CN110156803A - Dioxanes and quinolines and the preparation method and application thereof - Google Patents

Dioxanes and quinolines and the preparation method and application thereof Download PDF

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CN110156803A
CN110156803A CN201810983341.3A CN201810983341A CN110156803A CN 110156803 A CN110156803 A CN 110156803A CN 201810983341 A CN201810983341 A CN 201810983341A CN 110156803 A CN110156803 A CN 110156803A
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base
acid
compound
group
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张强
于善楠
王中祥
冯守业
孙月明
刘彦生
张宏波
杨磊夫
杨海龙
周利凯
郑南桥
胡晨明
徐占强
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Beijing Saite Mingqiang Medicine Technology Co Ltd
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Beijing Saite Mingqiang Medicine Technology Co Ltd
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Priority claimed from PCT/CN2018/076233 external-priority patent/WO2018153293A1/en
Application filed by Beijing Saite Mingqiang Medicine Technology Co Ltd filed Critical Beijing Saite Mingqiang Medicine Technology Co Ltd
Priority to KR1020207025607A priority Critical patent/KR102433023B1/en
Priority to ES19751025T priority patent/ES2945573T3/en
Priority to EP19751025.8A priority patent/EP3750893B1/en
Priority to DK19751025.8T priority patent/DK3750893T3/en
Priority to SG11202007554TA priority patent/SG11202007554TA/en
Priority to AU2019218187A priority patent/AU2019218187B2/en
Priority to PCT/CN2019/073260 priority patent/WO2019154133A1/en
Priority to US16/968,797 priority patent/US11407760B2/en
Priority to CA3090876A priority patent/CA3090876C/en
Priority to PL19751025.8T priority patent/PL3750893T3/en
Priority to JP2020542958A priority patent/JP7022454B2/en
Priority to CN201980012397.7A priority patent/CN111788207B/en
Publication of CN110156803A publication Critical patent/CN110156803A/en
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Abstract

The present invention relates to the dioxanes with formula (I) and quinolines or its officinal salts.The present invention also provides the preparation of a kind of formula (I) compound and its officinal salt and as the application of drug, the drug is as tyrosine kinase (such as VEGFR-2 and c-MET) inhibitor for treating disease relevant to tyrosine kinase.

Description

Dioxanes and quinolines and the preparation method and application thereof
Technical field
The present invention relates to dioxanes and quinolines, pharmaceutically acceptable salt, isomers, hydrate, solvents Compound or prodrug, and its preparation method and application.
Background technique
Receptor tyrosine kinase (RTKs) influences the cross-cell membrane transmission of biochemical signals, by containing across cell membrane There are extracellular domain, single pass transmembrane area, the intracellular domain containing protein tyrosine kinase activity in ligand binding site Three parts composition.The combination of ligand and receptor can the relevant tyrosine kinase activity of costimulatory receptor, which leads to receptor and its The phosphorylation of tyrosine residue on his intracellular molecules, and then cause the cascade signal for leading to various cell effects.Tyrosine The overexpression of receptor has activated downstream signal transduction access, eventually leads to the abnormal conversion and proliferation of cell, promotes tumour Occur, development.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) be one of receptor tyrosine kinase family, by with its ligand vascular endothelial growth factor (vascular Endothelial growth factor, VEGF) a series of biochemical and physiology courses of generation are combined, finally promote new vessels It is formed.Tumor vascular generation and their permeability mainly pass through vascular endothelial growth factor (VEGF) adjusting, lead to At least two different receptors (VEGFR-1, VEGFR-2) are crossed to play a role.According to Jakeman, Kolch, Connolly etc. Researches show that: VEGF be normal and pathologic vessels generate with the important stimulus object of vascular permeability (Jakeman etc., 1993, Endocrinology 133:848-859；Kolch etc., 1995, Breast Cancer Research and Treatment, 36:139-155；Connolly etc., 1989, J.Biol.Chem.264:20017-20024).Vascular endothelial growth factor By inducing cell proliferation, albumen expression of enzymes and migration and to subsequently form the cell tissue of capillary raw to induce vascular bud Phenotype.Therefore, the inhibition that can lead to tumour growth to the antagonism of VEGF generated by chelation of the antibody to VEGF (Kim etc., 1993, Nature 362:841-844).
It, can be with VEGF-A, VEGF-C, VEGF-D, VEGF-E since VEGFR-2 is mainly distributed in vascular endothelial cell In conjunction with.And the nucleus formation of the proliferation of VEGF stimulating endothelial cell, the permeability for increasing blood vessel and new blood vessel mainly passes through knot Close and activate VEGFR-2 to realize.If the activity of blocking VEGF R-2, tumour can be inhibited by directly or indirectly approach Growth and transfer, and then reach ideal antitumous effect.Therefore, finding has high activity, highly selective to VEGFR-2 Micromolecular inhibitor becomes very promising ideas of cancer therapy.
Hepatocyte growth factor receptor (hepatocyte growth factor receptor, c-MET) is tyrosine-kinase One kind of enzyme acceptor, abnormal activation play an important role in the occurrence and development that Several Kinds of Malignancy includes lung cancer.Liver Porcine HGF (HGF) be c-MET ligands specific, c-MET in conjunction with HGF after sent out by HGF/c-MET signal path Wave biological action.HGF/c-MET signal path can induce cell Proliferation, dispersion, migration, organ morphology formation, angiogenesis Etc. a series of biological effects.The abnormal activation of c-MET can behave as receptor overexpression, gene mutation, amplification, dystopy, rearrangement etc.. These variations can lead to downstream signaling pathway imbalance, such as serine/threonine protein kitase (AKT), extracellular signal kinases (ERK), phosphatidylinositols -3- hydroxyl kinases, retinoblastoma inhibit albumen (Rb) access etc., and mediate tumor occurs, invades Attack and shift, angiogenesis, Epithelial and stromal conversion etc. processes.C-MET the proliferation of cell, metabolism and tumour generation, turn It moves, play key player in angiogenesis, it has also become the important target spot of antineoplaston.It is controlled by the targeting of target spot of c-MET Treatment shows its significance in the treatment of the Several Kinds of Malignancy including lung cancer.
In the therapeutic process using anti-tumor drug, the interaction of multiple signal paths will affect anti-tumor drug Function and effect are produced if the interaction of HFG/c-MET signal path and other accesses affects the therapeutic effect of anti-tumor drug Raw drug resistance.Therefore, more kinases target spot drug combinations become new antineoplaston means, and Crizotinib and The successful listing of Cabozantinib illustrates that the exploitation of more kinases target spot inhibitor has good potentiality and application value.
Cabozantinib is a kind of micromolecular inhibitor of protein kinase, to c-MET, VEGFR-2, Ret, Kit, AXL There is inhibiting effect etc. a variety of kinases.Cabozantinib can inhibit the phosphorylation of c-MET and VEGFR-2 in tumor model, Effective antitumour transfer and anti-angiogenesis activity are shown in preclinical pharmacophore model.It is same to act solely on VEGFR target Inhibitor compare, do not found in the lung tumors metastasis model treated with Cabozantinib tumor load increase, say Bright Cabozantinib is the effective of Tumor Angiongesis and transfer in c-MET and VEGFR-2 signal path imbalance tumor patient Inhibitor.FDA is used for progressivity in approval Cabozantinib on November 29th, 2012 listing, shifts medullary carcinoma of thyroid gland (MTC) treatment of patient.
It does so similar to Cabozantinib and is had many advantages for the inhibitor of more targets, this type is inhibited The research of agent is also very burning hot.The drug listed at present is seldom, and the channel of acquisition is limited, and the drug listed is in use The problems such as will appear drug resistance and side effect.Therefore, for compared to the single target spot inhibitor listed, the small molecule of more targets Inhibitor has better therapeutic effect and application prospect.
Summary of the invention
The compound that formula (I) provided by the present invention indicates, pharmaceutically acceptable salt, isomers, hydrate, solvation Object or prodrug can be used as treating or preventing the disease as caused by tyrosine kinase (such as VEGFR-2 and/or c-MET), packet Include certain mutation of tyrosine kinase receptor.
In formula (I),
Q is CH；
G is O；
Z is CH；
L is selected from following groupWherein X is H or C1-C3Alkyl；Y is H or C1-C3Alkyl；n =0-3, and as n=0, L is indicated
R1For H, C1-C9Alkyl, C3-C7Naphthenic base, 4-7 circle heterocyclic ring base, C3-C7Naphthenic base replace C1-C6Alkyl, The C that 4-7 circle heterocyclic ring base replaces1-C6Alkyl, substituted C1-C9Alkyl, the substituted C1-C9The substituent group of alkyl be hydroxyl, C1-C6Alkoxy, C1-C6Alkylthio group or-NR6R7One of or more than one,
R6And R7It is separately H, C1-C6The C that alkyl, hydroxyl replace1-C6Alkyl, C1-C3The C that alkoxy replaces1-C6 Alkyl；
Above-mentioned 4-7 circle heterocyclic ring base is the 4-7 circle heterocyclic ring base containing the 1-2 atoms in N, O, S, 4-7 circle heterocyclic ring base It is not substituted or by C1-C3Alkyl, C1-C3Acyl group replaces or is aoxidized by one to two oxygen atom；
R2For H, C1-C3Alkyl or halogen；
R3For H, C1-C3Alkyl or halogen；
R4For H, C1-C3Alkyl or halogen；
R5For H, C1-C9Alkyl, C3-C7Naphthenic base, C3-C7The C that naphthenic base replaces1-C6Alkyl, aryl, what aryl replaced C1-C6The C that alkyl, heteroaryl or heteroaryl replace1-C6Alkyl；
The aryl, heteroaryl are not substituted or by C1-C3Alkyl, C1-C3Alkoxy, C1-C3Alkylthio group, Dan Huo Double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl, aryloxy group and methylsulfonyl or more than one substitutions；It is described Heteroaryl is containing the 1-3 hetero atoms in N, O, S and the monocycle or bicyclic radicals containing 5 to 10 annular atoms.
According to a preferred embodiment, R1For H, C1-C6Alkyl, C3-C6Naphthenic base, 5-6 circle heterocyclic ring base, C3-C6 Naphthenic base replace C1-C3Alkyl, the C that 5-6 circle heterocyclic ring base replaces1-C3Alkyl, substituted C1-C6Alkyl, it is described substituted C1-C6The substituent group of alkyl is hydroxyl, C1-C3Alkoxy, C1-C3Alkylthio group or-NR6R7,
R6And R7It is separately-H, C1-C3The C that alkyl, hydroxyl replace1-C3Alkyl, C1-C3The C that alkoxy replaces1- C3Alkyl,
Above-mentioned 5-6 circle heterocyclic ring base is the 5-6 circle heterocyclic ring base containing the 1-2 atoms in N, O, S, and the 5-6 member is miscellaneous Ring group is not substituted or by C1-C3Alkyl, C1-C3Acyl group replaces or is aoxidized by one to two oxygen atom.
According to a preferred embodiment, R1Selected from methyl, ethyl, propyl, isopropyl, methoxy ethyl, methoxyl group Propyl, methoxybutyl, methoxypentyl, methoxyethyl, tetrahydrofuran -3- base, tetrahydro -2H- pyrans -4- base, tetrahydro pyrrole Cough up -1- ethyl, nafoxidine -1- propyl, piperidines -1- ethyl, piperidines -1- propyl, piperazine -1- ethyl, piperazine -1- propyl, Quinoline -4- ethyl, morpholine -4- propyl, methyl piperazine -4- ethyl, methyl piperazine -4- propyl, N- formyl piperazine -4- ethyl, N- Formyl piperazine -4- propyl, N- Acetylpiperazine -4- ethyl, N- Acetylpiperazine -4- propyl, (1,1- dioxy thiomorpholine Base) -4- ethyl, (1,1- dioxidothiomorpholinyl) -4- propyl, methylmercaptoethyl, methylthio, dimethylaminoethyl, two Methylaminopropyl, dimethylaminobutyl, dimethylamino amyl, dimethylamino hexyl, diethyllaminoethyl, lignocaine propyl, Hydroxyethyl, hydroxypropyl, hydroxyethylaminoethyl, hydroxypropyl ethyl, hydroxyethylamino propyl, methoxyethylamino Ethyl, methoxy-propyl amino-ethyl, methoxyethylamino propyl, amino-ethyl, aminopropyl, aminobutyl, N- methyl- N- hydroxyethylaminoethyl, N- methyl-N- hydroxypropyl ethyl, N- methyl-N- hydroxyethylamino propyl, N- methyl-N- first Oxygroup ethylaminoethyl, N- methyl-N-methoxy propylaminoethyl, N- methyl-N-methoxy diethylaminobutyyl, 2- first Base -2- hydroxypropyl, 3- methyl -3- hydroxybutyl, (3S) -3- aminobutyl, (3R) -3- aminobutyl, (3S) -3- hydroxyl fourth One of base or (3R) -3- hydroxybutyl or more than one.
According to a preferred embodiment, R1It is selected from: butyl, isobutyl group, amyl, isopentyl, hexyl, cyclopropyl first Base, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4,4- lupetidine -1- second Base, 4,4- lupetidine -1- propyl, oxetanes -3- base.
According to a preferred embodiment, R2、R3、R4Described in halogen be Cl or F.
According to a preferred embodiment, R5For-H, C1-C6Alkyl, C3-C6Naphthenic base, C3-C6The C that naphthenic base replaces1- C3Alkyl, aryl, the C that aryl replaces1-C3The C that alkyl, heteroaryl or heteroaryl replace1-C3Alkyl, the aryl, heteroaryl Substituent group be C1-C3Alkyl, C1-C3Alkoxy, C1-C3Alkylthio group, single or double C1-C3Alkyl-substituted amino, halogen One of element, trifluoromethyl, aryloxy group and methylsulfonyl or more than one；
The heteroaryl is the hetero atom containing 1-2 in N, O, S and the monocycle containing 5 to 10 annular atoms or double Cyclic group.
It is highly preferred that R5Selected from H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, phenyl, 4- fluorophenyl, 3- fluorophenyl, 2- fluorophenyl, 4- chlorphenyl, 3- chlorphenyl, 2- chlorphenyl, 2,4 difluorobenzene base, Fluoro- 4- (the trifluoro of 2,5- difluorophenyl, 3,4- difluorophenyl, 2,4 dichloro benzene base, 2,5- dichlorophenyl, 3,4- dichlorophenyl, 2- Methyl) phenyl, 2- fluoro- 5- (trifluoromethyl) phenyl, 3- fluoro- 4- (trifluoromethyl) phenyl, 3- fluoro- 5- (trifluoromethyl) phenyl, The fluoro- 4- chlorphenyl of -4 fluorophenyl of 3- trifluoromethyl, 2-, the fluoro- 5- chlorphenyl of 2-, the fluoro- 4- chlorphenyl of 3-, the fluoro- 5- chlorphenyl of 3-, 3- Chloro- 4- fluorophenyl, 2- chloro- 4- (trifluoromethyl) phenyl, 2- chloro- 5- (trifluoromethyl) phenyl, 3- chloro- 4- (trifluoromethyl) benzene Base, 3- chloro- 5- (trifluoromethyl) phenyl, 3- trifluoromethyl-4-chlorophenyl, the chloro- 4- fluorophenyl of 2-, the chloro- 5- fluorophenyl of 2-, 3- Chloro- 4- fluorophenyl, benzyl, phenethyl, 4- luorobenzyl, naphthalene -1- base, 3- methyl-isoxazole -5- base, 4- Phenoxyphenyl, 3- (methylsulfonyl) phenyl, 4- (methylsulfonyl) phenyl, pyridine -2- base, pyridin-3-yl, pyridin-4-yl, 3- methoxy-benzyl or 4- first Oxy-benzyl.
The application also provides the compound that a kind of formula (I) indicates, its pharmaceutically acceptable salt, isomers, hydrate, molten Agent compound or prodrug,
In formula (I),
Q is CH；
G is O；
Z is CH；
L is selected from following groupWherein X is H or C1-C3Alkyl；Y is H or C1-C3Alkyl； N=0-3, and as n=0, L is indicated
R1To be selected from C by 1 to 31-C3Acyl group, halogen, trifluoromethyl, cyano ,-CONH2、-NRaRbOr 4-7 member heterolipid ring C replaced substituent group in base1-C6Alkyl, the 4-7 member heteroalicyclyl are to make containing the 1-2 atoms in N, O, S For the 4-7 member heteroalicyclyl of annular atom, and the 4-7 member heteroalicyclyl is selected from halogen, C by 1 to 31-C3Alkyl, hydroxyl ,- NH2、C1-C3Replaced substituent group in acyl group,
RaAnd RbIt is each independently-H, C1-C6Alkyl, C3-C6Naphthenic base, C1-C3The C that alkoxy replaces1-C6Alkyl, C1- C3The C that alkylthio group replaces1-C6Alkyl, single or double C1-C3The C that alkyl-substituted amino replaces1-C6Alkyl or non-substituted ammonia The C that base replaces1-C6Alkyl；
R2、R3、R4It is each independently H, C1-C3Alkyl or halogen；
R5For-H, C1-C9Alkyl, C3-C7Naphthenic base, C3-C7The C that naphthenic base replaces1-C6Alkyl, aryl, aryl replace C1-C6The C that alkyl, heteroaryl or heteroaryl replace1-C6Alkyl；
The aryl, heteroaryl are not substituted or are selected from hydroxyl, amino, cyano, C by 1-31-C3Alkyl, C1-C3's Alkoxy, C1-C3Alkylthio group, single or double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl and methylsulfonyl or A variety of substituent groups replace；
Above-mentioned heteroaryl is the hetero atom containing 1-3 in N, O, S and the monocycle containing 5 to 10 annular atoms or double Cyclic group.
According to a preferred embodiment, wherein R1To be selected from C by 1 to 31-C3Acyl group ,-F, trifluoromethyl, cyanogen Base ,-CONH2、-NRaRbOr C replaced the substituent group in 4-7 member heteroalicyclyl1-C6Alkyl, the 4-7 member heteroalicyclyl are Contain 1-2 4-7 member heteroalicyclyls of the atom as annular atom in N, O, S, and the 4-7 member heteroalicyclyl is by 1 to 3 It is a to be selected from-F, C1-C3Alkyl, hydroxyl ,-NH2、C1-C3Replaced substituent group in acyl group,
RaAnd RbIt is each independently-H, C1-C3Alkyl, C3-C6Naphthenic base, C1-C3The C that alkoxy replaces1-C3Alkyl, C1- C3The C that alkylthio group replaces1-C3Alkyl, single or double C1-C3The C that alkyl-substituted amino replaces1-C3Alkyl or non-substituted ammonia The C that base replaces1-C3Alkyl；
R2、R3、R4It is each independently-H ,-F or-Cl；
R5For-H, aryl, the C that aryl replaces1-C3The C that alkyl, heteroaryl or heteroaryl replace1-C3Alkyl, the virtue Base, heteroaryl are not to be substituted or be selected from hydroxyl, amino, cyano, C by 1-31-C3Alkyl, C1-C3Alkoxy, C1-C3 Alkylthio group, single or double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl and methylsulfonyl or a variety of substituent groups take Generation；
The heteroaryl is monocycle or bicyclic radicals containing 5 to 10 annular atoms；Heteroaryl contain 1-2 selected from N, O, Hetero atom in S.
It is highly preferred that R1Selected from cyano methyl, cyano ethyl, cyanopropyl ,-CH2CONH2、-CH2CF3、 - 4 hydroxy piperidine -1- propyl of 4- methyl, -4 hydroxy piperidine -1- ethyl of 4- methyl, -4 amino piperidine -1- propyl of 4- methyl, 4- first - 4 amino piperidine -1- ethyl of base, N- methyl-N- Cyclobutylamino propyl, N- methyl-N- cyclopropylamino propyl, N- methyl - N- clopentylamino propyl, N- methyl-N-cyclohexyl aminopropyl, N- methyl-N- Cyclobutylamino ethyl, N- methyl-N- ring Propylaminoethyl, N- methyl-N- clopentylamino ethyl, N- methyl-N-cyclohexyl amino-ethyl.
The present invention provides the pharmaceutical salt of formula (I) compound, wherein the salt is acidity/anion salt or alkali Property/cationic salts；The form that pharmaceutically acceptable acidity/anion salt is usually taken be allow basic nitrogen therein by inorganic or Organic acid protonation, representative organic or inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphorus Acid, formic acid, acetic acid, propionic acid, hydroxyacetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, Portugal Grape saccharic acid benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzene sulfonic acid, oxalic acid, palmitinic acid, 2- naphthalene sulfonic acids, to toluene sulphur Acid, cyclohexylamino sulfonic acid, salicylic acid, saccharinic acid, trifluoroacetic acid.Pharmaceutically acceptable basic/cationic salts class includes (certainly It is not limited only to this) aluminium, calcium, chloroprocanine, choline, diethanol amine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The present invention, which provides, a kind of prepares above compound or its pharmaceutically acceptable salt, isomers, hydrate, solvent The method of compound or prodrug, which is characterized in that include the following steps, the compound as shown in formula (II ') and formula (III ') shownization It closes object reaction and formula (I) compound is prepared, wherein Q, G, Z, L, R1、R2、R3、R4And R5As defined hereinabove,
The present invention, which provides, a kind of prepares above compound or its pharmaceutically acceptable salt, isomers, hydrate, solvent The method of compound or prodrug, which is characterized in that include the following steps, the compound as shown in formula (II ') and formula (III) shownization It closes object reaction and formula (I) compound is prepared, wherein Q, G, Z, L, R1、R2、R3、R4And R5As defined hereinabove,
The present invention provide preparation above compound intermediate, a kind of formula (II ') compound represented, wherein Q, G, Z, R1、R2、R3And R4As defined hereinabove,
Specific embodiment
Unless otherwise indicated, the following term used in the application (including specification and claims) has following The definition provided.In this application, unless otherwise stated, mean "and/or" using "or" or "and".In addition, term " packet Include " and other forms use, such as "comprising", " containing " and " having " are not limiting.Chapters and sections mark used herein Topic is used for the purpose of the purpose of tissue, and should not be construed as the limitation to the theme.
Term " substitution " referred to here, including complicated substituent group (for example, phenyl, aryl, miscellaneous alkyl, heteroaryl), Proper is 1 to 5 substituent group, preferably 1 to 3, preferably 1 to 2, can freely be selected from substituent group list It selects.
Unless there are specified otherwise, alkyl, including saturated straight chain, branched hydrocarbyl, C1-C9The carbon atom number for indicating alkyl is 1-9 Carbon atom, C similarly1-C3For example indicate that the carbon atom number of alkyl is the carbon atom of 1-3, for example, C1-C6Alkyl includes first Base, ethyl, propyl, isopropyl, n- butyl, isobutyl group, sec-butyl, tert-butyl, n- amyl, 3- (2- methyl) butyl, 2- penta Base, 2- methyl butyl, neopentyl, n- hexyl, 2- hexyl and 2- methyl amyl etc..Alkoxy is by previously described linear chain or branched chain The allcyl-O-groups that alkyl and-O- are formed.Similar, alkenyl and alkynyl include straight chain, branched-chain alkenyl or alkynyl.
Naphthenic base refers to the cyclic group that carbon atom is formed, for example, C3-C7Naphthenic base may include cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, suberyl, it is similar, it equally include cyclic alkenyl radical.
Term " aryl " used herein refers to unsubstituted or substituted virtue unless otherwise specified Perfume base, such as phenyl, naphthalene, anthryl.
" being aoxidized by one or two oxygen atom " refers to that sulphur atom is aoxidized to be formed between sulphur and oxygen with double bond by an oxygen atom Connection, or aoxidized to be formed between sulphur and two oxygen by two oxygen atoms and be connected with double bond.
Term " heterocycle " used herein represents unsubstituted or substituted steady unless there are specified otherwise 3 to 8 fixed unit monocycle saturated ring systems, they are made of carbon atom and 1 to 3 hetero atom selected from N, O, S, wherein N, S hetero atom can be aoxidized arbitrarily, and N hetero atom can also be by arbitrarily quaternized.The example of this kind of heterocycle includes (but not limiting to In) azetidinyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thiazoles base, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, Piperidyl, piperazinyl aoxidize piperazinyl, oxyl base, dioxolanes base, dioxocyclohex alkyl imidazolidine base, tetrahydro Oxazolyl, thiamorpholinyl sulfoxide, thiomorpholine sulfone and oxadiazoles base.
Term " heteroaryl " used herein represents unsubstituted or substituted stabilization unless otherwise specified 5 or 6 unit monocycle aromatic ring systems, the thick heteroaryl of unsubstituted or substituted 9 or 10 annular atoms benzene can also be represented Ring system or bicyclic heteroaromatic ring system, they are formed by carbon atom and by 1 to 3 hetero atom selected from N, O, S, wherein N, S hetero atom can be oxidized, and N hetero atom can also be quaternized.Heteroaryl can connect group with any hetero atom or carbon atom At a stable structure.Heteroaryl includes but is not limited to thienyl, furyl, imidazole radicals, pyrrole radicals, thiazolyl, evil Oxazolyl, isoxazolyl, pyranose, pyridyl group, piperazinyl, pyrimidine radicals, pyrazine, pyridazinyl, pyrazolyl, thiadiazolyl group, triazolyl, Indyl, azaindolyl, indazolyl, azaindazole base, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxa are disliked Oxazolyl, benzoxazolyl, benzopyrene oxazolyl, benzothiazolyl, diazosulfide base, benzotriazole base, adenyl, quinolyl Or isoquinolyl.
Term " carbonyl " refers to-C (O)-base.
No matter when term " alkyl " or " aryl " or they any prefix root appear in the title of a substituent In (for example, aralkyl, dialkyl amino), those of it will be considered containing the above are " alkyl " and " aryl " and provide limit System.The specified quantity of carbon atom is (for example, C1-C6) indicate independent in a moieties or in a bigger substituent group In moieties (wherein alkyl is as its prefix root) in carbon atom quantity.
The present invention also provides preparation respective compound method, can be used a variety of synthetic methods prepare it is as described herein Compound, including following methods, the compound of the present invention or its pharmaceutically acceptable salt, isomers or hydrate can be with Using synthetic method known to following methods and organic chemical synthesis field, or by those skilled in the art understand that these sides The changing method of method synthesizes, and preferred method includes but is not limited to following methods.
In an arrangement, formula (I) formula (II ') compound of the present invention is reacted with formula (III ') or formula (III) It prepares, wherein Q, G, Z, L, R1、R2、R3、R4And R5As mentioned before.
Invention further provides preparation formula (I) compound intermediates, i.e. formula (II ') compound represented, wherein Q, G、Z、R1、R2、R3And R4As defined hereinabove,
The compounds of this invention can by the following method or prepared by technical solution well known by persons skilled in the art,
Step 1) carries out nitration reaction, it is preferred that nitration reaction condition is nitric acid and acetic acid.
Step 2) carries out nitro-reduction reaction, and nitro reduction is carried out using those skilled in the art's routine operation；
Preferably, the condition of nitro-reduction reaction is including but not limited to hydrogen and Raney's nickel, hydrogen and palladium carbon, acid condition Lower iron powder or zinc powder or stannous chloride；
1- (8- methoxyl group -6- amino -2,3-d dihydrobenzo [b] [1,4] dioxanes -5-) second -1- ketone and first in step 3) Sour methyl esters or Ethyl formate in organic solvent, obtain 10- hydroxy-5-methyl oxygroup -2,3- dihydro-[Isosorbide-5-Nitrae] two under the catalysis of alkali Oxane simultaneously [2,3-f]-quinoline, wherein the organic solvent is including but not limited to dioxane, tetrahydrofuran, the tert-butyl alcohol, second Alcohol, methanol one or both of them more than combination；The alkali is including but not limited to sodium tert-butoxide, potassium tert-butoxide, first Sodium alkoxide, sodium ethoxide；The reaction can also be performed under heating conditions, and the temperature of heating is that room temperature extremely flows back.
10- hydroxy-5-methyl oxygroup -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline and chlorination reagent in step 4) Reaction prepares 10- chloro-5-methoxyl -2,3- dihydro-[Isosorbide-5-Nitrae] dioxanes simultaneously [2,3-f]-quinoline in organic solvent, wherein institute The chlorination reagent stated is phosphorus oxychloride；The organic solvent including but not limited to benzene, toluene, chlorobenzene, dimethylbenzene wherein one A or more than two combinations；The reaction carries out under the conditions of can also be existing for the organic base, and the organic base is triethylamine Or diisopropyl ethyl amine.
Step 4a) in 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline in organic solvent In, chloro- 2,3- dihydro-[Isosorbide-5-Nitrae] dioxanes of 5- hydroxyl -10- simultaneously [2,3-f]-quinoline is obtained under the action of lewis acid, wherein institute The lewis acid stated is Boron tribromide or boron chloride；Organic solvent is methylene chloride.
Step 4b) in chloro- 2,3- dihydro-[1,4] dioxanes of 5- hydroxyl -10- simultaneously [2,3-f]-quinoline and R1X is organic molten Compound shown in preparation formula III-A in agent, wherein R1As defined hereinabove；Organic solvent is including but not limited to tetrahydrofuran, two Combination more than one of six ring of oxygen, DMF, DMA, DMSO, acetonitrile or both；R1X in X is chlorine, bromine, iodine, methanesulfonates, right Tosylate or triflate.
Compound shown in formula III-A in organic solvent, is mixed and heated to 100 DEG C to 140 DEG C with Formula V ' and obtained by step 5) To compound shown in IV '；The organic solvent be selected from toluene, chlorobenzene, dimethylbenzene, DMF, DMA, DMSO one of them or More than two combinations.
Step 6) carries out nitro-reduction reaction, and nitro reduction can be operated routinely using those skilled in the art；
Preferably, nitro-reduction reaction condition is including but not limited under hydrogen and Raney's nickel, hydrogen and palladium carbon, acid condition Iron powder, zinc powder or stannous chloride；
In a preferred scheme, compound shown in formula (III ') reacts step 7) with compound shown in formula (II '-A) When, wherein formula (III ') can be reacted with acylating reagent, then be reacted with formula (II '-A).
Preferably, the acylating reagent include but is not limited to phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride or A combination of one or more in phosphorus pentachloride.
In another embodiment, compound shown in formula (III '), in the presence of condensing agent, and shown in formula (II '-A) Compound reaction, obtains compound shown in formula (I-C),
Preferably, the condensing agent includes but is not limited to carbodiimide type condensing agent, salt condensing agent, organic phosphates contracting The one or more of mixture and other classification condensing agents, preferably N, N- dicyclohexylcarbodiimide (DCC), N, N- diisopropyl Base carbodiimide (DIC), hydroxybenzotriazole (HOBt), n,N-diisopropylethylamine (DIEA), 1- hydroxyl -7- azo benzo three Nitrogen azoles (HOAt), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU), benzotriazole -1- base oxygen (dimethylamino) the phosphorus hexafluorophosphate of base three (BOP), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea six Fluorophosphoric acid ester (HBTU), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters (HCTU), (7- aoxidizes benzo to 2- Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), propylphosphonic anhydride (T3P), 1- (3- dimethylamino third Base) -3- ethyl-carbodiimide hydrochloride (EDCI), 1- ethyl (3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), six Fluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Wan Phosphonium (PyBOP), (3H-1, -3 oxygroup of 2,3 triazols [4,5-b] pyridine) Three -1- Bi cough up a combination of one or more in Wan Ji Phosphonium hexafluorophosphate (PyAOP)；
Preferably, this step can carry out in organic base, and the organic base is including but not limited to triethylamine, diisopropyl Ethylamine, pyridine, 4-dimethylaminopyridine, 2,6- lutidines, 1,8- diazabicylo, 11 carbon -7- alkene or N- methyl Quinoline a combination of one or more.
Work as R1For-CH3When, step 4a and step 4b can be omitted, the operation that step 4) carries out step 5) afterwards is completed.
Meanwhile such as step 4a and step 4b and step 5 sequence and be not fixed, such as can also first carry out step 5, then Carry out step 4a and step 4b.
It is clear that the compound of Formulas I, isomers, crystal form or prodrug and its officinal salt there may be solvation form and Nonsolvated forms.Such as solvation form can be water-soluble form.The present invention include all these solvations and non-solvent The form of change.
The compound of the present invention may have asymmetric carbon atom, according to their physical and chemical difference, by known technology Mature method, for example, this diastereoisomeric mixture can be separated into single by chromatography or Steppecd crystallization Diastereoisomer.The separation of enantiomter can be by first with suitably there is the compound of optically active to be reacted, right The mixture for reflecting isomery is converted to diastereoisomeric mixture, separates diastereoisomer, then single diastereoisomer (hydrolysis) is converted into corresponding pure enantiomter.All such isomers, including non-enantiomer mixture and pure Enantiomer is considered as a part of the invention.
As the compound of the present invention of active constituent, and the method for preparing the compound, it is all the contents of the present invention. Moreover, the crystalline forms of some compounds can be used as polycrystal presence, this form may also be included in that current invention In.In addition, some compounds can be formed together solvate, this solvent with water (i.e. hydrate) or common organic solvent Compound is also included in the scope of the present invention.
The compound of the present invention can be used to treat in a free form, or in the appropriate case with pharmaceutically acceptable Salt or other derivatives form for treating.As used herein, term " pharmaceutically acceptable salt " refers to of the invention The organic salt and inorganic salts of compound, this salt be suitable for the mankind and lower animal, no excessive toxicity, irritation, allergic reaction etc., With reasonable interests/Hazard ratio.The pharmaceutically acceptable salt of amine, carboxylic acid, phosphonate and other types of compound is in institute Category is well-known in field.The salt can be reacted by the compound of the present invention with suitable free alkali or acid.Including But be not limited to, with inorganic acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acid for example acetic acid, oxalic acid, maleic acid, The salt that tartaric acid, citric acid, succinic acid, malonic acid are formed, or by using method well known in the art, such as ion exchange Method, to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphor hydrochlorate, camsilate, citrate, two Portugals Sugar lime, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconic acid Salt, Hemisulphate, caproate, hydriodate, 2- isethionate, Lactobionate, lactate, laruate, lauryl sulphur It is hydrochlorate, malate, maleate, methane sulfonates, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, double Hydroxynaphthoate, persulfate, crosses 3- phenylpropionic acid salt, phosphate, picrate, propionate, stearate, sulphur at pectate Hydrochlorate, rhodanate, tosilate, undecanoate etc..Representative alkaline or alkaline-earth salts include sodium, lithium, potassium, Calcium, magnesium etc..Other pharmaceutically acceptable salts include nontoxic ammonium appropriate, quaternary ammonium, and using such as halogen ion, hydroxyl, The amido cation that carboxylate radical, sulfate radical, phosphate radical, nitrate anion, low-grade alkane sulfonate and arylsulphonate are formed.
In addition, terms used herein " prodrug ", which refers to a compound in vivo, can be converted into shown in formula (I) of the present invention Compound.This conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for parent compound It rings.
Pharmaceutical composition of the invention includes structure formula (I) compound described herein or its pharmaceutically acceptable salt, swashs Enzyme inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressor, anticarcinogen, antivirotic, anti-inflammatory agent, antifungal agent, antibiosis The other activating agent of plain or anti-angiogenic antihyperproliferative compound；And any pharmaceutically acceptable carrier, adjuvant or figuration Agent.
The compound of the present invention can be used as exclusive use, can also with one or more other the compound of the present invention or It is used with one or more other drug combinations.When being administered in combination, therapeutic agent can be configured to be administered simultaneously or sequentially exist Different time administrations or the therapeutic agent can be used as single composition administration.So-called " combination treatment ", refer to using The compound of the present invention is used together with another medicament, and administration mode is that co-administered or every kind of medicament are suitable simultaneously for every kind of medicament Sequence administration, no matter which kind of situation, purpose is all the optimum efficiency of drug to be reached.Co-administered includes while delivering dosage form, with And the independent dosage form of every kind of compound respectively.Therefore, the compound of the present invention administration can with known this field other Therapy uses simultaneously, for example, using radiotherapy or cytostatic agent, cytotoxic agent, Qi Takang in cancer treatment The adjunctive therapies such as cancer agent improve cancerous symptom.The present invention is not limited to the sequences of administration；The compound of the present invention can be applied previously With being administered simultaneously, or applied after other anticancer agents or cytotoxic agent.
In order to prepare the Pharmaceutical Compositions of this invention, one or more chemical combination of the molecule formula (I) as its active constituent Object or salt can be mixed closely with pharmaceutical carriers, this be carried out according to traditional pharmacy ingredients technical, wherein Carrier can be used a variety of more according to by different administration mode (for example, oral or parenteral administration) designed preparation form The form of sample.Pharmaceutically acceptable carrier appropriate is technically well-known.To some of such pharmaceutically acceptable The description of carrier can be found " pharmaceutical excipient handbook " is inner, and the book is by American Pharmaceutical Association and pharmacy society, Britain combined publication.
Pharmaceutical composition of the present invention can have following form, such as, it is suitble to oral administration, such as tablet, capsule, medicine Ball, medicinal powder, the form of sustained release, solution or suspension；For parental injection such as transparent liquid, suspension, emulsion；Or For local application's such as cream, frost；Or rectally is used for as suppository.Pharmaceutical Compositions can also be suitble in the form of unit dose Once daily for exact dose.The Pharmaceutical Compositions will be including a kind of traditional pharmaceutical carriers or excipient and according to mesh Compound made of preceding invention as active constituent, alternatively, it is also possible to include others medicine or pharmaceutical formulations, carrier, Adjuvant, etc..
Therapeutic compound can also award mammal and non-human.It will be taken to drug dose used in a mammal Certainly in the type of the animal and its disease condition or the de-synchronization state locating for it.Therapeutic compound can be with capsule, greatly The form of pill, tablet liquid medicine is fed for animal.Therapeutic compound can also be allowed to enter animal by way of injecting or inculcating In vivo.We prepare these medicament forms according to the traditional mode for meeting veterinary practice standard.As a kind of selectable Mode, pharmacy synthetic drug can mix with animal feed and be fed for animal, therefore, the feed addictive of concentration or mix and stir in advance Material can be in case of to mix common animal feed.
A further object of the present invention is to be to provide a kind of method for treating cancer in subject in need, packet Include a kind of method that the therapeutically effective amount of the composition containing the compound of the present invention is applied to subject.
The invention also includes the uses of the compound of the present invention or its pharmaceutically acceptable derivates, manufacture for treating Cancer (including non-physical knurl, solid tumor, primary or metastatic cancer, have as pointed by the other places this paper and including cancer anti- Property or refractory one or more other treatments) and Other diseases (including but not limited to fundus oculi disease, psoriasis, artery congee Sample, pulmonary fibrosis, liver fibrosis, myelofibrosis etc.) medicament.The cancer includes but is not limited to: non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, cervix cancer, colorectal cancer, It is melanoma, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic Granulocytic leukemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and T are thin Any one of born of the same parents' lymthoma, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.
In order to make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, to this Invention is further elaborated.It should be appreciated that described herein, specific examples are only used to explain the present invention, and does not have to It is of the invention in limiting.Particular technique or condition are not specified in embodiment, according to the literature in the art described technology or Condition is carried out according to product description.Reagents or instruments used without specified manufacturer is that can be obtained by commercially available The conventional products obtained.Term as used herein "and/or" includes the arbitrary and institute of one or more relevant listed items Some combinations.Examples provided below can better illustrate the present invention, and unless stated otherwise, all temperature are DEG C.
Intermediate: the preparation of 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline
Step 1) 1- (8- methoxyl group -6- nitro -2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) ethyl -1- ketone Preparation
By 1- (8- methoxyl group -2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) ethyl -1- ketone (20.8g, 100mmol), nitric acid (22mL) and acetic acid (44mL) are placed in round-bottomed flask and stir to end of reaction, pour into trash ice, filter, obtain 16.5 grams of yellow solid product, yield 66%.1HNMR (400MHz, Chloroform-d) δ 7.37 (s, 1H), 4.43 (dd, J= 5.4,2.7Hz, 2H), 4.35 (dd, J=5.3,2.7Hz, 2H), 3.98 (s, 3H), 2.57 (s, 3H)；MS:254[M+H]+。
Step 2) 1- (8- methoxyl group -6- amino -2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) ethyl -1- ketone Preparation
By 1- (8- methoxyl group -6- nitro -2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) ethyl -1- ketone (16.5g, It 65mmol) is placed in a reaction flask, palladium carbon (2g) is added, and to end of reaction, it is solid that suction filtration is concentrated to give off-white color for stirring under hydrogen environment 13.7 grams of body product, yield 95%.1HNMR(400MHz,DMSO-d6)δ6.90(s,2H),5.96(s,1H),4.32–4.25 (m,2H),4.18–4.09(m,2H),3.72(s,3H),2.41(s,3H)；MS:224[M+H]+。
The preparation of step 3) 10- hydroxy-5-methyl oxygroup -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline
By 1- (6- amino -8- methoxyl group -2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) ethyl -1- ketone (13.7g, It 62mmol) is dissolved in dioxane with Ethyl formate (27.5g, 372mmol), sodium tert-butoxide (17.8g, 186mmol) is added and stirs It mixes to raw material and disappears, be added 10 milliliters of methanol and continue stirring to end of reaction, filtered after hydrochloric acid neutralization reaction liquid to neutrality, is dense It contracts, obtain 14.4 grams of off-white powder product, yield 99%.1HNMR(400MHz,DMSO-d6)δ11.26(s,1H),7.59(d,J =7.3Hz, 1H), 6.55 (s, 1H), 5.77 (d, J=7.2Hz, 1H), 4.34-4.13 (m, 4H), 3.82 (s, 3H)；MS:234 [M+H]+。
The preparation of step 4) 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline
By 10- hydroxy-5-methyl oxygroup -2,3- dihydro-[1,4] dioxanes, simultaneously [2,3-f] quinoline (14.4g, 61mmol) is set In reaction flask, toluene dissolution is added, triethylamine (42mL, 305mmol) is added later, phosphorus oxychloride (17mL, 183mmol) adds Thermal agitation is boiled off after obtained solid after solvent is washed with sodium bicarbonate aqueous solution and is filtered, obtain off-white powder to end of reaction 14.1 grams, yield 92%.1HNMR(400MHz,DMSO-d6) δ 8.51 (d, J=4.9Hz, 1H), 7.38 (d, J=4.8Hz, 1H), 7.12(s,1H),4.49–4.29(m,4H),3.93(s,3H)；MS:252[M+H]+。
The preparation of intermediate 1- ((4- fluorophenyl) carbamoyl) cyclopropane -1- carboxylic acid
By in (1.04 grams) addition anhydrous tetrahydro furans (20mL) of 1,1- cyclopropyl dicarboxylic acids, to stirring under the conditions of ice-water bath Triethylamine (0.84g) is slowly added dropwise in the suspension mixed and stirs half an hour, thionyl chloride then is added dropwise under the conditions of 0 DEG C (1.1g) is added and is continued stirring 1 hour, be then separately added into triethylamine (0.8g), the tetrahydrofuran of tetrafluoroaniline (0.9g) (10mL) solution, reaction stirring finish for 2 hours；Concentration is dissolved in the sodium hydroxide of 1N, and ethyl acetate extraction, water intaking is mutually with 1N's Dilute hydrochloric acid solution adjusts pH to 2.0, continues to stir half an hour, filters to obtain white solid product 1.1g, yield 62%, MS:224 [M +H]+。
The preparation of intermediate 1- ((4- fluorophenyl) carbamoyl) cyclopropane -1- formyl chloride
The thionyl chloride (2mL) of 1- ((4- fluorophenyl) carbamoyl) cyclopropane -1- carboxylic acid (111mg, 0.5mmol) adds Hot return stirring reaction continues reflux 1 hour after reaction solution clarification, cooling, is concentrated to get product as light yellow solid 120mg, Yield 100%；
Embodiment 1.N- (4- fluorophenyl)-N- (4- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline Quinoline -10- base) oxygroup) phenyl) and cyclopropane -1,1- diformamide preparation
Step 1): by 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline (251mg, It 1mmol) is placed in a reaction flask with p-nitrophenol (139mg, 1mmol), chlorobenzene is added, be heated to return stirring to having reacted Finish.It is filtered after cooling, obtained solid obtains light yellow solid (5- methoxyl group -10- (4- nitrobenzene after being washed with wet chemical Oxygroup) -2,3- dihydro-[Isosorbide-5-Nitrae] dioxanes simultaneously [2,3-f] quinoline) 250 milligrams, yield 71%.MS:355[M+H]+。
Step 2): step 1) products obtained therefrom (250mg, 0.7mmol) is placed in a reaction flask, and methanol, Raney's nickel is added (250mg), under hydrogen environment stirring to end of reaction, filter, be concentrated to give off-white powder product (4- ((methoxyl group -2 5-, 3- dihydro-[Isosorbide-5-Nitrae] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) aniline) 226 milligrams, yield 99%.MS:325[M+H ]+。
Step 3): by step 2) products obtained therefrom (226mg, 0.7mmol) and 1- ((4- fluorophenyl) carbamoyl) cyclopropyl Alkane -1- carboxylic acid is placed in a reaction flask, and n,N-Dimethylformamide dissolution is added, and 2- (7- aoxidizes benzotriazole)-is then added N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (380mg, 1mmol) and diethyl isopropyl amine (0.25mL, 1.5mmol), stirring to end of reaction, the washing of addition aqueous sodium carbonate, suction filtration, column chromatographs to obtain 296 milligrams of white solid, produces Rate 80%.1HNMR(300MHz,DMSO-d6) δ 10.19-10.02 (m, 2H), 8.43 (d, J=5.2Hz, 1H), 7.78-7.67 (m, 2H), 7.67-7.56 (m, 2H), 7.22-7.01 (m, 5H), 6.42 (d, J=5.3Hz, 1H), 4.38-4.25 (m, 4H), 3.92(s,3H),1.50–1.40(m,4H).MS:530[M+H]+。
Embodiment 2.N- (the fluoro- 4- of 3- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline -10- Base) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
Step 1) 10- (the fluoro- 4-nitrophenoxy of 2-) -5- methoxyl group -2,3- dihydro-[1,4] dioxanes is simultaneously [2,3-f] - The preparation of quinoline
The operation of 1 step 1) of reference implementation example, substituting p-nitrophenol with fluoro- 4 nitrophenol of the 2- of identical molar equivalent is It can.1HNMR(400MHz,DMSO-d6) δ 8.67 (d, J=5.0Hz, 1H), 8.44-8.27 (m, 1H), 8.13-7.93 (m, 1H), 7.19 (s, 1H), 7.07 (d, J=4.9Hz, 1H), 6.98 (t, J=8.7Hz, 1H), 4.31-4.18 (m, 2H), 4.16-4.06 (m,2H),3.95(s,3H)；MS:373[M+H]+。
The fluoro- 4- of step 2) 3- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) The preparation of aniline
1 step 2) of reference implementation example operation, with 10- (the fluoro- 4-nitrophenoxy of 2-) -5- methoxy of identical molar equivalent Simultaneously [2,3-f] quinoline substitutes 5- methoxyl group -10- (4-nitrophenoxy) -2,3- dihydro-to base -2,3- dihydro-[1,4] dioxanes [1,4] dioxanes simultaneously [2,3-f]-quinoline.1HNMR (400Hz, DMSO-d6) δ 8.38 (d, J=5.2Hz, 1H), 7.05 (s, 1H), 6.99 (t, J=9.0Hz, 1H), 6.61-6.49 (m, 1H), 6.49-6.38 (m, 1H), 6.33 (d, J=5.3Hz, 1H),5.53–5.37(m,2H),4.36–4.38(m,4H),3.92(s,3H)；MS:343[M+H]+。
Step 3) N- (the fluoro- 4- of 3- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygen Base) phenyl)-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
1 step 3) of reference implementation example operation, with the fluoro- 4- of the 3- of identical molar equivalent ((5- methoxyl group -2,3- dihydro-[1, 4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes is simultaneously by aniline substitution 4- [2,3-f] quinoline -10- base) oxygroup) aniline.1HNMR(400MHz,DMSO-d6)δ10.30(s,1H),9.97(s,1H), 8.35 (d, J=5.2Hz, 1H), 7.94-7.69 (m, 1H), 7.64-7.52 (m, 2H), 7.48-7.32 (m, 1H), 7.19 (t, J =9.0Hz, 1H), 7.09 (t, J=8.8Hz, 2H), 7.01 (s, 1H), 6.32 (d, J=5.2Hz, 1H), 4.28 (s, 4H), 3.85(s,3H),1.55–1.28(m,4H).MS:548[M+H]+。
Embodiment 3.N- (the fluoro- 4- of 2- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) Oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
Step 1) 10- (the fluoro- 4-nitrophenoxy of 3-) -5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline The preparation of quinoline
The operation of 1 step 1) of reference implementation example, substituting p-nitrophenol with fluoro- 4 nitrophenol of the 3- of identical molar equivalent is It can.MS:373[M+H]+。
The fluoro- 4- of step 2) 2- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) The preparation of aniline
1 step 2) of reference implementation example operation, with 10- (the fluoro- 4-nitrophenoxy of 3-) -5- methoxy of identical molar equivalent Simultaneously [2,3-f] quinoline substitutes 5- methoxyl group -10- (4-nitrophenoxy) -2,3- dihydro-to base -2,3- dihydro-[1,4] dioxanes [1,4] dioxanes simultaneously [2,3-f] quinoline.1HNMR (400MHz, DMSO-d6) δ 8.38 (d, J=5.2Hz, 1H), 7.04 (s, 1H), 6.98-6.91 (m, 1H), 6.89-6.79 (m, 1H), 6.78-6.67 (m, 1H), 6.37 (d, J=5.2Hz, 1H), 5.14(s,2H),4.43–4.30(m,4H),3.91(s,3H)；MS:343[M+H]+。
Step 3) N- (the fluoro- 4- of 2- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygen Base) phenyl)-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
1 step 3) of reference implementation example operation, with the fluoro- 4- of the 2- of identical molar equivalent ((5- methoxyl group -2,3- dihydro-[1, 4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes is simultaneously by aniline substitution 4- [2,3-f] quinoline -10- base) oxygroup) aniline.1HNMR(400MHz,DMSO-d6)δ10.49(s,1H),9.97(s,1H), 8.50 (d, J=5.1Hz, 1H), 7.92-7.82 (m, 1H), 7.65-7.57 (m, 2H), 7.25-7.06 (m, 4H), 6.89-6.84 (m, 1H), 6.63 (d, J=5.1Hz, 1H), 4.33-4.22 (m, 4H), 3.92 (s, 3H), 1.63-1.52 (m, 4H)；MS:548 [M+H]+。
(((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes is simultaneously by 4- by embodiment 4.N- (4- fluorophenyl)-N- [2,3-f] quinoline -10- base) oxygroup) phenyl) and cyclopropane -1,1- diformamide preparation
Step 1) is by 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline (251mg, 1mmol) It is dissolved in methylene chloride, instills the dichloromethane solution (3mL, 3mmol) of 1 mole every liter of Boron tribromide, stirring is to having reacted Finish.It is concentrated to give light yellow solid product (chloro- 2,3- dihydro-[Isosorbide-5-Nitrae] dioxanes of 5- hydroxyl -10- simultaneously [2,3-f] quinoline) 236mg, Yield 99%.MS:238[M+H]+。
Step 1) products obtained therefrom (236mg, 1mmol) is dissolved in n,N-Dimethylformamide by step 2), and 4- (3- chlorine third is added Base) morpholine (163mg, 1mmol) and potassium carbonate (414mg, 3mmol), heating stirring to end of reaction.Water and ethyl acetate is added Extraction, organic phase concentration rear pillar chromatograph to obtain off-white powder (the chloro- 5- of 10- (3- morpholine the propoxyl group)-evil of 2,3- dihydro-[Isosorbide-5-Nitrae] two Alkane simultaneously [2,3-f]-quinoline) 291mg, yield 80%.1H NMR(400MHz,DMSO-d6) δ 8.50 (d, J=4.8Hz, 1H), 7.37 (d, J=4.8Hz, 1H), 7.10 (s, 1H), 4.47-4.30 (m, 4H), 4.17 (t, J=6.4Hz, 2H), 3.59 (t, J= 4.6Hz, 4H), 2.45 (t, J=7.1Hz, 2H), 2.39 (d, J=4.5Hz, 4H), 1.97-1.95 (m, 2H) .MS:365 [M+H ]+。
Step 3) 5- (3- morpholine propoxyl group) -10- (4-nitrophenoxy) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3- F] quinoline preparation
1 step 1) of reference implementation example operation, with the chloro- 5- of the 10- of identical molar equivalent (3- morpholine propoxyl group) -2,3- bis- Simultaneously [2,3-f] quinoline substitutes 10- chloro-5-methoxyl -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline to hydrogen-[1,4] dioxanes Quinoline.MS:468[M+H]+。
Step 4) 4- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline -10- base) Oxygroup) aniline preparation
1 step 2) of reference implementation example operation, with 5- (3- morpholine propoxyl group) -10- (4- nitrobenzene oxygen of identical molar equivalent Base) simultaneously [2,3-f] quinoline substitutes 5- methoxyl group -10- (4-nitrophenoxy) -2,3- dihydro-to -2,3- dihydro-[1,4] dioxanes [1,4] dioxanes simultaneously [2,3-f] quinoline.1H NMR (400MHz, DMSO-d6) δ 8.33 (d, J=5.3Hz, 1H), 7.00 (s, 1H), 6.84 (d, J=8.1Hz, 2H), 6.65 (d, J=8.2Hz, 2H), 6.29 (d, J=5.3Hz, 1H), 5.10 (s, 2H),4.35(s,4H),4.20–4.11(m,2H),3.62–3.56(m,4H),2.48–2.36(m,6H),2.00–1.91(m, 2H).MS:438[M+H]+。
Step 5) N- (4- fluorophenyl)-N- (4- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2, 3-f] quinoline -10- base) oxygroup) phenyl) cyclopropane -1,1- diformamide preparation
1 step 3) of reference implementation example operation, with 4- ((5- (3- morpholine propoxyl group) -2,3- dihydro-of identical molar equivalent [1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) aniline substitutes 4- ((5- methoxyl group -2,3- dihydro-[1,4] dioxanes And [2,3-f] quinoline -10- base) oxygroup) aniline.1HNMR(400MHz,DMSO-d6)δ10.14(s,1H),10.07(s, 1H), 8.41 (d, J=5.3Hz, 1H), 7.70 (d, J=8.6Hz, 2H), 7.63 (dd, J=9.1,5.1Hz, 2H), 7.18- 7.12 (m, 2H), 7.11-7.03 (m, 3H), 6.41 (d, J=5.2Hz, 1H), 4.37-4.26 (m, 4H), 4.26-4.10 (m, 2H),3.68–3.54(m,4H),2.44–2.39(m,4H),2.02–1.92(m,2H),1.52–1.41(m,6H)；13C NMR (101MHz,DMSO-d6)δ168.6,168.5,161.3,151.7,151.1,149.6,146.7,138.2,136.0,135.6, 132.28,122.9,122.8,122.6,120.7,115.6,115.3,108.7,105.7,102.2,67.1,66.7,64.4, 63.9,55.3,53.8,31.9,26.2,15.8；MS:643[M+H]+。
Embodiment 5.N- (the fluoro- 4- of 3- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
Step 1 is identical to step 2 as the step 1 of the preparation of embodiment 4 to step 2.
Step 3) 10- (the fluoro- 4-nitrophenoxy of 2-) -5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes is simultaneously The preparation of [2,3-f] quinoline
The operation of 4 step 3) of reference implementation example, substituting p-nitrophenol with fluoro- 4 nitrophenol of the 2- of identical molar equivalent is It can.MS:486[M+H]+。
The fluoro- 4- of step 4) 3- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- Base) oxygroup) aniline preparation
1 step 2) of reference implementation example operation, with 10- (the fluoro- 4-nitrophenoxy of 2-) -5- (3- of identical molar equivalent Quinoline propoxyl group) simultaneously [2,3-f] quinoline substitutes 5- methoxyl group -10- (4-nitrophenoxy) -2 to -2,3- dihydro-[1,4] dioxanes, 3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline.1H NMR(400MHz,DMSO-d6) δ 8.37 (d, J=5.3Hz, 1H), 7.08-6.88 (m, 2H), 6.60-6.49 (m, 1H), 6.48-6.40 (m, 1H), 6.32 (d, J=5.2Hz, 1H), 5.44 (s, 2H), 4.37-4.39 (m, 4H), 4.16 (t, J=6.4Hz, 2H), 3.59 (t, J=4.6Hz, 4H), 2.46 (d, J= 7.0Hz,2H),2.39(s,4H),1.95–1.97(m,2H)；MS:456[M+H]+。
Step 5) N- (the fluoro- 4- of 3- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline - 10- yl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
1 step 3) of reference implementation example operation, with the fluoro- 4- of the 3- of identical molar equivalent ((5- (3- morpholine propoxyl group) -2,3- Dihydro-[1,4] dioxanes simultaneously [2,3-f]-quinoline -10- base) oxygroup) aniline substitutes ((dihydro-[1,4] 5- methoxyl group -2,3- 4- Dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) aniline.1HNMR(400MHz,DMSO-d6)δ10.32(s,1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.98-7.79 (m, 1H), 7.67-7.59 (m, 2H), 7.53-7.39 (m, 1H), 7.24 (t, J=9.0Hz, 1H), 7.18-7.11 (m, 2H), 7.06 (s, 1H), 6.43-6.34 (m, 1H), 4.37-4.34 (m, 4H), 4.17 (t, J=6.4Hz, 2H), 3.59 (t, J=4.6Hz, 4H), 2.46 (t, J=7.1Hz, 2H), 2.39 (d, J= 4.6Hz, 4H), 2.08-1.79 (m, 2H), 1.47 (d, J=2.3Hz, 4H)；13C NMR(101MHz,DMSO-d6)δ168.7, 168.4,160.9,151.8,149.6,146.6,138.2,133.8,129.8,127.7,123.4,122.9,115.6, 115.4,107.9,102.2,67.1,66.7,64.4,63.97,55.2,53.8,32.3,26.2,15.7；MS:661[M+H]+。
Embodiment 6.N- (the fluoro- 4- of 2- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
Step 1 is identical to step 2 as the step 1 of the preparation of embodiment 4 to step 2.
Step 3) 10- (the fluoro- 4-nitrophenoxy of 3-) -5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes is simultaneously The preparation of [2,3-f] quinoline
The operation of 4 step 3) of reference implementation example, substituting p-nitrophenol with fluoro- 4 nitrophenol of the 3- of identical molar equivalent is It can.1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.29–8.09(m,1H),7.51–7.35(m,1H),7.22–7.08 (m,2H),6.97–6.72(m,1H),4.33–4.16(m,4H),4.12–3.98(m,2H),3.65–3.54(m,4H),2.47– 2.26(m,6H),2.05–1.82(m,2H).MS:486[M+H]+。
The fluoro- 4- of step 4) 2- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- Base) oxygroup) aniline preparation
1 step 2) of reference implementation example operation, with 10- (the fluoro- 4-nitrophenoxy of 3-) -5- (3- of identical molar equivalent Quinoline propoxyl group) simultaneously [2,3-f]-quinoline substitutes 5- methoxyl group -10- (4-nitrophenoxy) -2 to -2,3- dihydro-[1,4] dioxanes, 3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline.1H NMR (400MHz, DMSO-d6) δ 8.37 (d, J=5.2Hz, 1H), 7.02 (s, 1H), 6.98-6.92 (m, 1H), 6.89-6.80 (m, 1H), 6.78-6.70 (m, 1H), 6.36 (d, J= 5.2Hz, 1H), 5.13 (s, 2H), 4.35 (s, 4H), 4.15 (t, J=6.5Hz, 2H), 3.59 (t, J=4.6Hz, 4H), 2.47 (t, J=7.2Hz, 2H), 2.39 (d, J=4.9Hz, 4H), 1.95-1.97 (m, 2H) .MS:456 [M+H]+。
Step 5) N- (the fluoro- 4- of 2- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline - 10- yl) oxygroup) phenyl) and-N- (4- fluorophenyl) cyclopropane -1,1- diformamide preparation
1 step 3) of reference implementation example operation, with the fluoro- 4- of the 2- of identical molar equivalent ((5- (3- morpholine propoxyl group) -2,3- Dihydro-[1,4] dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) aniline substitutes ((dihydro-[1,4] 5- methoxyl group -2,3- 4- Dioxanes simultaneously [2,3-f] quinoline -10- base) oxygroup) aniline.1H NMR(400MHz,DMSO-d6)δ10.48(s,1H), 9.97 (s, 1H), 8.50 (d, J=5.1Hz, 1H), 7.86 (s, 1H), 7.71-7.48 (m, 2H), 7.16 (dd, J=9.9, 7.9Hz, 2H), 7.10 (d, J=10.5Hz, 2H), 6.95-6.80 (m, 1H), 6.63 (d, J=5.1Hz, 1H), 4.34-4.28 (m, 2H), 4.27-4.24 (m, 2H), 4.17 (t, J=6.4Hz, 2H), 3.59 (t, J=4.6Hz, 4H), 2.46 (t, J= 7.2Hz, 2H), 2.38 (d, J=4.8Hz, 4H), 1.95 (q, J=6.8Hz, 2H), 1.56-1.58 (m, 4H) .MS:661 [M+H ]+。
Embodiment 7.N- (4- ((5- ethyoxyl -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygen Base) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
Step 1.10- chloro-5-methoxyl -2,3- dihydro-[Isosorbide-5-Nitrae] dioxane [2,3-f] quinoline (2.5g, 10mmol), The DMF solution (20mL) of 2- fluoro-4-nitrophenol (1.6g, 10mmol) and potassium carbonate (2.1g, 15mmol) is heated to 80 DEG C instead It answers 3 hours, it is cooling, add water to be beaten, filtration drying obtains off-white powder product (10- (the fluoro- 4-nitrophenoxy of 2-) -5- methoxy Base -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline) 3.5g, yield 94%；
Step 1 resulting product (350mg, 1mmol) is added to the acetic acid solution (33%, 5mL) of hydrogen bromide by step 2., 90 DEG C are heated to react 15 hours, it is cooling, ethyl acetate (15mL) mashing is added, filtration drying obtains light green solid (10- (2- Fluoro- 4-nitrophenoxy) -2,3- dihydro-[Isosorbide-5-Nitrae] dioxane [2,3-f] quinoline -5- alcohol hydrogen bromide salt) 3.8g, yield 87%, MS:359 [M+H]+；
Step 3. will be separately added into bromoethane in DMF (5mL) solution of step 2 resulting product (440mg, 1mmol) (165mg, 1.5mmol) and potassium carbonate (280mg, 2mmol) is heated to 80 DEG C, reacts 10 hours, cooling, adds water, ethyl acetate Extraction, saturated sodium chloride solution washing, dry, concentration, column chromatographic purifying obtains product as light yellow solid (10- (the fluoro- 4- nitro of 2- Phenoxy group) -5- ethyoxyl -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline) 320mg, yield 83%；
Raney's nickel is added in methanol (30mL) solution of step 3 resulting product (320mg) by step 4., in nitrogen atmosphere foxing Reaction 3 hours is stirred at room temperature under part, filters, washing, filtrate is concentrated to give purple solid product (3- fluoro- 4- ((5- ethyoxyl -2,3- Dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) aniline) 290mg, yield 81%, MS:357 [M+H]+；
Step 5. is separately added into 1- ((4- fluorine into the nmp solution (1mL) of step 4 resulting product (36mg, 0.1mmol) Phenyl) amido formacyl) cyclopropyl -1- formyl chloride (24mg, 0.1mmol) methylene chloride (0.5mL) solution and triethylamine (0.1mL) is stirred at room temperature reaction 5 hours, adds water quenching to go out, light yellow solid is obtained by filtration, purify white solid by preparation liquid phase Body product 24mg, yield 43%；1H NMR(600MHz,DMSO-d6) δ 10.33 (s, 1H), 10.00 (s, 1H), 8.41 (d, J= 5.2Hz, 1H), 7.86 (d, J=13.1Hz, 1H), 7.63 (dd, J=8.7,5.0Hz, 2H), 7.45 (d, J=8.9Hz, 1H), 7.25-7.13 (m, 3H), 7.05 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.34 (s, 4H), 4.25-4.10 (m, 2H), 1.47 (d, J=3.9Hz, 4H), 1.41 (t, J=6.9Hz, 3H) .MS:562 [M+H]+
Embodiment 8.N- (4- ((5- (3- (dimethylamino) propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent dimethylamino third in step 3 Base chloro is reacted to obtain white solid product for bromoethane；1H NMR(400MHz,DMSO-d6)δ10.32(s,1H), 9.99 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.85 (dd, J=13.2,2.4Hz, 1H), 7.68-7.56 (m, 2H), 7.45 (d, J=8.7Hz, 1H), 7.23 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.05 (s, 1H), 6.40 (d, J= 5.2Hz, 1H), 4.35 (s, 4H), 4.16 (t, J=6.5Hz, 2H), 2.42-2.32 (m, 2H), 2.20 (s, 6H), 1.94 (t, J =6.9Hz, 2H), 1.47 (d, J=2.3Hz, 4H) .MS:619 [M+H]+
Embodiment 9.N- (4- ((5- (3- (piperidin-1-yl) propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] Quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent (piperidin-1-yl) in step 3 Propyl chloride replaces bromoethane to be reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H), 9.99 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.85 (d, J=13.1Hz, 1H), 7.69-7.59 (m, 2H), 7.45 (d, J =9.0Hz, 1H), 7.23 (t, J=9.0Hz, 1H), 7.20-7.10 (m, 2H), 7.05 (s, 1H), 6.40 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.16 (t, J=6.5Hz, 2H), 2.41 (d, J=29.1Hz, 6H), 1.95 (t, J=7.4Hz, 2H), 1.62–1.44(m,8H),1.39(Br,2H).MS:659[M+H]+
Embodiment 10.N- (the fluoro- 4- of 3- ((5- (2- methoxy ethoxy) -2,3- dihydro-[1,4] dioxane [2,3-f] Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent methoxy ethyl in step 3 Bromo is reacted to obtain white solid product for bromoethane；1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.99 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.3,2.5Hz, 1H), 7.72-7.56 (m, 2H), 7.50- 7.36 (m, 1H), 7.24 (t, J=9.0Hz, 1H), 7.18-7.11 (m, 2H), 7.08 (s, 1H), 6.40 (dd, J=5.2, 1.0Hz, 1H), 4.35 (s, 4H), 4.29-4.17 (m, 2H), 3.79-3.67 (m, 2H), 3.34 (s, 3H), 1.47 (d, J= 2.0Hz,4H).MS:592[M+H]+
Embodiment 11.N- (4- ((5- (cyclo propyl methoxy) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline - 10- yl) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent Cvclopropvlmethvl in step 3 Bromo is reacted to obtain white solid product for bromoethane；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.99 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 7.85 (dd, J=13.3,2.4Hz, 1H), 7.63 (dd, J=9.1,5.1Hz, 2H), 7.45 (d, J=8.8Hz, 1H), 7.26-7.20 (m, 1H), 7.15 (t, J=8.9Hz, 2H), 7.02 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 3.97 (d, J=7.1Hz, 2H), 1.47 (d, J=2.1Hz, 4H), 1.36-1.25 (m,1H),0.73–0.55(m,2H),0.43–0.31(m,2H).MS:588[M+H]+
Embodiment 12.N- (4- ((5- (isobutyl group oxygroup) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- Base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent isobutyl bromide generation in step 3 It is reacted to obtain white solid product for bromoethane；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.99(s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.85 (dd, J=13.3,2.4Hz, 1H), 7.69-7.57 (m, 2H), 7.50-7.39 (m, 1H), 7.23 (t, J=9.0Hz, 1H), 7.18-7.11 (m, 2H), 7.05 (s, 1H), 6.40 (dd, J=5.2,1.0Hz, 1H), 4.35 (s, 4H), 3.90 (d, J=6.5Hz, 2H), 2.11 (dt, J=13.3,6.7Hz, 1H), 1.47 (d, J=2.0Hz, 4H), 1.03 (d, J=6.7Hz, 6H) .MS:590 [M+H]+
Embodiment 13.N- (the fluoro- 4- of 3- ((5- (3- hydroxy propyloxy group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent 3- bromopropyl alcohol generation in step 3 It is reacted to obtain white solid product for bromoethane；1H NMR(600MHz,DMSO-d6)δ10.32(s,1H),10.00(s, 1H), 8.41 (dd, J=5.2,0.9Hz, 1H), 7.86 (d, J=12.6Hz, 1H), 7.63 (dd, J=9.0,4.9Hz, 2H), 7.45 (d, J=9.0Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.06 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.60 (t, J=5.1Hz, 1H), 4.35 (s, 4H), 4.19 (t, J=6.4Hz, 2H), 3.60 (q, J= 5.9Hz, 2H), 1.95 (t, J=6.3Hz, 2H), 1.46 (q, J=3.3Hz, 4H) .MS:592 [M+H]+
Embodiment 14.N- (the fluoro- 4- of 3- ((5- (3- methoxy propoxy) -2,3- dihydro-[1,4] dioxane [2,3-f] Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent methoxy-propyl in step 3 Bromo is reacted to obtain white solid product for bromoethane；1H NMR(600MHz,DMSO-d6)δ10.32(s,1H),10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.99-7.81 (m, 1H), 7.63 (dd, J=9.0,5.1Hz, 2H), 7.45 (d, J =9.0Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.06 (s, 1H), 6.40 (d, J= 5.2Hz, 1H), 4.35 (s, 4H), 4.17 (t, J=6.4Hz, 2H), 3.51 (t, J=6.3Hz, 2H), 3.27 (s, 3H), 2.03 (t, J=6.4Hz, 2H), 1.46 (q, J=3.4Hz, 4H) .MS:606 [M+H]+
Embodiment 15.N- (the fluoro- 4- of 3- ((5- (3- ((2- methoxy ethyl) (methyl) amino) propoxyl group) -2,3- dihydro - [1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with the bromo- N- (2- of equivalent 3- in step 3 Methoxy ethyl)-N- methyl-propyl -1- amine replace bromoethane reacted to obtain white solid product；1H NMR(600MHz, DMSO-d6) δ 10.33 (s, 1H), 10.01 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.4Hz, 1H), 7.68-7.59 (m, 2H), 7.45 (dt, J=8.8,1.6Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.20-7.09 (m, 2H), 7.05 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.15 (t, J=6.4Hz, 2H), 3.41 (t, J= 5.9Hz, 2H), 3.21 (s, 3H), 2.52 (td, J=6.6,6.1,4.4Hz, 4H), 2.22 (s, 3H), 1.93 (q, J=6.7Hz, 2H), 1.47 (q, J=3.3,2.9Hz, 4H) .MS:663 [M+H]+
Embodiment 16.N- (the fluoro- 4- of 3- ((5- isopropoxy -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- Base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent isopropyl bromide generation in step 3 It is reacted to obtain white solid product for bromoethane；1H NMR(600MHz,DMSO-d6)δ10.32(s,1H),10.00(s, 1H), 8.40 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.5Hz, 1H), 7.65-7.62 (m, 2H), 7.45 (dd, J= 8.9,1.9Hz, 1H), 7.22 (d, J=9.1Hz, 1H), 7.17-7.13 (m, 2H), 7.06 (s, 1H), 6.38 (d, J=5.2Hz, 1H), 4.82-4.80 (m, 1H), 4.34 (s, 4H), 1.47 (t, J=3.5Hz, 4H), 1.36 (d, J=6.0Hz, 6H) .MS:576 [M+H]+
Embodiment 17.N- (the fluoro- 4- of 3- ((5- ((tetrahydrofuran -3- base) oxygroup) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent p-methyl benzenesulfonic acid in step 3 Tetrahydrofuran -3- ester replaces bromoethane to be reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.33 (s, 1H), 10.00 (s, 1H), 8.42 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.4Hz, 1H), 7.67-7.57 (m, 2H), 7.45 (dd, J=8.4,2.1Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.03 (s, 1H), 6.40 (d, J=5.2Hz, 1H), 5.24-5.16 (m, 1H), 4.35 (s, 4H), 3.96 (dd, J=10.3,4.5Hz, 1H), 3.92-3.84 (m, 2H), 3.78 (td, J=8.3,4.7Hz, 1H), 2.36-2.29 (m, 1H), 2.09-2.03 (m, 1H), 1.47 (q, J=3.3Hz, 4H) .MS:604 [M+H]+
Embodiment 18.N- (the fluoro- 4- of 3- ((5- ((tetrahydropyran -4-base) oxygroup) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent p-methyl benzenesulfonic acid in step 3 Oxinane -4- ester replaces bromoethane to be reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.33 (s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.90-7.81 (m, 1H), 7.63 (dd, J=9.0,5.1Hz, 2H), 7.46 (d, J=8.8Hz, 1H), 7.24 (t, J=9.1Hz, 1H), 7.18-7.14 (m, 3H), 6.39 (d, J=5.2Hz, 1H), 4.80 (dt, J=9.0,4.7Hz, 1H), 4.35 (s, 4H), 3.89 (dt, J=11.6,4.3Hz, 2H), 3.55 (ddd, J =12.0,9.8,2.7Hz, 2H), 2.07 (d, J=10.7Hz, 2H), 1.67 (dtd, J=13.2,9.3,4.1Hz, 2H), 1.50–1.39(m,4H).MS:618[M+H]+
Embodiment 19.N- (4- ((5- (3- (4- Acetylpiperazine -1- base) propoxyl group) -2,3- dihydro-[1,4] dioxy six Ring [2,3-f] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent 4- acetyl group piperazine in step 3 Piperazine -1- base propyl chloride replaces bromoethane to be reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6)δ10.26 (s, 1H), 9.93 (s, 1H), 8.35 (d, J=5.2Hz, 1H), 7.79 (dd, J=13.3,2.4Hz, 1H), 7.64-7.49 (m, 2H), 7.42-7.33 (m, 1H), 7.17 (t, J=9.1Hz, 1H), 7.12-7.05 (m, 2H), 7.01 (s, 1H), 6.36-6.25 (m, 1H), 4.29 (s, 4H), 4.12 (t, J=6.4Hz, 2H), 3.38 (s, 4H), 2.48 (br, 2H), 2.41-2.11 (m, 4H), 1.93 (s, 5H), 1.40 (q, J=3.2Hz, 4H) .MS:702 [M+H]+
Embodiment 20.N- (4- ((5- (Cyanomethoxy) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- Base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with the replacement of equivalent bromoacetonitrile in step 3 Bromoethane is reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),10.00(s,1H), 8.47 (d, J=5.2Hz, 1H), 7.87 (dd, J=13.3,2.4Hz, 1H), 7.68-7.59 (m, 2H), 7.50-7.43 (m, 1H),7.33–7.23(m,2H),7.20–7.10(m,2H),6.49–6.43(m,1H),5.38(s,2H),4.38(s,4H), 1.47 (q, J=3.4Hz, 4H) .MS:573 [M+H]+
Embodiment 21.N- (4- ((5- (3- (4- methylpiperazine-1-yl) propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent 4- methyl piperazine-in step 3 1- base propyl bromide replaces bromoethane to be reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.32(s, 1H), 10.00 (s, 1H), 8.41 (dd, J=5.2,1.4Hz, 1H), 7.86 (d, J=13.2Hz, 1H), 7.63 (dd, J=8.7, 5.1Hz, 2H), 7.45 (d, J=8.9Hz, 1H), 7.24 (t, J=9.2Hz, 1H), 7.15 (td, J=8.8,1.5Hz, 2H), 7.05 (d, J=1.4Hz, 1H), 6.39 (d, J=5.3Hz, 1H), 4.35 (s, 4H), 4.18-4.13 (m, 2H), 2.45 (t, J= 7.2Hz, 2H), 2.40-2.29 (m, 8H), 2.14 (s, 3H), 1.94 (t, J=6.9Hz, 2H), 1.47 (d, J=3.8Hz, 4H) .MS:674[M+H]+
Embodiment 22.N- (the fluoro- 4- of 3- ((5- (3- (4- hydroxy-4-methyl piperidin-1-yl) propoxyl group) -2,3- dihydro - [1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide list first Hydrochlorate
It is prepared in method similar to Example 7, the difference is that, with equivalent (4- hydroxyl -4- in step 3 Methyl piperidine -1- base) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ 10.33 (s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J=13.1,2.4Hz, 1H), 7.66-7.60 (m, 2H), 7.45 (dt, J=8.5,1.7Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.17-7.11 (m, 2H), 7.05 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.16 (t, J=6.4Hz, 2H), 2.50 (br, 4H),2.42(br,2H),2.01–1.90(m,2H),1.55–1.42(m,8H),1.10(s,3H).MS:689[M+H]+
Embodiment 23.N- (4- ((5- (3- (cyclobutyl (methyl) amino) propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide list formates
It is prepared in method similar to Example 7, the difference is that, with equivalent 3- (cyclobutyl in step 3 (methyl) amino) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ 10.33 (s, 1H), 10.01 (s, 1H), 8.42 (d, J=5.2Hz, 1H), 8.19 (s, 1H), 7.87 (dd, J=13.2,2.5Hz, 1H), 7.67-7.59 (m, 2H), 7.46 (dt, J=8.9,1.7Hz, 1H), 7.25 (t, J=9.0Hz, 1H), 7.19-7.11 (m, 2H), 7.06 (s, 1H), 6.40 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.16 (t, J=6.4Hz, 2H), 2.79 (t, J= 7.6Hz, 1H), 2.38 (t, J=7.0Hz, 2H), 2.06 (s, 3H), 2.02-1.94 (m, 2H), 1.91 (p, J=6.7Hz, 2H), 1.76 (ddd, J=11.2,6.4,2.2Hz, 2H), 1.65-1.55 (m, 2H), 1.47 (dd, J=4.4,3.0Hz, 4H) .MS: 659[M+H]+
Embodiment 24.N- (4- ((5- (3- (1,1- thiomorpholine dioxide -4- base) propoxyl group) -2,3- dihydro-[1, 4] dioxane [2,3-f] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent 3-, (1,1- is thio in step 3 Morpholine dioxide -4- base) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz, DMSO-d6) δ 10.33 (s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.4Hz, 1H), 7.63 (dd, J=8.9,5.2Hz, 2H), 7.45 (dd, J=8.9,2.3Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.09 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.18 (t, J= 6.4Hz, 2H), 3.11 (t, J=5.2Hz, 4H), 2.92 (dd, J=7.2,3.5Hz, 4H), 2.65 (t, J=7.0Hz, 2H), 1.96 (p, J=6.7Hz, 2H), 1.47 (q, J=3.3Hz, 4H) .MS:709 [M+H]+
Embodiment 25.N- (the fluoro- 4- of 3- ((5- (3- (pyrroles -1- base) propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide list formates
It is prepared in method similar to Example 7, the difference is that, with equivalent 3- (pyrroles -1- in step 3 Base) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.34(s, 1H), 10.01 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.24 (s, 1H), 7.86 (dd, J=13.1,2.4Hz, 1H), 7.63 (dd, J=8.9,5.0Hz, 2H), 7.45 (dd, J=8.9,2.3Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J= 8.8Hz, 2H), 7.06 (s, 1H), 6.40 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.18 (t, J=6.4Hz, 2H), 2.73 (t, J=7.3Hz, 2H), 2.66 (d, J=5.9Hz, 4H), 2.03 (q, J=6.9Hz, 2H), 1.80-1.68 (m, 4H), 1.47 (t, J=3.9Hz, 4H) .MS:645 [M+H]+
Embodiment 26.N- (the fluoro- 4- of 3- ((5- (3- Cyano-propoxy) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with the replacement of equivalent bromine butyronitrile in step 3 Bromoethane is reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.33(s,1H),10.00(s,1H), 8.42 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.4Hz, 1H), 7.63 (dd, J=9.0,5.1Hz, 2H), 7.45 (dd, J=9.0,2.3Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.10 (s, 1H), 6.41 (d, J=5.2Hz, 1H), 4.36 (s, 4H), 4.20 (t, J=6.1Hz, 2H), 2.69 (t, J=7.2Hz, 2H), 2.12 (p, J= 6.7Hz, 2H), 1.47 (t, J=3.6Hz, 4H) .MS:601 [M+H]+
Embodiment 27.N- (4- ((5- ((6- (dimethylamino) hexyl) oxygroup) -2,3- dihydro-[1,4] dioxane [2, 3-f] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide list formates
It is prepared in method similar to Example 7, the difference is that, with equivalent 6- dimethylamino in step 3 Hexyl bromide replaces bromoethane to be reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ10.34(s,1H), 10.01 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.28 (s, 1H), 7.86 (d, J=13.0Hz, 1H), 7.63 (dd, J= 8.8,5.1Hz, 2H), 7.45 (d, J=8.9Hz, 1H), 7.24 (t, J=9.0Hz, 1H), 7.15 (t, J=8.7Hz, 2H), 7.05 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.12 (t, J=6.5Hz, 2H), 2.31 (t, J= 7.4Hz, 2H), 2.20 (s, 6H), 1.80 (q, J=7.1Hz, 2H), 1.49-1.43 (m, 8H), 1.36 (q, J=7.8Hz, 2H) .MS:661[M+H]+
Embodiment 28.N- (the fluoro- 4- of 3- ((5- (oxetanes -3- oxygroup) -2,3- dihydro-[1,4] dioxane [2, 3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent to methylbenzene sulphur in step 3 Sour oxetanes -3- ester replaces bromoethane to be reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ 10.33 (s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.87 (d, J=13.2Hz, 1H), 7.73-7.57 (m, 2H), 7.45 (s, 1H), 7.24 (s, 1H), 7.15 (t, J=8.8Hz, 2H), 6.70 (s, 1H), 6.41 (d, J=5.2Hz, 1H), 5.45 (h, J=5.1Hz, 1H), 5.07-4.87 (m, 2H), 4.62 (dd, J=7.4,4.9Hz, 2H), 4.38 (s, 4H), 1.45 (s,4H).MS:590[M+H]+
Embodiment 29.N- (the fluoro- 4- of 3- ((5- (3- (4,4- lupetidine -1- base) propoxyl group) -2,3- dihydro-[1,4] Dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent (4,4- dimethyl in step 3 Piperidin-1-yl) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ 10.32 (s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.89-7.81 (m, 1H), 7.63 (dd, J=9.0, 5.1Hz, 2H), 7.45 (d, J=8.7Hz, 1H), 7.24 (t, J=9.1Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.05 (s, 1H), 6.39 (d, J=5.2Hz, 1H), 4.35 (s, 4H), 4.15 (t, J=6.4Hz, 2H), 2.46-2.36 (m, 6H), 1.98- 1.92 (m, 2H), 1.47 (q, J=3.3Hz, 4H), 1.35-1.30 (m, 4H), 0.90 (s, 6H) .MS:687 [M+H]+；
Embodiment 30.N- (the fluoro- 4- of 3- ((5- (3- (4- amino -4- methyl piperidine -1- base) propoxyl group) -2,3- dihydro - [1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent (4- amino -4- in step 3 Methyl piperidine -1- base) propyl bromide replace bromoethane reacted to obtain white solid product；1H NMR(600MHz,DMSO-d6)δ 10.31 (s, 1H), 9.97 (s, 1H), 8.34 (d, J=5.2Hz, 1H), 8.30 (s, 2H), 7.79 (dd, J=13.2,2.4Hz, 1H), 7.61-7.50 (m, 2H), 7.39 (dt, J=8.7,1.7Hz, 1H), 7.17 (t, J=9.1Hz, 1H), 7.12-7.04 (m, 2H), 6.98 (s, 1H), 6.33 (d, J=5.2Hz, 1H), 4.28 (s, 4H), 4.09 (t, J=6.4Hz, 2H), 2.59-2.52 (m, 4H), 2.19 (s, 2H), 1.92-1.84 (m, 2H), 1.66-1.48 (m, 4H), 1.40 (dd, J=5.4,3.6Hz, 4H), 1.14(s,3H).MS:688[M+H]+
Embodiment 31.N- (the chloro- 4- of 3- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with 2- chloro- 4- nitrophenol generation in step 1 For 2- fluoro-4-nitrophenol, bromoethane is replaced to be reacted to obtain white solid product with morpholine -1- base propyl chloride in step 3 ；1H NMR(600MHz,DMSO-d6) δ 10.28 (s, 1H), 10.02 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 8.05 (d, J= 2.5Hz, 1H), 7.69-7.62 (m, 2H), 7.60 (dd, J=8.9,2.5Hz, 1H), 7.22-7.13 (m, 3H), 7.09 (s, 1H), 6.34 (d, J=5.2Hz, 1H), 4.38-4.30 (m, 4H), 4.20 (t, J=6.3Hz, 2H), 3.63 (s, 4H), 2.42 (br, 6H), 2.01 (d, J=16.4Hz, 2H), 1.47 (t, J=3.1Hz, 4H) .MS:677 [M+H]+
Embodiment 32.N- (the fluoro- 4- of 3- ((5- (2- hydroxyl-oxethyl) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with equivalent ethylene bromohyrin generation in step 3 It is reacted to obtain white solid product for bromoethane；1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),10.01(s, 1H), 8.44 (d, J=5.3Hz, 1H), 7.87 (dd, J=13.2,2.4Hz, 1H), 7.64 (dd, J=8.9,5.1Hz, 2H), 7.47 (dd, J=8.9,2.3Hz, 1H), 7.26 (t, J=9.0Hz, 1H), 7.15 (t, J=8.9Hz, 2H), 7.09 (s, 1H), 6.43 (d, J=5.3Hz, 1H), 4.96 (s, 1H), 4.36 (s, 4H), 4.15 (t, J=4.9Hz, 2H), 3.81 (t, J= 4.9Hz, 2H), 1.48 (t, J=2.9Hz, 4H) .MS:578 [M+H]+
Embodiment 33.N- (4- ((5- ((1- amino cyclopropyl) methoxyl group) -2,3- dihydro-[1,4] dioxane [2,3- F] quinoline -10- base) oxygroup) -3- fluorophenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide (0.35) formates
It is prepared in method similar to Example 7, the difference is that, with equivalent 4- methylbenzene sulphur in step 3 Sour (1- ((tetrabutyl oxygen carbonyl) amino) cyclopropyl) methyl ester replaces bromoethane to be reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6) δ 10.32 (s, 1H), 10.00 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 8.22 (s, 0.35H), 7.85 (dd, J=13.3,2.4Hz, 1H), 7.73-7.57 (m, 2H), 7.45 (dd, J=8.9,2.3Hz, 1H), 7.19 (dt, J=35.1,9.0Hz, 3H), 7.03 (s, 1H), 6.39 (d, J=5.1Hz, 1H), 4.36 (q, J=4.5Hz, 4H), 4.02 (s, 2H), 1.47 (t, J=2.9Hz, 4H), 0.62 (dt, J=9.6,2.1Hz, 4H) .MS:603 [M+H]+
Embodiment 34.N- (the fluoro- 4- of 3- ((5- (2- hydroxy-2-methyl propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with the bromo- 2- methyl of equivalent 1- in step 3 Propyl -2- alcohol replaces bromoethane to be reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6)δ10.32(s, 1H), 10.00 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 7.86 (dd, J=13.2,2.4Hz, 1H), 7.69-7.59 (m, 2H), 7.49-7.40 (m, 1H), 7.24 (t, J=9.0Hz, 1H), 7.19-7.11 (m, 2H), 7.04 (s, 1H), 6.40 (dd, J =5.2,1.0Hz, 1H), 4.69 (s, 1H), 4.36 (d, J=1.8Hz, 4H), 3.87 (s, 2H), 1.47 (t, J=2.7Hz, 4H),1.25(s,6H).MS:606[M+H]+
Embodiment 35.N- (the fluoro- 4- of the chloro- 5- of 2- ((5- methoxyl group -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline - 10- yl) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, it is fluoro- with the chloro- 2- of equivalent 5- in step 1 4- nitrophenol replaces 2- fluoro-4-nitrophenol to be reacted to obtain white solid product；1H NMR(400MHz,DMSO-d6)δ 11.37 (s, 1H), 9.72 (s, 1H), 8.46 (d, J=5.1Hz, 1H), 8.26 (d, J=12.8Hz, 1H), 7.63-7.48 (m, 3H), 7.18 (t, J=8.9Hz, 2H), 7.09 (s, 1H), 6.57 (d, J=5.2Hz, 1H), 4.32 (s, 4H), 3.92 (s, 3H), 1.71(s,2H),1.63(s,2H).MS:582[M+H]+；
Embodiment 36.N- (the chloro- 4- of 2- ((5- (3- morpholine propoxyl group) -2,3- dihydro-[1,4] dioxane [2,3-f] quinoline Quinoline -10- base) oxygroup) phenyl)-N- (4- fluorophenyl) cyclopropyl -1,1- diformamide
It is prepared in method similar to Example 7, the difference is that, with the chloro- 4- nitro of equivalent 3- in step 1 Phenol replaces 2- fluoro-4-nitrophenol, is reacted to obtain instead of bromoethane with equivalent morpholine -1- base propyl chloride in step 3 White solid product；1H NMR(600MHz,DMSO-d6) δ 10.83 (s, 1H), 9.89 (s, 1H), 8.51 (d, J=5.1Hz, 1H), 8.03 (d, J=9.0Hz, 1H), 7.59 (dd, J=8.9,5.1Hz, 2H), 7.28 (d, J=2.7Hz, 1H), 7.18 (t, J =8.9Hz, 2H), 7.13 (d, J=9.2Hz, 1H), 7.05 (dd, J=9.0,2.8Hz, 1H), 6.64 (d, J=5.1Hz, 1H), 4.36–4.14(m,6H),3.84–3.63(m,2H),3.26(s,4H),2.51(br,4H),2.26–2.11(m,2H),1.66 (q, J=4.3,3.7Hz, 2H), 1.60 (q, J=4.9,4.2Hz, 2H) .MS:677 [M+H]+；
The test of 1. small molecule compound of experimental example inhibition c-MET kinase activity
LANCE TR-FRET technology based on Perkin Elmer company, test method are as follows:
1. diluted chemical compound: (this experiment makes totally 11 concentration after 3 times of gradient dilutions of progress since maximum concentration 2500nM The maximum final concentration of 2500nM, minimum final concentration of 0.042nM of drug).
2. taking 2.5 compounds of the μ L through gradient dilution with the volley of rifle fire, it is added in 384 orifice plates.
3. enzyme: taking 5 μ L 2X c-MET kinase solutions (concentration 2nM) to be added to 384 orifice plates with the volley of rifle fire and react accordingly Kong Zhong, room temperature pre-reaction 5 minutes after mixing.
4. the volley of rifle fire takes 2.5 μ L 4X Ultra ULightTM- JAK-1 (Tyr1023) Peptide (concentration 400nM)/ATP (concentration is 40 μM) mixed liquor is added in the corresponding reacting hole of 384 orifice plates.
5. negative control: 2.5 μ L/ hole 4X substrates/ATP mixed liquor and 7.5 μ L 1X Kinase is added in 384 orifice bores Assay Buffe。
6. positive control: 2.5 μ L/ hole 4X substrates/ATP mixed liquor being added in 384 orifice plates, 2.5 holes μ L/ contain 16%DMSO 1X Kinase Assay Buffer, 5 hole μ L/ 2X c-MET kinase solutions.Final concentration of the 4% of DMSO in reaction system.
7. centrifugation mixes, it is protected from light room temperature reaction 60 minutes.
8. terminating enzymatic reaction: taking 5 μ L 4X terminate liquids to be added in 384 orifice plate mesoporous with the volley of rifle fire, centrifugation mixes, room temperature Reaction 5 minutes.
9. chromogenic reaction: it takes 5 μ L 4X detection liquid to be added in 384 orifice plate mesoporous with the volley of rifle fire and develops the color, centrifugation mixes, Room temperature reaction 60 minutes.
10. 384 orifice plates are put into Envision plate reader read plate, corresponding Programmable detection signal is transferred.
11. the analysis and processing of initial data:
12. drug concentration and corresponding inhibiting rate are inputted into GraphPad Prism5 calculation processing, the inhibiting rate of compound Calculation method is as follows: inhibiting rate (%)=(positive hole readings-experimental port readings)/(Positive control wells readings-negative control hole is read Value) x100%.It is handled with GraphPad Prism5 software and obtains corresponding IC50 value (chemical combination when enzyme highest inhibiting rate 50% Object concentration).
Table 1 lists in the present invention part of compounds to the measurement result of tyrosine kinase c-MET inhibitory activity, wherein A Indicate IC50IC is indicated less than or equal to 50nM, B50Greater than 50nM but it is less than or equal to 500nM, C indicates IC50Greater than 500nM but IC is indicated less than or equal to 5000nM, D50Greater than 5000nM.
Table 1, part of compounds of the present invention are to c-MET tyrosine-kinase enzyme inhibition activity measurement result
The test of 2. small molecule compound of experimental example inhibition VEGFR-2 kinase activity
LANCE TR-FRET technology based on Perkin Elmer company, test method are as follows:
1. diluted chemical compound: (this experiment makes totally 11 concentration after 3 times of gradient dilutions of progress since maximum concentration 2500nM The maximum final concentration of 2500nM, minimum final concentration of 0.042nM of drug).
2. taking 2.5 compounds of the μ L through gradient dilution with the volley of rifle fire, it is added in 384 orifice plates.
3. enzyme: taking 5 μ L 2X VEGFR-2 kinase solutions (concentration 0.5nM) to be added to 384 orifice plates with the volley of rifle fire corresponding In reacting hole, room temperature pre-reaction 30 minutes after mixing.
4. the volley of rifle fire takes 2.5 μ L 4X Ultra ULightTM- JAK-1 (Tyr1023) Peptide (concentration 200nM)/ATP (concentration is 40 μM) mixed liquor is added in the corresponding reacting hole of 384 orifice plates.
5. negative control: 2.5 μ L/ hole 4X substrates/ATP mixed liquor and 7.5 μ L 1X Kinase is added in 384 orifice bores Assay Buffe。
6. positive control: 2.5 μ L/ hole 4X substrates/ATP mixed liquor being added in 384 orifice plates, 2.5 holes μ L/ contain 16%DMSO 1X Kinase Assay Buffer, 5 hole μ L/ 2X VEGFR-2 kinase solutions.DMSO's is final concentration of in reaction system 4%.
7. centrifugation mixes, it is protected from light room temperature reaction 60 minutes.
8. terminating enzymatic reaction: taking 5 μ L 4X terminate liquids to be added in 384 orifice plate mesoporous with the volley of rifle fire, centrifugation mixes, room temperature Reaction 5 minutes.
9. chromogenic reaction: it takes 5 μ L 4X detection liquid to be added in 384 orifice plate mesoporous with the volley of rifle fire and develops the color, centrifugation mixes, Room temperature reaction 60 minutes.
10. 384 orifice plates are put into Envision plate reader read plate, corresponding Programmable detection signal is transferred.
11. the analysis and processing of initial data: drug concentration and corresponding inhibiting rate input GraphPad Prism5 are calculated Processing, the calculation method of the inhibiting rate of compound are as follows: inhibiting rate (%)=(positive hole readings-experimental port readings)/(positive right According to hole readings-negative control hole readings) x100%.It is handled with GraphPad Prism5 software and obtains corresponding IC50(enzyme is most for value Compound concentration when high inhibiting rate 50%).
Table 2 lists part of compounds in the present invention to the measurement result of tyrosine kinase VEGFR-2 inhibitory activity, wherein A indicates IC50IC is indicated less than or equal to 50nM, B50Greater than 50nM but it is less than or equal to 500nM, C indicates IC50Greater than 500nM but IC is indicated less than or equal to 5000nM, D50Greater than 5000nM.
Table 2, part of compounds of the present invention are to VEGFR-2 tyrosine-kinase enzyme inhibition activity measurement result
3. small molecule compound of experimental example is to the active test of MHCC97H cell inhibitory effect
Steps are as follows for specific experiment:
1. diluted chemical compound: (this experiment makes totally 9 concentration after 3 times of gradient dilutions of progress since maximum concentration 5000nM The maximum final concentration of 5000nM, minimum final concentration of 0.76nM of drug).
2. being transferred in 15mL centrifuge tube after collecting MHCC97H cell, it is centrifuged 5 minutes with the speed of 1000rpm.
3. discarding supernatant liquid, complete culture solution is added, piping and druming uniformly, takes 10 μ L cell suspending liquids and 10 μ L 0.4% to expect Indigo plant mixes, and is counted with cell counter, and cell number and survival rate are recorded；
4. every hole inoculation 5000 cells/80 μ L cell suspension is into 96 orifice plates；
5. the corresponding above-mentioned 5 × compound solution diluted with culture solution of 20 μ L is added in every hole, mixing is shaken up；
6. 10 μ L CCK-8 reagents are added in every hole after culture 72 hours, culture (can be adjusted for 2 hours according to shade Reaction time)；
7. reading its OD value at 450nm in multi-functional plate reading machine.
8. data processing: cell survival rate (%)=[(As-Ab)/(Ac-Ab)] * 100%
As: the OD value of experimental port (containing cell culture medium, CCK-8, compound),
Ac: the OD value of control wells (containing cell culture medium, CCK-8),
Ab: the OD value of blank well (culture medium, CCK-8 without cell and compound),
Then numerical value importing Graphpad Prism5 software is carried out curve fitting, calculates IC50.
Table 3 lists part of compounds in the present invention to the test result of MHCC97H cell line proliferation inhibitory activity,.
Table 3, part of compounds of the present invention are to the active test result of MHCC97H cell inhibitory effect
Biological data provided by the present invention shows that the compound of the present invention is conducive to treat or prevent due to VEGFR- Disease caused by 2 or c-MET kinases exception.Therefore, the compound of the present invention is conducive to treating cancer, including primary and turns Shifting property cancer, including solid tumor.Such cancer includes but is not limited to: non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, pancreas It is cancer, glioma, glioblastoma, oophoroma, cervix cancer, colorectal cancer, melanoma, carcinoma of endometrium, preceding Column gland cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelocytic leukemia, acute marrow are thin It is born of the same parents' property leukaemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and t cell lymphoma, lymthoma, multiple Myeloma, biliary tract carcinosarcoma, cholangiocarcinoma etc..The compound of the present invention also includes the resistance to one or more other treatment methods for the treatment of Cancer.The compound of the present invention can also be used in its other than cancer related with VEGFR-2 kinases and/or c-MET kinases His disease, including but not limited to fundus oculi disease, psoriasis, rheumatic arthritis, atheroma, pulmonary fibrosis, liver fibrosis. The compound of the present invention can be used as monotherapy or conjoint therapy, can with multiple the compound of the present invention drug combinations or with Other drugs drug combination other than the present invention.
The foregoing is merely better embodiments of the invention, are not intended to limit the invention, all of the invention Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within spirit and principle.

Claims (16)

1. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or prodrug that formula (I) indicates,
In formula (I),
Q is CH；
G is O；
Z is CH；
L is selected from following group
Wherein X is H or C1-C3Alkyl；Y is H or C1-C3Alkyl；N=0-3, and as n=0, L is indicated
R1For H, C1-C9Alkyl, C3-C7Naphthenic base, 4-7 circle heterocyclic ring base, C3-C7Naphthenic base replace C1-C6Alkyl, 4-7 member The C that heterocycle replaces1-C6Alkyl, substituted C1-C9Alkyl, the substituted C1-C9The substituent group of alkyl is hydroxyl, C1-C6's Alkoxy, C1-C6Alkylthio group or-NR6R7One of or more than one,
R6And R7It is separately H, C1-C6The C that alkyl, hydroxyl replace1-C6Alkyl, C1-C3The C that alkoxy replaces1-C6Alkyl；
Above-mentioned 4-7 circle heterocyclic ring base is the 4-7 circle heterocyclic ring base of the atom containing 1-2 in N, O, S, 4-7 circle heterocyclic ring base not by Replace or by C1-C3Alkyl, C1-C3Acyl group replaces or is aoxidized by one to two oxygen atom；
R2For H, C1-C3Alkyl or halogen；
R3For H, C1-C3Alkyl or halogen；
R4For H, C1-C3Alkyl or halogen；
R5For H, C1-C9Alkyl, C3-C7Naphthenic base, C3-C7The C that naphthenic base replaces1-C6Alkyl, aryl, the C that aryl replaces1-C6 The C that alkyl, heteroaryl or heteroaryl replace1-C6Alkyl；
The aryl, heteroaryl are not to be substituted or by C1-C3Alkyl, C1-C3Alkoxy, C1-C3Alkylthio group, single or double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl, aryloxy group and methylsulfonyl or more than one substitutions；
Above-mentioned heteroaryl is containing the 1-3 hetero atoms in N, O, S and the monocycle or bicyclic group containing 5 to 10 annular atoms Group.
2. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or preceding according to claim 1 Medicine, wherein R1For H, C1-C6Alkyl, C3-C6Naphthenic base, 5-6 circle heterocyclic ring base, C3-C6Naphthenic base replace C1-C3Alkyl, The C that 5-6 circle heterocyclic ring base replaces1-C3Alkyl, substituted C1-C6Alkyl, the substituted C1-C6The substituent group of alkyl be hydroxyl, C1-C3Alkoxy, C1-C3Alkylthio group or-NR6R7,
R6And R7It is separately-H, C1-C3The C that alkyl, hydroxyl replace1-C3Alkyl, C1-C3The C that alkoxy replaces1-C3Alkane Base,
Above-mentioned 5-6 circle heterocyclic ring base is the 5-6 circle heterocyclic ring base containing the 1-2 atoms in N, O, S, the 5-6 circle heterocyclic ring base It is not substituted or by C1-C3Alkyl, C1-C3Acyl group replaces or is aoxidized by one to two oxygen atom.
3. compound according to claim 1, its pharmaceutically acceptable salt, isomers, hydrate, solvate or Prodrug, wherein R1Selected from methyl, ethyl, propyl, isopropyl, methoxy ethyl, methoxy-propyl, methoxybutyl, methoxyl group Amyl, methoxyethyl, tetrahydrofuran -3- base, tetrahydro -2H- pyrans -4- base, nafoxidine -1- ethyl, nafoxidine -1- third Base, piperidines -1- ethyl, piperidines -1- propyl, piperazine -1- ethyl, piperazine -1- propyl, morpholine -4- ethyl, morpholine -4- propyl, first Base piperazine -4- ethyl, methyl piperazine -4- propyl, N- formyl piperazine -4- ethyl, N- formyl piperazine -4- propyl, N- acetyl Base piperazine -4- ethyl, N- Acetylpiperazine -4- propyl, (1,1- dioxidothiomorpholinyl) -4- ethyl, (1,1- sulphur dioxide generation Quinoline base) -4- propyl, methylmercaptoethyl, methylthio, dimethylaminoethyl, dimethylamino-propyl, dimethylaminobutyl, two Methylamino amyl, dimethylamino hexyl, diethyllaminoethyl, lignocaine propyl, hydroxyethyl, hydroxypropyl, ethoxy ammonia Base ethyl, hydroxypropyl ethyl, hydroxyethylamino propyl, methoxyethylamino ethyl, methoxy-propyl amino-ethyl, first Oxygroup diethylaminobutyyl, amino-ethyl, aminopropyl, aminobutyl, N- methyl-N- hydroxyethylaminoethyl, N- methyl-N- Hydroxypropyl ethyl, N- methyl-N- hydroxyethylamino propyl, N- methyl-N-methoxy ethylaminoethyl, N- methyl-N- Methoxy-propyl amino-ethyl, N- methyl-N-methoxy diethylaminobutyyl, 2- methyl -2- hydroxypropyl, 3- methyl -3- hydroxyl One in base butyl, (3S) -3- aminobutyl, (3R) -3- aminobutyl, (3S) -3- hydroxybutyl or (3R) -3- hydroxybutyl Kind or more than one.
4. compound according to claim 1, its pharmaceutically acceptable salt, isomers, hydrate, solvate or Prodrug, wherein R1It is selected from: butyl, isobutyl group, amyl, isopentyl, hexyl, Cvclopropvlmethvl, cyclopropylethyl, cyclopropyl third Base, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4,4- lupetidine -1- ethyl, 4,4- lupetidine -1- third Base, oxetanes -3- base.
5. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or preceding according to claim 1 Medicine, wherein R2、R3、R4In, the halogen is Cl or F.
6. compound according to claim 1, its pharmaceutically acceptable salt, isomers, hydrate, solvate or Prodrug, R5For-H, C1-C6Alkyl, C3-C6Naphthenic base, C3-C6The C that naphthenic base replaces1-C3Alkyl, aryl, the C that aryl replaces1-C3 The C that alkyl, heteroaryl or heteroaryl replace1-C3Alkyl, the aryl, heteroaryl substituent group be C1-C3Alkyl, C1-C3 Alkoxy, C1-C3Alkylthio group, single or double C1-C3Alkyl-substituted amino, halogen, trifluoromethyl, aryloxy group and methylsulfonyl One of or more than one；
The heteroaryl is containing the 1-2 hetero atoms in N, O, S and the monocycle or bicyclic group containing 5 to 10 annular atoms Group.
7. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or preceding according to claim 6 Medicine, R5Selected from H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, 4- fluorine Phenyl, 3- fluorophenyl, 2- fluorophenyl, 4- chlorphenyl, 3- chlorphenyl, 2- chlorphenyl, 2,4 difluorobenzene base, 2,5- difluorophenyl, 3,4- difluorophenyl, 2,4 dichloro benzene base, 2,5- dichlorophenyl, 3,4- dichlorophenyl, 2- fluoro- 4- (trifluoromethyl) phenyl, 2- Fluoro- 5- (trifluoromethyl) phenyl, 3- fluoro- 4- (trifluoromethyl) phenyl, 3- fluoro- 5- (trifluoromethyl) phenyl, 3- trifluoromethyl -4 The fluoro- 4- chlorphenyl of fluorophenyl, 2-, the fluoro- 5- chlorphenyl of 2-, the fluoro- 4- chlorphenyl of 3-, the fluoro- 5- chlorphenyl of 3-, the chloro- 4- fluorophenyl of 3-, 2- chloro- 4- (trifluoromethyl) phenyl, 2- chloro- 5- (trifluoromethyl) phenyl, 3- chloro- 4- (trifluoromethyl) phenyl, the chloro- 5- (three of 3- Methyl fluoride) phenyl, 3- trifluoromethyl-4-chlorophenyl, the chloro- 4- fluorophenyl of 2-, the chloro- 5- fluorophenyl of 2-, the chloro- 4- fluorophenyl of 3-, benzyl Base, phenethyl, 4- luorobenzyl, naphthalene -1- base, 3- methyl-isoxazole -5- base, 4- Phenoxyphenyl, 3- (methylsulfonyl) phenyl, 4- (methylsulfonyl) phenyl, pyridine -2- base, pyridin-3-yl, pyridin-4-yl, 3- methoxy-benzyl or 4- methoxy-benzyl.
8. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or prodrug that formula (I) indicates,
In formula (I),
Q is CH；
G is O；
Z is CH；
L is selected from following groupWherein X is H or C1-C3Alkyl；Y is H or C1-C3Alkyl；N=0- 3, and as n=0, L is indicated
R1To be selected from C by 1 to 31-C3Acyl group, halogen, trifluoromethyl, cyano ,-CONH2、-NRaRbOr in 4-7 member heteroalicyclyl Substituent group replaced C1-C6Alkyl, the 4-7 member heteroalicyclyl are to contain the 1-2 atoms in N, O, S as ring The 4-7 member heteroalicyclyl of atom, and the 4-7 member heteroalicyclyl is selected from halogen, C by 1 to 31-C3Alkyl, hydroxyl ,-NH2、 C1-C3Replaced substituent group in acyl group,
RaAnd RbIt is each independently-H, C1-C6Alkyl, C3-C6Naphthenic base, C1-C3The C that alkoxy replaces1-C6Alkyl, C1-C3Alkane The C that sulfenyl replaces1-C6Alkyl, single or double C1-C3The C that alkyl-substituted amino replaces1-C6Alkyl or non-substituted amino take The C in generation1-C6Alkyl；
R2、R3、R4It is each independently H, C1-C3Alkyl or halogen；
R5For-H, C1-C9Alkyl, C3-C7Naphthenic base, C3-C7The C that naphthenic base replaces1-C6Alkyl, aryl, the C that aryl replaces1- C6The C that alkyl, heteroaryl or heteroaryl replace1-C6Alkyl；
The aryl, heteroaryl are not substituted or are selected from hydroxyl, amino, cyano, C by 1-31-C3Alkyl, C1-C3Alcoxyl Base, C1-C3Alkylthio group, single or double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl and methylsulfonyl are a variety of Substituent group replaces；
Above-mentioned heteroaryl is containing the 1-3 hetero atoms in N, O, S and the monocycle or bicyclic group containing 5 to 10 annular atoms Group.
9. compound, its pharmaceutically acceptable salt, isomers, hydrate, solvate or preceding according to claim 8 Medicine, wherein R1To be selected from C by 1 to 31-C3Acyl group ,-F, trifluoromethyl, cyano ,-CONH2、-NRaRbOr 4-7 member heteroalicyclyl In substituent group replaced C1-C6Alkyl, the 4-7 member heteroalicyclyl are to contain the 1-2 atom conducts in N, O, S The 4-7 member heteroalicyclyl of annular atom, and the 4-7 member heteroalicyclyl is selected from-F, C by 1 to 31-C3Alkyl, hydroxyl ,-NH2、 C1-C3Replaced substituent group in acyl group,
RaAnd RbIt is each independently-H, C1-C3Alkyl, C3-C6Naphthenic base, C1-C3The C that alkoxy replaces1-C3Alkyl, C1-C3Alkane The C that sulfenyl replaces1-C3Alkyl, single or double C1-C3The C that alkyl-substituted amino replaces1-C3Alkyl or non-substituted amino take The C in generation1-C3Alkyl；
R2、R3、R4It is each independently-H ,-F or-Cl；
R5For-H, aryl, the C that aryl replaces1-C3The C that alkyl, heteroaryl or heteroaryl replace1-C3Alkyl, it is the aryl, miscellaneous Aryl is not to be substituted or be selected from hydroxyl, amino, cyano, C by 1-31-C3Alkyl, C1-C3Alkoxy, C1-C3Alkane sulphur Base, single or double C1-C3One of alkyl-substituted amino, halogen, trifluoromethyl and methylsulfonyl or a variety of substituent groups replace；
The heteroaryl is containing the 1-2 hetero atoms in N, O, S and the monocycle or bicyclic group containing 5 to 10 annular atoms Group.
10. according to claim 1 to formula described in 9 (I) compound pharmaceutically acceptable salt, wherein the salt be it is acid/ Anion salt or basic/cationic salts；The form that pharmaceutically acceptable acidity/anion salt is usually taken is to allow alkali therein Property nitrogen protonated by inorganic or organic acid, representative organic or inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulphur Acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, hydroxyacetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, citric acid, Fumaric acid, gluconic acid benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzene sulfonic acid, oxalic acid, palmitinic acid, 2- naphthalene sulfonic acids, P-methyl benzenesulfonic acid, cyclohexylamino sulfonic acid, salicylic acid, saccharinic acid, trifluoroacetic acid.Pharmaceutically acceptable basic/cationic salts class Including (being of course not solely limited to this) aluminium, calcium, chloroprocanine, choline, diethanol amine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
11. a kind of prepare compound described in claim 1-9, its pharmaceutically acceptable salt, isomers, hydrate, solvation The method of object or prodrug, which is characterized in that include the following steps, the compound as shown in formula (II ') and chemical combination shown in formula (III ') Formula (I) compound is prepared in object reaction, wherein Q, G, Z, L, R1、R2、R3、R4And R5If claim 1-9 is defined,
12. a kind of prepare compound described in claim 1-9, its pharmaceutically acceptable salt, isomers, hydrate, solvation The method of object or prodrug, which is characterized in that include the following steps, the compound as shown in formula (II ') and chemical combination shown in formula (III) Formula (I) compound is prepared in object reaction, wherein Q, G, Z, L, R1、R2、R3、R4And R5If claim 1-9 is defined,
13. a kind of formula (II ') compound represented, wherein Q, G, Z, R1、R2、R3And R4If claim 1-9 is defined,
14. a kind of Pharmaceutical composition, (I) compound of the formula as described in claim 1-9 or its pharmaceutically acceptable salt or Its hydrate or its prodrug and pharmaceutically acceptable carrier or excipient form.
15. a kind of Pharmaceutical composition, wherein the compound comprising formula (I) described in claim 1-9, its is pharmaceutically acceptable Salt, hydrate, solvate or prodrug are as active constituent, one or more of the other therapeutic agent and one or more medicines Acceptable carrier or excipient on.
16. the compound of formula (I) according to claim 1 to 9, its pharmaceutically acceptable salt, hydrate, The application of solvate or prodrug in the drug of preparation treatment and tyrosine kinase VEGFR-2 and/or c-MET related disease, The disease includes: fundus oculi disease, psoriasis, rheumatic arthritis, atheroma, pulmonary fibrosis, liver fibrosis, non-small thin Born of the same parents' lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, cervix cancer, colon The carcinoma of the rectum, melanoma, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid gland Cancer, chronic myelocytic leukemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B are thin Born of the same parents and t cell lymphoma, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.
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