CN110054584A - 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds and application - Google Patents
1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds and application Download PDFInfo
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
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Abstract
The invention belongs to pharmaceutical technology fields, are related to 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds and preparation method thereof and apply in the drug for preparing anti-tumor disease.The general structure of 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } carbamide compounds, its pro-drug and the pharmaceutical active metabolite and pharmaceutically acceptable salt is as follows: CH, N can be selected independently in X；R can be hydrogen, C1-C4 alkyl, the C1-C4 alkyl that halogen replaces, C1-C4 alkoxy, the C1-C4 alkoxy that halogen replaces, halogen；R can be single or multiple；R3、R4、R5The C1-C4 alkoxy that can replace independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, the C1-C4 alkoxy that C1-C4 alkoxy replaces.The simple synthetic method of the compound of the present invention is suitable for industrialized production, and it is a kind of new type antineoplastic medicine that biological activity test, which shows that such compound has anti-tumor activity,.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to 1- aryl -3- { 4- [(pyridine -2- ylmethyl) sulfenyl] phenyl } ureas
Compound and preparation method thereof further relates to it as BRaf the kinases, (Vascular of vascular endothelial growth factor receptor -2
Endothelial growth factor receptor-2, VEGFR-2), platelet derived growth factor receptor-β
(Platelet-derived growth factor receptors- β, PDGFR- β) and T-LAK cell source protein kinase (T-
LAK cell-originated protein kinase, TOPK) inhibitor application.
Background technique
In recent years, with constantly illustrating for Tumorigenesis and constantly discovering for antitumor action target spot, multiple target point
Tumor signal transduction is inhibited to become the important directions of tumour medicine exploitation.Relative to single target drug and a variety of single target drug connection
For, multiple target point drug has more superiority: can avoid generating drug interaction, reduces adverse reaction, therapeutic effect
Comprehensively etc..In various molecular targets, protein tyrosine kinase (protein tyrosine kinase, PTK) is current effect
One of anti-tumor drug target spot that is obvious and having a extensive future.
PTK can be divided into receptor PTK and non-receptor PTK according to its structure.Receptor PTK usually have one can with it is specific
The extracellular domain of ligand binding, a transmembrane region and a property of can choose and Binding Capacity and the cell by its phosphorylation
Interior kinase domain.When corresponding ligands specific is in conjunction with receptor PTK extracellular domain, receptor PTK eucaryotic cell structure changes
Become, form dimer, phosphorylation occurs in conjunction with ATP for intracellular kinase domain later, and then generates a series of enzyme catalysis.
Common receptor PTK has: (1) EGF-R ELISA (epidermal growth factor receptor, EGFR；
ErbB-1；HER1) family, including ErbB-1 (EGFR), ErbB-2 (HER-2), ErbB-3 (HER-3) and ErbB-4 (HER-4),
This receptoroid height is expressed in epithelial cell tumour；(2) platelet derived growth factor receptor (platelet derived
Growth factor receptor, PDGFR) family, including PDGFR α, PDGFR β, colony-stimulating factor -1 receptor (colony
Stimulating factor 1 receptor, CSF-1R) and stem cell factor receptor (stem cell growth
Factor receptor, SCFR；C-Kit), PDGF can act on endothelial cell and interstitial cell by a variety of effects, promote blood
Pipe is formed；(3) insulin receptor (insulin receptor, IR) family, including insulin receptor, insulin-like growth factor
Receptor (insulin-like growth factor receptor, IGFR) and insulin-related receptor (insulin
Related receptor, IRR), the often high expression in hematological system tumor of this receptoroid；(4) vascular endothelial cell growth because
Sub- receptor (vascular endothelial growth factor receptor, VEGFR) family, including VEGFR-1
(FLT-1), VEGFR-2 (FLK-1) and VEGFR-3 (FLT-4), VEGF are over-expressed in many tumor tissues, such as liver cancer, lung
Cancer, breast cancer etc., and play a crucial role in tumor angiogenesis；(5) fibroblast growth factor acceptor
(fibroblast growth factor receptor, FGFR) family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-
4, FGFR be a kind of multiple effect growth factor for being adjustable cell division, proliferation, migration and differentiation, this receptoroid is in angiogenesis side
Face plays an important role.In addition to the above common receptor PTK, there are also tropomyosin receptor kinase (the orginal myosin
Receptor kinase, TRK) family, hepatocyte growth factor receptor (hepatocyte growth factor
Receptor, HGFR) family and leucocyte tyrosine kinase (1eukocyte tyrosine kinase, LTK) family etc., it
Tumour cell signal transmitting, transfer and in terms of also play an important role.
The non-typically no extracellular structure of receptor PTK, they typically last for or are temporarily positioned in endochylema, or on the inside of cell membrane
In conjunction with transmembrane receptor, so also known as endochylema type PTK, passes through cytokine receptor, T cell receptor and other signal paths
Signal transduction functionality is executed, mainly includes the families such as SRC, ABL, JAK, ACK, CSK, FAK, FRK, TEC and SYK.
Currently, the multiple receptor tyrosine kinases inhibitor listed mainly has:
Imatinib mesylate (imatinib mesylate, Gleevec): imatinib mesylate belongs to 2- phenylamino
Yl pyrimidines class compound is the very strong tyrosine kinase inhibitor of a species specificity.The inhibition bcr-abl of its property of can choose,
The tyrosine kinase such as C-kit and platelet derived growth factor receptor (PDGFR), antitumor mechanism are as ATP competitiveness
Inhibitor blocks the phosphorylation of tyrosine kinase, inhibits bcr-abl expression.To prevent the proliferation of cell and tumour from being formed.
Sorafenib (sorafenib, Nexavar): Sorafenib is first oral multiple target point tyrosine kinase suppression
Preparation, structure are a kind of double aryl urea compounds.Clinical use is the toluene fulfonate of Sorafenib.It has dual
Antitumor action.On the one hand by inhibiting RAF/MEK/ERK signal transduction pathway directly to inhibit the growth of tumour, on the other hand
By inhibiting vascular endothelial growth factor and platelet derived growth factor receptor to block tumor neovasculature formation, cut off
The nutrition supply of tumour cell and achieve the purpose that inhibit tumour.
Sutent (sunitinib, Sutent): Sutent is that the most targeting of the action target spot that is currently known is anti-swollen
One of tumor medicine, the anti-tumor activity with wide spectrum.Be vascular endothelial growth factor receptor, platelet derived growth factor by
The inhibitor of body, stem cell factor receptor, tyrosine kinase etc..
Lapatinib (lapatinib, Tykerb): Lapatinib is double target spot tyrosine-kinases for EGFR/ErbB-2
Enzyme inhibitor.Lapatinib is 4- anilinoquinazoline class kinase inhibitor, is existed in the form of toluene fulfonate hyrate.It
It is reversible multiple receptor tyrosine kinases inhibitor.Its mechanism of action is to inhibit intracellular EGFR (ErbB-1)/HERE
(ErbB-2) the site ATP prevents tumour cell phosphorylation and activation, same by EGFR (ErbB-1)/HERE (ErbB-2)
Matter and heterodimer block the hyperplasia for lowering signal to inhibit breast cancer cell, apoptosis-induced to reach antitumor mesh
's.
Nilotinib (nilotinib, Tasigna): nilotinib is aniline pyrimidine analog derivative, and mechanism of action is choosing
The inhibition tyrosine kinase Bcr-Abl of selecting property, and to stem cell factor receptor Kit and platelet derived growth factor receptor
(PDGFR) kinases has antagonism.
Dasatinib (dasatinib, Sprycel): Dasatinib is for Buddhist nun's class ABL and SRC kinases double inhibitor.
Pazopanib (pazopanib, votrient): pazopanib is the exploitation of GlaxoSmithKline company, Britain
A kind of selectivity multiple target point TKI, there is more kinds of PDGFR α, PDGFR β, VEGFR-1, VEGFR-2, VEGFR-3 and C-Kit PTK
Inhibiting effect.
The research and development of multiple receptor tyrosine kinases inhibitor drug are the main research hotspots of current anti-tumor drug
One of.The treatment for being found to be tumor patient of this kind of medicine brings new selection and light, grinds to open anti-tumor drug
The new world studied carefully.Multiple receptor tyrosine kinases inhibitor has specificity and validity compared with traditional anti-tumor drug.Together
When to gastrointestinal reaction and hematology adverse reaction is few the advantages that, therefore it has more extensive development prospect.
In addition, recent studies suggest that TOPK is the killer T cell (lymphokine- from activated form Lymphokine
Activated killer T cells, T-LAK cells) cDNA library in the new silk-threonine egg of one kind that identifies
White kinases, scientist found in HeLa cell cdna library one can be with the kinases PBK (PDZ- in conjunction with the region PDZ2 of hDig
Bindingkinase, PBK) it with TOPK is same molecule, therefore also referred to as PBK/TOPK.T-cell-originated
Protein kinase (TOPK) is expressed in high in many malignant tumours, such as lung cancer, breast cancer, lymthoma, bladder cancer, knot
Intestinal cancer, gastric cancer, liver cancer, cancer of pancreas, prostate cancer, oophoroma etc., and TOPK expression degree is related to tumor prognosis, it is especially newborn
Gland cancer and lung cancer, TOPK expression is higher, and prognosis is poorer, but TOPK expression is very low in the normal tissue, and only in testis and
It is expressed in thymus gland.So TOPK becomes the novel targets of oncotherapy, and there is presently no on the drug specifically for the target spot
City, therefore the inhibitor that can be specifically bound with TOPK becomes the research hotspot of new type antineoplastic medicine.
Summary of the invention
It is living that technical problem solved by the invention is to provide one kind compound shown in formula I, its pro-drug and drug
Property metabolin and its pharmaceutically acceptable salt, and provide it and prevented and treated and BRaf kinases, blood vessel endothelium in preparation
Growth factor receptors -2 (Vascular endothelial growth factor receptor-2, VEGFR-2), blood platelet
Derived growth factor receptor-β (Platelet-derived growth factor receptors- β, PDGFR- β) and T-LAK
The drug of the relevant disease of cell source protein kinase (T-LAK cell-originated protein kinase, TOPK) imbalance
In application.
Wherein
X can be selected from CH, N；
R can be hydrogen, C1-C4 alkyl, the C1-C4 alkyl that halogen replaces, C1-C4 alkoxy, the C1-C4 alkane that halogen replaces
Oxygroup, halogen；R can be single or multiple；
R3、R4、R5The C1-C4 alkoxy that can replace independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen,
The C1-C4 alkoxy that C1-C4 alkoxy replaces.
Further, the present invention preferably have following compound of formula I, its pro-drug and pharmaceutical active metabolite and
Its pharmaceutically acceptable salt:
CH, N can be selected independently in X；
R can be hydrogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, the chloro- 3- trifluoromethyl of 4-, 3,5- difluoros,
Fluorine, chlorine, bromine；R can be single or multiple；
R3、R4、R5Hydrogen, methyl, 2,2,2- trifluoro ethoxies, methoxyl group, 3- methoxy propoxy can be selected from.
Further, the preferably following compound of the present invention:
1-4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- phenylurea；
1- 4- chlorphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- (4- bromophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base]
Methyl } sulfenyl } phenyl } urea；
1- (3,5- difluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulphur
Base } phenyl } urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [4- (trifluoro
Methoxyl group) phenyl] urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [3- (trifluoro
Methyl) phenyl] urea；
1- (4- fluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- (4- methoxyphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulphur
Base } phenyl } urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- (4- methyl
Pyridine -2- base) urea；
1- (6- bromopyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulphur
Base } phenyl } urea；
1- (5- chloropyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulphur
Base } phenyl } urea；
1- (the chloro- 4- picoline -3- base of 2-) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base]
Methyl } sulfenyl } phenyl } urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；
1- (4- chlorphenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- (4- bromophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } benzene
Base } urea；
1- (3,5- difluorophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoromethoxy) phenyl]
Urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [3- (trifluoromethyl) phenyl] urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- fluorophenyl) urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl) urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl]
Sulfenyl } phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoro methoxy
Base) phenyl] urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；
1- (4- chlorphenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } 3- [3- (trifluoromethyl) benzene
Base] urea；
1- (4- fluorophenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl)
Urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2-
Base] methyl } sulfenyl } phenyl } urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [4- (three
Fluorine methoxyl group) phenyl] urea；
1- (3,5- difluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulphur
Base } phenyl } urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- phenyl
Urea；1- (4- chlorphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl }
Urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [3- (three
Methyl fluoride) phenyl] urea；
1- (4- fluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl }
Phenyl } urea；
1- (4- methoxyphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulphur
Base } phenyl } urea；
1- (4- bromophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl }
Phenyl } urea.
" pharmaceutically acceptable salt " refers to the biopotency and property for remaining compound of formula I, and has with suitable non-toxic
The conventional acid addition salts or base addition salts that machine or inorganic acid or organic or inorganic alkali are formed.The example of acid-addition salts includes malic acid
Salt, maleate, sulfanilate, hydrochloride, acetate, adipate, alginates, aspartate, benzene first
Hydrochlorate, benzene sulfonate, tosilate, disulfate, butyrate, citrate, camphor hydrochlorate, camsilate, ring penta
Propionate, digluconate, lauryl sulfate, esilate, fumarate, gluceptate, glycerophosphate, half
Sulfate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2- isethionate, lactate, maleic acid
Salt, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectinic acid salt, persulfate, 3- phenyl
Propionate, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, toluene fulfonate
With undecylate etc..Alkali salt includes ammonium salt, alkali metal salt, such as sodium and sylvite, alkali salt, such as calcium and magnesium salts, organic
The salt of alkali, such as dicyclohexyl amine salt, the salt of N- methyl-D-glucamine salt and amino acid, such as arginine, lysine etc., and
And Basic nitrogen-containing groups can be quaternized with such reagent, such as elementary alkyl halide, such as methyl, ethyl, propyl and fourth
The chlorine of base, bromine and iodide；Dialkyl sulfate, such as dimethyl suflfate, diethylester, dibutyl ester and diamyl ester；Long chain halide,
Such as decyl, lauryl, the chlorine of myristyl and stearyl, bromine and iodide；Aralkyl halide, such as benzyl and phenethyl
Bromide etc..It is preferred for generating the acid of acid-addition salts including hydrochloric acid and acetic acid.
" pharmaceutically acceptable " such as pharmaceutically acceptable carrier, excipient, pro-drug, referring to can pharmacologically connect
It is receiving and substantially non-toxic to the patient of administration particular compound.
" pharmaceutical active metabolin " refers to the metabolite of pharmaceutically acceptable and effective compound of formula I.
The present invention also relates to the Pharmaceutical composition for inhibiting tyrosine kinase and T-LAK cell source protein kinase, the compositions
Contain compound of formula I or derivative or its pharmaceutically useful acid-addition salts and pharmaceutically useful carrier.
The term " halogen " applied in the present invention includes fluorine, chlorine, bromine or iodine.
The compounds of this invention can be taken by different methods to patient, such as oral with capsule or tablet, with nothing
Bacterium solution or suspensions administration, and in some cases, it can be injected intravenously with solution form.It can will be of the invention
Free alkali compound is prepared and is taken with its pharmaceutically useful acid addition salt form thereof.
BRaf kinases of the compound of the present invention as brand new type, vascular endothelial growth factor receptor -2
(Vascular endothelial growth factor receptor-2, VEGFR-2) and platelet derived growth factor by
Body-β (Platelet-derived growth factor receptors- β, PDGFR- β) and T-LAK cell source protein swash
It is novel to have structure type, and can make for enzyme (T-LAK cell-originated protein kinase, TOPK) inhibitor
The features such as multiple target spots, can be used to treat or prevent and BRaf the kinases, (Vascular of vascular endothelial growth factor receptor -2
Endothelial growth factor receptor-2, VEGFR-2) and platelet derived growth factor receptor-β
(Platelet-derived growth factor receptors- β, PDGFR- β) and T-LAK cell source protein kinase
(T-LAK cell-originated protein kinase, TOPK) relevant tumor disease such as Small Cell Lung Cancer, squamous carcinoma, gland
Cancer, large cell carcinoma, colorectal cancer, breast cancer, oophoroma, clear-cell carcinoma, before there are good application value and development and application
Scape.
Specific embodiment
By taking X is CH as an example, following process summarises the preparation step for preparing the compounds of this invention.
Process
Wherein, R, R3、R4、R5As previously described.
The present invention is described in detail with following examples.However, it should be understood that following realities that the present invention is not limited to specifically describe
Example.
Embodiment 1:1-4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3-
The preparation of phenylurea (compound Z01)
The preparation of step A:4- (3- methoxy propoxy) -3- methyl -2- { [(4- nitrobenzophenone) is thio] methyl } pyridine
4- nitro thiophenol (15.52g, 0.10mol) is added in 500mL eggplant-shape bottle, 2- chloromethyl -3- methyl -4- (first
Oxygen propoxyl group) pyridine hydrochloride (26.62g, 0.10mol) and dehydrated alcohol (200mL).3mol/L sodium hydroxide is added dropwise at room temperature
Aqueous solution (100mL).After being added dropwise, 6h is reacted at room temperature.After reaction, part ethyl alcohol is removed under reduced pressure, in residue
200mL water is added, a large amount of white solids are precipitated, filters, filter cake is washed with water, and air drying is placed, white solid 31.81g is obtained,
Yield 91.3%.Product is directly used in next step without being further purified.
The preparation of step B:4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } aniline
By 4- (3- methoxy propoxy) -3- methyl -2- { [(4- nitrobenzophenone) is thio] methyl } pyridine (19.22g,
0.05mol), 10% palladium carbon (1.00g) and anhydrous methanol (100mL) are placed in 250mL eggplant-shape bottle, and hydrogen is passed through in system, warp
After gas displacement, it is stirred to react 5h under room temperature and normal pressure, after fully reacting, pads suction filtered through kieselguhr, filtrate concentration obtains faint yellow
Grease 15.14g, yield 95.1%.Product is not purified to be directly used in next step.
Step C:1-4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- benzene
The preparation of base urea (compound Z01)
Phenyl isocyanate (0.12g, 1mmol) and methylene chloride (10mL) are added in 100mL eggplant-shape bottle, it at room temperature will be upper
Walk 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } aniline (0.32g, 1mmol) obtained
Dichloromethane solution (10mL) is added drop-wise in above-mentioned solution, after being added dropwise, continues that 2h is stirred at room temperature, and after fully reacting, is added
50mL water stirs 5min, separates organic layer, and organic phase saturated common salt water washing, anhydrous magnesium sulfate is dry, filters, is evaporated off molten
Agent, residue obtain white solid 0.24g through column chromatographic purifying (methylene chloride: methanol=60:1), yield 54.5%, m.p.:
105.2-106.8℃；1H NMR(400MHz,DMSO-d6) δ 8.74 (s, 1H), 8.69 (s, 1H), 8.17 (d, J=5.6Hz,
1H), 7.42 (dd, J=17.9,8.1Hz, 4H), 7.29 (dd, J=17.7,8.2Hz, 4H), 6.97 (t, J=7.4Hz, 1H),
6.90 (d, J=5.7Hz, 1H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.12
(s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z438.4 [M+H]+；460.2[M+Na]+。
Embodiment 2:1- 4- chlorphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl }
Sulfenyl } phenyl urea (compound Z02) preparation
Referring to the preparation method of embodiment 1, white solid 0.16g is obtained, yield 49%, m.p.:191.7-192.5 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.83 (s, 1H), 8.77 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 7.52-7.44 (m,
2H), 7.44-7.37 (m, 2H), 7.37-7.28 (m, 4H), 6.90 (d, J=5.7Hz, 1H), 4.22 (s, 2H), 4.08 (t, J=
6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.12 (s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-
MS:m/z472.4,474.0,475.1,476.0[M+H]+。
Embodiment 3:1- (4- bromophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl }
Sulfenyl } phenyl urea (compound Z03) preparation
Referring to the preparation method of embodiment 1, white solid 0.07g is obtained, yield 20%, m.p.:177.9-178.5 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.83 (s, 1H), 8.77 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 7.49-7.36 (m,
6H), 7.32 (d, J=8.7Hz, 2H), 6.90 (d, J=5.7Hz, 1H), 4.22 (s, 2H), 4.08 (t, J=6.2Hz, 2H),
3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.12 (s, 3H), 1.97 (p, J=6.3Hz, 3H) .ESI-MS:m/
z516.0,518.0[M+H]+。
Embodiment 4:1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [4- (3- methoxy propoxy) -3- methyl pyrrole
Pyridine -2- base] methyl sulfenyl phenyl urea (compound Z04) preparation
Referring to the preparation method of embodiment 1, white solid 0.11g is obtained, yield 30%, m.p.:136.0-137.0 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.16 (s, 1H), 8.89 (s, 1H), 8.16 (d, J=5.6Hz, 1H), 8.10 (d, J=
2.2Hz, 1H), 7.64-7.60 (m, 2H), 7.45-7.37 (m, 2H), 7.36-7.29 (m, 2H), 6.89 (d, J=5.7Hz,
1H), 4.23 (s, 2H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.13 (s, 3H),
1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z 540.2 [M+H]+,562.0[M+Na]+。
Embodiment 5:1- (3,5- difluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base]
Methyl } sulfenyl phenyl urea (compound Z05) preparation
Referring to the preparation method of embodiment 1, white solid 0.17g is obtained, yield 41%, m.p.:138.9-140.0 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.09 (s, 1H), 8.89 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 7.40 (d, J=
8.7Hz, 2H), 7.33 (d, J=8.7Hz, 2H), 7.22-7.14 (m, 2H), 6.90 (d, J=5.7Hz, 1H), 6.79 (tt, J=
9.5,2.4Hz, 1H), 4.23 (s, 2H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H),
2.13 (s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z 474.2 [M+H]+,496.3[M+Na]+。
Embodiment 6:1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3-
The preparation of [4- (trifluoromethoxy) phenyl] urea (compound Z06)
Referring to the preparation method of embodiment 1, white solid 0.25g, yield 61.0%, m.p.:132.0-133.7 are obtained
℃；1H NMR(400MHz,DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.16 (d, J=5.6Hz, 1H), 7.59-7.51
(m, 2H), 7.40 (d, J=8.7Hz, 2H), 7.30 (dd, J=14.1,8.6Hz, 4H), 6.89 (d, J=5.7Hz, 1H), 4.22
(s, 2H), 4.09 (t, J=6.3Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.13 (s, 3H), 1.97 (p, J
=6.3Hz, 2H) .ESI-MS:m/z522.3 [M+H]+。
Embodiment 7:1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3-
The preparation of [3- (trifluoromethyl) phenyl] urea (compound Z07)
Referring to the preparation method of embodiment 1, white solid 0.20g is obtained, yield 52%, m.p.:136.1-137.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.05 (s, 1H), 8.84 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 8.00 (d, J=
2.3Hz, 1H), 7.60-7.47 (m, 2H), 7.41 (d, J=8.7Hz, 2H), 7.32 (dd, J=8.0,5.8Hz, 3H), 6.90
(d, J=5.7Hz, 1H), 4.23 (s, 2H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s,
3H), 2.13 (s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z 506.3 [M+H]+。
Embodiment 8:1- (4- fluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl }
Sulfenyl } phenyl urea (compound Z08) preparation
Referring to the preparation method of embodiment 1, white solid 0.14g is obtained, yield 39%, m.p.:131.6-132.8 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.73 (d, J=6.6Hz, 2H), 8.18 (d, J=5.7Hz, 1H), 7.49-7.35 (m,
4H), 7.34-7.27 (m, 2H), 7.16-7.07 (m, 2H), 6.92 (d, J=5.7Hz, 1H), 4.22 (s, 2H), 4.10 (t, J=
6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.12 (s, 3H), 1.98 (p, J=6.2Hz, 2H) .ESI-
MS:m/z456.3[M+H]+。
Embodiment 9:1- (4- methoxyphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base]
Methyl } sulfenyl phenyl urea (compound Z09) preparation
Referring to the preparation method of embodiment 1, white solid 0.27g is obtained, yield 64%, m.p.:144.8-146.6 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.16 (d, J=5.6Hz, 1H), 7.43-7.26 (m,
6H), 6.92-6.82 (m, 3H), 4.21 (s, 2H), 4.08 (t, J=6.2Hz, 2H), 3.71 (s, 3H), 3.48 (t, J=
6.2Hz, 2H), 2.12 (s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z 468.4 [M+H]+,460.2[M+Na]+。
Embodiment 10:1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -
The preparation of 3- (4- picoline -2- base) urea (compound Z10)
Referring to the preparation method of embodiment 1, white solid 0.21g is obtained, yield 58%, m.p.:125.0-126.0 DEG C；1H NMR(400MHz,DMSO-d6) δ 10.72 (s, 1H), 9.40 (s, 1H), 8.15 (dd, J=12.2,5.4Hz, 2H), 7.51-
7.43 (m, 2H), 7.37-7.30 (m, 2H), 7.27 (s, 1H), 6.89 (d, J=5.7Hz, 1H), 6.87-6.83 (m, 1H),
4.23 (s, 2H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=6.3Hz, 2H), 3.24 (s, 3H), 2.29 (s, 3H), 2.13
(s, 3H), 1.97 (p, J=6.3Hz, 2H) .ESI-MS:m/z 453.2 [M+H]+。
Embodiment 11:1- (6- bromopyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2-
Base] methyl sulfenyl phenyl urea (compound Z11) preparation
Referring to the preparation method of embodiment 1, white solid 0.07g is obtained, yield 43%, m.p.:146.0-147.3 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.59 (s, 1H), 9.37 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 7.80-7.65 (m,
2H), 7.44-7.31 (m, 4H), 7.24 (d, J=7.5Hz, 1H), 6.90 (d, J=5.7Hz, 1H), 4.24 (s, 2H), 4.09
(t, J=6.2Hz, 2H), 3.48 (t, J=6.2Hz, 2H), 3.25 (s, 3H), 2.13 (s, 3H), 1.97 (p, J=6.0Hz,
2H).ESI-MS:m/z517.3,519.0[M+H]+,539.0,541.0[M+Na]+。
Embodiment 12:1- (5- chloropyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2-
Base] methyl sulfenyl phenyl urea (compound Z12) preparation
Referring to the preparation method of embodiment 1, white solid 0.22g is obtained, yield 53%, m.p.:155.6-156.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.86 (s, 1H), 9.49 (s, 1H), 8.32 (d, J=2.6Hz, 1H), 8.17 (d, J=
5.6Hz, 1H), 7.86 (dd, J=9.0,2.7Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 7.48-7.40 (m, 2H), 7.38-
7.31 (m, 2H), 6.90 (d, J=5.7Hz, 1H), 4.24 (s, 2H), 4.09 (t, J=6.2Hz, 2H), 3.48 (t, J=
6.2Hz, 2H), 3.24 (s, 3H), 2.13 (s, 3H), 1.97 (p, J=6.2Hz, 2H) .ESI-MS:m/z 473.3 [M+H]+,
495.2[M+Na]+。
Embodiment 13:1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- phenylurea (chemical combination
Object Z13) preparation
Referring to the preparation method of embodiment 1, white solid 0.15g is obtained, yield 37%, m.p.:127.7-128.5 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.70 (d, J=17.0Hz, 2H), 8.12 (d, J=5.5Hz, 1H), 7.42 (ddd, J=
15.5,7.7,1.8Hz,4H),7.36-7.23(m,4H),7.07-6.93(m,2H),4.17(s,2H),3.87(s,3H),3.74
(s,3H).ESI-MS:m/z396.3[M+H]+；418.2[M+Na]+。
Embodiment 14:1- (4- chlorphenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea
The preparation of (compound Z14)
Referring to the preparation method of embodiment 1, white solid 0.11g is obtained, yield 34%, m.p.:141.7-142.0 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.83 (s, 1H), 8.76 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 7.48 (d, J=
8.5Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.32 (d, J=8.5Hz, 4H), 7.03 (d, J=5.5Hz, 1H), 4.17 (s,
2H),3.87(s,3H),3.74(s,3H).ESI-MS:m/z430.6[M+H]+；452.1[M+Na]+。
Embodiment 15:1- (4- bromophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea
The preparation of (compound Z15)
Referring to the preparation method of embodiment 1, white solid 0.12g is obtained, yield 36%, m.p.:179.2-180.11 DEG C
；1H NMR(400MHz,DMSO-d6) δ 8.83 (s, 1H), 8.76 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 7.49-7.37 (m,
6H), 7.37-7.29 (m, 2H), 7.03 (d, J=5.6Hz, 1H), 4.17 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H) .ESI-
MS:m/z476.0,478.1[M+H]+,496.2,498.1[M+Na]+。
Embodiment 16:1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) first
Base] sulfenyl phenyl urea (compound Z16) preparation
Referring to the preparation method of embodiment 1, white solid 0.14g is obtained, yield 43%, m.p.:188.1-189.2 DEG C；1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.88(s,1H),8.14-8.07(m,2H),7.67-7.57(m,2H),
7.46-7.38 (m, 2H), 7.38-7.30 (m, 2H), 7.03 (d, J=5.5Hz, 1H), 4.17 (s, 2H), 3.88 (s, 3H),
3.74(s,3H).ESI-MS:m/z 498.2,500.2[M+H]+。
Embodiment 17:1- (3,5- difluorophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } benzene
Base } urea (compound Z17) preparation
Referring to the preparation method of embodiment 1, white solid 0.12g is obtained, yield 34%, m.p.:55.6-157.0 DEG C；1H
NMR(400MHz,DMSO-d6) δ 9.09 (s, 1H), 8.88 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 7.44-7.30 (m,
4H), 7.24-7.13 (m, 2H), 7.03 (d, J=5.6Hz, 1H), 6.79 (tt, J=9.4,2.4Hz, 1H), 4.17 (s, 2H),
3.87(s,3H),3.74(s,3H).ESI-MS:m/z 432.2[M+H]+。
Embodiment 18:1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoro methoxy
Base) phenyl] urea (compound Z18) preparation
Referring to the preparation method of embodiment 1, white solid 0.11g is obtained, yield 32%, m.p.:162.0-163.6 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.91 (s, 1H), 8.79 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 7.59-7.50 (m,
2H), 7.44-7.37 (m, 2H), 7.37-7.25 (m, 4H), 7.03 (d, J=5.5Hz, 1H), 4.17 (s, 2H), 3.87 (s,
3H),3.74(s,3H).ESI-MS:m/z 480.2[M+H]+,502.2[M+Na]+。
Embodiment 19:1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [3- (fluoroform
Base) phenyl] urea (compound Z19) preparation
Referring to the preparation method of embodiment 1, white solid 0.15g is obtained, yield 43%, m.p.:198.4-199.8 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 8.83 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 8.01 (d, J=
1.9Hz, 1H), 7.60-7.46 (m, 2H), 7.43 (d, J=2.0Hz, 1H), 7.41-7.28 (m, 4H), 7.03 (d, J=
5.6Hz,1H),4.17(s,2H),3.88(s,3H),3.75(s,3H).ESI-MS:m/z 464.2[M+H]+。
Embodiment 20:1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- fluorophenyl) urea
The preparation of (compound Z20)
Referring to the preparation method of embodiment 1, white solid 0.14g is obtained, yield 37%, m.p.:143.2-144.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.69 (d, J=1.5Hz, 2H), 8.11 (d, J=5.5Hz, 1H), 7.50-7.35 (m,
4H), 7.35-7.28 (m, 2H), 7.12 (t, J=8.9Hz, 2H), 7.03 (d, J=5.5Hz, 1H), 4.16 (s, 2H), 3.87
(s,3H),3.74(s,3H).ESI-MS:m/z 414.3[M+H]+,436.2[M+Na]+。
Embodiment 21:1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxybenzene
Base) urea (compound Z21) preparation
Referring to the preparation method of embodiment 1, white solid 0.08g is obtained, yield 25%, m.p.:179.0-180.6 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.62 (s, 1H), 8.46 (s, 1H), 8.11 (d, J=5.5Hz, 1H), 7.43-7.26 (m,
6H), 7.03 (d, J=5.5Hz, 1H), 6.91-6.82 (m, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.71
(s,3H).ESI-MS:m/z 426.3[M+H]+。
Embodiment 22:1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(4- methoxyl group -3,5- lutidines -2-
Base) methyl] sulfenyl phenyl urea (compound Z22) preparation
Referring to the preparation method of embodiment 1, white solid 0.36g is obtained, yield 72%, m.p.:152.3-153.1 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.18 (s, 1H), 8.91 (s, 1H), 8.14-8.07 (m, 2H), 7.63 (d, J=2.9Hz,
2H), 7.41 (d, J=8.7Hz, 2H), 7.36-7.28 (m, 2H), 4.22 (s, 2H), 3.70 (s, 3H), 2.19 (s, 3H), 2.18
(s,3H).ESI-MS:m/z 496.1,497.1,498.1,499.1[M+H]+。
Embodiment 23:1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- [4-
(trifluoromethoxy) phenyl] urea (compound Z23) preparation
Referring to the preparation method of embodiment 1, white solid 0.24g is obtained, yield 54%, m.p.:181.1-182.8 DEG C；1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.79(s,1H),8.11(s,1H),7.59-7.50(m,2H),7.44-
7.36 (m, 2H), 7.30 (dd, J=10.3,8.4Hz, 4H), 4.21 (s, 2H), 3.70 (s, 3H), 2.18 (d, J=1.9Hz,
6H).ESI-MS:m/z 478.3[M+H]+。
Embodiment 24:1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- phenyl
The preparation of urea (compound Z24)
Referring to the preparation method of embodiment 1, white solid 0.31g is obtained, yield 78%, m.p.:188.1-188.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.72 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 7.42 (ddd, J=17.9,7.6,
1.7Hz, 4H), 7.34-7.23 (m, 4H), 6.97 (t, J=7.4Hz, 1H), 4.21 (s, 2H), 3.70 (s, 3H), 2.18 (s,
6H).ESI-MS:m/z394.6[M+H]+,416.3[M+Na]+。
Embodiment 25:1- (4- chlorphenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl }
Phenyl } urea (compound Z25) preparation
Referring to the preparation method of embodiment 1, white solid 0.31g is obtained, yield 78%, m.p.:206.8-208.2 DEG C；1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.75(s,1H),8.11(s,1H),7.52-7.43(m,2H),7.43-
7.37 (m, 2H), 7.37-7.27 (m, 4H), 4.21 (s, 2H), 3.70 (s, 3H), 2.18 (d, J=1.5Hz, 6H) .ESI-MS:
m/z 428.7[M+H]+。
Embodiment 26:1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } 3- [3- (three
Methyl fluoride) phenyl] urea (compound Z26) preparation
Referring to the preparation method of embodiment 1, white solid 0.26g is obtained, yield 64%, m.p.:156.9-159.1 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.04 (s, 1H), 8.84 (s, 1H), 8.12 (s, 1H), 8.00 (d, J=2.0Hz, 1H),
7.61-7.47 (m, 2H), 7.46-7.37 (m, 2H), 7.31 (dd, J=8.8,2.4Hz, 3H), 4.22 (s, 2H), 3.70 (s,
3H),2.19(s,3H),2.18(s,3H).ESI-MS:m/z 462.3[M+H]+。
Embodiment 27:1- (4- fluorophenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl }
Phenyl } urea (compound Z27) preparation
Referring to the preparation method of embodiment 1, white solid 0.22g is obtained, yield 47%, m.p.:186.3-187.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.71 (d, J=5.9Hz, 2H), 8.11 (s, 1H), 7.47-7.43 (m, 2H), 7.41-
7.37 (m, 2H), 7.33-7.26 (m, 2H), 7.12 (t, J=8.9Hz, 2H), 4.20 (s, 2H), 3.70 (s, 3H), 2.18 (s,
6H).ESI-MS:m/z 412.3[M+H]+。
Embodiment 28:1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- (4- first
Phenyl) urea (compound Z28) preparation
Referring to the preparation method of embodiment 1, white solid 0.19g is obtained, yield 48%, m.p.:171.4-172.6 DEG C；1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.50(s,1H),8.15(s,1H),7.40-7.24(m,6H),6.87
(dq, J=10.2,3.5,2.8Hz, 2H), 4.21 (s, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 2.20 (s, 3H), 2.17 (s,
3H).ESI-MS:m/z 424.3[M+H]+。
Embodiment 29:1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [3- methyl -4- (2,2,2- trifluoroethoxy
Base) pyridine -2- base] methyl sulfenyl phenyl urea (compound Z29) preparation
Referring to the preparation method of embodiment 1, white solid 0.34g is obtained, yield 77%, m.p.:142.0-143.0 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.17 (s, 1H), 8.90 (s, 1H), 8.24 (d, J=5.7Hz, 1H), 8.10 (d, J=
2.2Hz, 1H), 7.68-7.57 (m, 2H), 7.45-7.37 (m, 2H), 7.36-7.29 (m, 2H), 7.04 (d, J=5.7Hz,
1H), 4.89 (q, J=8.8Hz, 2H), 4.26 (s, 2H), 2.16 (s, 3H) .ESI-MS:m/z 550.1,552.1,553.1 [M+
H]+。
Embodiment 30:1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } benzene
Base } -3- [4- (trifluoromethoxy) phenyl] urea (compound Z30) preparation
Referring to the preparation method of embodiment 1, white solid 0.10g is obtained, yield 37%, m.p.:173.2-174.9 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.24 (d, J=5.6Hz, 1H), 7.60-7.50 (m,
2H), 7.44-7.36 (m, 2H), 7.30 (dd, J=12.7,8.6Hz, 4H), 7.03 (d, J=5.7Hz, 1H), 4.88 (q, J=
8.7Hz,2H),4.25(s,2H),2.16(s,3H).ESI-MS:m/z 532.2[M+H]+,554.2[M+Na]+。
Embodiment 31:1- (3,5- difluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2-
Base] methyl sulfenyl phenyl urea (compound Z31) preparation
Referring to the preparation method of embodiment 1, white solid 0.13g is obtained, yield 47%, m.p.:181.2-182.7 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.14 (s, 1H), 8.95 (s, 1H), 8.24 (d, J=5.7Hz, 1H), 7.43-7.36 (m,
2H), 7.36-7.29 (m, 2H), 7.24-7.13 (m, 2H), 7.03 (d, J=5.7Hz, 1H), 6.79 (tt, J=9.4,2.4Hz,
1H), 4.88 (q, J=8.7Hz, 2H), 4.26 (s, 2H), 2.16 (s, 3H) .ESI-MS:m/z 484.2 [M+H]+,506.2[M+
Na]+。
Embodiment 32:1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } benzene
Base } -3- phenylurea (compound Z32) preparation
Referring to the preparation method of embodiment 1, white solid 0.06g is obtained, yield 21%, m.p.:143.3-145.1 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.73 (s, 1H), 8.67 (s, 1H), 8.24 (d, J=5.7Hz, 1H), 7.42 (dd, J=
18.1,8.3Hz, 4H), 7.29 (dd, J=16.8,8.3Hz, 4H), 7.03 (d, J=5.7Hz, 1H), 6.97 (t, J=7.3Hz,
1H), 4.89 (q, J=8.7Hz, 2H), 4.25 (s, 2H), 2.16 (s, 3H) .ESI-MS:m/z 448.4 [M+H]+,470.2[M+
Na]+。
Embodiment 33:1- (4- chlorphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] first
Base } sulfenyl phenyl urea (compound Z33) preparation
Referring to the preparation method of embodiment 1, white solid 0.14g is obtained, yield 43%, m.p.:203.6-205.2 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.81 (s, 1H), 8.75 (s, 1H), 8.23 (d, J=5.7Hz, 1H), 7.52-7.43 (m,
2H), 7.39 (d, J=8.7Hz, 2H), 7.37-7.27 (m, 4H), 7.03 (d, J=5.7Hz, 1H), 4.88 (q, J=8.7Hz,
2H),4.25(s,2H),2.16(s,3H).ESI-MS:m/z 482.6[M+H]+,504.3[M+Na]+。
Embodiment 34:1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } benzene
Base } -3- [3- (trifluoromethyl) phenyl] urea (compound Z34) preparation
Referring to the preparation method of embodiment 1, white solid 0.09g is obtained, yield 27%, m.p.:174.7-176.4 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.07 (s, 1H), 8.87 (s, 1H), 8.24 (d, J=5.7Hz, 1H), 8.01 (s, 1H),
7.61-7.47 (m, 2H), 7.46-7.37 (m, 2H), 7.37-7.28 (m, 3H), 7.04 (d, J=5.7Hz, 1H), 4.89 (q, J
=8.7Hz, 2H), 4.26 (s, 2H), 2.16 (s, 3H) .ESI-MS:m/z 516.2 [M+H]+。
Embodiment 35:1- (4- fluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] first
Base } sulfenyl phenyl urea (compound Z35) preparation
Referring to the preparation method of embodiment 1, white solid 0.21g is obtained, yield 56%, m.p.:163.4-165.1 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.70 (d, J=6.7Hz, 2H), 8.23 (d, J=5.6Hz, 1H), 7.48-7.42 (m,
2H), 7.42-7.36 (m, 2H), 7.35-7.26 (m, 2H), 7.17-7.06 (m, 2H), 7.03 (d, J=5.7Hz, 1H), 4.88
(q, J=8.8Hz, 2H), 2.16 (s, 3H) .ESI-MS:m/z 466.3 [M+H]+,488.2[M+Na]+。
Embodiment 36:1- (4- methoxyphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2-
Base] methyl sulfenyl phenyl urea (compound Z36) preparation
Referring to the preparation method of embodiment 1, white solid 0.17g is obtained, yield 55%, m.p.:171.3-172.1 DEG C；1H NMR(400MHz,DMSO-d6) δ 9.33 (s, 1H), 9.13 (s, 0H), 8.88 (d, J=22.7Hz, 1H), 8.60 (t, J=
5.8Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 7.52-7.43 (m, 2H), 7.37 (dt, J=11.9,9.0Hz, 3H), 7.28-
7.20 (m, 1H), 6.87 (ddd, J=8.9,6.0,2.8Hz, 2H), 5.11 (dq, J=25.3,8.6Hz, 2H), 3.72 (s,
2H),3.71(s,3H),1.24(s,3H).ESI-MS:m/z 478.3[M+H]+。
Embodiment 37:1- (4- bromophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] first
Base } sulfenyl phenyl urea (compound Z37) preparation
Referring to the preparation method of embodiment 1, white solid 0.17g is obtained, yield 55%, m.p.:153.4-154.2 DEG C；1H NMR(400MHz,DMSO-d6) δ 8.70 (d, J=6.7Hz, 2H), 8.23 (d, J=5.6Hz, 1H), 7.48-7.42 (m,
2H), 7.42-7.36 (m, 2H), 7.35-7.26 (m, 2H), 7.17-7.06 (m, 2H), 7.03 (d, J=5.7Hz, 1H), 4.88
(q, J=8.8Hz, 2H), 2.16 (s, 3H) .ESI-MS:m/z 526.2 [M+H]+,528.1[M+Na]+。
The above described is only a preferred embodiment of the present invention, being not that the invention has other forms of limitations, appoint
What those skilled in the art changed or be modified as possibly also with the technology contents of the disclosure above equivalent variations etc.
Imitate embodiment.But without departing from the technical solutions of the present invention, according to the technical essence of the invention to above embodiments institute
Any simple modification, equivalent variations and the remodeling made, still fall within the protection scope of technical solution of the present invention.
Pharmacological Examples
Embodiment 38: inhibitory activity (1) experimental material of test-compound to A549, HCT-116, PC3 cell Proliferation
Cell line: A549, HCT-116, PC3 cell are laid on 96 orifice plates with the density in 3000/ hole, every hole 100ul, for 24 hours after
It uses.
Number Z01 is to Z37 target compound: being dissolved with DMSO, is formulated as 50 μM, 20 μM, 10 μM, 5 μ with culture solution dilution
M, 2 μM of five various concentrations are stored in -20 DEG C for use, and final concentration of the DMSO in culture solution is lower than 0.1%.
Positive control drug: Sorafenib (sorafenib).
MTT: 5mg/mL is dissolved as with PBS, is stored in -20 DEG C.
(2) experimental method
Using MTT method, A549, HCT-116, PC3 cell are chosen to evaluate the antitumor increment activity of test sample.Carefully
Born of the same parents' strain is cultivated on 1640 culture medium of RPMI, which includes 10% calf serum (FBS).When cell Proliferation to 80-
So that it is merged the secondary culture then carried out no more than 20 generations when 90%, so that them is adapted to environment before next step is disposed and reach
To for 24 hours.These cells are placed on 96 orifice plates (8 × 104/mL), are then containing 5%CO2Moist environment in overnight incubation
And temperature control is at 37 DEG C.The invention representative compound of various concentration is added later for 24 hours.Using culture for 24 hours, it is added thereto
MTT (5mg/mL) simultaneously continues to cultivate 4h.It removes culture substrate and utilizes microplate reader (TECAN by dissolution of crystals in DMSO
SPECTRA, WetDar, Germany) under 490nm wavelength measure absorbance.According to formula: inhibitory rate of cell growth=(1- drug
Group OD value/control group OD value) × 100%, the inhibitory rate of cell growth under respective concentration is calculated, it is dense with the difference of test-compound
It spends and logarithmic curve is made to the inhibiting rate of cell, calculate the corresponding IC of test-compound50Value.This hair is measured according to the method described above
Bright representative compound, as a result shown in table 1:
Table 1
Embodiment 39: test-compound is to BRaf, VEGFR-2, the inhibitory activity of PDGFR- β and TOPK kinases
(1) experimental material
Kinases: BRaf kinases (wild type), VEGFR-2, PDGFR- β and TOPK kinases.
Number Z01 is to Z37 target compound: being dissolved with DMSO, reference substance does same processing.
Positive control drug: Sorafenib (sorafenib).
Kinase buffer liquid: containing 50mM HEPES, pH 7.5,10mM MgCl 2,0.0015%Brij-35 and 2mM
DTT。
Stop buffer: containing the coating reagent #3 of 100mM HEPES, pH 7.5,0.015%Brij-35,0.2% and
50mM ethylenediamine tetra-acetic acid (EDTA).
(2) experimental method
All kinase assays carry out in 50 μ L reaction volumes in 96 orifice plates.With DMSO by diluted chemical compound to 500 μM,
Then 10 μ L compounds are transferred in new 96 orifice plate as intermediate plate, and 90 μ L kinase buffer liquids is added into each hole.
Each hole of 5 microlitres of intermediate plates is transferred in 384 orifice plates.Every hole includes enzyme below and substrate: kinases alkali buffer, FAM
The peptide of label, ATP and enzyme solutions.The hole DMSO containing substrate, enzyme and without compound is compareed as DMSO.Only containing without enzyme
Substrate hole be used as low control.Compound is incubated at room temperature 10 minutes.It is added 10 μ L peptide solutions into each hole, and
It is incubated for specified a period of time at 28 DEG C, and is terminated and is reacted with 25 μ L stop buffers.Finally, being collected using Caliper program
Data measured value is converted to inhibiting rate by data, the program.
Inhibiting rate (%)=(max-conversion)/(max-min) × 100, wherein " max " represents DMSO control；
" min " represents low control.
Representative compound of the present invention is measured according to the method described above, is as a result shown in table 2:
Table 2
Example of formulations
The protection scope that following example of formulations only illustrates the present invention, but do not constitute and limit in any way.
Embodiment 40: gelatine capsule
The preparation of hard gelatin capsule uses:
Above-mentioned preparation can be improved according to provided reasonable change.
Embodiment 41: tablet
The preparation of tablet uses:
By said components mix and it is tabletted.
Embodiment 42: tablet
Tablet preparation in every containing 2.5-1000mg active component is as follows:
So that active constituent, starch and cellulose is passed through the mesh of the U.S. 45 and is thoroughly mixed.Polyvinylpyrrolidone is molten
Liquid is mixed with gained powder, through the mesh of the U.S. 14 after.The particle of generation is dried at 50-60 DEG C and through the mesh of the U.S. 18
Sieve.The sodium carboxymethylcellulose, magnesium stearate and talcum powder that first pass through No. 60 meshes in the U.S. in advance are added in above-mentioned particle, with
After mix, on tablet press machine compacting obtain tablet.
Embodiment 43: combined tablet-preparation
So that active constituent, starch and cellulose is passed through the mesh of the U.S. 45 and is thoroughly mixed.Polyvinylpyrrolidone is molten
Liquid is mixed with gained powder, through the mesh of the U.S. 14 after.The particle of generation is dried at 50-60 DEG C and through the mesh of the U.S. 18
Sieve.The sodium carboxymethylcellulose, magnesium stearate and talcum powder that first pass through No. 60 meshes in the U.S. in advance are added in above-mentioned particle, with
After mix, on tablet press machine compacting obtain tablet.
For above description, essential feature of the invention is readily understood in those skilled in the art, without departing substantially from the present invention
Spirit and scope, the present invention can carry out various changes and improve to adapt to different application and condition.
Claims (10)
1. a kind of compound of formula I, pro-drug and pharmaceutical active metabolite and above compound is pharmaceutically acceptable
Salt:
Wherein
X can be selected from CH, N；
R can be selected from hydrogen, C1-C4 alkyl, the C1-C4 alkyl that halogen replaces, C1-C4 alkoxy, the C1-C4 alcoxyl that halogen replaces
Base, halogen；R can be single or multiple；
R3、R4、R5The C1-C4 alkoxy that can replace independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4
The C1-C4 alkoxy that alkoxy replaces.
2. 1 compound of formula of claim 1, pro-drug and pharmaceutical active metabolite and above compound are pharmaceutically
Acceptable salt:
R be selected from hydrogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, the chloro- 3- trifluoromethyl of 4-, 3,5- difluoros, fluorine, chlorine,
Bromine；R can be single or multiple.
3. 1 compound of formula of claims 1 or 2, the pharmacy of pro-drug and pharmaceutical active metabolite and above compound
Upper acceptable salt:
R3、R4、R5Hydrogen, methyl, 2,2,2- trifluoro ethoxies, methoxyl group, 3- methoxy propoxy can be selected from.
4. compound as described below, pro-drug and pharmaceutical active metabolite and pharmaceutically acceptable salt, are selected from:
1-4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- phenylurea；
1- 4- chlorphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl }
Urea；
1- (4- bromophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl }
Urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] first
Base } sulfenyl } phenyl } urea；
1- (3,5- difluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [4- (trifluoro methoxy
Base) phenyl] urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- [3- (fluoroform
Base) phenyl] urea；
1- (4- fluorophenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl }
Urea；
1- (4- methoxyphenyl) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } phenyl } -3- (4- picoline -
2- yl) urea；
1- (6- bromopyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- (5- chloropyridine -2- base) -3- { 4- { { [4- (3- methoxy propoxy) -3- picoline -2- base] methyl } sulfenyl } benzene
Base } urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；
1- (4- chlorphenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- (4- bromophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl }
Urea；
1- (3,5- difluorophenyl) -3- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoromethoxy) phenyl] urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- [3- (trifluoromethyl) phenyl] urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- fluorophenyl) urea；
1- { 4- { [(3,4- dimethoxy-pyridine -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl) urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl }
Phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- [4- (trifluoromethoxy) benzene
Base] urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- phenylurea；
1- (4- chlorphenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } 3- [3- (trifluoromethyl) phenyl]
Urea；
1- (4- fluorophenyl) -3- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } urea；
1- { 4- { [(4- methoxyl group -3,5- lutidines -2- base) methyl] sulfenyl } phenyl } -3- (4- methoxyphenyl) urea；
1- [4- chloro- 3- (trifluoromethyl) phenyl] -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] first
Base } sulfenyl } phenyl } urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [4- (fluoroform
Oxygroup) phenyl] urea；
1- (3,5- difluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl }
Phenyl } urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- phenylurea；
1- (4- chlorphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl }
Urea；
1- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl } -3- [3- (fluoroform
Base) phenyl] urea；
1- (4- fluorophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl }
Urea；
1- (4- methoxyphenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl }
Phenyl } urea；
1- (4- bromophenyl) -3- { 4- { { [3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methyl } sulfenyl } phenyl }
Urea.
5. a kind of pharmaceutical composition, including compound described in the claim 1-4 any one as active constituent, precursor
Drug and pharmaceutical active metabolite and above compound pharmaceutically any one compound and drug in acceptable salt
Acceptable carrier or diluent.
6. the preparation method of compound of formula I as described in claim 1, which is characterized in that
Wherein, R, R3、R4、R5As described in claim 1.
7. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect
Application of the pharmaceutical composition described in the salt or claim 5 received in preparation tumor.
8. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect
The salt received or pharmaceutical composition are in preparation BRaf kinases, vascular endothelial growth factor receptor -2, platelet derived growth factor by
Application in body-β or T-LAK cell source kinases inhibitor.
9. compound described in claim 1-4 any one, its pro-drug and pharmaceutical active metabolite, and can pharmaceutically connect
The salt or pharmaceutical composition received are in preparation and BRaf kinases, vascular endothelial growth factor receptor -2, platelet derived growth factor
Application in the related disease drug of receptor-beta or T-LAK cell source disregulated protein kinases.
10. application as claimed in claim 9, wherein with BRaf kinases, vascular endothelial growth factor receptor -2, blood platelet spreads out
The related disease of raw growth factor receptors-β or T-LAK cell source disregulated protein kinases is lung cancer, liver cancer, melanoma, colon
Cancer, the carcinoma of the rectum, breast cancer, oophoroma, kidney.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116422A (en) * | 2019-12-30 | 2020-05-08 | 西南大学 | Paeonol etherified urea compound with anti-inflammatory activity and application thereof |
| CN113292515A (en) * | 2021-06-04 | 2021-08-24 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
| CN113354621A (en) * | 2021-06-04 | 2021-09-07 | 沈阳药科大学 | Pyridine group-containing 1-substituted benzyl-3-aryl urea compound and preparation method and application thereof |
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| CN111116422A (en) * | 2019-12-30 | 2020-05-08 | 西南大学 | Paeonol etherified urea compound with anti-inflammatory activity and application thereof |
| CN113292515A (en) * | 2021-06-04 | 2021-08-24 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
| CN113354621A (en) * | 2021-06-04 | 2021-09-07 | 沈阳药科大学 | Pyridine group-containing 1-substituted benzyl-3-aryl urea compound and preparation method and application thereof |
| CN113292515B (en) * | 2021-06-04 | 2022-05-20 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
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