CN107312009B

CN107312009B - Quinoline compound, preparation method, intermediate, pharmaceutical composition and application thereof

Info

Publication number: CN107312009B
Application number: CN201710587197.7A
Authority: CN
Inventors: 余建鑫; 赵菲; 郝宇; 夏广新
Original assignee: Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2013-04-17
Filing date: 2014-04-16
Publication date: 2022-09-20
Anticipated expiration: 2034-04-16
Also published as: CN104109166B; CN107312009A; CN104109166A; CN105968115B; CN105968115A

Abstract

The invention discloses a quinoline compound, a preparation method, an intermediate, a pharmaceutical composition and application thereof. The invention provides a quinoline compound shown as a formula 1, and pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof. The quinoline compound has good inhibition effect on tyrosine kinase C-Met, and can be used for preparing medicaments for preventing, treating or auxiliarily treating various diseases related to the expression or activity of the C-Met, especially tumor diseases.

Description

Quinoline compound, preparation method, intermediate, pharmaceutical composition and application thereof

The application is a divisional application of a patent application with the application number of CN201410152877.2 and the application date of 2014, 04, 16 and the name of quinoline compound, a preparation method, an intermediate, a pharmaceutical composition and application thereof.

Technical Field

The invention relates to quinoline compounds, a preparation method, intermediates, pharmaceutical compositions and applications thereof.

Background

C-Met is a protein product coded by C-Met proto-oncogene, is a hepatocyte growth factor receptor, has tyrosine kinase activity, is related to various oncogene products and regulatory proteins, participates in the regulation and control of cell information conduction and cytoskeleton rearrangement, and is an important factor of cell proliferation, differentiation and movement. It is now believed that C-Met is closely associated with the development and metastasis of a variety of cancers, and studies have shown that many tumor patients have C-Met overexpression and gene amplification during their development and metastasis. The relation between the activation of C-Met and canceration is mainly shown in the following steps:

1. hepatocyte Growth Factor (HGF) -dependent activation mechanism

There are many molecular mechanisms in tumor cells that can activate C-Met, the most common being through HGF and C-Met binding. Binding of HGF and C-Met leads to receptor autophosphorylation, which enhances the activity of C-Met tyrosine kinase, resulting in tyrosine phosphorylation of various substrate proteins. Under physiological conditions, the transient combination of the C-Met receptor and HGF exerts physiological effects, HGF and C-Met are simultaneously highly expressed in tumor tissues to form positive feedback, and the infinite growth and invasion behaviors of tumors are caused. This positive feedback has been demonstrated in malignant tumors such as gliomas, osteosarcomas, breast carcinomas, etc.

2. Hepatocyte Growth Factor (HGF) independent activation mechanism

C-Met can be activated independently of HGF, especially in tumors where Met is overexpressed. The high expression of the Met protein may be due to amplification, transcriptional enhancement or post-transcriptional mechanisms of the C-Met gene. The C-Met gene cloned by Cooper for the first time is an activated form after rearrangement, and is a chimeric gene formed by a promoter of chromosome 1, the N terminal of a TPR gene sequence and the C terminal of a Met sequence of chromosome 7, a cytoplasmic protein coded by the chimeric gene comprises a leucine zipper region coded by TPR and a tyrosine kinase region coded by Met, and due to the existence of the leucine zipper region, Met kinase is continuously activated to promote cell transformation to malignancy. In colon cancer LOVO cell line, Met exists on the cell surface in the form of monomer due to abnormal transcription, and thus has sustained tyrosine kinase activity. In the metastatic melanoma B16 cell line, Met protein is not dephosphorylated due to a decrease in intracellular phosphorylation enzymes and is continuously active. Point mutations in the Met gene may also lead to sustained activation of Met kinase.

The tyrosine kinase receptor C-Met plays an important role in the processes of cell metabolism, cell differentiation and signal transduction of dead cells, is combined with a ligand, can activate a signal path thereof, and participates in embryonic development, tissue injury repair and tumor occurrence and development. Therefore, the anti-tumor drug taking the tyrosine kinase receptor C-Met as the target has become a very active field in tumor research, and provides a new method for anti-tumor treatment.

The small molecule C-Met tyrosine kinase inhibitor is mostly a competitive inhibitor of ATP, and plays a role in inhibiting C-Met kinase by blocking tyrosine phosphorylation. Such compounds are classified as selective and non-selective tyrosine kinase inhibitors based on their selectivity for C-Met. Its advantages are high cell permeability and high oral bioavailability. The grizotinib approved by FDA to be marketed in 8 months in 2011 is a double inhibitor of C-Met/ALK, is effective on ALK-mutated non-small cell lung cancer, and embodies the characteristic of personalized treatment. The 11 month eelimixis company, 2012 announced that the drug cabozantinib (XL184) has been FDA approved for the treatment of non-surgically resectable malignant locally advanced or metastatic Medullary Thyroid Cancer (MTC). Cabozantinib is an oral drug, exerts an antitumor effect by targeting and inhibiting MET, VEGFR2 and RET signaling pathways, and can kill tumor cells, reduce metastasis and inhibit angiogenesis. Although there are no selective C-Met inhibitors currently on the market, many compounds have been developed which have C-Met inhibitory activity and which are capable of ameliorating diseases caused by C-Met abnormalities, such as JNJ-38877605 by Johnson & Johnson, AMG-458 by Amgen, E-7050 by Eisai and PF-04217903 by Pfizer.

Disclosure of Invention

The invention aims to solve the technical problem of providing a quinoline compound completely different from the prior art, a preparation method, an intermediate, a pharmaceutical composition and application thereof. The quinoline compound has good inhibition effect on tyrosine kinase C-Met, and can be used for preparing medicaments for preventing, treating or auxiliarily treating various diseases related to the expression or activity of the C-Met, especially tumor diseases.

The inventors of the present invention have found, through a large number of laborious experimental studies, a class of quinoline derivatives having a selective inhibitory effect on C-Met, and have completed the present invention.

The invention provides a quinoline compound shown as a formula 1, and pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof,

wherein, X ₁ 、X ₂ And X ₃ Each independently being C or N,

is shown when X ₁ When is C, X ₁ And R ₁ Is connected when X ₁ When N is, with X ₁ To which R is attached ₁ Is absent; and when X is ₁ Is CWhen, X ₂ And X ₃ One is C and the other is N, R ₁ Is hydrogen or hydroxy (preferably hydrogen); when X is present ₁ When is N, X ₂ Is N, X ₃ Is C; preferably, X ₁ Is C or N, X ₂ Is N, X ₃ Is C;

cy is 3-8 membered cycloalkyl (preferably 3-6 membered cycloalkyl, the "3-6 membered cycloalkyl" is preferably unsubstituted cyclopropyl), 3-8 membered heterocycloalkyl (preferably 3-6 membered heterocycloalkyl, the "3-6 membered heterocycloalkyl" is preferably 5-6 membered heterocycloalkyl in which the heteroatom is nitrogen atom and the number of the heteroatom is 1-2, the "heteroatom is nitrogen atom and the number of the heteroatom is 1-2 5-6 membered heterocycloalkyl", and C may be substituted _1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl); the 5-6 membered heterocycloalkyl with 1-2 heteroatoms is preferably piperazinyl, and the piperazinyl is preferably 4-piperazinyl; the "heteroatom substituted by methyl is nitrogen atom, and the 5-6 membered heterocycloalkyl group with 1-2 heteroatoms" is preferably N-methylpiperazinyl; the "N-methylpiperazinyl" is preferably N-methylpiperazin-1-yl), 5 to 8-membered cycloalkenyl, 5 to 8-membered heterocycloalkenyl (preferably 5 to 6-membered heterocycloalkenyl, the "5 to 6-membered heterocycloalkenyl" is preferably 5 to 6-membered heterocycloalkenyl having 1 to 2 heteroatoms as nitrogen atoms, and the "5 to 6-membered heterocycloalkenyl having 1 to 2 heteroatoms as nitrogen atoms" may be substituted "

Alkyl of (1) (wherein, C) _1-4 An alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl), or a salt may be formed with the free nitrogen atom of said "5-to 6-membered heterocycloalkenyl group in which the heteroatom is a nitrogen atom and the number of heteroatoms is 1 to 2"; the "5-to 6-membered heterocycloalkenyl group containing 1 to 2 heteroatoms as nitrogen atoms" is preferably a 1,2,3, 6-tetrahydropyridinyl group, and the "1, 2,3, 6-tetrahydropyridinyl group" is preferably a 1,2,3, 6-tetrahydropyridin-4-yl group; the heteroatom is nitrogen atom, and the free nitrogen atom on the 5-6 membered heterocyclic alkenyl group with 1-2 heteroatoms forms salt"preferred" to

Said "quilt

The alkyl group of (A) is preferably a 5-to 6-membered heterocycloalkenyl group having 1-to 2 hetero atoms and nitrogen atom as the hetero atom

) 6-to 10-membered aryl, 5-to 10-membered heteroaryl or "

Alkyl group of (2) (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl); the 3-to 8-membered cycloalkyl group, 3-to 8-membered heterocycloalkyl group, 5-to 8-membered cycloalkenyl group, 5-to 8-membered heterocycloalkenyl group, 6-to 10-membered aryl group or 5-to 10-membered heteroaryl group may be substituted with 1 to 2 groups selected from halogen (e.g., fluorine, chlorine or bromine), cyano, R ₅ 、

Wherein R is substituted with a group of ₅ And R ₆ Each independently is C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl), halogen-substituted C _1-6 Alkyl (preferably halogen-substituted C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl," halogen "such as fluorine, chlorine or bromine), hydroxy-substituted C _1-6 Alkyl (preferably hydroxy-substituted C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl)," 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl (preferably phenyl), halogen-substituted 6-10 membered aryl (preferably halogen-substituted phenyl, said "halogen" being for example fluorine, chlorine or bromine; ) 5-to 10-membered heteroaryl (preferably 5-to 10-membered heteroaryl having 1-2 heteroatoms, wherein "heteroatom" is nitrogen atom, 5-to 10-membered heteroaryl having 1-2 heteroatoms "is preferably quinolyl) or halogen-substituted 5-to 10-membered heteroaryl (wherein" halogen "is fluorine, chlorine or bromine; the 5-10 membered heteroaryl is preferably a 5-10 membered heteroaryl in which the heteroatom is a nitrogen atom and the number of the heteroatoms is 1-2, and the 5-10 membered heteroaryl in which the heteroatom is a nitrogen atom and the number of the heteroatoms is 1-2 is preferably a quinolyl);

l is

R ₂ 、R ₃ And R ₄ Each independently of the other being hydrogen, halogen (e.g. fluorine, chlorine or bromine) or C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl); preferably R ₂ And R ₃ Each independently being hydrogen, fluoro or methyl, R ₄ Is hydrogen; it is still further preferred when R ₂ When it is hydrogen, R ₃ Is hydrogen, fluorine or methyl, R ₄ Is hydrogen; when R is ₂ When it is fluorine, R ₃ Is fluorine, R ₄ Is hydrogen.

A is hydrogen, 6-to 10-membered aryl or 5-to 10-membered nitrogen-containing heteroaryl, wherein 1 to 2 of the 6-to 10-membered aryl or 5-to 10-membered nitrogen-containing heteroaryl are selected from halogen (e.g., fluorine, chlorine or bromine), C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl) and"

Alkyl group of (1) (wherein, C) _1-6 Alkyl is preferably C _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl);

when X is present ₁ Is C, X ₂ Is N and X ₃ When C is used, A is preferably hydrogen or a 5-to 10-membered nitrogen-containing heteroaryl group (preferably a 5-to 6-membered nitrogen-containing heteroaryl group having 1 to 2 nitrogen atoms, the "5-to 6-membered nitrogen-containing heteroaryl group having 1 to 2 hetero atoms" is preferably pyrazolyl), and the 5-to 10-membered nitrogen-containing heteroaryl group may be substituted with C _1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl); a 5-to 10-membered nitrogen-containing heteroaryl group substituted with a methyl group, preferably 1-methyl-1H-pyrazolyl group;

when X is present ₁ Is C, X ₂ Is C and X ₃ When N is used, A is preferably a 5-to 10-membered nitrogen-containing heteroaryl group (preferably a 5-to 6-membered nitrogen-containing heteroaryl group having 1 to 2 nitrogen atoms, wherein the "5-to 6-membered nitrogen-containing heteroaryl group having 1 to 2 hetero atoms" is preferably pyrazolyl), and the 5-to 10-membered nitrogen-containing heteroaryl group may be substituted with C _1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl); a 5-to 10-membered nitrogen-containing heteroaryl group substituted with a methyl group, preferably 1-methyl-1H-pyrazolyl group;

when X is present ₁ Is N, X ₂ Is N and X ₃ When C, A is preferably 6-to 10-membered aryl (preferably phenyl, said "phenyl" being optionally substituted by 1 to 2 groups selected from halogen (e.g. fluorine, chlorine or bromine, preferably fluorine) and "

Alkyl group of (1) (wherein, C) _1-6 Alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl) group) or 5 to 10-membered nitrogen-containing heteroaryl (preferably 5 to 10-membered nitrogen-containing heteroaryl having 1 to 2 nitrogen atoms, said "5 to 10-membered nitrogen-containing heteroaryl having 1 to 2 nitrogen atoms" being preferably pyrazolyl, pyridyl or quinolyl), said 6 to 10-membered aryl or 5 to 10-membered nitrogen-containing heteroaryl may be substituted with 1 to 2 groups selected from halogen (e.g. fluorine, chlorine or bromine), C _1-6 Alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl)Alkyl, isobutyl or tert-butyl) and "

Alkyl group of (1) ("C" as described therein) _1-6 Alkyl "is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl (5-to 10-membered nitrogen-containing heteroaryl having 1 to 2 nitrogen atoms substituted with methyl is preferably 1-methyl-1H-pyrazolyl).

In the invention, the quinoline compound shown in the formula 1, the pharmaceutically acceptable salt, the solvate, the metabolite, the metabolic precursor or the prodrug thereof is preferably a quinoline compound containing an imidazopyrazine structure shown in the formula 1-a, a quinoline compound containing a triazolopyrazine structure shown in the formula 1-b or a quinoline compound containing an imidazo [1,2-b ] [1,2,4] triazole structure shown in the formula 1-c,

in the compound 1-a, Cy is selected from the groups a) to e), preferably Cy is selected from the groups a) to d), more preferably Cy is selected from the groups d):

a) the 3-6 membered cycloalkyl group, the 3-6 membered cycloalkyl group is preferably cyclopropyl, and further preferably cyclopropyl;

b) a 3-to 6-membered heterocycloalkyl group, preferably a 5-to 6-membered heterocycloalkyl group having 1 to 2 hetero atoms as the hetero atom, wherein the 5-to 6-membered heterocycloalkyl group having 1 to 2 hetero atoms as the hetero atom may be substituted with C _1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl); the 5-6 membered heterocycloalkyl with 1-2 heteroatoms as nitrogen atoms is preferably piperazinyl, and the piperazinyl is preferably 4-piperazinyl; the "5-to 6-membered heterocycloalkyl group having 1 to 2 hetero atoms and nitrogen atoms as hetero atoms substituted with a methyl group" is preferably N-methylpiperazinyl, and the "N-methylpiperazinyl" is preferably N-methylpiperazinyl-1-yl;

c) 5-6 membered heterocycloalkenyl, preferably 5-6 membered heterocycloalkenyl having 1-2 heteroatoms as nitrogen atom, wherein the "5-6 membered heterocycloalkenyl having 1-2 heteroatoms as nitrogen atom" may be "

Alkyl group of (2) "(wherein, C _1-4 Alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl), or the free nitrogen atom of said "5-6 membered heterocycloalkenyl group in which the heteroatom is a nitrogen atom and the number of heteroatoms is 1-2" may be salified; the "5-to 6-membered heterocycloalkenyl group having 1 to 2 hetero atoms as a nitrogen atom" is preferably 1,2,3, 6-tetrahydropyridin-4-yl

The "salt formation of free nitrogen atom on 5-6 membered heterocycloalkenyl group containing 1-2 hetero atoms as nitrogen atom" is preferable

Said "quilt

d) 6-to 10-membered aryl or 5-to 10-membered heteroaryl; the 6-to 10-membered aryl is preferably phenyl or naphthyl (the naphthyl is preferably 1-naphthyl); the 5-to 10-membered heteroaryl group is preferably a monocyclic or fused 5-to 10-membered heteroaryl group having 1 to 2 hetero atoms of N, O or S atoms, the "monocyclic 5-to 10-membered heteroaryl group having 1 to 2 heteroatoms as a hetero atom of N, O or S" is preferably pyrazolyl (the "pyrazolyl" is preferably 1H-pyrazol-4-yl or 1H-pyrazol-5-yl), pyridyl (the "pyridyl" is preferably pyridin-4-yl or pyridin-3-yl), thienyl (the "thienyl" is preferably thiophen-3-yl or thiophen-2-yl), pyrimidinyl (the "pyrimidinyl" is preferably pyrimidin-5-yl) or furyl (the "furyl" is preferably furan-3-yl); the fused ring 5-to 10-membered heteroaryl group having 1 to 2 hetero atoms and N, O or S atoms as a hetero atom is preferably a quinolyl group (the quinolyl group is preferably a quinolin-4-yl group, a quinolin-3-yl group or a quinolin-7-yl group), isoquinolinyl (said "isoquinolinyl" is preferably isoquinolin-4-yl), benzothienyl (said "benzothienyl" is preferably benzothien-3-yl or benzothien-2-yl), indolyl (said "indolyl" is preferably indol-3-yl, indol-4-yl or indol-5-yl) or pyrrolopyridinyl (said "pyrrolopyridinyl" is preferably 1H-pyrrolo [2,3-b ] pyridin-5-yl);

the 6-to 10-membered aryl or 5-to 10-membered heteroaryl group may be substituted with 1 to 2 groups selected from halogen (e.g., fluorine, chlorine or bromine), cyano, R ₅ 、

(preferably N, N-dimethylamino),

(preferred)

)、

(preferred)

)、

(preferred)

) Wherein R is substituted with a group of ₅ 、R ₆ Each independently is C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl radicals "such as methyl,Ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl), halogen substituted C _1-6 Alkyl (said "halogen-substituted C) _1-6 "C" described for alkyl group _1-6 Alkyl "preferably C _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "halogen-substituted C _1-6 The "halogen" mentioned for alkyl "is preferably fluorine, chlorine or bromine; said "halogen-substituted C _1-6 Alkyl "preferably trifluoromethyl), hydroxy-substituted C _1-6 Alkyl (said "hydroxy-substituted C) _1-6 Alkyl "described for" C _1-6 Alkyl "preferably C _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "hydroxy-substituted C _1-6 Alkyl "is preferred

) 6-to 10-membered aryl (preferably phenyl), halogen-substituted 6-to 10-membered aryl (the "6-to 10-membered aryl" in the "halogen-substituted 6-to 10-membered aryl" is preferably phenyl, the "halogen" in the "halogen-substituted 6-to 10-membered aryl" is preferably fluorine, chlorine or bromine), a 5-to 10-membered heteroaryl (preferably a 5-to 10-membered heteroaryl having 1-2 heteroatoms as a nitrogen atom, the "5-to 10-membered heteroaryl group having 1 to 2 heteroatoms as a heteroatom" is preferably a quinolyl group) or a halogen-substituted 5-to 10-membered heteroaryl group (the "5-to 10-membered heteroaryl group" in the "5-to 10-membered heteroaryl group substituted with halogen" is preferably a 5-to 10-membered heteroaryl group having 1 to 2 heteroatoms as a heteroatom, the '5-10-membered heteroaryl with 1-2 heteroatoms as nitrogen atoms' is preferably a halogen substituted quinolyl; the "halogen" in the "halogen-substituted 5-to 10-membered heteroaryl" is preferably fluorine, chlorine or bromine; the "halogen-substituted 5-to 10-membered heteroaryl" is preferably

) (ii) a The substituents may be the sameOr may be different.

e)“

Alkyl group of (2) "(wherein, C _1-6 Alkyl is preferably C _1-4 Alkyl, said "C _1-6 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl);

l is

R ₁ Is hydrogen or hydroxy, preferably H;

R ₂ and R ₃ Each independently is H, F or methyl, R ₄ Is H; preferably, when R is ₂ When is H, R ₃ Is H, F or methyl, R ₄ Is H; when R is ₂ When is F, R ₃ Is F, R ₄ Is H;

a is H or 5-membered nitrogen-containing heteroaryl (preferably 5-6-membered nitrogen-containing heteroaryl having 1-2 nitrogen atoms, said "5-6-membered nitrogen-containing heteroaryl having 1-2 nitrogen atoms" is preferably pyrazolyl), said 5-membered nitrogen-containing heteroaryl may be substituted by C _1-4 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, 5-to 6-membered nitrogen-containing heteroaryl having 1 to 2 nitrogen atoms substituted with methyl, preferably 1-methyl-1H-pyrazolyl); a is preferably H.

In the compound 1-b, Cy is 6-10 membered aryl or 5-10 membered heteroaryl; the 6-to 10-membered aryl is preferably phenyl; the "5-to 10-membered heteroaryl group" is preferably a monocyclic or fused ring 5-to 10-membered heteroaryl group having 1-to 2 heteroatoms, each of which has N, O or S atoms, each of which has N, O or S atoms, each of which has 1-to 2 heteroatoms, and each of which has 5-to 10-membered heteroaryl groups, each of which has 5-to 2 heteroatoms, preferably a pyrazolyl group (preferably 1H-pyrazol-4-yl), a pyridyl group (preferably pyridin-4-yl or pyridin-3-yl), a thienyl group (preferably thiophen-3-yl or thiophen-2-yl), or a furyl group (preferably furanyl group, each of which has furan-2-yl); the "fused ring 5-to 10-membered heteroaryl group containing N, O or S atoms as a heteroatom and 1 to 2 heteroatoms" is preferably a quinolyl group (the "quinolyl group" is preferably a quinolin-3-yl group or a quinolin-7-yl group), an isoquinolyl group (the "isoquinolyl group" is preferably an isoquinolin-4-yl group), a benzothienyl group (the "benzothienyl group" is preferably a benzothiophen-3-yl group or a benzothiophen-2-yl group), or an indolyl group (the "indolyl group" is preferably an indol-5-yl group);

(preferably N, N-dimethylamino),

(preferred is

)、

(preferred is

)、

Wherein R is substituted with a group of ₅ 、R ₆ Each independently is C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl) or hydroxy-substituted C _1-6 Alkyl (said "hydroxy-substituted C _1-6 Alkyl "described for" C _1-6 Alkyl "preferably C _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; said "hydroxy-substituted C _1-6 Alkyl "is preferred

)；

L is

R ₂ 、R ₃ Each independently of the other is H or F, R ₄ Is H;

a is 6-10 membered aryl or 5-10 membered nitrogen-containing heteroaryl, the 6-10 membered aryl (preferably phenyl) or 5-10 membered nitrogen-containing heteroaryl (preferably 5-10 membered nitrogen-containing heteroaryl having 1-2 nitrogen atoms, the "5-10 membered nitrogen-containing heteroaryl having 1-2 nitrogen atoms" preferably pyridyl, pyrazolyl or quinolyl) may be substituted with 1-2 groups selected from halogen (e.g. fluorine, chlorine or bromine), C _1-6 Alkyl (preferably C) _1-4 Alkyl, said "C _1-4 Alkyl "such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, 5-to 6-membered nitrogen-containing heteroaryl having 1 to 2 nitrogen atoms substituted with methyl, preferably 1-methyl-1H-pyrazol-4-yl; ) And "

Alkyl group of (1) (wherein, C) _1-6 Alkyl is preferably C _1-4 Alkyl, said "C _1-6 Alkyl "for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl).

In the compounds 1-c, Cy is a phenyl group which may be substituted by 1 to 2 groups selected from halogen (e.g. fluorine, chlorine or bromine, preferably fluorine) and "

Alkyl group of (1) ("C" as defined herein) _1-4 Alkyl "for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably methyl); the "is 1-2 selected from halogen and"

The "phenyl group substituted with the group of" alkyl "of (a) is preferably 3-fluoro-4- (N-methylcarbamoyl) -1-phenyl;

l is

R ₁ 、R ₂ 、R ₃ 、R ₄ Are all H;

a is 1-methyl-1H-pyrazol-4-yl.

In the present invention, when L is

When used, the chiral carbon atom in L may be in the R configuration, the S configuration or the racemic configuration.

In the present invention, when Cy is a 6-to 10-membered aryl group, the "6-to 10-membered aryl group" is more preferably a phenyl group, a 2-fluoro-phenyl group, a 2-chloro-phenyl group, a 3-chloro-phenyl group, a 2-trifluoromethyl-phenyl group, a 4-trifluoromethylphenyl group, a 3, 4-dichlorophenyl group, a 4-trifluoromethoxy-phenyl group, a 3-cyano-phenyl group, a 4-cyanophenyl group, a 3-N, N-dimethylaminophenyl group, a 4-aminophenyl group, a2, 4-dimethoxy-phenyl group, a2, 6-dimethyl-phenyl group, a 2-methyl-4-methoxy-phenyl group, a 2-methyl-5-methoxyphenyl group, a 4-methylthio-phenyl group, a,

In the present invention, when Cy is a 5-to 10-membered heteroaryl group, the "5-to 10-membered heteroaryl group" is more preferably: thien-2-yl, thien-3-yl, furan-2-yl, pyridin-3-yl, pyridin-4-yl, 2-aminopyridin-3-yl, 2-fluoropyridin-3-yl, 2-aminopyridin-5-yl, 2-methylpyridin-5-yl, indol-4-yl, indol-5-yl, quinolin-7-yl, isoquinolin-4-yl, 5-cyanothien-2-yl, methyl-p-tolyl-N-acetyloxy-methyl-phenyl,

In the present invention, the quinoline compound represented by formula 1, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor, or prodrug thereof is preferably any one of the following compounds:

6- ((6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazine-1) -methylene) -quinoline (1-1),

6- (6-phenyl-1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-2),

6- (6- (pyridin-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-methylidene) -quinoline (1-3),

6- (6- (4-trifluoromethylphenyl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) quinoline (1-4),

4- (1- (quinoline-6-methylene) -1H-imidazo [4,5-b ] pyrazol-6-yl) -phenylamine (1-5),

6- (6- (4-trifluoromethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-methylene) -quinoline (1-6),

6- (6- (2-fluorophenyl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-7),

7-chloro-4- (1- (quinoline-6-methylene) -1H-imidazo [4,5-b ] pyrazin-6-yl) quinoline (1-8),

N, N-dimethyl-3- (1- (quinoline-6-methylene) -1H-imidazo [4,5-b ] pyrazin-6-yl) -phenylamine (1-9),

6- (6- (4-methoxy-2-methyl-l-phenyl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-10),

6- (6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-11),

6- (6- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-ylidene) -quinoline hydrochloride (1-12),

4- (1- (quinoline-6-methylene) -1H-imidazo [4,5-b ] pyrazin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ethyl ester (1-13),

6- (6- (2, 6-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-14),

6- (6- (2, 4-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-15),

3- (6- (quinolin-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-ylidene) quinoline (1-16),

6- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (1-17),

2- (4- (1- (quinoline-6-methylene) -1H-imidazo [4,5-b ] pyrazin-6-yl) -pyrazol-1-yl) -ethanol (1-18),

6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-19),

6- (1- (6-phenyl-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-20),

6- (1- (6- (4- (trifluoromethyl) phenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-21),

6- (1- (6- (4-pyridyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-22),

6- (1- (6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-23),

6- (1- (6- (4-methoxy-2-methylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-24),

N, N-dimethyl-3- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) aniline (1-25),

6- (1- (6- (1,2,3, 6-tetrahydropyridin-1-ium-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinolin-1-ium chloride (1-26),

2- (4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -1H-pyrazol-1-yl) ethanol (1-27),

6- (1- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-28),

6- (1- (6- (2, 6-dimethylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-29),

Methyl 2-fluoro-4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzoate (1-30),

6- (1- (6- (4- (methylthio) phenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-31),

6- (1- (6- (thiophen-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-32),

6- (1- (6- (benzo [ b ] thiophen-2-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-33),

4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzenesulfonamide (1-34),

6- (1- (6- (pyrimidin-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-35),

4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) furan-2-carbaldehyde (1-36),

4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzonitrile (1-37),

6- (1- (6- (6-methylpyridin-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-38),

6- (1- (6- (1H-pyrrolo [2,3-b ] pyridin-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-39),

N, N-dimethyl-5- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) pyridin-2-amine (1-40),

5- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) furan-3-carbaldehyde (1-41),

5- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) pyrimidin-2-amine (1-42),

5- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) pyridin-2-amine (1-43),

(5- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) furan-3-yl) methanol (1-44),

3- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) pyridin-2-amine (1-45),

2-fluoro-4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzamide (1-46),

N-ethyl-2-fluoro-4- (1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzamide (1-47),

2-fluoro-N-methyl-4- (1- (1-quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzamide (1-48),

6- (1-methyl-1H-pyrazol-4-yl) -1- (1- (quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-2-ol (1-49),

8-fluoro-6- ((6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-50),

8-fluoro-6- ((6-phenyl-1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-51),

8-fluoro-6- ((6- (1-naphthyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-52),

2- (4- (1- ((8-fluoroquinolin-6-yl) methyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -1H-pyrazol-1-yl) ethanol (1-53),

6- ((6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -8-fluoroquinoline (1-54),

8-fluoro-6- ((6- (3-quinolyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -quinoline (1-55),

8-fluoro-6- ((6- (4-pyridyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -quinoline (1-56),

8-fluoro- (6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-57),

8-fluoro-6- (1- (6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-58),

8-fluoro-6- (1- (6- (4-pyridyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-59),

8-fluoro-6- (1- (6-phenyl-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-60),

6- (1- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -8-fluoroquinoline (1-61),

8-fluoro-6- (1- (6- (3-quinolyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-62),

6- (1- (6- (3, 4-dichlorophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -8-fluoroquinoline (1-63), 6- (1- (6- (2, 4-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -8-fluoroquinoline (1-64),

6- (1- (6- (2, 6-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -8-fluoroquinoline (1-65),

8-fluoro-6- (1- (6- (2-trifluoromethylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-66),

8-fluoro-6- (1- (6- (4-trifluoromethylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-67),

8-fluoro-6- (1- (6- (1-naphthyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-68),

6- [6- (1-methyl-1H-pyrazol-4-yl) -imidazo [4,5-b ] pyrazin-1-ylidene ] -quinoline (1-69),

2- (4- (1- (7-fluoro-quinolin-6-methylene) -1H-imidazo [4,5-b ] pyrazin-6-yl) -1H-pyrazol-1-yl) -ethanol (1-70),

6- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazine-1-methylene) -7-fluoroquinoline (1-71),

7-fluoro-6- (6-phenyl-imidazo [4,5-b ] pyrazin-1-methylidene) -quinoline (1-72),

7-fluoro-6- (6- (pyridin-4-yl) -imidazo [4,5-b ] pyrazin-1-methylidene) -quinoline (1-73),

(3- (1- (7-fluoro-quinolin-6-ylidene) -1H-imidazo [4,5-b ] pyrazin-6-yl) -phenyl) -N, N-dimethylamine (1-74),

7-fluoro-6- (6- (4-methoxy-2-methyl-phenyl) -imidazo [4,5-b ] pyrazin-1-ylidene) -quinoline (1-75),

7-fluoro-6- (6- (quinolin-3-yl) -imidazo [4,5-b ] pyrazin-1-methylene) -quinoline (1-76),

4- (3- (7-fluoro-quinolin-6-methylene) -3H-imidazo [4,5-b ] pyrazin-5-yl) -phenylamine (1-77),

6- ((5- (7-chloro-4-quinolinyl) imidazo [4,5-b ] pyrazin-3-yl) methylene) -7-fluoro-quinoline (1-78),

7-chloro-4 '- (3- (7-fluoro-quinolin-6-methylene) -3H-imidazo [4,5-b ] pyrazin-5-yl) - [4,7' ] bisquinoline (1-79),

4- (3- (7-fluoro-quinoline-6-methylene) -3H-imidazo [4,5-b ] pyrazin-5-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1-80),

7-fluoro-6- [6- (1,2,3, 6-tetrahydro-pyridin-4-yl) -imidazo [4,5-b ] pyrazin-1-ylidene ] -quinoline hydrochloride (1-81),

7-fluoro-6- (6- (2-fluoro-phenyl) -imidazo [4,5-b ] pyrazin-1-methylene) -quinoline (1-82),

7-fluoro-6- (6- (pyridin-3-yl) -imidazo [4,5-b ] pyrazin-1-methylidene) -quinoline (1-83),

6- (6- (3-chlorophenyl) -imidazo [4,5-b ] pyrazine-1-methylene) -7-fluoro-quinoline (1-84),

7-fluoro-6- (6- (naphthalen-1-yl) -imidazo [4,5-b ] pyrazin-1-methylidene) -quinoline (1-85),

6- (6-cyclopropyl-imidazo [4,5-b ] pyrazine-1-methylene) -7-fluoro-quinoline (1-86),

7-fluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-87),

4- (1- (1- (7-fluoro-quinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) aniline (1-88),

6- (1- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-fluoroquinoline (1-89),

7-fluoro-6- (1- (6-phenyl-imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-90),

7-fluoro-6- (1- (6- (pyridin-4-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-91),

2- (4- (1- (1- (7-fluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -1H-pyrazol-1-yl) -ethanol (1-92),

7-fluoro-6- (1- (6- (quinolin-3-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-93),

2-fluoro-4- (1- (1- (7-fluoroquinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -benzoic acid methyl ester (1-94),

2-fluoro-4- (1- (1- (7-fluoro-quinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -benzamide (1-95),

2-fluoro-4- (1- (1- (7-fluoroquinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -N-methylbenzamide (1-96),

4- (1- (1- (7-fluoroquinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -benzenesulfonamide (1-97),

7-fluoro-6- (1- (6- (pyrimidin-5-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-98),

4- (1- (1- (7-fluoroquinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -furan-2-methanol (1-99),

4- (1- (1- (7-fluoroquinolin-6-yl) -ethyl) -3H-imidazo [4,5-b ] pyrazin-6-yl) benzonitrile (1-100),

7-fluoro-6- (1- (6- (thiophen-2-yl) imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-101),

7-fluoro-6- (1- (6- (thiophen-3-yl) imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-102),

6- (1- (6- (benzo [ b ] thiophen-2-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -7-fluoroquinoline (1-103),

6- (1- (6- (benzo [ b ] thiophen-3-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -7-fluoroquinoline (1-104),

7-fluoro-6- (1- (6- (4-methylthiophenyl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline (1-105),

6- (1- (6- (1H-pyrrolo [2,3-b ] pyridin-5-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -7-fluoroquinoline (1-106),

5- (1- (1- (7-fluoro-quinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -N, N-dimethylpyridin-2-amine (1-107),

7-fluoro-6- (1- (6- (6-methyl-pyridin-3-yl) -imidazo [4,5-b ] pyrazin-1-yl) -ethyl) -quinoline; (1-108),

3- (1- (1- (7-fluoro-quinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -pyridin-2-amine (1-109),

5- (1- (1- (7-fluoro-quinolin-6-yl) -ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -pyridin-2-amine (1-110),

5,7 difluoro-6- ((6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-111),

6- ((6- (2, 6-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -5, 7-difluoroquinoline (1-112),

5, 7-difluoro-6- ((6- (1-naphthyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-113),

6- ((6- (2, 4-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -5, 7-difluoroquinoline (1-114),

5, 7-difluoro-6- ((6- (4- (trifluoromethoxy) phenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (1-115),

4- (1- ((5, 7-difluoroquinolin-6-yl) methyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -2-fluorobenzoic acid methyl ester (1-116),

6- ((6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -5, 7-difluoroquinoline (1-117),

5, 7-difluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-118),

5, 7-difluoro-6- (1- (6-phenyl-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-119),

5, 7-difluoro-6- (1- (6- (pyridin-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-120),

3- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -N, N-dimethylaniline (1-121),

5, 7-difluoro-6- (1- (6- (quinolin-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-122),

6- (1- (6- (2, 6-dimethylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-123),

6- (1- (6- (3-chlorophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-124),

6- (1- (6-cyclopropyl-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-125),

2- (4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -1H-pyrazol-1-yl) ethan-1-ol (1-126),

4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) aniline (1-127),

6- (1- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-128),

6- (1- (6- (7-chloroquinolin-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-129),

5, 7-difluoro-6- (1- (6- (pyridin-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -quinoline (1-130),

5, 7-difluoro-6- (1- (6- (5-methoxy-2-methylphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -quinoline (1-131),

5, 7-difluoro-6- (1- (6- (2-fluorophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -quinoline (1-132),

6- (1- (6- (3-chlorophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-133),

6- (1- (6- (2, 6-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-134),

5, 7-difluoro-6- (1- (6- (1-naphthyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-135),

6- (1- (6- (2, 4-dimethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-136),

5, 7-difluoro-6- (1- (6- (4-trifluoromethoxyphenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-137),

4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -2-fluorobenzoic acid methyl ester (1-138),

4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -2-fluoro-N-methylbenzamide (1-139),

4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -2-fluoro-benzamide (1-140),

5, 7-difluoro-6- (1- (6- (4-methylthiophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-141),

5, 7-difluoro-6- (1- (6- (1- (benzenesulfonyl) -1H-indol-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-142),

6- (1- (6- (benzo [ b ] thiophen-2-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (1-143),

5, 7-difluoro-6- (1- (6- (pyrimidin-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-144),

5, 7-difluoro-6- (1- (6- (3-thienyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-145),

4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzonitrile (1-146),

7-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-147),

7-methyl-6- (1- (6- (3-quinolyl) -1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-148),

N, N-dimethyl-3- (1- (1- (7-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) aniline (1-149),

7-methyl-6- (1- (6- (4-pyridyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-150),

6- (1- (6- (2-fluorophenyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-methylquinoline (1-151),

Methyl 2-fluoro-4- (1- (1- (7-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzoate (1-152),

2-fluoro-4- (1- (1- (7-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzamide (1-153),

2-fluoro-N-methyl-4- (1- (1- (7-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzamide (1-154),

5-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-155),

5-methyl-6- (1- (6- (4-pyridyl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-156),

5-methyl-6- (1- (6- (1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-157),

2- (4- (1- (1- (5-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl-1H-pyrazol-1-yl) ethan-1-ol (1-158),

Methyl 2-fluoro-4- (1- (1- (5-methylquinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzoate (1-159),

5-methyl-6- (1- (6- (3-quinolyl) -1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-160),

3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (4-methylpiperazin-1-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-161),

3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (piperazin-1-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-162),

Methyl 2-fluoro-4- (1- (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) benzoate (1-163),

6- (1- (6- (1H-indol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (1-164),

4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H-imidazo [4,5-b ] pyrazin-6-yl) -2-fluorobenzoic acid methyl ester (1-165),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (quinolin-3-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-166),

6- (1- (6- (1H-indol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (1-167),

5, 7-difluoro-6- (1- (6- (isoquinolin-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (1-168),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (quinolin-7-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-169),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-170),

Ethyl 3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) -3H-imidazo [4,5-b ] pyrazine-5-carboxylate (1-171),

7-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (1-172),

3- (1-methyl-1H-4-pyrazolyl) -6- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazinylmethyl) quinoline (2-1),

3-phenyl-6- (6-phenyl- [1,2,3] triazolo [4,5-b ] pyrazinylmethyl) quinoline (2-2),

6- (6- (quinolin-3-yl) - [1,2,3] triazolo [4,5-b ] pyrazinylmethyl) - [3, 3' ] biquinoline (2-3),

3- (pyridin-4-yl) -6- (6- (pyridin-4-yl) - [1,2,3] triazolo [4,5-b ] pyrazinylmethyl) quinoline (2-4),

Methyl 2-fluoro-4- (6- (6- (3-fluoro-4-methoxycarbonylphenyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazinylmethyl) quinolin-3-yl) benzoate (2-5),

7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) quinoline (2-6),

7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) quinoline (2-7),

2- (4- (3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinolin-6-yl) ethyl) -3H- [1,2,3] triazolo [4,5-b ] pyrazin-5-yl) pyrazolyl) ethanol (2-8),

7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (pyridin-4-yl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) quinoline (2-9),

7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (quinolin-3-yl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) quinoline (2-10),

7-fluoro-6- (1- (6- (isoquinolin-4-yl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) -3- (1-methyl-1H-4-pyrazolyl) quinoline (2-11),

7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (4-methylthiophenyl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) quinoline (2-12),

6- (1- (6- (benzo [ b ] thiophen-3-yl) - [1,2,3] triazolo [4,5-b ] pyrazinyl) ethyl) -7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinoline (2-13),

2-fluoro-4- (3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinolyl) ethyl) -3H- [1,2,3] triazolo [4,5-b ] pyrazin-5-yl) methyl benzoate (2-14),

2-fluoro-4- (3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinolin-6-yl) ethyl) -3H- [1,2,3] triazolo [4,5-b ] pyrazin-5-yl) -N-methylbenzamide (2-15),

2-fluoro-4- (3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinolin-6-yl) ethyl) -3H- [1,2,3] triazolo [4,5-b ] pyrazin-5-yl) benzamide (2-16),

3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-17),

2-fluoro-N-methyl-4- (1- (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) benzamide (2-18),

2-fluoro-4- (1- (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) benzamide (2-19),

6- (1- (6- (benzo [ b ] thiophen-3-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-20),

6- (1- (6- (benzo [ b ] thiophen-2-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-21),

3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (thiophen-3-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-22),

6- (1- (6- (furan-2-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-23),

3- (4-fluorophenyl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-24),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-25),

6- (1-6- (1H-indol-5-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-26),

Methyl 4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) -2-fluorobenzoate (2-27),

5, 7-difluoro-6- (1- (6- (isoquinolin-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-28),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (quinolin-7-yl) -1H- [1,2,3] triazolo [41,5-b ] pyrazin-1-yl) ethyl) quinoline (2-29),

5- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) -N, N-dimethylpyridin-2-amine (2-30),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (4-methylthiophenyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-31),

5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (thiophen-3-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (2-32),

5, 7-difluoro-6- (1- (6- (2-fluoropyridin-3-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-33),

3- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) pyridin-2-amine (2-34),

6- (1- (6- (benzo [ b ] thiophen-2-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-35),

6- (1- (6- (benzo [ b ] thiophen-3-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-36),

5, 7-difluoro-6- (1- (6- (furan-2-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (2-37),

4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) -2-fluoro-N-methylbenzamide (2-38),

4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) aniline (2-39),

4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) benzenesulfonamide (2-40),

4- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) -2-fluorobenzamide (2-41),

5- (1- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-6-yl) thiophene-2-carbonitrile (2-42),

Or 2-fluoro-N-methyl-4- (7- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-ylmethyl) imidazo [1,2-b ] [1,2,4] triazin-2-yl) benzamide (3-1).

The invention also provides a preparation method of the quinoline compound shown in the formula 1, and pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, which comprises the following steps: in a solvent, carrying out Suzuki coupling reaction on the compound II and boric acid or boric acid ester to obtain a compound 1;

wherein, X is halogen (preferably chlorine, bromine or iodine); cy, X ₁ 、X ₂ 、X ₃ 、R ₁ 、R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The method for preparing compound 1, which is a conventional method in the art for performing Suzuki coupling reaction, is particularly preferred in the present invention for the following reaction conditions:

in the method for preparing the compound 1, the solvent is preferably water and/or a water-soluble organic solvent; the water-soluble organic solvent is preferably one or more of dioxane, tetrahydrofuran and N, N-Dimethylformamide (DMF).

In the method for producing the compound 1, the volume-to-mass ratio of the solvent to the compound II is preferably 100 to 500mL/g, and more preferably 200 to 400 mL/g.

In the method for preparing the compound 1, the boric acid or the boric acid ester is preferably a compound shown as a formula 6

Wherein R is ₁₇ Is hydrogen、C _1-6 Alkyl of (2) or

Wherein C is ₂ -C ₆ Represents an alkylene group; when p is 1, R ₁₇ Is composed of

When p is 2, R ₁₇ Is hydrogen or C _1-6 Alkyl group of (1).

In the method for preparing the compound 1, the molar ratio of the compound II to the boric acid or boric acid ester is preferably 1:1 to 1:3, and more preferably 1:1.2 to 1: 1.8.

In the method for preparing the compound 1, the temperature of the Suzuki coupling reaction may be a temperature ranging from the freezing point of the solvent to the boiling point of the solvent, preferably 90 to 150 ℃, and more preferably 100 to 120 ℃.

In the method for preparing the compound 1, the progress of the Suzuki coupling reaction can be determined by using a conventional test method in the field (such as nuclear magnetic resonance, infrared spectroscopy, spectrophotometry or mass spectrometry, HPLC or TLC), and taking disappearance of the compound II as a reaction endpoint, wherein the reaction time is preferably 2h to 10h, and further preferably 2.5h to 4 h.

In the process for preparing compound 1, said compound II can be prepared by a process comprising the steps of: reacting the compound III with carboxylic acid or ortho-carboxylic ester to obtain a compound II;

then preparing the compound 1 according to the method for preparing the compound 1; wherein, X, Cy, X ₁ 、X ₂ 、X ₃ 、R ₁ 、R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for the preparation of compound II, which is a conventional process in the art for carrying out such reactions, is particularly preferred in the present invention for the following reaction conditions:

in the process for preparing compound II, the carboxylic acid or orthocarboxylic ester serves as both a reaction reagent and a reaction solvent.

In the process for preparing compound II, the carboxylic acid or ester is preferably one or more of methyl orthoformate, ethyl orthoformate and methyl diethoxyacetate.

In the process for producing the compound II, the volume-to-mass ratio of the carboxylic acid or orthocarboxylic ester to the compound III is preferably 20 to 100mL/g, more preferably 40 to 80 mL/g.

In the process for preparing the compound II, the temperature of the reaction may be a temperature varying from the freezing point of the solvent to the boiling point of the solvent, preferably 120 to 180 ℃, and more preferably 140 to 160 ℃.

In the method for preparing the compound II, the progress of the reaction can be determined by a conventional test method in the field (such as nuclear magnetic resonance, infrared spectroscopy, spectrophotometry or mass spectrometry, HPLC or TLC), and the disappearance of the compound III is taken as a reaction endpoint, and the reaction time is preferably 15h to 30h, and further preferably 20h to 25 h.

In the process for preparing compound II, said compound III can be prepared by a process comprising the steps of: in a solvent, carrying out nucleophilic substitution reaction on a compound V or an acid salt thereof and a compound IV to obtain a compound III;

then preparing a compound II according to the method for preparing the compound II, and preparing a compound 1 according to the method for preparing the compound 1; wherein, X, X ₁ 、X ₂ 、X ₃ 、R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing compound III, which is a conventional process in the art for carrying out such nucleophilic substitution reactions, is particularly preferred in the present invention for the following reaction conditions:

in the process for producing compound III, the solvent is preferably a solvent having a boiling point of more than 130 ℃, and more preferably one or more of N, N-Dimethylformamide (DMF), N-Diethylformamide (DEF) and N-methylpyrrolidone

In the method for preparing the compound III, the volume-to-mass ratio of the solvent to the compound IV is preferably 10mL/g to 50mL/g, and more preferably 20mL/g to 30 mL/g.

In the process for preparing compound III, the molar ratio of compound V to compound IV is preferably 1: 1-1: 3, preferably 1: 1.2-1: 1.6.

In the process for preparing compound III, the temperature of the reaction may be varied from the freezing point of the solvent to the boiling point of the solvent, preferably from 150 ℃ to 250 ℃, more preferably from 190 ℃ to 210 ℃.

In the process for preparing compound III, the progress of the reaction can be determined by conventional testing methods in the art (such as nuclear magnetic resonance, infrared spectroscopy, spectrophotometry or mass spectrometry, HPLC or TLC), with disappearance of compound IV as the end point of the reaction, preferably for 20h to 30h, more preferably for 18h to 25 h.

The preparation of compounds may involve the protection and deprotection of multiple chemical groups. The need for protection and deprotection, and the choice of an appropriate protecting group, can be readily determined by those skilled in the art, and the chemistry of the protecting group is found, for example, in Greene et al, Protective Groups in Organic Synthesis, second edition, Wiley & Sons,1991, which is incorporated herein by reference in its entirety.

In the process for preparing compound III, the compound V can be prepared by the method 1 or the method 2, when L is

When L is

When, the method 2 is preferably employed;

the method comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound VI and hydrogen to obtain a compound V;

then preparing a compound III according to the method for preparing the compound III, preparing a compound II according to the method for preparing the compound II, and preparing a compound 1 according to the method for preparing the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The method 2 comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound VIII and hydrogen to obtain a compound V;

Method 1 for preparing compound V may be a conventional method in the art for such reduction reactions, and the following reaction methods and conditions are particularly preferred in the present invention:

process 1 for preparing compound V is preferably carried out in the presence of ammonia, which preferably takes part in the reaction in the form of an ammonia-alcohol solution.

The method 1 for preparing the compound V is preferably carried out in the presence of Raney nickel (Raney Ni), wherein the Raney nickel can be a conventional commercially available Raney nickel reagent, the mass percent of the Raney nickel is preferably 20-80%, and the mass percent refers to the mass percent of the nickel in the total mass of the Raney nickel reagent.

In the method 1 for preparing the compound V, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably methanol and/or ethanol.

In the process 1 for producing the compound V, the pressure of the reduction reaction is preferably 10 to 50bar, more preferably 20 to 30 bar.

In the method 1 for producing the compound V, the temperature of the reduction reaction is preferably 10 to 40 ℃.

In Process 1 for the preparation of Compound V, the progress of the reduction can be monitored by methods customary in the art (e.g., TLC, HPLC or NMR), generally by the end of the reaction when compound VI has disappeared, preferably for a period of from 1 hour to 48 hours.

In Process 1 for preparing Compound V, said Compound VI can be prepared by: carrying out nucleophilic substitution reaction on a compound VII and zinc cyanide in an organic solvent in the presence of a catalyst under the protection of gas to obtain a compound VI;

preparing a compound V according to the method 1 for preparing the compound V, preparing a compound III according to the method for preparing the compound III, preparing a compound II according to the method for preparing the compound II, and preparing the compound 1 according to the method for preparing the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing compound VI may be a conventional process for such nucleophilic substitution in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound VI, the organic solvent is preferably an amide-based solvent, and the amide-based solvent is preferably N, N-dimethylformamide.

In the process for preparing compound VI, the catalyst is preferably tris (dibenzylideneacetone) dipalladium and 1,1' -bis (diphenylphosphino) ferrocene.

In the method for preparing the compound VI, the molar ratio of the zinc cyanide to the compound VII is preferably 1-5, and more preferably 1-2.

In the method for preparing the compound VI, the molar ratio of the catalyst to the compound VII is preferably 0.1-1.

In the method for preparing the compound VI, when tris (dibenzylideneacetone) dipalladium and 1,1 '-bis (diphenylphosphino) ferrocene are used as catalysts, the molar ratio of the 1,1' -bis (diphenylphosphino) ferrocene to the tris (dibenzylideneacetone) dipalladium is preferably 2-3.

In the process for preparing compound VI, the temperature of the nucleophilic substitution reaction is preferably 80 ℃ to 150 ℃.

In the process for preparing compound VI, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (e.g., TLC, HPLC or NMR), and the reaction time is preferably 1 to 48 hours, more preferably 10 to 24 hours, with the disappearance of compound VII being generally used as the reaction end point.

In the process for preparing compound VI, said compound XII can be prepared by: in a solvent, carrying out condensation reaction on a compound XII and a compound XIII in the presence of sulfuric acid and a catalyst to obtain a compound VII;

preparing a compound VI according to the method for preparing the compound VI, preparing the compound V according to the method 1 for preparing the compound V, preparing the compound III according to the method for preparing the compound III, preparing the compound II according to the method for preparing the compound II, and preparing the compound 1 according to the method for preparing the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing the compound VII may be a conventional process for such condensation in the art, and the following reaction methods and conditions are particularly preferred in the present invention:

in the process for preparing compound VII, the solvent is preferably water.

In the method for preparing the compound VII, the catalyst is preferably sodium 3-nitrobenzenesulfonate.

In the method for preparing the compound VII, the molar ratio of the compound XIII to the compound XII is preferably 1-5, and more preferably 2-3.

In the method for preparing the compound VII, the molar ratio of the catalyst to the compound VII is preferably 1-3, and more preferably 1-1.5.

In the method for preparing the compound VII, the molar ratio of the sulfuric acid to the compound XII is preferably 0.5-2. The sulfuric acid can be a conventional commercially available sulfuric acid reagent in the field, and the mass percentage concentration of the sulfuric acid is preferably 30-98%, and the mass percentage concentration refers to the mass percentage of the sulfuric acid in the total mass of the sulfuric acid aqueous solution.

In the process for preparing the compound VII, the temperature of the condensation reaction is preferably 80 ℃ to 150 ℃.

In the process for preparing the compound VII, the progress of the nucleophilic substitution reaction can be monitored by a conventional test method in the art (such as TLC, HPLC or NMR), and the reaction time is preferably 1 to 48 hours, more preferably 10 to 24 hours, with the disappearance of the compound VII being generally used as the reaction end point.

Method 2 for preparing compound V may be a conventional method in the art for such reduction reactions, and the following reaction methods and conditions are particularly preferred in the present invention:

process 2 for preparing compound V is preferably carried out in the presence of ammonia, which preferably takes part in the reaction in the form of an ammonia-alcohol solution.

The method 2 for preparing the compound V is preferably carried out in the presence of Raney nickel (Raney Ni), wherein the Raney nickel can be a conventional commercially available Raney nickel reagent, the mass percent of the Raney nickel is preferably 20-80%, and the mass percent refers to the mass percent of the nickel in the total mass of the Raney nickel reagent.

In the method 2 for preparing the compound V, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably methanol and/or ethanol.

In the method 2 for producing the compound V, the temperature of the reduction reaction is preferably 10 to 40 ℃.

In method 2 for preparing compound V, the progress of the reduction reaction can be monitored by a conventional test method in the art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when compound VIII disappears, with the reaction time preferably being 1 to 48 hours.

In Process 2 for preparing Compound V, said Compound VIII can be prepared by: in an organic solvent, carrying out condensation reaction on hydroxylamine and a compound IX to obtain a compound VIII;

preparing a compound V according to the method 2 for preparing the compound V, preparing a compound III according to the method for preparing the compound III, preparing a compound II according to the method for preparing the compound II, and preparing a compound 1 according to the method for preparing the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing the compound VIII can be a conventional process for such condensation in the art, and the following reaction method and conditions are particularly preferred in the present invention:

in the method for preparing the compound VIII, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably methanol and/or ethanol.

In the process for producing the compound VIII, the hydroxylamine may be used in the form of its hydrochloride, and when the hydrochloride of hydroxylamine is used, it is preferable to first react the hydrochloride of hydroxylamine with a base, preferably an inorganic base, preferably strong sodium oxide, to obtain hydroxylamine, and then to perform a condensation reaction.

In the method for preparing the compound VIII, the molar ratio of the hydroxylamine to the compound IX is preferably 1 to 5, and more preferably 1 to 2.

In the process for preparing the compound VIII, the temperature of the condensation reaction is preferably 10 ℃ to 40 ℃.

In the process for preparing the compound VIII, the progress of the condensation reaction can be monitored by a conventional test method in the art (for example, TLC, HPLC or NMR), and the reaction time is generally 1 to 48 hours, more preferably 10 to 24 hours, with the disappearance of the compound IX as a reaction end point.

In the method for preparing the compound VIII, the compound IX can be prepared by the following method: under the protection of gas, reacting a compound X with methyl magnesium bromide in an organic solvent to obtain a compound IX;

preparing a compound VIII according to the method for preparing the compound VIII, preparing the compound V according to the method for preparing the compound V, preparing the compound III according to the method for preparing the compound V, preparing the compound II according to the method for preparing the compound III, and preparing the compound 1 according to the method for preparing the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing compound IX may be a conventional process in this type of reaction in the art, and the following reaction processes and conditions are particularly preferred in the present invention:

in the process for preparing compound IX, the "gas" as described in said "gas shield" is preferably one or more of helium, argon, neon and nitrogen.

In the method for preparing the compound IX, the organic solvent is preferably an ether solvent, and the ether solvent is preferably tetrahydrofuran.

In the method for preparing the compound IX, the molar ratio of the methyl magnesium bromide to the compound X is preferably 1 to 3, and more preferably 1 to 1.5.

In the process for preparing compound IX, the temperature of the reaction is preferably from 0 ℃ to 40 ℃.

In the process for preparing compound IX, the progress of the reaction can be monitored by a conventional test method in the art (e.g., TLC, HPLC or NMR), and the reaction time is preferably 1 hour to 48 hours, more preferably 10 hours to 24 hours, with the disappearance of compound X as a reaction end point.

In the process for preparing compound IX, said compound X can be prepared by the following method: under the protection of gas, in an organic solvent and in the presence of a catalyst, reacting a compound XI with dimethylhydroxylamine hydrochloride to obtain a compound X;

then preparing the compound IX according to the method for preparing the compound IX, the method for preparing the compound VIII to prepare the compound VIII, the method for preparing the compound V to prepare the compound V, the method for preparing the compound III to prepare the compound III, the method for preparing the compound II to prepare the compound II, and the method for preparing the compound 1 to prepare the compound 1; wherein, X, R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The process for preparing compound X may be a conventional process of such reactions in the art, and the following reaction processes and conditions are particularly preferred in the present invention:

in the process for producing compound X, the "gas" as described in said "gas shield" is preferably one or more of helium, argon, neon and nitrogen.

In the method for producing compound X, the organic solvent is preferably an amide-based solvent, and the amide-based solvent is preferably N, N-dimethylformamide.

In the method for preparing the compound X, the molar ratio of the dimethylhydroxylamine hydrochloride to the compound XI is preferably 1 to 3, and more preferably 1 to 1.5.

In the method for preparing the compound X, the catalyst is preferably 2- (7-azobenzene triazole-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU).

In the method for preparing the compound X, the molar ratio of the catalyst to the compound XI is preferably 1-3, and more preferably 1-1.5.

In the process for producing compound X, the reaction temperature is preferably 0 ℃ to 40 ℃.

In the process for preparing compound X, the progress of the reaction can be monitored by a conventional test method in the art (e.g., TLC, HPLC or NMR), and the reaction time is preferably 1 to 48 hours, more preferably 10 to 24 hours, with the disappearance of compound XI as a reaction end point.

In the present invention, said compound I can be prepared by route one or two,

route one:

and a second route:

wherein, X, X ₁ 、X ₂ 、X ₃ 、R ₁ 、R ₂ 、R ₃ 、R ₄ L and A are as defined above.

The invention also provides an intermediate compound II, a compound III or a compound V for preparing the compound 1,

The present invention also provides a process for the preparation of said compound II, preferably using route a or route B,

route a:

route B:

wherein, X, X ₁ 、X ₂ 、X ₃ 、R ₁ 、R ₂ 、R ₃ 、R ₄ L and A are as defined above; the specific reaction conditions of each step are the same as those described above.

The present invention also provides a process for the preparation of said compound III, preferably using route C or route D,

route C:

route D:

The present invention also provides a process for the preparation of said compound V, preferably according to scheme E or scheme F:

route E:

route F:

The invention also provides the application of the quinoline compound shown in the formula 1, pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof in preparing a medicament for treating and/or preventing diseases related to the expression or activity of tyrosine kinase C-Met.

The invention also provides a pharmaceutical composition which contains the quinoline compound shown as the formula 1, and pharmaceutically acceptable salts, solvates, metabolites, metabolic precursors or prodrugs thereof, and one or more pharmaceutically acceptable pharmaceutic adjuvants.

In the invention, the content of the quinoline compound shown as the formula 1, the pharmaceutically acceptable salt, the solvate, the metabolite, the metabolic precursor or the prodrug thereof in the pharmaceutical composition is a therapeutically effective amount, and the preferred mass percentage content is 1-99%; the mass percentage of the quinoline compound, the pharmaceutically acceptable salt, the solvate, the metabolite, the metabolic precursor and/or the prodrug thereof is represented by formula 1, and accounts for the total mass of the pharmaceutical composition. The sum of the mass fractions of the components of the pharmaceutical composition is 100%; the sum of the mass percentages of the components in the pharmaceutical composition is 100%.

In the invention, the pharmaceutical adjuvant is a conventional pharmaceutical adjuvant in the field, the selection of which varies with the administration route and the action characteristics, and preferably comprises a filler, a diluent, an adhesive, a wetting agent, a disintegrating agent, a lubricant, an emulsifier and a suspending agent.

In the present invention, the pharmaceutical composition may be administered by oral, injectable (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, urethral, vaginal, nasal, inhalational or topical routes. The preferred route is oral.

The invention also provides application of the pharmaceutical composition in preparing a medicament for treating and/or preventing diseases related to expression or activity of tyrosine kinase C-Met.

In the present invention, the diseases related to the expression or activity of tyrosine kinase C-Met are diseases caused by the change of tyrosine kinase C-Met, which are conventional in the art, and preferably comprise cancers, musculoskeletal sarcoma, soft tissue sarcoma, hematopoietic malignant tumors and other tumors. The cancer preferably comprises bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer and thyroid cancer; said musculoskeletal sarcoma preferably comprises: osteosarcoma, synovial sarcoma, and rhabdomyosarcoma; the soft tissue sarcoma preferably comprises: malignant fibrosarcoma/fibrosarcoma, leiomyosarcoma, and kaposi's sarcoma; the hematopoietic malignancy preferably comprises: multiple myeloma, lymphoma, adult T-cell leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia; said other tumors preferably include: glioblastoma, astrocytoma, melanoma, mesothelioma and embryonal carcinosarcoma.

Certain chemical or pharmaceutical terms:

unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications cited throughout this application are incorporated herein by reference in their entirety unless otherwise indicated.

Can be found in the reference (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4) ^TH ED. "Vols.A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terminology used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry is known in the art. The present application uses standard techniques in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, instructions for use of the kit by the manufacturer may be used, or may be followedThe reaction and purification are carried out in a manner known per se or as described in the present invention. The described techniques and methods can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

In the present invention, the term "C _1～4 "means that the group is defined as having 1 to 4 carbon atoms in the group, i.e., the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. For example, "C _1～4 The "alkyl group" means an alkyl group having 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The meaning of other terms described in a similar manner, such as "C", can be inferred therefrom _1～6 "and the like.

In the present invention, the term "6 to 10 membered" means that the number of atoms surrounding the closed ring skeleton itself in a closed ring system group (e.g., an aromatic ring, an aryl group, a heteroaryl group, a heteroaromatic ring, a cycloalkyl group, a heterocycloalkyl group, a heterocycloalkenyl group, etc.) defined by the term is 6, 7, 8, 9 or 10. The number may be varied depending on the number of rings of the closed ring system group, the degree of saturation, the nature of the atoms constituting the ring, and the like. The meaning of other terms described in a similar manner, such as "7-10 yuan" or the like, can be inferred.

In the present invention, the term "aromatic ring" or "aryl group" means an optionally substituted cyclic conjugated aromatic hydrocarbon group having 6 to 18 ring-forming carbon atoms, and may include monocyclic, bicyclic, tricyclic or higher rings. The remainder of the compound molecule may be attached to a carbon atom on the aryl ring by a single bond. When an aryl group is substituted, the substituent may be substituted at any available point of attachment. For the purposes of the present invention, aryl groups of 6 to 10-membered monocyclic or bicyclic ring systems, such as phenyl or naphthyl, are preferred.

As used herein, the term "heteroaromatic ring", "heteroaromatic ring" or "heteroaryl" refers to an optionally substituted conjugated aromatic ring system group consisting of carbon atoms and heteroatoms, including from about 5 to about 12 backbone ring atoms, wherein one or more (e.g., 1-6, 1-4, 1-3, 1-2) ring atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. Any ring-forming nitrogen atoms in the heteroaromatic ring may be oxidized to form a nitroxide component. In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other. The remainder of the compound molecule may be attached to a carbon or heteroatom of the heteroaromatic ring by a single bond. For example, an imidazole may be attached to the parent molecule through any of its carbon atoms (imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl) or a nitrogen atom (imidazol-1-yl or imidazol-3-yl). The heteroaromatic ring includes monocyclic and polycyclic (e.g., having 2,3 or 4 rings fused to each other) systems. For the purpose of the present invention, a monocyclic heteroaromatic ring or a fused heteroaromatic ring which is 5 to 10-membered and contains 1 to 2 heteroatoms selected from N, S and O is preferable, wherein the fused heteroaromatic ring is preferably a 7 to 10-membered bicyclic ring system, and atoms which may be shared between both rings include heteroatoms.

In the present invention, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, and may include a fused ring system, bridged ring system or spiro ring system, generally having 3 to 15 carbon atoms. It may be attached to the rest of the molecule by a single bond via any suitable carbon atom on the ring. Generally, examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. For the purposes of the present invention, cycloalkyl radicals of monocyclic ring systems having 3 to 6 carbon atoms are preferred.

In the present invention, the term "heterocycloalkyl" refers to a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, which may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also include fused, bridged or spiro ring systems. It may be attached to the rest of the molecule by a single bond via any suitable carbon or heteroatom in the ring. Wherein the nitrogen atom may be optionally further substituted with other groups to form tertiary or quaternary amine structures. In general, examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, tetrahydrofuryl, dioxolanyl, oxocyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazinyl, N-substituted homopiperazinyl, piperidinyl, N-substituted piperidinyl, dioxanyl, indolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, and the like. For the purposes of the present invention, preference is given to heterocyclic radicals of 3-to 6-membered monocyclic ring systems which contain at least 1 heteroatom from the group consisting of nitrogen, oxygen or sulfur.

As used herein, the term "cycloalkenyl" refers to an aliphatic cyclic group consisting of only carbon and hydrogen atoms containing a carbon-carbon double bond, which may include monocyclic or polycyclic systems, typically containing from 4 to 12 carbon atoms. For the purposes of the present invention, cycloalkenyl groups of 5 to 6 membered monocyclic systems are preferred.

As used herein, the term "heterocycloalkenyl" refers to an aliphatic cyclic group containing a carbon-carbon double bond consisting of 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, which may include monocyclic or polycyclic ring systems. For the purpose of the present invention, a 5 to 6-membered heterocyclic alkenyl group having a monocyclic ring system containing a nitrogen atom is preferable.

The term "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

In the present invention, the term "subject", "patient" or "individual" refers to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

In the present invention, the term "treating" and other similar synonyms include alleviating, alleviating or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating or preventing the underlying metabolic cause of the symptom, inhibiting the disease or disorder, e.g., arresting the development of the disease or disorder, alleviating the disease or disorder, ameliorating the disease or disorder, alleviating a symptom caused by the disease or disorder, or halting a symptom of the disease or disorder, and further, the term includes the purpose of prophylaxis. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the patient's condition is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.

As used herein, an "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refers to an amount of at least one agent or compound that is sufficient to alleviate, to some extent, one or more of the symptoms of the disease or condition being treated when administered. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

In the present invention, the terms "administering", "administration" and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Administration techniques useful in The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the term "acceptable" or "pharmaceutically acceptable" means having no long-term deleterious effect on the general health of the subject being treated.

In the present invention, the term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical ingredient, including but not limited to carriers, excipients and/or auxiliaries, such as stabilizers, diluents, dispersants, suspending agents, thickeners and the like.

In the present invention, the term "carrier" refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acid and free base of the specified compound, and that are not biologically or otherwise undesirable. The compounds of the present invention also include pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to the form in which the base group in the parent compound is converted to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. Pharmaceutically acceptable salts of the present invention may be synthesized from the parent compound by reacting a basic group in the parent compound with 1 to 4 equivalents of an acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical sciences, 17 ^th ed.,Mack Publishing CCompany, Easton, Pa.,1985, p.1418 and Journal of Pharmaceutical Science,66,2 (1977). Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Inorganic acids from which acid addition salts are derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which acid addition salts are derived include acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.

In the present invention, the term "solvate" refers to a combination of a compound of the present invention formed by solvation with a solvent molecule. In some cases, a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule.

In the present invention, the term "stereoisomer" refers to a compound composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The compounds of formula 1 described herein encompass a variety of possible optical isomers, cis-trans isomers, and mixtures thereof.

In the present invention, the term "tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds of formula 1 described herein encompass a variety of possible tautomers and mixtures thereof.

In the present invention, the term "polymorph" or "polymorph" refers to a compound of the invention in different crystal lattice forms.

The term "metabolite" or "metabolite" as used herein refers to a compound produced by in vivo biotransformation, such as functionalization reactions (I-phase biotransformation reactions, including oxidation, reduction, hydrolysis, etc.) and conjugation reactions (II-phase biotransformation reactions), under the action of enzymes after the compound of the present invention is absorbed by the body. For example, cytochrome P450 catalyzes a variety of redox reactions, while uridine diphosphate glucuronosyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. For more information on metabolism, see The Pharmacological Basis of Therapeutics,9th Edition, McGraw-Hill (1996).

In the present invention, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention, which is generally inactive, but which can be converted under in vivo physiological conditions to the parent compound of the invention, which is biologically active. The properties of the parent compound in terms of solubility, histocompatibility or pharmacokinetics may generally be improved.

In the present invention, the terms "pharmaceutical combination", "administering other treatment", "administering other therapeutic agent" and the like refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the administration of at least one compound described herein and at least one synergistic formulation to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapy, e.g. administering three or more active ingredients.

As used herein, the terms "co-administration," "administration in combination with … …," and synonyms thereof, refer to the administration of a selected therapeutic agent to the same patient and are intended to encompass therapeutic strategies in which the agents are administered by the same or different routes of administration or the same or different numbers of administrations. In some embodiments, the compounds described herein are administered in combination with other agents. These terms encompass the administration of two or more agents to an animal such that the agents and/or metabolites thereof are present simultaneously within the animal. These terms encompass the simultaneous administration of different compositions, the administration of different compositions at different times and/or the administration of one composition containing different active ingredients. Thus, in some embodiments, the compounds of the present invention and other agents are administered in admixture in one composition.

The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.

The room temperature in the present invention means an ambient temperature of 10 to 30 ℃.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the invention provides an imidazopyrazine compound completely different from the prior art, a preparation method, a pharmaceutical composition and application thereof. The imidazopyrazine compound has good inhibition effect on tyrosine kinase C-Met, and can be used for preventing, treating or adjunctively treating various diseases related to expression or activity of tyrosine kinase C-Met.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The reagents and starting materials used in the invention are commercially available except where specifically indicated.

Synthesis of intermediate quinolinamines

An intermediate A:

synthesis step 1: 6-cyanoquinoline (A-2)

6-bromoquinoline A-1(10.4g, 50mmol), zinc cyanide (8.8g, 75mmol), tris (dibenzylideneacetone) dipalladium (2.3g, 2.5mmol) and 1,1' -bis (diphenylphosphino) ferrocene (2.8g, 5mmol) were added to DMF (100mL) and heated to 130 ℃ under argon for 16 h. Cooling the reaction solution, adding into water (1L) while stirring, extracting with ethyl acetate (200 mL. times.3), combining ethyl acetate phases, washing with water, washing with saturated saline, drying, and purifying by column chromatography to obtain 6g of off-white solid compound A-2, with yield: 77% HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝155； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.07(dd,J ₁ ＝4.2Hz,J ₂ ＝1.5Hz,1H),8.25-8.19(m,3H),7.88(dd,J ₁ ＝8.7Hz,J ₂ ＝1.7Hz,1H),7.56(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)。

And a synthesis step 2: quinoline-6-methylene amine (A)

6-Cyanoquinoline A-2(4.7g, 30mmol) was dissolved in methanolic ammonia (7mol/L, 50mL) and reduced by hydrogenation using a hydrogenator H-cube (30bar, 25 ℃, flow rate 1mL/min, Raney Ni) to give the crude product, which was isolated in reverse phase to give 3.8g of quinoline-6-methyleneamine A, yield: 79% HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝159； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.84(dd,J ₁ ＝4.2Hz,J ₂ ＝1.3Hz,1H),8.28(d,J＝8.2Hz,1H),7.96(d,J＝8.6Hz,1H),7.88(s,1H),7.76(d,J＝8.6Hz,1H),7.48(dd,J ₁ ＝8.2Hz,J ₂ ＝4.2Hz,1H),3.97(s,2H)。

An intermediate B:

synthesis step 1: N-methoxy-N-methylquinoline-6-carboxamide (B-2)

Quinoline-6-carboxylic acid B-1(5g, 29mmol) was dissolved in anhydrous DMF (60mL), 2- (7-azobenzene benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (12.9g, 34mmol) and dimethylhydroxylamine hydrochloride (3.3g, 34mmol) were added under nitrogen protection, and the mixture was stirred at room temperature overnight. Dichloromethane (80mL) and water (80mL) were added to separate the organic phase, the aqueous phase was extracted with dichloromethane (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. times.2), and dried. Evaporation to dryness gave 4.6g of compound B-2 as a colorless oily liquid, yield: 74.5 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝217。

And 2, synthesis step: 6-quinolinone (B-3)

N-methoxy-N-methylquinoline-6-carboxamide B-2(6.1g, 28mmol) was dissolved in anhydrous THF (60mL) cooled in an ice bath to 0 deg.C and 3M methylmagnesium bromide (10mL) was added under nitrogen. The ice bath was removed and stirred at room temperature overnight. To the reaction mixture was slowly added a saturated aqueous ammonium chloride solution (12mL), and ethyl acetate (50mL)) And water (30mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution (50 mL. times.2) and dried. Evaporation to dryness gave 4.4g of pale yellow solid compound B-3, yield: 91.8 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝172。

And a synthesis step 3: 1- (quinolin-6-yl) ethanone oxime (B-4)

Hydroxylamine chloride (3.1g, 44.9mmol) and sodium hydroxide (1.7g, 44.9mmol) were dissolved in ethanol (100mL), stirred at room temperature for 1h, and the solid was filtered off. The filtrate was added to a solution of 6-quinolinemethone B-3(5.1g, 29.96mmol) in ethanol. The reaction was stirred overnight at room temperature. The solvent was distilled off to obtain 5.6g of a white solid compound B-4, yield: 99% and directly used in the next reaction without purification.

And 4, synthesis: 1- (quinolin-6-yl) ethylamine (B)

1- (Quinolinyl) ethanone oxime B-4(5.6g, 30.1mmol) was dissolved in ethanol (200mL) and a solution of ammonia in methanol (7mol/L, 13mL) and Rany nickel (alias Raney nickel or RanyNi) (3g) were added at room temperature. The mixture was stirred overnight at room temperature after hydrogenation, and the solid was filtered off. The filtrate was evaporated to dryness to obtain 9.7g of compound B, yield: 99% HPLC>96％。LC-MS(ESI)：[M+H] ⁺ ＝173； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.95-8.79(m,1H)，8.08(dd,J ₁ ＝22Hz,J ₂ ＝8.4Hz,2H)，7.82-7.64(m,2H)，7.36(dd,J ₁ ＝8.4Hz,J ₂ ＝4.2Hz,1H)，4.40-4.23(m,1H)，1.45(dd,J ₁ ＝6.6Hz,J ₂ ＝1.3Hz,3H)。

An intermediate C:

synthesis step 1: 8-fluoro-6-bromoquinoline (C-2)

Glycerol (14.5g, 158mmol) and sodium 3-nitrobenzenesulfonate (14.2g, 63mmol), a catalyst, were added to an aqueous solution of sulfuric acid (20mL concentrated sulfuric acid +15mL water), heated to 110 deg.C, the starting material, 2-fluoro-4-bromoaniline C-1(10g, 52.6mmol), and stirred overnight at 140 deg.C. Cooling to room temperature, adding into crushed ice, adjusting pH to about 8 with strong ammonia water, and adding ethyl acetateExtracting, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain 9.65g of white solid compound C-2 with yield of 81.2%. LC-MS (ESI): [ M + H ]] ⁺ ＝227； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.97(dd,J ₁ ＝4.4Hz,J ₂ ＝0.8Hz,1H)，8.10(d,J＝8.4Hz,1H)，7.79(s,1H)，7.54(dd,J ₁ ＝9.6Hz,J ₂ ＝2.0Hz,1H)，7.50(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)。

And 2, synthesis step: 6-cyano-8-fluoroquinoline (C-3)

Starting material 8-fluoro-6-bromoquinoline C-2(9.65g, 42.7mmol), zinc cyanide (7.49g, 64mmol), and the catalyst tris (dibenzylideneacetone) dipalladium (Pd) ₂ (dba) ₃ ) (1.96g, 2mmol) and ligand 1,1' bis (diphenylphosphino) ferrocene (dppf) (2.37g, 4.3mmol) were dissolved in anhydrous DMF (40mL) and reacted overnight at 130 ℃ under argon. Cooling to room temperature and adding saturated Na ₂ CO ₃ Aqueous solution (100mL), ethyl acetate extraction, water washing, saturated salt water washing, anhydrous sodium sulfate drying, filtration and evaporation to dryness, and crude product is purified by column chromatography to obtain 5.472g of a grayish green solid compound C-3, yield: 74.1 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝173； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.12(d,J＝4.4Hz,1H)，8.29(d,J＝8.4Hz,1H)，8.07(s,1H)，7.64(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，7.59(d,J＝9.6Hz,1H)。

And 3, synthesis step: 6-Aminomethyl-8-fluoroquinoline (C)

Dissolving 6-cyano-8-fluoroquinoline C-3(330mg, 1.92mmol) as a raw material in ammonia/methanol solution (30mL), reducing by using an instrument H-cube (30bar, 25 ℃, 1mL/min flow rate, Rani column), and evaporating the solvent to obtain 280mg of brown oily matter C, wherein the yield is 82.8 percent and HPLC (high performance liquid chromatography)>96％。LC-MS(ESI)：[M+H] ⁺ ＝177； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.89(dd,J ₁ ＝4.4Hz,J ₂ ＝1.2Hz,1H)，8.36(d,J＝8.4Hz,1H)，7.70(s,1H)，7.60(d,J＝10.8Hz,1H)，7.58(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，3.90(s,2H)。

An intermediate D:

the synthesis step 1: 8-fluoroquinoline-6-carboxylic acid (D-2)

Adding raw material 3-fluoro-4-aminobenzoic acid D-1(25g, 0.16mol) and catalyst sodium 3-nitrobenzenesulfonate (43.2g, 0.192mol) into a mixed solution of concentrated sulfuric acid (60mL) and water (24mL), heating to an internal temperature of 120 ℃, slowly adding glycerol (44.2g, 0.48mol, 3eq), heating to 130-140 ℃ after the addition is finished, reacting for 1.5 hours, and cooling. Pouring the reaction liquid into crushed ice, adjusting the pH value to 5-6 with concentrated ammonia water, filtering out precipitated solid, washing with water, drying, and purifying by column chromatography to obtain 8.7g of off-white solid compound D-2 with the yield of 28.2%. LC-MS (ESI): [ M + H ]] ⁺ ＝192； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：13.49(brs,1H)，9.08(s,1H)，8.66(d,J＝8.4Hz,1H)，8.54-8.53(m,1H)，7.93(d,J＝11.2Hz,1H)，7.76-7.72(m,1H)。

And 2, synthesis step: N-methyl-N-methoxy-8-fluoroquinoline-6-carboxamide (D-3)

The starting material 8-fluoroquinoline-6-carboxylic acid D-2(3.2g, 16.75mmol) and the reagent carbonyldiimidazole (3g, 18.42mmol) were dissolved in anhydrous DMF (30mL) and stirred at room temperature for 2h under argon protection, then dimethylhydroxylamine hydrochloride (1.64g, 16.75mmol) was added and stirred at room temperature overnight. After the reaction is completed, saturated NaHCO is added ₃ Aqueous solution (100mL), ethyl acetate extraction, water washing, saturated salt water washing, anhydrous sodium sulfate drying, filtration and evaporation to dryness, and the crude product is purified by column chromatography to obtain 1.73g of light yellow oily matter D-3, yield: 44.1 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝235； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.04(dd,J ₁ ＝4.0Hz,J ₂ ＝1.6Hz,1H)，8.27(d,J＝8.4Hz,1H)，8.06(s,1H)，7.76(dd,J ₁ ＝10.8Hz,J ₂ ＝1.6Hz,1H)，7.54(dd,J ₁ ＝8.4Hz,J ₂ ＝4.0Hz,1H)，3.58(s,3H)，3.44(s,3H)。

And 3, synthesis step: 1- (8-fluoro-6-quinolinyl) ethanone (D-4)

The starting N-methyl-N-methoxy-8-fluoroquinoline-6-carboxamide D-3(7.5g, 0.032mol) was dissolved in anhydrous THF (30mL), cooled to about 0 ℃ in an ice bath, and then slowly added under argon atmosphere with methylmagnesium bromide 2-methyltetrahydrofuran solution (2.8M, 17.2mL, 0.048mol) and stirred at room temperature overnight. After the reaction is completed, saturated NH is added under ice-bath cooling ₄ The reaction was quenched with Cl aqueous solution, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 5.5g of yellow solid D-4 with a yield of 91.3%. LC-MS (ESI): [ M + H ]] ⁺ ＝190； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.08(dd,J ₁ ＝4.4Hz,J ₂ ＝1.2Hz,1H)，8.33(d,J＝8.4Hz,1H)，8.26(s,1H)，7.96(dd,J ₁ ＝11.2Hz,J ₂ ＝1.6Hz,1H)，7.58(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，2.74(s,3H)。

And 4, synthesis: 1- (8-fluoro-6-quinolinyl) ethanol (D-5)

Dissolving raw material 1- (8-fluoro-6-quinolyl) ethanone D-4(5.52g, 0.029mol) in methanol (30mL), and adding NaBH in batches under ice bath ₄ (4.4g, 0.116mol), stirred at room temperature for 1 h. After the reaction is completed, water is added to quench the reaction, ethyl acetate is used for extraction, water washing is carried out, washing is carried out by saturated saline solution, anhydrous sodium sulfate is used for drying, and 4.9g of yellow oily matter D-5 is obtained by filtering and evaporating, and the yield is as follows: 88.4 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝192； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.87-8.85(m,1H)，8.10(d,J＝8.4Hz,1H)，7.55(s,1H)，7.44-7.40(m,2H)，5.06(q,J＝6.4Hz,1H)，3.18(brs,1H)，1.56(d,J＝6.4Hz,3H)。

And 5, synthesis: 6- (1-bromoethyl) -8-fluoroquinoline (D-6)

Starting material 1- (8-fluoro-6-quinolinyl) ethanol D-5(4.9g, 25.6mmol) was dissolved in chloroform (30mL) and PBr was added slowly under ice bath ₃ (10.42g, 38.5mmol) and heated at reflux for 2 hours. Cooling, evaporating the solvent, and slowly adding saturated NaHCO under ice bath ₃ Adjusting the pH value of the aqueous solution to be alkaline, extracting by dichloromethane, washing by water, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering and evaporating to dryness to obtain 3.8g of brown oily matter D-6, and obtaining the yield: 58.6 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝254； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.98(dd,J ₁ ＝4.4Hz,J ₂ ＝1.6Hz,1H)，8.19(d,J＝8.4Hz,1H)，7.62(s,1H)，7.56(dd,J ₁ ＝11.2Hz,J ₂ ＝2.0Hz,1H)，7.52(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，5.33(q,J＝6.8Hz,1H)，2.12(d,J＝6.8Hz,3H)。

And 6, synthesis: 2- (1- (8-fluoro-6-quinolinyl) ethyl) isoindole-1, 3-dione (D-7)

The starting material 6- (1-bromoethyl) -8-fluoroquinoline D-6(0.77g, 3.06mmol) and phthalimide potassium salt (0.68g, 3.672mmol) were dissolved in DMF (10mL), a little KI (potassium iodide) was added, and the reaction was heated at 120 ℃ for 2 h. After the reaction, water (50mL) was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 1g of a yellow oily substance, yield: 100 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝321； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.94(dd,J ₁ ＝4.4Hz,J ₂ ＝1.6Hz,1H)，8.18(d,J＝8.4Hz,1H)，7.84-7.82(m,2H)，7.74-7.71(m,3H)，7.58(dd,J ₁ ＝11.2Hz,J ₂ ＝1.6Hz,1H)，7.46(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，5.72(q,J＝7.2Hz,1H)，2.02(d,J＝7.2Hz,3H)。

And a synthesis step 7: 1- (8-fluoro-6-quinolinyl) ethylamine (D)

The starting material, 2- (1- (8-fluoro-6-quinolyl) ethyl) isoindole-1, 3-dione D-7(0.189g, 0.59mmol), was dissolved in ethanol (10mL), and hydrazine hydrate (0.138g, 1.77mmol) was added thereto, followed by heating and refluxing for 2 hours. Cooling, evaporating the solvent, adding a 5% NaOH aqueous solution (10mL), extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to obtain a yellow oily substance 79mg, and obtaining the yield: 70.5% HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝191； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.90(dd,J ₁ ＝4.0Hz,J ₂ ＝1.6Hz,1H)，8.14(d,J＝8.4Hz,1H)，7.57(s,1H)，7.46-7.43(m,2H)，4.30(q,J＝6.8Hz,1H)，1.95(s,2H)，1.45(d,J＝6.8Hz,3H)。

Intermediate E:

starting material E-1 was purchased from KERMANDA, reduced as per the synthesis of intermediate a, step 2, and the resulting product was the hydrochloride salt in diethyl ether as a light brown solid. Yield: 81% HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝177； ¹ H-NMR(δppm,CD ₃ OD,400MHz)：9.36-9.33(m,2H),8.67(d,J＝8.0Hz,1H),8.20-8.16(m,2H),4.53(s,2H).

An intermediate F:

synthesis step 1: 6-bromo-7-fluoroquinoline (F-2)

Referring to the synthesis method of the intermediate D, step 1, the product is purified by a silica gel column and then recrystallized by petroleum ether to obtain a white solid with a yield of 62%. LC-MS (ESI): [ M + H ]] ⁺ ＝226； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.93(dd,J ₁ ＝4.2Hz,J ₂ ＝1.5Hz,1H)，8.12-8.02(m,2H)，7.81(d,J＝9.5Hz,1H)，7.41(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)。

And a synthesis step 2: 1- (7-fluoro-quinolin-6-yl) -ethanone (F-3)

6-bromo-7-fluoroquinoline F-2(2.07g, 9.16mmol), tributyl (1-ethoxyethylene) tin (3.64g, 10.1mmol) and bis-triphenylphosphine palladium dichloride (0.32g, 0.46mmol) were added to dioxane (20mL) and reacted at 110 ℃ for 4h under argon. The reaction solution was cooled, and potassium fluoride dihydrate (2g) and water (4mL) were added. Stir at room temperature for 2h, filter, and wash the filter cake with dioxane (5mL × 3). The filtrates were combined, concentrated hydrochloric acid (2mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and a saturated aqueous sodium carbonate solution (50mL) was added thereto, followed by extraction with ethyl acetate (100 mL. times.2). The organic phases were combined, washed with water (50mL) and saturated brine (50mL), dried and purified by silica gel column chromatography to give 1.5g of off-white solid compound F-3, yield: 87 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝190； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.99(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.41(d,J＝7.8Hz,1H)，8.26(dd,J ₁ ＝8.3Hz,J ₂ ＝1.1Hz,1H)，7.81(d,J＝12.2Hz,1H)，7.44(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，2.76(d,J＝4.9Hz,3H)。

And a synthesis step 3: 1- (7-fluoro-quinolin-6-yl) -ethanol (F-4)

Referring to the synthesis of intermediate D, step 4, a white solid was obtained in 79% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝192； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.74(dd,J ₁ ＝4.3Hz,J ₂ ＝1.4Hz,1H)，8.06(d,J＝8.3Hz,1H)，7.97(d,J＝8.0Hz,1H)，7.57(d,J＝11.7Hz,1H)，7.29(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.32(q,J＝6.3Hz,1H)，4.45(s,1H)，1.58(d,J＝6.3Hz,3H)。

And 4, synthesis: 6- (1-bromo-ethyl) -7-fluoro-quinoline (F-5)

Referring to the synthesis of intermediate D, step 5, a white solid was obtained in 94% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝254； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.91(dd,J ₁ ＝4.3Hz,J ₂ ＝1.6Hz,1H)，8.16(dd,J ₁ ＝8.3Hz,J ₂ ＝1.2Hz,1H)，7.97(d,J＝8.0Hz,1H)，7.74(d,J＝11.6Hz,1H)，7.40(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.58(q,J＝7.0Hz,1H)，2.18(d,J＝7.0Hz,3H)。

And 5, synthesis: 2- (1- (7-fluoro-quinolin-6-yl) ethyl) -isoindole-1, 3-dione (F-6)

Referring to the synthesis of intermediate D, step 6, a white solid was obtained in 69% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝321； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.89(dd,J ₁ ＝4.3Hz,J ₂ ＝1.4Hz,1H)，8.21(d,J＝8.3Hz,1H)，8.12(d,J＝8.1Hz,1H)，7.85-7.68(m,5H)，7.39(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.98(q,J＝7.2Hz,1H)，2.01(d,J＝7.2Hz,3H)。

And a synthesis step 6: 1- (7-fluoro-quinolin-6-yl) -ethylamine (F)

Reference to the synthesis of intermediate D, step 7, gave a white solid in 60% yield by HPLC>96％。LC-MS(ESI)：[M+H] ⁺ ＝191； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.87(dd,J ₁ ＝4.3Hz,J ₂ ＝1.6Hz,1H)，8.14(dd,J ₁ ＝8.3Hz,J ₂ ＝1.1Hz,1H)，7.89(d,J＝8.1Hz,1H)，7.70(d,J＝12.0Hz,1H)，7.36(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，4.54(d,J＝6.6Hz,1H)，1.79(s,2H)，1.51(d,J＝6.6Hz,3H)。

Intermediate G:

synthesis step 1: 6-bromo-5, 7-difluoroquinoline (G-2)

Raw materials 4-bromo-3, 5-difluoroaniline G-1(5.6G, 27mmol) and sodium 3-nitrobenzenesulfonate (7.2G, 32mmol) were added to a mixed solution of concentrated sulfuric acid (15mL) and water (6mL), heated to an internal temperature of 120 deg.C, slowly added with glycerol (7.4G, 80mmol), heated to 130 deg.C after the addition, reacted for 1.5h, and cooled. Pouring the reaction liquid into crushed ice, adjusting the pH value to 5-6 with concentrated ammonia water, filtering out precipitated solid, washing with water, drying, and purifying by column chromatography to obtain 3.82G of a white solid compound G-2 with the yield of 58%. LC-MS (ESI): [ M + H ]] ⁺ ＝244； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.98-8.97(m,1H)，8.40-8.37(m,1H)，7.68(dd,J ₁ ＝8.5Hz,J ₂ ＝1.6Hz,1H)，7.47(dd,J ₁ ＝8.5Hz,J ₂ ＝4.2Hz,1H)。

And 2, synthesis step: 6-vinyl-5, 7-difluoroquinoline (G-3)

Starting materials 6-bromo-5, 7-difluoroquinoline G-2(1.0G,4.10mmol), tripropylvinyltin (1.34G, 4.10mmol) and Pd (PPh) ₃ ) ₂ Cl ₂ (47mg, 0.041mmol) was dissolved in dioxane (30mL) and stirred under argon at 140 ℃ for 4 h. After cooling, ethyl acetate (40mL), water (2mL) and KF (0.2g) were added, and the reaction mixture was stirred for 2 h. The ethyl acetate layer was separated, the aqueous phase was back extracted with ethyl acetate 2 times, the organic phases were combined, dried and filtered to give 0.55G of colorless liquid G-3 with a yield of 70.1%. LC-MS (ESI): [ M + H ]] ⁺ ＝192。

And 3, synthesis step: 5, 7-Difluoroquinoline-6-carbaldehyde (G-4)

Mixing 6-vinyl-5, 7-difluoroquinoline G-3(0.61G, 3.21mmol) and sodium periodate(2.75g, 12.85mmol) and 2.6-lutidine (0.761mL, 6.42mmol) were added to a mixture of dioxane (17mL) and water (6 mL). Osmium tetroxide (653mg, 0.064mmol) was added with stirring, stirring was continued for 15min, diluted with water (50mL), extracted with ethyl acetate (50mL), washed with ethyl acetate water, dried, and purified with silica gel column to give 0.56G of G-4 as a white solid, yield: 90 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝194； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：10.55(s,1H)，9.08(dd,J ₁ ＝4.0Hz,J ₂ ＝1.2Hz,1H)，8.54(d,J＝7.9Hz,1H)，7.67(d,J＝11.2Hz,1H)，7.57-7.54(m,1H)。

And 4, synthesis: (5, 7-Difluoroquinolin-6-yl) -methanol (G-5)

The synthesis of reference intermediate D, step 4, gave a white solid with yield: 88 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝196； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.98(dd,J ₁ ＝4.4Hz,J ₂ ＝1.6Hz,1H)，8.24(d,J＝8.4Hz,1H)，7.64(d,J＝10.8Hz,1H)，7.49-7.46(m,1H)，5.01(d,J＝6.0Hz,2H)，2.09(dd,J ₁ ＝6.4Hz,J ₂ ＝4.4Hz,1H)。

And a synthesis step 5: 6-bromomethyl-5, 7-difluoroquinoline (G-6)

The synthesis of step 5, referenced intermediate D, gave a brown oil G-6, yield: 61 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝258。

And 6, synthesis: synthesis of 2- [ (5, 7-difluoro-6-quinolinyl) methyl ] isoindoline-1, 3-dione (G-7)

Reference intermediate D, step 6, gave G-7 as a yellow oil, yield: 100 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝325。

And a synthesis step 7: 5, 7-Difluoroquinolin-6-yl-methylamine (G)

Reference intermediate D, step 7, synthesis method gave white solid, yield: 60.6%, HPLC>96％。LC-MS(ESI)：[M+H] ⁺ ＝195； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.95(d,J＝3.2Hz,1H)，8.40(d,J＝8.0Hz,1H)，7.61(d,J＝10.0Hz,1H)，7.47-7.44(m,1H)，4.14(s,1H)。

Intermediate H:

synthesis step 1: 1- (5, 7-difluoro-6-quinolinyl) ethanone (H-1)

Referring to the synthesis of intermediate F, step 2, light yellow solid H-1 was obtained in 80% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝208； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.02(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.46-8.44(m,1H)，7.65-7.62(m,1H)，7.50(dd,J ₁ ＝8.5Hz,J ₂ ＝4.3Hz,1H)，2.72(t,J＝1.7Hz,3H)。

And 2, synthesis step: 1- (5, 7-difluoro-6-quinolinyl) ethanol (H-2)

The synthesis of step 4 of reference intermediate D yielded H-2 as a white solid with a yield of 94%. LC-MS (ESI): [ M + H ]] ⁺ ＝210； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.92(dd,J ₁ ＝4.2Hz,J ₂ ＝1.8Hz,1H)，8.38(d,J＝7.7Hz,1H)，7.59-7.56(m,1H)，7.43(dd,J ₁ ＝8.5Hz,J ₂ ＝4.2Hz,1H)，5.46(q,J＝7.2Hz,1H)，1.73(d,J＝7.2Hz,3H)。

And 3, synthesis step: 6- (1-bromoethyl) -5, 7-difluoroquinoline (H-3)

The synthesis procedure of step 5 of reference intermediate D gave H-3 as a yellow solid with a yield of 75%. LC-MS (ESI): [ M + H ]] ⁺ ＝272； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96-8.94(m,1H)，8.41-8.39(m,1H)，7.60(d,J＝11.7Hz,1H)，7.44(dd,J ₁ ＝8.5Hz,J ₂ ＝4.3Hz,1H)，5.69(q,J＝7.2Hz,1H)，2.21(d,J＝7.2Hz,3H)。

And 4, synthesis: 2- [1- (5, 7-difluoro-6-quinolinyl) ethyl ] isoindole-1, 3-dione (H-4)

The synthesis method of step 6 of reference intermediate D gave H-4 as a yellow solid with a yield of 96%. LC-MS (ESI): [ M + H ]] ⁺ ＝339。

And 5, synthesis: 1- (5,7 difluoro-6-quinolinyl) ethylamine (H)

Reference intermediate D, step 7, gave a pale yellow oil H in 80% yield, HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝209； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.93(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.40-8.37(m,1H)，7.58(dd,J ₁ ＝12.1Hz,J ₂ ＝1.7Hz,1H)，7.44(dd,J ₁ ＝8.5Hz,J ₂ ＝4.3Hz,1H)，4.68(q,J＝6.9Hz,1H)，1.98(s,2H)，1.62(d,J＝6.9Hz,3H)。

Intermediate I:

synthesis step 1: 6-bromo-7-methylquinoline (I-2) and 6-bromo-5-methylquinoline (J-1)

A mixture of 6-bromo-7-methylquinoline (I-2) and 6-bromo-5-methylquinoline (J-1) was synthesized by the method of step 1 of synthesis of intermediate G. Then separating by supercritical preparative chromatography (SFC), IC-H column, mobile phase: isopropanol/carbon dioxide 18/82, detection wavelength: 254 nm. The first fraction was collected as 6-bromo-7-methylquinoline (I-2), white solid, yield: 25 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝222； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.90(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.07-8.06(m,2H)，8.00(s,1H)，7.38(dd,J ₁ ＝8.3Hz,J ₂ 4.3Hz,1H), 2.63(d, J ═ 1.0Hz, 3H). The second fraction was collected as a white solid of 6-bromo-5-methylquinoline (J-1), yield: 20 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝223； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96-8.93(m,1H)，8.40(dd,J ₁ ＝8.3Hz,J ₂ ＝1.7Hz,1H)，7.88(s,2H)，7.48(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，2.80(s,3H)。

And 2, synthesis step: 1- (7-methyl-6-quinolyl) ethanone (I-3)

Referring to the method for synthesizing the intermediate H in the step 1, 6-bromo-7-methylquinoline I-2 is used as a raw material to synthesize the 1- (7-methyl-6-quinolyl) ethanone I-3. Pale yellow solid, yield 91%. LC-MS (ESI): [ M + H ]] ⁺ ＝186； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.95(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.22-8.20(m,2H)，7.94(dd,J ₁ ＝1.4Hz,J ₂ ＝0.8Hz,1H)，7.44(dd,J ₁ ＝8.5Hz,J ₂ ＝4.3Hz,1H)，2.74-2.73(m,6H)。

And 3, synthesis step: 1- (7-methyl-6-quinolyl) ethanol (I-4)

1- (7-methyl-6-quinolinyl) ethanol I-4 was synthesized as a yellow solid in a yield of 96% by the method of step 4 of the synthesis of intermediate D. LC-MS (ESI): [ M + H ]] ⁺ ＝188； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.89-8.83(m,1H)，8.13(dt,J ₁ ＝8.3Hz,J ₂ ＝1.3Hz,1H)，7.98(s,1H)，7.85(s,1H)，7.34(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，5.29(q,J＝6.4Hz,1H)，2.55(d,J＝1.1Hz,3H)，1.68(d,J＝6.4Hz,3H)。

And 4, synthesis: 6- (1-bromoethyl) -7-methylquinoline (I-5)

Referring to the synthesis of intermediate D, step 5, starting material 1- (7-methyl-6-quinolinyl) ethanol was used to prepare I-5 as a yellow solid in 85% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝250； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.98-8.94(m,1H)，8.40-8.38(m,1H)，8.10(s,1H)，7.95(s,1H)，7.42(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.39(q,J＝7.2Hz,1H)，2.65(d,J＝1.1Hz,3H)，1.78(d,J＝7.2Hz,3H)。

And 5, synthesis: 2- (1- (7-methyl-6-quinolyl) ethyl) isoindole-1, 3-dione (I-6)

Referring to the synthesis of intermediate D, step 6, starting material 6- (1-bromoethyl) -7-methylquinoline I-5 was prepared to give I-6 as a white solid in 70% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝317； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.88(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.24-8.19(m,2H)，7.89(s,1H)，7.80(dd,J ₁ ＝5.5Hz,J ₂ ＝3.1Hz,2H)，7.72(dd,J ₁ ＝5.5Hz,J ₂ ＝3.1Hz,2H)，7.36(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，5.89(q,J＝7.2Hz,1H)，2.58(s,3H)，2.01(d,J＝7.2Hz,3H)。

And 6, synthesis: 1- (7-methyl-6-quinolyl) ethylamine (I)

Reference intermediate D stepThe synthesis method of step 7, using raw material 2- (1- (7-methyl-6-quinolyl) ethyl) isoindole-1, 3-dione I-6 to prepare pale yellow solid I with yield of 60%, HPLC>96％。LC-MS(ESI)：[M+H] ⁺ ＝187； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.98(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.30-8.27(m,1H)，8.12(s,1H)，7.98(s,1H)，7.46(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.43(q,J＝7.2Hz,1H)，2.68(d,J＝1.1Hz,3H)，1.98(s,2H)，1.80(d,J＝7.2Hz,3H)。

Intermediate J:

synthesis step 1: 1- (5-methyl-6-quinolyl) ethanone (J-2)

Referring to the method for synthesizing the intermediate H in the step 1, the 6-bromo-5-methylquinoline J-1 prepared in the step 1 for synthesizing the intermediate I is used as a raw material to synthesize the 1- (5-methyl-6-quinolyl) ethanone J-2, wherein the yield is 86 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝186； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.00(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.53(dt,J ₁ ＝8.5Hz,J ₂ ＝1.2Hz,1H)，8.04(d,J＝8.9Hz,1H)，7.85(d,J＝8.9Hz,1H)，7.52(dd,J ₁ ＝8.5Hz,J ₂ ＝4.3Hz,1H)，2.81(s,3H)，2.70(s,3H)。

And 2, synthesis step: 1- (5-methyl-6-quinolyl) ethanol (J-3)

1- (5-methyl-6-quinolinyl) ethanol J-3 was synthesized as a brown solid in 90% yield, according to the procedure of step 4 for the synthesis of intermediate D. LC-MS (ESI): [ M + H ]] ⁺ ＝188； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.88(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.42-8.40(m,1H)，7.99(q,J＝9.0Hz,2H)，7.44(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，5.48-5.46(m,1H)，2.65(s,3H)，1.56(d,J＝6.4Hz,3H)。

And 3, synthesis step: 6- (1-bromoethyl) -5-methylquinoline (J-4)

Reference intermediate D step 5Synthesis procedure starting from 1- (5-methyl-6-quinolinyl) ethanol J-3 gives J-4 as a yellow solid in 85% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝250； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.94(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.50-8.48(m,1H)，8.12-8.10(m,2H)，7.55-7.52(m,1H)，5.58-5.55(m,1H)，2.77(s,3H)，1.65(d,J＝6.4Hz,3H)。

And 4, synthesis: 2- (1- (5-methyl-6-quinolyl) ethyl) isoindole-1, 3-dione (J-5)

Referring to the synthesis of intermediate D, step 6, starting material 6- (1-bromoethyl) -5-methylquinoline J-4 was prepared to yield J-5 as a white solid in 40% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝317； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.91(dd,J ₁ ＝4.1Hz,J ₂ ＝1.6Hz,1H)，8.45(dt,J ₁ ＝8.7Hz,J ₂ ＝1.3Hz,1H)，8.22(d,J＝9.0Hz,1H)，8.05(d,J＝9.0Hz,1H)，7.90(dd,J ₁ ＝5.5Hz,J ₂ ＝3.0Hz,1H)，7.85-7.80(m,2H)，7.71(dd,J ₁ ＝5.5Hz,J ₂ ＝3.0Hz,1H)，7.43(dd,J ₁ ＝8.6Hz,J ₂ ＝4.1Hz,1H)，6.05(q,J＝7.2Hz,1H)，2.75(s,3H)，2.02(d,J＝7.2Hz,3H)。

And 5, synthesis: 1- (7-methyl-6-quinolyl) ethylamine (J)

Referring to the synthesis of intermediate D, step 7, starting material 2- (1- (7-methyl-6-quinolinyl) ethyl) isoindole-1, 3-dione J-5 was prepared as a pale yellow solid J, yield 60%, HPLC>97％。LC-MS(ESI)：[M+H] ⁺ ＝187； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.40-8.37(m,1H)，8.12-8.09(m,2H)，7.58-7.55(m,1H)，5.60-5.57(m,1H)，2.78(s,3H)，1.97(s,2H)，1.65(d,J＝6.4Hz,3H)。

An intermediate K:

the synthesis step 1: synthesis of 3-chloroquinoline-6-carboxylic acid methyl ester (K-2)

5g (27mmol) of quinoline-6-carboxylic acid methyl ester were dissolved in 50mL of anhydrous DMF, 11g (80mmol) of N-chlorosuccinimide were added, and the tube was sealed overnight by heating to 125 ℃. Quenching reaction by adding a proper amount of saturated solution of sodium bicarbonate, adding a small amount of water and ethyl acetate, separating an organic phase, extracting an aqueous phase by using 50mL of multiplied by 3 ethyl acetate, combining the organic phases, washing by using 50mL of multiplied by 2 saturated sodium chloride solution, drying and evaporating to dryness. The dot plate (developing solvent petroleum ether: ethyl acetate: 5: 1) is relatively pure, flash column purification (developing solvent petroleum ether: ethyl acetate: 80:20) gives 3.481g of white solid, yield: 57 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝222。

And 2, synthesis step: synthesis of methyl 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxylate (K-3)

500mg (2.26mmol) of 3-chloroquinoline-6-carboxylic acid methyl ester is dissolved in 24mL1, 4-dioxane, 165mg (0.23mmol) of [1, 1-bis (diphenylphosphino) ferrocene is respectively added under the protection of nitrogen]Palladium dichloride, 624mg (4.51mmol) potassium carbonate, 516mg (2.48mmol) 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and 6ml water, the reaction mixture is heated to 110 ℃ under nitrogen and the tube is sealed overnight. The solvent is removed, 50mL of water and 50mL of ethyl acetate are added, the organic phase is separated off, the aqueous phase is extracted with 50mL of × 3 ethyl acetate, the organic phases are combined, washed with 50mL of × 2 saturated sodium chloride solution, dried and evaporated to dryness. The dot plate (dichloromethane: methanol ═ 20:1 as developing solvent) was relatively pure and flash column purified (dichloromethane: methanol ═ 95:5 as developing solvent) to give 565mg of white solid, yield: LC-ms (esi): [ M + H ]] ⁺ ＝268， ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.17(d,J＝2.3Hz,1H),8.60(d,J＝1.8Hz,1H),8.29–8.24(m,2H),8.14(d,J＝8.8Hz,1H),7.95(s,1H),7.84(s,1H),4.04(s,3H),4.02(s,3H).

And a synthesis step 3: synthesis of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxylic acid (K-4)

565mg (2.11mmol) of methyl 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxylate was dissolved in 30ml of methanol, 266mg (6.34mmol) of lithium hydroxide and 5ml of water were added at room temperature, and the reaction mixture was stirred at room temperature overnight. The solvent was then removed to give 534mg of a white solid which was directly charged to the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝254。

And a synthesis step 4: synthesis of N-methoxy-N-methyl-3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxamide (K-5)

534mg (2.108mmol) of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxylic acid are dissolved in dichloromethane, and 411mg (4.22mmol) of N, O-dimethylhydroxylamine hydrochloride, 1.60g (4.22mmol) of O- (7-azabenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate and 3 mLN-ethyldiisopropylamine are added under nitrogen protection, and the mixture is stirred at room temperature overnight. The solvent was removed, 50mL of water and 50mL of ethyl acetate were added, the organic phase was separated off, the aqueous phase was extracted with 50mL of × 3 ethyl acetate, the organic phases were combined, washed with 50mL of × 2 saturated sodium chloride solution, dried and evaporated to dryness. Dot plate (developing solvent dichloromethane: methanol: 20:1) pure, flash column purification (developing solvent dichloromethane: methanol: 95:5) afforded 322mg of yellow solid, yield: and 52 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝297， ¹ H-NMR(δppm,CDCl ₃ ，400MHz)：9.16(s,1H),8.25(s,1H),8.21(d,J＝1.5Hz,1H),8.17(d,J＝8.7Hz,1H),8.00–7.91(m,2H),7.85(s,1H),4.04(s,3H),3.58(s,3H),3.45(s,3H).

And 5, synthesis: synthesis of 1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethanone (K-6)

504mg (1.701mmol) of N-methoxy-N-methyl-3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxamide are dissolved in 30mL of anhydrous THF, cooled to 0 ℃ in an ice bath, and 1.5mL of a 3M solution of methylmagnesium bromide are added under nitrogen. The ice bath was removed and stirred at room temperature overnight. 6mL of saturated aqueous ammonium chloride solution are slowly added, 30mL of ethyl acetate and 15mL of water are added, the organic phase is separated off and the aqueous phase is extracted with 30mL of X3 ethyl acetate. The combined organic phases were washed with 30mL of a saturated sodium chloride solution × 2, dried and evaporated to dryness. Spotting (developing solvent petroleum ether: ethyl acetate: 1) is relatively pure, flash column purification (developing solvent petroleum ether: ethyl acetate: 1:100) gives 280mg of white solid, yield: 66 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝252, ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.16(d,J＝2.3Hz,1H),8.46(d,J＝1.8Hz,1H),8.30(d,J＝2.1Hz,1H),8.22(dd,J ₁ ＝8.8Hz,J ₂ ＝1.9Hz,1H),8.15(d,J＝8.8Hz,1H),7.95(s,1H),7.85(s,1H),4.04(s,3H),2.77(s,3H)。

And 6, synthesis: synthesis of 1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethanone oxime (K-7)

232mg (3.34mmol) of hydroxylamine chloride are dissolved in 30ml of ethanol, after which 137mg (3.43mmol) of sodium hydroxide are added. After the mixed solution was stirred at room temperature for 1 hour, the solid was filtered off, and the filtrate was added to an ethanol solution containing 280mg (1.11mmol) of 1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethanone. The reaction mixture was stirred at room temperature overnight. The solvent was removed to give 919mg of a white solid, which was directly charged into the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝267。

And a synthesis step 7: synthesis of 1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethylamine (K)

556mg (2.09mmol) of 1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethanone oxime were dissolved in 20ml of ethanol, and 6ml of ammonia in methanol (7N) and 245mg of Raney nickel were added at room temperature. The reaction mixture was stirred under hydrogen at ambient temperature overnight. The solid was filtered off and the solvent was evaporated to dryness to give 385mg of crude product, which was pure and ready to be used in the next step. Dot plate (developing solvent dichloromethane: methanol 10: 1). LC-MS (ESI): [ M + H ]] ⁺ ＝253； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.11(d,J＝2.2Hz,1H),8.42(d,J＝2.0Hz,1H),8.39(s,1H),8.09(s,1H),7.92(d,J＝8.7Hz,1H),7.84(d,J＝1.3Hz,1H),7.73(dd,J＝8.7,1.8Hz,1H),4.18(q,J＝6.4Hz,1H),3.92(s,3H),1.34(d,J＝6.6Hz,3H).

Intermediate L:

synthesis step 1: 7-fluoro-6-bromoquinoline (L-2)

Adding a raw material of 3-fluoro-4-bromoaniline (20g, 0.105mol) and a catalyst of sodium 3-nitrobenzenesulfonate (28g, 0.124mol, 1.2eq) into a mixed solution of concentrated sulfuric acid (60ml) and water (24ml), heating to an internal temperature of 120 ℃, slowly adding glycerol (29g, 0.315mol, 3eq), heating to a temperature of 130-. Pouring the reaction solution into crushed ice, adjusting the pH value to 8 with concentrated ammonia water, extracting with dichloromethane, washing with water, drying, and purifying by column chromatography to obtain yellow20.3g of a colored solid, yield 85.8%. LC-MS (ESI): [ M + H ]] ⁺ ＝226； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.93(dd,J ₁ ＝4.2Hz,J ₂ ＝1.5Hz,1H)，8.12-8.02(m,2H)，7.81(d,J＝9.5Hz,1H)，7.41(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)。

And 2, synthesis step: 7-fluoro-6-quinolinetophenone (L-3)

The starting material, 7-fluoro-6-bromoquinoline (20.3g, 0.09mol), was dissolved in anhydrous dioxane (50ml) and the catalyst Pd (PPh) was added ₃ ) ₂ Cl ₂ (3.17g, 4.5mmol, 0.05eq) and reagent tributyl (1-ethoxyvinyl) tin (35.87g, 0.1mol, 1.1eq), under argon protection at 90 ℃ overnight. After cooling to room temperature, 2eq 10% aqueous potassium fluoride solution was added and stirred at room temperature for 2h, the mixture was filtered, the filter cake was washed several times with dichloromethane, the filtrate was evaporated to dryness, and 2eq 1N HCl was added and stirred at room temperature for 2 h. Adding sodium carbonate aqueous solution to adjust the pH value to 8, extracting by dichloromethane, washing by water, drying, and purifying by column chromatography to obtain 17g of yellow solid with the yield of 99%. LC-MS (ESI): [ M + H ]] ⁺ ＝190； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.99(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.41(d,J＝7.8Hz,1H)，8.26(dd,J ₁ ＝8.3Hz,J ₂ ＝1.1Hz,1H)，7.81(d,J＝12.2Hz,1H)，7.44(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，2.76(d,J＝4.9Hz,3H)。

And a synthesis step 3: 1- (7-fluoro-6-quinolinyl) ethanol (L-4)

The raw material 7-fluoro-6-quinolinetophenone (20.5g, 0.108mol) is dissolved in methanol (100ml), and NaBH is added in portions under ice bath ₄ (3.3g, 0.087mol, 0.8eq), and stirred for 0.5 h under ice bath. After the reaction is completed, water is added to quench the reaction, methanol is evaporated, ethyl acetate is extracted, the reaction product is washed with water, saturated saline solution is washed with water, anhydrous sodium sulfate is dried, and column chromatography purification is carried out to obtain 15.4g of yellow oily matter with the yield of 74.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝192； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.74(dd,J ₁ ＝4.3Hz,J ₂ ＝1.4Hz,1H)，8.06(d,J＝8.3Hz,1H)，7.97(d,J＝8.0Hz,1H)，7.57(d,J＝11.7Hz,1H)，7.29(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.32(q,J＝6.3Hz,1H)，4.45(s,1H)，1.58(d,J＝6.3Hz,3H)。

And 4, synthesis: 6- (1-bromoethyl) -7-fluoroquinoline (L-5)

The starting material, 1- (7-fluoro-6-quinolinyl) ethanol (6.2g, 0.03mol), was dissolved in chloroform (50ml) and PBr was added slowly under ice-bath ₃ (10.5g, 0.038mol, 1.2eq), heated at reflux for 2 hours. After the reaction was complete, the solvent was evaporated to dryness and saturated NaHCO was slowly added under ice bath ₃ Adjusting pH of the aqueous solution to be alkaline, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain a yellow solid 4.6g with the yield of 56.6%. LC-MS (ESI): [ M + H ]] ⁺ ＝254； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.91(dd,J ₁ ＝4.3Hz,J ₂ ＝1.6Hz,1H)，8.16(dd,J ₁ ＝8.3Hz,J ₂ ＝1.2Hz,1H)，7.97(d,J＝8.0Hz,1H)，7.74(d,J＝11.6Hz,1H)，7.40(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.58(q,J＝7.0Hz,1H)，2.18(d,J＝7.0Hz,3H)。

And 5, synthesis: 2- (1- (7-fluoro-6-quinolinyl) ethyl) isoindole-1, 3-dione (L-6)

The starting materials 6- (1-bromoethyl) -7-fluoroquinoline (4.8g, 0.019mol) and potassium phthalimide (4.2g, 0.023mol, 1.2eq) were dissolved in DMF (30ml), a little KI was added, and the reaction was heated at 120 ℃ for 2 hours. After the reaction is completed, DMF is evaporated, water is added, ethyl acetate is used for extraction, washing is carried out by saturated saline solution, drying is carried out by anhydrous sodium sulfate, and column chromatography purification is carried out to obtain 4.8g of yellow solid with the yield of 78.9%. LC-MS (ESI): [ M + H ]] ⁺ ＝321； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.89(dd,J ₁ ＝4.3Hz,J ₂ ＝1.4Hz,1H)，8.21(d,J＝8.3Hz,1H)，8.12(d,J＝8.1Hz,1H)，7.85-7.68(m,5H)，7.39(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.98(q,J＝7.2Hz,1H)，2.01(d,J＝7.2Hz,3H)。

And 6, synthesis: 2- (1- (7-fluoro-3-bromo-6-quinolinyl) ethyl) isoindole-1, 3-dione (L-7)

Dissolving 2- (1- (7-fluoro-6-quinolyl) ethyl) isoindole-1, 3-dione (4.8g, 0.015mol) as a raw material in carbon tetrachloride (100ml), and adding pyridine (2.38g, 0.03mol, 2eq) and liquid bromine (4.8g, 0.03mol) respectively2eq), at 70 ℃ overnight. After the reaction is completed, the solvent is evaporated to dryness, sodium carbonate aqueous solution is added to adjust the solution to be alkaline, dichloromethane is used for extraction, washing is carried out, saturated saline solution is used for washing, and column chromatography purification is carried out to obtain 2.8g of yellow solid with the yield of 46.8%. LC-MS (ESI): [ M + H ]] ⁺ ＝398.8； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.90(d,J＝2.0Hz,1H),8.40(d,J＝2.0Hz,1H),8.06(d,J＝8.0Hz,1H),7.85(dd,J ₁ ＝5.6Hz,J ₂ ＝2.8Hz,2H),7.74(dd,J ₁ ＝5.6Hz,J ₂ ＝2.8Hz,2H),7.69(d,J＝11.6Hz,1H),5.98(q,J＝7.2Hz,1H),2.01(d,J＝7.2Hz,3H).

And a synthesis step 7: 2- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) isoindole-1, 3-dione (L-8)

The starting materials 2- (1- (7-fluoro-3-bromo-6-quinolyl) ethyl) isoindole-1, 3-dione (1.18g, 3mmol), 1-methylpyrazole-4-boronic acid pinacol ester (0.92g, 4.4mmol, 1.5eq), catalyst Pd (dppf) Cl ₂ DCM (0.12g, 1.5mmol, 0.05eq) and K ₂ CO ₃ (1.23g, 9mmol, 3eq) was dissolved in dioxane + water (8ml +2ml) and reacted at 110 ℃ for 4 hours under argon. Cooling to room temperature, adding a large amount of water, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying by column chromatography to obtain 689mg of white solid with yield of 58.4%. LC-MS (ESI): [ M + H ]] ⁺ ＝400.9.

And a synthesis step 8: 1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethylamine (L)

The starting material, 2- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) isoindole-1, 3-dione (5.15g, 0.013mol), was dissolved in ethanol (150ml), hydrazine hydrate (2g, 0.034mol, 2.6eq) was added, and the mixture was refluxed for 5 hours. Cooling to room temperature, precipitating solid, filtering, washing filter cake with ethyl acetate for several times, evaporating mother liquor to dryness, adding a little 5% NaOH aqueous solution, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain white solid 1.66g with yield of 47.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝271.0； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.04(d,J＝2.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.91(s,1H),7.89(d,J＝8.0Hz,1H),7.79(s,1H),7.70(d,J＝11.6Hz,1H),4.56(q,J＝6.8Hz,1H),4.03(s,3H),1.54(d,J＝6.8Hz,3H).

An intermediate M:

synthesis step 1: 2- (1- (3-chloro-5, 7-difluoroquinolin-6-yl) ethyl) isoindoline-1, 3-dione (M-2)

1.65g (4.88mmol) of 2- (1- (5, 7-difluoroquinolin-6-yl) ethyl) isoindoline-1, 3-dione is introduced into 15mL of DMF, and 2.17g (16.3mmol) of 1-chloropyrrolidine-2, 5-dione is added thereto with stirring at room temperature. The reaction solution was heated to 125 ℃ and reacted for 24 hours. After workup 30ml of water were added and 3.2g of solid sodium bicarbonate were added to neutralize the reaction, which was stirred at room temperature for 30 minutes and then 4.8g of sodium thiosulfate was slowly added to remove excess 1-chloropyrrolidine-2, 5-dione. Ethyl acetate extraction (100mL x 3), organic phases were combined, washed with saturated sodium chloride solution, dried and the crude product obtained by evaporation to dryness was purified by flash column to obtain 0.6g of white solid, yield: 30 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝373， ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8,84(d,J＝2.4Hz,1H),8.38(d,J＝2.4Hz,1H),7.83(dt,J＝7.0,3.5Hz,2H),7.74(dt,J＝5.2,2.1Hz,2H),7.62-7.54(m,1H),6.00(q,J＝7.4Hz,1H),2.07(dt,J＝7.5,2.5Hz,3H).

And 2, synthesis step: 2- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) isoindoline-1, 3-dione (M-3)

2- (1- (3-chloro-5, 7-difluoroquinolin-6-yl) ethyl) isoindoline-1, 3-dione (7g, 18mmol) was dissolved in 250ml of 1, 4-dioxane, followed by addition of 1-methylpyrazole-4-boronic acid pinacol ester (7.8g, 37mmol), Pd (dppf) Cl ₂ 0.1eq, anhydrous potassium carbonate 2eq and 62.5ml water. The reaction solution was sealed overnight at 110 ℃ under argon. After concentrating the reaction solution, 1000mL of water and 1000mL of ethyl acetate were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (500mL × 3), the organic phases were combined, washed with brine, dried, concentrated, and the residual crude product was purified by flash column (the developing solvent was petroleum ether: dichloromethane 80:20) to obtain 3g of the objective compound, yield: 38 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝419， ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.08(d,J＝2.2Hz,1H),8.39(dd,J＝2.3Hz,1H),7.91(d,J＝0.8Hz,1H),7.89-7.78(m,3H),7.72(dd,J ₁ ＝5.5Hz,J ₂ ＝3.0Hz,2H),7.56(dd,J ₁ ＝11.4Hz,J ₂ ＝1.6Hz,1H),6.01(q,J＝7.4Hz,1H),4.02(s,3H),2.09(ddd,.J ₁ ＝7.4Hz,J ₂ ＝2.7Hz,J ₃ ＝1.5Hz,3H)。

And 3, synthesis step: 1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethylamine (M)

2- (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) isoindoline-1, 3-dione (0.5g, 1mmol) was dissolved in 30ml ethanol, after which hydrazine hydrate (179mg,3.6mmol) was added. After refluxing the reaction for 2 hours, the solid impurities were filtered off and washed with ethanol. The solvent was spun off, 100ml of ethyl acetate was added, the organic phase was washed with 50ml of saturated solution of sodium carbonate, brine washed (50ml x 2), dried, filtered, concentrated and the residue purified by flash column to give 0.3g of solid, yield: 90 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝289， ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.07(d,J＝2.2Hz,1H),8.37-8.32(m,1H),7.96-7.91(m,1H),7.83(s,1H),7.62-7.52(m,1H),4.68(q,J＝6.9Hz,1H),4.03(s,3H),1.82(s,4H),1.63(d.J＝6.9Hz,3H)。

An intermediate N:

synthesis step 1: 3-chloroquinoline-6-carboxylic acid methyl ester (K-2)

The synthesis method of the intermediate K-2 is the same as the synthesis method of the intermediate K in the step 1.

And 2, synthesis step: 3-chloroquinoline-6-carboxylic acid (N-3)

6.5g (29mmol) of methyl 3-chloroquinoline-6-carboxylate was added to 80ml of methanol, and 20ml of an aqueous solution of 1.4g of lithium hydroxide (59mmol) was added thereto with stirring at room temperature, and after the addition, the reaction was carried out overnight at room temperature. And (3) post-treatment, namely concentrating the reaction solution to about 30ml, adjusting the pH value to 5-6 with hydrochloric acid, filtering, washing a filter cake with water, drying to obtain 6.3g of a product, and directly carrying out the next reaction with the yield:99％,LC-MS(ESI)：[M+H] ⁺ ＝208。

and 3, synthesis step: 3-chloro-N-methoxy-N-methylquinoline-6-carboxamide (N-4)

4.3g (21mmol) of 3-chloroquinoline-6-carboxylic acid was added to 60ml of anhydrous DMF, and 12g (31mmol) of O- (7-azabenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate and 4g (31mmol) of diisopropylethylamine were added to the above reaction mixture under stirring, and after stirring at room temperature for 30min, 3g (31mmol) of N, O-dimethylhydroxylamine hydrochloride was added, and after completion of the addition, the mixture was reacted at room temperature under nitrogen overnight. Post-treatment, pouring the reaction solution into 300ml of water, extracting with ethyl acetate (100ml x 3), combining organic phases, washing with 2N sodium hydroxide solution, washing with water, washing with saturated sodium chloride solution, drying, evaporating to dryness to obtain a crude product 2.5g, yield: 48% and is directly used for the next reaction. LC-MS (ESI): [ M + H ]] ⁺ ＝251。

And 4, synthesis: 1- (3-chloroquinolin-6-yl) ethanone (N-5)

3.7g (15mmol) of 3-chloro-N-methoxy-N-methylquinoline-6-carboxamide are dissolved in 30ml of ultra-dry tetrahydrofuran under nitrogen protection, 6.4ml (19mmol) of 3mol/L methylmagnesium bromide is slowly added dropwise in ice bath, and the reaction is continued for 3h after slowly returning to room temperature. And (3) post-treatment, namely slowly dropwise adding 30ml of saturated ammonium chloride aqueous solution into the reaction solution in ice bath, continuously stirring for 30min after the addition is finished, extracting 20ml of ethyl acetate by using 20ml of ethyl acetate, combining organic phases, washing with saturated salt water, drying, filtering, evaporating the solvent to obtain 2.2g of a product, wherein the yield is as follows: 72 percent and is directly used for the next reaction. LC-MS (ESI): [ M + H ]] ⁺ ＝206， ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.94(d,J＝2.4Hz,1H),8.40(d,J＝1.7Hz,1H),8.29-8.27(m,2H),8.18(d,J＝8.8Hz,1H),2.76(s,3H).

And 5, synthesis: 1- (3- (4-fluorophenyl) quinolin-6-yl) ethanone (N-6)

20ml of 1, 4-dioxane and 4ml of water were charged into a sealed tube, followed by 1.36g of 4-fluorophenylboronic acid (9.7mmol), 1g of 1- (3-chloroquinolin-6-yl) ethanone (4.86mmol), 1.34g of potassium carbonate (9.7257mmol) and [1,1' -bis (diphenylphosphino) ferrocene]119mg (0.14mmol) of palladium dichloride and reacted at an external temperature of 110 ℃ for 4 h. The post-treatment is purified by silica gel column chromatography to obtain 1.3g of a product, and the yield is as follows: 99 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝266。

And 6-7: 1- (3- (4-fluorophenyl) quinolin-6-yl) ethylamine (N)

To a 250ml single-necked flask was added 100ml of anhydrous ethanol, and 1.3g (4.9mmol) of 1- (3- (4-fluorophenyl) quinolin-6-yl) ethanone, 0.39g (9.8mmol) of sodium hydroxide and 0.67g (9.8mmol) of hydroxylamine hydrochloride were successively added with stirring at room temperature, and after the addition, the reaction was carried out overnight at room temperature. Then, about 1g of Raney nickel was added to the reaction solution, and the mixture was reduced with 2atm of hydrogen at room temperature for 5 hours, and then it was checked that no raw material remained. Post-treatment, filtration, concentration of the filtrate, addition of 100ml dichloromethane, washing with water, drying and chromatography on silica gel column to obtain 800mg of product. The two-step yield was 61.5%. LC-MS (ESI): [ M + H ]] ⁺ ＝267， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.28(d,J＝2.3Hz,1H),8.63(d,J＝2.1Hz,1H),8.31(s,2H),8.17–8.05(m,2H),8.03–7.84(m,3H),7.42(t,J＝8.9Hz,2H),4.63(q,J＝6.8Hz,1H),1.62(d,J＝6.8Hz,3H).

Synthesis of Compounds

Example 1: 6- ((6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazine-1) -methylene) -quinoline (Compound 1-1)

Step 1 preparation of 6-bromo-N ² - (quinoline-6-methylene) pyrazine-2, 3-diamines

3, 5-dibromopyrazin-2-amine (6.1g, 24mmol), 6-quinolinylmethylene amine (3.8g, 24mmol) and N, N-Diisopropylethylamine (DIPEA) (8.6mL, 48mmol) were added to NMP (20mL) and reacted overnight at 130 ℃ under argon. The reaction solution was distilled off DIPEA, the residue was poured into water (100mL), extracted with dichloromethane (30mL × 3), the organic phase was washed with water, saturated brine was washed with water, dried and then subjected to rapid column chromatography to obtain 4.7g of a tan product, yield: 59 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝330； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.85(dd,J ₁ ＝4.2Hz,J ₂ ＝1.6Hz,1H)，8.33(d,J＝8.3Hz,1H)，7.99(d,J＝8.7Hz,1H)，7.87(s,1H)，7.73(dd,J ₁ ＝8.7Hz,J ₂ ＝1.9Hz,1H)，7.50(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，7.21(s,1H)，7.16(t,J＝5.4Hz,1H)，6.25(s,2H)，4.69(d,J＝5.4Hz,2H)。

Step 2 preparation of 6- (6-bromo-imidazo [4,5-b ] pyrazine-1-methylene) -quinoline

Reacting 6-bromo-N ² - (quinoline-6-methylene) pyrazine-2, 3-diamine (1.2g, 3.6mmol) was added to trimethyl orthoformate (30mL), 98% formic acid (1mL) was added with stirring at room temperature, after addition, the reaction solution was refluxed for 2 days, the solvent was evaporated, the crude product was washed with ethyl acetate/petroleum ether (1/1) to give 1.1g, yield: 89 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝340； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.01(s,1H)，8.88(dd,J ₁ ＝4.2Hz,J ₂ ＝1.6Hz,1H)，8.68(s,1H)，8.32(d,J＝8.4Hz,1H)，8.01(d,J＝8.7Hz,1H)，7.85(s,1H)，7.75(dd,J ₁ ＝8.7Hz,J ₂ ＝1.7Hz,1H)，7.51(dd,J ₁ ＝8.4Hz,J ₂ ＝4.2Hz,1H)，5.72(s,2H)。

Step 3 preparation of 6- (6- (1-methyl-1H-pyrazol-4-yl) -imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (Compound 1-1)

Reacting 6- (6-bromo-imidazo [4,5-b ]]Pyrazine-1-methylene) -quinoline (100mg, 0.29mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (121mg, 0.58mmol), potassium carbonate (122mg, 0.88mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (20mg) was added to a mixed solvent of dioxane (4mL) and water (1mL), and the reaction solution was purged with argon for 5min in a sealed tube and then reacted at 110 ℃ for 3 h. After reaction liquid is concentrated and separated by fast column chromatography, the obtained solid is washed by methanol to obtain 60mg of white solid, and the yield is as follows: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝342； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.93-8.85(m,3H)，8.42(s,1H)，8.36(d,J＝8.4Hz,1H)，8.13(s,1H)，8.03(d,J＝8.7Hz,1H)，7.98(s,1H)，7.85(dd,J ₁ ＝8.7Hz,J ₂ ＝2.0Hz,1H)，7.53(dd,J ₁ ＝8.4Hz,J ₂ ＝4.2Hz,1H)，5.73(s,2H)，3.91(s,3H)。

Examples 2 to 18

The compounds of examples 2 to 18 were prepared in the same manner as in example 1 using different boronic acids or boronic esters, and the specific experimental data are shown in Table 1.

TABLE 1 Experimental data Table for Compounds 1-2 through 1-18

Example 19: 6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-19)

Step 1 preparation of 6-bromo-N ² - (1- (6-quinolyl) ethyl) pyrazine-2, 3-diamines

Referring to the procedure of step 1 of example 1,1- (quinolin-6-yl) ethylamine was used instead of 6-quinolinylmethylene amine to give 6-bromo-N ² - (1- (6-quinolyl) ethyl) pyrazine-2, 3-diamine as a dark brown solid in 68% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝344； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.85(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.34(dd,J ₁ ＝8.4Hz,J ₂ ＝0.9Hz,1H)，7.99(d,J＝8.7Hz,1H)，7.89(d,J＝1.7Hz,1H)，7.79(dd,J ₁ ＝8.7Hz,J ₂ ＝2.0Hz,1H)，7.50(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，7.16(s,1H)，7.01(d,J＝7.1Hz,1H)，6.35(s,2H)，5.77(d,J＝3.3Hz,1H)，5.26(q,J＝6.9Hz,1H)，3.36(s,1H)，3.29(dd,J ₁ ＝8.8Hz,J ₂ ＝5.3Hz,1H)，2.53-2.46(m,1H)，2.17(t,J＝8.1Hz,1H)，1.95-1.82(m,1H)，1.58(d,J＝6.9Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline

Referring to the procedure of step 2 of example 1, 6-bromo-N ² Reaction of (1- (6-quinolyl) ethyl) pyrazine-2, 3-diamine with methyl diethoxyacetate gave a dark brown solid with a yield of 50.1%. LC-MS (ESI): [ M + H ]] ⁺ ＝354； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.18(s,1H),8.90(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.68(s,1H)，8.37(dd,J ₁ ＝8.5Hz,J ₂ ＝1.0Hz,1H)，8.02(d,J＝8.8Hz,1H)，7.95(d,J＝2.0Hz,1H)，7.81(dd,J ₁ ＝8.8Hz,J ₂ ＝2.1Hz,1H)，7.54(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，6.19(q,J＝7.1Hz,1H)，2.11(d,J＝7.2Hz,3H)。

Step 3 preparation of 6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-19)

Referring to the procedure of step 3 of example 1, 6- (1- (6-bromo-1H-imidazo [4, 5-b))]Pyrazine-1-yl) ethyl) quinoline reacted with 1-methylpyrazole-4-boronic acid pinacol ester to give a white solid with a yield of 53%. LC-MS (ESI): [ M + H ]] ⁺ ＝356； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.00(s,1H)，8.88(dd,J ₁ ＝4.2Hz,J ₂ ＝1.7Hz,1H)，8.85(s,1H)，8.40(d,J＝2.8Hz,2H)，8.37(s,1H)，8.11(d,J＝0.7Hz,1H)，8.06(d,J＝2.1Hz,1H)，8.02(s,1H)，8.00(s,1H)，7.90(d,J＝2.1Hz,1H)，7.88(d,J＝2.1Hz,1H)，7.53(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，6.19(q,J＝7.1Hz,1H)，3.91(s,3H)，2.15(d,J＝7.2Hz,3H)。

Examples 20 to 49

The compounds of example 20 to example 49 were prepared in the same manner as in example 19 using different boronic acids or boronic acid esters, and the specific experimental data are shown in Table 2.

TABLE 2 Experimental data Table for Compounds 1-20 through 1-49

Example 50: 8-fluoro-6- ((6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (compound 1-50)

Step 1 preparation of 6-bromo-N ² - ((8-fluoro-6-quinolinyl) methyl) pyrazine-2, 3-diamine

Referring to the procedure of step 1 of example 1, 6-bromo-N was obtained by substituting 6-aminomethyl-8-fluoroquinoline for 6-quinolinylmethylene amine ² - ((8-fluoro-6-quinolinyl) methyl) pyrazine-2, 3-diamine as an orange solid in 50.8% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝348； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.92(dd,J ₁ ＝4.0Hz,J ₂ ＝1.2Hz,1H)，8.43(d,J＝8.4Hz,1H)，7.75(s,1H)，7.64-7.59(m,2H)，7.25(s,1H)，7.19(t,J＝5.2Hz,1H)，6.27(s,2H)，4.70(d,J＝5.2Hz,2H)。

Step 2 preparation of 6- ((6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -8-fluoroquinoline

Referring to the procedure of step 2 of example 1, 6-bromo-N ² - ((8-fluoro-6-quinolinyl) methyl) pyrazine-2, 3-diamine reacted with diethoxy methyl acetate to give an orange solid with a yield of 71.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝358； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.01(s,1H)，8.95(dd,J ₁ ＝4.0Hz,J ₂ ＝1.6Hz,1H)，8.70(s,1H)，8.41(d,J＝8.4Hz,1H)，7.70(s,1H)，7.68(dd,J ₁ ＝9.6Hz,J ₂ ＝1.6Hz,1H)，7.64(dd,J ₁ ＝8.4Hz,J ₂ ＝4.0Hz,1H)，5.72(s,2H)。

Step 3 preparation of 8-fluoro-6- ((6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (compound 1-50)

Referring to the procedure of step 3 of example 1, 6- (a)6-bromo-1H-imidazo [4,5-b]Pyrazine-1-yl) methyl) -8-fluoroquinoline reacted with 1-methylpyrazole 4-boronic acid pinacol ester to give a white solid with a yield of 65.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝360； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.95(1H,s)，8.90-8.87(m,2H)，8.45(s,1H)，8.42(d,J＝4.4Hz,1H)，8.14(s,1H)，7.80(s,1H)，7.76(d,J＝12.0Hz,1H)，7.64(dd,J ₁ ＝8.0Hz,J ₂ ＝4.0Hz,1H)，5.72(s,2H)，3.91(s,3H)。

Example 51 to example 56

The compounds of examples 51 to 56 were prepared in the same manner as in example 50 using different boronic acids or boronic esters, the specific experimental data of which are given in Table 3.

TABLE 3 Experimental data Table for Compounds 1-51 through 1-56

Example 57: 8-fluoro- (6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-57)

Step 1 preparation of 6-bromo-N ² - (1- (8-fluoro-6-quinolinyl) ethyl) pyrazine-2, 3-diamine

Referring to the procedure of step 1 of example 1,1- (8-fluoroquinolin-6-yl) ethylamine was used instead of 6-quinolinylmethylene amine to give 6-bromo-N ² - (1- (8-fluoro-6-quinolinyl) ethyl) pyrazine-2, 3-diamine, yield 66.8%. LC-MS (ESI): [ M + H ]] ⁺ ＝362； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.91(s,1H)，8.08(s,1H)，7.49-7.41(m,4H)，5.43-5.36(m,1H)，5.10(brs,1H)，4.56(brs,2H)，1.65(d,J＝6.4Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -8-fluoroquinoline

Referring to the procedure of step 2 of example 1, 6-bromo-N ² The reaction of the- (1- (8-fluoro-6-quinolyl) ethyl) pyrazine-2, 3-diamine and diethoxy methyl acetate gave an orange solid with a yield of 65.6%. LC-MS (ESI): [ M + H ]] ⁺ ＝372； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：9.02(dd,J ₁ ＝4.4Hz,J ₂ ＝1.2Hz,1H)，8.67(s,1H)，8.39(s,1H)，8.18(d,J＝8.4Hz,1H)，7.58(s,1H)，7.54(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H)，7.42(dd,J ₁ ＝10.8Hz,J ₂ ＝1.6Hz,1H)，6.14(q,J＝7.2Hz,1H)，2.17(d,J＝7.2Hz,3H)。

Step 3 preparation of 8-fluoro- (6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-57)

Referring to the procedure of step 3 of example 1, 6- (1- (6-bromo-1H-imidazo [4, 5-b))]Pyrazine-1-yl) ethyl) -8-fluoroquinoline reacts with 1-methylpyrazole 4-boronic acid pinacol ester to obtain a yellow solid with a yield of 55.0%. LC-MS (ESI): [ M + H ]] ⁺ ＝374； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.92(dd,J ₁ ＝4.0Hz,J ₂ ＝1.6Hz,1H)，8.70(s,1H)，8.34(s,1H)，8.12(d,J＝8.4Hz,1H)，8.00(s,1H)，7.92(s,1H)，7.53(s,1H)，7.47-7.43(m,2H)，6.12(q,J＝7.2Hz,1H)，3.95(s,3H)，2.14(d,J＝7.2Hz,3H)。

Examples 58 to 68

The compounds of examples 58 to 68 were prepared in the same manner as in example 57 using different boronic acids or boronic esters, and the specific experimental data are given in Table 4.

TABLE 4 Experimental data Table for Compounds 1-58-1-68

Example 69: 6- [6- (1-methyl-1H-pyrazol-4-yl) -imidazo [4,5-b ] pyrazine-1-methylene ] -quinoline (compound 1-69)

Step 1 preparation of 6-bromo-N ² - (7-fluoroquinoline-6-methylene) pyrazine-2, 3-diamines

Referring to the procedure of step 1 of example 1, 7-fluoro-6-quinolinylmethylene amine hydrochloride was substituted for 6-quinolinylmethylene amine to give 6-bromo-N ² - (7-fluoroquinoline-6-methylene) pyrazine-2, 3-diamine, yield 75%. LC-MS (ESI): [ M + H ]] ⁺ 348. Step 2 preparation of 6- (6-bromo-imidazo [4,5-b ]]Pyrazine-1-methylene) -7-fluoroquinolines

Referring to the procedure of step 2 of example 1, 6-bromo-N ² Reaction of- (7-fluoroquinoline-6-methylene) pyrazine-2, 3-diamine with trimethyl orthoformate gave a brown solid in yield: 65 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝358； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.95(s,1H)，8.90(d,J＝2.9Hz,1H)，8.68(s,1H)，8.35(d,J＝7.9Hz,1H)，7.90(d,J＝8.3Hz,1H)，7.82(d,J＝11.7Hz,1H)，7.50(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，5.77(s,2H)。

Step 3 preparation of 7-fluoro-6- (6- (1-methyl-1H-pyrazol-4-yl) -imidazo [4,5-b ] pyrazine-1-methylene) -quinoline (compound 1-69)

Referring to the procedure of step 3 of example 1, 6- (6-bromo-imidazo [4, 5-b)]Pyrazine-1-methylene) -7-fluoroquinoline reacts with 1-methyl-1H-pyrazole-4-boronic acid pinacol ester to obtain a white solid, and the yield is as follows: 50 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝360； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.91(dd,J ₁ ＝4.3Hz,J ₂ ＝1.6Hz,1H)，8.87(s,1H)，8.82(s,1H)，8.42(d,J＝7.5Hz,1H)，8.38(s,1H)，8.10(s,1H)，8.05(d,J＝8.3Hz,1H)，7.84(d,J＝11.6Hz,1H)，7.52(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，5.78(s,2H)，3.90(s,3H)。

Examples 70 to 86

The compounds of example 70 to example 86 were prepared in the same manner as in example 69 using different boronic acids or boronic esters, and the specific experimental data are given in Table 5.

TABLE 5 Experimental data Table for Compounds 1-70 through Compounds 1-86

Example 87: 7-fluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-87)

Step 1 preparation of 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine

Referring to the procedure of step 1 of example 1,1- (7-fluoro-6-quinolyl) ethylamine was used in place of 6-quinolinylmethyleneamine to give 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine, yield: 50 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝362； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.89(s,1H)，8.39(d,J＝7.6Hz,1H)，7.97(d,J＝7.8Hz,1H)，7.77(d,J＝11.7Hz,1H)，7.50(d,J＝3.2Hz,1H)，7.18(s,1H)，7.05(d,J＝5.3Hz,1H)，6.38(s,2H)，5.43(s,1H)，1.61(d,J＝6.0Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-fluoroquinoline

Referring to the procedure of step 2 of example 1, 6-bromo-N ² Reaction of- (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine with diethoxymethyl acetate gave a brown solid in yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝372； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.10(s,1H)，8.93(d,J＝4.0Hz,1H)，8.67(s,1H)，8.43(d,J＝8.2Hz,1H)，8.11(d,J＝8.4Hz,1H)，7.81(d,J＝12.1Hz,1H)，7.55(dd,J ₁ ＝8.2Hz,J ₂ ＝4.0Hz,1H)，6.33(q,J＝7.1Hz,1H)，2.11(d,J＝7.1Hz,3H)。

Step 3 preparation of 7-fluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-87)

Referring to the procedure of step 3 of example 1, 6- (1- (6-bromo-1H-imidazo [4,5-b ])]Pyrazine-1-yl) ethyl) -7-fluoroquinoline reacts with 1-methylpyrazole-4-boronic acid pinacol ester to obtain a white solid, and the yield is as follows: 75 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝374； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.93(s,1H)，8.91(dd,J ₁ ＝4.2Hz,J ₂ ＝1.2Hz,1H)，8.83(s,1H)，8.47(d,J＝8.1Hz,1H)，8.35(s,1H)，8.27(d,J＝8.4Hz,1H)，8.05(s,1H)，7.79(d,J＝12.0Hz,1H)，7.54(dd,J ₁ ＝8.1Hz,J ₂ ＝4.2Hz,1H)，6.35(q,J＝7.1Hz,1H)，3.89(s,3H)，2.16(d,J＝7.1Hz,3H)。

Examples 88 to 110

The compounds of examples 88 to 110 were prepared in the same manner as in example 87 using different boronic acids or boronic esters, and the specific experimental data are shown in Table 6.

TABLE 6 Experimental data Table for Compounds 1-88 through Compounds 1-110

Example 111: 5, 7-difluoro-6- ((6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (compound 1-111)

Step 1 preparation of 6-bromo-N ² - ((5, 7-Difluoroquinolin-6-yl) methyl) pyrazine-2, 3-diamine

Reference example 1, synthesis of step 1, yield: 48.7 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝366； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.01(dd,J ₁ ＝4.4Hz,J ₂ ＝1.2Hz,1H),8.53(d,J＝8.0Hz,1H),7.73(d,J＝10.8Hz,1H),7.66-7.62(m,1H),7.02-7.00(m,1H),6.21(s,2H),4.71(d,J＝4.8Hz,2H)。

Step 2 preparation of 6- ((6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) -5, 7-difluoroquinoline

Reference example 1, synthesis of step 2, yield: 32 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝376； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.01(dd,J ₁ ＝4.4Hz,J ₂ ＝1.2Hz,1H),8.66(s,1H),8.40(s,1H),7.71(d,J＝10.0Hz,1H),7.54-7.51(m,1H),7.49-7.45(m,1H),5.75(s,2H)。

Step 3 preparation of 5, 7-difluoro-6- ((6- (1-methyl-1H-pyrazol-5-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) methyl) quinoline (Compound 1-111)

Reference example 1, synthesis of step 3, yield: 52 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝378； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.02(dd,J ₁ ＝4.0Hz,J ₂ ＝1.2Hz,1H)，8.90(s,1H)，8.57(s,1H)，8.44(d,J＝7.2Hz,1H)，7.69(d,J＝5.2Hz,1H)，7.58(d,J＝2.0Hz,1H)，7.54-7.50(m,1H)，6.76(d,J＝2.0Hz,1H)，5.80(s,2H)，4.30(s,3H)。

Examples 112 to 117

The compounds of example 112 to example 117 were prepared in the same manner as in example 111 using different boronic acids or boronic esters, and the specific experimental data are shown in Table 7.

TABLE 7 Experimental data Table for Compounds 1-112 to Compounds 1-117

Example 118: 5, 7-difluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-118)

Step 1 preparation of 6-bromo-N ² - (1- (5, 7-difluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine

3, 5-dibromopyrazin-2-amine (2.16g, 8.56mmol), 1- (5, 7-difluoroquinolin-6-yl) ethylamine (1.18g, 5.7mmol) and DIPEA (2.2g, 17mmol) were added to NMP (15mL) and reacted overnight at 200 ℃ under argon. The reaction mixture was cooled, poured into water (100mL), extracted with ethyl acetate (50 mL. times.3), washed with organic phase water (50 mL. times.2), washed with saturated brine (50mL), dried and then chromatographed on a fast column to give 1.3g of a yellow solid, yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝380； ¹ H NMR(δppm,CDCl ₃ ,400MHz)：8.92(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.39(dd,J ₁ ＝8.4Hz,J ₂ ＝1.7Hz,1H)，7.58-7.55(m,1H)，7.44-7.39(m,2H)，5.83(q,J＝7.1Hz,1H)，5.30(d,J＝8.5Hz,1H)，4.51(s,2H)，1.73(d,J＝7.1Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline

Will prepare 6-bromo-N ² - (1- (5, 7-Difluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine (1g,2.6mmol) was added to diethoxymethylacetate (9.2mL) and reacted at 150 ℃ in a sealed tube under argon atmosphereAnd (4) at night. The solvent was evaporated to dryness and the crude product was purified by silica gel column to give a brown solid 0.8g, yield: 80 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝390； ¹ H NMR(δppm,CDCl ₃ ,400MHz)：8.97(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.62(t,J＝1.3Hz,1H)，8.60(s,1H)，8.41(dd,J ₁ ＝8.4Hz,J ₂ ＝1.7Hz,1H)，7.64(dd,J ₁ ＝11.8Hz,J ₂ ＝1.7Hz,1H)，7.48(dd,J ₁ ＝8.4Hz,J ₂ ＝4.3Hz,1H)，6.55-6.49(m,1H)，2.23(d,J＝7.3Hz,3H)。

Step 3 preparation of 5, 7-difluoro-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-118)

Mixing 6- (1- (6-bromo-1H-imidazo [4,5-b ]]Pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline (113mg, 0.29mmol), 1-methylpyrazole-4-boronic acid pinacol ester (75mg, 0.6mmol), potassium carbonate (122mg, 0.88mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Adding palladium dichloride (20mg) into a mixed solvent of dioxane (4mL) and water (1mL), blowing argon for 5min in a sealed tube, reacting at 110 ℃ for 3h, and separating by flash column chromatography to obtain a brown solid 70mg, wherein the yield is as follows: 61 percent. LC-MS (ESI) [ M + H] ⁺ ＝392； ¹ H NMR(δppm,DMSO-d ₆ ,400MHz)：9.17(s,1H)，9.02(d,J＝4.2Hz,1H)，8.80(s,1H)，8.66(d,J＝8.4Hz,1H)，8.22(s,1H)，7.90(s,1H)，7.78(d,J＝11.7Hz,1H)，7.68(t,J＝5.7Hz,1H)，6.41(q,J＝7.4Hz,1H)，3.91(s,3H)，2.21(d,J＝7.4Hz,3H)。

Examples 119 to 146

The compounds of examples 119 to 146 were prepared in the same manner as in example 118 using different boronic acids or boronic esters, and the specific experimental data are given in Table 8.

TABLE 8 Experimental data Table for Compounds 1-119 to Compounds 1-146

Example 147: 7-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-147)

Step 1 preparation of 6-bromo-N ² - (1- (7-methylquinolin-6-yl) ethyl) pyrazine-2, 3-diamine

Referring to the legal method of step 1 of example 1, a pale yellow solid is obtained in yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝358； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.80(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.27(dt,J ₁ ＝8.4Hz,J ₂ ＝1.3Hz,1H)，7.88(s 1H)，7.82(s,1H)，7.42(dd,J ₁ ＝8.2Hz,J ₂ ＝4.3Hz,1H)，7.14-7.10(m,2H)，6.33(s,2H)，5.31(q,J＝6.8Hz,1H)，2.64(s,3H)，1.55(d,J＝6.8Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-methylquinoline

Referring to the legal method of step 2 of example 1, a grey solid was obtained in yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝368； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.67(s,1H)，8.18(dt,J ₁ ＝8.3Hz,J ₂ ＝1.3Hz,1H)，8.10(s,1H)，8.00(s,1H)，7.90(s,1H)，7.44(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，6.30(q,J＝7.4Hz,1H)，2.45(d,J＝1.0Hz,3H)，2.13(d,J＝7.4Hz,3H)。

Step 3 preparation of 7-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-147)

Referring to the legal method of step 3 of example 1, a pale yellow solid is obtained in yield: 71 percent. LC-MS (ESI) [ M + H] ⁺ ＝370； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.78(s,1H)，8.16-8.14(m,2H)，8.07(s,1H)，7.98(d,J＝13.8Hz,2H)，7.86(s,1H)，7.45(dd,J ₁ ＝8.3Hz,J ₂ ＝4.3Hz,1H)，6.36(q,J＝7.4Hz,1H)，4.02(s,3H)，2.55(d,J＝1.0Hz,3H)，2.12(d,J＝7.4Hz,3H)。

Example 148 to example 154

The compounds of example 148-example 154 were prepared in the same manner as in example 147 using different boronic acids or boronic esters, and the specific experimental data are given in Table 9.

TABLE 9 Experimental data Table for Compounds 1-148 through 1-154

Example 155: 5-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-155)

Step 1 preparation of 6-bromo-N ² - (1- (5-methylquinolin-6-yl) ethyl) pyrazine-2, 3-diamine

Referring to the legal method of step 1 of example 1, a pale yellow solid is obtained in yield: 30 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝358； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.84(dd,J ₁ ＝4.1Hz,J ₂ ＝1.6Hz,1H)，8.60-8.57(m,1H)，7.87-7.76(m,2H)，7.54(dd,J ₁ ＝8.6Hz,J ₂ ＝4.1Hz,1H)，7.16-7.11(m,2H)，6.32(s,2H)，5.49(q,J＝6.8Hz,1H)，2.79(s,3H)，1.53(d,J＝6.8Hz,3H)。

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5-methylquinoline

Referring to the legal method of step 2 of example 1, a brown solid was obtained in yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝368； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.22(s,1H)，8.89(dd,J ₁ ＝4.3Hz,J ₂ ＝1.7Hz,1H)，8.65-8.62(m,2H)，7.87(d,J＝9.0Hz,1H)，7.71(d,J＝9.0Hz,1H)，7.58(dd,J ₁ ＝8.6Hz,J ₂ ＝4.3Hz,1H)，6.47(q,J＝7.0Hz,1H)，2.51(d,J＝1.8Hz,3H)，2.05(d,J＝7.0Hz,3H)。

Step 3 preparation of 5-methyl-6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-155)

Referring to the legal process of step 3 of example 1, an orange solid is obtained in yield: 70 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝370； ¹ H-NMR(δppm,CDCl ₃ ,400MHz)：8.96(d,J＝3.2Hz,1H),8.75(s,1H),8.47(d,J＝8.4Hz,1H),8.27(s,1H),8.06(t,J＝4.4Hz,2H),7.94(s,1H),7.79(d,J＝9.2Hz,1H),7.50(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H),6.52(q,J＝7.2Hz,1H),4.01(s,3H),2.80(s,3H),2.14(d,J＝7.2Hz,3H).

Examples 156 to 160

The compounds of example 156 to example 160 were prepared by the same method as in example 155 using different boronic acids or boronic esters. Specific experimental data are shown in table 10.

TABLE 10 Experimental data Table for Compounds 1-156 to Compounds 1-160

Example 161: 3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (4-methylpiperazin-1-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-161)

Step 1 preparation of 6-bromo-N ² - (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine

2-amino-3, 5-dibromopyrazine (257mg,1.02mmol) was dissolved in 12ml of 1-methyl-2-pyrrolidone, and 1- (3- (1-methyl) -l-pyrrolidone was added thereto at ordinary temperatureYl-1H-pyrazol-4-yl) quinolin-6-yl) ethylamine (385mg, 1.53mmol) and 6ml of N, N-diisopropylethylamine. The reaction solution was heated to 210 ℃ under argon protection and sealed overnight. The reaction was concentrated and the crude product was purified by flash column (developing solvent dichloromethane: methanol: 95: 5). About 260mg of a brown solid are obtained in 60% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝424， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.14(d,J＝2.2Hz,1H),8.45(d,J＝2.0Hz,1H),8.40(s,1H),8.11(d,J＝0.6Hz,1H),7.95(d,J＝8.7Hz,1H),7.82(d,J＝1.7Hz,1H),7.71(dd,J＝8.7,2.0Hz,1H),7.17(s,1H),7.01(d,J＝7.0Hz,1H),6.35(s,2H),5.31–5.22(m,1H),3.92(d,J＝3.5Hz,3H),3.18(d,J＝5.2Hz,1H),1.59(d,J＝7.0Hz,3H).

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline

Reacting 6-bromo-N ² - (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine (100mg, 0.24mmol) was dissolved in 10ml diethoxymethyl acetate, and the reaction was heated to 150 ℃ and the tube was sealed overnight. The reaction solution was concentrated and the crude residue was purified by flash column (developing solvent methanol: dichloromethane ═ 0% to 5%). 59mg of a light brown solid are obtained in yield: 58 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝435， ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.10(d,J＝2.2Hz,1H),8.67(s,1H),8.37(s,1H),8.16(d,J＝2.1Hz,1H),8.12(d,J＝8.8Hz,1H),7.93(s,1H),7.82(s,1H),7.76(d,J＝1.7Hz,1H),7.63(dd,J＝8.8,2.1Hz,1H),6.18(q,J＝7.1Hz,1H),4.03(s,3H),2.17(d,J＝7.2Hz,3H).

Step 3 preparation of 3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (4-methylpiperazin-1-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 1-161)

Mixing 6- (1- (6-bromo-1H-imidazo [4,5-b ]]Pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (60mg, 0.14mmol) was dissolved in 5ml 1-methyl-2-pyrrolidone, and then 3 equivalents of 1-methylpiperazine, 5 equivalents of potassium fluoride and 4 equivalents of N, N-diisopropylethylamine were added in this order. The reaction solution was reacted at 170 ℃ for 2 hours with tube sealed. The reaction was concentrated and the crude residue purified by flash column (dichloromethane: methanol: 94: 6 as developing solvent) to give 287mg yellow solid powder, yield: and 69 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝454， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.16(d,J＝2.2Hz,1H),8.62(s,1H),8.44(d,J＝1.8Hz,1H),8.38(s,1H),8.20(s,1H),8.09(s,1H),7.95(d,J＝8.7Hz,1H),7.85(d,J＝1.3Hz,1H),7.74(dd,J＝8.7,1.9Hz,1H),6.02(q,J＝7.0Hz,1H),3.91(s,3H),3.54(s,4H),2.42–2.35(m,4H),2.18(d,J＝4.3Hz,1H),2.08(d,J＝7.2Hz,3H).

Examples 162 to 163

The compound of example 162 was prepared according to the same procedure as in example 161. The corresponding boronic ester was used in example 163 and was synthesized by the SUZUKI reaction. Specific experimental data are shown in table 11.

TABLE 11 Experimental data Table for Compounds 1-162 through Compounds 1-163

Example 164: 3- (1-methyl-1H-4-pyrazolyl) -6- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazin-1-ylmethyl) quinoline (compound 2-1)

3, 5-dibromopyrazin-2-amine (6.1g, 24mmol), 6-quinolinylmethylene amine (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) were added to NMP (20mL) and reacted overnight at 130 ℃ under argon. The reaction solution was distilled off DIPEA, the residue was poured into water (100ml), extracted with dichloromethane (30ml × 3), the organic phase was washed with water, saturated brine was washed with water, dried and then subjected to rapid column chromatography to obtain a tan product 4.7g, yield: 59 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝330； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.85(dd,J ₁ ＝4.2Hz,J ₂ ＝1.6Hz,1H)，8.33(d,J＝8.3Hz,1H)，7.99(d,J＝8.7Hz,1H)，7.87(s,1H)，7.73(dd,J ₁ ＝8.7Hz,J ₂ ＝1.9Hz,1H)，7.50(dd,J ₁ ＝8.3Hz,J ₂ ＝4.2Hz,1H)，7.21(s,1H)，7.16(t,J＝5.4Hz,1H)，6.25(s,2H)，4.69(d,J＝5.4Hz，2H)。

Step 2 preparation of 6- (6-bromo- [1,2,3] triazolo [4,5-b ] pyrazin-1-ylmethyl) quinoline

The raw material 6-bromo-N ² - (quinoline-6-methylene) pyrazine-2, 3-diamine (500mg, 1.5mmol) was dissolved in anhydrous DMF (10ml), isoamyl nitrite (356mg, 3mmol, 2eq) was added, and the reaction was carried out under argon atmosphere at 70 ℃ for 3 h. After the reaction was completed, the solvent was evaporated to dryness, and the crude product was purified by slurrying with ethyl acetate to give 217mg of a yellow solid with a yield of 42.0%. LC-MS (ESI): [ M + H ]] ⁺ ＝340.8； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.02(s,1H),8.91(dd,J ₁ ＝4.0Hz,J ₂ ＝2.0Hz,1H),8.36(dd,J ₁ ＝8.4Hz,J ₂ ＝0.8Hz,1H),8.03(d,J＝8.8Hz,1H),7.94(d,J＝2.0Hz,1H),7.78(dd,J ₁ ＝8.8Hz,J ₂ ＝2.0Hz,1H),7.54(dd,J ₁ ＝8.4Hz,J ₂ ＝4.0Hz,1H),6.19(s,2H).

Step 3 is to prepare 3-bromo-6- (6-bromo- [1,2,3] triazolo [4,5-b ] pyrazin-1-ylmethyl) quinoline

The raw material 6- (6-bromo- [1,2, 3)]Triazole [4,5-b ]]Pyrazin-1-ylmethyl) quinoline (100mg, 0.3mmol) was dissolved in carbon tetrachloride (10ml), pyridine (47mg, 0.6mmol, 2eq) and liquid bromine (94mg, 0.6mmol, 2eq) were added, respectively, and the reaction was carried out at 80 ℃ for 4 h. After the reaction is completed, the solvent is evaporated to dryness, sodium carbonate aqueous solution is added to adjust the solution to be alkaline, dichloromethane is used for extraction, water washing is carried out, saturated saline solution is used for washing, and column chromatography purification is carried out to obtain 82mg of yellow solid with the yield of 66.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝418.7； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.02(s,1H),8.94(d,J＝2.4Hz,1H),8.69(d,J＝2.4Hz,1H),8.05(d,J＝8.8Hz,1H),7.87(d,J＝2.0Hz,1H),7.83(dd,J ₁ ＝8.8Hz,J ₂ ＝2.0Hz,1H),6.21(s,2H).

Step 4 preparation of 3- (1-methyl-1H-4-pyrazolyl) -6- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazin-1-ylmethyl) quinoline (Compound 2-1)

The raw material 3-bromo-6- (6-bromo- [1,2, 3)]Triazole [4,5-b ]]Pyrazin-1-ylmethyl) quinoline (80mg, 0.19mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (100mg, 0.48mmol, 2.5eq), catalyst Pd (dppf) Cl ₂ DCM (8mg,0.01mmol, 0.05eq) and K ₂ CO ₃ (79mg, 0.57mmol, 3eq) was dissolved in dioxane + water (2ml +0.5ml) and reacted under argon at 110 ℃ overnight. The solvent was evaporated to dryness and the residue was purified on plate to give 56mg of a white solid in 70.0% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝422.9； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.22(s,1H),9.17(d,J＝2.4Hz,1H),8.64(s,1H),8.46(d,J＝1.6Hz,1H),8.37(s,1H),8.31(s,1H),8.07(s,1H),7.99(d,J＝8.8Hz,1H),7.84(d,J＝1.2Hz,1H),7.76(dd,J ₁ ＝8.4Hz,J ₂ ＝2.0Hz,1H),6.15(s,2H),3.95(s,3H),3.90(s,3H).

Examples 165 to 168

The compounds of example 165-example 168 were prepared in the same manner as in example 164 using different boronic acids or boronic esters. Specific experimental data are shown in table 12.

TABLE 12 Experimental data Table for Compound 2-2 to Compound 2-5

Example 169 7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 2-6)

Step 1 preparation of 5-bromo-N ³ - (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) pyrazine-2, 3-diamine

The starting materials 1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethylamine (403mg, 1.5mmol), 2-amino-3, 5-dibromopyrazine (453mg, 1.8mmol, 1.2eq) and DIPEA (578mg, 4.5mmol, 3eq) were dissolved in NMP (5ml) and reacted overnight at 200 ℃ under argon protection. After the reaction is completed, a large amount of water is added, ethyl acetate is used for extraction, water washing is carried out, washing is carried out by using saturated saline solution, anhydrous sodium sulfate is used for drying, filtration and evaporation are carried out, a crude product is subjected to column chromatography purification, and an orange solid 371mg is obtained, wherein the yield is 56.4%. LC-MS (ESI): [ M + H ]] ⁺ ＝441.9.

Step 2 preparation of 6- (1- (6-bromo- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinoline

The raw material 5-bromo-N ³ - (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) pyrazine-2, 3-diamine (462mg, 1.05mmol) was dissolved in anhydrous DMF (8ml), isoamyl nitrite (246mg, 2.1mmol, 2eq) was added, and the reaction was carried out under argon atmosphere at 80 ℃ for 2H. After the reaction is completed, the solvent is evaporated to dryness, and a crude product is purified by column chromatography to obtain 383mg of yellow solid with the yield of 80.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝452.8.

Step 3 preparation of 7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6- (1- (6- (1-methyl-1H-4-pyrazolyl) - [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 2-6)

The raw material 6- (1- (6-bromo- [1,2, 3)]Triazole [4,5-b ]]Pyrazin-1-yl) ethyl) -7-fluoro-3- (1-methyl-1H-4-pyrazolyl) quinoline (80mg, 0.18mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (55mg, 0.26mmol, 1.5eq), catalyst Pd (dppf) Cl ₂ DCM (7mg,0.008mmol, 0.05eq) and K ₂ CO ₃ (73mg, 0.53mmol, 3eq) was dissolved in dioxane + water (2ml +0.5ml) and reacted overnight at 110 ℃ under argon. Cooling to room temperature, adding a large amount of water, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, purifying crude product preparation plate to obtain yellow solid 45mg, and obtaining yield 56.3％。LC-MS(ESI)：[M+H] ⁺ ＝455.0； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.21(d,J＝2.0Hz,1H),9.20(s,1H),8.59(d,J＝2.0Hz,1H),8.58(s,1H),8.36(s,1H),8.23(s,1H),8.07(d,J＝7.2Hz,1H),8.06(s,1H),7.80(d,J＝11.6Hz,1H),6.73(q,J＝7.2Hz,1H),3.93(s,3H),3.91(s,3H),2.24(d,J＝7.2Hz,3H).

Examples 170 to 179

The compounds of examples 170 to 179 were prepared in the same manner as in example 169 using different boronic acids or boronic esters, and the specific experimental data are shown in Table 13.

TABLE 13 Experimental data Table for Compounds 2-8 to 2-9

Example 180: 3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 2-17)

2-amino-3, 5-dibromopyrazine (257mg,1.02mmol) was dissolved in 12ml of 1-methyl-2-pyrrolidone, and then 1- [3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl ] ethylamine (385mg, 1.53mmol) and 6ml of N, N-diisopropylethylamine were added at ordinary temperature. The reaction solution was heated to 190 ℃ under argon atmosphere for overnight reaction. The reaction was concentrated and the crude product was purified by flash column (developing solvent dichloromethane: methanol: 95: 5). About 260mg of a brown solid was obtained in a yield of 60.3%.

LC-MS(ESI)：[M+1] ⁺ ＝424, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.14(d,J＝2.2Hz,1H),8.45(d,J＝2.0Hz,1H),8.40(s,1H),8.11(d,J＝0.6Hz,1H),7.95(d,J＝8.7Hz,1H),7.82(d,J＝1.7Hz,1H),7.71(dd,J ₁ ＝8.7Hz,J ₂ ＝2.0Hz,1H),7.17(s,1H),7.01(d,J＝7.0Hz,1H),6.35(s,2H),5.31–5.22(m,1H),3.92(d,J＝3.5Hz,3H),3.18(d,J＝5.2Hz,1H),1.59(d,J＝7.0Hz,3H).

Step 2 preparation of 6- (1- (6-bromo-1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline

Reacting 6-bromo-N ² - (1- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine (100mg, 0.24mmol) was dissolved in 5mL of DMF, and isoamyl nitrite (56mg, 0.48mmol) was added thereto, and the mixture was heated to 70 ℃ to react for 2 hours. The reaction solution was concentrated and the residual crude product was purified by flash column (developing solvent methanol: dichloromethane ═ 0% to 5%). 59mg of a light brown solid are obtained in a yield of 57.6%. LC-MS (ESI): [ M +1 ]] ⁺ ＝435, ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.08(d,J＝2.2Hz,1H),8.78(s,1H),8.16(d,J＝1.9Hz,1H),8.09(d,J＝8.7Hz,1H),7.94–7.88(m,2H),7.84–7.77(m,2H),6.47(q,J＝7.2Hz,1H),4.03(s,3H),2.34(d,J＝7.2Hz,3H)。

Step 3 preparation of 3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 2-17)

Mixing 6- (1- (6-bromo-1H- [1,2, 3)]Triazolo [4,5-b ]]Pyrazin-1-yl) ethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (60mg, 0.14mmol) was dissolved in 12ml of 1, 4-dioxane, followed by addition of 1-methylpyrazole-4-boronic acid pinacol ester (44mg, 0.21mmol), Pd (dppf) ₂ Cl ₂ (11mg,0.014mmol), anhydrous potassium carbonate (39mg,0.28mmol) and 3ml water. The reaction solution is maintained under argonThe tube was sealed overnight at 110 ℃ under the protection. The reaction solution was concentrated, and the residual crude product was purified by flash column (developing solvent methanol: dichloromethane ═ 5: 95) to obtain the objective compound. The yield was 62.33%. LC-MS (ESI): [ M +1 ]] ⁺ ＝437, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.20(s,1H),9.17(d,J＝2.2Hz,1H),8.63(s,1H),8.49(d,J＝2.2Hz,1H),8.38(s,1H),8.29(s,1H),8.08(s,1H),7.99(d,J＝8.7Hz,1H),7.89(d,J＝2.0Hz,1H),7.82(dd,J ₁ ＝8.7Hz,J ₂ ＝2.0Hz,1H),6.59(q,J＝7.1Hz,1H),3.94(s,3H),3.90(s,3H)2.25(d,J＝7.1Hz,3H).

Examples 181 to 186

The compounds of example 181 to example 186 were prepared in the same manner as in example 180 using different boronic acids or boronic esters, and the specific experimental data are shown in Table 14.

TABLE 14 Experimental data Table for Compounds 2-18 through 2-23

Example 1873- (4-fluorophenyl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 2-24)

Step 1 preparation of 6-bromo-N ² - (1- (3- (4-fluorophenyl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine

10ml of N-methylpyrrolidone was charged into a single-necked flask, and 0.71g (2.8mmol) of 3, 5-dibromopyrazine-2-amine and 1- (3- (4 mmol) were sequentially charged-fluorophenyl) quinolin-6-yl) ethylamine 0.75g (2.8mmol) and diisopropylethylamine 0.73g (5.6mmol) were added and reacted overnight at 190 ℃ under nitrogen protection without starting material by LC-MS. And (2) post-treatment, namely adding 200ml of dichloromethane into the reaction solution, washing with a saturated sodium carbonate aqueous solution, washing with water, washing with saturated salt water, drying an organic layer, and separating by silica gel column chromatography to obtain 0.65g of a product, wherein the yield is as follows: 53 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝438， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.19(d,J＝2.3Hz,1H),8.61(d,J＝2.1Hz,1H),8.03(d,J＝8.7Hz,1H),7.98–7.88(m,3H),7.80(dd,J ₁ ＝8.7Hz,J ₂ ＝1.8Hz,1H),7.39(t,J＝8.9Hz,2H),7.17(s,1H),7.03(d,J＝7.0Hz,1H),6.35(s,2H),5.29(q,J＝7.0Hz，1H),1.60(d,J＝7.0Hz,3H).

Step 2 preparation of 6- (1- (6-bromo-1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -3- (4-fluorophenyl) quinoline

To a single necked flask was added 10ml of anhydrous DMF followed by 6-bromo-N ² - (1- (3- (4-fluorophenyl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine 650mg (1.48mmol) and isoamylnitrite 350mg (2.96mmol), after the addition, the temperature was raised to 75 ℃ under nitrogen protection, and the reaction was carried out for 3 hours. After-treatment, the solvent was evaporated to dryness, the crude product was dissolved in 100ml of dichloromethane, washed successively with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine, the organic layer was dried and separated by silica gel column chromatography to give 260mg of the product with a yield of 39%. LC-MS (ESI): [ M + H ]] ⁺ ＝449， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.24(d,J＝2.2Hz,1H),9.01(s,1H),8.64(d,J＝2.2Hz,1H),8.06(d,J＝8.7Hz,1H),7.99(d,J＝1.8Hz,1H),7.93(dd,J ₁ ＝8.8Hz,J ₂ ＝5.4Hz,2H),7.85(dd,J＝8.8,2.1Hz,1H),7.39(t,J＝8.9Hz,2H),6.63(q,J＝7.1Hz,1H),2.22(d,J＝7.1Hz,3H).

Step 3 preparation of 3- (4-fluorophenyl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (Compound 2-24)

Mixing 6- (1- (6-bromo-1H- [1,2, 3)]Triazolo [4,5-b]Pyrazin-1-yl) ethyl) -3- (4-fluorophenyl) quinoline (60mg, 0.13mmol) was dissolved in 12ml of 1, 4-dioxane, followed by addition (42mg, 0.20mmol) of 1-methyl-4-pyrazoleboronic acid pinacol ester, Pd (dppf) ₂ Cl ₂ (11mg,0.013mmol), anhydrous potassium carbonate (39mg,0.26mmol) and 3ml water. The reaction solution was sealed overnight at 110 ℃ under argon. The reaction solution was concentrated, and the residual crude product was purified by flash column (methanol: dichloromethane ═ 5: 95 as a developing solvent) to obtain 16mg of the objective compound, yield: 25%, LC-MS (ESI): [ M + H ]] ⁺ ＝451, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.23(d,J＝2.3Hz,1H),9.20(s,1H),8.67(d,J＝2.2Hz,1H),8.63(s,1H),8.29(s,1H),8.06(d,J＝8.7Hz,2H),7.97–7.88(m,3H),7.39(t,J＝8.9Hz,2H),6.61(q,J＝7.1Hz,1H),3.94(s,3H),2.27(d,J＝7.1Hz,3H).

Example 1882-fluoro-N-methyl-4- (7- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-ylmethyl) imidazo [1,2-b ] [1,2,4] triazin-2-yl) benzamide (Compound 3-1)

Step 1 preparation of quinoline-6-acetic acid ester

50ml of dry dichloromethane were added to a 100ml round bottom three necked flask, followed by the addition of 4.5g (31mmol) of 6-hydroxyquinoline and 2.9g (37mmol) of pyridine in that order with stirring, cooling to 0 ℃ and the dropwise addition of 2.9g (37mmol) of acetyl chloride slowly, after the addition was complete, stirring at room temperature and reaction overnight. And (3) post-treatment, pouring the reaction solution into 200ml of cold saturated sodium carbonate aqueous solution, separating an organic phase, extracting 50ml of 2 by using aqueous phase dichloromethane, combining the organic phases, washing by using saturated saline solution, drying to obtain 3g of a product, wherein the yield is 52%, and directly putting the product into the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝188.

Step 2 preparation of 3-Bromoquinoline-6-acetic acid ester

Adding 20ml of carbon tetrachloride into a 100ml single-neck bottle, adding 1g (5.34mmol) of quinoline-6-acetate, 1.06g (13.4mmol) of pyridine and 2.13g (13.4mmol) of liquid bromine in sequence under stirring, heating and refluxing for 2h after the addition is finished, cooling to room temperature, evaporating the solvent, adding 100ml of dichloromethane into the residue for dissolving, washing with a sodium thiosulfate solution and a sodium carbonate aqueous solution, washing with saturated salt water, drying and evaporating to dryness to obtain 1.1g of a product, wherein the yield is as follows: 77 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝266, ¹ H-NMR(δppm,CDCl ₃ ,400MHz):8.91(d,J＝2.3Hz,1H),8.29(d,J＝2.2Hz,1H),8.11(d,J＝9.0Hz,1H),7.52(d,J＝2.4Hz,1H),7.49(dd,J ₁ ＝9.0Hz,J ₂ ＝2.4Hz,1H),2.39(s,3H).

Step 3 preparation of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-acetate

A100 ml single neck flask was charged with 25ml dioxane and 5ml water, to which were added 1g (3.76mmol) 3-bromoquinoline-6-acetate, 1.56g (7.52mmol) 1-methylpyrazole-4-boronic acid pinacol ester, potassium carbonate 1.04g (7.52mmol) and 86mg (0.11mmol)1,1' -bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex, after which it was heated to 110 ℃ under nitrogen for 4 h. And (3) post-treatment, pouring the reaction solution into 100ml dichloromethane for washing, washing with saturated salt water, drying, filtering and evaporating the solvent to dryness to obtain 0.75g of crude product, wherein the yield is 75%, and directly putting the crude product into the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝268。

Step 4 preparation of 3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-ol

750mg (2.8mmol) of the crude product from the previous step are dissolved in 25ml of methanol, 235mg (5.6mol) of lithium hydroxide are dissolved in 5ml of water and then added to the methanol solution, and the reaction solution is heated to 60 ℃ for 2 h. And (3) post-treatment, namely concentrating the reaction solution to half, adding 10ml of water, adjusting the pH value to be about 6 by using 4N hydrochloric acid, filtering, washing a filter cake, and drying to obtain 600mg of a product with the yield of 95%. LC-MS (ESI): [ M + H ]] ⁺ ＝226, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):10.00(s,1H),8.93(d,J＝2.2Hz,1H),8.35(s,1H),8.25(d,J＝2.2Hz,1H),8.06(s,1H),7.82(d,J＝9.1Hz,1H),7.22(dd,J ₁ ＝9.1Hz,J ₂ ＝2.6Hz,1H),7.10(d,J＝2.6Hz,1H),3.91(s,3H).

Step 5 preparation of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-triflate

To 50ml of dry dichloromethane were added 600mg (2.66mmol) of 3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-ol and 809mg (7.99mmol) of triethylamine, and 902mg (3.20mmol) of trifluoromethanesulfonic anhydride was slowly added dropwise in an ice bath, and after completion of addition, the mixture was slowly returned to room temperature overnight. And (3) post-treatment, washing the reaction solution with saturated sodium carbonate and saturated salt, drying, and purifying by silica gel column chromatography to obtain 500mg of a product, wherein the yield is as follows: 52.5 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝226, ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.15(d,J＝2.2Hz,1H),8.23–8.16(m,2H),7.95(s,1H),7.85(s,1H),7.76(d,J＝2.7Hz,1H),7.56(dd,J ₁ ＝9.2Hz,J ₂ ＝2.7Hz,1H),4.04(s,3H).

Step 6 preparation of methyl (E) -3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) acrylate

430mg (1.2mmol) of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-trifluoromethanesulfonate are dissolved in 5ml of anhydrous DMF, and then 207mg (2.4mmol) of methyl acrylate, 487mg (4.8mmol) of triethylamine and 27mg of 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex are added, after completion of addition, nitrogen substitution is carried out, and reaction is carried out at an external temperature of 125 ℃ for 3 hours. Post-treatment, pouring the reaction solution into 50ml saturated sodium bicarbonate water solution, extracting 30ml x 3 with ethyl acetate, combining organic phases, washing with water, washing with saturated salt water, drying, evaporating the solvent to obtain a crude product 240mg, yield: 68 percent, and directly putting the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝294。

Step 7 preparation of methyl 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propionate

240mg (0.818mmol) of methyl (E) -3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) acrylate was dissolved in 50ml of methanol, 10mg (10%) of Pd/C was added, hydrogenation was performed at room temperature under 2-3atm overnight, and no starting material was detected by LC-MS. Filtering, concentrating the filtrate, and purifying by silica gel column chromatography to obtain 220mg of product, wherein the yield is as follows: 91 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝296, ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.01(d,J＝2.2Hz,1H),8.10(d,J＝2.2Hz,1H),8.01(d,J＝8.6Hz,1H),7.91(s,1H),7.79(s,1H),7.61(s,1H),7.52(dd,J ₁ ＝8.6Hz,J ₂ ＝2.0Hz,1H),4.01(s,3H),3.68(s,3H),3.15(t,J＝7.7Hz,2H),2.75(t,J＝7.7Hz,2H).

Step 8 preparation of 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propyl-1-ol

57mg (1.5mmol) of lithium aluminium hydride are added to 15ml of ultra-dry tetrahydrofuran, cooled to-10 ℃ under nitrogen, and 220mg (0.75mmol) of a solution of 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propionic acid methyl ester in tetrahydrofuran are slowly added dropwise, after the addition, the temperature is slowly raised to room temperature, and the reaction is carried out for 1H. After-treatment, saturated chlorine was added dropwise to the reaction solution in ice bath0.5ml of ammonium chloride aqueous solution and 10ml of ethyl acetate were added, followed by filtration. Washing a filter cake with ethyl acetate, combining filtrates, drying and evaporating to obtain a crude product of 180mg, and obtaining the yield: 90 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝268。

Step 9 preparation of 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propanal

290mg (1.1mmol) of 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propyl-1-ol was dissolved in 20ml of methylene chloride, and 552mg (1.3mmol) of Dess-Martin reagent was added thereto under ice bath, followed by reaction at room temperature overnight. Post-treatment, adding sodium thiosulfate aqueous solution and sodium bicarbonate aqueous solution into the reaction solution, stirring for 30min at room temperature, washing the organic phase with saturated salt water, drying, and purifying by silica gel column chromatography to obtain 240mg of product, wherein the yield is as follows: 83 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝266, ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.88(s,1H),9.02(s,1H),8.10(s,1H),8.01(d,J＝8.6Hz,1H),7.91(s,1H),7.79(s,1H),7.60(s,1H),7.51(d,J＝8.6Hz,1H),4.01(s,3H),3.16(t,J＝7.5Hz,2H),2.91(t,J＝7.5Hz,2H).

Step 10 preparation of 2-chloro-3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propanal

Dissolving 240mg (0.90mmol) of 3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propanal in 2ml of acetonitrile, adding 10mg (0.09mmol) of L-proline, 11mg (0.09mmol) of benzoic acid and 13mg (0.95mmol) of NCS in sequence under ice bath, reacting overnight at room temperature after the addition is finished, adding 2ml of ethyl acetate after the reaction is finished, stirring for 30min, filtering, washing a filter cake with ethyl acetate, and drying to obtain 185mg of a crude product, wherein the yield is as follows: 51%, directly putting the mixture into the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝300。

Step 11 preparation of methyl 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluorobenzoate

1g (5.7mmol) of 6-bromo-1, 2, 3-triazin-3-amine, 1.2g (6.3mmol) of 3-fluoro-4-methoxybenzoic acid phenylboronic acid, 0.95g (6.9mmol) of potassium carbonate and 20mg of 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex were added to 10ml of dioxane, 2.5ml of water was added thereto, and after nitrogen substitution, the mixture was allowed to react at an external temperature of 85 ℃ overnight. Post-treatment, pouring the reaction solution into 100ml dichloromethane, washing with water, washing with saturated salt water, drying, and purifying by silica gel column chromatography to obtain 1.2g of product, yield: 85％。LC-MS(ESI)：[M+H] ⁺ ＝249, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):8.93(s,1H),8.04–7.94(m,3H),7.64(s,2H),3.88(s,3H).

Step 12 preparation of 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluoro-N-methylaniline

To the sealed tube was added 20ml of a 33% methylamine alcohol solution, and 1.2g (4.8mmol) of methyl 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluorobenzoate was added to the above solution at room temperature, and the mixture was heated to 45 ℃ and sealed for reaction overnight. Post-treatment, cooling to room temperature, filtering, and drying a filter cake to obtain 1g of a product, wherein the yield is as follows: 83 percent, and directly putting the mixture into the next step. LC-MS (ESI): [ M + H ]] ⁺ ＝248。

Step 13 preparation of 2-fluoro-N-methyl-4- (7- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) methyl) imidazole [1,2-b ] [1,2,4] triazin-2-yl) benzamide (Compound 3-1)

185mg (0.75mmol) of 4- (3-amino-1, 2, 4-triazin-6-yl) -2-fluoro-N-methylaniline and 224mg (0.75mmol) of 2-chloro-3- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) propanal were added to 3ml of ethylene glycol and reacted at an external temperature of 150 ℃ overnight. And (3) post-treatment, pouring the reaction solution into 50ml of dichloromethane, washing with saturated sodium carbonate aqueous solution, washing with water, washing with saturated salt water, drying, and purifying by silica gel column chromatography to obtain 15mg of a product, wherein the yield is 4%. LC-MS (ESI): [ M + H ]] ⁺ ＝493, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.23(s,1H),9.13(d,J＝2.2Hz,1H),8.43–8.35(m,3H),8.09–7.99(m,4H),7.94(d,J＝8.6Hz,1H),7.86–7.78(m,2H),7.72(dd,J ₁ ＝8.6Hz,J ₂ ＝1.9Hz,1H),4.65(s,2H),3.91(s,3H),2.81(d,J＝4.6Hz,3H).

Example 1896- (1- (6- (1H-indol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (Compound 1-164)

Step 1 preparation of 6-bromo-N ² - (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine

2-amino-3, 5-dibromopyrazine (391mg,1.55mmol) was dissolved in 12ml of 1-methyl-2-pyrrolidone, after which 1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethylamine (300mg, 1.03mmol) and 3ml of N, N-diisopropylethylamine were added at ordinary temperature. The reaction solution was heated to 190 ℃ under argon protection and sealed overnight. The reaction was concentrated and the crude product was purified by flash column (developing solvent dichloromethane: methanol: 95: 5). About 303mg of a brown solid are obtained in yield: and 64 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝459； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.24(s,1H),8.51(d,J＝10.2Hz,2H),8.19(s,1H),7.61(d,J＝11.6Hz,1H),7.12(s,1H),6.39(s,2H),4.11(q,J＝5.2Hz,1H),3.91(s,3H),1.72(d,J＝7.1Hz,3H).

Step 2 preparation of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline

Reacting 6-bromo-N ² - (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine (285mg, 0.62mmol) was dissolved in 10ml diethoxymethylacetate and the reaction was heated to 150 ℃ and sealed overnight. The reaction solution was concentrated and the crude residue was purified by flash column (developing solvent methanol: dichloromethane ═ 0% to 5%). 220mg of a yellow solid are obtained, yield: and 76 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝471。

Step 3 preparation of 6- (1- (6- (1H-indol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl-5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (Compound 1-164)

Mixing 6- (1- (6-bromo-1H-imidazo [4,5-b ]]Pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (60mg, 0.14mmol) is dissolved in 12ml1, 4-dioxane, and then 1.5 equivalents of (1H-indol-4-yl) boronic acid, Pd (dppf) Cl, are added in succession ₂ (11mg,0.014mmol), anhydrous potassium carbonate (39mg,0.28mmol) and 3ml water. The reaction solution was sealed overnight at 110 ℃ under argon. The reaction was concentrated and the crude residue purified by flash column (dichloromethane: methanol 95:5 as developing solvent) and the final product washed once with methanol to yield 49.6mg of a yellow solid powder, yield: 77 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝507； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):11.22(d,J＝6.5Hz,1H),9.30(s,1H),9.20(s,1H),9.01(s,1H),8.54(d,J＝28.3Hz,2H),8.21(s,1H),7.71(d,J＝12.1Hz,1H),7.47(dd,J＝18.3,7.5Hz,2H),7.15(t,J＝7.4Hz,1H),7.04(s,1H),6.56–6.34(m,2H),3.91(s,3H),2.25(d,J＝6.6Hz,3H).

Examples 190 to 194

The compounds of example 190 to example 194 were prepared in the same manner as in example 189 using different boronic acids or boronic acid esters, and the specific experimental data are shown in Table 15.

TABLE 15 Experimental data Table for Compounds 1-165 to 1-169

Example 1965, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 2-25)

2-amino-3, 5-dibromopyrazine (391mg,1.55mmol) was dissolved in 12ml of 1-methyl-2-pyrrolidone, after which 1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethylamine (300mg, 1.03mmol) and 3ml of N, N-diisopropylethylamine were added at ordinary temperature. The reaction solution was heated to 190 ℃ under argon protection and sealed overnight. Concentrating the reaction solution, and purifying the crude product by flash column (dichloromethane as developing agent: methanol)95: 5). About 303mg of a brown solid are obtained in yield: and 64 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝459； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.24(s,1H),8.51(d,J＝10.2Hz,2H),8.19(s,1H),7.61(d,J＝11.6Hz,1H),7.12(s,1H),6.39(s,2H),4.11(q,J＝5.2Hz,1H),3.91(s,3H),1.72(d,J＝7.1Hz,3H).

Step 2 preparation of 6- (1- (6-bromo-1H- [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline

Reacting 6-bromo-N ² - (1- (5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyrazine-2, 3-diamine (439mg, 0.95mmol) was dissolved in 5ml DMF, and then 0.03ml isoamyl nitrite was slowly added to the solution at room temperature, and after stirring at room temperature for 15 minutes, the reaction was heated to 80 ℃ and sealed overnight. The reaction was quenched by addition of a saturated solution of sodium sulfite, after which a small amount of water and 30mL of ethyl acetate were added, the organic phase was separated and the aqueous phase was extracted with 30mL of x 3 ethyl acetate. The combined organic phases were washed with 30mL × 2 of saturated sodium chloride solution, dried and evaporated to dryness. Spotting plates (developing solvent dichloromethane: methanol: 20:1) are relatively pure, flash column purification (developing solvent dichloromethane: methanol: 96:4) gives 349mg of yellow solid, yield: 78 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝472； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.31(d,J＝2.2Hz,1H),8.97(s,1H),8.59(d,J＝1.8Hz,1H),8.50(s,1H),8.20(s,1H),7.73(d,J＝11.5Hz,1H),6.78(q,J＝7.1Hz,1H),3.91(s,3H),2.32(d,J＝7.1Hz,3H).

Step 3 preparation of 5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [1,2,3] triazolo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 2-25)

Mixing 6- (1- (6-bromo-1H- [1,2, 3)]Triazolo [4,5-b]Pyrazin-1-yl) ethyl) -5, 7-difluoro-3- (1-methyl-1H-pyrazol-4-yl) quinoline (60mg, 0.14mmol) was dissolved in 12ml of 1, 4-dioxane, and then 1.5 equivalents of 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole, Pd (dppf) were added successively ₂ Cl ₂ (11mg,0.014mmol), anhydrous potassium carbonate (39mg,0.28mmol) and 3ml water. The reaction solution was sealed overnight at 110 ℃ under argon. Concentrating the reaction solution, and purifying the residual crude product by flash column(developing solvent was dichloromethane: methanol 95:5) and the final product was washed with methanol solution (2 x 5 ml). 63mg of white solid powder are obtained in yield: 95 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝472； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.31(d,J＝2.2Hz,1H),9.15(s,1H),8.62(d,J＝1.6Hz,1H),8.49(d,J＝10.3Hz,2H),8.21(d,J＝0.6Hz,1H),8.08(d,J＝0.5Hz,1H),7.74(d,J＝11.7Hz,1H),6.77(q,J＝7.0Hz,1H),3.91(d,J＝1.2Hz,6H),2.36(d,J＝7.1Hz,3H).

Examples 197 to 213

The compounds of examples 197 to 213 were prepared in the same manner as in example 196 using different boronic acids or boronic esters, and the specific experimental data are given in Table 16.

TABLE 16 Experimental data Table for Compounds 2-26 through 2-42

Example 214: 3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) -3H-imidazo [4,5-b ] pyrazine-5-carboxylic acid ethyl ester (Compound 1-171)

3, 5-dibromopyrazine-2-amine (6.1g, 24mmol), 1- (7-fluoro-6-quinolyl) ethylamine (3.8g, 24mmol) and DIPEA (8.6mL, 48mmol) were added to NMP (20mL) and reacted overnight at 130 ℃ under argon. The reaction mixture was distilled to remove DIPEA, and the residue was poured into water (100ml), extracted with methylene chloride (30 ml. times.3), washed with organic phase and saturated brine to give 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine, yield: 50 percent.

LC-MS(ESI)：[M+H] ⁺ ＝362； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：8.89(s,1H)，8.39(d,J＝7.6Hz,1H)，7.97(d,J＝7.8Hz,1H)，7.77(d,J＝11.7Hz,1H)，7.50(d,J＝3.2Hz,1H)，7.18(s,1H)，7.05(d,J＝5.3Hz,1H)，6.38(s,2H)，5.43(s,1H)，1.61(d,J＝6.0Hz,3H)。

Reacting 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine (1.2g, 3.6mmol) was added to diethoxymethyl acetate (30ml), 98% formic acid (1ml) was added with stirring at room temperature, after the addition was completed, the reaction solution was refluxed for 2 days, the solvent was evaporated, and the crude product was washed with ethyl acetate/petroleum ether (1/1) to give a brown solid, yield: 60 percent. LC-MS (ESI): [ M + H ]] ⁺ ＝372； ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.10(s,1H)，8.93(d,J＝4.0Hz,1H)，8.67(s,1H)，8.43(d,J＝8.2Hz,1H)，8.11(d,J＝8.4Hz,1H)，7.81(d,J＝12.1Hz,1H)，7.55(dd,J ₁ ＝8.2Hz,J ₂ ＝4.0Hz,1H)，6.33(q,J＝7.1Hz,1H)，2.11(d,J＝7.1Hz,3H)。

Step 3 preparation of ethyl 3- (1- (7-fluoro-6-quinolyl) ethyl) -3H-imidazo [4,5-b ] pyrazine-5-carboxylate

Starting material 6- (1- (6-bromo-1H-imidazo [4, 5-b)]Pyrazin-1-yl) ethyl) -7-fluoroquinoline (150mg, 0.4mmol) was dissolved in anhydrous ethanol (50ml), and Pd (PPh) was added ₃ ) ₂ Cl ₂ (28mg, 0.04mmol, 0.1eq), DIPEA (3ml), reacted with carbon monoxide gas for 8h (10atm, 80 ℃). The solvent was evaporated to dryness and the crude preparation plate was purified to give 112mg of white solid with 75.9% yield. LC-MS (ESI): [ M + H ]] ⁺ ＝366.0； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.35(s,1H),8.95(dd,J ₁ ＝4.4Hz,J ₂ ＝2.0Hz,1H),8.64(s,1H),8.19(dd,J ₁ ＝8.4Hz,J ₂ ＝0.8Hz,1H),7.98(d,J＝8.0Hz,1H),7.78(d,J＝12.0Hz,1H),7.44(dd,J ₁ ＝8.4Hz,J ₂ ＝4.4Hz,1H),6.49(q,J＝7.2Hz,1H),4.52(q,J＝7.2Hz,2H),2.24(d,J＝7.2Hz,3H),1.48(t,J＝7.2Hz,3H).

Step 4 preparation of 3- (1- (3-bromo-7-fluoro-6-quinolinyl) ethyl) -3H-imidazo [4,5-b ] pyrazine-5-carboxylic acid ethyl ester

Starting material 3- (1- (7-fluoro-6-quinolinyl) ethyl) -3H-imidazo [4,5-b]Pyrazine-5-carboxylic acid ethyl ester (300mg, 0.8mmol) was dissolved in carbon tetrachloride (20ml), pyridine (263mg, 1.6mmol, 2eq) and liquid bromine (130mg, 1.6mmol, 2eq) were added, respectively, and the reaction was allowed to proceed overnight at 70 ℃. The solvent was evaporated to dryness, sodium carbonate aqueous solution was added to adjust to alkalinity, dichloromethane extraction, water washing, saturated brine washing, column chromatography purification to obtain 122mg of white solid with a yield of 33.4%. LC-MS (ESI): [ M + H ]] ⁺ ＝443.8； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.35(s,1H),8.94(d,J＝2.0Hz,1H),8.64(s,1H),8.34(d,J＝2.0Hz,1H),7.93(d,J＝7.6Hz,1H),7.77(d,J＝11.6Hz,1H),6.46(q,J＝7.2Hz,1H),4.52(q,J＝7.2Hz,2H),2.25(d,J＝7.2Hz,3H),1.48(t,J＝7.2Hz,3H).

Step 5 preparation of ethyl 3- (1- (7-fluoro-3- (1-methyl-1H-4-pyrazolyl) -6-quinolinyl) ethyl) -3H-imidazo [4,5-b ] pyrazine-5-carboxylate (Compound 1-171)

The raw material 3- (1- (3-bromo-7-fluoro-6-quinolyl) ethyl) -3H-imidazo [4,5-b]Pyrazine-5-carboxylic acid ethyl ester (120mg, 0.27mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (85mg, 0.41mmol, 1.5eq), catalyst Pd (dppf) Cl ₂ DCM (11mg,0.01mmol, 0.05eq) and K ₂ CO ₃ (112mg, 0.81mmol, 3eq) was dissolved in dioxane + water (4ml +1ml) and argon was used for protectionThe reaction is carried out for 4h at 110 ℃. After cooling to room temperature, adding a large amount of water, extracting with ethyl acetate, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying a crude product preparation plate to obtain an orange solid 14mg with the yield of 11.7%. LC-MS (ESI): [ M + H ]] ⁺ ＝446.0； ¹ H-NMR(δppm,CDCl ₃ ,400MHz):9.35(s,1H),9.08(d,J＝2.4Hz,1H),8.66(s,1H),8.18(s,1H),7.92(d,J＝8.0Hz,1H),7.91(s,1H),7.80(s,1H),7.76(d,J＝11.6Hz,1H),6.48(q,J＝7.2Hz,1H),4.52(q,J＝7.2Hz,2H),4.03(s,3H),2.24(d,J＝7.2Hz,3H),1.48(t,J＝7.2Hz,3H).

Example 215: 7-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-172)

Step 1 preparation of 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamines

Referring to the procedure of step 1 of example 1,1- (7-fluoro-6-quinolyl) ethylamine was used in place of 6-quinolinylmethyleneamine to give 6-bromo-N ² - (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine, yield 50%. LC-MS (ESI): [ M + H ]] ⁺ ＝362， ¹ H-NMR(δppm，DMSO-d ₆ ，400MHz):8.89(s，1H)，8.39(d，J＝7.6Hz，1H)，7.97(d，J＝7.8Hz,1H),7.77(d,J＝11.7Hz,1H),7.50(d,J＝3.2Hz,1H),7.18(s,1H),7.05(d,J＝5.3Hz,1H),6.38(s,2H),5.43(s,1H),1.61(d,J＝6.0Hz,3H).

Referring to the procedure of step 2 of example 1, 6-bromo-N ² Reaction of- (1- (7-fluoroquinolin-6-yl) ethyl) pyrazine-2, 3-diamine and diethoxymethyl acetate gave a brown solid in 60% yield, LC-ms (esi): [ M + H ]] ⁺ ＝372， ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz):9.10(s,1H),8.93(d,J＝4.0Hz,1H),8.67(s,1H),8.43(d,J＝8.2Hz,1H),8.11(d,J＝8.4Hz,1H),7.81(d,J＝12.1Hz,1H),7.55(dd,J ₁ ＝8.2Hz,J ₂ ＝4.0Hz,1H),6.33(q,J＝7.1Hz,1H),2.11(d,J＝7.1Hz,3H)。

Step 3 preparation of 3-bromo-6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-fluoroquinoline

372.2mg (1mmol) of 6- (1- (6-bromo-1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) -7-fluoroquinoline and 158mg (2mmol) of pyridine are added to 50ml of carbon tetrachloride and, with stirring, 320mg (2mmol) of liquid bromine are slowly added dropwise and, after the addition, the reaction is refluxed for 3H. After-treatment, the solvent was evaporated to dryness, the crude product was dissolved in dichloromethane, washed with saturated aqueous sodium carbonate solution, washed with saturated brine, and dried to dryness to obtain 300mg of crude product with a yield of 66%, which was directly put into the next step.

LC-MS(ESI)：[M+H] ⁺ ＝450。

Step 4 preparation of 7-fluoro-3- (1-methyl-1H-pyrazol-4-yl) -6- (1- (6- (1-methyl-1H-pyrazol-4-yl) -1H-imidazo [4,5-b ] pyrazin-1-yl) ethyl) quinoline (compound 1-172)

Referring to the procedure of step 4 of example 164, 3-bromo-6- (1- (6-bromo-1H-imidazo [4,5-b ])]Pyrazin-1-yl) ethyl) -7-fluoroquinoline is reacted with 1-methyl-1H-4-pyrazoleboronic acid pinacol ester to give a white solid in 33% yield, LC-ms (esi): [ M + H ]] ⁺ ＝454, ¹ H-NMR(δppm,DMSO-d ₆ ,400MHz)：9.19(d,J＝2.2Hz,1H),8.96(s,1H),8.85(s,1H),8.57(d,J＝1.9Hz,1H),8.36(s,1H),8.34(s,1H),8.06(s,1H),8.05(s,1H),8.03(d,J＝8.4Hz,1H),7.78(d,J＝11.9Hz,1H),6.35(q,J＝7.1Hz,1H),3.91(s,3H),3.88(s,3H),2.16(d,J＝7.1Hz,3H).

Effect example 1 inhibition of C-Met tyrosine kinase Activity by Compounds of the present invention

Half inhibitory concentration IC for kinase inhibitory Activity of test Compounds ₅₀ A value to represent. The assay uses homogeneous time-resolved fluorescence (HTRF) technology for determination, and the method comprises the following steps: incubating a series of compounds with gradient concentration with an enzyme solution with specific concentration for 5 minutes at room temperature, adding a proper amount of an enzyme reaction substrate and ATP, starting an enzyme reaction process, adding a proper amount of a reaction stopping solution and a detection solution into an enzyme reaction system after 30 minutes, incubating for 1 hour, and labeling with multiple EnVision 2104 of Perkinelmer companyOn a micropore detector, enzyme activity under specific compound concentration is measured under 665nm and 620nm wavelength, inhibitory activity of compounds with different concentrations to the enzyme activity is calculated, then according to a four-parameter equation, the inhibitory activity of the compounds with different concentrations to the enzyme activity is fitted, and IC is calculated ₅₀ The value is obtained. The kinase Met used in this example was purchased from Carna Biosciences, the detection kit HTRF KinEASE-TK was purchased from Cisbio Bioassays, and ATP was purchased from Sigma Aldrich. IC of the test Compound of the invention ₅₀ The data are shown in Table 17.

TABLE 17 data of inhibitory activity of compounds of the examples of the present invention on C-Met tyrosine kinase

Effect example 2 measurement of cell proliferation inhibitory Activity of Compound against H1993 and SNU-5

This example was conducted to determine the proliferation inhibitory activity of the compound of the present invention on c-Met-highly expressed lung cancer cell line H1993 and c-Met-highly expressed gastric cancer cell line SNU-5, and half inhibitory concentration IC for the cell proliferation inhibitory activity of the compound ₅₀ To indicate. The protocol was as follows: the c-Met high-expression lung cancer cell line H1993 and the c-Met high-expression gastric cancer cell line SNU-5 cells are purchased from ATCC, and the cells are inoculated on a white opaque 384-hole culture plate according to a proper cell concentration (H1993: 62500 cells/mlL culture medium; SNU-5: 62500 cells/mL culture medium); the cells were then placed at 37 ℃ in 5% CO ₂ After 24 hours, a series of concentration gradients of drugs is added to the cultured Cell culture medium, generally 10 concentrations are selected, then H1993 cells are put back into the original culture environment for further culture for 72 hours, SNU-5 cells are put back into the original culture environment for further culture for 48 hours, and then the effect of the tested compound on the proliferation of H1993 and SNU-5 cells is measured on an EnVision 2104 multi-labeled micropore detector of PerkinElmer according to the method of CellTiter-Glo luminescence Cell Viability Assay, and the inhibitory activity of different concentrations of the compound on the Cell proliferation is calculated. The CellTiter-Glo luminescence Cell Viability Assay reagent used in this example was purchased from Promega. Four parameter fits were then made to the H1993 and SNU-5 cell proliferation inhibitory activities at different concentrations of the compound and the IC50 data for the test compounds of the invention are shown in Table 18.

TABLE 18 data Table of the inhibitory activity of the compounds of the present examples on H1993 and SNU-5 cell proliferation

And (4) conclusion: the compound has obvious proliferation inhibiting activity on H1993 and SNU-5.

Effect example 3 detection of intracellular phosphorylation inhibitory Activity of the Compound of the present invention against c-Met-highly expressed Lung cancer cell line H1993

This example was conducted to determine the inhibitory activity of the compound of the present invention on c-Met phosphorylation in c-Met-highly expressed lung cancer cell line H1993 and the inhibitory activity of the compound on c-Met phosphorylation in cells by half inhibitory concentration IC ₅₀ To indicate. The test protocol is as follows: c-Met high-expression lung cancer cell line H1993 is purchased from ATCC and inoculated in a 96-well cell culture plate at a proper cell concentration (300000/mL culture medium); the cells were then placed at 37 ℃ in 5% CO ₂ Culturing in the environment, after 24 hours, adding a series of concentration gradient drugs into a cultured cell culture medium, generally selecting 10 concentrations, then putting H1993 cells back to the original culture environment to continue culturing for 1 hour, then sucking out culture solution in the pores, adding a proper amount of lysate to lyse the cells, transferring a proper amount of cell lysate into a shallow-pore opaque 384-pore plate, adding a proper amount of Acceptor mix, and then incubating at room temperature in a dark place for 2 hours; then adding a proper amount of Donor mix, and continuously incubating for 2 hours at room temperature in a dark place; the effect of the test compounds on the phosphorylation of c-Met in H1993 cells was examined using an EnVision 2104 multi-labeled micropore detector from Perkinelmer, Inc., and the inhibitory activity of compounds at different concentrations on cell phosphorylation was calculated. The AlphaScreen SureFire c-Met Assay kit used in this example was purchased from Perkinelmer. Four parameter fits were then made to the c-Met phosphorylation inhibitory activity in H1993 cells for various concentrations of the compound, and the IC50 data for the test compounds of the invention are shown in Table 19.

TABLE 19 data of intracellular phosphorylation inhibitory activities of compounds 1 to 87 and compounds 1 to 95 against c-Met-highly expressed lung cancer cell line H1993

Effect example 4 metabolic stability of Compounds in liver microsomes

This example is used to determine the activity of the compounds of the invention in human, rat and monkey liver microsomes; human, monkey S9; the metabolic stability of human and monkey cell cytosol is expressed as intrinsic clearance. The protocol was as follows: metabolic stability incubations were performed with human S9(HS9), monkey S9(MS9), human hepatocyte cytosol (Hcytosol), monkey hepatocyte cytosol (Mcytosol), Human Liver Microsomes (HLM), Rat Liver Microsomes (RLM) and Monkey Liver Microsomes (MLM) in a system of 150. mu.l, respectively, which contained both NADPH and phosphate buffer of the test compound. The enzyme reaction system is carried out at 37 ℃, the reaction is stopped by acetonitrile of internal standard sulfometronidazole at 0min, 5min, 10min and 30min respectively, the reaction solution is vortexed for 10min, and is centrifuged at 15000rmp for 10min, and 60 mu l of supernatant is sampled in a 96-well plate. A positive control adopts Midazolam (MDZ), and a negative control adopts Atenolol (ATE) to carry out a parallel test. This example measures the relative reduction of bulk drug by LC/MS/MS. Intrinsic clearance (Cl) _int (ii) a μ l/min/mg protein) of less than 100, the metabolic stability of the compound is considered to be good. The metabolic stability data for the test compounds of the present invention are shown in Table 20

TABLE 20 Metabolic stability data Table for Compounds

And (4) conclusion: most of the compounds of the invention were metabolically stable in liver microsome, S9 and cell cytosolic solutions.

Effect example 5 direct inhibition assay (DI assay) of Compounds on Metabolic enzymes

This example was used to determine the direct inhibitory effect of the compounds of the present invention on the metabolic enzymes CYP34A, CYP2D6, CYP2C9, CYP1a2 and CYP2C19, and the direct inhibitory effect of the compounds on the metabolic enzymes was expressed as the inhibition rate. The test protocol is as follows: the total reaction volume was 100. mu.l, which included human liver microsomes, NADPH, phosphate buffer, substrate mixture (Midazolam, Testosterone, Dextromethophan, Diclofenac, Phenaceti, Mephenotyin), and test compound. After the system is incubated at 37 ℃ for 20min, the reaction is terminated by acetonitrile of internal standard sulfometronidazole. Vortex for 10min, centrifuge for 10min at 15000rmp, and sample 60. mu.l of supernatant in 96-well plates. Inhibitor cocktail (Ketoconazole, Quinidine, Sulfaphenazone, Napthoflavone, Tranylpromamine) was used as a positive control, and DMSO was used as a negative control for a parallel control. The measurement of the substrate metabolite relative production amount indicates the relative activity of the enzyme, and the inhibition rate of the compound against the enzyme ═ 1 (enzyme relative activity of the test compound/negative control enzyme relative activity) × 100%. An inhibition greater than 50% is defined as a direct inhibition of CPY. The data for the inhibition of metabolic enzymes by the test compounds of the present invention are shown in Table 21.

TABLE 21 direct Metabolic enzyme inhibition data for compounds

And (4) conclusion: some of the compounds of the present invention do not have a direct inhibitory effect on metabolic enzymes.

Effect example 6 mechanism inhibition test (TDI test) of Metabolic enzyme by Compound

This example was used to determine the mechanism-inhibitory effect of the compounds of the invention on the metabolic enzymes CYP34A, CYP2D6, CYP2C9, CYP1A2, CYP2C19, expressed as the apparent inactivation rate constant k _obs . The protocol was as follows: the total volume of the reaction system was 200. mu.l, and the NADPH group included: human liver microsomes, a compound to be tested, NADPH and phosphate buffer salt; the non-NADPH group includes: human liver microsomes, a compound to be tested and phosphate buffer salt. The system is incubated for 0min, 5min, 10min and 20min respectively, then the reaction is stopped by acetonitrile containing internal standard sulfometronidazole, vortexed for 10min, centrifuged at 15000rmp for 10min, and 60 mul of supernatant is sampled in a 96-well plate. Positive controlInhibitor mixture (Troliable, Paraoxetine, Tienic Acid, Furafylline) is selected, and S-Fluoxetine is selected as positive control of compound Atenoll and CYP2C19 as negative control. The relative activity of the enzyme is expressed by measuring the relative production of the substrate metabolite, and the apparent inactivation rate constant k is calculated _obs (*10 ^-4 Min) when k of the compound _obs When the value is more than 200, it is considered that the organic suppression of CPY is attained. The data for the inhibition of metabolic enzymes by the test compounds of the present invention are shown in Table 22.

TABLE 22 mechanical inhibition of Metabolic enzymes by Compounds data Table TDI (kobs 10) ^-4 )

And (4) conclusion: some of the compounds of the present invention have no mechanism inhibitory effect on metabolic enzymes.

Effect example 7 test for inhibitory Effect of Compounds on mouse transplantation tumor

This example was conducted to determine the inhibitory effect of the compound of the present invention on SNU-5 transplantation tumor, a highly c-Met-amplified gastric cancer cell, and to show the in vivo efficacy of the compound in terms of relative tumor proliferation rate. The protocol was as follows: the SNU-5 cells of the gastric cancer with highly amplified c-MET are selected. The cell culture conditions comprise adding 20% fetal calf serum into IMDM culture medium at 37 deg.C and 5% CO ₂ Culturing in a constant temperature incubator. Passages were treated twice a week at a 1:4 ratio. When the cells are in the exponential growth phase, the cells are collected and counted. The Bulb/c nude mice were divided into 5 groups, and 5X 10 mice were divided ⁶ The SNU-5 cells were inoculated in the right axilla of nude mice. The administration concentration of the positive drug INCB28060 and the test compound is 10mg/kg, and the administration is performed by intragastric administration once a day and is continuously performed for 11 days. Animals were observed regularly for condition, body weight was measured and results were recorded. The volume and relative volume of the tumor were calculated according to the formula.

(1) Tumor Volume (Tumor Volume, TV), TV 1/2XaXb ² (ii) a a. b represents length and width, respectively.

(2) Relative Tumor Volume (RTV), RTV ═ TV _t /TV ₀ ；TV ₀ When divided into cages (i.e. d) ₀ ) Tumor volume, TV _t Tumor volume at each measurement.

(3) The relative tumor proliferation rate T/C (%) is calculated by the formula:

TRTV: treatment group RTV; CRTV: negative control group RTV. The evaluation criterion of the antitumor activity was the relative tumor proliferation rate T/C (%). The in vivo efficacy data for the test compounds of the invention are shown in table 23.

TABLE 23 in vivo efficacy data of Compound mice

Compound (I)	Dosage form	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％

And (4) conclusion: the compounds 1-170 in the invention can effectively inhibit the growth of stomach cancer cell SNU-5 transplantable tumor, the effect is slightly better than that of a control compound, and the anti-tumor effect of 1-172 is weak.

Claims

1. A quinoline compound or a pharmaceutically acceptable salt thereof, wherein the quinoline compound is any one of the following compounds:

5, 7-difluoro-6- (1- (6- (1-methyl-1)H-pyrazol-4-yl) -1HImidazo [4,5-b]Pyrazin-1-yl) ethyl) quinoline,

5, 7-difluoro-6- (1- (6- (quinolin-3-yl) -1-yl) -6- (I-phenyl) quinoline-4-carboxylic acidHImidazo [4,5-b]Pyrazin-1-yl) ethyl) quinoline,

2- (4- (1- (1- (5, 7-difluoroquinolin-6-yl) ethyl) -1HImidazo [4,5-b]Pyrazin-6-yl) -1H-pyrazol-1-yl) ethan-1-ol,

6-(1-(6-(1H-pyrazol-4-yl) -1HImidazo [4,5-b]Pyrazin-1-yl) ethyl) -5, 7-difluoroquinoline,

And, 5, 7-difluoro-6- (1- (6- (pyridin-3-yl) -1HImidazo [4,5-b]Pyrazin-1-yl) ethyl) -quinoline.

2. A compound represented by formula K or L,

。

3. use of a quinoline compound according to claim 1, or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with the expression or activity of the tyrosine kinase C-Met.

4. Use according to claim 3, characterized in that: the diseases related to the expression or activity of tyrosine kinase C-Met include cancer, musculoskeletal sarcoma, soft tissue sarcoma and other tumors.

5. The use of claim 4, wherein: the cancer comprises bladder cancer, breast cancer, cervical cancer, colon cancer, esophagus cancer, stomach cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, prostate cancer and thyroid cancer; said musculoskeletal sarcoma comprises: osteosarcoma, synovial sarcoma, and rhabdomyosarcoma; the soft tissue sarcoma includes: malignant fibrosarcoma/fibrosarcoma, leiomyosarcoma, and kaposi's sarcoma; such other tumors include: glioblastoma, astrocytoma, melanoma, mesothelioma and embryonal carcinosarcoma.

6. Use according to claim 3, characterized in that: the diseases related to the expression or activity of tyrosine kinase C-Met comprise hematopoietic system malignant tumors.

7. The use of claim 6, wherein: the hematopoietic malignancy includes: multiple myeloma, lymphoma, adult T-cell leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia.

8. A pharmaceutical composition characterized by: the quinoline compound or the pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises a therapeutically effective amount, and one or more pharmaceutically acceptable pharmaceutical excipients; the effective treatment amount is 1 to 99 percent by mass; the mass percentage of the imidazopyrazine compound or the pharmaceutically acceptable salt thereof is represented by formula 1, and accounts for the total mass percentage of the pharmaceutical composition; the sum of the mass percentages of the components in the pharmaceutical composition is 100%.