CN109134451A - 1,3- 2-substituted carbamide class and thiourea derivatives and its application - Google Patents

1,3- 2-substituted carbamide class and thiourea derivatives and its application Download PDF

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CN109134451A
CN109134451A CN201811051205.7A CN201811051205A CN109134451A CN 109134451 A CN109134451 A CN 109134451A CN 201811051205 A CN201811051205 A CN 201811051205A CN 109134451 A CN109134451 A CN 109134451A
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祁宝辉
何欢
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Zunyi Medical University
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    • 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
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    • 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
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Abstract

This programme discloses field of medicinal chemistry one kind 1,3- 2-substituted carbamide class and thiourea derivatives and its application, the general structure I of the derivative:

Description

1,3- 2-substituted carbamide class and thiourea derivatives and its application
Technical field
The present invention relates to field of medicinal chemistry, and in particular to one kind 1,3- 2-substituted carbamide class and thiourea derivatives and its answers With.
Background technique
Malignant tumour is a kind of disease for seriously endangering human life and health, with the change of the extraneous factors such as environmental pollution Change, whole world pathogenesis of cancer number is rising year by year, it has also become is only second to the second largest killer of the mankind of cardiovascular disease.
Protein kinase (Protein Kinases, PKs) is a biggish protein families, to cell function process Regulation has played crucial effect.Pass through tyrosine, serine and the threonine of the terminal phosphate transesterify catalytic proteins of ATP Di on residue, by signal transduction pathway, it is a series of that they adjust cell growth, differentiation, apoptosis and proliferation etc. Physiology course.Protein kinase activity exception and metabolic disease, skin disease and tumour etc..Protein kinase includes two classes: albumen junket Histidine kinase (Protein tyrosine kinases, PTKs) and serine-threonine kinase (Serine-threonine Kinases, STKs).The former passes through and growth factor ligand binding, and growth factor receptors is made to be changed into activated form, then with carefully The protein-interacting of after birth inner surface makes the tyrosine residue phosphorylation of receptor and other albumen and causes and various kinds of cell The compound of matter signaling molecule is formed in the cell, to influence various kinds of cell reaction such as cell Proliferation, differentiation, metabolism Deng.
It is known as receptor tyrosine kinase (Receptor tyrosine with the active growth factor receptors of PTKs Kinases, RTKs), it is the largest a kind of enzyme-linked receptor.Wherein, with human tumor it is closely related mainly have more than 20 kinds, such as EGFR, VEGFR, IGF-1R and c-Met etc..Under normal physiological conditions, c-Met kinases is in a large amount of tissues all in low water Flat expression, can promote epithelial cell to disperse, enhance the motility of cell, promote growth, proliferation, the differentiation, receipts of cell Multiple processes such as contracting, movement, secretion and mitosis adjust lung, nervous system, kidney for promoting the development of placenta and embryo And the development and structure formation of the organs such as mammary gland have highly important biological significance.
After hepatocyte growth factor growth HGF and c-Met is specifically bound, induction c-Met receptor protein occurred conformation changes, Tyrosine protein kinase in activated receptor intracellular protein kinase domain.In most of tumour cell, c-Met kinases was The state of expression, and high-caliber autophosphorylation is presented.Firstly, junket of the c-Met kinases close to 4 phosphorylation sites of intracellular region Autophosphorylation occurs for histidine residue, is especially located at the Tyr1234 and Tyr1235 of cyclic annular activating area, then passes through a system Column phosphorylation reaction activates phosphatidase (phosphatidase, PLC γ), Phosphoinositide-3 kinase (phosphatidylinositol 3 kinase, PI3K), extracellular regulated protein kinase (extracellular Regulated protein kinases, ERK1/2), signal transduction and activating transcription factor (signal transducers And activators of transcription, STAT), Src albumen, Focal adhesion kinase (focal adhesion Kinase, FAK), Ras albumen, adaptor protein Gab1 (Grb2-associated binding protein 1) and growth factor The important signaling molecules such as receptor binding protein 2 (growth factor receptor binding protein 2, Grb2) And corresponding signal path.Finally, the phosphorylation reaction through waterfall type, signal is amplified step by step, is finally transferred to endonuclear Mechanism is transcribed, to adjust the growth of tumour cell, proliferation, migration and invasive ability etc..Therefore, c-Met kinases has become anti- One of the important target of tumour medicine exploitation.
Summary of the invention
The invention is intended to provide one kind 1,3- 2-substituted carbamide class and thiourea derivatives and its application, main function is logical It crosses inhibition protein tyrosine kinase activity and plays its antitumor action, the main tyrosine protein kinase that such compound is inhibited Enzyme has c-Met, IGF-1R, Src and c-Kit etc..
The general structure of 1,3- 2-substituted carbamide class and thiourea derivatives in this programme, the derivative is following I:
Wherein, X is O or S；
Y1 is O or S；
Y2 is O or S；
M is N or CH；
M is 0,1 or 2；
N is 0,1 or 2；
P is 0,1 or 2；
Q is 0,1 or 2；
T is 0 or 1；
R1For hydrogen, NH2、NHS(O)0-2R6、C1-C3Alkylamidoalkyl or NHCONHR6；
R6For C1-C4Alkyl or heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-5 identical or different hydrogen or halogens of heteroaryl replace；
R2、R3For hydrogen or halogen atom, hydroxyl, cyano, nitro, halogenated C1-C2Alkyl, halogenated C1-C2Alkoxy, C1-C2Alcoxyl Base, C1-C2Alkyl or by 1-2 C1-C2Alkyl-substituted amino；
R4And R5It is identical or different, separately it is selected from C1-C3Alkyl, C3-C5Naphthenic base；
Or R4And R5It is formed together the single heterocycle of 4-10 member or double heterocycles with the nitrogen-atoms being connect with them, it is described miscellaneous Ring group in addition to R4And R5Outside the nitrogen-atoms of connection, the hetero atom of N, O and S are optionally selected from containing 0-2, in addition to R4And R5Company of institute Outside the nitrogen-atoms connect, the heterocycle optionally includes 0-2 carbon-carbon double bond, can be optionally by 0-3 identical or different C1-C3Alkane Base, C1-C3Acyl group, halogenated C1-C3Alkyl, halogen, methylene replace.
1,3- 2-substituted carbamide class of the invention and thiourea derivatives, R in general formula I4And R5For methyl, ethyl or R4With R5Piperidyl, morpholinyl, piperazinyl, high piperazine base, piperidyl, pyrrolidinyl, azelidinyl, sulphur is collectively formed with nitrogen-atoms For morpholinyl, thiazolinyl, piperidines bithiophene or hexahydroisoindoline.
1,3- 2-substituted carbamide class of the invention and thiourea derivatives can be used as active constituent and pharmaceutically acceptable Excipient.
1,3- 2-substituted carbamide class and thiourea derivatives of the invention is in preparation prevention or treatment proliferative disease drug Application.
1,3- 2-substituted carbamide class and thiourea derivatives of the invention is in preparation prevention or treatment proliferative disease drug Application.
1,3- 2-substituted carbamide class and thiourea derivatives of the invention answering in the drug of preparation prevention or treating cancer With.
Specific embodiment
Below by the further details of explanation of specific embodiment:
The general structure of 1,3- 2-substituted carbamide class and thiourea derivatives in this programme, the derivative is following I:
Wherein, X is O or S；
Y1 is O or S；
Y2 is O or S；
M is N or CH；
M is 0,1 or 2；
N is 0,1 or 2；
P is 0,1 or 2；
Q is 0,1 or 2；
T is 0 or 1；
R1For hydrogen, NH2、NHS(O)0-2R6、C1-C3Alkylamidoalkyl or NHCONHR6；
R6For C1-C4Alkyl or heteroaryl, wherein the heteroaryl is selected from the hetero atom containing 1-3 N, O or S, and The optional 0-5 hydrogen or halogen of heteroaryl replaces；
R2、R3For hydrogen or halogen atom, hydroxyl, cyano, nitro, halogenated C1-C2 alkyl, halogenated C1-C2 alkoxy, C1-C2 alkane Oxygroup, C1-C2 alkyl or by the alkyl-substituted amino of 1-2 C1-C2；
R4And R5For methyl, ethyl or R4And R5Piperidyl, morpholinyl, piperazinyl, homopiperazine is collectively formed with nitrogen-atoms Base, piperidyl, pyrrolidinyl, azelidinyl, thio-morpholinyl, thiazolinyl, piperidines bithiophene or hexahydroisoindoline.
1,3- 2-substituted carbamide class of the invention and thiourea derivatives, R in general formula I4And R5For methyl, ethyl or R4With R5Piperidyl, morpholinyl, piperazinyl, high piperazine base, piperidyl, pyrrolidinyl, azelidinyl, sulphur is collectively formed with nitrogen-atoms For morpholinyl, thiazolinyl, piperidines bithiophene or hexahydroisoindoline.
Embodiment 1:1,3- 2-substituted carbamide class and thiourea derivatives, structural formula are such as following formula II:
The preferred compound of structural formula II has:
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3(4- oxo -2- benzene Base thiazoline -3- base) urea；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- oxo -2- (4- Fluorophenyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- oxo -2- (3- Chlorphenyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- oxo -2- (4- Dimethylamino phenyl) thiazoline -3- base] urea；
N1[the fluoro- 4- of 3- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygroup] phenyl]-N3- (2- phenyl -1,3- thiazine -4- ketone -3- base) urea；
N1[the chloro- 4- of 3- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygroup] phenyl]-N3- [2- (3- chlorphenyl) -4- oxo -1,3- thiazine -3- base] urea；
N1[4- [the chloro- 6- methoxyl group -7- of 2- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygroup] phenyl]-N3- [2- (3- chlorphenyl) -4- oxo -1,3- thiazine -3- base] urea；
N1[the fluoro- 4- of 3- [6- methoxyl group -7- [3- (cis-hexahydroisoindoline base) propoxyl group] quinazoline -4- oxygroup] benzene Base]-N3[2- (3- bromophenyl) -4- oxo -1,3- thiazine -3- base] urea；
N1[3- methoxyl group -4- [6- methoxyl group -7- (3- diethylamine propoxyl group) quinazoline -4- oxygroup] phenyl]-N3-(2- Benzyl -4- oxo -1,3- thiazine -3- base) urea；
N1[3- methoxyl group -4- [6- methoxyl group -7- (3- diethylamine propoxyl group) quinazoline -4- oxygroup] phenyl]-N3-(2- Benzyl -4- oxo -6- methyl-1,3- thiazine -3- base) urea；
N1[4- [6- methoxyl group -7- [3- (4- methylenepiperidines base) propoxyl group] quinazoline -4- oxygroup] phenyl]-N3-[4- Oxo -2- (4- chlorphenyl) thiazoline -3- base] thiocarbamide；
N1[4- [6- methoxyl group -7- (3- (4- methylenepiperidines base) propoxyl group) quinazoline -4- oxygroup] phenyl]-N3-(4- Oxo -2- (4- chlorphenyl) thiazoline -3- base) thiocarbamide；
N1[4- [6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- is thio- 2- (4- chlorphenyl) thiazoline -3- base] thiocarbamide；
N1[4- [6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3(4- is thio- 2- phenethyl thiazoline -3- base) thiocarbamide；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3(1,1- dioxo- 4- oxo -2- (4- fluorophenyl) thiazoline -3- base) urea；
Embodiment 2:1,3- 2-substituted carbamide class and thiourea derivatives, structural formula are such as following formula III:
The preferred compound of structural formula III has:
N1[4- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- oxygroup] phenyl]-N3-(4- Oxo -2- phenyl thiazole quinoline -3- base) urea；
N1[4- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- oxygroup] phenyl]-N3-(4- Oxo -2- phenethyl thiazoline -3- base) urea；
N1[4- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- oxygroup] phenyl]-N3-[4- Oxo -2- (3- trifluoromethyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- sulfenyl] phenyl]-N3-[4- Oxo -2- (2- bromophenyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- oxygroup] phenyl]-N3(4- oxo- 2- phenyl thiazole quinoline -3- base) thiocarbamide；
N1[4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- oxygroup] phenyl]-N3[4- oxo- 5- methyl -2- (2- bromophenyl) thiazoline -3- base] urea；
N1[2- trifluoromethyl-4- [6- methoxyl group-7- [3- (4- methyl-1-piperidyl) propoxyl group] quinoline-4- oxygroup] Phenyl]-N3(4- oxo -2- benzyl thiazoline -3- base) urea；
N1[the bromo- 4- of 3- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- oxygroup] phenyl]- N3[2- (3,4- difluorophenyl) -4- oxo -1,3- thiazine -3- base] urea；
N1[the bromo- 4- of 3- [6- methoxyl group-7- [3- (4- methyl-1-piperazinyl) propoxyl group] quinoline-4- oxygroup] phenyl]- N3[2- (3,5- dichlorophenyl) -4- oxo -6- methyl-1,3- thiazine -3- base] urea；
Embodiment 3:1,3- 2-substituted carbamide class and thiourea derivatives, structural formula are such as following formula IV:
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- oxygroup] phenyl]-N3(4- oxo -2- phenyl Thiazoline -3- base) urea；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- oxygroup] phenyl]-N3[4- oxo -2- (2,3, 4- trifluorophenyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- oxygroup] phenyl]-N3[4- oxo -2- (3- tri- Fluorine methoxyl group phenyl) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- (3- Diethylaminopropoxy) quinoline -4- oxygroup] phenyl]-N3[4- oxo -5,5- Dimethyl -2- (3- Trifluoromethoxyphen-l) thiazoline -3- base] urea；
N1[4- [6- methoxyl group -7- (3- Diethylaminopropoxy) quinoline -4- oxygroup] phenyl]-N3(4- oxo -2- benzyl Base -5,5- dimethylthiazole quinoline -3- base) urea；
N1[the chloro- 4- of 3- [2- amino -6- methoxyl group -7- (1- pyrrolidinyl) quinoline -4- oxygroup] phenyl]-N3[4- oxygen Generation -2- (4- bromophenyl) thiazoline -3- base] urea；
N1[the chloro- 4- of 3- [2- amino -6- methoxyl group -7- (1- pyrrolidinyl) quinoline -4- oxygroup] phenyl]-N3[1,4- bis- Oxo -2- (4- bromophenyl) thiazoline -3- base] urea；
N1[2- acetylaminohydroxyphenylarsonic acid 4- [6- methoxyl group-7- (4- methyl-1-piperazinyl) quinoline-4- oxygroup] phenyl]-N3-(4- Oxo -2- benzyl thiazoline -3- base) urea；
N1[2- acetylaminohydroxyphenylarsonic acid 4- [6- methoxyl group-7- (4- methyl-1-piperazinyl) quinoline-4- oxygroup]-3- methoxybenzene Base]-N3[4- oxo -2- (4- dimethylamino phenyl) thiazoline -3- base] urea；
N1[2- methanesulfonamido -4- [6- methoxyl group -7- [3- (4- methylene -1- piperidyl) propoxyl group] quinoline -4- oxygen Base] phenyl]-N3[4- oxo -2- (2,4,6- trifluorophenyl) thiazoline -3- base] urea；
N1[2- methanesulfonamido -4- [6- methoxyl group -7- [3- (4- methylene -1- piperidyl) propoxyl group] quinoline -4- oxygen Base] phenyl]-N3[4- oxo -2- (2,4,6- trifluorophenyl) -1,3- thiazine -3- base] urea；
According to some usual methods of the art, 1, the 3- 2-substituted carbamide class and thiocarbamide of formula of I of the present invention Class compound can generate pharmaceutically acceptable salt with acid, and pharmaceutically acceptable addition salts include inorganic acid salt and acylate.Compare Common acylate includes methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, camphorsulfonic acid, naphthalenedisulfonic acid, acetic acid, third Acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc.；Inorganic acid salt mainly includes hydrogen Hydracid, sulfuric acid, phosphoric acid and nitric acid etc..
" halogen " refers to fluorine, chlorine, bromine or iodine in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" saturation or part The heterocycle of saturation " refers to containing one or more heteroatomic monocycles or polycyclic cyclic annular system for being selected from N, O, S, such as pyrroles Alkyl, morpholinyl, piperazinyl, piperidyl, pyrazolidinyl and thiazolinyl etc..
It has been found that the compounds of this invention has inhibition tumor cell growth activity in vitro, therefore, it may be used as making The drug of standby treatment and/or pre- anti-cancer, as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, Pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma etc..
By inhibiting Non-small cell lung carcinoma cell A549 and human colon cancer cell HT-29 activity test in vitro, the present invention Compound to colon cancer cell and lung cancer etc. have significantly inhibits effect, it is especially useful in preparation treat and/or prevent colon cancer and The drug of lung cancer.
It being found by testing c-Met kinase activity, the compounds of this invention has significant inhibition c-Met kinase activity, There is stronger inhibiting effect to the highly expressed colon cancer cell of c-Met, stomach cancer cell and breast cancer cell etc., it is especially useful in preparation The drug for the treatment of and/or prevention gastric cancer.
Reactive compound of the invention or its officinal salt can be used as unique anti-tumor drug and be used alone, or can be with With anti-tumor drug (such as platinum medicine cis-platinum, camptothecine Irinotecan, the vinca alkaloids drug Novi listed Sheet, deoxycytidine class drug gemcitabine, etoposide, taxol etc.) it is used in combination.Combination therapy is by by each treatment group Point simultaneously, sequence or administration is separated to realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It should be appreciated that the range of following examples and preparation example does not limit the scope of the invention in any way.
Following synthetic route is summarized and describes the preparation of I derivative of formula of the invention, and all raw materials all pass through Mode described in these schematic diagrames, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or can quotient Purchase.All final derivative of the invention is all by method described in these schematic diagrames or by similar method system Standby, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these schematic diagrames Definition in definition or such as claim as follows.
Compound of formula I can replace acid obtained (route 1) by formula following formula V compound from different sulfydryls:
More specifically, following synthetic route preparation can be used in II compound of formula:
More specifically, following synthetic route preparation can be used in III compound of formula:
More specifically, following synthetic route preparation can be used in IV compound of formula:
The nuclear magnetic resonance spectroscopy of compound is measured with Bruker ARX-400, mass spectrum 1100 level four bars liquid matter of Agilent Combined instrument measurement measurement；Agents useful for same is that analysis is pure or chemical pure.
Embodiment 4, N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3(4- oxygen Generation -2- phenyl thiazole quinoline -3- base) urea synthesis
The synthesis of step 1. 3- methoxyl group -4- (3- chloropropanol oxygen radical) methyl benzoate (II-1)
At room temperature, vanillic acid methyl esters (100.0g, 0.55mol) is dissolved in 600mL DMF, is added Enter Anhydrous potassium carbonate (151.6g, 1.10mol), after stirring 15min, 1,3- bromo-chloropropane is added, finishes, 3h is stirred at room temperature.It will Reaction solution pours into 2L ice water, filters, dry, obtains white solid 130.8g；ESI-MS[M+H](m/z):259.0.
The synthesis of step 2. 2- nitro -4- (3- chloropropanol oxygen radical) -5- methoxyl methyl benzoate (II-2)
130.0g II-1 is added into 900mL methylene chloride, -10 DEG C of instillation 60mL fuming nitric aicds, drop finishes, and continues to stir Mix about 5h.Reaction solution is poured into 500mL water, organic phase is separated, is evaporated, faint yellow solid 125.2 is obtained；ESI-MS[M+H](m/ z):304.0。
The synthesis of step 3. 2 amino -4- (3- chloropropanol oxygen radical) -5- methoxyl methyl benzoate (II-3)
Intermediate II -2 (120.0g, 0.40mol) is added into 90% ethyl alcohol of 1800mL, reduced iron powder is added (67.2g, 1.20mol) and glacial acetic acid 5mL, flow back 3h.It filters while hot, filtrate is evaporated, and obtains yellow-brown solid 86.9g；ESI-MS [M+H](m/z):274.1。
The synthesis of step 4. 6- methoxyl group -7- (3- chloropropanol oxygen radical) -5- methoxyquinazoline hydrochloride -4 (3H) -one (II-4)
Intermediate II -3 (80.0g, 0.29mol) and formamidine acetate (61.0g, 0.58mol) are added to the anhydrous second of 600mL In alcohol, flow back 9h.0 DEG C of cooling crystallization filters, obtains beige solid 72.9g；ESI-MS[M+H](m/z):269.1.
The conjunction of step 5. 6- methoxyl group -7- (morpholinyl propoxyl group) -5- methoxyquinazoline hydrochloride -4 (3H) -one (II-5) At
At room temperature, intermediate II -4 (70.0g, 0.26mol) and morpholine (113g, 1.3mol) are added to 600mL second In nitrile, flow back 10h, is evaporated, and is directly used in and reacts in next step；ESI-MS[M+H](m/z):320.1.
The synthesis of step 6. 4- chloro- 6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline (II-6)
Above-mentioned resulting intermediate II -5 is added into 500mL acetonitrile, after being slowly added to 350mL phosphorous oxychloride, reflux 8h.Residue is added into 500mL ice water solvent evaporated, sodium hydrate aqueous solution tune pH to 8-9, methylene chloride extraction (3 × 300mL), washing is primary, is evaporated organic phase, obtains light brown grease 62.3g；ESI-MS[M+H](m/z):338.0.
The synthesis of step 7. 4- (4-nitrophenoxy) -6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline (II-7)
The 4- nitrophenol of 60.0g intermediate II -6 and 31.7g are added into 600mL chlorobenzene, flow back 11h.It will be anti- It answers liquid to be evaporated, is added into 500mL methylene chloride, is washed (3 × 100mL) three times with 10% sodium hydrate aqueous solution, washing one It is secondary, after organic phase is evaporated, obtain colour of loess colour solid 57.1g；ESI-MS[M+H](m/z):441.1.
The conjunction of step 8. 4- [[6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- base] oxygroup] aniline (II-8) At
50.0g intermediate II -7 is added into 90% ethyl alcohol of 750mL, 31.8g reduced iron powder and the dense salt of 2mL are added Acid, flow back 4h.It filters while hot, filtrate cooling crystallization obtains yellow solid 42.1g；ESI-MS[M+H](m/z):411.1.
Step 9. 4- [4- [7- (morpholinyl propoxyl group) -6- methoxyquinazoline hydrochloride -4- oxygroup] phenyl] carbamic acid benzene The synthesis of ester (II-9)
At room temperature, 40.0g intermediate II -8 and 22.8g pyridine are added into 600mL methylene chloride, are instilled at 0 DEG C 22.9g phenyl chloroformate, drop finish, and 4h is stirred at room temperature.Saturated sodium bicarbonate aqueous solution is washed (2 × 100mL) twice, and washing is primary, It is evaporated to obtain yellow oily liquid 42.7g, is directly used in and reacts in next step.
Step 10. 4- [4- [7- (morpholinyl propoxyl group) -6- methoxyquinazoline hydrochloride -4- oxygroup] phenyl] semicarbazides (II-10) synthesis
Above-mentioned resulting intermediate II -9 and 80% hydrazine hydrate 215mL are added into 430mL dimethylbenzene, 70 DEG C of stirrings 5h.It is cooled to room temperature, filters, obtain beige solid 25.7g；ESI-MS[M+H](m/z):469.2.
Step 11.N1[4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- oxygroup] phenyl]-N4Benzylidene The synthesis of semicarbazones (II-11)
1.0g intermediate II -10 and 0.28g benzaldehyde are added into 10mL isopropanol, 2 drop glacial acetic acids, reflux is added 2h.It is cooling, it filters, filter cake is eluted with a small amount of isopropanol, obtains white solid 0.87g；ESI-MS[M+H](m/z):557.1.
Step 12.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3(4- oxygen Generation -2- phenyl thiazole quinoline -3- base) urea (embodiment 1) synthesis
At room temperature, 0.5g intermediate II -11 is added into 10mL methylene chloride, the silicon tetrachloride of 0.5mL is added, adds Finish, flow back 6h.Solvent evaporated, 10% sodium hydrate aqueous solution tune pH to 8, methylene chloride extract (2 × 10mL), organic phase nothing Aqueous sodium persulfate is dry, is evaporated, column chromatographic isolation and purification obtains white solid 0.16g, yield 28.2%.1H-NMR(400MHz, DMSO-d6) δ 9.06 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 7.47-7.62 (m, 4H), 7.42-7.46 (m, 4H), 7.19 (m, 2H), 6.42 (s, 1H), 5.86 (s, 1H), 4.21 (t, 2H), 3.95 (s, 3H), 3.88 (m, 1H), 3.82 (m, 1H), 3.61 (m, 4H), 2.30-2.45 (br, 6H), 2.00 (m, 2H)；ESI-MS[M+H](m/z):631.3.
It is that raw material reacts preparation with sulfydryl substituted carboxylic acid with different substituents intermediate II -11 according to the method for embodiment 4 Obtain the compound of embodiment 2-21.
Embodiment 5.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- oxygen Generation -2- (4- fluorophenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6)δ8.98-9.04(br,1H),8.56(s,1H),8.45(s,1H),7.54- 7.63 (m, 5H), 7.39 (s, 1H), 7.23-7.26 (m, 1H), 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 (m, 4H), 2.32-2.47 (br,6H),1.95-2.07(m,2H)；ESI-MS[M+H](m/z):649.1.
Embodiment 6.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[4- oxygen Generation -2- (3- chlorphenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (br, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 7.92 (m, 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), 7.18 (d, J=8.8Hz, 2H), 6.41 (m, 1H), 5.93 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.93 (m, 4H), 3.82 (s, 1H), 3.58-3.61 (m, 4H), 2.45-2.49 (m, 2H), 2.34-2.44 (br, 4H), 1.95-2.07 (m,2H)；ESI-MS[M+H](m/z):683.1.
Embodiment 7.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3[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 (s, 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), 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), 2.92 (s, 6H), 2.45-2.48 (m, 2H), 2.36-2.43 (br, 4H), 1.93-2.01 (m, 2H)；ESI-MS [M+H](m/z):692.2。
Embodiment 8.N1(2- benzyl -4- oxothiazoiium quinoline -3- base)-N3[4- [[6- methoxyl group -7- (the third oxygen of morpholinyl Base) quinazoline -4- base] oxygroup] phenyl] urea
1H-NMR(400MHz,DMSO-d6) δ 9.25 (s, 1H), 8.77 (s, 1H), 8.46 (s, 1H), 7.63 (d, J= 9.2Hz, 2H), 7.52 (s, 1H), 7.38 (s, 1H), 7.25-7.35 (m, 5H), 7.23 (d, J=9.2Hz, 2H), 4.94-5.01 (m, 1H), 4.19 (t, J=6.4Hz, 2H), 3.94 (s, 3H), 3.58-3.60 (m, 4H), 3.35-3.50 (m, 2H), 3.25- 3.29(m,1H),2.90-2.95(m,1H),2.45-2.52(m,2H),2.32-2.44(br,4H),1.95-2.01(m,2H)； ESI-MS[M+H](m/z):663.1。
Embodiment 9.N1[the fluoro- 4- of 3- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3- [4- oxo -2- (4- bromophenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6)δ8.96-9.02(br,1H),8.55(s,1H),8.47(s,1H),7.56- 7.64 (m, 5H), 7.38 (s, 1H), 7.23-7.27 (m, 1H), 7.17 (m, 2H), 5.87 (s, 1H), 4.20 (t, J=6.0Hz, 2H),3.93(s,3H),3.80-3.87(m,2H),3.57-3.65(m,4H),2.32-2.47(br,6H),1.95-2.07(m, 2H)；ESI-MS[M+H](m/z):727.1.
Embodiment 10.N1[the chloro- 4- of 2- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl] - N3[4- oxo -2- (3- chlorphenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6)δ9.02(br,1H),8.63(s,1H),8.46(s,1H),7.67-7.72(m, 2H), 7.46 (s, 1H), 7.18-7.27 (m, 4H), 7.04-7.10 (m, 2H), 5.85 (s, 1H), 4.21 (t, J=6.0Hz, 2H),3.92(s,3H),3.78-3.87(m,2H),3.56-3.65(m,4H),2.32-2.45(m,6H),1.95-2.06(m, 2H)；ESI-MS[M+H](m/z):727.1.
Embodiment 11.N1[2- trifluoromethyl -4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] Phenyl]-N3[4- oxo -2- (3- methoxyphenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6)δ8.97(br,1H),8.66(s,1H),8.45(s,1H),7.65-7.71(m, 2H), 7.44 (s, 1H), 7.18-7.26 (m, 4H), 7.03-7.10 (m, 2H), 5.85 (s, 1H), 4.20 (t, J=6.0Hz, 2H),3.92(s,3H),3.78-3.86(m,2H),3.71(s,3H),3.56-3.64(m,4H),2.32-2.43(m,6H), 1.95-2.05(m,2H)；ESI-MS[M+H](m/z):729.1.
Embodiment 12.N1[the fluoro- 4- of 3- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygen Base] phenyl]-N3(2- phenyl -4- oxo -1,3- thiazine -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.53-7.64 (m, 5H), 7.42 (s, 1H), 7.25-7.30 (m, 2H), 7.22 (m, 2H), 5.86 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.69 (m, 2H), 2.38 (m, 2H), 1.85-2.00 (m, 4H), 1.63 (m, 2H), 1.25-1.41 (m, 1H), 1.04-1.16 (m, 2H), 0.91 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z): 675.2。
Embodiment 13.N1[4- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygroup] benzene Base]-N3[2- (3- chlorphenyl) -4- oxo -1,3- thiazine -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.53-7.64 (m, 5H), 7.43 (s, 1H), 7.25-7.32 (m, 2H), 7.22 (m, 2H), 5.86 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.40 (m, 2H), 1.85-2.02 (m, 4H), 1.64 (m, 2H), 1.25-1.40 (m, 1H), 1.04-1.15 (m, 2H), 0.92 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z): 691.2。
Embodiment 14.N1[4- [6- methoxyl group -7- [3- (4- methylenepiperidines base) propoxyl group] quinazoline -4- oxygroup] benzene Base]-N3(2- phenyl -4- oxo -5- methyl-1,3- thiazine -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 8.99 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 7.53-7.65 (m, 5H), 7.45 (s, 1H), 7.24-7.32 (m, 3H), 7.22 (m, 2H), 5.85 (s, 1H), 4.62 (m, 2H), 4.20 (t, J= 6.4Hz, 2H), 3.95 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.40 (m, 2H), 1.87- 2.02(m,4H),1.64(m,2H),1.04-1.15(m,2H)；ESI-MS[M+H](m/z):691.2.
Embodiment 15.N1[4- [6- methoxyl group -7- [3- (3,5- lupetidine base) propoxyl group] quinazoline -4- oxygroup] Phenyl]-N3[4- oxo -2- (3- methoxyphenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.06 (s, 1H), 8.69 (s, 1H), 8.48 (s, 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), 7.16 (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), 3.71 (s, 3H), 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):687.2.
Embodiment 16.N1[the fluoro- 4- of 3- [6- methoxyl group -7- (3- (cis-hexahydroisoindoline base) propoxyl group) quinazoline -4- Oxygroup] phenyl]-N3[2- (3- bromophenyl) -4- oxo -1,3- thiazine -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.07 (s, 1H), 8.79 (s, 1H), 8.46 (s, 1H), 7.53-7.62 (m, 4H), 7.45 (s, 1H), 7.25-7.31 (m, 2H), 7.20 (m, 2H), 5.88 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.40 (m, 2H), 1.53-1.64 (m, 5H), 1.25- 1.40 (m, 6H), 1.15-1.19 (m, 2H), 1.10 (m, 1H)；ESI-MS[M+H](m/z):781.1.
17. 1- of embodiment [4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl] -3- (1- Oxidation -4- oxo -2- phenyl thiazole quinoline -3- base) urea synthesis
0.50g embodiment 4 is added into 3mL glacial acetic acid at room temperature, the hydrogen peroxide of 0.5mL is added, 3h is stirred at room temperature.Hydrogen Aqueous solution of sodium oxide tune pH to 8, methylene chloride extraction, is evaporated organic phase, column chromatography for separation obtains white solid 0.34g.1H-NMR (400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.47-7.63 (m, 4H), 7.41-7.46 (m, 4H), 7.20 (m, 2H), 6.42 (s, 1H), 5.91 (s, 1H), 4.21 (t, 2H), 3.95 (s, 3H), 3.89 (br, 1H), 3.824 (m, 1H), 3.61 (m, 4H), 2.30-2.44 (m, 6H), 2.01 (m, 2H)；ESI-MS[M+H](m/z):647.2.
According to the method for embodiment 17, the compound of following example 18 and 19 can be prepared.
Embodiment 18.N1[4- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinazoline -4- oxygroup] benzene Base]-N3[1- oxidation -2- (3- chlorphenyl) -4- oxo -1,3- thiazine -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.53-7.64 (m, 5H), 7.43 (s, 1H), 7.25-7.32 (m, 2H), 7.22 (m, 2H), 5.86 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.89 (m, 2H), 2.89 (m, 2H), 2.68 (m, 2H), 2.40 (m, 2H), 1.85-2.02 (m, 4H), 1.64 (m, 2H), 1.25-1.40 (m, 1H), 1.04-1.15 (m, 2H), 0.92 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z): 707.2。
Embodiment 19.N1(1- oxidation -2- benzyl -4- oxothiazoiium quinoline -3- base)-N3[4- [[6- methoxyl group -7- (3- Quinoline base propoxyl group) quinazoline -4- base] oxygroup] phenyl] urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.47-7.61 (m, 4H), 7.42-7.47 (m, 4H), 7.18 (m, 2H), 6.42 (s, 1H), 5.82 (s, 1H), 4.22 (m 2H), 3.95 (s, 3H), 3.81 (m, 1H), 3.77 (m, 1H), 3.61 (m, 4H), 3.02 (m, 2H), 2.30-2.45 (br, 6H), 2.01 (m, 2H)；ESI- MS[M+H](m/z):661.2。
Embodiment 20.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3-(1, 1- titanium dioxide -4- oxo -2- phenyl thiazole quinoline -3- base) urea synthesis
At room temperature by the object of 0.50g embodiment 4 --- N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline Oxazoline -4- oxygroup] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) urea is added into 3mL glacial acetic acid, and 0.5mL is added Hydrogen peroxide, 50 DEG C of stirring 3h.Sodium hydrate aqueous solution tune pH to 8, methylene chloride extraction, is evaporated organic phase, column chromatography for separation Obtain white solid 0.34g.1H-NMR(400MHz,DMSO-d6) δ 9.06 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 7.48- 7.62 (m, 4H), 7.42-7.48 (, 4H), 7.19 (m, 2H), 6.42 (s, 1H), 6.04 (s, 1H), 4.23 (t, 2H), 3.94- 3.98 (m, 2H), 3.91 (s, 3H), 3.61 (m, 4H), 2.30-2.45 (br, 6H), 2.00 (m, 2H)；ESI-MS[M+H](m/ z):663.1。
According to the method for embodiment 20, the compound of following example 21 and 22 can be prepared
Embodiment 21.N1[4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinazoline -4- oxygroup] phenyl] - N3[1,1- oxidation -4- oxo -2- (3- methoxyphenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.04 (br, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 7.62 (s, 1H), 7.73 (d, J=5.6Hz, 1H), 7.63-7.67 (m, 1H), 7.52 (d, J=8.8Hz, 2H), 7.48 (s, 1H), 7.11 (s, 1H), 7.07 (d, J=8.8Hz, 2H), 6.44 (d, J=5.2Hz, 1H), 6.08 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.73 (s, 3H), 2.65-2.74 (m, 2H), 2.54-2.61 (br, 4H), 1.98- 2.07 (m, 2H), 1.65-1.83 (m, 4H)；ESI-MS[M+H](m/z):678.2.
Embodiment 22.N1[4- [6- methoxyl group -7- (3- diethylin) propoxyl group] quinazoline -4- oxygroup] phenyl]-N3- [1,1- oxidation -4- oxo -2- (3- cyano-phenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.92 (br, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 7.60 (s, 1H), 7.72 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.51 (d, J=8.8Hz, 2H), 7.47 (s, 1H), 7.13 (s, 1H), 7.04 (d, J=8.8Hz, 2H), 6.46 (d, J=5.2Hz, 1H), 6.06 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.95-4.01 (m, 2H), 3.92 (s, 3H), 2.64-2.73 (m, 2H), 2.54-2.61 (m, 4H), 1.96-2.06 (m, 2H), 1.09-1.17(m,6H)；ESI-MS[M+H](m/z):674.2.
Embodiment 23.N1[4- [6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3- The synthesis of [4- oxo -2- (4- chlorphenyl) thiazoline -3- base] thiocarbamide
Step 1. 4- [4- [7- (3- thio-morpholinyl propoxyl group) -6- methoxyquinazoline hydrochloride -4- oxygroup] phenyl] amino sulphur The synthesis of urea (II-13)
By 4- ((6- methoxyl group -7- (the 3- thio-morpholinyl propoxyl group) quinazoline -4- base) oxygroup) aniline of 10.0g and 4.1g thiophosgene is added into 100mL methylene chloride, adds 100mL saturated sodium bicarbonate aqueous solution, stirs 6h.It separates organic Phase, washing twice (2 × 30mL), are evaporated, obtain yellow oil.Above-mentioned gained grease is added into 150mL methylene chloride, 50mL hydrazine hydrate is added, 2h is stirred at room temperature, separates organic phase, is evaporated, the white-yellowish solid 5.8g of column chromatographic isolation and purification； ESI-MS[M+H](m/z):501.1。
Step 2.N1[4- [6- methoxyl group -7- (3- thiomorpholine propoxyl group) quinazoline -4- oxygroup] phenyl]-N4Benzene is sub- The synthesis of methyl thiosemicarbazones (II-14)
3.0g intermediate II -13 is added into 21mL isopropanol, adds the drop glacial acetic acid of 0.76g and 3, flow back 3h.It is cold But, it filters, filter cake is eluted with a small amount of isopropanol, obtains white solid 2.85g；ESI-MS[M+H](m/z):589.2.
Step 3.N1[4- [6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl]-N3-(4- Oxo -2- phenyl thiazole quinoline -3- base) thiocarbamide (embodiment 20) synthesis
At room temperature, 1.0g intermediate II -14 is added into 15mL methylene chloride, the silicon tetrachloride of 1.0mL is added, adds Finish, flow back 6h.Solvent evaporated, 10% sodium hydrate aqueous solution tune pH to 8, methylene chloride extract (2 × 20mL), organic phase nothing Aqueous sodium persulfate is dry, is evaporated, column chromatographic isolation and purification obtains white solid 0.29g.1H-NMR(400MHz,DMSO-d6)δ9.67(s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 7.47-7.62 (m, 4H), 7.42-7.47 (m, 4H), 7.18 (m, 2H), 6.42 (s, 1H), 5.85 (s, 1H), 4.22 (t, 2H), 3.93 (s, 3H), 3.88 (m, 1H), 3.82 (m, 1H), 3.61 (m, 4H), 2.36- 2.49 (br, 6H), 2.03 (m, 2H)；ESI-MS[M+H](m/z):663.1.
It is that raw material reacts preparation with thioglycolic acid with different substituents intermediate II -13 according to the method for embodiment 23 Obtain the compound of following example 2 4-26.
Embodiment 24.N1[4- [2- trifluoromethoxy -6- methoxyl group -7- [3- (N- methylhomopiperazin base) propoxyl group] quinoline Oxazoline -4- oxygroup] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6)δ10.91(br,1H),10.47(s,1H),8.46(s,1H),7.64-7.72 (m, 2H), 7.47 (s, 1H), 7.18-7.27 (m, 4H), 7.03-7.11 (m, 3H), 5.86 (s, 1H), 4.21 (t, J=6.0Hz, 2H), 3.93 (s, 3H), 3.91 (s, 2H), 3.31 (s, 3H), 2.87 (m, 2H), 2.46 (m, 2H), 1.84-2.02 (m, 4H), 1.66 (m, 2H), 1.46-1.51 (m, 2H), 1.13-1.24 (m, 2H)；ESI-MS[M+H](m/z):758.2.
Embodiment 25.N1[4- [6- methoxyl group -7- [3- (6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-yl) third oxygen Base] quinazoline -4- oxygroup] phenyl]-N3(2- phenyl -4- oxo -1,3- thiazine -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.47 (s, 1H), 9.69 (s, 1H), 8.47 (s, 1H), 7.49-7.60 (m, 4H), 7.42-7.46 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H), 6.71 (d, 1H), 6.44 (s, 1H), 5.89 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.86 (m, 1H), 3.83 (m, 1H), 3.61 (m, 4H), 2.79-2.84 (m, 2H), 2.36- 2.47 (m, 4H), 2.02 (br, 2H)；ESI-MS[M+H](m/z):713.2.
Embodiment 26.N1[the fluoro- 4- of 3- [6- methoxyl group -7- (morpholinyl propoxyl group) quinazoline -4- oxygroup] phenyl] - N3[4- oxo -2- (4- bromophenyl) thiazoline -3- base] thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.86 (s, 1H), 9.84 (s, 1H), 8.45 (s, 1H), 7.45-7.59 (br, 3H), 7.42-7.49 (m, 5H), 6.42 (s, 1H), 5.86 (s, 1H), 4.21 (t, 2H), 3.93 (s, 3H), 3.88 (m, 1H), 3.81 (m, 1H), 3.60 (m, 4H), 2.32-2.45 (br, 6H), 1.99 (m, 2H)；ESI-MS[M+H](m/z):743.1.
Embodiment 27.N1[4- [6- methoxyl group -7- [3- (1- pyrrolidinyl) propoxyl group] quinoline -4- oxygroup] phenyl]-N3- The synthesis of (4- oxo -2- phenyl thiazole quinoline -3- base) urea
Step 1.1- [4- (3- chloropropanol oxygen radical) -3- methoxyl group] acetophenone (III -1)
At room temperature, the 3- methoxyl group -4-hydroxyacetophenone and 58.2g Anhydrous potassium carbonate of 50.0g are added to 200mL N, In dinethylformamide, 1, the 3- bromo-chloropropane of instillation 31.2mL after 30min is sufficiently stirred, drop finishes, and room temperature continues to stir 6h. Reaction solution is poured into 600mL ice water, is filtered, white solid 68.8g is obtained after filtration cakes torrefaction；ESI-MS[M+H](m/z): 243.0。
Step 2. 1- [4- (3- chloropropanol oxygen radical) -5- methoxyl group -2- nitro] acetophenone (III -2)
50.0g intermediate III -1 is added into 500mL methylene chloride.Keep reacting liquid temperature at -20 DEG C to -10 DEG C Between, 32.0g fuming nitric aicd is slowly added dropwise, drop finishes, -10 DEG C of reaction 2h.Reaction solution is poured into ice water, collected organic layer is organic Layer is washed till neutrality with saturated sodium bicarbonate aqueous solution, and anhydrous sodium sulfate is dry, and solvent evaporated obtains yellow solid 51.7g；ESI-MS [M+H](m/z):287.0。
Step 3. 1- [4- (3- chloropropanol oxygen radical) -5- methoxyl group -2- nitrobenzophenone] -3- (dimethylamino) propyl -2- alkene - 1- ketone (III -3)
50.0g intermediate III -2 is added into 500mL dimethylbenzene, the n,N-Dimethylformamide two of 103.5g is added Dimethoxym ethane, back flow reaction 12h.Reaction solution is cooled to -10 DEG C, is filtered, filter cake is washed with appropriate dimethylbenzene, obtains yellow after dry Solid 45.8g；ESI-MS[M+H](m/z):343.1.
Step 4. 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4 (1H)-quinolinone (III -4)
40.0g intermediate III -3 is added into 300mL glacial acetic acid, 60 DEG C is warming up to, 32.8g reduced iron is added portionwise Powder, 90 DEG C of reaction 2h.It filters while hot, filtrate is cooling, filters, and obtains khaki solid and obtains yellow solid after glacial acetic acid recrystallizes 22.9g；ESI-MS[M+H](m/z):267.1.
Step 5. 6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] -4 (1H)-quinolinones (III -5)
20.0g intermediate III -4 and 65mL morpholine are added into 200mL acetonitrile, back flow reaction 12h.Boil off major part Residual solution is cooled to -10 DEG C, solid is precipitated, filtered by solvent, and ethyl acetate washing obtains solid 20.7g；ESI-MS[M+H] (m/z):318.1。
The chloro- 6- methoxyl group -7- of step 6. 4- [3- (4- morpholinyl) propoxyl group] quinoline (III -6)
20.0g intermediate III -5 and 100mL phosphorous oxychloride are added into 100mL dry acetonitrile, back flow reaction 6h.Subtract Pressure is evaporated, and is vigorously stirred down, and concentrated liquid is added in ice water, with 10%NaOH aqueous solution tune pH to 8, CH2Cl2Extraction (3 × 100mL), merge organic layer, anhydrous sodium sulfate is dry, solvent evaporated, and it is cooling, obtain pale solid 17.6g；ESI-MS[M+ H](m/z):337.1。
Step 7. 4- (4- nitrophenylsulfenyl) -6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline (III -7)
The 4- nitro thiophenol of 15.0g intermediate III -6 and 8.0g is added into 60mL dry chlorobenzene, flow back 14h. Solvent evaporated obtains gray solid, is dissolved in CH2Cl2In, the washing of 10% sodium hydrate aqueous solution, organic layer anhydrous sodium sulfate Dry, solvent evaporated obtains solid 13.2g；ESI-MS[M+H](m/z):440.1.
Step 8. 4- [6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline -4- sulfenyl] aniline (III -8)
12.0g intermediate III -7,15.1g reduced iron powder and 1mL concentrated hydrochloric acid are added into 180mL 90%EtOH, added Finish, flow back 2h.It filters while hot, collects filtrate, be evaporated, obtain yellow solid 9.5g；ESI-MS[M+H](m/z):410.1.
Step 9. 4- [4- [6- methoxyl group -7- [3- (4- morpholinyl) propoxyl group] quinoline -4- sulfenyl] phenyl] carbamic acid Phenyl ester (III -9)
At room temperature, 100.0g intermediate III -8 and 101.8g Anhydrous potassium carbonate are added into 1.5L dry acetone, 0 DEG C Lower instillation 44.6mL phenyl chloroformate, drop finish, and 5h is stirred at room temperature.1L methylene chloride is added in solvent evaporated, wash (3 × 100mL), anhydrous sodium sulfate is dry, is evaporated to obtain yellow oily liquid 109.1g.
Step 10. 4- [4- [7- [3- (4- morpholinyl) propoxyl group] -6- methoxy quinoline -4- sulfenyl] phenyl] semicarbazides (Ⅲ-10)
50.0g intermediate III -9 is dissolved in 300mL dimethylbenzene, 80% hydrazine hydrate of 200mL is added thereto, 70 DEG C are stirred Mix 4h.It is cooling, it filters, obtains yellowish-white solid 32.6g；ESI-MS[M+H](m/z):484.1.
Step 11.N1[4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- sulfenyl] phenyl]-N4Benzylidene contracting Semicarbazides (III -11)
10.0g intermediate III -10 and 2.4g benzaldehyde are added into 80mL isopropanol, 0.5mL glacial acetic acid is added, flow back 5h. It is cooling, it filters, filter cake is eluted with a small amount of isopropanol, obtains white solid 8.7g；ESI-MS[M+H](m/z):572.2.
Step 12.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- sulfenyl] phenyl]-N3(4- oxo- 2- phenyl thiazole quinoline -3- base) urea (embodiment 24)
Room temperature Under, 1.0g intermediate III -11 and 1mL thioglycolic acid are added into 10mL dry methylene chloride, the four of 0.5mL are added Silicon chloride finishes, and flow back 5h.10% sodium hydrate aqueous solution tune pH to 8, methylene chloride extract (2 × 10mL), organic phase nothing Aqueous sodium persulfate is dry, is evaporated, column chromatographic isolation and purification obtains white solid 0.4g.1H-NMR(400MHz,DMSO-d6)δ9.04(s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.46-7.63 (m, 5H), 7.39-7.45 (m, 4H), 7.19 (m, 2H), 6.43 (s, 1H), 5.87 (s, 1H), 4.22 (t, 2H), 3.94 (s, 3H), 3.85 (m, 2H), 3.60 (br, 4H), 2.30-2.44 (br, 6H), 2.01(m,2H)；ESI-MS[M+H](m/z):646.2.
It is that raw material and sulfydryl substituted carboxylic acid are anti-with different substituents intermediate III -13 according to the method for embodiment 23 and 27 The compound of embodiment 28-34 should be prepared.
Embodiment 28.N1[4- [6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- sulfenyl] phenyl]-N3(4- oxygen Generation -2- phenylpropyl thiazoline -3- base) urea
1H NMR(DMSO-d6, 400MHz) δ: 9.19-9.25 (br, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60 (m, 2H),7.51(s,1H),7.38(s,1H),7.18-7.31(m,7H),6.43(s,1H),7.75-7.77(m,1H),4.19(t,J =6.4Hz, 2H), 3.93 (s, 3H), 3.58-3.69 (m, 6H), 2.66-2.75 (m, 2H), 2.45-2.49 (m, 2H), 2.38- 2.43(br,4H),2.22-2.31(m,1H),1.94-2.03(m,3H)；ESI-MS[M+H](m/z):674.2.
Embodiment 29.N1[the fluoro- 4- of 3- [6- methoxyl group -7- [3- (N methyl piperazine base) propoxyl group] quinoline -4- sulfenyl] Phenyl]-N3[4- oxo -2- (2- fluorophenyl) thiazoline -5- methyl -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.92-8.98 (br, 1H), 8.45 (d, J=5.2Hz, 1H), 8.41 (s, 1H), 7.52 (d, J=8.8Hz, 2H), 7.48 (s, 1H), 7.39 (s, 1H), 7.25-7.33 (m, 1H), 7.18 (d, J= 8.8Hz, 2H), 6.70 (d, J=8.8Hz, 2H), 6.40 (d, J=5.2Hz, 1H), 5.81 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.91 (s, 2H), 3.31 (s, 3H), 2.87 (m, 2H), 2.46 (m, 2H), 1.84-2.02 (m, 4H), 1.66 (m, 2H), 1.13-1.24 (m, 2H)；ESI-MS[M+H](m/z):695.2.
Embodiment 30.N1[the fluoro- 4- of 3- [6- methoxyl group -7- [3- (3,5- lupetidine base) propoxyl group] quinoline -4- oxygen Base] phenyl]-N3[4- oxo -2- (3- bromophenyl) thiazoline -5,5- dimethyl -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.01 (s, 1H), 8.62 (s, 1H), 8.44 (d, J=5.2Hz, 1H), 7.88- 7.94 (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), 7.46 (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), 2.42-2.49 (m, 2H), 1.92-2.04 (m, 2H), 1.53-1.66 (m, 2H), 1.49 (s, 6H), 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):796.2.
Embodiment 31.N1[2- trifluoromethoxy -4- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinoline - 4- oxygroup] phenyl]-N3[2- (3- chlorphenyl) -4- oxo -1,3- thiazine -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 9.00-9.11 (br, 1H), 8.69 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.90 (br, 1H), 7.81 (d, J=5.6Hz, 1H), 7.75 (d, J=5.6Hz, 1H), 7.62-7.68 (m, 1H), 7.55 (m, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.19 (m, 2H), 6.41 (d, J=5.2Hz, 1H), 5.94 (s, 1H), 4.22 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.80-3.87 (m, 2H), 2.87 (m, 2H), 2.74 (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), 0.92 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):790.2.
Embodiment 32.N1[the fluoro- 4- of 2,6- bis- [6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinoline -4- oxygen Base] phenyl]-N3[2- (4- aminomethyl phenyl) -4- oxo -1,3- thiazine -3- base] thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.14 (br, 1H), 9.95 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.90 (br, 1H), 7.62-7.68 (m, 2H), 7.51 (s, 1H), 7.38 (s, 2H), 7.19 (m, 2H), 6.41 (d, J=5.2Hz, 1H), 5.94 (s, 1H), 4.21 (m, 2H), 3.96 (s, 3H), 3.80-3.87 (m, 2H), 2.86 (m, 2H), 2.73 (m, 2H), 2.51 (m, 2H), 2.15 (s, 3H), 1.87-2.00 (m, 4H), 1.66 (m, 2H), 1.27-1.41 (m, 1H), 1.05-1.15 (m, 2H), 0.93 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):722.2.
Embodiment 33.N1[the fluoro- 4- of 2,6- bis- [6- methoxyl group -7- [3- (1- nafoxidine base) propoxyl group] quinoline -4- oxygen Base] phenyl]-N3(2- naphthalene -4- oxo -1,3- thiazine -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.98 (s, 1H), 10.15 (s, 1H), 8.41 (s, 1H), 7.89 (m, 1H), 7.55 (d, J=8.8Hz, 2H), 7.46 (s, 1H), 7.39 (s, 1H), 7.25-7.33 (m, 2H), 7.17 (m, 2H), 6.74 (m, 2H), 6.47 (d, J=5.2Hz, 1H), 5.96 (s, 1H), 4.21 (m, 2H), 3.95 (s, 3H), 3.78-3.83 (m, 2H), 2.67-2.74 (m, 2H), 2.54-2.63 (br, 4H), 2.51 (m, 2H), 1.98-2.06 (m, 2H), 1.61-1.71 (br, 4H)； ESI-MS[M+H](m/z):730.2。
Embodiment 34.N1[the fluoro- 4- of 2,6- bis- [6- methoxyl group -7- [3- (4- trifluoromethyl piperidine) propoxyl group] quinoline -4- Oxygroup] phenyl]-N3[4- oxo -2- (3- cyano-phenyl) thiazoline -3- base] thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.46 (br, 1H), 10.18 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.94 (br, 1H), 7.83 (m, 1H), 7.75 (m, 1H), 7.62-7.67 (m, 1H), 7.54 (d, J=8.8Hz, 2H), 7.19 (d, J=8.8Hz, 2H), 6.42 (d, J=5.2Hz, 1H), 5.97 (s, 1H), 4.22 (m, 2H), 3.96 (s, 3H), 3.80-3.87 (m, 2H), 3.04 (m, 1H), 2.87 (m, 2H), 2.49 (m, 2H), 1.88-2.01 (m, 3H), 1.65 (m, 2H), 1.27-1.40 (m, 1H), 1.05-1.17 (m, 2H)；ESI-MS[M+H](m/z):773.2.
Embodiment 35.N1[the chloro- 4- of 2- [6- methoxyl group -7- [3- (pipecoline base) propoxyl group] quinoline -4- oxygroup] Phenyl]-N3(2- phenyl -4- thioxothiazole quinoline -3- base) thiocarbamide
By the N of 0.5g1[the chloro- 4- of 2- [6- methoxyl group -7- [3- (pipecoline base) propoxyl group] quinoline -4- oxygroup] benzene Base]-N3(2- phenyl -4- oxothiazoiium quinoline -3- base) thiocarbamide and 0.66g phosphorus pentasulfide are added into 10mL acetonitrile, add 2mL triethylamine, flow back 7h.10mL methylene chloride is added in evaporating solvent under reduced pressure, and saturated sodium bicarbonate aqueous solution is washed twice, washing Once, it is evaporated, column chromatographic isolation and purification obtains faint yellow solid 0.2g.1H-NMR(400MHz,DMSO-d6) δ 10.87 (br, 1H), 10.36 (s, 1H), 8.45 (d, J=5.2Hz, 1H), 7.90 (br, 1H), 7.81 (d, J=5.6Hz, 1H), 7.75 (d, J= 5.6Hz, 1H), 7.62-7.68 (m, 1H), 7.55 (m, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.15 (m, 2H), 6.41 (d, J=5.2Hz, 1H), 5.94 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.89-3.95 (m, 2H), 2.87 (m, 2H), 2.75 (m, 2H), 2.49 (m, 2H), 1.88-2.00 (m, 4H), 1.64 (m, 2H), 1.27-1.40 (m, 1H), 1.05- 1.17 (m, 2H), 0.94 (m, 3H)；ESI-MS[M+H](m/z):708.2.
36. 4- of embodiment [the fluoro- 4- of 2- [3- [4- oxo -2- (3- Trifluoromethoxyphen-l) -1,3- thiazine -3- base] urea Base] phenoxy group] -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxide
Step 1. 3- methoxyl group -4- benzyloxy acetophenone (IV-1)
200.0g3- methoxyl group -4-hydroxyacetophenone is added into 1LDMF, 499.0g Anhydrous potassium carbonate, stirring is added After 15min, 215.1g cylite is instilled, drop finishes, and 4h is stirred at room temperature.Reaction solution is poured into 5L ice water, filters, obtains white solid Body 298.2g；ESI-MS[M+H](m/z):257.1.
Step 2. 2- nitro -4- benzyloxy -5- methoxyacetophenone (IV-2)
250.0g intermediate compound IV -1 is added into 1.5L methylene chloride.Between -20 DEG C to -10 DEG C, 150.0g is slowly added dropwise Fuming nitric aicd, drop finish, -10 DEG C of reaction 3h.Reaction solution is poured into ice water, collected organic layer, organic layer saturated sodium bicarbonate Aqueous solution is washed till neutrality, and anhydrous sodium sulfate is dry, and solvent evaporated obtains 261.6 g of yellow solid；ESI-MS[M+H](m/z): 302.1。
Step 3. 2- amino -4- benzyloxy -5- methoxyacetophenone (IV-3)
By 250.0g intermediate compound IV -2 be added into the alcohol-water of 2.5L 90%, add 139.5g reduced iron powder and 3mL glacial acetic acid, flow back 3h.It filters while hot, filtrate is cooled to 0 DEG C, filters, obtains yellow solid 174.7g；ESI-MS[M+H](m/ z):272.1。
- 4 (1H)-quinolinone (IV-4) of step 4. 6- methoxyl group -7- benzyloxy
150.0g intermediate compound IV -3 is added into 1200mL glycol dimethyl ether, 188.2g sodium ethoxide is added, finishes, room Temperature stirring 30min, is added 245.8g Ethyl formate, 7h is stirred at room temperature.300mL ice water is added, glacial acetic acid tune pH to 6 is filtered, obtained Pale solid 104.2g；ESI-MS[M+H](m/z):282.1.
The chloro- 6- methoxyl group -7- benyloxyquinoline (IV-5) of step 5. 4-
It will be dry that 100.0g intermediate compound IV -4 is added to 500mL POCl3, back flow reaction 9h.Evaporated under reduced pressure is acutely stirred It mixes down, concentrated liquid is added in ice water, with 10%NaOH aqueous solution tune pH to 8, filter, obtain gray solid 81.7g；ESI- MS[M+H](m/z):300.1。
Step 6. 4- (2- fluorine 4-nitrophenoxy) -6- methoxyl group -7- benyloxyquinoline (IV-6)
The 2- fluorine 4- nitrophenol of 80.0g intermediate compound IV -5 and 50.4g is added into 800mL dry chlorobenzene, reflux 17h.Solvent evaporated obtains gray solid, is dissolved in CH2Cl2In, the washing of 10% sodium hydrate aqueous solution, the anhydrous sulphur of organic layer Sour sodium is dry, and solvent evaporated obtains sticky oil object 67.2g；ESI-MS[M+H](m/z):421.1.
Step 7. 4- (the fluoro- 4-nitrophenoxy of 2-) -6- methoxyl group -7- benyloxyquinoline -1- oxide (IV-7)
60.0g intermediate compound IV -6 is added into 900mL methylene chloride, 0 DEG C of m-chloro mistake for being added portionwise 46.2g 80% Oxybenzoic acid finishes, and 3h is stirred at room temperature.Reaction solution is washed twice with saturated sodium bicarbonate aqueous solution, and organic phase is evaporated off, and obtains yellowish-brown Solid 50.7g；ESI-MS[M+H](m/z):437.1.
Step 8. 4- (2- fluorine 4-nitrophenoxy) -6- methoxyl group -7- oxyquinoline -1- oxide (IV-8)
In 33% hydrobromic acid glacial acetic acid solution, 4h will be stirred at room temperature in the addition of 50.0g intermediate compound IV -7.It filters, filter cake water It washes, obtains yellow solid 25.0g；ESI-MS[M+H](m/z):347.1.
Step 9. 4- (2- fluorine 4-nitrophenoxy) -6- methoxyl group -7- (3- chloropropanol oxygen radical) quinoline -1- oxide (IV- 9)
25.0g intermediate compound IV -8 is added into the DMF of 150mL, 29.9g Anhydrous potassium carbonate is added, after stirring 15min, 1, the 3- bromo-chloropropane of 13.6g is instilled, drop finishes, and 4h is stirred at room temperature.Reaction solution is poured into 800mL ice water, is stirred, filters, obtains White solid 26.5g；ESI-MS[M+H](m/z):423.0.
Step 10. 4- (the fluoro- 4-nitrophenoxy of 2-) -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxidation Object (IV-10)
25.0g intermediate compound IV -9 and 25.8g morpholine are added into 200mL acetonitrile, back flow reaction 12h.It removes under reduced pressure The brown oil 31.2g of solvent；ESI-MS[M+H](m/z):474.1.
Step 11. 4- (the fluoro- 4- amino-benzene oxygen of 2-) -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxidation Object (IV-11)
The above-mentioned resulting intermediate compound IV -10 of 30.0g, 10.6g reduced iron powder and 0.5mL concentrated hydrochloric acid are added to 300mL 90%EtOH-H2It in O, finishes, flow back 3h.It filters while hot, collects filtrate, be evaporated, obtain khaki solid 21.5g；ESI-MS [M+H](m/z):444.1。
Step 12. 6- methoxyl group -7- (morpholinyl propoxyl group) -4- [[2- fluoro- (4- benzene oxygen formamido)] phenoxy group] Quinoline -1- oxide (IV-12)
At room temperature, 20.0g intermediate compound IV -11 and 17.8g pyridine are added into 200mL dry methylene chloride, at 0 DEG C 14.2g phenyl chloroformate is instilled, drop finishes, and 4h is stirred at room temperature.Saturated sodium bicarbonate aqueous solution is washed (2 × 100mL) twice, and decompression is steamed Except organic phase, yellow oily liquid 28.9g is obtained, is directly used in next step.
Step 13. 4- [fluoro- (the 4- diazanyl formamido) phenoxy group of 2-] -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline Quinoline -1- oxide (IV-13)
Above-mentioned resulting intermediate compound IV -12 is dissolved in 100mL dimethylbenzene, 80% hydrazine hydrate of 100mL is added thereto, 70 DEG C of stirring 3h.It is cooling, it filters, obtains Off-white solid 12.6g；ESI-MS[M+H](m/z):502.2.
Step 14. 4- [the fluoro- 4- of 2- [2- (3- trifluoromethoxy benzylidene) diazanyl formamido] phenoxy group] -6- first Oxygroup -7- (morpholinyl propoxyl group) quinoline -1- oxide (IV-14)
The 3- trifluoro-methoxybenzaldehyde of 1.0g intermediate compound IV -13 and 0.46g are added into 10mL isopropanol, are added 0.1mL glacial acetic acid, flow back 4h.It is cooling, it filters, filter cake is eluted with a small amount of isopropanol, obtains white solid 0.94g；ESI-MS[M+H] (m/z):674.2。
Step 15. 4- [the fluoro- 4- of 2- [3- [4- oxo -2- (3- Trifluoromethoxyphen-l) -1,3- thiazine -3- base] urea groups] Phenoxy group] -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxide (embodiment 33)
By 0.5g intermediate compound IV -14 be added to 5mL it is dry in methylene chloride, add 0.2mL mercaptopropionic acid and 0.5mL silicon tetrachloride, finishes, and flow back 6h.10% sodium hydrate aqueous solution tune pH to 8, methylene chloride extracts (2 × 5mL), organic It is mutually dry with anhydrous sodium sulfate, it is evaporated, column chromatographic isolation and purification obtains white solid 0.23g；ESI-MS[M+H](m/z):762.2.
It is raw material and the sulfydryl substituted carboxylic acid system of reacting with different substituents intermediate compound IV -13 according to the method for embodiment 36 It is standby to obtain the compound of embodiment 37-42.
37. 4- of embodiment [the fluoro- 4- of 2- [3- [4- oxo -2- (4- cyano-phenyl) -1,3- thiazine -3- base] urea groups] benzene oxygen Base] -6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinoline -1- oxide
1H-NMR(400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.69 (s, 1H), 8.11 (d, J=5.2Hz, 1H), 7.88 (br, 1H), 7.78 (d, J=5.6Hz, 1H), 7.73 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.54 (m, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.20 (m, 2H), 6.44 (d, J=5.2Hz, 1H), 5.93 (s, 1H), 4.21 (t, J= 6.4Hz, 2H), 3.94 (s, 3H), 3.80-3.87 (m, 2H), 2.85-2.88 (m, 2H), 2.75 (m, 2H), 2.47 (m, 2H), 1.88-2.00 (m, 4H), 1.63 (m, 2H), 1.27-1.38 (m, 1H), 1.05-1.16 (m, 2H), 0.92 (d, J=6.4Hz, 3H)；ESI-MS[M+H](m/z):715.1.
38. 4- of embodiment [the bromo- 4- of 3- [3- [5- methyl -4- oxo -2- (4- methoxyphenyl) thiazoline -3- base] urea Base] phenoxy group] -6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinoline -1- oxide
1H-NMR(400MHz,DMSO-d6) δ 8.94 (s, 1H), 8.75 (s, 1H), 8.12 (d, J=5.2Hz, 1H), 7.88 (br, 1H), 7.78 (d, J=5.6Hz, 1H), 7.73 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.54 (m, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 7.20 (m, 2H), 6.44 (d, J=5.2Hz, 1H), 5.92 (s, 1H), 4.19 (t, J= 6.4Hz, 2H), 3.93 (s, 3H), 3.81-3.87 (m, 2H), 3.77 (s, 3H), 2.76 (m, 1H), 2.46 (m, 2H), 1.89- 2.01 (m, 4H), 1.63 (m, 2H), 1.42 (m, 3H), 1.27-1.36 (m, 1H), 1.05-1.14 (m, 2H), 0.94 (d, J= 6.4Hz,3H)；ESI-MS[M+H](m/z):780.1.
39. 4- of embodiment [3- cyano -4- [3- [5- methyl -4- oxo -2- (4- methoxyphenyl) thiazoline -3- base] Urea groups] phenoxy group] -6- [3- (4- methyl piperidine base) propoxyl group] -7- methoxy quinoline -1- oxide
1H-NMR(400MHz,DMSO-d6) δ 8.92 (s, 1H), 8.66 (s, 1H), 8.12 (d, J=5.2Hz, 1H), 7.85 (br, 1H), 7.76 (d, J=5.6Hz, 1H), 7.71 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.53 (m, 1H), 7.46 (s, 1H), 7.23 (s, 1H), 7.20 (m, 2H), 6.45 (d, J=5.2Hz, 1H), 5.94 (s, 1H), 4.16 (t, J= 6.4Hz, 2H), 3.88 (s, 3H), 3.81-3.86 (m, 2H), 3.77 (s, 3H), 2.76 (m, 1H), 2.46 (m, 2H), 1.89- 2.01 (m, 4H), 1.63 (m, 2H), 1.43 (m, 3H), 1.27-1.37 (m, 1H), 1.05-1.13 (m, 2H), 0.92 (d, J= 6.4Hz,3H)；ESI-MS[M+H](m/z):727.2.
40. 4- of embodiment [2- cyano -4- [3- [1- oxidation -4- oxo -2- (3,4- 3,5-dimethylphenyl) thiazoline -3- Base] urea groups] phenoxy group] -6- [3- (4- Acetylpiperazine) propoxyl group] -7- methoxy quinoline -1- oxide
1H-NMR(400MHz,DMSO-d6) δ 9.11 (s, 1H), 8.68 (s, 1H), 8.12 (d, J=5.2Hz, 1H), 7.86 (br, 1H), 7.78 (d, J=5.6Hz, 1H), 7.69 (d, J=5.6Hz, 1H), 7.62-7.67 (m, 1H), 7.52 (m, 1H), 6.89 (m, 2H), 6.83 (s, 1H), 6.45 (d, J=5.2Hz, 1H), 5.93 (s, 1H), 4.18 (t, J=6.4Hz, 2H), 3.87 (s, 3H), 3.80-3.85 (m, 2H), 3.77 (s, 3H), 2.76 (m, 1H), 2.46 (m, 2H), 2.35 (s, 6H), 2.29 (s, 3H), 2.04-2.12 (m, 4H), 1.63 (m, 2H)；ESI-MS[M+H](m/z):756.2.
Embodiment 41.N1[the fluoro- 4- of 3- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] oxygen Base] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) urea
Step 1.N1[the fluoro- 4- of 3- [[2- tertiary fourth amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] oxygen Base] phenyl]-N3The synthesis of (4- oxo -2- phenyl thiazole quinoline -3- base) urea (IV-15)
At room temperature, by 5.0g intermediate 4- [the fluoro- 4- of 2- [3- [4- oxo -2- phenyl thiazole quinoline -3- base] urea groups] benzene oxygen Base] -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -1- oxide is added into 50mL methylene chloride, the tertiary fourth of 2.8g is added 9.8g p-toluenesulfonic anhydride (Ts is added at 0 DEG C for amine2O), finish, 1h is stirred at room temperature.It filters, filtrate washing is evaporated to obtain brown color Solid 4.1g；ESI-MS[M+H](m/z):719.2.
Step 2.N1[the fluoro- 4- of 3- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinolyl-4] oxygroup] Phenyl]-N3The synthesis of (4- oxo -2- phenyl thiazole quinoline -3- base) urea (embodiment 38)
2.0g intermediate compound IV -15 is added into 10mL trifluoroacetic acid and 10mL methylene chloride, flow back 5h.It is evaporated reaction Liquid, saturated sodium bicarbonate aqueous solution are washed (2 × 10mL) twice, and organic phase is dry, are evaporated to obtain brown solid, column chromatographic isolation and purification Beige solid 0.7g.1H-NMR(400MHz,DMSO-d6) δ 9.12 (s, 1H), 8.76 (s, 1H), 7.86 (br, 2H), 7.47-7.60 (m, 5H), 7.40-7.45 (m, 4H), 7.17 (m, 2H), 5.86 (s, 1H), 4.21 (m, 2H), 3.95 (s, 3H), 3.89 (m, 1H), 3.82 (m, 1H), 3.62 (m 4H), 2.30-2.43 (m, 6H), 2.03 (m, 2H)；ESI-MS[M+H](m/z): 663.2。
It is the chemical combination that embodiment 42-43 is prepared in raw material with different intermediate compound IVs -15 according to the method for embodiment 41 Object.
Embodiment 42.N1[the fluoro- 4- of 2,6- bis- [[2- amino -6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- Base] oxygroup] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.89 (s, 1H), 10.41 (s, 1H), 7.86 (br, 2H), 7.48-7.59 (m, 5H), 7.39-7.43 (m, 3H), 7.17 (m, 2H), 5.86 (s, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.89 (m, 1H), 3.82 (m, 1H), 3.59-3.63 (m, 4H), 2.30-2.42 (br, 6H), 2.02-2.05 (m, 2H)；ESI-MS[M+H] (m/z):697.2。
Embodiment 43.N1[the chloro- 4- of 3- [[2- amino -6- methoxyl group -7- [3- (4- methyl piperidine base) propoxyl group] quinoline - 4- yl] oxygroup] phenyl]-N3(5- methyl -4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.03 (s, 1H), 8.57 (s, 1H), 7.85 (br, 2H), 7.53-7.65 (m, 5H), 7.41 (s, 1H), 7.25-7.31 (m, 2H), 7.23 (m, 3H), 5.86 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.96 (s, 3H), 3.82-3.891 (m, 1H), 2.89 (m, 2H), 2.69 (m, 2H), 2.38 (m, 2H), 1.85-2.00 (m, 2H), 1.63 (m, 2H), 1.43 (d, 3H), 1.25-1.41 (m, 1H), 1.04-1.16 (m, 2H), 0.91 (d, J=6.4Hz, 3H)；ESI-MS [M+H](m/z):705.2。
Embodiment 44.N1[the fluoro- 4- of 3- [[2- acetylaminohydroxyphenylarsonic acid 6- methoxyl group -7- (morpholinyl propoxyl group) quinoline -4- Base] oxygroup] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) urea
0.5g embodiment 40 is added into 10mL methylene chloride, 0.23g triethylamine is added, 0.12g second is added at 0 DEG C Acyl chlorides finishes, and 2h is stirred at room temperature.5mL saturated sodium bicarbonate aqueous solution is added into reaction solution, separates organic phase, is evaporated, column layer Analysis separates to obtain white solid 0.26g.1H-NMR(400MHz,DMSO-d6) δ 9.12 (s, 1H), 8.98 (br, 1H), 7.86 (br, 2H), 7.47-7.60 (m, 5H), 7.40-7.45 (m, 4H), 7.17 (m, 2H), 5.86 (s, 1H), 4.21 (t, 2H), 3.95 (s, 3H), 3.89 (m, 1H), 3.82 (m, 1H), 3.62 (m, 4H), 2.30-2.43 (br, 6H), 2.08 (s, 3H), 2.03 (m, 2H)； ESI-MS[M+H](m/z):705.2。
According to the method for embodiment 44, the embodiment replaced using different 2- amino is raw material, from different sulfonic acid chlorides, acyl The compound of embodiment 45-50 is prepared in the reactions such as chlorine or isocyanates.
Embodiment 45.N1[the fluoro- 4- of 3- [[2- methanesulfonamido -6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinoline Quinoline -4- base] oxygroup] phenyl]-N3(4- oxo -2- phenyl thiazole quinoline -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.86 (s, 1H), 10.62 (br, 1H), 7.86 (br, 1H), 7.47-7.59 (m, 5H), 7.40-7.46 (m, 4H), 7.16 (m, 2H), 5.85 (s, 1H), 4.20 (t, 2H), 3.94 (s, 3H), 3.86 (m, 1H), 3.82 (m, 1H), 3.62 (m, 4H), 2.30-2.43 (br, 6H), 2.18 (s, 3H), 2.11 (m, 2H)；ESI-MS[M+H] (m/z):773.1。
Embodiment 46.N1[4- [[2- (3- methyl urea groups) -6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinoline - 4- yl] oxygroup] phenyl]-N3(2- (4- cyano-phenyl) -4- oxo -1,3- thiazine -3- base) thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.68-10.75 (br, 1H), 10.26-10.34 (br, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 7.63 (d, 2H), 7.52 (d, 2H), 7.62-7.68 (m, 1H), 7.55 (m, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.19 (m, 2H), 6.41 (s, 1H), 5.85 (s, 1H), 4.22 (br, 2H), 3.93 (s, 3H), 3.88 (m, 1H), 3.82 (m, 1H), 3.61 (m, 4H), 2.81 (s, 3H), 2.68 (m, 2H), 2.36-2.49 (m, 6H), 2.03 (m, 2H)； ESI-MS[M+H](m/z):773.2。
Embodiment 47.N1[4- [[2- (3- ethyl urea groups) -6- methoxyl group -7- [3- (n-ethylpiperazine base) propoxyl group] quinoline Quinoline -4- base] oxygroup] phenyl]-N3[2- (2- chlorphenyl) -4- oxo -1,3- thiazine -3- base] thiocarbamide
1H-NMR(400MHz,DMSO-d6) δ 10.66 (s, 1H), 10.22 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.63 (m, 2H), 7.62-7.68 (m, 1H), 7.55 (m, 2H), 7.51 (s, 1H), 7.38 (s, 1H), 7.16-7.26 (m, 3H), 6.41 (s, 1H), 5.87 (s, 1H), 4.21 (t, 2H), 3.91 (s, 3H), 3.86 (m, 1H), 3.82 (m, 1H), 3.63 (m, 4H), 2.81 (m, 2H), 2.67 (m, 2H), 2.36-2.48 (br, 6H), 2.28 (s, 3H), 2.03 (m, 2H), 0.96 (t, 3H)；ESI- MS[M+H](m/z):821.2。
Embodiment 48.N1[4- [[2- (3- methyl urea groups) -6- methoxyl group -7- (3- thio-morpholinyl propoxyl group) quinoline - 4- yl] oxygroup] phenyl]-N3(5,5- dimethyl -4- oxo -2- phenyl thiazole quinoline -3- base) urea
1H-NMR(400MHz,DMSO-d6) δ 9.16 (br, 1H), 8.85 (br, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 7.62-7.69 (m, 1H), 7.56 (m, 1H), 7.49 (s, 1H), 7.38 (m, 2H), 7.22-7.31 (m, 4H), 7.19 (m, 2H), 6.41 (s, 1H), 5.85 (s, 1H), 4.22 (t, 2H), 3.93 (s, 3H), 3.61 (m, 4H), 2.81 (s, 3H), 2.36-2.49 (br, 6H), 2.03 (m, 2H), 1.46 (s, 6H)；ESI-MS[M+H](m/z):746.2.
Embodiment 49.N1(2- benzyl -4- oxothiazoiium quinoline -3- base)-N3[4- [[2- (2- furyl) urea groups -6- methoxy Base -7- (morpholinyl propoxyl group) quinazoline -4- base] oxygroup] phenyl] urea
1H-NMR(400MHz,DMSO-d6) δ 9.16 (br, 1H), 8.85 (br, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 7.73 (d, 1H), 7.62-7.68 (m, 1H), 7.55 (m, 1H), 7.51 (s, 1H), 7.38 (m, 2H), 7.22-7.31 (m, 4H), 7.19 (m, 2H), 7.09 (d, 1H), 6.72 (m, 1H), 6.41 (s, 1H), 5.45 (m, 1H), 4.19 (t, 2H), 3.92 (s, 3H), 3.60 (m, 4H), 3.06 (m, 2H), 2.81 (s, 3H), 2.37-2.51 (br, 6H), 2.04 (m, 2H)；ESI-MS[M+H](m/ z):768.2。
Embodiment 50.N1[the chloro- 4- of 2- [[2- (3- isopropylureido) -6- methoxyl group -7- [3- (1- pyrrolidinyl) third oxygen Base] quinolyl-4] oxygroup] phenyl]-N3[4- oxo -2- (2,3,4- trifluorophenyl) thiazoline -3- base] urea
1H-NMR(400MHz,DMSO-d6) δ 8.97 (br, 1H), 8.82 (br, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.46 (m, 1H), 7.39 (m, 2H), 7.22-7.28 (m, 2H), 7.16 (m, 2H), 6.43 (s, 1H), 5.86 (s, 1H), 4.21 (t, 2H), 3.91 (s, 3H), 3.85 (m, 1H), 3.59 (m, 4H), 2.80 (s, 3H), 2.36-2.49 (m, 5H), 2.01 (m, 2H), 1.13 (m, 6H)；ESI-MS[M+H](m/z):746.2.
The antitumor activity of product of the present invention
C-Met kinase inhibition assay
Test for measuring c-Met kinase activity is based on enzyme-linked immunosorbent assay.Concrete operations are:
At room temperature, on the coated plate of 0.25mg/mL PGT, embodiment compound, 50pM c-Met and 5 μM of ATP are existed Test (25mM MOPS, pH 7.4,5mM MgCl in buffer2,0.5raM MnCl2, 100 μM of sodium orthovanadates, 0.01% Triton X-100,1mM DTT, last DMSO concentration 1% (v/v)) incubate 20min.Reaction mixture is removed simultaneously by rinsing Phosphorylation is detected with the phosphotyrosine monoclonal antibody specific (PY20) of 0.2 μ g/mL conjugation horseradish peroxidase (HRP) Polymeric substrates.After 1M phosphoric acid color development stopping is added, pass through the substrate (TMB) of spectrophotometry quantitative chromogenic at 450nm Color.C-Met is swashed with the compound of embodiment 4~8,11,12,14,15,17~20,22~30,35~37,40~44,49 The inhibition data of enzyme are shown in Table 1.
The activity of extracorporeal suppression tumor cell proliferation
External inhibition human colon cancer cell HT-29 has been carried out to the compound of above formula I according to the invention and people is non-small thin The screening active ingredients of born of the same parents' lung cell A549.
1. the recovery of cell, passage and culture
(1) the recovery of cell: cryopreservation tube is taken out from refrigerator or liquid nitrogen, is put into 37 DEG C of water-baths and thaws rapidly.It draws and freezes It deposits liquid in pipe and 3mL culture solution is added in centrifuge tube, 800rpm is centrifuged 8min, collects cell, is incubated at containing 20% tire ox blood In clear culture solution, liquid is changed afterwards for 24 hours.
(2) the passage of cell: outwelling old culture solution in culture bottle, and 5mL digestive juice is added, is put into 37 DEG C, CO2In incubator, Culture bottle is patted after 2min, cell dissociation is got off, is poured into centrifuge tube, and 8mL or so is added to contain the culture solution of 10% fetal calf serum Terminate digestion.It is centrifuged 8min in 800rpm, discards supernatant liquid, is passed on after adding 4mL culture solution, piping and druming to mix in (1/4) ratio.
(3) the culture of cell: cell is put in 37 DEG C of CO after passage2It is cultivated in incubator, general cell can be used after passing for 2 generations In test.
2. buried plate
The cell pancreatin cultivated in culture bottle to cell log growth period is digested, with the culture for containing 10% serum Liquid terminates digestion, is fitted into centrifuge tube seals afterwards, and 800rpm is centrifuged 8min, abandons supernatant, is blown and beaten with the culture solution of 10% serum equal It is even to adjust concentration of cell suspension with culture solution again, it is added in 96 orifice plates, every 100 μ L of hole, about 1 × 104/ hole is placed in 37 DEG C, 5%CO2Incubator culture makes cell adherent for 24 hours, and microscopy cell is about 30% or so of every hole to be advisable.
3. dosing
Test medicine is first used 50 μ L DMSO be vortexed to mix, the culture solution that 10% serum Han 950 μ L is then added carries out It dilutes and mixes, from taking 50 μ L to be added in 24 orifice plate first row holes in the medical fluid diluted, then be added in the hole for having added medical fluid 950 μ L contain the culture solution of 10% serum, mix, and take 200 μ L that the second hole is added, and 800 μ containing 10% culture solution is added in the second hole L carries out 5 times of dilutions, and so on, one shares 24 orifice plates, and to be diluted to 5 various concentration drugs spare, will before prepared medicine Liquid is separately added into 96 orifice plates according to concentration sequence from low to high, and every hole adds 170 μ L, and every concentration adds 3 holes, and 170 μ L/ are added The hole of hole culture solution, the two rows of not cells in left and right is separately added into the maximum concentration of each adjacent drug, is placed in 37 DEG C, 5%CO2 72h is cultivated in incubator.
4. adding MTT solution
MTT is a kind of chemical reagent, chemical entitled 3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide, First microscopy observation blank well cell growing way is firmly thrown away in 96 orifice plates after there are nodeless mesh or other situations in drug concentration highest hole Liquid, every hole add 200 μ L physiological saline to clean, wash away left drug, throw away liquid.By pre-prepared 5%MTT liquid It is diluted to 0.5%MTT solution with culture solution, 96 orifice plates then are added according to 100 holes μ L/ in the MTT diluted, are placed in 37 DEG C, 5%CO24h is cultivated in incubator to promote its fully reacting.After 4h, liquid in 96 orifice plates is firmly thrown away, 100 μ L are added in every hole DMSO is placed on magnetic force oscillator and shakes 3min, dissolves crystal sufficiently, and double-wavelength method (490nm and 630nm) measures each hole Absorbance value.
5. calculated result
The half-inhibitory concentration IC of each drug is calculated with Bliss method according to absorbance50Value, Activity Results are shown in Table 1.
The anti tumor activity in vitro and c-Met inhibitory activity of 1. embodiment compound of table
From above-mentioned test result it can be clearly seen that the compound of the claimed general formula I of the present invention, has good Anti tumor activity in vitro.
The compound of formula of I of the present invention can be administered alone, but usually give 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 drug agent of such compound Type, such as the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, Illustrate its new opplication in pharmaceutical field.
Embodiment 51: tablet
It is pressed into after adding auxiliary material 20g to mix according to the general pressed disc method of pharmacy with the compound 10g of 4 structure of embodiment 100, every slice weight 300mg.
Embodiment 52: capsule
It is packed into after mixing auxiliary material 20g according to the requirement of pharmacy capsule with the compound 10g of 48 structure of embodiment Capsules, each capsule weight 300mg.
Embodiment 53: injection
Activated carbon adsorption is carried out, through 0.65 μm according to pharmacy conventional method with the compound 10g of 50 structure of embodiment After filtering with microporous membrane, hydro-acupuncture preparation is made in filling nitrogen gas tank, and every dress 2mL is filling 100 bottles total.
Embodiment 54: aerosol
With the compound 10g of 17 structure of embodiment, after the dissolution of appropriate propylene glycol, after distilled water and other spoke material are added, The clear solution of 500mL is made to obtain the final product.
Embodiment 55: suppository
With the compound 10g of 25 structure of embodiment, by finely ground addition glycerol it is appropriate, the glycerol melted is added after grinding well Gelatin, grinding uniformly, are poured into the model for having applied lubricant, and suppository 50 is made
Embodiment 56: film
With the compound 10g of 39 structure of embodiment, will be dissolved by heating after the stirrings such as polyvinyl alcohol, medicinal glycerin, water expansion, 80 mesh net filtrations, then 18 compound of embodiment is added to stirring and dissolving in filtrate, film applicator is film-made 100.
Embodiment 57: pill
Cryogenic liquid is instilled after mixing with matrix 50g heating fusings such as gelatin with the compound 10g of 49 structure of embodiment In paraffin, 1000 ball of dripping pill is made altogether.
Embodiment 58: externally-applied liniment
With the compound 10g of 32 structure of embodiment, mixes and grind with auxiliary materials 2.5g such as emulsifiers according to conventional dose method Mill, then plus distilled water to 200mL be made.
Embodiment 59: ointment
With the compound 10g of 21 structure of embodiment, ground well after finely ground with oleaginous bases 500g such as vaseline obtained.

Claims (6)

1.1,3- 2-substituted carbamide classes and thiourea derivatives, it is characterised in that: the general structure of the derivative is following I:
Wherein, X is O or S；
Y1For O or S；
Y2For O or S；
M is N or CH；
M is 0,1 or 2；
N is 0,1 or 2；
P is 0,1 or 2；
Q is 0,1 or 2；
T is 0 or 1；
R1For hydrogen, NH2、NHS(O)0-2R6、C1-C3Alkylamidoalkyl or NHCONHR6；
R6For C1-C4Alkyl or heteroaryl, wherein the heteroaryl is selected from the hetero atom containing 1-3 N, O or S, and heteroaryl The optional 0-5 hydrogen or halogen of base replaces；
R2、R3For hydrogen or halogen atom, hydroxyl, cyano, nitro, halogenated C1-C2Alkyl, halogenated C1-C2Alkoxy, C1-C2Alkoxy, C1-C2Alkyl or by 1-2 C1-C2Alkyl-substituted amino；
R4And R5It is identical or different, separately it is selected from C1-C3Alkyl or C3-C5Naphthenic base；
Or R4And R5The single heterocycle of 4-10 member or double heterocycles, the heterocycle are formed together with the nitrogen-atoms being connect with them In addition to R4And R5Outside the nitrogen-atoms of connection, the hetero atom of N, O and S are optionally selected from containing 0-2, in addition to R4And R5It is connected Outside nitrogen-atoms, the heterocycle optionally includes 0-2 carbon-carbon double bond, can be optionally by 0-3 identical or different C1-C3Alkyl, C1-C3Acyl group, halogenated C1-C3Alkyl, halogen or methylene replace.
2.1,3- 2-substituted carbamide classes and thiourea derivatives, it is characterised in that: the general structure of the derivative is following I:
Wherein, X is O or S；
Y1For O or S；
Y2For O or S；
M is N or CH；
M is 0,1 or 2；
N is 0,1 or 2；
P is 0,1 or 2；
Q is 0,1 or 2；
T is 0 or 1；
R1For hydrogen, NH2、NHS(O)0-2R6、C1-C3Alkylamidoalkyl or NHCONHR6；
R6For C1-C4Alkyl or heteroaryl, wherein the heteroaryl is selected from the hetero atom containing 1-3 N, O or S, and heteroaryl The optional 0-5 hydrogen or halogen of base replaces；
R2、R3For hydrogen or halogen atom, hydroxyl, cyano, nitro, halogenated C1-C2 alkyl, halogenated C1-C2 alkoxy, C1-C2 alcoxyl Base, C1-C2 alkyl or by the alkyl-substituted amino of 1-2 C1-C2；
R4And R5For methyl, ethyl or R4And R5Piperidyl, morpholinyl, piperazinyl, high piperazine base, piperidines is collectively formed with nitrogen-atoms Base, pyrrolidinyl, azelidinyl, thio-morpholinyl, thiazolinyl, piperidines bithiophene or hexahydroisoindoline.
3. 1,3- 2-substituted carbamide class according to claim 1 or 2 and thiourea derivatives can be used as active constituent and medicine Acceptable excipient on.
4. 1,3- 2-substituted carbamide class according to claim 1 or 2 and thiourea derivatives are in preparation prevention or treatment hyperplasia Application in property disease medicament.
5. 1,3- 2-substituted carbamide class according to claim 1 or 2 and thiourea derivatives are in preparation prevention or treating cancer Drug in application.
6. 1,3- 2-substituted carbamide class according to claim 5 and thiourea derivatives are in preparation prevention or treatment lung cancer, liver Cancer, gastric cancer, colon cancer, breast cancer drug in application.
CN201811051205.7A 2018-09-10 2018-09-10 1,3- 2-substituted carbamide class and thiourea derivatives and its application Pending CN109134451A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988110A (en) * 2019-01-22 2019-07-09 哈尔滨工业大学（威海） 4- phenoxyquinolines and sulfonyl urea compound, the intermediate for synthesizing the compound and its preparation method and application
CN111253385A (en) * 2020-02-12 2020-06-09 遵义医科大学珠海校区 Heterocyclic compound, preparation method and application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006081034A2 (en) * 2004-12-23 2006-08-03 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
CN1980918A (en) * 2004-06-04 2007-06-13 艾文蒂斯药品公司 Substituted indazoles, compositions containing the same, and the preparation and use thereof
WO2007076460A2 (en) * 2005-12-23 2007-07-05 Kalypsys, Inc. Substituted thiazole ureas useful as inhibitors of protein kinases
CN101260106A (en) * 2007-03-06 2008-09-10 中国药科大学 Raf kinase inhibitor, preparing method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1980918A (en) * 2004-06-04 2007-06-13 艾文蒂斯药品公司 Substituted indazoles, compositions containing the same, and the preparation and use thereof
WO2006081034A2 (en) * 2004-12-23 2006-08-03 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
WO2007076460A2 (en) * 2005-12-23 2007-07-05 Kalypsys, Inc. Substituted thiazole ureas useful as inhibitors of protein kinases
CN101260106A (en) * 2007-03-06 2008-09-10 中国药科大学 Raf kinase inhibitor, preparing method and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QI BAOHUI ET AL.: ""Identification of novel N1 -(2-aryl-1, 3-thiazolidin-4-one)-N3 -aryl ureas showing potent multi-tyrosine kinase inhibitory activities"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
QI. ZHANG ET AL.: ""A rapid and sensitive LC-MS/MS method for evaluation of the absolute oral bioavailability of a novel c-Met tyrosine kinase inhibitor QBH-196 in rats"", 《BIOMEDICAL CHROMATOGRAPHY》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988110A (en) * 2019-01-22 2019-07-09 哈尔滨工业大学（威海） 4- phenoxyquinolines and sulfonyl urea compound, the intermediate for synthesizing the compound and its preparation method and application
CN109988110B (en) * 2019-01-22 2022-07-01 威海海洋生物医药产业技术研究院有限公司 4-phenoxy quinoline sulfonylurea compound, intermediate for synthesizing the compound and its preparation method and use
CN111253385A (en) * 2020-02-12 2020-06-09 遵义医科大学珠海校区 Heterocyclic compound, preparation method and application
CN111253385B (en) * 2020-02-12 2023-11-24 遵义医科大学珠海校区 Heterocyclic compound, preparation method and application

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