CN105968115B - Quinolines, preparation method, intermediate, pharmaceutical composition and application - Google Patents

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

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CN105968115B
CN105968115B CN201610574409.3A CN201610574409A CN105968115B CN 105968115 B CN105968115 B CN 105968115B CN 201610574409 A CN201610574409 A CN 201610574409A CN 105968115 B CN105968115 B CN 105968115B
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quinoline
pyrazine
ethyl
imidazos
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CN105968115A (en
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余建鑫
赵菲
郝宇
李萍
夏广新
范艺
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Shanghai Pharmaceuticals Holding Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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

Abstract

The invention discloses quinolines, preparation method, intermediate, pharmaceutical composition and applications.The present invention provides a kind of quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor thereof or its prodrugs.The quinolines of the present invention have good inhibition to tyrosine kinase C-Met, can be used for preparing and prevent, treat or the drug of the expression of auxiliary treatment and C-Met or the related a variety of diseases of activity, especially tumor disease.

Description

Quinolines, preparation method, intermediate, pharmaceutical composition and application
The application is application No. is CN201410152877.2, and the applying date is on 04 16th, 2014, entitled " quinoline The divisional application of the patent application of quinoline class compound, preparation method, intermediate, pharmaceutical composition and application ".
Technical field
The present invention relates to quinolines, preparation method, intermediate, pharmaceutical composition and applications.
Background technology
C-Met is a kind of protein product encoded by C-Met proto-oncogenes, is hepatocyte growth factor receptor, has junket Histidine kinase activity, it is related to a variety of oncoproteins and regulatory protein, participate in cellular informatics conduct, the tune of cytoskeleton rearrangement An important factor for control is cell Proliferation, differentiation and movement.It is now recognized that generations and transfer close phase of the C-Met with a variety of cancers It closes, studies have shown that many tumour patients have C-Met overexpressions and gene to expand in the generation of its tumour and transfer process Increase.The relationship of activation and the canceration of C-Met is mainly manifested in：
1, the activation mechanism of hepatocyte growth factor (HGF) is relied on
It is by HGF and C-Met that can activate C-Met, most common mode in many of tumour cell molecular mechanism In conjunction with playing a role.HGF and C-Met, which is combined, leads to receptor auto-phosphorylation, enhances the activity of C-Met tyrosine kinase, leads Cause the tyrosine phosphorylation of a variety of substrate proteins.Under physiological conditions, C-Met receptors and the of short duration combinations of HGF play physiological effect, In tumor tissues, oncogenic indeterminate growth and invasion behavior are led in high expression HGF and C-Met, formation positive feedback simultaneously.It is this just Feedback is confirmed in the malignant tumours such as glioma, osteosarcoma, breast cancer.
2, the activation mechanism of hepatocyte growth factor (HGF) is not depended on
C-Met can not depend on HGF and be activated, especially the tumour in Met overexpressions.The high expression of Met albumen May be the amplification, transcription enhancing or post-transcriptional mechanism due to C-Met genes.The C-Met genes that Cooper is cloned for the first time are just It is the activation form after resetting, it is the N-terminal and No. 7 chromosome Met sequences of the promoter and TPR gene orders of No. 1 chromosome The cytoplasm protein of the mosaic gene that the C-terminal of row is formed, this mosaic gene coding includes the leucine zipper region of TPR codings With met coding tyrosine kinase area Met kinases sustained activations are led to due to the presence of leucine zipper region, 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 lead to Met kinases sustained activations.
Tyrosine kinase receptor C-Met is played during the signal transduction of the metabolism of cell, differentiation and dead cell Important role can activate its signal path with ligand binding, participate in embryonic development, tissue damage reparation and tumour Occurrence and development.Therefore, have become in tumor research very by the antitumor drug of target spot of tyrosine kinase receptor C-Met Active field provides new method for antineoplaston.
Small molecule C-Met tyrosine kinase inhibitors are mostly the competitive inhibitors of ATP, by blocking tyrosine phosphatase Change the effect for playing and inhibiting 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 the double inhibitor of a C-Met/ALK, effective to the non-small cell lung cancer of ALK mutation, body The characteristic of personalized treatment is showed.In November, 2012, Exelixis companies announced, drug cabozantinib (XL184) has been obtained Treatment of the FDA approvals for the pernicious Locally Advanced or metastatic medullary thyroid carcinoma (MTC) of the excision that can not perform the operation. 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 inhibit angiogenesis.Although at present there is no the C-Met inhibitor of selectivity Class drug lists, but has developed many compounds at present with C-Met inhibitory activity, and can improve since C-Met is different The disease often resulted in, this kind of compound have the JNJ-38877605 of Johnson&Johnson, the AMG-458 of Amgen, Eisai's The PF-04217903 of E-7050 and Pfizer.
Invention content
Technical problem to be solved by the invention is to provide a kind of with the entirely different quinolines of the prior art, Preparation method, intermediate, pharmaceutical composition and application.The quinolines of the present invention have tyrosine kinase C-Met good Good inhibition, can be used for preparing and prevents, treats or the expression of auxiliary treatment and C-Met or the related a variety of diseases of activity The drug of disease, especially tumor disease.
The present inventor, by a large amount of arduous experimental studies, it was found that a kind of inhibition selective to C-Met is made Quinoline derivatives complete the present invention.
The present 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 X3It is each independently C or N,It indicates, works as X1For C when, X1With R1It is connected, works as X1For N When, with X1Connected R1It is not present；Also, work as X1For C when, X2And X3In one be C, another is N, R1It is (excellent for hydrogen or hydroxyl Select hydrogen)；Work as X1For N when, X2For N, X3For C；It is preferred that X1For C or N, X2For N, X3For C；
Cy is 3~8 yuan of naphthenic base (preferably 3~6 yuan of naphthenic base, " 3~6 yuan of naphthenic base " preferably unsubstituted ring Propyl), 3~8 membered heterocycloalkyls (preferably 3~6 membered heterocycloalkyls, " 3~6 membered heterocycloalkyl " preferably hetero atom be nitrogen Atom, hetero atom number are 5~6 membered heterocycloalkyls of 1-2, and described " hetero atom is nitrogen-atoms, and hetero atom number is the 5 of 1-2 ~6 membered heterocycloalkyls " can be by C1-4Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) is taken Generation；Described " hetero atom is nitrogen-atoms, 5~6 membered heterocycloalkyls that hetero atom number is 1-2 " the preferred the piperazinyl, " 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；" the N methyl piperazine base " preferably N methyl piperazine -1- bases), 5~8 yuan of cyclenes (preferably 5~6 circle heterocyclic ring alkenyls, " 5~6 circle heterocyclic ring alkenyl " preferably hetero atom are that nitrogen is former for base, 5~8 circle heterocyclic ring alkenyls Son, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1-2, described " hetero atom is nitrogen-atoms, hetero atom number is 1-2 5~ 6 circle heterocyclic ring alkenyls " can by "Alkyl " replace (wherein, C1-4Alkyl such as methyl, ethyl, propyl, isopropyl Base, butyl, isobutyl group or tertiary butyl) or " 5~6 circle heterocyclic rings that hetero atom is nitrogen-atoms, hetero atom number is 1-2 The free nitrogen atom of alkenyl " can be at salt；" 5~6 circle heterocyclic ring 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, the 6- tetrahydropyridine -4- Base；" free nitrogen atom on 5~6 circle heterocyclic ring alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 is at the salt " It is preferred that " the quiltThe hetero atom that is replaced of alkyl be nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2 " are preferably), 6~10 yuan of aryl, 5~10 Unit's heteroaryl or "Alkyl " (preferably C1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, different Propyl, butyl, isobutyl group or tertiary butyl)；3~8 yuan of naphthenic base, 3~8 membered heterocycloalkyls, 5~8 member cycloalkenyls, 5~8 Circle heterocyclic ring alkenyl, 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, R5、 Group replaced, Middle R5And R6It is each independently C1-6Alkyl (preferably C1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl Base, butyl, isobutyl group or tertiary butyl), halogen substitution C1-6Alkyl (the preferably C of halogen substitution1-4The alkyl, " C1-4Alkane Base " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl, " halogen " such as fluorine, chlorine or bromine), The C of hydroxyl substitution1-6Alkyl (the preferably C of hydroxyl substitution1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, different Propyl, butyl, isobutyl group or tertiary butyl), 3~8 yuan of naphthenic base, 3~8 membered heterocycloalkyls, 6~10 yuan of aryl (preferably phenyl), 6~10 yuan of aryl (the preferably phenyl of halogen substitution, " halogen " such as fluorine, chlorine or bromine of halogen substitution；), 5~10 yuan (preferably hetero atom is nitrogen-atoms to heteroaryl, and hetero atom number is 5~10 unit's heteroaryls of 1-2, and described " hetero atom is that nitrogen is former Son, hetero atom number are 5~10 unit's heteroaryls of 1-2 " preferred quinolyl) or 5~10 unit's heteroaryls of halogen substitution it is (described " halogen " such as fluorine, chlorine or bromine；" 5~10 unit's heteroaryl " preferably hetero atom is nitrogen-atoms, and hetero atom number is 1-2 5~10 unit's heteroaryls, described " hetero atom is nitrogen-atoms, 5~10 unit's heteroaryls that hetero atom number is 1-2 " the preferred quinoline Base)；
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, isopropyl, butyl, isobutyl group or tertiary butyl)；It is preferred that R2And R3Each independently For hydrogen, fluorine or methyl, R4For hydrogen；Still further preferably work as R2For hydrogen when, R3For hydrogen, fluorine or methyl, R4For hydrogen；Work as R2For fluorine when, 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 by 1~2 selected from halogen (such as fluorine, chlorine or bromine), C1-6Alkyl (preferably C1-4The alkyl, " C1-4Alkyl " is for example Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) and "Alkyl " (wherein, C1-6Alkyl is excellent Select C1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) in base Group is replaced；
Work as X1For C, X2For N and X3For C when, A is preferably that (preferably nitrogen-atoms numbers are 1-2 for hydrogen or 5~10 membered nitrogen-containing heteroaryl bases 5~6 a membered nitrogen-containing heteroaryl bases, described " 5~6 membered nitrogen-containing heteroaryl bases that hetero atom number is 1-2 " the preferred pyrazolyl), institute Stating 5~10 membered nitrogen-containing heteroaryl bases can be by C1-6Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) Replaced；By the preferred 1- methyl-1s H- pyrazolyls of methyl substituted 5~10 membered nitrogen-containing heteroaryl base；
Work as X1For C, X2For C and X3For N when, A is preferably that (preferably nitrogen-atoms numbers are the 5 of 1-2 to 5~10 membered nitrogen-containing heteroaryl bases ~6 membered nitrogen-containing heteroaryl bases, described " 5~6 membered nitrogen-containing heteroaryl bases that hetero atom number is 1-2 " the preferred pyrazolyl), described 5~ 10 membered nitrogen-containing heteroaryl bases can be by C1-6Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) is taken Generation；By the preferred 1- methyl-1s H- pyrazolyls of methyl substituted 5~10 membered nitrogen-containing heteroaryl base；
Work as X1For N, X2For N and X3For C when, A be preferably 6~10 yuan of aryl (preferably phenyl, " 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, isopropyl, butyl, isobutyl group or tertiary butyl, preferably methyl) group replaced) or 5~10 membered nitrogen-containing heteroaryl bases (5~10 membered nitrogen-containing heteroaryl bases that preferably nitrogen-atoms numbers are 1-2, " 5~10 yuan of nitrogen-containing heteros that nitrogen-atoms numbers are 1-2 Aryl " preferably pyrazolyl, pyridyl group or quinolyl), described 6~10 yuan of aryl or 5~10 membered nitrogen-containing heteroaryl bases can be by 1~2 It is a to be selected from halogen (such as fluorine, chlorine or bromine), C1-6Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary fourth Base) and "Alkyl " (wherein described " the C1-6Alkyl " preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base or tertiary butyl) 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-1 H- pyrazolyls).
In the present invention, the quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvate, generation Product, metabolic precursor thereof or its prodrug are thanked, preferably the quinolines chemical combination containing Imidazopyrazines structure as shown in formula 1-a Object, 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 preferable Cy be it is following d) described in group：
A) 3~6 yuan of naphthenic base, described " 3~6 yuan of naphthenic base " the preferred cyclopropyl, further preferred cyclopropyl；
B) 3~6 membered heterocycloalkyl, " 3~6 membered heterocycloalkyl " preferably hetero atom is nitrogen-atoms, hetero atom number is 1 ~2 5~6 membered heterocycloalkyls, " hetero atom is nitrogen-atoms, 5~6 membered heterocycloalkyls that hetero atom number is 1~2 " can By C1-4Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) is replaced；" the hetero atom For nitrogen-atoms, 5~6 membered heterocycloalkyls that hetero atom number is 1~2 " preferred piperazinyl, " piperazinyl " preferably 4- piperazines Base；" being nitrogen-atoms, 5~6 membered heterocycloalkyls that hetero atom number is 1~2 by the hetero atom that methyl is replaced " is preferred N methyl piperazine base, " the N methyl piperazine base " preferably N methyl piperazine -1- bases；
C) 5~6 circle heterocyclic ring alkenyl, preferably hetero atom are nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2, " hetero atom is nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2 " can by "Alkyl " (wherein, C1-4Alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl) replaced or described Free nitrogen atom on " hetero atom is nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2 " can be at salt；Described " hetero atom is nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2 " preferably 1,2,3,6- tetrahydropyridine -4- bases" the nomadic nitrogen on 5~6 circle heterocyclic ring alkenyls that hetero atom is nitrogen-atoms, hetero atom number is 1~2 Atom is at salt " preferably" the quiltThe miscellaneous original that is replaced of alkyl Son is nitrogen-atoms, 5~6 circle heterocyclic ring alkenyls that hetero atom number is 1~2 " preferably
D) 6~10 yuan of aryl or 5~10 unit's heteroaryls；" 6~10 yuan of aryl " preferably phenyl or naphthyl is (described " naphthalene " preferably 1- naphthalenes)；Preferably hetero atom is N, O to " 5~10 unit's heteroaryl " or S atom, hetero atom number are 1~2 5~10 unit's heteroaryls of a monocycle or condensed ring, " hetero atom N, O or S atom, the list that hetero atom number is 1~2 5~10 unit's heteroaryl of ring " preferably pyrazolyl (" pyrazolyl " preferably 1H- pyrazoles -4- bases or 1H- pyrazoles -5- bases), pyridine Base (" pyridyl group " preferably pyridin-4-yl or pyridin-3-yl), thienyl (described " thienyl " preferred thiene-3-yl Or thiophene -2- bases), pyrimidine radicals (" pyrimidine radicals " preferably pyrimidine -5- bases) or furyl (described " furyl " preferred furan It mutters -3- bases)；Described " hetero atom N, O or S atom, 5~10 unit's heteroaryl of condensed ring that hetero atom number is 1~2 " the preferred quinoline Quinoline base (" quinolyl " preferably quinolyl-4, quinoline -3- bases or quinoline -7- bases), the isoquinolyl (" isoquinolin Base " preferably isoquinolin -4- bases), benzothienyl (" benzothienyl " preferably benzothiophene -3- bases or benzothiophene - 2- yls), indyl (" indyl " preferably indol-3-yl, indoles -4- bases or indoles -5- bases) or pyrrolopyridinyl (" 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, R5、(preferably N, N- dimethylamino),(preferably)、(preferably)、 (preferably) group replaced, wherein R5、R6It is each independently C1-6Alkyl (preferably C1-4The alkyl, " C1-4 Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl), halogen substitution C1-6Alkyl is (described " the C of halogen substitution1-6" C described in alkyl "1-6The preferred C of alkyl "1-4The alkyl, " C1-4Alkyl " for example methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group or tertiary butyl；" the C of halogen substitution1-6" halogen " described in alkyl " is preferred Fluorine, chlorine or bromine；" the C of halogen substitution1-6The preferred trifluoromethyl of alkyl "), hydroxyl substitution C1-6The alkyl (" hydroxyl The C of base substitution1-6" C described in alkyl "1-6The preferred C of alkyl "1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, third Base, isopropyl, butyl, isobutyl group or tertiary butyl；" the C of hydroxyl substitution1-6Alkyl " is preferred), 6~10 6~10 yuan of aryl that first aryl (preferably phenyl), halogen replace are (described in " 6~10 yuan of aryl of halogen substitution " " 6~10 yuan of aryl " preferred phenyl, " halogen " described in described " 6~10 yuan of aryl of halogen substitution " preferably fluorine, chlorine or Bromine), (preferably hetero atom is nitrogen-atoms, 5~10 unit's heteroaryls that hetero atom number is 1~2 to 5~10 unit's heteroaryls, described " hetero atom is nitrogen-atoms, 5~10 unit's heteroaryls that hetero atom number is 1~2 " preferred quinolyl) or halogen substitution 5~10 (" 5~10 unit's heteroaryl " preferably hetero atom described in " 5~10 unit's heteroaryls of halogen substitution " is nitrogen to unit's heteroaryl Atom, hetero atom number are 1~2 5~10 unit's heteroaryl, and described " hetero atom is nitrogen-atoms, hetero atom number is 1~2 The quinolyl of 5~10 unit's heteroaryls " preferably halogen substitution；" halogen described in " 5~10 unit's heteroaryls of halogen substitution " Element " preferably fluorine, chlorine or bromine；" 5~10 unit's heteroaryls of halogen substitution " are preferably)；The substituent group It can be identical or different.
e)“Alkyl " (wherein, C1-6The preferred C of alkyl1-4The alkyl, " C1-6Alkyl " such as methyl, Ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl, preferably methyl)；
L is
R1For hydrogen or hydroxyl, preferably H；
R2And R3It is each independently H, F or methyl, R4For H；Preferably, work as R2For H when, R3For H, F or methyl, R4For H； Work as R2For F when, 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, " the miscellaneous original The preferred pyrazolyl of 5~6 membered nitrogen-containing heteroaryl bases that subnumber is 1-2 "), the 5 membered nitrogen-containing heteroaryl base can be by C1-4Alkyl is replaced (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl, it is a 5 1-2 by methyl substituted nitrogen-atoms numbers The preferred 1- methyl-1s 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 " the preferred benzene Base；" 5~10 unit's heteroaryl " preferably hetero atom is N, O or S atom, the monocycle that hetero atom number is 1~2 or condensed ring 5~10 unit's heteroaryls, " hetero atom N, O or S atom, 5~10 unit's heteroaryl of monocycle that hetero atom number is 1~2 " It is preferred that pyrazolyl (" pyrazolyl " preferably 1H- pyrazoles -4- bases), pyridyl group (described " pyridyl group " preferred pyridin-4-yl Or pyridin-3-yl), thienyl (" thienyl " preferably thiene-3-yl or thiophene -2- bases) or the furyl (" furan Mutter base " preferred furans -2- bases)；It is described that " hetero atom N, O or S atom, 5~10 yuan of the condensed ring that hetero atom number is 1~2 are miscellaneous Aryl " preferably quinolyl (" quinolyl " preferably quinoline -3- bases or quinoline -7- bases), the isoquinolyl (" isoquinoline Quinoline base " preferably isoquinolin -4- bases), benzothienyl (" benzothienyl " preferably benzothiophene -3- bases or benzo thiophene Pheno -2- bases) or indyl (" 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, R5、(preferably N, N- dimethylamino),(preferably)、 (preferably)、WithGroup replaced, wherein R5、R6It is respectively independent Ground is C1-6Alkyl (preferably C1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group Or tertiary butyl, preferred methyl) or hydroxyl substitution C1-6The alkyl (" C of hydroxyl substitution1-6" C described in alkyl "1-6Alkane The preferred C of base "1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl； " the C of hydroxyl substitution1-6Alkyl " is preferred)；
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 1~2 5~10 membered nitrogen-containing heteroaryl base to membered nitrogen-containing heteroaryl base, and described " nitrogen-atoms numbers are 1~2 5~10 membered nitrogen-containing heteroaryl bases " preferably pyridyl group, pyrazolyl or quinolyl) and can by 1~2 selected from halogen (such as fluorine, chlorine or Bromine), C1-6Alkyl (preferably C1-4The alkyl, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group Or tertiary butyl, the preferred 1- methyl-1s H- pyrazoles -4- of 5~6 membered nitrogen-containing heteroaryl bases for being 1-2 by methyl substituted nitrogen-atoms numbers Base；) and "Alkyl " (wherein, C1-6The preferred C of alkyl1-4The alkyl, " C1-6Alkyl " for example methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group or tertiary butyl, preferably methyl) group replaced.
In compound 1-c, Cy is phenyl, and the phenyl can be by 1~2 selected from halogen (such as fluorine, chlorine or bromine, preferably fluorine) "Alkyl " (the wherein, " C1-4Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group Or tertiary butyl, 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-1 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, " 6~10 yuan of aryl " further preferably phenyl, 2- is fluoro- The chloro- phenyl of phenyl, 2-, the chloro- phenyl of 3-, 2- trifluoromethyl-phenyls, 4- trifluoromethyls, 3,4- dichlorophenyls, 4- fluoroforms Phenyl, 3- cvano-phenyls, 4- cyano-phenyls, 3-N, N- dimethylaminophenyls, 4- aminophenyls, 2,4- dimethoxys- Phenyl, 2,6- dimethoxy-phenylfs, 2,6- Dimethvl-phenyls, 2- methyl -4- methoxyl groups-phenyl, 2- methyl -5- methoxybenzenes Base, 4- methyl mercaptos-phenyl,
In the present invention, when Cy is 5~10 unit's heteroaryl, " 5~10 unit's heteroaryl " is further preferred：Thiophene- 2- bases, thiene-3-yl, furans -2- bases, pyridin-3-yl, pyridin-4-yl, 2-aminopyridine -3- bases, 2- fluorine pyridin-3-yl, 2- Aminopyridine -5- bases, 2- picoline -5- bases, indoles -4- bases, indoles -5- bases, quinoline -7- bases, isoquinolin -4- bases, 5- cyanogen Base 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-1 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-1 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)-ethyl alcohol (1- 18)、
6- (1- (6- (1- methyl-1 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- pyridyl groups) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-22),
6- (1- (6- (1- methyl-1 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) Ethyl alcohol (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-1 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-1 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- naphthalenes) -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) ethyl alcohol (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- pyridyl groups) -1H- imidazos [4,5-b] pyrazine -1- bases) methyl)-quinoline (1-56),
Fluoro- (6- (1- (6- (1- methyl-1 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-1 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- pyridyl groups) -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- naphthalenes) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-68),
6- [6- (1- methyl-1 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)-ethyl alcohol (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-1 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)-ethyl alcohol (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- (- 6 base of 7- fluorine quinoline)-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-1 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)、
Bis- fluoro- 6- of 5,7- ((6- (1- naphthalenes) -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)、
Bis- fluoro- 6- of 5,7- ((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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline (1-118),
Bis- fluoro- 6- of 5,7- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-119),
Bis- fluoro- 6- of 5,7- (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),
Bis- fluoro- 6- of 5,7- (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)、
Bis- fluoro- 6- of 5,7- (1- (6- (pyridin-3-yl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl)-quinoline (1- 130)、
Bis- fluoro- 6- of 5,7- (1- (6- (5- methoxyl group -2- aminomethyl phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base)-quinoline (1-131),
Bis- fluoro- 6- of 5,7- (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)、
Bis- fluoro- 6- of 5,7- (1- (6- (1- naphthalenes) -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)、
Bis- fluoro- 6- of 5,7- (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- Amide (1-140),
Bis- fluoro- 6- of 5,7- (1- (6- (4- first sulfur phenenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 141)、
Bis- fluoro- 6- of 5,7- (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),
Bis- fluoro- 6- of 5,7- (1- (6- (pyrimidine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1- 144)、
Bis- fluoro- 6- of 5,7- (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-1 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] pyrroles Piperazine -6- bases) aniline (1-149),
7- methyl -6- (1- (6- (4- pyridyl groups) -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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) Quinoline (1-155),
5- methyl -6- (1- (6- (4- pyridyl groups) -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-1 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-1 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-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] Pyrazine -6- bases) methyl benzoate (1-163),
Two fluoro- 3- (1- of 6- (1- (6- (1H- indoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- Methyl-1 H- pyrazoles -4- bases) quinoline (1-164),
4- (1- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) -1H- imidazos [4, 5-b] pyrazine -6- bases) -2- fluorophenyl carbamates (1-165),
Bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] Pyrazine -1- bases) ethyl) quinoline (1-166),
Two fluoro- 3- (1- of 6- (1- (6- (1H- indoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- Methyl-1 H- pyrazoles -4- bases) quinoline (1-167),
Bis- fluoro- 6- of 5,7- (1- (6- (isoquinolin -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -3- (1- Methyl-1 H- pyrazoles -4- bases) quinoline (1-168),
Bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (quinoline -7- bases) -1H- imidazos [4,5-b] Pyrazine -1- bases) ethyl) quinoline (1-169),
Bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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-1 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-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (1-172),
3- (1- methyl-1 H-4- pyrazolyls) -6- (6- (1- methyl-1 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-1 H-4- pyrazolyls) -6- (1- (6- (1- methyl-1 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-1 H-4- pyrazolyls) -6- (1- (6- (1H-4- pyrazolyls)-[1,2,3] triazole simultaneously [4, 5-b] pyrazinyl) ethyl) quinoline (2-7),
2- (4- ([1,2,3] three nitrogen of 3- (1- (the fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) quinoline -6- bases) ethyl) -3H- Azoles simultaneously [4,5-b] pyrazine -5- bases) pyrazolyl) ethyl alcohol (2-8),
The fluoro- 3- of 7- (1- methyl-1 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-1 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-1 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-1 H-4- pyrazolyls) quinoline (2-13),
The fluoro- 4- of 2- ([1,2,3] three nitrogen of 3- (1- (the fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) quinolyl) ethyl) -3H- 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-1 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-1 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-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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-1 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-1 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-1 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-1 H- pyrazoles -4- bases) quinoline (2-21),
3- (1- methyl-1 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-1 H- pyrazoles -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrroles Piperazine -1- bases) ethyl) quinoline (2-24),
Bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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-1 H- pyrazoles -4- bases) quinoline (2-26),
4- (1- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 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),
Bis- fluoro- 6- of 5,7- (1- (6- (isoquinolin -4- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) second Base) -3- (1- methyl-1 H- pyrazoles -4- bases) quinoline (2-28),
Bis- fluoro- 3- of 5,7- (1- methyl-1 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 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),
Bis- fluoro- 3- of 5,7- (1- methyl-1 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),
Bis- fluoro- 3- of 5,7- (1- methyl-1 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),
Bis- fluoro- 6- of 5,7- (1- (6- (2- fluorine pyridin-3-yl) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) second Base) -3- (1- methyl-1 H- pyrazoles -4- bases) quinoline (2-33),
3- (1- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 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, Bis- fluoro- 3- of 7- (1- methyl-1 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, Bis- fluoro- 3- of 7- (1- methyl-1 H- pyrazoles -4- bases) quinoline (2-36),
Bis- fluoro- 6- of 5,7- (1- (6- (furans -2- bases) -1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) - 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline (2-37),
4- (1- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 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-1 H- pyrazoles -4- bases) quinoline -6- ylmethyls) imidazo [1, 2-b] [1,2,4] triazine -2- bases) benzamide (3-1).
The present invention also provides the quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvations The preparation method of object, metabolite, metabolic precursor thereof or its prodrug comprising following steps：In a solvent, by compound II Suzuki coupling reactions are carried out with boric acid or borate, obtain compound 1；
Wherein, X is halogen (preferably chlorine, bromine or iodine)；Cy,X1、X2、X3、R1、R2、R3、R4, L and A the same institute of definition It states.
The method of prepare compound 1 is the conventional method that Suzuki coupling reactions are carried out in this field, special in of the invention It is preferred that following reaction conditions：
In the method for prepare compound 1, the preferred water of the solvent and/or water-miscible organic solvent；Described is water-soluble It is one or more in the preferred dioxane of property organic solvent, tetrahydrofuran and N,N-dimethylformamide (DMF).
In the method for prepare compound 1, the volume mass of the solvent and compound II than preferred 100mL/g~ 500mL/g, further preferred 200mL/g~400mL/g.
In the method for prepare compound 1, the boric acid or the preferred compound as shown in Equation 6 of borateWherein R17For hydrogen, C1-6Alkyl orWherein C2-C6Indicate alkylidene；When p is 1, R17ForWhen p is 2, R17For hydrogen or C1-6Alkyl.
In the method for prepare compound 1, the molar ratio preferably 1 of the 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 the Suzuki coupling reactions can the freezing point from solvent to The temperature changed in the boiling point temperature range of solvent, preferably 90 DEG C~150 DEG C, further preferred 100 DEG C~120 DEG C.
In the method for prepare compound 1, routine in this field may be used in the process of the Suzuki coupling reactions Test method (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) determines, 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, the compound II can be prepared by following methods comprising following step Suddenly：Compound III is reacted with carboxylic acid or original carboxylic acid ester, obtains compound II；
Compound 1 is made according still further to the method for the prepare compound 1；Wherein, X, Cy, X1、X2、X3、R1、R2、 R3、R4, L and A definition as described above.
The method of prepare compound II, it is particularly preferred in of the invention to carry out the conventional method of such reaction in this field Following reaction conditions：
In the method for prepare compound II, the carboxylic acid or original carboxylic acid ester had both done reaction reagent or had done reaction dissolvent.
In the method for prepare compound II, the carboxylic acid or the preferred original acid A ester of original carboxylic acid ester, ethyl orthoformate With it is one or more in diethoxy methyl acetate.
In the method for prepare compound II, the volume mass of the carboxylic acid or original carboxylic acid ester and compound III are than excellent 20mL/g~100mL/g is selected, further excellent 40mL/g~80mL/g.
In the method for prepare compound II, the temperature of the reaction can be from the freezing point of solvent to the boiling point of solvent The temperature changed in temperature range, preferably 120 DEG C~180 DEG C, further preferred 140 DEG C~160 DEG C.
In the method for prepare compound II, traditional test methods in this field may be used in the process of the reaction (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) is determined, is disappeared for reaction with compound III Terminal, preferred reaction time 15h~30h, further preferred 20h~25h.
In the method for prepare compound II, the compound III can be prepared by following methods comprising following Step：In a solvent, compound V or its acid salt are subjected to nucleophilic substitution with compound IV, obtain compound III；
Compound II, the method system of the prepare compound 1 is made according still further to the method for the prepare compound II Obtain compound 1；Wherein, X, X1、X2、X3、R2、R3、R4, the definition of L and A it is same as above.
The method of prepare compound III, to carry out the conventional method of such nucleophilic substitution in this field, in of the invention Particularly preferred following reaction conditions：
In the method for prepare compound III, the preferred boiling point of the solvent is more than 130 DEG C of solvent, further preferably N,N-dimethylformamide (DMF), N, it is one or more in N- diethylformamides (DEF) and N-Methyl pyrrolidone
In the method for prepare compound III, the volume mass of the solvent and compound IV than preferred 10mL/g~ 50mL/g, further preferred 20mL/g~30mL/g.
In the method for prepare compound III, the molar ratio preferably 1 of the compound V and compound IV：1~1:3, Further preferred 1：1.2~1:1.6.
In the method for prepare compound III, the temperature of the reaction can be from the freezing point of solvent to the boiling of solvent The temperature changed in point temperature range, preferably 150 DEG C~250 DEG C, further preferred 190 DEG C~210 DEG C.
In the method for prepare compound III, traditional test methods in this field may be used in the process of the reaction (such as nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) is determined, is disappeared for reaction eventually with compound IV 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 It wants, and the selection of protecting group appropriate can readily be determined by those skilled in the art, the chemical mistake of protecting group Journey is in such as Greene et al., Protective Groups in Organic Synthesis, the second edition, Wiley&Sons, 1991, in find, be incorporated herein by reference in the form of whole herein.
In the method for prepare compound III, method 1 or method 2 may be used in the compound V, when L is Shi Youxuan uses 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；
Compound III, the method for the prepare compound II is made according still further to the method for the prepare compound III Compound II is made, compound 1 is made in the method for the 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；
Compound III, the method for the prepare compound II is made according still further to the method for the prepare compound III Compound II is made, compound 1 is made in the method for the prepare compound 1；Wherein, X, R2、R3、R4, L and A definition It is same as above.
The method 1 of prepare compound V can be the conventional method of such reduction reaction in this field, specifically preferred according to the invention Following reaction methods and condition：
The method 1 of prepare compound V preferably existing for ammonia under the conditions of carry out, the ammonia is preferably with the shape of ammonia alcoholic solution Formula participates in reaction.
The method 1 of prepare compound V preferably carries out under the conditions of Raney's nickel (Raney Ni) is existing, the Raney's nickel Can be conventional commercial Raney's nickel reagent, the mass percent preferably 20%~80% of the Raney's nickel, the quality hundred It refers to that the quality of nickel accounts for the percentage of Raney's nickel reagent gross mass to divide ratio.
In the method 1 of prepare compound V, the preferred alcohols solvent of the organic solvent, the alcohols solvent is preferred Methanol and/or ethyl alcohol.
In the method 1 of prepare compound V, the preferred 10bar~50bar of pressure of the reduction reaction is further excellent Select 20bar~30bar.
In the method 1 of prepare compound V, preferably 10 DEG C~40 DEG C of the temperature of the reduction reaction.
In the method 1 of prepare compound V, routine test side in this field may be used in the process of the reduction reaction Method (such as TLC, HPLC or NMR) is monitored, and as reaction end when generally being disappeared using compound VI, the reaction time preferably 1 is small When~48 hours.
In the method 1 of prepare compound V, following methods preparation may be used in the compound VI：Under gas shield, In organic solvent, under the conditions of catalyst is existing, compound VII and zinc cyanide is subjected to nucleophilic substitution, obtain chemical combination Object VI；
Compound V, the method system of the prepare compound III is made according still further to the method 1 of the prepare compound V Compound II is made in the method for obtaining compound III, the prepare compound II, and the method for the prepare compound 1 is made Compound 1；Wherein, X, R2、R3、R4, the definition of L and A it is same as above.
The method of prepare compound VI can be the conventional method of such nucleophilic displacement of fluorine in this field, especially excellent in of the invention Select following reaction methods and condition：
In the method for prepare compound VI, the organic solvent preferred amide class solvent, the amide solvent It is preferred that N,N-dimethylformamide.
In the method for prepare compound VI, the preferred tris(dibenzylideneacetone) dipalladium of the catalyst and 1,1'- is bis- (diphenylphosphine) ferrocene.
In the method for prepare compound VI, the molar ratio preferably 1 of the zinc cyanide and the compound VII~ 5, further preferred 1~2.
In the method for prepare compound VI, the molar ratio preferably 0.1 of the catalyst and the compound VII ~1.
In the method for prepare compound VI, when using tris(dibenzylideneacetone) dipalladium and 1,1'- bis- (diphenylphosphines) When ferrocene makees catalyst, bis- (diphenylphosphine) ferrocene of 1, the 1'- and the tris(dibenzylideneacetone) dipalladium Molar ratio preferably 2~3.
In the method for prepare compound VI, preferably 80 DEG C~150 DEG C of the temperature of the nucleophilic substitution.
In the method for prepare compound VI, the process of the nucleophilic substitution, which may be used in this field, routinely to be surveyed Method for testing (such as TLC, HPLC or NMR) is monitored, and as reaction end when generally being disappeared using compound VII, the reaction time is excellent It selects 1 hour~48 hours, further preferred 10 hours~24 hours.
In the method for prepare compound VI, the compound XII can be prepared by following methods：In a solvent, Under the conditions of sulfuric acid and catalyst are existing, compound XII and compound XIII are subjected to condensation reaction, obtain compound VII；
The system of method 1 of compound VI, the prepare compound V are made according still further to the method for the prepare compound VI The method that compound III, the prepare compound II is made in the method for obtaining compound V, the prepare compound III is made Compound 1 is made in the method for compound II, the prepare compound 1；Wherein, X, R2、R3、R4, the definition of L and A it is same It is upper described.
The method of prepare compound VII can be the conventional method that such in this field is condensed, particularly preferred in of the invention Following reaction methods and condition：
In the method for prepare compound VII, the preferred water of the solvent.
In the method for prepare compound VII, the preferred 3- nitrobenzene sodium sulfonates of the catalyst.
In the method for prepare compound VII, the molar ratio of the compound XIII and the compound XII are excellent Select 1~5, further preferred 2~3.
In the method for prepare compound VII, the molar ratio preferably 1 of the catalyst and the compound VII ~3, further preferred 1~1.5.
In the method for prepare compound VII, the molar ratio preferably 0.5 of the sulfuric acid and the compound XII ~2.The sulfuric acid can be conventional commercial sulphate reagent in this field, the mass percentage concentration preferably 30% of the sulfuric acid ~98%, the mass percentage concentration refers to that the quality of sulfuric acid accounts for the percentage of aqueous sulfuric acid gross mass.
In the method for prepare compound VII, preferably 80 DEG C~150 DEG C of the temperature of the condensation reaction.
In the method for prepare compound VII, routine in this field may be used in the process of the nucleophilic substitution Test method (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound VII, the reaction time It is preferred that 1 hour~48 hours, further preferred 10 hours~24 hours.
The method 2 of prepare compound V can be the conventional method of such reduction reaction in this field, specifically preferred according to the invention Following reaction methods and condition：
The method 2 of prepare compound V preferably existing for ammonia under the conditions of carry out, the ammonia is preferably with the shape of ammonia alcoholic solution Formula participates in reaction.
The method 2 of prepare compound V preferably carries out under the conditions of Raney's nickel (Raney Ni) is existing, the Raney's nickel Can be conventional commercial Raney's nickel reagent, the mass percent preferably 20%~80% of the Raney's nickel, the quality hundred It refers to that the quality of nickel accounts for the percentage of Raney's nickel reagent gross mass to divide ratio.
In the method 2 of prepare compound V, the preferred alcohols solvent of the organic solvent, the alcohols solvent is preferred Methanol and/or ethyl alcohol.
In the method 2 of prepare compound V, preferably 10 DEG C~40 DEG C of the temperature of the reduction reaction.
In the method 2 of prepare compound V, routine test side in this field may be used in the process of the reduction reaction Method (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound VIII, the reaction time preferably 1 Hour~48 hours.
In the method 2 of prepare compound V, following methods preparation may be used in the compound VIII：Organic molten In agent, azanol and compound IX are subjected to condensation reaction, obtain compound VIII；
Compound V, the method system of the prepare compound III is made according still further to the method 2 of the prepare compound V Compound II is made in the method for obtaining compound III, the prepare compound II, and the method for the prepare compound 1 is made Compound 1；Wherein, X, R2、R3、R4, the definition of L and A it is same as above.
The method of prepare compound VIII can be the conventional method that such in this field is condensed, particularly preferred in of the invention Following reaction methods and condition：
In the method for prepare compound VIII, the preferred alcohols solvent of the organic solvent, the alcohols solvent is excellent Select methanol and/or ethyl alcohol.
In the method for prepare compound VIII, the azanol can use in the form of the hydrochloride salt, when using hydroxyl When the hydrochloride of amine, preferably first carry out the hydrochloride of azanol and the alkali azanol is obtained by the reaction carrying out condensation reaction, the alkali again It is preferred that inorganic base, the preferred Strong oxdiative sodium of the inorganic base.
In the method for prepare compound VIII, the molar ratio preferably 1 of the azanol and the compound IX~ 5, further preferred 1~2.
In the method for prepare compound VIII, preferably 10 DEG C~40 DEG C of the temperature of the condensation reaction.
In the method for prepare compound VIII, routine test in this field may be used in the process of the condensation reaction Method (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound IX, the reaction time preferably 1 Hour~48 hours, further preferred 10 hours~24 hours.
In the method for prepare compound VIII, following methods preparation may be used in the compound IX：Gas shield Under, in organic solvent, compound X with methyl-magnesium-bromide carries out that compound IX is obtained by the reaction；
Compound VIII, the side of the prepare compound V is made according still further to the method for the prepare compound VIII Compound III, the side of the prepare compound II is made in the method that compound V, the prepare compound III is made in method 2 Legal system obtains compound II, and compound 1 is made in the method for the prepare compound 1；Wherein, X, R2、R3、R4, L and A determine Justice is same as above.
The method of prepare compound IX can be such reaction conventional method in this field, particularly preferably following in of the invention Reaction method and condition：
In the method for prepare compound IX, " gas " preferably helium, argon gas, neon described in " gas shield " It is one or more in gas and nitrogen.
In the method for prepare compound IX, the preferred ether solvent of the organic solvent, the ether solvent is preferred Tetrahydrofuran.
In the method for prepare compound IX, the molar ratio preferably 1 of the methyl-magnesium-bromide and the compound X ~3, further preferred 1~1.5.
In the method for prepare compound IX, preferably 0 DEG C~40 DEG C of the temperature of the reaction.
In the method for prepare compound IX, traditional test methods in this field may be used in the process of the reaction (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound X, preferably 1 hour reaction time~ 48 hours, further preferred 10 hours~24 hours.
In the method for prepare compound IX, the compound X may be used following methods and be made：Under gas shield, In organic solvent, under the conditions of catalyst is existing, compound XI is reacted with hydrochloride base azanol, obtains compound X；
Compound IX, the method for the prepare compound VIII is made according still further to the method for the prepare compound IX Compound V, the method for the prepare compound III is made in the method 2 that compound VIII, the prepare compound V is made Compound II, the method system of the prepare compound 1 is made in the method that compound III, the prepare compound II is made Obtain compound 1；Wherein, X, R2、R3、R4, the definition of L and A it is same as above.
The method of prepare compound X can be such reaction conventional method in this field, particularly preferably following in of the invention Reaction method and condition：
In the method for prepare compound X, " gas " preferably helium, argon gas, neon described in " gas shield " It is one or more in gas and nitrogen.
In the method for prepare compound X, the organic solvent preferred amide class solvent, the amide solvent is excellent Select N,N-dimethylformamide.
In the method for prepare compound X, the molar ratio of the hydrochloride base azanol and the compound XI It is preferred that 1~3, further preferred 1~1.5.
In the method for prepare compound X, the preferred 2- of the catalyst (7- azo phenylpropyl triazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU).
In the method for prepare compound X, the molar ratio preferably 1~3 of the catalyst and the compound XI, Further preferred 1~1.5.
In the method for prepare compound X, preferably 0 DEG C~40 DEG C of the temperature of the reaction.
In the method for prepare compound X, traditional test methods (example in this field may be used in the process of the reaction Such as TLC, HPLC or NMR) it is monitored, as reaction end when generally being disappeared using compound XI, the reaction time preferably 1 hour~48 Hour, further preferred 10 hours~24 hours.
In the present invention, the preparation of route one or two may be used in the compound I,
Route one：
Route two：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition as described above.
The present invention also provides 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 as described above.
The present invention also provides the preparation methods of the compound II, preferably use route A or route B,
Route A：
Route B：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition as described above；The specific reaction condition of each step is equal As described above.
The present invention also provides the preparation methods of the compound III, preferably use route C or route D,
Route C：
Route D：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition as described above；The specific reaction condition of each step is equal As described above.
The present invention also provides the preparation methods of the compound V, preferably use route E or route F：
Route E：
Route F：
Wherein, X, X1、X2、X3、R1、R2、R3、R4, L and A definition as described above；The specific reaction condition of each step is equal As described above.
The present invention also provides the quinolines as shown in Equation 1, its pharmaceutically acceptable salt, solvations Object, metabolite, metabolic precursor thereof or its prodrug, prepare treatment and/or prevent with the expression of tyrosine kinase C-Met or Application in the drug of the relevant disease of activity.
The present invention also provides a kind of pharmaceutical composition, containing 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 the pharmaceutical composition, its is pharmaceutically acceptable Salt, solvate, metabolite, metabolic precursor thereof or its prodrug content be therapeutically effective amount, preferred mass percentage composition It is 1%~99%；The mass percentage 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 the pharmaceutical composition It is 100% to divide the sum of content.
In the present invention, the pharmaceutic adjuvant is the conventional pharmaceutical adjuvants in this field, is selected because of administration method and work It is different with feature, preferably include filler, diluent, adhesive, wetting agent, disintegrant, lubricant, emulsifier, suspending agent.
In the present invention, the pharmaceutical composition can take orally, inject (vein, muscle, in subcutaneous and coronary artery), tongue Under, buccal, per rectum, per urethra, Via vagina, intranasal, sucking or topic route application.Preferred approach is oral.
The present invention also provides the pharmaceutical compositions to prepare treatment and/or prevent with tyrosine kinase C-Met's Application in the drug of expression or the relevant disease of activity.
In the present invention, the expression or the relevant disease of activity with tyrosine kinase C-Met is conventional in this field The variation by tyrosine kinase C-Met caused by disease, preferably include cancer, musculoskeletal sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours.The cancer preferably includes carcinoma of urinary bladder, breast cancer, cervical carcinoma, colon cancer, food Road cancer, gastric 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；The soft tissue sarcoma preferably wraps It includes：Malignant fibrous histiocytoma/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma；The hemopoietic system is pernicious swollen Tumor 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.
Certain chemistry or technical term of pharmacology：
Unless otherwise defined, the connotation that all scientific and technical terminologies of the application have usually is managed with one of ordinary skill in the art The connotation of solution is identical.Unless otherwise indicated, all patents, patent application, the public material of text of the statement reference pass through reference Mode is integrally incorporated herein.
It 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 within the scope of art technology, as mass spectrum, NMR, IR and UV/Vis spectroscopic methodology and Pharmacological method.Unless proposing to be specifically defined, otherwise the application is in analytical chemistry, Synthetic Organic Chemistry and drug and drug The term used in the related 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 manufacturer to the operation instruction of kit, or Person implements to react and purify according to the explanation of mode well known in the art or the present invention.It usually can be according in this specification Description in reference and the multiple summary and more specific document that discuss, described in conventional method well known in the art implementation Technology and methods.In the present specification, group and its substituent group 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 group, which similarly includes from right to left Write obtained equivalent substituent group in chemistry when 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 may include 1 in its defined group A carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.For example, " C1~4Alkyl " refers to having 1~4 carbon original The alkyl of son, i.e., the described alkyl are selected from methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and tertiary butyl.By This can deduce the meaning for the term that other are described in a similar manner, such as " C1~6" etc..
In the present invention, term " 6~10 yuan " refer to be closed defined in it ring system group (such as aromatic ring, aryl, heteroaryl, Hetero-aromatic ring, naphthenic base, Heterocyclylalkyl, heterocycloalkenyl etc.) in surround the closure ring skeleton itself atom number be 6,7,8,9 or 10.Different numbers can be taken according to the number of rings of ring system group, saturation degree and atomic property for constituting the ring etc. is closed.Thus It can deduce the meaning for the term that other are described in a similar manner, such as " 7~10 yuan ".
In the present invention, term " aromatic ring " or " aryl " refer to the cyclic conjugated aryl radical optionally replaced, have 6~18 A ring carbons, it may include monocycle, bicyclic, tricyclic or more ring.The rest part of compound molecule can pass through singly-bound and virtue Carbon atom on basic ring is connected.When aryl is substituted, substituent group 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 replacing by carbon atom and miscellaneous The conjugation armaticity ring system group that atom collectively constitutes, 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 formed by oxidation Nitrogen oxygen ingredient.Occur in ring in two or more heteroatomic embodiments, described two or more hetero atoms can phase each other Some or all of together or described two or more hetero atoms are different from each other.The rest part of compound molecule can pass through Singly-bound on hetero-aromatic ring carbon atom or hetero atom be connected.For example, imidazoles can pass through 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 monocycle and polycyclic (such as having 2,3 or 4 rings to be fused to each other).For purposes of the invention, preferably 5~ 10 yuan and containing 1~2 selected from N, S and O heteroatomic monocycle hetero-aromatic ring or fused heteroaromatic ring, wherein fused heteroaromatic ring it is preferred 7~10 yuan of bicyclic system, and the atom that can be shared between two rings includes hetero atom.
In the present invention, term " naphthenic base " refer to the stabilization being only made of carbon atom and hydrogen atom non-aromatic monocyclic or Multi-ring alkyl, it may include condensed ring system, bridged-ring system or spiro ring system usually have 3 to 15 carbon atoms.It can be via ring Upper any suitable carbon atom is connected by the rest part of singly-bound and molecule.In general, the example of naphthenic base includes but not limited to Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..For purposes of the invention, preferably there are 3 to 6 The naphthenic base 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 collectively constitutes can be monocycle, bicyclic, tricyclic or more ring to 20 yuan of non-aromatic cyclic groups Member ring systems, may also comprise condensed 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 rest part of singly-bound and molecule.Nitrogen-atoms therein can optionally by other groups be further substituted with Form tertiary amine or quaternary ammonium structure.In general, the example of heterocycle includes but 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, high piperazine base, N- replace homopiperazine Base, piperidyl, N- substituted piperidines base, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc..With regard to this 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 fat be only made of carbon atom and hydrogen atom, containing carbon-carbon double bond Race's cyclic group may include monocycle or polycyclic system, usually contain 4~12 carbon atoms.For purposes of the invention, excellent Select the cycloalkenyl group of 5~6 unit monocycle systems.
In the present invention, term " heterocycloalkenyl " refers to by the hetero atom of 3~9 carbon atoms and 1~3 selected from nitrogen, oxygen, sulphur Aliphatic cyclic group being formed, containing carbon-carbon double bond, may include monocycle 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 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 Object, such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy etc..Non-human mammal Example include but not limited to birds and fish etc..In a method provided by the present application and the embodiment of composition, 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 prevents the potential metabolism reason for leading to symptom, inhibit disease or illness, such as prevent disease Or the development of illness, alleviate disease or illness, disease or illness is made to improve, alleviates the symptom caused by disease or illness, or Stop the symptom of disease or illness, in addition, the term includes the purpose prevented.The term further include obtain therapeutic effect and/or Preventive effect.The therapeutic effect refers to curing or improving treated potential disease.In addition, pair with potential disease relevant one The healing or improvement of kind or a variety of physiological signs are also therapeutic effect, such as although patient may nevertheless suffer from the shadow of potential disease It rings, but observes that patient profiles improve.For preventive effect, described group can be applied to the patient for suffering from specified disease risk Close object, even if 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 quantity ", " therapeutically effective amount " or " pharmacy effective dose " refers to taking metapedes with to a certain degree At least one medicament of the upper one or more symptoms for alleviating treated disease or illness or the amount of compound.Its result can be with For the abatement of sign, symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for treatment " effective quantity " is the amount for including the composition that compound is disclosed herein clinically provided needed for significant remission effect. The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.
In the present invention, term " taking ", " application ", " administration " etc. are to refer to compound or composition being delivered to progress The method in the required site of biological effect.These methods include but not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.Art technology It can be used for the application technique of herein described Compounds and methods for known to personnel, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's, It is discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa Those of.In a preferred embodiment, the compound of the application discussion and composition pass through oral administration.
In institute of the invention, term " acceptable " or " pharmaceutically acceptable " refer to dock treated subject one As the not long-term adverse effect of health condition.
In the present invention, term " pharmaceutical composition " refer to be optionally mixed at least one pharmaceutically acceptable chemistry at The bioactive compound divided, the pharmaceutically acceptable chemical composition include but not limited to carrier, excipient and/or help 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, helps to draw compound Enter into cell or tissue.
In the present invention, term " pharmaceutically acceptable salt " refers to the free acid and free alkali for remaining appointed compound Biopotency, and biologically or otherwise on not no ill-effect salt.The compounds of this invention further 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 are 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 It is reacted in agent system.Suitable salt is enumerated in Remingtong ' s Pharmaceutical Scicences, and 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..Organic acid by derivative acid-addition salts includes acetic acid, propionic acid, ethyl alcohol Acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Chinese cassia tree Acid, mandelic acid, methanesulfonic acid, ethanesulfonic 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 is hydrone.
In the present invention, term " stereoisomer " refers to being made of same atoms, is bonded by identical key, but with not With the compound of three-dimensional structure.1 compound of formula of the present invention cover various possible optical isomers, cis-trans-isomer and Its mixture.
In the present invention, it is another from an atom transfer of molecule to identical molecule that term " tautomer " refers to proton A atom and the isomers formed.1 compound of formula of the present invention covers various possible tautomers and its mixture.
In the present invention, term " polymorph " or " polymorph " refer to chemical combination of the present invention existing for different form crystal lattices Object.
Term used herein " metabolin " or " metabolite " refer to after the compounds of this invention is absorbed by organisms, in enzyme Effect is lower by internal function dough reaction (I phases biological conversion reaction, including oxidation, reduction, hydrolysis etc.) and association reaction Bioconversions such as (II phases biological conversion reaction) and the compound generated.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 about 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 does not have activity usually, but can be converted to the parent chemical combination of the biologically active present invention under physiological condition in vivo Object.Can usually improve parent compound solubility, histocompatbility or pharmacokinetics etc. property.
In the present invention, term " pharmaceutical composition ", " applying other treatments ", " applying other therapeutic agents " etc. refer to passing through mixing Or combination more than one active constituent and the drug therapy that obtains comprising combination is fixed and be not fixed to active constituent.Term " fixed Combination " refers to that at least one chemical combination as described herein is administered simultaneously to patient in the form of single entity or single dosage form Object and at least one collaboration medicament.Term " being not fixed combination " refers to being administered simultaneously, being shared to patient in the form of corpus separatum 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 patient's body provides effective level.These are also applied in cocktail therapy, such as apply With three or more active constituents.
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 cover apply by identical or different administration route 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 is covered applies two or more medicaments so as to exist simultaneously the medicament and/or its metabolin in animal body to animal.These Term includes that different compositions is administered simultaneously, different time apply different composition and/or application containing different activities at A kind of composition divided.Therefore, in some embodiments, the compound of the present invention and other medicaments are blended in a kind of combination It is applied in object.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention Example.
Room temperature in the present invention refers to environment temperature, is 10 DEG C~30 DEG C.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that：The present invention provides a kind of and entirely different imidazo pyrroles of the prior art Piperazine class compound, preparation method, pharmaceutical composition and application.The imidazopyrazines of the present invention are to tyrosine kinase C-Met has good inhibition, can be used for preventing, treating or the expression or work of auxiliary treatment and tyrosine kinase C-Met The related a variety of diseases of property.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient Product specification selects.
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), tris(dibenzylideneacetone) dipalladium (2.3g, 2.5mmol) and 1, bis- (diphenylphosphine) ferrocene (2.8g, 5mmol) of 1'- are added in DMF (100mL), and argon gas is protected Under shield, 130 DEG C are heated to, reacts 16h.Reaction solution cools down, and is added with stirring in water (1L), ethyl acetate (200mL × 3) extraction It takes, combined ethyl acetate phase, washes, saturated common salt washing, dry, column chromatography purifies to obtain 6g off-white powder compound A-2, receives 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), using adding hydrogen instrument 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 anhydrous DMF (60mL), 2- is added under nitrogen protection, and (7- is even Nitrogen phenylpropyl triazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid esters (12.9g, 34mmol) and hydrochloride base azanol (3.3g, 34mmol), is stirred overnight at room temperature.Dichloromethane (80mL) and water (80mL) is added, separates organic phase, water phase dichloro Methane (50mL × 3) extracts, and merges organic phase, and saturated sodium-chloride (50mL × 2) is washed, dry.It is evaporated to obtain 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 3M methyl-magnesium-bromides (10mL) solution is added under nitrogen protection.Ice bath is removed, is stirred overnight at room temperature.Reaction solution In be slowly added to saturated aqueous ammonium chloride (12mL), ethyl acetate (50mL) and water (30mL) is added, separates organic phase.Water phase It is extracted with ethyl acetate (50mL × 3).Merge organic phase, is washed with saturated nacl aqueous solution (50mL × 2), it is dry.It is evaporated to obtain 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 ethyl alcohol (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, obtains 5.6g compound as white solid B-4, yield：99%, without further purification, directly It connects for reacting in next step.
Synthesis step 4：1- (quinoline -6- bases) ethamine (B)
1- (quinoline 6- yls) acetophenone oxime B-4 (5.6g, 30.1mmol) is dissolved in ethyl alcohol (200mL), and the first of ammonia is added in room temperature Alcoholic solution (7mol/L, 13mL) and Rany nickel (alias Raney's nickel or RanyNi) (3g).Add hydrogen to be stirred overnight at room temperature, 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 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), it is stirred overnight for 140 DEG C.It is cooled to room temperature, pours into trash ice, concentrated ammonia liquor adjusts pH 8 or so, ethyl acetate extraction It takes, washes, 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 -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 ' bis- (diphenylphosphine) ferrocene (dppf) (2.37g, 4.3mmol) is dissolved in anhydrous DMF (40mL), and the lower 130 DEG C of reactions of argon gas protection are overnight.It is cooled to room temperature addition saturation Na2CO3Aqueous solution (100mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering are 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 -8- fluorine quinoline C-3 (330mg, 1.92mmol) are dissolved in ammonia/methanol solution (30mL), are used Instrument H-cube (30bar, 25 DEG C, 1mL/min flow velocitys, RaNi columns) is restored, 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- 4-aminobenzoic acid D-1 (25g, 0.16mol) of raw material 3- and catalyst 3- nitrobenzene sodium sulfonates (43.2g, It 0.192mol) is added in the mixed solution of the concentrated sulfuric acid (60mL) and water (24mL), after being heated to 120 DEG C of interior temperature, is slowly added into Glycerine (44.2g, 0.48mol, 3eq) is warming up to 130 DEG C~140 DEG C and reacts 1.5 hours after charging, cooling.By reaction solution It pours into trash ice, concentrated ammonia liquor tune pH to 5~6, solid is precipitated and filters out, washes, it is solid that dry rear pillar chromatographic purifying obtains 8.7g canescence 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, It 18.42mmol) is dissolved in anhydrous 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 the reaction was complete3Aqueous 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 the reaction was complete, ice bath cooling is lower to be added saturation NH4Cl aqueous solutions Be quenched reaction, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering be evaporated 5.5g yellow is solid 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-) ethyl alcohol (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 the reaction was complete, water quenching is added to go out reaction, ethyl acetate extraction, Washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering are 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-) ethyl alcohol 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.It cools down, solvent evaporated, is slowly added to be saturated under ice bath NaHCO3Aqueous solution tune pH is dried to alkalinity, dichloromethane extraction, washing, saturated common salt water washing, anhydrous sodium sulfate, 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), and a little KI (potassium iodide), 120 DEG C of heating reaction 2h is added.Reaction terminates, Water (50mL) is added, ethyl acetate extraction is washed, saturated common salt water washing, and 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 ethyl alcohol (10mL), hydrazine hydrate (0.138g, 1.77mmol) is added, is heated to reflux 2 hours.Cooling, solvent evaporated is added 5%NaOH aqueous solutions (10mL), ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, filtering are 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, the synthetic method of restoring method reference intermediate A step 2, and 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, product is recrystallized to give white admittedly 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, It 10.1mmol) is added in dioxane (20mL) with bis-triphenylphosphipalladium palladium dichloride (0.32g, 0.46mmol), argon gas protection Lower 110 DEG C of reactions 4h.Reaction solution cools down, and potassium fluoride dihydrate (2g) and water (4mL) is added.2h is stirred at room temperature, filters, filter cake It is washed with dioxane (5mL × 3).Merging filtrate is added concentrated hydrochloric acid (2mL), 1h is stirred at room temperature.Reaction solution concentrates, and saturation is added Aqueous sodium carbonate (50mL), ethyl acetate (100mL × 2) extraction.Organic phase merges, and washes (50mL), saturated salt solution (50mL) is washed, and purifies to obtain 1.5g off-white powder compound F-3, yield through silica gel column chromatography after dry：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-)-ethyl alcohol (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) Be added in the mixed solution of the concentrated sulfuric acid (15mL) and water (6mL), after being heated to 120 DEG C of interior temperature, be slowly added into glycerine (7.4g, 80mmol), 130 DEG C of reaction 1.5h, cooling are warming up to after charging.Reaction solution is poured into trash ice, concentrated ammonia liquor tune pH to 5~ 6, solid is precipitated and filters out, washes, dry rear pillar chromatographic purifying obtains 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) and Pd (PPh3)2Cl2(47mg, 0.041mmol) is dissolved in dioxane (30mL), and argon gas is protected lower 140 DEG C and stirred Mix 4h.It is cooling, ethyl acetate (40mL), water (2mL) and KF (0.2g) is added, reaction solution stirs 2h.Separate ethyl acetate layer, water Mutually extraction being returned with ethyl acetate 2 times, merging organic phase, dry, 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) It is added to 2.6- lutidines (0.761mL, 6.42mmol) in the mixed liquor of dioxane (17mL) and water (6mL).It stirs It mixes and osmium tetroxide (653mg, 0.064mmol) is added, continue to stir 15min, water (50mL) is added and dilutes, uses ethyl acetate (50mL) is extracted, and ethyl acetate washing, dry, silica gel column purification obtains 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- [(bis- fluoro- 6- quinolyls of 5,7-) 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- (bis- fluoro- 6- quinolyls of 5,7-) 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- (bis- fluoro- 6- quinolyls of 5,7-) ethyl alcohol (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 Overcritical prepared chromatographic (SFC) is used to detach, IC-H columns, mobile phase：Isopropanol/carbon dioxide= 18/82, Detection wavelength：254nm.It is 6- bromine-7-methyls quinoline (I-2), white solid, yield to collect the first fraction：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).It is bromo- 5- methylquinolines (J-1) white solids of 6-, yield to collect the second fraction：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) ethyl alcohol (I-4)
With reference to the method for intermediate D synthesis steps 4,1- (7- methyl -6- quinolyls) ethyl alcohol 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) ethyl alcohol 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, it is 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, Faint yellow solid I, yield 60%, HPLC is prepared in 3- diketone I-6>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) ethyl alcohol (J-3)
With reference to the method for intermediate D synthesis steps 4,1- (5- methyl -6- quinolyls) ethyl alcohol 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, it is solid to obtain yellow with raw material 1- (5- methyl -6- quinolyls) ethyl alcohol J-3 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, it is 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, Faint yellow solid J, yield 60%, HPLC is prepared in 3- diketone J-5>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
It takes 5g (27mmol) QUINOLINE-6-CARBOXYLIC ACID's methyl esters to be dissolved in 50mL anhydrous DMFs, 11g (80mmol) N- chloro fourths is added Imidodicarbonic diamide is heated to 125 DEG C of tube sealings and stays overnight.The saturated solution quenching reaction of suitable sodium bicarbonate is first added, is added later A small amount of water and ethyl acetate separates organic phase, and water phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, saturated sodium-chloride Solution 50mL × 2 are washed, dry, are evaporated.(solvent is petroleum ether to contact plate：Ethyl acetate=5：1) purer, dodge column purification (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-1 H- pyrazoles -4- bases) quinoline -6- methyl formates
500mg (2.26mmol) 3- chloroquinoline -6- methyl formates are taken to be dissolved in 24mL Isosorbide-5-Nitraes-dioxane, nitrogen protection Under be separately added into 165mg (0.23mmol) [bis- (diphenylphosphine) ferrocene of 1,1-] palladium chloride, 624mg (4.51mmol) carbonic acid Potassium, 516mg (2.48mmol) 1- methyl -4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) -1H- pyrazoles and 6ml water, the reaction mixture are heated to 110 DEG C under a nitrogen, and tube sealing is overnight.Solvent is removed, 50ml water and 50ml acetic acid is added Ethyl ester separates organic phase, and water phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, and saturated nacl aqueous solution 50mL × 2 are washed, It is dry, it is evaporated.(solvent is dichloromethane to contact plate：Methanol=20：1) purer, dodging column purification, (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-1 H- pyrazoles -4- bases) QUINOLINE-6-CARBOXYLIC ACID
565mg (2.11mmol) 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- methyl formates are taken to be dissolved in 30ml methanol In, 266mg (6.34mmol) lithium hydroxides are added at room temperature and 5ml water, reaction are stirred overnight at room temperature.Then solvent is removed, is obtained To 534mg white solids, direct plunge into next step.LC-MS(ESI)：[M+H]+=254.
Synthesis step 4：The synthesis of N- methoxy-. N-methyls -3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- formamides (K-5)
3- (1- methyl-1 H- pyrazoles -4- bases) QUINOLINE-6-CARBOXYLIC ACID of 534mg (2.108mmol) 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 are stirred overnight at room temperature.It removes molten 50mL water and 50mL ethyl acetate is added in agent, separates organic phase, and water phase is extracted with the ethyl acetate of 50mL × 3, merges organic phase, Saturated nacl aqueous solution 50mL × 2 are washed, dry, are evaporated.(solvent is dichloromethane to contact plate：Methanol=20：1) purer, dodge column (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-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl ketone
Take 504mg (1.701mmol) N- methoxy-. N-methyls -3- (1- methyl-1 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, and the 3M methyl magnesium bromide solutions of 1.5mL are added under nitrogen protection.It removes 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, water phase are extracted with the ethyl acetate of 30mL × 3.Merge organic phase, saturated nacl aqueous solution 30mL × 2 are washed, dry, are evaporated. (solvent is petroleum ether to contact plate：Ethyl acetate=1:1) purer, dodging column purification, (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-1 H- pyrazoles -4- bases) quinoline -6- bases) acetophenone oxime
It takes 232mg (3.34mmol) hydroxylamine chloride to be dissolved in 30ml ethyl alcohol, 137mg (3.43mmol) hydroxide is added later Sodium.After the mixed solution stirs 1 hour at normal temperatures, solid is filtered out, filtrate is added to containing 280mg (1.11mmol) 1- In the ethanol solution of (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl ketone.Under room temperature, reaction mixture is stirred overnight. Solvent is removed, 919mg white solids are obtained, is direct plungeed into next step.LC-MS(ESI)：[M+H]+=267.
Synthesis step 7：The synthesis (K) of 1- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethamine
556mg (2.09mmol) 1- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) acetophenone oxime is dissolved in 20ml second In alcohol, under room temperature, the Raney nickel of methanol solution (7N) 6ml and 245mg of ammonia is added.The reaction mixture under hydrogen, room temperature It is stirred overnight.Solid is filtered out, solvent is evaporated, obtains 385mg crude products, which 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, It 1.2eq) is added in the mixed solution of the concentrated sulfuric acid (60ml) and water (24ml), after being heated to 120 DEG C of interior temperature, is slowly added into glycerine (29g, 0.315mol, 3eq) is warming up to 130-140 DEG C of reaction overnight after charging, cooling.Reaction solution is poured into trash ice, Concentrated ammonia liquor tune pH to 8, dichloromethane extraction, washing, dry rear pillar chromatographic purifying obtain 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), the lower 90 DEG C of reactions of argon gas protection are overnight.It is cooled to room temperature, the potassium fluoride aqueous solution room of 2eq 10% is added Temperature stirring 2h, filtering, filter cake dichloromethane wash for several times, and filtrate is evaporated, and 2eq 1N HCl are added, 2h is stirred at room temperature.Carbonic acid is added Sodium water solution tune pH to 8, dichloromethane extraction, washing, dry rear pillar chromatographic purifying obtain 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-) ethyl alcohol (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 NaBH4(3.3g, 0.087mol, 0.8eq) is stirred 0.5 hour under ice bath.After the reaction was complete, adds water quenching to go out reaction, boil off first Alcohol, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purify 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-) ethyl alcohol (6.2g, 0.03mol) is dissolved in chloroform (50ml), under ice bath slowly PBr is added3(10.5g, 0.038mol, 1.2eq) is heated to reflux 2 hours.After the reaction was complete, solvent evaporated, under ice bath slowly plus Enter to be saturated NaHCO3Aqueous solution tune pH is washed, saturated common salt water washing to alkalinity, ethyl acetate extraction, and anhydrous sodium sulfate is dried, 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), a little KI is added, 120 DEG C of heating are reacted 2 hours.After the reaction was complete, boil off DMF, is added water, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purify yellow is solid 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 the reaction was complete is added aqueous sodium carbonate and is adjusted to alkalinity, dichloromethane extraction, washing, saturated common salt Water washing, column chromatography purify 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-1 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 frequencies are 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 cooled to room temperature, a large amount of water is added, ethyl acetate extraction is washed, and 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-1 H-4- pyrazolyls) -6- quinolyls) ethamine (L)
By raw material 2- (1- (the fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) -6- quinolyls) ethyl) iso-indoles -1,3- diketone (5.15g, 0.013mol) is dissolved in ethyl alcohol (150ml), and hydrazine hydrate (2g, 0.034mol, 2.6eq) is added, it is small to be heated to reflux 5 When.It is cooled to room temperature, solid filtering is precipitated, filter cake ethyl acetate washs for several times, and mother liquor is evaporated, and it is water-soluble that a little 5%NaOH is added Liquid, ethyl acetate extraction, washing, saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purify 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 be added 30ml water simultaneously 3.2g sodium bicarbonate solid neutralization reactions are added, be stirred at room temperature 30 minutes it It is slowly added to 4.8g sodium thiosulfate afterwards and removes extra 1- chlorine pyrrolidine-2,5-diones.Ethyl acetate extracts (100mL*3), Merging organic phase, saturated nacl aqueous solution is washed, dry, and the crude product being evaporated is purified by dodging column, obtains 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), 7.62-7.54 (m, 1H), 6.00 (q, J=7.4Hz, 1H), 2.07 (dt, J=7.5,2.5Hz, 3H)
Synthesis step 2：2- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 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) is then added Cl20.1 equivalent, 2 equivalent of Anhydrous potassium carbonate and 62.5ml water.The reaction solution under protection of argon gas, stay overnight by 110 DEG C of tube sealings.Concentration 1000ml water and 1000ml ethyl acetate is added in reaction solution later, separates organic phase, and water phase ethyl acetate extracts (500mL*3), Merge organic phase, salt washing, dry, concentration, (solvent is petroleum ether to remaining crude product by dodging column 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethamine (M)
By 2- (1- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) isoindoline -1,3- Diketone (0.5g, 1mmol) is dissolved in 30ml ethyl alcohol, and (179mg, 3.6mmol) hydrazine hydrate is added later.Reaction solution reflux 2 is small Shi Hou filters out solid impurity, which is washed with ethyl alcohol.Solvent is screwed out, 100ml ethyl acetate, organic phase 50ml carbonic acid is added Sodium saturated solution is washed, and salt washes (50ml*2), dry, is filtered, concentration, and residue is purified by dodging column, 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 synthetic method of intermediate K-2 with intermediate K synthesis steps 1.
Synthesis step 2：- 6-formic acid of 3- chloroquinolines (N-3)
It takes 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), finishes, and reaction at room temperature is stayed overnight.Post-processing, concentration of reaction solution to 30ml or so, Hydrochloric acid tune PH=5-6, filtering, dry product 6.3g after filter cake washing directly 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-
3--6-formic acid of chloroquinoline of 4.3g (21mmol) is added in 60ml anhydrous DMFs, is stirred into above-mentioned reaction solution Lower addition 12g (31mmol) O- (7- nitrogen benzotriazole)-N, N, N, N- tetramethylurea hexafluorophosphoric acid esters and 4g (31mmol) two Diisopropylethylamine is added 3g (31mmol) N, O- dimethyl hydroxylamine hydrochloride after 30min is stirred at room temperature, finishes, room under nitrogen Temperature reaction is overnight.Post-processing, reaction solution is poured into 300ml water, and ethyl acetate extracts (100ml*3), merges organic phase, 2N's Sodium hydroxide solution is washed, and washing, saturated nacl aqueous solution is washed, dry, 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 the 3- of 3.7g (15mmol) 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, and is slowly restored to room The reaction was continued after temperature 3h.It post-processes, the aqueous ammonium chloride solution 30ml of saturation is slowly added dropwise under ice bath into reaction solution, finishes continuation 20ml*3 is extracted with ethyl acetate after stirring 30min, merges organic phase, saturated common salt washing is filtered, solvent evaporated obtains after dry To product 2.2g, yield：72%, it is directly used in and reacts in next step.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'- Bis- (diphenylphosphino) ferrocene] palladium chloride 119mg (0.14mmol), 110 DEG C of reaction 4h of outer 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), add Finish, room temperature reaction is overnight.Then 1g or so Raney's nickel is added to reaction solution, uses the hydrogen reducing 5h of 2atm at room temperature, detection is extremely Without starting material left.100ml dichloromethane is added in post-processing, filtering after filtrate concentration, washing obtains after dry 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-1 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 3,5-, bis- bromo-pyrazine -2- amine (6.1g, 24mmol), 6- quinoline benzylidene amino (3.8g, 24mmol) and N, N- bis- Wopropyl ethyl amine (DIPEA) (8.6mL, 48mmol) is added in NMP (20mL), and the lower 130 DEG C of reactions of argon gas protection are overnight.Reaction DIPEA is evaporated off in liquid, and residue pours into water (100mL), dichloromethane (30mL × 3) extraction, organic phase washing, saturated salt solution It washes, crossing rapid column chromatography after dry 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 product 1.1g, yield are obtained：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-1 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-1s H- Pyrazoles -4- pinacol borates (121mg, 0.58mmol), potassium carbonate (122mg, 0.88mmol) and [1,1'- bis- (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 reaction solution concentration after rapid column chromatography detaches, obtained 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
2~embodiment of embodiment 18 is prepared using different boric acid or borate according to the same procedure of embodiment 1 Compound, specific experiment data are shown in Table 1.
The experimental data table of 1 compound 1-2 of table~compound 1-18
Embodiment 19：6- (1- (6- (1- methyl-1 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
It is bromo- to be obtained 6- by the method for 1 step 1 of reference implementation example for 1- (quinoline -6- bases) ethamine replacement 6- quinoline benzylidene aminos N2(1- (6- quinolyls) ethyl) pyrazine -2,3- diamines, dark brown solid, yield 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 1 step 2 of reference implementation example, 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, yield 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) second Base) quinoline (compound 1-19)
The method of 1 step 3 of reference implementation example, 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
20~embodiment of embodiment 49 is prepared using different boric acid or borate according to the same procedure of embodiment 19 Compound, specific experiment data are shown in Table 2.
The experimental data table of 2 compound 1-20 of table~compound 1-49
Embodiment 50：The fluoro- 6- of 8- ((6- (1- methyl-1 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
It is bromo- to be obtained 6- by the method for 1 step 1 of reference implementation example for 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 1 step 2 of reference implementation example, 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) Methyl) quinoline (compound 1-50)
The method of 1 step 3 of reference implementation example, 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
51~embodiment of embodiment 56 is prepared using different boric acid or borate according to the same procedure of embodiment 50 Compound, specific experiment data are shown in Table 3.
The experimental data table of 3 compound 1-51 of table~compound 1-56
Embodiment 57：Fluoro- (6- (1- (6- (1- methyl-1 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 1 step 1 of reference implementation example obtains 1- (8- fluorine quinoline -6- bases) ethamine replacement 6- quinoline benzylidene aminos 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 1 step 2 of reference implementation example, 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- of 8- Base) ethyl) quinoline (compound 1-57)
The method of 1 step 3 of reference implementation example, 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
58~embodiment of embodiment 68 is prepared using different boric acid or borate according to the same procedure of embodiment 57 Compound, specific experiment data are shown in Table 4.
The experimental data table of 4 compound 1-58~1-68 of table
Embodiment 69：6- [6- (1- methyl-1 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 fluoro- 6- quinoline benzylidene amino hydrochlorides of 7- are substituted 6- quinoline benzylidene aminos by the method for 1 step 1 of reference implementation example 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 1 step 2 of reference implementation example, 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)。
Step 3 prepares the fluoro- 6- of 7- (6- (1- methyl-1 H- pyrazoles -4- bases)-imidazo [4,5-b] pyrazine -1- methylene) - Quinoline (compound 1-69)
The method of 1 step 3 of reference implementation example, 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-1 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
70~embodiment of embodiment 86 is prepared using different boric acid or borate according to the same procedure of embodiment 69 Compound, specific experiment data are shown in Table 5.
The experimental data table of 5 compound 1-70 of table~compound 1-86
Embodiment 87：The fluoro- 6- of 7- (1- (6- (1- methyl-1 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 1 step 1 of reference implementation example obtains 1- (the fluoro- 6- quinolyls of 7-) ethamine replacement 6- quinoline benzylidene aminos 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 1 step 2 of reference implementation example, by the bromo- N of 6-2(1- (7- fluorine quinoline -6- bases) ethyl) pyrazine -2,3- diamines Brown solid, yield is obtained by the reaction with 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-87)
The method of 1 step 3 of reference implementation example, 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
88~embodiment of embodiment 110 is prepared using different boric acid or borate according to the same procedure of embodiment 87 Compound, specific experiment data are shown in Table 6.
The experimental data table of 6 compound 1-88 of table~compound 1-110
Embodiment 111：Bis- fluoro- 6- of 5,7- ((6- (1- methyl-1 H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazines - 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 1 step 1 of reference implementation example, 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 1 step 2 of reference implementation example, 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 bis- fluoro- 6- of 5,7- ((6- (1- methyl-1 H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) methyl) quinoline (compound 1-111)
The synthetic method of 1 step 3 of reference implementation example, 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
112~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 111 117 compound, specific experiment data are shown in Table 7.
The experimental data table of 7 compound 1-112 of table~compound 1-117
Embodiment 118：Bis- fluoro- 6- of 5,7- (1- (6- (1- methyl-1 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 3,5-, bis- bromo-pyrazine -2- amine (2.16g, 8.56mmol), 1- (5,7- difluoro-quinoline -6- bases) ethamine (1.18g, It 5.7mmol) is added in NMP (15mL) with DIPEA (2.2g, 17mmol), the lower 200 DEG C of reactions of argon gas protection are overnight.Reaction solution It is cooling, it pours into water (100mL), ethyl acetate (50mL × 3) extraction, organic phase water (50mL × 2) is washed, saturated salt solution (50mL) is washed, and crossing rapid column chromatography after dry 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).
Step 3 prepares 5,7 2 fluoro- 6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazines - 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, Bis- (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 detaches 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
119~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 118 146 compound, specific experiment data are shown in Table 8.
The experimental data table of 8 compound 1-119 of table~compound 1-146
Embodiment 147：7- methyl -6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazines - 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 1 step 1 of reference implementation example, 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 1 step 2 of reference implementation example, 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-147)
The legal manner of 1 step 3 of reference implementation example, 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
148~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 147 154 compound, specific experiment data are shown in Table 9.
The experimental data table of 9 compound 1-148 of table~compound 1-154
Embodiment 155：5- methyl -6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazines - 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 1 step 1 of reference implementation example, 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 1 step 2 of reference implementation example, 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-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- Base) ethyl) quinoline (compound 1-155)
The legal manner of 1 step 3 of reference implementation example, 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
156~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 155 160 compound.Specific experiment data are shown in Table 10.
The experimental data table of 10 compound 1-156 of table~compound 1-160
Embodiment 161：3- (1- methyl-1 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-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- Diamines
Bis- bromo-pyrazine of 2- amino -3,5- (257mg, 1.02mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower to be added 1- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethamine (385mg, 1.53mmol) and 6ml N, N- bis- Wopropyl ethyl amine.The reaction solution under protection of argon gas, is heated to 210 DEG C of tube sealings and stays overnight.Crude product is passed through sudden strain of a muscle by concentration of reaction solution (solvent is dichloromethane for column 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-1 H- pyrroles Azoles -4- bases) quinoline
By the bromo- N of 6-2(1- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- diamines (100mg, 0.24mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, which is heated to 150 DEG C of tube sealings and stays overnight.Concentration reaction Liquid, by dodging column 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-1 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-1 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 n,N-diisopropylethylamine of the potassium fluoride and 4 equivalents of 5 equivalents.170 DEG C of reaction solution tube sealing reaction 2 hours.Concentration Reaction solution, by dodging column 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 is using phase The borate answered is reacted by SUZUKI and is synthesized.Specific experiment data are shown in Table 11.
The experimental data table of 11 compound 1-162 of table~compound 1-163
Embodiment 164：3- (1- methyl-1 H-4- pyrazolyls) -6- (6- (1- methyl-1 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 3,5-, bis- bromo-pyrazine -2- amine (6.1g, 24mmol), 6- quinoline benzylidene amino (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) is added in NMP (20ml), and the lower 130 DEG C of reactions of argon gas protection are overnight.DIPEA, residue is evaporated off in reaction solution It pours into water (100ml), dichloromethane (30ml × 3) extraction, organic phase washing, saturated common salt washing, excessively quick column 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 anhydrous DMF In (10ml), isoamyl nitrite (356mg, 3mmol, 2eq), the lower 70 DEG C of reactions 3h of argon gas protection is added.After the reaction was complete, steam Dry solvent, the mashing of crude product ethyl acetate purify 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 the reaction was complete is added aqueous sodium carbonate and is adjusted to alkalinity, and dichloromethane extraction is washed, saturation Brine It, column chromatography purify 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-1 H-4- pyrazolyls) -6- (6- (1- methyl-1 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-1s 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, the lower 110 DEG C of reactions of argon gas protection are overnight.Solvent evaporated, residue prepare plate and purify 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
165~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 164 168 compound.Specific experiment data are shown in Table 12.
The experimental data table of 12 compound 2-2 of table~compound 2-5
Embodiment 169:The fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) -6- (1- (6- (1- methyl-1 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-1 H-4- pyrazolyls) -6- quinolyls) ethyl) pyrazine - 2,3- diamines
By raw material 1- (the fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) -6- quinolyls) ethamine (403mg, 1.5mmol), 2- Bis- bromo-pyrazine of amino -3,5- (453mg, 1.8mmol, 1.2eq) and DIPEA (578mg, 4.5mmol, 3eq) are dissolved in NMP (5ml) In, the lower 200 DEG C of reactions of argon gas protection are overnight.After the reaction was complete, a large amount of water, ethyl acetate extraction, washing, saturated salt solution is added Washing, anhydrous sodium sulfate drying, filtering are 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-1 H-4- pyrazolyls) quinoline
By the bromo- N of raw material 5-3(1- (the fluoro- 3- of 7- (1- methyl-1 H-4- pyrazolyls) -6- quinolyls) ethyl) pyrazine -2,3- Diamines (462mg, 1.05mmol) is dissolved in anhydrous DMF (8ml), and isoamyl nitrite (246mg, 2.1mmol, 2eq), argon is added The lower 80 DEG C of reactions 2h of gas shielded.After the reaction was complete, 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-1 H-4- pyrazolyls) -6- (1- (6- (1- methyl-1 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-1 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, the lower 110 DEG C of reactions of argon gas protection are overnight.It is down to room A large amount of water are added in Wen Hou, and ethyl acetate extraction is washed, saturated common salt water washing, and anhydrous sodium sulfate drying, filtering is evaporated, crude product It prepares plate and purifies 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
The change of embodiment 170~179 is prepared using different boric acid or borate according to the same procedure of embodiment 169 Object is closed, specific experiment data are shown in Table 13.
The experimental data table of 13 compound 2-8 of table~compound 2-9
Embodiment 180：3- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- Diamines
Bis- bromo-pyrazine of 2- amino -3,5- (257mg, 1.02mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower to be added 1- [3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases] ethamine (385mg, 1.53mmol) and 6ml N, N- bis- Wopropyl ethyl amine.The reaction solution under protection of argon gas, is heated to 190 DEG C of reactions overnight.Crude product is passed through sudden strain of a muscle by concentration of reaction solution (solvent is dichloromethane for column purification：Methanol=95:5).Obtain about 260mg brown solids, yield 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-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2,3- diamines (100mg, 0.24mmol) is dissolved in 5mL DMF, and isoamyl nitrite (56mg, 0.48mmol) is added and is heated to 70 DEG C, reaction 2h.Concentration of reaction solution, by dodging column purification, (solvent is methanol to remaining crude product：Dichloromethane=0% to 5%).Obtain 59mg Light tan solid, yield 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-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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-1 H- pyrroles Azoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in Isosorbide-5-Nitrae-dioxane 12ml, 1- methylpyrazole -4- boric acid frequencies are then added Any alcohol ester (44mg, 0.21mmol), Pd (dppf)2Cl2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.The reaction solution under protection of argon gas, stay overnight by 110 DEG C of tube sealings.Concentration of reaction solution, remaining crude product is by dodging column purification (expansion 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
181~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 180 186 compound, specific experiment data are shown in Table 14.
The experimental data table of 14 compound 2-18 of table~compound 2-23
187 3- of embodiment (4- fluorophenyls) -6- (1- (6- (1- methyl-1 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, sequentially add 3,5-, bis- bromo-pyrazine -2- amine 0.71g (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 overnight, LC-MS is detected without raw material the lower 190 DEG C of reactions of nitrogen protection.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 anhydrous 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), it finishes, nitrogen protection Under be warming up to 75 DEG C, react 3h.Post-processing, solvent evaporated, crude product 100ml dichloromethane dissolve, and use saturated sodium carbonate successively 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-1 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, and (42mg, 0.20mmol) 1- methyl -4- pyrazoles boron is then added Sour pinacol ester, Pd (dppf)2Cl2(11mg, 0.013mmol), Anhydrous potassium carbonate (39mg, 0.26mmol) and 3ml water.This is anti- Answer liquid under protection of argon gas, 110 DEG C of tube sealings are stayed overnight.Concentration of reaction solution, by dodging column 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), 6.61 (q, J=7.1Hz, 1H), 3.94 (s, 3H), 2.27 (d, J=7.1Hz, 3H)
The fluoro- N- methyl -4- of 188 2- of embodiment (7- (3- (1- methyl-1 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 It mixes, reaction is overnight.Post-processing, reaction solution is poured into the cold saturated aqueous sodium carbonates of 200ml, organic phase, water phase two are separated Chloromethanes extracts 50ml*2, merges organic phase, and saturated salt solution washing obtains product 3g, yield 52% is directly cast after dry 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 add 100ml dichloromethane to dissolve, and hypo solution and aqueous sodium carbonate are washed, saturated common salt washing, dry After be evaporated to 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-1 H- pyrazoles -4- bases) quinoline -6- acetic acid esters
25ml dioxane and 5ml water are added in 100ml single port bottles, 1g (3.76mmol) 3- bromoquinolines-are added thereto 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, finishes, is heated under nitrogen protection 110 DEG C of reaction 4h.Post-processing, reaction solution is poured into 100ml dichloromethane and is washed, and saturated common salt washing crosses filtration after dry Dry solvent, obtains crude product 0.75g, and yield 75% is directly thrown in next step.LC-MS(ESI)：[M+H]+=268.
Step 4 prepares 3- (1- methyl-1 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 It in 5ml water, is then added in methanol solution, reaction solution is heated to 60 DEG C, reacts 2h.Post-processing, reaction solution is concentrated into 10ml water, hydrochloric acid tune PH=6 of 4N or so, filtering, dry product 600mg after filter cake washing, yield 95% is added in half. 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-1 H- pyrazoles -4- bases) quinoline -6- triflates
600mg (2.66mmol) 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline-is added in the dichloromethane dried to 50ml 6- alcohol and 809mg (7.99mmol) triethylamine are slowly added dropwise 902mg (3.20mmol) trifluoromethanesulfanhydride anhydride under ice bath, finish, and delay It is slow to restore to ambient temperature overnight.Post-processing, reaction solution are 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-1 H- pyrazoles -4- bases) quinoline -6- bases) methyl acrylate
It is anhydrous that 430mg (1.2mmol) 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- triflates are dissolved in 5ml In DMF, 207mg (2.4mmol) methyl acrylate, 487mg (4.8mmol), triethylamine and 1, bis- (diphenyl of 1'- is then added Phosphine) ferrocene palladium chloride chloride dichloromethane complex 27mg, it finishes, nitrogen displacement, 125 DEG C of reaction 3h of outer temperature.Post-processing, will be anti- Liquid is answered to pour into 50ml saturated sodium bicarbonate aqueous solutions, ethyl acetate extracts 30ml*3, merges organic phase, washing, saturated common salt Washing boils off solvent afforded crude material 240mg, yield after dry：68%, it directly throws in next step.LC-MS(ESI)：[M+H]+=294.
Step 7 prepares 3- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) methyl propionate
By 240mg (0.818mmol) (E) -3- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) methyl acrylate It is dissolved in 50ml methanol, 10mg (10%) Pd/C is added, 2-3atm hydrogenation reactions are stayed overnight at room temperature, and LC-MS is detected without raw material.It crosses Filter purifies to obtain product 220mg, yield through silica gel column chromatography after filtrate concentration：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), 4.01 (s, 3H), 3.68 (s, 3H), 3.15 (t, J=7.7Hz, 2H), 2.75 (t, J=7.7Hz, 2H)
Step 8 prepares 3- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) propyl -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-1 H- pyrazoles -4- bases) quinoline -6- bases) methyl propionate is slowly added dropwise Tetrahydrofuran solution finishes, and reacts 1h after being slowly raised to room temperature.It post-processes, into reaction solution, dropwise addition saturated ammonium chloride is water-soluble under ice bath Liquid 0.5ml, ethyl acetate 10ml, filtering.Filter cake ethyl acetate is washed, and merging filtrate drying is evaporated to obtain crude product 180mg, receives Rate：90%.LC-MS(ESI)：[M+H]+=268.
Step 9 prepares 3- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde
290mg (1.1mmol) 3- (3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) propyl -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 overnight.Post-processing, to anti- It answers and sodium thiosulfate solution and sodium bicarbonate aqueous solution is added in liquid, 30min is stirred at room temperature, organic phase is through saturated salt solution It washes, purifies to obtain product 240mg, yield through silica gel column chromatography after dry：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-1 H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde
240mg (0.90mmol) 3- (3- (1- methyl-1 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 overnight, 2ml ethyl acetate is added after reaction, stirs 30min, filtering, filter cake ethyl acetate It washes, crude product 185mg, yield is obtained after dry：51%, it directly throws in next step.LC-MS(ESI)：[M+H]+=300.
Step 11 prepares 4- (3- amino -1,2,4- triazine -6- bases) -2- fluorophenyl carbamates
Bromo- 1,2,3- triazine -3- amine of 1g (5.7mmol) 6-, 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, 2.5ml water is added, after nitrogen displacement, the 85 DEG C of reactions of outer temperature are overnight.Post-processing, reaction solution is poured into In 100ml dichloromethane, washing, saturated common salt washing purifies to obtain product 1.2g, yield through silica gel column chromatography after dry： 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 be added 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 are added in above-mentioned solution, are heated to 45 DEG C of confined reactions and stay overnight.Post-processing, it is cooling To room temperature, filtering, filtration cakes torrefaction obtains product 1g, yield：83%, it directly throws in next step.LC-MS(ESI)：[M+H]+=248.
Step 13 prepares 2- fluoro- N- methyl -4- (7- ((3- (1- methyl-1 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-1 H- pyrazoles -4- bases) quinoline -6- bases) propionic aldehyde is added in 3ml ethylene glycol, outer temperature 150 DEG C of reactions are overnight.Post-processing, reaction solution is poured into 50ml dichloromethane, and saturated aqueous sodium carbonate is washed, and is washed, saturation Salt is washed, and purifies to obtain product 15mg, yield 4% through silica gel column chromatography after dry.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), 4.65 (s, 2H), 3.91 (s, 3H), 2.81 (d, J=4.6Hz, 3H)
189 6- of embodiment (1- (6- (1H- indoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) -5,7- Two fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline (compound 1-164)
Step 1 prepares the bromo- N of 6-2(1- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) Pyrazine -2,3- diamines
Bis- bromo-pyrazine of 2- amino -3,5- (391mg, 1.55mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower be added 1- (5,7- bis- fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethamine (300mg, 1.03mmol) and 3ml N, N- diisopropylethylamine.The reaction solution under protection of argon gas, is heated to 190 DEG C of tube sealings and stays overnight.Concentration of reaction solution, will By dodging column 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 two fluoro- 3- (1- first of 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5,7- Base -1H- pyrazoles -4- bases) quinoline
By the bromo- N of 6-2(1- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) pyrazine -2, 3- diamines (285mg, 0.62mmol) is dissolved in 10ml acetic acid diethoxy methyl esters, which is heated to 150 DEG C of tube sealings and stays overnight.It is dense Contracting reaction solution, by dodging column 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-1 H- pyrazoles -4- bases) quinoline (compound 1-164)
By two fluoro- 3- (1- methyl-1 H- pyrroles of 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -5,7- Azoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in 12ml1, in 4- dioxane, then sequentially add (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.It should Reaction solution under protection of argon gas, stay overnight by 110 DEG C of tube sealings.Concentration of reaction solution, by dodging column 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
190~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 189 194 compound, specific experiment data are shown in Table 15.
The experimental data table of 15 compound 1-165 of table~compound 1-169
196 5,7- of embodiment, bis- fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 H- pyrazoles -4- 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- (bis- fluoro- 3- of 5,7- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethyl) Pyrazine -2,3- diamines
Bis- bromo-pyrazine of 2- amino -3,5- (391mg, 1.55mmol) is dissolved in 1-Methyl-2-Pyrrolidone 12ml, Zhi Houchang Temperature is lower be added 1- (5,7- bis- fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) quinoline -6- bases) ethamine (300mg, 1.03mmol) and 3ml N, N- diisopropylethylamine.The reaction solution under protection of argon gas, is heated to 190 DEG C of tube sealings and stays overnight.Concentration of reaction solution, will By dodging column 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-1 H- pyrazoles -4- bases) quinoline
By the bromo- N of 6-2(1- (bis- fluoro- 3- of 5,7- (1- methyl-1 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 is stayed overnight.The saturated solution quenching that sodium sulfite is added is anti- It answers, a small amount of water and 30ml ethyl acetate is added later, separate organic phase, water phase is extracted with the ethyl acetate of 30mL × 3.Merge organic Phase, saturated nacl aqueous solution 30mL × 2 are washed, dry, are evaporated.(solvent is dichloromethane to contact plate：Methanol=20:1) purer, it dodges (solvent is dichloromethane to column purification：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 5,7- bis- fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 H- pyrazoles -4- Base) -1H- imidazos [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 2-25)
By two fluoro- 3- (1- first of 6- (1- (6- bromo- 1H- [1,2,3] triazol [4,5-b] pyrazine -1- bases) ethyl) -5,7- Base -1H- pyrazoles -4- bases) quinoline (60mg, 0.14mmol) is dissolved in 12ml Isosorbide-5-Nitraes-dioxane, then sequentially adds 1.5 and work as Measure 1- methyl -4- (4,4,5,5- tetramethyls -1,3, penta ring -2- bases of 2- dioxies boron) -1H- pyrazoles, Pd (dppf)2Cl2(11mg, 0.014mmol), Anhydrous potassium carbonate (39mg, 0.28mmol) and 3ml water.The reaction solution under protection of argon gas, 110 DEG C of tube sealing mistakes Night.Concentration of reaction solution, by dodging column 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
197~embodiment of embodiment is prepared using different boric acid or borate according to the same procedure of embodiment 196 213 compound, specific experiment data are shown in Table 16.
The experimental data table of 16 compound 2-26 of table~compound 2-42
Embodiment 214：3- (1- (the fluoro- 3- of 7- (1- methyl-1 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 3,5-, bis- bromo-pyrazine -2- amine (6.1g, 24mmol), 1- (the fluoro- 6- quinolyls of 7-) ethamine (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) is added in NMP (20ml), and the lower 130 DEG C of reactions of argon gas protection are overnight.DIPEA is evaporated off in reaction solution, Residue pours into water (100ml), dichloromethane (30ml × 3) extraction, organic phase washing, and it is bromo- to obtain 6- for saturated common salt washing 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 are washed with ethyl acetate/petroleum ether (1/1), obtain 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, It 0.4mmol) is dissolved in absolute ethyl alcohol (50ml), Pd (PPh is added3)2Cl2(28mg, 0.04mmol, 0.1eq), DIPEA (3ml), With carbon monoxide gas precursor reactant 8h (10atm, 80 DEG C).Solvent evaporated, crude product prepare plate and purify 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 overnight.Solvent evaporated is added aqueous sodium carbonate and is adjusted to alkalinity, dichloromethane extraction, water It washes, 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), 4.52 (q, J=7.2Hz, 2H), 2.25 (d, J=7.2Hz, 3H), 1.48 (t, J=7.2Hz, 3H)
Step 5 prepares 3- (1- (the fluoro- 3- of 7- (1- methyl-1 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-1 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 cooled to room temperature, a large amount of water, ethyl acetate extraction, water is added It washes, saturated common salt water washing, anhydrous sodium sulfate drying, filtering is evaporated, and 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-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 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 1 step 1 of reference implementation example obtains 1- (the fluoro- 6- quinolyls of 7-) ethamine replacement 6- quinoline benzylidene aminos 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 1 step 2 of reference implementation example, 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) is obtained by the reaction with 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 6- (1- (bromo- 1H- imidazos [4,5-b] pyrazine -1- bases of 6-) ethyl) -7- fluorine quinoline of 372.2mg (1mmol) It is added in 50ml carbon tetrachloride with the pyridine of 158mg (2mmol), 320mg (2mmol) bromine is slowly added dropwise under stirring, finishes, Reaction reflux 3h.Post-processing, solvent evaporated, crude product are dissolved with dichloromethane, and saturated aqueous sodium carbonate is washed, saturated salt solution It washes, 300mg crude products is obtained after dry solvent evaporated, yield=66% is directly thrown in next step.LC-MS(ESI)：[M+H]+= 450。
Step 4 prepares 7- fluoro- 3- (1- methyl-1 H- pyrazoles -4- bases) -6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) - 1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline (compound 1-172)
The method of 164 step 4 of reference implementation example, by the bromo- 6- of 3- (1- (bromo- 1H- imidazos [4, the 5-b] pyrazine -1- bases of 6-) Ethyl) -7- fluorine quinoline reacts to obtain white solid, yield=33%, LC-MS with 1- methyl-1 H-4- pyrazoles pinacol borates (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)
Inhibiting effect of 1 the compounds of this invention of effect example to C-Met tyrosine kinase activities
Inhibitory activity 503nhibiting concentration IC of the test-compound to kinases50Value indicates.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 suitable enzyme reaction substrate, ATP are added later, start enzyme reaction process, and 30 After minute, suitable reaction terminating liquid and detection liquid are added into enzyme reaction system, after being incubated 1 hour, in PerkinElmer public affairs On the 2104 multiple labeling micropore detectors of EnVision of department, measured under specific compound concentration under 665nm and 620nm wavelength Enzyme activity, and the inhibitory activity of the compounds on enzyme activities of various concentration is calculated, later according to quadruplex parameters, to different dense The inhibitory activity of enzyme activity is fitted under degree compound, calculates IC50Value.Kinases Met used by the present embodiment 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 17 compound of the embodiment of the present invention of table to C-Met tyrosine kinase
2 compound of effect example is to H1993 and SNU-5 cell inhibitory effect determinations of activity
This example expresses stomach for measuring the compounds of this invention for c-Met high expression lung cancer cell lines H1993 and c-Met high The proliferation inhibition activity of cancer cell line SNU-5, the inhibitory activity half-inhibition concentration IC of compound on intracellular proliferation50Carry out table Show.Testing program is as follows：It is equal that c-Met high expresses lung cancer cell line H1993 and c-Met high expression stomach cancer cell line SNU-5 cells It is purchased from ATCC, with suitable cell concentration (H1993：62500 cells/mlL culture mediums；SNU-5：62500 cells/mL trainings Support base) by cell inoculation on 384 well culture plates of White-opalescent；Cell is positioned over 37 DEG C later, 5%CO2Environment In cultivated, after 24 hours, a series of drug of concentration gradients is added into the cell culture medium of culture, is typically chosen 10 H1993 cells are put back in former culture environment continue culture 72 hours later by concentration, and SNU-5 cells are put back in former culture environment Continue culture 48 hours, later according to the method for CellTiter-Glo Luminescent Cell Viability Assay, Test-compound is measured to H1993 and SNU-5 in the 2104 multiple labeling micropore detectors of EnVision of PerkinElmer companies The influence of cell Proliferation, and calculate the inhibitory activity of the compound on intracellular proliferation of various concentration.It is used in the present embodiment CellTiter-Glo Luminescent Cell Viability Assay detection reagents are purchased from Promega.Later 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.
18 compound of the embodiment of the present invention of table is to H1993 and SNU-5 cell inhibitory effect activity data tables
Conclusion：The compounds of this invention has apparent Inhibit proliferaton activity to H1993 and SNU-5.
3 the compounds of this invention of effect example inhibits to live to c-Met high expression lung cancer cell line H1993 Intracellular phosphorylations Property detection
This example expresses the intracellular c-Met phosphoric acid of lung cancer cell line H1993 for measuring the compounds of this invention for c-Met high Change inhibitory activity, the inhibitory activity half-inhibition concentration IC of c-Met phosphorylations in compound on intracellular50To indicate.Experiment side Case is as follows：C-Met high expression lung cancer cell line H1993 is purchased from ATCC, is connect with suitable cell concentration (300000/mL culture mediums) Kind is in 96 porocyte culture plates；Cell is positioned over 37 DEG C later, 5%CO2Environment in cultivated, after 24 hours, to A series of drug of concentration gradients is added in the cell culture medium of culture, is typically chosen 10 concentration, later puts H1993 cells It returns in former culture environment and continues culture 1 hour, sop up culture solution in hole later, appropriate lysate lytic cell is added, it will be appropriate Cell pyrolysis liquid is transferred in opaque 384 orifice plate of shallow bore hole, and after appropriate Acceptor mix are added, it is small that room temperature is protected from light incubation 2 When；Appropriate Donor mix are added later, continues room temperature and is protected from light incubation 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.C- intracellular to H1993 to the compound of various concentration later 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.
Table 19 compound 1-87 and compound 1-95 is to c-Met high expression lung cancer cell line H1993 Intracellular phosphorylations suppressions Activity data table processed
Metabolic stability of 4 compound of effect example in hepatomicrosome
This example is for measuring the compounds of this invention in people, rat and monkey hepatomicrosome；People, monkey S9；People, monkey cells cytoplasm are molten The metabolic stability of liquid, metabolic stability are indicated with intrinsic clearance.Testing program is as follows：It is the people of 150 μ l to use system respectively 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 includes simultaneously The phosphate buffer of NADPH and untested compound.Enzyme reaction system is carried out at 37 DEG C, and respectively at 0min, 5min, 10min Reaction is terminated with the acetonitrile 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 it is flat that negative control selects atenolol (ATE) to do Row experiment.The present embodiment measures the opposite 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 20 compound of table
Conclusion：Most of the compounds of this invention metabolic stability in hepatomicrosome, S9 and cell cytoplasm solution is good.
5. compound of effect example directly inhibits experiment (DI experiments) to metabolic enzyme
This example for measuring the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, CYP2C9, CYP1A2, CYP2C19's Direct repression, compound are expressed as inhibiting rate to the direct repression of metabolic enzyme.Testing program is as follows：React total volume For 100 μ l, including people's hepatomicrosome, NADPH, phosphate buffer, substrate mixture (Midazolam, Testosterone, Dextromethophan, Diclofenac, Phenaceti, Mephenytoin), untested compound.Body It is to be reacted with the acetonitrile termination of internal standard fasigyne after 37 DEG C of temperature incubate 20min.Vortex 10min, 15000rmp centrifuge 10min, Take 60 μ l supernatants sample introduction in 96 orifice plates.Positive control selection/inhibitor mixture (Ketoconazole, Quinidine, Sulfaphenazole, Naphthoflavone, Tranylcypromine), negative control selects DMSO to do parallel control examination It tests.Measure the relative activity that substrate utilization object indicates enzyme with respect to production quantity, inhibiting rate=(1- untested compound of the compound to enzyme Enzyme relative activity/negative control enzyme relative activity) × 100%.Inhibiting rate is defined as having direct inhibition to CPY more than 50%. Test-compound of the present invention is shown in Table 21 to the inhibiting effect data of metabolic enzyme.
21 compound of table 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.
6 compound of effect example inhibits experiment (TDI experiments) to the mechanism of metabolic enzyme
This example for measuring the compounds of this invention to metabolic enzyme CYP34A, CYP2D6, CYP2C9, CYP1A2, CYP2C19's Mechanism inhibiting effect, compound are expressed as apparent decay rate constants k to the mechanism inhibiting effect of metabolic enzymeobs.Experiment side Case is as follows：Reaction system total volume is that 200 μ l, NADPH groups include：People's hepatomicrosome, untested compound, NADPH, phosphoric acid buffer Salt；Non- NADPH groups include：People's hepatomicrosome, untested compound, phosphate-buffered salt.Temperature incubates 0min, 5min, 10min to system respectively It is reacted with using the acetonitrile of containing the internal standard fasigyne to terminate after 20min, vortex 10min, 15000rmp centrifugation 10min takes 60 μ l Supernatant sample introduction in 96 orifice plates.Positive control selection/inhibitor mixture (Troleandomycin, Paroxetine, Tienilic Acid, Furafylline), negative control select compound Atenolol, CYP2C19 positive control select S- Fluoxetine.Enzyme relative activity is indicated by measuring the opposite production quantity of substrate utilization object, and it is normal to calculate apparent deactivation rate Number kobs(*10-4/ min), as the k of compoundobsWhen value is more than 200, it is believed that it has mechanism inhibition to CPY.Testedization of the invention It closes object and 22 is shown in Table to the inhibiting effect data of metabolic enzyme.
22 compound of table is to metabolic enzyme mechanism inhibiting effect tables of data TDI (kobs*10-4)
Conclusion：A part of compound does not have mechanism inhibiting effect to metabolic enzyme in the present invention.
7 compound of effect example tests mice-transplanted tumor inhibiting effect
This example is used to measure the stomach cancer cell SNU-5 transplantable tumor inhibiting effect that the compounds of this invention expands c-Met high, with Relative tumor proliferation rate indicates the internal drug effect of compound.Testing program is as follows：Select the gastric cancer SNU-5 of c-MET height amplification Cell.Cell culture condition is in IMDM culture mediums plus 20% fetal calf serum, in 37 DEG C, containing 5%CO2Constant incubator in train It supports.By 1:4 biweekly processing passages.When cell exponentially growth period, collects cell and counted.Bulb/c is naked small Mouse is divided into 5 groups, by 5 × 106A SNU-5 cell inoculations are at the armpit of nude mouse right side.Positive drug INCB28060 and test compounds Object administration concentration is 10mg/kg, and daily gastric infusion is primary, successive administration 11 days.Routine observation animal state measures weight 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 indicates length and width respectively.
(2) relative tumour volume (Relative Tumor Volume, RTV), RTV=TVt/TV0；TV0When to divide cage (i.e. d0) gross tumor volume, TVtGross tumor volume when to measure every time.
(3) Relative tumor proliferation rate T/C (%), calculation formula are：
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 23 compound Mice Body of table
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 inhibit the growth of stomach cancer cell SNU-5 transplantable tumors, effect slightly good in the present invention In control compound, 1-172 antitumor actions are weak.

Claims (16)

1. a kind of quinolines as shown in Equation 1 or its pharmaceutically acceptable salt,
Wherein, X1For C, X2For N, X3For C；R1For hydrogen；
Cy is 5~8 circle heterocyclic ring alkenyls, 6~10 yuan of aryl or 5~10 unit's heteroaryls, 5~8 circle heterocyclic ring alkenyls, 6~10 First aryl or 5~10 unit's heteroaryls can be by 1~2 selected from halogen, cyano, R5、 Group replaced, wherein R5And R6It is each independently C1-6Alkyl, halogen take The C in generation1-6Alkyl or the C of hydroxyl substitution1-6Alkyl；Wherein, 6~10 yuan of aryl are phenyl；5~8 circle heterocyclic rings Alkenyl be 1,2,3,6- tetrahydro pyridyls,5~10 unit's heteroaryls are quinolyl, pyrazoles Base, pyridyl group, thienyl, benzothienyl, pyrimidine radicals, furyl or pyrrolopyridinyl；
L is
R2、R3And R4It is each independently hydrogen；A is H.
2. quinolines as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that：
As the R described in the Cy5And R6It is each independently C1-6When alkyl, " the C1-6Alkyl " is C1-4Alkyl；
As the R described in the Cy5And R6It is each independently the C of halogen substitution1-6When alkyl, " the C1-6Alkyl " is C1-4Alkyl, " halogen " are fluorine, chlorine or bromine；
As the R described in the Cy5And R6It is each independently the C of hydroxyl substitution1-6When alkyl, " the C1-6Alkyl " is C1-4Alkyl.
3. quinolines as claimed in claim 2 or its pharmaceutically acceptable salt, it is characterised in that：
When the Cy is phenyl, the phenyl by 1~2 selected from halogen andGroup taken Generation；
As the R described in the Cy5And R6It is each independently C1-4When alkyl, " the C1-4Alkyl " be methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group or tertiary butyl；
As the R described in the Cy5And R6It is each independently the C of halogen substitution1-4When alkyl, " the C1-4Alkyl " is Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl；
As the R described in the Cy5And R6It is each independently the C of hydroxyl substitution1-4When alkyl, " the C1-4Alkyl " is Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl.
4. quinolines as claimed in claim 3 or its pharmaceutically acceptable salt, it is characterised in that：
When the Cy is quiltWhen 5~6 circle heterocyclic ring alkenyl replaced, " the quilt5~6 circle heterocyclic ring alkenyls replaced " are
When the Cy is phenyl and the phenyl quiltWhen substitution, " the C1-4Alkyl " is first Base, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary butyl；
When the Cy is pyrazolyl, " pyrazolyl " is 1H- pyrazoles -4- bases or 1H- pyrazoles -5- bases；
When the Cy is pyridyl group, " pyridyl group " is pyridin-4-yl or pyridin-3-yl；
When the Cy is thienyl, " thienyl " is thiene-3-yl or thiophene -2- bases；
When the Cy is pyrimidine radicals, " pyrimidine radicals " is pyrimidine -5- bases；
When the Cy is furyl, " furyl " is furans -3- bases or furans -2- bases；
When the Cy is quinolyl, " quinolyl " is quinolyl-4, quinoline -3- bases or quinoline -7- bases)；
When the Cy is benzothienyl, " benzothienyl " is benzothiophene -3- bases or benzothiophene -2- Base；
When the Cy is pyrrolopyridinyl, " pyrrolopyridinyl " is 1H- pyrrolo-es [2,3-b] pyridine -5- Base.
5. quinolines as claimed in claim 4 or its pharmaceutically acceptable salt, it is characterised in that：
When the 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 the Cy is 1, when 2,3,6- tetrahydro pyridyl, " 1,2,3, the 6- tetrahydro pyridyl " is 1,2,3,6- tetrahydrochysenes Pyridin-4-yl.
6. quinolines as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that：When Cy be 6~ When 10 yuan of aryl, " 6~10 yuan of aryl " is phenyl, 2- fluoro-phenyls, the chloro- phenyl of 2-, the chloro- phenyl of 3-, 2- fluoroforms Base-phenyl, 4- trifluoromethyls, 3,4- dichlorophenyls, 4- Trifluoromethoxyphen-ls, 3- cvano-phenyls, 4- cyano-phenyls, 3-N, N- dimethylaminophenyl, 4- aminophenyls, 2,4- dimethoxy-phenylfs, 2,6- dimethoxy-phenylfs, 2,6- diformazans Base-phenyl, 2- methyl -4- methoxyl groups-phenyl, 2- methyl -5- methoxyphenyls, 4- methyl mercaptos-phenyl,
When Cy is 5~10 unit's heteroaryl, " 5~10 unit's heteroaryl " is thiophene -2- bases, thiene-3-yl, furans -2- Base, pyridin-3-yl, pyridin-4-yl, 2-aminopyridine -3- bases, 2- fluorine pyridin-3-yl, 2-aminopyridine -5- bases, 2- methyl pyrroles Pyridine -5- bases, quinoline -7- bases, 5- cyano thiophene -2- bases,
7. quinolines or its pharmaceutically acceptable salt, feature shown in formula I as described in claim 1 exist In：Quinolines as shown in Equation 1 or its pharmaceutically acceptable salt are any compound as described below：
6- ((6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1)-methylene)-quinoline,
6- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (pyridin-4-yl) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (4- trifluoromethyls) -1H- imidazos [4,5-b] pyrazine -1- methylene) quinoline,
4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazoles -6- bases)-aniline,
6- (6- (4- Trifluoromethoxyphen-ls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (2- fluorophenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
The chloro- 4- of 7- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases) quinoline,
N, N- dimethyl -3- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases)-aniline,
6- (6- (4- methoxyl group -2- methyl-l- phenyl) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (1- methyl-1 H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (1,2,3,6- tetrahydropyridine -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline hydrochloride,
4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases) -3,6- dihydropyridines -1 (2H)-formic acid second Ester,
6- (6- (2,6- Dimethoxyphenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
6- (6- (2,4- Dimethoxyphenyls) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
3- (6- (quinoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene) quinoline,
6- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- methylene)-quinoline,
2- (4- (1- (quinoline -6- methylene) -1H- imidazos [4,5-b] pyrazine -6- bases)-pyrazol-1-yl)-ethyl alcohol,
6- (1- (6- (1- methyl-1 H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- phenyl -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (4- (trifluoromethyl) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (4- pyridyl groups) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (1- methyl-1 H- pyrazoles -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (4- methoxyl group -2- aminomethyl phenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
N, N- dimethyl -3- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) aniline,
6- (1- (6- (1,2,3,6- tetrahydropyridine -1--4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline - 1- chlorides,
2- (4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) -1H- pyrazol-1-yls) ethyl alcohol,
6- (1- (6- (1H- pyrazoles -4- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (2,6- 3,5-dimethylphenyls) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
The fluoro- 4- of 2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) methyl benzoate,
6- (1- (6- (4- (methyl mercapto) phenyl) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (thiene-3-yl) -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) quinoline,
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzsulfamide,
6- (1- (6- (pyrimidine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -2- formaldehyde,
4- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzonitrile,
6- (1- (6- (6- picoline -3- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
6- (1- (6- (1H- pyrrolo-es [2,3-b] pyridine -5- bases) -1H- imidazos [4,5-b] pyrazine -1- bases) ethyl) quinoline,
N, N- dimethyl -5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- amine,
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -3- formaldehyde,
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyrimidine -2- amine,
5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- amine,
(5- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) furans -3- bases) methanol,
3- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) pyridine -2- amine,
The fluoro- 4- of 2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzamide,
The fluoro- 4- of N- ethyls -2- (1- (1- (quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzamide,
The fluoro- N- methyl -4- of 2- (1- (1- quinoline -6- bases) ethyl) -1H- imidazos [4,5-b] pyrazine -6- bases) benzamide.
8. such as the preparation method of claim 1~7 any one of them quinolines or its pharmaceutically acceptable salt, It is characterized in that including the following steps：In a solvent, compound II and boric acid or borate are subjected to Suzuki coupling reactions, obtained Compound 1；
Wherein, X is halogen；The definition of Cy is as described in any one of claim 1~7；X1、X2、X3、A、L、R1、R2、R3And R4Determine It is adopted as described in claim 1.
9. preparation method as claimed in claim 8, it is characterised in that include the following steps：By compound III and carboxylic acid or original Carboxylate is reacted, and the compound II is obtained；
Wherein, X is halogen；X1、X2、X3、A、L、R1、R2、R3And R4Definition it is as described in claim 1.
10. preparation method as claimed in claim 9, it is characterised in that include the following steps：In a solvent, by compound V or Its acid salt carries out nucleophilic substitution with compound IV, obtains the compound III；
Wherein, X is halogen；X1、X2、X3、A、L、R2、R3And R4Definition it is as described in claim 1.
11. a kind of such as Formula II compound represented,
Wherein, X is halogen；X1、X2、X3、A、L、R1、R2、R3And R4Definition it is as described in claim 1.
12. such as claim 1~7 any one of them quinolines as shown in Equation 1 or its pharmaceutically acceptable salt It is preparing for treating and/or preventing and the application in the drug of the expression of tyrosine kinase C-Met or the relevant disease of activity.
13. a kind of pharmaceutical composition, it is characterised in that：Such as containing therapeutically effective amount such as claim 1~7 any one of them Quinolines or its pharmaceutically acceptable salt shown in formula 1 and pharmaceutically acceptable one or more medicinal auxiliary Material；The therapeutically effective amount is that mass percentage is 1%~99%；The mass percentage is as shown in Equation 1 Imidazopyrazines or its pharmaceutically acceptable salt, account for the percentage of pharmaceutical composition gross mass；The drug The sum of mass percentage of each component is 100% in composition.
14. pharmaceutical composition as claimed in claim 13 is being prepared for treating and/or preventing with tyrosine kinase C-Met's Application in the drug of expression or the relevant disease of activity.
15. pharmaceutical composition as claimed in claim 14 is being prepared for treating and/or preventing with tyrosine kinase C-Met's Application in the drug of expression or the relevant disease of activity, it is characterised in that：The described expression with tyrosine kinase C-Met or The relevant disease of activity includes cancer, musculoskeletal sarcoma, soft tissue sarcoma, Hematopoietic Malignancies and other tumours.
16. pharmaceutical composition as claimed in claim 15 is being prepared for treating and/or preventing with tyrosine kinase C-Met's Application in the drug of expression or the relevant disease of activity, it is characterised in that：The cancer includes carcinoma of urinary bladder, breast cancer, palace Neck cancer, colon cancer, cancer of the esophagus, gastric cancer, head and neck cancer, kidney, lung cancer, liver cancer, nasopharyngeal carcinoma, oophoroma, cancer of pancreas, prostate cancer and Thyroid cancer；The musculoskeletal sarcoma includes：Osteosarcoma, synovial sarcoma and rhabdomyosarcoma；The soft tissue sarcoma Including：Malignant fibrous histiocytoma/fibrosarcoma, leiomyosarcoma and Kaposi's sarcoma；The hemopoietic system is pernicious Tumour includes：Huppert's disease, lymthoma, adult T cell leukemia, acute myelogenous leukemia and chronic granulocyte are white Blood disease；Other described tumours include：Glioblastoma, astrocytoma, melanoma, celiothelioma and embryonal carcinoma meat Tumor.
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