acyl piperazine base, N- alkyl carboxyl amide piperazidines base, N- mesylpiperazinyls, N- (4- nitrobenzophenones) sulfonyl piperazinium base, N- trifyls piperazinyl, N- p-toluenesulfonyls piperazinyl, N- are to tnBuoromethyl-benzenesulfonyl piperazinyl, thiophene, furan It mutters, tetrahydrofuran, ring [2.2.2] heptenyl, methyl, ethyl, cyclopropyl, isopropyl, tertiary butyl, methoxyethylamino, first Oxygroup methyl, methoxy ethyl ethylamino, dimethylamino, dimethylamino propoxy, halogenophenyl, carboxyl phenyl, carboxylic Base anilino-, hydroxypyrrolyl, carboxy pyrrole alkyl, formamido pyrrolidinyl, azanol acyl pyrroline alkyl, sulfoamido pyrrole Cough up alkyl, tetrazole base pyrrolidinyl, hydroxy piperidine base, carboxypiperidin base, formamido piperidyl, azanol acylpiperidine base, Sulfoamido piperidyl, tetrazole phenylpiperidines base, carboxypiperazinyl, formamido piperazinyl, azanol acyl piperazine base, sulfonamide One kind in base piperazinyl, tetrazole base piperazinyl；Alternatively, in general formula (I) or (II)：
Wherein, A is selected from the bioisostere of carboxyl, amide groups, ester group or carboxyl；
Y is-(CH2)m-、-O-、-S-、-S(O)nOr-N (R5)-；
B is-(CH2)p-；
C is-(CH2)t-；
R5Selected from H or C1-C4Alkyl, hydroxyl, amino, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Alkyl-OC (O) NH- Or C1-C4Alkyl-C (O) O-；
A and R5The chiral configuration of the carbon atom of group connection is each independently R configurations or S configurations；
M, n, p, t are respectively 0,1,2,3,4.
The R3In when containing amino, the nitrogen-atoms of amino is free alkali form either pharmacy acceptable salt or season Ammonium salt.
R4And R4’The one kind being each independently selected from following groups：Methyl, cyclopropyl, ethyl, isopropyl, propyl, uncle Butyl, cyclopenta, phenyl, COOH, CO2Me、CH2OH、CH2OMe、CH2CH2CH2OH、CH2CH2CH2OMe、 CH2CH2CH2OCH2Ph、CH2CH2CH2NH2、CH2CH2CH2NHCOOtBu、CONHiPr、CONHCH2CH=CH2、 CONHCH2CH2OMe、CONHCH2Ph, CONH (cyclohexyl), CON (Et)2、CON(Me)(CH2Ph)、CONH(nPr)、CON(Et) (nPr)、CONHCH2CH(CH3)2、CON(nPr)2, CO (3- methoxy 1- pyrrole radicals), CONH (3- tolyls), CONH (4- tolyls), CONHMe, CO (1- morpholinyls), CO (4- methyl 1- piperazinyls), CONHCH2CH2OH、CONH2, CO (1- piperidines Base)；Or R4And R4’It is one of following with the twin nuclei that pyrazoles in general formula (I) or (II) is formed：
The compound is chosen in particular from any one of following structural：
A kind of pharmaceutical composition, including at least one of following substance：A) compound, b) compound pharmaceutically may be used The polymorph of the solvate of the hydrate of the salt of receiving, c) compound, d) compound, e) compound, f) change The prodrug of the tautomer of conjunction object, g) compound；Wherein, the compound is the chemical combination shown in general formula (I) or (II) Object.
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline The application of type object, tautomer or prodrug in the drug for inhibiting Aurora A is prepared.
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline Type object, tautomer or prodrug prepare treatment and/or prevention and/or delay and/or auxiliary treatment and/or processing proliferative Application in the drug of disease.
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline Type object, tautomer or prodrug application in preparation of anti-tumor drugs.
The beneficial effects of the invention are as follows：
In the present invention by 2,4,7- of quinazoline ring, introducing different pharmacophores, provide a kind of newly synthesized Quinazoline derivative, this newly synthesized quinazoline derivative show Aurora A preferable inhibitory activity.
The series compound of the present invention is preparing treatment and/or prevention and/or is delaying and/or auxiliary treatment and/or processing In the drug of proliferative diseases, there is preferable prospect.
Specific embodiment
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline Type object, tautomer or prodrug,
Wherein：
R1It is H ,-N (R)2,-OR ,-SR, halogen etc., R1In R be H, unsubstituted low alkyl group ,-C (O) H ,-OH；R2 It is H, substitution is either without the aryl or heterocyclic aryl of substitution, and wherein substituent group is halogen ,-NO2,-CN ,-CF3,-CF2R ,-C (R)=CR '2,-C (R)=C (R ') (R ") ,-C ≡ C-R ,-OR ,-SR ,-S (O) R ,-SO2R ,-SO2N(R)2,-N (R)2,- OCO2R ,-OC (O) NR2,-OC (O) R ,-CO2R ,-C (O) R ,-C (O) NR2,-C (=NR)-NR '2,-C (=NR)-OR ' ,-NRC (=NR ')-NR "2,-NRSO2R ' ,-NRSO2NR’2Or-P (O) R2,-P (O) (OR)2；R2Middle R, R ' and R " be H, do not take The low alkyl group in generation, phenyl or substituted-phenyl；
R3It is the heterocyclic aryl or Non-aromatic heterocyclic of 4-6 round ringss, C1-C6Aliphatic group, Alkoxyalkylamino, alkoxy Alkyl, amino, alkyl or dialkyl amido, alkyl or dialkylaminoalkoxy groups, acetylamino, alkoxy carbonyl, alkyl and Dialkyl amino carbonyl or substituted-phenyl；
R4And R4’It is to be each independently hydrogen, C1-C4Aliphatic group, alkoxy carbonyl, substituted or unsubstituted phenyl, The amino carbonyl of hydroxy alkyl, alkoxyalkyl, amino carbonyl, monoalkyl or double alkyl, aminoalkyl, alkylaminoalkyl group, Dialkyl aminoalkyl, phenyl amino carbonyl or (N- heterocycles) carbonyl；Or R4And R4’With pyrazoles shape in general formula (I) or (II) Into bicyclic structure；
X is carbon atom or nitrogen-atoms.
Preferably, the R1It is NH2。
Preferably, the R2It is substituted-phenyl, 2- pyridyl groups, 3- pyridyl groups, substituent group is on 4- pyridyl groups, wherein phenyl 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-CONH2- 3-F, 3-CONH2, 2-CH2OH, 4-CONHMe, 2, 4-diOMe, 2,5-diOMe, 2-Me-4-OMe, 2,4-diCl, 3,4-diCl, 2- morpholinyls, morpholinyl, 4- morpholinyls, 3, 4- methylene-dioxies, 4-CH2COOEt, 4-NO2, 3-NO2, 2-NO2, 2-CN, 3-CN, 2-CF3Or 3-CF3。
Preferably, R3It is 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, pyrrole radicals, piperidyl, morpholinyl, carboxyl, azete Piperidinyl, hydroxy piperidine base, N- (4- hydroxy piperidines base), O- (4- piperidyls), piperazinyl, alkylpiperazinyl, 4- methyl piperazine bases, N- acetylpiperazinyls, N- alkyl carboxyl amide piperazidine bases, N- mesylpiperazinyls, N- (4- nitrobenzophenones) sulfonyl piperazinium Base, N- trifyl piperazinyls, N- p-toluenesulfonyl piperazinyls, N- is to tnBuoromethyl-benzenesulfonyl piperazinyl, thiophene, Furans, tetrahydrofuran, ring [2.2.2] heptenyl, methyl, ethyl, cyclopropyl, isopropyl, tertiary butyl, methoxyethylamino, Methoxy, methoxy ethyl ethylamino, dimethylamino, dimethylamino propoxy, halogenophenyl, carboxyl phenyl, Carboxyanilino, hydroxypyrrolyl, carboxy pyrrole alkyl, formamido pyrrolidinyl, azanol acyl pyrroline alkyl, sulfoamido Pyrrolidinyl, tetrazole base pyrrolidinyl, hydroxy piperidine base, carboxypiperidin base, formamido piperidyl, azanol acylpiperidine Base, sulfoamido piperidyl, tetrazole phenylpiperidines base, carboxypiperazinyl, formamido piperazinyl, azanol acyl piperazine base, sulphur Amide groups piperazinyl, tetrazole base piperazinyl；
Or R3Structure be：
I.e. in general formula (I) or (II),
Wherein, A be carboxyl, amide groups, ester group or be carboxyl bioisostere, such as sulfoamido, hydroximic acid Base, tetrazole base, sulfonic acid amide group, sulfonylurea base, trifluoroethanol base, trifluoroethanone base etc.；
Y is-(CH2)m-、-O-、-S-、-S(O)nOr-N (R5)-；
B is-(CH2)p-；
C is-(CH2)t-；
R5For H or C1-C4Alkyl, hydroxyl, amino, C1-C4Alkoxy, C1-C4Alkylamino, C1-C4Alkyl-OC (O) NH- or C1-C4Alkyl-C (O) O-；
A and R5The chiral configuration of the carbon atom of group connection can be R configurations or S configurations respectively；
M, n, p, t are respectively 0,1,2,3,4.
It is further preferred that the R3In when containing amino, the nitrogen-atoms of amino is that free alkali form or pharmacy can be with The salt or quaternary ammonium salt of receiving.
Preferably, R4And R4’The one kind being each independently selected from following groups：Methyl, cyclopropyl, ethyl, isopropyl, Propyl, tertiary butyl, cyclopenta, phenyl, COOH, CO2Me, CH2OH, CH2OMe, CH2CH2CH2OH, CH2CH2CH2OMe, CH2CH2CH2OCH2Ph, CH2CH2CH2NH2, CH2CH2CH2NHCOOtBu, CONHiPr, CONHCH2CH=CH2, CONHCH2CH2OMe, CONHCH2Ph, CONH (cyclohexyl), CON (Et)2, CON (Me) (CH2Ph), CONH (nPr), CON (Et) (nPr), CONHCH2CH(CH3)2, CON (nPr)2, CO (3- methoxy 1- pyrrole radicals), CONH (3- tolyls), CONH (4- tolyls), CONHMe, CO (1- morpholinyls), CO (4- methyl 1- piperazinyls), CONHCH2CH2OH, CONH2Or CO (1- Piperidyl)；Or R4And R4’It is one of following with the twin nuclei that pyrazoles in general formula (I) or (II) is formed：
Still more preferably, the compound is chosen in particular from any one of following structural：
A kind of pharmaceutical composition, including general formula (I) or (II) compound represented or its pharmaceutically acceptable salt, water Close object, solvate, polymorph, tautomer or prodrug.
Preferably, pharmaceutically acceptable auxiliary material is further included.
It is further preferred that the auxiliary material includes at least one of following substance：It is solvent, propellant, solubilizer, steady Determine agent, glidant, corrigent, preservative, suspending agent, coating material, aromatic, anti-binder, integrated agent, penetration enhancer, PH adjusting agent, buffer, plasticizer, cosolvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, profit Humectant, osmotic pressure regulator, surfactant, foaming agent, antifoaming agent, thickener, inclusion agents, moisturizer, absorbent, dilution Agent, flocculant and deflocculant, filter aid, release retarding agent.
The pharmaceutical composition of the present invention can be made into various dosage forms：Classify according to the decentralized system of dosage form：Specifically, Following dosage form can be made：Solution-type, colloidal solution type, emulsion-type, suspension type, gas dispersing type, microdispersed form, solid point Dissipate type；According to typoiogical classification, specifically, following dosage form can be made：Liquid dosage form (such as aromatic waters, solution, injection Agent, mixture, lotion, liniment etc.), gas formulation (such as aerosol, spray), solid dosage forms (such as powder, pill, tablet, film Agent etc.), semisolid dosage form (such as ointment, suppository, paste)；Classify according to administration route：Specifically, it can be made following Dosage form：Dosage form through gastrointestinal administration, the dosage form without gastrointestinal administration.
Application of the above-mentioned pharmaceutical composition in the drug for inhibiting Aurora A is prepared.
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline The application of type object, tautomer or prodrug in the drug for inhibiting Aurora A is prepared.
Preferably, the Aurora A is one kind in AuroraA kinases, Aurora B kinases.
General formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvate, polycrystalline Type object, tautomer or prodrug prepare treatment and/or prevention and/or delay and/or auxiliary treatment and/or processing proliferative Application in the drug of disease.
Preferably, the proliferative diseases are gastric cancer, colorectal cancer, lung cancer, breast cancer, liver cancer, prostate cancer, first shape Gland cancer, cancer of pancreas, carcinoma of urinary bladder, kidney, brain tumor, neck cancer, cancer, glioblastoma, the myelosis of CNS (central nervous system) Disease, atherosclerosis, leukaemia, pulmonary fibrosis, lymph cancer, rheumatic disease, chronic inflammation, non-lymphoreticular system swell Knurl, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, isolates cryoglobulinemia Property plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, monocytic leukemia, half molecule It is disease, primary macroglobulinaemia, primary macroglobulinaemia purpura, secondary benign monoclonal gammopathy, molten Bone lesion, lymphoblastoma, part non-Hodgkin lymphoma, Sezary syndromes, infects at acute lymphoblastic leukemia Property monocytosis,mononucleosis, acute histocytic increase disease, hairy cell leukemia, Hodgkin lymphoma, colon and rectum carcinoma, Polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell swell Knurl, islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, uterine cancer, chronic hepatitis, hepatic sclerosis, oophoroma, retina are female thin Born of the same parents' knurl, cholecystitis, G. cephalantha, malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus, carcinoma of urinary bladder, bone At least one of myeloma.
Particularly, general formula (I) or (II) compound represented or its pharmaceutically acceptable salt, hydrate, solvent conjunction Object, polymorph, tautomer or prodrug application in preparation of anti-tumor drugs；
Preferably, at least one of following compounds or its pharmaceutically acceptable salt, hydrate, solvate, Polymorph, tautomer or prodrug application in preparation of anti-tumor drugs.
As it is used herein, if it is specific restriction is provided, term of the invention has following meanings.
" halogen " includes fluorine, chlorine, bromine and iodine.
" alkyl " refers to linear or branched saturated hydrocarbon group, such as C1-C20Alkyl, preferably C1-C12Alkyl, more preferably C1-C6Alkyl is further preferably C1-C4Alkyl, in particular, for example methyl (Me), ethyl (Et), propyl is (for example, n-propyl and isopropyl Base), butyl (for example, normal-butyl, isobutyl group, tertiary butyl), amyl (for example, n-pentyl, isopentyl, neopentyl), n-hexyl etc.. Wherein, in each substitution alkyl or alkyl-substituted group, alkyl is defined as above.
" low alkyl group " refers to C1-C4Alkyl.
" therapeutically effective amount " is referred to when giving the mammal for needing such treatment, it is sufficient to the general formula effectively treated The amount of compound.Therapeutically effective amount by dependent on the age of the given activity of healing potion used, patient, physiological status, its The presence and nutrition condition of its morbid state and change.In addition, will influence will be to for the other medicines treatment that patient may just receive The therapeutically effective amount of the healing potion given determines.
" treatment " means any treatment for disease in mammal body, including：
(I) disease is prevented, that is, the clinical symptoms of disease is caused not develop；
(II) inhibit disease, that is, prevent the development of clinical symptoms；And/or
(III) mitigate disease, that is, cause the recession of clinical symptoms.
In many cases, the compound of the present invention can be due to amino and/or carboxylic group, acid group or similar Group presence and formed acid and/or basic salt.
The compound of the present invention further includes tautomeric forms.Tautomeric forms from singly-bound with it is adjacent Double bond exchange and together with the migration of a proton.
Pharmaceutically acceptable salt refers to the basic group in parent compound to be converted into the form of salt.It can pharmaceutically connect The salt received is include but are not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.The present invention can pharmaceutically connect The salt received can be synthesized by parent compound, i.e., the acid of the basic group in parent compound and 1-4 equivalents is in a solvent system It is reacted in system.Suitable salt is enumerated in Remington ' s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,1418 and Journal ofPharmaceutical Science, 66, In 2,1977.
Pharmaceutically acceptable acid-addition salts can be prepared by inorganic and organic acid.By the inorganic acid packet of derivative acid-addition salts Include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..Acetic acid, propionic acid, glycolic, third are included by the organic acid of derivative acid-addition salts Ketone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond Acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, benzene sulfonic acid etc..The inorganic acid and organic acid of derivative acid-addition salts are especially Selected from hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, acetic acid, benzoic acid and p-methyl benzenesulfonic acid.
The composition is preferably formulated as unit dosage forms.Term " unit dosage forms " refers to being suitable for use as giving human subjects The physical discrete unit of the single dose of person and other mammals, per unit, which contains, to be calculated to generate required control Treat the scheduled amount of effective active material and relevant suitable pharmaceutical excipient (such as tablet, capsule, ampoule).General formula (I) or the compound of (II) is effective in extensive dosage range and usually gives active drug amount.Preferably for Oral medication, each dosage unit include the general formula (I) of 10mg to 2g or (II) compound, and more preferably 10 to 700mg, and right In parenteral administration, preferably 10 to 700mg general formula (I) or (II) compound, more preferably from about 50 to 200mg.It however, should Understand, the general formula (I) or the amount of (II) compound actually given will be determined by doctor according to related situation, including to treat Illness, the administration route of selection, the practical compound given and its relative activity, age of each patient, weight and Reaction, seriousness of patient symptom etc..
In order to prepare solid composite such as tablet, main active component is mixed with drug excipient (or carrier) To form solid preformulation composition, it includes the homogeneous mixtures of the compound of the present invention.When these preformulation compositions of title When being uniform, it refers to that active component is dispersed in entire composition, so that composition can be easily thin It is divided into identical effective unit dosage forms such as tablet, pill and capsule.
The tablet or pill of the present invention can be applied or otherwise have extension effect by compound to provide one kind The dosage form of advantage protects tablet or pill from the effect of acid condition in stomach.For example, tablet or pill can include interior dose Amount and external dose ingredient, the latter have the form of the crust on the former.Two kinds of ingredients can be separated with enteric layer, wherein Enteric layer is used for preventing ingredient in disintegration and permission under one's belt completely to enter duodenum or be delayed by release.A variety of materials It can be used for such enteric layer or coating, above-mentioned material includes many polymer acids and polymer acid and such material such as The mixture of shellac, hexadecanol and cellulose acetate.
For inhalation or insufflation composition be included in pharmaceutically acceptable aqueous solvent or organic solvent or its Solution and suspension and powder in mixture.Liquid or solid composition can include suitable medicine as described above Use excipient.Preferably, these compositions are given by oral or nasal respiratory route to obtain locally or systemically effect.It can lead to Cross the composition being atomized in preferred pharmaceutically acceptable solvent using inert gas.It can directly be sucked from atomising device Atomized soln or atomising device can be connected to mask account shape object or intermittent positive pressure breathing machine.It can be by delivering in a suitable manner The device of dosage form, preferably oral or nose approach, gives solution, suspension or powder composite.
The compound of the present invention and pharmaceutically acceptable salt further include the form of solvate or hydrate.It is general next It says, the form of solvate or hydrate is equal with non-solvated or non-hydrated form, and covers in the scope of the present invention It is interior.Certain compounds in the present invention there may be polycrystal or unbodied form.Generally speaking, all physical forms With equal purposes, and cover within the scope of the invention.
The invention also includes the prodrugs of the compound.Prodrug is a pharmacological agents (drug), is derived by parent drug .Once entering in vivo, prodrug, which is just metabolized, is transformed into parent drug.Prodrug can pass through the one or more to parent drug Functional group is replaced and is prepared, and substituent group will be degraded and release parent compound in vivo.The preparation of prodrug Can be in T.Higuchi and V.Stella with using, " Pro-drugs as Novel Delivery Systems, " Vol.14of the A.C.S.Symposium Series and Bioreversible Carriers in Drug Design, ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987 In find.
The present invention also provides including general formula (I) or (II) compound or its pharmaceutically acceptable salt or its prodrug and at least A kind of pharmaceutical composition of pharmaceutically acceptable carrier.The pharmaceutical composition of the present invention is orally available, and injection injection, spraying is inhaled Enter, skin external application, rectum is used, and nasal cavity is used, and vagina is used, and abdominal cavity is used or used by being implanted into the approach such as reservoir or transdermal patch.
On the other hand, it is of the invention have the compound represented by general formula (I) or (II) or its can pharmaceutically connect Salt, solvate, polymorph, tautomer or the prodrug received or the compound including being represented by general formula (I) or (II) Pharmaceutical composition inhibit Aurora A drug in application, especially inhibit AuroraA kinases drug in Using.
On the other hand, the present invention provides the method for inhibiting Aurora A with general formula (I) or (II) compound.Including By a effective amount of above-mentioned compound represented by general formula (I) or (II) or its pharmaceutically acceptable salt, solvate, Polymorph, tautomer, prodrug or the pharmaceutical composition of compound including being represented by general formula (I) or (II) are used for Inhibit Aurora A.
" inhibit Aurora A activity " term herein it is meant that Aurora A once 2,4,7- with the present invention Substituted quinazoline derivative contact, activity relative to not contacted with the compound in the case of declined.Therefore, The present invention provides a kind of quinazoline derivatives with 2,4,7- substitutions to contact with Aurora A that Aurora to be inhibited to swash The method of enzymatic activity.The present invention's has the compound of general formula (I) or (II) mainly inhibiting AuroraA kinase activities.This There is the compound of general formula (I) or (II) can be used for inhibiting growth of tumour cell for invention.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or (II).Following reaction scheme and embodiment are for further citing Illustrate present disclosure.
Unless otherwise instructed, the present invention relates to the unit " degree " of reaction temperature mean " DEG C "；Concentration unit " M " is meant “mol/L”。
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.It for example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate blocking group, by using other known reagent in addition to described in the invention or Reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also admittedly fitted For the preparation of the other compounds of the present invention.
Following process description prepares the universal method of the compounds of this invention.
Reaction scheme I
Compound 5 is prepared by reaction scheme 1, wherein R1,R2,R3,R4And R4’With defining as described herein. The synthons such as raw material 1 and carboxylic acid or acyl chlorides react generation amido bond and obtain compound 2.Cyclization later generates Quinazol derivative 3.Carbon nitrogen coupling reaction generation compound 4 occurs again with amine for compound 3.With pyrazole derivatives direct amination occurs for compound 4 Compound 5 is obtained by the reaction.
Reaction scheme II
Compound 5 can also be prepared by scheme II, wherein R1,R2,R3,R4And R4’With defining as described herein. The reduction under palladium carbon and hydrogen atmosphere of compound 9 obtains compound 10, and amidation further occurs for the amino restored later, takes Compound 5 is obtained by the reaction in generation reaction, reduction amination etc..
Reaction scheme III
Compound 15 can also be prepared by scheme III, wherein R1,R2,R3,R4And R4’With fixed as described herein Justice.Compound 12 is reacted by the nucleophilic displacement of fluorine such as compound 11 and corresponding amine reagent to be generated.Compound 12 is in palladium carbon and hydrazine hydrate Under the conditions of reductive hydrolysis generation compound 13.Compound 13 passes through amidation, ring closure reaction generation Quinazol derivative 14.Change It closes object 14 and obtains compound 15 with the direct ammoxidation of pyrazole derivatives generation.
Reaction scheme IV
Compound 5 can also be prepared by scheme IV, wherein R1,R2,R3,R4And R4’With defining as described herein. Compound 16 is obtained by the reaction with pyrazole derivatives in compound 3, and pyrazolyl is protected to obtain compound 17 with THP later.Chemical combination Halogen Cl in object 17 occurs carbon nitrogen with corresponding amine and is coupled to obtain compound 18.The Deprotection in acid condition of compound 18 Obtain compound 5.
The following examples can be with the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright range.
With reference to specific embodiment, the present invention is described further：
First, it prepares such as representative compound in the following table 1
Embodiment 1
N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -4- amino -2- phenethyl quinazolines
Step 1：The chloro- 2- of 4- (3- hydrocinnamamides base) benzoic acid
By 2- amino -4- chlorobenzoic acids (10.3g, 60mmol), potassium carbonate (24.9g, 180mmol) is added to 200mL's In acetonitrile, the phenylpropyl alcohol acyl chlorides (72mmol) of existing system is slowly dropped into, rear temperature of reaction system is added dropwise and is raised to 80 degree, is heated to reflux 5 hours, a large amount of precipitations of reaction system generation, the hydrochloric acid solution adjusting pH value for adding in 1N was 2, adds in about 100mL dichloromethane, acute Amide intermediate (12.4g, 68%) is filtered to obtain after strong stirring.1H NMR(400MHz,DMSO-d6)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)13C NMR(100MHz,DMSO-d6)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：Chloro- 2- phenethyls quinazoline -4 (3H) -one of 7-
It will be equipped in the round-bottomed flask of the chloro- 2- of 4- (3- benzenpropanoic acids amide) benzoic acid (2.43g, 8mmol) and add in 15mL second Acid anhydrides, 140 degree of reflux 3h after contact plate detection raw material has reacted, are removed under reduced pressure residual acetic acid acid anhydride, anhydrous acetic acid ammonium are added in, 170 The lower reaction of degree is overnight.Water is added in after being cooled to room temperature, there are a large amount of Precipitations, adds in after 20mL dichloromethane is vigorously stirred and filters Obtain target product (1.51g, 66%).1H NMR(400MHz,DMSO-d6)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)13C NMR(100MHz,DMSO-d6)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-1s-(tetrahydrochysene -2H- furans -2- bases) -1H- pyrazole-3-yls) -7- (4- methyl piperazines -1- Base) -4- amino -2- phenethyl quinazolines
By chloro- 2- phenethyls quinazoline -4 (3H) -one (854mg, 3mmol) of 7-, PyBrop (1.8g, 3.9mmol) and DBU (1.3mL, 9mmol) is dissolved in 5mL acetonitriles, after stirring 30min at room temperature, addition 3- amino-5-methylpyrazoles (728mg, It 7.5mmol) is reacted 24 hours under 70 degree, there are a large amount of yellow mercury oxides to be precipitated, filter to obtain intermediate.Intermediate is suspended in 10mL In acetonitrile, 3,4- dihydro -2H- pyrans (821 μ L, 9mmol) is added in, being heated to 75 degree after trifluoroacetic acid (222 μ L, 3mmol) stirs It mixes 3 hours, after organic solvent is removed under reduced pressure, adds in saturated sodium carbonate solution quaternization system, extracted with dichloromethane, it is organic Mutually dried with anhydrous sodium sulfate, after reduced pressure, crude by column chromatography purifying (MeOH：CH2Cl2=2：98) light green color is obtained Solid (642mg, 48%).Due in the tautomerism of pyrazoles and tetrahydrochysene -2H- furans 2- bases there are chiral centre, Obtained spectrogram is complex.MS(ESI+APCI)m/z 448.2[M+H]+。
Step 4：N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -4- amino -2- phenethyl quinoline azoles Quinoline
Past N- (5- methyl-1s-(tetrahydrochysene -2H- furans -2- bases) -1H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) - 4- amino -2- phenethyls quinazolines (224mg, 0.5mmol), Pd2(dba)3(9mg, 0.01mmol), Xphos (12mg, 0.025mmol), sodium tert-butoxide (144mg, 1.5mmol), N methyl piperazine (111 μ L, 1.0mmol) is under the conditions of anhydrous and oxygen-free Dry dioxane (5mL) is added in, is reacted 11 hours under 90 degree, after organic solvent is removed under reduced pressure, purifies to obtain through column chromatography The midbody product of THP protections.Intermediate is dissolved in trifluoroacetic acid：Dichloromethane (1：1) in the mixed solvent stirs 12 at room temperature Hour, after solvent is removed under reduced pressure, with saturated sodium carbonate solution regulation system pH to alkalinity, add in dichloromethane：Methanol (10：1) Solvent detaches organic phase, through column chromatography (CH after concentration2Cl2：MeOH=1：9) target product (67mg, 31%) is purified to obtain.
Embodiment 2
2- (1- amino -2- phenethyls)-N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) quinoline azoles Quinoline -4- amine
Step 1：2- amino -4- (4- methylpiperazine-1-yls) benzamide
By chloro- 2 nitrobenzonitriles (5.5g, 30mmol) of 4-, methyl piperazine (7.4mL, 66mmol) is dissolved in 50mL dioxies six It in ring, flows back 16 hours in 110 degree of reactions, dichloromethane extraction, the anhydrous sulphur of organic phase is added in after dioxane is removed under reduced pressure The drying of sour sodium, the intermediate being concentrated to give are dissolved in 100mL ethyl alcohol, add in wet Pd/C (300mg) and hydrazine hydrate (5.8mL, 120mmol), reaction system is stayed overnight in 80 degree of reactions, after organic solvent is removed under reduced pressure, adds in MeOH：CH2Cl2(1：10) solvent is about 150mL lysates cross siliceous earth column, MeOH：CH2Cl2(1：10) solvent washs, and the solid obtained after organic phase concentration is with less Dichloromethane washing is measured, obtains target product (6.4g, 91%).1H NMR(400MHz,DMSO-d6)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).13C NMR(100MHz,DMSO-d6)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/z 235.2[M+H]+.
Step 2：(1- (7- (4- methylpiperazine-1-yls) -4- oxa- -3,4- dihydroquinazoline -2- bases) -2- phenethyls) ammonia Base t-butyl formate
By N- tertbutyloxycarbonyls phenylalanine (796mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, After 6mmol) being stirred at room temperature 1 hour, addition 2- amino -4- (4- methylpiperazine-1-yls) benzamide (703mg, 3mmol), it is reacted under 50 degree overnight, after reaction is quenched with water, adds in dichloromethane extraction, anhydrous sodium sulfate drying, after concentration It is dissolved in 20mL ethyl alcohol, 10M NaOH solutions (1.2mL) is added in after being cooled to 0 degree, after stirring 30 minutes at room temperature, use concentrated hydrochloric acid PH value is adjusted after ethyl alcohol is removed under reduced pressure, to be extracted to neutrality with dichloromethane, anhydrous sodium sulfate drying, column chromatography obtains light brown after concentration Color solid (1.2g, 86%).1HNMR(400MHz,DMSO-d6)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).13C NMR(100MHz,DMSO-d6)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/z 464.3[M+H]+.
Step 3：2- (1- amino -2- phenethyls)-N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) Quinazoline -4- amine
By (1- (7- (4- methylpiperazine-1-yls) -4- oxa- -3,4- dihydroquinazoline -2- bases) -2- phenethyls) amino first Tert-butyl acrylate (232mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) are dissolved in acetonitrile After stirring 30 minutes at room temperature, 70 degree are heated to after addition 3- amino-5-methylpyrazoles (97mg, 1.0mmol) and is reacted 3 days, is subtracted Directly column chromatography obtains Boc protection products after pressure removes acetonitrile, is dissolved in trifluoroacetic acid later：Dichloromethane (1：1) in solvent It stirs 2 hours at room temperature, after organic solvent is removed under reduced pressure, in saturated sodium carbonate solution and system, adds in dichloromethane：Methanol (10：1) solvent detaches organic phase, through column chromatography (CH after concentration2Cl2：MeOH=1：9) purify target product (45mg, 20%).
Embodiment 3
N- (5- methyl-1 H- pyrazole-3-yls) -2- vinylbenzene base quinazoline -4- amine
Step 1：- 4 (3H) -one of 2- vinylbenzene bases quinazoline
By 2- aminobenzamides (8.2g, 60mmol), potassium carbonate (2equiv.) is suspended in dry acetonitrile, is gradually added Enter phenylpropyl alcohol acyl chlorides (9.8mL, 66mmol), after being added dropwise, system rises to 80 degree, is heated to reflux 5 hours, adds in 100mL water, takes out Filter obtains intermediate, and intermediate is dissolved in 100mL ethyl alcohol, and 10MNaOH (4equiv.) solution is added dropwise under 0 degree, stirs at room temperature After mixing 30 minutes, under 0 degree in concentrated hydrochloric acid and, a large amount of solids are precipitated, after ethanol in proper amount is removed under reduced pressure, adds in 100mL water, takes out Filter to obtain target product (13.2g, 88%).
Step 2：N- (5- methyl-1 H- pyrazole-3-yls) -2- vinylbenzene base quinazoline -4- amine
By -4 (3H) -one (125mg, 0.5mmol) of 2- vinylbenzene bases quinazoline, PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) is dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- amino-5-methylpyrazoles (97mg, It is heated to 70 degree after 1.0mmol) to react 1 day, directly column chromatography obtains target product (82mg, 50%) after acetonitrile is removed under reduced pressure.
Embodiment 4
N- (5- methyl-1 H- pyrazole-3-yls) -2- vinylbenzenes yl pyridines simultaneously [3,2-d] pyrimidine -4- amine
Step 1：3- (3- benzenpropanoic acids amide) -2- pyridine carboxylic acids
3- amino -2- pyridine carboxylic acids (4.4g, 30mmol) are dissolved in 80mL pyridines, phenylpropyl alcohol acyl chlorides is slowly added dropwise After being stirred at room temperature 6 hours, solvent is removed under reduced pressure in (4.9mL, 33mmol), and residue is purified by column chromatography, obtains target Product (6.2g, 76%).
Step 2：2- vinylbenzenes yl pyridines simultaneously [3,2-d] pyrimidine -4 (3H) -one
It is small that 3- (3- benzenpropanoic acids amide) -2- pyridine carboxylic acids (1.4g, 5mmol) are heated to 140 degree of stirrings 3 in acetic anhydride Shi Hou, is removed under reduced pressure solvent, and residue is heated to 185 degree in dry formamide (50mL) and stirs 9 hours.150mL water is added in, It is extracted with chloroform, the organic phase saturated common salt water washing of separation, column chromatographic isolation and purification obtains target after solvent is removed under reduced pressure Product (460mg, 36%).
Step 3：N- (5- methyl-1 H- pyrazole-3-yls) -2- vinylbenzenes yl pyridines simultaneously [3,2-d] pyrimidine -4- amine
By 2- vinylbenzenes yl pyridines simultaneously [3,2-d] pyrimidine -4 (3H) -one (125mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) is dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- amino -5- methyl pyrroles 70 degree are heated to after azoles (97mg, 1.0mmol) to react 1 day, be removed under reduced pressure after acetonitrile directly column chromatography obtain target product (71mg, 43%).
Embodiment 5
2- (the chloro- 2- vinylbenzenes bases of 1-)-N- (5- methyl-1 H- pyrazole-3-yls) quinazoline -4- amine
Step 1：2- (the chloro- 2- vinylbenzenes bases of 1-)-N- (5- methyl-1 H- pyrazole-3-yls) quinazoline -4- amine
By 2- (the chloro- 2- vinylbenzenes bases of 1-) quinazoline -4 (3H) -one (142mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) is dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- amino -5- methyl pyrroles 70 degree are heated to after azoles (97mg, 1.0mmol) to react 1 day, be removed under reduced pressure after acetonitrile directly column chromatography obtain target product (63mg, 35%).
Embodiment 6
N- (5- methyl-1 H- pyrazole-3-yls) -7- nitro -2- vinylbenzene base quinazoline -4- amine
Step 1：- 4 (3H) -one of 7- nitro -2- vinylbenzene bases quinazoline
By 2- amino -4- nitrobenzamides (1.8g, 10mmol), potassium carbonate (2equiv.) is suspended in dry acetonitrile, Phenylpropyl alcohol acyl chlorides (1.6mL, 11mmol) is gradually added into, after being added dropwise, system rises to 80 degree, heats faint reflux 5 hours, adds in 20mL water, suction filtration obtain intermediate, intermediate are dissolved in 20mL ethyl alcohol, and it is molten that 10M NaOH (4equiv.) are added dropwise under 0 degree Liquid, after stirring 30 minutes at room temperature, under 0 degree in concentrated hydrochloric acid with a large amount of solids are precipitated, after ethanol in proper amount is removed under reduced pressure, add Enter 20mL water, filter to obtain target product (2.6g, 88%).
Step 2：N- (5- methyl-1 H- pyrazole-3-yls) -7- nitro -2- vinylbenzene base quinazoline -4- amine
By -4 (3H) -one (148mg, 0.5mmol) of 7- nitro -2- vinylbenzene bases quinazoline, PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) is dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- amino -5- methyl pyrroles 70 degree are heated to after azoles (97mg, 1.0mmol) to react 1 day, be removed under reduced pressure after acetonitrile directly column chromatography obtain target product (159mg, 85%).
Embodiment 7
N4(5- methyl-1 H- pyrazole-3-yls) -2- phenylquinazoline -4,7- diamines
Example compound 6 (200mg, 0.58mmol) is dissolved in 10mL ethyl alcohol, is added in Pd/C about 10mg, is put with nitrogen It changes in reaction bulb after air, is passed through hydrogen, be stirred at room temperature 12 hours, contact plate finds that its fundamental reaction is complete, and column chromatography is pure Change (CH2Cl2：MeOH=1：1) target product (75mg, 38%) is obtained
Embodiment 8
N- (5- methyl-1 H- pyrazole-3-yls) -7- morpholine -2s-vinylbenzene base quinazoline -4- amine
Past N- (5- methyl-1s-(tetrahydrochysene -2H- furans -2- bases) -1H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) - 4- amino -2- phenethyls quinazolines (224mg, 0.5mmol), Pd2(dba)3(9mg, 0.01mmol), Xphos (12mg, 0.025mmol), sodium tert-butoxide (144mg, 1.5mmol), morpholine (87 μ L, 1.0mmol) add in drying under the conditions of anhydrous and oxygen-free Dioxane (5mL) reacts 11 hours under 90 degree, after organic solvent is removed under reduced pressure, purifies to obtain THP protections through column chromatography Midbody product.Intermediate is dissolved in trifluoroacetic acid：Dichloromethane (1：1) in the mixed solvent stirs 12 hours at room temperature, decompression After removing solvent, with saturated sodium carbonate solution regulation system pH value alkalinity, dichloromethane is added in：Methanol (10：1) solvent, separation Organic phase, through column chromatography (CH after concentration2Cl2：MeOH=1：9) target product (80mg, 39%) is purified to obtain.
Embodiment 9
Operating procedure is similar with the synthesis of embodiment 8.Yield is 55%.
Embodiment 10
Operating procedure is similar with the synthesis of embodiment 8.Yield is 39%.
Embodiment 11
Operating procedure is similar with the synthesis of embodiment 8.Yield is 55%.
Embodiment 12
N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -2- (3- nitrophenethyls) quinazoline -4- Amine
Step 1：7- (4- methylpiperazine-1-yls) -2- (3- nitrophenethyls) quinazoline -4 (3H) -one
By 3- nitros benzenpropanoic acid (796mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) exists After stirring 1 hour at room temperature, 2- amino -4- (4- methylpiperazine-1-yls) benzamide (703mg, 5mmol) is added in, at 50 degree Lower reaction overnight, after reaction is quenched with water, adds in dichloromethane extraction, anhydrous sodium sulfate drying is dissolved in 20mL ethyl alcohol after concentration In, 10M NaOH solutions (1.2mL) are added in after being cooled to 0 degree, after stirring 30 minutes at room temperature, with concentrated hydrochloric acid tune pH value into Property, it after ethyl alcohol is removed under reduced pressure, is extracted with dichloromethane, anhydrous sodium sulfate drying, column chromatography obtains Light brown solid after concentration (1.1g, 93%).
Step 2：N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -2- (3- nitrophenethyls) quinoline Oxazoline -4- amine
By 7- (4- methylpiperazine-1-yls) -2- (3- nitrophenethyls) quinazoline -4 (3H) -one (393mg, 1.0mmol), PyBrop (606mg, 1.3mmol), DBU (224 μ L, 1.5mmol) are dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- ammonia It is heated to 70 degree after base -5- methylpyrazoles (194mg, 2.0mmol) to react 3 days, directly column chromatography purifying after acetonitrile is removed under reduced pressure Obtain target product (176mg, 37%).
Embodiment 13
N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -2- (3- (trifluoromethyl) phenethyl) quinoline Oxazoline -4- amine
Operating procedure is similar with the synthesis of embodiment 12.Yield is 29%.
Embodiment 14
N- (5- methyl-1 H- pyrazole-3-yls) -2- (1- (methylamino) -2- phenethyls) -7- (4- methylpiperazine-1-yls) quinoline Oxazoline -4- amine
Step 1：N- methyl (1- (7- (4- methylpiperazine-1-yls)-quinazolinone -2- bases) -2- phenethyls) tertiary fourth of formyl Ester
By N- tertbutyloxycarbonyl-N- methylphenylalanines (837mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA After (1.0mL, 6mmol) is stirred at room temperature 1 hour, 2- amino -4- (4- methylpiperazine-1-yls) benzamide is added in (703mg, 3mmol) reacts overnight under 50 degree, after reaction is quenched with water, adds in dichloromethane extraction, anhydrous sodium sulfate is done It is dry, it is dissolved in after concentration in 20mL ethyl alcohol, 10M NaOH solutions (1.2mL) is added in after being cooled to 0 degree, stirred 30 minutes at room temperature Afterwards, it with concentrated hydrochloric acid tune pH value to neutrality, after ethyl alcohol is removed under reduced pressure, is extracted with dichloromethane, anhydrous sodium sulfate drying concentrates rear pillar Chromatograph to obtain Light brown solid (1.1g, 77%).1H NMR(400MHz,DMSO-d6)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-1 H- pyrazole-3-yls) -2- (1- (methylamino) -2- phenethyls) -7- (4- methyl piperazines - 1- yls) quinazoline -4- amine
By N- methyl (1- (7- (4- methylpiperazine-1-yls)-quinazolinone -2- bases) -2- phenethyls) the formyl tert-butyl ester (239mg, 0.5mmol), PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) are dissolved in acetonitrile and stirring at room temperature After mixing 30 minutes, 70 degree are heated to after addition 3- amino-5-methylpyrazoles (97mg, 1.0mmol) and is reacted 3 days, second is removed under reduced pressure Direct column chromatography obtains Boc protection products after nitrile, is dissolved in trifluoroacetic acid later：Dichloromethane (1：1) it is stirred at room temperature in solvent It mixes 2 hours, after organic solvent is removed under reduced pressure, in saturated sodium carbonate solution and system, adds in dichloromethane：Methanol (10：1) it is molten Agent detaches organic phase, through column chromatography (CH after concentration2Cl2：MeOH=1：9) target product (166mg, 73%) is purified to obtain.
Embodiment 15
(E)-N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -2- styryl quinazoline -4- amine
Step 1：(E) -4 (3H) -one of -7- (4 methylpiperazine-1-yl) -2- styryls quinazoline
By cinnamic acid (444mg, 3mmol), HATU (1.37g, 3.6mmol), DIPEA (1.0mL, 6mmol) is at room temperature After stirring 1 hour, 2- amino -4- (4- methylpiperazine-1-yls) benzamide (703mg, 3mmol) is added in, is reacted under 50 degree Overnight, after reaction is quenched with water, dichloromethane extraction is added in, anhydrous sodium sulfate drying is dissolved in 20mL ethyl alcohol after concentration, cools down 10M NaOH solutions (1.2mL) are added in after to 0 degree, after stirring 30 minutes at room temperature, with concentrated hydrochloric acid tune pH value to neutrality, decompression removes It after removing ethyl alcohol, is extracted with dichloromethane, anhydrous sodium sulfate drying, column chromatography obtains Light brown solid (910mg, 88%) after concentration.
Step 2：(E)-N- (5- methyl-1 H- pyrazole-3-yls) -7- (4- methylpiperazine-1-yls) -2- styryl quinoline azoles Quinoline -4- amine
By -4 (3H) -one (173mg, 0.5mmol) of (E) -7- (4 methylpiperazine-1-yl) -2- styryls quinazoline, PyBrop (303mg, 0.65mmol), DBU (112 μ L, 0.75mmol) are dissolved in acetonitrile stir 30 minutes at room temperature after, add in 3- It is heated to 70 degree after amino-5-methylpyrazole (97mg, 1.0mmol) to react 3 days, directly column chromatography obtains after acetonitrile is removed under reduced pressure Boc protects product, is dissolved in trifluoroacetic acid later：Dichloromethane (1：1) it stirs 2 hours, is removed under reduced pressure at room temperature in solvent After organic solvent, in saturated sodium carbonate solution and system, dichloromethane is added in：Methanol (10：1) solvent detaches organic phase, dense Through column chromatography (CH after contracting2Cl2：MeOH=1：9) target product (77mg, 36%) is purified to obtain.
It is prepared in the present invention while also such as compounds other in the following table 1, the synthetic method of these compounds is with reference to upper State method.The characterize data of these compounds, it is as shown in table 1 including nuclear magnetic data and high resolution mass spectrum data.
Table 1
Compound synthesized by the present invention is to Aurora A Inhibition test
Aurora A active testing is measured by Caliper Mobility ShiftAssay methods.By compound from 10 μM start three times successively and dilute, and 10 concentration are always obtained, and add in Aurora A, FAM labeling polypeptides and ATP, 25 degree Lower reaction adds in terminate liquid and terminates reaction after sixty minutes；Finally using Caliper reading and converting rate data, it is converted into inhibiting rate number IC is obtained according to rear calculated by Xlfit statistical softwares50Data.To be not added with the solvent blank of drug as negative control, with SNS314 is positive control.Each compound all has Aurora A inhibiting effect in above-mentioned table 1, and test result is as shown in table 2.
Aurora kinase inhibitory activity (the IC of 2 embodiment compound of table50, nM)
aCompound 18T is L- (+)-tartrate of compound 18.
The activity experiment of compound on tumor cell strain synthesized by the present invention
Tumor cell line includes：Human tissue cell lymphoma cell strain U937, human cervical carcinoma cell lines Hela, the chronic grain of people Cell leukemia cell line K562, people breast adenocarcinoma cell strain SK-BR-3, MCF-7 cell strainHJ2mm, human prostata cancer are thin Born of the same parents' strain DU145, people's acute lymphoblastic leukemia cell strain Molt-4.
Experimental method：Cell strain is grown in the DMEM/RPMI culture mediums of 10%FBS and 1% penicillin/streptomysin to be deposited It is living.All cell strains all deposit in Thermo/Forma Scientific CO2It is grown in cell incubator, condition：Containing 5%CO2 Air, temperature be 37 DEG C.Cell activation assay is measured by CCK8 (DojinDo) method.With the thin of 400-800/ holes Born of the same parents' density is inoculated in 384 well culture plates, adds in the compound of various concentration, after 72 hours are incubated, adds in CCK8 reagents, Light absorption value under 450nM wavelength is measured with 2104 multi-functional micropore analyzers (Perkin Elmer) of Envision, is finally used Prism (Version5, GraphPad software) calculates anti-tumour cell proliferative IC by amount effect curve50Value..
It tests with taxol (Taxol) as positive control, the IC of embodiment compound and reference material50It is worth as shown in the table.
Anti-tumour cell proliferative activity (the IC of 3 the compounds of this invention of table50,μM)
aEmbodiment compound 18T is L- (+)-tartrate of embodiment compound 18.
It these are only the preferred embodiment of the present invention, be not intended to restrict the invention, for those skilled in the art For member, the invention may be variously modified and varied.Any modification for all within the spirits and principles of the present invention, being made, Equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims (5)

1. any one of following structural compound or its pharmaceutically acceptable salt,
2. a kind of pharmaceutical composition, it is characterised in that：Including at least one of following substance：A) compound, b) compound Pharmaceutically acceptable salt；Wherein, the compound is the chemical combination shown in any structural formula described in claim 1 Object.
3. any structural formula compound represented described in claim 1 or its pharmaceutically acceptable salt presses down preparing Application in the drug of Aurora A processed.
4. any structural formula compound represented described in claim 1 or its pharmaceutically acceptable salt is controlled in preparation Treat and/or prevention and/or delay and/or auxiliary treatment and/or handle proliferative diseases drug in application.
5. any structural formula compound represented described in claim 1 or its pharmaceutically acceptable salt prepare it is anti- Application in tumour medicine.
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