CN107312009A - Quinolines, its preparation method, intermediate, pharmaceutical composition and application - Google Patents

Quinolines, its preparation method, intermediate, pharmaceutical composition and application Download PDF

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CN107312009A
CN107312009A CN201710587197.7A CN201710587197A CN107312009A CN 107312009 A CN107312009 A CN 107312009A CN 201710587197 A CN201710587197 A CN 201710587197A CN 107312009 A CN107312009 A CN 107312009A
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pyrazine
quinoline
ethyl
imidazos
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CN107312009B (en
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余建鑫
赵菲
郝宇
夏广新
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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

Abstract

The invention discloses quinolines, its preparation method, intermediate, pharmaceutical composition and application.The invention provides a kind of quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor thereof or its prodrug.The quinolines of the present invention have good inhibition to EGFR-TK C Met, can be used for preparing the medicine of the relevant a variety of diseases of prevention, expression or activity with C Met for the treatment of or auxiliary treatment, especially tumor disease.

Description

Quinolines, its preparation method, intermediate, pharmaceutical composition and application
The application is Application No. CN201410152877.2, and the applying date is 16 days 04 month, entitled " quinoline in 2014 The divisional application of the patent application of quinoline class compound, 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 encoded by C-Met proto-oncogenes, is hepatocyte growth factor receptor, with junket Histidine kinase activity, it is related to a variety of oncoproteins and regulatory protein, participate in cellular informatics conduction, the tune of cytoskeleton rearrangement Control, is cell propagation, differentiation and the key factor of motion.It is now recognized that generations and transfer close phase of the C-Met with a variety of cancers Close, research shows, many tumour patients have C-Met overexpressions and gene to expand in the generation of its tumour and transfer process Increase.The relation of C-Met activation and canceration is mainly manifested in：
1st, the activation mechanism of HGF (HGF) is relied on
There are many molecular mechanisms to activate C-Met in tumour cell, most common mode is by HGF and C-Met With reference to playing a role.HGF and C-Met, which is combined, causes receptor auto-phosphorylation, enhances the activity of C-Met EGFR-TKs, leads Cause the tyrosine phosphorylation of a variety of substrate proteins.Under physiological conditions, C-Met acceptors and the of short duration combinations of HGF play physiological effect, In tumor tissues high expression HGF and C-Met, formation positive feedback simultaneously, oncogenic indeterminate growth and invasion and attack behavior are led.It is this just Feedback is confirmed in the malignant tumours such as glioma, osteosarcoma, breast cancer.
2nd, the activation mechanism independent of HGF (HGF)
C-Met can be activated independent of HGF, the tumour particularly over-expressed in Met.The high expression of Met albumen It is probably the amplification, transcription enhancing or post-transcriptional mechanism due to C-Met genes.The C-Met genes that Cooper is cloned first are just It is the activation form after resetting, it is the promoter and the N-terminal of TPR gene orders and No. 7 chromosome Met sequences of No. 1 chromosome The mosaic gene of the C-terminal formation of row, the cytoplasm protein of this mosaic gene coding includes the leucine zipper region that TPR is encoded With met encode EGFR-TK area, due to the presence of leucine zipper region, cause Met kinases sustained activations, promote cell to Vicious transformation.It is abnormal due to transcription in colon cancer LOVO cell lines, Met be present in cell surface in the form of monomer and With lasting tyrosine kinase activity.In transfer Melanoma B16 cell system, due to the reduction of Intracellular phosphorylation enzyme, Met Albumen is unable to dephosphorylation and has continuous activity.The point mutation of Met genes can also cause Met kinases sustained activations.
Tyrosine kinase receptor C-Met is played during the signal transduction of the metabolism, differentiation and dead cell of cell Important effect, itself and ligand binding can activate its signal path, participate in embryonic development, tissue damage reparation and tumour Occurrence and development.Therefore, the antineoplastic using tyrosine kinase receptor C-Met as target spot is had become in tumor research very Active field, new method is provided for antineoplaston.
Small molecule C-Met tyrosine kinase inhibitors are mostly ATP competitive inhibitors, by blocking tyrosine phosphatase Change the effect for playing and suppressing C-Met kinases.This kind of compound is divided into selective and non-selective junket according to the selectivity to C-Met Histidine kinase inhibitor.It the advantage is that with cell permeability and preferable oral administration biaavailability.In August, 2011 FDA batches The crizotinib of quasi- listing is C-Met/ALK double inhibitor, and the non-small cell lung cancer being mutated to ALK is effective, body The characteristic of personalized treatment is showed.In November, 2012, Exelixis companies were announced, medicine cabozantinib (XL184) has been obtained FDA ratify for can not surgery excision pernicious Locally Advanced or metastatic medullary thyroid carcinoma (MTC) treatment. Cabozantinib is a kind of oral drugs, and antitumor work is played by targeted inhibition MET, VEGFR2 and RET signal path With it can kill tumour cell, reduce and shift and suppress angiogenesis.Although the C-Met inhibitor of current temporarily non-selectivity Class medicine is listed, but having developed many compounds has C-Met inhibitory activity at present, and can be improved because C-Met is different The disease often resulted in, this kind of compound has Johnson＆Johnson JNJ-38877605, Amgen AMG-458, Eisai's E-7050 and Pfizer PF-04217903.
The content of the invention
The technical problems to be solved by the invention there is provided it is a kind of with the entirely different quinolines of prior art, Its preparation method, intermediate, pharmaceutical composition and application.The quinolines of the present invention have good to EGFR-TK C-Met Good inhibition, can be used for a variety of diseases that preparation prevents, the expression or activity for the treatment of or auxiliary treatment with C-Met are relevant The medicine of disease, especially tumor disease.
The present inventor, by a large amount of arduous experimental studies a, it was found that class is selective to C-Met to be suppressed to make Quinoline derivatives, complete the present invention.
The invention provides a kind of quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, Metabolite, metabolic precursor thereof or its prodrug,
Wherein, X1、X2And X3C or N is each independently,Represent, work as X1During for C, X1With R1It is connected, works as X1For N When, with X1Connected R1It is not present；Also, work as X1During for C, X2And X3In one be C, another is N, R1It is that hydrogen or hydroxyl are (excellent Select hydrogen)；Work as X1During for N, X2For N, X3For C；It is preferred that, X1For C or N, X2For N, X3For C；
Cy is 3~8 yuan of cycloalkyl (preferably 3~6 yuan cycloalkyl, described " 3~6 yuan of cycloalkyl " preferably unsubstituted ring Propyl group), (preferably 3~6 circle heterocycles alkyl, described " 3~6 circle heterocycles alkyl " preferably hetero atom is nitrogen to 3~8 circle heterocycles alkyl Atom, hetero atom number is 1-2 5~6 circle heterocycles alkyl, and described " hetero atom is nitrogen-atoms, and hetero atom number is the 5 of 1-2 ~6 circle heterocycles alkyl " can be by C1-4Alkyl (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) is taken Generation；Described " hetero atom is nitrogen-atoms, and hetero atom number is 5~6 circle heterocycles alkyl of 1-2 " preferably piperazinyl, described " piperazine Piperazine base " preferably 4- piperazinyls；It is described that " hetero atom replaced by methyl is nitrogen-atoms, and hetero atom number is 5~6 yuan of 1-2 Heterocyclylalkyl " preferably N methyl piperazine base；Described " N methyl piperazine base " preferably N methyl piperazine -1- bases), 5~8 yuan of cyclenes (preferably 5~6 circle heterocycles alkenyls, described " 5~6 circle heterocycles alkenyl " preferably hetero atom is that nitrogen is former for base, 5~8 circle heterocycles alkenyls Son, hetero atom number are 5~6 circle heterocycles alkenyls of 1-2, described " hetero atom is nitrogen-atoms, hetero atom number is 1-2 5~ 6 circle heterocycles alkenyls " can by "Alkyl " replace (wherein, C1-4Alkyl such as methyl, ethyl, propyl group, isopropyl Base, butyl, isobutyl group or the tert-butyl group), or described " 5~6 circle heterocycles that hetero atom is nitrogen-atoms, hetero atom number is 1-2 The free nitrogen atom of alkenyl " can be into salt；Described " 5~6 circle heterocycles alkene that hetero atom is nitrogen-atoms, hetero atom number is 1-2 Base " preferably 1,2,3,6- tetrahydro pyridyls, described " 1,2,3,6- tetrahydro pyridyl " preferably 1,2,3,6- tetrahydropyridine -4- Base；Described " free nitrogen atom on 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 into salt " It is preferred that Described " quiltThe hetero atom that is replaced of alkyl be nitrogen-atoms, Hetero atom number is 5~6 circle heterocycles alkenyls of 1~2 " preferably), 6~10 yuan of aryl, 5~ 10 unit's heteroaryls or "Alkyl " (preferably C1-4Alkyl, described " C1-4Alkyl " for example methyl, ethyl, propyl group, Isopropyl, butyl, isobutyl group or the tert-butyl group)；Described 3~8 yuan of cycloalkyl, 3~8 circle heterocycles alkyl, 5~8 member cycloalkenyls, 5 ~8 circle heterocycles alkenyls, 6~10 yuan of aryl or 5~10 unit's heteroaryls can by 1~2 selected from halogen (such as fluorine, chlorine or bromine), Cyano group, R5、 Group replaced, Wherein R5And R6It is each independently C1-6Alkyl (preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, different Propyl group, butyl, isobutyl group or the tert-butyl group), halogen substitution C1-6Alkyl (the preferably C of halogen substitution1-4Alkyl, described " C1-4 Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group, described " halogen " such as fluorine, chlorine or Bromine), hydroxyl substitution C1-6Alkyl (the preferably C of hydroxyl substitution1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, third Base, isopropyl, butyl, isobutyl group or the tert-butyl group), 3~8 yuan of cycloalkyl, 3~8 circle heterocycles alkyl, 6~10 yuan of aryl (preferably Phenyl), halogen substitution 6~10 yuan of aryl (preferably halogen substitution phenyl, described " halogen " such as fluorine, chlorine or bromine；)、5 (preferably hetero atom is nitrogen-atoms to~10 unit's heteroaryls, and hetero atom number is 5~10 unit's heteroaryls of 1-2, described " hetero atom For nitrogen-atoms, hetero atom number is 5~10 unit's heteroaryls of 1-2 " preferred quinolyl) or halogen substitution 5~10 unit's heteroaryls (described " halogen " such as fluorine, chlorine or bromine；Described " 5~10 unit's heteroaryl " preferably hetero atom is nitrogen-atoms, and hetero atom number is 5~10 unit's heteroaryls of 1-2, described " hetero atom is nitrogen-atoms, and hetero atom number is 5~10 unit's heteroaryls of 1-2 " is excellent Select quinolyl)；
L is
R2、R3And R4It is each independently hydrogen, halogen (such as fluorine, chlorine or bromine) or C1-6Alkyl (preferably C1-4Alkyl, it is described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group)；It is preferred that R2And R3Independently of one another For hydrogen, fluorine or methyl, R4For hydrogen；Still further preferably work as R2During for hydrogen, R3For hydrogen, fluorine or methyl, R4For hydrogen；Work as R2During for fluorine, R3For fluorine, R4For hydrogen.
A is hydrogen, 6~10 yuan of aryl or 5~10 membered nitrogen-containing heteroaryl bases, described 6~10 yuan of aryl or 5~10 yuan of nitrogen-containing heteros Aryl can be selected from halogen (such as fluorine, chlorine or bromine), C by 1~21-6Alkyl (preferably C1-4Alkyl, described " C1-4Alkyl " is for example Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) and "Alkyl " (wherein, C1-6Alkyl is excellent Select C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) in base Group is replaced；
Work as X1For C, X2For N and X3During for C, A is preferably that (preferably nitrogen-atoms numbers are 1-2 for hydrogen or 5~10 membered nitrogen-containing heteroaryl bases 5~6 individual membered nitrogen-containing heteroaryl bases, described " hetero atom number is 5~6 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl), institute Stating 5~10 membered nitrogen-containing heteroaryl bases can be by C1-6Alkyl (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) Replaced；By the preferred 1- methyl isophthalic acids H- pyrazolyls of methyl substituted 5~10 membered nitrogen-containing heteroaryl base；
Work as X1For C, X2For C and X3During for N, A is preferably that (preferably nitrogen-atoms numbers are individual 5 of 1-2 to 5~10 membered nitrogen-containing heteroaryl bases ~6 membered nitrogen-containing heteroaryl bases, described " hetero atom number is 5~6 membered nitrogen-containing heteroaryl bases of 1-2 " preferably pyrazolyl), described 5~ 10 membered nitrogen-containing heteroaryl bases can be by C1-6Alkyl (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) is taken Generation；By the preferred 1- methyl isophthalic acids H- pyrazolyls of methyl substituted 5~10 membered nitrogen-containing heteroaryl base；
Work as X1For N, X2For N and X3During for C, A be preferably 6~10 yuan of aryl (preferred phenyl, described " phenyl " can by 1~ 2 selected from halogen (such as fluorine, chlorine or bromine, preferably fluorine) and "Alkyl " (wherein, C1-6Alkyl such as methyl, second Base, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group, preferably methyl) group replaced) or 5~10 membered nitrogen-containing heteroaryl bases (preferably nitrogen-atoms numbers are 1-2 5~10 membered nitrogen-containing heteroaryl bases, and described " nitrogen-atoms numbers are 5~10 yuan of nitrogen-containing heteros of 1-2 Aryl " preferably pyrazolyl, pyridine radicals or quinolyl), described 6~10 yuan of aryl or 5~10 membered nitrogen-containing heteroaryl bases can be by 1~2 It is individual to be selected from halogen (such as fluorine, chlorine or bromine), C1-6Alkyl (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or tertiary fourth Base) and "Alkyl " (wherein described " C1-6Alkyl " preferably methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base or the tert-butyl group) in group replace it is (preferred by 5~10 membered nitrogen-containing heteroaryl bases that methyl substituted nitrogen-atoms numbers are 1-2 1- methyl isophthalic acid H- pyrazolyls).
In the present invention, described quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, generation Product, metabolic precursor thereof or its prodrug are thanked, the quinolines chemical combination containing Imidazopyrazines structure preferably as shown in formula 1-a Thing, the quinolines containing triazole and pyrazine structure as shown in formula 1-b contain imidazo as shown in formula 1-c The quinolines of [1,2-b] [1,2,4] triazole structure,
In compound 1-a, Cy be selected from it is following a)~e) described in group, preferably Cy be selected from it is following a)~d) described in base Group, more preferably Cy for it is following d) described in group：
A) 3~6 yuan of cycloalkyl, described " 3~6 yuan of cycloalkyl " preferably cyclopropyl, further preferred cyclopropyl；
B) 3~6 circle heterocycles alkyl, described " 3~6 circle heterocycles alkyl " preferably hetero atom is that nitrogen-atoms, hetero atom number are 1 5~6 circle heterocycles alkyl of~2, " 5~6 circle heterocycles alkyl that hetero atom is nitrogen-atoms, hetero atom number is 1~2 " can By C1-4Alkyl (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) is replaced；Described " hetero atom For nitrogen-atoms, 5~6 circle heterocycles alkyl that hetero atom number is 1~2 " preferred piperazinyl, described " piperazinyl " preferably 4- piperazines Base；Described " 5~6 circle heterocycles alkyl that by the hetero atom that methyl is replaced be nitrogen-atoms, hetero atom number is 1~2 " are preferably N methyl piperazine base, described " N methyl piperazine base " preferably N methyl piperazine -1- bases；
C) 5~6 circle heterocycles alkenyls that 5~6 circle heterocycles alkenyl, preferably hetero atom are nitrogen-atoms, hetero atom number is 1~2, Described " 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 " can by "Alkyl " (wherein, C1-4Alkyl such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group) replaced, or it is described Free nitrogen atom on " 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 " can be into salt；Described " 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 " preferably 1,2,3,6- tetrahydropyridine -4- basesDescribed " the nomadic nitrogen original on 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 Son is into salt " preferablyDescribed " quiltThe hetero atom that is replaced of alkyl For nitrogen-atoms, 5~6 circle heterocycles alkenyls that hetero atom number is 1~2 " preferably
D) 6~10 yuan of aryl or 5~10 unit's heteroaryls；Described " 6~10 yuan of aryl " preferably phenyl or naphthyl is (described " naphthyl " preferably 1- naphthyls)；Described " 5~10 unit's heteroaryl " preferably hetero atom is N, O or S atom, hetero atom number are 1~2 Individual monocyclic or condensed ring 5~10 unit's heteroaryls, the described " list that hetero atom is N, O or S atom, hetero atom number is 1~2 The unit's heteroaryl of ring 5~10 " preferably pyrazolyl (described " pyrazolyl " preferably 1H- pyrazoles -4- bases or 1H- pyrazoles -5- bases), pyridine Base (described " pyridine radicals " preferably pyridin-4-yl or pyridin-3-yl), thienyl (described " thienyl " preferably thiene-3-yl Or thiophene -2- bases), pyrimidine radicals (described " pyrimidine radicals " preferably pyrimidine -5- bases) or furyl (described " furyl " preferably furan Mutter -3- bases)；Described " unit's heteroaryl of condensed ring 5~10 that hetero atom is N, O or S atom, hetero atom number is 1~2 " preferably quinoline Quinoline base (described " quinolyl " preferably quinolyl-4, quinoline -3- bases or quinoline -7- bases), isoquinolyl (described " isoquinolin Base " preferably isoquinolin -4- bases), benzothienyl (described " benzothienyl " preferably benzothiophene -3- bases or benzothiophene - 2- yls), indyl (described " indyl " preferably indol-3-yl, indoles -4- bases or indoles -5- bases) or pyrrolopyridinyl (described " pyrrolopyridinyl " preferably 1H- pyrrolo- [2,3-b] pyridine -5- bases)；
6~10 yuan of aryl or 5~10 unit's heteroaryls can by 1~2 selected from halogen (such as fluorine, chlorine or bromine), cyano group, R5、(preferably N, N- dimethylamino), (preferably)、(preferably)、(preferably) group institute Substitution, wherein R5、R6It is each independently C1-6Alkyl (preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, third Base, isopropyl, butyl, isobutyl group or the tert-butyl group), halogen substitution C1-6Alkyl (described " the C of halogen substitution1-6In alkyl " Described " C1-6Alkyl " preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base or the tert-butyl group；Described " the C of halogen substitution1-6" halogen " preferably fluorine, chlorine or bromine described in alkyl "；It is described that " halogen takes The C in generation1-6Alkyl " preferably trifluoromethyl), hydroxyl substitution C1-6Alkyl (described " the C of hydroxyl substitution1-6Described in alkyl " “C1-6Alkyl " preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or uncle Butyl；Described " the C of hydroxyl substitution1-6Alkyl " is preferably), 6~10 yuan of aryl (preferably phenyl), halogens substitution 6~10 yuan of aryl (" 6~10 yuan of aryl " preferably phenyl described in described " 6~10 yuan of aryl of halogen substitution ", it is described 6~10 yuan of aryl of substitution " halogen " described in " halogen " preferably fluorine, chlorine or bromine), 5~10 unit's heteroaryls (preferably miscellaneous original 5~10 unit's heteroaryls that son is nitrogen-atoms, hetero atom number is 1~2, described " hetero atom is that nitrogen-atoms, hetero atom number are 1 5~10 unit's heteroaryls of~2 " preferably quinolyl) or halogen substitution 5~10 unit's heteroaryls (described " the 5 of halogen substitution " 5~10 unit's heteroaryl " preferred hetero atom described in~10 unit's heteroaryls " is nitrogen-atoms, hetero atom number is 1~2 5~ 10 unit's heteroaryls, described " 5~10 unit's heteroaryls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 " preferably halogen substitution Quinolyl；" halogen " preferably fluorine, chlorine or bromine described in described " 5~10 unit's heteroaryls of halogen substitution "；Described " halogen 5~10 unit's heteroaryls of element substitution " are preferably)；Described substituent can be with identical or different.
e)“Alkyl " (wherein, C1-6The preferred C of alkyl1-4Alkyl, described " C1-6Alkyl " such as methyl, Ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group, preferably methyl)；
L is
R1For hydrogen or hydroxyl, preferably H；
R2And R3It is each independently H, F or methyl, R4For H；Preferably, R is worked as2During for H, R3For H, F or methyl, R4For H； Work as R2During for F, R3For F, R4For H；
A is H or 5 membered nitrogen-containing heteroaryl bases (5~6 membered nitrogen-containing heteroaryl bases that preferably nitrogen-atoms numbers are 1-2, described " miscellaneous original Subnumber is 5~6 membered nitrogen-containing heteroaryl bases of 1-2 " preferred pyrazolyl), the 5 membered nitrogen-containing heteroaryl base can be by C1-4Alkyl is replaced (such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group are individual 5 of 1-2 by methyl substituted nitrogen-atoms numbers The preferred 1- methyl isophthalic acids H- pyrazolyls of~6 membered nitrogen-containing heteroaryl bases；)；A is preferably H.
In compound 1-b, Cy is 6~10 yuan of aryl or 5~10 unit's heteroaryls；Described " 6~10 yuan of aryl " preferably benzene Base；Described " 5~10 unit's heteroaryl " the monocyclic or condensed ring that preferably hetero atom is N, O or S atom, hetero atom number are 1~2 5~10 unit's heteroaryls, described " monocyclic 5~10 unit's heteroaryl that hetero atom is N, O or S atom, hetero atom number are 1~2 " It is preferred that pyrazolyl (described " pyrazolyl " preferably 1H- pyrazoles -4- bases), pyridine radicals (described " pyridine radicals " preferably pyridin-4-yl Or pyridin-3-yl), thienyl (described " thienyl " preferably thiene-3-yl or thiophene -2- bases) or furyl (described " furan Mutter base " preferred furans -2- bases)；It is described that " 5~10 yuan of the condensed ring that hetero atom is N, O or S atom, hetero atom number is 1~2 is miscellaneous Aryl " preferably quinolyl (described " quinolyl " preferably quinoline -3- bases or quinoline -7- bases), isoquinolyl (described " isoquinoline Quinoline base " preferably isoquinolin -4- bases), benzothienyl (described " benzothienyl " preferably benzothiophene -3- bases or benzo thiophene Fen -2- bases) or indyl (described " indyl " preferably indoles -5- bases)；
6~10 yuan of aryl or 5~10 unit's heteroaryls can by 1~2 selected from halogen (such as fluorine, chlorine or bromine), cyano group, R5、(preferably N, N- dimethylamino),(preferably)、 (preferably)、Group replaced, wherein R5、R6It is each independent Ground is C1-6Alkyl (preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group Or the tert-butyl group, preferred methyl) or hydroxyl substitution C1-6Alkyl (described " the C of hydroxyl substitution1-6" C described in alkyl "1-6Alkane Base " preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group； Described " the C of hydroxyl substitution1-6Alkyl " is preferably)；
L is
R2、R3It is each independently H or F, R4For 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 (preferably nitrogen-atoms numbers are 5~10 membered nitrogen-containing heteroaryl bases of 1~2 to membered nitrogen-containing heteroaryl base, and described " nitrogen-atoms numbers are 1~2 5~10 membered nitrogen-containing heteroaryl bases " preferably pyridine radicals, pyrazolyl or quinolyl) can by 1~2 selected from halogen (such as fluorine, chlorine or Bromine), C1-6Alkyl (preferably C1-4Alkyl, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group Or the tert-butyl group, by the preferred 1- methyl isophthalic acids H- pyrazoles -4- of 5~6 membered nitrogen-containing heteroaryl bases that methyl substituted nitrogen-atoms numbers are 1-2 Base；) and "Alkyl " (wherein, C1-6The preferred C of alkyl1-4Alkyl, described " C1-6Alkyl " for example methyl, ethyl, Propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group, preferably methyl) group replaced.
In compound 1-c, Cy is phenyl, and the phenyl can be selected from halogen (such as fluorine, chlorine or bromine, preferably fluorine) by 1~2 "Alkyl " (wherein, described " C1-4Alkyl " such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group Or the tert-butyl group, preferred methyl) group replaced；It is described " by 1~2 selected from halogen and "Alkyl " base The replaced phenyl of group " preferably 3- fluoro- 4- (N- methylcarbamoyls) -1- phenyl；
L is
R1、R2、R3、R4It is H；
A is 1- methyl isophthalic acid H- pyrazoles -4- bases.
In the present invention, when L isWhen, the asymmetric carbon atom in L can be R configurations, S configurations or racemic configuration.
In the present invention, when Cy is 6~10 yuan of aryl, the further preferred phenyl of described " 6~10 yuan of aryl ", The chloro- phenyl of 2- fluoro-phenyls, 2-, the chloro- phenyl of 3-, 2- trifluoromethyl-phenyls, 4- trifluoromethyls, 3,4- dichloro-benzenes Base, 4- Trifluoromethoxyphen-ls, 3- cvano-phenyls, 4- cyano-phenyls, 3-N, N- dimethylaminophenyls, 4- aminophenyls, 2, 4- dimethoxy-phenylfs, 2,6- dimethoxy-phenylfs, 2,6- Dimethvl-phenyls, 2- methyl -4- methoxyl groups-phenyl, 2- first Base -5- methoxyphenyls, 4- methyl mercaptos-phenyl,
In the present invention, when Cy is 5~10 unit's heteroaryl, described " 5~10 unit's heteroaryl " is further preferably：Thiophene Fen -2- bases, thiene-3-yl, furans -2- bases, pyridin-3-yl, pyridin-4-yl, PA -3- bases, 2- fluorine pyridines -3- Base, PA -5- bases, 2- picoline -5- bases, indoles -4- bases, indoles -5- bases, quinoline -7- bases, isoquinolin -4- bases, 5- cyano thiophene -2- bases,
In the present invention, quinolines, its pharmaceutically acceptable salt, solvate, metabolite shown in formula 1, Metabolic precursor thereof or the further preferred any compound as described below of its prodrug：
6- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1)-methylene)-quinoline (1- 1)、
6- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-2),
6- (6- (pyridin-4-yl) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-3),
6- (6- (4- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- methylene) quinoline (1-4),
4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazoles -6- bases)-aniline (1-5),
6- (6- (4- Trifluoromethoxyphen-ls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-6),
6- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-7),
The chloro- 4- of 7- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases) quinoline (1-8),
N, N- dimethyl -3- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases)-aniline (1-9),
6- (6- (4- methoxyl group -2- methyl-l- phenyl) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1- 10)、
6- (6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-11),
6- (6- (1,2,3,6- tetrahydropyridine -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline hydrochloric acid Salt (1-12),
4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases) -3,6- dihydropyridines -1 (2H)-first Acetoacetic ester (1-13),
6- (6- (2,6- Dimethoxyphenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-14),
6- (6- (2,4- Dimethoxyphenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-15),
3- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene) quinoline (1-16),
6- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline (1-17),
2- (4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyrazol-1-yl)-ethanol (1- 18)、
6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 19)、
6- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-20),
6- (1- (6- (4- (trifluoromethyl) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-21),
6- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-22),
6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 23)、
6- (1- (6- (4- methoxyl group -2- aminomethyl phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 24)、
N, N- dimethyl -3- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline (1- 25)、
6- (1- (6- (1,2,3,6- tetrahydropyridine -1--4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline -1- chlorides (1-26),
2- (4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazol-1-yls) Ethanol (1-27),
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-28),
6- (1- (6- (2,6- 3,5-dimethylphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-29),
The fluoro- 4- of 2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) methyl benzoate (1- 30)、
6- (1- (6- (4- (methyl mercapto) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-31),
6- (1- (6- (thiene-3-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-32),
6- (1- (6- (benzo [b] thiophene -2- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-33),
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzsulfamide (1-34),
6- (1- (6- (pyrimidine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-35),
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -2- formaldehyde (1-36),
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile (1-37),
6- (1- (6- (6- picoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-38),
6- (1- (6- (1H- pyrrolo-es [2,3-b] pyridine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline Quinoline (1-39),
N, N- dimethyl -5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- Amine (1-40),
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -3- formaldehyde (1-41),
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyrimidine -2- amine (1-42),
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- amine (1-43),
(5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -3- bases) methanol (1- 44)、
3- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- amine (1-45),
The fluoro- 4- of 2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzamide (1- 46)、
The fluoro- 4- of N- ethyls -2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzoyl Amine (1-47),
The fluoro- N- methyl -4- of 2- (1- (1- quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzoyl Amine (1-48),
6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -2- Alcohol (1-49),
The fluoro- 6- of 8- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline (1-50)、
The fluoro- 6- of 8- ((6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline (1-51),
The fluoro- 6- of 8- ((6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline (1-52),
2- (4- (1- ((8- fluorine quinoline -6- bases) methyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazoles -1- Base) ethanol (1-53),
6- ((6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -8- fluorine quinoline (1-54),
The fluoro- 6- of 8- ((6- (3- quinolyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl)-quinoline (1-55),
The fluoro- 6- of 8- ((6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl)-quinoline (1-56),
Fluoro- (6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinolines of 8- Quinoline (1-57),
The fluoro- 6- of 8- (1- (6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline Quinoline (1-58),
The fluoro- 6- of 8- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-59),
The fluoro- 6- of 8- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-60),
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline (1- 61)、
The fluoro- 6- of 8- (1- (6- (3- quinolyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-62),
6- (1- (6- (3,4- dichlorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline (1- 63), 6- (1- (6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline (1-64),
6- (1- (6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline (1- 65)、
The fluoro- 6- of 8- (1- (6- (2- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 66)、
The fluoro- 6- of 8- (1- (6- (4- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 67)、
The fluoro- 6- of 8- (1- (6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-68),
6- [6- (1- methyl isophthalic acid H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene]-quinoline (1-69),
2- (4- (1- (the fluoro- quinoline -6- methylene of 7-) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazoles -1- Base)-ethanol (1-70),
6- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene) -7- fluorine quinoline (1-71),
The fluoro- 6- of 7- (6- phenyl imidazoles simultaneously [4,5-b] pyrazine -1- methylene)-quinoline (1-72),
The fluoro- 6- of 7- (6- (pyridin-4-yl)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1-73),
(3- (1- (the fluoro- quinoline -6- methylene of 7-) -1H- imidazos [4,5-b] pyrazine -6- bases)-phenyl)-N, N- diformazans Base amine (1-74),
The fluoro- 6- of 7- (6- (4- methoxyl group -2- methylphenyls)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1- 75)、
The fluoro- 6- of 7- (6- (quinoline -3- bases)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1-76),
4- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases)-aniline (1-77),
6- ((5- (the chloro- 4- quinolyls of 7-) imidazo [4,5-b] pyrazine -3- bases) methylene) fluoro- quinoline of -7- (1-78),
The chloro- 4'- of 7- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases)-[4,7'] double quinolines Quinoline (1-79),
4- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases) -3,6- dihydro -2H- pyrroles Pyridine -1- carboxylic acid tert-butyl esters (1-80),
The fluoro- 6- of 7- [6- (1,2,3,6- Tetrahydro-pyridine -4- bases)-imidazo [4,5-b] pyrazine -1- methylene]-quinolinium Hydrochlorate (1-81),
The fluoro- 6- of 7- (6- (2- fluoro-phenyls)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1-82),
The fluoro- 6- of 7- (6- (pyridin-3-yl)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1-83),
6- (6- (3- chlorphenyls)-imidazo [4,5-b] pyrazine -1- methylene) fluoro- quinoline of -7- (1-84),
The fluoro- 6- of 7- (6- (naphthalene -1- bases)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (1-85),
6- (6- cyclopropyl-imidazo [4,5-b] pyrazine -1- methylene) fluoro- quinoline of -7- (1-86),
The fluoro- 6- of 7- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H-- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline Quinoline (1-87),
4- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline (1-88),
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -7- fluorine quinoline (1- 89)、
The fluoro- 6- of 7- (1- (6- phenyl imidazoles simultaneously [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-90),
The fluoro- 6- of 7- (1- (6- (pyridin-4-yl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-91),
2- (4- (1- (1- (7- fluorine quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazoles -1- Base)-ethanol (1-92),
The fluoro- 6- of 7- (1- (6- (quinoline -3- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-93),
The fluoro- 4- of 2- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-benzoic acid Methyl esters (1-94),
The fluoro- 4- of 2- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-benzoyl Amine (1-95),
The fluoro- 4- of 2- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N- methyl Benzamide (1-96),
4- (1- (1- (base of 7- fluorine quinoline -6)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-benzsulfamide (1- 97)、
The fluoro- 6- of 7- (1- (6- (pyrimidine -5- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-98),
4- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-furans -2- methanol (1-99)、
4- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -3H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile (1- 100)、
The fluoro- 6- of 7- (1- (6- (thiophene -2- bases) imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-101),
The fluoro- 6- of 7- (1- (6- (thiene-3-yl) imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1-102),
6- (1- (6- (benzo [b] thiophene -2- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine quinoline (1- 103)、
6- (1- (6- (benzo [b] thiene-3-yl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine quinoline (1- 104)、
The fluoro- 6- of 7- (1- (6- (4- methyl mercaptos phenyl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline (1- 105)、
6- (1- (6- (1H- pyrroles [2,3-b] pyridine -5- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine Quinoline (1-106),
5- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N, N- dimethyl Pyridine -2- amine (1-107),
The fluoro- 6- of 7- (1- (6- (6- methvl-pyridinium -3- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline； (1-108)、
3- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyridine -2- amine (1-109)、
5- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyridine -2- amine (1-110)、
5,7 2 fluoro- 6- ((6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinolines Quinoline (1-111),
6- ((6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines (1-112)、
The fluoro- 6- of 5,7- bis- ((6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline (1-113),
6- ((6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines (1-114)、
The fluoro- 6- of 5,7- bis- ((6- (4- (trifluoro methoxy) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline (1-115)、
4- (1- ((5,7- difluoro-quinoline -6- bases) methyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -2- fluobenzoic acids Methyl esters (1-116),
6- ((6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines (1- 117)、
5,7 2 fluoro- 6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline (1-118),
The fluoro- 6- of 5,7- bis- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-119),
The fluoro- 6- of 5,7- bis- (1- (6- (pyridin-4-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 120)、
3- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N, N- diformazans Base aniline (1-121),
The fluoro- 6- of 5,7- bis- (1- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 122)、
6- (1- (6- (2,6- 3,5-dimethylphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-123)、
6- (1- (6- (3- chlorphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1- 124)、
6- (1- (6- cyclopropyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-125),
2- (4- (1- (1- (5,7-difluoro-quinoline-6- bases) ethyl)-1H- imidazos [4,5-b] pyrazine-6- bases)-1H- pyrroles Azoles -1- bases) second -1- alcohol (1-126),
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline (1- 127)、
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-128)、
6- (1- (6- (7- chloroquinoline -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-129)、
The fluoro- 6- of 5,7- bis- (1- (6- (pyridin-3-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline (1- 130)、
The fluoro- 6- of 5,7- bis- (1- (6- (5- methoxyl group -2- aminomethyl phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base)-quinoline (1-131),
The fluoro- 6- of 5,7- bis- (1- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline (1- 132)、
6- (1- (6- (3- chlorphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1- 133)、
6- (1- (6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-134)、
The fluoro- 6- of 5,7- bis- (1- (6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-135),
6- (1- (6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines (1-136)、
The fluoro- 6- of 5,7- bis- (1- (6- (4- trifluoromethoxy benzaldehydes base) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-137)、
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -2- fluorobenzene first Sour methyl esters (1-138),
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) fluoro- N- first of -2- Yl-benzamide (1-139),
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) fluoro- benzene first of -2- Acid amides (1-140),
The fluoro- 6- of 5,7- bis- (1- (6- (4- first sulfur phenenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 141)、
The fluoro- 6- of 5,7- bis- (1- (6- (1- (benzenesulfonyl) -1H- indol-3-yls) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (1-142),
6- (1- (6- (benzo [b] thiophene -2- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro quinolines Quinoline (1-143),
The fluoro- 6- of 5,7- bis- (1- (6- (pyrimidine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 144)、
The fluoro- 6- of 5,7- bis- (1- (6- (3- thienyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 145)、
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile (1- 146)、
7- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline (1-147),
7- methyl -6- (1- (6- (3- quinolyls) -1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline (1-148),
N, N- dimethyl -3- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) Aniline (1-149),
7- methyl -6- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-150),
6- (1- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -7- methylquinolines (1-151),
The fluoro- 4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzoic acid Methyl esters (1-152),
The fluoro- 4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzoyl Amine (1-153),
The fluoro- N- methyl -4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) Benzamide (1-154),
5- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline (1-155),
5- methyl -6- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-156),
5- methyl -6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 157)、
2- (4- (1- (1- (5- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- base -1H- pyrazoles - 1- yls) second -1- alcohol (1-158),
The fluoro- 4- of 2- (1- (1- (5- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzoic acid Methyl esters (1-159),
5- methyl -6- (1- (6- (3- quinolyls) -1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline (1-160),
3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (4- methylpiperazine-1-yls) -1H- imidazos [4,5-b] pyrroles Piperazine -1- bases) ethyl) quinoline (1-161),
3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (piperazine -1- bases) -1H- imidazos [4,5-b] pyrazines -1- Base) ethyl) quinoline (1-162),
The fluoro- 4- of 2- (1- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] Pyrazine -6- bases) methyl benzoate (1-163),
6- (1- (6- (1H- indoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) fluoro- 3- (1- of -5,7- two Methyl isophthalic acid H- pyrazoles -4- bases) quinoline (1-164),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- imidazos [4, 5-b] pyrazine -6- bases) -2- fluorophenyl carbamates (1-165),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] Pyrazine -1- bases) ethyl) quinoline (1-166),
6- (1- (6- (1H- indoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) fluoro- 3- (1- of -5,7- two Methyl isophthalic acid H- pyrazoles -4- bases) quinoline (1-167),
The fluoro- 6- of 5,7- bis- (1- (6- (isoquinolin -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -3- (1- Methyl isophthalic acid H- pyrazoles -4- bases) quinoline (1-168),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (quinoline -7- bases) -1H- imidazos [4,5-b] Pyrazine -1- bases) ethyl) quinoline (1-169),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- miaows Azoles simultaneously [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-170),
3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) -3H- imidazos [4,5-b] pyrrole Piperazine -5- Ethyl formates (1-171),
The fluoro- 3- of 7- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-172),
3- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (6- (1- methyl isophthalic acid H-4- pyrazolyls)-[1,2,3] triazole simultaneously [4,5- B] pyrazinyl-methyl) quinoline (2-1),
3- phenyl -6- (6- phenyl-[1,2,3] triazole simultaneously [4,5-b] pyrazinyl-methyl) quinoline (2-2),
6- (6- (quinoline -3- bases)-[1,2,3] triazole simultaneously [4,5-b] pyrazinyl-methyl)-[3,3 '] two quinoline (2-3),
3- (pyridin-4-yl) -6- (6- (pyridin-4-yl)-[1,2,3] triazole simultaneously [4,5-b] pyrazinyl-methyl) quinoline (2-4)、
The fluoro- 4- of 2- (6- (6- (the fluoro- 4- methoxycarbonyl groups phenyl of 3-) -1H- [1,2,3] triazole simultaneously [4,5-b] pyrazinyl first Base) quinoline -3- bases) methyl benzoate (2-5),
The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (1- methyl isophthalic acid H-4- pyrazolyls)-[1,2,3] three nitrogen Azoles simultaneously [4,5-b] pyrazinyl) ethyl) quinoline (2-6),
The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (1H-4- pyrazolyls)-[1,2,3] triazole simultaneously [4, 5-b] pyrazinyl) ethyl) quinoline (2-7),
2- (4- (the nitrogen of 3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) quinoline -6- bases) ethyl) -3H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -5- bases) pyrazolyl) ethanol (2-8),
The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (pyridin-4-yl)-[1,2,3] triazole simultaneously [4,5- B] pyrazinyl) ethyl) quinoline (2-9),
The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (quinoline -3- bases)-[1,2,3] triazole simultaneously [4,5- B] pyrazinyl) ethyl) quinoline (2-10),
The fluoro- 6- of 7- (1- (6- (isoquinolin -4- bases)-[1,2,3] triazole simultaneously [4,5-b] pyrazinyl) ethyl) -3- (1- first Base -1H-4- pyrazolyls) quinoline (2-11),
The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (4- methyl mercaptos phenyl)-[1,2,3] triazole simultaneously [4, 5-b] pyrazinyl) ethyl) quinoline (2-12),
6- (1- (6- (benzo [b] thiene-3-yl)-[1,2,3] triazole simultaneously [4,5-b] pyrazinyl) ethyl) the fluoro- 3- of -7- (1- methyl isophthalic acid H-4- pyrazolyls) quinoline (2-13),
The fluoro- 4- of the 2- (nitrogen of 3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) quinolyl) ethyl) -3H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -5- bases) methyl benzoate (2-14),
The fluoro- 4- of 2- (3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) quinoline -6- bases) ethyl) -3H- [1,2,3] three Nitrogen azoles simultaneously [4,5-b] pyrazine -5- bases)-N-methyl-benzamide (2-15),
The fluoro- 4- of 2- (3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) quinoline -6- bases) ethyl) -3H- [1,2,3] three Nitrogen azoles simultaneously [4,5-b] pyrazine -5- bases) benzamide (2-16),
3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazoles And [4,5-b] pyrazine -1- bases) ethyl) quinoline (2-17),
The fluoro- N- methyl -4- of 2- (1- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2, 3] triazol [4,5-b] pyrazine -6- bases) benzamide (2-18),
The fluoro- 4- of 2- (1- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] triazols [4,5-b] pyrazine -6- bases) benzamide (2-19),
6- (1- (6- (benzo [b] thiene-3-yl) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-20),
6- (1- (6- (benzo [b] thiophene -2- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-21),
3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (thiene-3-yl) -1H- [1,2,3] triazol [4,5-b] pyrroles Piperazine -1- bases) ethyl) quinoline (2-22),
6- (1- (6- (furans -2- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -3- (1- methyl - 1H- pyrazoles -4- bases) quinoline (2-23),
3- (4- fluorophenyls) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrroles Piperazine -1- bases) ethyl) quinoline (2-24),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- miaows Azoles simultaneously [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) quinoline (2-25),
6- (1-6- (1H- indoles -5- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5,7- two Fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-26),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) -2- fluorophenyl carbamates (2-27),
The fluoro- 6- of 5,7- bis- (1- (6- (isoquinolin -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) second Base) -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-28),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (quinoline -7- bases) -1H- [1,2,3] triazols [41,5-b] pyrazine -1- bases) ethyl) quinoline (2-29),
5- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases)-N, N- lutidines -2- amine (2-30),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (4- methyl mercaptos phenyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -1- bases) ethyl) quinoline (2-31),
The fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (thiene-3-yl) -1H- [1,2,3] triazols [4,5-b] pyrazine -1- bases) ethyl) quinoline (2-32),
The fluoro- 6- of 5,7- bis- (1- (6- (2- fluorine pyridin-3-yl) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) second Base) -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-33),
3- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) pyridine -2- amine (2-34),
6- (1- (6- (benzo [b] thiophene -2- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5, The fluoro- 3- of 7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-35),
6- (1- (6- (benzo [b] thiene-3-yl) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5, The fluoro- 3- of 7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-36),
The fluoro- 6- of 5,7- bis- (1- (6- (furans -2- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) - 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (2-37),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) the fluoro- N-methyl-benzamides of -2- (2-38),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) aniline (2-39),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) benzsulfamide (2-40),
4- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) -2- fluorobenzamides (2-41),
5- (1- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- [1,2,3] three Azoles simultaneously [4,5-b] pyrazine -6- bases) thiophene -2- formonitrile HCNs (2-42),
Or the fluoro- N- methyl -4- of 2- (7- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- ylmethyls) imidazo [1, 2-b] [1,2,4] triazine -2- bases) benzamide (3-1).
Present invention also offers described quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvation Thing, metabolite, the preparation method of metabolic precursor thereof or its prodrug, it comprises the following steps：In a solvent, by compound II Suzuki coupling reactions are carried out with boric acid or borate, compound 1 is obtained；
Wherein, X is halogen (preferably chlorine, bromine or iodine)；Cy、X1、X2、X3、R1、R2、R3、R4, the same institute of L and A definition State.
The method of prepare compound 1, be in the conventional method that Suzuki coupling reactions are carried out in this area, the present invention especially It is preferred that following reaction conditions：
In the method for prepare compound 1, the preferred water of described solvent and/or water-miscible organic solvent；Described is water-soluble One or more in the preferred dioxane of property organic solvent, tetrahydrofuran and N,N-dimethylformamide (DMF).
In the method for prepare compound 1, described solvent and compound II volume mass than preferred 100mL/g~ 500mL/g, further preferred 200mL/g~400mL/g.
In the method for prepare compound 1, described boric acid or the preferred compound as shown in Equation 6 of borateWherein R17For hydrogen, C1-6Alkyl orWherein C2-C6Represent alkylidene；When p is 1, R17ForWhen p is 2, R17For hydrogen or C1-6Alkyl.
In the method for prepare compound 1, the mol ratio preferably 1 of described compound II and boric acid or borate:1~1: 3, further preferred 1:1.2~1:1.8.
In the method for prepare compound 1, the temperature of described Suzuki coupling reactions can the freezing point from solvent to The temperature of change, preferably 90 DEG C~150 DEG C, further preferred 100 DEG C~120 DEG C in the boiling point temperature range of solvent.
In the method for prepare compound 1, the process of described Suzuki coupling reactions can use conventional in this area Method of testing (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) is determined, is disappeared with compound II For reaction end, preferred reaction time 2h~10h, further preferred 2.5h~4h.
In the method for prepare compound 1, described compound II can be prepared by following methods, and it includes following step Suddenly：Compound III is reacted with carboxylic acid or original carboxylic acid ester, compound II is obtained；
Compound 1 is made in method according still further to described prepare compound 1；Wherein, X, Cy, X1、X2、X3、R1、R2、 R3、R4, L and A definition be the same as those described above.
Prepare compound II method, be in the conventional method that such reaction is carried out in this area, the present invention particularly preferably Following reaction conditions：
In prepare compound II method, described carboxylic acid or original carboxylic acid ester had both done reaction reagent or had done reaction dissolvent.
In prepare compound II method, the described preferred original acid A ester of carboxylic acid or original carboxylic acid ester, ethyl orthoformate With the one or more in diethoxy methyl acetate.
In prepare compound II method, described carboxylic acid or original carboxylic acid ester and compound III volume mass are than excellent 20mL/g~100mL/g is selected, further excellent 40mL/g~80mL/g.
In prepare compound II method, the temperature of described reaction can be from the freezing point of solvent to the boiling point of solvent The temperature of change, preferably 120 DEG C~180 DEG C, further preferred 140 DEG C~160 DEG C in temperature range.
In prepare compound II method, the process of described reaction can use traditional test methods in this area (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) is determined, is disappeared with compound III for reaction Terminal, preferred reaction time 15h~30h, further preferred 20h~25h.
In prepare compound II method, described compound III can be prepared by following methods, and it includes following Step：In a solvent, compound V or its acid salt are subjected to nucleophilic substitution with compound IV, obtain compound III；
Method according still further to described prepare compound II is made compound II, the method system of described prepare compound 1 Obtain compound 1；Wherein, X, X1、X2、X3、R2、R3、R4, L and A definition it is same as above.
Prepare compound III method, in being the conventional method that such nucleophilic substitution is carried out in this area, the present invention Particularly preferred following reaction conditions：
In prepare compound III method, the preferred boiling point of described solvent is more than 130 DEG C of solvent, further preferably One or more in N,N-dimethylformamide (DMF), N, N- diethylformamides (DEF) and 1-METHYLPYRROLIDONE
In prepare compound III method, described solvent and compound IV volume mass than preferred 10mL/g~ 50mL/g, further preferred 20mL/g~30mL/g.
In prepare compound III method, described compound V and compound IV mol ratio preferably 1：1~1:3, Further preferred 1：1.2~1:1.6.
In prepare compound III method, the temperature of described reaction can be from the freezing point of solvent to the boiling of solvent The temperature of change, preferably 150 DEG C~250 DEG C, further preferred 190 DEG C~210 DEG C in point temperature range.
In prepare compound III method, the process of described reaction can use traditional test methods in this area (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) is determined, is disappeared with compound IV for reaction eventually Point, preferred reaction time 20h~30h, further preferred 18h~25h.
The preparation of compound can be related to the protection and deprotection of multiple chemical groups.For the need protected and be deprotected Will, and the selection of appropriate protection group can readily be determined by those skilled in the art, the chemical mistake of protection group Journey is in such as Greene et al., Protective Groups in Organic Synthesis, the second edition, Wiley＆Sons, 1991, in find, it is incorporated herein by reference in the form of overall herein.
In prepare compound III method, described compound V can use method 1 or method 2, when L is When be preferred to use method 1, when L isWhen, it is preferred to use method 2；
Method 1：In organic solvent, compound VI and hydrogen are subjected to reduction reaction and obtain compound V；
Method according still further to described prepare compound III is made compound III, described prepare compound II method Compound II is made, compound 1 is made in the method for described prepare compound 1；Wherein, X, R2、R3、R4, L and A definition It is same as above.
Method 2：In organic solvent, compound VIII and hydrogen are subjected to reduction reaction and obtain compound V；
Method according still further to described prepare compound III is made compound III, described prepare compound II method Compound II is made, compound 1 is made in the method for described prepare compound 1；Wherein, X, R2、R3、R4, L and A definition It is same as above.
Prepare compound V method 1 can be the conventional method of such reduction reaction in this area, specifically preferred according to the invention Following reaction methods and condition：
Prepare compound V method 1 is preferably carried out under conditions of ammonia presence, and described ammonia is preferably with the shape of ammonia alcoholic solution Formula participates in reaction.
Prepare compound V method 1 is carried out preferably under conditions of Raney's nickel (Raney Ni) is present, described Raney's nickel Can be conventional commercial Raney's nickel reagent, the mass percent preferably 20%~80% of described Raney's nickel, described quality hundred Divide than referring to that the quality of nickel accounts for the percentage of Raney's nickel reagent gross mass.
In prepare compound V method 1, the preferred alcohols solvent of described organic solvent, described alcohols solvent is preferred Methanol and/or ethanol.
In prepare compound V method 1, the preferred 10bar~50bar of pressure of described reduction reaction is further excellent Select 20bar~30bar.
In prepare compound V method 1, preferably 10 DEG C~40 DEG C of the temperature of described reduction reaction.
In prepare compound V method 1, the process of described reduction reaction can use conventionally test side in this area Method (such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using compound VI, and the reaction time preferably 1 is small When~48 hours.
In prepare compound V method 1, described compound VI can be prepared using following methods：Under gas shield, In organic solvent, under conditions of catalyst is present, compound VII and zinc cyanide is subjected to nucleophilic substitution, chemical combination is obtained Thing VI；
Method 1 according still further to described prepare compound V is made compound V, described prepare compound III method system Compound II is made in the method for obtaining compound III, described prepare compound II, and the method for described prepare compound 1 is made Compound 1；Wherein, X, R2、R3、R4, L and A definition it is same as above.
Prepare compound VI method can be this area in such nucleophilic displacement of fluorine conventional method, the present invention in it is especially excellent Select following reaction methods and condition：
In prepare compound VI method, described organic solvent preferred amide class solvent, described amide solvent It is preferred that N,N-dimethylformamide.
In prepare compound VI method, the described palladium of catalyst preferably three (dibenzalacetone) two and 1,1'- are double (diphenylphosphine) ferrocene.
In prepare compound VI method, described zinc cyanide and described compound VII molar ratio preferably 1~ 5, further preferred 1~2.
In prepare compound VI method, the molar ratio preferably 0.1 of described catalyst and described compound VII ~1.
In prepare compound VI method, when double (diphenylphosphine) using three (dibenzalacetone) two palladiums and 1,1'- When ferrocene makees catalyst, double (diphenylphosphine) ferrocene of 1 described, 1'- and described three (dibenzalacetone) two palladium Molar ratio preferably 2~3.
In prepare compound VI method, preferably 80 DEG C~150 DEG C of the temperature of described nucleophilic substitution.
In prepare compound VI method, the process of described nucleophilic substitution can be used routinely to be surveyed in this area Method for testing (such as TLC, HPLC or NMR) is monitored, and as reaction end when typically being disappeared using compound VII, the reaction time is excellent Select 1 hour~48 hours, further preferred 10 hours~24 hours.
In prepare compound VI method, described compound XII can be prepared by following methods：In a solvent, Under conditions of sulfuric acid and catalyst are present, compound XII and compound XIII is subjected to condensation reaction, compound VII is obtained；
Compound VI is made in method according still further to described prepare compound VI, and described prepare compound V method 1 is made Compound III is made in the method for obtaining compound V, described prepare compound III, and described prepare compound II method is made Compound 1 is made in compound II, the method for described prepare compound 1；Wherein, X, R2、R3、R4, L and A definition it is same It is upper described.
In the conventional method that prepare compound VII method can be condensed for such in this area, the present invention particularly preferably Following reaction methods and condition：
In prepare compound VII method, the preferred water of described solvent.
In prepare compound VII method, the preferred 3- nitrobenzene sodium sulfonates of described catalyst.
In prepare compound VII method, described compound XIII and described compound XII molar ratio is excellent Select 1~5, further preferred 2~3.
In prepare compound VII method, the molar ratio preferably 1 of described catalyst and described compound VII ~3, further preferred 1~1.5.
In prepare compound VII method, the molar ratio preferably 0.5 of described sulfuric acid and described compound XII ~2.Described sulfuric acid can be conventional commercial sulphate reagent in this area, the mass percentage concentration preferably 30% of described sulfuric acid ~98%, described mass percentage concentration refers to that the quality of sulfuric acid accounts for the percentage of aqueous sulfuric acid gross mass.
In prepare compound VII method, preferably 80 DEG C~150 DEG C of the temperature of described condensation reaction.
In prepare compound VII method, the process of described nucleophilic substitution can use conventional in this area Method of testing (such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using compound VII, the reaction time It is preferred that 1 hour~48 hours, further preferred 10 hours~24 hours.
Prepare compound V method 2 can be the conventional method of such reduction reaction in this area, specifically preferred according to the invention Following reaction methods and condition：
Prepare compound V method 2 is preferably carried out under conditions of ammonia presence, and described ammonia is preferably with the shape of ammonia alcoholic solution Formula participates in reaction.
Prepare compound V method 2 is carried out preferably under conditions of Raney's nickel (Raney Ni) is present, described Raney's nickel Can be conventional commercial Raney's nickel reagent, the mass percent preferably 20%~80% of described Raney's nickel, described quality hundred Divide than referring to that the quality of nickel accounts for the percentage of Raney's nickel reagent gross mass.
In prepare compound V method 2, the preferred alcohols solvent of described organic solvent, described alcohols solvent is preferred Methanol and/or ethanol.
In prepare compound V method 2, preferably 10 DEG C~40 DEG C of the temperature of described reduction reaction.
In prepare compound V method 2, the process of described reduction reaction can use conventionally test side in this area Method (such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using compound VIII, the reaction time preferably 1 Hour~48 hours.
In prepare compound V method 2, described compound VIII can be prepared using following methods：Organic molten In agent, azanol and compound IX are subjected to condensation reaction, compound VIII is obtained；
Method 2 according still further to described prepare compound V is made compound V, described prepare compound III method system Compound II is made in the method for obtaining compound III, described prepare compound II, and the method for described prepare compound 1 is made Compound 1；Wherein, X, R2、R3、R4, L and A definition it is same as above.
In the conventional method that prepare compound VIII method can be condensed for such in this area, the present invention particularly preferably Following reaction methods and condition：
In prepare compound VIII method, the preferred alcohols solvent of described organic solvent, described alcohols solvent is excellent Select methanol and/or ethanol.
In prepare compound VIII method, described azanol can be used in the form of the hydrochloride salt, when using hydroxyl During the hydrochloride of amine, the hydrochloride of azanol and alkali preferably first react to obtaining azanol and carry out condensation reaction, described alkali again It is preferred that inorganic base, the preferred Strong oxdiative sodium of described inorganic base.
In prepare compound VIII method, described azanol and described compound IX molar ratio preferably 1~ 5, further preferred 1~2.
In prepare compound VIII method, preferably 10 DEG C~40 DEG C of the temperature of described condensation reaction.
In prepare compound VIII method, the process of described condensation reaction can use conventionally test in this area Method (such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using compound IX, the reaction time preferably 1 Hour~48 hours, further preferred 10 hours~24 hours.
In prepare compound VIII method, described compound IX can be prepared using following methods：Gas shield Under, in organic solvent, compound X with methyl-magnesium-bromide react obtaining compound IX；
Method according still further to described prepare compound VIII is made compound VIII, described prepare compound V side Method 2 is made compound V, and described prepare compound III method is made compound III, described prepare compound II side Legal system obtains compound II, and compound 1 is made in the method for described prepare compound 1；Wherein, X, R2、R3、R4, L and A determine Justice is same as above.
Prepare compound IX method can react particularly preferably following in conventional method, the present invention for such in this area Reaction method and condition：
In prepare compound IX method, " gas " preferably helium, argon gas, neon described in described " gas shield " One or more in gas and nitrogen.
In prepare compound IX method, the preferred ether solvent of described organic solvent, described ether solvent is preferred Tetrahydrofuran.
In prepare compound IX method, the molar ratio preferably 1 of described methyl-magnesium-bromide and described compound X ~3, further preferred 1~1.5.
In prepare compound IX method, preferably 0 DEG C~40 DEG C of the temperature of described reaction.
In prepare compound IX method, the process of described reaction can use traditional test methods in this area (such as TLC, HPLC or NMR) is monitored, as reaction end when typically being disappeared using compound X, and preferably 1 hour reaction time~ 48 hours, further preferred 10 hours~24 hours.
In prepare compound IX method, described compound X can be made using following methods：Under gas shield, In organic solvent, under conditions of catalyst is present, compound XI is reacted with hydrochloride base azanol, compound X is obtained；
Method according still further to described prepare compound IX is made compound IX, described prepare compound VIII method The method 2 that compound VIII, described prepare compound V is made is made compound V, described prepare compound III method It is made compound III, described prepare compound II method is made compound II, the method system of described prepare compound 1 Obtain compound 1；Wherein, X, R2、R3、R4, L and A definition it is same as above.
Prepare compound X method can react particularly preferably following in conventional method, the present invention for such in this area Reaction method and condition：
In prepare compound X method, " gas " preferably helium, argon gas, neon described in described " gas shield " One or more in gas and nitrogen.
In prepare compound X method, described organic solvent preferred amide class solvent, described amide solvent is excellent Select N,N-dimethylformamide.
In prepare compound X method, the molar ratio of described hydrochloride base azanol and described compound XI It is preferred that 1~3, further preferred 1~1.5.
In prepare compound X method, the preferred 2- of described catalyst (7- azo phenylpropyl alcohol triazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU).
In prepare compound X method, the molar ratio preferably 1~3 of described catalyst and described compound XI, Further preferred 1~1.5.
In prepare compound X method, preferably 0 DEG C~40 DEG C of the temperature of described reaction.
In prepare compound X method, the process of described reaction can use traditional test methods (example in this area Such as TLC, HPLC or NMR) it is monitored, as reaction end when typically being disappeared using compound XI, the reaction time preferably 1 hour~48 Hour, further preferred 10 hours~24 hours.
In the present invention, described compound I can be prepared using route one or two,
Route one：
Route two：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition be the same as those described above.
Present invention also offers the midbody compound II of prepare compound 1, compound III or compound V,
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition be the same as those described above.
Present invention also offers described compound II preparation method, it is preferred to use route A or route B,
Route A：
Route B：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition be the same as those described above；The specific reaction condition of each step is equal It is the same as those described above.
Present invention also offers described compound III preparation method, it is preferred to use route C or route D,
Route C：
Route D：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition be the same as those described above；The specific reaction condition of each step is equal It is the same as those described above.
Present invention also offers described compound V preparation method, it is preferred to use route E or route F：
Route E：
Route F：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition be the same as those described above；The specific reaction condition of each step is equal It is the same as those described above.
Present invention also offers described quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvation Thing, metabolite, metabolic precursor thereof or its prodrug, prepare treatment and/or prevention and EGFR-TK C-Met expression or Application in the medicine of active related disease.
Present invention also offers a kind of pharmaceutical composition, it contains quinolines as shown in Equation 1, it pharmaceutically may be used Salt, solvate, metabolite, metabolic precursor thereof or its prodrug of receiving, and pharmaceutically acceptable one or more Pharmaceutic adjuvant.
In the present invention, quinolines as shown in Equation 1 in described pharmaceutical composition, its is pharmaceutically acceptable Salt, solvate, metabolite, the content of metabolic precursor thereof or its prodrug are therapeutically effective amount, preferred mass percentage composition For 1%~99%；Described weight/mass percentage composition is quinolines as shown in Equation 1, its pharmaceutically acceptable salt, molten Agent compound, metabolite, metabolic precursor thereof and/or its prodrug, account for the percentage of pharmaceutical composition gross mass.Institute in the present invention The summation of the mass fraction for the pharmaceutical composition each component stated is 100%；The quality hundred of each component in described pharmaceutical composition It is 100% to divide content sum.
In the present invention, described pharmaceutic adjuvant is the conventional pharmaceutical adjuvants in this area, and it is selected because of route of administration and work It is different with feature, preferably including filler, diluent, adhesive, wetting agent, disintegrant, lubricant, emulsifying agent, suspending agent.
In the present invention, described pharmaceutical composition can orally, injection (vein, muscle, in subcutaneous and coronary artery), tongue Under, buccal, per rectum, per urethra, Via vagina, intranasal, suction or topic route apply.It is preferred that approach be oral.
Treatment and/or prevention and EGFR-TK C-Met's are being prepared present invention also offers described pharmaceutical composition Application in the medicine of expression or the related disease of activity.
In the present invention, the expression to EGFR-TK C-Met or active related disease are routine in this area As the disease caused by EGFR-TK C-Met change, preferably including cancer, musculoskeletal sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours.Described cancer preferably includes carcinoma of urinary bladder, breast cancer, cervical carcinoma, colon cancer, food Road cancer, stomach cancer, head and neck cancer, kidney, lung cancer, liver cancer, nasopharyngeal carcinoma, oophoroma, cancer of pancreas, prostate cancer and thyroid cancer；It is described Musculoskeletal sarcoma preferably include：Osteosarcoma, synovial sarcoma and rhabdomyosarcoma；Described soft tissue sarcoma preferably wraps Include：MFH/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma；Described hemopoietic system is pernicious swollen Knurl preferably includes：Huppert's disease, lymthoma, adult T cell leukemia, acute myelogenous leukemia and chronic grain are thin Born of the same parents' leukaemia；Other described tumours preferably include：Glioblastoma, astrocytoma, melanoma, celiothelioma and embryo Tire carcinosarcoma.
Some chemistry or technical term of pharmacology：
Unless otherwise defined, the connotation that otherwise all scientific and technical terminologies of the application have generally is managed with one of ordinary skill in the art The connotation of solution is identical.Unless otherwise indicated, all patents of text of the statement reference, patent application, open material, which pass through, quotes Mode is integrally incorporated herein.
Can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method in the range of art technology, such as mass spectrum, NMR, IR and UV/Vis spectroscopic methodology and Pharmacological method.Unless proposed to be specifically defined, otherwise the application is in analytical chemistry, Synthetic Organic Chemistry and medicine and medicine The term used in the relevant description learned is known in the art.The application is in chemical synthesis, chemical analysis, medicine preparation, system Agent and delivering, and to using standard technique in the treatment of patient.For example, using operation instruction of the manufacturer to kit, or Person implements to react and purified according to the explanation of mode well known in the art or the present invention.Generally can be according in this specification Description in reference and the multiple summary discussed and more specific document, implements described according to conventional method well known in the art Technology and method.In this manual, group and its substituent can be selected to provide stable knot by those skilled in the art Structure part and compound.
When the conventional chemical formulas by writing from left to right describes substituent, the substituent is similarly included from right to left Write substituent equivalent in chemistry resulting during structural formula.For example ,-CH2O- is equal to-OCH2-。
In the present invention, term " C1~4" refer to that there is 1~4 carbon atom, i.e. group can include 1 in its defined group Individual carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.For example, " C1~4Alkyl " refers to there is 1~4 carbon original The alkyl of son, i.e., described alkyl is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.By This can deduce the implication of other terms described in a similar manner, such as " C1~6" etc..
In the present invention, term " 6~10 yuan " refer to closure ring system group defined in it (such as aromatic ring, aryl, heteroaryl, Hetero-aromatic ring, cycloalkyl, Heterocyclylalkyl, heterocycloalkenyl etc.) in surround the atom number of closure ring skeleton in itself for 6,7,8,9 or 10.Different numbers can be taken according to the number of rings of closure ring system group, saturation degree and the atomic property for constituting the ring etc..Thus The implication of other terms described in a similar manner can be deduced, such as " 7~10 yuan ".
In the present invention, term " aromatic ring " or " aryl " refer to optionally substituted cyclic conjugated aryl radical, and it has 6~18 Individual ring carbons, it may include monocyclic, bicyclic, three rings or more ring.The remainder of compound molecule can pass through singly-bound and virtue Carbon atom on basic ring is connected.When aryl is substituted, substituent can be replaced on any workable tie point. For purposes of the invention, the preferably aryl of 6~10 unit monocycles or bicyclic system, such as phenyl or naphthyl.
In the present invention, term " hetero-aromatic ring ", " aromatic heterocycle " or " heteroaryl " refers to, optionally substituted by carbon atom and miscellaneous The conjugation armaticity ring system group that atom is collectively constituted, it includes about 5 to about 12 skeleton ring member nitrogen atoms, wherein one or more (such as 1~6,1~4,1~3,1~2) ring member nitrogen atoms be hetero atom, the hetero atom independently selected from oxygen, nitrogen, sulphur, Hetero atom in phosphorus, silicon, selenium and tin, but not limited to this.Any ring member nitrogen atoms in hetero-aromatic ring can be oxidized and be formed Nitrogen oxygen composition.Occur in ring in two or more heteroatomic embodiments, described two or more hetero atoms can phase each other Together, or some or all of described two or more hetero atom is different from each other.The remainder of compound molecule can pass through Singly-bound is connected with the carbon atom or hetero atom on hetero-aromatic ring.For example, imidazoles can by its arbitrary carbon atom (imidazoles- 2- bases, imidazol-4 yl or imidazoles -5- bases) or nitrogen-atoms (imidazoles -1- bases or imidazo-3-yl) be connected with parent molecule.It is described miscellaneous Aromatic ring includes the system of monocyclic and polycyclic (for example having 2,3 or 4 rings are fused to each other).For purposes of the invention, preferably 5~ 10 yuan and heteroatomic monocyclic hetero-aromatic ring or fused heteroaromatic ring selected from N, S and O containing 1~2, wherein fused heteroaromatic ring are preferred The atom that can be shared between 7~10 yuan of bicyclic system, and two rings includes hetero atom.
In the present invention, term " cycloalkyl " refer to the stabilization being only made up of carbon atom and hydrogen atom non-aromatic monocyclic or Multi-ring alkyl, it may include fused ring system, bridged-ring system or spiro ring system, generally has 3 to 15 carbon atoms.It can be via ring Upper any suitable carbon atom is connected by the remainder of singly-bound and molecule.Generally, the example of cycloalkyl includes but is not limited to Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..For purposes of the invention, preferably with 3 to 6 The cycloalkyl of the single ring systems of carbon atom.
In the present invention, term " Heterocyclylalkyl " refers to by 2 to 14 carbon atoms and 1 to 6 selected from the miscellaneous of nitrogen, oxygen and sulphur 3 yuan of the stabilization that atom is collectively constituted are to 20 yuan of non-aromatic cyclic groups, and it can be monocyclic, bicyclic, three rings or more ring Member ring systems, may also comprise fused ring system, bridged-ring system or spiro ring system.It can via any suitable on ring carbon atom or Person's hetero atom is connected by the remainder of singly-bound and molecule.Nitrogen-atoms therein can optionally by other groups be further substituted with Form tertiary amine or quaternary ammonium structure.Generally, the example of heterocyclic radical includes but is not limited to aziridinyl, azelidinyl, oxa- ring Butyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, tetrahydrochysene Furyl, dioxolanyl, oxacyclohexyl, morpholinyl, piperazinyl, N- substituted piperazinyls, homopiperazine base, N- substitution homopiperazines Base, piperidyl, N- substituted piperidines base, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc..Just originally For the purpose of invention, preferably 3 yuan to 6 yuan and the heterocycle at least containing 1 heteroatomic single ring systems selected from nitrogen, oxygen or sulphur Base.
In the present invention, term " cycloalkenyl group " refers to only be made up of the carbon atom and hydrogen atom, fat containing carbon-carbon double bond Race's cyclic group, it may include monocyclic or polycyclic system, usually contain 4~12 carbon atoms.For purposes of the invention, it is excellent Select the cycloalkenyl group of 5~6 unit monocycle systems.
In the present invention, term " heterocycloalkenyl " refers to by 3~9 carbon atoms and 1~3 hetero atom for being selected from nitrogen, oxygen, sulphur Aliphatic cyclic group being constituted, containing carbon-carbon double bond, it may include monocyclic or polycyclic system.With regard to the purpose of the present invention Speech, the heterocycloalkenyl of preferably 5~6 yuan and the single ring systems containing 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 " subject ", " patient " or " individual " refers to the individual with disease, illness or the patient's condition etc., Including mammal and nonmammalian.The example of mammal includes but is not limited to any member of class of mammals：People is non- The primate (such as chimpanzee and other apes and monkey) of people；Domestic animal, such as ox, horse, sheep, goat, pig；It is domestic dynamic Thing, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy.Non-human mammal Example include but is not limited to birds and fish etc..In a method and the embodiment of composition that the application is provided, The mammal is behaved.
In the present invention, term " treatment " includes alleviating, mitigate or improving disease or illness disease with other similar synonyms Shape, prevents other symptoms, improves or prevention causes the potential metabolism reason of symptom, suppress disease or illness, for example, prevent disease Or the development of illness, alleviate disease or illness, disease or illness is taken a turn for the better, alleviate the symptom caused by disease or illness, or Stop the symptom of disease or illness, in addition, the term includes the purpose of prevention.The term also include obtain therapeutic effect and/or Preventive effect.The therapeutic effect refers to cure or improves treated potential disease.In addition, pair related to potential disease one Plant or the healing or improvement of a variety of physiological signs are also therapeutic effect, although for example patient may nevertheless suffer from the shadow of potential disease Ring, but observe that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk Compound, even if or not yet make medical diagnosis on disease, but apply institute to the patient for one or more physiological signs of the disease occur State composition.
In the present invention, " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " refers to take metapedes with to a certain degree At least one medicament or the amount of compound of one or more symptoms of the treated disease of upper alleviation or illness.Its result can be with Abatement and/or alleviation for sign, symptom or the cause of disease, or biosystem it is any other needed for change.For example, for treatment " effective dose " is clinically to provide the amount for including the composition that compound is disclosed herein needed for significant remission effect. The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.
In the present invention, term " taking ", " administration ", " administration " etc. are to refer to compound or composition being delivered to progress The method in the required site of biological agent.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Art technology Personnel know the application technique available for herein described Compounds and methods for, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, Discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa Those.In a preferred embodiment, the compound and composition of the application discussion are by orally administering.
In institute of the invention, term " acceptable " or " pharmaceutically acceptable " refer to dock the one of treated subject As health condition there is no long-term adverse effect.
In the present invention, term " pharmaceutical composition " refer to be optionally mixed with least one pharmaceutically acceptable chemistry into The bioactive compound divided, the pharmaceutically acceptable chemical composition includes but is not limited to carrier, excipient and/or helped Agent, such as stabilizer, diluent, dispersant, suspending agent, thickener.
In the present invention, term " carrier " refers to the chemical compound or reagent of relative nontoxic, and it helps to draw compound Enter into cell or tissue.
In the present invention, term " pharmaceutically acceptable salt " refers to the free acid for remaining appointed compound and free alkali Biopotency, and there is no on biology or other side the salt of ill-effect.The compounds of this invention also includes pharmaceutically may be used With the salt of receiving.Pharmaceutically acceptable salt refers to the form for the base group in parent compound being converted into salt.Pharmaceutically Acceptable salt is include but not limited to, the inorganic or organic acid salt of base group such as amine (ammonia) base.The present invention is pharmaceutically Acceptable salt can be synthesized by parent compound, i.e. the acid of basic group in parent compound and 1-4 equivalents is molten at one Reacted in agent system.Suitable salt is set forth in Remingtong ' s Pharmaceutical Scicences, 17th ed.,Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, In 66,2 (1977).Pharmaceutically acceptable acid-addition salts can be prepared by inorganic and organic acid.By the nothing of derivative acid-addition salts Machine acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..Acetic acid, propionic acid, ethanol are included by the organic acid of derivative acid-addition salts Acid, pyruvic acid, oxalic acid, malic acid, malonic acid, butanedioic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Chinese cassia tree Acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..
In the present invention, term " solvate " refers to the compounds of this invention and solvent molecule formed by solvation Combination.In some cases, solvate refers to hydrate, i.e. solvent molecule for hydrone.
In the present invention, term " stereoisomer " refers to be made up of same atoms, is bonded by identical key, but with not With the compound of three-dimensional structure.The compound of formula 1 of the present invention cover various possible optical isomers, cis-trans-isomer and Its mixture.
In the present invention, term " dynamic isomer " refers to that proton is another from an atom transfer of molecule to identical molecule Isomers formed by individual atom.The compound of formula 1 of the present invention covers various possible dynamic isomers and its mixture.
In the present invention, term " polymorph " or " polymorph " refer to the chemical combination of the present invention of different form crystal lattice presence Thing.
After term used herein " metabolin " or " metabolite " refer to that the compounds of this invention is absorbed by organisms, in enzyme Effect is lower by internal function dough reaction (I phase biology conversion reaction, including oxidation, reduction, hydrolyze etc.) and association reaction Bioconversions such as (II phases biology conversion reaction) and the compound produced.For example, Cytochrome P450 is catalyzed a variety of redox Reaction, and the glucuronic acid molecule of UDPglucuronyl transferase catalytic activation is to aromatic alcohol, fatty alcohol, carboxylic The transfer of acid, amine and free thiohydroxy group.More information on metabolism can be found in The Pharmacological Basis of Therapeutics,9th Edition,McGraw-Hill(1996)。
In the present invention, term " prodrug or prodrug " refers to the compounds of this invention pharmaceutically before acceptable metabolism Body, it can change into the parent chemical combination of the invention with bioactivity under physiological condition in vivo generally without activity Thing.Property of the parent compound in terms of solubility, histocompatbility or pharmacokinetics can generally be improved.
In the present invention, term " drug regimen ", " applying other treatments ", " applying other therapeutic agents " etc. refer to by mixing Or the drug therapy for combining more than one active component and obtaining, its fixation for including active component and non-fixed Combination.Term " fixed Combination " refers at least one chemical combination as described herein is administered simultaneously to patient in the form of single entity or single formulation Thing and at least one collaboration medicament.Term " not fixed Combination " is referred to be administered simultaneously to patient in the form of corpus separatum, shared Or at least one compound as described herein and at least one collaboration preparation are sequentially applied with variable interval time, wherein such It is applied in two or more compounds that level of significance is provided in patient's body.These are also applied in HAART, for example, apply Use three or more active components.
Term used herein " combined administration ", " with ... be administered in combination " and its synonym etc. be directed to same patient and apply With selected therapeutic agent, and it is intended to apply by identical or different method of administration or identical or different administration number of times The therapeutic strategy of medicament.In some embodiments, compound described herein and other drug combinations are applied.These arts Language, which is covered to animal, applies two or more medicaments so that while there is the medicament and/or its metabolin in animal body.These Term includes being administered simultaneously different compositions, different time apply different composition and/or apply containing different activities into A kind of composition divided.Therefore, in some embodiments, the compound and other medicaments of the present invention are blended in a kind of combination Applied in thing.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and produce the present invention each preferably Example.
Room temperature in the present invention refers to environment temperature, is 10 DEG C~30 DEG C.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：The invention provides a kind of and entirely different imidazo pyrrole of prior art Piperazine class compound, its preparation method, pharmaceutical composition and application.The imidazopyrazines of the present invention are to EGFR-TK C-Met has good inhibition, can be used for preventing, treat or auxiliary treatment and EGFR-TK C-Met expression or work The relevant a variety of diseases of property.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product specification is selected.
Agents useful for same and raw material of the present invention are unless otherwise specified, commercially available.
The synthesis of intermediate quinolinamine
Intermediate A：
Synthesis step 1：6- cyano quinolines (A-2)
By 6- bromoquinolines A-1 (10.4g, 50mmol), zinc cyanide (8.8g, 75mmol), three (dibenzalacetone) two palladium Double (diphenylphosphine) ferrocene (2.8g, 5mmol) of (2.3g, 2.5mmol) and 1,1'- are added in DMF (100mL), and argon gas is protected Under shield, 130 DEG C are heated to, 16h is reacted.Reaction solution is cooled down, and is added under stirring in water (1L), ethyl acetate (200mL × 3) extraction Take, combined ethyl acetate phase, wash, saturated common salt washing is dried, column chromatography purifies to obtain 6g off-white powder compound A-2, received Rate：77%, HPLC>97%.LC-MS(ESI)：[M+H]+=155；1H-NMR(δppm,CDCl3,400MHz)：9.07(dd,J1 =4.2Hz, J2=1.5Hz, 1H), 8.25-8.19 (m, 3H), 7.88 (dd, J1=8.7Hz, J2=1.7Hz, 1H), 7.56 (dd, J1=8.3Hz, J2=4.2Hz, 1H).
Synthesis step 2：Quinoline -6- benzylidene aminos (A)
6- cyano quinolines A-2 (4.7g, 30mmol) is dissolved in methanolic ammonia solution (7mol/L, 50mL), hydrogenation instrument is used H-cube (30bar, 25 DEG C, flow velocity 1mL/min, Raney Ni) hydrogenating reduction, obtains crude product, reverse phase separation obtains 3.8g quinolines Quinoline -6- benzylidene amino A, yield：79%, HPLC>97%.LC-MS(ESI)：[M+H]+=159；1H-NMR(δppm,DMSO-d6, 400MHz)：8.84(dd,J1=4.2Hz, J2=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, J1=8.2Hz, J2=4.2Hz, 1H), 3.97 (s, 2H).
Intermediate B：
Synthesis step 1：N- methoxy-. N-methyl quinoline -6- formamides (B-2)
QUINOLINE-6-CARBOXYLIC ACID B-1 (5g, 29mmol) is taken to be dissolved in dry DMF (60mL), nitrogen protection is lower to add 2- (7- idols Nitrogen phenylpropyl alcohol triazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (12.9g, 34mmol) and hydrochloride base azanol (3.3g, 34mmol), is stirred overnight at room temperature.Dichloromethane (80mL) and water (80mL) are added, organic phase, aqueous phase dichloro is separated Methane (50mL × 3) is extracted, and merges organic phase, and saturated sodium-chloride (50mL × 2) is washed, and is dried.It is evaporated and obtains 4.6g colorless oils Liquid compound B-2, yield：74.5%.LC-MS(ESI)：[M+H]+=217.
Synthesis step 2：6- quinoline ketone (B-3)
N- methoxy-. N-methyl quinoline -6- formamides B-2 (6.1g, 28mmol) are dissolved in anhydrous THF (60mL), ice Bath is cooled to 0 DEG C, and nitrogen protection is lower to add 3M methyl-magnesium-bromides (10mL) solution.Ice bath is removed, is stirred overnight at room temperature.Reaction solution In be slowly added to saturated aqueous ammonium chloride (12mL), add ethyl acetate (50mL) and water (30mL), separate organic phase.Aqueous phase Extracted with ethyl acetate (50mL × 3).Merge organic phase, washed with saturated nacl aqueous solution (50mL × 2), dried.It is evaporated and obtains 4.4g faint yellow solid compound B-3, yield：91.8%.LC-MS(ESI)：[M+H]+=172.
Synthesis step 3：1- (quinoline -6- bases) acetophenone oxime (B-4)
Hydroxylamine chloride (3.1g, 44.9mmol) and sodium hydroxide (1.7g, 44.9mmol) are dissolved in ethanol (100mL), Stirring at normal temperature 1 hour, filters out solid.Filtrate is added to the ethanol solution containing 6- quinoline ketone B-3 (5.1g, 29.96mmol) In.Reaction solution is stirred overnight at room temperature.Solvent is evaporated off, 5.6g compound as white solid B-4, yield is obtained：99%, it is not purified, directly Connect for next step reaction.
Synthesis step 4：1- (quinoline -6- bases) ethamine (B)
1- (quinoline 6- yls) acetophenone oxime B-4 (5.6g, 30.1mmol) is dissolved in ethanol (200mL), and room temperature adds the first of ammonia Alcoholic solution (7mol/L, 13mL) and Rany nickel (alias Raney's nickel or RanyNi) (3g).Hydrogenation is stirred overnight at room temperature, and filters out solid Body.Filtrate is evaporated to obtain 9.7g compound B, yield：99%, HPLC>96%.LC-MS(ESI)：[M+H]+=173；1H-NMR(δ ppm,CDCl3,400MHz):8.95-8.79 (m, 1H), 8.08 (dd, J1=22Hz, J2=8.4Hz, 2H), 7.82-7.64 (m, 2H), 7.36 (dd, J1=8.4Hz, J2=4.2Hz, 1H), 4.40-4.23 (m, 1H), 1.45 (dd, J1=6.6Hz, J2= 1.3Hz,3H)。
Intermediate C：
Synthesis step 1：The fluoro- 6- bromoquinolines (C-2) of 8-
Glycerine (14.5g, 158mmol) and catalyst 3- nitrobenzene sodium sulfonates (14.2g, 63mmol) are added to sulfuric acid In the aqueous solution (the 20mL concentrated sulfuric acid+15mL water), be heated to 110 DEG C, be slowly added into the fluoro- 4- bromanilines C-1 of raw material 2- (10g, 52.6mmol), 140 DEG C are stirred overnight.It is down to after room temperature, pours into trash ice, concentrated ammonia liquor regulation pH 8 or so, ethyl acetate extraction Take, wash, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, and crude product column chromatography purifies to obtain 9.65g white solids Compound C-2, yield 81.2%.LC-MS(ESI)：[M+H]+=227；1H-NMR(δppm,CDCl3,400MHz)：8.97(dd, J1=4.4Hz, J2=0.8Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 7.79 (s, 1H), 7.54 (dd, J1=9.6Hz, J2= 2.0Hz, 1H), 7.50 (dd, J1=8.4Hz, J2=4.4Hz, 1H).
Synthesis step 2：6- cyano group -8- fluorine quinoline (C-3)
By the fluoro- 6- bromoquinolines C-2 (9.65g, 42.7mmol) of raw material 8-, zinc cyanide (7.49g, 64mmol), catalyst three (dibenzalacetone) two palladium (Pd2(dba)3) (1.96g, 2mmol) and ligand 1,1 ' double (diphenylphosphine) ferrocene (dppf) (2.37g, 4.3mmol) is dissolved in dry DMF (40mL), and argon gas protects lower 130 DEG C of reactions to stay overnight.It is down to after room temperature and adds saturation Na2CO3The aqueous solution (100mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, Crude product purifies to obtain 5.472g celadon solid chemical compound C-3, yield through column chromatography：74.1%.LC-MS(ESI)：[M+H]+= 173；1H-NMR(δppm,CDCl3,400MHz)：9.12 (d, J=4.4Hz, 1H), 8.29 (d, J=8.4Hz, 1H), 8.07 (s, 1H), 7.64 (dd, J1=8.4Hz, J2=4.4Hz, 1H), 7.59 (d, J=9.6Hz, 1H).
Synthesis step 3：6- amine methyl -8- fluorine quinoline (C)
Raw material 6- cyano group -8- fluorine quinoline C-3 (330mg, 1.92mmol) are dissolved in ammonia/methanol solution (30mL), used Instrument H-cube (30bar, 25 DEG C, 1mL/min flow velocitys, RaNi posts) is reduced, and 280mg brown oil C are obtained after solvent evaporated, is received Rate 82.8%, HPLC>96%.LC-MS(ESI)：[M+H]+=177；1H-NMR(δppm,DMSO-d6,400MHz)：8.89(dd, J1=4.4Hz, J2=1.2Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.70 (s, 1H), 7.60 (d, J=10.8Hz, 1H), 7.58(dd,J1=8.4Hz, J2=4.4Hz, 1H), 3.90 (s, 2H).
Intermediate D：
Synthesis step 1：8- fluorine quinoline -6- formic acid (D-2)
By the fluoro- PABA D-1 (25g, 0.16mol) of raw material 3- and catalyst 3- nitrobenzene sodium sulfonates (43.2g, In the mixed solution for 0.192mol) being added to the concentrated sulfuric acid (60mL) and water (24mL), it is heated to after interior 120 DEG C of temperature, is slowly added into Glycerine (44.2g, 0.48mol, 3eq), charging is warming up to 130 DEG C~140 DEG C and reacted 1.5 hours after finishing, cooling.By reaction solution Pour into trash ice, concentrated ammonia liquor adjusts pH to 5~6, separate out solid and filter out, wash, dry rear pillar chromatographic purifying obtains 8.7g canescence and consolidated Body compound D-2, yield 28.2%.LC-MS(ESI)：[M+H]+=192；1H-NMR(δppm,DMSO-d6,400MHz)： 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-methoxy -8- fluorine quinoline -6- formamides (D-3)
By raw material 8- fluorine quinoline -6- formic acid D-2 (3.2g, 16.75mmol) and reagent carbonyl dimidazoles (3g, 18.42mmol) it is dissolved in dry DMF (30mL), 2h is stirred at room temperature under argon gas protection, hydrochloride azanol is then added (1.64g, 16.75mmol), is stirred overnight at room temperature.Saturation NaHCO is added after reaction completely3The aqueous solution (100mL), ethyl acetate Extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, crude product through column chromatography purify 1.73g is yellowish Color grease D-3, yield：44.1%.LC-MS(ESI)：[M+H]+=235；1H-NMR(δppm,CDCl3,400MHz)：9.04 (dd,J1=4.0Hz, J2=1.6Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.06 (s, 1H), 7.76 (dd, J1=10.8Hz, J2=1.6Hz, 1H), 7.54 (dd, J1=8.4Hz, J2=4.0Hz, 1H), 3.58 (s, 3H), 3.44 (s, 3H).
Synthesis step 3：1- (the fluoro- 6- quinolyls of 8-) ethyl ketone (D-4)
Raw material N- methyl-N-methoxy -8- fluorine quinoline -6- formamides D-3 (7.5g, 0.032mol) are dissolved in anhydrous THF In (30mL), ice bath is cooled to 0 DEG C or so, and methyl-magnesium-bromide 2- methyltetrahydrofuran solution is slowly added under argon gas protection (2.8M, 17.2ml, 0.048mol), is stirred overnight at room temperature.After reaction completely, ice bath cooling is lower to add saturation NH4The Cl aqueous solution Be quenched reaction, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering be evaporated 5.5g yellow is consolidated Body D-4, yield 91.3%.LC-MS(ESI)：[M+H]+=190；1H-NMR(δppm,CDCl3,400MHz)：9.08(dd,J1= 4.4Hz,J2=1.2Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 8.26 (s, 1H), 7.96 (dd, J1=11.2Hz, J2= 1.6Hz, 1H), 7.58 (dd, J1=8.4Hz, J2=4.4Hz, 1H), 2.74 (s, 3H).
Synthesis step 4：1- (the fluoro- 6- quinolyls of 8-) ethanol (D-5)
Raw material 1- (the fluoro- 6- quinolyls of 8-) ethyl ketone D-4 (5.52g, 0.029mol) is dissolved in methanol (30mL), under ice bath NaBH is added portionwise4(4.4g, 0.116mol), is stirred at room temperature 1h.After reaction completely, add water and reaction is quenched, ethyl acetate extraction, Washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated to obtain 4.9g yellow oil D-5, yield：88.4%. LC-MS(ESI)：[M+H]+=192；1H-NMR(δppm,CDCl3,400MHz)：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- bromoethyls) -8- fluorine quinoline (D-6)
Raw material 1- (the fluoro- 6- quinolyls of 8-) ethanol D-5 (4.9g, 25.6mmol) is dissolved in chloroform (30mL), under ice bath It is slowly added to PBr3(10.42g, 38.5mmol), is heated to reflux 2 hours.Saturation is slowly added under cooling, solvent evaporated, ice bath NaHCO3The aqueous solution adjusts pH to alkalescence, and dichloromethane extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying crosses filtration Do to obtain 3.8g brown oil D-6, yield：58.6%.LC-MS(ESI)：[M+H]+=254；1H-NMR(δppm,CDCl3, 400MHz)：8.98(dd,J1=4.4Hz, J2=1.6Hz, 1H), 8.19 (d, J=8.4Hz, 1H), 7.62 (s, 1H), 7.56 (dd,J1=11.2Hz, J2=2.0Hz, 1H), 7.52 (dd, J1=8.4Hz, J2=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- quinolyls of 8-) ethyl) iso-indoles -1,3- diketone (D-7)
By raw material 6- (1- bromoethyls) -8- fluorine quinoline D-6 (0.77g, 3.06mmol) and potassium phthalimide (0.68g, 3.672mmol) is dissolved in DMF (10mL), adds a little KI (KI), 120 DEG C of heating response 2h.Reaction terminates, Water (50mL) is added, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated to obtain 1g yellow Grease, yield：100%.LC-MS(ESI)：[M+H]+=321；1H-NMR(δppm,CDCl3,400MHz)：8.94(dd,J1 =4.4Hz, J2=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,J1=11.2Hz, J2=1.6Hz, 1H), 7.46 (dd, J1=8.4Hz, J2=4.4Hz, 1H), 5.72 (q, J= 7.2Hz, 1H), 2.02 (d, J=7.2Hz, 3H).
Synthesis step 7：1- (the fluoro- 6- quinolyls of 8-) ethamine (D)
Raw material 2- (1- (the fluoro- 6- quinolyls of 8-) ethyl) iso-indoles -1,3- diketone D-7 (0.189g, 0.59mmol) is molten In ethanol (10mL), hydrazine hydrate (0.138g, 1.77mmol) is added, is heated to reflux 2 hours.Cooling, solvent evaporated is added The 5%NaOH aqueous solution (10mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated Obtain yellow oil 79mg, yield：70.5%, HPLC>97%.LC-MS(ESI)：[M+H]+=191；1H-NMR(δppm, CDCl3,400MHz)：8.90(dd,J1=4.0Hz, J2=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 companies, and the synthetic method of restoring method reference intermediate A step 2, products therefrom exists Hydrochloric acid salt in ether, is light tan solid.Yield：81%, HPLC>97%.LC-MS(ESI)：[M+H]+=177；1H-NMR (δppm,CD3OD,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：
Synthesis step 1：The bromo- 7- fluorine quinoline (F-2) of 6-
With reference to the synthetic method of intermediate D steps 1, it is solid that product is recrystallized to give white with petroleum ether after purification through silicagel column Body, yield 62%.LC-MS(ESI)：[M+H]+=226；1H-NMR(δppm,CDCl3,400MHz)：8.93(dd,J1= 4.2Hz,J2=1.5Hz, 1H), 8.12-8.02 (m, 2H), 7.81 (d, J=9.5Hz, 1H), 7.41 (dd, J1=8.3Hz, J2= 4.2Hz,1H)。
Synthesis step 2：1- (the fluoro- quinoline -6- bases of 7-)-ethyl ketone (F-3)
The bromo- 7- fluorine quinoline F-2 (2.07g, 9.16mmol) of 6-, tributyl (1- ethoxy ethylenes) tin (3.64g, 10.1mmol) it is added to bis-triphenylphosphipalladium palladium dichloride (0.32g, 0.46mmol) in dioxane (20mL), argon gas protection Lower 110 DEG C of reactions 4h.Reaction solution is cooled down, and adds potassium fluoride dihydrate (2g) and water (4mL).2h is stirred at room temperature, filters, filter cake Washed with dioxane (5mL × 3).Merging filtrate, adds concentrated hydrochloric acid (2mL), 1h is stirred at room temperature.Reaction solution is concentrated, and adds saturation Aqueous sodium carbonate (50mL), ethyl acetate (100mL × 2) extraction.Organic phase merges, and washes (50mL), saturated aqueous common salt (50mL) is washed, and 1.5g off-white powder compound F-3, yield are obtained through silica gel column chromatography purifying after drying：87%.LC-MS (ESI)：[M+H]+=190；1H-NMR(δppm,CDCl3,400MHz)：8.99(dd,J1=4.2Hz, J2=1.7Hz, 1H), 8.41 (d, J=7.8Hz, 1H), 8.26 (dd, J1=8.3Hz, J2=1.1Hz, 1H), 7.81 (d, J=12.2Hz, 1H), 7.44 (dd,J1=8.3Hz, J2=4.2Hz, 1H), 2.76 (d, J=4.9Hz, 3H).
Synthesis step 3：1- (the fluoro- quinoline -6- bases of 7-)-ethanol (F-4)
With reference to the synthetic method of intermediate D steps 4, white solid, yield=79% are obtained.LC-MS(ESI)：[M+H]+ =192；1H-NMR(δppm,CDCl3,400MHz)：8.74(dd,J1=4.3Hz, J2=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, J1=8.3Hz, J2= 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- ethyls of 1-) fluoro- quinoline of -7- (F-5)
With reference to the synthetic method of intermediate D steps 5, white solid, yield=94% are obtained.LC-MS(ESI)：[M+H]+ =254；1H-NMR(δppm,CDCl3,400MHz)：8.91(dd,J1=4.3Hz, J2=1.6Hz, 1H), 8.16 (dd, J1= 8.3Hz,J2=1.2Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.74 (d, J=11.6Hz, 1H), 7.40 (dd, J1= 8.3Hz,J2=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- bases of 7-) ethyl)-iso-indoles -1,3- diketone (F-6)
With reference to the synthetic method of intermediate D steps 6, white solid, yield=69% are obtained.LC-MS(ESI)：[M+H]+ =321；1H-NMR(δppm,CDCl3,400MHz)：8.89(dd,J1=4.3Hz, J2=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, J1=8.3Hz, J2=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- bases of 7-)-ethamine (F)
With reference to the synthetic method of intermediate D steps 7, white solid, yield=60%, HPLC are obtained>96%.LC-MS (ESI)：[M+H]+=191；1H-NMR(δppm,CDCl3,400MHz)：8.87(dd,J1=4.3Hz, J2=1.6Hz, 1H), 8.14(dd,J1=8.3Hz, J2=1.1Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.70 (d, J=12.0Hz, 1H), 7.36 (dd,J1=8.3Hz, J2=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：The bromo- 5,7- difluoro-quinolines (G-2) of 6-
By bromo- 3, the 5- difluoroanilines G-1 (5.6g, 27mmol) of raw material 4- and 3- nitrobenzene sodium sulfonates (7.2g, 32mmol) In the mixed solution for being added to the concentrated sulfuric acid (15mL) and water (6mL), be heated to after interior 120 DEG C of temperature, be slowly added into glycerine (7.4g, 80mmol), charging is warming up to 130 DEG C of reaction 1.5h, cooling after finishing.Reaction solution is poured into trash ice, concentrated ammonia liquor tune pH to 5~ 6, separate out solid and filter out, wash, dry rear pillar chromatographic purifying and obtain 3.82g compound as white solid G-2, yield 58%.LC-MS (ESI)：[M+H]+=244；1H-NMR(δppm,CDCl3,400MHz)：8.98-8.97 (m, 1H), 8.40-8.37 (m, 1H), 7.68(dd,J1=8.5Hz, J2=1.6Hz, 1H), 7.47 (dd, J1=8.5Hz, J2=4.2Hz, 1H).
Synthesis step 2：6- vinyl -5,7- difluoro-quinolines (G-3)
By bromo- 5, the 7- difluoro-quinolines G-2 (1.0g, 4.10mmol) of raw material 6-, tripropyl vinyl tin (1.34g, 4.10mmol) with Pd (PPh3)2Cl2(47mg, 0.041mmol) is dissolved in dioxane (30mL), and argon gas is protected lower 140 DEG C and stirred Mix 4h.Cooling, adds ethyl acetate (40mL), water (2mL) and KF (0.2g), reaction solution stirring 2h.Separate ethyl acetate layer, water Extraction is returned with ethyl acetate 2 times, merges organic phase, dries, and filtering 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 metaperiodate (2.75g, 12.85mmol) In the mixed liquor that dioxane (17mL) and water (6mL) are added to 2.6- lutidines (0.761mL, 6.42mmol).Stir Addition osmium tetroxide (653mg, 0.064mmol) is mixed, continues to stir 15min, water (50mL) dilution is added, uses ethyl acetate (50mL) is extracted, ethyl acetate washing, is dried, silicagel column purifies to obtain 0.56g white solid G-4, yield：90%.LC-MS (ESI)：[M+H]+=194；1H-NMR(δppm,CDCl3,400MHz)：10.55 (s, 1H), 9.08 (dd, J1=4.0Hz, J2= 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- bases)-methanol (G-5)
White solid, yield are obtained with reference to the synthetic method of intermediate D steps 4：88%.LC-MS(ESI)：[M+H]+= 196；1H-NMR(δppm,CDCl3,400MHz)：8.98(dd,J1=4.4Hz, J2=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, J1= 6.4Hz,J2=4.4Hz, 1H).
Synthesis step 5：6- bromomethyl -5,7- difluoro-quinolines (G-6)
Brown oil G-6, yield are obtained with reference to the synthetic method of intermediate D steps 5：61%.LC-MS(ESI)：[M+H]+ =258.
Synthesis step 6：The synthesis (G-7) of 2- [(the fluoro- 6- quinolyls of 5,7- bis-) methyl] isoindoline -1,3- diketone
Yellow oil G-7, yield are obtained with reference to the synthetic method of intermediate D steps 6：100%.LC-MS(ESI)：[M+H ]+=325.
Synthesis step 7：5,7- difluoro-quinoline -6- bases) methylamine (G)
White solid, yield are obtained with reference to the synthetic method of intermediate D steps 7：60.6%, HPLC>96%.LC-MS (ESI)：[M+H]+=195；1H-NMR(δppm,CDCl3,400MHz)：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- quinolyls of 5,7- bis-) ethyl ketone (H-1)
With reference to the synthetic method of intermediate F-step 2, faint yellow solid H-1, yield 80% are obtained.LC-MS(ESI)：[M+ H]+=208；1H-NMR(δppm,CDCl3,400MHz)：9.02(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.46-8.44 (m, 1H), 7.65-7.62 (m, 1H), 7.50 (dd, J1=8.5Hz, J2=4.3Hz, 1H), 2.72 (t, J=1.7Hz, 3H).
Synthesis step 2：1- (the fluoro- 6- quinolyls of 5,7- bis-) ethanol (H-2)
White solid H-2, yield 94% are synthesized to obtain with reference to intermediate D steps 4.LC-MS(ESI)：[M+H]+=210；1H-NMR(δppm,CDCl3,400MHz)：8.92(dd,J1=4.2Hz, J2=1.8Hz, 1H), 8.38 (d, J=7.7Hz, 1H), 7.59-7.56 (m, 1H), 7.43 (dd, J1=8.5Hz, J2=4.2Hz, 1H), 5.46 (q, J=7.2Hz, 1H), 1.73 (d, J= 7.2Hz,3H)。
Synthesis step 3：6- (1- bromoethyls) -5,7 difluoro-quinolines (H-3)
Yellow solid H-3, yield 75% are obtained with reference to the synthetic method of intermediate D steps 5.LC-MS(ESI)：[M+H]+= 272；1H-NMR(δppm,CDCl3,400MHz)：8.96-8.94 (m, 1H), 8.41-8.39 (m, 1H), 7.60 (d, J= 11.7Hz, 1H), 7.44 (dd, J1=8.5Hz, J2=4.3Hz, 1H), 5.69 (q, J=7.2Hz, 1H), 2.21 (d, J= 7.2Hz,3H)。
Synthesis step 4：2- [1- (5,7 2 fluoro- 6- quinolyls) ethyl] iso-indoles -1,3- diketone (H-4)
Yellow solid H-4, yield 96% are obtained with reference to the synthetic method of intermediate D steps 6.LC-MS(ESI)：[M+H]+= 339。
Synthesis step 5：1- (5,7 2 fluoro- 6- quinolyls) ethamine (H)
Pale yellow oil H, yield 80%, HPLC are obtained with reference to the synthetic method of intermediate D steps 7>97%.LC-MS (ESI)：[M+H]+=209；1H-NMR(δppm,CDCl3,400MHz)：8.93(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.40-8.37 (m, 1H), 7.58 (dd, J1=12.1Hz, J2=1.7Hz, 1H), 7.44 (dd, J1=8.5Hz, J2=4.3Hz, 1H), 4.68 (q, J=6.9Hz, 1H), 1.98 (s, 2H), 1.62 (d, J=6.9Hz, 3H).
Intermediate compound I：
Synthesis step 1：6- bromine-7-methyls quinoline (I-2) and the bromo- 5- methylquinolines (J-1) of 6-
With reference to the method for intermediate G synthesis steps 1, synthesis 6- bromine-7-methyls quinoline (I-2) and the bromo- 5- methylquinolines of 6- (J-1) mixture.Then separated with Overcritical prepared chromatographic (SFC), IC-H posts, mobile phase：Isopropanol/carbon dioxide= 18/82, Detection wavelength：254nm.The first cut is collected for 6- bromine-7-methyls quinoline (I-2), white solid, yield：25%. LC-MS(ESI)：[M+H]+=222；1H-NMR(δppm,CDCl3,400MHz)：8.90(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.07-8.06 (m, 2H), 8.00 (s, 1H), 7.38 (dd, J1=8.3Hz, J2=4.3Hz, 1H), 2.63 (d, J= 1.0Hz,3H).The second cut is collected for bromo- 5- methylquinolines (J-1) white solids of 6-, yield：20%.LC-MS(ESI)：[M+ H]+=223；1H-NMR(δppm,CDCl3,400MHz)：8.96-8.93 (m, 1H), 8.40 (dd, J1=8.3Hz, J2=1.7Hz, 1H), 7.88 (s, 2H), 7.48 (dd, J1=8.3Hz, J2=4.3Hz, 1H), 2.80 (s, 3H).
Synthesis step 2：1- (7- methyl -6- quinolyls) ethyl ketone (I-3)
With reference to the method for intermediate H synthesis steps 1, using 6- bromine-7-methyl quinoline I-2 as Material synthesis 1- (7- methyl -6- Quinolyl) ethyl ketone I-3.Faint yellow solid, yield 91%.LC-MS(ESI)：[M+H]+=186；1H-NMR(δppm,CDCl3, 400MHz)：8.95(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.22-8.20 (m, 2H), 7.94 (dd, J1=1.4Hz, J2= 0.8Hz, 1H), 7.44 (dd, J1=8.5Hz, J2=4.3Hz, 1H), 2.74-2.73 (m, 6H).
Synthesis step 3：1- (7- methyl -6- quinolyls) ethanol (I-4)
With reference to the method for intermediate D synthesis steps 4,1- (7- methyl -6- quinolyls) ethanol I-4 is synthesized, yellow solid is received Rate 96%.LC-MS(ESI)：[M+H]+=188；1H-NMR(δppm,CDCl3,400MHz)：(8.89-8.83 m, 1H), 8.13 (dt,J1=8.3Hz, J2=1.3Hz, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.34 (dd, J1=8.3Hz, J2=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- bromoethyls) -7- methylquinolines (I-5)
With reference to the synthetic method of intermediate D steps 5, yellow is prepared with raw material 1- (7- methyl -6- quinolyls) ethanol Solid I-5, yield 85%.LC-MS(ESI)：[M+H]+=250；1H-NMR(δppm,CDCl3,400MHz)：8.98-8.94(m, 1H), 8.40-8.38 (m, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.42 (dd, J1=8.3Hz, J2=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- quinolyls) ethyl) iso-indoles -1,3- diketone (I-6)
With reference to the synthetic method of intermediate D steps 6, prepared with raw material 6- (1- bromoethyls) -7- methylquinolines I-5 white Color solid I-6, yield 70%.LC-MS(ESI)：[M+H]+=317；1H-NMR(δppm,CDCl3,400MHz):8.88(dd,J1 =4.3Hz, J2=1.7Hz, 1H), 8.24-8.19 (m, 2H), 7.89 (s, 1H), 7.80 (dd, J1=5.5Hz, J2=3.1Hz, 2H), 7.72 (dd, J1=5.5Hz, J2=3.1Hz, 2H), 7.36 (dd, J1=8.3Hz, J2=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- quinolyls) ethamine (I)
With reference to the synthetic method of intermediate D steps 7, with raw material 2- (1- (7- methyl -6- quinolyls) ethyl) iso-indoles -1, 3- diketone I-6 prepares faint yellow solid I, yield 60%, HPLC>96%.LC-MS(ESI)：[M+H]+=187；1H-NMR (δppm,CDCl3,400MHz)：8.98(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.30-8.27 (m, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.46 (dd, J1=8.3Hz, J2=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- quinolyls) ethyl ketone (J-2)
With reference to the method for intermediate H synthesis steps 1, with the bromo- 5- methylquinolines of the 6- prepared in intermediate compound I synthesis step 1 J-1 is Material synthesis 1- (5- methyl -6- quinolyls) ethyl ketone J-2, faint yellow solid, yield 86%.LC-MS(ESI)：[M+H]+ =186；1H-NMR(δppm,CDCl3,400MHz)：9.00(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.53 (dt, J1= 8.5Hz,J2=1.2Hz, 1H), 8.04 (d, J=8.9Hz, 1H), 7.85 (d, J=8.9Hz, 1H), 7.52 (dd, J1=8.5Hz, J2=4.3Hz, 1H), 2.81 (s, 3H), 2.70 (s, 3H).
Synthesis step 2：1- (5- methyl -6- quinolyls) ethanol (J-3)
With reference to the method for intermediate D synthesis steps 4,1- (5- methyl -6- quinolyls) ethanol J-3 is synthesized, brown solid is received Rate 90%.LC-MS(ESI)：[M+H]+=188；1H-NMR(δppm,CDCl3,400MHz)：8.88(dd,J1=4.2Hz, J2= 1.7Hz, 1H), 8.42-8.40 (m, 1H), 7.99 (q, J=9.0Hz, 2H), 7.44 (dd, J1=8.3Hz, J2=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- bromoethyls) -5- methylquinolines (J-4)
With reference to the synthetic method of intermediate D steps 5, yellow is obtained with raw material 1- (5- methyl -6- quinolyls) ethanol J-3 and is consolidated Body J-4, yield 85%.LC-MS(ESI)：[M+H]+=250；1H-NMR(δppm,CDCl3,400MHz)：8.94(dd,J1= 4.2Hz,J2=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- quinolyls) ethyl) iso-indoles -1,3- diketone (J-5)
With reference to the synthetic method of intermediate D steps 6, prepared with raw material 6- (1- bromoethyls) -5- methylquinolines J-4 white Color solid J-5, yield 40%.LC-MS(ESI)：[M+H]+=317；1H-NMR(δppm,CDCl3,400MHz):8.91(dd,J1 =4.1Hz, J2=1.6Hz, 1H), 8.45 (dt, J1=8.7Hz, J2=1.3Hz, 1H), 8.22 (d, J=9.0Hz, 1H), 8.05 (d, J=9.0Hz, 1H), 7.90 (dd, J1=5.5Hz, J2=3.0Hz, 1H), 7.85-7.80 (m, 2H), 7.71 (dd, J1= 5.5Hz,J2=3.0Hz, 1H), 7.43 (dd, J1=8.6Hz, J2=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- quinolyls) ethamine (J)
With reference to the synthetic method of intermediate D steps 7, with raw material 2- (1- (7- methyl -6- quinolyls) ethyl) iso-indoles -1, 3- diketone J-5 prepares faint yellow solid J, yield 60%, HPLC>97%.LC-MS(ESI)：[M+H]+=187；1H-NMR (δppm,CDCl3,400MHz)：8.96(dd,J1=4.2Hz, J2=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：
Synthesis step 1：The synthesis (K-2) of 3- chloroquinoline -6- methyl formates
Take 5g (27mmol) QUINOLINE-6-CARBOXYLIC ACID's methyl esters to be dissolved in 50mL dry DMFs, add 11g (80mmol) N- chloro fourths Imidodicarbonic diamide, is heated to 125 DEG C of tube sealings and stays overnight.The saturated solution quenching reaction of appropriate sodium acid carbonate is first added, is added afterwards A small amount of water and ethyl acetate, separates organic phase, and aqueous phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, saturated sodium-chloride Solution 50mL × 2 are washed, and are dried, are evaporated.(solvent is petroleum ether to point plate：Ethyl acetate=5：1) it is purer, dodge post purifying (expansion Agent is petroleum ether：Ethyl acetate=80:20) white solid 3.481g, yield are obtained：57%.LC-MS(ESI)：[M+H]+= 222。
Synthesis step 2：The synthesis (K-3) of 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- methyl formates
500mg (2.26mmol) 3- chloroquinoline -6- methyl formates are taken to be dissolved in 24mL1,4- dioxane, under nitrogen protection It is separately added into 165mg (0.23mmol) [double (diphenylphosphine) ferrocene of 1,1-] palladium chloride, 624mg (4.51mmol) carbonic acid Potassium, 516mg (2.48mmol) 1- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles and 6ml water, the reactant mixture is heated to 110 DEG C under a nitrogen, and tube sealing is stayed overnight.Solvent is removed, 50ml water and 50ml acetic acid is added Ethyl ester, separates organic phase, and aqueous phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, saturated nacl aqueous solution 50mL × 2 are washed, Dry, be evaporated.(solvent is dichloromethane to point plate：Methanol=20：1) purer, dodging post purifying, (solvent is dichloromethane：First Alcohol=95:5) white solid 565mg, yield are obtained：94%.LC-MS (ESI)：[M+H]+=268,1H-NMR(δppm,CDCl3, 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).
Synthesis step 3：The synthesis (K-4) of 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) QUINOLINE-6-CARBOXYLIC ACID
565mg (2.11mmol) 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- methyl formates are taken to be dissolved in 30ml methanol In, 266mg (6.34mmol) lithium hydroxides and 5ml water are added at room temperature, and reaction is stirred overnight at room temperature.Then solvent is removed, is obtained To 534mg white solids, next step is direct plungeed into.LC-MS(ESI)：[M+H]+=254.
Synthesis step 4：The synthesis of N- methoxy-. N-methyls -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- formamides (K-5)
534mg (2.108mmol) 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) QUINOLINE-6-CARBOXYLIC ACID is dissolved in dichloromethane, 411mg (4.22mmol) N, O- dimethyl hydroxylamine hydrochloride, 1.60g (4.22mmol) O- (7- pyridines are added under nitrogen protection And triazole)-N, N, N, N- tetramethylurea hexafluorophosphoric acid esters and 3mLN- ethyl diisopropylamines, it is stirred overnight at room temperature.Remove molten Agent, adds 50mL water and 50mL ethyl acetate, separates organic phase, and aqueous phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, Saturated nacl aqueous solution 50mL × 2 are washed, and are dried, are evaporated.(solvent is dichloromethane to point plate：Methanol=20：1) it is purer, dodge post (solvent is dichloromethane for purifying：Methanol=95:5) yellow solid 322mg, yield are obtained：52%.LC-MS(ESI)：[M+H ]+=297,1H-NMR(δppm,CDCl3, 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).
Synthesis step 5：The synthesis (K-6) of 1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl ketone
Take 504mg (1.701mmol) N- methoxy-. N-methyls -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- formyls Amine is dissolved in the anhydrous THF of 30mL, and ice bath is cooled to 0 DEG C, the lower 3M methyl magnesium bromide solutions for adding 1.5mL of nitrogen protection.Remove Ice bath, is stirred overnight at room temperature.6ml saturated aqueous ammonium chlorides are slowly added to, 30mL ethyl acetate and 15mL water is added, has separated Machine phase, aqueous phase is extracted with the ethyl acetate of 30mL × 3.Merge organic phase, saturated nacl aqueous solution 30mL × 2 are washed, dry, be evaporated. (solvent is petroleum ether to point plate：Ethyl acetate=1:1) purer, dodging post purifying, (solvent is petroleum ether：Ethyl acetate=1: 100) white solid 280mg, yield are obtained：66%.LC-MS(ESI)：[M+H]+=252,1H-NMR(δppm,CDCl3, 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, J1=8.8Hz, J2=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)。
Synthesis step 6：The synthesis (K-7) of 1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) acetophenone oxime
Take 232mg (3.34mmol) hydroxylamine chloride to be dissolved in 30ml ethanol, 137mg (3.43mmol) hydroxide is added afterwards Sodium.The mixed solution was stirred after 1 hour at normal temperatures, filtered out solid, and filtrate is added to containing 280mg (1.11mmol) 1- In the ethanol solution of (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl ketone.Under normal temperature, reactant mixture is stirred overnight. Solvent is removed, 919mg white solids is obtained, direct plunges into next step.LC-MS(ESI)：[M+H]+=267.
Synthesis step 7：The synthesis (K) of 1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethamine
556mg (2.09mmol) 1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) acetophenone oxime is dissolved in 20ml second In alcohol, under normal temperature, methanol solution (7N) 6ml and 245mg of ammonia Raney nickel is added.The reactant mixture under hydrogen, normal temperature It is stirred overnight.Solid is filtered out, solvent is evaporated, 385mg crude products are obtained, the product purity can direct plunge into next step.Point Plate (solvent dichloromethane：Methanol=10:1).LC-MS(ESI)：[M+H]+=253；1H-NMR(δppm,DMSO-d6, 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：
Synthesis step 1：The fluoro- 6- bromoquinolines (L-2) of 7-
By the fluoro- 4- bromanilines (20g, 0.105mol) of raw material 3- and catalyst 3- nitrobenzene sodium sulfonates (28g, 0.124mol, In the mixed solution for 1.2eq) being added to the concentrated sulfuric acid (60ml) and water (24ml), it is heated to after interior 120 DEG C of temperature, is slowly added into glycerine (29g, 0.315mol, 3eq), charging is warming up to 130-140 DEG C of reaction after finishing and stayed overnight, and cools down.Reaction solution is poured into trash ice, Concentrated ammonia liquor adjusts pH to 8, and dichloromethane extraction, washing dries rear pillar chromatographic purifying and obtains yellow solid 20.3g, yield 85.8%. LC-MS(ESI)：[M+H]+=226；1H-NMR(δppm,CDCl3,400MHz)：8.93(dd,J1=4.2Hz, J2=1.5Hz, 1H), 8.12-8.02 (m, 2H), 7.81 (d, J=9.5Hz, 1H), 7.41 (dd, J1=8.3Hz, J2=4.2Hz, 1H).
Synthesis step 2：The fluoro- 6- quinoline ethyl ketones (L-3) of 7-
The fluoro- 6- bromoquinolines (20.3g, 0.09mol) of raw material 7- are dissolved in anhydrous dioxane (50ml), catalyst is added Pd(PPh3)2Cl2(3.17g, 4.5mmol, 0.05eq) and reagent tributyl (1- ethoxy ethylenes base) tin (35.87g, 0.1mol, 1.1eq), argon gas protects lower 90 DEG C of reactions to stay overnight.It is down to after room temperature, adds 2eq 10% potassium fluoride aqueous solution room Temperature stirring 2h, filtering, filter cake dichloromethane is washed for several times, and filtrate is evaporated, and adds 2eq 1N HCl and 2h is stirred at room temperature.Add carbonic acid Sodium water solution adjusts pH to 8, and dichloromethane extraction, washing dries rear pillar chromatographic purifying and obtains yellow solid 17g, yield 99%.LC- MS(ESI)：[M+H]+=190；1H-NMR(δppm,CDCl3,400MHz)：8.99(dd,J1=4.2Hz, J2=1.7Hz, 1H), 8.41 (d, J=7.8Hz, 1H), 8.26 (dd, J1=8.3Hz, J2=1.1Hz, 1H), 7.81 (d, J=12.2Hz, 1H), 7.44 (dd,J1=8.3Hz, J2=4.2Hz, 1H), 2.76 (d, J=4.9Hz, 3H).
Synthesis step 3：1- (the fluoro- 6- quinolyls of 7-) ethanol (L-4)
The fluoro- 6- quinoline ethyl ketones (20.5g, 0.108mol) of raw material 7- are dissolved in methanol (100ml), are added portionwise under ice bath NaBH4Stirred 0.5 hour under (3.3g, 0.087mol, 0.8eq), ice bath.After reaction completely, add water and reaction is quenched, boil off first Alcohol, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifies to obtain yellow oil 15.4g, yield 74.7%.LC-MS(ESI)：[M+H]+=192；1H-NMR(δppm,CDCl3,400MHz)：8.74(dd,J1= 4.3Hz,J2=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, J1=8.3Hz, J2=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- bromoethyls) -7- fluorine quinoline (L-5)
Raw material 1- (the fluoro- 6- quinolyls of 7-) ethanol (6.2g, 0.03mol) is dissolved in chloroform (50ml), it is slow under ice bath Add PBr3(10.5g, 0.038mol, 1.2eq), is heated to reflux 2 hours.After reaction completely, solvent evaporated, under ice bath slowly plus Enter saturation NaHCO3The aqueous solution adjusts pH to alkalescence, and ethyl acetate extraction is washed, saturated common salt water washing, anhydrous sodium sulfate drying, Column chromatography purifies to obtain yellow solid 4.6g, yield 56.6%.LC-MS(ESI)：[M+H]+=254；1H-NMR(δppm,CDCl3, 400MHz)：8.91(dd,J1=4.3Hz, J2=1.6Hz, 1H), 8.16 (dd, J1=8.3Hz, J2=1.2Hz, 1H), 7.97 (d, J=8.0Hz, 1H), 7.74 (d, J=11.6Hz, 1H), 7.40 (dd, J1=8.3Hz, J2=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- quinolyls of 7-) ethyl) iso-indoles -1,3- diketone (L-6)
By raw material 6- (1- bromoethyls) -7- fluorine quinoline (4.8g, 0.019mol) and potassium phthalimide (4.2g, 0.023mol, 1.2eq) it is dissolved in DMF (30ml), add a little KI, 120 DEG C of heating responses 2 hours.After reaction completely, boil off DMF, add water, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purify yellow consolidate Body 4.8g, yield 78.9%.LC-MS(ESI)：[M+H]+=321；1H-NMR(δppm,CDCl3,400MHz)：8.89(dd,J1 =4.3Hz, J2=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, J1=8.3Hz, J2=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- quinolyls of the fluoro- 3- of 7-) ethyl) iso-indoles -1,3- diketone (L-7)
Raw material 2- (1- (the fluoro- 6- quinolyls of 7-) ethyl) iso-indoles -1,3- diketone (4.8g, 0.015mol) is dissolved in tetrachloro Change in carbon (100ml), be separately added into pyridine (2.38g, 0.03mol, 2eq) and bromine (4.8g, 0.03mol, 2eq), 70 DEG C anti- It should stay overnight.Solvent evaporated after reaction completely, adds aqueous sodium carbonate and is adjusted to alkalescence, dichloromethane extraction, washing, saturated common salt Water washing, column chromatography purifies to obtain yellow solid 2.8g, yield 46.8%.LC-MS(ESI)：[M+H]+=398.8；1H-NMR(δ ppm,CDCl3,400MHz):8.90 (d, J=2.0Hz, 1H), 8.40 (d, J=2.0Hz, 1H), 8.06 (d, J=8.0Hz, 1H),7.85(dd,J1=5.6Hz, J2=2.8Hz, 2H), 7.74 (dd, J1=5.6Hz, J2=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- pyrazolyls) -6- quinolyls) ethyl) iso-indoles -1,3- Diketone (L-8)
By raw material 2- (1- (the bromo- 6- quinolyls of the fluoro- 3- of 7-) ethyl) iso-indoles -1,3- diketone (1.18g, 3mmol), 1- first Base pyrazoles -4- boric acid frequency is which ester (0.92g, 4.4mmol, 1.5eq), catalyst Pd (dppf) Cl2DCM (0.12g, 1.5mmol, 0.05eq) and K2CO3(1.23g, 9mmol, 3eq) is dissolved in dioxane+water (8ml+2ml) solution, argon gas protection Lower 110 DEG C are reacted 4 hours.It is down to after room temperature, adds a large amount of water, ethyl acetate extraction, washing, saturated common salt water washing is anhydrous Sodium sulphate is dried, and filtering is evaporated, and crude product column chromatography purifies to obtain 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- pyrazolyls) -6- quinolyls) ethamine (L)
By raw material 2- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) iso-indoles -1,3- diketone (5.15g, 0.013mol) is dissolved in ethanol (150ml), is added hydrazine hydrate (2g, 0.034mol, 2.6eq), is heated to reflux 5 small When.It is down to after room temperature, separates out solid filtering, filter cake ethyl acetate is washed for several times, and mother liquor is evaporated, and adds a little 5%NaOH water-soluble Liquid, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifies to obtain white solid 1.66g, Yield 47.7%.LC-MS(ESI)：[M+H]+=271.0；1H-NMR(δppm,CDCl3,400MHz):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- (the chloro- 5,7-difluoro-quinoline-6- bases of 3-) ethyl) isoindoline-1,3- diketone (M-2)
2- (1- (5,7- difluoro-quinoline -6- bases) ethyl) isoindoline -1,3- diketone 1.65g (4.88mmol) is taken to be added to In 15mL DMF, lower addition 1- chlorine pyrrolidines -2,5- diketone 2.17g (16.3mmol) are stirred at room temperature.The reaction solution is heated to 125 DEG C reaction 24 hours.Post processing add 30ml water simultaneously add 3.2g sodium bicarbonate solid neutralization reactions, be stirred at room temperature 30 minutes it 4.8g sodium thiosulfate is slowly added to afterwards removes unnecessary 1- chlorine pyrrolidine-2,5-diones.Ethyl acetate extracts (100mL*3), Merge organic phase, saturated nacl aqueous solution is washed, dry, be evaporated obtained crude product and purified by dodging post, obtain 0.6g white solids, Yield：30%.LC-MS(ESI)：[M+H]+=373,1H-NMR(δppm,CDCl3,400MHz)：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), (dt, J=7.5,2.5Hz, the 3H) of 7.62-7.54 (m, 1H), 6.00 (q, J=7.4Hz, 1H), 2.07
Synthesis step 2：2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) iso-indoles Quinoline -1,3- diketone (M-3)
2- (1- (chloro- 5, the 7- difluoro-quinolines -6- bases of 3-) ethyl) isoindoline -1,3- diketone (7g, 18mmol) is dissolved in In Isosorbide-5-Nitrae-dioxane 250ml, 1- methylpyrazole -4- pinacol borates (7.8g, 37mmol), Pd (dppf) are then added Cl20.1 equivalent, the equivalent of Anhydrous potassium carbonate 2 and 62.5ml water.The reaction solution is under argon gas protection, and 110 DEG C of tube sealings are stayed overnight.Concentration Reaction solution, adds 1000ml water and 1000ml ethyl acetate afterwards, separates organic phase, and aqueous phase ethyl acetate extracts (500mL*3), Merge organic phase, salt washing is dried, concentration, (solvent is petroleum ether to remaining crude product by dodging post purification：Dichloromethane=80: 20) target compound 3g, yield, are obtained：38%.LC-MS(ESI)：[M+H]+=419,1H-NMR(δppm,CDCl3, 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,J1=5.5Hz, J2=3.0Hz, 2H), 7.56 (dd, J1=11.4Hz, J2=1.6Hz, 1H), 6.01 (q, J=7.4Hz, 1H), 4.02 (s, 3H), 2.09 (ddd .J1=7.4Hz, J2=2.7Hz, J3=1.5Hz, 3H).
Synthesis step 3：1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethamine (M)
By 2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) isoindoline -1,3- Diketone (0.5g, 1mmol) is dissolved in 30ml ethanol, and (179mg, 3.6mmol) hydrazine hydrate is added afterwards.Reaction solution backflow 2 is small Shi Hou, filters out solid impurity, and the impurity is washed with ethanol.Solvent is screwed out, 100ml ethyl acetate, organic phase 50ml carbonic acid is added Sodium saturated solution is washed, salt washing (50ml*2), is dried, and is filtered, concentration, and residue is purified by dodging post, obtains 0.3g solids, is received Rate：90%.LC-MS(ESI)：[M+H]+=289,1H-NMR(δppm,CDCl3,400MHz):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 formates (K-2)
Method of the intermediate K-2 synthetic method with intermediate K synthesis steps 1.
Synthesis step 2：- 6-formic acid of 3- chloroquinolines (N-3)
Take 3--6-methyl formate of chloroquinoline 6.5g (29mmol) to be added in 80ml methanol, lower addition 1.4g is stirred at room temperature The aqueous solution 20ml of lithium hydroxide (59mmol), is finished, and reaction at room temperature is stayed overnight.Post processing, concentration of reaction solution to 30ml or so, Hydrochloric acid adjusts PH=5-6, filtering, dry product 6.3g after filter cake washing directly to cast single step reaction, yield：99%, LC-MS (ESI)：[M+H]+=208.
Synthesis step 3：The chloro- N- methoxy-. N-methyls quinoline -6- formamides (N-4) of 3-
4.3g (21mmol) 3--6-formic acid of chloroquinoline is added in 60ml dry DMFs, stirred into above-mentioned reaction solution Lower addition 12g (31mmol) O- (7- nitrogen BTA)-N, N, N, N- tetramethylurea hexafluorophosphoric acid esters and 4g (31mmol) two Diisopropylethylamine, is stirred at room temperature addition 3g (31mmol) N, O- dimethyl hydroxylamine hydrochloride after 30min, finishes, room under nitrogen Temperature reaction is stayed overnight.Post processing, reaction solution is poured into 300ml water, ethyl acetate extraction (100ml*3), merges organic phase, 2N's Sodium hydroxide solution is washed, and washing, saturated nacl aqueous solution is washed, and is dried, is evaporated to obtain crude product 2.5g, yield：48%, it is directly used in down Single step reaction.LC-MS(ESI)：[M+H]+=251.
Synthesis step 4：1- (3- chloroquinoline -6- bases) ethyl ketone (N-5)
The chloro- N- methoxy-. N-methyls quinoline -6- formamides of 3.7g (15mmol) 3- are dissolved under nitrogen protection super dry The methyl-magnesium-bromide 6.4ml (19mmol) that 3mol/L is slowly added dropwise in 30ml tetrahydrofurans, under ice bath is finished, slow to recover to room Continue to react 3h after temperature.The aqueous ammonium chloride solution 30ml of saturation is slowly added dropwise under post processing, ice bath into reaction solution, continuation is finished 20ml*3 is extracted with ethyl acetate after stirring 30min, merges organic phase, saturated common salt washing is filtered, solvent evaporated is obtained after drying To product 2.2g, yield：72%, it is directly used in next step reaction.LC-MS(ESI)：[M+H]+=206,1H-NMR(δppm, CDCl3,400MHz):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- fluorophenyls) quinoline -6- bases) ethyl ketone (N-6)
Isosorbide-5-Nitrae-dioxane 20ml, water 4ml are added in tube sealing, 1.36g 4- flurophenyl boronic acids are then added (9.7mmol), 1g 1- (3- chloroquinoline -6- bases) ethyl ketone (4.86mmol), potassium carbonate 1.34g (9.7257mmol) and [1,1'- Double (diphenylphosphino) ferrocene] palladium chloride 119mg (0.14mmol), outer 110 DEG C of reaction 4h of temperature.Silicagel column is passed through in post processing Chromatographic purifying obtains product 1.3g, yield：99%.LC-MS(ESI)：[M+H]+=266.
Synthesis step 6-7：1- (3- (4- fluorophenyls) quinoline -6- bases) ethamine (N)
100ml absolute ethyl alcohols are added into the mono- neck bottles of 250ml, is stirred at room temperature down and sequentially adds 1- (3- (4- fluorophenyls) quinolines Quinoline -6- bases) ethyl ketone 1.3g (4.9mmol), sodium hydroxide 0.39g (9.8mmol) and hydroxylamine hydrochloride 0.67g (9.8mmol), plus Finish, room temperature reaction is stayed overnight.Then 1g or so Raney's nickel is added to reaction solution, at room temperature with 2atm hydrogen reducing 5h, detection is extremely Without starting material left.Post processing, filtering adds 100ml dichloromethane after filtrate concentration, washing is obtained after drying through silica gel column chromatography To product 800mg.Two step yields 61.5%.LC-MS(ESI)：[M+H]+=267,1H-NMR(δppm,DMSO-d6,400MHz): 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)
The synthesis of compound
Embodiment 1：6- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1)-methylene) - Quinoline (compound 1-1)
Step 1 prepares the bromo- N of 6-2- (quinoline -6- methylene) pyrazine -2,3- diamines
By the bromo-pyrazine -2- amine (6.1g, 24mmol) of 3,5- bis-, 6- quinoline benzylidene amino (3.8g, 24mmol) and N, N- bis- Wopropyl ethyl amine (DIPEA) (8.6mL, 48mmol) is added in NMP (20mL), and argon gas protects lower 130 DEG C of reactions to stay overnight.Reaction DIPEA is evaporated off in liquid, and residue is poured into water (100mL), dichloromethane (30mL × 3) extraction, organic phase washing, saturated aqueous common salt Wash, crossing rapid column chromatography after drying obtains 4.7g brown color products, yield：59%.LC-MS(ESI)：[M+H]+=330；1H-NMR (δppm,DMSO-d6,400MHz)：8.85(dd,J1=4.2Hz, J2=1.6Hz, 1H), 8.33 (d, J=8.3Hz, 1H), 7.99 (d, J=8.7Hz, 1H), 7.87 (s, 1H), 7.73 (dd, J1=8.7Hz, J2=1.9Hz, 1H), 7.50 (dd, J1=8.3Hz, J2=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 prepares 6- (the bromo- imidazos of 6- [4,5-b] pyrazine -1- methylene)-quinoline
By the bromo- N of 6-2- (quinoline -6- methylene) pyrazine -2,3- diamines (1.2g, 3.6mmol) is added to orthoformic acid front three In ester (30mL), the formic acid (1mL) of lower addition 98% is stirred at room temperature, finishes, reaction solution flows back 2 days, solvent evaporated, crude product second Acetoacetic ester/petroleum ether (1/1) is washed, and obtains product 1.1g, yield：89%.LC-MS(ESI)：[M+H]+=340；1H-NMR(δ ppm,DMSO-d6,400MHz)：9.01 (s, 1H), 8.88 (dd, J1=4.2Hz, J2=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, J1=8.7Hz, J2=1.7Hz, 1H), 7.51 (dd, J1=8.4Hz, J2=4.2Hz, 1H), 5.72 (s, 2H).
Step 3 prepares 6- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline (compound 1-1)
By 6- (the bromo- imidazos of 6- [4,5-b] pyrazine -1- methylene)-quinoline (100mg, 0.29mmol), 1- methyl isophthalic acids H- Pyrazoles -4- pinacol borates (121mg, 0.58mmol), potassium carbonate (122mg, 0.88mmol) and [1,1'- double (diphenyl Phosphorus) ferrocene] palladium chloride (20mg) is added to the in the mixed solvent of dioxane (4mL) and water (1mL), and reaction solution is in tube sealing Middle bulging argon gas 5min, then reacts 3h at 110 DEG C.After being separated after reaction solution concentration through rapid column chromatography, gained solid first Alcohol washes to obtain white solid 60mg, yield：60%.LC-MS(ESI)：[M+H]+=342；1H-NMR(δppm,DMSO-d6, 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, J1=8.7Hz, J2=2.0Hz, 1H), 7.53 (dd, J1=8.4Hz, J2= 4.2Hz, 1H), 5.73 (s, 2H), 3.91 (s, 3H).
2~embodiment of embodiment 18
According to the same procedure of embodiment 1, using different boric acid or borate, 2~embodiment of embodiment 18 is prepared Compound, specific experiment data are shown in Table 1.
The compound 1-2 of table 1~compound 1-18 experimental data table
Embodiment 19：6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline (compound 1-19)
Step 1 prepares the bromo- N of 6-2- (1- (6- quinolyls) ethyl) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1, obtains 6- bromo- by 1- (quinoline -6- bases) ethamine replacement 6- quinoline benzylidene aminos N2- (1- (6- quinolyls) ethyl) pyrazine -2,3- diamines, dark brown solid, yield is 68%.LC-MS(ESI)：[M+H]+= 344；1H-NMR(δppm,DMSO-d6,400MHz)：8.85(dd,J1=4.2Hz, J2=1.7Hz, 1H), 8.34 (dd, J1= 8.4Hz,J2=0.9Hz, 1H), 7.99 (d, J=8.7Hz, 1H), 7.89 (d, J=1.7Hz, 1H), 7.79 (dd, J1=8.7Hz, J2=2.0Hz, 1H), 7.50 (dd, J1=8.3Hz, J2=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, J1= 8.8Hz,J2=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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- (1- (6- quinolyls) ethyl) pyrazine -2,3- diamines and two Ethyoxyl methyl acetate reacts to obtain dark brown solid, and yield is 50.1%.LC-MS(ESI)：[M+H]+=354；1H-NMR(δ ppm,DMSO-d6,400MHz)：9.18(s,1H),8.90(dd,J1=4.2Hz, J2=1.7Hz, 1H), 8.68 (s, 1H), 8.37 (dd,J1=8.5Hz, J2=1.0Hz, 1H), 8.02 (d, J=8.8Hz, 1H), 7.95 (d, J=2.0Hz, 1H), 7.81 (dd, J1 =8.8Hz, J2=2.1Hz, 1H), 7.54 (dd, J1=8.3Hz, J2=4.2Hz, 1H), 6.19 (q, J=7.1Hz, 1H), 2.11 (d, J=7.2Hz, 3H).
Step 3 prepares 6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline (compound 1-19)
The method of the step 3 of reference implementation example 1, by 6- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) ethyl) quinoline Quinoline reacts to obtain white solid, yield 53% with 1- methylpyrazole -4- pinacol borates.LC-MS(ESI)：[M+H]+=356；1H-NMR(δppm,DMSO-d6,400MHz)：9.00 (s, 1H), 8.88 (dd, J1=4.2Hz, J2=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, J1= 8.3Hz,J2=4.2Hz, 1H), 6.19 (q, J=7.1Hz, 1H), 3.91 (s, 3H), 2.15 (d, J=7.2Hz, 3H).
20~embodiment of embodiment 49
According to the same procedure of embodiment 19, using different boric acid or borate, 20~embodiment of embodiment 49 is prepared Compound, specific experiment data are shown in Table 2.
The compound 1-20 of table 2~compound 1-49 experimental data table
Embodiment 50：The fluoro- 6- of 8- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) Methyl) quinoline (compound 1-50)
Step 1 prepares the bromo- N of 6-2- ((the fluoro- 6- quinolyls of 8-) methyl) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1, obtains 6- bromo- by 6- aminomethyl -8- fluorine quinoline replacement 6- quinoline benzylidene aminos N2- ((the fluoro- 6- quinolyls of 8-) methyl) pyrazine -2,3- diamines, orange solid, yield 50.8%.LC-MS(ESI)：[M+H]+= 348；1H-NMR(δppm,DMSO-d6,400MHz)：8.92(dd,J1=4.0Hz, J2=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 prepares 6- ((bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) methyl) -8- fluorine quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- ((the fluoro- 6- quinolyls of 8-) methyl) pyrazine -2,3- diamines with Diethoxy methyl acetate reacts to obtain orange solid, yield 71.7%.LC-MS(ESI)：[M+H]+=358；1H-NMR(δppm, DMSO-d6,400MHz)：9.01 (s, 1H), 8.95 (dd, J1=4.0Hz, J2=1.6Hz, 1H), 8.70 (s, 1H), 8.41 (d, J =8.4Hz, 1H), 7.70 (s, 1H), 7.68 (dd, J1=9.6Hz, J2=1.6Hz, 1H), 7.64 (dd, J1=8.4Hz, J2= 4.0Hz, 1H), 5.72 (s, 2H).
Step 3 prepares the fluoro- 6- of 8- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) Methyl) quinoline (compound 1-50)
The method of the step 3 of reference implementation example 1, by 6- ((bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) methyl) -8- Fluorine quinoline reacts to obtain white solid, yield 65.7% with 1- methylpyrazole 4- pinacol borates.LC-MS(ESI)：[M+H]+= 360；1H-NMR(δppm,DMSO-d6,400MHz)：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, J1=8.0Hz, J2= 4.0Hz, 1H), 5.72 (s, 2H), 3.91 (s, 3H).
51~embodiment of embodiment 56
According to the same procedure of embodiment 50, using different boric acid or borate, 51~embodiment of embodiment 56 is prepared Compound, specific experiment data are shown in Table 3.
The compound 1-51 of table 3~compound 1-56 experimental data table
Embodiment 57：Fluoro- (6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- of 8- Base) ethyl) quinoline (compound 1-57)
Step 1 prepares the bromo- N of 6-2- (1- (the fluoro- 6- quinolyls of 8-) ethyl) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1,1- (8- fluorine quinoline -6- bases) ethamine replacement 6- quinoline benzylidene aminos are obtained The bromo- N of 6-2- (1- (the fluoro- 6- quinolyls of 8-) ethyl) pyrazine -2,3- diamines, yield 66.8%.LC-MS(ESI)：[M+H]+= 362；1H-NMR(δppm,CDCl3,400MHz)：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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -8- fluorine quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- (1- (the fluoro- 6- quinolyls of 8-) ethyl) pyrazine -2,3- diamines Orange solid, yield 65.6% are reacted to obtain with diethoxy methyl acetate.LC-MS(ESI)：[M+H]+=372；1H-NMR(δ ppm,CDCl3,400MHz)：9.02(dd,J1=4.4Hz, J2=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, J1=8.4Hz, J2=4.4Hz, 1H), 7.42 (dd, J1=10.8Hz, J2=1.6Hz, 1H), 6.14 (q, J=7.2Hz, 1H), 2.17 (d, J=7.2Hz, 3H).
Step 3 prepares fluoro- (6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- of 8- Base) ethyl) quinoline (compound 1-57)
The method of the step 3 of reference implementation example 1, by 6- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) ethyl) - 8- fluorine quinoline reacts to obtain yellow solid, yield 55.0% with 1- methylpyrazole 4- pinacol borates.LC-MS(ESI)：[M+H]+ =374；1H-NMR(δppm,CDCl3,400MHz)：8.92(dd,J1=4.0Hz, J2=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).
58~embodiment of embodiment 68
According to the same procedure of embodiment 57, using different boric acid or borate, 58~embodiment of embodiment 68 is prepared Compound, specific experiment data are shown in Table 4.
The compound 1-58 of table 4~1-68 experimental data table
Embodiment 69：6- [6- (1- methyl isophthalic acid H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene]-quinoline (compound 1-69)
Step 1 prepares the bromo- N of 6-2- (7- fluorine quinoline -6- methylene) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1,6- quinoline benzylidene aminos are substituted by the fluoro- 6- quinoline benzylidene amino hydrochlorides of 7- Obtain the bromo- N of 6-2- (7- fluorine quinoline -6- methylene) pyrazine -2,3- diamines, yield=75%.LC-MS(ESI)：[M+H]+= 348.Step 2 prepares 6- (the bromo- imidazos of 6- [4,5-b] pyrazine -1- methylene) -7- fluorine quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- (7- fluorine quinoline -6- methylene) pyrazine -2,3- diamines and original Trimethyl orthoformate reacts, and obtains brown solid, yield：65%.LC-MS(ESI)：[M+H]+=358；1H-NMR(δppm,DMSO- d6,400MHz)：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, J1=8.3Hz, J2=4.2Hz, 1H), 5.77 (s, 2H)。
The step 3 preparation fluoro- 6- of 7- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene) - Quinoline (compound 1-69)
The method of the step 3 of reference implementation example 1, by 6- (the bromo- imidazos of 6- [4,5-b] pyrazine -1- methylene) -7- fluorine quinoline White solid, yield are reacted to obtain with 1- methyl isophthalic acid H- pyrazoles -4- pinacol borates：50%.LC-MS(ESI)：[M+H]+= 360；1H-NMR(δppm,DMSO-d6,400MHz)：8.91(dd,J1=4.3Hz, J2=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, J1=8.3Hz, J2=4.3Hz, 1H), 5.78 (s, 2H), 3.90 (s, 3H).
70~embodiment of embodiment 86
According to the same procedure of embodiment 69, using different boric acid or borate, 70~embodiment of embodiment 86 is prepared Compound, specific experiment data are shown in Table 5.
The compound 1-70 of table 5~compound 1-86 experimental data table
Embodiment 87：The fluoro- 6- of 7- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-87)
Step 1 prepares the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1,1- (the fluoro- 6- quinolyls of 7-) ethamine replacement 6- quinoline benzylidene aminos are obtained The bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines, yield：50%.LC-MS(ESI)：[M+H]+=362 ；1H-NMR(δppm,DMSO-d6,400MHz)：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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines Brown solid, yield are obtained with the reaction of acetic acid diethoxy methyl esters：60%.LC-MS(ESI)：[M+H]+=372；1H-NMR(δ ppm,DMSO-d6,400MHz)：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, J1=8.2Hz, J2= 4.0Hz, 1H), 6.33 (q, J=7.1Hz, 1H), 2.11 (d, J=7.1Hz, 3H).
Step 3 prepares the fluoro- 6- of 7- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-87)
The method of the step 3 of reference implementation example 1, by 6- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) ethyl) - 7- fluorine quinoline reacts to obtain white solid, yield with 1- methylpyrazole -4- pinacol borates：75%.LC-MS(ESI)：[M+H]+ =374；1H-NMR(δppm,DMSO-d6,400MHz)：8.93 (s, 1H), 8.91 (dd, J1=4.2Hz, J2=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, J1=8.1Hz, J2=4.2Hz, 1H), 6.35 (q, J=7.1Hz, 1H), 3.89 (s, 3H), 2.16 (d, J=7.1Hz, 3H).
88~embodiment of embodiment 110
According to the same procedure of embodiment 87, using different boric acid or borate, 88~embodiment of embodiment 110 is prepared Compound, specific experiment data are shown in Table 6.
The compound 1-88 of table 6~compound 1-110 experimental data table
Embodiment 111：The fluoro- 6- of 5,7- bis- ((6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine - 1- yls) methyl) quinoline (compound 1-111)
Step 1 prepares the bromo- N of 6-2- ((5,7- difluoro-quinoline -6- bases) methyl) pyrazine -2,3- diamines
The synthetic method of the step 1 of reference implementation example 1, yield：48.7%.LC-MS(ESI)：[M+H]+=366；1H-NMR(δ ppm,DMSO-d6,400MHz)：9.01(dd,J1=4.4Hz, J2=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 prepares 6- ((bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) methyl) -5,7- difluoro-quinolines
The synthetic method of the step 2 of reference implementation example 1, yield：32%.LC-MS(ESI)：[M+H]+=376；1H-NMR(δ ppm,DMSO-d6,400MHz)：9.01(dd,J1=4.4Hz, J2=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 prepares the fluoro- 6- of 5,7- bis- ((6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) methyl) quinoline (compound 1-111)
The synthetic method of the step 3 of reference implementation example 1, yield：52%.LC-MS(ESI)：[M+H]+=378；1H-NMR(δ ppm,DMSO-d6,400MHz)：9.02(dd,J1=4.0Hz, J2=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).
112~embodiment of embodiment 117
According to the same procedure of embodiment 111, using different boric acid or borate, 112~embodiment of embodiment is prepared 117 compound, specific experiment data are shown in Table 7.
The compound 1-112 of table 7~compound 1-117 experimental data table
Embodiment 118：The fluoro- 6- of 5,7- bis- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrroles Piperazine -1- bases) ethyl) quinoline (compound 1-118)
Step 1 prepares the bromo- N of 6-2- (1- (5,7- difluoro-quinoline -6- bases) ethyl) pyrazine -2,3- diamines
By the bromo-pyrazine -2- amine (2.16g, 8.56mmol) of 3,5- bis-, 1- (5,7- difluoro-quinoline -6- bases) ethamine (1.18g, 5.7mmol) it is added to DIPEA (2.2g, 17mmol) in NMP (15mL), argon gas protects lower 200 DEG C of reactions to stay overnight.Reaction solution Cooling, is poured into water (100mL), and ethyl acetate (50mL × 3) extraction, organic phase water (50mL × 2) is washed, saturated aqueous common salt (50mL) is washed, and crossing rapid column chromatography after drying obtains yellow solid 1.3g, yield：60%.LC-MS(ESI)：[M+H]+=380；1H NMR(δppm,CDCl3,400MHz)：8.92(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.39 (dd, J1=8.4Hz, J2= 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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5,7- difluoro-quinolines
The bromo- N of 6- will be prepared2- (1- (5,7- difluoro-quinoline -6- bases) ethyl) pyrazine -2,3- diamines (1g, 2.6mmol) adds Enter into diethoxy methyl acetic acid ester (9.2mL), 150 DEG C of argon gas protection tube sealing reactions are stayed overnight.Solvent evaporated, crude product is through silicagel column Purifying, obtains brown solid 0.8g, yield：80%.LC-MS(ESI)：[M+H]+=390；1H NMR(δppm,CDCl3, 400MHz)：8.97(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.62 (t, J=1.3Hz, 1H), 8.60 (s, 1H), 8.41 (dd,J1=8.4Hz, J2=1.7Hz, 1H), 7.64 (dd, J1=11.8Hz, J2=1.7Hz, 1H), 7.48 (dd, J1=8.4Hz, J2=4.3Hz, 1H), 6.55-6.49 (m, 1H), 2.23 (d, J=7.3Hz, 3H).
The fluoro- 6- of step 3 preparation 5,7 2 (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine - 1- yls) ethyl) quinoline (compound 1-118)
By 6- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) ethyl) -5,7- difluoro-quinolines (113mg, 0.29mmol), 1- methylpyrazoles -4- pinacol borates (75mg, 0.6mmol), potassium carbonate (122mg, 0.88mmol) and [1, Double (diphenylphosphine) ferrocene of 1'-] palladium chloride (20mg) is added to the in the mixed solvent of dioxane (4mL) and water (1mL), Reaction solution drum argon gas 5min in tube sealing, then reacts 3h, reaction solution separates to obtain brown solid through rapid column chromatography at 110 DEG C 70mg, yield：61%.LC-MS(ESI):[M+H]+=392；1H NMR(δppm,DMSO-d6,400MHz)：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).
119~embodiment of embodiment 146
According to the same procedure of embodiment 118, using different boric acid or borate, 119~embodiment of embodiment is prepared 146 compound, specific experiment data are shown in Table 8.
The compound 1-119 of table 8~compound 1-146 experimental data table
Embodiment 147：7- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine - 1- yls) ethyl) quinoline (compound 1-147)
Step 1 prepares the bromo- N of 6-2- (1- (7- methylquinoline -6- bases) ethyl) pyrazine -2,3- diamines
The legal manner of the step 1 of reference implementation example 1, obtains faint yellow solid, yield：60%.LC-MS(ESI)：[M+H]+ =358；1H-NMR(δppm,DMSO-d6,400MHz)：8.80(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.27 (dt, J1= 8.4Hz,J2=1.3Hz, 1H), 7.88 (s 1H), 7.82 (s, 1H), 7.42 (dd, J1=8.2Hz, J2=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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- methylquinolines
The legal manner of the step 2 of reference implementation example 1, obtains gray solid, yield：60%.LC-MS(ESI)：[M+H]+= 368；1H-NMR(δppm,CDCl3,400MHz)：8.96(dd,J1=4.3Hz, J2=1.7Hz, 1H), 8.67 (s, 1H), 8.18 (dt,J1=8.3Hz, J2=1.3Hz, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.44 (dd, J1= 8.3Hz,J2=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 prepares 7- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-147)
The legal manner of the step 3 of reference implementation example 1, obtains faint yellow solid, yield：71%.LC-MS(ESI):[M+H]+ =370；1H-NMR(δppm,CDCl3,400MHz)：8.96(dd,J1=4.3Hz, J2=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, J1=8.3Hz, J2=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)。
148~embodiment of embodiment 154
According to the same procedure of embodiment 147, using different boric acid or borate, 148~embodiment of embodiment is prepared 154 compound, specific experiment data are shown in Table 9.
The compound 1-148 of table 9~compound 1-154 experimental data table
Embodiment 155：5- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine - 1- yls) ethyl) quinoline (compound 1-155)
Step 1 prepares the bromo- N of 6-2- (1- (5- methylquinoline -6- bases) ethyl) pyrazine -2,3- diamines
The legal manner of the step 1 of reference implementation example 1, obtains faint yellow solid, yield：30%.LC-MS(ESI)：[M+H]+ =358；1H-NMR(δppm,DMSO-d6,400MHz)：8.84(dd,J1=4.1Hz, J2=1.6Hz, 1H), 8.60-8.57 (m, 1H), 7.87-7.76 (m, 2H), 7.54 (dd, J1=8.6Hz, J2=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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5- methylquinolines
The legal manner of the step 2 of reference implementation example 1, obtains brown solid, yield：60%.LC-MS(ESI)：[M+H]+= 368；1H-NMR(δppm,DMSO-d6,400MHz)：9.22 (s, 1H), 8.89 (dd, J1=4.3Hz, J2=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, J1=8.6Hz, J2= 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 prepares 5- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-155)
The legal manner of the step 3 of reference implementation example 1, obtains crocus solid, yield：70%.LC-MS(ESI)：[M+H]+ =370；1H-NMR(δppm,CDCl3,400MHz)：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,J1=8.4Hz, J2=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)
156~embodiment of embodiment 160
According to the same procedure of embodiment 155, using different boric acid or borate, 156~embodiment of embodiment is prepared 160 compound.Specific experiment data are shown in Table 10.
The compound 1-156 of table 10~compound 1-160 experimental data table
Embodiment 161：3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (4- methylpiperazine-1-yls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 1-161)
Step 1 prepares the bromo- N of 6-2- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- Diamines
The bromo-pyrazine of 2- amino -3,5- bis- (257mg, 1.02mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower to add 1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethamine (385mg, 1.53mmol) and 6ml N, N- bis- Wopropyl ethyl amine.The reaction solution is heated to 210 DEG C of tube sealings and stayed overnight under argon gas protection.Concentration of reaction solution, by crude product by dodging (solvent is dichloromethane for post purification：Methanol=95:5).Obtain about 260mg brown solids, yield 60%.LC-MS(ESI)： [M+H]+=424,1H-NMR(δppm,DMSO-d6,400MHz):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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -3- (1- methyl isophthalic acid H- pyrroles Azoles -4- bases) quinoline
By the bromo- N of 6-2- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- diamines (100mg, 0.24mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, and the reaction is heated to 150 DEG C of tube sealings and stayed overnight.Concentration reaction Liquid, by dodging post purification, (solvent is methanol to remaining crude product：Dichloromethane=0% to 5%).59mg light tan solids are obtained, Yield：58%.LC-MS(ESI)：[M+H]+=435,1H-NMR(δppm,CDCl3,400MHz):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 prepares 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (4- methylpiperazine-1-yls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 1-161)
By 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -3- (1- methyl isophthalic acid H- pyrazoles -4- bases) Quinoline (60mg, 0.14mmol) is dissolved in 5ml1- N-methyl-2-2-pyrrolidone Ns, then sequentially adds the 1- methyl piperazines of 3 equivalents Piperazine, the potassium fluoride of 5 equivalents and the DIPEA of 4 equivalents.170 DEG C of reaction solution tube sealing reaction 2 hours.Concentration Reaction solution, by dodging post purification, (solvent is dichloromethane to remaining crude product：Methanol=94：6) 28.7mg yellow solid powder, is obtained End, yield：69%.LC-MS(ESI)：[M+H]+=454,1H-NMR(δppm,DMSO-d6,400MHz):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)
162~embodiment of embodiment 163
According to the same procedure of embodiment 161, the compound of embodiment 162 is prepared.Wherein embodiment 163 uses phase The borate answered, is reacted by SUZUKI and synthesized.Specific experiment data are shown in Table 11.
The compound 1-162 of table 11~compound 1-163 experimental data table
Embodiment 164：3- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (6- (1- methyl isophthalic acid H-4- pyrazolyls)-[1,2,3] three Nitrogen azoles simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline (compound 2-1)
Step 1 prepares the bromo- N of 6-2- (quinoline -6- methylene) pyrazine -2,3- diamines
By the bromo-pyrazine -2- amine (6.1g, 24mmol) of 3,5- bis-, 6- quinoline benzylidene amino (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) is added in NMP (20ml), and argon gas protects lower 130 DEG C of reactions to stay overnight.DIPEA, residue is evaporated off in reaction solution Pour into water (100ml), dichloromethane (30ml × 3) extraction, organic phase washing, saturated common salt washing, excessively quick post after drying Chromatograph to obtain brown color product 4.7g, yield：59%.LC-MS(ESI)：[M+H]+=330；1H-NMR(δppm,DMSO-d6, 400MHz)：8.85(dd,J1=4.2Hz, J2=1.6Hz, 1H), 8.33 (d, J=8.3Hz, 1H), 7.99 (d, J=8.7Hz, 1H), 7.87 (s, 1H), 7.73 (dd, J1=8.7Hz, J2=1.9Hz, 1H), 7.50 (dd, J1=8.3Hz, J2=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 prepares 6- (bromo- [1,2,3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline
By the bromo- N of raw material 6-2- (quinoline -6- methylene) pyrazine -2,3- diamines (500mg, 1.5mmol) is dissolved in dry DMF In (10ml), isoamyl nitrite (356mg, 3mmol, 2eq), the lower 70 DEG C of reactions 3h of argon gas protection are added.After reaction completely, steam Dry solvent, crude product ethyl acetate mashing purifies to obtain yellow solid 217mg, yield 42.0%.LC-MS(ESI)：[M+H]+= 340.8；1H-NMR(δppm,DMSO-d6,400MHz):9.02(s,1H),8.91(dd,J1=4.0Hz, J2=2.0Hz, 1H), 8.36(dd,J1=8.4Hz, J2=0.8Hz, 1H), 8.03 (d, J=8.8Hz, 1H), 7.94 (d, J=2.0Hz, 1H), 7.78 (dd,J1=8.8Hz, J2=2.0Hz, 1H), 7.54 (dd, J1=8.4Hz, J2=4.0Hz, 1H), 6.19 (s, 2H)
Step 3 prepares 3- bromo- 6- (bromo- [1,2,3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline
By raw material 6- (bromo- [1,2, the 3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline (100mg, 0.3mmol) It is dissolved in carbon tetrachloride (10ml), is separately added into pyridine (47mg, 0.6mmol, 2eq) and bromine (94mg, 0.6mmol, 2eq), 80 DEG C of reaction 4h.Solvent evaporated after reaction completely, adds aqueous sodium carbonate and is adjusted to alkalescence, dichloromethane extraction, washing, saturation Brine It, column chromatography purifies to obtain yellow solid 82mg, yield 66.7%.LC-MS(ESI)：[M+H]+=418.7；1H-NMR (δppm,DMSO-d6,400MHz):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, J1=8.8Hz, J2=2.0Hz, 1H), 6.21 (s, 2H).
Step 4 prepares 3- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (6- (1- methyl isophthalic acid H-4- pyrazolyls)-[1,2,3] three nitrogen Azoles simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline (compound 2-1)
By the bromo- 6- of raw material 3- (bromo- [1,2, the 3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- ylmethyls) quinoline (80mg, 0.19mmol), 1- methyl isophthalic acids H- pyrazoles -4- pinacol borates (100mg, 0.48mmol, 2.5eq), catalyst Pd (dppf) Cl2DCM (8mg, 0.01mmol, 0.05eq) and K2CO3(79mg, 0.57mmol, 3eq) is dissolved in dioxane+water (2ml+ 0.5ml) in solution, argon gas protects lower 110 DEG C of reactions to stay overnight.Solvent evaporated, residue prepares plate and purifies to obtain white solid 56mg, Yield 70.0%.LC-MS(ESI)：[M+H]+=422.9；1H-NMR(δppm,DMSO-d6,400MHz):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, J1=8.4Hz, J2=2.0Hz, 1H),6.15(s,2H),3.95(s,3H),3.90(s,3H).
165~embodiment of embodiment 168
According to the same procedure of embodiment 164, using different boric acid or borate, 165~embodiment of embodiment is prepared 168 compound.Specific experiment data are shown in Table 12.
The compound 2-2 of table 12~compound 2-5 experimental data table
Embodiment 169:The fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (1- methyl isophthalic acid H-4- pyrazolyls) - [1,2,3] triazole simultaneously [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-6)
Step 1 prepares the bromo- N of 5-3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) pyrazine - 2,3- diamines
By raw material 1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethamine (403mg, 1.5mmol), 2- The bromo-pyrazine of amino -3,5- bis- (453mg, 1.8mmol, 1.2eq) and DIPEA (578mg, 4.5mmol, 3eq) are dissolved in NMP (5ml) In, argon gas protects lower 200 DEG C of reactions to stay overnight.After reaction completely, a large amount of water, ethyl acetate extraction, washing, saturated aqueous common salt are added Washing, anhydrous sodium sulfate drying, filtering is evaporated, and crude product column chromatography purifies to obtain orange solid 371mg, yield 56.4%.LC-MS (ESI)：[M+H]+=441.9.
Step 2 prepares 6- (1- (bromo- [1,2,3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- bases) ethyl) the fluoro- 3- (1- of -7- Methyl isophthalic acid H-4- pyrazolyls) quinoline
By the bromo- N of raw material 5-3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) pyrazine -2,3- Diamines (462mg, 1.05mmol) is dissolved in dry DMF (8ml), adds isoamyl nitrite (246mg, 2.1mmol, 2eq), argon The lower 80 DEG C of reactions 2h of gas shielded.After reaction completely, solvent evaporated, crude product column chromatography purifies to obtain yellow solid 383mg, yield 80.7%.LC-MS(ESI)：[M+H]+=452.8.
Step 3 preparation 7- fluoro- 3- (1- methyl isophthalic acid H-4- pyrazolyls) -6- (1- (6- (1- methyl isophthalic acid H-4- pyrazolyls)-[1, 2,3] triazole simultaneously [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-6)
By raw material 6- (1- (bromo- [1,2,3] triazoles of 6- simultaneously [4,5-b] pyrazine -1- bases) ethyl) -7- fluoro- 3- (1- first Base -1H-4- pyrazolyls) quinoline (80mg, 0.18mmol), 1- methyl isophthalic acid H- pyrazoles -4- pinacol borates (55mg, 0.26mmol, 1.5eq), catalyst Pd (dppf) Cl2DCM (7mg, 0.008mmol, 0.05eq) and K2CO3(73mg, 0.53mmol, 3eq) it is dissolved in dioxane+water (2ml+0.5ml) solution, argon gas protects lower 110 DEG C of reactions to stay overnight.It is down to room Wen Hou, adds a large amount of water, and ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, crude product Prepare plate and purify to obtain yellow solid 45mg, yield 56.3%.LC-MS(ESI)：[M+H]+=455.0；1H-NMR(δppm,DMSO- d6,400MHz):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)
170~embodiment of embodiment 179
According to the same procedure of embodiment 169, using different boric acid or borate, the change of embodiment 170~179 is prepared Compound, specific experiment data are shown in Table 13.
The compound 2-8 of table 13~compound 2-9 experimental data table
Embodiment 180：3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-17)
Step 1 prepares the bromo- N of 6-2- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- Diamines
The bromo-pyrazine of 2- amino -3,5- bis- (257mg, 1.02mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower to add 1- [3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases] ethamine (385mg, 1.53mmol) and 6ml N, N- bis- Wopropyl ethyl amine.The reaction solution is heated to 190 DEG C of reactions and stayed overnight under argon gas protection.Concentration of reaction solution, by crude product by dodging (solvent is dichloromethane for post purification：Methanol=95:5).About 260mg brown solids are obtained, yield is 60.3%.
LC-MS(ESI)：[M+1]+=424,1H-NMR(δppm,DMSO-d6,400MHz):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, J1=8.7Hz, J2=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 prepares 6- (1- (6- bromo- 1H- [1,2,3] triazole simultaneously [4,5-b] pyrazine -1- bases) ethyl) -3- (1- first Base -1H- pyrazoles -4- bases) quinoline
By the bromo- N of 6-2- (1- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- diamines (100mg, 0.24mmol) is dissolved in 5mL DMF, is added isoamyl nitrite (56mg, 0.48mmol) and is heated to 70 DEG C, reaction 2h.Concentration of reaction solution, by dodging post purification, (solvent is methanol to remaining crude product：Dichloromethane=0% to 5%).Obtain 59mg Light tan solid, yield is 57.6%.LC-MS(ESI)：[M+1]+=435,1H-NMR(δppm,CDCl3,400MHz):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 preparation 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1, 2,3] triazole simultaneously [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-17)
By 6- (1- (6- bromo- 1H- [1,2,3] triazole simultaneously [4,5-b] pyrazine -1- bases) ethyl) -3- (1- methyl isophthalic acid H- pyrroles Azoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in Isosorbide-5-Nitrae-dioxane 12ml, then adds 1- methylpyrazole -4- boric acid frequency Which alcohol ester (44mg, 0.21mmol), Pd (dppf)2Cl2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.The reaction solution is under argon gas protection, and 110 DEG C of tube sealings are stayed overnight.Concentration of reaction solution, remaining crude product purifies (expansion by dodging post Agent is methanol：Dichloromethane=5：95) target compound, is obtained.Yield=62.33%.LC-MS(ESI)：[M+1]+=437,1H-NMR(δppm,DMSO-d6,400MHz):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,J1=8.7Hz, J2=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)
181~embodiment of embodiment 186
According to the same procedure of embodiment 180, using different boric acid or borate, 181~embodiment of embodiment is prepared 186 compound, specific experiment data are shown in Table 14.
The compound 2-18 of table 14~compound 2-23 experimental data table
The 3- of embodiment 187 (4- fluorophenyls) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazols [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-24)
Step 1 prepares the bromo- N of 6-2- (1- (3- (4- fluorophenyls) quinoline -6- bases) ethyl) pyrazine -2,3- diamines
10mlN- methyl pyrrolidones are added in single neck bottle, the bromo-pyrazine -2- amine 0.71g of 3,5- bis- are sequentially added (2.8mmol), 1- (3- (4- fluorophenyls) quinoline -6- bases) ethamine 0.75g (2.8mmol) and diisopropyl ethyl amine 0.73g (5.6mmol) is finished, and nitrogen protects lower 190 DEG C of reactions to stay overnight, and LC-MS is detected without raw material.Post processing, is added into reaction solution 200ml dichloromethane, is washed with saturated aqueous sodium carbonate successively, washing, saturated common salt washing, through silicagel column after organic layer drying Chromatography obtains product 0.65g, yield：53%.LC-MS(ESI)：[M+H]+=438,1H-NMR(δppm,DMSO-d6, 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,J1=8.7Hz, J2=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 prepares 6- (1- (6- bromo- 1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -3- (4- fluorobenzene Base) quinoline
10ml dry DMFs are added into single neck bottle, the bromo- N of 6- are then added2- (1- (3- (4- fluorophenyls) quinoline -6- bases) Ethyl) pyrazine -2,3- diamines 650mg (1.48mmol) and isoamyl nitrite 350mg (2.96mmol), finish, nitrogen protection Under be warming up to 75 DEG C, react 3h.Post processing, solvent evaporated, crude product 100ml dichloromethane is dissolved, and saturated sodium carbonate is used successively The aqueous solution is washed, washing, saturated common salt washing, through the isolated product 260mg of silica gel column chromatography, yield after organic layer drying 39%.LC-MS(ESI)：[M+H]+=449,1H-NMR(δppm,DMSO-d6,400MHz):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,J1=8.8Hz, J2=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 prepares 3- (4- fluorophenyls) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazols [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-24)
By 6- (1- (6- bromo- 1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -3- (4- fluorophenyls) quinoline (60mg, 0.13mmol) is dissolved in Isosorbide-5-Nitrae-dioxane 12ml, then adds (42mg, 0.20mmol) 1- methyl -4- pyrazoles boron Sour pinacol ester, Pd (dppf)2Cl2(11mg, 0.013mmol), Anhydrous potassium carbonate (39mg, 0.26mmol) and 3ml water.This is anti- Answer liquid under argon gas protection, 110 DEG C of tube sealings are stayed overnight.Concentration of reaction solution, by dodging post purification, (solvent is methanol to remaining crude product： Dichloromethane=5：95) target compound 16mg, yield, are obtained：25%, LC-MS (ESI)：[M+H]+=451,1H-NMR(δ ppm,DMSO-d6,400MHz):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), (d, J=7.1Hz, the 3H) of 6.61 (q, J=7.1Hz, 1H), 3.94 (s, 3H), 2.27
The fluoro- N- methyl -4- of the 2- of embodiment 188 (7- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- ylmethyls) imidazoles And [1,2-b] [1,2,4] triazine -2- bases) benzamide (compound 3-1)
Step 1 prepares quinoline -6- acetic acid esters
Dry methylene chloride 50ml is added into 100ml round bottom three-necked bottles, 6- oxyquinolines 4.5g is sequentially added under stirring (31mmol) and pyridine 2.9g (37mmol), is cooled to 0 DEG C, and chloroacetic chloride 2.9g (37mmol) is slowly added dropwise, finishes, room temperature is stirred Mix, reaction is stayed overnight.Post processing, reaction solution is poured into the cold saturated aqueous sodium carbonates of 200ml, organic phase, aqueous phase two is separated Chloromethanes extracts 50ml*2, merges organic phase, and saturated aqueous common salt washing obtains product 3g, yield 52% is directly cast after drying One step.LC-MS(ESI)：[M+H]+=188.
Step 2 prepares 3- bromoquinoline -6- acetic acid esters
20ml carbon tetrachloride is added into 100ml single port bottles, 1g (5.34mmol) quinoline -6- acetic acid is sequentially added under stirring Ester, 1.06g (13.4mmol) pyridines and 2.13g (13.4mmol) bromine, finish, are heated to reflux 2h, be cooled to room temperature, steam molten Agent, residue adds 100ml dichloromethane to dissolve, and hypo solution and aqueous sodium carbonate are washed, saturated common salt washing, dries After be evaporated and obtain product 1.1g, yield：77%.LC-MS(ESI)：[M+H]+=266,1H-NMR(δppm,CDCl3,400MHz): 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,J1=9.0Hz, J2=2.4Hz, 1H), 2.39 (s, 3H)
Step 3 prepares 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- acetic acid esters
25ml dioxane and 5ml water are added in 100ml single port bottles, add thereto 1g (3.76mmol) 3- bromoquinolines- 6- acetic acid esters, 1.56g (7.52mmol) 1- methylpyrazole -4- pinacol borates, potassium carbonate 1.04g (7.52mmol) and 86mg (0.11mmol) 1,1'- bis- (diphenylphosphine) ferrocene palladium chloride chloride dichloromethane complex, is finished, and is heated under nitrogen protection 110 DEG C of reaction 4h.Post processing, reaction solution is poured into 100ml dichloromethane and washed, saturated common salt washing, and filtration is crossed after drying Dry solvent, obtains crude product 0.75g, and yield 75% directly throws next step.LC-MS(ESI)：[M+H]+=268.
Step 4 prepares 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- alcohol
The crude product 750mg (2.8mmol) of previous step is dissolved in 25ml methanol, takes 235mg (5.6mol) lithium hydroxide molten In 5ml water, it is then added in methanol solution, reaction solution is heated to 60 DEG C, reacts 2h.Post processing, reaction solution is concentrated into Half, adds 10ml water, and 4N hydrochloric acid adjusts PH=6 or so, filtering, dry product 600mg, yield 95% after filter cake washing. LC-MS(ESI)：[M+H]+=226,1H-NMR(δppm,DMSO-d6,400MHz):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,J1=9.1Hz, J2=2.6Hz, 1H), 7.10 (d, J=2.6Hz, 1H), 3.91 (s, 3H)
Step 5 prepares 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- triflates
In the dichloromethane dried to 50ml add 600mg (2.66mmol) 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline - 902mg (3.20mmol) trifluoromethanesulfanhydride anhydride is slowly added dropwise under 6- alcohol and 809mg (7.99mmol) triethylamine, ice bath, finishes, delays It is slow to recover to ambient temperature overnight.Post processing, reaction solution is washed with saturated sodium carbonate, saturated common salt washing, through silica gel column chromatography after drying 500mg products, yield are obtained after purification：52.5%.LC-MS(ESI)：[M+H]+=226,1H-NMR(δppm,CDCl3, 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,J1=9.2Hz, J2=2.7Hz, 1H), 4.04 (s, 3H)
Step 6 prepares (E) -3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) methyl acrylate
430mg (1.2mmol) 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- triflates are dissolved in 5ml anhydrous In DMF, 207mg (2.4mmol) methyl acrylate, 487mg (4.8mmol), triethylamine and the (diphenyl of 1,1'- bis- are then added Phosphine) ferrocene palladium chloride chloride dichloromethane complex 27mg, finish, nitrogen displacement, outer 125 DEG C of reaction 3h of temperature.Post processing, will be anti- Liquid is answered to pour into 50ml saturated sodium bicarbonate aqueous solutions, ethyl acetate extraction 30ml*3 merges organic phase, washing, saturated common salt Washing, solvent afforded crude material 240mg, yield are boiled off after drying：68%, directly throw next step.LC-MS(ESI)：[M+H]+=294.
Step 7 prepares 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) methyl propionate
By 240mg (0.818mmol) (E) -3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) methyl acrylate It is dissolved in 50ml methanol, adds 10mg (10%) Pd/C, 2-3atm hydrogenation reactions are stayed overnight at room temperature, LC-MS is detected without raw material.Cross Filter, product 220mg, yield are obtained after filtrate concentration through silica gel column chromatography purifying：91%.LC-MS(ESI)：[M+H]+=296,1H-NMR(δppm,CDCl3,400MHz):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,J1=8.6Hz, J2=2.0Hz, 1H), (t, J=7.7Hz, the 2H) of 4.01 (s, 3H), 3.68 (s, 3H), 3.15 (t, J=7.7Hz, 2H), 2.75
Step 8 prepares 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propyl group -1- alcohol
57mg (1.5mmol) lithium aluminium hydride reduction is added in the super dry tetrahydrofurans of 15ml, -10 are cooled under nitrogen protection DEG C, the tetrahydrochysene of 220mg (0.75mmol) 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) methyl propionate is slowly added dropwise Tetrahydrofuran solution, is finished, and is slowly raised to after room temperature react 1h.Into reaction solution, dropwise addition saturated ammonium chloride is water-soluble under post processing, ice bath Liquid 0.5ml, ethyl acetate 10ml, filtering.Filter cake ethyl acetate is washed, and merging filtrate, which is dried to be evaporated, obtains crude product 180mg, receives Rate：90%.LC-MS(ESI)：[M+H]+=268.
Step 9 prepares 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde
290mg (1.1mmol) 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propyl group -1- alcohol is dissolved in 20ml bis- Dess-Martin reagents 552mg (1.3mmol) is added in chloromethanes, under ice bath to finish, room temperature reaction is stayed overnight.Post processing, to anti- Answer and sodium thiosulfate solution and sodium bicarbonate aqueous solution are added in liquid, 30min is stirred at room temperature, organic phase is through saturated aqueous common salt Wash, product 240mg, yield are obtained through silica gel column chromatography purifying after drying：83%.LC-MS(ESI)：[M+H]+=266,1H-NMR (δppm,CDCl3,400MHz):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 prepares 2- chloro- 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde
240mg (0.90mmol) 3- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde is dissolved in 2ml acetonitriles In, 10mg (0.09mmol) L-PROLINE, 11mg (0.09mmol) benzoic acid and 13mg (0.95mmol) are sequentially added under ice bath NCS, finishes reaction at room temperature and stays overnight, reaction adds 2ml ethyl acetate after terminating, stir 30min, filtering, filter cake ethyl acetate Wash, crude product 185mg, yield are obtained after drying：51%, directly throw next step.LC-MS(ESI)：[M+H]+=300.
Step 11 prepares 4- (3- amino -1,2,4- triazine -6- bases) -2- fluorophenyl carbamates
Triazine -3- the amine of 1g (5.7mmol) 6- bromo- 1,2,3-, the fluoro- 4- methoxyl groups formic acid phenyl boric acids of 1.2g (6.3mmol) 3-, Potassium carbonate 0.95g (6.9mmol) and 1,1'- bis- (diphenylphosphine) ferrocene palladium chloride chloride dichloromethane complex 20mg are added to In 10ml dioxane, add after 2.5ml water, nitrogen displacement, outer 85 DEG C of reactions of temperature are stayed overnight.Post processing, reaction solution is poured into In 100ml dichloromethane, washing, saturated common salt washing obtains product 1.2g, yield after drying through silica gel column chromatography purifying： 85%.LC-MS(ESI)：[M+H]+=249,1H-NMR(δppm,DMSO-d6,400MHz):8.93(s,1H),8.04–7.94 (m,3H),7.64(s,2H),3.88(s,3H).
Step 12 prepares 4- (3- amino -1,2,4- triazine -6- bases) fluoro- methylphenylamines of -2-
Into tube sealing add 33% methylamine alcohol solution 20ml, at room temperature by 1.2g (4.8mmol) 4- (3- amino -1,2, 4- triazine -6- bases) -2- fluorophenyl carbamates add in above-mentioned solution, are heated to 45 DEG C of confined reactions and stay overnight.Post processing, cooling To room temperature, filtering, filtration cakes torrefaction obtains product 1g, yield：83%, directly throw next step.LC-MS(ESI)：[M+H]+=248.
Step 13 prepares 2- fluoro- N- methyl -4- (7- ((3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) methyl) miaows Azoles [1,2-b] [1,2,4] triazine -2- bases) benzamide (compound 3-1)
By 185mg (0.75mmol) 4- (3- amino -1,2,4- triazine -6- bases) fluoro- methylphenylamines of -2- and 224mg The chloro- 3- of (0.75mmol) 2- (3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde is added in 3ml ethylene glycol, outer temperature 150 DEG C of reactions are stayed overnight.Post processing, reaction solution is poured into 50ml dichloromethane, saturated aqueous sodium carbonate is washed, and is washed, saturation Salt is washed, and product 15mg, yield 4% are obtained through silica gel column chromatography purifying after drying.LC-MS(ESI)：[M+H]+=493,1H- NMR(δppm,DMSO-d6,400MHz):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, J1=8.6Hz, J2=1.9Hz, 1H), (d, J=4.6Hz, the 3H) of 4.65 (s, 2H), 3.91 (s, 3H), 2.81
The 6- of embodiment 189 (1- (6- (1H- indoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- Two fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (compound 1-164)
Step 1 prepares the bromo- N of 6-2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) Pyrazine -2,3- diamines
The bromo-pyrazine of 2- amino -3,5- bis- (391mg, 1.55mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower add 1- (5,7- bis- fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethamine (300mg, 1.03mmol) and 3ml N, N- diisopropylethylamine.The reaction solution is heated to 190 DEG C of tube sealings and stayed overnight under argon gas protection.Concentration of reaction solution, will By dodging post purification, (solvent is dichloromethane to crude product：Methanol=95:5).Obtain about 303mg brown solids, yield：64%. LC-MS(ESI)：[M+H]+=459；1H-NMR(δppm,DMSO-d6,400MHz):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 prepares fluoro- 3- (the 1- first of 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5,7- two Base -1H- pyrazoles -4- bases) quinoline
By the bromo- N of 6-2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2, 3- diamines (285mg, 0.62mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, and the reaction is heated to 150 DEG C of tube sealings and stayed overnight.It is dense Contracting reaction solution, by dodging post purification, (solvent is methanol to remaining crude product：Dichloromethane=0% to 5%).Obtain 220mg yellow Solid, yield：76%.LC-MS(ESI)：[M+H]+=471.
Step 3 prepares 6- (1- (6- (1H- indoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl -5,7- two Fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline (compound 1-164)
By fluoro- 3- (the 1- methyl isophthalic acid H- pyrroles of 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5,7- two Azoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in 12ml1,4- dioxane, then sequentially adds (the 1H- Yin of 1.5 equivalents Diindyl -4- bases) boric acid, Pd (dppf) Cl2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.Should Reaction solution is under argon gas protection, and 110 DEG C of tube sealings are stayed overnight.Concentration of reaction solution, by dodging post purification, (solvent is dichloro to remaining crude product Methane：Methanol=95：5), final products are washed once with methanol, obtain 49.6mg yellow solid powder, yield：77%.LC-MS (ESI)：[M+H]+=507；1H-NMR(δppm,DMSO-d6,400MHz):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)
190~embodiment of embodiment 194
According to the same procedure of embodiment 189, using different boric acid or borate, 190~embodiment of embodiment is prepared 194 compound, specific experiment data are shown in Table 15.
The compound 1-165 of table 15~compound 1-169 experimental data table
Fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (the 1- methyl isophthalic acid H- pyrazoles -4- of 196 5,7- of embodiment bis- Base) -1H- imidazos [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-25)
Step 1 prepares the bromo- N of 6-2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) Pyrazine -2,3- diamines
The bromo-pyrazine of 2- amino -3,5- bis- (391mg, 1.55mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower add 1- (5,7- bis- fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethamine (300mg, 1.03mmol) and 3ml N, N- diisopropylethylamine.The reaction solution is heated to 190 DEG C of tube sealings and stayed overnight under argon gas protection.Concentration of reaction solution, will By dodging post purification, (solvent is dichloromethane to crude product：Methanol=95:5).Obtain about 303mg brown solids, yield：64%. LC-MS(ESI)：[M+H]+=459；1H-NMR(δppm,DMSO-d6,400MHz):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)
It is fluoro- that step 2 prepares 6- (1- (6- bromo- 1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5,7- two 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline
By the bromo- N of 6-2- (1- (the fluoro- 3- of 5,7- bis- (1- methyl isophthalic acid H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2, 3- diamines (439mg, 0.95mmol) is dissolved in 5mlDMF, and then 0.03ml isoamyl nitrites are slowly added to solution at room temperature In, the reaction is heated to 80 DEG C of tube sealings after being stirred at room temperature 15 minutes and stayed overnight.The saturated solution quenching for adding sodium sulfite is anti- Should, a small amount of water and 30ml ethyl acetate are added afterwards, organic phase is separated, and aqueous phase is extracted with the ethyl acetate of 30mL × 3.Merge organic Phase, saturated nacl aqueous solution 30mL × 2 are washed, and are dried, are evaporated.(solvent is dichloromethane to point plate：Methanol=20:1) it is purer, dodge (solvent is dichloromethane for post purifying：Methanol=96:4) yellow solid 349mg, yield are obtained：78%.LC-MS(ESI)：[M+ H]+=472；1H-NMR(δppm,DMSO-d6,400MHz):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 fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- the bases) -6- of 5,7- bis- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- Base) -1H- imidazos [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-25)
By fluoro- 3- (the 1- first of 6- (1- (6- bromo- 1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5,7- two Base -1H- pyrazoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in 12ml Isosorbide-5-Nitraes-dioxane, and then sequentially add 1.5 and work as Measure 1- methyl -4- (4,4,5,5- tetramethyls -1,3, the ring -2- bases of 2- dioxies boron penta) -1H- pyrazoles, Pd (dppf)2Cl2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.The reaction solution is under argon gas protection, 110 DEG C of tube sealing mistakes Night.Concentration of reaction solution, by dodging post purification, (solvent is dichloromethane to remaining crude product：Alkane methanol=95：5), final products first Alcoholic solution is washed (2*5ml).Obtain 63mg white solid powders, yield：95%.LC-MS(ESI)：[M+H]+=472；1H- NMR(δppm,DMSO-d6,400MHz):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)
197~embodiment of embodiment 213
According to the same procedure of embodiment 196, using different boric acid or borate, 197~embodiment of embodiment is prepared 213 compound, specific experiment data are shown in Table 16.
The compound 2-26 of table 16~compound 2-42 experimental data table
Embodiment 214：3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) -3H- imidazos [4,5-b] pyrazine -5- Ethyl formates (compound 1-171)
Step 1 prepares the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines
By the bromo-pyrazine -2- amine (6.1g, 24mmol) of 3,5- bis-, 1- (the fluoro- 6- quinolyls of 7-) ethamine (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) is added in NMP (20ml), and argon gas protects lower 130 DEG C of reactions to stay overnight.DIPEA is evaporated off in reaction solution, Residue is poured into water (100ml), dichloromethane (30ml × 3) extraction, organic phase washing, and saturated common salt washing obtains 6- bromo- N2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines, yield：50%.
LC-MS(ESI)：[M+H]+=362；1H-NMR(δppm,DMSO-d6,400MHz)：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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline
By the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines (1.2g, 3.6mmol) is added to second In sour diethoxy methyl esters (30ml), the formic acid (1ml) of lower addition 98% is stirred at room temperature, finishes, reaction solution flows back 2 days, is evaporated Solvent, crude product is washed with ethyl acetate/petroleum ether (1/1), obtains brown solid, yield：60%.LC-MS(ESI)：[M+H]+= 372；1H-NMR(δppm,DMSO-d6,400MHz)：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, J1=8.2Hz, J2 =4.0Hz, 1H), 6.33 (q, J=7.1Hz, 1H), 2.11 (d, J=7.1Hz, 3H).
Step 3 prepares 3- (1- (the fluoro- 6- quinolyls of 7-) ethyl) -3H- imidazos [4,5-b] pyrazine -5- Ethyl formates
Raw material 6- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline (150mg, 0.4mmol) it is dissolved in absolute ethyl alcohol (50ml), adds Pd (PPh3)2Cl2(28mg, 0.04mmol, 0.1eq), DIPEA (3ml), With carbon monoxide gas precursor reactant 8h (10atm, 80 DEG C).Solvent evaporated, crude product prepares plate and purifies to obtain white solid 112mg, yield 75.9%.LC-MS(ESI)：[M+H]+=366.0；1H-NMR(δppm,CDCl3,400MHz):9.35(s,1H),8.95(dd, J1=4.4Hz, J2=2.0Hz, 1H), 8.64 (s, 1H), 8.19 (dd, J1=8.4Hz, J2=0.8Hz, 1H), 7.98 (d, J= 8.0Hz, 1H), 7.78 (d, J=12.0Hz, 1H), 7.44 (dd, J1=8.4Hz, J2=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 prepares 3- (1- (the fluoro- 6- quinolyls of the bromo- 7- of 3-) ethyl) -3H- imidazos [4,5-b] pyrazine -5- formic acid second Ester
Raw material 3- (1- (the fluoro- 6- quinolyls of 7-) ethyl) -3H- imidazos [4,5-b] pyrazine -5- Ethyl formates (300mg, 0.8mmol) be dissolved in carbon tetrachloride (20ml), be separately added into pyridine (263mg, 1.6mmol, 2eq) and bromine (130mg, 1.6mmol, 2eq), 70 DEG C of reactions are stayed overnight.Solvent evaporated, adds aqueous sodium carbonate and is adjusted to alkalescence, dichloromethane extraction, water Wash, saturated common salt water washing, column chromatography purifies to obtain white solid 122mg, yield 33.4%.LC-MS(ESI)：[M+H]+= 443.8；1H-NMR(δppm,CDCl3,400MHz):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), (t, J=7.2Hz, the 3H) of 4.52 (q, J=7.2Hz, 2H), 2.25 (d, J=7.2Hz, 3H), 1.48
Step 5 prepares 3- (1- (the fluoro- 3- of 7- (1- methyl isophthalic acid H-4- pyrazolyls) -6- quinolyls) ethyl) -3H- imidazos [4,5-b] pyrazine -5- Ethyl formates (compound 1-171)
By raw material 3- (1- (the fluoro- 6- quinolyls of the bromo- 7- of 3-) ethyl) -3H- imidazos [4,5-b] pyrazine -5- Ethyl formates (120mg, 0.27mmol), 1- methyl isophthalic acid H- pyrazoles -4- pinacol borates (85mg, 0.41mmol, 1.5eq), catalyst Pd (dppf)Cl2DCM (11mg, 0.01mmol, 0.05eq) and K2CO3(112mg, 0.81mmol, 3eq) is dissolved in dioxane+water In (4ml+1ml) solution, the lower 110 DEG C of reactions 4h of argon gas protection.It is down to after room temperature, adds a large amount of water, ethyl acetate extraction, water Wash, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, crude product prepares plate and purifies to obtain crocus solid 14mg, yield 11.7%.LC-MS(ESI)：[M+H]+=446.0；1H-NMR(δppm,CDCl3,400MHz):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)
Embodiment 215：The fluoro- 3- of 7- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) - 1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 1-172)
Step 1 prepares the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines
The method of the step 1 of reference implementation example 1,1- (the fluoro- 6- quinolyls of 7-) ethamine replacement 6- quinoline benzylidene aminos are obtained The bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines, yield=50%.LC-MS(ESI)：[M+H]+= 362,1H-NMR (δ ppm, DMSO-d6, 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 prepares 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline
The method of the step 2 of reference implementation example 1, by the bromo- N of 6-2- (1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines Brown solid, yield=60%, LC-MS (ESI) are obtained with the reaction of acetic acid diethoxy methyl esters：[M+H]+=372,1H-NMR(δ ppm,DMSO-d6,400MHz):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, J1=8.2Hz, J2= 4.0Hz, 1H), 6.33 (q, J=7.1Hz, 1H), 2.11 (d, J=7.1Hz, 3H).
Step 3 prepares 3- bromo- 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline
By 372.2mg (1mmol) 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline It is added to 158mg (2mmol) pyridine in 50ml carbon tetrachloride, 320mg (2mmol) bromine is slowly added dropwise under stirring, finishes, Reaction backflow 3h.Post processing, solvent evaporated, crude product dichloromethane is dissolved, and saturated aqueous sodium carbonate is washed, saturated aqueous common salt Wash, obtain 300mg crude products after drying solvent evaporated, yield=66% directly throws next step.
LC-MS(ESI)：[M+H]+=450.
Step 4 preparation 7- fluoro- 3- (1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) - 1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 1-172)
The method of the step 4 of reference implementation example 164, by the bromo- 6- of 3- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) Ethyl) -7- fluorine quinoline and 1- methyl isophthalic acid H-4- pyrazoles pinacol borates react to obtain white solid, yield=33%, LC-MS (ESI)：[M+H]+=454,1H-NMR(δppm,DMSO-d6,400MHz)：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)
Inhibitory action of the compounds of this invention of effect example 1 to C-Met tyrosine kinase activities
Test-compound is to the inhibitory activity of kinases 503nhibiting concentration IC50Value is represented.When such experiment uses homogeneous Between resolved fluorometric (HTRF) technology be measured, method is as follows：By a series of compound of gradient concentrations, at ambient temperature with The enzyme solutions of certain concentration are incubated 5 minutes jointly, and appropriate enzyme reaction substrate, ATP are added afterwards, start enzyme reaction process, 30 After minute, appropriate reaction terminating liquid and detection liquid are added into enzyme reaction system, it is public in PerkinElmer after being incubated 1 hour On the multiple labeling micropore detectors of EnVision 2104 of department, determined under 665nm and 620nm wavelength under specific compound concentration Enzyme activity, and calculate the inhibitory activity of the compounds on enzyme activities of various concentrations, it is dense to difference afterwards according to quadruplex parameters The inhibitory activity of enzyme activity is fitted under degree compound, calculates IC50Value.The kinases Met that the present embodiment is used is purchased from Carna Biosciences, detection kit HTRF KinEASE-TK are purchased from Cisbio Bioassays companies, and ATP is purchased from Sigma Aldriches.The IC of test-compound of the present invention50Data are shown in Table 17.
Inhibitory activity tables of data of the compound of the embodiment of the present invention of table 17 to C-Met EGFR-TKs
The compound of effect example 2 is to H1993 and SNU-5 cell inhibitory effect determinations of activity
This example is used to determine the compounds of this invention for c-Met height expression lung cancer cell line H1993 and c-Met height expression stomaches JEG-3 SNU-5 proliferation inhibition activity, the inhibitory activity half-inhibition concentration IC of compound on intracellular propagation50Carry out table Show.Testing program is as follows：C-Met height expression lung cancer cell line H1993 and c-Met height expression stomach cancer cell line SNU-5 cells are equal ATCC is purchased from, with suitable cell concentration (H1993：62500 cell/mlL culture mediums；SNU-5：62500 cell/mL trainings Support base) cell is inoculated on 384 well culture plates of White-opalescent；Cell is positioned over 37 DEG C, 5%CO afterwards2Environment It is middle to be cultivated, after 24 hours, a series of medicine of concentration gradients is added into the cell culture medium of culture, 10 are typically chosen Concentration, H1993 cells are put back in former culture environment continue to cultivate 72 hours afterwards, SNU-5 cells are put back in former culture environment Continue to cultivate 48 hours, afterwards according to CellTiter-Glo Luminescent Cell Viability Assay method, Test-compound is determined to H1993 and SNU-5 in the multiple labeling micropore detectors of EnVision 2104 of PerkinElmer companies The influence of cell propagation, and calculate the inhibitory activity of the compound on intracellular propagation of various concentrations.Used in the present embodiment CellTiter-Glo Luminescent Cell Viability Assay detection reagents are purchased from Promega.Afterwards to difference H1993 and SNU-5 cell inhibitory effects activity carries out four parameter fittings under the compound of concentration, test-compound of the present invention IC50 data are shown in Table 18.
The compound of the embodiment of the present invention of table 18 is to H1993 and SNU-5 cell inhibitory effect activity data tables
Conclusion：The compounds of this invention has obvious Inhibit proliferaton activity to H1993 and SNU-5.
The compounds of this invention of effect example 3 suppresses to live to c-Met height expression lung cancer cell line H1993 Intracellular phosphorylations Property detection
This example is used to determine the compounds of this invention for the c-Met height expression intracellular c-Met phosphoric acid of lung cancer cell line H1993 Change the inhibitory activity half-inhibition concentration IC of c-Met phosphorylations in inhibitory activity, compound on intracellular50To represent.Experiment side Case is as follows：C-Met height expression lung cancer cell line H1993 is purchased from ATCC, is connect with suitable cell concentration (300000/mL culture mediums) Plant in 96 porocyte culture plates；Cell is positioned over 37 DEG C, 5%CO afterwards2Environment in cultivated, after 24 hours, to A series of medicine of concentration gradients is added in the cell culture medium of culture, 10 concentration is typically chosen, afterwards puts H1993 cells Return and continue to cultivate 1 hour in former culture environment, nutrient solution in hole is sopped up afterwards, appropriate lysate cell lysis is added, will be appropriate Cell pyrolysis liquid is transferred in opaque 384 orifice plate of shallow bore hole, is added after appropriate Acceptor mix, and it is small that room temperature lucifuge is incubated 2 When；Appropriate Donor mix are added afterwards, are continued room temperature lucifuge and are incubated 2 hours；Using the EnVision of PerkinElmer companies 2104 multiple labeling micropore detectors detect the influence of test-compound c-Met phosphorylations intracellular to H1993, and calculate different dense The inhibitory activity of the compound on intracellular phosphorylation of degree.The AlphaScreen SureFire c-Met used in the present embodiment Assay Kits detection kits are purchased from PerkinElmer companies.Afterwards to the compound c- intracellular to H1993 of various concentrations Met phosphorylation inhibition activities carry out four parameter fittings, and the IC50 data of test-compound of the present invention are shown in Table 19.
The compound 1-87 of table 19 and compound 1-95 presses down to c-Met height expression lung cancer cell line H1993 Intracellular phosphorylations Activity data table processed
Metabolic stability of the compound of effect example 4 in hepatomicrosome
This example is used to determine the compounds of this invention in people, rat and monkey hepatomicrosome；People, monkey S9；People, monkey cells kytoplasm are molten The metabolic stability of liquid, metabolic stability is represented with intrinsic clearance.Testing program is as follows：Respectively with the people that system is 150 μ l S9 (HS9), monkey S9 (MS9), human liver cell cytoplasmic solution (Hcytosol), monkey liver cell cytoplasmic solution (Mcytosol), people liver Microsome (HLM), rat liver microsomes (RLM) and monkey hepatomicrosome (MLM) carry out that metabolic stability is warm-natured to incubate, and system is included simultaneously NADPH and testing compound phosphate buffer.Enzyme reaction system is carried out at 37 DEG C, and respectively at 0min, 5min, 10min With the acetonitrile terminating reaction of 30min internal standard fasigynes, reaction solution vortex 10min, 15000rmp centrifugation 10min takes 60 μ L supernatants sample introduction in 96 orifice plates.Positive control selects midazolam (MDZ), and negative control does flat from atenolol (ATE) Row experiment.The present embodiment determines the relative decrement of active compound by LC/MS/MS.Intrinsic clearance (Clint；μl/min/mg When protein) being less than 100, it is believed that the metabolic stability of this compound is relatively good.The metabolic stability of test-compound of the present invention Data are shown in Table 20
The metabolic stability data table of the compound of table 20
Conclusion：Most of the compounds of this invention metabolic stability in hepatomicrosome, S9 and cell cytoplasm solution is good.
(DI experiments) is tested in direct suppression of the compound of effect example 5. to metabolic enzyme
This example is used to determine the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, CYP2C9, CYP1A2, CYP2C19's Direct repression, compound is expressed as inhibiting rate to the direct repression of metabolic enzyme.Testing program is as follows：React cumulative volume For 100 μ l, including people's hepatomicrosome, NADPH, phosphate buffer, substrate mixture (Midazolam, Testosterone, Dextromethophan, Diclofenac, Phenaceti, Mephenytoin), testing compound.Body It is that 37 DEG C of temperature incubate the acetonitrile terminating reaction that internal standard fasigyne is used after 20min.Vortex 10min, 15000rmp centrifugation 10min, Take 60 μ l supernatants sample introduction in 96 orifice plates.Positive control from/inhibitor mixture (Ketoconazole, Quinidine, Sulfaphenazole, Naphthoflavone, Tranylcypromine), negative control does parallel control examination from DMSO Test.Determine the relative activity that substrate utilization thing represents enzyme with respect to growing amount, inhibiting rate=(1- testing compound of the compound to enzyme Enzyme relative activity/negative control enzyme relative activity) × 100%.Inhibiting rate is defined as having direct suppression to CPY more than 50%. Test-compound of the present invention is shown in Table 21 to the inhibitory action data of metabolic enzyme.
The compound of table 21 is to metabolic enzyme direct repression tables of data
Conclusion：A part of compound does not have direct repression to metabolic enzyme in the present invention.
The compound of effect example 6 suppresses experiment (TDI experiments) to the mechanism of metabolic enzyme
This example is used to determine the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, CYP2C9, CYP1A2, CYP2C19's Mechanism inhibitory action, compound is expressed as apparent decay rate constants k to the mechanism inhibitory action of metabolic enzymeobs.Experiment side Case is as follows：Reaction system cumulative volume is that 200 μ l, NADPH groups include：People's hepatomicrosome, testing compound, NADPH, phosphoric acid buffer Salt；Non- NADPH groups include：People's hepatomicrosome, testing compound, phosphate-buffered salt.Temperature incubates 0min, 5min, 10min to system respectively With the acetonitrile terminating reaction that containing the internal standard fasigyne is used after 20min, vortex 10min, 15000rmp centrifugation 10min takes 60 μ l Supernatant sample introduction in 96 orifice plates.Positive control from/inhibitor mixture (Troleandomycin, Paroxetine, Tienilic Acid, Furafylline), negative control select S- from the positive control of compound Atenolol, CYP2C19 Fluoxetine.Enzyme relative activity is represented by determining the relative growing amount of substrate utilization thing, apparent deactivation rate is calculated normal Number kobs(*10-4/ min), as the k of compoundobsWhen value is more than 200, it is believed that it has mechanism suppression to CPY.Testedization of the invention Compound is shown in Table 22 to the inhibitory action data of metabolic enzyme.
The compound of table 22 is to metabolic enzyme mechanism inhibitory action tables of data TDI (kobs*10-4)
Conclusion：A part of compound does not have mechanism inhibitory action to metabolic enzyme in the present invention.
The compound of effect example 7 is tested mice-transplanted tumor inhibitory action
This example is used to determine stomach cancer cell SNU-5 transplantable tumor inhibitory action of the compounds of this invention to c-Met height amplifications, with Relative tumor proliferation rate represents the internal drug effect of compound.Testing program is as follows：The stomach cancer SNU-5 highly expanded from c-MET Cell.Cell culture condition is adds 20% hyclone in IMDM culture mediums, in 37 DEG C, containing 5%CO2Constant incubator in train Support.By 1:4 biweekly processing passages.When cell exponentially growth period, collect cell and counted.Bulb/c is naked small Mouse is divided into 5 groups, by 5 × 106Individual SNU-5 cells are inoculated on the right side of nude mouse at armpit.Positive drug INCB28060 and test compounds Thing administration concentration be 10mg/kg, daily gastric infusion once, successive administration 11 days.Routine observation animal state, measurement body weight are simultaneously Record result.The volume and relative volume of tumour are calculated according to formula.
(1) gross tumor volume (Tumor Volume, TV), TV=1/2XaXb2；A, b represent length and width respectively.
(2) relative tumour volume (Relative Tumor Volume, RTV), RTV=TVt/TV0；TV0During for point cage ( d0) gross tumor volume, TVtGross tumor volume during for measurement every time.
(3) Relative tumor proliferation rate T/C (%), calculation formula is：
TRTV：Treatment group RTV；CRTV：Negative control group RTV.Antitumor activity evaluation standard is Relative tumor proliferation rate T/C (%).Efficacy data is shown in Table 23 in test-compound body of the present invention.
Efficacy data table in the compound Mice Body of table 23
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：Compound 1-170 can effectively suppress the growth of stomach cancer cell SNU-5 transplantable tumors in the present invention, and it is slightly good to act on In control compound, 1-172 antitumor actions are weak.

Claims (18)

1. before a kind of quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Body or its prodrug,
Wherein, X1、X2And X3C or N is each independently,Represent, work as X1During for C, X1With R1It is connected, works as X1During for N, with X1Connected R1It is not present；Also, work as X1During for C, X2And X3In one be C, another is N, R1For hydrogen or hydroxyl；Work as X1For N When, X2For N, X3For C；
Cy is 3~8 yuan of cycloalkyl, 3~8 circle heterocycles alkyl, 5~8 member cycloalkenyls, 5~8 circle heterocycles alkenyls, 6~10 yuan of aryl, 5 ~10 unit's heteroaryls orDescribed 3~8 yuan of cycloalkyl, 3~8 circle heterocycles alkyl, 5~8 yuan of cyclenes Base, 5~8 circle heterocycles alkenyls, 6~10 yuan of aryl or 5~10 unit's heteroaryls can be selected from halogen, cyano group, R by 1~25、 Group replaced, wherein R5And R6 It is each independently C1-6Alkyl, the C of halogen substitution1-6Alkyl, the C of hydroxyl substitution1-6Alkyl, 3~8 yuan of cycloalkyl, 3~8 yuan it is miscellaneous 5~10 yuan of heteroaryls that cycloalkyl, 6~10 yuan of aryl, 6~10 yuan of aryl, 5~10 unit's heteroaryls or halogens of halogen substitution replace Base；
L is
A is H；
R2For halogen or C1-6Alkyl, R3And R4It is each independently hydrogen, halogen or C1-6Alkyl；Or, R2For hydrogen, R3For halogen or C1-6Alkyl, R4For hydrogen, halogen or C1-6Alkyl；Or, R2For hydrogen, R3For hydrogen, R4For halogen or C1-6Alkyl.
2. quinolines as claimed in claim 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：
When described Cy is 3~8 yuan of cycloalkyl, described " 3~8 yuan of cycloalkyl " is 3~6 yuan of cycloalkyl；
When described Cy is 3~8 circle heterocycles alkyl, described " 3~8 circle heterocycles alkyl " is 3~6 circle heterocycles alkyl；
When described Cy is 5~8 circle heterocycles alkenyl, described " 5~8 circle heterocycles alkenyl " is 5~6 circle heterocycles alkenyls；
When described Cy isWhen, wherein, described " C1-6Alkyl " is C1-4Alkyl；
When described Cy is 6~10 yuan of aryl, described " 6~10 yuan of aryl " is phenyl or naphthyl；
When described Cy is 5~10 unit's heteroaryl, described " 5~10 unit's heteroaryl " be hetero atom be N, O or S atom, it is miscellaneous Atomicity is monocyclic or condensed ring 5~10 unit's heteroaryls of 1~2；
3~8 yuan of cycloalkyl, 3~8 circle heterocycles alkyl described in the described Cy, 5~8 member cycloalkenyls, 5~8 circle heterocycles alkene When base, 6~10 yuan of aryl or 5~10 unit's heteroaryls are replaced by halogen, described " halogen " is fluorine, chlorine or bromine；
As the R described in described Cy5And R6It is each independently C1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl；
As the R described in described Cy5And R6It is each independently the C of halogen substitution1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl, described " halogen " is fluorine, chlorine or bromine；
As the R described in described Cy5And R6It is each independently the C of hydroxyl substitution1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl；
As the R described in described Cy5And R6When being each independently 6~10 yuan of aryl that 6~10 yuan of aryl or halogen replace, Described " 6~10 yuan of aryl " is phenyl, and described " halogen " is fluorine, chlorine or bromine；
As the R described in described Cy5And R6It is each independently 5~10 unit's heteroaryls of 5~10 unit's heteroaryls or halogen substitution When, described " 5~10 unit's heteroaryl " is that hetero atom is nitrogen-atoms, and hetero atom number is 5~10 unit's heteroaryls of 1-2, described " halogen " be fluorine, chlorine or bromine；
As described R2During for halogen, described " halogen " is fluorine, chlorine or bromine；
As described R3During for halogen, described " halogen " is fluorine, chlorine or bromine；
As described R4During for halogen, described " halogen " is fluorine, chlorine or bromine；
As described R2For C1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl；
As described R3For C1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl；
As described R4For C1-6During alkyl, described " C1-6Alkyl " is C1-4Alkyl；
3. quinolines as claimed in claim 2, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：
When described Cy is 3~6 yuan of cycloalkyl, described " 3~6 yuan of cycloalkyl " is cyclopropyl；
When described Cy is 3~6 circle heterocycles alkyl, described " 3~6 circle heterocycles alkyl " is that hetero atom is nitrogen-atoms, miscellaneous original Subnumber is 5~6 circle heterocycles alkyl of 1-2；It is described that " hetero atom is nitrogen-atoms, and hetero atom number is 5~6 circle heterocycles of 1-2 Alkyl " can be by C1-4Alkyl is replaced, wherein, described " C1-4Alkyl " is methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base or the tert-butyl group；
When described Cy is 5~6 circle heterocycles alkenyl, described " 5~6 circle heterocycles alkenyl " is that hetero atom is nitrogen-atoms, miscellaneous original Subnumber is 5~6 circle heterocycles alkenyls of 1-2；Described " 5~6 circle heterocycles that hetero atom is nitrogen-atoms, hetero atom number is 1-2 Alkenyl " can quiltReplace or described " hetero atom is nitrogen-atoms, hetero atom number is 1-2 5 The free nitrogen atom of~6 circle heterocycles alkenyls " can be into salt；Described " C1-4Alkyl " be methyl, ethyl, propyl group, isopropyl, butyl, Isobutyl group or the tert-butyl group；
When described Cy isWherein, described C1-6Alkyl is C1-4During alkyl, described " C1-4Alkane Base " is methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group；
When described Cy is phenyl, described phenyl by 1~2 selected from halogen andGroup taken Generation；
When described Cy is naphthyl, described naphthyl is 1- naphthyls；
It is described when described Cy is monocyclic 5~10 unit's heteroaryl that hetero atom is N, O or S atom, hetero atom number is 1~2 " monocyclic 5~10 unit's heteroaryl that hetero atom is N, O or S atom, hetero atom number are 1~2 " be pyrazolyl, pyridine radicals, thiophene Fen base, pyrimidine radicals or furyl；
It is described when described Cy is 5~10 unit's heteroaryl of condensed ring that hetero atom is N, O or S atom, hetero atom number is 1~2 " unit's heteroaryl of condensed ring 5~10 that hetero atom is N, O or S atom, hetero atom number is 1~2 " for quinolyl, isoquinolyl, Benzothienyl, indyl or pyrrolopyridinyl；
As the R described in described Cy5And R6It is each independently C1-4During alkyl, described " C1-4Alkyl " be methyl, ethyl, Propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group；
As the R described in described Cy5And R6It is each independently the C of halogen substitution1-4During alkyl, described " C1-4Alkyl " is Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group；
As the R described in described Cy5And R6It is each independently the C of hydroxyl substitution1-4During alkyl, described " C1-4Alkyl " is Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group；
As the R described in described Cy5And R6Hetero atom is each independently for nitrogen-atoms, hetero atom number is the 5~10 of 1-2 Unit's heteroaryl or the hetero atom of halogen substitution are nitrogen-atoms, described when hetero atom number is 5~10 individual unit's heteroaryls of 1-2 " hetero atom is nitrogen-atoms, and hetero atom number is 5~10 unit's heteroaryls of 1-2 " is quinolyl；
As described R2For C1-4During alkyl, described " C1-4Alkyl " be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or The tert-butyl group；
As described R3For C1-4During alkyl, described " C1-4Alkyl " be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or The tert-butyl group；
As described R4For C1-4During alkyl, described " C1-4Alkyl " be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or The tert-butyl group；
4. quinolines as claimed in claim 3, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：
When described Cy is that hetero atom is nitrogen-atoms, when hetero atom number is 5~6 circle heterocycles alkyl of 1-2, described " miscellaneous original Son is nitrogen-atoms, and hetero atom number is 5~6 circle heterocycles alkyl of 1-2 " it is piperazinyl；
When described Cy is by C1-4The hetero atom that alkyl is replaced is nitrogen-atoms, and hetero atom number is 5~6 circle heterocycles alkane of 1-2 During base, described " hetero atom replaced by methyl is nitrogen-atoms, and hetero atom number is 5~6 circle heterocycles alkyl of 1-2 " is N- Methyl piperazine base；
When described Cy is 5~6 circle heterocycles alkenyl that hetero atom is nitrogen-atoms, hetero atom number is 1-2, described " miscellaneous original 5~6 circle heterocycles alkenyls that son is nitrogen-atoms, hetero atom number is 1-2 " are 1,2,3,6- tetrahydro pyridyls；
When free on 5~6 circle heterocycles alkenyls that the hetero atom described in described Cy is nitrogen-atoms, hetero atom number is 1~2 When nitrogen-atoms is into salt, the described " nomadic nitrogen on 5~6 circle heterocycles alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 Atom is into salt " be
When described Cy is quiltThe hetero atom replaced is nitrogen-atoms, hetero atom number is 1~2 5 During~6 circle heterocycles alkenyl, described " quiltThe hetero atom replaced is that nitrogen-atoms, hetero atom number are 1~2 5~6 individual circle heterocycles alkenyls " are
When described Cy is phenyl and described phenyl is optionally substituted by halogen, described " halogen " is fluorine, chlorine or bromine；
When described Cy is phenyl and described phenyl quiltDuring substitution, described " C1-4Alkyl " is first Base, ethyl, propyl group, isopropyl, butyl, isobutyl group or the tert-butyl group；
When described Cy is pyrazolyl, described " pyrazolyl " is 1H- pyrazoles -4- bases or 1H- pyrazoles -5- bases；
When described Cy is pyridine radicals, described " pyridine radicals " is pyridin-4-yl or pyridin-3-yl；
When described Cy is thienyl, described " thienyl " is thiene-3-yl or thiophene -2- bases；
When described Cy is pyrimidine radicals, described " pyrimidine radicals " is pyrimidine -5- bases；
When described Cy is furyl, described " furyl " is furans -3- bases or furans -2- bases；
When described Cy is quinolyl, described " quinolyl " is quinolyl-4, quinoline -3- bases or quinoline -7- bases)；
When described Cy is isoquinolyl, described " isoquinolyl " is isoquinolin -4- bases；
When described Cy is benzothienyl, described " benzothienyl " is benzothiophene -3- bases or benzothiophene -2- Base；
When described Cy is indyl, described " indyl " is indol-3-yl, indoles -4- bases or indoles -5- bases；
When described Cy is pyrrolopyridinyl, described " pyrrolopyridinyl " is 1H- pyrrolo-es [2,3-b] pyridine -5- Base；
As the R described in described Cy5And R6The hetero atom for being each independently halogen substitution is nitrogen-atoms, and hetero atom number is 1-2 During individual 5~10 unit's heteroaryl, described " hetero atom of halogen substitution is nitrogen-atoms, and hetero atom number is 5~10 yuan of 1-2 Heteroaryl " is
5. quinolines as claimed in claim 4, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：
When described Cy is piperazinyl, described piperazinyl is 4- piperazinyls；
When described Cy is N methyl piperazine base, described " N methyl piperazine base " is N methyl piperazine -1- bases；
When described Cy be by 1~2 selected from halogen andGroup replaced phenyl when, it is described " by 1~2 selected from halogen andThe phenyl that is replaced of group " be the fluoro- 4- of 3- (N- methyl carbamyls Base) -1- phenyl；
When described Cy is 1, during 2,3,6- tetrahydro pyridyl, described " 1,2,3,6- tetrahydro pyridyl " is 1,2,3,6- tetrahydrochysenes Pyridin-4-yl.
6. quinolines as claimed in claim 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：R2And R3It is each independently H, F or methyl, R4For H.
7. quinolines as claimed in claim 6, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug, it is characterised in that：Work as R2During for H, R3For H, F or methyl, R4For H；Work as R2During for F, R3For F, R4For H。
8. quinolines as claimed in claim 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor thereof Or its prodrug, it is characterised in that：When Cy is 6~10 yuan of aryl, described " 6~10 yuan of aryl " is phenyl, the fluoro- benzene of 2- The chloro- phenyl of base, 2-, the chloro- phenyl of 3-, 2- trifluoromethyl-phenyls, 4- trifluoromethyls, 3,4- dichlorophenyls, 4- trifluomethoxybenzenes Base, 3- cvano-phenyls, 4- cyano-phenyls, 3-N, N- dimethylaminophenyls, 4- aminophenyls, 2,4- dimethoxy-phenylfs, 2,6- Dimethoxy-phenylf, 2,6- Dimethvl-phenyls, 2- methyl -4- methoxyl groups-phenyl, 2- methyl -5- methoxyphenyls, 4- methyl mercaptos - Phenyl,
When Cy is 5~10 unit's heteroaryl, described " 5~10 unit's heteroaryl " is thiophene -2- bases, thiene-3-yl, furans -2- Base, pyridin-3-yl, pyridin-4-yl, PA -3- bases, 2- fluorine pyridin-3-yl, PA -5- bases, 2- methyl pyrroles Pyridine -5- bases, indoles -4- bases, indoles -5- bases, quinoline -7- bases, isoquinolin -4- bases, 5- cyano thiophene -2- bases,
9. quinolines, its pharmaceutically acceptable salt as described in any one of claim 1~8, solvate, metabolism Product, metabolic precursor thereof or its prodrug, it is characterised in that：Described quinolines are to contain miaow as shown in formula 1-a The quinolines of azoles and pyrazine structure, the quinolines containing triazole and pyrazine structure as shown in formula 1-b or The quinolines containing imidazo [1,2-b] [1,2,4] triazole structure as shown in formula 1-c,
Wherein, Cy definition is as described in Claims 1 to 5 or 8 any one；L definition is as claimed in claim 1；R1、R2、R3With R4Definition as described in any one of claim 1~7.
10. a kind of quinolines, its pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor thereof or its medicine Precursor, it is characterised in that：Described quinolines, its pharmaceutically acceptable salt, solvate, metabolite, metabolism Precursor or its prodrug are any compound as described below：
The fluoro- 6- of 8- ((6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
The fluoro- 6- of 8- ((6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
The fluoro- 6- of 8- ((6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
2- (4- (1- ((8- fluorine quinoline -6- bases) methyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazol-1-yls) second Alcohol,
6- ((6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -8- fluorine quinoline,
The fluoro- 6- of 8- ((6- (3- quinolyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl)-quinoline,
The fluoro- 6- of 8- ((6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl)-quinoline,
8- it is fluoro- (6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 8- (1- (6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 8- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 8- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline,
The fluoro- 6- of 8- (1- (6- (3- quinolyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (3,4- dichlorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline,
6- (1- (6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline,
6- (1- (6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -8- fluorine quinoline,
The fluoro- 6- of 8- (1- (6- (2- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 8- (1- (6- (4- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 8- (1- (6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
(3- (1- (the fluoro- quinoline -6- methylene of 7-) -1H- imidazos [4,5-b] pyrazine -6- bases)-phenyl)-N, N- dimethyl amines,
4- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases) -3,6- dihydro -2H- pyridines -1- Carboxylic acid tert-butyl ester,
6- (6- (3- chlorphenyls)-imidazo [4,5-b] pyrazine -1- methylene) fluoro- quinoline of -7-,
The fluoro- 4- of 2- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-benzamide,
6- ((6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines,
The fluoro- 6- of 5,7- bis- ((6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
6- ((6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines,
3- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N, N- dimethyl benzenes Amine,
6- (1- (6- (2,6- 3,5-dimethylphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
6- (1- (6- (3- chlorphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
6- (1- (6- (3- chlorphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
6- (1- (6- (2,6- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
The fluoro- 6- of 5,7- bis- (1- (6- (1- naphthyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (2,4- dimethoxy phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) fluoro- benzoyls of -2- Amine,
The fluoro- 6- of 5,7- bis- (1- (6- (1- (benzenesulfonyl) -1H- indol-3-yls) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline,
N, N- dimethyl -3- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline,
The fluoro- 4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzamide,
3- (4- fluorophenyls) -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- Base) ethyl) quinoline,
6- [6- (1- methyl isophthalic acid H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene]-quinoline,
2- (4- (1- (the fluoro- quinoline -6- methylene of 7-) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazol-1-yls)-second Alcohol,
6- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene) -7- fluorine quinoline,
The fluoro- 6- of 7- (6- phenyl imidazoles simultaneously [4,5-b] pyrazine -1- methylene)-quinoline,
The fluoro- 6- of 7- (6- (pyridin-4-yl)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
The fluoro- 6- of 7- (6- (4- methoxyl group -2- methylphenyls)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
The fluoro- 6- of 7- (6- (quinoline -3- bases)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
4- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases)-aniline,
6- ((5- (the chloro- 4- quinolyls of 7-) imidazo [4,5-b] pyrazine -3- bases) methylene) fluoro- quinoline of -7-,
The chloro- 4'- of 7- (3- (the fluoro- quinoline -6- methylene of 7-) -3H- imidazos [4,5-b] pyrazine -5- bases)-[4,7'] double quinoline,
The fluoro- 6- of 7- [6- (1,2,3,6- Tetrahydro-pyridine -4- bases)-imidazo [4,5-b] pyrazine -1- methylene]-quinoline hydrochloric acid Salt,
The fluoro- 6- of 7- (6- (2- fluoro-phenyls)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
The fluoro- 6- of 7- (6- (pyridin-3-yl)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
The fluoro- 6- of 7- (6- (naphthalene -1- bases)-imidazo [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- cyclopropyl-imidazo [4,5-b] pyrazine -1- methylene) fluoro- quinoline of -7-,
The fluoro- 6- of 7- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H-- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
4- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline,
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -7- fluorine quinoline,
The fluoro- 6- of 7- (1- (6- phenyl imidazoles simultaneously [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
The fluoro- 6- of 7- (1- (6- (pyridin-4-yl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
2- (4- (1- (1- (7- fluorine quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazol-1-yls) - Ethanol,
The fluoro- 6- of 7- (1- (6- (quinoline -3- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
The fluoro- 4- of 2- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-methyl benzoate,
The fluoro- 4- of 2- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N- methylbenzene first Acid amides,
4- (1- (1- (base of 7- fluorine quinoline -6)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-benzsulfamide,
The fluoro- 6- of 7- (1- (6- (pyrimidine -5- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
4- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-furans -2- methanol,
4- (1- (1- (7- fluorine quinoline -6- bases)-ethyl) -3H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile,
The fluoro- 6- of 7- (1- (6- (thiophene -2- bases) imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
The fluoro- 6- of 7- (1- (6- (thiene-3-yl) imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
6- (1- (6- (benzo [b] thiophene -2- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine quinoline,
6- (1- (6- (benzo [b] thiene-3-yl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine quinoline,
The fluoro- 6- of 7- (1- (6- (4- methyl mercaptos phenyl)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline,
6- (1- (6- (1H- pyrroles [2,3-b] pyridine -5- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl) -7- fluorine quinoline,
5- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-N, N- lutidines - 2- amine,
The fluoro- 6- of 7- (1- (6- (6- methvl-pyridinium -3- bases)-imidazo [4,5-b] pyrazine -1- bases)-ethyl)-quinoline；、
3- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyridine -2- amine,
5- (1- (1- (the fluoro- quinoline -6- bases of 7-)-ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyridine -2- amine,
5,7 2 fluoro- 6- ((6- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
The fluoro- 6- of 5,7- bis- ((6- (4- (trifluoro methoxy) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) quinoline,
4- (1- ((5,7- difluoro-quinoline -6- bases) methyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -2- fluorophenyl carbamates,
6- ((6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl) -5,7- difluoro-quinolines,
5,7 2 fluoro- 6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinolines Quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (pyridin-4-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- cyclopropyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
2- (4- (1- (1- (5,7-difluoro-quinoline-6- bases) ethyl)-1H- imidazos [4,5-b] pyrazine-6- bases)-1H- pyrazoles-1- Base) second -1- alcohol,
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline,
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
6- (1- (6- (7- chloroquinoline -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
The fluoro- 6- of 5,7- bis- (1- (6- (pyridin-3-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (5- methoxyl group -2- aminomethyl phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline Quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (4- trifluoromethoxy benzaldehydes base) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -2- fluobenzoic acid first Ester,
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) fluoro- N- methylbenzenes of -2- Formamide,
The fluoro- 6- of 5,7- bis- (1- (6- (4- first sulfur phenenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (benzo [b] thiophene -2- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- difluoro-quinolines,
The fluoro- 6- of 5,7- bis- (1- (6- (pyrimidine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 6- of 5,7- bis- (1- (6- (3- thienyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
4- (1- (1- (5,7- difluoro-quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile,
7- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
7- methyl -6- (1- (6- (3- quinolyls) -1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline Quinoline,
7- methyl -6- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -7- methylquinolines,
The fluoro- 4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) methyl benzoate,
The fluoro- N- methyl -4- of 2- (1- (1- (7- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzene first Acid amides,
5- methyl -6- (1- (6- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
5- methyl -6- (1- (6- (4- pyridine radicals) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
5- methyl -6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
2- (4- (1- (1- (5- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- base -1H- pyrazol-1-yls) Second -1- alcohol,
The fluoro- 4- of 2- (1- (1- (5- methylquinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) methyl benzoate,
5- methyl -6- (1- (6- (3- quinolyls) -1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline Quinoline,.
11. quinolines as shown in Equation 1, its pharmaceutically acceptable salt as described in any one of claim 1~10, Solvate, metabolite, the preparation method of metabolic precursor thereof or its prodrug, it is characterised in that comprise the following steps：Molten In agent, compound II and boric acid or borate are subjected to Suzuki coupling reactions, compound 1 is obtained；
Wherein, X is halogen；Wherein, Cy definition is as described in Claims 1 to 5 or 8 any one；L definition such as claim 1 It is described；R1、R2、R3And R4Definition as described in any one of claim 1~7.
12. preparation method as claimed in claim 11, it is characterised in that comprise the following steps：By compound III and carboxylic acid or Original carboxylic acid ester is reacted, and obtains described compound II；
13. preparation method as claimed in claim 12, it is characterised in that comprise the following steps：In a solvent, by compound V or Its acid salt carries out nucleophilic substitution with compound IV, obtains described compound III；
14. a kind of compound as shown in Formula II, III or V,
Wherein, Cy definition is as described in Claims 1 to 5 or 8 any one；A definition is as claimed in claim 1；L definition is such as Described in claim 1；R1、R2、R3And R4Definition as described in any one of claim 1~7.
15. quinolines as shown in Equation 1, its pharmaceutically acceptable salt as described in any one of claim 1~10, Solvate, metabolite, metabolic precursor thereof or its prodrug, are used to treat and/or prevent and EGFR-TK C- preparing Application in Met expression or the medicine of the related disease of activity.
16. application as claimed in claim 15, it is characterised in that：Described expression or activity with EGFR-TK C-Met Related disease includes cancer, musculoskeletal sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours.
17. application as claimed in claim 15, it is characterised in that：Described cancer include carcinoma of urinary bladder, breast cancer, cervical carcinoma, Colon cancer, cancer of the esophagus, stomach cancer, head and neck cancer, kidney, lung cancer, liver cancer, nasopharyngeal carcinoma, oophoroma, cancer of pancreas, prostate cancer and first shape Gland cancer；Described musculoskeletal sarcoma includes：Osteosarcoma, synovial sarcoma and rhabdomyosarcoma；Described soft tissue sarcoma includes： MFH/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma；Described Hematopoietic Malignancies bag Include：Huppert's disease, lymthoma, adult T cell leukemia, acute myelogenous leukemia and chronic myelocytic leukemia； Other described tumours include：Glioblastoma, astrocytoma, melanoma, celiothelioma and embryonal carcinosarcoma.
18. a kind of pharmaceutical composition, it is characterised in that：Containing therapeutically effective amount as described in any one of claim 1~10 Quinolines, its pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor thereof or its medicine as shown in Equation 1 Precursor, and pharmaceutically acceptable one or more pharmaceutic adjuvants；Described therapeutically effective amount is that weight/mass percentage composition is 1% ~99%；Described weight/mass percentage composition be imidazopyrazines as shown in Equation 1, its pharmaceutically acceptable salt, Solvate, metabolite, metabolic precursor thereof and/or its prodrug, account for the percentage of pharmaceutical composition gross mass；Described medicine The weight/mass percentage composition sum of each component is 100% in compositions.
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