CN104109119A - N'-aryl formyl o-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof - Google Patents

N'-aryl formyl o-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN104109119A
CN104109119A CN201310141617.0A CN201310141617A CN104109119A CN 104109119 A CN104109119 A CN 104109119A CN 201310141617 A CN201310141617 A CN 201310141617A CN 104109119 A CN104109119 A CN 104109119A
Authority
CN
China
Prior art keywords
trifluoromethyl
phenyl
pyridine
urea
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201310141617.0A
Other languages
Chinese (zh)
Other versions
CN104109119B (en
Inventor
冯志强
陈晓光
李燕
张莉婧
王克
唐克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN201310141617.0A priority Critical patent/CN104109119B/en
Publication of CN104109119A publication Critical patent/CN104109119A/en
Application granted granted Critical
Publication of CN104109119B publication Critical patent/CN104109119B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses N'-aryl formyl o-pyridine hydrazide derivatives represented by the formula I and pharmaceutically acceptable salts and preparation methods thereof, a composition containing one or more of the compounds, and an application of the compounds in treatment of protein kinase related diseases, such as immune disorder and tumor disease.

Description

The adjacent pyridine hydrazide derivatives of N '-sweet-smelling formacyl and method for making and pharmaceutical composition and purposes
Invention field
The present invention relates to the adjacent pyridine hydrazide derivatives of the N ' shown in formula I-sweet-smelling formacyl; its pharmacologically acceptable salt; and preparation method thereof; the composition that contains one or more these compounds; with this compounds in the treatment disease relevant with protein kinase as the purposes aspect immune disorder and tumor disease, belong to medical technical field.
Background of invention
Recent years, due to the raising of the understanding of the biomolecules to enzyme and some other and disease-related, discovery or the development of the new drug for the treatment of disease are greatly promoted, protein kinase is exactly an a kind of important class of broad research, it is extended familys, relevant with the control of various signal transduction processes in cell.Due to they structure and the conservative property of catalysis they be considered to evolve from a common ancestral gene.Nearly all kinases all contains a similar 250-300 amino acid catalytic domain.These protein kinases are divided into multiple families according to the difference of phosphorylated substrate, as protein tyrosine kinase, and albumen serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote and is carried out signal transduction in mediated cell by affecting a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, be finally excited and reacted in various extracellulars and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, can reduce the vasculogenesis of tumour copying of inhibition tumor cell simultaneously, thereby hinder the growth of tumour.
Raf kinases is the protein product of being encoded by proto-oncogene raf, formed by 648 amino acid, molecular weight is 70000～74000D, contains 3 conserved regions in its structure, is respectively CR1 (61～194D), CR2 (254～269D), CR3 (335～627D).CR1 is positioned at its molecules of ammonia cardinal extremity, is rich in halfcystine, contains zinc-finger structure, with the ligand binding domain structural similitude of protein kinase C, is the Ras main position of being combined with Raf-1 protein kinase of activation.CR2 also, near aminoterminal, is rich in Serine and Threonine.CR3 is positioned at the carboxyl terminal of its molecule, is the catalysis district of protein kinase.As a crucial kinases in Ras/Raf/MEK/ERK path, Raf can bring into play its signal conduction regulating effect by relying on or do not rely on the mode of Ras.As the kinase whose downstream of Raf substrate, the MEK phosphorylation ERK of activation, regulates various cell functions.Once this path generation excessive activation, causes cell proliferation acceleration and the prolongation of cells survival phase, thereby leads oncogenic generation.
Research shows, more than 80% oncogene and proto-oncogene are present in people's cancer proteins encoded Tyrosylprotein kinase (PTK), the generation of the various cancers of the mankind is relevant with the abnormal cells signal conduction that comes from protein tyrosine kinase with development, an increase that principal feature is tyrosine kinase activity of malignant cell.Therefore, suppress the activation of Tyrosylprotein kinase or block its signal conducting path to become the new way of controlling tumour.
Endothelial growth factor receptor (EGFR) is a kind of protein tyrosine kinase receptor (RTK), be positioned at karyomit(e) p13～q22 district No. 7, total length 200kb, formed by 28 exons, 1186 amino acid of encoding, the about 170kDa of its glycoprotein molecule amount, is distributed widely in all histocytes except ripe Skeletal Muscle Cell, body wall entoderm and hemopoietic tissue.There are the acceptor molecule of 4 structural similitudies: ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), ErbtM (HER4) in EGFR family, belongs to receptor tyrosine kinase (RTKS).They all contain the outer ligand binding domains of 1 born of the same parents, and 1 membrane spaning domain and 1 have the endochylema structural domain of tyrosine kinase activity.Its intracellular region territory and erbB oncoprotein height homology.The receptor dimerization that the activation of EGFR can be induced by part turns into realizing.In ErbB receptor family, except HER2, other members have its respective ligand, and various parts are to be come through proteolysis by corresponding transmembrane protein precursor, have 1 EGF spline structure territory.Comprise Urogastron (EGF), transforming growth factor-alpha (TGF α), two-ways regulation albumen (AR), beta cell element (BTC), Heparin-binding EGF like growth factor (HB-EGF), epiregulin (EPR) etc. with the part of EGFR specific binding.After the outer ligands, EGF (endothelial cell growth factor (ECGF)) of born of the same parents and ErbB2 specific binding, cause that ErbB2 configuration changes, thereby cause receptor dimerization to activate their endochylema site.After the intracellular region territory tyrosine phosphorylation of ErbB2 and then activation second messenger transduction, the activation (regulating kinases Erkl and Er1) by MAPK (mitogen protein kinase) approach inducing cell external signal: by PDK (phosphatidyl inositol kinase) pathway activation signal transducer JAK; Further start transcription activating of STAT1, STATS3; On the other hand, thin intracellular signal is by the ERK (extracellular regulated protein kinase) in Grb2 (growth factor receptors is in conjunction with albumen) activation downstream, and then mediation ATF, NF-kB, Ap-1, the transcription activating of C-fos and C-Jun.These are all the growth that mediates of EGFR or carcinogenic basic downstream pathway.Abnormal EGFR activate mechanism comprises the amplification of acceptor itself, the shortage of crossing expression, activation sudden change and negativity adjusting approach of receptors ligand, therefore EGFR induction cancer is at least by 3 kinds of mechanism: crossing of EGFR part expressed, the amplification of EGFR or the sudden change of EGFR activation.In these 3 kinds of mechanism, the sudden change activation of EGFR is the main factor that causes the abnormal biological behaviour of tumour cell.Some sudden change of EGFR gene can cause the enhancing of acceptor effect and the prolongation of time length.The proof variation acceptors such as Lynch do not affect the stability of receptor protein, find by Tyr1068 phosphorylation assay EGFR activation, the activation 15min of wild-type receptor lowers, and variation acceptor shows than the effect of high 2 times of normal EGFR, and exceedes the continuous activation of 3h.
EGFR sudden change does not affect the ability of tumour cell and TKI (tyrosine kinase inhibitor) combination.TKI can explain by oncogeneaddiction model because sudden change causes the reason of EGFR activation those.By Ras.Raf-MEK.ERK1/ERK2, PI3K.Akt, STAT3/STAT5 path, EGFR sudden change highly activates downstream signal, start EGFR and regulate anti-apoptosis and survival signaling, cause cancer cell to become and rely on this signal to maintain its existence--there is the oncogene (feature that the EG of sudden change relies on; When using after specificity T KI blocking-up EGFR signal, will eliminate its proliferative impact and output survival signaling, cause death of neoplastic cells.Therefore think, in cancer cell, the variation of signal transduction pathway is to occur the high responsive basis of medicine.On the contrary, the tumour cell (reactionless to Gefitinib, Erlotinib) that normal cell or non-EGFR rely on is unaffected.Because ordered about by other genes for survival, or after suppressing, EGFR can be made up by other RTK.Rely in model oncogene, the oncogene that cell cancer relies on can produce the output of apoptosis and 2 signals of existence simultaneously.Under general Sui condition, oncogene is activated.Survival signaling is occupied an leading position, and apoptotic signal is in relatively low-level, makes cancer cell maintain growth and propagation.When after the acute inactivation of oncogene, at crucial window phase, be first to survive in significantly weakening rapidly.And apoptotic signal slow decreasing.Therefore causing signal imbalance (apoptotic signal accounts for leading), there is irreversible apoptosis in active cell.Research is found with tyrosine kinase inhibitor Gefitinib (gefitinib)/Tarceva (Erlotinib) treatment NSCLC patient, about 10% patient shows rapidly and satisfied clinical effectiveness, and further research finds that these patient's overwhelming majority exist EGFR transgenation.Be confined to several as follows in the known transgenation relevant with EGFR-TKI (endothelial growth factor receptor tyrosine kinase inhibitor) at present: G719X (18 exon), E746-A450 lacks (19 exon), L858R (21 exon), L861Q (21 exon), T790M (20 exon) and D770-N771 (20 exon).Wherein E746-A450 disappearance and the sudden change of L858R and the curative effect height correlation of TKI.Mitsudomi T, the analytical results of Yatabe Y to 568 routine Patients with Non-small-cell Lungs: about 90% EGFR transgenation concentrates in 19 or 21 exons in all Patients with Non-small-cell Lungs, wherein the patient of the point mutation in the deletion mutantion of 19 exons and 21 exons takes the efficient of EGFR-TKI and all reaches more than 70%.Recent research prompting, the slotting human nature sudden change (D770-N771) of EGFR extron 20 can make acceptor to 100 times of the Reduced susceptibilities of EGFR-TKI, and the patient who also finds clinically to have this sudden change is not obvious to EGFR-TKI therapeutic response.The amplified production of extron 20 is carried out to subcloning analysis discovery, T79OM sudden change is that the change from cytidine(C (C) to thymidine (T) occurs a base pair, the Threonine that at protein level is exactly EGFR Tyrosylprotein kinase functional domain 790 sites is replaced (T790M) by methionine(Met), this sudden change can make EGFR again in the state of being activated, thereby cause the acquired resistance of TKI, the reason of resistance is that sudden change causes EGFR structure to change, and makes TKI and its combination occur steric effect.
Having research prompting KRAS sudden change may be the reason of former resistance of Gefitinib, Erlotinib.The Meta of Helena linardou has summed up 1008 routine NSCLC patients' TKI result for the treatment of in analyzing, in 165 patients of generation K-ras sudden change, 94% patient treats without significant reaction TKI.In general, KRAS and EGFR sudden change NSCLC repel mutually. and in different tumors subtypes, exist notable difference: EGFR sudden change to be mainly seen in non-smoker, and KRAS sudden change is more common in the cancer that smoking is relevant.Because KRAS sudden change always betides in the NSCLC with Wild type EGFR, be because KRAS suddenlys change on earth so be difficult to distinguish insensitive to EGFR-TKI, or because suddenly change without EGFR.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) family includes 3 kinds of hypotypes, that is: VEGFR-1 (also can write Flt-1 simultaneously), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt 1), in addition, also have neural pilin (neuropilin) l and 2 two collaborative acceptors.Wherein VEGFR-1 is mainly distributed in vascular endothelial cell, hemopoietic stem cell, scavenger cell and monocyte, can be combined with VEGF-A, VEGF-B and P1GF, main relevant with the growth regulating of hemopoietic stem cell.VEGFR-2 is mainly distributed in vascular endothelial cell and lymph endotheliocyte, can be combined with VEGF-A, VEGF-C, VEGF-D, VEGF-E.The effect that VEGF stimulating endothelial cell propagation, increase vascular permeability and neovascularity generate mainly realizes with activation VEGFR-2 by combination. compared with VEGFR-2, the avidity of VEGFR-l and VEGF is high 10 times, but regulating the activity of endotheliocyte much lower, may be that VEGFR-2 activity is had to negative regulation effect.VEGFR-3 mainly expresses at lymphatic endothelial cells, can be combined with VEGF-C and VEGF-D, and the growth of regulation and control lymph endotheliocyte.
Research shows: in the time that diameter of tumor is greater than 2mm, need to have new vessel that nutritive substance and excretion metabolism refuse are provided.VEGF/VEGFR signal path plays key effect in tumor vascular generation, can be by blocking or disturb the new life of VEGF/VEGFR signal path inhibition blood vessel, to reach the curative effect of the growth of controlling tumour.Compared with traditional cytotoxic drug, antitumor drug taking VEGF/VEGFR-2 as target has very large advantage. under normal physiological conditions, angiogenesis only works in the physiological activity such as wound healing and menstrual cycle, so use anti-angiogenic medicaments treatment tumour, little to human toxicity effect, vascular endothelial cell directly contacts with blood, make medicine be more prone to arrive action site. by the understanding to VEGF/VEGFR signal path mechanism of action at present, can obtain following several possible inhibitor research direction: a. utilizes monoclonal antibody to suppress VEGF or VEGFR, make it can not specific binding, disabling signal conduction.Can certainly utilize gene engineering to suppress their expression, weaken its activity.B. design specific micromolecular inhibitor, be attached to the outer VEGF calmodulin binding domain CaM of VEGFR born of the same parents, competitive antagonism VEGF, in like manner, can be also the particular combination territory that is attached to the upper VEGFR of VEGF, competitive antagonism VEGFR.C. suppressing the intracellular kinase territory of VEGFR, is mainly the binding site of ATP, and antagonism ATP competitively makes it that phosphate cannot be provided.D. suppress the key albumen of the VEGFR downstream signal in born of the same parents. consider patient's compliance, can may there is good prospect by oral micromolecular inhibitor.
Thr6 PDGF BB (platelet.derived growth factor, PDGF) be induction and promote vascularization effect the most by force, one of the most single-minded angiogenesis factor.PDGF mainly by with pdgf receptor (PDGFR) combination, and then activated protein kinase signal transduction pathway and playing a role.PDGFR is made up of α and two kinds of subunits of β, have 3 kinds of dimers (PDGFR-α α, α β, β β), wherein β β dimer acceptor (PDGFR-β) is the most important, its molecular weight is about 180～190ku, belong to tyrosine kinase receptor (receptor tyrosine kinase, RTK) family.PDGFR also plays an important role in tumour formation and development process.The overexpression of PDGFR-β or overactivity all can stimulate intratumoral vasculature to generate, and promote tumor growth.PDGFR-β is one of molecular marker of tumor vascular endothelial cell, high expression level in endothelial cells in tumor neogenetic blood vessels, and closely related with growth, the Metastasis and prognosis of some tumour.So PDGFR-β is a comparatively desirable neoplasm targeted therapy target.
The Raf/MEK/ERK path of Raf kinases and mediation thereof has remarkable effect in tumour progression and transfer process, and comprises that with many somatomedins Urogastron (EGF), vascular endothelial growth factor (VEGF) and PDGF (PDGF) etc. are closely related.People have thought that multiple way regulates this path, comprising farnesylation, the inhibition Rat " expression, inhibition Raf kinases and the kinase whose activity of MEK of I kinases (also claiming C-RAF kinases) that suppress Ras albumen.Above-mentioned method has not only suppressed the signal transduction of ERK but also has successfully suppressed the growth of xenotransplantation tumour.In addition, existing evidence demonstration, most of tumour is not arranged by single signal conduction path, suppresses to obtain larger curative effect for many target spots.
Numerous disease is that the abnormal cell response causing with protein kinase mediated event is associated.These diseases include, but not limited to tumour, inflammatory disease, Immunological diseases, osteopathia, metabolic trouble, sacred disease, cardiovascular and cerebrovascular diseases, the disease that hormone is relevant etc.Therefore find and find kinases inhibitor to be very important as medicine.Although many inventions have been made very large contribution to this area, for improving medication effect, research is still being continued in this area.
Summary of the invention
The object of the present invention is to provide the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-sweet-smelling formacyl, its pharmacologically acceptable salt.
Another object of the present invention is to provide the preparation method of the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-sweet-smelling formacyl.
A further object of the present invention is to provide a kind of pharmaceutical composition that contains the adjacent pyridine hydrazide derivatives of the N ' shown in general formula I-sweet-smelling formacyl.
Another object of the present invention is to provide this compounds anticancer, and with the medicine of protein kinase related disorder in purposes.
In order to complete the present invention's object, can adopt following technical scheme:
The present invention relates to have the adjacent pyridine hydrazide derivatives of the lower array structure N ' shown in general formula I-sweet-smelling formacyl:
Or its pharmacologically acceptable salt; In formula:
A can be selected from hydrogen, halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, trifluoromethoxy, cyano group, amino, methylamino-, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ester group, ethanoyl, aryl;
A is more preferably from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl; hydroxyl, methoxyl group, oxyethyl group, isopropoxy, trifluoromethoxy, cyano group, amino, methylamino-; sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethoxycarbonyl, ethanoyl.n=0-5
A is more preferably from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, cyano group, methylamino-, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethoxycarbonyl, ethanoyl.
A is particularly preferably from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, cyano group, methylamino-, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethanoyl.
A is most preferably from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, cyano group, methylamino-, methylsulfonyl, sulfamyl, carboxyl, ethanoyl.n=0-5
X can be selected from hydrogen, halogen, methyl, trifluoromethyl;
X is more preferably from hydrogen, F, Cl, Br, methyl, trifluoromethyl.
X is more preferably from hydrogen, F, Cl, methyl, trifluoromethyl
Optional aromatic ring and the hetero-aromatic ring from replacing or do not replace of Ar; Substituting group is selected from: halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group; trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy; amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido; to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl; ester group, ethanoyl, benzoyl, aryl, 5; 6,7,8-tetralyl, 4-hydroxyl-3,5-di-t-butyl benzoylamino.
Ar is more preferably from the benzene replacing or do not replace, pyridine, naphthalene, indoles, thiazole, benzothiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, quinoline, quinazoline, substituting group is selected from halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, aryl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
Ar is more preferably from the benzene replacing or do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, quinoline, substituting group is selected from F, Cl, Br, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
Ar is particularly preferably from the benzene replacing or do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, substituting group is selected from F, Cl, Br, methyl, ethyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
Ar is most preferably from the benzene replacing or do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, substituting group is selected from F, Cl, Br, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
Described in formula I, pharmacy acceptable salt comprises different acid salt, as following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid, tartrate, fumaric acid, citric acid, lactic acid.All these salt within the scope of the present invention all can adopt ordinary method preparation.
The invention also discloses the method for preparing the compounds of this invention, comprise following route steps:
The method of the described compound of preparation claim 1, comprises the steps:
Route 1
In step (a), taking hydrazides 1 as raw material, be easy to obtain N '-Fang formyl hydrazine derivative 2 with common method and acyl chlorides or acid anhydrides or acid-respons.
In step (b), under alkaline environment, obtain compound 3 by the chlorine substituted ether in hydrazides 2 with para hydroxybenzene sulfonamide derivatives.
In step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
Route 2
In step (a), taking methyl esters 1 as raw material, obtain hydrazide compound 2 by hydrazinolysis.
In step (b), make compound 2 and acyl chlorides or acid anhydrides or acid-respons be easy to obtain N '-Fang acethydrazide derivatives 3 by common method.
In step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
Route 3
In step (a), taking ester 4 or acyl chlorides 5 as raw material, react and obtain bishydrazide derivative 2 with N '-Fang formyl hydrazine 6.
In step (b), PAP derivative obtains compound 3 by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment.
In step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
Route 4
In step (a), phenolic compound 7 obtains urea derivatives I by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment.In step (b), ester cpds 8 reacts the same urea derivatives I that obtains with N '-Fang formyl hydrazine 6.
Route 5
This route is taking hydrazides 9 as raw material, itself and aromatic acid derivative or acyl chlorides or anhydride reaction is easy to obtain urea derivatives I by common method.
In addition, starting raw material and intermediate in above-mentioned reaction easily obtain, or can be easy to synthesize by the ordinary method in organic synthesis to those skilled in the art.
The invention still further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be suitable for any formulation of human or animal's use by pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, making.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the compounds of this invention is made to tablet, can be widely used various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in administration unit, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in to hard capsule or soft capsule.Also can by effective constituent the compounds of this invention first with thinner, tamanori, disintegrating agent granulation or micropill, then be placed in hard capsule or soft capsule.Also can be used for preparing the capsule of the compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of the compounds of this invention tablet.
For the compounds of this invention is made to injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH to adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.In the time of compound of the present invention and other medicine existence synergy, should adjust according to practical situation its dosage.
The compounds of this invention is many target point proteins kinase inhibitor or its precursor, and these protein kinases are divided into multiple families according to the difference of phosphorylated substrate, as protein tyrosine kinase, and albumen serine/threonine kinase, lipoid etc.Generally, protein kinase is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote and is carried out signal transduction in mediated cell by affecting a phosphoryl.These phosphorylated events regulate the biological function of target protein as molecular switch, be finally excited and reacted in various extracellulars and other stimulation.Kinases is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at the upstream of tumor-blood-vessel growth Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine protein kitase is positioned at the downstream of the Signal transduction pathway of tumour and tumor-blood-vessel growth cell.Research shows, by upstream retardance VEGFR and pdgf receptor, at downstream retardance Raf/MEK/ERK, can reduce the vasculogenesis of tumour copying of inhibition tumor cell simultaneously, thereby hinder the growth of tumour.The compounds of this invention has higher bioavailability, can be used for the treatment of multiple human malignancies, comprise that described tumor disease is liver cancer, cancer of the stomach, kidney, lung cancer, carcinoma of the pancreas, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, leukemia, incidence cancer.
Embodiment
Below with reference to embodiment, invention is described further, but does not limit the scope of the invention.
Determining instrument: Vaariaan Mercury300 or 400 type nuclear magnetic resonance analyser for NMR (Nuclear Magnetic Resonance) spectrum.ZAD-2F and VG300 mass spectrograph for mass spectrum.
Embodiment 1.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to methoxybenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
N '-synthesizing anisoyl-4-chloropyridine-2-hydrazides
Anisic acid 1.1g (7.0mmol) is dissolved in 3mL DMF, add raw material 4-chloropyridine-2-hydrazides 1g (5.8mmol), HATU2.7g (7.0mmol), triethylamine 1.8g (17.4mmol), stirring at room temperature, TLC monitoring raw material reaction is complete, adds 100mL water, there are a large amount of off-white color solids to separate out, obtain product 1.67g. 1H?NMR(400MHz,DMSO-d 6):10.68(s,1H,-CONH-),10.44(s,1H,-CONH-),8.70(d,1H,Ar-H),8.07(s,1H,Ar-H),7.90(d,2H,Ar-H),7.84(d,1H,Ar-H),7.05(d,2H,Ar-H),3.84(s,3H,-O-CH 3).MS(FAB):(M ++1=306).
N '-synthesizing anisoyl-4-(p-aminophenyl oxygen base) pyridine-2-hydrazides
P-aminophenol 469mg (4.3mmol) is dissolved in DMF10mL; under nitrogen protection, add potassium tert.-butoxide 648mg (5.3mmol); after stirring at room temperature 3h; add intermediate 31.0g (3.3mmol); salt of wormwood 276mg (2mmol); 80oC reacts 12h; TLC monitoring raw material, to reacting completely, adds 100mL water, ethyl acetate extraction 3 times; merge organic phase; saturated common salt is washed once, and anhydrous sodium sulfate drying filters afterwards; filtrate is concentrated, obtains purple solid 0.84g. 1H?NMR(300MHz,DMSO-d 6):δ(ppm):10.40(s,3H,-CONHNH-,Ar-NH),8.70(d,1H,Ar-H),8.32(s,1H,Ar-NH),8.07(d,1H,Ar-H),7.94(d,2H,Ar-H),7.83(m,1H,Ar-H),7.71(d,1H,Ar-H),7.05(d,2H,Ar-H),6.91(d,1H,Ar-H),6.42(dd,2H,Ar-H),3.84(s,3H,-O-CH 3).MS(FAB):(M ++1=379).
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to methoxybenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea is by 1.12g(6.9mmol) CDI is dissolved in the methylene dichloride that 7mL is dry, beginning solution is white opacity, to be dissolved with 1.2g(6.2mmol) 4 ?Lv ?3 ?the 10mL dichloromethane solution of 5-trifluoromethylaniline, splash in above-mentioned solution, solution becomes clarification gradually, after stirring at room temperature 8h, add and be dissolved with 0.794g(2.1mmol) the dichloromethane solution 5mL of N '-to anisoyl-4-(p-aminophenyl oxygen base) pyridine-2-hydrazides, after reflux 10h, stopped reaction, column chromatography separates target compound 0.32g. 1H?NMR(300MHz,DMSO-d 6):δ(ppm):10.57(s,1H,-CONH-),10.38(br,1H,-CONH-),9.33(s,1H,-CONH-),9.11(s,1H,-CONH-),8.58(d,1H,Ar-H),8.12(d,1H,Ar-H),7.89(d,2H,Ar-H),7.65(m,4H,Ar-H),7.41(d,1H,Ar-H),7.21(m,3H,Ar-H),7.04(d,2H,Ar-H),3.83(s,3H,O-CH 3).MS(FAB):(M ++1=600).
Embodiment 2.1-(4-(2-(2-(6-hydroxyl nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 6-hydroxy niacin to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 175mg. 1H?NMR(300MHz,DMSO-d 6):10.86(m,2H,-CONH-),9.33(s,1H,-CONH-),9.11(s,1H,-CONH-),8.53(dd,1H,Ar-H),8.12(m,2H,Ar-H),7.86(d,1H,Ar-H),7.63(m,4H,Ar-H),7.36(m,1H,Ar-H),7.19(m,3H,Ar-H),6.38(d,1H,Ar-H).MS(FAB)（M ++1=587）
Embodiment 3.1-(4-(2-(2-(pyridine-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize pyridine-2-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H?NMR(300MHz,DMSO-d 6):10.59(br,2H,-CONH-),9.39(s,1H,-CONH-),9.17(s,1H,-CONH-),8.69(s,1H,Ar-H),8.58(s,1H,Ar-H),8.13(s,1H,Ar-H),8.04(s,2H,Ar-H),7.63(m,5H,Ar-H),7.41(s,1H,Ar-H),7.21(m,3H,Ar-H).MS(FAB)（M ++1=571）
Embodiment 4.1-(4-(2-(2-(is to dimethylamino benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize p-(dimethylamino)-benzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H?NMR(300MHz,DMSO-d 6):10.89(s,1H,-CONH-),10.89(s,1H,-CONH-),9.33(s,1H,-CONH-),9.10(s,1H,-CONH-),8.49(dd,1H,Ar-H),8.13(s,1H,Ar-H),8.04(s,2H,Ar-H),7.77(d,1H,Ar-H),7.63(m,4H,Ar-H),7.38(d,1H,Ar-H),7.11(m,3H,Ar-H),6.89(d,1H,Ar-H),6.73(d,1H,Ar-H),2.98(s,3H),2.82(s,3H).MS(FAB)（M ++1=613）
Embodiment 5.1-(4-(2-(2-(5,6,7,8-naphthane-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 5,6,7,8-naphthane-2-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H?NMR(300MHz,DMSO-d 6):10.56(s,1H,-CONH-),10.39(br,1H,-CONH-),9.35(s,1H,-CONH-),9.12(s,1H,-CONH-),8.57(d,1H,Ar-H),8.12(s,1H,Ar-H),7.62(m,5H,Ar-H),7.41(d,1H,Ar-H),7.18(m,4H,Ar-H),2.77(m,4H),1.75(m,4H).MS(FAB)（M ++1=624）
Embodiment 6.1-(4-(2-((2-hydroxybenzoyl) between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize m-Salicylic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H?NMR(300MHz,DMSO-d 6):10.58(s,1H,-CONH-),10.40(br,1H,-CONH-),9.72(s,1H,-CONH-),9.26(s,1H,-CONH-),9.05(s,1H,Ar-H),8.58(d,1H,Ar-H),8.11(s,1H,Ar-H),7.62(m,4H,Ar-H),7.40(d,1H,Ar-H),7.22(m,5H,Ar-H),6.95(d,1H,Ar-H).MS(FAB)（M ++1=586）
Embodiment 7.1-(4-(2-(2-(naphthalene-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize naphthalene-2-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 150mg. 1H?NMR(400MHz,DMSO-d 6):10.74(s,1H,-CONH-),10.46(br,1H,-CONH-),9.46(s,1H,-CONH-),9.23(s,1H,-CONH-),8.59(t,1H,Ar-H),8.38(d,1H,Ar-H),8.14(s,1H,Ar-H),8.06(m,2H,Ar-H),7.64(m,9H,Ar-H),7.23(m,3H,Ar-H).MS(FAB)（M ++1=620）
Embodiment 8.1-(4-(2-(2-(pyridine-4-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize pyridine-4-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H?NMR(400MHz,DMSO-d 6):9.93(br,2H,-CONH-),9.24(s,1H,-CONH-),9.02(s,1H,-CONH-),8.53(m,1H,Ar-H),8.12(s,1H,Ar-H),7.39(m,6H,Ar-H),7.19(m2H,Ar-H),7.13(m,4H,Ar-H).MS(FAB)（M ++1=571）。
Embodiment 9.1-(4-(2-(2-(5-fluorine nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 5-fluorine nicotinic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 122mg. 1H?NMR(300MHz,DMSO-d 6):10.82(m,2H,-CONH-),9.38(s,1H,-CONH-),9.16(s,1H,-CONH-),8.94(s,1H,Ar-H),8.80(d,1H,Ar-H),8.59(d,1H,Ar-H),8.13(m,2H,Ar-H),7.63(m,4H,Ar-H),7.42(d,1H,Ar-H),7.22(m,3H,Ar-H).MS(FAB)（M ++1=589）
Embodiment 10.1-(4-(2-(2-(6-fluorine nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 6-fluorine nicotinic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H?NMR(300MHz,DMSO-d 6):10.74(br,2H,-CONH-),9.29(s,1H,-CONH-),9.07(s,1H,-CONH-),8.73(s,1H,Ar-H),8.57(s,1H,Ar-H),8.42(m,1H,Ar-H),8.11(s,1H,Ar-H),7.61(m,4H,Ar-H),7.36(m,2H,Ar-H),7.21(m,3H,Ar-H).MS(FAB)（M ++1=589）
Embodiment 11.1-(4-(2-(2-(2,3-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 2 3,dichloro benzoic acid 99 to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 132mg. 1H?NMR(300MHz,DMSO-d 6):10.74(br,1H,-CONH-),9.37(s,1H,-CONH-),9.14(s,1H,-CONH-),8.56(d,1H,Ar-H),8.12(s,1H,Ar-H),7.69(m,6H,Ar-H),7.44(m,2H,Ar-H),7.18(m,3H,Ar-H).MS(FAB)（M ++1=638）
Embodiment 12.1-(4-(2-(2-(2,4-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 2,4 dichloro benzene formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 165mg. 1H?NMR(300MHz,DMSO-d 6):9.37(s,1H,-CONH-),9.15(s,1H,-CONH-),8.58(d,1H,Ar-H),8.13(d,1H,Ar-H),7.60(m,7H,Ar-H),7.35(d,1H,Ar-H),7.19(m,3H,Ar-H).MS(FAB)（M ++1=638）
Embodiment 13.1-(4-(2-(2-(2,6-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 2,6-dichlorobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 105mg. 1H?NMR(300MHz,DMSO-d 6):10.77(s,1H,-CONH-),10.45(br,1H,-CONH-),10.11(s,1H,-CONH-),9.85(s,1H,-CONH-),8.58(d,1H,Ar-H),8.19(d,1H,Ar-H),7.91(m,3H,Ar-H),7.63(m,4H,Ar-H),7.43(d,1H,Ar-H),7.22(m,3H,Ar-H).MS(FAB)（M ++1=638）
Embodiment 14.1-(4-(2-(2-(3,4-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 3,4-dichlorobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 147mg. 1H?NMR(300MHz,DMSO-d 6):10.76(s,2H,-CONH-),9.49(s,1H,-CONH-),9.26(s,1H,-CONH-),8.58(d,1H,Ar-H),8.12(m,2H,Ar-H),7.82(m,2H,Ar-H),7.63(m,4H,Ar-H),7.42(d,1H,Ar-H),7.19(m,3H,Ar-H).MS(FAB)（M ++1=638）
Embodiment 15.1-(4-(2-(2-(2,5-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 2,5-dichlorobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 143mg. 1H?NMR(300MHz,DMSO-d 6):10.67(br,2H,-CONH-),9.38(s,1H,-CONH-),9.16(s,1H,-CONH-),8.58(d,1H,Ar-H),8.14(m,1H,Ar-H),7.64(m,6H,Ar-H),7.53(s,1H,Ar-H),7.42(s,1H,Ar-H),7.20(m,3H,Ar-H).MS(FAB)（M ++1=638）
Embodiment 16.1-(4-(2-(the adjacent fluorobenzoyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize o-fluorobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 125mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.60(brs,2H,-CON H-),9.35(s,1H,-CON H-),9.12(s,1H,-CON H-),8.57(d,1H,Ar H),8.12(s,1H,Ar H),7.65-7.59(m,6H,Ar H),7.41(s,1H,Ar H),7.31-7.29(m,2H,Ar H),7.20-7.18(m,3H,Ar H).MS(FAB)（M ++1=588）
Embodiment 17.1-(4-(2-(the adjacent bromobenzene formyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize o-bromobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 123mg. 1H-NMR(400MHz,DMSO-d 6):δ(ppm):10.67(brs,2H,-CON H-),9.36(s,1H,-CON H-),9.14(s,1H,-CON H-),8.58(d,1H,Ar H),8.13(s,1H,Ar H),7.70-7.61(m,5H,Ar H),7.50-7.32(m,4H,Ar H),7.22-7.19(m,3H,Ar H);MS(FAB)（M ++1=648）.
Embodiment 18.1-(4-(2-(2-(is to fluorobenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize parafluorobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(400MHz,DMSO-d 6):δ(ppm):10.58(brs,2H,-CON H-),9.31(s,1H,-CON H-),9.09(s,1H,-CON H-),8.58(d,1H,Ar H),8.13(s,1H,Ar H),7.68-7.61(m,6H,Ar H),7.42(s,1H,Ar H),7.33-7.30(m,2H,Ar H),7.22-7.16(m,3H,Ar H);MS(FAB)（M ++1=588）
Embodiment 19.1-(4-(2-(2-(is to bromobenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize parabromobenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H-NMR(400MHz,DMSO-d 6):δ(ppm):10.68(brs,2H,-CON H-),9.33(s,1H,-CON H-),9.11(s,1H,-CON H-),8.58(d,1H,Ar H),8.13(s,1H,Ar H),7.85-7.83(d,2H,Ar H),7.74-7.60(m,6H,Ar H),7.42(s,1H,Ar H),7.21-7.19(m,3H,Ar H);MS(FAB)（M ++1=648）
Embodiment 20.1-(4-(2-(2-(is to acetyl oxygen benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize globentyl is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 148mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.66(brs,2H,-CON H-),9.51(s,1H,-CON H-),9.28(s,1H,-CON H-),8.58(d,1H,Ar H),8.14(s,1H,Ar H),7.94(d,1H,Ar H),7.66-7.60(m,5H,Ar H),7.42(s,1H,Ar H),7.29-7.19(m,5H,Ar H),2.30(s,3H,-C H 3 );MS(FAB)（M ++1=628）
Embodiment 21.1-(4-(2-(2-(is to tert.-butylbenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize p-tert-butyl benzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 156mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.60(brs,2H,-CON H-),9.52(s,1H,-CON H-),9.28(s,1H,-CON H-),8.58(d,1H,Ar H),8.14(s,1H,Ar H),7.85-7.83(d,2H,Ar H),7.69-7.42(m,7H,Ar H),7.21-7.19(m,3H,Ar H),1.31(s,9H,-C(C H 3 ) 3 );MS(FAB)（M ++1=626）
Embodiment 22.1-(4-(2-(2-(is to bromine Meta-dihydroxybenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize bromine m-dihydroxy-benzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 102mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):9.62(s,1H,-CON H-),9.38(s,1H,-CON H-),8.57-8.51(m,1H,Ar H),8.15(s,1H,Ar H),7.67-7.36(m,6H,Ar H),7.22-7.16(m,4H,Ar H);MS(FAB)（M ++1=680）
Embodiment 23.1-(4-(2-(2-(o-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize o-trifluoromethyl phenylformic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.67(brs,2H,-CON H-),9.34(s,1H,-CON H-),9.12(s,1H,-CON H-),8.58(d,1H,Ar H),8.13(s,1H,Ar H),7.84-7.60(m,8H,Ar H),7.43(d,1H,Ar H),7.24-7.16(m,3H,Ar H);MS(FAB)（M ++1=638）
Embodiment 24.1-(4-(2-(2-(m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize m-trifluoromethylbenzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 125mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.77(brs,2H,-CON H-),9.34(s,1H,-CON H-),9.12(s,1H,-CON H-),8.59(d,1H,Ar H),8.23-8.19(m,2H,Ar H),8.13(s,1H,Ar H),7.97(d,1H,Ar H),7.80-7.75(t,1H,Ar H),7.68-7.60(m,4H,Ar H),7.43(d,1H,Ar H),7.24-7.19(m,3H,Ar H);MS(FAB)（M ++1=638）
Embodiment 25.1-(4-(2-(2-(is to trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.75(brs,2H,-CON H-),9.39(s,1H,-CON H-),9.17(s,1H,-CON H-),8.59(d,1H,Ar H),8.13-8.08(m,3H,Ar H),7.91-7.89(d,2H,Ar H),7.69-7.60(m,4H,Ar H),7.43(d,1H,Ar H),7.24-7.19(m,3H,Ar H);MS(FAB)（M ++1=638）
Embodiment 26.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 144mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.78(brs,2H,-CON H-),9.46(s,1H,-CON H-),9.23(s,1H,-CON H-),8.59(d,1H,Ar H),8.33(s,1H,Ar H),8.19(d,1H,Ar H),8.13(s,1H,Ar H),7.89(d,2H,Ar H),7.69-7.59(m,4H,Ar H),7.43(d,1H,Ar H),7.21-7.18(m,3H,Ar H);MS(FAB)（M ++1=672）
Embodiment 27.1-(4-(2-(2-(m-dimethyl amino benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize m-dimethyl amino benzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.59(brs,2H,-CON H-),9.33(s,1H,-CON H-),9.11(s,1H,-CON H-),8.59(d,1H,Ar H),8.13(s,1H,Ar H),7.68-7.60(m,4H,Ar H),7.42(s,1H,Ar H),7.31-7.16(m,6H,Ar H),6.92-6.90(d,1H,Ar H),2.94(s,6H,-NC H 3 );MS(FAB)（M ++1=613）
Embodiment 28.1-(4-(2-(the adjacent chlorine of 2-(is to methylsulfonyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize adjacent chlorine to replace anisic acid to methyl sulfonylbenzoic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.84(brs,2H,-CON H-),9.34(s,1H,-CON H-),9.12(s,1H,-CON H-),8.59(d,1H,Ar H),8.12(s,1H,Ar H),8.06(s,1H,Ar H),7.97(d,1H,Ar H),7.75(d,1H,Ar H),7.68-7.59(m,4H,Ar H),7.43(s,1H,Ar H),7.22-7.19(m,3H,Ar H),3.32(s,3H,-C H 3 );MS(FAB)（M ++1=682）
Embodiment 29.1-(4-(2-(2-(is to (2-hydroxybenzoyl) between methoxyl group) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize methoxyl group m-Salicylic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 113mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):9.35(s,1H,-CON H-),9.13(s,1H,-CON H-),8.58(brs,1H,Ar H),8.13(s,1H,Ar H),7.62-7.60(m,5H,Ar H),7.41-7.35(m,2H,Ar H),7.21-7.12(m,3H,Ar H),7.02-6.99(d,1H,Ar H),3.87(s,3H,-OC H 3 );MS(FAB)（M ++1=616）.
Embodiment 30.1-(4-(2-(2-(bis-m-trifluoromethyl benzoyls) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize two m-trifluoromethylbenzoic acids to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):9.75(s,1H,-CON H-),9.50(s,1H,-CON H-),8.60(d,1H,Ar H),8.54(s,1H,Ar H),8.38(s,1H,Ar H),8.16(brs,2H,Ar H),7.68-7.59(m,4H,Ar H),7.45(s,1H,Ar H),7.22-7.19(m,3H,Ar H);MS(FAB)（M ++1=706）.
Embodiment 31.1-(4-(2-(2-(is to the adjacent chlorobenzoyl of fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize fluorine 0-chloro-benzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 151mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.70(brs,2H,-CON H-),9.37(s,1H,-CON H-),9.14(s,1H,-CON H-),8.57(d,1H,Ar H),8.12(s,1H,Ar H),7.65-7.51(m,6H,Ar H),7.42-7.32(m,2H,Ar H),7.21-7.13(m,3H,Ar H);MS(FAB)（M ++1=622）.
Embodiment 32.1-(4-(2-(2-(is to chlorobenzoyl between fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize fluorine m-chlorobenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.71(brs,2H,-CON H-),9.51(s,1H,-CON H-),9.27(s,1H,-CON H-),8.58(d,1H,Ar H),8.13-8.09(m,2H,Ar H),7.93(brs,1H,Ar H),7.66-7.55(m,5H,Ar H),7.41(s,1H,Ar H),7.21-7.18(m,3H,Ar H);MS(FAB)（M ++1=622）.
Embodiment 33.1-(4-(2-(2-(is to the adjacent bromobenzene formyl of fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize fluorine o-bromobenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 132mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.68(brs,2H,-CON H-),9.41(s,1H,-CON H-),9.18(s,1H,-CON H-),8.57(d,1H,Ar H),8.13(s,1H,Ar H),7.78-7.53(m,6H,Ar H),7.41-7.37(m,2H,Ar H),7.21-7.13(m,3H,Ar H);MS(FAB)（M ++1=666）.
Embodiment 34.1-(4-(2-(2-(is to fluorobenzoyl between bromine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize bromine m-fluorobenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.77(brs,2H,-CON H-),9.33(s,1H,-CON H-),9.11(s,1H,-CON H-),8.58(d,1H,Ar H),8.11(s,1H,Ar H),7.90-7.80(m,2H,Ar H),7.71-7.59(m,5H,Ar H),7.41(s,1H,Ar H),7.21-7.18(m,3H,Ar H);MS(FAB)（M ++1=666）.
Embodiment 35.1-(4-(2-(the adjacent chlorobenzoyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 0-chloro-benzoic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.66(brs,2H,-CON H-),9.35(s,1H,-CON H-),9.16(s,1H,-CON H-),8.57(s,1H,Ar H),8.13(s,1H,Ar H),7.61-7.42(m,9H,Ar H),7.21(brs,3H,Ar H);MS(FAB)（M ++1=604）.
Embodiment 36.1-(4-(2-(2-(is to fluorobenzoyl between methoxy) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize methoxy m-fluorobenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 137mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.63(s,1H,-CON H-),10.46(s,1H,-CON H-),9.38(s,1H,-CON H-),9.16(s,1H,-CON H-),8.57(d,1H,Ar H),8.13(s,1H,Ar H),7.76-7.61(m,6H,Ar H),7.41(s,1H,Ar H),7.32-7.21(m,4H,Ar H),3.91(s,3H,-OC H 3 );MS(FAB)（M ++1=618）.
Embodiment 37.1-(4-(2-(methoxycarbonyl base benzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Between utilization, methoxycarbonyl yl benzoic acid replaces anisic acid, carries out with reference to the operation of embodiment 1, and obtaining target compound is white solid 143mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.71(brs,2H,-CON H-),9.45(s,1H,-CON H-),9.22(s,1H,-CON H-),8.58(d,1H,Ar H),8.50(s,1H,Ar H),8.17-8.19(m,3H,Ar H),7.66-7.62(m,5H,Ar H),7.43(s,1H,Ar H),7.22-7.19(m,3H,Ar H),3.90(s,3H,-OC H 3 );MS(FAB)（M ++1=628）.
Embodiment 38.1-(4-(2-(2-(is to methylsulfonyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize methyl sulfonylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 127mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.83(brs,2H,-CON H-),9.31(s,1H,-CON H-),9.09(s,1H,-CON H-),8.58(d,1H,Ar H),8.11-8.03(m,5H,Ar H),7.62-7.59(m,4H,Ar H),7.42(s,1H,Ar H),7.22(brs,3H,Ar H),3.27(s,3H,-C H 3 );MS(FAB)（M ++1=648）.
Embodiment 39.1-(4-(2-(2-(5-methylpyrazine-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 5-methylpyrazine-2-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 112mg. 1h-NMR (300MHz, DMSO-d 6): δ (ppm): 10.71 (brs, 2H ,-CON h-), 9.30-9.04 (m, 3H ,-CON h-, Ar h), 8.65 (s, 1H, Ar h), 8.58 (s, 1H, Ar h), 8.12 (s, 1H, Ar h), 7.61-7.20 (m, 8H, Ar h), 2.60 (s, 3H ,-C h 3 ); MS (FAB) (M ++ 1=586). embodiment 40.1-(4-(2-(nitre acyloxy benzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Between utilization, nitryl aminobenzoic acid replaces anisic acid, carries out with reference to the operation of embodiment 1, and obtaining target compound is white solid 101mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.68(brs,2H,-CON H-),9.47(s,1H,-CON H-),9.27(s,1H,-CON H-),8.81(d,1H,Ar H),8.58(s,1H,Ar H),8.13-8.07(m,2H,Ar H),7.66-7.61(m,6H,Ar H),7.51(s,1H,Ar H),7.21-7.19(m,3H,Ar H);MS(FAB)（M ++1=631）.
Embodiment 41.1-(4-(2-(2-(indazole-3-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize indazole-3-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):13.71(s,1H,-N H),10.59(brs,2H,-CON H-),9.35(s,1H,-CON H-),9.13(s,1H,-CON H-),8.59(m,1H,Ar H),8.12(s,2H,Ar H),7.62-7.19(m,11H,Ar H,=C H);MS(FAB)（M ++1=610）.
Embodiment 42.1-(4-(2-(2-(2-methyl-4-first sulfophenyl thiazole-5-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Utilize 2-methyl-4-first sulfophenyl thiazole-5-formic acid to replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 143mg. 1H-NMR(300MHz,DMSO-d 6):δ(ppm):10.86-10.61(m,2H,-CON H-),9.39(s,1H,-CON H-),9.16(s,1H,-CON H-),8.59(d,1H,Ar H),8.18-8.10(m,3H,Ar H),7.97-7.94(d,2H,Ar H,),7.70-7.62(m,4H,Ar H),7.45(s,1H,Ar H),7.24-7.21(m,3H,Ar H),3.26(s,3H,-C H 3 ),2.76(s,3H,-C H 3 );MS(FAB)（M ++1=745）.
Embodiment 43.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to cyano group benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Replace anisic acid with paracyanobenzoic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 132mg. 1H?NMR(300MHz,DMSO-d 6):10.90(m,2H,-CO-NH-NH-),9.30(s,1H,-CONH-),9.11(s,1H,-CONH-),8.58(d,1H,Ar-H),8.48(d,1H,Ar-H),8.12(s,1H,Ar-H),8.05(m,1H,Ar-H),7.98(d,1H,Ar-H),7.61(m,4H,Ar-H),7.39(dd,1H,Ar-H),7.16(m,3H,Ar-H),7.11(m,1H,Ar-H).MS(FAB):(M ++1=595).
Embodiment 44.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(p-nitrophenyl formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Replace anisic acid with p-nitrobenzoic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H?NMR(300MHz,DMSO-d 6):10.85(m,2H,-CO-NH-NH-),9.36(s,1H,-CONH-),9.14(s,1H,-CONH-),8.59(d,1H,Ar-H),8.35(d,1H,Ar-H),8.14(m,3H,Ar-H),7.63(m,4H,Ar-H),7.42(d,1H,Ar-H),7.20(m,3H,Ar-H).MS(FAB):(M ++1=615).
Embodiment 45.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(2-benzoyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
With 2-benzoyl phenylformic acid replacement anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 123mg. 1H?NMR(300MHz,DMSO-d 6):10.15(s,1H,-CONH-),9.63(s,1H,-CONH-),9.13(s,1H,-CONH-),8.54(d,1H,Ar-H),8.13(d,1H,Ar-H),7.79(d,1H,Ar-H),7.66(m,8H,Ar-H),7.23(m,9H,Ar-H,-CONH-).MS(FAB):(M ++1=674).
Embodiment 46.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to sulfamyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
With sulfamoylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 131mg. 1H?NMR(400MHz,DMSO-d 6):10.71(br,3H,-CONH-,-SONH 2),9.25(s,1H,-CONH-),9.04(s,1H,-CONH-),8.59(d,1H,Ar-H),8.13(s,1H,Ar-H),8.06(d,2H,Ar-H),7.94(d,2H,Ar-H),7.68(m,4H,Ar-H),7.52(s,1H,Ar-H),7.43(s,1H,Ar-H),7.22(m,3H,Ar-H).MS(FAB):(M ++1=649).
Embodiment 47.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Replace anisic acid with nicotinic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 155mg. 1H?NMR(400MHz,DMSO-d 6):δ(ppm):10.76(s,2H,-NHCO-CH 2-,Ar),9.33(s,1H,-NHCO-),9.11(s,1H,-NHCO-),9.05(s,1H,-NHCO-),8.75(d,1H,ArH),8.59(d,1H,ArH),8.23(d,1H,ArH),8.12(s,1H,ArH),7.68～7.60(m,4H,ArH),7.57～7.53(m,1H,ArH),7.42(d,1H,ArH),7.22～7.20(m,3H,ArH).MS(FAB)（M ++1=571）
Embodiment 48.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to chlorobenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Replace anisic acid with Chlorodracylic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.66(s,1H,-CON H-),10.62(s,1H,-CON H-),9.22(s,1H,-CON H-),9.01(s,1H,-CON H-),8.58(d,1H,Ar H),8.10(brs,1H,Ar H),7.92～7.89(d,2H,Ar H),7.67～7.58(m,6H,Ar H),7.40(d,1H,Ar H),7.23～7.18(m,3H,Ar H);MS(FAB):(M ++1=604).
Embodiment 49.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(fluorobenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
Replace anisic acid with m-fluorobenzoic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 153mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.69(brs,2H,-CON H-),9.30(s,1H,-CON H-),9.09(s,1H,-CON H-),8.58(d,1H,Ar H),8.12(brs,1H,Ar H),7.77(d,1H,Ar H),7.69～7.53(m,6H,Ar H),7.46～7.42(m,2H,Ar H),7.22～7.19(m,3H,Ar H);MS(FAB):(M ++1=588).
Embodiment 50.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to methoxycarbonyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
With methoxycarbonyl phenylformic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 125mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.74(brs,2H,-CON H-),9.31(s,1H,-CON H-),9.09(s,1H,-CON H-),8.58(d,1H,Ar H),8.12～8.00(m,5H,Ar H),7.65～7.59(m,4H,Ar H),7.42(d,1H,Ar H),7.22～7.19(m,3H,Ar H),3.89(s,3H,-COOC H 3 );MS(FAB):(M ++1=628).
Embodiment 51.1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(3,5-dinitrobenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
With 3,5-dinitrobenzoic acid replacement anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 175mg. 1H?NMR(400MHz,DMSO-d 6):11.23(s,1H,-CONH-),10.18(s,1H,-CONH-),9.31(s,1H,-CONH-),9.10(s,1H,-CONH-),9.05(s,2H,Ar-H),8.85(s,1H,Ar-H),8.56(d,1H,Ar-H),8.11(s,1H,Ar-H),7.62(m,4H,Ar-H),7.43(s,1H,Ar-H),7.20(m,3H,Ar-H).MS(FAB):(M ++1=660).
Embodiment 52.1-(4-(2-(2-(is to toluyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
Replace anisic acid with p-methylbenzoic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 155mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.59-10.44(m,2H,-CON H-),9.46(s,1H,-CON H-),9.23(s,1H,-CON H-),8.58(d,1H,Ar H),8.14(s,1H,Ar H),7.81(d,2H,Ar H),7.70～7.61(m,4H,Ar H),7.42(s,1H,Ar H),7.31(d,2H,Ar H),7.25～7.19(m,3H,Ar H),2.37(s,3H,-C H 3 );MS(FAB):(M ++1=584).
Embodiment 53.1-(4-(2-(2-(4-(is to di-t-butyl benzamido between hydroxyl) benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With 4-(to di-t-butyl benzamido between hydroxyl) phenylformic acid replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 75mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.61(s,1H,-CON H-),10.29(s,1H,-CON H-),9.55(s,1H,-CON H-),9.30(s,1H,-CON H-),8.59(d,1H,Ar H),8.15(s,1H,Ar H),7.93～7.88(m,4H,Ar H),7.69～7.63(m,6H,Ar H),7.44(s,1H,Ar H),7.23～7.20(m,3H,Ar H),1.44(s,18H,-C H 3 );MS(FAB):(M ++1=817).
Embodiment 54.1-(4-(2-(2-(4-(is to cyano group benzamido) benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With 4-(to cyano group benzamido) phenylformic acid replace anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 115mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.74(s,1H,-CON H-),10.62(s,1H,-CON H-),10.45(brs,1H,-CON H-),9.44(s,1H,-CON H-),9.21(s,1H,-CON H-),8.59(d,1H,Ar H),8.14-8.03(m,5H,Ar H),7.93-7.86(m,4H,Ar H),7.70～7.61(m,4H,Ar H),7.42(d,1H,Ar H),7.23-7.20(m,3H,Ar H);MS(FAB):(M ++1=714).
Embodiment 55.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base)-2-fluorophenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
With chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, use amino m fluorophenol is replaced to p-aminophenol, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 135mg. 1H-NMR(400MHz,DMSO-d6):δ(ppm):10.84(brs,2H,-CON H-),9.774(brs,1H,-CON H-),8.94(s,1H,-CON H-),8.61(d,1H,Ar H),8.34(s,1H,Ar H),8.20-8.14(m,3H,Ar H),7.90-7.88(d,1H,Ar H),7.64(s,2H,Ar H),7.47(s,1H,Ar H),7.38-7.36(d,1H,Ar H),7.25(d,1H,Ar H),7.11-7.09(d,1H,Ar H),7.04(t,1H,.Ar H);MS(FAB):(M ++1=690).
Embodiment 56.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(2,4 difluorobenzene base) urea
Replace chlorine 3-Aminotrifluorotoluene with 2,4 difluorobenzene amine, use chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 145mg. 1H-NMR(400MHz,DMSO-d6):δ(ppm):10.77(brs,1H,-CON H-),10.61(brs,1H,-CON H-),9.31(s,1H,-CON H-),8.60-8.56(m,2H,-CON H-,Ar H),8.32(s,1H,Ar H),8.19-8.17(d,1H,Ar H),8.09-8.03(dd,1H,Ar H),7.91-7.89(d,1H,Ar H),7.58-7.56(d,2H,Ar H),7.41(s,1H,Ar H),7.29(t,1H,Ar H),7.19-7.17(m,3H,Ar H),7.04(t,1H,Ar H);MS(FAB):(M ++1=606).
Embodiment 57.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-trifluoromethyl) urea
Replace chlorine 3-Aminotrifluorotoluene with 4-5-trifluoromethylaniline, use chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 155mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.90(brs,2H,-CON H-),9.25(s,1H,-CON H-),9.07(s,1H,-CON H-),8.57(d,1H,Ar H),8.33(s,1H,Ar H),8.18(d,1H,Ar H),7.85(d,1H,Ar H),7.66-7.60(m,6H,Ar H),7.43(s,1H,Ar H),7.21-7.19(m,3H,Ar H);MS(FAB):(M ++1=638).
Embodiment 58.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-chloro-phenyl-) urea
Replace chlorine 3-Aminotrifluorotoluene with p-Chlorobenzoic acid amide, use chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 153mg. 1H-NMR(300MHz,DMSO-d6):δ(ppm):10.88(brs,2H,-CON H-),8.94(s,2H,-CON H-),8.57(d,1H,Ar H),8.33(s,1H,Ar H),8.18(d,1H,Ar H),7.85(d,1H,Ar H),7.60-7.58(d,2H,Ar H),7.51-7.49(d,2H,Ar H),7.42(s,1H,Ar H),7.34-7.31(d,2H,Ar H),7.20-7.17(m,3H,Ar H);MS(FAB):(M ++1=604).
Embodiment 59.1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-chloro-phenyl-) urea
With methyl m-chloro aniline is replaced chlorine 3-Aminotrifluorotoluene, use chlorine m-trifluoromethylbenzoic acid is replaced to anisic acid, carry out with reference to the operation of embodiment 1, obtaining target compound is white solid 150mg. 1H-NMR(400MHz,DMSO-d6):δ(ppm):10.82(brs,2H,-CON H-),8.94(s,1H,-CON H-),8.89(s,1H,-CON H-),8.56(d,1H,Ar H),8.32(s,1H,Ar H),8.18-8.16(d,1H,Ar H),7.87-7.85(d,1H,Ar H),7.68(s,1H,Ar H),7.58-7.56(d,2H,Ar H),7.41(s,1H,Ar H),7.23-7.16(m,5H,Ar H),2.24(s,3H,-C H 3 );MS(FAB):(M ++1=618).
Pharmacologically active
External activity is evaluated:
Mtt assay is measured tumour cell survival rate
Be 0.8～2 × 10 by the cell of logarithmic phase with being mixed with concentration after trysinization 4the enchylema of cell/ml, is inoculated in 96 orifice plates by 1000/hole, and every hole adds 100 μ l.Add the fresh culture containing different concns medicine and coordinative solvent contrast next day, every hole adds 100 μ l(DMSO final concentration <0.5%), every medicine is established 5～7 dosage groups, at least establish three parallel holes for every group, continue to cultivate after 120hr in 37 DEG C, abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/ml MTT of 100 μ l, continue to cultivate 4hr, abandon culture supernatant, every hole adds 200 μ l DMSO and dissolves MTT first hairpin precipitation, vibrate and mix with microoscillator, by MK3 type microplate reader at reference wavelength 450nm, detect under wavelength 570nm condition and measure optical density value (OD), taking the tumour cell of solvent control processing as control group, inhibiting rate with the medicine of formula calculating below to tumour cell, and by middle effect Equation for Calculating IC 50:
MTT the selection result
MTT the selection result

Claims (18)

1. the adjacent pyridine hydrazide derivatives of the N ' shown in formula I-sweet-smelling formacyl and pharmacologically acceptable salt thereof,
In formula: A can be selected from hydrogen, halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, trifluoromethoxy, cyano group, amino, methylamino-, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ester group, ethanoyl, aryl;
N is selected from the integer of 0-5;
X can be selected from hydrogen, halogen, methyl, trifluoromethyl;
Optional aromatic ring and the hetero-aromatic ring from replacing or do not replace of Ar; Substituting group is selected from: halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group; trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy; amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido; to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl; ester group, ethanoyl, benzoyl, aryl, 5; 6,7,8-tetralyl, 4-hydroxyl-3,5-di-t-butyl benzoylamino.
2. according to compound and the pharmacologically acceptable salt thereof of claim 1, it is characterized in that,
A is selected from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, isopropoxy, trifluoromethoxy, cyano group, amino, methylamino-, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethoxycarbonyl, ethanoyl;
N is selected from the integer of 0-5;
X is selected from hydrogen, F, Cl, Br, methyl, trifluoromethyl;
Ar is selected from benzene replacement or that do not replace, pyridine, naphthalene, indoles, thiazole, benzothiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, quinoline, quinazoline, substituting group is selected from halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, aryl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
3. according to compound and the pharmacologically acceptable salt thereof of claim 2, it is characterized in that,
A is selected from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, cyano group, methylamino-, sulfonamido, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethoxycarbonyl, ethanoyl;
N is selected from the integer of 0-5;
X is selected from hydrogen, F, Cl, methyl, trifluoromethyl;
Ar is selected from benzene replacement or that do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, quinoline, substituting group is selected from F, Cl, Br, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
4. according to compound and the pharmacologically acceptable salt thereof of claim 3, it is characterized in that,
A is selected from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, cyano group, methylamino-, methanesulfonamido, methylsulfonyl, sulfamyl, carboxyl, ethanoyl;
N is selected from the integer of 0-5;
X is selected from hydrogen, F, Cl, methyl, trifluoromethyl;
Ar is selected from benzene replacement or that do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, substituting group is selected from F, Cl, Br, methyl, ethyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
5. according to compound and the pharmacologically acceptable salt thereof of claim 4, it is characterized in that,
Wherein A is most preferably from hydrogen, fluorine, chlorine, bromine, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, cyano group, methylamino-, methylsulfonyl, sulfamyl, carboxyl, ethanoyl;
N is selected from the integer of 0-5;
X is most preferably from hydrogen, F, Cl, methyl, trifluoromethyl;
Ar is most preferably from the benzene replacing or do not replace, pyridine, naphthalene, indoles, thiazole, furans, pyrroles, thiophene, imidazoles, indazole, benzoglyoxaline, pyrazoles, benzopyrazoles, pyrimidine, oxazole, pyrazine, substituting group is selected from F, Cl, Br, methyl, sec.-propyl, the tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, acetoxyl group, cyano group, nitro, nitre acyloxy, amino, methylamino-, dimethylamino, sulfonamido, methanesulfonamido, to benzonitrile formamido group, methylsulfonyl, methylsulfonyl phenyl, sulfamyl, carboxyl, methoxycarbonyl base, ethoxycarbonyl, ethanoyl, benzoyl, phenyl, 5, 6, 7, 8-tetralyl, 4-hydroxyl-3, 5-di-t-butyl benzoylamino.
6. according to compound and the pharmacologically acceptable salt thereof of claim 1-5 any one, described compound is selected from:
1-(4-(2-(2-(is to methoxybenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(6-hydroxyl nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(pyridine-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to dimethylamino benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(5,6,7,8-naphthane-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(hydroxybenzoyl hydrazine carbonyl between 2-) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(naphthalene-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(pyridine-4-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(5-fluorine nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(6-fluorine nicotinoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(2,3-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(2,4-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(2,6-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(3,4-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(2,5-dichloro-benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(the adjacent fluorobenzoyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(the adjacent bromobenzene formyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to fluorobenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to bromobenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to acetyl oxygen benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to tert.-butylbenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to bromine Meta-dihydroxybenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(o-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(m-dimethyl amino benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to the adjacent chlorobenzoyl of methylsulfonyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to (2-hydroxybenzoyl) between methoxyl group) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(two (trifluoromethyl) benzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to the adjacent chlorobenzoyl of fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to chlorobenzoyl between fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to the adjacent bromobenzene formyl of fluorine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to fluorobenzoyl between bromine) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(the adjacent chlorobenzoyl of 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to fluorobenzoyl between methoxyl group) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(methoxycarbonyl base benzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to methylsulfonyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(5-methylpyrazine-2-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(nitre acyloxy benzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(indazole-3-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(2-methyl-4-first sulfophenyl thiazole-5-formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to cyano group benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(p-nitrophenyl formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(2-benzoyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
1-(the chloro-3-trifluoromethyl of 4-)-3-(4-(2-(2-(to sulfamyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl) urea
1-(4-(2-(2-nicotinic acid hydrazide carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to chlorobenzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(fluorobenzoyl between 2-() hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to methoxycarbonyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(Meta-dinitrobenzene formyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to toluyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(4-(is to di-t-butyl benzamido between hydroxyl) benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(4-(is to cyano group benzamido) benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base)-2-fluorophenyl)-3-(the chloro-3-trifluoromethyl of 4-) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(2,4 difluorobenzene base) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-trifluoromethyl) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-chloro-phenyl-) urea
1-(4-(2-(2-(is to chlorine m-trifluoromethyl benzoyl) hydrazine carbonyl) pyridine-4-oxygen base) phenyl)-3-(4-methyl-3-chloro-phenyl-) urea
7. according to the compound of any one in claim 1-6, it is characterized in that, described pharmacologically acceptable salt comprises: hydrochloride, hydrobromate, phosphoric acid salt, vitriol, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino acid salts, matrimony vine hydrochlorate, maleate, tartrate, fumarate, Citrate trianion, lactic acid salt.
In preparation claim 1-7 any one described compound and the method for pharmacologically acceptable salt, be selected from following 5 in method any one:
Route 1
Route 2
Route 3
Route 4
Route 5
9. preparation method according to Claim 8, is characterized in that, in step in route 1 (a), taking hydrazides 1 as raw material, is easy to obtain N '-sweet-smelling formacyl hydrazine derivative 2 with common method and acyl chlorides or acid anhydrides or acid-respons; In step (b), under alkaline environment, obtain compound 3 by the chlorine substituted ether in hydrazides 2 with para hydroxybenzene sulfonamide derivatives, in step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
10. preparation method according to Claim 8, is characterized in that, in step in route 2 (a), taking methyl esters 1 as raw material, obtains hydrazide compound 2 by hydrazinolysis; In step (b), make compound 2 and acyl chlorides or acid anhydrides or acid-respons be easy to obtain N '-Fang ethanoyl hydrazine derivative 3 by common method; In step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
11. preparation methods according to Claim 8, is characterized in that, in step in route 3 (a), taking ester 4 or acyl chlorides 5 as raw material, react and obtain bishydrazide derivative 2 with N '-Fang formyl hydrazine 6; In step (b), PAP derivative obtains compound 3 by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment; In step (c), can generate urea derivatives I by the aniline condensation of CDI and replacement; Also can obtain urea derivatives I by nucleophilic addition with the phenyl isocyanate replacing; Also can obtain urea derivatives I by nucleophilic substitution reaction with the phenylamino formic acid 4-nitro phenyl ester replacing.
12. preparation methods according to Claim 8, is characterized in that, in step in route 4 (a), phenolic compound 7 obtains urea derivatives I by the chlorine substituted ether in bishydrazide derivative 2 under alkaline environment; In step (b), ester cpds 8 reacts the same urea derivatives I that obtains with N '-Fang formyl hydrazine 6.
13. preparation methods according to Claim 8, is characterized in that, in route 5, taking hydrazides 9 as raw material, itself and aromatic acid derivative or acyl chlorides or anhydride reaction are easy to obtain urea derivatives I by common method.
The composition of 14. 1 kinds of medicines, is characterized in that, the compound that contains any one in claim 1-7 and pharmacologically acceptable salt thereof and technology of pharmaceutics acceptable carrier.
The compound of any one and pharmacologically acceptable salt thereof the application in the medicine of the preparation prevention disease relevant with protein kinase with treatment in 15. claim 1-7.
The compound of any one and pharmacologically acceptable salt thereof the application in the medicine of the preparation prevention disease relevant with Tyrosylprotein kinase with treatment in 16. claim 1-7.
17. according to the application of claim 16, it is characterized in that, the described disease relevant with Tyrosylprotein kinase is selected from tumour, immune disorder, sacred disease.
18. according to the application of claim 17, it is characterized in that, described tumor disease is selected from liver cancer, kidney, lung cancer, carcinoma of the pancreas, cancer of the stomach, colorectal cancer, bladder cancer and mammary cancer, ovarian cancer, squamous cell carcinoma, neurospongioma, incidence cancer.
CN201310141617.0A 2013-04-22 2013-04-22 N '-sweet-smelling formacyls neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes Active CN104109119B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310141617.0A CN104109119B (en) 2013-04-22 2013-04-22 N '-sweet-smelling formacyls neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310141617.0A CN104109119B (en) 2013-04-22 2013-04-22 N '-sweet-smelling formacyls neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes

Publications (2)

Publication Number Publication Date
CN104109119A true CN104109119A (en) 2014-10-22
CN104109119B CN104109119B (en) 2018-09-25

Family

ID=51706130

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310141617.0A Active CN104109119B (en) 2013-04-22 2013-04-22 N '-sweet-smelling formacyls neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes

Country Status (1)

Country Link
CN (1) CN104109119B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105017350A (en) * 2014-04-18 2015-11-04 杭州师范大学 Sugar-based pyridine type compound as well as preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078128A2 (en) * 2003-02-28 2004-09-16 Bayer Pharmaceuticals Corporation Substituted pyridine derivatives useful in the treatment of cancer and other disorders
WO2008115263A2 (en) * 2007-03-20 2008-09-25 Curis, Inc. Raf kinase inhibitors containing a zinc binding moiety
CN101381379A (en) * 2003-04-25 2009-03-11 吉里德科学公司 Kinase inhibitor phosphonate conjugates
CN102786469A (en) * 2011-05-18 2012-11-21 中国医学科学院药物研究所 O-pyridylhydrazide derivatives, and preparation method, medicinal composition and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078128A2 (en) * 2003-02-28 2004-09-16 Bayer Pharmaceuticals Corporation Substituted pyridine derivatives useful in the treatment of cancer and other disorders
CN101381379A (en) * 2003-04-25 2009-03-11 吉里德科学公司 Kinase inhibitor phosphonate conjugates
WO2008115263A2 (en) * 2007-03-20 2008-09-25 Curis, Inc. Raf kinase inhibitors containing a zinc binding moiety
CN102786469A (en) * 2011-05-18 2012-11-21 中国医学科学院药物研究所 O-pyridylhydrazide derivatives, and preparation method, medicinal composition and uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
史祥飞: "新型芳基脲类酪氨酸激酶抑制剂设计、合成及抗肿瘤活性评价", 《中国人民解放军军事医学科学院硕士学位论文》 *
孙超: "索拉非尼的合成工艺研究", 《黑龙江大学硕士研究生学位论文》 *
秦爱方，等: "含吡啶-2-酰肼结构的索拉非尼类似物的设计、合成及其抗肿瘤活性", 《药学学报》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105017350A (en) * 2014-04-18 2015-11-04 杭州师范大学 Sugar-based pyridine type compound as well as preparation method and application thereof
CN105017350B (en) * 2014-04-18 2018-03-16 杭州师范大学 A kind of glycosyl pyridine compounds and their and its preparation and application

Also Published As

Publication number Publication date
CN104109119B (en) 2018-09-25

Similar Documents

Publication Publication Date Title
CN101558055B (en) Spiro substituted compounds as angiogenesis inhibitors
CN101835752A (en) Heterocyclic amides useful for the treatment of cancer and psoriasis
CN102786469B (en) Adjacent pyridine hydrazide derivatives and preparation method thereof and pharmaceutical composition and purposes
WO2019031472A1 (en) NOVEL ANTHRANILIC ACID-BASED COMPOUND, AND Pin1 INHIBITOR, THERAPEUTIC AGENT FOR INFLAMMATORY DISEASES AND THERAPEUTIC AGENT FOR CANCER THAT USE THE SAME
CN105585565B (en) - 4- thiazole the pyridine derivative of anilino- containing 2- and its preparation method and pharmaceutical composition and purposes
CN105085406A (en) Benzimidazole ring-containing propiolamide derivative, preparation method, pharmaceutical composition and application thereof
CN104140395A (en) Butynoic amide derivative, and preparation process, pharmaceutical composition and uses thereof
CN101265274B (en) Pyrimidinthiazolamine derivatives, and preparation method, medicament composition and use thereof
CN102531949A (en) Substituted benzamide compounds and preparation method and application thereof
CN104109121A (en) N&#39;-aryl acetyl o-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof
CN104109119A (en) N&#39;-aryl formyl o-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof
CN110467616B (en) Preparation and application of triazolopyrazine compound containing heteroaryl substituted pyridazinone structure
CN104974109A (en) Propynamide derivatives containing thiazole as well as preparation method, drug composition and application thereof
CN104109118A (en) O-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof
CN105017221B (en) Benzimidizole derivatives and its preparation method and pharmaceutical composition and purposes
CN104211661A (en) Chalcone compound, preparation method and medicinal application thereof
CN104109120A (en) N&#39;-aryl acryloyl o-pyridine hydrazide derivatives, and preparation methods, pharmaceutical composition and application thereof
CN105461708A (en) Quinazoline tyrosine kinase inhibitor, and preparation method and application thereof
CN104230890A (en) Pyridine-2-amine derivative as well as preparation method, medicine compositions and application thereof
CN104974104A (en) Propynamide derivatives containing oxazole as well as preparation method, drug composition and application thereof
CN104684913A (en) Tris(hetero)arylpyrazoles and use thereof
CN104016942B (en) Thiazolinone analog derivative and pharmaceutical composition thereof and application
CN101423513B (en) Amine pyrimidine derivates, and production method thereof, and medicament composition and use
CN103570616A (en) N&#39;-straight chain alkylacyl o-pyridine hydrazide derivative, its preparation method, medicinal composition and use
CN102887867B (en) Triazine compound and preparation method and application of triazine compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant