CN104109166A - Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof - Google Patents

Quinoline compound, and preparation method, intermediate, medicinal composition and application thereof Download PDF

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CN104109166A
CN104109166A CN201410152877.2A CN201410152877A CN104109166A CN 104109166 A CN104109166 A CN 104109166A CN 201410152877 A CN201410152877 A CN 201410152877A CN 104109166 A CN104109166 A CN 104109166A
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quinoline
pyrazine
ethyl
imidazo
fluoro
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CN104109166B (en
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余建鑫
郭利军
赵菲
郝宇
李萍
徐磊
夏广新
范艺
沈竞康
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Shanghai Pharmaceuticals Holding Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses a quinoline compound, and a preparation method, an intermediate, a medicinal composition and an application thereof/ The invention provides a quinoline compound represented by formula 1 shown in the specification, and its pharmaceutically acceptable salts, solvates, metabolites, metabolism precursors or medicinal precursors. The quinoline compound has a good inhibition effect on tyrosine kinases C-Met, and can be used for preparing medicines for prevention, treatment or adjuvant treatment of many C-Met expression or activity related diseases, especially tumor diseases.

Description

Quinolines, its preparation method, intermediate, pharmaceutical composition and application
Technical field
The present invention relates to quinolines, its preparation method, intermediate, pharmaceutical composition and application.
Background technology
C-Met is a kind of protein product of being encoded by C-Met proto-oncogene, for hepatocyte growth factor receptor, there is tyrosine kinase activity, relevant with adjusting albumen to multiple oncoprotein, participating in the regulation and control of cell Information Conduction, cytoskeleton rearrangement, is the important factor of cell proliferation, differentiation and motion.Think at present, the generation of C-Met and multiple cancer and shift closely relatedly, research shows, many tumour patients all have C-Met overexpression and gene amplification in the generation of its tumour and transfer process.The activation of C-Met and the relation of canceration are mainly manifested in:
1, rely on the activation mechanism of pHGF (HGF)
In tumour cell, have many molecular mechanisms can activate C-Met, modal mode is to play a role by HGF and C-Met combination.HGF and C-Met, in conjunction with causing acceptor autophosphorylation, have strengthened the activity of C-Met Tyrosylprotein kinase, cause the tyrosine phosphorylation of multiple substrate protein.Under physiological conditions, the of short duration combination performance of C-Met acceptor and HGF physiological effect, at tumor tissues high expression level HGF and C-Met simultaneously, forms positive regeeration, leads oncogenic indeterminate growth and invasion and attack behavior.This positive regeeration is confirmed in the malignant tumours such as neurospongioma, osteosarcoma, mammary cancer.
2, do not rely on the activation mechanism of pHGF (HGF)
C-Met can not rely on HGF and be activated, particularly in the tumour of Met overexpression.The high expression level of Met albumen may be due to the amplification of C-Met gene, transcribes enhancing or transcribe rear mechanism.The C-Met gene that Cooper clones is first exactly the activation form after resetting, it is the mosaic gene that No. 1 chromosomal promotor and the N-terminal of TPR gene order and the C-terminal of No. 7 karyomit(e) Met sequences form, the cytoplasm protein of this mosaic gene coding comprises the leucine zipper district of TPR coding and the Tyrosylprotein kinase district of met coding, due to the existence in leucine zipper district, cause Met kinases sustained activation, impel cell to vicious transformation.In colorectal carcinoma LOVO clone, undesired due to what transcribe, Met is present in cell surface and has lasting tyrosine kinase activity with the form of monomer.Shifting melanin tumour b16 clone, due to the minimizing of endocellular phosphorus acidifying enzyme, Met albumen can not dephosphorylation and have continuous activity.The point mutation of Met gene also can cause Met kinases sustained activation.
Tyrosine kinase receptor C-Met plays an important role in the signal conductive process of metabolism, differentiation and the dead cell of cell, and itself and ligand binding can activate its signal path, participates in generation and the development of fetal development, tissue injury reparation and tumour.Therefore, the antitumor drug taking tyrosine kinase receptor C-Met as target spot has become field very active in tumor research, for antineoplaston provides novel method.
Small molecules C-Met tyrosine kinase inhibitor is mostly the competitive inhibitor of ATP, suppresses the kinase whose effect of C-Met by the performance of blocking-up tyrosine phosphorylation.This compounds is according to the selectivity of C-Met is divided into selectivity and non-selective tyrosine kinase inhibitor.Its advantage is to have cell permeability and good oral administration biaavailability.In August, 2011, the crizotinib of FDA approval listing was the double inhibitor of a C-Met/ALK, effective to the nonsmall-cell lung cancer of ALK sudden change, had embodied the characteristic of personalized treatment.In November, 2012, Exelixis company announced, medicine cabozantinib (XL184) has obtained FDA approval for pernicious local late period that can not excision or the treatment of metastatic medullary thyroid carcinoma (MTC).Cabozantinib is a kind of oral pharmaceutical, suppresses MET, VEGFR2 and RET signal path is brought into play antitumor action by target, and it can kill tumour cell, reduces and shifts and suppress vasculogenesis.Although the C-Met inhibitor class medicine of non-selectivity listing temporarily at present, but develop at present chemical compound lot and there is C-Met inhibition activity, and can improve the disease extremely causing due to C-Met, this compounds has the JNJ-38877605 of Johnson & Johnson, the AMG-458 of Amgen, the E-7050 of Eisai and the PF-04217903 of Pfizer.
Summary of the invention
Technical problem to be solved by this invention has been to provide a kind of and the diverse quinolines of prior art, its preparation method, intermediate, pharmaceutical composition and application.Quinolines of the present invention has good inhibition to Tyrosylprotein kinase C-Met, can be for the preparation of prevention, treatment or assisting therapy and the expression of C-Met or the medicine of active relevant various diseases, especially tumor disease.
The present inventor, through a large amount of arduous experimental studies, has found that a class, to the selective inhibiting quinoline derivatives of C-Met, has completed the present invention.
The invention provides a kind of quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug as shown in Equation 1,
Wherein, X 1, X 2and X 3be C or N independently of one another, represent, work as X 1during for C, X 1with R 1be connected, work as X 1during for N, with X 1connected R 1do not exist; And, work as X 1during for C, X 2and X 3in one be C, another is N, R 1for hydrogen or hydroxyl (preferably hydrogen); Work as X 1during for N, X 2for N, X 3for C; Preferably, X 1for C or N, X 2for N, X 3for C;
Cy is 3～8 yuan of cycloalkyl (preferably 3～6 yuan of cycloalkyl, described " 3～6 yuan of cycloalkyl " preferred unsubstituted cyclopropyl), 3～8 yuan of Heterocyclylalkyl (preferably 3～6 yuan of Heterocyclylalkyls, described " 3～6 yuan of Heterocyclylalkyls " preferably heteroatoms is nitrogen-atoms, heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2, described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " can be by C 1-4alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) replaces; Described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " preferably piperazinyl, described " piperazinyl " be 4-piperazinyl preferably; Described " be nitrogen-atoms by the heteroatoms that methyl replaced, heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " preferably N methyl piperazine base; Described " N methyl piperazine base " be N methyl piperazine-1-yl preferably), 5～8 yuan of cycloalkenyl groups, 5～8 yuan of heterocycloalkenyl (preferably 5～6 yuan of heterocycloalkenyl, described " 5～6 yuan of heterocycloalkenyl " preferably heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2, and described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " can quilt institute replaces (wherein, C 1-4alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl for example), or the nomadic nitrogen atom of described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " can salify; Described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " preferably 1,2,3,6-tetrahydro pyridyl, described " 1,2,3,6-tetrahydro pyridyl " preferably 1,2,3,6-tetrahydropyridine-4-base; Described " heteroatoms is that nitrogen-atoms, heteroatoms number are the nomadic nitrogen atom salify in 5～6 yuan of heterocycloalkenyl of 1～2 " preferably or described " quilt the heteroatoms replacing is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " preferably ), 6～10 yuan of aryl, 5～10 yuan of heteroaryls or (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl); Described 3～8 yuan of cycloalkyl, 3～8 yuan of Heterocyclylalkyls, 5～8 yuan of cycloalkenyl groups, 5～8 yuan of heterocycloalkenyl, 6～10 yuan of aryl or 5～10 yuan of heteroaryls can by 1～2 be selected from halogen (for example fluorine, chlorine or bromine), cyano group, group replace, wherein R 5and R 6be C independently of one another 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), halogen replace C 1-6alkyl (the C that preferably halogen replaces 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, described " halogen " for example fluorine, chlorine or bromine), hydroxyl replace C 1-6alkyl (the C that preferably hydroxyl replaces 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl ;), 6～10 yuan of aryl replacing of 3～8 yuan of cycloalkyl, 3～8 yuan of Heterocyclylalkyls, 6～10 yuan of aryl (preferably phenyl), halogens (phenyl that preferably halogen replaces, described " halogen " for example fluorine, chlorine or bromine; ), (preferably heteroatoms is nitrogen-atoms for 5～10 yuan of heteroaryls, heteroatoms number is 5～10 yuan of heteroaryls of 1-2, described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～10 yuan of heteroaryls of 1-2 " preferably quinolyl) or halogen 5～10 yuan of heteroaryls (described " halogen " for example fluorine, the chlorine or bromine that replace; Described " 5～10 yuan of heteroaryls " preferably heteroatoms is nitrogen-atoms, and heteroatoms number is 5～10 yuan of heteroaryls of 1-2, described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～10 yuan of heteroaryls of 1-2 " preferably quinolyl);
L is or
R 2, R 3and R 4be hydrogen, halogen (for example fluorine, chlorine or bromine) or C independently of one another 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl); Preferably R 2and R 3be hydrogen, fluorine or methyl independently of one another, R 4for hydrogen; Further preferably work as again R 2during for hydrogen, R 3for hydrogen, fluorine or methyl, R 4for hydrogen; Work as R 2during for fluorine, R 3for fluorine, R 4for hydrogen.
A is hydrogen, 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases, and described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases can be selected from halogen (for example fluorine, chlorine or bromine), C by 1～2 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) and (wherein, C 1-6the preferred C of alkyl 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) in group replace;
Work as X 1for C, X 2for N and X 3during for C, A is preferably hydrogen or 5～10 membered nitrogen-containing heteroaryl bases (preferred nitrogen atomicity is 5～6 membered nitrogen-containing heteroaryl bases of 1-2, described " heteroatoms number is 5～6 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl), and described 5～10 membered nitrogen-containing heteroaryl bases can be by C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) replaces; By the preferred 1-methyl isophthalic acid of methyl substituted 5～10 membered nitrogen-containing heteroaryl base H-pyrazolyl;
Work as X 1for C, X 2for C and X 3during for N, A is preferably 5～10 membered nitrogen-containing heteroaryl bases (preferred nitrogen atomicity is 5～6 membered nitrogen-containing heteroaryl bases of 1-2, described " heteroatoms number is 5～6 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl), and described 5～10 membered nitrogen-containing heteroaryl bases can be by C 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) replaces; By the preferred 1-methyl isophthalic acid of methyl substituted 5～10 membered nitrogen-containing heteroaryl base H-pyrazolyl;
Work as X 1for N, X 2for N and X 3during for C, A be preferably 6～10 yuan of aryl (preferably phenyl, described " phenyl " can by 1～2 be selected from halogen (for example fluorine, chlorine or bromine, preferably fluorine) and (wherein, C 1-6alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl for example, preferable methyl) group replace) or 5～10 membered nitrogen-containing heteroaryl bases (preferred nitrogen atomicity is 5～10 membered nitrogen-containing heteroaryl bases of 1-2, described " nitrogen-atoms number is 5～10 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl, pyridyl or quinolyl), described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases can be selected from halogen (for example fluorine, chlorine or bromine), C by 1～2 1-6alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) and (wherein said " C 1-6alkyl " preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) in group replace (being the preferred 1-methyl isophthalic acid of 5～10 membered nitrogen-containing heteroaryl base H-pyrazolyl of 1-2 by methyl substituted nitrogen-atoms number).
In the present invention, described quinolines as shown in Equation 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, preferably suc as formula the quinolines that contains Imidazopyrazines structure shown in 1-a, suc as formula the quinolines that contains triazole pyrazine structure shown in 1-b or suc as formula containing imidazo [1 shown in 1-c, 2-b] [1,2,4] quinolines of triazole structure
In compound 1-a, Cy be selected from following a)～e) described group, preferably Cy be selected from following a)～d) described group, more preferably Cy is following d) described group:
A) 3～6 yuan of cycloalkyl, described " 3～6 yuan of cycloalkyl " be cyclopropyl preferably, further preferred cyclopropyl;
B) 3～6 yuan of Heterocyclylalkyls, described " 3～6 yuan of Heterocyclylalkyls " preferably heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of Heterocyclylalkyls of 1～2, described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of Heterocyclylalkyls of 1～2 " can be by C 1-4alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) replaces; Described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of Heterocyclylalkyls of 1～2 " be piperazinyl preferably, and described " piperazinyl " be 4-piperazinyl preferably; Described " being that nitrogen-atoms, heteroatoms number are 5～6 yuan of Heterocyclylalkyls of 1～2 by the heteroatoms that methyl replaced " be N methyl piperazine base preferably, and described " N methyl piperazine base " be N methyl piperazine-1-base preferably;
C) 5～6 yuan of heterocycloalkenyl, preferably heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2, described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " can quilt (wherein, C 1-4alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl for example) institute replaces, or nomadic nitrogen atom on described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " can salify; Described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " preferably 1,2,3,6-tetrahydropyridine-4-base described " heteroatoms is that nitrogen-atoms, heteroatoms number are the nomadic nitrogen atom salify in 5～6 yuan of heterocycloalkenyl of 1～2 " preferably described " quilt the heteroatoms replacing is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " preferably
D) 6～10 yuan of aryl or 5～10 yuan of heteroaryls, described " 6～10 yuan of aryl " be phenyl or naphthyl (described " naphthyl " be 1-naphthyl preferably) preferably, described " 5～10 yuan of heteroaryls " preferably heteroatoms is N, O or S atom, heteroatoms number is the monocycle of 1～2 or 5～10 yuan of heteroaryls of condensed ring, it is described that " heteroatoms is N, O or S atom, heteroatoms number is 5～10 yuan of heteroaryls of monocycle of 1～2 " preferred pyrazolyl (described " pyrazolyl " be 1H-pyrazoles-4-base or 1H-pyrazoles-5-yl preferably), pyridyl (described " pyridyl " be pyridin-4-yl or pyridin-3-yl preferably), thienyl (described " thienyl " be thiene-3-yl-or thiophene-2-yl preferably), pyrimidyl (described " pyrimidyl " be pyrimidine-5-yl preferably) or furyl (described " furyl " be furans-3-yl preferably), it is described that " heteroatoms is N, O or S atom, heteroatoms number is 5～10 yuan of heteroaryls of condensed ring of 1～2 " (described " quinolyl " be quinolyl-4 preferably for preferred quinolyl, quinoline-3-base or quinoline-7-yl), isoquinolyl (described " isoquinolyl " be isoquinoline 99.9-4-yl preferably), benzothienyl (described " benzothienyl " be thionaphthene-3-base or thionaphthene-2-yl preferably), (described " indyl " be indol-3-yl preferably for indyl, indoles-4-base or indoles-5-yl) or pyrrolopyridinyl (the preferred 1H-pyrrolo-[2 of described " pyrrolopyridinyl ", 3-b] pyridine-5-yl),
Described 6～10 yuan of aryl or 5～10 yuan of heteroaryls can by 1～2 be selected from halogen (for example fluorine, chlorine or bromine), cyano group, (preferably N, N-dimethylamino), (preferably or ), (preferably or ), with (preferably ) group replace, wherein R 5, R 6be C independently of one another 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), halogen replace C 1-6alkyl (described " the C that halogen replaces 1-6alkyl " described in " C 1-6alkyl " preferred C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, described " the C that halogen replaces 1-6alkyl " described in " halogen " preferably fluorine, chlorine or bromine, described " the C that halogen replaces 1-6alkyl " preferred trifluoromethyl), the C that replaces of hydroxyl 1-6alkyl (described " the C that hydroxyl replaces 1-6alkyl " described in " C 1-6alkyl " preferred C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, described " the C that hydroxyl replaces 1-6alkyl " preferably or ), 6～10 yuan of aryl (preferably phenyl), 6～10 yuan of aryl (" 6～10 yuan of aryl " preferably phenyl described in described " 6～10 yuan of aryl that halogen replaces " that halogen replaces, " halogen " preferably fluorine described in described " 6～10 yuan of aryl that halogen replaces ", chlorine or bromine), (preferably heteroatoms is nitrogen-atoms to 5～10 yuan of heteroaryls, heteroatoms number is 5～10 yuan of heteroaryls of 1～2, it is described that " heteroatoms is nitrogen-atoms, heteroatoms number is 5～10 yuan of heteroaryls of 1～2 " preferred quinolyl) or 5～10 yuan of heteroaryls replacing of halogen (" 5～10 yuan of heteroaryls " described in described " 5～10 yuan of heteroaryls that halogen replaces " preferably heteroatoms is nitrogen-atoms, heteroatoms number is 5～10 yuan of heteroaryls of 1～2, it is described that " heteroatoms is nitrogen-atoms, heteroatoms number is 5～10 yuan of heteroaryls of 1～2 " quinolyl that preferably halogen replaces, " halogen " preferably fluorine, chlorine or bromine described in described " 5～10 yuan of heteroaryls that halogen replaces ", described " 5～10 yuan of heteroaryls that halogen replaces " are preferred ), described substituting group can be identical or different.
E) (wherein, C 1-6the preferred C of alkyl 1-4alkyl, described " C 1-6alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, preferable methyl);
L is or
R 1for hydrogen or hydroxyl, be preferably H;
R 2and R 3be H, F or methyl independently of one another, R 4for H; Preferably, work as R 2during for H, R 3for H, F or methyl, R 4for H; Work as R 2during for F, R 3for F, R 4for H;
A is H or 5 membered nitrogen-containing heteroaryl bases (preferred nitrogen atomicity is 5～6 membered nitrogen-containing heteroaryl bases of 1-2, described " heteroatoms number is 5～6 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl), and described 5 membered nitrogen-containing heteroaryl bases can be by C 1-4alkyl replaces that (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl are the preferred 1-methyl isophthalic acid of 5～6 membered nitrogen-containing heteroaryl base H-pyrazolyl of 1-2 by methyl substituted nitrogen-atoms number; ); A is preferably H.
In compound 1-b, Cy is 6～10 yuan of aryl or 5～10 yuan of heteroaryls, described " 6～10 yuan of aryl " be phenyl preferably, described " 5～10 yuan of heteroaryls " preferably heteroatoms is N, O or S atom, heteroatoms number is the monocycle of 1～2 or 5～10 yuan of heteroaryls of condensed ring, it is described that " heteroatoms is N, O or S atom, heteroatoms number is 5～10 yuan of heteroaryls of monocycle of 1～2 " preferred pyrazolyl (described " pyrazolyl " be 1H-pyrazoles-4-yl preferably), pyridyl (described " pyridyl " be pyridin-4-yl or pyridin-3-yl preferably), thienyl (described " thienyl " be thiene-3-yl-or thiophene-2-yl preferably) or furyl (described " furyl " be furans-2-yl preferably), described " heteroatoms is that N, O or S atom, heteroatoms number are 5～10 yuan of heteroaryls of condensed ring of 1～2 " preferably quinolyl (described " quinolyl " be quinoline-3-base or quinoline-7-yl preferably), isoquinolyl (described " isoquinolyl " be isoquinoline 99.9-4-yl preferably), benzothienyl (described " benzothienyl " be thionaphthene-3-base or thionaphthene-2-yl preferably) or indyl (described " indyl " be indoles-5-yl preferably),
Described 6～10 yuan of aryl or 5～10 yuan of heteroaryls can by 1～2 be selected from halogen (for example fluorine, chlorine or bromine), cyano group, (preferably N, N-dimethylamino), (preferably ), (preferably ), with group replace, wherein R 5, R 6be C independently of one another 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, preferable methyl) or hydroxyl replace C 1-6alkyl (described " the C that hydroxyl replaces 1-6alkyl " described in " C 1-6alkyl " preferred C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl; Described " the C that hydroxyl replaces 1-6alkyl " preferably );
L is or
R 2, R 3be H or F independently of one another, R 4for H;
A is 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases, described 6～10 yuan of aryl (preferably phenyl) or 5～10 membered nitrogen-containing heteroaryl bases (preferred nitrogen atomicity is 5～10 membered nitrogen-containing heteroaryl bases of 1～2, and described " nitrogen-atoms number is 5～10 membered nitrogen-containing heteroaryl bases of 1～2 " be pyridyl, pyrazolyl or quinolyl preferably) can be selected from halogen (for example fluorine, chlorine or bromine), C by 1～2 1-6alkyl (preferably C 1-4alkyl, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl are the individual preferred 1-methyl isophthalic acid of 5～6 membered nitrogen-containing heteroaryl base H-pyrazoles-4-base of 1-2 by methyl substituted nitrogen-atoms number; ) and (wherein, C 1-6the preferred C of alkyl 1-4alkyl, described " C 1-6alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, preferable methyl) group replace.
In compound 1-c, Cy is phenyl, described phenyl can by 1～2 be selected from halogen (for example fluorine, chlorine or bromine, preferably fluorine) and (wherein, described " C 1-4alkyl " for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, preferable methyl) group replace; Described " by 1～2 be selected from halogen and the phenyl that replaces of group " the preferred fluoro-4-of 3-(N-methylcarbamoyl)-1-phenyl;
L is
R 1, R 2, R 3, R 4be H;
A is 1-methyl isophthalic acid H-pyrazoles-4-base.
In the present invention, when L is time, the chiral carbon atom in L can be R configuration, S configuration or racemize configuration.
In the present invention, in the time that Cy is 6～10 yuan of aryl, the further preferred phenyl of described " 6～10 yuan of aryl ", the fluoro-phenyl of 2-, the chloro-phenyl of 2-, the chloro-phenyl of 3-, 2-trifluoromethyl-phenyl, 4-trifluoromethyl, 3,4-dichlorophenyl, 4-Trifluoromethoxyphen-l, 3-cyano group-phenyl, 4-cyano-phenyl, 3-N, N-dimethylaminophenyl, 4-aminophenyl, 2,4-dimethoxy-phenyl, 2,6-dimethoxy-phenyl, 2,6-dimethyl-phenyl, 2-methyl-4-methoxyl group-phenyl, 2-methyl-5-p-methoxy-phenyl, 4-methylthio group-phenyl,
In the present invention, in the time that Cy is 5～10 yuan of heteroaryls, described " 5～10 yuan of heteroaryls " is further preferred: thiophene-2-base, thiene-3-yl-, furans-2-base, pyridin-3-yl, pyridin-4-yl, PA-3-base, 2-fluorine pyridin-3-yl, PA-5-base, 2-picoline-5-base, indoles-4-base, indoles-5-base, quinoline-7-base, isoquinoline 99.9-4-base, 5-cyano thiophene-2-base,
In the present invention, the quinolines shown in formula 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug are further preferably as follows described arbitrary compound:
6-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1)-methylene radical)-quinoline (1-1),
6-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-2),
6-(6-(pyridin-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-3),
6-(6-(4-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical) quinoline (1-4),
4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazoles-6-yl)-aniline (1-5),
6-(6-(4-Trifluoromethoxyphen-l)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-6),
6-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-7),
The chloro-4-of 7-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl) quinoline (1-8),
N, N-dimethyl-3-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-aniline (1-9),
6-(6-(4-methoxyl group-2-methyl-l-phenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-10),
6-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-11),
6-(6-(1,2,3,6-tetrahydropyridine-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline hydrochloride (1-12),
4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-3,6-dihydropyridine-1 (2H)-ethyl formate (1-13),
6-(6-(2,6-Dimethoxyphenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-14),
6-(6-(2,4-Dimethoxyphenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-15),
3-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical) quinoline (1-16),
6-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-17),
2-(4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyrazol-1-yl)-ethanol (1-18),
6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-19),
6-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-20),
6-(1-(6-(4-(trifluoromethyl) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-21),
6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-22),
6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-23),
6-(1-(6-(4-methoxyl group-2-aminomethyl phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-24),
N, N-dimethyl-3-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline (1-25),
6-(1-(6-(1,2,3,6-tetrahydropyridine-1--4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline-1-muriate (1-26),
2-(4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) ethanol (1-27),
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-28),
6-(1-(6-(2,6-3,5-dimethylphenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-29),
The fluoro-4-of 2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate (1-30),
6-(1-(6-(4-(methylthio group) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-31),
6-(1-(6-(thiene-3-yl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-32),
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-33),
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzsulfamide (1-34),
6-(1-(6-(pyrimidine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-35),
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-2-formaldehyde (1-36),
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzonitrile (1-37),
6-(1-(6-(6-picoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-38),
6-(1-(6-(1H-pyrrolo-[2,3-b] pyridine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-39),
N, N-dimethyl-5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine (1-40),
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-3-formaldehyde (1-41),
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyrimidine-2-amine (1-42),
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine (1-43),
(5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-3-yl) methyl alcohol (1-44),
3-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine (1-45),
The fluoro-4-of 2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide (1-46),
The fluoro-4-of N-ethyl-2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide (1-47),
The fluoro-N-methyl-4-of 2-(1-(1-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide (1-48),
6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-2-alcohol (1-49),
The fluoro-6-of 8-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-50),
The fluoro-6-of 8-((6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-51),
The fluoro-6-of 8-((6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-52),
2-(4-(1-((8-fluorine quinoline-6-yl) methyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) ethanol (1-53),
6-((6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-8-fluorine quinoline (1-54),
The fluoro-6-of 8-((6-(3-quinolyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-quinoline (1-55),
The fluoro-6-of 8-((6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-quinoline (1-56),
8-fluoro-(6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-57),
The fluoro-6-of 8-(1-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-58),
The fluoro-6-of 8-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-59),
The fluoro-6-of 8-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-60),
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline (1-61),
The fluoro-6-of 8-(1-(6-(3-quinolyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-62),
6-(1-(6-(3,4-dichlorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline (1-63), 6-(1-(6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline (1-64),
6-(1-(6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline (1-65),
The fluoro-6-of 8-(1-(6-(2-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-66),
The fluoro-6-of 8-(1-(6-(4-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-67),
The fluoro-6-of 8-(1-(6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-68),
6-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical]-quinoline (1-69),
2-(4-(1-(the fluoro-quinoline-6-of 7-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl)-ethanol (1-70),
6-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-7-fluorine quinoline (1-71),
The fluoro-6-of 7-(6-phenyl-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-72),
The fluoro-6-of 7-(6-(pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-73),
(3-(1-(the fluoro-quinoline-6-of 7-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-phenyl)-N, N-dimethyl amine (1-74),
The fluoro-6-of 7-(6-(4-methoxyl group-2-methyl-phenyl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-75),
The fluoro-6-of 7-(6-(quinoline-3-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-76),
4-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-aniline (1-77),
6-((5-(the chloro-4-quinolyl of 7-) imidazo [4,5-b] pyrazine-3-yl) methylene radical) the fluoro-quinoline of-7-(1-78),
The chloro-4'-of 7-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-[4,7'] two quinoline (1-79),
4-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1-80),
The fluoro-6-[6-of 7-(1,2,3,6-tetrahydrochysene-pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical]-quinoline hydrochloride (1-81),
The fluoro-6-of 7-(6-(the fluoro-phenyl of 2-)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-82),
The fluoro-6-of 7-(6-(pyridin-3-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-83),
6-(6-(3-chloro-phenyl-)-imidazo [4,5-b] pyrazine-1-methylene radical) the fluoro-quinoline of-7-(1-84),
The fluoro-6-of 7-(6-(naphthalene-1-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (1-85),
6-(6-cyclopropyl-imidazo [4,5-b] pyrazine-1-methylene radical) the fluoro-quinoline of-7-(1-86),
The fluoro-6-of 7-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H--imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-87),
4-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline (1-88),
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline (1-89),
The fluoro-6-of 7-(1-(6-phenyl-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-90),
The fluoro-6-of 7-(1-(6-(pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-91),
2-(4-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl)-ethanol (1-92),
The fluoro-6-of 7-(1-(6-(quinoline-3-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-93),
The fluoro-4-of 2-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-methyl benzoate (1-94),
The fluoro-4-of 2-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-benzamide (1-95),
The fluoro-4-of 2-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-N-methyl-benzamide (1-96),
4-(1-(1-(7-fluorine quinoline-6 base)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-benzsulfamide (1-97),
The fluoro-6-of 7-(1-(6-(pyrimidine-5-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-98),
4-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-furans-2-methyl alcohol (1-99),
4-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-3H-imidazo [4,5-b] pyrazine-6-yl) cyanobenzene (1-100),
The fluoro-6-of 7-(1-(6-(thiophene-2-yl) imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-101),
The fluoro-6-of 7-(1-(6-(thiene-3-yl-) imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-102),
6-(1-(6-(benzo [b] thiophene-2-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline (1-103),
6-(1-(6-(benzo [b] thiene-3-yl-)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline (1-104),
The fluoro-6-of 7-(1-(6-(4-methylthio group phenyl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline (1-105),
6-(1-(6-(1H-pyrroles [2,3-b] pyridine-5-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline (1-106),
5-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-N, N-lutidine-2-amine (1-107),
The fluoro-6-of 7-(1-(6-(6-methyl-pyridin-3-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline; (1-108),
3-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyridine-2-amine (1-109),
5-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyridine-2-amine (1-110),
5,7 two fluoro-6-((6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-111),
6-((6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline (1-112),
The fluoro-6-of 5,7-bis-((6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-113),
6-((6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline (1-114),
The fluoro-6-of 5,7-bis-((6-(4-(trifluoro methoxy) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (1-115),
4-(1-((5,7-difluoro-quinoline-6-yl) methyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate (1-116),
6-((6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline (1-117),
5,7 two fluoro-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-118),
The fluoro-6-of 5,7-bis-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-119),
The fluoro-6-of 5,7-bis-(1-(6-(pyridin-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-120),
3-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-DMA (1-121),
The fluoro-6-of 5,7-bis-(1-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-122),
6-(1-(6-(2,6-3,5-dimethylphenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-123),
6-(1-(6-(3-chloro-phenyl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-124),
6-(1-(6-cyclopropyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-125),
2-(4-(1-(1-(5,7 – difluoro-quinoline-6-yls) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) second-1-alcohol (1-126),
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline (1-127),
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-128),
6-(1-(6-(7-chloroquinoline-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-129),
The fluoro-6-of 5,7-bis-(1-(6-(pyridin-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline (1-130),
The fluoro-6-of 5,7-bis-(1-(6-(5-methoxyl group-2-aminomethyl phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline (1-131),
The fluoro-6-of 5,7-bis-(1-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline (1-132),
6-(1-(6-(3-chloro-phenyl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-133),
6-(1-(6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-134),
The fluoro-6-of 5,7-bis-(1-(6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-135),
6-(1-(6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-136),
The fluoro-6-of 5,7-bis-(1-(6-(4-trifluoromethoxy benzaldehyde base)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-137),
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate (1-138),
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) the fluoro-N-methyl-benzamide of-2-(1-139),
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) the fluoro-benzamide of-2-(1-140),
The fluoro-6-of 5,7-bis-(1-(6-(4-first sulfur phenenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-141),
The fluoro-6-of 5,7-bis-(1-(6-(1-(benzenesulfonyl)-1H-indol-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-142),
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (1-143),
The fluoro-6-of 5,7-bis-(1-(6-(pyrimidine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-144),
The fluoro-6-of 5,7-bis-(1-(6-(3-thienyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-145),
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) cyanobenzene (1-146),
7-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-147),
7-methyl-6-(1-(6-(3-quinolyl)-1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-148),
N, N-dimethyl-3-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline (1-149),
7-methyl-6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-150),
6-(1-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-7-toluquinoline (1-151),
The fluoro-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate (1-152),
The fluoro-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide (1-153),
The fluoro-N-methyl-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide (1-154),
5-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-155),
5-methyl-6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-156),
5-methyl-6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-157),
2-(4-(1-(1-(5-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-base-1H-pyrazol-1-yl) second-1-alcohol (1-158),
The fluoro-4-of 2-(1-(1-(5-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate (1-159),
5-methyl-6-(1-(6-(3-quinolyl)-1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-160),
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylpiperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-161),
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(piperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-162),
The fluoro-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate (1-163),
6-(1-(6-(1H-indoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (1-164),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate (1-165),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-166),
6-(1-(6-(1H-indoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (1-167),
The fluoro-6-of 5,7-bis-(1-(6-(isoquinoline 99.9-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (1-168),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-7-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-169),
The fluoro-3-(1-methyl isophthalic acid of 5,7-bis-H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-170),
3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate (1-171),
The fluoro-3-of 7-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (1-172),
3-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(also [4,5-b] pyrazinyl methyl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) quinoline (2-1),
3-phenyl-6-(also [4,5-b] pyrazinyl methyl of 6-phenyl-[1,2,3] triazole) quinoline (2-2),
6-(also [4,5-b] pyrazinyl methyl of 6-(quinoline-3-yl)-[1,2,3] triazole)-[3,3 '] two quinoline (2-3),
3-(pyridin-4-yl)-6-(also [4,5-b] pyrazinyl methyl of 6-(pyridin-4-yl)-[1,2,3] triazole) quinoline (2-4),
The fluoro-4-of 2-(6-(6-(the fluoro-4-methoxycarbonyl of 3-phenyl)-1H-[1,2,3] also [4,5-b] pyrazinyl methyl of triazole) quinoline-3-yl) methyl benzoate (2-5),
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(6-(1-methyl isophthalic acid H-4-pyrazolyl)-also [4,5-b] pyrazinyl of [1,2,3] triazole) ethyl) quinoline (2-6),
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(1H-4-pyrazolyl)-[1,2,3] triazole) ethyl) quinoline (2-7),
2-(4-(3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) pyrazolyl) ethanol (2-8),
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(pyridin-4-yl)-[1,2,3] triazole) ethyl) quinoline (2-9),
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(quinoline-3-yl)-[1,2,3] triazole) ethyl) quinoline (2-10),
The fluoro-6-of 7-(1-(also [4,5-b] pyrazinyl of 6-(isoquinoline 99.9-4-yl)-[1,2,3] triazole) ethyl)-3-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline (2-11),
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(4-methylthio group phenyl)-[1,2,3] triazole) ethyl) quinoline (2-12),
6-(1-(6-(benzo [b] thiene-3-yl-)-also [4,5-b] pyrazinyl of [1,2,3] triazole) ethyl) the fluoro-3-of-7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline (2-13),
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinolyl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) methyl benzoate (2-14),
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole)-N-methyl-benzamide (2-15),
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) benzamide (2-16),
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-17),
The fluoro-N-methyl-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzamide (2-18),
The fluoro-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzamide (2-19),
6-(1-(6-(benzo [b] thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-20),
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-21),
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-22),
6-(1-(6-(furans-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-23),
3-(4-fluorophenyl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-24),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [1,2,3] triazolos [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-25),
6-(1-6-(1H-indoles-5-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-26),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate (2-27),
The fluoro-6-of 5,7-bis-(1-(6-(isoquinoline 99.9-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-28),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-7-yl)-1H-[1,2,3] triazolo [41,5-b] pyrazine-1-yl) ethyl) quinoline (2-29),
5-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-N, N-lutidine-2-amine (2-30),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylthio group phenyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-31),
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (2-32),
The fluoro-6-of 5,7-bis-(1-(6-(2-fluorine pyridin-3-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-33),
3-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) pyridine-2-amine (2-34),
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-35),
6-(1-(6-(benzo [b] thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-36),
The fluoro-6-of 5,7-bis-(1-(6-(furans-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (2-37),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) the fluoro-N-methyl-benzamide of-2-(2-38),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) aniline (2-39),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzsulfamide (2-40),
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-2-fluorobenzamide (2-41),
5-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) thiophene-2-formonitrile HCN (2-42),
Or the fluoro-N-methyl-4-of 2-(7-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-yl) benzamide (3-1).
The preparation method of quinolines as shown in Equation 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug described in the present invention also provides, it comprises the following steps: in solvent, Compound I I and boric acid or boric acid ester are carried out to Suzuki linked reaction, obtain compound 1;
Wherein, X is halogen (preferably chlorine, bromine or iodine); Cy, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in.
Prepare the method for compound 1, for carrying out the ordinary method of Suzuki linked reaction in this area, following reaction conditions particularly preferably in the present invention:
Preparing in the method for compound 1, described solvent preferably water and/or water-miscible organic solvent; One or more in the preferred dioxane of described water-miscible organic solvent, tetrahydrofuran (THF) and DMF (DMF).
Preparing in the method for compound 1, described solvent with the volume mass of Compound I I than preferred 100mL/g～500mL/g, further preferred 200mL/g～400mL/g.
Preparing in the method for compound 1, preferably compound as shown in Equation 6 of described boric acid or boric acid ester wherein R 17for hydrogen, C 1-6alkyl or wherein C 2-c 6represent alkylidene group; In the time that p is 1, R 17for in the time that p is 2, R 17for hydrogen or C 1-6alkyl.
Preparing in the method for compound 1, the preferred 1:1～1:3 of the mol ratio of described Compound I I and boric acid or boric acid ester, further preferred 1:1.2～1:1.8.
Preparing in the method for compound 1, the temperature of described Suzuki linked reaction can be in the freezing point from solvent to the temperature changing within the scope of the boiling temperature of solvent, and preferably 90 DEG C～150 DEG C, further preferably 100 DEG C～120 DEG C.
Preparing in the method for compound 1, the process of described Suzuki linked reaction can adopt conventionally test method in this area (as nucleus magnetic resonance, infrared spectra, spectrophotometric or mass spectroscopy, HPLC or TLC) to determine, disappear as reaction end taking Compound I I, preferred reaction time 2h～10h, further preferred 2.5h～4h.
Preparing in the method for compound 1, described Compound I I can be prepared by following method, and it comprises the following steps: compound III is reacted with carboxylic acid or original carboxylic acid ester, obtain Compound I I;
Make compound 1 according to the described method of preparing compound 1 again; Wherein, X, Cy, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in.
Prepare the method for Compound I I, for carrying out the ordinary method of such reaction in this area, following reaction conditions particularly preferably in the present invention:
Preparing in the method for Compound I I, described carboxylic acid or original carboxylic acid ester had both done reaction reagent and had also done reaction solvent.
Preparing in the method for Compound I I, one or more in the preferred original acid A ester of described carboxylic acid or original carboxylic acid ester, ethyl orthoformate and diethoxy ritalin.
Preparing in the method for Compound I I, described carboxylic acid or original carboxylic acid ester with the volume mass of compound III than preferred 20mL/g～100mL/g, further excellent 40mL/g～80mL/g.
Preparing in the method for Compound I I, the temperature of described reaction can be in the freezing point from solvent to the temperature changing within the scope of the boiling temperature of solvent, and preferably 120 DEG C～180 DEG C, further preferably 140 DEG C～160 DEG C.
Preparing in the method for Compound I I, the process of described reaction can adopt conventionally test method in this area (as nucleus magnetic resonance, infrared spectra, spectrophotometric or mass spectroscopy, HPLC or TLC) to determine, taking compound III disappearance as reaction end, preferred reaction time 15h～30h, further preferred 20h～25h.
Preparing in the method for Compound I I, described compound III can be prepared by following method, and it comprises the following steps: in solvent, compound V or its acid salt and compound IV are carried out to nucleophilic substitution reaction, obtain compound III;
Make Compound I I according to the described method of preparing Compound I I again, the described method of preparing compound 1 makes compound 1; Wherein, X, X 1, X 2, X 3, R 2, R 3, R 4, L and A definition all same as above.
Prepare the method for compound III, for carrying out the ordinary method of such nucleophilic substitution reaction in this area, following reaction conditions particularly preferably in the present invention:
In the method for preparing compound III, the solvent that the preferred boiling point of described solvent is greater than 130 DEG C, further preferred DMF (DMF), N, one or more in N-diethylformamide (DEF) and N-Methyl pyrrolidone
In the method for preparing compound III, described solvent with the volume mass of compound IV than preferred 10mL/g～50mL/g, further preferably 20mL/g～30mL/g.
In the method for preparing compound III, the preferred 1:1～1:3 of mol ratio of described compound V and compound IV, further preferred 1:1.2～1:1.6.
In the method for preparing compound III, the temperature of described reaction can be in the freezing point from solvent to the temperature changing within the scope of the boiling temperature of solvent, and preferably 150 DEG C～250 DEG C, further preferably 190 DEG C～210 DEG C.
In the method for preparing compound III, the process of described reaction can adopt conventionally test method in this area (as nucleus magnetic resonance, infrared spectra, spectrophotometric or mass spectroscopy, HPLC or TLC) to determine, taking compound IV disappearance as reaction end, preferred reaction time 20h～30h, further preferred 18h～25h.
The preparation of compound can relate to protection and the deprotection of multiple chemical groups.For the needs of protection and deprotection; and can be easy to be determined by those skilled in the art to the selection of suitable protecting group; the chemical process of protecting group is people such as such as Greene; Protective Groups in Organic Synthesis; the second edition, Wiley & Sons, 1991; in find, it is incorporated herein by reference with overall form at this.
In the method for preparing compound III, described compound V can adopt method 1 or method 2, when L is shi Youxuan employing method 1, when L is time, preferably adopt method 2;
Method 1: in organic solvent, compound VI and hydrogen are carried out to reduction reaction and obtain compound V;
Make compound III according to the described method of preparing compound III again, the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
Method 2: in organic solvent, compound VI II and hydrogen are carried out to reduction reaction and obtain compound V;
Make compound III according to the described method of preparing compound III again, the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method 1 of preparing compound V can be the ordinary method of such reduction reaction in this area, and the present invention is following reaction method and condition particularly preferably:
Prepare the method 1 of compound V and preferably under the condition of ammonia existence, carry out, described ammonia preferably participates in reaction with the form of ammonia alcoholic solution.
Prepare the method 1 of compound V preferably carries out under the condition of Raney's nickel (Raney Ni) existence, described Raney's nickel can be conventional commercially available Raney's nickel reagent, the mass percent of described Raney's nickel preferably 20%～80%, described mass percent refers to that the quality of nickel accounts for the per-cent of Raney's nickel reagent total mass.
In the method 1 of preparing compound V, described organic solvent preferred alcohols kind solvent, described alcoholic solvent particular methanol and/or ethanol.
In the method 1 of preparing compound V, the preferred 10bar～50bar of pressure of described reduction reaction, further preferred 20bar～30bar.
In the method 1 of preparing compound V, preferably 10 DEG C～40 DEG C of the temperature of described reduction reaction.
In the method 1 of preparing compound V, the process of described reduction reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compound VI as reaction end, preferably 1 hour～48 hours reaction times.
In the method 1 of preparing compound V, described compound VI can adopt following method preparation: under gas shield, in organic solvent, under the condition that catalyzer exists, compound VI I and zinc cyanide are carried out to nucleophilic substitution reaction, obtain compound VI;
Make compound V according to the described method of preparing compound V 1 again, the described method of preparing compound III makes compound III, and the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method of preparing compound VI can be the ordinary method of such nucleophilic substitution in this area, particularly preferably following reaction method and condition in the present invention:
In the method for preparing compound VI, described organic solvent preferred amide kind solvent, the preferred DMF of described amide solvent.
In the method for preparing compound VI, described catalyzer is three (dibenzalacetone) two palladiums and two (diphenylphosphine) ferrocene of 1,1'-preferably.
In the method for preparing compound VI, the molar ratio of described zinc cyanide and described compound VI I preferably 1～5, further preferably 1～2.
In the method for preparing compound VI, the molar ratio of described catalyzer and described compound VI I preferably 0.1～1.
In the method for preparing compound VI, when adopting three (dibenzalacetone) two palladiums and 1, when two (diphenylphosphine) ferrocene of 1'-make catalyzer, described 1, the molar ratio of two (diphenylphosphine) ferrocene of 1'-and described three (dibenzalacetone) two palladiums preferably 2～3.
In the method for preparing compound VI, preferably 80 DEG C～150 DEG C of the temperature of described nucleophilic substitution reaction.
In the method for preparing compound VI, the process of described nucleophilic substitution reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compound VI I as reaction end, preferably 1 hour～48 hours reaction times, further preferably 10 hours～24 hours.
In the method for preparing compound VI, described compounds X II can be prepared by following method: in solvent, under the condition that sulfuric acid and catalyzer exist, compounds X II and compounds X III are carried out to condensation reaction, obtain compound VI I;
Make compound VI according to the described method of preparing compound VI again, the described method of preparing compound V 1 makes compound V, the described method of preparing compound III makes compound III, the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method of preparing compound VI I can be the ordinary method of such condensation in this area, particularly preferably following reaction method and condition in the present invention:
Preparing in the method for compound VI I, described solvent preferably water.
Preparing in the method for compound VI I, the preferred 3-nitrobenzene sodium sulfonate of described catalyzer.
Preparing in the method for compound VI I, the molar ratio of described compounds X III and described compounds X II preferably 1～5, further preferably 2～3.
Preparing in the method for compound VI I, the molar ratio of described catalyzer and described compound VI I preferably 1～3, further preferably 1～1.5.
Preparing in the method for compound VI I, the molar ratio of described sulfuric acid and described compounds X II preferably 0.5～2.Described sulfuric acid can be conventional commercial sulfuric acid reagent in this area, the mass percentage concentration of described sulfuric acid preferably 30%～98%, and described mass percentage concentration refers to that the quality of sulfuric acid accounts for the per-cent of aqueous sulfuric acid total mass.
Preparing in the method for compound VI I, preferably 80 DEG C～150 DEG C of the temperature of described condensation reaction.
Preparing in the method for compound VI I, the process of described nucleophilic substitution reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compound VI I as reaction end, preferably 1 hour～48 hours reaction times, further preferably 10 hours～24 hours.
The method 2 of preparing compound V can be the ordinary method of such reduction reaction in this area, and the present invention is following reaction method and condition particularly preferably:
Prepare the method 2 of compound V and preferably under the condition of ammonia existence, carry out, described ammonia preferably participates in reaction with the form of ammonia alcoholic solution.
Prepare the method 2 of compound V preferably carries out under the condition of Raney's nickel (Raney Ni) existence, described Raney's nickel can be conventional commercially available Raney's nickel reagent, the mass percent of described Raney's nickel preferably 20%～80%, described mass percent refers to that the quality of nickel accounts for the per-cent of Raney's nickel reagent total mass.
In the method 2 of preparing compound V, described organic solvent preferred alcohols kind solvent, described alcoholic solvent particular methanol and/or ethanol.
In the method 2 of preparing compound V, preferably 10 DEG C～40 DEG C of the temperature of described reduction reaction.
In the method 2 of preparing compound V, the process of described reduction reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compound VI II as reaction end, preferably 1 hour～48 hours reaction times.
In the method 2 of preparing compound V, described compound VI II can adopt following method preparation: in organic solvent, azanol and Compound I X are carried out to condensation reaction, obtain compound VI II;
Make compound V according to the described method of preparing compound V 2 again, the described method of preparing compound III makes compound III, and the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method of preparing compound VI II can be the ordinary method of such condensation in this area, particularly preferably following reaction method and condition in the present invention:
Preparing in the method for compound VI II, described organic solvent preferred alcohols kind solvent, described alcoholic solvent particular methanol and/or ethanol.
Preparing in the method for compound VI II, described azanol can use with the form of its hydrochloride, in the time adopting the hydrochloride of azanol, preferably first the hydrochloride of azanol is reacted with alkali and obtain azanol and carry out again condensation reaction, the preferred mineral alkali of described alkali, the preferably strong sodium oxide of described mineral alkali.
Preparing in the method for compound VI II, the molar ratio of described azanol and described Compound I X preferably 1～5, further preferably 1～2.
Preparing in the method for compound VI II, preferably 10 DEG C～40 DEG C of the temperature of described condensation reaction.
Preparing in the method for compound VI II, the process of described condensation reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking Compound I X as reaction end, preferably 1 hour～48 hours reaction times, further preferably 10 hours～24 hours.
Preparing in the method for compound VI II, described Compound I X can adopt following method preparation: under gas shield, in organic solvent, compounds X reacts with methyl-magnesium-bromide and obtains Compound I X;
Make compound VI II according to the described method of preparing compound VI II again, the described method of preparing compound V 2 makes compound V, the described method of preparing compound III makes compound III, the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method of preparing Compound I X can be such reaction ordinary method in this area, particularly preferably following reaction method and condition in the present invention:
Preparing in the method for Compound I X, " gas " described in described " gas shield " is one or more in helium, argon gas, neon and nitrogen preferably.
Preparing in the method for Compound I X, the preferred ether solvent of described organic solvent, the preferred tetrahydrofuran (THF) of described ether solvent.
Preparing in the method for Compound I X, the molar ratio of described methyl-magnesium-bromide and described compounds X preferably 1～3, further preferably 1～1.5.
Preparing in the method for Compound I X, preferably 0 DEG C～40 DEG C of the temperature of described reaction.
Preparing in the method for Compound I X, the process of described reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compounds X as reaction end, preferably 1 hour～48 hours reaction times, further preferably 10 hours～24 hours.
Preparing in the method for Compound I X, described compounds X can adopt following method to make: under gas shield, in organic solvent, under the condition that catalyzer exists, compounds X I is reacted with hydrochloric acid dimethyl hydroxylamine, obtain compounds X;
Make Compound I X according to the described method of preparing Compound I X again, the described method of preparing compound VI II makes compound VI II, the described method of preparing compound V 2 makes compound V, the described method of preparing compound III makes compound III, the described method of preparing Compound I I makes Compound I I, and the described method of preparing compound 1 makes compound 1; Wherein, X, R 2, R 3, R 4, L and A definition all same as above.
The method of preparing compounds X can be such reaction ordinary method in this area, particularly preferably following reaction method and condition in the present invention:
In the method for preparing compounds X, one or more in the preferred helium of " gas " described in described " gas shield ", argon gas, neon and nitrogen.
In the method for preparing compounds X, described organic solvent preferred amide kind solvent, the preferred DMF of described amide solvent.
In the method for preparing compounds X, the molar ratio of described hydrochloric acid dimethyl hydroxylamine and described compounds X I preferably 1～3, further preferably 1～1.5.
In the method for preparing compounds X, the preferred 2-of described catalyzer (7-azo phenylpropyl alcohol triazole-1-yl)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).
In the method for preparing compounds X, the molar ratio of described catalyzer and described compounds X I preferably 1～3, further preferably 1～1.5.
In the method for preparing compounds X, preferably 0 DEG C～40 DEG C of the temperature of described reaction.
In the method for preparing compounds X, the process of described reaction can adopt conventionally test method in this area (for example TLC, HPLC or NMR) to monitor, while generally disappearance taking compounds X I as reaction end, preferably 1 hour～48 hours reaction times, further preferably 10 hours～24 hours.
In the present invention, described Compound I can adopt route one or two preparations,
Route one:
Route two:
Wherein, X, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in.
The present invention also provides the midbody compound II, compound III or the compound V that prepare compound 1,
Wherein, X, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in.
The preparation method of Compound I I described in the present invention also provides, it preferably adopts route A or route B,
Route A:
Route B:
Wherein, X, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in; Described in the concrete reaction conditions of each step is all the same.
The preparation method of the compound III described in the present invention also provides, it preferably adopts route C or route D,
Route C:
Route D:
Wherein, X, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in; Described in the concrete reaction conditions of each step is all the same.
The preparation method of compound V described in the present invention also provides, it preferably adopts route E or route F:
Route E:
Route F:
Wherein, X, X 1, X 2, X 3, R 1, R 2, R 3, R 4, L and A definition all the same described in; Described in the concrete reaction conditions of each step is all the same.
The present invention also provides described quinolines as shown in Equation 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, treats and/or prevents and application in the expression of Tyrosylprotein kinase C-Met or the medicine of active relevant disease in preparation.
The present invention also provides a kind of pharmaceutical composition, and it contains quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug as shown in Equation 1, and pharmaceutically acceptable one or more pharmaceutical excipients.
In the present invention, in described pharmaceutical composition, the content of quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug is as shown in Equation 1 treatment significant quantity, and preferred mass percentage composition is 1%～99%; Described quality percentage composition is quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof and/or its prodrug as shown in Equation 1, accounts for the per-cent of pharmaceutical composition total mass.The summation of the massfraction of the each component of pharmaceutical composition described in the present invention is 100%; In described pharmaceutical composition, the quality percentage composition sum of each component is 100%.
In the present invention, described pharmaceutical excipient is the conventional pharmaceutical excipient in this area, its select because of route of administration and effect feature different, preferably comprise weighting agent, thinner, tackiness agent, wetting agent, disintegrating agent, lubricant, emulsifying agent, suspending agent.
In the present invention, described pharmaceutical composition can be oral, injection (in vein, muscle, subcutaneous and coronary artery), hypogloeeis, use through cheek, per rectum, per urethra, transvaginal, intranasal, suction or local approach.Preferred approach is oral.
The present invention also provides described pharmaceutical composition to treat and/or prevent and application in the expression of Tyrosylprotein kinase C-Met or the medicine of active relevant disease in preparation.
In the present invention, the caused disease of the variation by Tyrosylprotein kinase C-Met that described expression or active relevant disease to Tyrosylprotein kinase C-Met is routine in this area, preferably comprises cancer, muscle skeleton sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours.Described cancer preferably comprises bladder cancer, mammary cancer, cervical cancer, colorectal carcinoma, esophagus cancer, cancer of the stomach, head and neck cancer, kidney, lung cancer, liver cancer, nasopharyngeal carcinoma, ovarian cancer, carcinoma of the pancreas, prostate cancer and thyroid carcinoma; Described muscle skeleton sarcoma preferably comprises: osteosarcoma, synovial sarcoma and rhabdosarcoma; Described soft tissue sarcoma preferably comprises: malignant fibrous histiocytoma/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma; Described Hematopoietic Malignancies preferably comprises: multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia and chronic myelocytic leukemia; Other described tumours preferably comprise: glioblastoma multiforme, astrocytoma, melanoma, mesothelioma and embryonal carcinosarcoma.
Some chemistry or technical term of pharmacology:
Unless otherwise defined, otherwise the connotation that the connotation that all scientific and technical terminologies of the application have and one of ordinary skill in the art understand is conventionally identical.Except as otherwise noted, the application quotes in full all patents, patent application, open material by reference entirety are incorporated to herein.
Can be at reference (" the ADVANCED ORGANIC CHEMISTRY4 that comprises Carey and Sundberg tHeD. " Vols.A (2000) and B (2001), Plenum Press, New York) in find the definition to standard chemical term.Except as otherwise noted, otherwise adopt the ordinary method within the scope of art technology, as mass spectrum, NMR, IR and UV/Vis spectrography and pharmacological method.Unless proposition specific definition, the application analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemical about describe in adopt term be known in the art.The application is at chemosynthesis, chemical analysis, medicine preparation, preparation and send, and to using standard technique in patient's treatment.For example, can utilize the operation instruction of manufacturer to test kit, or implement reaction and carry out purifying according to mode well known in the art or explanation of the present invention.Conventionally can, according to the description in multiple summary of quoting in this specification sheets and discussing and more concrete document, implement described technology and method according to ordinary method well known in the art.In this manual, can select group and substituting group thereof so that stable structure part and compound to be provided by those skilled in the art.
In the time that the conventional chemical formula by writing is from left to right described substituting group, this substituting group comprises the substituting group being chemically equal to obtaining while writing structural formula from right to left too.For example ,-CH 2be equal to-OCH of O- 2-.
In the present invention, term " C 1～4" refer in its defined group to there is 1～4 carbon atom, group can comprise 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.For example, " C 1～4alkyl " refer to the alkyl with 1～4 carbon atom, described alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Can know thus the implication of other terms of describing in a similar manner by inference, as " C 1～6" etc.
In the present invention, term " 6～10 yuan " refers to that the atom number that surrounds this closed hoop skeleton itself in its defined closed ring system group (as aromatic ring, aryl, heteroaryl, hetero-aromatic ring, cycloalkyl, Heterocyclylalkyl, heterocycloalkenyl etc.) is 6,7,8,9 or 10.Can get different numbers according to the number of rings of closed ring system group, saturation ratio and the atomic property that forms this ring etc.Can know thus the implication of other terms of describing in a similar manner by inference, as " 7～10 yuan " etc.
In the present invention, term " aromatic ring " or " aryl " refer to the cyclic conjugated aryl radical of optional replacement, and it has 6～18 and becomes ring carbon atom, can comprise monocycle, dicyclo, three ring or more rings.The rest part of compound molecule can be connected with the carbon atom in aryl rings by singly-bound.In the time that aryl is substituted, substituting group can replace on any spendable tie point.With regard to object of the present invention, the preferably aryl of 6～10 yuan of monocycles or bicyclic system, for example phenyl or naphthyl.
In the present invention, term " hetero-aromatic ring ", " aromatic heterocycle " or " heteroaryl " refer to, the optional conjugation aromaticity ring system group jointly being formed by carbon atom and heteroatoms replacing, it comprises approximately 5 to approximately 12 skeletons and becomes annular atoms, wherein one or more (as 1～6,1～4,1～3,1～2) one-tenth annular atomses are heteroatoms, described heteroatoms is independently selected from the heteroatoms in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to this.Any one-tenth theheterocyclic nitrogen atom in hetero-aromatic ring can be oxidized and form nitrogen oxygen composition.In ring, occur that, in two or more heteroatomic embodiments, described two or more heteroatomss can be mutually the same, or some or all in described two or more heteroatomss differ from one another.The rest part of compound molecule can be connected with carbon atom or heteroatoms on hetero-aromatic ring by singly-bound.For example, imidazoles can by it, carbon atom (imidazoles-2-base, imidazol-4 yl or imidazoles-5-yl) or nitrogen-atoms (imidazoles-1-base or imidazo-3-yl) be connected with parent molecule arbitrarily.Described hetero-aromatic ring comprises the system of monocycle and many rings (for example having 2,3 or 4 rings mutually to condense).With regard to object of the present invention, preferably 5～10 yuan and contain 1～2 heteroatomic monocycle hetero-aromatic ring or fused heteroaromatic ring that is selected from N, S and O, the wherein preferably bicyclic system of 7～10 yuan of fused heteroaromatic ring, and can comprise heteroatoms by shared atom between two rings.
In the present invention, term " cycloalkyl " refers to stable non-aromatic monocycle or the multi-ring alkyl that are only made up of carbon atom and hydrogen atom, can comprise fused rings system, bridged-ring system or volution system, conventionally has 3 to 15 carbon atoms.It can be connected with the rest part of molecule by singly-bound via the upper any suitable carbon atom of ring.Conventionally, the example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.With regard to object of the present invention, preferably there is the cycloalkyl of the monocycle system of 3 to 6 carbon atoms.
In the present invention, term " Heterocyclylalkyl " refers to by 2 to 14 carbon atoms and 1 to 6 and is selected from 3 yuan to the 20 yuan stable non-aromatic cyclic groups that the heteroatoms of nitrogen, oxygen and sulphur forms jointly, it can be the member ring systems of monocycle, dicyclo, three rings or more rings, also can comprise fused rings system, bridged-ring system or volution system.It can be connected with the rest part of molecule by singly-bound via carbon atom or the heteroatoms of the upper any suitable of ring.Nitrogen-atoms wherein can optionally further be replaced to form tertiary amine or quaternary ammonium structure by other groups.Conventionally, the example of heterocyclic radical includes but not limited to that nitrogen heterocyclic propyl group, azelidinyl, oxa-cyclobutyl, pyrrolidyl, imidazolinyl, pyrazolidyl, imidazolidyl, thiazolidyl, isothiazole alkyl, isoxazole alkyl, tetrahydrofuran base, dioxolanyl, oxa-cyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazine base, N-replace homopiperazine base, piperidyl, N-substituted piperidine base, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc.With regard to object of the present invention, preferably 3 yuan to 6 yuan and at least contain 1 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen, oxygen or sulphur.
In the present invention, term " cycloalkenyl group " refers to the only aliphatics cyclic group that form, that contain carbon-carbon double bond by carbon atom and hydrogen atom, and it can comprise monocycle or polycyclic system, conventionally contains 4～12 carbon atoms.With regard to object of the present invention, the preferably cycloalkenyl group of 5～6 yuan of monocycle systems.
In the present invention, term " heterocycloalkenyl " refers to the heteroatoms aliphatics cyclic group that form, that contain carbon-carbon double bond that is selected from nitrogen, oxygen, sulphur by 3～9 carbon atoms and 1～3, and it can comprise monocycle or polycyclic system.With regard to object of the present invention, the preferably heterocycloalkenyl of 5～6 yuan and the monocycle system that contains nitrogen-atoms.
In the present invention, the term " halogen " being used alone or in combination refers to fluorine, chlorine, bromine or iodine.
In the present invention, term " experimenter ", " patient " or " individuality " refer to suffer from disease, the individuality of illness or patient's condition etc., comprise Mammals and nonmammalian.Mammiferous example includes but not limited to any member of class of mammals: people, inhuman primate (for example chimpanzee and other apes and monkey); Domestic animal, for example ox, horse, sheep, goat, pig; Domestic animal, for example rabbit, dog and cat; Laboratory animal, comprises rodent, such as rat, mouse and cavy etc.The example of non-human mammal includes but not limited to birds and fish etc.In method that the application provides and the embodiment of composition, described Mammals is behaved.
In the present invention, term " treatment " and other similar synonym comprise alleviation, alleviate or improve disease or condition symptoms, prevent other symptom, improve or prevent to cause the potential metabolism reason of symptom, suppress disease or illness, for example stop the development of disease or illness, alleviate disease or illness, disease or illness are taken a turn for the better, alleviate the symptom being caused by disease or illness, or end the symptom of disease or illness, in addition, the object that this term comprises prevention.This term also comprises acquisition result for the treatment of and/or preventive effect.Described result for the treatment of refers to cures or improves the potential disease for the treatment of.In addition, the healing to one or more physiological signs relevant to potential disease or improvement are also results for the treatment of, although for example patient may still be subject to the impact of potential disease, observe patient's condition improved.With regard to preventive effect, can be to thering is patient's applying said compositions of suffering from specified disease risk, even if or not yet make medical diagnosis on disease, but to the patient's applying said compositions of one or more physiological signs that occurs this disease.
In the present invention, " significant quantity ", " treatment significant quantity " or " pharmacy effective dose " refer to takes metapedes to alleviate to a certain extent at least one medicament of one or more symptoms of the disease of being treated or illness or the amount of compound.Its result can be subduing and/or alleviating of sign, symptom or the cause of disease, or any other required variation of biosystem.For example, " significant quantity " being used for the treatment of is the amount that the required composition that comprises the compound of coming into the open herein of significant illness remission effect is provided clinically.Can use such as the technical measurement of dosage escalation test and be suitable for the significant quantity in any individual case.
In the present invention, term " is taken ", " using ", " administration " etc. refer to the method that compound or composition can be delivered to the required site of carrying out biological action.These methods include but not limited to oral route, through duodenum approach, parenteral injection (comprising intravenously, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Those skilled in the art know the application technique that can be used for Compounds and methods for described in the application, for example, at Goodman and Gilman, and The Pharmacological Basis of Therapeutics, current ed.; Pergamon; And Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those that discuss in Pa.In a preferred embodiment, the compound that the application discusses and composition are by Orally administered.
In the present invention institute, term " acceptable " or " pharmaceutically acceptable " refer to that the subject experimenter's of docking general health situation does not have long-term harmful effect.
In the present invention, term " pharmaceutical composition " refers to the bioactive compounds that is optionally mixed with at least one pharmaceutically acceptable chemical composition, described pharmaceutically acceptable chemical composition includes but not limited to carrier, vehicle and/or auxiliary agent, as stablizer, thinner, dispersion agent, suspension agent, thickening material etc.
In the present invention, term " carrier " refers to relatively nontoxic chemical compound or reagent, and it contributes to compound to be incorporated in cell or tissue.
In the present invention, term " pharmacy acceptable salt " refers to the biopotency of the free acid and the free alkali that have retained appointed compound, and in biology or other side, there is no the salt of undesirable action.The compounds of this invention also comprises pharmaceutically acceptable salt.Pharmacy acceptable salt refers to the form of the base group conversion salify in parent compound.Pharmacy acceptable salt include but not limited to, the inorganic or organic acid salt of for example amine of base group (ammonia) base.Pharmacy acceptable salt of the present invention can be synthesized by parent compound, and the basic group in parent compound reacts in a solvent systems with the acid of 1-4 equivalent.Suitable salt is set forth in Remingtong ' s Pharmaceutical Scicences, 17 thed., Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, in 66,2 (1977).Pharmaceutically acceptable acid salt can be prepared by inorganic and organic acid.Comprise hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. by the mineral acid of derived acids additive salt.Comprise acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, oxysuccinic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc. by the organic acid of derived acids additive salt.
In the present invention, term " solvate " refers to the compounds of this invention that forms by solvation and the combination of solvent molecule.In some cases, solvate refers to hydrate, and solvent molecule is water molecules.
In the present invention, term " steric isomer " refers to by same atoms and forms, and by identical key bonding, but has the compound of different three-dimensional structures.Formula 1 compound of the present invention is contained various possible optically active isomers, cis-trans-isomer and composition thereof.
In the present invention, term " tautomer " refers to another atom from an atom transfer of molecule to same molecular of proton and the isomer that forms.Formula 1 compound of the present invention is contained various possible tautomers and composition thereof.
In the present invention, term " polymorphic form " or " polymorph " refer to the compounds of this invention existing with different form crystal lattices.
After term used herein " metabolite " or " meta-bolites " refer to that the compounds of this invention is absorbed by body, the compound producing through the bio-transformation such as functionalization reaction (I phase bioconversion reaction, comprises oxidation, reduction, hydrolysis etc.) and association reaction (II phase bioconversion reaction) in body under the effect of enzyme.For example, the multiple redox reaction of Cytochrome P450 catalysis, and the glucal acid molecule of UDPglucuronyl transferase catalytic activation is to the transfer of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group.More information about metabolism can be referring to The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
In the present invention, term " prodrug or prodrug " refers to pharmaceutically acceptable metabolic precursor thereof of the compounds of this invention, and it does not have activity conventionally, but changes under physiological condition and have bioactive parent compound of the present invention in vivo.Conventionally can improve the character of parent compound at aspects such as solubleness, histocompatibility or pharmacokinetics.
In the present invention, term " drug regimen ", " use other treatment ", " using other therapeutical agent " etc. refer to by mixing or combining the pharmacological agent that more than a kind of activeconstituents obtains, and it comprises the fixing of activeconstituents and fixed combination not.Term " fixed combination " refers to the form of single entity or single formulation uses at least one compound as herein described and at least one collaborative medicament to patient simultaneously.Term " not fixed combination " refers to the form of separate entity and uses simultaneously, share or to use in turn at least one compound as herein described and at least one collaborative preparation variable interval time, wherein this type of is applied in two or more compounds that level of significance is provided in patient body to patient.These are also applied in drug cocktail therapy (treatment), for example, use three kinds or more kinds of activeconstituents.
Term used herein " co-administered ", " with ... combined administration " and its synonym etc. are to point to same patient to use selected therapeutical agent, and are intended to contain the therapeutic strategy of using medicament by identical or different route of administration or identical or different administration number of times.In some embodiments, by co-administered to the compound described in the application and other medicament.These terms are contained to animal and are used two or more medicaments so that there is described medicament and/or its metabolite in animal body simultaneously.These terms comprise uses different compositions simultaneously, and different time is used different compositions and/or used a kind of composition that contains different activities composition.Therefore, in some embodiments, compound of the present invention and other medicament are blended in a kind of composition and are used.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Room temperature in the present invention refers to envrionment temperature, is 10 DEG C～30 DEG C.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the invention provides a kind of and the diverse imidazopyrazines of prior art, its preparation method, pharmaceutical composition and application.Imidazopyrazines of the present invention has good inhibition to Tyrosylprotein kinase C-Met, can be for the expression of prevention, treatment or assisting therapy and Tyrosylprotein kinase C-Met or active relevant various diseases.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.
Agents useful for same of the present invention and raw material except specified otherwise, all commercially available obtaining.
Synthesizing of intermediate quinolyl amine
Intermediate A:
Synthesis step 1:6-cyano quinolines (A-2)
By 6-bromoquinoline A-1(10.4g; 50mmol), zinc cyanide (8.8g; 75mmol), three (dibenzalacetone) two palladium (2.3g; 2.5mmol) He 1; two (diphenylphosphine) ferrocene (2.8g, 5mmol) of 1'-join DMF(100mL) in, under argon shield; be heated to 130 DEG C, reaction 16h.Reaction solution is cooling, joins in water (1L) ethyl acetate (200mL × 3) extraction, combined ethyl acetate phase under stirring, washing, saturated common salt washing, dry, column chromatography purification obtains 6g off-white color solid chemical compound A-2, yield: 77%, HPLC>97%.LC-MS(ESI)：[M+H] +=155； 1H-NMR(δppm,CDCl 3,400MHz)：9.07(dd,J 1=4.2Hz,J 2=1.5Hz,1H),8.25-8.19(m,3H),7.88(dd,J 1=8.7Hz,J 2=1.7Hz,1H),7.56(dd,J 1=8.3Hz,J 2=4.2Hz,1H)。
Synthesis step 2: quinoline-6-benzylidene amino (A)
By 6-cyano quinolines A-2(4.7g, 30mmol) be dissolved in methanolic ammonia solution (7mol/L, 50mL), use hydrogenation instrument H-cube(30bar, 25 DEG C, flow velocity 1mL/min, Raney Ni) hydrogenating reduction, obtain crude product, reverse phase separation obtains 3.8g quinoline-6-benzylidene amino A, yield: 79%, HPLC>97%.LC-MS(ESI)：[M+H] +=159； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.84(dd,J 1=4.2Hz,J 2=1.3Hz,1H),8.28(d,J=8.2Hz,1H),7.96(d,J=8.6Hz,1H),7.88(s,1H),7.76(d,J=8.6Hz,1H),7.48(dd,J 1=8.2Hz,J 2=4.2Hz,1H),3.97(s,2H)。
Intermediate B:
Synthesis step 1:N-methoxyl group-N-toluquinoline-6-methane amide (B-2)
Get QUINOLINE-6-CARBOXYLIC ACID B-1(5g; 29mmol) be dissolved in dry DMF (60mL); under nitrogen protection, add 2-(7-azo phenylpropyl alcohol triazole-1-yl)-N; N; N ', N '-tetramethyl-urea phosphofluoric acid ester (12.9g, 34mmol) and hydrochloric acid dimethyl hydroxylamine (3.3g; 34mmol), stirred overnight at room temperature.Add methylene dichloride (80mL) and water (80mL), separate organic phase, methylene dichloride for water (50mL × 3) extraction, merges organic phase, and saturated sodium-chloride (50mL × 2) is washed, dry.Evaporate to dryness obtains 4.6g colourless oil liquid compd B-2, yield: 74.5%.LC-MS(ESI)：[M+H] +=217。Synthesis step 2:6-quinoline ketone (B-3)
By N-methoxyl group-N-toluquinoline-6-methane amide B-2(6.1g, 28mmol) be dissolved in anhydrous THF(60mL) in, ice bath is cooled to 0 DEG C, adds 3M methyl-magnesium-bromide (10mL) solution under nitrogen protection.Remove ice bath, stirred overnight at room temperature.In reaction solution, slowly add saturated aqueous ammonium chloride (12mL), add ethyl acetate (50mL) and water (30mL), separate organic phase.Ethyl acetate for water (50mL × 3) extraction.Merge organic phase, wash with saturated nacl aqueous solution (50mL × 2), be dried.Evaporate to dryness obtains 4.4g faint yellow solid compd B-3, yield: 91.8%.LC-MS(ESI)：[M+H] +=172。Synthesis step 3:1-(quinoline-6-yl) ethyl ketone oxime (B-4)
Hydroxylamine chloride (3.1g, 44.9mmol) and sodium hydroxide (1.7g, 44.9mmol) are dissolved in ethanol (100mL), and stirring at normal temperature 1 hour, leaches solid.Filtrate joining contained 6-quinoline ketone B-3(5.1g, 29.96mmol) ethanolic soln in.Reaction solution stirred overnight at room temperature.Steaming desolventizes, and obtains 5.6g white solid compd B-4, yield: 99%, and not purified, be directly used in next step reaction.
Synthesis step 4:1-(quinoline-6-yl) ethamine (B)
1-(quinoline 6-yl) ethyl ketone oxime B-4(5.6g, 30.1mmol) be dissolved in ethanol (200mL), room temperature adds the methanol solution (7mol/L, 13mL) of ammonia and Rany nickel (another name Raney's nickel or RanyNi) (3g).Hydrogenation stirred overnight at room temperature, leaches solid.Filtrate evaporate to dryness obtains 9.7g compd B, yield: 99%, HPLC>96%.LC-MS(ESI)：[M+H] +=173； 1H-NMR(δppm,CDCl 3,400MHz):8.95-8.79(m,1H)，8.08(dd,J 1=22Hz,J 2=8.4Hz,2H)，7.82-7.64(m,2H)，7.36(dd,J 1=8.4Hz,J 2=4.2Hz,1H)，4.40-4.23(m,1H)，1.45(dd,J 1=6.6Hz,J 2=1.3Hz,3H)。
Intermediate C:
The fluoro-6-bromoquinoline of synthesis step 1:8-(C-2)
Glycerine (14.5g, 158mmol) and catalyzer 3-nitrobenzene sodium sulfonate (14.2g, 63mmol) are joined to (the 20mL vitriol oil+15mL water) in sulphur aqueous acid, be heated to 110 DEG C, slowly add the fluoro-4-bromaniline of raw material 2-C-1(10g, 52.6mmol), 140 DEG C of stirrings are spent the night.Be down to after room temperature, pour in trash ice, strong aqua regulates pH8 left and right, ethyl acetate extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product column chromatography purification obtains 9.65g white solid Compound C-2, yield 81.2%.LC-MS(ESI)：[M+H] +=227； 1H-NMR(δppm,CDCl 3,400MHz)：8.97(dd,J 1=4.4Hz,J 2=0.8Hz,1H)，8.10(d,J=8.4Hz,1H)，7.79(s,1H)，7.54(dd,J 1=9.6Hz,J 2=2.0Hz,1H)，7.50(dd,J 1=8.4Hz,J 2=4.4Hz,1H)。
Synthesis step 2:6-cyano group-8-fluorine quinoline (C-3)
By fluoro-raw material 8-6-bromoquinoline C-2(9.65g, 42.7mmol), zinc cyanide (7.49g, 64mmol), catalyzer three (dibenzalacetone) two palladium (Pd 2(dba) 3) (1.96g, 2mmol) and ligand 1,1 ' two (diphenylphosphine) ferrocene (dppf) (2.37g, 4.3mmol) are dissolved in dry DMF (40mL), and the lower 130 DEG C of reactions of argon shield are spent the night.After being down to room temperature, add saturated Na 2cO 3the aqueous solution (100mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product obtains 5.472g greyish-green solid chemical compound C-3, yield: 74.1% through column chromatography purification.LC-MS(ESI)：[M+H] +=173； 1H-NMR(δppm,CDCl 3,400MHz)：9.12(d,J=4.4Hz,1H)，8.29(d,J=8.4Hz,1H)，8.07(s,1H)，7.64(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，7.59(d,J=9.6Hz,1H)。
Synthesis step 3:6-amine methyl-8-fluorine quinoline (C)
By raw material 6-cyano group-8-fluorine quinoline C-3(330mg, 1.92mmol) be dissolved in ammonia/methanol solution (30mL), use instrument H-cube(30bar, 25 DEG C, 1mL/min flow velocity, RaNi post) reduction, after solvent evaporated, obtain 280mg brown oil C, yield 82.8%, HPLC>96%.LC-MS(ESI)：[M+H] +=177； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.89(dd,J 1=4.4Hz,J 2=1.2Hz,1H)，8.36(d,J=8.4Hz,1H)，7.70(s,1H)，7.60(d,J=10.8Hz,1H)，7.58(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，3.90(s,2H)。
Intermediate D:
Synthesis step 1:8-fluorine quinoline-6-formic acid (D-2)
By fluoro-raw material 3-PABA D-1(25g, 0.16mol) with catalyzer 3-nitrobenzene sodium sulfonate (43.2g, 0.192mol) join in the mixing solutions of the vitriol oil (60mL) and water (24mL), be heated to after 120 DEG C of interior temperature, slowly add glycerine (44.2g, 0.48mol, 3eq), after reinforced, be warmed up to 130 DEG C～140 DEG C reactions 1.5 hours, cooling.Reaction solution is poured in trash ice, and strong aqua is adjusted pH to 5～6, and separate out solid and leach, washing, dry rear column chromatography purification obtains 8.7g pale solid Compound D-2, yield 28.2%.LC-MS(ESI)：[M+H] +=192； 1H-NMR(δppm,DMSO-d 6,400MHz)：13.49(brs,1H)，9.08(s,1H)，8.66(d,J=8.4Hz,1H)，8.54-8.53(m,1H)，7.93(d,J=11.2Hz,1H)，7.76-7.72(m,1H)。
Synthesis step 2:N-methyl-N-methoxyl group-8-fluorine quinoline-6-methane amide (D-3)
By raw material 8-fluorine quinoline-6-formic acid D-2(3.2g, 16.75mmol) and reagent carbonyl dimidazoles (3g, 18.42mmol) be dissolved in dry DMF (30mL); stirring at room temperature 2h under argon shield; then add hydrochloric acid diformazan azanol (1.64g, 16.75mmol), stirred overnight at room temperature.After reacting completely, add saturated NaHCO 3the aqueous solution (100mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product obtains the faint yellow oily matter D-3 of 1.73g, yield: 44.1% through column chromatography purification.LC-MS(ESI)：[M+H] +=235； 1H-NMR(δppm,CDCl 3,400MHz)：9.04(dd,J 1=4.0Hz,J 2=1.6Hz,1H)，8.27(d,J=8.4Hz,1H)，8.06(s,1H)，7.76(dd,J 1=10.8Hz,J 2=1.6Hz,1H)，7.54(dd,J 1=8.4Hz,J 2=4.0Hz,1H)，3.58(s,3H)，3.44(s,3H)。Synthesis step 3:1-(the fluoro-6-quinolyl of 8-) ethyl ketone (D-4)
By raw material N-methyl-N-methoxyl group-8-fluorine quinoline-6-methane amide D-3(7.5g; 0.032mol) be dissolved in anhydrous THF(30mL) in; ice bath is cooled to 0 DEG C of left and right; under argon shield, slowly add methyl-magnesium-bromide 2-methyltetrahydrofuran solution (2.8M; 17.2ml; 0.048mol), stirred overnight at room temperature.After reacting completely, under ice bath is cooling, add saturated NH 4cl aqueous solution cancellation reaction, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness and obtains 5.5g yellow solid D-4, yield 91.3%.LC-MS(ESI)：[M+H] +=190； 1H-NMR(δppm,CDCl 3,400MHz)：9.08(dd,J 1=4.4Hz,J 2=1.2Hz,1H)，8.33(d,J=8.4Hz,1H)，8.26(s,1H)，7.96(dd,J 1=11.2Hz,J 2=1.6Hz,1H)，7.58(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，2.74(s,3H)。
Synthesis step 4:1-(the fluoro-6-quinolyl of 8-) ethanol (D-5)
By raw material 1-(the fluoro-6-quinolyl of 8-) ethyl ketone D-4(5.52g, 0.029mol) be dissolved in methyl alcohol (30mL), under ice bath, add NaBH in batches 4(4.4g, 0.116mol), stirring at room temperature 1h.After reacting completely, the cancellation that adds water reaction, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness and obtains 4.9g yellow oil D-5, yield: 88.4%.LC-MS(ESI)：[M+H] +=192； 1H-NMR(δppm,CDCl 3,400MHz)：8.87-8.85(m,1H)，8.10(d,J=8.4Hz,1H)，7.55(s,1H)，7.44-7.40(m,2H)，5.06(q,J=6.4Hz,1H)，3.18(brs,1H)，1.56(d,J=6.4Hz,3H)。
Synthesis step 5:6-(1-bromotrifluoromethane)-8-fluorine quinoline (D-6)
By raw material 1-(the fluoro-6-quinolyl of 8-) ethanol D-5(4.9g, 25.6mmol) be dissolved in chloroform (30mL), under ice bath, slowly add PBr 3(10.42g, 38.5mmol), reflux 2 hours.Cooling, solvent evaporated, slowly adds saturated NaHCO under ice bath 3the aqueous solution adjusts pH to alkalescence, dichloromethane extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness and obtains 3.8g brown oil D-6, yield: 58.6%.LC-MS(ESI)：[M+H] +=254； 1H-NMR(δppm,CDCl 3,400MHz)：8.98(dd,J 1=4.4Hz,J 2=1.6Hz,1H)，8.19(d,J=8.4Hz,1H)，7.62(s,1H)，7.56(dd,J 1=11.2Hz,J 2=2.0Hz,1H)，7.52(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，5.33(q,J=6.8Hz,1H)，2.12(d,J=6.8Hz,3H)。
Synthesis step 6:2-(1-(the fluoro-6-quinolyl of 8-) ethyl) isoindole-1,3-diketone (D-7)
By raw material 6-(1-bromotrifluoromethane)-8-fluorine quinoline D-6(0.77g, 3.06mmol) and potassium phthalimide (0.68g, 3.672mmol) be dissolved in DMF(10mL) in, add a little KI(potassiumiodide), 120 DEG C of reacting by heating 2h.Reaction finishes, and adds water (50mL), ethyl acetate extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness and obtains 1g yellow oil, yield: 100%.LC-MS(ESI)：[M+H] +=321； 1H-NMR(δppm,CDCl 3,400MHz)：8.94(dd,J 1=4.4Hz,J 2=1.6Hz,1H)，8.18(d,J=8.4Hz,1H)，7.84-7.82(m,2H)，7.74-7.71(m,3H)，7.58(dd,J 1=11.2Hz,J 2=1.6Hz,1H)，7.46(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，5.72(q,J=7.2Hz,1H)，2.02(d,J=7.2Hz,3H)。
Synthesis step 7:1-(the fluoro-6-quinolyl of 8-) ethamine (D)
By raw material 2-(1-(the fluoro-6-quinolyl of 8-) ethyl) isoindole-1,3-diketone D-7(0.189g, 0.59mmol) be dissolved in ethanol (10mL), add hydrazine hydrate (0.138g, 1.77mmol), reflux 2 hours.Cooling, solvent evaporated, adds the 5%NaOH aqueous solution (10mL), ethyl acetate extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness and obtains yellow oil 79mg, yield: 70.5%, HPLC>97%.LC-MS(ESI)：[M+H] +=191； 1H-NMR(δppm,CDCl 3,400MHz)：8.90(dd,J 1=4.0Hz,J 2=1.6Hz,1H)，8.14(d,J=8.4Hz,1H)，7.57(s,1H)，7.46-7.43(m,2H)，4.30(q,J=6.8Hz,1H)，1.95(s,2H)，1.45(d,J=6.8Hz,3H)。
Intermediate E:
Raw material E-1 is purchased from KERMANDA company, and method of reducing is with reference to the synthetic method of intermediate A step 2, and products therefrom becomes hydrochloride in ether, is light brown solid.Yield: 81%, HPLC>97%.LC-MS(ESI)：[M+H] +=177； 1H-NMR(δppm,CD 3OD,400MHz)：9.36-9.33(m,2H),8.67(d,J=8.0Hz,1H),8.20-8.16(m,2H),4.53(s,2H).
Intermediate F:
The bromo-7-fluorine of synthesis step 1:6-quinoline (F-2)
With reference to the synthetic method of intermediate D step 1, product obtains white solid with sherwood oil recrystallization after silicagel column purifying, yield 62%.LC-MS(ESI)：[M+H] +=226； 1H-NMR(δppm,CDCl 3,400MHz)：8.93(dd,J 1=4.2Hz,J 2=1.5Hz,1H)，8.12-8.02(m,2H)，7.81(d,J=9.5Hz,1H)，7.41(dd,J 1=8.3Hz,J 2=4.2Hz,1H)。
Synthesis step 2:1-(the fluoro-quinoline-6-of 7-yl)-ethyl ketone (F-3)
The bromo-7-fluorine of 6-quinoline F-2(2.07g; 9.16mmol), tributyl (1-vinyl ethyl ether) tin (3.64g; 10.1mmol) join in dioxane (20mL) the lower 110 DEG C of reaction 4h of argon shield with bi triphenyl phosphine dichloride palladium (0.32g, 0.46mmol).Reaction solution is cooling, adds Potassium monofluoride dihydrate (2g) and water (4mL).Stirring at room temperature 2h, filters, and dioxane for filter cake (5mL × 3) is washed.Merging filtrate, adds concentrated hydrochloric acid (2mL), stirring at room temperature 1h.Reaction solution is concentrated, adds saturated aqueous sodium carbonate (50mL), ethyl acetate (100mL × 2) extraction.Organic phase merges, washing (50mL), and saturated aqueous common salt (50mL) is washed, and after being dried, obtains 1.5g off-white color solid chemical compound F-3, yield: 87% through purification by silica gel column chromatography.LC-MS(ESI)：[M+H] +=190； 1H-NMR(δppm,CDCl 3,400MHz)：8.99(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.41(d,J=7.8Hz,1H)，8.26(dd,J 1=8.3Hz,J 2=1.1Hz,1H)，7.81(d,J=12.2Hz,1H)，7.44(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，2.76(d,J=4.9Hz,3H)。
Synthesis step 3:1-(the fluoro-quinoline-6-of 7-yl)-ethanol (F-4)
With reference to the synthetic method of intermediate D step 4, obtain white solid, yield=79%.LC-MS(ESI)：[M+H] +=192； 1H-NMR(δppm,CDCl 3,400MHz)：8.74(dd,J 1=4.3Hz,J 2=1.4Hz,1H)，8.06(d,J=8.3Hz,1H)，7.97(d,J=8.0Hz,1H)，7.57(d,J=11.7Hz,1H)，7.29(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.32(q,J=6.3Hz,1H)，4.45(s,1H)，1.58(d,J=6.3Hz,3H)。
Synthesis step 4:6-(the bromo-ethyl of 1-) the fluoro-quinoline of-7-(F-5)
With reference to the synthetic method of intermediate D step 5, obtain white solid, yield=94%.LC-MS(ESI)：[M+H] +=254； 1H-NMR(δppm,CDCl 3,400MHz)：8.91(dd,J 1=4.3Hz,J 2=1.6Hz,1H)，8.16(dd,J 1=8.3Hz,J 2=1.2Hz,1H)，7.97(d,J=8.0Hz,1H)，7.74(d,J=11.6Hz,1H)，7.40(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.58(q,J=7.0Hz,1H)，2.18(d,J=7.0Hz,3H)。
Synthesis step 5:2-(1-(the fluoro-quinoline-6-of 7-yl) ethyl)-isoindole-1,3-diketone (F-6)
With reference to the synthetic method of intermediate D step 6, obtain white solid, yield=69%.LC-MS(ESI)：[M+H] +=321； 1H-NMR(δppm,CDCl 3,400MHz)：8.89(dd,J 1=4.3Hz,J 2=1.4Hz,1H)，8.21(d,J=8.3Hz,1H)，8.12(d,J=8.1Hz,1H)，7.85-7.68(m,5H)，7.39(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.98(q,J=7.2Hz,1H)，2.01(d,J=7.2Hz,3H)。
Synthesis step 6:1-(the fluoro-quinoline-6-of 7-yl)-ethamine (F)
With reference to the synthetic method of intermediate D step 7, obtain white solid, yield=60%, HPLC>96%.LC-MS(ESI)：[M+H] +=191； 1H-NMR(δppm,CDCl 3,400MHz)：8.87(dd,J 1=4.3Hz,J 2=1.6Hz,1H)，8.14(dd,J 1=8.3Hz,J 2=1.1Hz,1H)，7.89(d,J=8.1Hz,1H)，7.70(d,J=12.0Hz,1H)，7.36(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，4.54(d,J=6.6Hz,1H)，1.79(s,2H)，1.51(d,J=6.6Hz,3H)。
Intermediate G:
Synthesis step 1:6-is bromo-5,7-difluoro-quinoline (G-2)
By bromo-raw material 4-3,5-difluoroaniline G-1(5.6g, 27mmol) with 3-nitrobenzene sodium sulfonate (7.2g, 32mmol) join in the mixing solutions of the vitriol oil (15mL) and water (6mL), be heated to after 120 DEG C of interior temperature, slowly add glycerine (7.4g, 80mmol), after reinforced, be warmed up to 130 DEG C of reaction 1.5h, cooling.Reaction solution is poured in trash ice, and strong aqua is adjusted pH to 5～6, and separate out solid and leach, washing, dry rear column chromatography purification obtains 3.82g white solid compound G-2, yield 58%.LC-MS(ESI)：[M+H] +=244； 1H-NMR(δppm,CDCl 3,400MHz)：8.98-8.97(m,1H)，8.40-8.37(m,1H)，7.68(dd,J 1=8.5Hz,J 2=1.6Hz,1H)，7.47(dd,J 1=8.5Hz,J 2=4.2Hz,1H)。
Synthesis step 2:6-vinyl-5,7-difluoro-quinoline (G-3)
By bromo-raw material 6-5,7-difluoro-quinoline G-2(1.0g, 4.10mmol), tripropyl vinyl tin (1.34g, 4.10mmol) and Pd (PPh 3) 2cl 2(47mg, 0.041mmol) is dissolved in dioxane (30mL), the lower 140 DEG C of stirring 4h of argon shield.Cooling, add ethyl acetate (40mL), water (2mL) and KF(0.2g), reaction solution stirs 2h.Separate ethyl acetate layer, water returns extraction 2 times by ethyl acetate, merges organic phase, dry, filters, and obtains 0.55g colourless liquid G-3, yield 70.1%.LC-MS(ESI)：[M+H] +=192。
Synthesis step 3:5,7-difluoro-quinoline-6-formaldehyde (G-4)
By 6-vinyl-5,7-difluoro-quinoline G-3(0.61g, 3.21mmol), sodium periodate (2.75g, 12.85mmol) and 2.6-lutidine (0.761mL, 6.42mmol) join in the mixed solution of dioxane (17mL) and water (6mL).Stirring adds perosmic anhydride (653mg, 0.064mmol), continues to stir 15min, adds water (50mL) dilution, and with ethyl acetate (50mL) extraction, ethyl acetate washing, dry, silicagel column purifying obtains 0.56g white solid G-4, yield: 90%.LC-MS(ESI)：[M+H] +=194； 1H-NMR(δppm,CDCl 3,400MHz)：10.55(s,1H)，9.08(dd,J 1=4.0Hz,J 2=1.2Hz,1H)，8.54(d,J=7.9Hz,1H)，7.67(d,J=11.2Hz,1H)，7.57-7.54(m,1H)。
Synthesis step 4:(5,7-difluoro-quinoline-6-yl)-methyl alcohol (G-5)
Synthetic method with reference to intermediate D step 4 obtains white solid, yield: 88%.LC-MS(ESI)：[M+H] +=196； 1H-NMR(δppm,CDCl 3,400MHz)：8.98(dd,J 1=4.4Hz,J 2=1.6Hz,1H)，8.24(d,J=8.4Hz,1H)，7.64(d,J=10.8Hz,1H)，7.49-7.46(m,1H)，5.01(d,J=6.0Hz,2H)，2.09(dd,J 1=6.4Hz,J 2=4.4Hz,1H)。
Synthesis step 5:6-brooethyl-5,7-difluoro-quinoline (G-6)
Synthetic method with reference to intermediate D step 5 obtains brown oil G-6, yield: 61%.LC-MS(ESI)：[M+H] +=258。
Synthesis step 6:2-[(5, the fluoro-6-quinolyl of 7-bis-) methyl] isoindoline-1, synthetic (G-7) of 3-diketone
Synthetic method with reference to intermediate D step 6 obtains yellow oil G-7, yield: 100%.LC-MS(ESI)：[M+H] +=325。
Synthesis step 7:5,7-difluoro-quinoline-6-yl) methylamine (G)
Synthetic method with reference to intermediate D step 7 obtains white solid, yield: 60.6%, HPLC>96%.LC-MS(ESI)：[M+H] +=195； 1H-NMR(δppm,CDCl 3,400MHz)：8.95(d,J=3.2Hz,1H)，8.40(d,J=8.0Hz,1H)，7.61(d,J=10.0Hz,1H)，7.47-7.44(m,1H)，4.14(s,1H)。
Intermediate H:
Synthesis step 1:1-(the fluoro-6-quinolyl of 5,7-bis-) ethyl ketone (H-1)
With reference to the synthetic method of intermediate F step 2, obtain faint yellow solid H-1, yield 80%.LC-MS(ESI)：[M+H] +=208； 1H-NMR(δppm,CDCl 3,400MHz)：9.02(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.46-8.44(m,1H)，7.65-7.62(m,1H)，7.50(dd,J 1=8.5Hz,J 2=4.3Hz,1H)，2.72(t,J=1.7Hz,3H)。
Synthesis step 2:1-(the fluoro-6-quinolyl of 5,7-bis-) ethanol (H-2)
With reference to synthetic white solid H-2, the yield 94% of obtaining of intermediate D step 4.LC-MS(ESI)：[M+H] +=210； 1H-NMR(δppm,CDCl 3,400MHz)：8.92(dd,J 1=4.2Hz,J 2=1.8Hz,1H)，8.38(d,J=7.7Hz,1H)，7.59-7.56(m,1H)，7.43(dd,J 1=8.5Hz,J 2=4.2Hz,1H)，5.46(q,J=7.2Hz,1H)，1.73(d,J=7.2Hz,3H)。
Synthesis step 3:6-(1-bromotrifluoromethane)-5,7 difluoro-quinolines (H-3)
Synthetic method with reference to intermediate D step 5 obtains yellow solid H-3, yield 75%.LC-MS(ESI)：[M+H] +=272； 1H-NMR(δppm,CDCl 3,400MHz)：8.96-8.94(m,1H)，8.41-8.39(m,1H)，7.60(d,J=11.7Hz,1H)，7.44(dd,J 1=8.5Hz,J 2=4.3Hz,1H)，5.69(q,J=7.2Hz,1H)，2.21(d,J=7.2Hz,3H)。
Synthesis step 4:2-[1-(5,7 two fluoro-6-quinolyl) ethyl] isoindole-1,3-diketone (H-4)
Synthetic method with reference to intermediate D step 6 obtains yellow solid H-4, yield 96%.LC-MS(ESI)：[M+H] +=339。
Synthesis step 5:1-(5,7 two fluoro-6-quinolyl) ethamine (H)
Obtain faint yellow oily matter H, yield 80%, HPLC>97% with reference to the synthetic method of intermediate D step 7.LC-MS(ESI)：[M+H] +=209； 1H-NMR(δppm,CDCl 3,400MHz)：8.93(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.40-8.37(m,1H)，7.58(dd,J 1=12.1Hz,J 2=1.7Hz,1H)，7.44(dd,J 1=8.5Hz,J 2=4.3Hz,1H)，4.68(q,J=6.9Hz,1H)，1.98(s,2H)，1.62(d,J=6.9Hz,3H)。
Intermediate compound I:
The bromo-5-toluquinoline of synthesis step 1:6-bromine-7-methyl quinoline (I-2) and 6-(J-1)
With reference to the method for intermediate G synthesis step 1, the mixture of synthetic 6-bromine-7-methyl quinoline (I-2) and the bromo-5-toluquinoline of 6-(J-1).Then use Overcritical prepared chromatographic (SFC) to separate, IC-H post, moving phase: Virahol/carbonic acid gas=18/82, detect wavelength: 254nm.Collecting the first cut is 6-bromine-7-methyl quinoline (I-2), white solid, yield: 25%.LC-MS(ESI)：[M+H] +=222； 1H-NMR(δppm,CDCl 3,400MHz)：8.90(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.07-8.06(m,2H)，8.00(s,1H)，7.38(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，2.63(d,J=1.0Hz,3H)。Collecting the second cut is the bromo-5-toluquinoline of 6-(J-1) white solid, yield: 20%.LC-MS(ESI)：[M+H] +=223； 1H-NMR(δppm,CDCl 3,400MHz)：8.96-8.93(m,1H)，8.40(dd,J 1=8.3Hz,J 2=1.7Hz,1H)，7.88(s,2H)，7.48(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，2.80(s,3H)。Synthesis step 2:1-(7-methyl-6-quinolyl) ethyl ketone (I-3)
With reference to the method for intermediate H synthesis step 1, synthetic 1-(7-methyl-6-quinolyl) the ethyl ketone I-3 taking 6-bromine-7-methyl quinoline I-2 as raw material.Faint yellow solid, yield 91%.LC-MS(ESI)：[M+H] +=186； 1H-NMR(δppm,CDCl 3,400MHz)：8.95(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.22-8.20(m,2H)，7.94(dd,J 1=1.4Hz,J 2=0.8Hz,1H)，7.44(dd,J 1=8.5Hz,J 2=4.3Hz,1H)，2.74-2.73(m,6H)。
Synthesis step 3:1-(7-methyl-6-quinolyl) ethanol (I-4)
With reference to the method for intermediate D synthesis step 4, synthetic 1-(7-methyl-6-quinolyl) ethanol I-4, yellow solid, yield 96%.LC-MS(ESI)：[M+H] +=188； 1H-NMR(δppm,CDCl 3,400MHz)：8.89-8.83(m,1H)，8.13(dt,J 1=8.3Hz,J 2=1.3Hz,1H)，7.98(s,1H)，7.85(s,1H)，7.34(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，5.29(q,J=6.4Hz,1H)，2.55(d,J=1.1Hz,3H)，1.68(d,J=6.4Hz,3H)。
Synthesis step 4:6-(1-bromotrifluoromethane)-7-toluquinoline (I-5)
With reference to the synthetic method of intermediate D step 5, prepare yellow solid I-5, yield 85% with raw material 1-(7-methyl-6-quinolyl) ethanol.LC-MS(ESI)：[M+H] +=250； 1H-NMR(δppm,CDCl 3,400MHz)：8.98-8.94(m,1H)，8.40-8.38(m,1H)，8.10(s,1H)，7.95(s,1H)，7.42(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.39(q,J=7.2Hz,1H)，2.65(d,J=1.1Hz,3H)，1.78(d,J=7.2Hz,3H)。
Synthesis step 5:2-(1-(7-methyl-6-quinolyl) ethyl) isoindole-1,3-diketone (I-6)
With reference to the synthetic method of intermediate D step 6, prepare white solid I-6, yield 70% with raw material 6-(1-bromotrifluoromethane)-7-toluquinoline I-5.LC-MS(ESI)：[M+H] +=317； 1H-NMR(δppm,CDCl 3,400MHz):8.88(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.24-8.19(m,2H)，7.89(s,1H)，7.80(dd,J 1=5.5Hz,J 2=3.1Hz,2H)，7.72(dd,J 1=5.5Hz,J 2=3.1Hz,2H)，7.36(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，5.89(q,J=7.2Hz,1H)，2.58(s,3H)，2.01(d,J=7.2Hz,3H)。
Synthesis step 6:1-(7-methyl-6-quinolyl) ethamine (I)
With reference to the synthetic method of intermediate D step 7, with raw material 2-(1-(7-methyl-6-quinolyl) ethyl) isoindole-1,3-diketone I-6 prepares faint yellow solid I, yield 60%, HPLC>96%.LC-MS(ESI)：[M+H] +=187； 1H-NMR(δppm,CDCl 3,400MHz)：8.98(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.30-8.27(m,1H)，8.12(s,1H)，7.98(s,1H)，7.46(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.43(q,J=7.2Hz,1H)，2.68(d,J=1.1Hz,3H)，1.98(s,2H)，1.80(d,J=7.2Hz,3H)。
Intermediate J:
Synthesis step 1:1-(5-methyl-6-quinolyl) ethyl ketone (J-2)
With reference to the method for intermediate H synthesis step 1, taking the bromo-5-toluquinoline of the 6-J-1 of preparation in intermediate compound I synthesis step 1 as synthetic 1-(5-methyl-6-quinolyl) the ethyl ketone J-2 of raw material, faint yellow solid, yield 86%.LC-MS(ESI)：[M+H] +=186； 1H-NMR(δppm,CDCl 3,400MHz)：9.00(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.53(dt,J 1=8.5Hz,J 2=1.2Hz,1H)，8.04(d,J=8.9Hz,1H)，7.85(d,J=8.9Hz,1H)，7.52(dd,J 1=8.5Hz,J 2=4.3Hz,1H)，2.81(s,3H)，2.70(s,3H)。
Synthesis step 2:1-(5-methyl-6-quinolyl) ethanol (J-3)
With reference to the method for intermediate D synthesis step 4, synthetic 1-(5-methyl-6-quinolyl) ethanol J-3, brown solid, yield 90%.LC-MS(ESI)：[M+H] +=188； 1H-NMR(δppm,CDCl 3,400MHz)：8.88(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.42-8.40(m,1H)，7.99(q,J=9.0Hz,2H)，7.44(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，5.48-5.46(m,1H)，2.65(s,3H)，1.56(d,J=6.4Hz,3H)。
Synthesis step 3:6-(1-bromotrifluoromethane)-5-toluquinoline (J-4)
With reference to the synthetic method of intermediate D step 5, obtain yellow solid J-4, yield 85% with raw material 1-(5-methyl-6-quinolyl) ethanol J-3.LC-MS(ESI)：[M+H] +=250； 1H-NMR(δppm,CDCl 3,400MHz)：8.94(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.50-8.48(m,1H)，8.12-8.10(m,2H)，7.55-7.52(m,1H)，5.58-5.55(m,1H)，2.77(s,3H)，1.65(d,J=6.4Hz,3H)。
Synthesis step 4:2-(1-(5-methyl-6-quinolyl) ethyl) isoindole-1,3-diketone (J-5)
With reference to the synthetic method of intermediate D step 6, prepare white solid J-5, yield 40% with raw material 6-(1-bromotrifluoromethane)-5-toluquinoline J-4.LC-MS(ESI)：[M+H] +=317； 1H-NMR(δppm,CDCl 3,400MHz):8.91(dd,J 1=4.1Hz,J 2=1.6Hz,1H)，8.45(dt,J 1=8.7Hz,J 2=1.3Hz,1H)，8.22(d,J=9.0Hz,1H)，8.05(d,J=9.0Hz,1H)，7.90(dd,J 1=5.5Hz,J 2=3.0Hz,1H)，7.85-7.80(m,2H)，7.71(dd,J 1=5.5Hz,J 2=3.0Hz,1H)，7.43(dd,J 1=8.6Hz,J 2=4.1Hz,1H)，6.05(q,J=7.2Hz,1H)，2.75(s,3H)，2.02(d,J=7.2Hz,3H)。
Synthesis step 5:1-(7-methyl-6-quinolyl) ethamine (J)
With reference to the synthetic method of intermediate D step 7, with raw material 2-(1-(7-methyl-6-quinolyl) ethyl) isoindole-1,3-diketone J-5 prepares faint yellow solid J, yield 60%, HPLC>97%.LC-MS(ESI)：[M+H] +=187； 1H-NMR(δppm,CDCl 3,400MHz)：8.96(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.40-8.37(m,1H)，8.12-8.09(m,2H)，7.58-7.55(m,1H)，5.60-5.57(m,1H)，2.78(s,3H)，1.97(s,2H)，1.65(d,J=6.4Hz,3H)。
Intermediate K:
Synthetic (K-2) of synthesis step 1:3-chloroquinoline-6-methyl-formiate
Get 5g(27mmol) QUINOLINE-6-CARBOXYLIC ACID methyl esters is dissolved in 50mL dry DMF, adds 11g(80mmol) N-chlorosuccinimide, be heated to 125 DEG C of tube sealings and spend the night.The saturated solution quencher reaction that first adds appropriate sodium bicarbonate, adds a small amount of water and ethyl acetate afterwards, separates organic phase, and the extraction of 50mL for water × 3 ethyl acetate, merges organic phase, and saturated nacl aqueous solution 50mL × 2 are washed, dry, evaporate to dryness.Point plate (developping agent is sherwood oil: ethyl acetate=5:1) is purer, dodges column purification (developping agent is sherwood oil: ethyl acetate=80:20) and obtains white solid 3.481g, yield: 57%.LC-MS(ESI)：[M+H] +=222。
Synthetic (K-3) of synthesis step 2:3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-methyl-formiate
Get 500mg (2.26mmol) 3-chloroquinoline-6-methyl-formiate and be dissolved in 24mL1; in 4-dioxane; under nitrogen protection, add respectively 165mg(0.23mmol) [1,1-two (diphenylphosphine) ferrocene] palladium chloride, 624mg(4.51mmol) salt of wormwood, 516mg (2.48mmol) 1-methyl-4-(4,4; 5; 5-tetramethyl--1,3,2-dioxy boron, penta encircle-2-yl)-1H-pyrazoles and 6ml water; this reaction mixture is heated to 110 DEG C under nitrogen, and tube sealing spends the night.Except desolventizing, add 50ml water and 50ml ethyl acetate, separate organic phase, the extraction of 50mL for water × 3 ethyl acetate, merges organic phase, and saturated nacl aqueous solution 50mL × 2 are washed, dry, evaporate to dryness.Point plate (developping agent is methylene dichloride: methyl alcohol=20:1) is purer, dodges column purification (developping agent is methylene dichloride: methyl alcohol=95:5) and obtains white solid 565mg, yield: 94%.LC-MS (ESI): [M+H] +=268, 1h-NMR (δ ppm, CDCl 3, 400MHz): 9.17 (d, J=2.3Hz, 1H), 8.60 (d, J=1.8Hz, 1H), 8.29 – 8.24 (m, 2H), 8.14 (d, J=8.8Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H).
Synthetic (K-4) of synthesis step 3:3-(1-methyl isophthalic acid H-pyrazoles-4-yl) QUINOLINE-6-CARBOXYLIC ACID
Get 565mg (2.11mmol) 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-methyl-formiate and be dissolved in 30ml methyl alcohol, under room temperature, add 266mg (6.34mmol) lithium hydroxide and 5ml water, reaction stirred overnight at room temperature.Then except desolventizing, obtain 534mg white solid, directly drop into next step.LC-MS(ESI)：[M+H] +=254。
Synthetic (K-5) of synthesis step 4:N-methoxyl group-N-methyl-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-methane amide
The 3-of 534mg (2.108mmol) (1-methyl isophthalic acid H-pyrazoles-4-yl) QUINOLINE-6-CARBOXYLIC ACID is dissolved in methylene dichloride; under nitrogen protection, add 411mg (4.22mmol) N; O-dimethyl hydroxylamine hydrochloride, 1.60g (4.22mmol) O-(7-nitrogen benzotriazole)-N; N; N; N-tetramethyl-urea phosphofluoric acid ester and 3mLN-ethyl diisopropylamine, stirred overnight at room temperature.Except desolventizing, add 50mL water and 50mL ethyl acetate, separate organic phase, the extraction of 50mL for water × 3 ethyl acetate, merges organic phase, and saturated nacl aqueous solution 50mL × 2 are washed, dry, evaporate to dryness.Point plate (developping agent is methylene dichloride: methyl alcohol=20:1) is purer, dodges column purification (developping agent is methylene dichloride: methyl alcohol=95:5) and obtains yellow solid 322mg, yield: 52%.LC-MS(ESI)：[M+H] +=297， 1H-NMR(δppm,CDCl 3，400MHz)：9.16(s,1H),8.25(s,1H),8.21(d,J=1.5Hz,1H),8.17(d,J=8.7Hz,1H),8.00–7.91(m,2H),7.85(s,1H),4.04(s,3H),3.58(s,3H),3.45(s,3H).
Synthetic (K-6) of synthesis step 5:1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl ketone
Get 504mg(1.701mmol) N-methoxyl group-N-methyl-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-methane amide is dissolved in the anhydrous THF of 30mL, and ice bath is cooled to 0 DEG C, adds the 3M methyl-magnesium-bromide solution of 1.5mL under nitrogen protection.Remove ice bath, stirred overnight at room temperature.Slowly add 6ml saturated aqueous ammonium chloride, add 30mL ethyl acetate and 15mL water, separate organic phase, the extraction of 30mL for water × 3 ethyl acetate.Merge organic phase, saturated nacl aqueous solution 30mL × 2 are washed, dry, evaporate to dryness.Point plate (developping agent is sherwood oil: ethyl acetate=1:1) is purer, dodges column purification (developping agent is sherwood oil: ethyl acetate=1:100) and obtains white solid 280mg, yield: 66%.LC-MS(ESI)：[M+H] +=252, 1H-NMR(δppm,CDCl 3,400MHz)：9.16(d,J=2.3Hz,1H),8.46(d,J=1.8Hz,1H),8.30(d,J=2.1Hz,1H),8.22(dd,J 1=8.8Hz,J 2=1.9Hz,1H),8.15(d,J=8.8Hz,1H),7.95(s,1H),7.85(s,1H),4.04(s,3H),2.77(s,3H)。
Synthetic (K-7) of synthesis step 6:1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl ketone oxime
Get 232mg (3.34mmol) hydroxylamine chloride and be dissolved in 30ml ethanol, add afterwards 137mg(3.43mmol) sodium hydroxide.This mixing solutions stirs after 1 hour at normal temperatures, leaches solid, in the ethanolic soln that filtrate joining contained to 280mg (1.11mmol) 1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl ketone.Under normal temperature, reaction mixture stirs and spends the night.Except desolventizing, obtain 919mg white solid, directly drop into next step.LC-MS(ESI)：[M+H] +=267。
Synthetic (K) of synthesis step 7:1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethamine
556mg (2.09mmol) 1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl ketone oxime is dissolved in 20ml ethanol, under normal temperature, adds methanol solution (7N) 6ml of ammonia and the Raney nickel of 245mg.This reaction mixture is under hydrogen, and stirring at normal temperature is spent the night.Leach solid, by solvent evaporate to dryness, obtain the thick product of 385mg, this product purity can directly drop into next step.Point plate (developping agent methylene dichloride: methyl alcohol=10:1).LC-MS(ESI)：[M+H] +=253； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.11(d,J=2.2Hz,1H),8.42(d,J=2.0Hz,1H),8.39(s,1H),8.09(s,1H),7.92(d,J=8.7Hz,1H),7.84(d,J=1.3Hz,1H),7.73(dd,J=8.7,1.8Hz,1H),4.18(q,J=6.4Hz,1H),3.92(s,3H),1.34(d,J=6.6Hz,3H).
Intermediate L:
The fluoro-6-bromoquinoline of synthesis step 1:7-(L-2)
By fluoro-raw material 3-4-bromaniline (20g, 0.105mol) with catalyzer 3-nitrobenzene sodium sulfonate (28g, 0.124mol, 1.2eq) join in the mixing solutions of the vitriol oil (60ml) and water (24ml), be heated to after 120 DEG C of interior temperature, slowly add glycerine (29g, 0.315mol, 3eq), after feeding in raw material, be warmed up to 130-140 DEG C of reaction and spend the night, cooling.Reaction solution is poured in trash ice, and strong aqua is adjusted pH to 8, dichloromethane extraction, and washing, dry rear column chromatography purification obtains yellow solid 20.3g, yield 85.8%.LC-MS(ESI)：[M+H] +=226； 1H-NMR(δppm,CDCl 3,400MHz)：8.93(dd,J 1=4.2Hz,J 2=1.5Hz,1H)，8.12-8.02(m,2H)，7.81(d,J=9.5Hz,1H)，7.41(dd,J 1=8.3Hz,J 2=4.2Hz,1H)。
The fluoro-6-quinoline of synthesis step 2:7-ethyl ketone (L-3)
Fluoro-raw material 7-6-bromoquinoline (20.3g, 0.09mol) is dissolved in anhydrous dioxane (50ml), adds catalyst P d (PPh 3) 2cl 2(3.17g, 4.5mmol, 0.05eq) and reagent tributyl (1-vinyl ethyl ether base) tin (35.87g, 0.1mol, 1.1eq), the lower 90 DEG C of reactions of argon shield are spent the night.Be down to after room temperature, add the potassium fluoride aqueous solution stirring at room temperature 2h of 2eq10%, filter, for several times, filtrate evaporate to dryness, adds 2eq1N HCl stirring at room temperature 2h to filter cake washed with dichloromethane.Add aqueous sodium carbonate to adjust pH to 8, dichloromethane extraction, washing, dry rear column chromatography purification obtains yellow solid 17g, yield 99%.LC-MS(ESI)：[M+H] +=190； 1H-NMR(δppm,CDCl 3,400MHz)：8.99(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.41(d,J=7.8Hz,1H)，8.26(dd,J 1=8.3Hz,J 2=1.1Hz,1H)，7.81(d,J=12.2Hz,1H)，7.44(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，2.76(d,J=4.9Hz,3H)。
Synthesis step 3:1-(the fluoro-6-quinolyl of 7-) ethanol (L-4)
Fluoro-raw material 7-6-quinoline ethyl ketone (20.5g, 0.108mol) is dissolved in methyl alcohol (100ml), under ice bath, adds NaBH in batches 4(3.3g, 0.087mol, 0.8eq), stirs under ice bath 0.5 hour.After reacting completely, the cancellation that adds water reaction, boils off methyl alcohol, ethyl acetate extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purification obtains yellow oil 15.4g, yield 74.7%.LC-MS(ESI)：[M+H] +=192； 1H-NMR(δppm,CDCl 3,400MHz)：8.74(dd,J 1=4.3Hz,J 2=1.4Hz,1H)，8.06(d,J=8.3Hz,1H)，7.97(d,J=8.0Hz,1H)，7.57(d,J=11.7Hz,1H)，7.29(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.32(q,J=6.3Hz,1H)，4.45(s,1H)，1.58(d,J=6.3Hz,3H)。
Synthesis step 4:6-(1-bromotrifluoromethane)-7-fluorine quinoline (L-5)
Raw material 1-(the fluoro-6-quinolyl of 7-) ethanol (6.2g, 0.03mol) is dissolved in chloroform (50ml), under ice bath, slowly adds PBr 3(10.5g, 0.038mol, 1.2eq), reflux 2 hours.After reacting completely, solvent evaporated, slowly adds saturated NaHCO under ice bath 3the aqueous solution adjusts pH to alkalescence, ethyl acetate extraction, and washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purification obtains yellow solid 4.6g, yield 56.6%.LC-MS(ESI)：[M+H] +=254； 1H-NMR(δppm,CDCl 3,400MHz)：8.91(dd,J 1=4.3Hz,J 2=1.6Hz,1H)，8.16(dd,J 1=8.3Hz,J 2=1.2Hz,1H)，7.97(d,J=8.0Hz,1H)，7.74(d,J=11.6Hz,1H)，7.40(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.58(q,J=7.0Hz,1H)，2.18(d,J=7.0Hz,3H)。
Synthesis step 5:2-(1-(the fluoro-6-quinolyl of 7-) ethyl) isoindole-1,3-diketone (L-6)
Raw material 6-(1-bromotrifluoromethane)-7-fluorine quinoline (4.8g, 0.019mol) and potassium phthalimide (4.2g, 0.023mol, 1.2eq) are dissolved in to DMF(30ml) in, add a little KI, 120 DEG C of reacting by heating 2 hours.After reacting completely, boil off DMF, add water, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purification obtains yellow solid 4.8g, yield 78.9%.LC-MS(ESI)：[M+H] +=321； 1H-NMR(δppm,CDCl 3,400MHz)：8.89(dd,J 1=4.3Hz,J 2=1.4Hz,1H)，8.21(d,J=8.3Hz,1H)，8.12(d,J=8.1Hz,1H)，7.85-7.68(m,5H)，7.39(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.98(q,J=7.2Hz,1H)，2.01(d,J=7.2Hz,3H)。
Synthesis step 6:2-(1-(the bromo-6-quinolyl of the fluoro-3-of 7-) ethyl) isoindole-1,3-diketone (L-7)
By raw material 2-(1-(the fluoro-6-quinolyl of 7-) ethyl) isoindole-1,3-diketone (4.8g, 0.015mol) is dissolved in tetracol phenixin (100ml), add respectively pyridine (2.38g, 0.03mol, 2eq) and bromine (4.8g, 0.03mol, 2eq), 70 DEG C of reactions are spent the night.Solvent evaporated after reacting completely, adds aqueous sodium carbonate to be adjusted to alkalescence, dichloromethane extraction, and washing, saturated common salt water washing, column chromatography purification obtains yellow solid 2.8g, yield 46.8%.LC-MS(ESI)：[M+H] +=398.8； 1H-NMR(δppm,CDCl 3,400MHz):8.90(d,J=2.0Hz,1H),8.40(d,J=2.0Hz,1H),8.06(d,J=8.0Hz,1H),7.85(dd,J 1=5.6Hz,J 2=2.8Hz,2H),7.74(dd,J 1=5.6Hz,J 2=2.8Hz,2H),7.69(d,J=11.6Hz,1H),5.98(q,J=7.2Hz,1H),2.01(d,J=7.2Hz,3H).
Synthesis step 7:2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl) isoindole-1,3-diketone (L-8)
By raw material 2-(1-(the bromo-6-quinolyl of the fluoro-3-of 7-) ethyl) isoindole-1,3-diketone (1.18g, 3mmol), 1-methylpyrazole-4-boric acid is which ester (0.92g, 4.4mmol, 1.5eq) frequently, catalyst P d(dppf) Cl 2dCM(0.12g, 1.5mmol, 0.05eq) and K 2cO 3(1.23g, 9mmol, 3eq) is dissolved in dioxane+water (8ml+2ml) solution, the lower 110 DEG C of reactions of argon shield 4 hours.Be down to after room temperature, add large water gaging, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product column chromatography purification obtains white solid 689mg, yield 58.4%.LC-MS(ESI)：[M+H] +=400.9.
Synthesis step 8:1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethamine (L)
By raw material 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl) isoindole-1,3-diketone (5.15g, 0.013mol) be dissolved in ethanol (150ml), add hydrazine hydrate (2g, 0.034mol, 2.6eq), reflux 5 hours.Be down to after room temperature, separate out solid filtering, filter cake ethyl acetate washing several, mother liquor evaporate to dryness, add a little 5%NaOH aqueous solution, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purification obtains white solid 1.66g, yield 47.7%.LC-MS(ESI)：[M+H] +=271.0； 1H-NMR(δppm,CDCl 3,400MHz):9.04(d,J=2.0Hz,1H),8.16(d,J=2.0Hz,1H),7.91(s,1H),7.89(d,J=8.0Hz,1H),7.79(s,1H),7.70(d,J=11.6Hz,1H),4.56(q,J=6.8Hz,1H),4.03(s,3H),1.54(d,J=6.8Hz,3H).
Intermediate M:
Synthesis step 1:2-(1-(chloro-5, the 7 – difluoro-quinoline-6-yls of 3-) ethyl) isoindoline-1,3-diketone (M-2)
Get 2-(1-(5,7-difluoro-quinoline-6-yl) ethyl) isoindoline-1,3-diketone 1.65g(4.88mmol) join in 15mL DMF, under stirring at room temperature, add 1-chlorine tetramethyleneimine-2,5-diketone 2.17g (16.3mmol).This reaction solution is heated to 125 DEG C of reactions 24 hours.Aftertreatment adds 30ml water and adds 3.2g sodium bicarbonate solid neutralization reaction, and stirring at room temperature slowly added 4.8g Sulfothiorine to remove unnecessary 1-chlorine tetramethyleneimine-2,5-diketone after 30 minutes.Ethyl acetate extraction (100mL*3), merges organic phase, and saturated nacl aqueous solution is washed, dry, and the crude product that evaporate to dryness obtains is purified by dodging post, obtains 0.6g white solid, yield: 30%.LC-MS(ESI)：[M+H] +=373， 1H-NMR(δppm,CDCl 3,400MHz)：8,84(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),7.83(dt,J=7.0,3.5Hz,2H),7.74(dt,J=5.2,2.1Hz,2H),7.62-7.54(m,1H),6.00(q,J=7.4Hz,1H),2.07(dt,J=7.5,2.5Hz,3H).
Synthesis step 2:2-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) isoindoline-1,3-diketone (M-3)
By 2-(1-(3-chloro-5,7-difluoro-quinoline-6-yl) ethyl) isoindoline-1,3-diketone (7g, 18mmol) be dissolved in Isosorbide-5-Nitrae-dioxane 250ml, then add 1-methylpyrazole-4-pinacol borate (7.8g, 37mmol), Pd (dppf) Cl 20.1 equivalent, Anhydrous potassium carbonate 2 equivalents and 62.5ml water.This reaction solution is under argon shield, and 110 DEG C of tube sealings spend the night.Concentration of reaction solution, add afterwards 1000ml water and 1000ml ethyl acetate, separate organic phase, water ethyl acetate extraction (500mL*3), merges organic phase, salt washing, dry, concentrated, remaining crude product is by dodging post purification (developping agent is sherwood oil: methylene dichloride=80:20), obtain target compound 3g, yield: 38%.LC-MS(ESI)：[M+H] +=419， 1H-NMR(δppm,CDCl 3,400MHz):9.08(d,J=2.2Hz,1H),8.39(dd,J=2.3Hz,1H),7.91(d,J=0.8Hz,1H),7.89-7.78(m,3H),7.72(dd,J 1=5.5Hz,J 2=3.0Hz,2H),7.56(dd,J 1=11.4Hz,J 2=1.6Hz,1H),6.01(q,J=7.4Hz,1H),4.02(s,3H),2.09(ddd,.J 1=7.4Hz,J 2=2.7Hz,J 3=1.5Hz,3H)。
Synthesis step 3:1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethamine (M)
By 2-(1-(5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) isoindoline-1,3-diketone (0.5g, 1mmol) is dissolved in 30ml ethanol, add afterwards (179mg, 3.6mmol) hydrazine hydrate.This reaction solution leaches solid impurity after refluxing 2 hours, and this impurity is washed with ethanol.Screw out solvent, add 100ml ethyl acetate, organic phase is washed by 50ml saturated solution of sodium carbonate, and salt washing (50ml*2) is dry, filters, concentrated, and resistates is purified by dodging post, obtains 0.3g solid, yield: 90%.LC-MS(ESI)：[M+H] +=289， 1H-NMR(δppm,CDCl 3,400MHz):9.07(d,J=2.2Hz,1H),8.37-8.32(m,1H),7.96-7.91(m,1H),7.83(s,1H),7.62-7.52(m,1H),4.68(q,J=6.9Hz,1H),4.03(s,3H),1.82(s,4H),1.63(d.J=6.9Hz,3H)。
Intermediate N:
Synthesis step 1:3-chloroquinoline-6-methyl-formiate (K-2)
The synthetic method of intermediate K-2 is with the method for intermediate K synthesis step 1.
Synthesis step 2:3-chloroquinoline-6 – formic acid (N-3)
Get 3-chloroquinoline-6 – methyl-formiate 6.5g(29mmol) join in 80ml methyl alcohol, under stirring at room temperature, add the aqueous solution 20ml of 1.4g lithium hydroxide (59mmol), finish, under room temperature, reaction is spent the night.Aftertreatment, concentration of reaction solution is to about 30ml, and hydrochloric acid is adjusted PH=5-6, filters, and after filter cake washing, the dry product 6.3g that to obtain, directly casts single step reaction, yield: 99%, LC-MS (ESI): [M+H] +=208.
Synthesis step 3:3-chloro-N-methoxyl group-N-toluquinoline-6-methane amide (N-4)
3-chloroquinoline-6 – the formic acid of 4.3g (21mmol) is joined in 60ml dry DMF, under stirring in above-mentioned reaction solution, add 12g (31mmol) O-(7-nitrogen benzotriazole)-N, N, N, N-tetramethyl-urea phosphofluoric acid ester and 4g(31mmol) diisopropyl ethyl amine, after stirring at room temperature 30min, add 3g (31mmol) N, O-dimethyl hydroxylamine hydrochloride, finish, under nitrogen, room temperature reaction spends the night.Aftertreatment, pours reaction solution in 300ml water into, and ethyl acetate extraction (100ml*3) merges organic phase, and the sodium hydroxide solution of 2N is washed, washing, and saturated nacl aqueous solution is washed, and dry, evaporate to dryness obtains crude product 2.5g, yield: 48%, be directly used in next step reaction.LC-MS(ESI)：[M+H] +=251。
Synthesis step 4:1-(3-chloroquinoline-6-yl) ethyl ketone (N-5)
Under nitrogen protection by 3.7g(15mmol) the chloro-N-methoxyl group-N-of 3-toluquinoline-6-methane amide be dissolved in super dry 30ml tetrahydrofuran (THF); under ice bath, slowly drip the methyl-magnesium-bromide 6.4ml(19mmol of 3mol/L) finish, continue reaction 3h after slowly returning to room temperature.Aftertreatment, in ice bath downhill reaction liquid, slowly drip saturated aqueous ammonium chloride solution 30ml, finish and continue to be extracted with ethyl acetate 20ml*3 after stirring 30min, merge organic phase, saturated common salt washing, dry rear filtration, solvent evaporated obtains product 2.2g, yield: 72%, be directly used in next step reaction.LC-MS(ESI)：[M+H] +=206， 1H-NMR(δppm,CDCl 3,400MHz):8.94(d,J=2.4Hz,1H),8.40(d,J=1.7Hz,1H),8.29-8.27(m,2H),8.18(d,J=8.8Hz,1H),2.76(s,3H).
Synthesis step 5:1-(3-(4-fluorophenyl) quinoline-6-yl) ethyl ketone (N-6)
In tube sealing, add 1,4-dioxane 20ml, water 4ml, then add 1.36g4-fluorophenyl boric acid (9.7mmol), 1g1-(3-chloroquinoline-6-yl) ethyl ketone (4.86mmol), salt of wormwood 1.34g(9.7257mmol) and [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride 119mg(0.14mmol), 110 DEG C of reaction 4h of outer temperature.Aftertreatment obtains product 1.3g, yield through purification by silica gel column chromatography: 99%.LC-MS(ESI)：[M+H] +=266。
Synthesis step 6-7:1-(3-(4-fluorophenyl) quinoline-6-yl) ethamine (N)
In the mono-neck bottle of 250ml, add 100ml dehydrated alcohol, under stirring at room temperature, add successively 1-(3-(4-fluorophenyl) quinoline-6-yl) ethyl ketone 1.3g(4.9mmol), sodium hydroxide 0.39g(9.8mmol) and oxammonium hydrochloride 0.67g(9.8mmol), finish, room temperature reaction spends the night.Then add 1g left and right Raney's nickel to reaction solution, under room temperature, with the hydrogen reducing 5h of 2atm, detect to remaining without raw material.Aftertreatment, filters, and after filtrate is concentrated, adds 100ml methylene dichloride, and washing, obtains product 800mg through silica gel column chromatography after being dried.Two step yields 61.5%.LC-MS(ESI)：[M+H] +=267， 1H-NMR(δppm,DMSO-d 6,400MHz):9.28(d,J=2.3Hz,1H),8.63(d,J=2.1Hz,1H),8.31(s,2H),8.17–8.05(m,2H),8.03–7.84(m,3H),7.42(t,J=8.9Hz,2H),4.63(q,J=6.8Hz,1H),1.62(d,J=6.8Hz,3H).
Synthesizing of compound
Embodiment 1:6-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1)-methylene radical)-quinoline (compound 1-1)
Step 1 is prepared the bromo-N of 6- 2-(quinoline-6-methylene radical) pyrazine-2,3-diamines
By 3,5-, bis-bromo-pyrazines-2-amine (6.1g, 24mmol), 6-quinoline benzylidene amino (3.8g, 24mmol) and DIPEA (DIPEA) (8.6mL, 48mmol) join NMP(20mL) in, the lower 130 DEG C of reactions of argon shield are spent the night.Reaction solution steams and removes DIPEA, and residue is poured in water (100mL), methylene dichloride (30mL × 3) extraction, and organic phase washing, saturated common salt washing, the dry rear rapid column chromatography of crossing obtains 4.7g brown color product, yield: 59%.LC-MS(ESI)：[M+H] +=330； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.85(dd,J 1=4.2Hz,J 2=1.6Hz,1H)，8.33(d,J=8.3Hz,1H)，7.99(d,J=8.7Hz,1H)，7.87(s,1H)，7.73(dd,J 1=8.7Hz,J 2=1.9Hz,1H)，7.50(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，7.21(s,1H)，7.16(t,J=5.4Hz,1H)，6.25(s,2H)，4.69(d,J=5.4Hz,2H)。
Step 2 is prepared 6-(the bromo-imidazo of 6-[4,5-b] pyrazine-1-methylene radical)-quinoline
By bromo-6-N 2-(quinoline-6-methylene radical) pyrazine-2,3-diamines (1.2g, 3.6mmol) join in trimethyl orthoformate (30mL), under stirring at room temperature, add 98% formic acid (1mL), finish, reaction solution refluxes 2 days, solvent evaporated, ethyl acetate/petroleum ether for crude product (1/1) is washed, and obtains product 1.1g, yield: 89%.LC-MS(ESI)：[M+H] +=340； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.01(s,1H)，8.88(dd,J 1=4.2Hz,J 2=1.6Hz,1H)，8.68(s,1H)，8.32(d,J=8.4Hz,1H)，8.01(d,J=8.7Hz,1H)，7.85(s,1H)，7.75(dd,J 1=8.7Hz,J 2=1.7Hz,1H)，7.51(dd,J 1=8.4Hz,J 2=4.2Hz,1H)，5.72(s,2H)。
Step 3 is prepared 6-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (compound 1-1)
By 6-(the bromo-imidazo [4 of 6-, 5-b] pyrazine-1-methylene radical)-quinoline (100mg, 0.29mmol), 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate (121mg, 0.58mmol), salt of wormwood (122mg, 0.88mmol) with [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (20mg) joins in the mixed solvent of dioxane (4mL) and water (1mL), and reaction solution is bulging argon gas 5min in tube sealing, then at 110 DEG C, reacts 3h.After reaction solution is concentrated, after rapid column chromatography separates, gained solid is washed to obtain white solid 60mg, yield: 60% with methyl alcohol.LC-MS(ESI)：[M+H] +=342； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.93-8.85(m,3H)，8.42(s,1H)，8.36(d,J=8.4Hz,1H)，8.13(s,1H)，8.03(d,J=8.7Hz,1H)，7.98(s,1H)，7.85(dd,J 1=8.7Hz,J 2=2.0Hz,1H)，7.53(dd,J 1=8.4Hz,J 2=4.2Hz,1H)，5.73(s,2H)，3.91(s,3H)。
Embodiment 2～embodiment 18
According to the same procedure of embodiment 1, adopt different boric acid or boric acid ester, the compound of Preparation Example 2～embodiment 18, specific experiment data are in table 1.
The experimental data table of table 1 compound 1-2～compound 1-18
Embodiment 19:6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-19)
Step 1 is prepared the bromo-N of 6- 2-(1-(6-quinolyl) ethyl) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by 1-(quinoline-6-yl) ethamine and obtains the bromo-N of 6- 2-(1-(6-quinolyl) ethyl) pyrazine-2,3-diamines, dark brown solid, productive rate is 68%.LC-MS(ESI)：[M+H] +=344； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.85(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.34(dd,J 1=8.4Hz,J 2=0.9Hz,1H)，7.99(d,J=8.7Hz,1H)，7.89(d,J=1.7Hz,1H)，7.79(dd,J 1=8.7Hz,J 2=2.0Hz,1H)，7.50(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，7.16(s,1H)，7.01(d,J=7.1Hz,1H)，6.35(s,2H)，5.77(d,J=3.3Hz,1H)，5.26(q,J=6.9Hz,1H)，3.36(s,1H)，3.29(dd,J 1=8.8Hz,J 2=5.3Hz,1H)，2.53-2.46(m,1H)，2.17(t,J=8.1Hz,1H)，1.95-1.82(m,1H)，1.58(d,J=6.9Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl) quinoline
The method of reference example 1 step 2, by bromo-6-N 2-(1-(6-quinolyl) ethyl) pyrazine-2,3-diamines reacts to obtain dark brown solid with diethoxy ritalin, and productive rate is 50.1%.LC-MS(ESI)：[M+H] +=354； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.18(s,1H),8.90(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.68(s,1H)，8.37(dd,J 1=8.5Hz,J 2=1.0Hz,1H)，8.02(d,J=8.8Hz,1H)，7.95(d,J=2.0Hz,1H)，7.81(dd,J 1=8.8Hz,J 2=2.1Hz,1H)，7.54(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，6.19(q,J=7.1Hz,1H)，2.11(d,J=7.2Hz,3H)。
Step 3 is prepared 6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-19)
The method of reference example 1 step 3, reacts 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl) quinoline to obtain white solid, productive rate 53% with 1-methylpyrazole-4-pinacol borate.LC-MS(ESI)：[M+H] +=356； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.00(s,1H)，8.88(dd,J 1=4.2Hz,J 2=1.7Hz,1H)，8.85(s,1H)，8.40(d,J=2.8Hz,2H)，8.37(s,1H)，8.11(d,J=0.7Hz,1H)，8.06(d,J=2.1Hz,1H)，8.02(s,1H)，8.00(s,1H)，7.90(d,J=2.1Hz,1H)，7.88(d,J=2.1Hz,1H)，7.53(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，6.19(q,J=7.1Hz,1H)，3.91(s,3H)，2.15(d,J=7.2Hz,3H)。
Embodiment 20～embodiment 49
According to the same procedure of embodiment 19, adopt different boric acid or boric acid ester, the compound of Preparation Example 20～embodiment 49, specific experiment data are in table 2.
The experimental data table of table 2 compound 1-20～compound 1-49
The fluoro-6-of embodiment 50:8-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (compound 1-50)
Step 1 is prepared the bromo-N of 6- 2-((the fluoro-6-quinolyl of 8-) methyl) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by 6-aminomethyl-8-fluorine quinoline and obtains the bromo-N of 6- 2-((the fluoro-6-quinolyl of 8-) methyl) pyrazine-2,3-diamines, orange solid, yield 50.8%.LC-MS(ESI)：[M+H] +=348； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.92(dd,J 1=4.0Hz,J 2=1.2Hz,1H)，8.43(d,J=8.4Hz,1H)，7.75(s,1H)，7.64-7.59(m,2H)，7.25(s,1H)，7.19(t,J=5.2Hz,1H)，6.27(s,2H)，4.70(d,J=5.2Hz,2H)。
Step 2 is prepared 6-((the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) methyl)-8-fluorine quinoline
The method of reference example 1 step 2, by bromo-6-N 2-((the fluoro-6-quinolyl of 8-) methyl) pyrazine-2,3-diamines reacts to obtain orange solid, yield 71.7% with diethoxy ritalin.LC-MS(ESI)：[M+H] +=358； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.01(s,1H)，8.95(dd,J 1=4.0Hz,J 2=1.6Hz,1H)，8.70(s,1H)，8.41(d,J=8.4Hz,1H)，7.70(s,1H)，7.68(dd,J 1=9.6Hz,J 2=1.6Hz,1H)，7.64(dd,J 1=8.4Hz,J 2=4.0Hz,1H)，5.72(s,2H)。
Step 3 is prepared the fluoro-6-of 8-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (compound 1-50)
The method of reference example 1 step 3, reacts 6-((the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) methyl)-8-fluorine quinoline to obtain white solid, yield 65.7% with 1-methylpyrazole 4-pinacol borate.LC-MS(ESI)：[M+H] +=360； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.95(1H,s)，8.90-8.87(m,2H)，8.45(s,1H)，8.42(d,J=4.4Hz,1H)，8.14(s,1H)，7.80(s,1H)，7.76(d,J=12.0Hz,1H)，7.64(dd,J 1=8.0Hz,J 2=4.0Hz,1H)，5.72(s,2H)，3.91(s,3H)。
Embodiment 51～embodiment 56
According to the same procedure of embodiment 50, adopt different boric acid or boric acid ester, the compound of Preparation Example 51～embodiment 56, specific experiment data are in table 3.
The experimental data table of table 3 compound 1-51～compound 1-56
Fluoro-(6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4, the 5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-57) of embodiment 57:8-
Step 1 is prepared the bromo-N of 6- 2-(1-(the fluoro-6-quinolyl of 8-) ethyl) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by 1-(8-fluorine quinoline-6-yl) ethamine and obtains the bromo-N of 6- 2-(1-(the fluoro-6-quinolyl of 8-) ethyl) pyrazine-2,3-diamines, yield 66.8%.LC-MS(ESI)：[M+H] +=362； 1H-NMR(δppm,CDCl 3,400MHz)：8.91(s,1H)，8.08(s,1H)，7.49-7.41(m,4H)，5.43-5.36(m,1H)，5.10(brs,1H)，4.56(brs,2H)，1.65(d,J=6.4Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline
The method of reference example 1 step 2, by bromo-6-N 2-(1-(the fluoro-6-quinolyl of 8-) ethyl) pyrazine-2,3-diamines reacts to obtain orange solid, yield 65.6% with diethoxy ritalin.LC-MS(ESI)：[M+H] +=372； 1H-NMR(δppm,CDCl 3,400MHz)：9.02(dd,J 1=4.4Hz,J 2=1.2Hz,1H)，8.67(s,1H)，8.39(s,1H)，8.18(d,J=8.4Hz,1H)，7.58(s,1H)，7.54(dd,J 1=8.4Hz,J 2=4.4Hz,1H)，7.42(dd,J 1=10.8Hz,J 2=1.6Hz,1H)，6.14(q,J=7.2Hz,1H)，2.17(d,J=7.2Hz,3H)。
Step 3 is prepared fluoro-(6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4, the 5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-57) of 8-
The method of reference example 1 step 3, reacts 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline to obtain yellow solid, yield 55.0% with 1-methylpyrazole 4-pinacol borate.LC-MS(ESI)：[M+H] +=374； 1H-NMR(δppm,CDCl 3,400MHz)：8.92(dd,J 1=4.0Hz,J 2=1.6Hz,1H)，8.70(s,1H)，8.34(s,1H)，8.12(d,J=8.4Hz,1H)，8.00(s,1H)，7.92(s,1H)，7.53(s,1H)，7.47-7.43(m,2H)，6.12(q,J=7.2Hz,1H)，3.95(s,3H)，2.14(d,J=7.2Hz,3H)。
Embodiment 58～embodiment 68
According to the same procedure of embodiment 57, adopt different boric acid or boric acid ester, the compound of Preparation Example 58～embodiment 68, specific experiment data are in table 4.
The experimental data table of table 4 compound 1-58～1-68
Embodiment 69:6-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical]-quinoline (compound 1-69)
Step 1 is prepared the bromo-N of 6- 2-(7-fluorine quinoline-6-methylene radical) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by fluoro-7-6-quinoline benzylidene amino hydrochloride and obtains the bromo-N of 6- 2-(7-fluorine quinoline-6-methylene radical) pyrazine-2,3-diamines, yield=75%.LC-MS(ESI)：[M+H] +=348。Step 2 is prepared 6-(the bromo-imidazo of 6-[4,5-b] pyrazine-1-methylene radical)-7-fluorine quinoline
The method of reference example 1 step 2, by bromo-6-N 2-(7-fluorine quinoline-6-methylene radical) pyrazine-2,3-diamines and trimethyl orthoformate reaction, obtain brown solid, yield: 65%.LC-MS(ESI)：[M+H] +=358； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.95(s,1H)，8.90(d,J=2.9Hz,1H)，8.68(s,1H)，8.35(d,J=7.9Hz,1H)，7.90(d,J=8.3Hz,1H)，7.82(d,J=11.7Hz,1H)，7.50(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，5.77(s,2H)。
Step 3 is prepared the fluoro-6-of 7-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline (compound 1-69)
The method of reference example 1 step 3, reacts 6-(the bromo-imidazo of 6-[4,5-b] pyrazine-1-methylene radical)-7-fluorine quinoline to obtain white solid, yield with 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate: 50%.LC-MS(ESI)：[M+H] +=360； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.91(dd,J 1=4.3Hz,J 2=1.6Hz,1H)，8.87(s,1H)，8.82(s,1H)，8.42(d,J=7.5Hz,1H)，8.38(s,1H)，8.10(s,1H)，8.05(d,J=8.3Hz,1H)，7.84(d,J=11.6Hz,1H)，7.52(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，5.78(s,2H)，3.90(s,3H)。
Embodiment 70～embodiment 86
According to the same procedure of embodiment 69, adopt different boric acid or boric acid ester, the compound of Preparation Example 70～embodiment 86, specific experiment data are in table 5.
The experimental data table of table 5 compound 1-70～compound 1-86
The fluoro-6-of embodiment 87:7-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-87)
Step 1 is prepared the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by 1-(the fluoro-6-quinolyl of 7-) ethamine and obtains the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines, yield: 50%.LC-MS(ESI)：[M+H] +=362； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.89(s,1H)，8.39(d,J=7.6Hz,1H)，7.97(d,J=7.8Hz,1H)，7.77(d,J=11.7Hz,1H)，7.50(d,J=3.2Hz,1H)，7.18(s,1H)，7.05(d,J=5.3Hz,1H)，6.38(s,2H)，5.43(s,1H)，1.61(d,J=6.0Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline
The method of reference example 1 step 2, by bromo-6-N 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines and the reaction of acetic acid diethoxy methyl esters obtain brown solid, yield: 60%.LC-MS(ESI)：[M+H] +=372； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.10(s,1H)，8.93(d,J=4.0Hz,1H)，8.67(s,1H)，8.43(d,J=8.2Hz,1H)，8.11(d,J=8.4Hz,1H)，7.81(d,J=12.1Hz,1H)，7.55(dd,J 1=8.2Hz,J 2=4.0Hz,1H)，6.33(q,J=7.1Hz,1H)，2.11(d,J=7.1Hz,3H)。
Step 3 is prepared the fluoro-6-of 7-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-87)
The method of reference example 1 step 3, reacts 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline to obtain white solid, yield with 1-methylpyrazole-4-pinacol borate: 75%.LC-MS(ESI)：[M+H] +=374； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.93(s,1H)，8.91(dd,J 1=4.2Hz,J 2=1.2Hz,1H)，8.83(s,1H)，8.47(d,J=8.1Hz,1H)，8.35(s,1H)，8.27(d,J=8.4Hz,1H)，8.05(s,1H)，7.79(d,J=12.0Hz,1H)，7.54(dd,J 1=8.1Hz,J 2=4.2Hz,1H)，6.35(q,J=7.1Hz,1H)，3.89(s,3H)，2.16(d,J=7.1Hz,3H)。
Embodiment 88～embodiment 110
According to the same procedure of embodiment 87, adopt different boric acid or boric acid ester, the compound of Preparation Example 88～embodiment 110, specific experiment data are in table 6.
The experimental data table of table 6 compound 1-88～compound 1-110
Embodiment 111:5, the fluoro-6-of 7-bis-((6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (compound 1-111)
Step 1 is prepared the bromo-N of 6- 2-((5,7-difluoro-quinoline-6-yl) methyl) pyrazine-2,3-diamines
The synthetic method of reference example 1 step 1, yield: 48.7%.LC-MS(ESI)：[M+H] +=366； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.01(dd,J 1=4.4Hz,J 2=1.2Hz,1H),8.53(d,J=8.0Hz,1H),7.73(d,J=10.8Hz,1H),7.66-7.62(m,1H),7.02-7.00(m,1H),6.21(s,2H),4.71(d,J=4.8Hz,2H)。
Step 2 is prepared 6-((the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline
The synthetic method of reference example 1 step 2, yield: 32%.LC-MS(ESI)：[M+H] +=376； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.01(dd,J 1=4.4Hz,J 2=1.2Hz,1H),8.66(s,1H),8.40(s,1H),7.71(d,J=10.0Hz,1H),7.54-7.51(m,1H),7.49-7.45(m,1H),5.75(s,2H)。
Step 3 is prepared the fluoro-6-of 5,7-bis-((6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline (compound 1-111)
The synthetic method of reference example 1 step 3, yield: 52%.LC-MS(ESI)：[M+H] +=378； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.02(dd,J 1=4.0Hz,J 2=1.2Hz,1H)，8.90(s,1H)，8.57(s,1H)，8.44(d,J=7.2Hz,1H)，7.69(d,J=5.2Hz,1H)，7.58(d,J=2.0Hz,1H)，7.54-7.50(m,1H)，6.76(d,J=2.0Hz,1H)，5.80(s,2H)，4.30(s,3H)。
Embodiment 112～embodiment 117
According to the same procedure of embodiment 111, adopt different boric acid or boric acid ester, the compound of Preparation Example 112～embodiment 117, specific experiment data are in table 7.
The experimental data table of table 7 compound 1-112～compound 1-117
Embodiment 118:5, the fluoro-6-of 7-bis-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-118)
Step 1 is prepared the bromo-N of 6- 2-(1-(5,7-difluoro-quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 3,5-, bis-bromo-pyrazines-2-amine (2.16g, 8.56mmol), 1-(5; 7-difluoro-quinoline-6-yl) ethamine (1.18g; 5.7mmol) and DIPEA (2.2g, 17mmol) join in NMP (15mL), the lower 200 DEG C of reactions of argon shield are spent the night.Reaction solution is cooling, pours in water (100mL), and ethyl acetate (50mL × 3) extraction, organic phase water (50mL × 2) is washed, and saturated aqueous common salt (50mL) is washed, and the dry rear rapid column chromatography of crossing obtains yellow solid 1.3g, yield: 60%.LC-MS(ESI)：[M+H] +=380； 1H?NMR(δppm,CDCl 3,400MHz)：8.92(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.39(dd,J 1=8.4Hz,J 2=1.7Hz,1H)，7.58-7.55(m,1H)，7.44-7.39(m,2H)，5.83(q,J=7.1Hz,1H)，5.30(d,J=8.5Hz,1H)，4.51(s,2H)，1.73(d,J=7.1Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline
To prepare the bromo-N of 6- 2-(1-(5,7-difluoro-quinoline-6-yl) ethyl) pyrazine-2,3-diamines (1g, 2.6mmol) joins in diethoxy methyl acetic acid ester (9.2mL), and 150 DEG C of argon shield tube sealing reactions spend the night.Solvent evaporated, crude product, through silicagel column purifying, obtains brown solid 0.8g, yield: 80%.LC-MS(ESI)：[M+H] +=390； 1H?NMR(δppm,CDCl 3,400MHz)：8.97(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.62(t,J=1.3Hz,1H)，8.60(s,1H)，8.41(dd,J 1=8.4Hz,J 2=1.7Hz,1H)，7.64(dd,J 1=11.8Hz,J 2=1.7Hz,1H)，7.48(dd,J 1=8.4Hz,J 2=4.3Hz,1H)，6.55-6.49(m,1H)，2.23(d,J=7.3Hz,3H)。
Step 3 is prepared 5,7 two fluoro-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-118)
By 6-(1-(the bromo-1H-imidazo [4 of 6-, 5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline (113mg, 0.29mmol), 1-methylpyrazole-4-pinacol borate (75mg, 0.6mmol), salt of wormwood (122mg, 0.88mmol) with [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (20mg) joins in the mixed solvent of dioxane (4mL) and water (1mL), reaction solution is drum argon gas 5min in tube sealing, then at 110 DEG C, react 3h, reaction solution separates to obtain brown solid 70mg through rapid column chromatography, yield: 61%.LC-MS(ESI):[M+H] +=392； 1H?NMR(δppm,DMSO-d 6,400MHz)：9.17(s,1H)，9.02(d,J=4.2Hz,1H)，8.80(s,1H)，8.66(d,J=8.4Hz,1H)，8.22(s,1H)，7.90(s,1H)，7.78(d,J=11.7Hz,1H)，7.68(t,J=5.7Hz,1H)，6.41(q,J=7.4Hz,1H)，3.91(s,3H)，2.21(d,J=7.4Hz,3H)。
Embodiment 119～embodiment 146
According to the same procedure of embodiment 118, adopt different boric acid or boric acid ester, the compound of Preparation Example 119～embodiment 146, specific experiment data are in table 8.
The experimental data table of table 8 compound 1-119～compound 1-146
Embodiment 147:7-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-147)
Step 1 is prepared the bromo-N of 6- 2-(1-(7-toluquinoline-6-yl) ethyl) pyrazine-2,3-diamines
The legal method of reference example 1 step 1, obtains faint yellow solid, yield: 60%.LC-MS(ESI)：[M+H] +=358； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.80(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.27(dt,J 1=8.4Hz,J 2=1.3Hz,1H)，7.88(s1H)，7.82(s,1H)，7.42(dd,J 1=8.2Hz,J 2=4.3Hz,1H)，7.14-7.10(m,2H)，6.33(s,2H)，5.31(q,J=6.8Hz,1H)，2.64(s,3H)，1.55(d,J=6.8Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-toluquinoline
The legal method of reference example 1 step 2, obtains gray solid, yield: 60%.LC-MS(ESI)：[M+H] +=368； 1H-NMR(δppm,CDCl 3,400MHz)：8.96(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.67(s,1H)，8.18(dt,J 1=8.3Hz,J 2=1.3Hz,1H)，8.10(s,1H)，8.00(s,1H)，7.90(s,1H)，7.44(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，6.30(q,J=7.4Hz,1H)，2.45(d,J=1.0Hz,3H)，2.13(d,J=7.4Hz,3H)。
Step 3 is prepared 7-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-147)
The legal method of reference example 1 step 3, obtains faint yellow solid, yield: 71%.LC-MS(ESI):[M+H] +=370； 1H-NMR(δppm,CDCl 3,400MHz)：8.96(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.78(s,1H)，8.16-8.14(m,2H)，8.07(s,1H)，7.98(d,J=13.8Hz,2H)，7.86(s,1H)，7.45(dd,J 1=8.3Hz,J 2=4.3Hz,1H)，6.36(q,J=7.4Hz,1H)，4.02(s,3H)，2.55(d,J=1.0Hz,3H)，2.12(d,J=7.4Hz,3H)。
Embodiment 148～embodiment 154
According to the same procedure of embodiment 147, adopt different boric acid or boric acid ester, the compound of Preparation Example 148～embodiment 154, specific experiment data are in table 9.
The experimental data table of table 9 compound 1-148～compound 1-154
Embodiment 155:5-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-155)
Step 1 is prepared the bromo-N of 6- 2-(1-(5-toluquinoline-6-yl) ethyl) pyrazine-2,3-diamines
The legal method of reference example 1 step 1, obtains faint yellow solid, yield: 30%.LC-MS(ESI)：[M+H] +=358； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.84(dd,J 1=4.1Hz,J 2=1.6Hz,1H)，8.60-8.57(m,1H)，7.87-7.76(m,2H)，7.54(dd,J 1=8.6Hz,J 2=4.1Hz,1H)，7.16-7.11(m,2H)，6.32(s,2H)，5.49(q,J=6.8Hz,1H)，2.79(s,3H)，1.53(d,J=6.8Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-5-toluquinoline
The legal method of reference example 1 step 2, obtains brown solid, yield: 60%.LC-MS(ESI)：[M+H] +=368； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.22(s,1H)，8.89(dd,J 1=4.3Hz,J 2=1.7Hz,1H)，8.65-8.62(m,2H)，7.87(d,J=9.0Hz,1H)，7.71(d,J=9.0Hz,1H)，7.58(dd,J 1=8.6Hz,J 2=4.3Hz,1H)，6.47(q,J=7.0Hz,1H)，2.51(d,J=1.8Hz,3H)，2.05(d,J=7.0Hz,3H)。
Step 3 is prepared 5-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-155)
The legal method of reference example 1 step 3, obtains safran solid, yield: 70%.LC-MS(ESI)：[M+H] +=370； 1H-NMR(δppm,CDCl 3,400MHz)：8.96(d,J=3.2Hz,1H),8.75(s,1H),8.47(d,J=8.4Hz,1H),8.27(s,1H),8.06(t,J=4.4Hz,2H),7.94(s,1H),7.79(d,J=9.2Hz,1H),7.50(dd,J 1=8.4Hz,J 2=4.4Hz,1H),6.52(q,J=7.2Hz,1H),4.01(s,3H),2.80(s,3H),2.14(d,J=7.2Hz,3H).
Embodiment 156～embodiment 160
According to the same procedure of embodiment 155, adopt different boric acid or boric acid ester, the compound of Preparation Example 156～embodiment 160.Specific experiment data are in table 10.
The experimental data table of table 10 compound 1-156～compound 1-160
Embodiment 161:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylpiperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-161)
Step 1 is prepared the bromo-N of 6- 2-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 2-amino-3,5-bis-bromo-pyrazines (257mg, 1.02mmol) are dissolved in 1-Methyl-2-Pyrrolidone 12ml, add afterwards 1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethamine (385mg under normal temperature, 1.53mmol) with 6ml DIPEA.This reaction soln, under argon shield, is heated to 210 DEG C of tube sealings and spends the night.Concentration of reaction solution, by crude product by dodge post purify (developping agent is methylene dichloride: methyl alcohol=95:5).Obtain about 260mg brown solid, yield 60%.LC-MS(ESI)：[M+H] +=424， 1H-NMR(δppm,DMSO-d 6,400MHz):9.14(d,J=2.2Hz,1H),8.45(d,J=2.0Hz,1H),8.40(s,1H),8.11(d,J=0.6Hz,1H),7.95(d,J=8.7Hz,1H),7.82(d,J=1.7Hz,1H),7.71(dd,J=8.7,2.0Hz,1H),7.17(s,1H),7.01(d,J=7.0Hz,1H),6.35(s,2H),5.31–5.22(m,1H),3.92(d,J=3.5Hz,3H),3.18(d,J=5.2Hz,1H),1.59(d,J=7.0Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline
By bromo-6-N 2-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines (100mg, 0.24mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, and this reaction is heated to 150 DEG C of tube sealings and spends the night.Concentration of reaction solution, remaining crude product is by dodging post purification (developping agent is methyl alcohol: methylene dichloride=0% is to 5%).Obtain 59mg light brown solid, yield: 58%.LC-MS(ESI)：[M+H] +=435， 1H-NMR(δppm,CDCl 3,400MHz):9.10(d,J=2.2Hz,1H),8.67(s,1H),8.37(s,1H),8.16(d,J=2.1Hz,1H),8.12(d,J=8.8Hz,1H),7.93(s,1H),7.82(s,1H),7.76(d,J=1.7Hz,1H),7.63(dd,J=8.8,2.1Hz,1H),6.18(q,J=7.1Hz,1H),4.03(s,3H),2.17(d,J=7.2Hz,3H).
Step 3 is prepared 3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylpiperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-161)
By 6-(1-(the bromo-1H-imidazo [4 of 6-, 5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (60mg, 0.14mmol) be dissolved in 5ml1-N-methyl-2-2-pyrrolidone N-, then add successively the 1-methylpiperazine of 3 equivalents, the DIPEA of the Potassium monofluoride of 5 equivalents and 4 equivalents.170 DEG C of tube sealing reactions of this reaction solution 2 hours.Concentration of reaction solution, remaining crude product is purified (developping agent is methylene dichloride: methyl alcohol=94:6) by dodging post, obtains 28.7mg yellow solid powder, yield: 69%.LC-MS(ESI)：[M+H] +=454， 1H-NMR(δppm,DMSO-d 6,400MHz):9.16(d,J=2.2Hz,1H),8.62(s,1H),8.44(d,J=1.8Hz,1H),8.38(s,1H),8.20(s,1H),8.09(s,1H),7.95(d,J=8.7Hz,1H),7.85(d,J=1.3Hz,1H),7.74(dd,J=8.7,1.9Hz,1H),6.02(q,J=7.0Hz,1H),3.91(s,3H),3.54(s,4H),2.42–2.35(m,4H),2.18(d,J=4.3Hz,1H),2.08(d,J=7.2Hz,3H).
Embodiment 162～embodiment 163
According to the same procedure of embodiment 161, the compound of Preparation Example 162.What wherein embodiment 163 adopted is corresponding boric acid ester, reacts synthetic by SUZUKI.Specific experiment data are in table 11.
The experimental data table of table 11 compound 1-162～compound 1-163
Embodiment 164:3-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(also [4,5-b] pyrazine-1-ylmethyl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) quinoline (compound 2-1)
Step 1 is prepared the bromo-N of 6- 2-(quinoline-6-methylene radical) pyrazine-2,3-diamines
By 3,5-, bis-bromo-pyrazines-2-amine (6.1g, 24mmol), 6-quinoline benzylidene amino (3.8g, 24mmol) and DIPEA(8.6mL, 48mmol) join NMP(20ml) in, the lower 130 DEG C of reactions of argon shield are spent the night.Reaction solution steams and removes DIPEA, and residue is poured in water (100ml), methylene dichloride (30ml × 3) extraction, and organic phase washing, saturated common salt washing, the dry rear rapid column chromatography of crossing obtains brown color product 4.7g, yield: 59%.LC-MS(ESI)：[M+H] +=330； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.85(dd,J 1=4.2Hz,J 2=1.6Hz,1H)，8.33(d,J=8.3Hz,1H)，7.99(d,J=8.7Hz,1H)，7.87(s,1H)，7.73(dd,J 1=8.7Hz,J 2=1.9Hz,1H)，7.50(dd,J 1=8.3Hz,J 2=4.2Hz,1H)，7.21(s,1H)，7.16(t,J=5.4Hz,1H)，6.25(s,2H)，4.69(d,J=5.4Hz,2H)。
Step 2 is prepared 6-(also [4,5-b] pyrazine-1-ylmethyl of 6-bromo-[1,2,3] triazole) quinoline
By bromo-raw material 6-N 2-(quinoline-6-methylene radical) pyrazine-2,3-diamines (500mg, 1.5mmol) is dissolved in dry DMF (10ml), adds Isopentyl nitrite (356mg, 3mmol, 2eq), the lower 70 DEG C of reaction 3h of argon shield.After reacting completely, solvent evaporated, crude product ethyl acetate making beating purifying obtains yellow solid 217mg, yield 42.0%.LC-MS(ESI)：[M+H] +=340.8； 1H-NMR(δppm,DMSO-d 6,400MHz):9.02(s,1H),8.91(dd,J 1=4.0Hz,J 2=2.0Hz,1H),8.36(dd,J 1=8.4Hz,J 2=0.8Hz,1H),8.03(d,J=8.8Hz,1H),7.94(d,J=2.0Hz,1H),7.78(dd,J 1=8.8Hz,J 2=2.0Hz,1H),7.54(dd,J 1=8.4Hz,J 2=4.0Hz,1H),6.19(s,2H).
Step 3 is prepared the bromo-6-of 3-(also [4,5-b] pyrazine-1-ylmethyl of 6-bromo-[1,2,3] triazole) quinoline
By raw material 6-(also [4,5-b] pyrazine-1-ylmethyl of 6-bromo-[1,2,3] triazole) quinoline (100mg, 0.3mmol) be dissolved in tetracol phenixin (10ml), add respectively pyridine (47mg, 0.6mmol, 2eq) and bromine (94mg, 0.6mmol, 2eq), 80 DEG C of reaction 4h.Solvent evaporated after reacting completely, adds aqueous sodium carbonate to be adjusted to alkalescence, dichloromethane extraction, and washing, saturated common salt water washing, column chromatography purification obtains yellow solid 82mg, yield 66.7%.LC-MS(ESI)：[M+H] +=418.7； 1H-NMR(δppm,DMSO-d 6,400MHz):9.02(s,1H),8.94(d,J=2.4Hz,1H),8.69(d,J=2.4Hz,1H),8.05(d,J=8.8Hz,1H),7.87(d,J=2.0Hz,1H),7.83(dd,J 1=8.8Hz,J 2=2.0Hz,1H),6.21(s,2H).
Step 4 is prepared 3-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(also [4,5-b] pyrazine-1-ylmethyl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) quinoline (compound 2-1)
By bromo-raw material 3-6-(6-bromo-[1,2,3] triazole also [4,5-b] pyrazine-1-ylmethyl) quinoline (80mg, 0.19mmol), 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate (100mg, 0.48mmol, 2.5eq), catalyst P d(dppf) Cl 2dCM(8mg, 0.01mmol, 0.05eq) and K 2cO 3(79mg, 0.57mmol, 3eq) is dissolved in dioxane+water (2ml+0.5ml) solution, and the lower 110 DEG C of reactions of argon shield are spent the night.Solvent evaporated, residue is prepared plate purifying and is obtained white solid 56mg, yield 70.0%.LC-MS(ESI)：[M+H] +=422.9； 1H-NMR(δppm,DMSO-d 6,400MHz):9.22(s,1H),9.17(d,J=2.4Hz,1H),8.64(s,1H),8.46(d,J=1.6Hz,1H),8.37(s,1H),8.31(s,1H),8.07(s,1H),7.99(d,J=8.8Hz,1H),7.84(d,J=1.2Hz,1H),7.76(dd,J 1=8.4Hz,J 2=2.0Hz,1H),6.15(s,2H),3.95(s,3H),3.90(s,3H).
Embodiment 165～embodiment 168
According to the same procedure of embodiment 164, adopt different boric acid or boric acid ester, the compound of Preparation Example 165～embodiment 168.Specific experiment data are in table 12.
The experimental data table of table 12 compound 2-2～compound 2-5
The fluoro-3-of embodiment 169:7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazine-1-yl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) ethyl) quinoline (compound 2-6)
Step 1 is prepared the bromo-N of 5- 3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl) pyrazine-2,3-diamines
By raw material 1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethamine (403mg; 1.5mmol); 2-amino-3; 5-bis-bromo-pyrazine (453mg; 1.8mmol, 1.2eq) and DIPEA(578mg, 4.5mmol; 3eq) be dissolved in NMP(5ml) in, the lower 200 DEG C of reactions of argon shield are spent the night.After reacting completely, add large water gaging, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product column chromatography purification obtains orange solid 371mg, yield 56.4%.LC-MS(ESI)：[M+H] +=441.9.
Step 2 is prepared 6-(1-(also [4,5-b] pyrazine-1-yl of 6-bromo-[1,2,3] triazole) ethyl) the fluoro-3-of-7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline
By bromo-raw material 5-N 3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl) pyrazine-2; 3-diamines (462mg; 1.05mmol) be dissolved in dry DMF (8ml); add Isopentyl nitrite (246mg; 2.1mmol; 2eq), the lower 80 DEG C of reaction 2h of argon shield.After reacting completely, solvent evaporated, crude product column chromatography purification obtains yellow solid 383mg, yield 80.7%.LC-MS(ESI)：[M+H] +=452.8.
Step 3 is prepared the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazine-1-yl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) ethyl) quinoline (compound 2-6)
By raw material 6-(1-(6-bromo-[1,2,3] triazole also [4,5-b] pyrazine-1-yl) ethyl) the fluoro-3-of-7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline (80mg, 0.18mmol), 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate (55mg, 0.26mmol, 1.5eq), catalyst P d(dppf) Cl 2dCM(7mg, 0.008mmol, 0.05eq) and K 2cO 3(73mg, 0.53mmol, 3eq) is dissolved in dioxane+water (2ml+0.5ml) solution, and the lower 110 DEG C of reactions of argon shield are spent the night.Be down to after room temperature, add large water gaging, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product is prepared plate purifying and is obtained yellow solid 45mg, yield 56.3%.LC-MS(ESI)：[M+H] +=455.0； 1H-NMR(δppm,DMSO-d 6,400MHz):9.21(d,J=2.0Hz,1H),9.20(s,1H),8.59(d,J=2.0Hz,1H),8.58(s,1H),8.36(s,1H),8.23(s,1H),8.07(d,J=7.2Hz,1H),8.06(s,1H),7.80(d,J=11.6Hz,1H),6.73(q,J=7.2Hz,1H),3.93(s,3H),3.91(s,3H),2.24(d,J=7.2Hz,3H).
Embodiment 170～embodiment 179
According to the same procedure of embodiment 169, adopt different boric acid or boric acid ester, the compound of Preparation Example 170～179, specific experiment data are in table 13.
The experimental data table of table 13 compound 2-8～compound 2-9
Embodiment 180:3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 2-17)
Step 1 is prepared the bromo-N of 6- 2-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 2-amino-3,5-bis-bromo-pyrazines (257mg, 1.02mmol) are dissolved in 1-Methyl-2-Pyrrolidone 12ml, add afterwards 1-[3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl under normal temperature] ethamine (385mg, 1.53mmol) with 6ml DIPEA.This reaction soln, under argon shield, is heated to 190 DEG C of reactions and spends the night.Concentration of reaction solution, by crude product by dodge post purify (developping agent is methylene dichloride: methyl alcohol=95:5).Obtain about 260mg brown solid, productive rate is 60.3%.LC-MS(ESI)：[M+1] +=424, 1H-NMR(δppm,DMSO-d 6,400MHz):9.14(d,J=2.2Hz,1H),8.45(d,J=2.0Hz,1H),8.40(s,1H),8.11(d,J=0.6Hz,1H),7.95(d,J=8.7Hz,1H),7.82(d,J=1.7Hz,1H),7.71(dd,J 1=8.7Hz,J 2=2.0Hz,1H),7.17(s,1H),7.01(d,J=7.0Hz,1H),6.35(s,2H),5.31–5.22(m,1H),3.92(d,J=3.5Hz,3H),3.18(d,J=5.2Hz,1H),1.59(d,J=7.0Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-[1 of 6-, 2,3] also [4,5-b] pyrazine-1-yl of triazole) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline
By bromo-6-N 2-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines (100mg, 0.24mmol) is dissolved in 5mL DMF, adds Isopentyl nitrite (56mg, 0.48mmol) be heated to 70 DEG C, reaction 2h.Concentration of reaction solution, remaining crude product is by dodging post purification (developping agent is methyl alcohol: methylene dichloride=0% is to 5%).Obtain 59mg light brown solid, productive rate is 57.6%.LC-MS（ESI）：[M+1] +=435, 1H-NMR(δppm,CDCl 3,400MHz):9.08(d,J=2.2Hz,1H),8.78(s,1H),8.16(d,J=1.9Hz,1H),8.09(d,J=8.7Hz,1H),7.94–7.88(m,2H),7.84–7.77(m,2H),6.47(q,J=7.2Hz,1H),4.03(s,3H),2.34(d,J=7.2Hz,3H)。
Step 3 is prepared 3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] also [4,5-b] pyrazine-1-yl of triazole) ethyl) quinoline (compound 2-17)
By 6-(1-(the bromo-1H-[1 of 6-, 2,3] triazole also [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (60mg, 0.14mmol) be dissolved in Isosorbide-5-Nitrae-dioxane 12ml, then add 1-methylpyrazole-4-pinacol borate (44mg, 0.21mmol), Pd (dppf) 2cl 2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.This reaction solution is under argon shield, and 110 DEG C of tube sealings spend the night.Concentration of reaction solution, remaining crude product is purified (developping agent is methyl alcohol: methylene dichloride=5:95) by dodging post, obtains target compound.Yield=62.33%.LC-MS(ESI)：[M+1] +=437, 1H-NMR(δppm,DMSO-d 6,400MHz):9.20(s,1H),9.17(d,J=2.2Hz,1H),8.63(s,1H),8.49(d,J=2.2Hz,1H),8.38(s,1H),8.29(s,1H),8.08(s,1H),7.99(d,J=8.7Hz,1H),7.89(d,J=2.0Hz,1H),7.82(dd,J 1=8.7Hz,J 2=2.0Hz,1H),6.59(q,J=7.1Hz,1H),3.94(s,3H),3.90(s,3H)2.25(d,J=7.1Hz,3H).
Embodiment 181～embodiment 186
According to the same procedure of embodiment 180, adopt different boric acid or boric acid ester, the compound of Preparation Example 181～embodiment 186, specific experiment data are in table 14.
The experimental data table of table 14 compound 2-18～compound 2-23
Embodiment 1873-(4-fluorophenyl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 2-24)
Step 1 is prepared the bromo-N of 6- 2-(1-(3-(4-fluorophenyl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines
In single neck bottle, add 10mlN-methyl-2-pyrrolidone; add successively 3; 5-bis-bromo-pyrazines-2-amine 0.71g(2.8mmol); 1-(3-(4-fluorophenyl) quinoline-6-yl) ethamine 0.75g(2.8mmol) and diisopropyl ethyl amine 0.73g(5.6mmol) finish; the lower 190 DEG C of reactions of nitrogen protection are spent the night, and LC-MS detects without raw material.Aftertreatment adds 200ml methylene dichloride in reaction solution, washes with saturated aqueous sodium carbonate successively, and washing, saturated common salt washing, separates and obtains product 0.65g, yield: 53% through silica gel column chromatography after organic layer is dry.LC-MS(ESI)：[M+H] +=438， 1H-NMR(δppm,DMSO-d 6,400MHz):9.19(d,J=2.3Hz,1H),8.61(d,J=2.1Hz,1H),8.03(d,J=8.7Hz,1H),7.98–7.88(m,3H),7.80(dd,J 1=8.7Hz,J 2=1.8Hz,1H),7.39(t,J=8.9Hz,2H),7.17(s,1H),7.03(d,J=7.0Hz,1H),6.35(s,2H),5.29(q,J=7.0Hz，1H),1.60(d,J=7.0Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-[1 of 6-, 2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(4-fluorophenyl) quinoline
In single neck bottle, add 10ml dry DMF, then add the bromo-N of 6- 2-(1-(3-(4-fluorophenyl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines 650mg(1.48mmol) and Isopentyl nitrite 350mg(2.96mmol), finish, under nitrogen protection, be warmed up to 75 DEG C, reaction 3h.Aftertreatment, solvent evaporated, crude product dissolves with 100ml methylene dichloride, washes with saturated aqueous sodium carbonate successively, washing, saturated common salt washing, separates and obtains product 260mg, yield 39% through silica gel column chromatography after organic layer is dry.LC-MS(ESI)：[M+H] +=449， 1H-NMR(δppm,DMSO-d 6,400MHz):9.24(d,J=2.2Hz,1H),9.01(s,1H),8.64(d,J=2.2Hz,1H),8.06(d,J=8.7Hz,1H),7.99(d,J=1.8Hz,1H),7.93(dd,J 1=8.8Hz,J 2=5.4Hz,2H),7.85(dd,J=8.8,2.1Hz,1H),7.39(t,J=8.9Hz,2H),6.63(q,J=7.1Hz,1H),2.22(d,J=7.1Hz,3H).
Step 3 is prepared 3-(4-fluorophenyl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 2-24)
By 6-(1-(the bromo-1H-[1 of 6-, 2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(4-fluorophenyl) quinoline (60mg, 0.13mmol) be dissolved in Isosorbide-5-Nitrae-dioxane 12ml, then add (42mg, 0.20mmol) 1-methyl-4-pyrazoles pinacol borate, Pd (dppf) 2cl 2(11mg, 0.013mmol), Anhydrous potassium carbonate (39mg, 0.26mmol) and 3ml water.This reaction solution is under argon shield, and 110 DEG C of tube sealings spend the night.Concentration of reaction solution, remaining crude product is purified (developping agent is methyl alcohol: methylene dichloride=5:95) by dodging post, obtains target compound 16mg, yield: 25%, LC-MS (ESI): [M+H] +=451, 1h-NMR (δ ppm, DMSO-d 6, 400MHz): 9.23 (d, J=2.3Hz, 1H), 9.20 (s, 1H), 8.67 (d, J=2.2Hz, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 8.06 (d, J=8.7Hz, 2H), 7.97 – 7.88 (m, 3H), 7.39 (t, J=8.9Hz, 2H), 6.61 (q, J=7.1Hz, 1H), 3.94 (s, 3H), 2.27 (d, J=7.1Hz, 3H).
The fluoro-N-methyl-4-of embodiment 1882-(7-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-yl) benzamide (compound 3-1)
Step 1 is prepared quinoline-6-acetic ester
In 100ml round bottom three-necked bottle, add dry methylene chloride 50ml, under stirring, add successively 6-hydroxyquinoline 4.5g(31mmol) and pyridine 2.9g(37mmol), be cooled to 0 DEG C, slowly drip Acetyl Chloride 98Min. 2.9g(37mmol), finish, stirring at room temperature, reaction is spent the night.Aftertreatment, pours reaction solution in the saturated aqueous sodium carbonate that 200ml is cold into, separates organic phase, and water dichloromethane extraction 50ml*2 merges organic phase, and saturated aqueous common salt washing obtains product 3g after being dried, and yield 52%, directly throws next step.LC-MS(ESI)：[M+H] +=188.
Step 2 is prepared 3-bromoquinoline-6-acetic ester
In 100ml single port bottle, add 20ml tetracol phenixin, under stirring, add successively 1g(5.34mmol) quinoline-6-acetic ester, 1.06g(13.4mmol) pyridine and 2.13g(13.4mmol) bromine, finish, reflux 2h, be chilled to room temperature, steam solvent, residue adds 100ml methylene dichloride and dissolves, hypo solution and aqueous sodium carbonate are washed, saturated common salt washing, dry rear evaporate to dryness obtains product 1.1g, yield: 77%.LC-MS(ESI)：[M+H] +=266, 1H-NMR(δppm,CDCl 3,400MHz):8.91(d,J=2.3Hz,1H),8.29(d,J=2.2Hz,1H),8.11(d,J=9.0Hz,1H),7.52(d,J=2.4Hz,1H),7.49(dd,J 1=9.0Hz,J 2=2.4Hz,1H),2.39(s,3H).
Step 3 is prepared 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-acetic ester
In 100ml single port bottle, add 25ml dioxane and 5ml water; add wherein 1g(3.76mmol) 3-bromoquinoline-6-acetic ester; 1.56g(7.52mmol) 1-methylpyrazole-4-pinacol borate; salt of wormwood 1.04g(7.52mmol) and 86mg(0.11mmol) 1; 1'-bis-(diphenylphosphine) ferrocene palladium chloride methylene dichloride mixture; finish, under nitrogen protection, be heated to 110 DEG C of reaction 4h.Aftertreatment, pours reaction solution in 100ml methylene dichloride into and washes, saturated common salt washing, and the dry rear solvent evaporated of filtering, obtains crude product 0.75g, and yield 75%, directly throws next step.LC-MS(ESI)：[M+H] +=268。
Step 4 is prepared 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-alcohol
By the crude product 750mg(2.8mmol of previous step) be dissolved in 25ml methyl alcohol, get 235mg(5.6mol) lithium hydroxide is dissolved in 5ml water, then joins in methanol solution, reaction solution is heated to 60 DEG C, reaction 2h.Aftertreatment, is concentrated into half by reaction solution, adds 10ml water, and the hydrochloric acid tune PH=6 left and right of 4N, filters, and after filter cake washing, is dried to obtain product 600mg, yield 95%.LC-MS(ESI)：[M+H] +=226, 1H-NMR(δppm,DMSO-d 6,400MHz):10.00(s,1H),8.93(d,J=2.2Hz,1H),8.35(s,1H),8.25(d,J=2.2Hz,1H),8.06(s,1H),7.82(d,J=9.1Hz,1H),7.22(dd,J 1=9.1Hz,J 2=2.6Hz,1H),7.10(d,J=2.6Hz,1H),3.91(s,3H).
Step 5 is prepared 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-triflate
In the dry methylene dichloride of 50ml, add 600mg(2.66mmol) 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-alcohol and 809mg(7.99mmol) triethylamine, under ice bath, slowly drip 902mg (3.20mmol) trifluoromethanesulfanhydride anhydride, finish, slowly return to ambient temperature overnight.Aftertreatment, reaction solution is washed with saturated sodium carbonate, and saturated common salt washing obtains 500mg product, yield after being dried: 52.5% after purification by silica gel column chromatography.LC-MS(ESI)：[M+H] +=226, 1H-NMR(δppm,CDCl 3,400MHz):9.15(d,J=2.2Hz,1H),8.23–8.16(m,2H),7.95(s,1H),7.85(s,1H),7.76(d,J=2.7Hz,1H),7.56(dd,J 1=9.2Hz,J 2=2.7Hz,1H),4.04(s,3H).
Step 6 is prepared (E)-3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) methyl acrylate
By 430mg(1.2mmol) 3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-triflate is dissolved in 5ml dry DMF, then add 207mg (2.4mmol) methyl acrylate, 487mg (4.8mmol), triethylamine and 1,1'-bis-(diphenylphosphine) ferrocene palladium chloride methylene dichloride mixture 27mg, finish nitrogen replacement, 125 DEG C of reaction 3h of outer temperature.Aftertreatment, pours reaction solution in 50ml saturated sodium bicarbonate aqueous solution into, and ethyl acetate extraction 30ml*3, merges organic phase, washing, and saturated common salt washing, boils off solvent after being dried and obtains crude product 240mg, yield: 68%, directly throw next step.LC-MS(ESI)：[M+H] +=294。
Step 7 is prepared 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) methyl propionate
By 240mg(0.818mmol) (E)-3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) methyl acrylate is dissolved in 50ml methyl alcohol, add 10mg(10%) Pd/C, under room temperature, 2-3atm hydrogenation reaction is spent the night, and LC-MS detects without raw material.Filter, after filtrate is concentrated, obtain product 220mg through purification by silica gel column chromatography, yield: 91%.LC-MS(ESI)：[M+H] +=296, 1H-NMR(δppm,CDCl 3,400MHz):9.01(d,J=2.2Hz,1H),8.10(d,J=2.2Hz,1H),8.01(d,J=8.6Hz,1H),7.91(s,1H),7.79(s,1H),7.61(s,1H),7.52(dd,J 1=8.6Hz,J 2=2.0Hz,1H),4.01(s,3H),3.68(s,3H),3.15(t,J=7.7Hz,2H),2.75(t,J=7.7Hz,2H).
Step 8 is prepared 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propyl group-1-alcohol
By 57mg(1.5mmol) lithium aluminum hydride joins in the super dry tetrahydrofuran (THF) of 15ml; under nitrogen protection, be cooled to-10 DEG C; slowly drip 220mg(0.75mmol) tetrahydrofuran solution of 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) methyl propionate; finish, react 1h after being slowly raised to room temperature.Aftertreatment, drips saturated aqueous ammonium chloride 0.5ml in ice bath downhill reaction liquid, and ethyl acetate 10ml filters.Filter cake ethyl acetate is washed, and the dry evaporate to dryness of merging filtrate obtains thick product 180mg, yield: 90%.LC-MS(ESI)：[M+H] +=268。
Step 9 is prepared 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propionic aldehyde
290mg(1.1mmol) 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propyl group-1-alcohol is dissolved in 20ml methylene dichloride, adds Dess-Martin reagent 552mg(1.3mmol under ice bath) finish, room temperature reaction spends the night.Aftertreatment adds sodium thiosulfate solution and sodium bicarbonate aqueous solution in reaction solution, stirring at room temperature 30min, and organic phase is washed through saturated common salt, obtains product 240mg, yield: 83% after being dried through purification by silica gel column chromatography.LC-MS(ESI)：[M+H] +=266, 1H-NMR(δppm,CDCl 3,400MHz):9.88(s,1H),9.02(s,1H),8.10(s,1H),8.01(d,J=8.6Hz,1H),7.91(s,1H),7.79(s,1H),7.60(s,1H),7.51(d,J=8.6Hz,1H),4.01(s,3H),3.16(t,J=7.5Hz,2H),2.91(t,J=7.5Hz,2H).
Step 10 is prepared the chloro-3-of 2-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propionic aldehyde
By 240mg(0.90mmol) 3-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propionic aldehyde is dissolved in 2ml acetonitrile, under ice bath, add successively 10mg(0.09mmol) L-PROLINE, 11mg(0.09mmol) phenylformic acid and 13mg(0.95mmol) NCS, finish reaction under room temperature and spend the night, after finishing, reaction adds 2ml ethyl acetate, stir 30min, filter, filter cake ethyl acetate is washed, and after being dried, obtains crude product 185mg, yield: 51%, directly throw next step.LC-MS(ESI)：[M+H] +=300。
Step 11 is prepared 4-(3-amino-1,2,4-triazine-6-yl)-2-fluorophenyl carbamate
1g(5.7mmol) 6-bromo-1,2,3-triazine-3-amine, 1.2g(6.3mmol) the fluoro-4-methoxyl group of 3-formic acid phenylo boric acid, salt of wormwood 0.95g(6.9mmol) and 1,1'-bis-(diphenylphosphine) ferrocene palladium chloride methylene dichloride mixture 20mg join in 10ml dioxane, then add 2.5ml water, after nitrogen replacement, 85 DEG C of reactions of outer temperature are spent the night.Aftertreatment, pours reaction solution in 100ml methylene dichloride into, washing, and saturated common salt washing, obtains product 1.2g through purification by silica gel column chromatography, yield after being dried: 85%.LC-MS(ESI)：[M+H] +=249, 1H-NMR(δppm,DMSO-d 6,400MHz):8.93(s,1H),8.04–7.94(m,3H),7.64(s,2H),3.88(s,3H).
Step 12 is prepared 4-(3-amino-1,2,4-triazine-6-yl) the fluoro-methylphenylamine of-2-
To the methylamine alcohol solution 20ml that adds 33% in tube sealing, under room temperature by 1.2g(4.8mmol) 4-(3-amino-1,2,4-triazine-6-yl)-2-fluorophenyl carbamate adds in above-mentioned solution, is heated to 45 DEG C of confined reactions and spends the night.Aftertreatment, is cooled to room temperature, filters, and filtration cakes torrefaction obtains product 1g, yield: 83%, directly throw next step.LC-MS(ESI)：[M+H] +=248。
Step 13 is prepared the fluoro-N-methyl-4-of 2-(7-((3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) methyl) imidazoles [1,2-b] [1,2,4] triazine-2-yl) benzamide (compound 3-1)
By 185mg(0.75mmol) 4-(3-amino-1,2,4-triazine-6-yl) the fluoro-methylphenylamine of-2-and 224mg(0.75mmol) the chloro-3-of 2-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) propionic aldehyde joins in 3ml ethylene glycol, and 150 DEG C of reactions of outer temperature are spent the night.Aftertreatment, pours reaction solution in 50ml methylene dichloride into, and saturated aqueous sodium carbonate is washed, washing, and saturated common salt washing, obtains product 15mg through purification by silica gel column chromatography, yield 4% after being dried.LC-MS(ESI)：[M+H] +=493, 1H-NMR(δppm,DMSO-d 6,400MHz):9.23(s,1H),9.13(d,J=2.2Hz,1H),8.43–8.35(m,3H),8.09–7.99(m,4H),7.94(d,J=8.6Hz,1H),7.86–7.78(m,2H),7.72(dd,J 1=8.6Hz,J 2=1.9Hz,1H),4.65(s,2H),3.91(s,3H),2.81(d,J=4.6Hz,3H).
Embodiment 1896-(1-(6-(1H-indoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (compound 1-164)
Step 1 is prepared the bromo-N of 6- 2-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 2-amino-3,5-bis-bromo-pyrazine (391mg, 1.55mmol) be dissolved in 1-Methyl-2-Pyrrolidone 12ml, under normal temperature, add afterwards 1-(5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethamine (300mg, 1.03mmol) and 3mlN, N-diisopropylethylamine.This reaction soln, under argon shield, is heated to 190 DEG C of tube sealings and spends the night.Concentration of reaction solution, by crude product by dodge post purify (developping agent is methylene dichloride: methyl alcohol=95:5).Obtain about 303mg brown solid, yield: 64%.LC-MS(ESI)：[M+H] +=459； 1H-NMR(δppm,DMSO-d 6,400MHz):9.24(s,1H),8.51(d,J=10.2Hz,2H),8.19(s,1H),7.61(d,J=11.6Hz,1H),7.12(s,1H),6.39(s,2H),4.11(q,J=5.2Hz,1H),3.91(s,3H),1.72(d,J=7.1Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline
By bromo-6-N 2-(1-(5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines (285mg, 0.62mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, and this reaction is heated to 150 DEG C of tube sealings and spends the night.Concentration of reaction solution, remaining crude product is by dodging post purification (developping agent is methyl alcohol: methylene dichloride=0% is to 5%).Obtain 220mg yellow solid, yield: 76%.LC-MS(ESI)：[M+H] +=471。
Step 3 is prepared 6-(1-(6-(1H-indoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (compound 1-164)
By 6-(1-(the bromo-1H-imidazo [4 of 6-, 5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (60mg, 0.14mmol) be dissolved in 12ml1, in 4-dioxane, then add successively (1H-indoles-4-yl) boric acid of 1.5 equivalents, Pd (dppf) Cl 2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.This reaction solution is under argon shield, and 110 DEG C of tube sealings spend the night.Concentration of reaction solution, remaining crude product is purified (developping agent is methylene dichloride: methyl alcohol=95:5) by dodging post, and the finished product are washed once with methyl alcohol, obtain 49.6mg yellow solid powder, yield: 77%.LC-MS(ESI)：[M+H] +=507； 1H-NMR(δppm,DMSO-d 6,400MHz):11.22(d,J=6.5Hz,1H),9.30(s,1H),9.20(s,1H),9.01(s,1H),8.54(d,J=28.3Hz,2H),8.21(s,1H),7.71(d,J=12.1Hz,1H),7.47(dd,J=18.3,7.5Hz,2H),7.15(t,J=7.4Hz,1H),7.04(s,1H),6.56–6.34(m,2H),3.91(s,3H),2.25(d,J=6.6Hz,3H).
Embodiment 190～embodiment 194
According to the same procedure of embodiment 189, adopt different boric acid or boric acid ester, the compound of Preparation Example 190～embodiment 194, specific experiment data are in table 15.
The experimental data table of table 15 compound 1-165～compound 1-169
Embodiment 1965, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 2-25)
Step 1 is prepared the bromo-N of 6- 2-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 2-amino-3,5-bis-bromo-pyrazine (391mg, 1.55mmol) be dissolved in 1-Methyl-2-Pyrrolidone 12ml, under normal temperature, add afterwards 1-(5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethamine (300mg, 1.03mmol) and 3mlN, N-diisopropylethylamine.This reaction soln, under argon shield, is heated to 190 DEG C of tube sealings and spends the night.Concentration of reaction solution, by crude product by dodge post purify (developping agent is methylene dichloride: methyl alcohol=95:5).Obtain about 303mg brown solid, yield: 64%.LC-MS(ESI)：[M+H] +=459； 1H-NMR(δppm,DMSO-d 6,400MHz):9.24(s,1H),8.51(d,J=10.2Hz,2H),8.19(s,1H),7.61(d,J=11.6Hz,1H),7.12(s,1H),6.39(s,2H),4.11(q,J=5.2Hz,1H),3.91(s,3H),1.72(d,J=7.1Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-[1 of 6-, 2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline
By bromo-6-N 2-(1-(5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl) pyrazine-2,3-diamines (439mg, 0.95mmol) be dissolved in 5mlDMF, then under room temperature, 0.03ml Isopentyl nitrite slowly adds in solution, and stirring at room temperature is heated to 80 DEG C of tube sealings by this reaction after 15 minutes and spends the night.The saturated solution quencher reaction that adds S-WAT, adds a small amount of water and 30ml ethyl acetate afterwards, separates organic phase, the extraction of 30mL for water × 3 ethyl acetate.Merge organic phase, saturated nacl aqueous solution 30mL × 2 are washed, dry, evaporate to dryness.Point plate (developping agent is methylene dichloride: methyl alcohol=20:1) is purer, dodges column purification (developping agent is methylene dichloride: methyl alcohol=96:4) and obtains yellow solid 349mg, yield: 78%.LC-MS(ESI)：[M+H] +=472； 1H-NMR(δppm,DMSO-d 6,400MHz):9.31(d,J=2.2Hz,1H),8.97(s,1H),8.59(d,J=1.8Hz,1H),8.50(s,1H),8.20(s,1H),7.73(d,J=11.5Hz,1H),6.78(q,J=7.1Hz,1H),3.91(s,3H),2.32(d,J=7.1Hz,3H).
Step 3 prepares 5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 2-25)
By 6-(1-(and the bromo-1H-[1 of 6-, 2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline (60mg, 0.14mmol) is dissolved in 12ml1, in 4-dioxane, then add successively 1.5 equivalent 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta encircle-2-yl)-1H-pyrazoles, Pd (dppf) 2cl 2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.This reaction solution is under argon shield, and 110 DEG C of tube sealings spend the night.Concentration of reaction solution, remaining crude product is purified (developping agent is dichloromethane: alkane methyl alcohol=95:5) by dodging post, and the finished product are washed (2*5ml) with methanol solution.Obtain 63mg white solid powder, yield: 95%.LC-MS(ESI)：[M+H] +=472； 1H-NMR(δppm,DMSO-d 6,400MHz):9.31(d,J=2.2Hz,1H),9.15(s,1H),8.62(d,J=1.6Hz,1H),8.49(d,J=10.3Hz,2H),8.21(d,J=0.6Hz,1H),8.08(d,J=0.5Hz,1H),7.74(d,J=11.7Hz,1H),6.77(q,J=7.0Hz,1H),3.91(d,J=1.2Hz,6H),2.36(d,J=7.1Hz,3H).
Embodiment 197～embodiment 213
According to the same procedure of embodiment 196, adopt different boric acid or boric acid ester, the compound of Preparation Example 197～embodiment 213, specific experiment data are in table 16.
The experimental data table of table 16 compound 2-26～compound 2-42
Embodiment 214:3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate (compound 1-171)
Step 1 is prepared the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines
By 3,5-, bis-bromo-pyrazines-2-amine (6.1g, 24mmol), 1-(the fluoro-6-quinolyl of 7-) ethamine (3.8g, 24mmol) and DIPEA(8.6mL, 48mmol) join NMP(20ml) in, the lower 130 DEG C of reactions of argon shield are spent the night.Reaction solution steams except DIPEA, and residue is poured in water (100ml), methylene dichloride (30ml × 3) extraction, and organic phase washing, saturated common salt washing, obtains the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines, yield: 50%.
LC-MS(ESI)：[M+H] +=362； 1H-NMR(δppm,DMSO-d 6,400MHz)：8.89(s,1H)，8.39(d,J=7.6Hz,1H)，7.97(d,J=7.8Hz,1H)，7.77(d,J=11.7Hz,1H)，7.50(d,J=3.2Hz,1H)，7.18(s,1H)，7.05(d,J=5.3Hz,1H)，6.38(s,2H)，5.43(s,1H)，1.61(d,J=6.0Hz,3H)。
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline
By bromo-6-N 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines (1.2g, 3.6mmol) join in acetic acid diethoxy methyl esters (30ml), under stirring at room temperature, add 98% formic acid (1ml), finish, reaction solution refluxes 2 days, solvent evaporated, ethyl acetate/petroleum ether for crude product (1/1) is washed, and obtains brown solid, yield: 60%.LC-MS(ESI)：[M+H] +=372； 1H-NMR(δppm,DMSO-d 6,400MHz)：9.10(s,1H)，8.93(d,J=4.0Hz,1H)，8.67(s,1H)，8.43(d,J=8.2Hz,1H)，8.11(d,J=8.4Hz,1H)，7.81(d,J=12.1Hz,1H)，7.55(dd,J 1=8.2Hz,J 2=4.0Hz,1H)，6.33(q,J=7.1Hz,1H)，2.11(d,J=7.1Hz,3H)。
Step 3 is prepared 3-(1-(the fluoro-6-quinolyl of 7-) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate
Raw material 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline (150mg, 0.4mmol) is dissolved in dehydrated alcohol (50ml), adds Pd (PPh 3) 2cl 2(28mg, 0.04mmol, 0.1eq), DIPEA(3ml), with carbon monoxide gas precursor reactant 8h(10atm, 80 DEG C).Solvent evaporated, crude product is prepared plate purifying and is obtained white solid 112mg, yield 75.9%.LC-MS(ESI)：[M+H] +=366.0； 1H-NMR(δppm,CDCl 3,400MHz):9.35(s,1H),8.95(dd,J 1=4.4Hz,J 2=2.0Hz,1H),8.64(s,1H),8.19(dd,J 1=8.4Hz,J 2=0.8Hz,1H),7.98(d,J=8.0Hz,1H),7.78(d,J=12.0Hz,1H),7.44(dd,J 1=8.4Hz,J 2=4.4Hz,1H),6.49(q,J=7.2Hz,1H),4.52(q,J=7.2Hz,2H),2.24(d,J=7.2Hz,3H),1.48(t,J=7.2Hz,3H).
Step 4 is prepared 3-(1-(the fluoro-6-quinolyl of the bromo-7-of 3-) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate
Raw material 3-(1-(the fluoro-6-quinolyl of 7-) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate (300mg, 0.8mmol) be dissolved in tetracol phenixin (20ml), add respectively pyridine (263mg, 1.6mmol, 2eq) and bromine (130mg, 1.6mmol, 2eq), 70 DEG C of reactions are spent the night.Solvent evaporated, adds aqueous sodium carbonate to be adjusted to alkalescence, dichloromethane extraction, and washing, saturated common salt water washing, column chromatography purification obtains white solid 122mg, yield 33.4%.LC-MS(ESI)：[M+H] +=443.8； 1H-NMR(δppm,CDCl 3,400MHz):9.35(s,1H),8.94(d,J=2.0Hz,1H),8.64(s,1H),8.34(d,J=2.0Hz,1H),7.93(d,J=7.6Hz,1H),7.77(d,J=11.6Hz,1H),6.46(q,J=7.2Hz,1H),4.52(q,J=7.2Hz,2H),2.25(d,J=7.2Hz,3H),1.48(t,J=7.2Hz,3H).
Step 5 is prepared 3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate (compound 1-171)
By raw material 3-(1-(the fluoro-6-quinolyl of the bromo-7-of 3-) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate (120mg, 0.27mmol), 1-methyl isophthalic acid H-pyrazoles-4-pinacol borate (85mg, 0.41mmol, 1.5eq), catalyst P d(dppf) Cl 2dCM(11mg, 0.01mmol, 0.05eq) and K 2cO 3(112mg, 0.81mmol, 3eq) is dissolved in dioxane+water (4ml+1ml) solution, the lower 110 DEG C of reaction 4h of argon shield.Be down to after room temperature, add large water gaging, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters evaporate to dryness, and crude product is prepared plate purifying and is obtained safran solid 14mg, yield 11.7%.LC-MS(ESI)：[M+H] +=446.0； 1H-NMR(δppm,CDCl 3,400MHz):9.35(s,1H),9.08(d,J=2.4Hz,1H),8.66(s,1H),8.18(s,1H),7.92(d,J=8.0Hz,1H),7.91(s,1H),7.80(s,1H),7.76(d,J=11.6Hz,1H),6.48(q,J=7.2Hz,1H),4.52(q,J=7.2Hz,2H),4.03(s,3H),2.24(d,J=7.2Hz,3H),1.48(t,J=7.2Hz,3H).
The fluoro-3-of embodiment 215:7-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-172)
Step 1 is prepared the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines
The method of reference example 1 step 1, substitutes 6-quinoline benzylidene amino by 1-(the fluoro-6-quinolyl of 7-) ethamine and obtains the bromo-N of 6- 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines, yield=50%.LC-MS(ESI)：[M+H] +=362， 1H-NMR(δppm，DMSO-d 6，400MHz):8.89(s，1H)，8.39(d，J=7.6Hz，1H)，7.97(d，J=7.8Hz,1H),7.77(d,J=11.7Hz,1H),7.50(d,J=3.2Hz,1H),7.18(s,1H),7.05(d,J=5.3Hz,1H),6.38(s,2H),5.43(s,1H),1.61(d,J=6.0Hz,3H).
Step 2 is prepared 6-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline
The method of reference example 1 step 2, by bromo-6-N 2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines and the reaction of acetic acid diethoxy methyl esters obtain brown solid, yield=60%, LC-MS (ESI): [M+H] +=372, 1h-NMR (δ ppm, DMSO-d 6, 400MHz): 9.10 (s, 1H), 8.93 (d, J=4.0Hz, 1H), 8.67 (s, 1H), 8.43 (d, J=8.2Hz, 1H), 8.11 (d, J=8.4Hz, 1H), 7.81 (d, J=12.1Hz, 1H), 7.55 (dd, J 1=8.2Hz, J 2=4.0Hz, 1H), 6.33 (q, J=7.1Hz, 1H), 2.11 (d, J=7.1Hz, 3H).
Step 3 is prepared the bromo-6-of 3-(1-(the bromo-1H-imidazo of 6-[4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline
By 372.2mg(1mmol) 6-(1-(the bromo-1H-imidazo [4 of 6-, 5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline and 158mg(2mmol) pyridine join in 50ml tetracol phenixin, stir the lower 320mg(2mmol that slowly drips) bromine, finish reaction backflow 3h.Aftertreatment, solvent evaporated, crude product dissolves with methylene dichloride, and saturated aqueous sodium carbonate is washed, and saturated common salt washing obtains 300mg crude product after dry solvent evaporated, and yield=66%, directly throws next step.
LC-MS(ESI)：[M+H] +=450。
Step 4 is prepared the fluoro-3-of 7-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline (compound 1-172)
The method of reference example 164 steps 4, by bromo-3-6-(1-(the bromo-1H-imidazo [4 of 6-, 5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline reacts to obtain white solid with 1-methyl isophthalic acid H-4-pyrazoles pinacol borate, yield=33%, LC-MS (ESI): [M+H] +=454, 1h-NMR (δ ppm, DMSO-d 6, 400MHz): 9.19 (d, J=2.2Hz, 1H), 8.96 (s, 1H), 8.85 (s, 1H), 8.57 (d, J=1.9Hz, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 8.05 (s, 1H), 8.03 (d, J=8.4Hz, 1H), 7.78 (d, J=11.9Hz, 1H), 6.35 (q, J=7.1Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.16 (d, J=7.1Hz, 3H).
The restraining effect of effect embodiment 1 the compounds of this invention to C-Met tyrosine kinase activity
Test-compound is to the active 503nhibiting concentration IC that uses of kinase whose inhibition 50value represents.Such test adopts homogeneous phase time discrimination fluorescence (HTRF) technology to measure, method is as follows: by the compound of a series of gradient concentrations, jointly hatch 5 minutes with the enzyme solution of certain concentration at ambient temperature, add afterwards appropriate enzyme reaction substrate, ATP, start enzyme reaction process, after 30 minutes, in enzyme reaction system, add appropriate reaction terminating liquid and detect liquid, hatch after 1 hour, on the EnVision2104 of PerkinElmer company multiple labeling micropore detector, under 665nm and 620nm wavelength, measure the enzyme activity under specific compound concentration, and calculate the compound of different concns to the inhibition activity of enzyme activity, afterwards according to four parametric equations, inhibition activity to enzyme activity under different concns compound is carried out matching, calculate IC 50value.The kinases Met that the present embodiment adopts is purchased from Carna Biosciences, and detection kit HTRF KinEASE-TK is purchased from Cisbio Bioassays company, and ATP is purchased from Sigma Aldrich company.The IC of test-compound of the present invention 50data are in table 17.
The inhibition activity data table of table 17 embodiment of the present invention compound to C-Met Tyrosylprotein kinase
Effect embodiment 2 compounds are to H1993 and the determination of activity of SNU-5 cell inhibitory effect
This example is used for measuring the proliferation inhibition activity of the compounds of this invention for c-Met high expression level lung cancer cell line H1993 and c-Met high expression level stomach cancer cell line SNU-5, the active half-inhibition concentration IC that uses of inhibition of compound on cell proliferation 50represent.Testing program is as follows: c-Met high expression level lung cancer cell line H1993 and c-Met high expression level stomach cancer cell line SNU-5 cell are all purchased from ATCC, with suitable cell concn (H1993:62500 cell/mlL substratum, SNU-5:62500 cell/mL substratum) cell is inoculated on 384 well culture plates of White-opalescent, cell is positioned over to 37 DEG C afterwards, 5%CO 2environment in cultivate, after 24 hours, to the medicine that adds a series of concentration gradients in cultured cells substratum, 10 concentration of general selection, afterwards H1993 cell is put back in former culture environment and continued to cultivate 72 hours, SNU-5 cell is put back in former culture environment and is continued to cultivate 48 hours, afterwards according to the method for CellTiter-Glo Luminescent Cell Viability Assay, measure the impact of test-compound on H1993 and SNU-5 cell proliferation at the EnVision2104 of PerkinElmer company multiple labeling micropore detector, and calculate the inhibition activity of the compound on cell proliferation of different concns.The CellTiter-Glo Luminescent Cell Viability Assay detection reagent adopting in the present embodiment is purchased from Promega.Afterwards H1993 under the compound of different concns and SNU-5 cell inhibitory effect activity are carried out to four parameter fittings, the IC50 data of test-compound of the present invention are in table 18.
Table 18 embodiment of the present invention compound is to H1993 and SNU-5 cell inhibitory effect activity data table
Conclusion: the compounds of this invention has obvious inhibition proliferation activity to H1993 and SNU-5.
Effect embodiment 3 the compounds of this invention suppress active to the acidifying of c-Met high expression level lung cancer cell line H1993 endocellular phosphorus and detect
This example is used for measuring the compounds of this invention and suppresses active for c-Met phosphorylation in c-Met high expression level lung cancer cell line H1993 cell, and compound is to the active half-inhibition concentration IC that uses of the inhibition of c-Met phosphorylation in cell 50represent.Testing program is as follows: c-Met high expression level lung cancer cell line H1993 is purchased from ATCC, is inoculated in 96 porocyte culture plates with suitable cell concn (300000/mL substratum); Cell is positioned over to 37 DEG C afterwards, 5%CO 2environment in cultivate, after 24 hours, to the medicine that adds a series of concentration gradients in cultured cells substratum, 10 concentration of general selection, put back to H1993 cell afterwards in former culture environment and continue to cultivate 1 hour, sop up afterwards nutrient solution in hole, add appropriate lysate lysing cell, appropriate cell pyrolysis liquid is transferred in opaque 384 orifice plates of shallow bore hole, added after appropriate Acceptor mix, room temperature lucifuge is hatched 2 hours; Add afterwards appropriate Donor mix, continue room temperature lucifuge and hatch 2 hours; Adopt the EnVision2104 multiple labeling micropore detector of PerkinElmer company to detect the impact of test-compound on c-Met phosphorylation in H1993 cell, and calculate the compound of different concns to the inhibition activity of cells phosphorylation.The AlphaScreen SureFire c-Met Assay Kits detection kit adopting in the present embodiment is purchased from PerkinElmer company.Afterwards the compound of different concns is suppressed to activity to c-Met phosphorylation in H1993 cell and carry out four parameter fittings, the IC50 data of test-compound of the present invention are in table 19.
Table 19 compound 1-87 and compound 1-95 suppress activity data table to the acidifying of c-Met high expression level lung cancer cell line H1993 endocellular phosphorus
Effect embodiment 4 compounds are at the metabolic stability of hepatomicrosome
This example is used for measuring the compounds of this invention at people, rat and monkey hepatomicrosome; People, monkey S9; The metabolic stability of people, MC kytoplasm solution, metabolic stability represents with intrinsic clearance.Testing program is as follows: be respectively the people S9(HS9 of 150 μ l by system), monkey S9 (MS9), human liver cell kytoplasm solution (Hcytosol), monkey liver cell kytoplasm solution (Mcytosol), people's hepatomicrosome (HLM), rat liver microsomes (RLM) and monkey hepatomicrosome (MLM) carry out that metabolic stability is warm in nature incubates, system comprises the phosphate buffered saline buffer of NADPH and testing compound simultaneously.Enzyme reaction system is carried out at 37 DEG C, and respectively at 0min, 5min, 10min and 30min the acetonitrile termination reaction with interior mark fasigyne, reaction solution vortex 10min, the centrifugal 10min of 15000rmp, gets 60 μ l supernatant liquors sample introduction in 96 orifice plates.Positive control is selected midazolam (MDZ), and negative control selects atenolol USP 23 (ATE) to do parallel test.The present embodiment is measured the relative reduction of former medicine by LC/MS/MS.Intrinsic clearance (Cl int; μ l/min/mg protein) be less than at 100 o'clock, think that the metabolic stability of this compound is relatively good.The metabolic stability data of test-compound of the present invention is in table 20
The metabolic stability data table of table 20 compound
Conclusion: most of the compounds of this invention metabolic stability in hepatomicrosome, S9 and cell cytoplasm solution is good.
The direct inhibition test (DI test) of effect embodiment 5. compounds to metabolic enzyme
This example is used for measuring the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, and CYP2C9, CYP1A2, the direct repression of CYP2C19, compound is expressed as inhibiting rate to the direct repression of metabolic enzyme.Testing program is as follows: reaction cumulative volume is 100 μ l, comprising people's hepatomicrosome, NADPH, phosphate buffered saline buffer, substrate mixture (Midazolam, Testosterone, Dextromethophan, Diclofenac, Phenaceti, Mephenytoin), testing compound.37 DEG C of temperature of system are incubated the acetonitrile termination reaction with interior mark fasigyne after 20min.Vortex 10min, the centrifugal 10min of 15000rmp, gets 60 μ l supernatants sample introduction in 96 orifice plates.Positive control is selected inhibitor mixed thing (Ketoconazole, Quinidine, Sulfaphenazole, Naphthoflavone, Tranylcypromine), and negative control selects DMSO to do parallel check experiment.Measure the relative reactivity that the relative growing amount of substrate utilization thing represents enzyme, inhibiting rate=(the enzyme relative reactivity/negative control enzyme relative reactivity of 1-testing compound) × 100% of compound to enzyme.Inhibiting rate is greater than 50% and is defined as CPY is had to direct inhibition.Test-compound of the present invention to the restraining effect data of metabolic enzyme in table 21.
Table 21 compound is to metabolic enzyme direct repression data sheet
Compound number 3A4-MDZ 3A4-testosterone 2D6 2C9 1A2 2C19
+control 98% 98% 100% 99% 100% 96%
1-172 54% 44% 31% 61% 26% 38%
2-1 22% Unrestraint 12% 31% 21% 19%
2-6 6% Unrestraint 9% 45% 2% Unrestraint
2-8 27% 14% 11% 55% 10% 19%
2-9 18% 10% 11% 33% 16% 18%
2-10 72% 72% 11% 76% 36% 56%
2-11 18% 10% 13% 48% 18% 36%
2-12 82% 78% 50% 74% 30% 50%
2-14 10% 10% 6% 48% 0% 44%
2-15 12% Unrestraint 2% 26% 0% 32%
2-16 8% 26% 6% 17% Unrestraint 18%
2-17 4% 22% Unrestraint 32% Unrestraint 5%
2-18 5% 67% 5% 16% Unrestraint 10%
2-19 9% 39% 2% 22% Unrestraint 15%
2-25 44% 31% 28% 74% 22% 81%
2-27 28% 19% 13% 41% 16% 50%
2-30 45% 26% 11% 68% 22% 75%
2-31 30% 22% 12% 82% 22% 96%
2-32 67% 67% 58% 81% 45% 86%
2-33 53% 39% 22% 78% 25% 89%
2-34 41% 33% 17% 78% 27% 46%
2-35 27% 10% 13% 70% 13% 71%
2-36 31% 72% 22% 73% 20% 49%
2-37 65% 78% 38% 84% 34% 89%
3-1 24% 8% 28% 64% 27% 37%
INCB28060 13% 1% 13% 43% 17% 39%
Conclusion: in the present invention, a part of compound does not have direct repression to metabolic enzyme.
The mechanism inhibition test (TDI test) of effect embodiment 6 compounds to metabolic enzyme
This example is used for measuring the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, and CYP2C9, CYP1A2, the mechanism restraining effect of CYP2C19, compound is expressed as apparent decay rate constants k to the mechanism restraining effect of metabolic enzyme obs.Testing program is as follows: reaction system cumulative volume is 200 μ l, and NADPH group comprises: people's hepatomicrosome, testing compound, NADPH, phosphate-buffered salt; Non-NADPH group comprises: people's hepatomicrosome, testing compound, phosphate-buffered salt.System respectively temperature is used the acetonitrile termination reaction containing interior mark fasigyne after incubating 0min, 5min, 10min and 20min, vortex 10min, and the centrifugal 10min of 15000rmp, gets 60 μ l supernatants sample introduction in 96 orifice plates.Positive control selects inhibitor mixed thing (Troleandomycin, Paroxetine, Tienilic Acid, Furafylline), negative control to select the positive control of compd A tenolol, CYP2C19 to select S-Fluoxetine.Represent enzyme relative reactivity by the relative growing amount of measuring substrate utilization thing, calculate apparent decay rate constants k obs(* 10 -4/ min), as the k of compound obsvalue is greater than at 200 o'clock, thinks that it has mechanism to suppress to CPY.Test-compound of the present invention to the restraining effect data of metabolic enzyme in table 22.
Table 22 compound is to metabolic enzyme mechanism restraining effect data sheet TDI (kobs*10 -4)
Conclusion: in the present invention, a part of compound does not have mechanism restraining effect to metabolic enzyme.
Effect embodiment 7 compounds are tested mice-transplanted tumor restraining effect
This example is for measuring the stomach cancer cell SNU-5 transplanted tumor restraining effect of the compounds of this invention to the high amplification of c-Met, represents drug effect in the body of compound with relative tumor proliferation rate.Testing program is as follows: the cancer of the stomach SNU-5 cell of selecting c-MET highly to increase.Cell culture condition is in IMDM substratum, to add 20% foetal calf serum, in 37 DEG C, containing 5%CO 2constant incubator in cultivate.Biweekly process and go down to posterity by 1:4.In the time that cell is exponential phase of growth, collecting cell is also counted.Bulb/c nude mouse is divided into 5 groups, by 5 × 10 6individual SNU-5 cell is inoculated in armpit place, nude mouse right side.Positive drug INCB28060 and testing compound administration concentration are 10mg/kg, every day gastric infusion once, successive administration 11 days.Routine observation animal situation, measure body weight and record result.Calculate volume and the relative volume of tumour according to formula.
(1) gross tumor volume (Tumor Volume, TV), TV=1/2XaXb 2; A, b represent respectively length and width.
(2) relative tumour volume (Relative Tumor Volume, RTV), RTV=TV t/ TV 0; TV 0(d during for point cage 0) gross tumor volume, TV tgross tumor volume during for each measurement.
(3) relative tumor proliferation rate T/C(%), calculation formula is:
T / C ( % ) = T RTV C RTV × 100 %
TRTV: treatment group RTV; CRTV: negative control group RTV.Anti-tumor activity judgement criteria is relative tumor proliferation rate T/C(%).In test-compound body of the present invention, drug effect data are in table 23.
Drug effect data sheet in table 23 compound Mice Body
Compound Dosage Gross tumor volume T/C(%)
Control(0.5%CMC-Na) 200μl 574.94±152.26 ?
1-170 10mg/kg 114.47±40.06 19.27%
1-172 10mg/kg 538.21±150 98.53%
INCB28060 10mg/kg 132.15±31.4 23.06%
Conclusion: in the present invention, compound 1-170 can effectively suppress the growth of stomach cancer cell SNU-5 transplanted tumor, effect is slightly better than control compound, a little less than 1-172 antitumor action.

Claims (22)

1. quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug as shown in Equation 1,
Wherein, X 1, X 2and X 3be C or N independently of one another, represent, work as X 1during for C, X 1with R 1be connected, work as X 1during for N, with X 1connected R 1do not exist; And, work as X 1during for C, X 2and X 3in one be C, another is N, R 1for hydrogen or hydroxyl; Work as X 1during for N, X 2for N, X 3for C;
Cy be 3～8 yuan of cycloalkyl, 3～8 yuan of Heterocyclylalkyls, 5～8 yuan of cycloalkenyl groups, 5～8 yuan of heterocycloalkenyl, 6～10 yuan of aryl, 5～10 yuan of heteroaryls or described 3～8 yuan of cycloalkyl, 3～8 yuan of Heterocyclylalkyls, 5～8 yuan of cycloalkenyl groups, 5～8 yuan of heterocycloalkenyl, 6～10 yuan of aryl or 5～10 yuan of heteroaryls can by 1～2 be selected from halogen, cyano group, group replace, wherein R 5and R 6be C independently of one another 1-6the C that alkyl, halogen replace 1-6the C that alkyl, hydroxyl replace 1-65～10 yuan of heteroaryls that 6～10 yuan of aryl that alkyl, 3～8 yuan of cycloalkyl, 3～8 yuan of Heterocyclylalkyls, 6～10 yuan of aryl, halogens replace, 5～10 yuan of heteroaryls or halogen replace;
L is or
R 2, R 3and R 4be hydrogen, halogen or C independently of one another 1-6alkyl;
A is H, 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases, and described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases can be selected from halogen, C by 1～2 1-6alkyl and group replace.
2. quinolines as claimed in claim 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that: work as X 1for C, X 2for N and X 3during for C, A is H or 5～10 membered nitrogen-containing heteroaryl bases, and described 5～10 membered nitrogen-containing heteroaryl bases can be by C 1-6alkyl replaces; Work as X 1for C, X 2for C and X 3during for N, A is 5～10 membered nitrogen-containing heteroaryl bases, and described 5～10 membered nitrogen-containing heteroaryl bases can be by C 1-6alkyl replaces; Work as X 1for N, X 2for N and X 3during for C, A is 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases, and described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases can be selected from halogen, C by 1～2 1-6alkyl and group replace.
3. quinolines as claimed in claim 2, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that:
Work as X 1for C, X 2for N and X 3for C, when A is 5～10 membered nitrogen-containing heteroaryl base, described " 5～10 membered nitrogen-containing heteroaryl base " for nitrogen-atoms number be 5～6 membered nitrogen-containing heteroaryl bases of 1-2; Work as X 1for C, X 2for N and X 3for C, A is by C 1-6when 5～10 membered nitrogen-containing heteroaryl base that alkyl replaces, described " C 1-6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
Work as X 1for C, X 2for C and X 3for N, when A is 5～10 membered nitrogen-containing heteroaryl base, described " 5～10 membered nitrogen-containing heteroaryl base " for nitrogen-atoms number be 5～6 membered nitrogen-containing heteroaryl bases of 1-2; Work as X 1for C, X 2for C and X 3for N, A is by C 1-6when 5～10 membered nitrogen-containing heteroaryl base that alkyl replaces, described " C 1-6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
Work as X 1for N, X 2for N and X 3for C, when A is 6～10 yuan of aryl, described " 6～10 yuan of aryl " is phenyl; Work as X 1for N, X 2for N and X 3for C, when A is 5～10 membered nitrogen-containing heteroaryl base, described " 5～10 membered nitrogen-containing heteroaryl base " for nitrogen-atoms number be 5～10 membered nitrogen-containing heteroaryl bases of 1-2;
In the time that described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases are replaced by halogen, described " halogen " is fluorine, chlorine or bromine;
When described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl bases are by C 1-6when alkyl replaces, described " C 1-6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When described 6～10 yuan of aryl or 5～10 membered nitrogen-containing heteroaryl base quilts when replacement, described described in " C 1-6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
4. quinolines as claimed in claim 3, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that: work as X 1for C, X 2for N and X 3for C, A is nitrogen-atoms number while being 5～6 membered nitrogen-containing heteroaryl base of 1-2, and described " nitrogen-atoms number is 5～6 membered nitrogen-containing heteroaryl bases of 1-2 " is pyrazolyl; Work as X 1for C, X 2for N and X 3for C, A is when by 5～10 membered nitrogen-containing heteroaryl base that methyl replaced, and described " 5～10 membered nitrogen-containing heteroaryl bases that methyl replaces " are 1-methyl isophthalic acid H-pyrazolyl;
Work as X 1for C, X 2for C and X 3for N, A is nitrogen-atoms number while being 5～6 membered nitrogen-containing heteroaryl base of 1-2, and described " nitrogen-atoms number is 5～6 membered nitrogen-containing heteroaryl bases of 1-2 " is pyrazolyl; Work as X 1for C, X 2for C and X 3for N, A is when by 5～10 membered nitrogen-containing heteroaryl base that methyl replaced, and described " 5～10 membered nitrogen-containing heteroaryl bases that methyl replaces " are 1-methyl isophthalic acid H-pyrazolyl;
Work as X 1for N, X 2for N, and X 3for C, A is nitrogen-atoms number while being 5～10 membered nitrogen-containing heteroaryl base of 1-2, and described " nitrogen-atoms number is 5～10 membered nitrogen-containing heteroaryl bases of 1-2 " is pyrazolyl, pyridyl or quinolyl;
Work as X 1for N, X 2for N and X 3for C, A is while being 5～10 membered nitrogen-containing heteroaryl base of 1-2 by methyl substituted nitrogen-atoms number, and described " being 5～10 membered nitrogen-containing heteroaryl bases of 1-2 by methyl substituted nitrogen-atoms number " is 1-methyl isophthalic acid H-pyrazolyl.
5. quinolines as claimed in claim 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that:
In the time that described Cy is 3～8 yuan of cycloalkyl, described " 3～8 yuan of cycloalkyl " is 3～6 yuan of cycloalkyl;
In the time that described Cy is 3～8 yuan of Heterocyclylalkyls, described " 3～8 yuan of Heterocyclylalkyls " is 3～6 yuan of Heterocyclylalkyls;
In the time that described Cy is 5～8 yuan of heterocycloalkenyl, described " 5～8 yuan of heterocycloalkenyl " is 5～6 yuan of heterocycloalkenyl;
When described Cy is time, wherein, described " C 1-6alkyl " be C 1-4alkyl;
In the time that described Cy is 6～10 yuan of aryl, described " 6～10 yuan of aryl " is phenyl or naphthyl;
In the time that described Cy is 5～10 yuan of heteroaryls, described " 5～10 yuan of heteroaryls " preferably heteroatoms is that N, O or S atom, heteroatoms number are the monocycle of 1～2 or 5～10 yuan of heteroaryls of condensed ring;
In the time that 3～8 yuan of cycloalkyl described in described Cy, 3～8 yuan of Heterocyclylalkyls, 5～8 yuan of cycloalkenyl groups, 5～8 yuan of heterocycloalkenyl, 6～10 yuan of aryl or 5～10 yuan of heteroaryls are replaced by halogen, described " halogen " is fluorine, chlorine or bromine;
As the R described in described Cy 5and R 6be C independently of one another 1-6when alkyl, described " C 1-6alkyl " be C 1-4alkyl;
As the R described in described Cy 5and R 6the C replacing for halogen independently of one another 1-6when alkyl, described " C 1-6alkyl " be C 1-4alkyl, described " halogen " is fluorine, chlorine or bromine;
As the R described in described Cy 5and R 6the C replacing for hydroxyl independently of one another 1-6when alkyl, described " C 1-6alkyl " be C 1-4alkyl;
As the R described in described Cy 5and R 6while being independently of one another 6～10 yuan of aryl of 6～10 yuan of aryl or halogen replacement, described " 6～10 yuan of aryl " is phenyl, and described " halogen " is fluorine, chlorine or bromine;
As the R described in described Cy 5and R 6while being independently of one another 5～10 yuan of heteroaryls of 5～10 yuan of heteroaryls or halogen replacement, described " 5～10 yuan of heteroaryls ", for heteroatoms is nitrogen-atoms, heteroatoms number is 5～10 yuan of heteroaryls of 1-2, and described " halogen " is fluorine, chlorine or bromine;
As described R 2, R 3and R 4while being halogen independently of one another, described " halogen " is fluorine, chlorine or bromine;
As described R 2, R 3and R 4be C independently of one another 1-6when alkyl, described " C 1-6alkyl " be C 1-4alkyl;
In the time that 6～10 yuan of aryl described in described A or 5～10 membered nitrogen-containing heteroaryl bases are replaced by halogen, described " halogen " is fluorine, chlorine or bromine;
When 6～10 yuan of aryl described in described A or 5～10 membered nitrogen-containing heteroaryl bases are by C 1-6when alkyl replaces, described " C 1-6alkyl " be C 1-4alkyl;
When 6～10 yuan of aryl described in described A or 5～10 membered nitrogen-containing heteroaryl base quilts while replacing, described " C 1-6alkyl " be C 1-4alkyl.
6. quinolines as claimed in claim 5, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that:
In the time that described Cy is 3～6 yuan of cycloalkyl, described " 3～6 yuan of cycloalkyl " is cyclopropyl;
In the time that described Cy is 3～6 yuan of Heterocyclylalkyls, described " 3～6 yuan of Heterocyclylalkyls ", for heteroatoms is nitrogen-atoms, heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2; Described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " can be by C 1-4alkyl replaces, wherein, and described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
In the time that described Cy is 5～6 yuan of heterocycloalkenyl, described " 5～6 yuan of heterocycloalkenyl " for heteroatoms be that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2; Described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " can quilt replace or the nomadic nitrogen atom of described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " can salify; Described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When described Cy is wherein, described C 1-6alkyl is C 1-4when alkyl, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
In the time that described Cy is phenyl, described phenyl by 1～2 be selected from halogen and group replace;
In the time that described Cy is naphthyl, described naphthyl is 1-naphthyl;
When described Cy is that heteroatoms is N, O or S atom, heteroatoms number while being 5～10 yuan of heteroaryls of monocycle of 1～2, described " heteroatoms is that N, O or S atom, heteroatoms number are 5～10 yuan of heteroaryls of monocycle of 1～2 " is pyrazolyl, pyridyl, thienyl, pyrimidyl or furyl;
When described Cy is that heteroatoms is N, O or S atom, heteroatoms number while being 5～10 yuan of heteroaryls of condensed ring of 1～2, described " heteroatoms is that N, O or S atom, heteroatoms number are 5～10 yuan of heteroaryls of condensed ring of 1～2 " is quinolyl, isoquinolyl, benzothienyl, indyl or pyrrolopyridinyl;
As the R described in described Cy 5and R 6be C independently of one another 1-4when alkyl, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As the R described in described Cy 5and R 6the C replacing for halogen independently of one another 1-4when alkyl, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As the R described in described Cy 5and R 6the C replacing for hydroxyl independently of one another 1-4when alkyl, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As the R described in described Cy 5and R 6independently of one another for heteroatoms is nitrogen-atoms, heteroatoms number is that 5～10 yuan of heteroaryls of 1-2 or heteroatoms that halogen replaces are nitrogen-atoms, when heteroatoms number is 5～10 yuan of heteroaryls of 1-2, described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～10 yuan of heteroaryls of 1-2 " is quinolyl;
As described R 2, R 3and R 4be C independently of one another 1-4when alkyl, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When 6～10 yuan of aryl described in described A or 5～10 membered nitrogen-containing heteroaryl bases are by C 1-4when alkyl replaces, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When 6～10 yuan of aryl described in described A or 5～10 membered nitrogen-containing heteroaryl base quilts while replacing, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
7. quinolines as claimed in claim 6, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that:
When described Cy is that heteroatoms is nitrogen-atoms, when heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2, described " heteroatoms is nitrogen-atoms, and heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " is piperazinyl;
When described Cy is by C 1-4the heteroatoms that alkyl replaces is nitrogen-atoms, and when heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2, described " be nitrogen-atoms by the heteroatoms that methyl replaced, heteroatoms number is 5～6 yuan of Heterocyclylalkyls of 1-2 " is N methyl piperazine base;
When described Cy is that heteroatoms is nitrogen-atoms, heteroatoms number while being 5～6 yuan of heterocycloalkenyl of 1-2, described " heteroatoms is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1-2 " is 1,2,3,6-tetrahydro pyridyl;
When the heteroatoms described in described Cy is nitrogen-atoms, heteroatoms number while being the nomadic nitrogen atom salify in 5～6 yuan of heterocycloalkenyl of 1～2, described " heteroatoms is that nitrogen-atoms, heteroatoms number are the nomadic nitrogen atom salify in 5～6 yuan of heterocycloalkenyl of 1～2 " is
When described Cy is quilt the heteroatoms replacing is nitrogen-atoms, heteroatoms number while being 5～6 yuan of heterocycloalkenyl of 1～2, described " quilt the heteroatoms replacing is that nitrogen-atoms, heteroatoms number are 5～6 yuan of heterocycloalkenyl of 1～2 " be or
When described Cy is phenyl and described phenyl while being replaced by halogen, described " halogen " is fluorine, chlorine or bromine;
When described Cy is phenyl and described phenyl quilt when replacement, described " C 1-4alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
In the time that described Cy is pyrazolyl, described " pyrazolyl " is 1H-pyrazoles-4-base or 1H-pyrazoles-5-base;
In the time that described Cy is pyridyl, described " pyridyl " is pyridin-4-yl or pyridin-3-yl;
In the time that described Cy is thienyl, described " thienyl " is thiene-3-yl-or thiophene-2-base;
In the time that described Cy is pyrimidyl, described " pyrimidyl " is pyrimidine-5-base;
In the time that described Cy is furyl, described " furyl " is furans-3-base or furans-2-base;
In the time that described Cy is quinolyl, described " quinolyl " is quinolyl-4, quinoline-3-base or quinoline-7-yl);
In the time that described Cy is isoquinolyl, described " isoquinolyl " is isoquinoline 99.9-4-base;
In the time that described Cy is benzothienyl, described " benzothienyl " is thionaphthene-3-base or thionaphthene-2-base;
In the time that described Cy is indyl, described " indyl " is indol-3-yl, indoles-4-base or indoles-5-base;
In the time that described Cy is pyrrolopyridinyl, described " pyrrolopyridinyl " is 1H-pyrrolo-[2,3-b] pyridine-5-base;
As the R described in described Cy 5and R 6the heteroatoms replacing for halogen is independently of one another nitrogen-atoms, and when heteroatoms number is 5～10 yuan of heteroaryls of 1-2, described " heteroatoms that halogen replaces is nitrogen-atoms, and heteroatoms number is 5～10 yuan of heteroaryls of 1-2 " is
8. quinolines as claimed in claim 7, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that:
In the time that described Cy is piperazinyl, described piperazinyl is 4-piperazinyl;
In the time that described Cy is N methyl piperazine base, described " N methyl piperazine base " is N methyl piperazine-1-base;
When described Cy for by 1～2 be selected from halogen and group replace phenyl time, described " by 1～2 be selected from halogen and the phenyl that replaces of group " be the fluoro-4-of 3-(N-methylcarbamoyl)-1-phenyl;
In the time that described Cy is 1,2,3,6-tetrahydro pyridyl, described " 1,2,3,6-tetrahydro pyridyl " is 1,2,3,6-tetrahydropyridine-4-base.
9. quinolines as claimed in claim 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that: R 2and R 3be H, F or methyl independently of one another, R 4for H.
10. quinolines as claimed in claim 9, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, is characterized in that: work as R 2during for H, R 3for H, F or methyl, R 4for H; Work as R 2during for F, R 3for F, R 4for H.
11. quinolines as claimed in claim 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, it is characterized in that: in the time that Cy is 6～10 yuan of aryl, described " 6～10 yuan of aryl " is phenyl, the fluoro-phenyl of 2-, the chloro-phenyl of 2-, the chloro-phenyl of 3-, 2-trifluoromethyl-phenyl, 4-trifluoromethyl, 3, 4-dichlorophenyl, 4-Trifluoromethoxyphen-l, 3-cyano group-phenyl, 4-cyano-phenyl, 3-N, N-dimethylaminophenyl, 4-aminophenyl, 2, 4-dimethoxy-phenyl, 2, 6-dimethoxy-phenyl, 2, 6-dimethyl-phenyl, 2-methyl-4-methoxyl group-phenyl, 2-methyl-5-p-methoxy-phenyl, 4-methylthio group-phenyl,
In the time that Cy is 5～10 yuan of heteroaryls, described " 5～10 yuan of heteroaryls " be thiophene-2-base, thiene-3-yl-, furans-2-base, pyridin-3-yl, pyridin-4-yl, PA-3-base, 2-fluorine pyridin-3-yl, PA-5-base, 2-picoline-5-base, indoles-4-base, indoles-5-base, quinoline-7-base, isoquinoline 99.9-4-base, 5-cyano thiophene-2-base,
12. quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrugs as described in claim 1～11 any one, it is characterized in that: described quinolines is suc as formula the quinolines that contains Imidazopyrazines structure shown in 1-a, suc as formula the quinolines that contains triazole pyrazine structure shown in 1-b or suc as formula containing imidazo [1 shown in 1-c, 2-b] [1,2,4] quinolines of triazole structure
Wherein, the definition of Cy is as described in claim 1,5,6,7,8 or 11 any one; The definition of A is as described in claim 1～6 any one; The definition of L as claimed in claim 1; R 1, R 2, R 3and R 4definition as described in claim 1,5,6,7,8,9 or 10 any one.
13. is as claimed in claim 12 suc as formula the quinolines shown in I, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug, it is characterized in that: quinolines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug is as shown in Equation 1 arbitrary compound as described below:
6-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1)-methylene radical)-quinoline,
6-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(pyridin-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(4-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical) quinoline,
4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazoles-6-yl)-aniline,
6-(6-(4-Trifluoromethoxyphen-l)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
The chloro-4-of 7-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl) quinoline,
N, N-dimethyl-3-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-aniline,
6-(6-(4-methoxyl group-2-methyl-l-phenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(1,2,3,6-tetrahydropyridine-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline hydrochloride,
4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-3,6-dihydropyridine-1 (2H)-ethyl formate,
6-(6-(2,6-Dimethoxyphenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(2,4-Dimethoxyphenyl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
3-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical) quinoline,
6-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
2-(4-(1-(quinoline-6-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyrazol-1-yl)-ethanol,
6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(4-(trifluoromethyl) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(4-methoxyl group-2-aminomethyl phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
N, N-dimethyl-3-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline,
6-(1-(6-(1,2,3,6-tetrahydropyridine-1--4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline-1-muriate,
2-(4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) ethanol,
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(2,6-3,5-dimethylphenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-4-of 2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate,
6-(1-(6-(4-(methylthio group) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(thiene-3-yl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzsulfamide,
6-(1-(6-(pyrimidine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-2-formaldehyde,
4-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzonitrile,
6-(1-(6-(6-picoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(1H-pyrrolo-[2,3-b] pyridine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
N, N-dimethyl-5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine,
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-3-formaldehyde,
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyrimidine-2-amine,
5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine,
(5-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) furans-3-yl) methyl alcohol,
3-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) pyridine-2-amine,
The fluoro-4-of 2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide,
The fluoro-4-of N-ethyl-2-(1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide,
The fluoro-N-methyl-4-of 2-(1-(1-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide,
6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1-(1-(quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-2-alcohol,
The fluoro-6-of 8-((6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
The fluoro-6-of 8-((6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
The fluoro-6-of 8-((6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
2-(4-(1-((8-fluorine quinoline-6-yl) methyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) ethanol,
6-((6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-8-fluorine quinoline,
The fluoro-6-of 8-((6-(3-quinolyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-quinoline,
The fluoro-6-of 8-((6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-quinoline,
8-fluoro-(6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 8-(1-(6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 8-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 8-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline,
The fluoro-6-of 8-(1-(6-(3-quinolyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(3,4-dichlorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline, 6-(1-(6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline,
6-(1-(6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-8-fluorine quinoline,
The fluoro-6-of 8-(1-(6-(2-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 8-(1-(6-(4-trifluoromethyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 8-(1-(6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-[6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical]-quinoline,
2-(4-(1-(the fluoro-quinoline-6-of 7-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl)-ethanol,
6-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-methylene radical)-7-fluorine quinoline,
The fluoro-6-of 7-(6-phenyl-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
The fluoro-6-of 7-(6-(pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
(3-(1-(the fluoro-quinoline-6-of 7-methylene radical)-1H-imidazo [4,5-b] pyrazine-6-yl)-phenyl)-N, N-dimethyl amine,
The fluoro-6-of 7-(6-(4-methoxyl group-2-methyl-phenyl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
The fluoro-6-of 7-(6-(quinoline-3-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
4-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-aniline,
6-((5-(the chloro-4-quinolyl of 7-) imidazo [4,5-b] pyrazine-3-yl) methylene radical) the fluoro-quinoline of-7-,
The chloro-4'-of 7-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-[4,7'] two quinoline,
4-(3-(the fluoro-quinoline-6-of 7-methylene radical)-3H-imidazo [4,5-b] pyrazine-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester,
The fluoro-6-[6-of 7-(1,2,3,6-tetrahydrochysene-pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-methylene radical]-quinoline hydrochloride,
The fluoro-6-of 7-(6-(the fluoro-phenyl of 2-)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
The fluoro-6-of 7-(6-(pyridin-3-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-(3-chloro-phenyl-)-imidazo [4,5-b] pyrazine-1-methylene radical) the fluoro-quinoline of-7-,
The fluoro-6-of 7-(6-(naphthalene-1-yl)-imidazo [4,5-b] pyrazine-1-methylene radical)-quinoline,
6-(6-cyclopropyl-imidazo [4,5-b] pyrazine-1-methylene radical) the fluoro-quinoline of-7-,
The fluoro-6-of 7-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H--imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
4-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline,
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline,
The fluoro-6-of 7-(1-(6-phenyl-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
The fluoro-6-of 7-(1-(6-(pyridin-4-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
2-(4-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl)-ethanol,
The fluoro-6-of 7-(1-(6-(quinoline-3-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
The fluoro-4-of 2-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-methyl benzoate,
The fluoro-4-of 2-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-benzamide,
The fluoro-4-of 2-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-N-methyl-benzamide,
4-(1-(1-(7-fluorine quinoline-6 base)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-benzsulfamide,
The fluoro-6-of 7-(1-(6-(pyrimidine-5-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
4-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-furans-2-methyl alcohol,
4-(1-(1-(7-fluorine quinoline-6-yl)-ethyl)-3H-imidazo [4,5-b] pyrazine-6-yl) cyanobenzene,
The fluoro-6-of 7-(1-(6-(thiophene-2-yl) imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
The fluoro-6-of 7-(1-(6-(thiene-3-yl-) imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
6-(1-(6-(benzo [b] thiophene-2-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline,
6-(1-(6-(benzo [b] thiene-3-yl-)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline,
The fluoro-6-of 7-(1-(6-(4-methylthio group phenyl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline,
6-(1-(6-(1H-pyrroles [2,3-b] pyridine-5-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-7-fluorine quinoline,
5-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-N, N-lutidine-2-amine,
The fluoro-6-of 7-(1-(6-(6-methyl-pyridin-3-yl)-imidazo [4,5-b] pyrazine-1-yl)-ethyl)-quinoline; ,
3-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyridine-2-amine,
5-(1-(1-(the fluoro-quinoline-6-of 7-yl)-ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-pyridine-2-amine,
5,7 two fluoro-6-((6-(1-methyl isophthalic acid H-pyrazoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
6-((6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-((6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
6-((6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-((6-(4-(trifluoro methoxy) phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl) quinoline,
4-(1-((5,7-difluoro-quinoline-6-yl) methyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate,
6-((6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) methyl)-5,7-difluoro-quinoline,
5,7 two fluoro-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-phenyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(pyridin-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
3-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-DMA,
The fluoro-6-of 5,7-bis-(1-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(2,6-3,5-dimethylphenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
6-(1-(6-(3-chloro-phenyl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
6-(1-(6-cyclopropyl-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
2-(4-(1-(1-(5,7 – difluoro-quinoline-6-yls) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-1H-pyrazol-1-yl) second-1-alcohol,
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline,
6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
6-(1-(6-(7-chloroquinoline-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(pyridin-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(5-methoxyl group-2-aminomethyl phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-quinoline,
6-(1-(6-(3-chloro-phenyl-)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
6-(1-(6-(2,6-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(1-naphthyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(2,4-dimethoxy phenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(4-trifluoromethoxy benzaldehyde base)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate,
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) the fluoro-N-methyl-benzamide of-2-,
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) the fluoro-benzamide of-2-,
The fluoro-6-of 5,7-bis-(1-(6-(4-first sulfur phenenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(1-(benzenesulfonyl)-1H-indol-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5,7-difluoro-quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(pyrimidine-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(3-thienyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
4-(1-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) cyanobenzene,
7-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
7-methyl-6-(1-(6-(3-quinolyl)-1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
N, N-dimethyl-3-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) aniline,
7-methyl-6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(2-fluorophenyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-7-toluquinoline,
The fluoro-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate,
The fluoro-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide,
The fluoro-N-methyl-4-of 2-(1-(1-(7-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) benzamide,
5-methyl-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
5-methyl-6-(1-(6-(4-pyridyl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
5-methyl-6-(1-(6-(1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
2-(4-(1-(1-(5-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-base-1H-pyrazol-1-yl) second-1-alcohol,
The fluoro-4-of 2-(1-(1-(5-toluquinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate,
5-methyl-6-(1-(6-(3-quinolyl)-1H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylpiperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(piperazine-1-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl) methyl benzoate,
6-(1-(6-(1H-indoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-imidazo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-3-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(1H-indoles-5-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(isoquinoline 99.9-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-7-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-3-(1-methyl isophthalic acid of 5,7-bis-H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-quinolyl) ethyl)-3H-imidazo [4,5-b] pyrazine-5-ethyl formate,
The fluoro-3-of 7-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
3-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(also [4,5-b] pyrazinyl methyl of 6-(1-methyl isophthalic acid H-4-pyrazolyl)-[1,2,3] triazole) quinoline,
3-phenyl-6-(also [4,5-b] pyrazinyl methyl of 6-phenyl-[1,2,3] triazole) quinoline,
6-(also [4,5-b] pyrazinyl methyl of 6-(quinoline-3-yl)-[1,2,3] triazole)-[3,3 '] two quinoline,
3-(pyridin-4-yl)-6-(also [4,5-b] pyrazinyl methyl of 6-(pyridin-4-yl)-[1,2,3] triazole) quinoline,
The fluoro-4-of 2-(6-(6-(the fluoro-4-methoxycarbonyl of 3-phenyl)-1H-[1,2,3] also [4,5-b] pyrazinyl methyl of triazole) quinoline-3-yl) methyl benzoate,
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(6-(1-methyl isophthalic acid H-4-pyrazolyl)-also [4,5-b] pyrazinyl of [1,2,3] triazole) ethyl) quinoline,
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(1H-4-pyrazolyl)-[1,2,3] triazole) ethyl) quinoline,
2-(4-(3-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) pyrazolyl) ethanol,
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(pyridin-4-yl)-[1,2,3] triazole) ethyl) quinoline,
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(quinoline-3-yl)-[1,2,3] triazole) ethyl) quinoline,
The fluoro-6-of 7-(1-(also [4,5-b] pyrazinyl of 6-(isoquinoline 99.9-4-yl)-[1,2,3] triazole) ethyl)-3-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline,
The fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl)-6-(1-(also [4,5-b] pyrazinyl of 6-(4-methylthio group phenyl)-[1,2,3] triazole) ethyl) quinoline,
6-(1-(6-(benzo [b] thiene-3-yl-)-also [4,5-b] pyrazinyl of [1,2,3] triazole) ethyl) the fluoro-3-of-7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline,
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinolyl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) methyl benzoate,
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole)-N-methyl-benzamide,
The fluoro-4-(3-of 2-(1-(the fluoro-3-of 7-(1-methyl isophthalic acid H-4-pyrazolyl) quinoline-6-yl) ethyl)-3H-[1,2,3] also [4,5-b] pyrazine-5-yl of triazole) benzamide,
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-N-methyl-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzamide,
The fluoro-4-of 2-(1-(1-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzamide,
6-(1-(6-(benzo [b] thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
3-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-(6-(furans-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
3-(4-fluorophenyl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-imidazo [1,2,3] triazolos [4,5-b] pyrazine-1-yl) ethyl) quinoline,
6-(1-6-(1H-indoles-5-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-2-fluorophenyl carbamate,
The fluoro-6-of 5,7-bis-(1-(6-(isoquinoline 99.9-4-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(quinoline-7-yl)-1H-[1,2,3] triazolo [41,5-b] pyrazine-1-yl) ethyl) quinoline,
5-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-N, N-lutidine-2-amine,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(4-methylthio group phenyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl)-6-(1-(6-(thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(2-fluorine pyridin-3-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
3-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) pyridine-2-amine,
6-(1-(6-(benzo [b] thiophene-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
6-(1-(6-(benzo [b] thiene-3-yl-)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-5, the fluoro-3-of 7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
The fluoro-6-of 5,7-bis-(1-(6-(furans-2-yl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) the fluoro-N-methyl-benzamide of-2-,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) aniline,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) benzsulfamide,
4-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl)-2-fluorobenzamide,
5-(1-(1-(the fluoro-3-of 5,7-bis-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) thiophene-2-formonitrile HCN
Or the fluoro-N-methyl-4-of 2-(7-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-yl) benzamide.
The preparation method of 14. quinolines as shown in Equation 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrugs as described in claim 1～13 any one, it is characterized in that comprising the following steps: in solvent, Compound I I and boric acid or boric acid ester are carried out to Suzuki linked reaction, obtain compound 1;
Wherein, X is halogen; Wherein, the definition of Cy is as described in claim 1,5,6,7,8 or 11 any one; The definition of A is as described in claim 1～6 any one; The definition of L as claimed in claim 1; R 1, R 2, R 3and R 4definition as described in claim 1,5,6,7,8,9 or 10 any one.
15. preparation methods as claimed in claim 14, is characterized in that comprising the following steps: compound III is reacted with carboxylic acid or original carboxylic acid ester, obtain described Compound I I;
Wherein, the definition of Cy is as described in claim 1,5,6,7,8 or 11 any one; The definition of A is as described in claim 1～6 any one; The definition of L as claimed in claim 1; R 1, R 2, R 3and R 4definition as described in claim 1,5,6,7,8,9 or 10 any one.
16. preparation methods as claimed in claim 15, is characterized in that comprising the following steps: in solvent, compound V or its acid salt and compound IV are carried out to nucleophilic substitution reaction, obtain described compound III;
Wherein, the definition of Cy is as described in claim 1,5,6,7,8 or 11 any one; The definition of A is as described in claim 1～6 any one; The definition of L as claimed in claim 1; R 1, R 2, R 3and R 4definition as described in claim 1,5,6,7,8,9 or 10 any one.
17. 1 kinds suc as formula the compound shown in II, III or V,
Wherein, the definition of Cy is as described in claim 1,5,6,7,8 or 11 any one; The definition of A is as described in claim 1～6 any one; The definition of L as claimed in claim 1; R 1, R 2, R 3and R 4definition as described in claim 1,5,6,7,8,9 or 10 any one.
18. quinolines as shown in Equation 1, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrugs as described in claim 1～13 any one, for the preparation for the treatment of and/or preventing and application in the expression of Tyrosylprotein kinase C-Met or the medicine of active relevant disease.
19. 1 kinds of pharmaceutical compositions, it is characterized in that: contain the quinolines as shown in Equation 1 as described in claim 1～13 any one, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof or its prodrug for the treatment of significant quantity, and pharmaceutically acceptable one or more pharmaceutical excipients; Described treatment significant quantity is that quality percentage composition is 1%～99%; Described quality percentage composition is imidazopyrazines, its pharmacy acceptable salt, solvate, meta-bolites, metabolic precursor thereof and/or its prodrug as shown in Equation 1, accounts for the per-cent of pharmaceutical composition total mass; In described pharmaceutical composition, the quality percentage composition sum of each component is 100%.
20. pharmaceutical compositions as claimed in claim 19 are for the preparation for the treatment of and/or preventing and application in the medicine of the expression of Tyrosylprotein kinase C-Met or active relevant disease.
21. pharmaceutical compositions as claimed in claim 20, for the preparation for the treatment of and/or preventing and application in the medicine of the expression of Tyrosylprotein kinase C-Met or active relevant disease, is characterized in that: described comprises cancer, muscle skeleton sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours to expression or the active relevant disease of Tyrosylprotein kinase C-Met.
22. pharmaceutical compositions as claimed in claim 21, for the preparation for the treatment of and/or preventing and application in the medicine of the expression of Tyrosylprotein kinase C-Met or active relevant disease, is characterized in that: described cancer comprises bladder cancer, mammary cancer, cervical cancer, colorectal carcinoma, esophagus cancer, cancer of the stomach, head and neck cancer, kidney, lung cancer, liver cancer, nasopharyngeal carcinoma, ovarian cancer, carcinoma of the pancreas, prostate cancer and thyroid carcinoma; Described muscle skeleton sarcoma comprises: osteosarcoma, synovial sarcoma and rhabdosarcoma; Described soft tissue sarcoma comprises: malignant fibrous histiocytoma/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma; Described Hematopoietic Malignancies comprises: multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia and chronic myelocytic leukemia; Other described tumours comprise: glioblastoma multiforme, astrocytoma, melanoma, mesothelioma and embryonal carcinosarcoma.
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CN106928232B (en) * 2015-12-31 2019-07-09 上海医药集团股份有限公司 The crystal form of quinolines and its salt, preparation method, composition and application
CN106397218A (en) * 2016-09-04 2017-02-15 王际菊 S-alpha-cyclohexyl benzene methanamine
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CN114195710A (en) * 2021-12-20 2022-03-18 上海彩迩文生化科技有限公司 Preparation method of quinoline aminomethyl compound

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