CN107151240A - Polysubstituted carbostyril compound of one class and its production and use - Google Patents

Polysubstituted carbostyril compound of one class and its production and use Download PDF

Info

Publication number
CN107151240A
CN107151240A CN201610124218.7A CN201610124218A CN107151240A CN 107151240 A CN107151240 A CN 107151240A CN 201610124218 A CN201610124218 A CN 201610124218A CN 107151240 A CN107151240 A CN 107151240A
Authority
CN
China
Prior art keywords
compound
group
preparation
unsubstituted
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610124218.7A
Other languages
Chinese (zh)
Inventor
龙亚秋
耿美玉
李博文
艾菁
许忠良
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201610124218.7A priority Critical patent/CN107151240A/en
Publication of CN107151240A publication Critical patent/CN107151240A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention provides polysubstituted carbostyril compound of a class and its production and use, specifically, the invention provides a kind of polysubstituted quinolone compounds as shown in following formula I, its optical isomer, and pharmaceutically acceptable salt or solvate, wherein the definition of each group is as noted in the discussion.The quinolone compounds of the present invention have excellent c-Met inhibitory activity, can be used for the treatment of c-Met activity or expression quantity relevant disease.

Description

Polysubstituted carbostyril compound of one class and its production and use
Technical field
The present invention relates to pharmaceutical technology field, and in particular to carbostyril compound, and its isomers and can pharmaceutically connect The salt received, preparation method and use and the composition for including the compound.The invention further relates to the compound, Its isomers and pharmaceutically acceptable salt and the composition for containing it are used to treat as protein kinase c-Met inhibitor Tumor disease.
Background technology
At present, malignant tumour is just seriously threaten the life of the mankind, it has also become cause the first reason of human death, to the greatest extent Present medical technique level is managed to be greatly improved, but tumor patient cure rate is still very low, and it brings nothing The pain of limit.All exist that toxicity is big due to antineoplastic, be also easy to produce drug resistance, it is expensive the shortcomings of, therefore The research and development of new construction and novel mechanism antineoplastic are always emphasis of concern.
In recent years, people are by studying the various signal transduction paths in normal cell and malignant cell, to swollen Neoplasia and breeding have deeper into understanding, while have also discovered a variety of antineoplastic novel targets, wherein c-Met Received much concern as only one in family tyrosine kinase and HGF highly affine transmembrane receptor, The important target of antitumor research is turned at present.C-Met paths and cell propagation, invasion and attack, migration, suppress cell Tune is died, and is promoted angiogenesis etc. relevant, is played an important role in the formation of tumour and breeding.Research is also It was found that, the key reason that EGFR kinase inhibitor produces drug resistance is relevant with the amplification of c-Met genes, and this discovery is pushed away The development and exploitation of targeting c-Met antineoplastics are moved.
At present, in the research of HGF/c-Met signal paths is blocked, though the relative starting of the research of micromolecular inhibitor compared with Evening, but a variety of micromolecular compounds with preferable c-Met inhibitory activity are had been found that by the exploitation of people in recent years, Wherein the overwhelming majority is in preclinical study, and minority enters clinical investigation phase.From clinically confirm c-Met make For the validity of anticancer target.Although kinase inhibitor clinically shows excellent targeted therapy effect, tumour Drug-resistant variants greatly reduce the validity of this kind of medicine long-term treatment.The similar of chemical constitution also to swash The crossing drug resistant sex chromosome mosaicism of enzyme inhibitor is increasingly serious.
In summary, the antineoplastic for being the discovery that targeting c-Met kinases at present of new construction new mechanism lead compound The focus of research and development.
The content of the invention
In order to solve the above-mentioned technical problem, it is an object of the present invention to provide a kind of polysubstituted carbostyril compound, Its isomers, pharmaceutically acceptable salt or pharmaceutically acceptable solvate, and the medicine comprising the compound Composition.
The purpose of another aspect of the present invention is to provide the preparation method of above-mentioned carbostyril compound.
The purpose of another aspect of the invention is to provide above-mentioned carbostyril compound and prepared for suppressing EGFR-TK C-Met activity medicine in application, prepare be used for prevent or treat with the HGF in organism and The related abnormal cell proliferation of its acceptor (c-Met), metamorphosis and the related disease of hypoerkinesia and with Application in angiogenesis or the medicine of the related disease of metastasis of cancer, in particular for preparing prevention or treatment tumour growth With the application in the medicine of transfer.
In order to realize foregoing invention purpose, the present invention is adopted the following technical scheme that：
There is provided a kind of polysubstituted quinolone compounds as shown in following formula I, its optical siomerism for the first aspect of the present invention Body, and pharmaceutically acceptable salt or solvate：
Ring AFor phenyl ring, or the heteroatomic hexa-atomic unsaturated heterocycle base containing 1 or 2 in N, O, S Or heteroaryl；
X and Y are each independently selected from N, O, CH and S；
R1For nothing, or the group to be selected from the group：Hydrogen, substituted or unsubstituted C1-C6Alkyl, substitution or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl or take Generation or unsubstituted heteroatomic five yuan or hexa-atomic saturation or unsaturated heterocycle base for containing 1-2 in N, O, S；
R2Represent the substituent that 1-5 (being preferably 1-3) being located on ring A is selected from the group：Hydrogen, halogen, hydroxyl, Nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C3-C6 Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl or substitution do not take Generation containing heteroatomic 5-10 member saturations of the 1-2 in N, O or unsaturated heterocycle base,
It is described to replace the one or more hydrogen atoms referred on group to be each independently the substituent substitution being selected from the group： Halogen ,-CN ,-CF3、-NO2, hydroxyl, amino, tertbutyloxycarbonyl, C1-C6Alkyl, C1-C6Alkoxy, five First or hexa-atomic saturated heterocyclyl-C1-C6Alkoxy or substituted or unsubstituted miscellaneous in N, O containing 1-2 Five yuan or hexa-atomic saturated heterocyclic group of atom；
R3Selected from hydrogen or halogen；
Z is fluorine, or the structure being selected from the group that is unsubstituted or being replaced by one or more halogen atoms：
M is selected from the group：Nothing, NH, O, S, C1-C10Alkyl, C5-C10Aryl or C5-C10Heteroaryl；Upper State in formula II, III, IV, V, dotted line represents singly-bound or double bond；
R4Selected from amino,C1-C10Alkyl, C5-C10Aryl or C5-C10Heteroaryl；Wherein, Described alkyl is arbitrarily replaced by one or more groups being selected from the group：C1-C10Alkoxy, C5-C10Aryl, 5-7 Circle heterocycles base or C5-C10Heteroaryl；
R5And R6It is each independently selected from the following group：Hydrogen, C1-C6Alkyl, C1-C6Alkoxy, C5-C10Aryl or It is substituted or unsubstituted to contain 1-2 heteroatomic five yuan or hexa-atomic saturation or unsaturated heterocycles in N, O or S Group；
B, C1, D, D1, E is each independently selected from the following group：Nothing, N, NH, O, CH, CH2And S；It is preferred that Ground, B, C1, D, D1, E is each independently selected from N, NH, CH and S.
In another preference, X and Y are each independently selected from N, O, CH；Preferably, X is selected from N or O, and Y is selected from N or C.
In another preference, ring A is phenyl ring or containing 1 or 2 heteroatomic hexa-atomic saturation in N or O or not Saturated heterocyclic group or miscellaneous aromatic group；
In another preference, ring A is phenyl ring or hexa-atomic unsaturated heterocycle group or aromatic radical containing 1 N atom Group；
In another preference, ring A is pyridine or phenyl ring.
In another preference, R1For nothing, or the group to be selected from the group：Hydrogen, substituted or unsubstituted C1-C6Alkane Base, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical, it is substituted or unsubstituted C6-C10Aryl.
In another preference, R1For nothing, or the group to be selected from the group：Hydrogen, substituted or unsubstituted C1-C6Alkane Base, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical；Preferably, R1For nothing, Or the group to be selected from the group：Hydrogen, C1-C3Alkyl, C3-C6Cycloalkyl, substituted or unsubstituted piperidyl, Pyrans.
In another preference, R2Represent the substituent that 1-5 (being preferably 1-3) being located on ring A is selected from the group： Hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, 2- (methoxyl group)-ethyoxyl, sulfydryl ,-CF3、-CN、-NO2、-NH2、 Or substituted or unsubstituted five yuan or hexa-atomic saturation or unsaturated heterocycle base；Wherein, described substitution refer to optionally by 1 or 2 substituent for being each independently selected from the following group replaces：Halogen, C1-C6Alkyl, C1-C6Alkoxy or contain There are the heteroatomic hexa-atomic saturated heterocyclic group substitutions of 1-2 N and/or O.
In another preference, R2For the 1-3 groups being selected from the group：Hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, -CF3、-CN、-NO2、-NH2Or it is substituted or unsubstituted containing 1-2 in N, O heteroatomic five First or hexa-atomic saturated heterocyclic group or simultaneously ring；Wherein, described substitution refers to optionally by 1-2 C1-C6Alkoxy, Or contain the heteroatomic hexa-atomic saturated heterocyclic group substitution of 1-2 N and/or O；
In another preference, R2For the 1-3 groups being selected from the group：Hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, -CF3、-CN、-NO2、-NH2Or substituted or unsubstituted contain the hexa-atomic saturated heterocyclics that 1-2 is selected from N atoms Or simultaneously ring；Wherein, described substitution refers to optionally by 1-2 methoxyl group or containing the miscellaneous originals of 1-2 N and/or O The hexa-atomic saturated heterocyclic group substitution of son.
In another preference, R3Selected from hydrogen, F, Cl and Br；It is highly preferred that R3Positioned at the ortho position of Z bases.
In another preference, described R4Selected from amino or C1-C10Alkyl.
In another preference, described R5And R6It is each independently selected from the following group：Hydrogen, substituted or unsubstituted contain There are 1-2 heteroatomic five yuan or hexa-member heterocycle groups in N or S；It is highly preferred that R5And R6Selected from hydrogen, benzene Base, N-methyl imidazole radicals, thiazolyl.
In another preference, ring A, X, Y, R1、R2、R3、Z、R4、R5And R6, B, C1, D, D1, E is each independently in embodiment the group corresponding to particular compound.
In another preference, described Z is selected from the group：Fluorine, or following any structure：
In another preference, the compound is particular compound in embodiment, or embodiment part institute The compound stated.
The second aspect of the present invention there is provided a kind of preparation method of compound of formula I as described in the first aspect of the invention, Methods described includes step：
In atent solvent, in the presence of alkali and condensing agent, it is condensed with quinolone parent nucleus with amine fragment, obtains formula I；Wherein, the definition of each group is as described in first aspect present invention.
In another preference, described condensing agent is selected from the group：Carbodiimide class condensing agent, the condensation of phosphorus ionic Agent.
In another preference, described condensing agent is selected from the group：N, N '-dicyclohexylcarbodiimide (DCC), N, N '- DIC (DIC), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI), Ka Te contractings Mixture (BOP), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl (PyBOP), O- BTAs - N, N, N ', N '-tetramethylurea tetrafluoro boric acid (TBTU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU), 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU) or double (2- oxygen Generation -3- oxazolidinyls) secondary phosphoryl chloride phosphorus oxychloride (BOP-Cl).
In another preference, described condensing agent is selected from the group：BOP、PyBOP、HBTU、TBTU、EDC·HCl.
In another preference, described alkali is TEA or DIEA.
In another preference, described atent solvent is selected from the group：DMF, dichloromethane, THF, or its combination.
In another preference, described quinolone parent nucleus including following one or more steps method by preparing：
Wherein, each group is as defined above described in text；
1) compound S2 synthesis：Chlorination is carried out by raw material of substituted 2- fluoro aryls formic acid, wherein, chloro Reagent is selected from the group：Thionyl chloride, oxalyl chloride, POCl3, preferably thionyl chloride, oxalyl chloride.
2) compound S3 synthesis：Reacted with formula S2 compounds and 3- (dimethylamino) ethyl acrylate, the reaction Carry out in the presence of a base；Preferably, alkali used is Anhydrous potassium carbonate, cesium carbonate, triethylamine, N, N- diisopropyls Ethamine (DIEA), pyridine；More preferably triethylamine, DIEA, pyridine.
3) compound S4 synthesis：It is stirred at room temperature and is obtained with corresponding amine with formula S3 compounds.
4) preparation of formula S5 compounds：In the presence of a base, ring-closure reaction is carried out with formula S4 compounds to prepare；Its In, solvent used in ring-closure reaction is DMA (DMF), 1-METHYLPYRROLIDONE (NMP), used Alkali be Anhydrous potassium carbonate, cesium carbonate, triethylamine, DIEA, pyridine.
5) preparation of formula S6 compounds：Be hydrolyzed with formula S5 compounds it is obtained, wherein, used in described hydrolysis Reagent is lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid；It is preferred that sodium hydroxide.
6) preparation of formula S7 compounds：Elimination reaction is carried out with the formula S6 compounds that R1 is benzyl, wherein, it is described Removal methods are palladium carbon reduction, trifluoromethanesulfonic acid or ammonium ceric nitrate；It is preferred that the de- benzyl of palladium carbon reduction.
In another preference, described amine fragment is prepared via a method which：
In atent solvent, reacted with the fluoro- PAPs of 2- and Z-Cl, obtain described amine fragment.
In another preference, described reaction is carried out in the presence of organic base or inorganic base, it is preferable that described Alkali be selected from the group：Anhydrous potassium carbonate, cesium carbonate, triethylamine (TEA), DIEA, potassium tert-butoxide, sodium hydride, first Sodium alkoxide, caustic alcohol, or its combination；More preferably Anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, Or its combination.
In another preference, described solvent is selected from the group：DMF, NMP, tetrahydrofuran (THF), or its group Close.
Wherein, each group is as defined above.
The third aspect of the present invention includes there is provided a kind of pharmaceutical composition, described pharmaceutical composition：Treatment is effective The combination of compound or a variety of compound of formula I shown in the Formulas I of amount, or its optical isomer, pharmaceutically acceptable salt, Or pharmaceutically acceptable solvate；And pharmaceutically acceptable carrier.
There is provided a kind of compound of formula I as described in the first aspect of the invention, or its isomery for the fourth aspect of the present invention Body, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or the medicine containing described compound of formula I The purposes of composition, it is characterised in that for preparing the medicine being selected from the group：It is used as Mutiple Targets kinases inhibitor Medicine, the medicine for suppressing EGFR-TK c-Met activity, the liver cell for preventing or treating and in organism give birth to The medicine of the related abnormal cell proliferation of growth factor receptor body (c-Met), metamorphosis and the related disease of hypoerkinesia Thing, or the disease related to angiogenesis or metastases medicine (especially prepare prevention or treatment tumour growth with The medicine of transfer).
In another preference, the medicine is used to treat and/or prevent the disease relevant with protein kinase particularly c-Met Disease.
In another preference, the tumour is the tumour being selected from the group：Lung cancer, thyroid gland encephaloid, pernicious glue Matter knurl, stomach cancer, clear-cell carcinoma, breast cancer, oophoroma, prostate cancer, or colorectal cancer.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.It is limited to a piece Width, no longer tires out state herein one by one.
Embodiment
The present inventor's in-depth study by long-term, it was found that there is a class excellent EGFR-TK c-Met to suppress The polysubstituted carbostyril compound of activity.Described compound shows high suppression for EGFR-TK c-Met and lived Property (part of compounds can be less than 10nM), therefore be a kind of c-Met inhibitor of excellent performance, it can be used for c-Met The treatment or prevention of active related disease.Based on above-mentioned discovery, inventor completes the present invention.
Term
As used herein, term " C1-C6Alkyl " refers to the straight or branched alkyl with 1~6 carbon atom, for example Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, or similar group.Shape such as " C1-C6 " Statement be intended to include the corresponding group with 1,2,3,4,5 or 6 carbon atom, for example, " C1-C6 Alkyl " refers to the alkyl with 1,2,3,4,5 or 6 carbon atom, " C6-C10Aryl " refer to 6, The non-heteroaryl of 7,8,9 or 10 carbon atoms.
As used herein, term " C1-C6 alkyl " refers to the straight or branched alkyl with 1~6 carbon atom, for example Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, or similar group.
Term " C6-C10 aryl " refers to the aromatic yl group with 6-10 carbon atom, such as phenyl.
Term " 6 unit's heteroaryl " or " hexa-atomic miscellaneous aromatic group " refer to one or more with having in 6 yuan of ring system Heteroatomic unsaturation ring system substituent selected from O, S, N, such as pyridine radicals, thienyl, or similar group.
As used herein, term " heterocyclic radical " refers into ring skeleton that to there is at least one (be preferably 1-5, more preferably For 1-3, such as 1,2 or 3) heteroatomic ring group in N, O, S.Described heterocyclic radical can be this Any group for meeting chemical bonding rule, such as monocyclic, polycyclic and ring or condensed cyclic structure in field.Described is miscellaneous Ring group can be the undersaturated group of whole saturations or part, it is preferable that herein, described heterocyclic radical does not include Heteroaryl.
As used herein, term " C1-C6Alkoxy " finger-type is as " having the straight or branched alkane of 1~6 carbon atom The substituent of base-epoxide " structure, such as ethyoxyl, propoxyl group, butoxy, or similar group.
Term " halogen " refers to F, Cl, Br and I.
In the present invention, term " containing ", "comprising" or " comprising " represent that various composition can be applied to this together In the mixture or composition of invention.Therefore, term " mainly by ... constitute " and " consist of " are included in art In language " containing ".
In the present invention, term " pharmaceutically acceptable " composition refers to suitable for people and/or animal without excessively bad Side reaction (such as toxicity, stimulation and allergy), that is, have rational benefit/risk than material.
In the present invention, term " effective dose " refers to therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, Or show the amount of detectable treatment or prevention effect.Accurate effective dose for a certain object depends on the object Build and the combination of therapeutic agent and/or therapeutic agent given of health status, the nature and extent of illness and selection. Therefore, it is useless to preassign accurate effective dose.However, for certain given situation, routine can be used Test to determine the effective dose, clinician can interpolate that out.
Herein, except special instruction part, one or more hydrogen atoms that term " substitution " refers on group are chosen Replace from the substituent of the following group：Halogen ,-CN ,-CF3、-NO2, hydroxyl, amino, C1-C6Alkyl, C1-C6Alkane Epoxide, five yuan or hexa-atomic saturated heterocyclyl-C1-C6Alkoxy or it is substituted or unsubstituted containing 1-2 selected from N, Heteroatomic five yuan in O or hexa-atomic saturated heterocyclic group.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical siomerism The compound of body, such as single chiral, or various different chipal compounds mixture (i.e. racemic modification).The present invention's Among all compounds, each asymmetric carbon atom can be optionally R configurations or S configurations, or R configurations and S configurations Mixture.
As used herein, term " the compounds of this invention " refers to the compound shown in Formulas I.The term also includes and compound of formula I Various crystalline forms, pharmaceutically acceptable salt, hydrate or solvate.
Compound of formula I and its preparation
The invention provides a kind of compound with structure shown in following formula.
Wherein, each group is as defined above described in text.
It is preferred that the compound be selected from the group：
The preparation method of formula I structural compounds, but these specific sides are more specifically described in Examples below Method does not constitute any limitation to the present invention.The compounds of this invention can also be optionally by describe in this manual or ability Various synthetic methods combine and are easily made known to domain, and such combination can be by skill of the art Art personnel are readily carried out.
The quinolone parent nucleus that the present invention is used can be obtained with amine fragment by commercially available approach, or using commercial compound as Raw material, is prepared according to conventional methods by those skilled in the art, in content basis disclosed in this invention, this The operation of sample belongs within those skilled in the art's limit of power.
Generally, in preparation flow, each reaction is carried out generally in atent solvent under room temperature to reflux temperature.Instead It is usually -60 hours 0.1 hour, preferably 0.5-48 hours between seasonable.
Pharmaceutical composition and application process
Because the compounds of this invention has the excellent inhibitory activity to EGFR-TK c-Met, therefore the present inventionization Compound and its various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain this Invention compound for the pharmaceutical composition of main active can be used for treating, prevent and alleviates with c-Met it is active or The related disease of expression quantity.According to prior art, the compounds of this invention can be used for treating following disease：Lung cancer, first shape Gland encephaloid, glioblastoma, stomach cancer, clear-cell carcinoma, breast cancer, oophoroma, prostate cancer, or colorectal cancer.
The pharmaceutical composition of the present invention comprising the compounds of this invention in the range of safe and effective amount or its be pharmacologically subjected to Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " is referred to：The amount foot of compound To be obviously improved the state of an illness, and it is unlikely to produce serious side effect.Generally, pharmaceutical composition contains 1-2000mg sheets Invention compound/agent, more preferably, contains 5-200mg the compounds of this invention/agent.It is preferred that described " one " For a capsule or tablet.
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or gel Material, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein Refer to each component energy in composition and the compound of the present invention and they between mutually admix, and significantly reducing The drug effect of compound.Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as carboxymethyl cellulose Sodium, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, kollag (such as stearic acid, stearic acid Magnesium), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propane diols, sweet Oil, mannitol, sorbierite etc.), emulsifying agent (such as), wetting agent (such as lauryl sodium sulfate), colouring agent, Flavor enhancement, stabilizer, antioxidant, preservative, apirogen water etc..
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to)：Orally, in knurl, rectum, parenteral (intravenous, intramuscular is subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.It is solid at these In body formulation, reactive compound is mixed with least one conventional inert excipients (or carrier), such as sodium citrate or phosphoric acid Dicalcium, or mixed with following compositions：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, Mannitol and silicic acid；(b) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone Ketone, sucrose and Arabic gum；(c) NMF, for example, glycerine；(d) disintegrant, for example, agar, calcium carbonate, Farina or tapioca, alginic acid, some composition silicates and sodium carbonate；(e) retarding solvent, such as paraffin； (f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as cetanol and glycerin monostearate； (h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, magnesium stearate, solid (i) Body polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also be included Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can be prepared using coating and shell material, such as intestines Clothing and other materials well known in the art.They can include reactive compound in opacifying agent, also, this composition Or the release of compound can discharge in certain part in a delayed fashion in alimentary canal.Adoptable embedding component Example is polymeric material and Wax.If necessary, reactive compound also can be with the one or more in above-mentioned excipient Form microencapsulation form.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture Agent.Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent that routinely uses in this area, such as water or its Its solvent, solubilizer and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3- Butanediol, dimethylformamide and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil With the mixture of sesame oil or these materials etc..
In addition to these inert diluents, composition also can include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, Sweetener, tender taste agent and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxy Mixture of ethene sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.Suitable contains Water and nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and suction Agent.Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary The propellant that may be needed is mixed together.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment during using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for the people of 60kg body weight, Day dosage is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that method of administration, The factors such as patient health situation, within the scope of these are all skilled practitioners technical ability.
Compared with prior art, the method have the advantages that：
By being screened to c-Met kinase activities, inventor has found：The compound that above-mentioned formula I is represented is right under 10nM C-Met kinases has efficient inhibitory activity, can be used in and the relevant disease such as tumour caused by the overexpression of c-Met kinases Treatment.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate this hair Bright rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to Normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number be by weight Calculate.
Prepare embodiment
Mass spectrum EI-MS uses Finnigan MAT-95 type mass spectrographs, and ESI-MS uses Finnigan LCQ Deca type matter Spectrometer is determined.Mass spectrum EI-MS is using high resolution mass spectrum by Finnigan MAT Instrument measurings.
1The measurement of H-NMR spectroscopic datas uses Varian Mercury-300MHz or Varian Mercury-400MHz NMR, with tetramethylsilane (tetramethylsilane, TMS) for internal standard.
All solvents are that AR largely comes from Chemical Reagent Co., Ltd., Sinopharm Group, other reagents one As be purchased from Chemical Reagent Co., Ltd., Sinopharm Group, the biochemical (Shanghai) Co., Ltd. of gill, lark prestige, it is splendid it is remote, Acros, Bi get Deng Reagent Company, unless specifically mentioned, these reagents are all unprocessed directly to be used.Anhydrous solvent Purifying reference Purification of laboratory Chemicals, D.D.Perrin and W.L.F.Armarego, Pergamon Press:Oxford,1980。
In addition to explanation, all reactions all pass through thin-layered chromatography tracking and monitoring.The tlc silica gel template number used For HSGF 254, from Qingdao marine chemical industry factory.Conventional post-processing step is first to be added to specific organic solvent Among reaction system, then it is diluted with water, extracts 3 times repeatedly, by the organic phase saturated aqueous common salt or saturation of merging Ammonium chloride solution is washed, and is collected organic phase and is used anhydrous Na 2SO4Dry, then removed with Rotary Evaporators organic Solvent obtains reacting crude product, and crude product passes through rapid column chromatography method institute (the normal phase column chromatography silica gel used, model For：Zcx-11,200-300) or recrystallized or washed with specific solvent and obtain sterling.
Embodiment 1N- (4- ((2- amino -3- chloropyridine -4- bases) epoxide -3- fluorophenyls) fluoro- 4- carbonyls -1,4- two of -7- The preparation of hydrogen azanaphthalene -3- formamides (1)
(Z)-ethyl -2- (2,4 difluorobenzene formoxyl) -3- (dimethylamino) acrylate
Compound 2 is taken, 4- difluoro-benzoic acids (950mg, 6mmol) are dissolved in 2ml thionyl chlorides, be heated to 80 DEG C of backflows 2 hours, after completion of the reaction, solvent is spin-dried for, obtains oily compound, oily compound is placed on oil pump to take out half small When, next step is put at once.Previous step compound is quickly dissolved in dry toluene, and adds 3- (dimethylamino) Ethyl acrylate (1g, 7mmol), triethylamine (1.01g, 10mmol) is heated to 90 DEG C, is sufficiently stirred for 12h, Room temperature is cooled to, solvent is spin-dried for, ethyl acetate is dissolved in and is washed with water repeatedly, pass through column chromatography gradient elution after concentration (petroleum ether：Ethyl acetate=10:1 to 2:1) yellow oily compound 1a (1.42g, 85%) is taken.1H NMR(400 MHz,CDCl3)：δ7.81(s,1H),7.57–7.47(m,1H),7.00–6.86(m,2H), (t, J=7.1Hz, the 3H) of 4.84 (s, 6H), 3.94 (q, J=7.1Hz, 2H), 0.95
(Z)-ethyl -3- (2,4 difluorobenzene formoxyl) -3- (dimethylamino) acrylate
1a (1.2g, 4.24mmol) is taken to be dissolved in ether：Ethanol (1:3) in the mixed solvent, then by benzylamine (856mg, 8mmol) it is added dropwise in reaction solution, being stirred at room temperature has substantial amounts of white solid powder to separate out for 15 minutes, filtering is received Collect yellow solid powder to be washed with ethanol again, obtain white solid powder 1b (1.3g, 91%).1H NMR(400MHz, CDCl3)δ11.14(s,1H),8.37–8.12(s,1H),7.76–7.24(m,6H),7.06– 6.71 (m, 2H), 4.62 (q, J=7.1Hz, 2H), 4.10 (m, 2H), 1.06 (t, J=7.1Hz, 3H).
The fluoro- miscellaneous naphthalene -3- carboxylates of 4- carbonyls -1,4- dihydros of 1- benzyls -7-
Take 1b (1g, 2.9mmol) to be dissolved in 5ml DMF and add lower 90 DEG C of potassium carbonate (828mg, 6mmol) oil bath 1h is heated, is filtered to remove after potassium carbonate, DMF is spin-dried for and adds 200ml ethyl acetate and organic phase washed with water, satisfy And brine It, anhydrous magnesium sulfate drying.Filtering is spin-dried for after solvent obtaining pale yellow powder, after acetone recrystallization Obtain white powder 1c (920mg, 96%).1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.55(dd, J=8.9,6.5Hz, 1H), 7.53-7.32 (m, 3H), 7.27-7.07 (m, 3H), 6.99 (dd, J=10.2,2.2Hz, 1H), 5.36 (s, 2H), 4.42 (q, J=7.1Hz, 2H), 1.43 (t, J= 7.1Hz,3H).
The fluoro- miscellaneous naphthalene -3- carboxylic acids of 4- carbonyls -1,4- dihydros of 1- benzyls -7-
Compound 1c (975mg, 3mmol) is dissolved in 10ml 6N hydrochloric acid, and added, 80 DEG C of 10ml ethanol Backflow is stayed overnight, and has substantial amounts of white powder to separate out, and is spin-dried for solvent and is directly used acetone recrystallization, obtains white powder 1d (887 Mg, 91%).1H NMR(300MHz,CDCl3)δ8.91(s,1H),8.70–8.46(m,1H),7.25 (dd, J=42.4,22.0Hz, 7H), 5.39 (d, J=51.5Hz, 2H)
The fluoro- miscellaneous naphthalene -3- carboxylic acids of 4- carbonyls -1,4- dihydros of 7-
Take compound 1d (887mg, 2.9mmol) to be dissolved in 50ml ethanol, 80mg hydroxide palladium carbons are added, in hydrogen Atmosphere encloses lower stirring 12h.Palladium carbon is filtered to remove, solvent is spin-dried for, pale powder is obtained with re-crystallizing in ethyl acetate 1e (550mg, 89%).1H NMR(400MHz,d6-DMSO)δ13.40(s,1H),8.96(s,1H),8.37 (dd, J=8.9,6.1Hz, 1H), 7.59 (d, J=9.8Hz, 1H), 7.50 (t, J=7.8Hz, 1H)
3,4- dichloropyridine acid amides
Take compound tetramethyl piperazine (311mg, 2.2mmol) to be dissolved in 8ml absolute ethers, be then added dropwise at 0 DEG C N-BuLi (138mg, 2.2mmol), and stir 30min under ice bath.At this moment reaction temperature is down to -78 DEG C Lower stirring 30min, while 3,4- dichloropyridines (296mg, 2mmol) are dissolved in into 2ml absolute ethers is added dropwise reaction In, reacted 2 hours at -78 DEG C, reaction is finished, add trimethyl silicane based isocyanate (400ul, 3mmol) and rise To room temperature reaction 1h.Question response is finished, and adds acetic acid：Water (1:4) solution 50ml.It is stirred overnight, uses acetic acid Ethyl ester is extracted, and saturated sodium bicarbonate, saturated common salt water washing obtains brown oil, passes through column chromatography (methanol： Dichloromethane=1:100 to 1:30) pink powder 1f (150mg, 39.6%) is obtained.1H NMR(400MHz,d6-DMSO) (d, J=5.2Hz, the 2H) of δ 8.49 (d, J=5.2Hz, 1H), 8.10 (s, 1H), 7.83
4- (4- amino -2- fluorophenoxies) -3- chloropyridine acid amides
Previous step is reacted to obtained fluoro- 4 amino-phenol (127mg, 1mmol) of compound 1f (110mg 0.6mmol), 2- It is dissolved in after 1ml DMF, is sufficiently stirred for and adds potassium tert-butoxide (112mg, 1mmol), is then reacted at 80 DEG C of microwave 1h, after completion of the reaction, is spin-dried for DMF, is dissolved in ethyl acetate and is washed with water, saturated aqueous ammonium chloride.It is spin-dried for molten Dark oil thing is obtained after agent, passes through column chromatography (ethyl acetate：Petroleum ether=1:1) obtain brown powder 1g (131mg, 81%).1H NMR(300MHz,CD3OD) δ 8.28 (d, J=3.0Hz, 1H), 6.98 (t, J=8.7 Hz, 1H), 6.75 (dt, J=11.2,5.6Hz, 1H), 6.63-6.50 (m, 2H)
N- (4- ((2- carbamyl -3- chloropyridine -4- bases) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls -1,4- dihydros of -7- Miscellaneous naphthalene -3- formamides
By compound 1e (103mg, 0.5mmol), HATU (190mg, 0.5mmol) and DIEA (200 μ l, 0.8 Mmol) it is dissolved in DMF and stirs 0.5h at room temperature.Then 1g (140mg, 0.5mmol) reaction 5h are added, reaction is finished 100ml ethyl acetate is added afterwards, then is washed with water, saturated aqueous ammonium chloride and saturated sodium-chloride water solution.It is spin-dried for Brown oil is obtained after solvent, passes through column chromatography (methanol：Dichloromethane=1:30) obtain brown powder 1h (100mg, 42%).1H NMR(300MHz,d6-DMSO)δ12.66(s,1H),8.93(s,1H),8.46–8.32 (m, 2H), 8.10 (d, J=10.4Hz, 2H), 7.78 (s, 1H), 7.63-7.37 (m, 4H), 6.88 (d, J=5.4Hz, 1H)
N- (4- ((2- amino -3- chloropyridine -4- bases) epoxide -3- fluorophenyls) fluoro- 4- carbonyls -1,4- dihydro azepines of -7- Naphthalene -3- formamides (1)
Compound 1h (47mg, 0.1mmol) is dissolved in ethyl acetate：Acetonitrile：Water is respectively 2:2:1 mixed solvent In, iodobenzene acetate (65mg, 0.2mmol) is added under ice-water bath, reaction 2h is warmed to room temperature, after completion of the reaction, plus Enter ethyl acetate 50ml, respectively with saturated sodium bicarbonate, saturated common salt water washing obtains brown oil, passed through Column chromatography (methanol：Dichloromethane=1:30) light red powder 1 (25mg, 65%) is obtained1H NMR(300MHz,DMSO) δ 12.59 (s, 1H), 8.94 (s, 1H), 8.44-8.33 (m, 1H), 8.04 (d, J=13.0Hz, 1H), 7.78 (d, J=5.6Hz, 1H), 7.42 (ddd, J=24.0,21.5,9.5Hz, 4H), 6.43 (s, 2H), 5.97 (d, J=5.5Hz, 1H)13C NMR(125MHz,DMSO)δ176.23,163.87, 163.44,160.16,157.97,152.75,147.76,145.80,141.25,141.14,137.92, 137.84,136.28,136.18,124.12,123.39,116.75,114.91,114.72,110.88, 108.96,108.78,105.28,105.08,100.68,100.62.MS-ESI m/z:441.3(M-H)-； HR-ESI MS calcd for C21H14ClF2N4O3(M+H)+:443.0644,found:443.0733。
Embodiment 2N- (4- ((6,7- dimethoxyquinazoline -4- bases) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls of -7- The preparation of -1,4 EEDQ -3- formamides (2)
4- ((6,7- dimethoxyquinazoline -4- bases) epoxide) -3- fluoroanilines
Take compound 4-chloro -6,7- dimethoxyquinazoline (448mg, 2mmol) and 2- fluoro-4-nitrophenols (381 Mg, 3mmol) it is dissolved in 10ml methyl ethyl ketones, then add catalytic amount TBAB 100mg, 2ml 2 N sodium hydroxide solutions, are sufficiently stirred for and are heated to reflux 0.5h, question response is finished after cooling, add 200ml bis- Chloromethanes is diluted, and PH is transferred into neutrality with 2N HCl, respectively with saturated sodium bicarbonate and saturated common salt water washing, Brown powder crude product is obtained, brown powder 2a (580mg, 95%) is obtained with recrystallizing methanol.1H NMR(400 MHz,CDCl3) δ 8.65 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.09 (t, J=8.5Hz, 1H), 6.58 (dd, J=11.7,2.6Hz, 1H), 6.53 (ddd, J=8.6,2.7,1.1Hz, 1H), 4.09 (dd, J=5.0,3.0Hz, 6H) .MS-ESI m/z:316.2(M+H)+
N- (4- ((6,7- dimethoxyquinazoline -4- bases) epoxide) -3- fluorophenyls) fluoro- dihydro quinolines of 4- carbonyls -1,4 of -7- Quinoline -3- formamides (2)
By compound 1e (103mg, 0.5mmol), HATU (190mg, 0.5mmol) and DIEA (200 μ l, 0.8 Mmol) it is dissolved in DMF and stirs 0.5h at room temperature.Then 2a (158mg, 0.5mmol) reaction 5h are added, reaction is finished 100ml ethyl acetate is added afterwards, then is washed with water, saturated aqueous ammonium chloride and saturated sodium-chloride water solution.It is spin-dried for Brown oil is obtained after solvent, passes through column chromatography (methanol：Dichloromethane=1:30) obtain brown powder 2 (125mg, 49%).1H NMR(400MHz,d6-DMSO)δ13.07(s,1H),12.60(s,1H),8.96(d,J =5.0Hz, 1H), 8.58 (s, 1H), 8.40 (dd, J=9.0,6.2Hz, 1H), 8.09-7.99 (m, 1H), 7.62-7.38 (m, 6H), 4.00 (d, J=4.1Hz, 6H)13C NMR(125MHz,d6-DMSO) δ175.74,164.69,162.13,159.31,159.03,158.35,155.45,150.87,144.32, 142.28,139.83,137.25,128.85,127.72,127.30,126.29,122.44,115.34, 110.97,103.38,103.01,42.53.MS-EIm/z:504(M)+,HR-EI MS Calc’d for C26H18F2N4O5(M+):504.1245,Found:526.1246。
Embodiment 3N- (4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls -1,4 of -7- The preparation of EEDQ -3- formamides (3)
4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -3- fluoroanilines
Take compound 4-chloro -6,7- dimethoxy-quinoline (110mg, 0.5mmol), the fluoro- PAPs of 2- (127mg, 1mmol) it is dissolved in after 1ml DMF, is sufficiently stirred for and adds potassium tert-butoxide (112mg, 1mmol), then 80 DEG C of microwave Lower reaction 1.5h, after completion of the reaction, is spin-dried for DMF, is dissolved in ethyl acetate and is washed with water, saturated aqueous ammonium chloride. It is spin-dried for obtaining dark oil thing after solvent, passes through column chromatography (ethyl acetate：Petroleum ether=1:1) brown powder is obtained 3a (100mg, 66%).1H NMR(300MHz,d6- DMSO) δ 8.46 (d, J=5.2Hz, 1H), 7.45 (d, J=37.8Hz, 2H), 7.08 (t, J=9.0Hz, 1H), 6.63-6.35 (m, 3H), 5.50 (s,2H),3.95(s,6H).
N- (4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -3- fluorophenyls) fluoro- EEDQs of 4- carbonyls -1,4 of -7- - 3- formamides
By compound 1e (80mg, 0.38mmol), HOBt (191mg, 0.5mmol) and EDCI (67mg, 0.5 Mmol) it is dissolved in DMF and stirs 0.5h at room temperature.Then 80 DEG C of reaction 3h of 3a (70mg, 0.25mmol), reaction are added 100ml ethyl acetate is added after finishing, then is washed with water, saturated aqueous ammonium chloride and saturated sodium-chloride water solution. It is spin-dried for after solvent obtaining brown oil, passes through column chromatography (methanol：Dichloromethane=1:30) brown powder 3 (40 is obtained Mg, 35%)1H NMR(300MHz,d6-DMSO)δ13.08(s,1H),12.63(s,1H),8.96(s, 1H), 8.45 (d, J=32.0Hz, 2H), 8.11 (d, J=12.5Hz, 1H), 7.77-7.30 (m, 5H),6.52(s,1H),3.97(s,6H)δ13C NMR(125MHz,d6-DMSO)δ176.24,165.85, 163.86,163.45,159.85,155.04,153.13,146.73,145.62,141.16,141.06, 138.08,136.17,136.08,129.39,129.31,124.75,123.38,116.90,115.00, 114.90,114.71,110.90,109.06,108.88,108.20,105.21,105.01,99.42, 56.21.EI-MS m/z:503(M)+.HR-EI MS calcd for C27H19F2N3O5(M)+:503.1293,found: 503.1309.
The preparation method of embodiment 4
The fluoro- N- of 7- (3- fluoro- 4 ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- Miscellaneous naphthalene -3- the formamides of carbonyl -1,4- dihydros
4- (3- ((the chloro- 6- methoxy quinolines -7- bases of 4-) epoxide) propyl group) morpholine
Take the chloro- 6 methoxyl group -7- oxyquinolines (210mg, 1mmol) of 4-, potassium carbonate (1.38g, 10mmol) molten In 5ml DMF, it is sufficiently stirred for then, bromo- 3- chloropropanes (1.26g, 8mmol) the room temperature reaction 24h of 1- being added dropwise, Potassium carbonate is filtered to remove, solvent is spin-dried for, next step is direct plungeed into.By upper step product crude product potassium carbonate (690mg, 5 Mmol 5ml DMF) are directly dissolved in, are stirred at room temperature, morpholine (600mg, 6mmol) is then added dropwise and is warming up to 70 DEG C of reaction 20h, reaction is finished, and is filtered to remove unnecessary potassium carbonate, is added and use water after 200ml ethyl acetate respectively, Saturated ammonium chloride solution is washed, and after anhydrous magnesium sulfate is dried, then all dark yellow solids powder after concentration passes through post Chromatograph (methanol：Dichloromethane=1:50) yellow solid powder 4a (300mg, 69%) is obtained.1H NMR(300MHz, CDCl3) δ 8.56 (d, J=4.8Hz, 1H), 7.40 (d, J=11.8Hz, 2H), 7.33 (d, J= 4.9Hz, 1H), 4.25 (t, J=6.6Hz, 2H), 4.03 (s, 3H), 3.79-3.65 (m, 4H), (m, the 2H) of 2.59 (t, J=7.1Hz, 2H), 2.50 (s, 4H), 2.20-2.07
The fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide aniline
Compound 4a (110mg, 0.33mmol), the fluoro- PAPs of 2- (127mg, 1mmol) is taken to be dissolved in 1ml After DMF, it is sufficiently stirred for and adds potassium tert-butoxide (112mg, 1mmol), then reacts 1h at 105 DEG C of microwave, instead After should finishing, DMF is spin-dried for, ethyl acetate is dissolved in and is washed with water, saturated aqueous ammonium chloride.It is spin-dried for obtaining after solvent To dark oil thing, pass through column chromatography (methanol：Dichloromethane=1:50) brown powder 4b (100mg, 66%) is obtained.1H NMR(300MHz,CDCl3) δ 8.46 (d, J=5.2Hz, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.03 (t, J=8.7Hz, 1H), 6.53 (dd, J=17.6,10.8Hz, 2H), 6.39 (d, J =5.2Hz, 1H), 4.26 (t, J=6.6Hz, 2H), 4.03 (s, 3H), 3.71 (d, J=4.2Hz, 4H), (dd, J=13.3,6.3Hz, the 2H) of 2.57 (t, J=7.1Hz, 2H), 2.48 (s, 4H), 2.13 MS-ESI m/z:428.3(M+H)+.
The fluoro- N- of 7- (3- fluoro- 4 ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- Miscellaneous naphthalene -3- the formamides of carbonyl -1,4- dihydros
By compound 1e (21mg, 0.1mmol), HOBt (22mg, 0.15mmol) and EDCI (30mg, 0.15mmol) DIEA (50ul, 0.15mmol) is dissolved in DMF and stirs 0.5h at room temperature.Then add 4b (30mg, 0.25mmol) 60 DEG C of reaction 3h, add 100ml ethyl acetate after completion of the reaction, then with water, saturated ammonium chloride water Solution and saturated sodium-chloride water solution washing.It is spin-dried for after solvent obtaining brown oil, passes through column chromatography (methanol：Two Chloromethanes=1:30) brown powder 4 (33mg, 55%) is obtained.1H NMR(300MHz,d6-DMSO)δ12.71(s, 1H), 8.97 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 8.44-8.34 (m, 1H), 8.11 (d, J=13.1Hz, 1H), 7.62-7.36 (m, 6H), 6.50 (d, J=5.3Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.61 (s, 4H), 2.49 (dd, J=16.1,14.4Hz, 6H), 2.00 (s, 2H).13C NMR(125MHz,d6-DMSO)δ176.04,163.69,159.72,152.34,150.08,149.29, 146.79,146.33,136.06,135.96,124.68,123.97,123.48,116.78,114.88, 110.68,110.13,108.93,108.77,102.47,99.45,67.09,66.63,56.19,55.24, 53.80,26.10.MS-EIm/z:616(M)+,HR-EI MS Calc’d for C33H30F2N4O6(M+):616.2133, Found:616.2146
The preparation method of embodiment 5
N- (4- ((1H- pyrroles [2,3-b] pyridin-4-yl) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls -1,4- dihydros of -7- Miscellaneous naphthalene -3- formamides (5)
4- (the fluoro- 4-nitrophenoxys of 2-) -1H- pyrroles [2,3-b] pyridine
Take compound 4-chloro pyridine diindyl (703mg, 4.2mmol), 2- fluoro-4-nitrophenols (456mg, 3mmol) It is dissolved in after 1ml NMP, is sufficiently stirred for and adds DIEA (583mg, 4.2mmol), then reacts 1 at 200 DEG C of microwave H, after completion of the reaction, is dissolved in ethyl acetate and is washed with water, saturated aqueous ammonium chloride.It is spin-dried for obtaining bright after solvent Yellow oil, passes through column chromatography (petroleum ether：Ethyl acetate=1:1) yellow color powder 5a (330mg, 40%) is obtained.1H NMR(400MHz,d6- Acetone) δ 8.31 (dd, J=10.5,2.7Hz, 1H), 8.25 (d, J =5.3Hz, 1H), 8.22-8.15 (m, 1H), 7.52-7.41 (m, 2H), 6.76 (d, J=5.4 Hz, 1H), 6.36 (dd, J=3.5,1.5Hz, 1H)
4- ((1H- pyrroles [2,3-b] pyridin-4-yl) epoxide) -3- fluoroanilines
Compound 5a (300mg, 1.1mmol) is taken to be dissolved in methanol：Tetrahydrofuran (1:2) mixed solvent, and add Zinc powder (350mg, 5.5mmol) and ammonium chloride (294mg, 5.5mmol) are stirred overnight at room temperature, are filtered to remove zinc Powder, is dissolved in dichloromethane and uses water, saturated common salt water washing.It is spin-dried for arriving gray solid after solvent, passes through column chromatography (petroleum ether：Ethyl acetate=1:1) white powder 5b is obtained.(210mg, 80%).1H NMR(300MHz,d6-DMSO) δ 8.58 (s, 2H), 8.06 (d, J=5.2Hz, 1H), 7.25 (dd, J=30.7,22.0Hz, 2H), 6.76 (dd, J=30.8,10.5Hz, 2H), 6.37-6.19 (m, 2H) .MS-ESI m/z:244.1(M+H)+
N- (4- ((1H- pyrroles [2,3-b] pyridin-4-yl) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls -1,4- dihydros of -7- Miscellaneous naphthalene -3- formamides (5)
Compound 1e (80mg, 0.38mmol), HOBt (191mg, 0.5mmol) and EDCI (67mg, 0.5mmol) DIEA (120ul, 0.6mmol) is dissolved in DMF and stirs 0.5h at room temperature.Then 5b (70mg, 0.28 are added Mmol) 80 DEG C of reaction 3h, add 100ml ethyl acetate after completion of the reaction, then with water, saturated aqueous ammonium chloride and Saturated sodium-chloride water solution is washed.It is spin-dried for after solvent obtaining yellow oil, passes through column chromatography (methanol：Dichloromethane =1:30) white powder 5 (12mg, 25%) is obtained.1H NMR(300MHz,d6-DMSO)δ12.62(s,1H), 11.79 (s, 1H), 8.96 (s, 1H), 8.47-8.32 (m, 1H), 8.08 (t, J=8.8Hz, 2H), (s, the 1H) .MS-EIm/z of 7.62-7.21 (m, 5H), 6.42 (d, J=5.4Hz, 1H), 6.28:432 (M)+,HR-EI MS Calc’d for C23H14F2N4O3(M+):432.1034,Found:432.1028。
The preparation method of embodiment 6
The fluoro- N of 7- (the fluoro- 4- of 3- ((5- tolylthiophenes [2,3-d] pyrimidine-4-yl) epoxide) phenyl) -4- carbonyls -1,4- two Miscellaneous naphthalene -3- the formamides (6) of hydrogen
2- (1- phenyl-ethylenes) malononitrile
Take acetophenone (3g, 25mmol), malononitrile (3g, 50mmol) and ammonium acetate (1g, 14mmol) molten Stirred in dimethylbenzene, 4ml glacial acetic acid is then added dropwise and flows back and stays overnight, after completion of the reaction, is spin-dried for solvent and obtains Dark oil thing, crude product recrystallizing methanol obtains white crystal 6a (3g, 70%).1H NMR(300MHz, CDCl3)δ7.62–7.45(m,5H),2.68–2.60(m,3H).
4- amino -2- tolylthiophene -3- formonitrile HCNs
Take compound 6a (1.68g, 10mmol), that sulphur powder (480mg, 15mmol) is dissolved in 10ml tetrahydrofurans is molten Liquid, is then added dropwise 20ml sodium acid carbonates (7%aq) and is warming up to 35 DEG C, be stirred overnight, filter after completion of the reaction Sulphur powder is removed, solvent is spin-dried for and obtains yellow oil, pass through column chromatography (petroleum ether：Ethyl acetate=4:1) yellow is obtained Solid powder 6b (1.61g, 80%).1H NMR(300MHz,CDCl3)δ7.66–7.51(m,2H),7.49 –7.30(m,3H),6.37(s,1H),4.87(s,2H).
5- tolylthiophenes [2,3-d] pyrimidine -4 (3H) -one
Take compound 6b (1g, 5mmol) to be dissolved in 5ml formic acid and make solvent, 130 DEG C of backflows 6 are warming up to after being stirred at room temperature h.Question response is spin-dried for solvent after finishing, add 200ml ethyl acetate and PH is adjusted into neutrality, saturated carbon is used respectively Sour hydrogen sodium, saturated common salt water washing, anhydrous magnesium sulfate are dried.It is spin-dried for solvent and obtains pink solid powder, uses acetic acid Ethyl ester is recrystallized to give white solid powder 6c (1.05g, 92%).1H NMR(300MHz,CDCl3)δ11.92 (s, 1H), 7.64-7.50 (m, 2H), 7.50-7.35 (m, 3H), 7.18 (d, J=3.6Hz, 1H)
Chloro- 5- tolylthiophenes [2,3-d] pyrimidines of 4-
Take compound 6c (456mg, 2mmol) be dissolved in 2ml POCl3s be warming up to 110 DEG C flow back 4 hours, reacted After finishing plus reaction solution be added in frozen water it is rapid be quenched and PH be adjusted to neutrality with 2N sodium hydroxide, add acetic acid second Ester extracts and uses saturated sodium bicarbonate, saturated common salt water washing, obtains yellow powder, passes through column chromatography (petroleum ether： Ethyl acetate=4:1) yellow solid powder 6d (470mg, 96%) is obtained.1H NMR(300MHz,CDCl3)δ8.88 (s,1H),7.52–7.34(m,6H).
The fluoro- 4- of 3- ((5- tolylthiophenes [2,3-d] pyrimidine-4-yl) epoxide) aniline
Compound 6d (246mg, 1mmol), the fluoro- PAPs of 2- (254mg, 2mmol) is taken to be dissolved in 1ml DMF Afterwards, it is sufficiently stirred under ice bath and adds sodium hydride (48mg, 2mmol), 2h is reacted at 0 DEG C, after completion of the reaction, DMF is spin-dried for, ethyl acetate is dissolved in and is washed with water, saturated aqueous ammonium chloride.It is spin-dried for after solvent obtaining dark oil Thing, passes through column chromatography (petroleum ether：Ethyl acetate=4:1) brown powder 6e (310mg, 95%) is obtained.1H NMR(300 MHz,CDCl3) δ 8.64 (d, J=1.7Hz, 1H), 7.67-7.56 (m, 2H), 7.48-7.29 (m, 4H), 6.96-6.83 (m, 1H), 6.50 (dd, J=11.8,2.5Hz, 1H), 6.42 (ddd, J=8.6,2.6,1.2Hz, 1H), 3.76 (s, 2H)
The fluoro- N of 7- (the fluoro- 4- of 3- ((5- tolylthiophenes [2,3-d] pyrimidine-4-yl) epoxide) phenyl) -4- carbonyls -1,4- two Miscellaneous naphthalene -3- the formamides of hydrogen
By compound 1e (103mg, 0.5mmol), HOBt (191mg, 0.5mmol) and EDCI (67mg, 0.5 Mmol) DIEA (120 μ l, 0.6mmol) is dissolved in DMF and stirs 0.5h at room temperature.Then 6e (163mg, 0.5 are added Mmol) 80 DEG C of reaction 3h, add 100ml ethyl acetate after completion of the reaction, then with water, saturated aqueous ammonium chloride and Saturated sodium-chloride water solution is washed.It is spin-dried for after solvent obtaining yellow oil, passes through column chromatography (methanol：Dichloromethane =1:50) white powder 6 (131mg, 50%) is obtained.1H NMR(300MHz,d6-DMSO)δ12.56(s,1H), 8.94(s,1H),8.69(s,1H),8.38(s,1H),8.06–7.87(m,2H),7.69(s,2H), 7.49 (d, J=34.2Hz, 7H)13C NMR(100MHz,d6-DMSO)δ176.18,170.34,163.37, 163.10,153.33,145.70,141.17,141.04,138.10,138.00,135.61,135.14, 134.48,134.35,125.42,124.89,123.36,116.42,114.85,114.62,110.90, 108.57,108.33,105.21,104.97.MS-EIm/z:526(M)+,HR-EI MS Calc’d for C26H15F2N5O3S(M+):526.0911,Found:526.0902。
The preparation method of embodiment 7
N- (4- ((6,7- bis- (2- methoxyethoxies) quinolyl-4) oxo) -3- fluorophenyls) -1- cyclopropyl -7- fluorine - 4- oxygen -1,4- EEDQ -3- acid amides (7)
1,2- bis- (2- methoxy ethoxies) -4- nitrobenzene (7a)
By 4- nitros -1,2- phenol (3g, 19.3mmol) and the bromo- 2- Ethyl Methyl Ethers (5.9g, 42.5mmol) of 1- 10mLDMF is dissolved in, with potassium carbonate (8g, 58mmol) to react 16h at 100 DEG C of alkali, DMF is removed after completion of the reaction, It is extracted with ethyl acetate and obtains yellow oil 7a.1H NMR(300MHz,CDCl3) δ 7.81 (dd, J=8.9, 2.6Hz, 1H), 7.71 (d, J=2.6Hz, 1H), 6.88 (d, J=9.0Hz, 1H), 4.21-4.13 (m, 4H), 3.77-3.70 (m, 4H), 3.39 (d, J=2.0Hz, 6H)
3,4- bis- (2- methoxy ethoxies) aniline (7b)
7a (4.65g, 18mmol) is dissolved in 20mL methanol, added under the conditions of 500mg palladium carbons/hydrogen room temperature React 8h.Reaction is finished, and is filtered to remove palladium carbon, is obtained yellow oily 7b by column chromatography, is directly thrown next step.
2- (((3,4- bis- (2- methoxy ethoxies) phenyl) amino) methylene) diethyl malonate (7c)
7b (2.0g, 8.3mmol) is added to 2- (ethoxymeyhylene) diethyl malonate (2.3g, 10mmol) It is heated to reacting 3h at 100 DEG C, is cooled to after room temperature and compound 7c is directly obtained by column chromatography.1H NMR(300MHz, CDCl3) δ 10.83 (d, J=13.7Hz, 1H), 8.29 (d, J=13.7Hz, 1H), 6.79 (d, J =8.5Hz, 1H), 6.64-6.53 (m, 2H), 4.22-3.96 (m, 8H), 3.67-3.57 (m, 4H), 3.30 (d, J=3.3Hz, 6H), 1.21 (dt, J=14.4,7.1Hz, 6H)
6,7- bis- (2- methoxy ethoxies) -4- oxygen -1,4- EEDQ -3- carboxylic acid, ethyl esters (7d)
7c (1.0g, 2.4mmol) is dissolved in phenylate and is heated to reacting 2h at 280 DEG C, is cooled to after room temperature and adds There are a large amount of solids to separate out after bulk petroleum ether, stirring 10min, be filtrated to get brown solid powder, obtained by column chromatography To compound 7d.1H NMR(400MHz,DMSO)δ12.07(s,1H),8.45(s,1H),7.54(s, 1H), 7.08 (s, 1H), 4.21 (s, 6H), 3.74 (s, 4H), 3.36 (s, 6H), 1.28 (d, J=6.4 Hz,3H).
6,7- bis- (2- methoxy ethoxies) -4- oxygen -1,4- EEDQ -3- carboxylic acids (7e)
7d (730mg, 2mmol) is dissolved in 10mL 2N NaOH (aq) solution and 10mL methanol and is heated to 80 DEG C Lower reaction 3h, is cooled to after room temperature and adds 2N HCl (aq), and removing reaction solution after stirring 10min obtains crude product 7e.1H NMR(300MHz,DMSO)δ8.65(s,1H),7.49(s,1H),7.17(s,1H),4.21(s, 4H),3.74(s,4H).
6,7- bis- (2- methoxy ethoxies) quinoline -4 (1 hydrogen) -one (7f)
7e (500mg, 1.7mmol) is dissolved in phenylate heated under microwave conditions to 2h is reacted at 280 DEG C, it is cold But to addition bulk petroleum ether after room temperature, there are a large amount of solids to separate out after stirring 10min, be filtrated to get gray solid powder, Compound 7f is obtained by column chromatography.1H NMR(300MHz,CDCl3)δ12.87(s,1H),7.69(d,J =7.7Hz, 2H), 7.04 (s, 1H), 6.23 (d, J=7.2Hz, 1H), 4.17-4.08 (m, 2H), (t, J=8.9Hz, the 6H) of 4.05-3.97 (m, 2H), 3.77-3.63 (m, 4H), 3.34
4- chloro- 6,7- bis- (2- methoxy ethoxies) quinoline (7g)
Take compound 7f (426mg, 1.5mmol) be dissolved in 2ml POCl3s be warming up to 110 DEG C flow back 4 hours, reaction After finishing plus reaction solution be added in frozen water it is rapid be quenched and PH be adjusted to neutrality with 2N sodium hydroxide, add acetic acid Ethyl ester extracts and uses saturated sodium bicarbonate, saturated common salt water washing, obtains yellow powder, passes through column chromatography (petroleum ether： Ethyl acetate=4:1) yellow solid powder 7g (401mg, 89%) is obtained.
1H NMR(300MHz,CDCl3) δ 8.51 (d, J=4.9Hz, 1H), 7.37 (d, J=3.1Hz, 2H), 7.28 (d, J=4.9Hz, 1H), 4.27 (dd, J=9.3,3.5Hz, 4H), 3.86-3.81 (m, 4H), 3.46 –3.43(m,6H).
4- ((6,7- bis- (2- methoxy ethoxies) quinolyl-4) epoxide) -3- fluoroanilines (7h)
Compound 7h preparation method is similar with compound 4b preparation method, using 7g as raw material, and reaction is finished, and is obtained To 7h.1H NMR(300MHz,CDCl3) δ 8.44 (d, J=5.3Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 6.98 (t, J=8.6Hz, 1H), 6.56-6.41 (m, 2H), 6.38 (d, J=5.3Hz, 1H), (s, the 6H) of 4.29 (dd, J=9.0,4.4Hz, 4H), 3.85 (t, J=4.5Hz, 4H), 3.47
N- (4- ((6,7- bis- (2- methoxyethoxies) quinolyl-4) oxo) -3- fluorophenyls) -1- cyclopropyl -7- fluorine - 4- oxygen -1,4- EEDQ -3- acid amides (7)
The preparation method of compound 7 is similar with the preparation method of compound 4, using 7e as raw material, and reaction is finished, and obtains 7.1H NMR(300MHz,CDCl3) δ 12.25 (s, 1H), 8.82 (s, 1H), 8.39 (t, J=6.6Hz, 2H), 7.89 (dd, J=12.5,1.9Hz, 1H), 7.60-7.51 (m, 2H), 7.32 (d, J=8.7 Hz, 2H), 7.14 (t, J=8.6Hz, 2H), 6.37 (d, J=5.1Hz, 1H), 4.25 (dd, J= 9.7,6.0Hz, 4H), 3.83 (d, J=14.7Hz, 4H), 3.44 (d, J=9.7Hz, 6H), 1.31 (d, J=6.5Hz, 2H), 1.13 (s, 2H) .MS-ESI m/z:632.6(M+H)+；HR-ESI MS calcd for C34H32F2N3O7(M+H)+:632.2208,found:632.2195.
The preparation method of embodiment 8
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) phenyl) -6,7- two (2- methoxy ethoxies) quinoline -4- Oxy-1s, 4- EEDQ -3- formamides (8)
The preparation method of compound 8 is similar with the preparation method of compound 4, using 7e and 4b as raw material, and reaction is finished, Obtain 8.1H NMR(300MHz,CDCl3) δ 12.89 (s, 1H), 8.78 (s, 1H), 8.47 (d, J= 5.3Hz, 1H), 7.97 (dd, J=12.4,1.8Hz, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.38 (d, J=13.7Hz, 2H), 7.21 (dd, J=16.4,7.7Hz, 1H), 6.89 (s, 1H), 6.47 (d, J=5.1Hz, 1H), 4.20 (dd, J=12.6,5.6Hz, 4H), 4.02 (d, J=8.1Hz, 4H), 3.78 (s, 2H), 3.71-3.61 (m, 5H), 3.36 (d, J=26.2Hz, 6H), 2.50 (dd, J =19.8,12.6Hz, 6H), 2.12-2.00 (m, 2H) .MS-ESI m/z:747.3(M+H)+；HR-ESI MS calcd for C39H44FN4O10(M+H)+:747.3041,found:747.3022.
The preparation method of embodiment 9
The fluoro- N- of 7- (the fluoro- 4- of 3- ((thiophene -2- bases) -3H- indoles [4,5-b] pyridin-7-yl) epoxide) phenyl) -4- carbonyls Miscellaneous naphthalene -3- the formamides (9) of base -1,4- dihydros
4- (4- amino -2- fluorophenoxies) -3- nitropyridine -2- amino
Take the fluoro- 4- chlorophenols (508mg, 4mmol) of 2- amino -3- nitro -4- chloropyridines (346mg, 2mmol), 2- It is dissolved in after 1ml DMF, is sufficiently stirred under ice bath and adds potassium tert-butoxide (448mg, 4mmol), 2 are reacted at 0 DEG C H, after completion of the reaction, is spin-dried for DMF, is dissolved in ethyl acetate and is washed with water, saturated aqueous ammonium chloride.It is spin-dried for solvent After obtain dark oil thing, pass through column chromatography (methanol：Dichloromethane=1:50) obtain brown powder 2-9a (310mg, 45%).1H NMR(400MHz,d6- DMSO) δ 7.96 (d, J=5.7Hz, 1H), 7.15 (s, 2H), 6.98 (t, J=9.0Hz, 1H), 6.49 (dd, J=13.2,2.5Hz, 1H), 6.41 (d, J=9.0Hz, 1H), 5.92 (d, J=5.7Hz, 1H), 5.52 (s, 2H)
N- (4- ((2- amino -3- nitropyridine -4- bases) epoxide) 3- fluorophenyls) fluoro- 4- carbonyls -1,4- dihydros of -7- are miscellaneous Naphthalene -3- formamides
By compound 1e (207mg, 1mmol), HATU (380mg, 1mmol) and DIEA (400ul, 1.6mmol) It is dissolved in DMF and stirs 0.5h at room temperature.Then 9a (298mg, 1mmol) reaction 5h are added, are added after completion of the reaction 100ml ethyl acetate, then washed with water, saturated aqueous ammonium chloride and saturated sodium-chloride water solution.It is spin-dried for after solvent Brown oil is obtained, is washed with methanol, acetone solvent and obtains pink powder 9b (253mg, 56%).1H NMR(300 MHz,d6-DMSO)δ12.63(s,1H),8.95(s,1H),8.46–8.34(m,1H),8.14– 7.97 (m, 2H), 7.46 (dt, J=16.8,9.2Hz, 4H), 7.25 (s, 2H), 6.03 (d, J=5.6 Hz,1H).
N- (4- ((2,3- aminopyridine -4- bases) epoxide) 3- fluorophenyls) fluoro- 4- carbonyls-miscellaneous naphthalene -3- of Isosorbide-5-Nitrae-dihydro of -7- Formamide
Take compound 9b (223mg, 0.5mmol) to be dissolved in 50ml ethanol, add 25mg hydroxide palladium carbons, 3h is stirred under atmosphere of hydrogen.Palladium carbon is filtered to remove, solvent is spin-dried for, pale powder is obtained with re-crystallizing in ethyl acetate 9c (200mg, 91%).1H NMR(400MHz,d6-DMSO)δ12.54(s,1H),8.93(s,1H),8.38 (dd, J=9.0,6.2Hz, 1H), 8.00 (dd, J=13.1,2.5Hz, 1H), 7.52 (dd, J=9.7, 2.5Hz, 1H), 7.46-7.35 (m, 2H), 7.23 (d, J=5.7Hz, 1H), 7.14 (t, J=9.0 Hz, 1H), 5.95 (d, J=5.7Hz, 1H), 5.71 (d, J=27.7Hz, 2H), 4.57 (s, 2H)
The fluoro- N- of 7- (the fluoro- 4- of 3- ((thiophene -2- bases) -3H- indoles [4,5-b] pyridin-7-yl) epoxide) phenyl) -4- carbonyls Miscellaneous naphthalene -3- the formamides of base -1,4- dihydros
Take compound 9c (106mg, 0.25mmol) to be dissolved in 1ml nitrobenzene, add excessive 2- thiophene aldehydes, 210 DEG C of 1 hours of stirring of microwave.After completion of the reaction to direct column chromatography (methanol：Dichloromethane=1:50) post is crossed to obtain Brownish compound 9 (50mg, 44%).1H NMR(400MHz,d6-DMSO)δ13.75(s,1H),13.04(s, 1H), 12.59 (d, J=21.7Hz, 1H), 8.95 (d, J=10.5Hz, 1H), 8.39 (dd, J=9.0, 6.2Hz, 1H), 8.12 (dd, J=18.2,9.1Hz, 2H), 7.94 (d, J=3.1Hz, 1H), 7.78 (d, J=4.8Hz, 1H), 7.57-7.48 (m, 2H), 7.48-7.38 (m, 2H), 7.29-7.22 (m, 1H), 6.49 (d, J=5.4Hz, 1H) δ13C NMR(125MHz,d6-DMSO)δ176.23,165.85, 163.86,163.52,162.78,155.00,153.05,145.96,141.43,141.32,133.56, 130.17,129.40,129.32,128.92,128.35,124.36,123.45,116.85,114.87, 114.68,110.89,109.05,108.87,105.38,105.18,103.68. MS-EIm/z:515(M)+,HR-EI MS Calc’d for C26H15F2N5O3S(M+):515.0864,Found: 515.0861
The preparation method of embodiment 10
The fluoro- N- of 7- (the fluoro- 4- of 3- ((2- (1- Methyl-1H-indole -5- bases) thiophene [3,2-b] pyridin-7-yl) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
Thiophene -3- amino
2- methyl esters -3- aminothiophenes (1.0g, 6.3mmol) are dissolved in 2N NaOH, 100 DEG C is warming up to and reacts 2h, it is cold But solvent is spin-dried for after PH being adjusted into 2 to addition 2N HCl after room temperature, single step reaction is directly cast.
Not purified compound is dissolved in 10ml isopropanols and excessive oxalic acid, 45min is reacted at room temperature, is reacted Cooled the temperature to after finishing and substantial amounts of ether is added after 0 DEG C just have solid precipitation, be then filtrated to get compound 10a (320mg, 45%)1H-NMR(400MHz,CDCl3):δ7.13-7.11(m,1H),6.65-6.63(m,1H), 6.17-6.16(m,1H),3.60(brs,2H).
2,2- dimethyl -5- ((thiophene -3- amino) methylene) -1,3- dioxane -4,6- diketone
Malonic acid ring (Asia) isopropyl ester (1.44g, 10mmol) is dissolved in isopropanol and then triethyl orthoformate is added, risen Temperature is to 100 DEG C of reaction 1h, and being cooled to after room temperature just has a large amount of solids to separate out, and is filtrated to get compound as white solid, not It is purified directly to cast single step reaction.By compound 10a (990mg, 10mmol) and the unpurified compound of upper step (2.5g, 12mmol) is dissolved in 5ml isopropanols, then heats to after backflow, reaction 0.5h, stops reaction cooling To room temperature, have a large amount of solids and produce, filtering can obtain white powder 10b (2.4g, 82%)
Thiophene [3,2-b] pyridine -7 (4H) -one
Compound 10b (1.1g, 10mmol) is dissolved in 10ml diphenyl ether and then heats to 240 DEG C of reaction 30min, instead Cooled the temperature to after should finishing and substantial amounts of petroleum ether is added after 0 DEG C just have solid precipitation, be then filtrated to get brown solid 10c (2g, 53%)1H-NMR(300MHz,d6- DMSO) δ 12.15 (brs, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.82 (d, J=10.8Hz, 1H), 7.24 (d, J=7.8Hz, 1H), 6.01 (d, J=10.8Hz, 1H).
7- chlorothiophenes [3,2-b] pyridine
Compound 10c (2.5g, 16mmol) is dissolved in 5ml acetonitriles and then 2ml POCl3s are added to 90 DEG C of reactions 90 Min, adds substantial amounts of ice cube after temperature is dropped into room temperature after completion of the reaction, is then extracted and passed through with ethyl acetate Column chromatography obtains 10d (1.5g, 63%)1H-NMR(300MHz,d6- DMSO) δ 8.23 (d, J=8.4Hz, 1H), (d, J=10.8Hz, the 1H) of 7.72 (d, J=10.8Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 6.12
Chloro- 2- iodos thiophene [3,2-b] pyridines of 7-
Compound 10d (1.5g, 8.8mmol) is dissolved in 5ml THF and then -70 DEG C are cooled to, after stirring 20min by It is added dropwise to n-BuLi (2.5M in hexane, 6ml, 14mmol) reactions 1h.Then iodine powder is dissolved in THF dropwise It is added in reaction system and reacts 1h, adds substantial amounts of ice cube after temperature is dropped into room temperature after completion of the reaction, then use second Acetoacetic ester is extracted and obtains 10e (1.5g, 63%) by column chromatography1H-NMR(300MHz,d6-DMSO)δ (d, J=7.2Hz, the 1H) of 8.32 (d, J=7.2Hz, 1H), 7.68 (d, J=9Hz, 1H), 7.24
The chloro- 2- of 7- (1- Methyl-1H-indole -5- bases) thiophene [3,2-b] pyridine
N- methylimidazoles (4.0mL, 50mmol) are dissolved in 50ml THF and then -78 DEG C, stirring 30min are cooled to After be added dropwise n-BuLi (2.5M in hexane, 22M ml, 55mmol) reaction 1h.Then by tetrabutyl diformazan Base stannic chloride is added dropwise in reaction system in THF reacts 30min, then is warmed to room temperature reaction 24h.After completion of the reaction Substantial amounts of saturated aqueous ammonium chloride is added, is then extracted with ethyl acetate, anhydrous magnesium sulfate is dried to obtain thick production Product (6.2g, 65%), not purified direct throwing next step.By 10e (1.12g, 3.79mmol) and crude product (1.57g, 4.22mmol) it is dissolved in 10ml DMF and then adds Pd (Ph3P)4(219mg, 0.189mmol, 5mol%) anhydrous nothing Oxygen is operated, and is warming up to 90 DEG C of reaction 22h.1N hydrochloric acid solution is added after completion of the reaction, is then carried out with dichloromethane Extraction, anhydrous magnesium sulfate is dried and obtains product 10f (0.73g, 45%) by column chromatography.1H NMR(300MHz, CD3OD) δ 8.57 (t, J=4.7Hz, 1H), 7.85 (s, 1H), 7.68-7.61 (m, 1H), 7.44 (dd, J=9.7,5.5Hz, 2H), 3.94 (s, 3H)
The fluoro- 4- of 3- ((2- (1- Methyl-1H-indole -5- bases) thiophene [3,2-b] pyridin-7-yl) epoxide) aniline
Compound 10g preparation method is similar with compound 4b preparation method, using 10f as raw material, and reaction is finished, Obtain 10g
The fluoro- N- of 7- (the fluoro- 4- of 3- ((2- (1- Methyl-1H-indole -5- bases) thiophene [3,2-b] pyridin-7-yl) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 10 is similar with the preparation method of compound 4, using 10g as raw material, and reaction is finished, and is obtained To 10.1H NMR(300MHz,DMSO)δ12.62(s,1H),8.94(s,1H),8.55(s,1H), 8.40 (s, 1H), 8.09 (d, J=12.7Hz, 1H), 7.83 (d, J=26.9Hz, 2H), 7.48 (d, J=33.5Hz, 4H), 6.71 (s, 1H), 3.91 (s, 3H) .MS-ESI m/z:530.2(M+H)+；HR-ESI MS calcd for C27H18F2N5O3S(M+H)+:530.1098found:530.1113.
The preparation method of embodiment 11
The fluoro- N- of 7- (the fluoro- 4- of 3- ((3- (4- methylpiperazine-1-yls) propyl group) amino) pyridin-4-yl) epoxide) phenyl -4- Miscellaneous naphthalene -3- the formoxyls (11) of carbonyl -1,4- dihydros
4- (the fluoro- 4-nitrophenoxys of 2-) picolinamide
2- acetyl group -4- chloropyridines and 4- nitro -2- fluorophenols (4.0mL, 50mmol) are dissolved in 10ml DMF, so Afterwards using potassium tert-butoxide as alkali, 80 DEG C of reaction 2h are warming up to.Solvent is removed after completion of the reaction, is then carried out with ethyl acetate Extraction, anhydrous magnesium sulfate is dried and obtains product 11a (0.73g, 45%) by column chromatography.1H NMR(300MHz, CDCl3) δ 8.16-7.95 (m, 3H), 7.24 (t, J=8.4Hz, 1H), 6.29 (dd, J=5.8, 2.0Hz, 1H), 6.04 (d, J=1.7Hz, 1H)
4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- aniline
Compound 11a (47mg, 0.1mmol) is dissolved in ethyl acetate：Acetonitrile：Water is respectively 2:2:1 mixing is molten In agent, iodobenzene acetate (65mg, 0.2mmol) is added under ice-water bath, reaction 2h is warmed to room temperature, after completion of the reaction, Ethyl acetate 50ml is added, respectively with saturated sodium bicarbonate, saturated common salt water washing obtains brown oil, led to Cross column chromatography and obtain light red powder 11b (660mg, 95%).1H NMR(300MHz,DMSO)δ8.41(dd,J =10.5,2.6Hz, 1H), 8.22-8.14 (m, 1H), 7.90 (d, J=5.8Hz, 1H), 7.58- 7.48 (m, 1H), 6.27 (dd, J=5.7,2.3Hz, 1H), 6.12 (s, 2H), 6.00 (d, J=2.2 Hz,1H).
The chloro- N- of 3- (4- (the fluoro- 4- nitrobenzophenones of 2-) pyridine -2- bases) propionamide
3- chlorpromazine chlorides (400 μ L, 5mmol) and 11b are dissolved in 5ml (1g, 4mmol) dichloromethane, so Afterwards using triethylamine as alkali, 12h is reacted at room temperature.Solvent is removed after completion of the reaction, is then extracted with ethyl acetate, Anhydrous magnesium sulfate is dried and obtains product 11c (781mg, 75%) by column chromatography.1H NMR(400MHz,CDCl3) δ 9.08 (s, 1H), 8.24 (d, J=5.7Hz, 1H), 8.16 (t, J=6.8Hz, 2H), 7.94 (s, 1H), 7.36 (t, J=8.4Hz, 1H), 6.76 (d, J=5.6Hz, 1H), 3.91-3.81 (m, 2H), 2.93–2.82(m,2H).
N- (4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- bases) -3- (4- methylpiperazine-1-yls) propionamide
11c (1.02g, 44mmol) and N methyl piperazine (410 μ L, 4mmol) are dissolved in 5mL DMF, so Afterwards using triethylamine as alkali, to 80 DEG C of reaction 12h under heating.Solvent is removed after completion of the reaction, is then entered with ethyl acetate Row extraction, anhydrous magnesium sulfate is dried and obtains product 11d (732mg, 85%) by column chromatography.1H NMR(300MHz, CDCl3) δ 11.33 (s, 1H), 8.22 (d, J=5.7Hz, 1H), 8.08 (ddd, J=6.4,3.9, 1.9Hz, 2H), 7.84 (d, J=2.1Hz, 1H), 7.30-7.22 (m, 1H), 6.65 (dd, J= 5.7,2.3Hz,1H),2.75–2.67(m,3H),2.58(s,6H),2.53–2.44(m,3H), 2.34(s,3H).
N- (4- (the fluorine-based phenoxy groups of 4- amino -2-) pyridine -2- bases) -3- (4- methylpiperazine-1-yls) propionamide
Take compound 11d (887mg, 2.9mmol) to be dissolved in 5ml THF, Lithium Aluminium Hydride added under condition of ice bath, 2h is reacted in heating at room temperature.Solid is filtered to remove, solvent is spin-dried for, product is obtained with ethyl acetate and by column chromatography 11e (411mg, 48%).1H NMR(300MHz,CDCl3) δ 8.28 (d, J=5.1Hz, 1H), 8.02 (dd, J=6.9,3.9Hz, 2H), 7.84 (d, J=2.1Hz, 1H), 7.30-7.22 (m, 1H), 6.65 (d, J=5.1Hz, 1H), 3.32 (m, 2H), 2.81-2.67 (m, 3H), 2.58 (s, 6H), 2.53–2.44(m,3H),2.34(s,3H).
4- (4- amino -2- fluorophenoxies)-N- (3- (4- methylpiperazine-1-yls) propyl group) pyridine -2- aniline
Take compound 11e (407mg, 1mmol) to be dissolved in 50ml ethanol, 40mg hydroxide palladium carbons are added, in hydrogen Atmosphere encloses lower stirring 12h.Palladium carbon is filtered to remove, solvent is spin-dried for, pale powder 11f is obtained with re-crystallizing in ethyl acetate (359mg, 84%).MS-ESI m/z:360(M+H)+
The fluoro- N- of 7- (the fluoro- 4- of 3- ((3- (4- methylpiperazine-1-yls) propyl group) amino) pyridin-4-yl) epoxide) phenyl -4- Miscellaneous naphthalene -3- the formoxyls of carbonyl -1,4- dihydros
The preparation method of compound 11 is similar with the preparation method of compound 4, using 11f as raw material, and reaction is finished, and is obtained To 11.1H NMR(300MHz,d6- DMSO) δ 12.71 (s, 1H), 8.97 (s, 1H), 8.49 (d, J= 5.2Hz, 1H), 8.44-8.34 (m, 1H), 8.11 (d, J=13.1Hz, 1H), 7.62-7.36 (m, 6H), 6.50 (d, J=5.3Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.61 (s, 4H), (s, the 3H) of 2.49 (dd, J=16.1,14.4Hz, 6H), 3.32 (m, 2H), 2.51 (m, 2H), 2.34 MS-ESI m/z:549.3(M+H)+；HR-ESI MS calcd for C29H30F2N6O3(M+H)+:549.2347found: 549.2352.
The preparation method of embodiment 12
N- benzyls -6- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) -4- carbonyls -1,4- two Miscellaneous naphthalene -3- the formoxyls (12) of hydrogen
4- acetoxyl group -2- fluobenzoic acids
The fluoro- 4-HBAs of 2- (936mg, 6mmol) are dissolved in 20ml pyridine, then add excessive second Acid anhydrides, is heated to 70 DEG C of reaction 6h, and reaction finishes, is spin-dried for solvent, carried out being recrystallized to give white powder with acetone 12a (1.02g, 92%).1H NMR (400MHz, CD3OD) δ 7.99 (dd, J=12.1,5.2Hz, 1H), 7.12–7.03(m,2H),2.31(s,3H).
(Z)-ethyl 2- (4- acetoxyl group -2- fluoro benzoyls) -3- (dimethylamino) acrylate
Take compound 12a (1g, 5.04mmol) to be dissolved in 3ml thionyl chlorides, be heated to 80 DEG C and flow back 2 hours, reaction After finishing, solvent is spin-dried for, oily compound 12a acyl chlorides is obtained.Previous step compound is quickly dissolved in dry first In benzene, and add 3- (dimethylamino) ethyl acrylate (1g, 7mmol), triethylamine (1.01g, 10mmol) 90 DEG C are heated to, 12h is sufficiently stirred for, room temperature is cooled to, solvent is spin-dried for, ethyl acetate is dissolved in and is washed with water repeatedly, Pass through column chromatography gradient elution (petroleum ether after concentration：Ethyl acetate=10:1 to 2:1) yellow oily compound is taken 12b (1.31g, 81%).1H NMR(300MHz,d6- DMSO) δ 8.51 (s, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 6.85 (d, J=8.5Hz, 2H), 6.35 (d, J=8.9 Hz, 1H), 6.14 (s, 1H), 5.23 (s, 2H), 4.18 (q, J=7.1Hz, 2H), 3.83-3.65 (m, 3H), 1.27 (t, J=7.1Hz, 3H)
(Z)-ethyl -2- (4- acetoxyl group -2- fluoro benzoyls) -3- ((4- methoxy-benzyls) amino) acrylate
12b (970mg, 3mmol) is taken to be dissolved in ether：Ethanol (1:3) in the mixed solvent, then will be to methoxyl group Benzylamine (548mg, 4mmol) is added dropwise in reaction solution, and being stirred at room temperature 15 minutes has substantial amounts of white solid powder Separate out, yellow solid powder is collected by filtration and is washed again with ethanol, white solid powder 12c (1.0g, 88%) is obtained.1H NMR(300MHz,d6- DMSO) δ 8.81 (s, 1H), 8.09 (d, J=8.8Hz, 1H), 7.43- 7.26 (m, 3H), 7.22 (d, J=7.4Hz, 2H), 6.88 (d, J=8.8Hz, 1H), 6.80 (s, 1H), (t, J=7.1Hz, the 3H) of 5.56 (s, 2H), 4.23 (q, J=7.0Hz, 2H), 1.29
Miscellaneous naphthalene -3- the formamides of ethyl -7- hydroxyls -1- (4- methoxy-benzyls) -4- carbonyl -1,4- dihydros
12c (710mg, 2.0mmol) is taken to be dissolved in 5ml DMF and add under potassium carbonate (414mg, 3mmol) oil bath 80 DEG C of heating 1h, are filtered to remove after potassium carbonate, are spin-dried for DMF and add 200ml ethyl acetate and organic phase washed with water, Saturated common salt water washing, anhydrous magnesium sulfate is dried.Filtering is spin-dried for after solvent obtaining pale yellow powder, uses acetone recrystallization After obtain white powder 12d (620mg, 90%).1H NMR(300MHz,CDCl3) δ 8.52 (dd, J=10.5, 8.1Hz, 2H), 7.17-6.95 (m, 4H), 6.89 (d, J=8.7Hz, 2H), 5.26 (s, 2H), (t, J=7.1Hz, the 3H) of 4.39 (q, J=7.1Hz, 2H), 3.79 (s, 3H), 1.40
Miscellaneous naphthalene -3- the carboxylic acids of dihydro of 7- hydroxyls -1- (4- methoxy-benzyls) -4- carbonyls -1,4
Compound 12d (600mg, 1.7mmol) is dissolved in 10ml 6N hydrochloric acid, and adds 10ml ethanol 80 DEG C of backflows are stayed overnight, and have substantial amounts of white powder to separate out, and are spin-dried for solvent and are directly used acetone recrystallization, obtain white powder 12e (510mg, 92%).1H NMR(400MHz,CD3OD)δ15.52(s,1H),11.02(s,1H),9.13 (s, 1H), 8.25-8.18 (m, 1H), 7.22 (d, J=8.7Hz, 2H), 7.07 (dd, J=7.1, 2.2Hz,2H),6.96–6.89(m,2H),5.64(s,2H),3.72(s,3H).
Benzyl -1- (4- methoxy-benzyls) -4- carbonyls -7- ((the positive phosphorus base of three (pyrrolidin-1-yls)) epoxide) -1,4- two Miscellaneous naphthalene -3- the formamides of hydrogen
By compound 12e (325mg, 1mmol), PyBOP (624mg, 1.2mmol) and DIEA (195mg, 1.5 Mmol DMF) is dissolved in, reaction 1h is stirred at room temperature, benzylamine (214mg, 2mmol) is then added and is stirred overnight at room temperature, After completion of the reaction, add 200ml ethyl acetate and washed with saturated ammonium chloride solution, the saturated common salt aqueous solution, it is anhydrous Magnesium sulfate is dried.It is spin-dried for solvent and obtains yellow oily compound 12f directly throwing next step.
N- benzyl -7- hydroxyls -1- (4- methoxy-benzyls) -4- carbonyls -- the miscellaneous naphthalene -3- formamides of 1,4- dihydros
12f (325mg, 0.5mmol) is taken to be dissolved in 5ml DMF and add under potassium carbonate (138mg, 1mmol) oil bath 80 DEG C of heating 12h, are filtered to remove after potassium carbonate, are spin-dried for DMF and add 200ml ethyl acetate and organic phase is used successively Water, saturated common salt water washing, anhydrous magnesium sulfate is dried.Filtering is spin-dried for after solvent obtaining pale yellow powder, uses acetone weight White powder 12g (400mg, 95%) is obtained after crystallization.1H NMR(300MHz,d6-DMSO)δ10.48(s,1H), 8.97 (s, 1H), 8.16 (d, J=8.9Hz, 1H), 7.54-7.08 (m, 6H), 7.04-6.88 (m, 3H), 5.56 (s, 2H), 4.57 (d, J=5.6Hz, 2H), 3.73 (s, 3H)
N- benzyls -6- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) -1- (4- methoxybenzyls Base) the miscellaneous naphthalene -3- formoxyls of -4- carbonyl -1,4- dihydros
The 12h same 4b of synthesis, initiation material is 12g and 4a.Column chromatography obtains pale solid, is directly used in next step.
N- benzyls -6- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) -4- carbonyls -1,4- two Miscellaneous naphthalene -3- the formoxyls of hydrogen
Compound 12h (58mg, 0.1mmol) is dissolved in 2ml trifluoracetic acid, 100 DEG C are heated to, 24h is reacted, After completion of the reaction, 2N sodium hydrate aqueous solutions are added dropwise, PH is tuned into neutrality, is then extracted with ethyl acetate, Saturated ammonium chloride solution, saturated common salt water washing are used respectively, and anhydrous magnesium sulfate is dried.It is spin-dried for column chromatography and obtains 12.1H NMR (300MHz,d6- DMSO) δ 11.66 (s, 1H), 8.99 (s, 1H), 8.49 (d, J=5.4Hz, 1H), 8.23 (t, J=5.4Hz, 1H), 7.45-7.32 (m, 4H), 7.31-7.25 (m, 2H), 7.15 (dd, J=8.9,2.2Hz, 1H), 7.07-6.99 (m, 3H), 6.88-6.82 (m, 2H), 6.69 (d, J=5.3Hz, 1H), 5.33 (s, 2H), 4.22 (s, 2H), 3.97 (s, 3H), 3.61 (s, 4H), 2.49 (dd, J=16.1,14.4Hz, 6H), 2.00 (s, 2H)
The preparation method of embodiment 13
N- (3- fluoro- 4 ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- nitros Miscellaneous naphthalene -3- the formamides (13) of -4- carbonyl -1,4- dihydros
Miscellaneous naphthalene -3- the carboxylic acids of 7- nitro -4- carbonyl -1,4- dihydros
Compound 13a preparation method is similar with compound 1e preparation method, using the fluoro- 4- nitrobenzoic acids of 2- as original Material, obtains 13a.1H NMR (300MHz, DMSO) δ 9.15 (s, 1H), 8.68 (d, J=2.1Hz, 1H), 8.53 (d, J=8.9Hz, 1H), 8.31 (dd, J=8.9,2.2Hz, 1H)
N- (3- fluoro- 4 ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- nitros Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 13 is similar with the preparation method of compound 4, using 13a and 4b as raw material, and reaction is finished, Obtain 13.1H NMR(300MHz,DMSO)δ12.67(s,1H),9.12(s,1H),8.55(dd,J =21.5,12.5Hz, 3H), 8.18 (dd, J=33.8,10.7Hz, 2H), 7.49 (dd, J=24.8, 16.2Hz,4H),6.52(s,1H),4.22(s,2H),3.97(s,3H),3.63(s,4H),2.53 (s,6H),2.02(s,2H).MS-ESI m/z:644.2(M+H)+；HR-ESI MS calcd for C33H31FN5O8(M+H)+:644.2157,found:632.2149.
The preparation method of embodiment 14
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- trifluoros Miscellaneous naphthalene -3- the formamides (14) of methyl -4- carbonyl -1,4- dihydros
Miscellaneous naphthalene -3- the carboxylic acids of 4- carbonyls -7- (trifluoromethyl) -1,4- dihydros
Compound 14a preparation method is similar with compound 1e preparation method, with the fluoro- 4- trifluoromethylbenzoic acids of 2- For raw material, 14a is obtained.
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- trifluoros Miscellaneous naphthalene -3- the formamides of methyl -4- carbonyl -1,4- dihydros
The preparation method of compound 14 is similar with the preparation method of compound 4, using 14a and 4b as raw material, and reaction is finished, Obtain 14.1H NMR (300MHz, DMSO) δ 12.61 (s, 1H), 9.09 (s, 1H), 8.52 (dd, J= 13.4,6.8Hz, 2H), 8.12 (d, J=16.2Hz, 2H), 7.85 (d, J=8.5Hz, 1H), 7.62 - 7.38 (m, 4H), 6.51 (d, J=4.5Hz, 1H), 4.23 (t, J=6.3Hz, 2H), 3.97 (s, 3H),3.62(s,4H),2.52(s,6H),2.06–1.94(m,2H).MS-ESI m/z:667.2(M+H)+； HR-ESI MS calcd for C34H31F4N4O6(M+H)+:667.2180found:667.2198.
The preparation method of embodiment 15
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- hydroxyls Miscellaneous naphthalene -3- the formamides (15) of -4- carbonyl -1,4- dihydros
7- hydroxyl -4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 15a preparation method is similar with compound 1e preparation method, with the fluoro- 4- trifluoromethylbenzoic acids of 2- For raw material, 15a. is obtained1H NMR(300MHz,DMSO)δ13.09(s,1H),10.93(s,1H),8.81 (m, the 2H) of-8.72 (m, 1H), 8.15 (d, J=8.7Hz, 1H), 7.12-6.99
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- hydroxyls Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 15 is similar with the preparation method of compound 4, using 15a and 4b as raw material, and reaction is finished, Obtain 15.1H NMR (300MHz, DMSO) δ 12.91 (s, 1H), 8.78 (s, 1H), 8.49 (d, J= 5.2Hz, 1H), 8.20-8.06 (m, 2H), 7.57-7.41 (m, 4H), 7.01 (dd, J=11.1, 2.3Hz, 2H), 6.50 (d, J=5.3Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.63- (d, J=6.7Hz, 2H) the .MS-ESI m/z of 3.59 (m, 4H), 2.43 (s, 6H), 1.99:615.2(M+H)+； HR-ESI MS calcd for C33H32FN4O7(M+H)+:615.2266found:615.2255.
The preparation method of embodiment 16
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- methoxies Miscellaneous naphthalene -3- the formamides (16) of base -4- carbonyl -1,4- dihydros
7- methoxyl group -4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 16a preparation method is similar with compound 1e preparation method, with the fluoro- 4- trifluoromethylbenzoic acids of 2- For raw material, with reference to right 6-1) in quinolone acid parent nucleus synthetic route, reaction finishes, and obtains 16a.1H NMR(300 MHz, DMSO) δ 13.01 (s, 1H), 8.84 (m, 1H), 8.42 (d, J=8.7Hz, 1H), 7.22- 7.03(m,2H),4.01(s,3H).
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- methoxies Miscellaneous naphthalene -3- the formamides of base -4- carbonyl -1,4- dihydros
The preparation method of compound 16 is similar with the preparation method of compound 4, using 16a and 4b as raw material, and reaction is finished, Obtain 16.1H NMR (300MHz, DMSO) δ 12.84 (s, 1H), 8.84 (s, 1H), 8.49 (t, J= 5.3Hz, 1H), 8.24 (d, J=9.0Hz, 1H), 8.10 (d, J=15.3Hz, 1H), 7.59-7.43 (m, 4H), 7.23-7.12 (m, 2H), 6.51 (d, J=5.1Hz, 1H), 4.23 (t, J=6.1Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.63 (d, J=4.5Hz, 4H), 2.66-2.52 (m, 6H),2.03(s,2H).MS-ESI m/z:629.2(M+H)+；HR-ESI MS calcd for C34H34FN4O7(M+H)+: 629.2412found:629.2397.
The preparation method of embodiment 17
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- bromines Miscellaneous naphthalene -3- the formamides (17) of -4- carbonyl -1,4- dihydros
The bromo- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 7-
Compound 17a preparation method is similar with compound 1e preparation method, using the fluoro- 4- tribromos benzoic acid of 2- as original Material, obtains 17a.1H NMR (300MHz, DMSO) δ 8.95 (s, 1H), 8.22 (d, J=8.8Hz, 1H), 8.02 (s, 1H), 7.75 (d, J=9.0Hz, 1H)
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -7- bromines Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 17 is similar with the preparation method of compound 4, using 17a and 4b as raw material, and reaction is finished, Obtain 17.1H NMR (300MHz, DMSO) δ 12.60 (s, 1H), 8.96 (s, 1H), 8.50 (d, J= 5.2Hz, 1H), 8.25 (d, J=8.7Hz, 1H), 8.11 (d, J=12.7Hz, 1H), 7.98 (d, J=9.5Hz, 1H), 7.72 (dd, J=8.4,1.1Hz, 1H), 7.58-7.39 (m, 5H), 6.51 (d, J=5.2Hz, 1H), 4.23 (d, J=5.9Hz, 2H), 3.97 (s, 3H), 3.67 (s, 4H), 2.71 (dd, J=27.5,12.4Hz, 6H), 2.07 (s, 2H) .MS-ESI m/z:675.3(M-H)-；HR-ESI MS calcd for C33H31FN4O6Br(M+H)+:677.1411,found:677.1395.
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -6- hydroxyls Miscellaneous naphthalene -3- the formamides (18) of -4- carbonyl -1,4- dihydros
6- hydroxyl -4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 18a preparation method is similar with compound 1e preparation method, using the fluoro- 5- hydroxybenzoic acids of 2- as original Material, with reference to right 6-1) in quinolone acid parent nucleus synthetic route, reaction finishes, and obtains 18a.1H NMR(300MHz, DMSO) δ 9.15 (s, 1H), 8.68 (d, J=2.1Hz, 1H), 8.53 (d, J=8.9Hz, 1H), 8.31 (dd, J=8.9,2.2Hz, 1H)
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -6- hydroxyls Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 18 is similar with the preparation method of compound 4, using 18a and 4b as raw material, and reaction is finished, Obtain 18.1H NMR (300MHz, DMSO) δ 12.94 (d, J=14.9Hz, 2H), 10.16 (s, 1H), 8.80 (s, 1H), 8.51 (d, J=5.2Hz, 1H), 8.12 (d, J=13.8Hz, 1H), 7.69- 7.43 (m, 6H), 7.33 (d, J=9.1Hz, 1H), 6.53 (d, J=5.2Hz, 1H), 4.26 (s, 2H),3.98(s,3H),3.68(s,4H),2.52(s,6H),2.25–2.01(m,2H).MS-ESI m/z:615.2(M+H)+；HR-ESI MS calcd for C33H32FN4O7(M+H)+:615.2255found: 615.2269.
The preparation method of embodiment 19
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls Miscellaneous naphthalene -3- the formamides (19) of -6- hydroxyl -4- carbonyl -1,4- dihydros
6- fluorin-4-oxygens generation -1,4- EEDQ -3- carboxylic acids (19a)
Compound 19a preparation method is similar with compound 1e preparation method, with 2,5- difluoro-benzoic acids for raw material, Reaction is finished, and obtains 19a
6- hydroxy-ns-(the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 19 is similar with the preparation method of compound 4, using 19a and 4b as raw material, and reaction is finished, Obtain 19.1H NMR (400MHz, DMSO) δ 12.66 (s, 1H), 8.93 (s, 1H), 8.48 (d, J= 5.2Hz, 1H), 8.09 (d, J=12.9Hz, 1H), 7.96 (d, J=7.5Hz, 1H), 7.85 (dd, J=9.0,4.5Hz, 1H), 7.74 (t, J=8.7Hz, 1H), 7.53 (d, J=8.2Hz, 2H), 7.50 - 7.39 (m, 2H), 6.49 (d, J=5.2Hz, 1H), 4.21 (t, J=6.3Hz, 2H), 3.96 (s, 3H), 3.60 (t, J=4.0Hz, 4H), 2.47 (s, 2H), 2.41 (s, 4H), 2.04-1.94 (m, 2H).MS-ESI m/z:617.2(M+H)+；HR-ESI MS calcd for C33H31FN4O6(M+H)+:617.2212, found:617.2210
The preparation method of embodiment 20
The fluoro- N- of 5- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides (20) of -4- carbonyl -1,4- dihydros
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 5-
Compound 20a preparation method is similar with compound 1e preparation method, and with 2,6-difluoro-benzoic acid is original Material, reaction is finished, and obtains 20a.1H NMR(300MHz,DMSO)δ13.48(s,1H),8.89(s,1H), (m, the 1H) of 7.92-7.82 (m, 1H), 7.64 (d, J=8.4Hz, 1H), 7.39-7.29
The fluoro- N- of 5- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 20 is similar with the preparation method of compound 4, using 20a and 4b as raw material, and reaction is finished, 20.1H NMR (400MHz, DMSO) δ 12.59 (s, 1H), 8.85 (s, 1H), 8.49 (s, 1H) are obtained, 8.10 (d, J=13.1Hz, 1H), 7.78 (s, 1H), 7.50 (d, J=49.8Hz, 5H), 7.25 (s, 1H), 6.51 (s, 1H), 4.25 (s, 2H), 3.97 (s, 3H), 3.68 (d, J=63.0Hz, 4H), 3.34 (s,4H),2.18(s,2H),1.27(s,4H).MS-ESI m/z:617.2(M+H)+；HR-ESI MS calcd for C33H31F2N4O6(M+H)+:617.2212found:617.2204.
The preparation method of embodiment 21
The fluoro- N- of 8- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides (21) of -4- carbonyl -1,4- dihydros
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 8-
Compound 21a preparation method is similar with compound 1e preparation method, and with 2,3-difluoro-benzoic acid is original Material, reaction is finished, and obtains 21a.1H NMR(300MHz,DMSO)δ13.46(s,1H),8.98(s,1H), (m, the 1H) of 7.96-7.88 (m, 1H), 7.45 (d, J=8.4Hz, 1H), 7.48-7.41
The fluoro- N- of 8- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 21 is similar with the preparation method of compound 6, using 21a and 6b as raw material, and reaction is finished, Obtain 21.1H NMR (300MHz, DMSO) δ 12.63 (s, 1H), 8.78 (s, 1H), 8.50 (d, J= 5.3Hz, 1H), 8.20-8.08 (m, 2H), 7.76 (d, J=10.5Hz, 1H), 7.60-7.38 (m, 5H), 6.51 (d, J=5.3Hz, 1H), 4.23 (t, J=6.2Hz, 2H), 3.97 (s, 3H), 3.64(s,4H),2.76–2.54(m,6H),2.03(s,2H).MS-ESI m/z:617.2(M+H)+； HR-ESI MS calcd for C39H41F2N4O6(M+H)+:617.2212found:617.2222.
The preparation method of embodiment 22
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls Miscellaneous naphthalene -3- the formamides (22) of -1,4- dihydros
4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 22a preparation method is similar with compound 1e preparation method, and with 2,3-difluoro-benzoic acid is original Material, reaction is finished, and obtains 22a.1H NMR(300MHz,DMSO)δ13.39(s,1H),8.92(s,1H), (d, J=11.4Hz, the 1H) of 8.56 (d, J=5.1Hz, 1H), 8.32 (d, J=8.4Hz, 1H), 7.92
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls Miscellaneous naphthalene -3- the formamides of -1,4- dihydros
The preparation method of compound 22 is similar with the preparation method of compound 4, using 22a and 4b as raw material, and reaction is finished, Obtain 22.1H NMR (300MHz, DMSO) δ 12.79 (s, 1H), 8.93 (s, 1H), 8.50 (d, J= 5.3Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.13 (d, J=12.3Hz, 1H), 7.81 (dd, J=15.4,7.8Hz, 2H), 7.64-7.38 (m, 5H), 6.51 (d, J=5.3Hz, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.61 (s, 4H), 2.44 (d, J=15.6Hz, 6H), 2.01 (d, J =6.4Hz, 2H) .MS-ESI m/z:599.2(M+H)+；HR-ESI MS calcd for C39H41F2N4O6(M+H)+: 599.2306found:599.2306.
The preparation method of embodiment 23
7,8- bis- fluoro- N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides (23) of -4- carbonyl -1,4- dihydros
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 7,8- bis-
Compound 23a preparation method is similar with compound 1e preparation method, with 2, and 3,4-trifluoro-benzoic acid is Raw material, obtains 23a.1H NMR(300MHz,DMSO)δ8.84(s,1H),8.17–8.06(m,1H), 7.56 (dd, J=16.4,9.4Hz, 1H)
7,8- bis- fluoro- N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 23 is similar with the preparation method of compound 4, using 23a and 4b as raw material, and reaction is finished, Obtain 23.MS-ESI m/z:635.2(M+H)+；HR-ESI MS calcd for C33H30F3N4O6(M+H)+:635.2117 found:635.2132.
The preparation method of embodiment 24
The fluoro- N- of 6,7- bis- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides (24) of -4- carbonyl -1,4- dihydros
6,8- bis- fluoro- 4- carbonyls-Isosorbide-5-Nitrae-EEDQ -3- carboxylic acids
Compound 24a preparation method is similar with compound 1e preparation method, with 2, and 4,5-trifluoro-benzoic acid is Raw material, obtains 24a.1H NMR (300MHz, DMSO) δ 8.69 (s, 1H), 8.06 (ddd, J=11.2,8.7, 2.8Hz, 1H), 7.85 (ddd, J=8.7,2.7,1.5Hz, 1H)
The fluoro- N- of 6,8- bis- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) benzene Base) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 24 is similar with the preparation method of compound 6, using 24a and 6b as raw material, and reaction is finished, Obtain 24.1H NMR (300MHz, DMSO) δ 13.09 (s, 1H), 8.82 (s, 1H), 8.49 (d, J= 5.3Hz, 1H), 8.13 (d, J=12.7Hz, 1H), 7.78 (t, J=9.2Hz, 2H), 7.57-7.40 (m, 4H), 6.51 (d, J=5.2Hz, 1H), 5.98 (s, 1H), 4.22 (s, 2H), 3.97 (s, 3H), 3.62(s,4H),2.70(s,2H),2.47(s,4H),2.01(s,2H).MS-ESI m/z:635.2(M+H)+； HR-ESI MS calcd for C33H30F3N4O6(M+H)+:635.2117found:635.2126.
The preparation method of embodiment 25
The fluoro- N- of 6,7,8- bis- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) Phenyl) the miscellaneous naphthalene -3- formamides (25) of -4- carbonyl -1,4- dihydros
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 6,7,8- tri-
Compound 25a preparation method is similar with compound 1e preparation method, with 2,4,5,6-tetrafluorobenzoic aid For raw material, 25a is obtained.1H NMR(300MHz,DMSO)δ8.87(s,1H),8.03(s,1H).
5,6,7- tri- fluoro- N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) Phenyl) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 25 is similar with the preparation method of compound 4, using 25a and 4b as raw material, and reaction is finished, Obtain 25.1H NMR(300MHz,DMSO)δ10.11(s,1H),8.97(s,1H),8.87(m,1H), 7.77-7.26 (m, 6H), 6.62 (d, J=5.4Hz, 1H), 4.28 (s, 2H), 3.98 (s, 3H), (s, the 2H) of 3.51 (s, 4H), 2.27 (dd, J=15.7,14.2Hz, 6H), 2.00
The preparation method of embodiment 26
The fluoro- N- of 7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides (26) of -1- methyl -4- carbonyl -1,4- dihydros
The fluoro- 1- methyl 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 7-
Compound 26a preparation method is similar with compound 1d preparation method, and with 2,4-difluoro-benzoic acid is raw material, Obtain 26a.1H NMR(300MHz,DMSO)δ9.07(s,1H),8.50–8.39(m,1H),7.88(d, J=10.8Hz, 1H), 7.58 (t, J=8.7Hz, 1H), 4.08 (s, 3H)
The fluoro- N- of 7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) Miscellaneous naphthalene -3- the formamides of -1- methyl -4- carbonyl -1,4- dihydros
The preparation method of compound 26 is similar with the preparation method of compound 4, using 26a and 4b as raw material, and reaction is finished, Obtain 26.1H NMR(300MHz,DMSO)δ12.61(s,1H),9.06(s,1H),8.54–8.43 (m, 2H), 8.11 (d, J=12.9Hz, 1H), 7.82 (d, J=11.2Hz, 1H), 7.63-7.41 (m, 5H), 6.52 (d, J=5.3Hz, 1H), 4.25 (s, 2H), 4.07 (s, 3H), 3.98 (s, 3H), 3.72(s,4H),2.52(s,6H),2.09–1.94(m,2H).MS-ESI m/z:653.1(M+H)+； HR-ESI MS calcd for C33H29F4N4O6(M+H)+:653.2023found:653.2035.
The preparation method of embodiment 27
The fluoro- N- of 1- cyclopropyl -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides (27) of -4- carbonyl -1,4- dihydros
The fluoro- 1- methyl 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 1- cyclopropyl -7-
Compound 27a preparation method is similar with compound 1d preparation method, and with 2,4-difluoro-benzoic acid is raw material, Obtain 27a.1H NMR(300MHz,DMSO)δ8.78(s,1H),8.50–8.41(m,1H),8.09(d, J=9.4Hz, 1H), 7.60 (s, 1H), 3.82 (s, 1H), 1.37-1.20 (m, 4H)
The fluoro- N- of 1- cyclopropyl -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 27 is similar with the preparation method of compound 4, using 27a and 4b as raw material, and reaction is finished, Obtain 27.MS-ESI m/z:657.2(M+H)+；HR-ESI MS calcd for C36H35F2N4O6(M+H)+:657.2525 found:657.2531.
The preparation method of embodiment 28
The fluoro- N- of 1- cyclopenta -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides (28) of -4- carbonyl -1,4- dihydros
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylic acids of 1- cyclopenta -7-
Compound 28a preparation method is similar with compound 1d preparation method, and with 2,4-difluoro-benzoic acid is raw material, Obtain 28a.1H NMR (300MHz, DMSO) δ 8.79 (s, 1H), 8.48 (dd, J=9.0,6.6Hz, 1H), 8.17 (d, J=9.9Hz, 1H), 7.59 (t, J=8.5Hz, 1H), 5.33-5.18 (m, 1H), 2.40 –2.20(m,2H),2.04–1.79(m,6H).
The fluoro- N- of 1- cyclopenta -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 28 is similar with the preparation method of compound 4, using 28a and 4b as raw material, and reaction is finished, Obtain 28.1H NMR(300MHz,CDCl3)δ12.48(s,1H),8.97(s,1H),8.62–8.53 (m, 1H), 8.44 (d, J=5.5Hz, 1H), 8.00 (dd, J=12.5,2.2Hz, 1H), 7.76 (d, J=7.9Hz, 1H), 7.54 (d, J=11.0Hz, 2H), 7.46-7.34 (m, 3H), 7.18 (s, 1H), 6.46 (d, J=5.3Hz, 1H), 4.98-4.83 (m, 1H), 4.16 (t, J=6.2Hz, 2H), 3.99 (s, 3H), 3.75 (t, J=4.4Hz, 4H), 2.70 (dd, J=18.4,10.9Hz, 6H), 2.34 (d, J=7.7Hz, 2H), 2.02 (ddd, J=24.6,20.8,8.7Hz, 8H) .MS-ESI m/z:685.3 (M+H)+；HR-ESI MS calcd for C38H39F2N4O6(M+H)+:685.2838found:685.2829.
The preparation method of embodiment 29
The fluoro- N- of 1- cyclohexyl -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides (29) of -4- carbonyl -1,4- dihydros
The fluoro- miscellaneous naphthalene -3- carboxylic acids of 1- methyl 4- carbonyls -1,4- dihydros of 1- cyclohexyl -7-
Compound 29a preparation method is similar with compound 1d preparation method, and with 2,4-difluoro-benzoic acid is raw material, Obtain 29a.1H NMR(300MHz,DMSO)δ8.89(s,1H),8.59–8.39(m,1H),8.19(d, J=12.1Hz, 1H), 7.59 (t, J=8.5Hz, 1H), 4.83 (s, 1H), 2.05 (s, 2H), 1.87 (d, J=10.9Hz, 4H), 1.68 (t, J=13.4Hz, 3H), 1.36 (s, 1H)
The fluoro- N- of 1- cyclohexyl -7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) oxygen Base) phenyl) the miscellaneous naphthalene -3- formamides of -4- carbonyl -1,4- dihydros
The preparation method of compound 29 is similar with the preparation method of compound 4, using 29a and 4b as raw material, and reaction is finished, Obtain 29.1H NMR(300MHz,CDCl3)δ12.50(s,1H),9.01(s,1H),8.59(dd,J =8.9,6.5Hz, 1H), 8.44 (d, J=5.6Hz, 1H), 8.01 (dd, J=12.4,2.2Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.61-7.48 (m, 2H), 7.41 (q, J=8.9Hz, 2H), 7.20 (dd, J=8.4,3.3Hz, 2H), 6.47 (d, J=5.5Hz, 1H), 4.34 (t, J=11.8Hz, 1H), 4.16 (t, J=6.2Hz, 2H), 3.97 (d, J=13.5Hz, 3H), 3.82-3.71 (m, 4H), 3.45 (s, 1H), 2.81-2.59 (m, 6H), 2.26-1.96 (m, 6H), 1.84 (t, J= 12.1Hz,2H),1.66–1.18(m,4H).MS-ESI m/z:699.3(M+H)+；HR-ESI MS calcd for C39H41F2N4O6(M+H)+:699.2994found:699.2999.
The preparation method of embodiment 30
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (tetrahydrochysene -2H- pyrans -4- bases) -1,4- EEDQ -3- formamides (30)
4- carbonyls -1- (tetrahydrochysene -2H- pyrans -4- bases) -1,4- EEDQ -3- carboxylic acids
Compound 30a preparation method is similar with compound 1d preparation method, using 2- fluobenzoic acids as raw material, obtains 30a。1H NMR (300MHz, DMSO) δ 8.87 (s, 1H), 8.46 (dd, J=8.1,1.6Hz, 1H), 8.33 (d, J=8.8Hz, 1H), 8.01 (dd, J=11.5,4.4Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 5.19 (d, J=5.5Hz, 1H), 4.06 (d, J=11.3Hz, 2H), 3.70 (t, J= 10.7Hz, 2H), 2.11 (dd, J=12.1,7.7Hz, 4H)
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (tetrahydrochysene -2H- pyrans -4- bases) -1,4- EEDQ -3- formamides
The preparation method of compound 30 is similar with the preparation method of compound 4, using 30a and 4b as raw material, and reaction is finished, Obtain 30.1H NMR (300MHz, DMSO) δ 8.89 (s, 1H), 8.50 (dd, J=8.1,1.6Hz, 1H), 8.38 (d, J=8.8Hz, 1H), 8.00 (dd, J=11.5,4.4Hz, 1H), 7.89-7.22 (m, 7H), 5.20 (m, J=5.4Hz, 1H), 4.25 (s, 2H), 4.00 (d, J=10.5Hz, 2H), 3.88 (s, 3H),3.72-3.48(m,6H),2.35-2.18(m,10H),1.92(s,2H).MS-ESI m/z:683.3 (M+H)+；HR-ESI MS calcd for C38H40FN4O7(M+H)+:683.2881found:683.2877.
The preparation method of embodiment 31
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (piperazine -4- bases) -1,4- EEDQ -3- formamides (31)
4- carbonyls -1- (piperazine -4- bases) -1,4- EEDQ -3- carboxylic acids
Compound 31a preparation method is similar with compound 1d preparation method, using 2- fluobenzoic acids as raw material, obtains 31a。1H NMR (300MHz, DMSO) δ 8.77 (s, 1H), 8.42 (dd, J=13.9,8.5Hz, 2H), 8.02 (t, J=7.9Hz, 1H), 7.72 (t, J=7.6Hz, 1H), 5.40 (s, 1H), 3.45 (dd, J=18.4,10.3Hz, 2H), 3.28 (d, J=11.1Hz, 2H), 2.34 (dd, J=38.6,11.5 Hz,4H).
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (piperazine -4- bases) -1,4- EEDQ -3- formamides
The preparation method of compound 31 is similar with the preparation method of compound 4, using 31a and 4b as raw material, and reaction is finished, Obtain 31.1H NMR(300MHz,CDCl3)δ12.51(s,1H),9.03(s,1H),8.50(dd,J =27.2,6.6Hz, 2H), 7.91 (d, J=12.5Hz, 1H), 7.75 (s, 2H), 7.63-7.31 (m, 4H), 7.16 (t, J=8.8Hz, 1H), 6.39 (d, J=4.9Hz, 1H), 4.81 (s, 1H), 4.26 (t, J=6.3Hz, 2H), 4.00 (d, J=14.1Hz, 3H), 3.73 (s, 4H), 3.58 (d, J=11.2Hz, 2H), 3.13 (s, 3H), 2.57 (dd, J=20.2,13.2Hz, 6H), 2.17 (dd, J=30.2,23.1Hz, 6H) .MS-ESI m/z:682.4(M+H)+；HR-ESI MS calcd for C38H41FN5O6(M+H)+:682.3041,found:682.3039.
The preparation method of embodiment 32
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (1- methyl piperazine -4- bases) -1,4- EEDQ -3- formamides (32)
1- (1- methyl piperazine -4- bases) -4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 32a preparation method is similar with compound 1d preparation method, using 2- fluobenzoic acids as raw material, obtains 32a。1H NMR (300MHz, DMSO) δ 8.74 (s, 1H), 8.40 (dd, J=28.3,8.2Hz, 2H), 8.03 (t, J=7.3Hz, 1H), 7.73 (t, J=7.4Hz, 1H), 5.36 (s, 1H), 3.63 (d, J=10.9Hz, 3H), 3.38 (d, J=10.9Hz, 2H), 2.81 (d, J=4.3Hz, 3H), 2.34 (d, J=12.7Hz, 2H)
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 1- (1- methyl piperazine -4- bases) -1,4- EEDQ -3- formamides
The preparation method of compound 32 is similar with the preparation method of compound 4, using 32a and 4b as raw material, and reaction is finished, Obtain 32.1H NMR(300MHz,CDCl3) δ 12.53 (s, 1H), 9.08 (s, 1H), 8.61 (d, J= 8.2Hz, 1H), 8.48 (d, J=5.2Hz, 1H), 8.00 (d, J=12.7Hz, 1H), 7.87-7.64 (m, 3H), 7.61-7.39 (m, 4H), 6.44 (d, J=5.1Hz, 1H), 4.52 (s, 1H), 4.26 (t, J=6.6Hz, 2H), 4.03 (s, 3H), 3.72 (s, 4H), 3.11 (s, 2H), 2.57 (d, J= 7.1Hz,2H),2.49(s,4H),2.39(s,3H),2.34–2.04(m,9H).MS-ESI m/z: 696.3(M+H)+；HR-ESI MS calcd for C39H43FN5O6(M+H)+:696.3197,found:696.3206.
The preparation method of embodiment 33
The fluoro- N- of 7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrrolidin-1-yl) propoxyl group) quinolyl-4) epoxide) benzene Base) -4- carbonyls -1- (1- methyl piperazine -4- bases) -1,4- EEDQ -3- formamides (33)
The chloro- 6- methoxyl groups -7- of 4- (3- (pyrrolidin-1-yl) propoxyl group) quinoline
Compound 33a preparation method is similar with compound 4b preparation method, using 7- hydroxyl -6- methoxy quinolines as Raw material, obtains 33a.1H NMR (300MHz, DMSO) δ 7.60 (d, J=5.4Hz, 1H), 6.84 (d, J =1.8Hz, 1H), 6.54 (s, 1H), 6.25 (t, J=8.6Hz, 1H), 5.89-5.74 (m, 2H), 5.67 (dd, J=5.4,1.2Hz, 1H), 3.45 (t, J=6.0Hz, 2H), 3.26-3.20 (m, 3H), 2.05-1.94 (m, 2H), 1.87 (s, 4H), 1.38 (d, J=6.0Hz, 2H), 1.07 (s, 4H).
The fluoro- N- of 7- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- (pyrrolidin-1-yl) propoxyl group) quinolyl-4) epoxide) benzene Base) -4- carbonyls -1- (1- methyl piperazine -4- bases) -1,4- EEDQ -3- formamides
The preparation method of compound 33 is similar with compound 1h preparation method, using 33a and 1e as raw material, and reaction is finished, Obtain 33.1H NMR (300MHz, DMSO) δ 13.02 (s, 1H), 8.95 (s, 1H), 8.50 (d, J= 5.3Hz, 1H), 8.42-8.32 (m, 1H), 8.12 (d, J=13.3Hz, 1H), 7.59-7.31 (m, 6H), 6.51 (d, J=5.3Hz, 1H), 4.24 (s, 2H), 3.98 (s, 3H), 2.75 (d, J= 25.2Hz,6H),2.06(s,2H),1.78(s,4H).
The preparation method of embodiment 34
The fluoro- N- of 7- (the fluoro- 4- of 3- ((7-(3- morpholines propoxyl group)-1,6- naphthyridines-4- bases) epoxide) phenyl)-4- carbonyls - 1,4- EEDQ -3- formamides (34)
The bromo- 2- methoxypyridines -4- amino of 3-
2- methoxyl groups -4-aminopyridine (3.81g, 27.5mmol) and NBS (5g, 28mmol) are dissolved in 25ml respectively In 40ml acetonitriles, then the NBS for being dissolved in acetonitrile is added dropwise in the reaction solution under ice bath, it is then anti-at room temperature Answer 1h.After completion of the reaction, remove reaction dissolvent to be extracted with ethyl acetate, after extraction is finished, remove solvent, Carried out being recrystallized to give compound 34a (895mg, 81%) with acetone
1H NMR(400MHz,DMSO-d6):D 7.58 (d, J=5.7Hz, 1H), 6.13 (dd, J=5.7 Hz, 1.6Hz, 1H), 5.92 (s, 2H), 5.80 (d, J=1.6Hz, 1H), 3.72 (s, 3H)
(E) -5- (((the bromo- 2- methoxypyridines -4- bases of 3-) imino group) methyl) -2,2,-dimethyl -1,3- dioxies six Alkyl -4,6- diketone
Malonic acid ring (Asia) isopropyl ester (1.44g, 10mmol) is dissolved in isopropanol and then triethyl orthoformate is added, risen Temperature is to 100 DEG C of reaction 1h, and being cooled to after room temperature just has a large amount of solids to separate out, and is filtrated to get compound as white solid, not It is purified directly to cast single step reaction.Not purified compound and 34a (1.05g, 5mmol) are dissolved in isopropanol, 80 DEG C of reaction 1h are warming up to, after completion of the reaction, room temperature is cooled to, there are a large amount of white solids to produce.Obtained after filtering Solid powder, obtains a large amount of white powder 34b (1.5g, 92%) after being washed with a small amount of ethyl acetate.1H NMR(400 MHz,DMSO-d6):D 11.58 (d, J=13.6Hz, 1H), 8.87 (d, J=13.6Hz, 1H), 8.15 (d, J=5.8Hz, 1H), 7.57 (d, J=5.8Hz, 1H), 3.96 (s, 3H), 1.71 (s, 6H)
Bromo- 7- methoxyl groups -1,6- naphthyridines -4 (1H) -one of 8-
Take 34c (714mg, 2mmol) to be dissolved in 20ml phenylates, be warming up to 220 DEG C of reaction half an hour, be cooled to room temperature Afterwards, adding has a large amount of solids to separate out after 200ml petroleum ethers, be filtrated to get brown powder, then carried out with ethyl acetate Recrystallization, obtains gray solid 34c (502mg, 85%).1H NMR(300MHz,DMSO-d6):11.18(s,1H), 8.85 (s, 1H), 7.80 (d, J=7.8Hz, 1H), 6.09 (d, J=7.8Hz, 1H), 4.03 (s, 3H).
(1H) -one of 7- methoxyl group -1,6- naphthyridines -4
Take 34c (918mg, 3.6mmol) be dissolved in addition 20ml methanol, be then respectively adding ammonium chloride (900mg, 14.4mmol), 90mg palladiums back flow reaction 3.5h.Palladium catalyst and chloride solid are filtered to remove while hot, are removed molten Agent, white powder 34d (600mg, 94%) is obtained by the method for column chromatography for separation.1H NMR(300MHz,DMSO-d6): 11.16 (s, 1H), 8.89 (s, 1H), 7.86 (d, J=7.6Hz, 1H), 6.67 (s, 1H), 5.97 (d, J=7.6Hz, 1H), 3.92 (s, 3H)
The chloro- 1,6- naphthyridines -7- alcohol of 4-
Take 34d (352mg, 2mmol) to be dissolved in 2mL trifluoromethanesulfonic acid, be warming up to 150 DEG C of reaction 3h.React PH, is adjusted to for 7, be extracted with ethyl acetate, after extraction is finished, with dichloromethane and first by Bi Hou with potassium carbonate Alcohol system carries out column chromatography, obtains yellow solid 34e (120mg, 36%).1H NMR(300MHz,DMSO)δ9.19 (s, 1H), 8.86 (d, J=4.7Hz, 1H), 7.55 (d, J=4.7Hz, 1H), 7.04 (s, 1H)
4- (3- ((the chloro- 1,6- naphthyridines -7- bases of 4-) epoxide) propyl group) morpholine
34e (180mg, 1mmol) is taken, 2- morpholines propyl alcohol (290mg, 2mmol) is dissolved in 10mL THF, so Add triphenyl phosphorus (655mg, 2.5mmol) afterwards and anhydrous magnesium sulfate first stirs 0.5h.Be subsequently added into (0.4mL, 2.5mmol) EDAD reacts 1h, is extracted after completion of the reaction with ethyl acetate, concentrates, dichloromethane and methanol body System carries out column chromatography, obtains yellow powder 34f.
The fluoro- 4- of 3- ((7- (3- morpholines propoxyl group) -1,6- naphthyridines -4- bases) epoxide) aniline
Compound 34g preparation method is similar with compound 4b preparation method, using 34f as raw material, obtains 34g.1H NMR (300MHz,CD3OD)δ9.44–9.35(m,1H),8.68–8.61(m,1H),7.16–6.99 (m,2H),6.63–6.42(m,3H),4.61–4.49(m,2H),3.75–3.66(m,4H), 2.86 (dd, J=7.6,3.6Hz, 2H), 2.62 (s, 4H)
The fluoro- N- of 7- (the fluoro- 4- of 3- ((7-(3- morpholines propoxyl group)-1,6- naphthyridines-4- bases) epoxide) phenyl)-4- carbonyls - 1,4- EEDQ -3- formamides
The preparation method of compound 34 is similar with compound 1h preparation method, using 34a and 1e as raw material, and reaction is finished, Obtain 34.1H NMR(300MHz,CD3OD)δ9.45(s,1H),8.82(s,1H),8.64(s,1H), 8.43 (s, 1H), 8.00 (d, J=12.7Hz, 1H), 7.35 (d, J=54.1Hz, 5H), 6.45 (s, 1H), (s, the 2H) .MS-ESI of 4.42 (s, 2H), 3.74 (s, 4H), 2.61 (d, J=25.7Hz, 6H), 2.09 m/z:588.2(M+H)+；HR-ESI MS calcd for C31H28F2N5O6(M+H)+:588.2059found: 588.2042.
The preparation method of embodiment 35
The fluoro- N- of 7- (the fluoro- 4- of 3- ((7- (2- morpholines propoxyl group) -1,6- naphthyridines -4- bases) epoxide) phenyl) -4- carbonyls - 1,4- EEDQ -3- formamides (35)
4- (2- ((the chloro- 1,6- naphthyridines -7- bases of 4-) epoxide) propyl group) morpholine
34e (180mg, 1mmol) is taken, 2- morpholines propyl alcohol (276mg, 2mmol) is dissolved in 10mL THF, so Add triphenyl phosphorus (655mg, 2.5mmol) afterwards and anhydrous magnesium sulfate first stirs 0.5h.Be subsequently added into (0.4mL, 2.5mmol) EDAD reacts 1h, is extracted after completion of the reaction with ethyl acetate, concentrates, dichloromethane and methanol body System carries out column chromatography, obtains yellow powder 35a
The fluoro- 4- of 3- ((7- (2- morpholines propoxyl group) -1,6- naphthyridines -4- bases) epoxide) aniline
Compound 35b preparation method is similar with compound 4b preparation method, using 35a as raw material, obtains 35b.
The fluoro- N- of 7- (the fluoro- 4- of 3- ((7- (2- morpholines propoxyl group) -1,6- naphthyridines -4- bases) epoxide) phenyl) -4- carbonyls - 1,4- EEDQ -3- formamides
The preparation method of compound 35 is similar with compound 1h preparation method, using 35a and 1e as raw material, and reaction is finished, Obtain 35.1H NMR(300MHz,DMSO)δ12.70(s,1H),9.47(s,1H),8.97(s,1H), 8.79 (d, J=5.0Hz, 1H), 8.40 (s, 1H), 8.14 (d, J=13.9Hz, 1H), 7.63- 7.23 (m, 5H), 6.56 (d, J=4.5Hz, 1H), 4.53 (s, 2H), 3.59 (d, J=4.8Hz, 4H),2.79(s,2H).MS-ESI m/z:574.1(M+H)+；HR-ESI MS calcd for C30H26F2N5O5(M+H)+: 574.1902,found:574.1915.
The preparation method of embodiment 36
The fluoro- N- of 1- ethyls -6- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) benzene Base) -4- carbonyls -7- (piperazine -1- bases) -1,4- EEDQ -3- formamides (36)
The fluoro- 4- carbonyls -1,4- EEDQs -3- carboxylics of 7- (4- (di-tert-butyl dicarbonate) piperazine -1- bases) -1- ethyls -6- Acid
Take Norfloxacin (319mg, 1mmol), Boc2O (220mg, 1mmol) is dissolved in 5mL dichloromethane, room After the lower stirring 0.5h of temperature, add after (202mg, 2mmol) triethylamine, reaction 2h, remove solvent and pass through column chromatography Obtain compound 36a.1H NMR(300MHz,CDCl3) δ 8.64 (s, 1H), 8.03 (d, J=12.9Hz, 1H), 6.82 (d, J=6.8Hz, 1H), 4.30 (q, J=7.2Hz, 2H), 3.71-3.58 (m, 4H), (s, the 9H) of 3.30-3.19 (m, 4H), 1.57 (t, J=7.2Hz, 3H), 1.47
The fluoro- N- of 1- ethyls -6- (di-tert-butyl dicarbonate)-(the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) Quinolyl-4) epoxide) phenyl) -4- carbonyls -7- (piperazine -1- bases) -1,4- EEDQ -3- formamides
Compound 36b preparation method is similar with the preparation method of compound 4, using 36a and 4b as raw material, and reaction is finished, Obtain 36b.1H NMR(300MHz,CDCl3)δ12.54(s,1H),8.77(s,1H),8.47(d,J =5.3Hz, 1H), 8.09 (d, J=13.0Hz, 1H), 7.99 (dd, J=12.4,2.2Hz, 1H), 7.56 (s, 1H), 7.42 (d, J=12.3Hz, 2H), 7.20 (d, J=8.8Hz, 1H), 6.81 (d, J=6.8Hz, 1H), 6.44 (d, J=5.2Hz, 1H), 4.34-4.21 (m, 4H), 4.02 (s, 3H), 3.77-3.70 (m, 4H), 3.64 (s, 4H), 3.22 (s, 4H), 2.60 (dd, J=20.1,12.7 Hz, 6H), 2.21-2.09 (m, 2H), 1.57 (t, J=7.1Hz, 3H), 1.47 (s, 9H)
The fluoro- N- of 1- ethyls -6- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) benzene Base) -4- carbonyls -7- (piperazine -1- bases) -1,4- EEDQ -3- formamides
Take compound 36b (83mg, 0.1mmol) to be dissolved in 5mL dichloromethane, then add 0.5mL trifluoro vinegar Acid, reacts at room temperature 2h, PH is adjusted to for 7,36 are obtained by column chromatography.1H NMR(300MHz,CDCl3)δ12.54 (s, 1H), 8.79 (s, 1H), 8.48 (s, 1H), 8.06 (dd, J=37.2,12.7Hz, 2H), 7.58 (s,1H),7.43(s,2H),7.23–7.16(m,1H),6.86(s,1H),6.44(s,1H),4.29 (d, J=16.3Hz, 4H), 4.03 (s, 3H), 3.73 (s, 4H), 3.28 (d, J=43.1Hz, 8H), (s, 3H) the .MS-ESI m/z of 2.55 (d, J=25.8Hz, 6H), 2.14 (s, 2H), 1.59:729.3(M+H)+； HR-ESI MS calcd for C39H43F2N6O6(M+H)+:729.3212,found:729.3193.
The preparation method of embodiment 37
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) phenyl -4- carbonyls - 1,4- dihydro -1,7- naphthyridines -3- formamides (37)
4- carbonyl -1,4- dihydro -1,7- naphthyridines -3- carboxylic acids
Compound 37a preparation method is similar with compound 1e preparation method, using 4- carboxyl 3- fluorine pyridines as raw material, Obtain 37a.1H NMR (300MHz, DMSO) δ 9.10 (s, 1H), 9.02 (s, 1H), 8.59 (d, J=5.2 Hz,1H),8.10–8.01(m,1H).
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) phenyl -4- carbonyls - 1,4- dihydro -1,7- naphthyridines -3- formamides
The preparation method of compound 37 is similar with the preparation method of compound 4, using 37a and 4b as raw material, and reaction is finished, Obtain 37.1H NMR(300MHz,CDCl3)δ12.30(s,1H),9.15(s,1H),8.98(s,1H), 8.67 (d, J=5.3Hz, 1H), 8.48 (d, J=5.6Hz, 1H), 8.22 (d, J=5.3Hz, 1H), 7.98 (d, J=11.2Hz, 1H), 7.57 (s, 1H), 7.43 (d, J=12.2Hz, 2H), 6.48 (d, J=5.4Hz, 1H), 4.26 (s, 2H), 4.03 (s, 3H), 3.77 (s, 4H), 2.71-2.56 (m, 6H), 2.18 (d, J=6.5Hz, 2H) .MS-ESI m/z:600.2(M+H)+；HR-ESI MS calcd for C32H31FN5O6(M+H)+:600.2258found:600.2276.
The preparation method of embodiment 38
The fluoro- N- of 1- ethyls -6- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) benzene Base) -4- carbonyls -7- (piperazine -1- bases) -1,4- EEDQ -3- carboxamide hydrochlorides (38)
Take compound 36 (73mg, 0.1mmol) to be dissolved in 2mL 22%HCl (MeOH, aq), then react at room temperature 2h, After completion of the reaction, rotation to obtained crude product is washed except solvent and then with methanol solvate, obtains pure compound 38.1H NMR(300MHz,CDCl3)δ12.54(s,1H),8.79(s,1H),8.48(s,1H),8.06(dd, J=37.2,12.7Hz, 2H), 7.58 (s, 1H), 7.43 (s, 2H), 7.23-7.16 (m, 1H), 6.86 (s, 1H), 6.44 (s, 1H), 4.29 (d, J=16.3Hz, 4H), 4.03 (s, 3H), 3.73 (s, 4H), 3.28 (d, J=43.1Hz, 8H), 2.55 (d, J=25.8Hz, 6H), 2.14 (s, 2H), 1.59 (s, 3H).MS-ESI m/z:729.3(M+H)+；HR-ESI MS calcd for C39H43F2N6O6(M+H)+:729.3212, found:729.3193.
The preparation method of embodiment 39
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholine bases propoxyl group) quinolyl-4) epoxide) phenyl) -4- carbonyls - 4H- chromone -3- formamides (39)
The preparation method of compound 39 is similar with the preparation method of compound 4, using chromone -3- formic acid and 4b as raw material,.1H NMR(400MHz,CDCl3) δ 11.66 (s, 1H), 9.11 (s, 1H), 8.51 (d, J=5.3Hz, 1H), 8.36 (d, J=8.0Hz, 1H), 7.99 (dd, J=12.1,2.1Hz, 1H), 7.84 (t, J =7.9Hz, 1H), 7.66-7.56 (m, 3H), 7.47 (d, J=6.0Hz, 2H), 7.29 (d, J= 6.4Hz, 1H), 6.46 (d, J=5.3Hz, 1H), 4.33-4.24 (m, 2H), 4.06 (s, 3H), 3.77 (t, J=4.4Hz, 4H), 2.62 (dd, J=24.9,17.8Hz, 7H), 2.22-2.12 (m, 2H).MS-ESI m/z:600.2(M+H)+；HR-ESI MS calcd for C33H31FN3O7(M+H)+:600.2146, found:632.2161.
The preparation method of embodiment 40
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) phenyl) -6- nitros - 4- carbonyl -1,4- EEDQs (40)
6- nitro -4- carbonyl -1,4- EEDQ -3- carboxylic acids
Compound 40a preparation method is similar with compound 1e preparation method, using 5- nitro -2- fluobenzoic acids as original Material, obtains 40a.1H NMR(300MHz,DMSO)δ13.88(s,1H),9.06(s,1H),8.99(s, 1H), 8.64 (d, J=9.2Hz, 1H), 8.03 (d, J=9.1Hz, 1H)
N- (the fluoro- 4- of 3- ((6- methoxyl groups -7- (3- morpholines propoxyl group) quinolyl-4) epoxide) phenyl) -6- nitros - 4- carbonyl -1,4- EEDQs
The preparation method of compound 40 is similar with the preparation method of compound 4, using 40a and 4b as raw material, and reaction is finished, Obtain 40.1H NMR(300MHz,CDCl3)δ12.19(s,1H),9.14(s,1H),8.72(s,1H), 8.28 (dd, J=38.9,7.3Hz, 2H), 7.84 (s, 1H), 7.56 (d, J=8.8Hz, 1H), 7.43 (s, 1H), 7.13 (d, J=15.0Hz, 2H), 6.31 (s, 1H), 4.06 (dd, J=22.4,18.8 Hz, 5H), 3.57 (s, 3H), 2.44 (d, J=25.5Hz, 4H), 2.00 (s, 2H), 1.06 (s, 3H) MS-ESI m/z:644.1(M+H)+；HR-ESI MS calcd for C33H31FN5O8(M+H)+:644.2157found: 644.2165.
The preparation method of embodiment 41
N- (the fluoro- 4- of 3- ((2- (3- morpholines propoxyl group) pyridin-4-yl) epoxide) phenyl) -4- carbonyl -1,4- dihydros - 1,7- naphthyridines -3- formamides (41)
4- ((2- chloropyridine -4- bases) methoxyl group) -3- fluoroanilines
Take the fluoro- PAPs of 2- (635mg, 5mmol) and the chloro- 4- nitropyridines (471mg, 3mmol) of 2- molten In DMF, the lower reaction 12h of potassium tert-butoxide (560mg, 5mmol) nitrogen protection is then added, is removed after completion of the reaction molten Agent, is extracted with ethyl acetate, and 41a (505mg, 69%) is obtained by column chromatography.1H NMR(300MHz,CDCl3) δ 8.22-8.15 (m, 1H), 6.92 (t, J=8.7Hz, 1H), 6.76 (d, J=5.1Hz, 2H), 6.55–6.40(m,2H),3.82(s,2H).
The fluoro- 4- of 3- ((2- (3- morpholines propoxyl group) pyridin-4-yl) epoxide) aniline
Compound 41a (238mg, 1mmol) and 2- morpholines propyl alcohol (290mg, 2mmol) is taken to be dissolved in 1mL THF, Then potassium tert-butoxide (242mg, 2mmol) is added, microwave 100w reacts 30min under the conditions of 70 DEG C.Reaction is finished Afterwards, remove after solvent, compound 41b (330mg, 95%) is obtained by column chromatography.1H NMR(300MHz,CD3OD) δ 7.92 (d, J=5.9Hz, 1H), 6.90 (t, J=8.8Hz, 1H), 6.62-6.40 (m, 3H), 6.08 (s, 1H), 4.24 (t, J=6.2Hz, 2H), 3.66 (d, J=4.2Hz, 4H), 2.48 (d, J=15.3Hz, 6H), 1.91 (dd, J=13.5,6.5Hz, 2H)
N- (the fluoro- 4- of 3- ((2- (3- morpholines propoxyl group) pyridin-4-yl) epoxide) phenyl) -4- carbonyl -1,4- dihydros - 1,7- naphthyridines -3- formamides
The preparation method of compound 41 is similar with the preparation method of compound 4, using 37a and 41b as raw material, and reaction is finished, Obtain 41.1H NMR(300MHz,CDCl3)δ12.33(s,1H),9.10(s,1H),8.94(s,1H), 8.61 (d, J=5.4Hz, 1H), 8.20 (d, J=5.0Hz, 1H), 8.04-7.86 (m, 2H), 7.35 (d, J=7.6Hz, 1H), 7.12 (t, J=8.7Hz, 1H), 6.53 (d, J=3.7Hz, 1H), 6.14 (s, 1H), 4.28 (t, J=6.4Hz, 2H), 3.73-3.57 (m, 4H), 2.97 (s, 1H), 2.90 (d, J=0.6Hz, 1H), 2.49-2.40 (m, 4H), 2.00-1.84 (m, 2H) .MS-ESI m/z: 520.1(M+H)+；HR-ESI MS calcd for C27H27FN5O5(M+H)+:520.1996found:520.2008.
The preparation method of embodiment 42
1- cyclopentamines -7-N- (the fluoro- 4- of 3- ((2- (3- morpholines propoxyl group) pyridin-4-yl) epoxide) phenyl) -4- carbonyls - 1,4- dihydro-pyrido -3- formamides (42)
The preparation method of compound 42 is similar with the preparation method of compound 4, using 28a and 41b as raw material, and reaction is finished, Obtain 42.1H NMR(300MHz,CDCl3) δ 12.42 (s, 1H), 8.96 (d, J=15.6Hz, 1H), 8.59 (s, 1H), 7.95 (d, J=11.7Hz, 2H), 7.25 (t, J=39.1Hz, 5H), 6.58 (s, 1H), 6.14 (s, 1H), 4.92 (s, 1H), 4.34 (s, 2H), 3.89 (d, J=45.1Hz, 4H), 3.16 (d, J=8.0Hz, 2H), 2.58 (d, J=143.4Hz, 8H), 2.25-1.81 (m, 6H) .MS-ESI m/z:605.1(M+H)+；HR-ESI MS calcd for C33H35F2N4O5(M+H)+:605.2576,found: 605.2591.
The preparation method of embodiment 43
1- cyclopenta-N- (4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls of -7- - 1,4- EEDQ -3- formamides (43)
The preparation method of compound 43 is similar with the preparation method of compound 4, using 28a and 3a as raw material, and reaction is finished, Obtain 43.1H NMR(300MHz,CDCl3)δ12.48(s,1H),8.97(s,1H),8.63–8.51 (m, 1H), 8.44 (d, J=5.5Hz, 1H), 8.00 (dd, J=12.5,2.2Hz, 1H), 7.76 (d, J=7.9Hz, 1H), 7.54 (d, J=11.1Hz, 2H), 7.47-7.35 (m, 2H), 7.18 (dd, J=18.1,9.3Hz, 2H), 6.46 (d, J=5.3Hz, 1H), 4.98-4.84 (m, 1H), 4.09 - 3.96 (m, 3H), 3.75 (s, 3H), 2.88 (d, J=22.1Hz, 1H), 2.70 (dd, J=18.4, 10.8Hz, 5H), 2.34 (d, J=7.5Hz, 2H) .MS-ESI m/z:572.3(M+H)+；HR-ESI MS calcd for C32H28F2N3O5(M+H)+:572.1997,found:572.1984
The preparation method of embodiment 44
1- cyclopenta-N- (4- ((6,7- dimethoxy-quinoline -4- bases) epoxide) -3- fluorophenyls) fluoro- 4- carbonyls of -6- - 1,4- EEDQ -3- formamides (44)
The preparation method of compound 44 is similar with the preparation method of compound 4, using 3a as raw material, and reaction is finished, and is obtained 44。1H NMR(300MHz,CDCl3)δ12.13(s,1H),8.77(s,1H),8.55–8.44(m, 1H), 8.34 (d, J=5.7Hz, 1H), 7.88 (dd, J=12.1,2.4Hz, 1H), 7.72 (d, J =6.9Hz, 1H), 7.44 (d, J=13.1Hz, 2H), 7.32-7.15 (m, 2H), 7.07 (dd, J =18.1,9.3Hz, 2H), 6.33 (d, J=5.4Hz, 1H), 4.92-4.82 (m, 1H), 4.02 - 3.91 (m, 3H), 3.71 (s, 3H), 2.81 (d, J=21.1Hz, 1H), 2.56 (dd, J=18.4, 10.8Hz, 5H), 2.24 (d, J=7.2Hz, 2H)
MS-ESI m/z:572.3(M+H)+；HR-ESI MS calcd for C32H28F2N3O5(M+H)+:572.1997, found:572.2004.
The test example of biological activity
Detection method：Enzyme linked immunosorbent assay (ELISA) (ELISA)
Reagent, consumptive material and instrument：
Kinases used recombinates egg by this laboratory using insect baculovirus expression system expression and purification protein kinase area in experiment In vain；Polyglutamic acid-tyrosine peptide fragment【Poly(Glu,Tyr)4:1】And sodium vanadate is purchased from Sigma companies；Anti- phosphorylation Monoclonal antibody PY99 is purchased from Santa Cruz companies；Horseradish peroxidase-labeled sheep anti mouse secondary antibody is purchased from Calbiochem companies； ATP and OPD gives birth to work purchased from Shanghai；Remaining agents useful for same is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.React ELISA Plate (#2592) is purchased from Corning companies.It is Molecular Device Products with all-wave elongated ELIASA to test read plate, Model：SpectraMax 190；Experimental water is that Chinese medicines group produces distilled water.
Compound is prepared：
Compound 12000g centrifuges 5min, adds DMSO and is configured to 10-2M liquid storages, the uniform rear ultrasound 10min that is vortexed is stand-by, - 40 DEG C of preservations.With DMSO compound is diluted into 100 times of institute's test concentrations from liquid storage during test, and (DMSO is dense in system Spend for 1%).
Test method：
1st, enzyme reaction substrate Poly (Glu, Tyr) 4:1 with PBS (10mM sodium phosphate buffers, 150mM without potassium ion NaCl, pH 7.2-7.4) 20 μ g/mL are diluted to, 125 μ L/ holes coated elisa plates are put 37 DEG C and reacted 12-16 hours. Discard liquid in hole.Board-washing, with T-PBS (PBS without potassium ion containing 0.1%Tween-20,200 μ L/ holes) board-washing Three times, every time 5 minutes.ELISA Plate is dried in 37 DEG C of baking ovens 1-2 hours.
2nd, added per hole with reaction buffer (50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2, 0.2mM Na3VO4, 1mM DTT) dilution the μ L of ATP solution 49, per adding 1 μ L compounds to be tested in hole, then The c-Met kinase domains recombinant protein startup reaction that 50 μ L are diluted with reaction buffer is added, experiment every time need to set no ATP Control wells holes.37 DEG C of shaking tables (100rpm) are put to react 1 hour.Discard liquid in hole, T-PBS board-washings three times.
3rd, antibody PY99 dilutions (antibody 5mg/mL containing BSA T-PBS 1 is added:500 dilutions), 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS board-washings three times.
4th, sheep anti mouse secondary antibody dilution (antibody 5mg/ml containing the BSA T-PBS of horseradish peroxidase-labeled is added 1:2000 dilutions), 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS board-washings three times.
5th, the 2mg/ml μ L/ holes of OPD nitrite ions 100 are added【With containing 0.03%H2O20.1M citric acid-sodium citrates Buffer solution (pH=5.4) dilutes】, 25 DEG C of lucifuges react 1-10 minutes.
6th, 2M H are added2SO450 μ L/ holes stopped reactions, declined orifice plate ELIASA VERSAmax readings with wavelengthtunable, Wavelength is 490nm.
7th, interpretation of result
IC50Value is used the random bundled software of ELIASA to be returned with four parametric methods and tried to achieve.
Influence of the compound of the present invention of table 1 to c-Met kinase inhibiting activitiesa
A test compounds suppress c-Met kinases and are divided into four region A:1nM<IC50<10nM；B:10nM< IC50<100nM；C:100nM<IC50<1μM；D:100μM<IC50<1μM；
As a result showing the compound of the present invention has different degrees of inhibitory activity to c-Met kinases, and part of compounds is right C-Met kinase inhibitions IC50Value is even up to below 10nM, is effective c-Met kinase inhibitor, and inhibitory activity is super Existing other c-Met kinase inhibitors such as NPS-1034, Tivantinib etc. are crossed.
All documents referred in the present invention are all incorporated as reference in this application, just as each document coverlet Solely it is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, this area skill Art personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims Book limited range.

Claims (10)

1. a kind of polysubstituted quinolone compounds as shown in following formula I, its optical isomer, and pharmaceutically acceptable salt Or solvate：
Ring AFor phenyl ring, or the heteroatomic hexa-atomic unsaturated heterocycle base containing 1 or 2 in N, O, S Or heteroaryl；
X and Y are each independently selected from N, O, CH and S；
R1For nothing, or the group to be selected from the group：Hydrogen, substituted or unsubstituted C1-C6Alkyl, substitution or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl or take Generation or unsubstituted heteroatomic five yuan or hexa-atomic saturation or unsaturated heterocycle base for containing 1-2 in N, O, S；
R2Represent the substituent that 1-5 (being preferably 1-3) being located on ring A is selected from the group：Hydrogen, halogen, hydroxyl, Nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C3-C6 Cycloalkyl, substituted or unsubstituted C1-C6Heterocyclic radical, substituted or unsubstituted C6-C10Aryl or substitution do not take Generation containing heteroatomic 5-10 member saturations of the 1-2 in N, O or unsaturated heterocycle base,
It is described to replace the one or more hydrogen atoms referred on group to be each independently the substituent substitution being selected from the group： Halogen ,-CN ,-CF3、-NO2, hydroxyl, amino, tertbutyloxycarbonyl, C1-C6Alkyl, C1-C6Alkoxy, five First or hexa-atomic saturated heterocyclyl-C1-C6Alkoxy or substituted or unsubstituted miscellaneous in N, O containing 1-2 Five yuan or hexa-atomic saturated heterocyclic group of atom；
R3Selected from hydrogen or halogen；
Z is fluorine, or the structure being selected from the group that is unsubstituted or being replaced by one or more halogen atoms：
M is selected from the group：Nothing, NH, O, S, C1-C10Alkyl, C5-C10Aryl or C5-C10Heteroaryl；Upper State in formula II, III, IV, V, dotted line represents singly-bound or double bond；
R4Selected from amino,C1-C10Alkyl, C5-C10Aryl or C5-C10Heteroaryl；Wherein, Described alkyl is arbitrarily replaced by one or more groups being selected from the group：C1-C10Alkoxy, C5-C10Aryl, 5-7 Circle heterocycles base or C5-C10Heteroaryl；
R5And R6It is each independently selected from the following group：Hydrogen, C1-C6Alkyl, C1-C6Alkoxy, C5-C10Aryl or It is substituted or unsubstituted to contain 1-2 heteroatomic five yuan or hexa-atomic saturation or unsaturated heterocycles in N, O or S Group；
B, C1, D, D1, E is each independently selected from the following group：Nothing, N, NH, O, CH, CH2And S；It is preferred that Ground, B, C1, D, D1, E is each independently selected from N, NH, CH and S.
2. compound as claimed in claim 1, it is characterised in that X and Y are each independently selected from N, O, CH； Preferably, X is selected from N or O, and Y is selected from N or C.
3. compound as claimed in claim 1, it is characterised in that R1For nothing, or the group to be selected from the group： Hydrogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C1-C6 Heterocyclic radical；Preferably, R1For nothing, or the group to be selected from the group：Hydrogen, C1-C3Alkyl, C3-C6Cycloalkyl, Substituted or unsubstituted piperidyl, pyrans.
4. compound as claimed in claim 1, it is characterised in that R2Representing 1-5 be located on ring A (is preferably 1-3) substituent that is selected from the group：Hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, 2- (methoxyl group)-ethyoxyl, mercapto Base ,-CF3、-CN、-NO2、-NH2Or substituted or unsubstituted five yuan or hexa-atomic saturation or unsaturated heterocycle base； Wherein, described substitution refers to optionally is replaced by 1 or 2 substituent for being each independently selected from the following group：Halogen, C1-C6 Alkyl, C1-C6Alkoxy or contain the heteroatomic hexa-atomic saturated heterocyclic group substitution of 1-2 N and/or O.
5. compound as claimed in claim 1, it is characterised in that R3Selected from hydrogen, F, Cl and Br；It is highly preferred that R3Positioned at the ortho position of Z bases.
6. compound as claimed in claim 1, it is characterised in that described Z is selected from the group：Fluorine, or following One structure：
7. compound as claimed in claim 1, it is characterised in that the compound is selected from the group：
8. the preparation method of compound of formula I as claimed in claim 1, it is characterised in that including step：
In atent solvent, in the presence of alkali and condensing agent, it is condensed with quinolone parent nucleus with amine fragment, obtains formula I；Wherein, the definition of each group is as described in the appended claim 1.
9. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes：The Formulas I institute of therapeutically effective amount Show the combination of compound or a variety of compound of formula I, or its optical isomer, pharmaceutically acceptable salt or pharmaceutically Acceptable solvate；And pharmaceutically acceptable carrier.
10. compound of formula I as claimed in claim 1, or its isomers, pharmaceutically acceptable salt, pharmaceutically may be used The solvate of receiving, or the pharmaceutical composition containing described compound of formula I purposes, it is characterised in that be used for Prepare the medicine being selected from the group：As the medicine of Mutiple Targets kinases inhibitor, suppress EGFR-TK c-Met work Property medicine, abnormal for preventing or treating the cell related to the hepatocyte growth factor receptor (c-Met) in organism The medicine of the related disease of propagation, metamorphosis and hypoerkinesia, or it is related to angiogenesis or metastases Disease medicine (especially prepare prevention or treatment tumour growth with transfer medicine).
CN201610124218.7A 2016-03-04 2016-03-04 Polysubstituted carbostyril compound of one class and its production and use Pending CN107151240A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610124218.7A CN107151240A (en) 2016-03-04 2016-03-04 Polysubstituted carbostyril compound of one class and its production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610124218.7A CN107151240A (en) 2016-03-04 2016-03-04 Polysubstituted carbostyril compound of one class and its production and use

Publications (1)

Publication Number Publication Date
CN107151240A true CN107151240A (en) 2017-09-12

Family

ID=59792069

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610124218.7A Pending CN107151240A (en) 2016-03-04 2016-03-04 Polysubstituted carbostyril compound of one class and its production and use

Country Status (1)

Country Link
CN (1) CN107151240A (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108314682A (en) * 2018-01-31 2018-07-24 江西科技师范大学 The preparation and application of the miscellaneous quinolines of the disubstituted -4- virtues of 6,7-
CN108948014A (en) * 2018-08-24 2018-12-07 江西科技师范大学 1- aryl -4- Oxy-1, the preparation and application of the pyrido heterocycle compound of 4- dihydroquinoline structure
WO2019185064A1 (en) * 2018-03-30 2019-10-03 暨南大学 Quinoline or quinazoline compound and application thereof
JP2021512055A (en) * 2018-01-17 2021-05-13 南京薬捷安康生物科技有限公司 TAM Family Kinase / and CSF1R Kinase Inhibitors and Their Applications
CN113429422A (en) * 2021-07-26 2021-09-24 中国人民解放军军事科学院军事医学研究院 Thienoquinolone compound and preparation method and application thereof
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
WO2022253283A1 (en) * 2021-06-01 2022-12-08 中国科学院上海有机化学研究所 Protein kinase degradant and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011063516A (en) * 2009-09-15 2011-03-31 Daiichi Sankyo Co Ltd Amide derivative
WO2012011548A1 (en) * 2010-07-23 2012-01-26 国立大学法人 東京大学 Nitrogen-containing heterocyclic derivative
CN102643268A (en) * 2011-12-30 2012-08-22 沈阳药科大学 Quinoline and cinnoline compound and application thereof
CN106467541A (en) * 2015-08-18 2017-03-01 暨南大学 Substituted quinolone analog derivative or its pharmaceutically acceptable salt or stereoisomer and its Pharmaceutical composition and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011063516A (en) * 2009-09-15 2011-03-31 Daiichi Sankyo Co Ltd Amide derivative
WO2012011548A1 (en) * 2010-07-23 2012-01-26 国立大学法人 東京大学 Nitrogen-containing heterocyclic derivative
CN102643268A (en) * 2011-12-30 2012-08-22 沈阳药科大学 Quinoline and cinnoline compound and application thereof
CN106467541A (en) * 2015-08-18 2017-03-01 暨南大学 Substituted quinolone analog derivative or its pharmaceutically acceptable salt or stereoisomer and its Pharmaceutical composition and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAI LI ET AL.: "Synthesis and Antitumor Activity of Novel 4-(2-Fluorophenoxy)-quinoline Derivatives Bearing the 4-Oxo-1,4-dihydroquinoline-3-carboxamide Moiety", 《ARCH. PHARM. CHEM. LIFE SCI.》 *
李博文: "基于药效团的HIV-1整合酶抑制剂和c-Met抑制剂的设计、合成和构效关系的研究", 《道客巴巴》 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021512055A (en) * 2018-01-17 2021-05-13 南京薬捷安康生物科技有限公司 TAM Family Kinase / and CSF1R Kinase Inhibitors and Their Applications
JP7282397B2 (en) 2018-01-17 2023-05-29 薬捷安康（南京）科技股▲分▼有限公司 TAM family kinase/and CSF1R kinase inhibitor and use thereof
CN108314682A (en) * 2018-01-31 2018-07-24 江西科技师范大学 The preparation and application of the miscellaneous quinolines of the disubstituted -4- virtues of 6,7-
WO2019185064A1 (en) * 2018-03-30 2019-10-03 暨南大学 Quinoline or quinazoline compound and application thereof
CN112351971A (en) * 2018-03-30 2021-02-09 上海海和药物研究开发股份有限公司 Quinoline or quinazoline compound and application thereof
JP2021519345A (en) * 2018-03-30 2021-08-10 上海海和薬物研究開発股▲ふん▼有限公司 Quinoline or quinazoline compounds and their applications
JP7036332B2 (en) 2018-03-30 2022-03-15 上海海和薬物研究開発股▲ふん▼有限公司 Quinoline or quinazoline compounds and their applications
CN112351971B (en) * 2018-03-30 2022-11-22 上海海和药物研究开发股份有限公司 Quinoline or quinazoline compound and application thereof
CN108948014A (en) * 2018-08-24 2018-12-07 江西科技师范大学 1- aryl -4- Oxy-1, the preparation and application of the pyrido heterocycle compound of 4- dihydroquinoline structure
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
WO2022253283A1 (en) * 2021-06-01 2022-12-08 中国科学院上海有机化学研究所 Protein kinase degradant and use thereof
CN113429422A (en) * 2021-07-26 2021-09-24 中国人民解放军军事科学院军事医学研究院 Thienoquinolone compound and preparation method and application thereof
CN113429422B (en) * 2021-07-26 2022-05-10 中国人民解放军军事科学院军事医学研究院 Thienoquinolone compound and preparation method and application thereof

Similar Documents

Publication Publication Date Title
CN107151240A (en) Polysubstituted carbostyril compound of one class and its production and use
CN109988144A (en) Aromatic ethylene or fragrant ethyl analog derivative, preparation method, intermediate, pharmaceutical composition and application
CN104902895B (en) It can be used as the dihydronaphthridine and related compound of the kinase inhibitor for treating proliferative disease
CN103987700B (en) 4-quinazoline amine derivant and application thereof
CN102643268B (en) Quinoline and cinnoline compound and application thereof
CN102977014B (en) New quinoline compounds and uses thereof
CN104119317B (en) Quinolines containing 1,2,3-triazole and its preparation method and application
CN101948425A (en) As the compound of glucocorticoid ligands, the pharmaceutical composition that comprises them, test kit and preparation method thereof
CN106715440A (en) Imidazo isoindole derivative, preparation method therefor and medical use thereof
TWI448461B (en) 4-aniline-6-butenamide-7-alkyl ether quinazoline derivatives, methods and uses thereof
CN104045642A (en) Fused ring compound containing pyrimidine or pyridine and its application as antitumor drug
WO2015188681A1 (en) Novel heterocyclic compound and preparation method therefor and use thereof as kinase inhibitor
CN104211686A (en) Quinoline derivatives and treatment use thereof
EP3661935A1 (en) Substituted pyrazolopyrimidines useful as kinases inhibitors
CN113480543B (en) 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and synthetic method and application thereof
CN102633812B (en) Oxazolone quinazoline derivatives as well as preparation method and application thereof
WO2015021894A1 (en) Novel hydroximic acid derivative and medical application thereof
WO2017181974A1 (en) Five-membered heterocyclic compound, preparation method therefor, pharmaceutical composition and use
CN105461687A (en) Dihydropyridazinone containing quinoline compound and use thereof
CN105461708A (en) Quinazoline tyrosine kinase inhibitor, and preparation method and application thereof
CN105017217A (en) Pyrazolone-containing quinoline compound and preparation method and application thereof
CN103965107B (en) 2-aryl substituted quinoline derivatives and application thereof
CN104926789A (en) 4-phenoxyl substituted quinoline compound containing imidazolone and application thereof
WO2010083649A1 (en) Bisarylurea derivatives and their use
CN106810553B (en) 3- (4, 5-substituted aminopyrimidine) phenyl derivative and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20170912