CN106496116A - Quinolines containing double aryl urea structures and application thereof - Google Patents

Quinolines containing double aryl urea structures and application thereof Download PDF

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CN106496116A
CN106496116A CN201610915918.8A CN201610915918A CN106496116A CN 106496116 A CN106496116 A CN 106496116A CN 201610915918 A CN201610915918 A CN 201610915918A CN 106496116 A CN106496116 A CN 106496116A
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phenyl
epoxide
fluoro
urea
quinolyl
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赵燕芳
刘亚婧
翟鑫
宫平
王昱
类红瑞
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to application of the quinolines containing double aryl urea structures and their pharmaceutically acceptable salts and the pharmaceutical composition with the compound as active component shown in formula I in the medicine for treatment and/or prevention due to FLT3 kinases unconventionality expression diseases caused is prepared, wherein substituent R1、R2, Ar, X, Y, Z, n there is the implication that is given in the description.

Description

Quinolines containing double aryl urea structures and application thereof
Technical field
The present invention relates to quinolines containing double aryl urea structures and application thereof, and in particular to quinolines and Its pharmaceutically acceptable salt and the pharmaceutical composition containing the compound prepare for treatment and/or prevention due to Application in the medicine of FLT3 kinases unconventionality expression diseases caused.
Background technology
The research of kinases target drug has become the important directions of current antineoplastic research and development.Had now been found that swashs In enzyme target drug, protein kinases are classes of known most study.Protein kinase can cause signal due to being mutated or resetting There is exception in transductive process obstacle, causes cell growth, differentiation, metabolism and biological behaviour exception, thus can induce multiple Tumour.
Protein kinase (Protein Kinases, PKs), is a kind of terminal phosphate transesterify catalytic proteins by ATP Tyrosine, the enzyme of di in serine and threonine residues, mainly include protein tyrosine kinase (Protein Tyrosine kinase, PTK) and serine-threonine kinase (Serine-threonine kinase, STK).By signal Transduction pathway, these enzyme adjustment cell growth, differentiation and propagation etc..PTK passes through and growth factor ligand binding, makes growth factor Acceptor is changed into the protein-interacting of activated form, the latter and cell membrane inner surface.This causes the junket of acceptor and other albumen Histidine residue phosphorylation and cause to be formed with the compound of various kinds of cell matter signaling molecule in the cell, such as thin so as to affect The reaction of the various kinds of cell such as born of the same parents' division (propagation), cell differentiation, cell growth, metabolism.
The growth factor receptors for having PTK active referred to as receptor tyrosine kinase (Receptor tyrosine kinase, RTK), which includes the transmembrane receptor with diversity biologically active of extended familys.Fms sample EGFR-TK (Fms like Tyosine kinase 3, following Flt-3) it is belonging to the receptor type of platelet derived growth factor receptor (PDGFR) family Protein tyrosine kinase (PTK).It is near by 5, extracellular N' ends immunoglobulin like domain, 1 membrane spaning domain, intracellular 1 Spanning domain (juxtamembrane, JM), 2 by the separate kinase domain of Kinase insert Domain and 1 C' terminal domains Constitute, its ectodomain high glycosylation.FLT3 genes are located at chromosome 13q12, total length about 100kb, have 24 extrons, 993 amino acid of coding.There is receptor dimer after FLT3 and its receptor binding, the tyrosine residue in kinase domain is certainly Body phosphorylation, the phosphorylation of further catalytic substrate albumen, many important signal transducers such as signal transduction and transcription Activation 5 (signaltransducer and activator of transcription 5, STAT5) of son, phosphoinositide 3 swash Enzyme (phosphoinositide3-kinase, PI3K), Phospholipase C-gamma (phospholipase C gamma, PLC- γ), RAS, MAPK (mitogen-activated protein kinase, MAPK), extracellular signal are adjusted Kinases (extra cellularly-responsive kinase, ERK), src is homologous and the collagen factor (src homologous And collagengene, SHC) and Src families EGFR-TK etc. be activated, so as to mediate a series of signal to transduce, cause The propagation of cell, differentiation.
In malignant hematologic disease, high-caliber FLT3 is expressed, or FLT3 mutation cause FLT3 acceptors and downstream molecules logical The uncontrolled induction in road.Malignant hematologic disease includes leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma-such as, ALL (ALL), acute myeloid leukemia (AML), acute morning Myelocyte leukaemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic grain Chronic myeloid leukemia (CNL), acute undifferentiated cell leukemia (AUL), primary cutaneous type (ALCL), young lamphocyte Leukaemia (PML), juvenile myelomonocytic type leukaemia (JMML), adult T-cell ALL, AML are that cell is different with marrow three Chang Zengsheng (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease, (MM) and medullary sarcoma (Kottaridis, P.D., R.E.Gale etc. (2003)." Flt3mutations and leukaemia."Br J Haematol122(4):523-38).Medullary sarcoma is also mutated with FLT3 Correlation (the FLT3mutations in myeloid sarcoma.British Journal of such as Ansari-Lari, Ali Haematology.2004Sep.126(6):785-91).
In about 30% patients with acute myeloid leukemia and a small amount of ALL or myeloproliferative disorder synthesis Levy.Patient's often poor prognosis of FLT3 mutation, and remission time shortens and DFS rate Reduce.Have two kinds oneself know the Activating mutations of the FLT3 of type.One kind is 4-40 amino in this receptor membrane-proximal region (ITD mutation) Acid repeats (patient of 25-30%), another kind of point mutation (patient of 5-7%) for kinase domain.These mutation are most of It is related to the Short tandem repeatSTR of the nearly spanning domain amino acid of acceptor, causes tyrosine kinase activity.Saltant type in murine myeloid cells The expression of FLT3 acceptors causes fatal myelodysplastic syndrome, Primary Study (Blood.2002；100:1532-42) table Bright, the phenotype that saltant type FLT3 is cooperated with other leukaemia oncogenes and brings invasion higher.
Foretinib (GSK1363089, XL880) belongs to quinolines, is a kind of oral c-Met and VEGFR/ KDR kinase inhibitors, which is to c-Met kinases and the IC of VEGFR kinases50Value is respectively 0.4 and 0.8nM, has been enter into for II phase at present Clinical investigation phase (WO2010036831A1).
The present inventor has designed and synthesized a series of new quinolines containing double aryl urea structures on the basis of bibliography Oxazoline derivates.Screen through external activity, show that there is such compound good c-Met kinase inhibitory activities, later stage to live Property garbled data shows that such compound has good inhibitory activity to FLT3 kinases.
Content of the invention
The present invention relates to quinolines containing double aryl urea structures shown in formula I and they are pharmaceutically acceptable Salt,
Wherein,
X is O, S, NH, NCH3；
Y is optional 1-2 following substituent：Halogen, halo C1-C4Alkyl, C1-C4Alkyl, cyano group, nitro；
Z is O, S；
N is the integer between 1-6；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) alkene Base or (C2-C10) alkynyl, they can optionally by 1-3 identical or different R3Replace；
Or R1And R25-10 circle heterocycles base or 5-10 unit's heteroaryls is formed together with the nitrogen-atoms being connected with them, described Heterocyclic radical and heteroaryl except with R1And R2Outside the nitrogen-atoms of connection, containing the 1-4 hetero atom selected from N, O or S, except R1With R2Outside the nitrogen-atoms for being connected, the heterocyclic radical can optionally include 1-2 carbon-carbon double bond or three key, the heterocyclic radical and heteroaryl Base is optionally by 1-3 identical or different R3Replace；
R3H, (C are separately selected from6-C10) aryl, 5-10 unit's heteroaryls, (C1-C6) alkyl, (C3-C7) cycloalkyl, institute State heteroaryl and contain the 1-3 hetero atom selected from N, O or S, and R3Optionally 1-3 identical or different R4Replace；
Ar is (C6-C10) aryl, 5-10 unit's heteroaryls, wherein, the heteroaryl contains the miscellaneous original of 1-3 selected from N, O or S Son, and the optional 1-3 identical or different R of Ar4Replace；
R4For H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, (C1- C6) alkoxyl, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxyl, by 1-2 (C1-C6) alkyl Substituted amino, (C1-C6) alkylamidoalkyl, free, into salt, esterification and amidated carboxyl, (C1-C6) alkyl Asia Sulfonyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkoxyl, (C1-C6) alkyl, (C1-C6) alkyl acyl, carbamoyl, quilt 1-2 (C1-C6) alkyl-substituted carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
Quinolines containing double aryl urea structures shown in preferred formula of the present invention I and they are pharmaceutically acceptable Salt, wherein
N is the integer between 1-3；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C2-C6) alkene Base and (C2-C6) alkynyl, they can optionally by 1-3 identical or different R3Replace；
Or R1And R2Form 5-10 circle heterocycles bases together with the nitrogen-atoms being connected with them, the heterocyclic radical except with R1 And R2Outside the nitrogen-atoms of connection, optionally containing the 1-4 hetero atom selected from N, O or S, except R1And R2Outside the nitrogen-atoms for being connected, The heterocyclic radical optionally includes 1-2 carbon-carbon double bond or three key, and the heterocyclic radical is optionally by 1-3 identical or different R3Take Generation.
Quinolines containing double aryl urea structures shown in preferred formula of the present invention I and they are pharmaceutically acceptable Salt, wherein
X is O, S；
Y is halogen, halo C1-C4Alkyl；
Quinolines containing double aryl urea structures shown in preferred formula of the present invention I and they are pharmaceutically acceptable Salt, wherein
X is O；
N is 2,3；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C4) alkyl, (C3-C5) cycloalkyl；
Or R1And R2Form 5-6 circle heterocycles bases together with the nitrogen-atoms being connected with them, the heterocyclic radical except with R1With R2Outside the nitrogen-atoms of connection, optionally containing 1-2 selected from N, O and S hetero atom, the heterocyclic radical optionally by 1-3 identical or Different R3Replace；
R3For H, (C1-C4) alkyl.
The present invention is more highly preferred to the quinolines containing double aryl urea structures shown in formula I and they can pharmaceutically connect The salt that receives, wherein
Y is F；
N is 2,3；
Ar is phenyl, and the optional 1-3 identical or different R of Ar4Replace；R4For H, halogen, hydroxyl, nitro, cyano group, Halo (C1-C4) alkyl, halo (C1-C4) alkoxyl, (C1-C4) alkyl, (C1-C4) alkoxyl, pi-allyl, dimethylamino, first sulphur Acyl group.
R1And R2Dimethylamino, lignocaine, 1- piperidyls, 4- morpholines is formed together with the nitrogen-atoms being connected with them Base, 4- methyl isophthalic acids-piperazinyl, 1- piperazinyls, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls, 4- thio-morpholinyls.Preferably 1- Piperidyl, 4- morpholinyls, 4- methyl isophthalic acids-piperazinyl, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls.
According to some usual methods of the art, the quinoline derivatives of formula of of the present invention I can be with acid Generate pharmaceutically acceptable salt.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, and the salt with following sour addition is Particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, second Acid, propionic 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 derivative of the present invention.The prodrug of derivative of the present invention is the derivative of formula I Thing, their own may have weaker activity even without activity, but upon administration, (for example pass through in physiological conditions Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine generation；" alkyl " refers to the alkyl of straight or branched；" alkylidene " Refer to the alkylidene of straight or branched；" cycloalkyl " refers to substituted or unsubstituted cycloalkyl.
According to the present invention, the quinolines containing double aryl urea structures of particularly preferred above formula I include：
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- (fluoroforms Base) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- (fluoroforms Base) phenylurea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- (fluoroforms Base) phenyl) urea；
1- (3,4- difluorophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) Phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- fluorophenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- methoxyl groups Phenyl) urea
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (4- methoxyphenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- methoxyl groups Phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (3- methoxyphenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- fluorophenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (4- fluorophenyls) urea；
1- (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) benzene Base) urea；
1- (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline - 4- yls) epoxide) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- methylbenzenes Base) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (4- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- nitrobenzene Base) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (3- nitrobenzophenones) urea；
1- (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) benzene Base) urea；
1- (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline - 4- yls) epoxide) phenyl) urea
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (2- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (2- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl - 3- (2- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- methylbenzenes Base) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (3- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl - 3- (3- aminomethyl phenyls) urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) benzene Base) urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinolines Quinoline -4- bases) epoxide) phenyl) urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinoline - 4- yls) epoxide) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- isopropyls Phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (4- isopropyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl - 3- (4- isopropyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) benzene Base -3- (4- trifluoromethyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl - 3- (4- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl - 3- (4- aminomethyl phenyls) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) oxygen Base) phenyl) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) the third oxygen Base) quinolyl-4) epoxide) phenyl) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolines Quinoline -4- bases) epoxide) phenyl) urea；
The reactive compound or its officinal salt of the present invention and its solvate can be independent as unique antineoplastic Use, or can be with the antineoplastic for having listed (such as platinum medicine cis-platinum, camptothecine Irinotecan, Changchun Flower bases medicine NVB, deoxycytidine class medicine gemcitabine, etoposide, taxol etc.) it is used in combination.Therapeutic alliance is led to Cross each therapeutic component while, order or separate administration to 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.
Synthetic route A describes the preparation of the type I compound of the present invention below, and all of raw material is all in pass course A The method of description, prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or commercially available.The present invention's is complete Portion's final compound is prepared by the method described in this route or by similar method, and these methods are that have Chemical machine field is well-known to the ordinarily skilled artisan.The definition or such as of the whole variable factor following articles that applies in these synthetic routes Definition in claim.
Specific embodiment：
Contact following examples, are better understood with compound and their preparation of the present invention, and these embodiments are intended to Illustrate rather than limit the scope of the present invention.
1 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- (trifluoromethyl) phenyl) urea
Step A：4- (3- chlorine propoxyl group) -3- methoxyacetophenone (A1) preparation
3- methoxyl groups -4-hydroxyacetophenone (16.6g, 0.1mol) is dissolved in 100mL acetone, Anhydrous potassium carbonate is added (19.3g, 0.14mol), is stirred at room temperature 0.5h, and 0 DEG C of instillation 1- is bromo- 3- chloropropanes (21.9g, 0.14mol), controls during dropwise addition Temperature processed is less than 25 DEG C.Drop finishes, 25 DEG C of stirring reaction about 20h.After completion of the reaction, suction filtration, filtrate is poured slowly into 200mL ice In water, after stirring 15min, suction filtration, filtration cakes torrefaction obtain white solid 22.2g, yield 91.3%.
Step B：2- nitro -4- (3- chlorine propoxyl group) -5- methoxyacetophenone (A2) preparation
By intermediate A1(12.1g, 0.05mol) is dissolved in 50mL dichloromethane, is stirred well to after being completely dissolved, cooling To -20 DEG C, fuming nitric aicd (8.46mL, 0.18mol) is slowly dropped into, control reacting liquid temperature is less than -15 DEG C.Drop finishes, -15 DEG C Continue reaction 8h.After completion of the reaction, during be poured slowly into reactant liquor to 100mL mixture of ice and water, while being stirred vigorously, two are collected Chloromethanes layer, dichloromethane layer are washed with water four times, and saturated common salt is washed four times, and collected organic layer, anhydrous sodium sulfate drying are evaporated Red oil is obtained, petroleum ether is beaten, and obtains light yellow solid 12.4g, and yield is 86.7%.
Step C：1- { 4- [(3- chloropropyls) epoxide] -5- methoxyl group -2- nitros } phenyl -3- dimethylamino -2- alkene -1- third Ketone (A3) preparation
By intermediate A2(14.35g, 0.05mol) is dissolved in 100mL toluene, until completely dissolved, adds DMF-DMA (16.6mL, 0.125mol), is warming up to 113 DEG C of back flow reactions 10h.After completion of the reaction, sufficiently cool reactant liquor, separates out a large amount of yellow Color solid, suction filtration obtain yellow powder 13.1g, and yield is 76.8%.
Step D：6- methoxyl group -7- [(3- chloropropyls) epoxide] -4- oxyquinoline (A4) preparation
By intermediate A3(6.9g, 0.02mol) is added in 50mL glacial acetic acids, after dissolving is stirred at room temperature, in 40 DEG C in batches Reduced iron powder (14g, 0.06mol) is added, and 2h is reacted in 80 DEG C.Suction filtration, collects filtrate while hot, and filter cake is placed in 80 DEG C in glacial acetic acid Stirring 0.5h, suction filtration, merging filtrate, cooling, separate out a large amount of pale yellow solids while hot, and suction filtration, filter cake massive laundering are washed to pH Neutrality is close to, yellow solid 4.43g is obtained, yield is 83.1%.
Step E：6- methoxyl group -7- [(3- morpholine propyl group) epoxide] -4- oxyquinoline (A5-1) preparation
By intermediate A4During (5.34g, 0.02mol) and morpholine (0.08mol) are added to 80mL acetonitriles, it is warming up to 80 DEG C and returns Stream reaction about 12h.After completion of the reaction, sufficiently cool reactant liquor, separates out solid, and suction filtration, filtrate are evaporated to obtain dark oil thing, adds 100mL ethyl acetate, is stirred at room temperature 1.5h, and suction filtration is merged with filter cake, obtains pulverulent solids 6.02g, and yield is 95.2%.
Step F：The chloro- 6- methoxyl groups -7- of 4- [(3- morpholine propyl group) epoxide] quinoline (A6-1) preparation
By dried intermediate A5-1(0.05mol) add in 50mL acetonitriles, being sufficiently stirred for 5-10min under room temperature must hang After supernatant liquid, POCl3 (5V/m) is disposably rapidly joined, is finished, be warming up to 80 DEG C of back flow reactions 5h.After completion of the reaction, cool down Reactant liquor, is evaporated off most of solvent, obtains dark oil liquid, and dark oil liquid is poured slowly into 200mL with vigorous stirring The light brown solution of clarification in mixture of ice and water, is obtained, and in the case where control temperature is less than 25 DEG C, pH is adjusted extremely with potassium hydroxide 12, there are a large amount of solids to separate out, suction filtration after stirring 0.5h obtains pale solid powder 14.3g, and yield is 85.4%.
Step G：4- (the fluoro- 4- nitros -1- phenoxy groups of 2-) -6- methoxyl group -7- [(3- morpholine propyl group) epoxide] quinoline (A7-1) Preparation
By fully dried intermediate A6-1(0.02mol) add to 50mL with 2- fluoro-4-nitrophenols (0.03mol) In dry chlorobenzene, 135 DEG C of reaction about 8h are warming up to.After completion of the reaction, cooling reactant liquor, a large amount of yellow solids of precipitation, suction filtration, Filter cake is dissolved in q. s. methylene chloride, and with saturated aqueous sodium carbonate repeated washing 6-7 time, organic layer is dried, and is evaporated to obtain black Grease, adds isopropyl ether beating, separates out a large amount of yellow solids, suction filtration after stirring 1h, dry yellow solid powder 8.23g, Yield 90.4%.
Step H:The fluoro- 4- of 3- { 6- methoxyl group -7- [(3- substituted-amino propyl group) epoxide] quinoline -4- epoxides } aniline (A8-1) Preparation
Iron powder (0.06mol) and concentrated hydrochloric acid (0.002mol) are added in 90% ethanol of 20mL, return stirring 30min, Intermediate A is dividedly in some parts after slightly reducing temperature7-1(0.01mol), temperature rising reflux reaction about 1h.After reaction completely, reactant liquor is dropped Temperature is heated to reflux 30min to 50 DEG C or so addition activated carbons, pads diatomite suction filtration while hot, concentrates filtrate to 1/3rd volumes, Room temperature is cooled to, under stirring, is adjusted after pH to 12 with 5%NaOH solution, is added 100mL water, there are a large amount of white-yellowish solids to separate out, stir Suction filtration after 1h is mixed, pale solid powder 3.6g, yield 85.5% is obtained.
Step J:1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- (trifluoromethyl) phenyl) urea preparation
By 1mmol intermediate As8-1It is dissolved in 10mL dichloromethane, is slowly added dropwise 3- trifluoromethylbenzene based isocyanates 1.2mmol, the reaction system after drop finishes are stirred at room temperature overnight.The solid suction filtration of generation, filter cake are washed with dichloromethane To target compound 0.51g, it is faint yellow solid, yield 83.1%.
MS (ESI) m/z (%):615.3[M+H]+；H NMR(400MHz,DMSO)δ9.32(d,2H),8.48(d,1H), 8.03(s,1H),7.77(dd,1H),7.62(d,1H),7.58–7.51(m,2H),7.46–7.37(m,2H),7.37–7.26 (m,2H),6.46(s,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s,3H), 2.08–1.92(m,2H).
The compounds process for production thereof of 2 embodiment 38 of embodiment is with embodiment 1.
2 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- (trifluoromethyl) phenylurea
MS (ESI) m/z (%):615.2[M+H]+；1H NMR(400MHz,DMSO)δ9.69(s,1H),8.32(d,2H), 7.62(dd,9H),6.44(s,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40(s, 3H),2.08–1.92(m,2H).
3 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- (trifluoromethyl) phenyl) urea
MS (ESI) m/z (%):615.2[M+H]+；1H NMR(400MHz,DMSO)δ8.63–8.51(m,1H),8.38– 8.30(m,1H),8.19–8.10(m,1H),7.52–7.45(m,1H),7.48–7.40(m,1H),7.39–7.32(m,1H), 7.34–7.28(m,1H),7.28–7.19(m,1H),6.95–6.81(m,1H)4.20(t,2H),3.96(s,3H),3.60(t, 4H),3.35(s,3H),2.40(s,3H),2.08–1.92(m,2H).
4 1- of embodiment (3,4- difluorophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- Base) epoxide) phenyl) urea
MS (ESI) m/z (%):583.3[M+H]+；1H NMR(400MHz,DMSO)δ11.22(s,1H),9.95(d,1H), 7.51(ddd,5H),4.38(s,1H),4.17–3.94(m,3H),3.51(s,3H),3.13(s,1H),2.52(s,2H),2.40 (s,1H).
5 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- fluorophenyls) urea
MS (ESI) m/z (%):565.3[M+H]+；1H NMR(400MHz,DMSO)δ9.22(d,1H),8.47(s,1H), 8.04–6.97(m,4H),6.63(d,1H),4.20(t,2H),3.96(s,3H),3.60(t,4H),3.35(s,3H),2.40 (s,3H),2.08–1.92(m,2H).
6 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- methoxyphenyls) urea
MS (ESI) m/z (%):577.3[M+H]+；1H NMR(400MHz,DMSO)δ9.32(d,2H),8.48(d,1H), 8.03(s,1H),7.77(dd,1H),7.62(d,1H),7.58–7.51(m,2H),7.46–7.37(m,2H),7.37–7.26 (m,2H),6.46(s,1H),δ4.14(t,1H),4.05–3.95(m,1H),3.88(s,1H),3.75–3.54(m,2H),2.80 (q,1H),2.52–2.39(m,1H),2.39–2.29(m,1H),1.89(ddt,1H).
7 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (4- methoxyphenyls) urea
MS (ESI) m/z (%):589.3[M+H]+；1H NMR(400MHz,DMSO)δ9.34(s,1H),8.91(s,1H), 8.48(d,1H),7.77(dd,1H),7.55(s,1H),7.40(s,2H),7.38(dd,5H),7.39–7.34(m,2H), 7.28 7.23 (m, 1H), 7.31 7.20 (m, 1H), 6.89 (d, 2H), 6.45 (d, J=4.8Hz, 1H), 4.19 (t, 3H), 3.96(s,3H),3.73(s,3H),2.94(d,2H),2.51(dd,2H),2.29–1.82(m,7H),2.06–1.94(m,4H), 1.60(d,2H),1.45–1.28(m,2H),0.89(d,3H).
8 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- methoxyphenyls) urea
MS (ESI) m/z (%):577.2[M+H]+；1H NMR(400MHz,DMSO)δ9.34(s,1H),8.91(s,1H), 8.48(d,1H),7.77(dd,1H),7.55(s,1H),7.40(s,2H),7.38(dd,5H),7.39–7.34(m,2H), 7.28–7.23(m,1H),7.31–7.20(m,1H),6.89(d,2H),6.45(d,1H),δ4.14(t,1H),4.05–3.95 (m,1H),3.88(s,1H),3.75–3.54(m,2H),2.80(q,1H),2.52–2.39(m,1H),2.39–2.29(m,1H), 1.89(ddt,1H).
9 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (3- methoxyphenyls) urea
MS (ESI) m/z (%):589.3[M+H]+；1H NMR(400MHz,DMSO)δ9.60(s,1H),9.27(s,1H), 8.51(d,1H),7.77(d,1H),7.58(s,1H),7.47(s,1H),7.40(t,1H),7.26(d,1H),7.18(dd, 2H),6.96(d,1H),6.57(d,1H),6.51(d,1H),4.27(s,2H),3.98(s,3H),3.74(s,3H),3.53(d, 2H),3.23(s,2H),2.94(d,2H),2.30(s,2H),1.81(d,2H),1.62(s,1H),1.53–1.34(m,2H), 0.94(d,3H).
10 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- fluorophenyls) urea
MS (ESI) m/z (%):565.2[M+H]+；1H NMR(400MHz,DMSO)δ9.19(d,1H),9.01–8.91(m, 1H),8.51–8.43(m,1H),7.74(dd,1H),7.61–7.20(m,7H),7.14(dd,2H),6.46(d,1H),4.29– 4.17(m,2H),3.96(d,3H),3.61(d,4H),2.66(s,2H),2.32(s,2H),1.99(d,2H).
11 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline -4- Base) epoxide) phenyl -3- (4- fluorophenyls) urea
MS (ESI) m/z (%):577.3[M+H]+；1H NMR(400MHz,DMSO)δ9.57(s,1H),9.29(s,1H), 8.53(d,1H),7.77(dd,1H),7.59(s,1H),7.48(t,3H),7.40(t,1H),7.27(d,1H),7.14(t, 2H),6.53(d,1H),4.28(t,2H),3.98(s,3H),3.53(d,2H),3.23(s,2H),3.01–2.88(m,2H), 2.35–2.24(m,2H),1.81(d,2H),1.63(s,1H),1.44(dd,2H),0.94(d,3H).
12 1- of embodiment (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) Epoxide) phenyl) urea
MS (ESI) m/z (%):625.1[M+H]+；1H NMR(400MHz,DMSO)δ9.13(d,2H),8.50(s,1H), 7.88(s,1H),7.77(d,1H),7.56(s,1H),7.48–7.13(m,5H),6.47(s,1H),4.34–4.13(m,2H), 3.98(s,3H),3.62(s,3H),2.55(s,2H),2.42(s,4H),2.02(s,2H).
13 1- of embodiment (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) third Epoxide) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):637.2[M+H]+；1H NMR(400MHz,DMSO)δ9.25(s,1H),9.14(s,1H), 9.05(s,1H),8.48(d,1H),7.85(d,2H),7.75(d,1H),7.54(s,1H),7.40(d,2H),7.17(t,3H), 6.45(d,1H),4.20(s,2H),3.96(s,3H),2.54(s,2H),2.49–2.44(m,2H),2.01(d,2H),1.63 (s,2H),1.39(s,1H),1.18(t,2H),0.90(d,3H).
14 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- aminomethyl phenyls) urea
MS (ESI) m/z (%):561.2[M+H]+；1H NMR(400MHz,DMSO)δ9.03(s,1H),8.73(s,1H), 8.47(d,1H),7.75(dd,1H),7.53(s,1H),7.37(dd,4H),7.25(dd,1H),7.11(d,2H),6.44(d, 1H),4.20(t,2H),3.95(s,3H),3.60(s,4H),2.37(d,4H),2.25(s,3H),2.04–1.95(m,2H), 1.23(s,1H).
15 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (4- aminomethyl phenyls) urea
MS (ESI) m/z (%):573.2[M+H]+；1H NMR(400MHz,DMSO)δ9.63(s,1H),9.45(s,1H), 9.04(s,1H),8.49(d,1H),7.76(dd,1H),7.57(s,1H),7.45(s,1H),7.37(dd,3H),7.27–7.22 (m,1H),7.10(d,2H),6.48(d,1H),4.27(t,2H),3.97(s,3H),3.58–3.46(m,2H),3.23(d, 2H),2.94(dt,2H),2.28(d,2H),2.25(s,3H),1.81(dd,2H),1.51–1.35(m,2H),0.94(d,3H).
16 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- nitrobenzophenones) urea
MS (ESI) m/z (%):592.2[M+H]+；1H NMR (400MHz, DMSO) δ 8.76 (s, 1H), 8.55 (d, 1H), 8.34(s,1H),8.28(t,1H),8.10(dt,1H),7.74(dt,1H),7.48(t,1H),7.33(dt,2H),7.20(s, 1H),7.07(s,1H),6.91–6.86(m,2H),4.12(t,2H),3.98(s,3H),3.67(t,4H),2.65–2.60(m, 4H),2.40(t,2H),1.91(ddd,2H).
17 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (3- nitrobenzophenones) urea
MS (ESI) m/z (%):604.3[M+H]+；1H NMR(400MHz,DMSO)δ9.42(s,1H),9.28(s,1H), 8.57(d,1H),8.48(d,1H),7.86(dd,1H),7.81–7.72(m,1H),7.59(t,1H),7.54(s,1H),7.47– 7.37(m,1H),7.32(d,1H),6.45(d,1H),4.19(t,1H),3.96(s,1H),2.86(s,1H),2.04–1.90 (m,1H),1.58(d,1H),1.32(s,1H),1.14(dd,1H),0.89(d,1H),0.89(d,1H).
18 1- of embodiment (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) Epoxide) phenyl) urea
MS (ESI) m/z (%):581.2[M+H]+；1H NMR(400MHz,DMSO)δ9.03(d,2H),8.48(s,1H), 7.75(d,1H),7.61–7.22(m,9H),6.45(s,1H),4.21(s,2H),3.96(s,3H),3.60(s,4H),2.40 (s,4H),1.99(s,2H),1.77(s,1H).
19 1- of embodiment (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) third Epoxide) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):593.2[M+H]+；1H NMR(400MHz,DMSO)δ9.20(s,1H),9.07(s,1H), 8.47(d,1H),7.75(dd,1H),7.58–7.48(m,3H),7.44–7.31(m,4H),7.27(d,1H),6.44(d,1H), 4.19(t,2H),3.95(s,3H),2.90(s,2H),2.00(s,4H),1.60(s,2H),1.36(s,1H),1.18(s,2H), 0.90(d,3H).
20 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (3- (trifluoromethyl) phenyl) urea
MS (ESI) m/z (%):627.3[M+H]+；1H NMR(400MHz,DMSO)δ9.57(s,2H),8.49(d,1H), 8.02(s,1H),7.77(d,1H),7.62(d,1H),7.58–7.49(m,2H),7.46–7.37(m,2H),7.31(dd,2H), 6.47(d,1H),4.25(s,2H),3.97(s,3H),2.20(s,2H),1.75(s,2H),1.56(s,1H),1.36(s,2H), 0.93(d,3H).
21 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (2- aminomethyl phenyls) urea)
MS (ESI) m/z (%):561.3[M+H]+；1H NMR(400MHz,DMSO)δ9.40(s,1H),8.48(d,1H), 8.07(s,1H),7.87–7.71(m,3H),7.54(s,1H),7.46–7.32(m,2H),7.24(d,1H),7.15–7.10(m, 1H),6.96(dt,2H),6.45(d,1H),4.21(t,2H),3.96(s,3H),3.60(s,4H),3.32(s,3H),2.26 (s,6H),1.99(s,2H).
22 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (2- aminomethyl phenyls) urea
MS (ESI) m/z (%):573.3[M+H]+；1H NMR(400MHz,DMSO)δ9.89(s,1H),9.63(s,1H), 8.64–8.28(m,2H),7.79(s,2H),7.65–6.86(m,8H),6.49(s,1H),4.28(s,2H),3.97(s,2H), 3.52(s,2H),3.27(d,5H),2.93(s,2H),2.28(s,4H),1.80(s,2H),1.52(d,3H),0.93(s,3H).
23 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) oxygen Base) phenyl -3- (2- aminomethyl phenyls) urea
MS (ESI) m/z (%):547.3[M+H]+；1H NMR(400MHz,DMSO)δ10.15(s,1H),9.35(s,1H), 8.97(s,1H),8.51(d,1H),7.77(dd,1H),7.58(s,1H),7.46(s,1H),7.39(t,1H),7.30(s, 1H),7.26(d,2H),7.17(t,1H),6.81(d,1H),6.50(d,1H),4.28(t,3H),3.97(s,4H),3.74(s, 2H),3.55(d,3H),3.12(s,2H),2.29(s,6H),1.76(s,1H).
24 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- aminomethyl phenyls) urea
MS (ESI) m/z (%):561.3[M+H]+；1H NMR(400MHz,DMSO)δ10.15(s,1H),9.35(s,1H), 8.97(s,1H),8.51(d,1H),7.77(dd,1H),7.58(s,1H),7.46(s,1H),7.39(t,1H),7.30(s, 1H),7.26(d,2H),7.17(t,1H),6.81(d,1H),6.50(d,1H),4.28(t,3H),3.97(s,4H),3.74(s, 2H),3.55(d,3H),3.12(s,2H),2.29(s,6H),1.76(s,1H).
25 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (3- aminomethyl phenyls) urea
MS (ESI) m/z (%):573.3[M+H]+；1H NMR(400MHz,DMSO)δ9.61(d,1H),9.11(s,1H), 8.51(s,1H),7.78(s,1H),7.51(d,1H),7.28(s,1H),6.82(s,1H),6.49(s,1H),4.28(s,1H), 3.98(s,1H),3.55(s,1H),2.95(s,1H),2.30(s,1H),1.80(s,1H),1.52(d,1H),0.94(s,1H).
26 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) oxygen Base) phenyl -3- (3- aminomethyl phenyls) urea
MS (ESI) m/z (%):545.3[M+H]+；1H NMR(400MHz,DMSO)δ9.36(s,1H),8.97(s,1H), 8.49(d,1H),7.76(dd,1H),7.57(s,1H),7.45(s,1H),7.38(t,1H),7.26(dd,3H),7.16(dd, 1H),6.81(d,1H),6.47(d,1H),4.28(t,2H),3.96(d,3H),3.60(t,2H),3.07(s,2H),2.51(s, 14H),2.35–2.16(m,5H),1.96(d,4H),1.83–1.70(m,1H).
27 1- of embodiment (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- Base) epoxide) phenyl) urea
MS (ESI) m/z (%):575.3[M+H]+；1H NMR(400MHz,DMSO)δ9.00(s,1H),8.70(s,1H), 8.47(d,1H),7.75(dd,1H),7.54(s,1H),7.44–7.31(m,4H),7.25(dd,1H),7.14(d,2H),6.44 (d,1H),4.21(t,2H),3.96(s,3H),3.60(s,4H),2.55(dd,5H),2.40(s,4H),1.99(s,2H), 1.17(t,3H).
28 1- of embodiment (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) Propoxyl group) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):587.3[M+H]+；1H NMR(400MHz,DMSO)δ9.25(s,1H),8.89(s,1H), 8.49(d,1H),7.75(d,1H),7.57(s,1H),7.45(s,1H),7.37(d,3H),7.25(d,1H),7.13(d,2H), 6.48(d,1H),4.27(t,2H),3.97(s,3H),3.54(d,2H),3.25(s,2H),2.95(d,2H),2.27(s,2H), 1.82(d,2H),1.62(s,1H),1.38(d,2H),1.16(t,3H),0.94(d,3H).
29 1- of embodiment (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) the third oxygen Base) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):558.3[M+H]+；1H NMR(400MHz,DMSO)δ9.42(s,1H),9.03(s,1H), 8.48(d,1H),7.76(dd,1H),7.56(s,1H),7.43(s,1H),7.37(dd,3H),7.24(dd,1H),7.13(d, 2H),6.46(d,1H),4.26(t,2H),3.97(s,3H),3.32(s,4H),2.55(d,2H),2.27–2.14(m,2H), 1.93(s,4H),1.16(t,4H).
30 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- isopropyl phenyls) urea
MS (ESI) m/z (%):589.3[M+H]+；1H NMR(400MHz,DMSO)δ8.48(d,1H),7.54(s,1H), 7.44(s,1H),7.07(t,1H),6.56(dd,1H),6.47(dd,1H),6.43(d,1H),4.26(t,2H),3.96(s, 4H),3.33(s,4H),2.28(s,2H).
31 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (4- isopropyl phenyls) urea
MS (ESI) m/z (%):601.3[M+H]+；1H NMR(400MHz,DMSO)δ9.75(s,1H),8.47(d,1H), 7.54(s,1H),7.43(s,1H),7.07(t,1H),6.55(d,1H),6.44(dd,2H),5.51(s,2H),4.25(s, 2H),3.92(s,4H),3.51(d,2H),3.22(s,3H),2.93(d,2H),2.28(s,2H),1.99(s,1H),1.79(d, 3H),1.62(s,1H),1.43(d,2H),1.17(d,1H),0.93(d,4H).
32 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) oxygen Base) phenyl -3- (4- isopropyl phenyls) urea
MS (ESI) m/z (%):573.3[M+H]+；1H NMR(400MHz,DMSO)δ8.59(d,1H),7.61(s,1H), 7.53(s,1H),7.09(s,1H),6.59(d,1H),6.56(d,1H),6.49(dd,1H),4.30(t,2H),3.99(s, 3H),3.60(d,2H),3.08–2.96(m,2H),2.31–2.24(m,2H),2.03(s,2H),1.89(d,2H).
33 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl -3- (4- trifluoromethyls) urea
MS (ESI) m/z (%):627.3[M+H]+；1H NMR(400MHz,DMSO)δ9.49(d,1H),9.30(s,1H), 8.49(d,1H),7.76(d,1H),7.67(d,2H),7.57(s,1H),7.48–7.37(m,1H),7.29(d,1H),6.48 (d,1H),4.32–4.21(m,1H),3.97(s,2H),3.54(d,1H),3.24(s,1H),2.95(s,1H),2.27(s, 1H),1.82(d,1H),1.63(s,1H),1.44–1.33(m,1H),0.94(d,1H).
34 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) oxygen Base) phenyl -3- (4- (trifluoromethyl) phenyl) urea
MS (ESI) m/z (%):599.3[M+H]+；1H NMR(400MHz,DMSO)δ9.81(s,1H),9.48(d,2H), 8.49(d,1H),7.78(d,1H),7.67(d,4H),7.57(s,1H),7.45(s,1H),7.40(d,1H),7.29(dd, 1H),6.48(d,1H),4.27(t,2H),3.97(s,4H),3.63(s,2H),3.06(s,2H),2.24(dt,3H),1.97 (d,5H).
35 1- of embodiment (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) oxygen Base) phenyl -3- (4- aminomethyl phenyls) urea
MS (ESI) m/z (%):545.3[M+H]+；1H NMR(400MHz,DMSO)δ9.05(s,1H),8.72(s,1H), 8.47(d,1H),7.75(dd,1H),7.54(s,1H),7.40(s,1H),7.34(d,3H),7.24(d,1H),7.10(d, 3H),6.45(d,1H),4.22(t,2H),3.96(s,3H),2.66(s,5H),2.24(d,4H),2.04(s,2H),1.76(s, 4H).
36 1- of embodiment (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolines Quinoline -4- bases) epoxide) phenyl) urea
MS (ESI) m/z (%):575.3[M+H]+；1H NMR(400MHz,DMSO)δ9.18(s,1H),8.76(s,1H), 8.48(d,1H),7.76(dd,1H),7.55(s,1H),7.43(s,1H),7.37(t,1H),7.23(d,2H),7.19(dd, 1H),7.04(d,1H),6.46(d,1H),4.25(s,3H),3.96(s,4H),3.66(s,3H),3.32(s,7H),2.17 (dd,8H).
37 1- of embodiment (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- Base) propoxyl group) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):587.3[M+H]+；1H NMR(400MHz,DMSO)δ9.27(s,1H),8.82(s,1H), 8.50(d,1H),7.76(d,1H),7.57(s,1H),7.45(s,1H),7.41–7.32(m,1H),7.24(s,2H),7.19 (d,1H),7.04(d,1H),6.46(d,1H),4.27(s,2H),3.97(s,3H),3.54(d,2H),3.24(s,3H),2.94 (s,2H),2.21(t,8H),1.82(d,2H),1.62(s,1H),1.40(d,2H),0.94(d,3H).
38 1- of embodiment (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) Propoxyl group) quinolyl-4) epoxide) phenyl) urea
MS (ESI) m/z (%):559.3[M+H]+；1H NMR(400MHz,DMSO)δ9.38(s,1H),8.91(s,1H), 8.49(d,1H),7.76(d,1H),7.56(s,1H),7.44(s,1H),7.38(d,1H),7.24(s,2H),7.18(s,1H), 7.04(d,1H),6.47(d,1H),4.27(t,2H),3.97(s,3H),3.61(s,1H),3.06(s,1H),2.20(t,8H), 1.97(s,3H).
The pharmacological research of product of the present invention
By suppressing the quinoline derivatives of Leukemia Cell Lines MV4-11 activity tests to the above formula I of the present invention in vitro In vitro biological activity is evaluated.
Experiment material：
MV4-11, IMDM (Hyclone, SH30228.01B, China), FBS (Gibco, 10099-141, Austrilia), 96 orifice plates (Cornng, 3599, America), MTT (Sigma, M2128, America).
Experimental technique：
By 90 μ L MV4-11 cells according to 1 × 104/ hole is seeded in 96 orifice plates, is made into testing compound using DMSO 10mM mother liquors, compound is aseptically diluted to respectively during use 10 times of preset concentration with IMDM (containing 10%FBS), And take 10 μ L and be added in 96 orifice plates, 37 DEG C of CO2Cultivate 48 hours in incubator, add per hole 10 μ LMTT to continue culture 4 hours Afterwards, 100 μ L SDS- isopropanols-HCl, three liquid is added overnight per hole, determine the suction at 570nM wavelength using multi-function microplate reader Luminosity.Calculate the inhibitory activity of compound on intracellular MV4-11.
Computing formula：
Single dose cell proliferation inhibition rate=(blank solvent control group-medicine effect group)/blank solvent control group * 100%
IC50Computing formula
The measurement result of the part of compounds of the present invention is as follows：
Compound name IC50(nM)
Embodiment 14 3.22
Embodiment 15 1.11
Embodiment 21 7.84
Embodiment 22 5.56
Embodiment 23 289
Embodiment 24 91.0
Embodiment 25 14.4
Embodiment 26 0.43
Embodiment 28 0.93
Embodiment 29 0.35
Embodiment 32 0.37
Embodiment 34 0.98
Embodiment 35 0.47
AC220 0.84

Claims (10)

1. quinolines containing double aryl urea structures and their pharmaceutically acceptable salts of formula I,
Wherein,
X is O, S, NH, NCH3；
Y is optional 1-2 following substituent：Halogen, halo C1-C4Alkyl, C1-C4Alkyl, cyano group, nitro；
Z is O, S；
N is the integer between 1-6；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C10) alkyl, (C3-C7) cycloalkyl, (C2-C10) thiazolinyl or (C2-C10) alkynyl, they can optionally by 1-3 identical or different R3Replace；
Or R1And R25-10 circle heterocycles base or 5-10 unit's heteroaryls, the heterocycle is formed together with the nitrogen-atoms being connected with them Base and heteroaryl except with R1And R2Outside the nitrogen-atoms of connection, containing the 1-4 hetero atom selected from N, O or S, except R1And R2Institute Outside the nitrogen-atoms of connection, the heterocyclic radical optionally includes 1-2 carbon-carbon double bond or three key, the heterocyclic radical and heteroaryl optionally quilt 1-3 identical or different R3Replace；
R3H, (C are separately selected from6-C10) aryl, 5-10 unit's heteroaryls, (C1-C6) alkyl, (C3-C7) cycloalkyl, described miscellaneous Aryl contains the 1-3 hetero atom selected from N, O or S, and R3Optionally 1-3 identical or different R4Replace；
Ar is (C6-C10) aryl, 5-10 unit's heteroaryls, wherein, the heteroaryl contains the hetero atom of 1-3 selected from N, O or S, And the optional 1-3 identical or different R of Ar4Replace；
R4For H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, (C1-C6) alkane Epoxide, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxyl, by 1-2 (C1-C6) alkyl-substituted Amino, (C1-C6) alkylamidoalkyl, free, into salt, esterification and amidated carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkoxyl, (C1-C6) alkyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl-substituted carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
2. the compound and their pharmaceutically acceptable salts of the formula I of claim 1, wherein
N is the integer between 1-3；
R1And R2Identical or different, separately selected from hydrogen, (C1-C6) alkyl, (C3-C5) cycloalkyl, (C2-C6) thiazolinyl or (C2-C6) alkynyl, they can optionally by 1-3 identical or different R3Replace；
Or R1And R2Form 5-10 circle heterocycles bases together with the nitrogen-atoms being connected with them, the heterocyclic radical except with R1And R2Even Outside the nitrogen-atoms for connecing, optionally containing the 1-4 hetero atom selected from N, O and S, the heterocyclic radical is optionally identical or different by 1-3 R3Replace.
3. the compound and their pharmaceutically acceptable salts of the formula I of claim 1 or 2, wherein
N is 2,3；
R1And R2Identical or different, separately it is selected from hydrogen, (C1-C4) alkyl, (C3-C5) cycloalkyl；
Or R1And R2Form 5-6 circle heterocycles bases together with the nitrogen-atoms being connected with them, the heterocyclic radical except with R1And R2Even Outside the nitrogen-atoms for connecing, optionally containing the 1-2 hetero atom selected from N, O and S, the heterocyclic radical is optionally identical or different by 1-3 R3Replace；
R3For H, (C1-C4) alkyl.
4. the compound and their pharmaceutically acceptable salts of the formula I of claim 1-3 any one, wherein
Y is F；
N is 2,3；
R1And R2Dimethylamino, lignocaine, 1- piperidyls, 4- morpholinyls, 4- is formed together with the nitrogen-atoms being connected with them Methyl isophthalic acid-piperazinyl, 1- piperazinyls, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls, 4- thio-morpholinyls.
5. the compound and their pharmaceutically acceptable salts of the formula I of claim 1-4 any one, wherein
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridine radicals, furyl, thienyl, pyrroles Base, pyrimidine radicals, preferably phenyl；And the optional 1-3 identical or different R of Ar4Replace, R4Preferably halogen, hydroxyl, nitro, Cyano group, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxyl, pi-allyl, dimethylamino, mesyl.
6. the compound and their pharmaceutically acceptable salts of the formula I of claim 1-5 any one, wherein
R1And R21- piperidyls, 4- morpholinyls, 4- methyl isophthalic acids-piperazinyl, 4- first is formed together with the nitrogen-atoms being connected with them Base -1- piperidyls, 1- pyrrolidinyls.
7. the quinolines and their pharmaceutically acceptable salts containing double aryl urea structures, are selected from：
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- (trifluoromethyl) Phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- (trifluoromethyl) Phenylurea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- (trifluoromethyl) Phenyl) urea；
1- (3,4- difluorophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) benzene Base) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- fluorophenyls) ureas；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- methoxyphenyls) Urea
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- methoxyphenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- methoxyphenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- methoxyphenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- fluorophenyls) ureas；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- fluorophenyls) urea；
1- (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl) urea；
1- (3- bromophenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline -4- Base) epoxide) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- aminomethyl phenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- nitrobenzophenones) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- nitrobenzophenones) urea；
1- (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl) urea；
1- (4- chlorphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline -4- Base) epoxide) phenyl) urea
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (2- Aminomethyl phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- aminomethyl phenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- aminomethyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (3- Aminomethyl phenyl) urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl) Urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinoline -4- Base) epoxide) phenyl) urea；
1- (4- ethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) Epoxide) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- isopropyl phenyls) Urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- isopropyl phenyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- Isopropyl phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- trifluoromethyls) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinolyl-4) epoxide) phenyl -3- (4- Aminomethyl phenyl) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinolyl-4) epoxide) benzene Base) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (4- methyl piperidines) -1- bases) propoxyl group) quinolines Quinoline -4- bases) epoxide) phenyl) urea；
1- (3,4- 3,5-dimethylphenyls) -3- (the fluoro- 4- of 3- ((6- methoxyl group -7- (3- (nafoxidine -1- bases) propoxyl group) quinoline - 4- yls) epoxide) phenyl) urea.
8. a kind of Pharmaceutical composition, the compound comprising any one in claim 1-7 and its pharmaceutically acceptable salt are made For active component.
9. the compound and its pharmaceutically acceptable salt of any one or the combination described in claim 8 in claim 1-7 Application of the thing in the medicine for the treatment of and/or prevention due to FLT3 kinases unconventionality expression diseases caused is prepared.
10. the compound and its pharmaceutically acceptable salt of any one or the combination described in claim 8 in claim 1-7 Application of the thing in treatment and/or prevention acute myeloid leukaemia, the medicine of chronic myelogenous leukemia is prepared.
CN201610915918.8A 2016-10-21 2016-10-21 Quinolines containing double aryl urea structures and application thereof Pending CN106496116A (en)

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CN1344254A (en) * 1999-01-22 2002-04-10 麒麟麦酒株式会社 Quinoline derivatives and quinazoline derivatives
CN101316590A (en) * 2005-11-07 2008-12-03 卫材R&D管理有限公司 Use of combination of anti-angiogenic substance and c-kit kinase inhibitor
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CN1344254A (en) * 1999-01-22 2002-04-10 麒麟麦酒株式会社 Quinoline derivatives and quinazoline derivatives
CN101316590A (en) * 2005-11-07 2008-12-03 卫材R&D管理有限公司 Use of combination of anti-angiogenic substance and c-kit kinase inhibitor
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Application publication date: 20170315