CN106478621A - Quinoline or quinazoline derivative, preparation method and applications - Google Patents

Quinoline or quinazoline derivative, preparation method and applications Download PDF

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CN106478621A
CN106478621A CN201610877470.5A CN201610877470A CN106478621A CN 106478621 A CN106478621 A CN 106478621A CN 201610877470 A CN201610877470 A CN 201610877470A CN 106478621 A CN106478621 A CN 106478621A
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base
quinoline
epoxide
phenyl
thiazoline
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CN106478621B (en
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祁宝辉
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Zunyi Medical University
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Zunyi Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The present invention relates to a kind of quinoline or quinazoline derivative, preparation method and applications, i.e. quinoline shown in formula I or quinazoline derivative and their pharmaceutically acceptable salts, hydrate or prodrug, structure is as described below：Wherein A1、A2、R1、R2、R3、R4、R5、R6、X、Y、Z、M、W、Cy1、Cy2, m, n there is the implication being given in the description.The invention still further relates to the compound of formula I has the effect of suppression MET kinases, and such compound and its pharmaceutically acceptable salt, hydrate in preparation treatment due to the purposes in the medicine of MET kinases overexpression diseases caused, particularly treat and prevent the purposes in the medicine of cancer in preparation.

Description

Quinoline or quinazoline derivative, preparation method and applications
Technical field
The present invention relates to quinoline or quinazoline derivative and its pharmaceutically acceptable salt, hydrate, solvate or Its prodrug, their preparation method and the pharmaceutical composition containing described compound.The invention still further relates to quinoline or quinazoline The effect of the stronger suppression MET kinases of analog derivative, and further relate to such compound and its pharmaceutically acceptable salt, hydration Thing, solvate or its prodrug are in preparation treatment due to the purposes in the medicine of MET kinases overexpression diseases caused, spy It is not the purposes in the medicine of preparation treatment and/or prophylaxis of cancer.
Background technology
Malignant tumor is a kind of disease of serious harm human life and health, with the change of the extraneous factors such as environmental pollution Change, whole world pathogenesis of cancer number rises it is contemplated that will have 21,400,000 new cases, death toll to the year two thousand thirty whole world year by year Reach 13,200,000 people, wherein 70% occurs the developing country in middle and low income.According to World Health Organization's statistics, the current whole world About it is diagnosed to be 10,000,000 tumor patients every year, 7,000,000 people die from the relevant disease being caused by tumor, and therefore malignant tumor becomes It is only second to the second largest killer of the mankind of cardiovascular disease.
Protein kinase (Protein Kinases, PKs) can pass through the cheese of the terminal phosphate transesterify catalytic proteins of ATP Di in propylhomoserin, serine and threonine residues, by signal transduction pathway, they adjust cell growth, differentiation And propagation.In addition, PKs activity is abnormal related to the disease of host, such as metabolic disease, dermatosiss, tumor etc..Protein kinase bag Include two classes：Protein tyrosine kinase (Protein tyrosine kinases, PTKs) and serine-threonine kinase (Serine-threonine kinases, STKs).The former passes through and somatomedin ligand binding, so that growth factor receptorses is changed For activated form, then the protein-interacting with cell membrane inner surface, make the tyrosine residue phosphorylation of receptor and other albumen And lead to be formed in the cell with the complex of various kinds of cell matter signaling molecule, thus affect various kinds of cell reaction such as cell Propagation, differentiation, metabolism etc..
The growth factor receptorses with PTKs activity are referred to as receptor tyrosine kinase (Receptor tyrosine kinases,RTKs).MET is one of member of tyrosine kinase growth factor receptor extended familys, and it is unique energy and hepatocyte The high affinity receptor that somatomedin (Hepatocyte Growth Factor, HGF) combines, therefore also referred to as hepatocyte growth factor Sub- receptor, its expression product is the transmembrane receptor protein with tyrosine kinase activity.
Under normal physiological conditions, MET kinases and HGF have expression in a large amount of organizing, but MET RNA is in low water Flat expression status, of short duration rising only after tissue injury, recovers normal level immediately again, shows that normal cell is had the ability by subtracting The expression of few MET kinases controls its reaction to HGF.After MET kinases is combined with HGF, epithelial cell can be promoted to disperse, Strengthen the mobility of cell, promote multiple processes such as growth, propagation, differentiation, contraction, motion, secretion and the mitosiss of cell, For the growth promoting Placenta Hominiss and embryo, adjust the growths of organ such as lung, nervous system, kidney and mammary gland and structure forms and has ten Divide important biological significance.
However, the HGF/MET activity of exception and the generation of tumor, growth, division, angiogenesis, aggressive, transfer and resistance to Property of medicine etc. has very close relationship, and it assumes abnormal high expression, mutation and activity change etc. in kinds of tumors tissue Feature, such as pulmonary carcinoma, breast carcinoma, colon cancer, carcinoma of prostate, cancer of pancreas, ovarian cancer, incidence cancer and malignant glioblastoma Deng.Additionally, the high expression of MET kinases and HGF is also relevant with processes such as the poor prognosis of tumor.Therefore, MET kinases has become anti- One of important target of tumour medicine exploitation.
Cabozantinib (Fig.1) belongs to quinolines, be a kind of oral, MET can be suppressed and other are multiple The antitumor drug of kinase activity, its IC to MET kinases50Value is respectively 1.3nM, is approved by the FDA in the United States in 2012 City, is unable to pernicious Locally Advanced or the metastatic medullary thyroid of excision for treatment.
The present inventor, on the basis of list of references, has designed and synthesized series of new quinoline and quinoline azole derivative； Through external activity screening, show that such compound has obvious anti-tumor activity.
Content of the invention
The present invention relates to the quinoline shown in formula I or quinazoline derivative and its pharmaceutically acceptable salt, hydrate, Solvate or prodrug,
Wherein,
A1For N；
A2, Y, Z be N, CH；
X is O, S, NH；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described Heteroaryl contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1- C6) Alkyl, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and Optionally 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1- C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alcoxyl Base, by 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidatioon Carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl replace carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
Present invention is preferably related to the novel quinoline shown in formula I and quinoline azole compounds and its pharmaceutically acceptable salt, Hydrate, solvate or prodrug,
Wherein,
A1For N；
A2For CH；
Y, Z are N, CH；
X is O, S, NH；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described Heteroaryl contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkane Base, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and appoints Select 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1- C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alcoxyl Base, by 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidatioon Carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl replace carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
The present invention is also preferably relate to the quinoline shown in formula I and quinoline azole compounds and its pharmaceutically acceptable salt, water Compound, solvate or prodrug,
Wherein,
A1For N；
A2For CH；
Y, Z are CH；
X is O；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described Heteroaryl contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkane Base, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and appoints Select 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1- C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alcoxyl Base, by 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidatioon Carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 Individual (C1-C6) alkyl replace carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
The quinoline being related to shown in formula I specifically preferred according to the invention and quinoline azole compounds and its pharmaceutically acceptable salt, Hydrate, solvate or prodrug,
Wherein,
A1For N；
A2For CH；
Y, Z are CH；
X is O；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described Heteroaryl contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkane Base, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and appoints Select 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1- C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alcoxyl Base, by 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidatioon Carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl replace carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
The quinoline being related to shown in formula I specifically preferred according to the invention or quinazoline derivative and its pharmaceutically acceptable Salt, hydrate, solvate or prodrug,
Wherein,
A1For N；
A2For CH；
Y, Z are CH；
X is O；
M is 1；
N is 3；
M is O, S；
W is S；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described Heteroaryl contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkane Base, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and appoints Select 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1- C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alcoxyl Base, by 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidatioon Carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl replace carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
The quinoline being related to shown in formula I specifically preferred according to the invention and quinoline azole compounds and its pharmaceutically acceptable salt, Hydrate, solvate or prodrug,
Wherein,
A1For N；
A2For CH；
Y, Z are CH；
X is O；
M is 1；
N is 3；
M is O, S；
W is S；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkane Base, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and appoints Select 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, it is miscellaneous selected from N, O or S that described heteroaryl contains 1-3 Atom, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from The hetero atom of N, O or S, and Cy2Optionally 0-5 identical or different R5Replace；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1And R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, described heterocyclic radical and heteroaryl Base is optionally by 0-3 identical or different R7Replace；
R7For (C1-C4) alkyl；
Cy1For phenyl, naphthyl, quinolyl, pyridine radicals, furyl, thienyl and pyrrole radicals, and Cy1Optionally 0-5 phase With or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl Amide groups, NHCONHR8；
Cy2Can not exist or for phenyl, naphthyl, quinolyl, pyridine radicals, furyl, thienyl and pyrrole radicals, and Cy2Appoint Select 0-5 identical or different R5Replace；
R5、R6For hydrogen or 0-5 optionally from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl, trifluoromethyl and trifluoro methoxy The substituent group of base.
The quinoline being related to shown in formula I specifically preferred according to the invention or quinazoline derivative and its pharmaceutically acceptable Salt, hydrate, solvate or prodrug,
Wherein,
X is O；
A2, Y, Z be respectively N, CH, CH；
A1For N；
M is 1；
N is 3；
M is O；
W is S；
R1And R2With and their nitrogen-atoms of being connected together with formed piperidino, 4- morpholinyl, 4- methyl isophthalic acid-piperazinyl, 4- ethyl -1- piperazinyl, 4- methyl isophthalic acid-piperidyl, 4- methylene-piperidino, 1- pyrrolidinyl, azelidinyl, 4- sulfur For morpholinyl；
R3For hydrogen, amino, acetamido, fluoroform sulfoamido, propylureido, butyl urea groups, substituted-phenyl urea groups；
Cy1For phenyl, naphthyl, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Do not exist or be phenyl, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, trifluoromethyl, methyl.
And, according to some usual methods of the art, the quinoline of formula of I of the present invention or quinazoline ditosylate salt spread out Biology can generate pharmaceutically acceptable salt with acid.Pharmaceutically acceptable addition salts include mineral acid and organic acid addition salt, and following The salt of sour addition is particularly preferred：Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, Naphthalenedisulfonic acid, acetic acid, propanoic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
Additionally, present invention additionally comprises the prodrug of derivant of the present invention.The prodrug of derivant of the present invention is the derivative of formula I Thing, their own is likely to be of weaker activity even without activity, but upon administration, (for example passes through in physiological conditions Metabolism, solvolysiss or other mode) it is converted to corresponding biologically active form.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine；" alkyl " refers to the alkyl of straight or branched；" alkylidene " is Refer to the alkylidene of straight or branched；" cycloalkyl " refers to substituted or unsubstituted cycloalkyl；" aryl " refers to unsubstituted or company The phenyl or naphthyl of substituted base；" heteroaryl " refers to containing one or more heteroatomic monocyclic or multi-ring selected from N, O, S Ring-type system, ring-type system is armaticity, such as imidazole radicals, pyridine radicals, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, Furyl, thienyl, pyrrole radicals, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, benzo miaow Oxazolyl and benzoxazolyl group etc.；" heterocyclic radical of saturation or fractional saturation " refers to containing one or more miscellaneous former selected from N, O, S The monocyclic or multi-ring ring-type system of son, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, pyrazolidinyl, imidazolidinyl and Thiazolinyl etc..
It has been found that the compounds of this invention has suppression tumor cell growth activity in vitro, therefore, it can serve as making Standby treatment and/or the medicine of prophylaxis of cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, Pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid, the cancer of esophagus and leukemia, neuroblastoma etc..
By vitro inhibition colon cancer cell HT-29, gastric carcinoma cells MKN-45 and human breast cancer cell MDA-MB-231 Activity test, the compounds of this invention has, to colon cancer cell, stomach cancer cell, breast carcinoma hepatocarcinoma etc., the effect of significantly inhibiting, especially For preparation treatment and/or prevent colon cancer, the medicine of gastric cancer and breast carcinoma.
Found by testing to MET kinase activity, the compounds of this invention has significant suppression MET kinase activity, to MET The colon cancer cell of high expression, stomach cancer cell and breast cancer cell etc. have stronger inhibitory action, it is especially useful in preparation treatment and/ Or the medicine of prevention gastric cancer.
The reactive compound of the present invention or its officinal salt and its solvate can be independent as unique antitumor drug Use, or can be with the antitumor drug having listed (as platinum medicine cisplatin, camptothecine irinotecan, Changchun Flower bases medicine Navelbine, deoxycytidine class medicine gemcitabine, etoposide, paclitaxel etc.) it is used in combination.Therapeutic alliance By by each therapeutic component simultaneously, order or separate administration and realize.
Examples provided hereinafter and preparation example are further elucidated with and illustrate the compounds of this invention and its preparation side Method.It should be appreciated that the scope of following examples and preparation example never in any form restriction the scope of the present invention.
Following synthetic route (route 1) summarize and describe the present invention formula I derivant preparation, all of raw material is all Be by way of described in these flow line, by organic chemistry filed well-known to the ordinarily skilled artisan method preparation or Person is commercially available.The whole final derivant of the present invention is all by the method described in these flow line or by similar with it Method preparation, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.In these flow line, application is complete Definition in the definition of portion's variable factor following article or such as claim.
According to the formula I derivant of the present invention, all can according to the method for route 1 by intermediate Q in the presence of Silicon chloride., With corresponding sulfydryl replacing acid, it is obtained by addition and dehydration.Wherein, the A in compound1、A2、R1、R2、R3、R4、R5、R6、X、 Y、Z、M、W、Cy1、Cy2, m and n as defined in the claims.
When M is O, R3During for H, the preparation method of intermediate Q-1 is shown in route 2：
When M is S, R3During for H, the preparation method of intermediate Q-2 is shown in route 3：
When M is O, R3For NH2When, the preparation method of intermediate Q-3 is shown in route 4：
The substituent A of all intermediate in above 3 routes1、A2、R1、R2、R3、R4、R5、R6、X、Y、Z、M、W、Cy1、 Cy2, m and n as defined in the claims.
Specific embodiment
Embodiment is intended to illustrate rather than limits the scope of the present invention.The proton nmr spectra Bruker of compound ARX-400 measures, and mass spectrum is measured with Agilent 1100 level Four bar LC-MS instrument；Agents useful for same is to be analyzed pure or changes Learn pure.
Embodiment 1：
Step (1) 1- [4- (3- chlorine propoxyl group) -3- methoxyl group] 1-Phenylethanone. (III)
Under room temperature, will be anhydrous to 500.0g (3.01mol) 3- methoxyl group -4-hydroxyacetophenone II and 581.7g (4.22mol) Potassium carbonate adds to 2L DMF (DMF), instills 311.7mL (3.16mol) 1 after being sufficiently stirred for 30min, 3- bromo-chloropropane, drips and finishes, and room temperature continues stirring 6h.Reactant liquor is poured in 5L frozen water, sucking filtration, obtains white solid after filtration cakes torrefaction Body 692.2g.
Step (2) 1- [4- (3- chlorine propoxyl group) -5- methoxyl group -2- nitro] 1-Phenylethanone. (IV)
500.0g (2.05mol) intermediate III is added to 2.5L dichloromethane.Keep reacting liquid temperature at -20 DEG C To -10 DEG C between, it is slowly added dropwise 320.0g fuming nitric aicd, drip and finish, -10 DEG C of reaction 2h.Reactant liquor is poured in frozen water, collects organic Layer, organic layer saturated sodium bicarbonate aqueous solution is washed till neutrality, anhydrous sodium sulfate drying, solvent evaporated, obtains yellow solid 521.4g.
Step (3) 1- [4- (3- chlorine propoxyl group) -5- methoxyl group -2- nitrobenzophenone] -3- (dimethylamino) propyl group -2- alkene -1- Ketone (V)
500.0g (1.74mol) intermediate IV is added to 2.5L dimethylbenzene, adds 1035g (8.69mol) N, N- Dimethylformamide dimethyl acetal (DMF-DMA), back flow reaction 15h.Reactant liquor is cooled to -10 DEG C, sucking filtration, filter cake is with right amount Dimethylbenzene washs, and obtains yellow solid 442.0g after being dried.
Step (4) 7- (3- chlorine propoxyl group) -6- methoxyl group -4 (1H)-quinolinone (VI)
400.0g (1.17mol) intermediate V is added to 3L glacial acetic acid, is warming up to 60 DEG C, is dividedly in some parts 328.3g (5.85mol) reduced iron powder, 90 DEG C of reaction 2h.Sucking filtration while hot, filtrate cools down, and sucking filtration obtains khaki solid.Glacial acetic acid recrystallization Afterwards, obtain yellow solid 216.5g.
Step (5) 6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] -4 (1H)-quinolinones (VII)
200.0g (0.75mol) intermediate VI and 650mL (7.5mol) morpholine are added to 2L acetonitrile, back flow reaction 12h.Boil off most of solvent, residual solution is cooled to -10 DEG C, separate out solid, sucking filtration, ethyl acetate is washed, and obtains solid 211.9g.
Step (6) 4- chloro- 6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline (VIII)
200.0g (0.63mol) intermediate VII and 1L phosphorous oxychloride are added in the acetonitrile being dried to 1L, back flow reaction 6h. Evaporated under reduced pressure, is stirred vigorously down, and concentrated liquid is added in frozen water, adjusts pH to 8, CH with 10%NaOH aqueous solution2Cl2Extraction (3 × 500mL), merges organic layer, anhydrous sodium sulfate drying, solvent evaporated, cooling, obtains pale solid 184.2g.
Step (7) 4- (4-nitrophenoxy) -6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline (Ⅸ)
150.0g (0.48mol) intermediate VIII and 77.8g (0.56mol) 4- nitrophenol are added to 600mL drying In chlorobenzene, flow back 20h.Solvent evaporated, obtains gray solid, is dissolved in CH2Cl2In, 10% sodium hydrate aqueous solution washing, have Machine layer anhydrous sodium sulfate drying, solvent evaporated, obtain solid 125.6g.
Step (8) 4- [6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline -4- epoxide] aniline (Ⅹ)
120.0g (0.27mol) intermediate Ⅸ, 152.7g (2.72mol) reduced iron powder and 15mL concentrated hydrochloric acid are added to 2L 90%EtOH-H2In O, finish, flow back 2h.Sucking filtration while hot, collects filtrate, is evaporated, obtains yellow solid 111.8g.
Step (9) 4- [4- [7- [3- (4- morpholinyl) propoxyl group] -6- methoxy quinoline -4- epoxide] phenyl] carbamic acid Phenyl ester (Ⅺ)
Under room temperature, 100.0g (0.24mol) intermediate X and 101.2g (0.73mol) Anhydrous potassium carbonate are added to 1.5L In the acetone being dried, at 0 DEG C, instill 44.8mL (0.26mol) phenyl chloroformate, drip and finish, 5h is stirred at room temperature.Solvent evaporated, plus Enter 1L dichloromethane, wash (3 × 100mL), anhydrous sodium sulfate drying, be evaporated to obtain yellow oily liquid 109.6g.
Step (10) 4- [4- [7- [3- (4- morpholinyl) propoxyl group] -6- methoxy quinoline -4- epoxide] phenyl] semicarbazides (XII)
100.0g (0.19mol) intermediate Ⅺ is dissolved in 400mL dioxane, is added thereto to 500mL 80% and is hydrated Hydrazine, flow back about 8h.Boil off most of dioxane, cooling, sucking filtration, obtain yellowish-white solid 79.8g.
Step (11) (E)-N1- (4- (6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- epoxide) phenyl)-N4- benzene methylene Base semicarbazones (Q-1)
20.0g (42.8mmol) intermediate X II and 5.0g (47.1mmol) benzaldehyde are added to 200mL isopropanol, Add 1mL glacial acetic acid, flow back 5h.Cooling, sucking filtration, filter cake, with a small amount of isopropanol drip washing, obtains white solid 17.3g.
Step (12) 1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl] -3- (4- oxo -2- Phenyl thiazole quinoline -3- base) urea (embodiment 1)
Under room temperature, 10.0g (18.0mmol) intermediate Q-1 is added to 40mL thioglycolic acid, add the tetrachloro of 1mL SiClx, finishes, and about 6h is stirred at room temperature.10% sodium hydrate aqueous solution adjusts pH to 8, and dichloromethane extracts (2 × 100mL), organic Mutually use anhydrous sodium sulfate drying, be evaporated, column chromatographic isolation and purification obtains white solid 5.8g.
1H-NMR(400MHz,DMSO-d6) δ 9.06 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 7.47-7.62 (br, 5H), 7.42-7.46 (br, 4H), 7.19 (m, 2H), 6.42 (s, 1H), 5.86 (s, 1H), 4.21 (br, 2H), 3.95 (s, 3H), 3.88 (br, 1H), 3.82 (br, 1H), 3.61 (br, 4H), 2.30-2.45 (br, 6H), 2.00 (br, 2H)；ESI-MS[M+H] (m/z):630.2.
According to the method for embodiment 1, carry out addition, take off for raw material and thioglycolic acid with different substituents intermediate Q-1 Water reaction prepares the compound of embodiment 2-21.
Embodiment 2 1- [4- [6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- epoxide] benzene Base] -3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.97-9.03 (br, 1H), 8.58 (s, 1H), 8.44 (d, J=5.2Hz, 1H), 7.54-7.65 (m, 6H), 7.37 (s, 1H), 7.22-7.28 (m, 2H), 7.19 (m, 2H), 6.44 (d, J=5.2Hz, 1H), 5.85 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.80-3.86 (m, 2H), 2.87 (m, 2H), 2.45 (m, 2H), 1.84-2.01 (m, 4H), 1.60 (m, 2H), 1.23-1.40 (m, 1H), 1.03-1.21 (m, 2H), 0.90 (d, J= 6.4Hz,3H)；ESI-MS[M+H](m/z):642.3.
Embodiment 3 1- [4- [6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinoline -4- epoxide] phenyl] - 3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (br, 1H), 8.66 (s, 1H), 8.47 (d, J=5.2Hz, 1H), 7.91 (br, 1H), 7.82 (d, J=5.6Hz, 1H), 7.73 (d, J=5.6Hz, 1H), 7.63-7.67 (m, 1H), 7.52 (d, J= 8.8Hz, 2H), 7.51 (s, 1H), 7.37 (s, 1H), 7.19 (d, J=8.8Hz, 2H), 6.44 (d, J=5.2Hz, 1H), 5.94 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.79-3.84 (m, 2H), 2.65-2.74 (m, 2H), 2.54- 2.61 (br, 4H), 1.98-2.07 (m, 2H), 1.65-1.83 (br, 4H)；ESI-MS[M+H](m/z):614.3.
Embodiment 4 1- [4- [6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- epoxide] benzene Base] -3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.86-8.94 (br, 1H), 8.45 (d, J=5.2Hz, 1H), 8.39 (s, 1H), 7.54 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 7.39 (s, 1H), 7.24-7.32 (m, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8Hz, 2H), 6.42 (d, J=5.2Hz, 1H), 5.71 (s, 1H), 4.37 (d, J=5.9Hz, 2H), 4.07 (s, 3H), 3.85-3.92 (m, 2H), 3.44 (m, 10H), 2.85 (s, 3H), 2.39 (s, 2H)；ESI-MS[M+H] (m/z):643.3.
Embodiment 5 1- [4- [6- methoxyl group -7- [3- (4- methylenepiperidines -1- base) propoxyl group] quinoline -4- epoxide] benzene Base] -3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.92-9.01 (br, 1H), 8.43 (d, J=5.2Hz, 1H), 8.35 (s, 1H), 7.51 (d, J=8.8Hz, 2H), 7.47 (s, 1H), 7.37 (s, 1H), 7.21-7.30 (m, 2H), 7.17 (d, J= 8.8Hz, 2H), 6.72 (d, J=8.8Hz, 2H), 6.40 (d, J=5.2Hz, 1H), 5.70 (s, 1H), 4.94-5.08 (m, 2H), 4.34 (d, J=6.0Hz, 2H), 4.03 (s, 3H), 3.83-3.90 (m, 2H), 3.38-3.46 (m, 8H), 2.04-2.09 (m, 4H)；ESI-MS[M+H](m/z):640.2.
Embodiment 6 1- [4- [6- methoxyl group -7- [3- (3,5- lupetidine -1- base) propoxyl group] quinoline -4- epoxide] Phenyl] -3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.06 (s, 1H), 8.69 (s, 1H), 8.48 (d, J=5.2Hz, 1H), 7.90 (br, 1H), 7.83 (d, J=5.6Hz, 1H), 7.72 (d, J=5.6Hz, 1H), 7.61-7.66 (m, 1H), 7.54 (d, J= 8.8Hz, 2H), 7.53 (s, 1H), 7.35 (s, 1H), 7.16 (d, J=8.8Hz, 2H), 6.41 (d, J=5.2Hz, 1H), 6.17 (s, 1H), 4.18 (t, J=6.4Hz, 2H), 3.94 (s, 3H), 3.84 (s, 2H), 2.81-2.89 (m, 2H), 2.41-2.48 (m, 2H), 1.91-2.01 (m, 2H), 1.52-1.71 (m, 2H), 1.36-1.48 (m, 2H), 0.83 (d, J=6.4Hz, 6H), 0.45- 0.54(m,1H)；ESI-MS[M+H](m/z):655.4.
Embodiment 7 1- [4- [6- methoxyl group -7- [3- (4- ethyl piperazidine -1- base) propoxyl group] quinoline -4- epoxide] benzene Base] -3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
ESI-MS[M+H](m/z):630.2；1H-NMR(400MHz,DMSO-d6) δ 8.97-9.03 (br, 1H), 8.58 (s, 1H), 8.44 (d, J=5.2Hz, 1H), 7.54-7.65 (m, 6H), 7.37 (s, 1H), 7.22-7.28 (m, 2H), 7.19 (m, 2H), 6.44 (d, J=5.2Hz, 1H), 5.97 (s, 1H), 4.37 (d, J=6.4Hz, 2H), 4.07 (s, 3H), 3.89 (s, 2H), 3.44 (m, 10H), 2.93 (q, 2H), 2.39 (s, 2H), 1.04 (t, 3H).ESI-MS[M+H](m/z):656.4.
Embodiment 8 1- [4- [6- methoxyl group -7- [3- (N- heterocycle butyl- 1- yl) propoxyl group] quinoline -4- epoxide] phenyl] - 3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 8.66 (s, 1H), 8.46 (d, J=5.2Hz, 1H), 7.93 (m, 1H), 7.81 (d, J=5.6Hz, 1H), 7.75 (d, J=5.6Hz, 1H), 7.64-7.69 (m, 1H), 7.54 (d, J= 8.8Hz, 2H), 7.52 (s, 1H), 7.39 (s, 1H), 7.17 (d, J=8.8Hz, 2H), 6.47 (d, J=5.2Hz, 1H), 5.98 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.97 (s, 3H), 3.77-3.83 (m, 2H), 2.66-2.72 (m, 2H), 2.52- 2.60 (br, 4H), 1.98-2.06 (m, 2H), 1.63-1.74 (br, 4H)；ESI-MS[M+H](m/z):600.3.
Embodiment 9 1- [6- [6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinoline -4- epoxide] pyridine -3- Base] and -3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.97-9.03 (br, 1H), 8.53 (s, 1H), 8.42 (d, J=5.2Hz, 1H), 7.50-7.61 (m, 6H), 7.37 (s, 1H), 7.21-7.26 (m, 2H), 7.17 (m, 2H), 6.41 (d, J=5.2Hz, 1H), 5.85 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.79-3.83 (m, 2H), 2.66-2.72 (m, 2H), 2.52-2.60 (br, 4H), 1.98-2.06 (m, 2H), 1.63-1.74 (br, 4H)；ESI-MS[M+H](m/z):631.2.
Embodiment 10 1- [6- [6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- epoxide] pyrrole Pyridine -3- base] and -3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.03-9.11 (br, 1H), 8.57 (s, 1H), 8.46 (d, J=5.2Hz, 1H), 7.53-7.64 (m, 6H), 7.42 (s, 1H), 7.25-7.30 (m, 2H), 7.22 (m, 2H), 6.44 (d, J=5.2Hz, 1H), 5.87 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.47 (m, 2H), 1.85-2.00 (m, 4H), 1.63 (m, 2H), 1.25-1.41 (m, 1H), 1.04-1.19 (m, 2H), 0.92 (d, J= 6.4Hz,3H)；ESI-MS[M+H](m/z):659.3.
Embodiment 11 1- [6- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] pyridin-3-yl] -3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.98-9.05 (br, 1H), 8.55 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.51-7.63 (m, 6H), 7.39 (s, 1H), 7.23-7.27 (m, 2H), 7.19 (m, 2H), 6.42 (d, J=5.2Hz, 1H), 5.86 (s, 1H), 4.21 (t, J=6.0Hz, 2H), 3.94 (s, 3H), 3.80-3.87 (m, 2H), 3.57-3.67 (br, 4H),2.32-2.47(br,6H),1.95-2.07(br,2H)；ESI-MS[M+H](m/z):647.2.
Embodiment 12 1- [6- [6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- epoxide] pyrrole Pyridine -3- base] and -3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.02 (s, 1H), 8.59 (s, 1H), 8.48 (d, J=5.2Hz, 1H), 7.55- 7.65 (m, 6H), 7.44 (s, 1H), 7.23-7.31 (m, 2H), 7.23 (m, 2H), 6.47 (d, J=5.2Hz, 1H), 5.93 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 3.91 (s, 2H), 3.32 (s, 3H), 2.88 (m, 2H), 2.46 (m, 2H), 1.82-2.01 (m, 4H), 1.59 (m, 2H), 1.12-1.24 (m, 2H)；ESI-MS[M+H](m/z):660.3.
Embodiment 13 1- [4- [6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinoline -4- epoxide] phenyl] - 3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.01-9.09 (br, 1H), 8.63 (s, 1H), 8.47 (d, J=5.2Hz, 1H), 7.91-7.94 (br, 1H), 7.84 (d, J=5.6Hz, 1H), 7.72 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.54 (d, J=8.8Hz, 2H), 7.49 (s, 1H), 7.39 (s, 1H), 7.19 (d, J=8.8Hz, 2H), 6.43 (d, J= 5.2Hz, 1H), 5.94 (s, 1H), 4.23 (t, J=6.4Hz, 2H), 3.97 (s, 3H), 3.78-3.84 (m, 2H), 2.67-2.73 (m, 2H), 2.54-2.62 (br, 4H), 1.98-2.04 (m, 2H), 1.61-1.72 (br, 4H)；ESI-MS[M+H](m/z): 681.2.
Embodiment 14 1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl] -3- [4- oxygen Generation -2- (3- trifluoromethyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (br, 1H), 8.65 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.92 (br, 1H), 7.82 (d, J=5.6Hz, 1H), 7.73 (d, J=5.6Hz, 1H), 7.63-7.67 (m, 1H), 7.52 (d, J= 8.8Hz, 2H), 7.50 (s, 1H), 7.38 (s, 1H), 7.18 (d, J=8.8Hz, 2H), 6.40 (d, J=5.2Hz, 1H), 5.96 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.93 (m, 4H), 3.81 (s, 1H), 3.58-3.60 (m, 4H), 2.45-2.49 (m, 2H), 2.34-2.43 (br, 4H), 1.94-2.07 (br, 2H)；ESI-MS[M+H](m/z):698.2.
Embodiment 15 1- [4- [6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- epoxide] benzene Base] -3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.06 (s, 1H), 8.64 (s, 1H), 8.42 (d, J=5.2Hz, 1H), 7.88- 7.93 (br, 1H), 7.83 (d, J=5.6Hz, 1H), 7.76 (d, J=5.6Hz, 1H), 7.63-7.71 (m, 1H), 7.59 (d, J =8.8Hz, 2H), 7.53 (s, 1H), 7.45 (s, 1H), 7.26 (d, J=8.8Hz, 2H), 6.48 (d, J=5.2Hz, 1H), (6.12 s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.31 (s, 3H), 2.86 (m, 2H), 2.45 (m, 2H), 1.83-2.02 (m, 4H), 1.62 (m, 2H), 1.13-1.25 (m, 2H)；ESI-MS[M+H](m/z):711.3.
Embodiment 16 1- [6- [6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- epoxide] pyrrole Pyridine -3- base] -3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.00-9.11 (br, 1H), 8.66 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.94 (br, 1H), 7.83 (d, J=5.6Hz, 1H), 7.75 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.54 (d, J=8.8Hz, 2H), 7.53 (s, 1H), 7.40 (s, 1H), 7.19 (d, J=8.8Hz, 2H), 6.42 (d, J=5.2Hz, 1H), 5.97 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.80-3.87 (m, 2H), 2.87 (m, 2H), 2.49 (m, 2H), 1.88-2.01 (m, 4H), 1.65 (m, 2H), 1.27-1.40 (m, 1H), 1.05-1.17 (m, 2H), 0.91 (d, J= 6.4Hz,3H)；ESI-MS[M+H](m/z):710.3.
Embodiment 17 1- [4- [6- methoxyl group -7- [3- (3,5- lupetidine -1- base) propoxyl group] quinoline -4- epoxide] Phenyl] -3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.01 (s, 1H), 8.62 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 7.88- 7.95 (br, 1H), 7.81 (d, J=5.6Hz, 1H), 7.78 (d, J=5.6Hz, 1H), 7.63-7.69 (m, 1H), 7.56 (d, J =8.8Hz, 2H), 7.51 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.8Hz, 2H), 6.46 (d, J=5.2Hz, 1H), 6.03 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.84 (s, 2H), 2.83-2.89 (m, 2H), 2.42- 2.49 (m, 2H), 1.92-2.04 (m, 2H), 1.53-1.66 (m, 2H), 1.34-1.43 (m, 2H), 0.83 (d, J=6.4Hz, 6H), 0.47-0.59 (m, 1H)；ESI-MS[M+H](m/z):723.4.
Embodiment 18 1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl] -3- [4- oxygen Generation -2- [(4- dimethylamino) phenyl] thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.86-8.96 (br, 1H), 8.43 (d, J=5.2Hz, 1H), 8.38 (s, 1H), 7.51 (d, J=8.8Hz, 2H), 7.50 (s, 1H), 7.38 (s, 1H), 7.24-7.33 (m, 2H), 7.18 (d, J= 8.8Hz, 2H), 6.72 (d, J=8.8Hz, 2H), 6.39 (d, J=5.2Hz, 1H), 5.72 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.75-3.79 (m, 1H), 3.58-3.61 (m, 4H), 2.91 (s, 6H), 2.45-2.47 (m, 2H), 2.35-2.43 (br, 4H), 1.94-2.01 (m, 2H)；ESI-MS[M+H](m/z):672.3.
Embodiment 19 1- [4- [6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- epoxide] benzene Base] -3- [4- oxo -2- [(4- dimethylamino) phenyl] thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.92-8.98 (br, 1H), 8.45 (d, J=5.2Hz, 1H), 8.42 (s, 1H), 7.52 (d, J=8.8Hz, 2H), 7.48 (s, 1H), 7.39 (s, 1H), 7.25-7.35 (m, 2H), 7.19 (d, J= 8.8Hz, 2H), 6.71 (d, J=8.8Hz, 2H), 6.41 (d, J=5.2Hz, 1H), 5.79 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.91 (s, 2H), 3.30 (s, 3H), 2.90 (s, 6H), 2.85 (m, 2H), 2.47 (m, 2H), 1.83- 2.01 (m, 4H), 1.64 (m, 2H), 1.13-1.25 (m, 2H)；ESI-MS[M+H](m/z):685.3.
Embodiment 20 1- [4- [6- methoxyl group -7- [3- (4- methylenepiperidines -1- base) propoxyl group] quinoline -4- epoxide] benzene Base] -3- [4- oxo -2- [(4- dimethylamino) phenyl] thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.92 (s, 1H), 8.47 (d, J=5.2Hz, 1H), 8.43 (s, 1H), 7.54 (d, J=8.8Hz, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.26-7.35 (m, 2H), 7.21 (d, J=8.8Hz, 2H), 6.72 (d, J=8.8Hz, 2H), 6.44 (d, J=5.2Hz, 1H), 5.88 (s, 1H), 4.87-5.05 (m, 2H), 4.21 (t, J= 6.4Hz, 2H), 3.95 (s, 3H), 3.78-3.84 (m, 2H), 2.93 (s, 6H), 2.67-2.74 (m, 2H), 2.55-2.65 (br, 4H), 1.96-2.07 (m, 2H), 1.63-1.72 (br, 2H)；ESI-MS[M+H](m/z):682.3.
Embodiment 21 1- [4- [6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinoline -4- epoxide] phenyl] - 3- [4- oxo -2- [(4- dimethylamino) phenyl] thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.98 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 8.41 (s, 1H), 7.55 (d, J=8.8Hz, 2H), 7.46 (s, 1H), 7.39 (s, 1H), 7.25-7.33 (m, 2H), 7.17 (d, J=8.8Hz, 2H), 6.74 (d, J=8.8Hz, 2H), 6.47 (d, J=5.2Hz, 1H), 5.96 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.78-3.83 (m, 2H), 2.93 (s, 6H), 2.67-2.74 (m, 2H), 2.54-2.63 (br, 4H), 1.98-2.06 (m, 2H), 1.61-1.71 (br, 4H)；ESI-MS[M+H](m/z):656.3.
Embodiment 22
Step (1) 3- methoxyl group -4- benzyloxy acetophenone (XIV)
Under room temperature, 400g (2.41mol) 3- methoxyl group -4-hydroxyacetophenone II is added to 2L DMF, add 997.7g (7.23mol) Anhydrous potassium carbonate, after stirring 15min, instills 430.2g (2.53mol) cylite, drips and finish, be stirred at room temperature 4h.Reactant liquor is poured in 10L frozen water, sucking filtration, obtains white solid 594.5g.
Step (2) 2- nitro -4- benzyloxy -5- methoxyacetophenone (XV)
500.0g (1.95mol) intermediate X IV is added to 2.5L dichloromethane.Between -20 DEG C to -10 DEG C, slow Plus 300.0g fuming nitric aicd, drip and finish, -10 DEG C of reaction 2h.Reactant liquor is poured in frozen water, collected organic layer, organic layer saturation Sodium bicarbonate aqueous solution is washed till neutrality, anhydrous sodium sulfate drying, solvent evaporated, obtains yellow solid 513.6g.
Step (3) 1- [2- nitro -4- benzyloxy -5- methoxyphenyl] -3- (dimethylamino) propyl group -2- alkene -1- ketone (XVI)
500.0g (1.66mol) intermediate X V is added to 2.5L dimethylbenzene, adds 1.05Kg (8.80mol) DMF- DMA, flow back 15h.Reactant liquor is cooled to -10 DEG C, sucking filtration, filter cake is washed with appropriate dimethylbenzene, obtains yellow solid after being dried 463.4g.
Step (4) 6- methoxyl group -7- benzyloxy -4 (1H)-quinolinone (XVII)
400.0g (1.12mol) intermediate X VI is added to 3L glacial acetic acid, is warming up to 60 DEG C, is dividedly in some parts 313.6g (5.60mol) reduced iron powder, 90 DEG C of reaction 2h.Sucking filtration while hot, filtrate cools down, and sucking filtration obtains khaki solid.Glacial acetic acid recrystallization Afterwards, obtain beige solid 229.8g.
Step (5) 4- chloro- 6- methoxyl group -7- benyloxyquinoline (XVIII)
By 200.0g (0.71mol) intermediate X VII and 1L POCl3Add in the acetonitrile being dried to 1L, back flow reaction 6h. Evaporated under reduced pressure, is stirred vigorously down, and concentrated liquid is added in frozen water, adjusts pH to 8, sucking filtration with 10%NaOH aqueous solution, obtains grey White solid 174.8g.
Step (7) 4- (4-nitrophenoxy) -6- methoxyl group -7- benyloxyquinoline (XIX)
200.0g (0.67mol) intermediate VXIII and 111.6g (0.80mol) 4- nitrophenol is added and does to 800mL In dry chlorobenzene, flow back 20h.Solvent evaporated, obtains gray solid, is dissolved in CH2Cl2In, 10% sodium hydrate aqueous solution is washed Wash, organic layer anhydrous sodium sulfate drying, solvent evaporated, obtain solid 201.8g.
Step (8) 4- (4-nitrophenoxy) -6- methoxyl group -7- benyloxyquinoline -1- oxide (XX)
200.0g (0.50mol) intermediate X IX is added to 2L dichloromethane, 0 DEG C is dividedly in some parts 160.9g (0.75mol) 80% metachloroperbenzoic acid (m-CPBA), finishes, 6h is stirred at room temperature.Reactant liquor uses unsaturated carbonate hydrogen respectively Sodium water solution and washing, organic faciess anhydrous sodium sulfate drying, it is evaporated, obtain yellow-brown solid 157.9g.
Step (9) 4- (4-nitrophenoxy) -6- methoxyl group -7- hydroxyquinoline -1- oxide (XXI)
In 30% hydrobromic acid glacial acetic acid solution during 150.0g (0.36mol) intermediate X X is added, 2h is stirred at room temperature.Take out Filter, filter cake is washed, and obtains pale solid 108.7g.
Step (10) 4- (4-nitrophenoxy) -6- methoxyl group -7- (3- chlorine propoxyl group) quinoline -1- oxide (XXII)
100.0g (0.30mo) intermediate X X is added to 1L acetone, adds 126.2g (0.91mol) Anhydrous potassium carbonate, After stirring 15min, instill 52.9g (0.35mol) 1,3- bromo-chloropropane, drip and finish, 4h is stirred at room temperature.It is evaporated, add into residue About 500mL dichloromethane, washing, it is dried, be evaporated to obtain yellow solid 89.5g.
Step (11) 4- (4-nitrophenoxy) -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxide (XXIII)
100.0g (0.25mol) intermediate X XII and 217mL (2.5mol) morpholine are added to 1L acetonitrile, backflow is anti- Answer 12h.Boil off most of solvent, residual solution is cooled to -10 DEG C, separate out solid, sucking filtration, ethyl acetate is washed, and obtains solid 91.4g.
Step (12) 4- (4- amino-benzene oxygen) -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxide (XXIV)
By 80.0g (0.18mol) intermediate X XIII, 49.2g (0.90mol) reduced iron powder and 5mL concentrated hydrochloric acid add to 800mL 90%EtOH-H2In O, finish, flow back 2h.Sucking filtration while hot, collects filtrate, is evaporated, obtains faint yellow solid 66.4g.
Step (13) 6- methoxyl group -7- (morpholinyl propoxyl group) -4- [(4- benzene oxygen formamido) phenoxy group] quinoline -1- oxygen Compound (XXV)
Under room temperature, 50.0g (0.12mol) intermediate X and 50.6g (0.37mol) Anhydrous potassium carbonate are added and is dried to 1L Acetone in, at 0 DEG C instill 22.4mL (0.13mol) phenyl chloroformate, drip finish, 6h is stirred at room temperature.Solvent evaporated, adds 500mL dichloromethane, washes (2 × 100mL), anhydrous sodium sulfate drying, is evaporated to obtain yellow oily liquid 51.6g.
Step (14) 4- [(4- diazanyl formamido) phenoxy group] -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxygen Compound (XXVI)
50.0g (91.7mmol) intermediate X XV is dissolved in 300mL dioxane, is added thereto to 300mL 80% water Close hydrazine, flow back about 5h.Boil off most of dioxane, cooling, sucking filtration, obtain white solid 32.5g.
Step (15) 4- [4- [2- (2,4 dichloro benzene methylene) diazanyl formamido] phenoxy group] -6- methoxyl group -7- (3- Quinoline base propoxyl group) quinoline -1- oxide (Q-3)
30.0g (62.1mmol) intermediate X XVI and 12.0g (68.3mmol) 2,4 dichloro benzene formaldehyde are added to 150mL In isopropanol, add 1mL glacial acetic acid, flow back 4h.Cooling, sucking filtration, filter cake, with a small amount of isopropanol drip washing, obtains white solid 28.8g.
Step (16) 4- [4- [3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea groups] phenoxy group] -6- methoxy Base -7- (morpholinyl propoxyl group) quinoline -1- oxide (Q-3-1)
Under room temperature, 20.0g (31.3mmol) intermediate Q-3 is added to 80mL thioglycolic acid, add the tetrachloro of 2mL SiClx, finishes, and about 6h is stirred at room temperature.10% sodium hydrate aqueous solution adjusts pH to 8, and dichloromethane extracts (2 × 150mL), organic Mutually use anhydrous sodium sulfate drying, be evaporated, column chromatographic isolation and purification obtains white solid 10.9g.
Step (17) 1- [4- [[2- tert-butylamine base -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] epoxide] benzene Base] -3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea (Q-3-2)
Under room temperature, 10.0g (14.0mmol) intermediate Q-3-1 is added to 100mL dichloromethane, add 5.2g (70.0mmol) tert-butylamine, adds 9.1g (28.0mmol) p-toluenesulfonic anhydride (Ts at 0 DEG C2O), finish, be stirred at room temperature 30min.Sucking filtration, filtrate is washed, and is evaporated to obtain yellow solid 10.6g.
Step (18) 1- [4- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] epoxide] phenyl] - 3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea (embodiment 22)
10.0g (13.0mmol) intermediate Q-3-2 is added to 100mL trifluoroacetic acid, flow back 5h.It is evaporated reactant liquor, It is added thereto to 100mL dichloromethane, saturated sodium bicarbonate aqueous solution is washed (2 × 50mL) twice, organic faciess are dried, and are evaporated brown Color solid, the white solid 7.3g of column chromatographic isolation and purification.
According to the method for embodiment 22, reacted through addition, dehydration and amination etc. with different substituents intermediate Q-3 for raw material Prepare the compound of embodiment 23-30.
Embodiment 23 1- [4- [[2- amino -6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinolyl-4] Epoxide] phenyl] -3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 10.03 (s, 1H), 9.37 (s, 1H), 8.42 (d, J=8.4Hz, 1H), 8.32 (s, 1H), 7.87-7.92 (dd, J1=17.6Hz, J2=2.8Hz, 1H), 7.70 (d, J=2.8Hz, 1H), 7.61-7.65 (m, 1H), 7.59 (s, 1H), 7.52 (d, J=11.2Hz, 1H), 7.39-7.45 (m, 2H), 6.46 (s, 1H), 6.02 (s, 1H), 4.24 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.78-3.84 (m, 2H), 2.76-2.98 (m, 6H), 2.08-2.13 (m, 2H), 1.78-1.84 (m, 4H)；ESI-MS[M+H](m/z):696.2,698.2.
Embodiment 24 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.08 (s, 1H), 8.79 (s, 1H), 8.41 (d, J=8.4Hz, 1H), 8.31 (s, 1H), 7.87-7.94 (dd, J1=17.6Hz, J2=2.8Hz, 1H), 7.67 (d, J=2.8Hz, 1H), 7.61-7.67 (m, 1H), 7.57 (s, 1H), 7.53 (d, J=11.2Hz, 1H), 7.39-7.46 (m, 2H), 6.44 (s, 1H), 5.87 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.87 (m, 2H), 2.89 (m, 2H), 2.47 (m, 2H), 1.85- 2.00 (m, 4H), 1.63 (m, 2H), 1.25-1.41 (m, 1H), 1.04-1.19 (m, 2H), 0.92 (d, J=6.4Hz, 3H)； ESI-MS[M+H](m/z):725.2,727.2.
Embodiment 25 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methylenepiperidines -1- base) propoxyl group] quinoline - 4- yl] epoxide] phenyl] -3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.87 (s, 1H), 9.12 (s, 1H), 8.45 (d, J=8.4Hz, 1H), 8.34 (s, 1H), 7.87-7.93 (dd, J1=17.6Hz, J2=2.8Hz, 1H), 7.73 (d, J=2.8Hz, 1H), 7.62-7.67 (m, 1H), 7.57 (s, 1H), 7.53 (d, J=11.2Hz, 1H), 7.39-7.46 (m, 2H), 6.45 (s, 1H), 5.97 (s, 1H), 4.87-5.02 (m, 2H), 4.20 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 3.78-3.85 (m, 2H), 2.66-2.75 (m, 2H), 2.58-2.67 (br, 4H), 1.96-2.05 (m, 2H), 1.63-1.74 (br, 2H)；ESI-MS[M+H](m/z):723.2, 725.2.
Embodiment 26 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- [2- (2,4 dichloro benzene base) -4- oxothiazoiium quinoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.87 (s, 1H), 9.04 (s, 1H), 8.44 (d, J=8.4Hz, 1H), 8.34 (s, 1H), 7.87-7.93 (dd, J1=17.6Hz, J2=2.8Hz, 1H), 7.68 (d, J=2.8Hz, 1H), 7.61-7.66 (m, 1H), 7.57 (s, 1H), 7.51 (d, J=11.2Hz, 1H), 7.39-7.46 (m, 2H), 6.45 (s, 1H), 6.11 (s, 1H), (4.19 t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.32 (s, 3H), 2.91 (s, 6H), 2.86 (m, 2H), 2.47 (m, 2H), 1.83-2.00 (m, 4H), 1.65 (m, 2H), 1.12-1.24 (m, 2H)；ESI-MS[M+H](m/z):726.2, 728.2.
Embodiment 27 1- [4- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] epoxide] benzene Base] -3- (2- naphthyl -4- oxothiazoiium quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.02-9.09 (br, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 7.92- 7.98 (m, 2H), 7.64-7.71 (m, 1H), 7.50-7.58 (m, 5H), 7.38 (s, 1H), 7.17 (d, J=9.2Hz, 1H), 6.40 (s, 1H), 6.00 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.81-3.98 (m, 2H), 3.58- 3.60 (m, 4H), 2.45-2.49 (m, 2H), 2.33-2.43 (br, 4H), 1.94-2.01 (m, 2H)；ESI-MS[M+H](m/z): 695.3.
Embodiment 28 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- (2- naphthyl -4- oxothiazoiium quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.01-9.07 (br, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.91- 7.96 (m, 2H), 7.63-7.70 (m, 1H), 7.51-7.58 (m, 5H), 7.37 (s, 1H), 7.18 (d, J=9.2Hz, 1H), 6.41 (s, 1H), 6.01 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.97 (s, 3H), 3.81-3.87 (m, 2H), 2.87 (m, 2H), 2.45 (m, 2H), 1.83-2.00 (m, 4H), 1.62 (m, 2H), 1.24-1.40 (m, 1H), 1.03-1.15 (m, 2H), 0.91 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):707.3.
Embodiment 29 1- [4- [[2- amino -6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinolyl-4] Epoxide] phenyl] -3- (2- naphthyl -4- oxothiazoiium quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.06-9.13 (br, 1H) .69 (s, 1H), 7.99 (s, 1H), 7.93-7.97 (m, 2H), 7.64-7.72 (m, 1H), 7.52-7.59 (m, 5H), 7.39 (s, 1H), 7.21 (d, J=9.2Hz, 1H), 6.43 (d, J=5.2Hz, 1H), 6.01 (s, 1H), 4.24 (t, J=6.4Hz, 2H), 3.99 (s, 3H), 3.79-3.86 (m, 2H), 2.68- 2.75 (m, 2H), 2.55-2.64 (br, 4H), 1.98-2.06 (m, 2H), 1.64-1.73 (br, 4H)；ESI-MS[M+H](m/ z):678.2.
Embodiment 30 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- (2- naphthyl -4- oxothiazoiium quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.01-9.07 (br, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.91- 7.96 (m, 2H), 7.63-7.70 (m, 1H), 7.51-7.58 (m, 5H), 7.37 (s, 1H), 7.18 (d, J=9.2Hz, 1H), (6.41 s, 1H), 6.01 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 3.91 (s, 2H), 3.32 (s, 3H), 2.88 (m, 2H), 2.46 (m, 2H), 1.82-2.01 (m, 4H), 1.59 (m, 2H), 1.12-1.24 (m, 2H)；ESI-MS[M+H] (m/z):708.2.
Embodiment 31
Step (1) 4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] PITC (X-1)
Under room temperature, 50g (122.2mmol) intermediate X is dissolved in 500mL dichloromethane, adds 100mL unsaturated carbonate hydrogen Sodium water solution.0 DEG C of instillation 11.4mL (28.2mmol) thiophosgene, drips and finishes, 6h is stirred at room temperature, separates organic faciess, anhydrous sodium sulfate It is dried, be evaporated to obtain yellow oily liquid 38.1g.
Step (2) 4- [4- [7- (morpholinyl propoxyl group) -6- methoxy quinoline -4- epoxide] phenyl] thiosemicarbazides (X-2)
Under room temperature, 30.0g (66.5mmol) intermediate X -1 is dissolved in 150mL dichloromethane, adds 1500mL80% water Close hydrazine, stir 12h.Separate organic layer, wash (3 × 50mL), anhydrous sodium sulfate drying, be evaporated to obtain yellow-brown solid, column chromatography Separate to obtain faint yellow solid 17.9g.
Step (3) N1- [4- [7- (morpholinyl propoxyl group) -6- methoxy quinoline -4- epoxide] phenyl]-N4- (2,6- difluoro Benzaldehyde) thiosemicarbazones (Q-2)
10.0g (20.7mmol) X-2 and 3.2g (22.8mmol) 2,6- difluorobenzaldehyde is added to 50mL isopropanol, Add 1mL glacial acetic acid, flow back 4h.It is cooled to room temperature, sucking filtration, filter cake, with a small amount of isopropanol drip washing, obtains yellow solid 8.5g.
Step (4) 1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl] -3- [2- (2,6- bis- Fluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea (embodiment 31)
Under room temperature, 5.0g (31.3mmol) intermediate Q-2 is added to 20mL thioglycolic acid, add the four of 0.5mL Silicon chloride, finishes, and about 6h is stirred at room temperature.10% sodium hydrate aqueous solution adjusts pH to 8, and dichloromethane extracts (2 × 50mL), organic Mutually use anhydrous sodium sulfate drying, be evaporated, column chromatographic isolation and purification obtains white solid 3.1g.
According to the method for embodiment 31, prepared through addition, dehydration with different substituents intermediate Q-2 for raw material The compound of embodiment 32-39.
Embodiment 32 1- [4- [[6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinolyl-4] epoxide] Phenyl] -3- [2- (2,6- difluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.07 (s, 1H), 8,98 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 7.74-7.49 (m, 1H), 7.38 (s, 1H), 7.16-7.21 (m, 4H), 6.42 (d, J=5.2Hz, 1H), 6.17 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.75-3.83 (m, 2H), 3.31 (s, 3H), 2.85 (m, 2H), 2.45 (m, 2H), 1.82-2.02 (m, 4H), 1.58 (m, 2H), 1.07-1.22 (m, 2H)；ESI- MS[M+H](m/z):695.2.
Embodiment 33 1- [4- [[6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinolyl-4] epoxide] benzene Base] -3- [2- (2,6- difluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 8,94 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 7.54 (d, J=8.8Hz, 2H), 7.50 (s, 1H), 7.73-7.47 (m, 1H), 7.36 (s, 1H), 7.15-7.20 (m, 4H), 6.41 (d, J=5.2Hz, 1H), 6.14 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.75-3.83 (m, 2H), 2.66- 2.72 (m, 2H), 2.53-2.61 (br, 4H), 1.97-2.03 (m, 2H), 1.60-1.71 (br, 4H)；ESI-MS[M+H](m/ z):666.2.
Embodiment 34 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- [2- (2,6- difluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.08-9.17 (br, 1H), 8,96-9.03 (br, 1H), 8.46 (d, J= 5.2Hz, 1H), 7.57 (d, J=8.8Hz, 2H), 7.53 (s, 1H), 7.54-7.69 (m, 1H), 7.39 (s, 1H), 7.17-7.23 (m, 4H), 6.44 (d, J=5.2Hz, 1H), 6.14 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.97 (s, 3H), 3.80- (3.87 m, 2H), 2.86 (m, 2H), 2.47 (m, 2H), 1.86-2.03 (m, 4H), 1.65 (m, 2H), 1.26-1.42 (m, 1H), 1.06-1.18 (m, 2H), 0.91 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):694.2.
Embodiment 35 1- [4- [[6- methoxyl group -7- [3- (4- ethyl piperazidine -1- base) propoxyl group] quinolyl-4] epoxide] Phenyl] -3- [2- (2,6- difluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.97 (s, 1H), 8.98 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 7.54 (d, J=8.8Hz, 2H), 7.53 (s, 1H), 7.49-7.67 (m, 1H), 7.41 (s, 1H), 7.16-7.23 (m, 4H), 6.45 (d, J=5.2Hz, 1H), 6.12 (s, 1H), 4.31 (d, J=6.4Hz, 2H), 4.06 (s, 3H), 3.85 (s, 2H), 3.43 (m, 10H), 2.92 (q, 2H), 2.37 (s, 2H), 1.02 (t, 3H)；ESI-MS[M+H](m/z):709.2.
Embodiment 36 1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl] -3- [2- (2, 4- difluorophenyl) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.02-9.09 (br, 1H), 8.68 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.67-7.75 (m, 1H), 7.55 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 7.38 (s, 1H), 7.31-7.35 (m, 1H), 7.20 (m, 3H), 6.40 (d, J=5.2Hz, 1H), 6.04 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.87-3.94 (m, 2H), 3.58-3.61 (m, 4H), 2.45-2.49 (m, 2H), 2.35-2.43 (br, 2H), 1.95-2.01 (m, 2H)；ESI- MS[M+H](m/z):682.1.
Embodiment 37 1- [4- [[2- amino -6- methoxyl group -7- [3- (4- methyl piperidine -1- base) propoxyl group] quinoline -4- Base] epoxide] phenyl] -3- [2- (2,4 difluorobenzene base) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.14-9.22 (br, 1H), 8.66 (s, 1H), 8.46 (d, J=5.2Hz, 1H), 7.63-7.72 (m, 1H), 7.51 (d, J=8.8Hz, 2H), 7.48 (s, 1H), 7.36 (s, 1H), 7.30-7.35 (m, 1H), 7.18 (m, 3H), 6.42 (d, J=5.2Hz, 1H), 6.00 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.95 (s, 3H), 3.81-3.87 (m, 2H), 2.87 (m, 2H), 2.48 (m, 2H), 1.83-1.96 (m, 4H), 1.65 (m, 2H), 1.23-1.40 (m, 1H), 1.06-1.17 (m, 2H), 0.93 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):694.2.
Embodiment 38 1- [4- [[6- methoxyl group -7- [3- (nafoxidine -1- base) propoxyl group] quinolyl-4] epoxide] benzene Base] -3- [2- (2,4 difluorobenzene base) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.21-9.34 (br, 1H), 8.66 (s, 1H), 8.47 (d, J=5.2Hz, 1H), 7.68-7.76 (m, 1H), 7.57 (d, J=8.8Hz, 2H), 7.52 (s, 1H), 7.41 (s, 1H), 7.33-7.37 (m, 1H), 7.22 (m, 3H), 6.43 (d, J=5.2Hz, 1H), 6.01 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.99 (s, 3H), 3.76-3.83 (m, 2H), 2.68-2.75 (m, 2H), 2.55-2.64 (br, 4H), 1.99-2.06 (m, 2H), 1.63-1.74 (br,4H)；ESI-MS[M+H](m/z):666.1.
Embodiment 39 1- [4- [[6- methoxyl group -7- [3- (4- methylpiperazine-1-yl) propoxyl group] quinolyl-4] epoxide] Phenyl] -3- [2- (2,4 difluorobenzene base) -4- oxothiazoiium quinoline -3- base] thiourea
1H-NMR(400MHz,DMSO-d6) δ 9.12 (s, 1H), 8.69 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 7.65- 7.73 (m, 1H), 7.59 (d, J=8.8Hz, 2H), 7.55 (s, 1H), 7.44 (s, 1H), 7.34-7.39 (m, 1H), 7.25 (m, 3H), 6.46 (d, J=5.2Hz, 1H), 6.12 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.98 (s, 3H), 3.91 (s, 2H), 3.32 (s, 3H), 2.88 (m, 2H), 2.46 (m, 2H), 1.82-2.01 (m, 4H), 1.59 (m, 2H), 1.12-1.24 (m, 2H)； ESI-MS[M+H](m/z):695.2.
The antitumor activity of product of the present invention
MET kinase inhibition assay
Test for measuring MET kinase activity is based on elisa (ELISA).Concrete operations are：
Under room temperature, on the coated plate of 0.25mg/mL PGT, by embodiment compound, the 50pM MET (weight of His- labelling Group people MET (aminoacid 974- end), by baculovirus expression) and 5 μM of ATP (25mM MOPS, pH in test buffer 7.4,5mM MgCl2,0.5raM MnCl2, 100 μM of sodium orthovanadates, 0.01%Triton X-100,1mM DTT, last DMSO are dense Degree 1% (v/v)) incubate 20min.It is conjugated horseradish peroxidase by flushing removing reactant mixture and with 0.2 μ g/mL (HRP) phosphotyrosine monoclonal antibody specific (PY20) detection phosphorylated polymer substrate.1M phosphoric acid is added to terminate aobvious At 450nm, after color, pass through the color of the substrate (TMB) of spectrophotography quantitative chromogenic.Embodiment compound is to MET kinases Suppression data is shown in Table 1.
The inhibitory activity to MET kinases for the table 1 embodiment compound
The activity of extracorporeal suppression tumor cell propagation
Quinoline to the upper formula I according to the present invention or quinazoline derivative have carried out vitro inhibition colon cancer cell HT- 29th, human breast cancer cell MDA-MB-231 and gastric carcinoma cells MKN-45 screening active ingredients.
1. the recovery of cell, pass on and cultivate
(1) the recovery of cell：Cryopreservation tube is taken out from refrigerator or liquid nitrogen, puts in 37 DEG C of water-baths and thaw rapidly.Draw and freeze Deposit liquid in pipe and, in centrifuge tube, add 2-3mL culture fluid, 800rpm is centrifuged 8min, collects cell, in containing 20% hyclone Cultivate in culture fluid, after 24h, change liquid.
(2) the passing on of cell：Outwell old culture fluid in culture bottle, add 5-7mL Digestive system, put into 37 DEG C, CO2Incubator In, after 2min pat culture bottle, cell dissociation is got off, pours in centrifuge tube, plus 8mL about containing 10% hyclone culture Liquid terminates digestion.It is centrifuged 8min, abandoning supernatant, plus 4mL culture fluid in 800rpm, piping and druming is passed in (1/4) ratio after mixing.
(3) the culture of cell：Pass on the CO that rear cell is put in 37 DEG C2Cultivate in incubator, general cell can use after passing for 2 generations In test.
2. buried plate
The cell pancreatin cultivating cell log trophophase in culture bottle is digested, with the culture containing 10% serum Liquid terminates digestion, loads in centrifuge tube afterwards and seals, and 800rpm is centrifuged 8min, abandons supernatant, is blown and beaten all with the culture fluid of 10% serum Even adjust concentration of cell suspension with culture fluid again, add in 96 orifice plates, every hole 100 μ L, about 1 × 104/ hole, is placed in 37 DEG C, 5%CO2Incubator culture 24h makes cell attachment, and the 30% about of microscopy cell about every hole is advisable.
3. dosing
Test medicine is first vortexed with 50 μ L DMSO and mixes, be subsequently adding the culture fluid containing 950 μ L 10% serum and carry out Dilute and mix, take 50 μ L to add in 24 orifice plate first row holes from the medicinal liquid having diluted, then add in the hole adding good medicinal liquid 950 μ L contain the culture fluid of 10% serum, are mixed with liquid-transfering gun, take 200 μ L to add the second hole, add containing 10% training in the second hole Nutrient solution 800 μ l carries out 5 times of dilutions, and the rest may be inferred, and one shares 24 orifice plates standby, such as 100 μ that are diluted to 5 variable concentrations medicines G/mL, 20 μ g/mL, 4 μ g/mL, 0.8 μ g/mL and 0.16 μ g/mL.Culture fluid in 96 orifice plates having buried cell is firmly thrown away, 96 orifice plate crosses are equally divided into four regions, the upper and lower two row holes of 96 orifice plates as blank control wells, by prepare before Medicinal liquid is separately added in 96 orifice plates (96 orifice plates add) according to order from right to left according to concentration order from low to high, and every hole adds 170 μ L, every concentration adds 3 holes, adds 170 μ L/ hole culture fluid, it is each adjacent that left and right two row does not have the hole of cell to be separately added into The maximum concentration of medicine, is placed in 37 DEG C, 5%CO272h is cultivated in incubator.
4. add MTT
First microscopy observes blank well cell growing way, after there are nodeless mesh or other situations in drug level highest hole, firmly throws away Liquid in 96 orifice plates, every hole adds 200 μ L normal saline cleanings, so that left drug is washed away, throws away liquid.By prepare in advance 5%MTT liquid culture fluid is diluted to 0.5%MTT solution, then according to 100 μ l/ holes, the MTT having diluted is added 96 holes Plate, is placed in 37 DEG C, 5%CO2In incubator, culture 4h is to promote its reaction completely.After 4h, firmly throw away liquid in 96 orifice plates, often Hole adds 100 μ L DMSO, is placed in concussion 3min on magnetic force oscillator, so that crystal is fully dissolved, on enzyme-linked immunosorbent assay instrument Measure the absorbance in each hole with double-wavelength method (490nm and 630nm).
5. result of calculation
Calculate the half-inhibition concentration IC of each medicine according to absorbance with Bliss method50Value, Activity Results are shown in Table 2.
The anti tumor activity in vitro of table 2 embodiment compound
From above-mentioned result of the test it can be clearly seen that the compound of the claimed formula I of the present invention, have good Anti tumor activity in vitro, the antitumor drug Cabozantinib quite or better than listing.
The compound of formula of I of the present invention can be administered alone, but typically gives with pharmaceutical carrier mixture, described medicinal The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various medicine agent of such compound The preparation method of type, such as tablet, capsule, injection, aerosol, suppository, membrane, drop pill, externally-applied liniment and ointment, Its new opplication in pharmaceutical field is described.
Embodiment 40：Tablet
With the compound containing compound in claim 1 () 10g, according to pharmaceuticss one taking embodiment 12 compound as a example As pressed disc method add adjuvant 20g mix after, be pressed into 100, every weight 300mg.
Embodiment 41：Capsule
With containing the compound () 10g in claim 1, according to pharmaceuticss capsule taking embodiment 36 compound as a example After requiring to mix adjuvant 20g, load Capsuleses, each capsule weight 300mg.
Embodiment 42：Injection
With containing the compound () 10g in claim 1, according to pharmaceuticss conventional method taking embodiment 1 compound as a example, Carry out activated carbon adsorption, after 0.65 μm of filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, every dress 2mL, fill altogether 100 bottles.
Embodiment 43：Aerosol
With containing the compound () 10g in claim 1, with the dissolving of appropriate propylene glycol taking embodiment 22 compound as a example Afterwards, after adding distilled water and other spoke material, the settled solution making 500mL obtains final product.
Embodiment 44：Suppository
With containing the compound () 10g in claim 1 taking embodiment 19 compound as a example, by finely ground addition glycerol fit Amount, adds the glycerin gelatine of fusing after grinding well, grind uniformly, be poured in the model applying lubricant, prepared suppository 50
Embodiment 45：Membrane
With containing the compound () 10g in claim 1, by polyvinyl alcohol, medicinal sweet taking embodiment 30 compound as a example Oil, water etc. stirring expand post-heating dissolving, 80 mesh sieve net filtrations, then embodiment 18 compound is added in filtrate stir molten Solution, film applicator masking 100.
Embodiment 46：Drop pill
With containing the compound () 10g in claim 1, adding with substrate 50g such as gelatin taking embodiment 17 compound as a example After heat fusing mixes, instill in cryogenic liquid paraffin, drop pill 1000 ball is obtained altogether.
Embodiment 47：Externally-applied liniment
With containing the compound () 10g in claim 1, according to conventional dose method taking embodiment 29 compound as a example With the adjuvant 2.5g mixed grindings such as emulsifying agent, then plus distilled water to 200mL be obtained.
Embodiment 48：Ointment
With containing the compound () 10g in claim 1 taking embodiment 37 compound as a example, finely ground after and the oil such as vaseline Property substrate 500g grinds well prepared.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field Will be apparent from for technical staff, and they are included within the scope of the invention.

Claims (21)

1. the compound of formula I and its pharmaceutically acceptable salt, hydrate or prodrug,
Wherein,
A1For N；
A2, Y, Z be N, CH；
X is O, S, NH；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described heterocycle Base and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1With R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are appointed Choosing is by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described heteroaryl Base contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl amide Base, NHCONHR8；
R8For (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl, (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and optionally 0-5 identical or different R6Replace；
Cy1For (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, And Cy1Optionally 0-5 identical or different R6Replace；
Cy2Can not exist or be (C6-C10) aryl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains 1-3 and is selected from N, O or S Hetero atom, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, haloalkyl, hydroxyl, cyano group, amino, nitro, (C1-C6) alcoxyl (sulfur) base, (C1-C6) alkane Base, (C2-C6) thiazolinyl, (C2-C6) alkynyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxyl, quilt 1-2 (C1-C6) alkyl replace amino, (C1-C6) alkylamidoalkyl, free, become salt, esterification and amidated carboxylic Base, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1- C6) alkyl replace carbamyl, (C1-C3) alkylenedioxy group, pi-allyl.
2. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
A1For N；
A2For CH；
X is O, S, NH；
M is the integer between 1-3；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described heterocycle Base and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1With R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are appointed Choosing is by 0-3 identical or different R7Replace；
R7Separately it is selected from (C6-C10) aryl, 5-10 unit's heteroaryl, (C1-C6) alkyl, (C3-C7) cycloalkyl, described heteroaryl Base contains the 1-3 hetero atom selected from N, O or S, and R7Optionally 0-3 identical or different R6Replace；
Cy1For phenyl, naphthyl, 5-10 unit's heteroaryl, wherein, described heteroaryl contains the 1-3 hetero atom selected from N, O or S, and And Cy1Optionally 0-5 identical or different R6Replace.
3. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
X is O；
M is 1；
N is the integer between 1-6；
M is O, S；
W is S (O)0-2；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described heterocycle Base and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1With R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are appointed Choosing is by 0-3 identical or different R7Replace.
4. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
N is 3；
M is O；
W is S；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described heterocycle Base and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1With R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are appointed Choosing is by 0-3 identical or different R7Replace.
5. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl and (C2-C10) alkynyl, they can be optionally by 0-3 identical or different R7Replace；
Or R1And R2With and their nitrogen-atoms of being connected together with form 5-10 circle heterocycles base or 5-10 unit's heteroaryl, described heterocycle Base and heteroaryl except with R1And R2Outside the nitrogen-atoms connecting, optionally containing the 0-4 hetero atom selected from N, O and S, except R1With R2Outside the nitrogen-atoms being connected, described heterocyclic radical optionally includes 0-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are appointed Choosing is by 0-3 identical or different R7Replace；
R7For (C1-C4) alkyl；
R6For hydrogen or 0-5 optionally from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl, the taking of trifluoromethyl and trifluoromethoxy Dai Ji.
6. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
N is 3；
Cy1For phenyl, naphthyl, quinolyl, pyridine radicals, furyl, thienyl and pyrrole radicals, and Cy1Optionally 0-5 identical or Different R6Replace；
R6For hydrogen or 0-5 optionally from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl, the taking of trifluoromethyl and trifluoromethoxy Dai Ji.
7. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
R3For H, NH2、NHS(O)0-2R8、(C1-C6) alkylamidoalkyl, optional 1-5 identical or different R4Substituted aryl amide Base, NHCONHR8；
Cy2Can not exist or for phenyl, naphthyl, quinolyl, pyridine radicals, furyl, thienyl and pyrrole radicals, and Cy2Optionally 0- 5 identical or different R5Replace；
R5、R6For hydrogen or 0-5 optionally from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl, trifluoromethyl and trifluoromethoxy Substituent group.
8. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
R1And R2With and their nitrogen-atoms of being connected together with form piperidino, 4- morpholinyl, 4- methyl isophthalic acid-piperazinyl, 4- second Base -1- piperazinyl, 4- methyl isophthalic acid-piperidyl, 4- methylene-piperidino, 1- pyrrolidinyl, azelidinyl, 4- are thio Quinoline base；
Cy1For phenyl, and Cy1Optionally 0-5 identical or different R6Replace.
9. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
X is S.
10. the compound of the formula I of claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
X is NH.
The compound of the formula I of 11. claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
M is S.
The compound of the formula I of 12. claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
W is S (O)2.
The compound of the formula I of 13. claim 1 and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, its In,
X is O；
A2, Y, Z be respectively N, CH, CH；
A1For N；
M is 1；
N is 3；
M is O；
W is S；
R1And R2With and their nitrogen-atoms of being connected together with form piperidino, 4- morpholinyl, 4- methyl isophthalic acid-piperazinyl, 4- second Base -1- piperazinyl, 4- methyl isophthalic acid-piperidyl, 4- methylene-piperidino, 1- pyrrolidinyl, azelidinyl, 4- are thio Quinoline base；
R3For hydrogen, amino, acetamido, fluoroform sulfoamido, propylureido, butyl urea groups, substituted-phenyl urea groups；
Cy1For phenyl, naphthyl, and Cy1Optionally 0-5 identical or different R6Replace；
Cy2Do not exist or be phenyl, and Cy2Optionally 0-5 identical or different R5Replace；
R4、R5、R6For hydrogen, halogen, trifluoromethyl, methyl.
The compound of 14. general formula I and its pharmaceutically acceptable salt, hydrate, solvate or prodrug：
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- (4- oxo -2- phenyl thiazole Quinoline -3- base) urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- chlorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4,6- tri- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluoroform Base phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4- dichloro Phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- methylbenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxo- 2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperazinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxo -2- benzene Base thiazoline -3- base) urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- Chlorphenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2, 4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- Trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2, 4- Dichlorobenzene base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- Aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxo- 2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxygen Generation -2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (4- methylene-piperidino) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- (4- oxo -2- phenyl thiazole Quinoline -3- base) urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- fluorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- chlorobenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2,4,6- tri- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- fluoroform Base phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2,4- dichloro Phenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- methylbenzene Base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- (4- oxo -2- benzene Base thiazoline -3- base) urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- Fluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Chlorphenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2, 4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- Trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2, 4- Dichlorobenzene base) thiazoline -3- base] urea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Aminomethyl phenyl) thiazoline -3- base] urea.
The compound of 15. general formula I and its pharmaceutically acceptable salt, hydrate, solvate or prodrug：
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- (4- oxo -2- benzene Base thiazoline -3- base) urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxygen Generation -2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxygen Generation -2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- (4- oxo -2- benzene Base thiazoline -3- base) urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- 4- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- aminomethyl phenyl) thiazoline -3- base] urea.
The compound of 16. general formula I and its pharmaceutically acceptable salt, hydrate, solvate or prodrug：
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- (4- oxo- 2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- aminomethyl phenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxo -2- phenyl thiazole quinoline -3- base) urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- chlorphenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4 dichloro benzene base) thiazoline -3- base] urea；
N1- [4- [2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- aminomethyl phenyl) thiazoline -3- base] urea.
The compound of 17. general formula I and its pharmaceutically acceptable salt, hydrate, solvate or prodrug：
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- (4- oxo -2- phenyl thiazole Quinoline -3- base) thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- fluorobenzene Base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2- fluorobenzene Base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluorobenzene Base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- chlorobenzene Base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4,6- tri- Fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (3- fluoroform Base phenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (2,4- dichloro Phenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- epoxide] phenyl]-N3- [4- oxo -2- (4- methylbenzene Base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- (4- oxo- 2- phenyl thiazole quinoline -3- base) thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2- fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- chlorphenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4,6- trifluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (3- trifluoromethyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (2,4 dichloro benzene base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (4- methyl isophthalic acid-piperidyl) propoxyl group] quinoline -4- epoxide] phenyl]-N3- [4- oxo- 2- (4- aminomethyl phenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- (4- oxo -2- benzene Base thiazoline -3- base) thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2- Fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- Fluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Chlorphenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2, 4,6- trifluorophenyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (3- Trifluoromethyl) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (2, 4- Dichlorobenzene base) thiazoline -3- base] thiourea；
N1- [4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- epoxide] naphthyl]-N3- [4- oxo -2- (4- Aminomethyl phenyl) thiazoline -3- base] thiourea.
A kind of 18. Pharmaceutical compositions, comprise in claim 1-17 the compound of any one and its pharmaceutically acceptable salt, Hydrate, solvate or prodrug are as active component and pharmaceutically acceptable excipient.
The compound of any one and its pharmaceutically acceptable salt, hydrate, solvate or front in 19. claim 1-17 Application in preparation treatment and/or prevention proliferative disease medicine for the medicine.
The compound of any one and its pharmaceutically acceptable salt, hydrate, solvate or front in 20. claim 1-17 Application in the medicine of preparation treatment and/or prophylaxis of cancer for the medicine.
The compound of any one and its pharmaceutically acceptable salt, hydrate, solvate or front in 21. claim 1-17 Application in preparation treatment and/or prevention pulmonary carcinoma, hepatocarcinoma, gastric cancer, colon cancer, the medicine of breast carcinoma for the medicine.
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