CN103570614B - The hydrazide derivatives of pyridine 2 and its preparation method and pharmaceutical composition and purposes - Google Patents

The hydrazide derivatives of pyridine 2 and its preparation method and pharmaceutical composition and purposes Download PDF

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CN103570614B
CN103570614B CN201210249999.4A CN201210249999A CN103570614B CN 103570614 B CN103570614 B CN 103570614B CN 201210249999 A CN201210249999 A CN 201210249999A CN 103570614 B CN103570614 B CN 103570614B
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phenyl
urea
pyridine
chloro
epoxides
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CN103570614A (en
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冯志强
陈晓光
秦爱芳
李燕
张莉婧
唐克
霍连超
尹桂林
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Institute of Materia Medica of CAMS
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    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to the hydrazide derivatives of pyridine 2 shown in Formulas I and II, its officinal salt, hydrate and solvate, and preparation method thereof, composition containing this one or more compound, and purposes of such compound in terms of the disease relevant with protein kinase such as immune disorder and tumor disease is treated.

Description

Pyridine -2- hydrazide derivatives and its preparation method and pharmaceutical composition and purposes
Invention field
The present invention relates to pyridine -2- hydrazide derivatives shown in Formulas I and II, its officinal salt, its hydrate and solvate, Its polycrystalline and eutectic, the precursor or derivative of its same biological function, and preparation method thereof, contain this one or more compound Composition, and use of such compound in terms of the disease relevant with protein kinase such as immune disorder and tumor disease is treated On the way.
Background of invention
Recent years, due to the raising to enzyme and the understanding of some other biomolecule related to disease, greatly promote The discovery or development of the new drug for the treatment of disease are entered, protein kinase is exactly a kind of widely studied important one kind, and it is one Extended familys, it is relevant with the control of intracellular various signal transduction processes.Due to they structure and catalysis conservative it Be considered as evolving from a common ancestral gene.Nearly all kinases is all containing a 250-300 similar ammonia Base acid catalysis domain.These protein kinases are divided into multiple families, such as protein tyrosine kinase, egg according to the difference of phosphorylated substrate White serine/threonine kinase, lipoid etc..Typically, protein kinase is turned by influenceing a phosphoryl from a ribonucleoside triphosphote Move on to a protein receptor related to signal transduction pathway and carry out signal transduction in mediated cell.These phosphorylated events, which are used as, divides Sub switch adjusts the biological function of target protein, is finally excited and various extracellular and other stimulations are reacted.Kinases is present In multilayer signal transduction path, receptor tyrosine kinase be located at Tumor Angiongesis Signal transduction pathway upstream and tumour it is thin The upstream of born of the same parents' Signal transduction pathway.Serine/threonine protein kitase is located at tumour and the signal of Tumor Angiongesis cell turns The downstream of guiding path.Study and show, by blocking VEGFR and pdgf receptor in upstream, to block Raf/MEK/ERK in downstream, can Reduce the angiogenesis of tumour simultaneously and suppress the duplication of tumour cell, so as to hinder the growth of tumour.
Raf kinases is the protein product encoded by proto-oncogene raf, is made up of 648 amino acid, molecular weight 70000 ~74000D, contains 3 conserved regions in its structure, respectively CR1 (61~194D), CR2 (254~269D), CR3 (335~ 627D).CR1 is located at its molecule possessing amino, rich in cysteine, containing zinc-finger structure, the ligand binding domain with protein kinase C Structure is similar, is the main portions that the Ras of activation is combined with Raf-1 protein kinases.CR2 is also close to aminoterminal, rich in serine And threonine.CR3 is located at the c-terminus of its molecule, is the catalysis area of protein kinase.As Ras/Raf/MEK/ERK paths In a Key kinases, Raf can rely on or independent of Ras by way of play its signal transduction adjustment effect.As Raf The stream substrates of kinases, the MEK phosphorylated CREBs of activation, adjust various cell functions.Once excessive activation occurs for the path, then Cell propagation is caused to accelerate to extend with the cells survival phase, so as to lead oncogenic generation.Research shows, more than 80% oncogene It is present in the cancer encoding proteins EGFR-TK of people with proto-oncogene（PTK）In, the generation and development of the various cancers of the mankind be with Come from that the abnormal cell signal transduction of protein tyrosine kinase is relevant, one of malignant cell is mainly characterized by tyrosine-kinase The increase of enzymatic activity.Therefore, suppress the activation of EGFR-TK or block its signal transduction path to turn into the new way for controlling tumour Footpath.
Endothelial growth factor receptor (EGFR) is a kind of protein tyrosine kinase receptor (RTK), positioned at No. 7 chromosome P13~q22 areas, total length 200kb, it is made up of 28 extrons, encodes 1186 amino acid, its glycoprotein molecule amount is about 170kDa, it is distributed widely in all histocytes in addition to ripe Skeletal Muscle Cell, parietal endoderm and hematopoietic tissue.EGFR There is the similar acceptor molecule of 4 structures in family：ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), ErbtM (HER4), Belong to receptor tyrosine kinase (RTKS).They all contain 1 extracellular ligand binding domains, 1 membrane spaning domain and 1 Cytoplasmic domain with tyrosine kinase activity.Its intracellular region and erbB oncoprotein very high homologies.EGFR activation The Receptor dimerization that can be induced by part, which acts on, to be realized.In ErbB receptor family, in addition to HER2, other members have it Respective ligand, various parts are to pass through proteolysis by corresponding transmembrane protein precursor, there is 1 EGF sample Domain.Include EGF (EGF), transforming growth factor α (TGF-α), two-way tune with the part of EGFR specific bindings Save albumen (AR), beta cell plain (BTC), Heparin-binding EGF like growth factors (HB-EGF), epiregulin (EPR) etc..It is extracellular Cause ErbB2 configurations to change after ligands, EGF (endothelial growth factors) and ErbB2 specific binding, cause Receptor dimerization so as to Activate their cytoplasmic location.After ErbB2 intracellular region tyrosine phosphorylation and then second messenger's transduction is activated, passes through MAPK The activation (regulation kinases Erkl and Er1) of (mitogen protein kinase) approach inducing cell external signal：Pass through PDK (phosphatidyl-4s Alcohol kinases) pathway activation signal transducer JAK；Further start STAT1, STATS3 transcription activators；On the other hand, cell Interior signal activates the ERK (extracellular regulated protein kinase), Jin Erjie in downstream by Grb2 (growth factor receptor binding protein precursor) Lead ATF, NF-kB, Ap-1, C-fos and C-Jun transcription activating.These are all the growths that EGFR is mediated or carcinogenic Basic downstream pathway.Abnormal EGFR activation mechanisms include acceptor amplification in itself, the overexpression of receptors ligand, Activating mutations with And the shortage of negativity regulation approach, therefore EGFR induced cancers are at least through 3 kinds of mechanism：The overexpression of EGFR parts, EGFR's Amplification or EGFR mutation activation.In this 3 kinds of mechanism, EGFR mutation activation is to cause tumour cell aberrant biological behavior Main factor.Some mutation of EGFR gene can cause the enhancing of acceptor effect and the extension of duration.Lynch etc. is proved Become isoreceptor and have no effect on the stability of receptor protein, activated and found by Tyr1068 phosphorylation assay EGFR, wild type by The activation 15min of body is lowered, and becomes the effect that isoreceptor shows 2 times higher than normal EGFR, and the continuous activation more than 3h.
EGFR mutation do not have an impact the ability that tumour cell combines with TKI (tyrosine kinase inhibitor).TKI is to those The reason for causing EGFR to activate because of mutation, can be explained by oncogeneaddiction models.Pass through Ras.Raf- MEK.ERK1/ERK2, PI3K.Akt, STAT3/STAT5 path, EGFR discontinuity heights activation downstream signal, start EGFR regulations Anti-apoptotic and survival signaling, cause cancer cell to become dependent upon this signal to maintain its existence -- i.e. with oncogene (mutation The feature that EG is relied on；After EGFR signals are blocked using specificity T KI, its proliferative effects and output survival signaling will be eliminated, Cause death of neoplastic cells.Result, it is believed that the variation of signal transduction pathway is that the high sensitive basis of medicine occur in cancer cell. On the contrary, the tumour cell (reactionless to Gefitinib, Erlotinib) that normal cell or non-EGFR are relied on is unaffected.Because Existence is also driven by other genes, or can be made up after EGFR suppression by other RTK.In oncogene relies on model, The oncogene that cell carcinomas relies on can produce the output of apoptosis and 2 signals of surviving simultaneously.Under general Sui condition, oncogene is swashed It is living.Survival signaling is occupied an leading position, and apoptotic signal is in low relative levels, cancer cell is maintained growth and propagation.Work as cancer It is that existence significantly weakens rapidly first in the window phase of key after the acute inactivation of gene.And apoptotic signal slowly declines.Cause This causes signal uneven (apoptotic signal accounts for leading), and irreversible apoptosis occurs for active cell.Research finds to use tyrosine-kinase Enzyme inhibitor Gefitinib (gefitinib)/Tarceva (Erlotinib) treatment NSCLC patient, about 10% patient performance Go out rapid and satisfied clinical effectiveness, further study show that these patient's overwhelming majority have EGFR genetic mutation.Current The known gene mutation relevant with EGFR-TKI (endothelial growth factor receptor tyrosine kinase inhibitor) is confined to following several Kind：G719X (18 extron), E746-A450 lack (19 extron), L858R (21 extron), L861Q (21 extron), T790M (20 extron) and D770-N771 (20 extron).Wherein E746-A450 is lacked and L858R mutation and TKI treatment Imitate height correlation.Analysis results of Mitsudomi T, the Yatabe Y to 568 Patients with Non-small-cell Lung：All non-small thin About 90% EGFR genetic mutation is concentrated in 19 or 21 extrons in born of the same parents' patients with lung cancer, wherein the deletion mutation of 19 extrons And the patient of 21 point mutation in extron takes EGFR-TKI effective percentage and reaches more than 70%.Recent research prompting, The slotting human nature mutation (D770-N771) of EGFR extron 20s can make acceptor reduce by 100 times to EGFR-TKI sensitiveness, face It has also been found that the patient with this mutation is to EGFR-TKI therapeutic response unobvious on bed.The amplified production of extron 20 is carried out Subcloning analysis finds that T79OM mutation are that a base-pair occurs from cytidine (C) changing to thymidine (T) Become, be exactly that the threonine in the site of EGFR tyrosine kinase domains 790 is substituted (T790M) by methionine in protein level, it is this Mutation can make EGFR again in being activated state, be that mutation causes the reason for resistance so as to cause TKI acquired resistance EGFR structures change, and make TKI is in connection steric effect occur.
There is the reason for research prompting KRAS is probably Gefitinib, Erlotinib initial drug-resistant.Helena The TKI therapeutic effects of 1008 NSCLC patients are summarized in linardou Meta analyses, at 165 of generation K-ras mutation In patient, 94% patient is treated without significant reaction to TKI.In general, KRAS and EGFR mutation NSCLC is excluded each other Notable difference be present in different tumors subtypes：EGFR mutation are mainly seen in non-smoker, and KRAS is more often seen The related cancer of smoking.Because KRAS is always betided in the NSCLC with Wild type EGFR, it is difficult to differentiate between pair EGFR-TKI insensitive is mutated because of KRAS, or because of without EGFR on earth.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) family includes 3 kinds of hypotypes, i.e.,:VEGFR-1 (while Flt-1 can also be write), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt 1), in addition, also l and 2 two cooperative expert systems of neuropilin (neuropilin).Wherein VEGFR-1 Vascular endothelial cell, candidate stem cell, macrophage and monocyte are mainly distributed on, can be with VEGF-A, VEGF-B and P1GF With reference to mainly relevant with the growth regulating of candidate stem cell.VEGFR-2 is mainly distributed on vascular endothelial cell and lymphatic endothelia is thin In born of the same parents, it can be combined with VEGF-A, VEGF-C, VEGF-D, VEGF-E.VEGF stimulating endothelial cells propagation, increase vascular permeability Property and the effect of new vascular generation mainly realize compared with VEGFR-2 by combining and activating VEGFR-2, VEGFR-l with VEGF affinity is high 10 times, but adjusts the active much lower of endothelial cell, it may be possible to has negative regulation to VEGFR-2 activity Effect.VEGFR-3 is mainly expressed in lymphatic endothelial cells, can be combined with VEGF-C and VEGF-D, regulates and controls lymphatic endothelium Growth.
Research shows：Given up when diameter of tumor is more than 2mm, it is necessary to there is new vessels to provide nutriment and excretion metabolism Thing.VEGF/VEGFR signal paths serve in tumor vascular generation it is key, can be by blocking or disturbing VEGF/ VEGFR signal paths suppress the new life of blood vessel, to reach the effect of growth for controlling tumour.With traditional cytotoxic drug phase Than the antineoplastic using VEGF/VEGFR-2 as target has very big advantage under normal physiological conditions, and angiogenesis only exists Worked in the physiological activity such as wound healing and menstrual cycle, so tumour is treated using anti-angiogenic medicaments, to human body poison Property effect it is small, vascular endothelial cell directly contacts with blood, make medicine be more prone to reach action site pass through it is current right The understanding of VEGF/VEGFR signal path mechanism of action, following several possible inhibitor research directions can be obtained：A. utilize Monoclonal antibody suppresses VEGF or VEGFR, prevents it from specifically binding, disabling signal conduction.Gene can certainly be utilized Technology suppresses their expression, weakens its activity.B. specific micromolecular inhibitor is designed, is attached to the extracellular VEGF knots of VEGFR Close region, competitive antagonism VEGF, similarly or be attached to the particular combination domain of VEGFR on VEGF, competitive antagonism VEGFR.C. VEGFR intracellular kinase domain, mainly ATP binding site are suppressed, competitively antagonism ATP, makes it not carry Phosphorus supply acidic group.D. the critical proteins for suppressing the VEGFR downstream signals of intracellular considers the compliance of patient, can be oral it is small Molecule inhibitor may have good prospect.
Platelet derived growth factor (platelet.derived growth factor, PDGF) is induction and promotes blood Pipe formation acts on one of most strong, most single-minded angiogenesis factor.PDGF mainly by being combined with pdgf receptor (PDGFR), enters And activated protein kinase signal transduction pathway and play a role.PDGFR is made up of two kinds of subunits of α and β, shares 3 kinds of dimers (PDGFR- α α, α β, β β), wherein β β dimerization receptor body (PDGFR- β) are mostly important, and its molecular weight is about 180~190ku, category In tyrosine kinase receptor (receptor tyrosine kinase, RTK) family.PDGFR is in tumour formation and development process In also play an important role.PDGFR- β overexpression or overactivity can stimulate intratumoral vasculature to generate, and promote tumour Growth.PDGFR- β are one of molecular markers of tumor vascular endothelial cell, the high expression in endothelial cells in tumor neogenetic blood vessels, It is and closely related with the growth, transfer and prognosis of some tumours.So PDGFR- β are an ideal neoplasm targeted therapies Target.
Raf kinases and its Raf/MEK/ERK paths of mediation have remarkable effect in tumour progression and transfer process, and Include EGF (EGF), VEGF (VEGF) and platelet growth factor with many growth factors (PDGF) it is etc. closely related.People have thought a variety of methods to adjust this path, including the farnesyl for suppressing Ras albumen Change, suppress the expression of Rat "-I kinases (also referred to as C-RAF kinases), suppress the activity of Raf kinases and MEK kinases.Above-mentioned method Not only inhibit ERK signal transduction but also successfully inhibit the growth of xenograft tumours.In addition, existing evidence is shown, greatly Partial tumors are not dominated by single signal conduction path, carry out suppressing that bigger curative effect may be obtained for Mutiple Targets.
Many diseases are that the abnormal cell effect triggered with protein kinase mediated event is associated.These disease bags Include, but be not limited to, tumour, inflammation disease, immunological diseases, bone disease, metabolic disease, sacred disease, cardiovascular and cerebrovascular disease, hormone Related disease etc..Consequently found that it is very important with searching kinases inhibitor as medicine.Although many hairs It is bright that very big contribution has been made to this area, but to improve medication effect, this area still is continuing to study.
Goal of the invention
It is an object of the invention to provide pyridine -2- hydrazide derivatives, its officinal salt, its solvate, its prodrug, its Polycrystalline or eutectic.
Another object of the present invention is to provide the preparation method of pyridine -2- hydrazide derivatives.
It is still another object of the present invention to provide a kind of drug regimen containing this compound of pyridine -2- hydrazide derivatives Thing.
A further object of the present invention is to provide such compound in anticancer, and with the medicine of protein kinase related disorder Purposes.
The content of the invention
In order to complete the purpose of the present invention, can adopt the following technical scheme that：
The present invention is to be related to the pyridine -2- hydrazide derivatives with having structure：
Or its officinal salt, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function or spread out Biology.
In the embodiment of formula I and II pyridine -2- hydrazide derivatives,
R1H can be following structural
Wherein X and Y can be independently selected from hydrogen, halogen, trifluoromethyl, methyl, methoxyl group, dimethylamino, cyano group, nitre Base, ester group, methylamino, mesyl, sulfamoyl, diformazan sulfamic, hydroxyl, amino, carboxyl.
Wherein n may be selected from 0,1,2,3,4,5.
R2And R3Hydrogen can be independently selected from, substituted C1-8 alkyl, substituted C1-8 cycloalkyl, substituted C1-8 is miscellaneous Cycloalkyl, substituted C2-8 alkoxyalkyls, substituted C2-8 alkane aminoalkyls, substituted C5-10 aryl, substituted C3-8 heteroaryls Base, substituted C5-12 aralkyl, substituted C5-12 heteroarylalkyls；Wherein alkyl includes saturation with undersaturated, and substituent can Selected from hydrogen, halogen, hydroxyl, methoxyl group, C1-6 alkyl, amino, dimethylamino, nitro, carboxyl, ester group, cyano group, mesyl, Trifluoromethyl, Carboxvmethoxv.R2And R3C2-7 ring can be connected into during selected from alkyl.When Y is hydrogen atom, R2And R3It is different When be methyl.For II formulas, R2And R3It is asynchronously hydrogen.
In the embodiment of formula I and II pyridine -2- hydrazide derivatives：
X and Y independently can be more preferably from hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, dimethylamino, cyanogen Base, nitro, methylamino, mesyl, sulfamoyl, hydroxyl, amino, carboxyl.
Wherein n may be selected from 0,1,2,3,4.
R2And R3Can be independently more preferably from hydrogen, substituted C1-8 alkyl, substituted C1-8 cycloalkyl, substituted C1- 8 Heterocyclylalkyls, substituted C2-8 alkoxyalkyls, substituted C2-8 alkane aminoalkyls, substituted C5-10 aryl, substituted C3-8 are miscellaneous Aryl, substituted C5-12 aralkyl, substituted C5-12 heteroarylalkyls；Wherein alkyl includes saturation with undersaturated, substituent It may be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, methyl, ethyl, the tert-butyl group, amino, dimethylamino, nitro, carboxyl, ester group, Cyano group, mesyl, trifluoromethyl, Carboxvmethoxv.R2And R3C2-6 ring can be connected into during selected from alkyl.When Y is hydrogen atom When, R2And R3It is asynchronously methyl.For II formulas, R2And R3It is asynchronously hydrogen.
In the embodiment of formula I and II pyridine -2- hydrazide derivatives：
Wherein X and Y independently more preferably from hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, dimethylamino, Cyano group, nitro, methylamino, mesyl, sulfamoyl, hydroxyl, amino.
Wherein n may be selected from 0,1,2,3.
R2And R3Can be independently more preferably from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, n-pentyl, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, iso-amylene Base, carboxymethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, expoxy propane base, epoxy butane base, epoxy penta Alkyl, cyclohexene oxide groups, nafoxidine base, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxyl methyl, methoxycarbonyl Methyl, ethoxymethyl, ethoxycarbonyl methyl, the third oxygen methyl, the third oxygen formyl methyl, fourth oxygen methyl, aminomethyl, first carbamyl first Base, dimethyl aminomethyl, second aminomethyl, second carbamoylmethyl, the third aminomethyl, fourth aminomethyl, dimethylamino acrylic, methoxy propyl Alkenyl, phenyl, difluorophenyl, chlorophenyl, bromo phenyl, fluorine chlorophenyl, fluorine bromo phenyl, bromine chlorophenyl, methylbenzene Base, trifluoromethyl, hydroxy phenyl, dimethylamino phenyl, Dimethoxyphenyl, dihydroxy phenyl, cyano-phenyl, carboxyl first Phenyl, methoxycarbonyl phenyl, methoxyl group hydroxy phenyl, carboxyl phenyl, di-t-butyl hydroxy phenyl, naphthyl, furyl, fourth Lactone group, pyrrole radicals, oxo-pyrrolidine base, thienyl, thiazolyl, halo thiazole base, ester is for thiazolyl, methyl thiazolium oxazolyl, miaow Oxazolyl, quinolyl, pyridine radicals, halogenated pyridyl, picolyl, ester is for pyridine radicals, pyrimidine radicals, a chlorophenylmethyl, to amino Benzyl, indole methyl, picolyl.R2And R3C3-6 ring can be connected into during selected from alkyl, including：When Y is hydrogen atom, R2And R3It is asynchronously methyl.For II formulas, R2And R3 It is asynchronously hydrogen.
In the embodiment of formula I and II pyridine -2- hydrazide derivatives：
Wherein X and Y independently particularly preferably from hydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, methoxyl group, dimethylamino, Cyano group, nitro, methylamino, mesyl, sulfamoyl.
Wherein n may be selected from 0,1,2,3.
R2And R3Can be independently particularly preferably from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, n-pentyl, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, iso-amylene Base, carboxymethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, epoxy butane base, epoxypentane base, epoxy oneself Alkyl, nafoxidine base, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxycarbonyl methyl, ethoxycarbonyl methyl, third Oxygen methyl, aminomethyl, first carbamoylmethyl, dimethyl aminomethyl, second aminomethyl, second carbamoylmethyl, dimethylamino acrylic, Methoxvpropenvl, phenyl, difluorophenyl, chlorophenyl, fluorine chlorophenyl, aminomethyl phenyl, trifluoromethyl, hydroxy benzenes Base, dimethylamino phenyl, Dimethoxyphenyl, dihydroxy phenyl, cyano-phenyl, 3- hydroxyl -4- methoxyphenyls, carboxy-methoxy Base phenyl, methoxycarbonyl phenyl, 3- methoxyl group -4- hydroxy phenyls, carboxyl phenyl, 3,5- di-tert-butyl-hydroxy phenyls, furans Base, butyrolactone base, pyrrole radicals, oxo-pyrrolidine base, thienyl, thiazolyl, halo thiazole base, methyl thiazolium oxazolyl, imidazole radicals, quinoline Quinoline base, pyridine radicals, halogenated pyridyl, picolyl, ester is for pyridine radicals, pyrimidine radicals, a chlorophenylmethyl, p-aminophenyl methyl, Indole methyl, picolyl.R2And R3C3-6 ring can be connected into during selected from alkyl, including：When Y is hydrogen atom, R2And R3It is asynchronously methyl.
For II formulas, R2And R3It is asynchronously hydrogen.
In the embodiment of formula I and II pyridine -2- hydrazide derivatives：
Wherein X and Y independently most preferably from hydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, methoxyl group, dimethylamino, Cyano group, nitro, methylamino, mesyl, sulfamoyl.
Wherein n may be selected from 0,1,2,3.
R2And R3Can be independently most preferably from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, n-pentyl, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, iso-amylene Base, carboxymethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, epoxy butane base, epoxypentane base, epoxy oneself Alkyl, nafoxidine base, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxycarbonyl methyl, ethoxycarbonyl methyl, third Oxygen methyl, first carbamoylmethyl, dimethyl aminomethyl, second carbamoylmethyl, dimethylamino acrylic, phenyl, a fluorophenyl, to chlorine Phenyl, Chloro-O-Phenyl, chlorphenyl fluorine, p-methylphenyl, o-methyl-phenyl, p-trifluoromethyl phenyl, m-trifluoromethyl benzene Base, p-hydroxybenzene, a hydroxy phenyl, to dimethylamino phenyl, m-dimethyl amino phenyl, 3,4- Dimethoxyphenyls, 3,4- Dihydroxy phenyl, to cyano-phenyl, a cyano-phenyl, to carboxyl phenyl, 3,5- di-tert-butyl-hydroxy phenyls, 3- hydroxyls -4- Methoxyphenyl, it is right（Carboxvmethoxv）Phenyl, to methoxycarbonyl phenyl, furyl, butyrolactone base, pyrrole radicals, oxo pyrroles Alkyl, thienyl, thiazolyl, chloro-thiazole base, fluoro thiazolyl, methyl thiazolium oxazolyl, imidazole radicals, quinolyl, pyridine radicals, chloro Pyridine radicals, picolyl, pyrimidine radicals, a chlorophenylmethyl, p-aminophenyl methyl, indole methyl, picolyl.R2And R3It is selected from C3-6 ring can be connected into during alkyl, including：When Y is hydrogen atom, R2And R3 It is asynchronously methyl.For II formulas, R2And R3It is asynchronously hydrogen.
The invention also discloses the method for preparing the compounds of this invention, including following route steps：
Route 1
Step（a）In with hydrazides 1 be raw material, being readily available hydrazides with common method and ketone or aldehyde carbonyl groups condensation derives Thing 2.Step（b）In, to R1H is under alkaline environment by obtaining compound 3 or formula Iization to the chlorine substituted ether in hydrazides 2 Compound, then in step（c）Middle reduced provides compound 4 or Compounds of formula II.
Route 2
Step（a）In, be raw material with hydrazide derivatives 2, with para hydroxybenzene amine under alkaline environment by hydrazides 2 Chlorine substituted ether obtains compound 5, then step（b）In can be spread out by CDI and 4- chloro- 3- 5-trifluoromethylanilines condensation generation urea Biology 6;Also urea derivative 6 can be obtained by nucleophilic addition with 4- chloro- 3- trifluoromethylbenzenes based isocyanates；Also can be with 4- Chloro- 3- trifluoromethyls phenylamino formic acid 4- nitro phenyl esters cross nucleophilic substitution and obtain urea derivative 6.Step（c）In gone back again Original provides compound 7.
Route 3
Step（a）In, it is raw material with ester 8 or acyl chlorides 9, hydrazide derivatives 11 is obtained with the reaction of alkyl hydrazine 10.
Step（b）In, the fluoro- PAPs of 3- are under alkaline environment by the chlorine substituted ether in hydrazide derivatives 11 Obtain compound 12.Step（c）In, compound 12 can pass through the chloro- 3- 5-trifluoromethylanilines condensation generation urea derivatives of CDI and 4- 13;Also urea derivative 13 can be obtained by nucleophilic addition with 4- chloro- 3- trifluoromethylbenzenes based isocyanates；Also can be with 4- Chloro- 3- trifluoromethyls phenylamino formic acid 4- nitro phenyl esters cross nucleophilic substitution and obtain urea derivative 13.
Route 4
Step（a）In, the chloro- 3- 5-trifluoromethylanilines 14 of 4- and para-aminophenol or derivatives thereof such as the fluoro- 4- aminobenzenes of 3- Phenol can be condensed generation urea derivative 15 by CDI;The fluoro- PAPs of 3- also can be with the chloro- 4- NCOs trifluoromethyls of 2- Benzene obtains urea derivative 15 by nucleophilic addition.Step（b）In, urea derivative 15 is under alkaline environment by spreading out to hydrazides The nucleophilic displacement of fluorine of chlorine is etherified to obtain compound 17 in biology 11；Also can be first under alkaline environment by chlorine in ester compounds 8 Nucleophilic displacement of fluorine is etherified to obtain compound 16, then obtains compound 17 with the reaction of alkyl hydrazine 10.
Route 5
It is raw material with N- methyl nitrosoureas 18, is first etherified under alkaline environment with para hydroxybenzene amine or derivatives thereof reaction Product 19, then basic hydrolysis acid amides 19 obtains carboxylic acid 20, then esterification generates compound 21, can pass through CDI and the chloro- 3- tri- of 4- Methyl fluoride aniline condensation generates urea derivative 22;Also can be anti-by nucleophilic addition with the chloro- 3- trifluoromethylbenzenes based isocyanates of 4- Urea derivative 22 should be obtained；Also nucleophilic substitution can be crossed with the chloro- 3- trifluoromethyls phenylamino formic acid 4- nitro phenyl esters of 4- and obtains urea Derivative 22.Then urea derivative 22 obtains hydrazides 23 with hydrazine reaction, then is condensed itself and ketone or aldehyde carbonyl groups with common method Hydrazide derivatives 24 are readily available, is then reduced and provides compound 25.
In addition, the initiation material and intermediate in above-mentioned reaction are readily obtained, or to those skilled in the art It can be easy to synthesize with the conventional method in organic synthesis.
Pyridine -2- hydrazide derivatives described in Formulas I and II can exist in the form of solvate or non-solvent compound, using not Same solvent carries out crystallization and is likely to be obtained different solvates.Pharmaceutically acceptable salt described in Formulas I and II includes different acid Addition salts, such as acid-addition salts of following inorganic acid or organic acid：Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, to toluene sulphur Acid, trifluoroacetic acid, matrimony vine acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.Pharmaceutically acceptable salt also wraps described in I Include different alkali metal salts（Lithium, sodium, sylvite）, alkali salt（Calcium, magnesium salts）.Pharmaceutically acceptable salt described in Formulas I and II is also Including different alkali metal salts（Lithium, sodium, sylvite）, alkali salt（Calcium, magnesium salts）And ammonium salt, and can provide physiologically acceptable The salt of the organic base of cation, such as methylamine, dimethylamine, trimethylamine, piperidines, morpholine and three（2- ethoxys）The salt of amine.In this hair All these salt in bright scope can all use conventional method to prepare.In described 2- pyridines hydrazide derivatives and its solvate In the preparation process of its salt, different crystallization conditions are likely to occur polycrystalline or eutectic.
The invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition can basis It is prepared by method well known in the art.Can be by by the compounds of this invention and one or more pharmaceutically acceptable solids or liquid Excipient and/or assistant agent combine, and any formulation used suitable for human or animal is made.The compounds of this invention is in its pharmaceutical composition In content be usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and method of administration can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution（Including True solution and colloidal solution）, emulsion（Including o/w types, w/o types and emulsion）, supensoid agent, injection（Including liquid drugs injection, powder-injection And transfusion）, eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet（Including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet）, capsule（Including hard shell capsules, soft capsule, capsulae enterosolubilis）, granule, dissipate Agent, micropill, dripping pill, suppository, film, paster, gas（Powder）Mist agent, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.
In order to which the compounds of this invention is made into tablet, various excipient well known in the art can be widely used, including it is dilute Release agent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, breast Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Ripple nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double Synusia and multilayer tablet.
In order to which administration unit is made into capsule, active ingredient the compounds of this invention and diluent, glidant can be mixed Close, mixture is placed directly within hard shell capsules or soft capsule.Also can active ingredient the compounds of this invention is first and diluent, bonding Particle or micropill is made in agent, disintegrant, then is placed in hard shell capsules or soft capsule.For preparing each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For the compounds of this invention is made into injection, water, ethanol, isopropanol, propane diols or their mixture can be used Make solvent and add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure regulator.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Injection, it can also add mannitol, glucose etc. and be used as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or treated disease The individual instances of degree, patient or animal, method of administration and formulation etc. can have large-scale change.In general, the present inventionization The daily Suitable dosage ranges of compound are 0.001-150mg/Kg body weight, preferably 0.01-100mg/Kg body weight.Above-mentioned dosage With a dosage unit or several dosage unit administrations can be divided into, this depends on the clinical experience of doctor and including with other The dosage regimen for the treatment of means.
The compound or composition of the present invention can individually be taken, or merge use with other treatment medicine or symptomatic drugs. When the compound of the present invention exists with other medicines to act synergistically, its dosage should be adjusted according to actual conditions.
The compounds of this invention is Mutiple Targets kinases inhibitor or its precursor, and these protein kinases are according to phosphorylated substrate Difference be divided into multiple families, such as protein tyrosine kinase, Protein Serine/threonine kinase, lipoid etc..Typically, albumen Kinases is transferred to a protein receptor related to signal transduction pathway by influenceing a phosphoryl from a ribonucleoside triphosphote Carry out signal transduction in mediated cell.Biological function of these phosphorylated events as molecular switch regulation target protein, is finally swashed Hair is reacted to various extracellular and other stimulations.Kinases is present in multilayer signal transduction path, receptor tyrosine kinase Positioned at the upstream of Tumor Angiongesis Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine Protein kinase is located at the downstream of the Signal transduction pathway of tumour and Tumor Angiongesis cell.Research shows by blocking in upstream VEGFR and pdgf receptor, block Raf/MEK/ERK in downstream, the angiogenesis of tumour can be reduced simultaneously and to suppress tumour thin The duplication of born of the same parents, so as to hinder the growth of tumour.The compounds of this invention has higher bioavilability, is disliked available for a variety of mankind The treatment of property tumour, including described tumor disease is liver cancer, kidney, lung cancer, cancer of pancreas, colorectal cancer, carcinoma of urinary bladder and mammary gland Cancer, oophoroma, squamous cell carcinoma, glioma, leukaemia, incidence cancer.
Embodiment
Invention is described further below with reference to embodiment, but not limit the scope of the invention.
Determining instrument：The NMR spectrum type NMRs of Vaariaan Mercury 300.Mass spectrum ZAD-2F With VG300 mass spectrographs.
Embodiment 1. (E)-N- (butyl- 2- pitches base) 4- chloropyridine -2- hydrazides
By 1.7g（10mmol）4- chloropyridine -2- hydrazides is dissolved in 20mL absolute ethyl alcohols, and solution is milky, to reaction solution In sequentially add 0.72g（10mmol）The glacial acetic acid of 2- butanone and catalytic amount, it is heated to flowing back, solution gradually becomes clarification, after 12h Stop reaction, steam partial solvent, there is solid precipitation after cooling, filter, 95% ethanol is washed 3 times, obtains colorless solid 0.7g.1H NMR(300MHz,DMSO-d6):δ(ppm):10.71(s,1H,-NHCO-),8.67(d,1H,ArH),8.09(s,1H,ArH), 7.82(d,1H,ArH),2.34(q,2H,-CH2-),1.97(s,3H,-CH3),1.09(t,3H,-CH3)..MS(FAB):（M++1 =226）.
Embodiment 2. (E)-N- (butyl- 2- pitches base) -4- (4- phenalgins epoxide) pyridine -2- hydrazides
By 0.7g（6.48mmol）PAP is dissolved in the DMF of 6mL dryings, under stirring, adds 0.8g （6.48mmol）T-BuOK, lead to N2Protection, after reacting at room temperature 5h, add 1.2g（5.4mmol）(E)-N- (butyl- 2- pitches base) 4- chlorine Pyridine -2- hydrazides and 0.44g（3.24mmol）Potassium carbonate, after rise temperature reacts 48h to 80 °C, stop reaction, decompression steams Most of solvent, is diluted with water, and ethyl acetate extraction, water and saturated sodium-chloride water solution are respectively washed 3 times, anhydrous sodium sulfate drying, Filtering, column chromatography, obtains yellow oil 0.63g.1H NMR(300MHz,DMSO-d6):δ(ppm):10.68(s,1H,- NHCO-),8.48(d,1H,ArH),7.37(d,1H,ArH),7.12(m,1H,ArH),6.87(d,2H,ArH),6.64(d,2H, ArH),5.18(s,2H,-NH2),2.31(q,2H,-CH2-),1.94(s,3H,-CH3),1.06(t,3H,-CH3).MS(FAB): （M++1=299）
Embodiment 3. (E) -1- (4- (2- (2- (butyl- 2- pitches base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) -3- (chloro- 3- of 4- Trifluoromethyl) urea
By 1.12g（6.9mmol）CDI is dissolved in the dichloromethane of 7mL dryings, and beginning solution is white opacity, will be dissolved with 1.2g（6.2mmol）The 10mL dichloromethane solutions of the chloro- 3- 5-trifluoromethylanilines of 4-, are instilled in above-mentioned solution, solution gradually becomes Clarification, after 8h is stirred at room temperature, is added dissolved with 0.625g（2.1mmol）(E)-N- (butyl- 2- pitches base) -4- (4- phenalgins epoxide) pyrrole The dichloromethane solution 5mL of pyridine -2- hydrazides, after being heated to reflux 10h, stop reaction, column chromatography separates object 0.32g.1H NMR(300MHz,DMSO-d6):δ(ppm):10.70(s,1H,-NHCO-),9.21(s,1H,-NHCO-),9.00(s,1H,- NHCO-),8.54(d,1H,ArH),8.11(d,1H,ArH),7.68~7.62(m,2H,ArH),7.60(d,2H,ArH),7.41 (d,1H,ArH),7.20~7.17(m,3H,ArH),2.32(q,2H,-CH2-),1.94(s,3H,-CH3),1.06(t,3H,- CH3).MS(FAB)（M++1=520）
Embodiment 4.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (sec- butyl) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
By (E) -1- (4- (2- (2- (butyl- 2- pitches base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) -3- (the chloro- 3- fluoroforms of 4- Base phenyl) urea 150mg（0.29mmol）It is dissolved in 7mL absolute methanols, adds 36.3mg（0.58mmol）Sodium cyanoborohydride and The glacial acetic acid of equivalent, 18h is reacted at room temperature, raw material has reacted complete, and decompression steams solvent, ethyl acetate extraction, water and saturation chlorine Change sodium solution respectively to wash 2 times, anhydrous sodium sulfate drying, filter solvent evaporated, obtain yellow solid 133mg.1H NMR(300MHz, DMSO-d6):δ(ppm):10.30(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.50 (d,1H,ArH),8.12(s,1H,ArH),7.69~7.64(m,2H,ArH),7.60(d,2H,ArH),7.35(d,1H,ArH), 7.20~7.14(m,3H,ArH),4.89(brs,1H,-NH-),2.90~2.84(m,1H,-CH<),1.52~1.44(m,1H,- CH2-),1.28~1.19(m,1H,-CH2-),0.96(d,3H,-CH3),0.86(t,3H,-CH3).MS(FAB)（M++1=522）.
Embodiment 5.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- cyclopentylidene base hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
2- butanone is replaced with cyclopentanone, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 2.39g。1H NMR(300MHz,DMSO-d6):δ(ppm):10.49(s,1H,-NHCO-),9.42(s,1H,-NHCO-),9.17 (s,1H,-NHCO-),8.53(d,1H,ArH),8.11(d,1H,ArH),7.67~7.62(m,2H,ArH),7.59(d,2H, ArH),7.42(d,1H,ArH),7.21~7.17(m,3H,ArH),2.41(d,4H,2×-CH2-),1.82~1.68(m,4H,2 ×-CH2-).MS(FAB)（M++1=532）.
Embodiment 6. (E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (2- methyl propylidene base) hydrazine carbonyl) Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 2 methyl propanal, is carried out with reference to the operation of embodiment 3, obtained target compound is solid for white Body 110mg.1H NMR(300MHz,CD3OD-d4):δ(ppm):8.43(d,1H,ArH),7.34(d,1H,ArH),7.63~7.42 (m,6H,ArH,-N=CH-),7.08~7.02(m,3H,ArH),2.58~2.51(m,1H,-CH<),1.09(d,6H,2×- CH3).MS(FAB)（M++1=520）.
Embodiment 7.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (amyl- 3- pitches base) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with propione, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 115mg。1H NMR(300MHz,DMSO-d6):δ(ppm):10.81(s,1H,-NHCO-),9.24(s,1H,-NHCO-),9.02 (s,1H,-NHCO-),8.55(d,1H,ArH),8.12(d,1H,ArH),7.69~7.64(m,2H,ArH),7.61(d,2H, ArH),7.43(d,1H,ArH),7.21~7.18(m,3H,ArH),2.36(m,4H,2×-CH2-),1.08(m,6H,2×- CH3).MS(FAB)（M++1=534）
Embodiment 8. (E) -3- (adjacent pyridine hydrazides forks of 4- (4- (3- (the chloro- 3- trifluoromethyls of 4-) urea groups) phenoxy group) Base) ethyl butyrate
2- butanone is replaced with ethyl acetoacetate, is carried out with reference to the operation of embodiment 3, obtained target compound is white Solid 180mg.1H NMR(300MHz,DMSO-d6):δ(ppm):10.83(s,1H,-NHCO-),9.23(s,1H,-NHCO-), 9.02(s,1H,-NHCO-),8.57(d,1H,ArH),8.12(s,1H,ArH),7.69~7.59(m,4H,ArH),7.43(d, 1H,ArH),7.24~7.19(m,3H,ArH),4.11(q,2H,-CH2-),3.44(s,2H,-CH2-),2.08(s,3H,-CH3), 1.21(t,3H,-CH3).MS(FAB)（M++1=578）.
Embodiment 9. (E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (butane) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with n-butanal, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 110mg。1H NMR(300MHz,DMSO-d6):δ(ppm):11.72(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.01 (s,1H,-NHCO-),8.55(d,1H,ArH),8.13(d,1H,ArH),7.91(t,1H,-N=CH-),7.69~7.59(m,4H, ArH),7.43(d,1H,ArH),7.21~7.18(m,3H,ArH),2.27~2.20(m,2H,-CH2-),1.56~1.44(m, 2H,-CH2-),0.92(t,3H,-CH3).MS(FAB)（M++1=520）
Embodiment 10. (E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (the methene base of ring penta) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with cyclopenta formaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is solid for white Body 120mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.64(s,1H,-NHCO-),9.23(s,1H,-NHCO-), 9.01(s,1H,-NHCO-),8.54(d,1H,ArH),8.12(d,1H,ArH),7.85(d,1H,-N=CH-),7.69~7.64 (m,2H,ArH),7.60(d,2H,ArH),7.42(d,1H,),7.21~7.18(m,3H,ArH),2.73~2.65(m,1H,-CH <),1.79~1.55(m,8H,4×-CH2-).MS(FAB)（M++1=546）
Embodiment 11.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (amyl- 3- yls) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 50mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.01(s,1H,-NHCO-),9.27(s,1H,-NHCO-),9.05(s,1H,-NHCO-),8.55(d,1H,ArH),8.12(s, 1H,ArH),7.69~7.64(m,2H,ArH),7.61(d,2H,ArH),7.34(d,1H,ArH),7.18(d,2H,ArH),7.15 ~7.13(m,1H,ArH),4.89(brs,1H,-NH-),2.36(m,1H,-CH<),1.36(m,4H,2×-CH2-),0.87(m, 6H,2×-CH3).MS(FAB)（M++1=536）
Embodiment 12. (E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (furans -2- methenes base) hydrazine carbonyls Base) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with furfural, is carried out with reference to the operation of embodiment 3, obtained target compound is yellow solid 116mg。1H NMR(300MHz,DMSO-d6):δ(ppm):12.19(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01 (s,1H,-NHCO-),8.59(d,1H,ArH),8.54(s,1H,ArH),8.12(s,1H,ArH),7.85(s,1H,-N=CH-), 7.69~7.64(m,2H,ArH),7.61(d,2H,ArH),7.47(d,1H,ArH),7.23~7.20(m,3H,ArH),6.92(d, 1H,ArH),6.64(s,1H,ArH).MS(FAB)（M++1=544）
Embodiment 13.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (isobutyl group) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 25mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.11(d,1H,-NHCO-),9.39(s,1H,-NHCO-),9.15(s,1H,-NHCO-),8.49(d,1H,ArH),8.12(d, 1H,ArH),7.69~7.63(m,2H,ArH),7.60(d,2H,ArH),7.35(d,1H,ArH),7.18(d,2H,ArH),7.15 ~7.13(m,1H,ArH),5.07(d,1H,-NH-),2.61(t,2H,-CH2-),1.75~1.66(m,1H,-CH<),0.89(d, 6H,2×-CH3).MS(FAB)（M++1=522）.
Embodiment 14.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (normal-butyl) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain 30mg white solids.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.12(d,1H,-NHCO-),9.54(s,1H,-NHCO-),9.27(s,1H,-NHCO-),8.49(d,1H,ArH),8.12(s, 1H,ArH),7.68~7.63(m,2H,ArH),7.59(d,2H,ArH),7.35(d,1H,ArH),7.18(d,2H,ArH),7.15 ~7.12(m,1H,ArH),5.02(d,1H,-NH-),2.78~2.74(m,2H,-CH2-),1.40~1.27(m,4H,2×- CH2-),0.86(t,3H,-CH3).MS(FAB)（M++1=522）
Embodiment 15.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (cyclopenta) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain yellow solid 80mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.10(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.50(d,1H,ArH),8.12(s, 1H,ArH),7.68~7.64(m,2H,ArH),7.59(d,2H,ArH),7.35(s,1H,ArH),7.20~7.15(m,3H, ArH),4.87(brs,1H,-NH-),3.45(brs,1H,-CH<),1.63~1.47(m,8H,4×-CH2-).MS(FAB)（M++1 =534）.
Embodiment 16.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (methyl cyclopentane) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain 29mg light green solids.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.14(d,1H,-NHCO-NH-),9.22(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.49(d,1H,ArH),8.12 (s,1H,ArH),7.69~7.64(m,2H,ArH),7.60(d,2H,ArH),7.35(d,1H,ArH),7.18(d,2H,ArH), 7.14(d,1H,ArH),5.00(s,1H,-NH-),2.74~2.69(m,2H,-CH2-),1.99~1.92(m,1H,-CH2<), 1.71~1.49(m,8H,4×-CH2-).MS(FAB)（M++1=548）.
Embodiment 17.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (methene base) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
2- butanone is replaced with formaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 60mg。1H NMR(300MHz,DMSO-d6):δ(ppm):12.05(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01 (s,1H,-NHCO-),8.57(d,1H,ArH),8.13(d,1H,ArH),7.69~7.64(m,2H,ArH),7.60(d,2H, ArH),7.54(d,1H,-N=CH2),7.45(d,1H,ArH),7.23~7.19(m,3H,ArH),6.70(d,1H,-N=CH2).MS (FAB)（M++1=478）.
Embodiment 18. (E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (ethidine) hydrazines carbonyl) pyridine - 4- epoxides) phenyl) urea
2- butanone is replaced with acetaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is white powder 135mg。1H NMR(300MHz,DMSO-d6):δ(ppm):11.76(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01 (s,1H,-NHCO-),8.55(d,1H,ArH),8.12(s,1H,ArH),7.92(d,1H,-N=CH-),7.69~7.63(m,2H, ArH),7.60(d,2H,ArH),7.43(d,1H,ArH),7.21~7.18(m,3H,ArH),1.92(d,3H,-CH3).MS (FAB)（M++1=492）.
Embodiment 19.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (ethyl) hydrazines carbonyl) pyridine -4- epoxides) Phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 35mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.12(d,1H,-NHCO-),9.22(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.50(d,1H,ArH),8.12(s, 1H,ArH),7.69~7.64(m,2H,ArH),7.60(d,2H,ArH),7.35(d,1H,ArH),7.20~7.14(m,3H, ArH),5.01(dd,1H,ArH),2.81(m,2H,-CH2-),1.00(t,3H,-CH3).MS(FAB)（M++1=494）.
Embodiment 20.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (furfuryl) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain 40mg white solids.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.12(d,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.49(d,1H,ArH),8.12(s, 1H,ArH),7.69~7.56(m,5H,ArH),7.34(d,1H,ArH),7.23~7.20(m,3H,ArH),6.36(d,1H, ArH),6.30(d,1H,ArH),5.44(d,1H,-NHCH2-),3.97(d,2H,-CH2-).MS(FAB)（M++1=546）.
Embodiment 21.1- (the chloro- 3- trifluoromethyls of 4-) -3- (the fluoro- 4- of 2- (2- (2- (propyl- 2- pitches base) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with acetone, PAP is replaced with the fluoro- PAPs of 3-, enters with reference to the operation of embodiment 3 OK, the target compound obtained is white solid 0.35g.1H NMR(300MHz,DMSO-d6):δ(ppm):10.74(s,1H,- NHCO-),9.53(s,1H,-NHCO-),8.75(s,1H,-NHCO-),8.57(d,1H,ArH),8.20~8.13(m,2H, ArH),7.63(s,2H,ArH),7.47(d,1H,ArH),7.36(d,1H,ArH),7.24(m,1H,ArH),7.10(d,1H, ArH),2.03(s,3H,-CH3),1.96(s,3H,-CH3).MS(FAB)（M++1=524）.
Embodiment 22.1- (the chloro- 3- trifluoromethyls of 4-) -3- (the fluoro- 4- of 2- (2- (2- (isopropyl) hydrazines carbonyl) pyridine - 4- epoxides) phenyl) urea
By 0.12g（0.23mmol）1- (the chloro- 3- trifluoromethyls of 4-) -3- (the fluoro- 4- of 2- (2- (2-（Propyl- 2- pitches base） Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea is dissolved in 10mL methanol, add 0.8mL glacial acetic acid and 0.029g（0.46mmol）Cyano group Sodium borohydride, 12h is reacted, raw material reaction is complete, and decompression steams most of solvent, adds ethyl acetate dissolving, 2.5% Na2CO3 Solution is washed 5 times, and saturated nacl aqueous solution is washed 3 times, anhydrous sodium sulfate drying, filtering, solvent evaporated, obtains pale solid 0.11g 。1H NMR(300MHz,DMSO-d6):δ(ppm):10.07(d,1H,-NHCO-),9.55(s,1H,-NHCO-),8.76(s, 1H,-NHCO-),8.53(d,1H,ArH),8.20~8.13(m,2H,ArH),7.39(d,1H,ArH),7.38~7.33(m,1H, ArH),7.21~7.18(m,1H,ArH),7.13(d,1H,ArH),4.87(brs,1H,-NH-),3.10(m,1H,-CH<), 0.99(d,6H,J=6.3Hz,-CH3×2).MS(FAB)（M++1=526）.
Embodiment 23.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzal) hydrazines carbonyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with benzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 205mg。1H NMR(300MHz,DMSO-d6):δ(ppm):11.14(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.02 (s,1H,-NHCO-),8.66(s,1H,-N=CH-),8.60(d,1H,ArH),8.13(d,1H,ArH),7.72~7.69(m,2H, ArH),7.66~7.60(m,4H,ArH),7.49~7.45(m,4H,ArH),7.23~7.20(m,3H,ArH).MS(FAB)（M++1 =555）.
Embodiment 24.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzyl) hydrazines carbonyl) pyridine -4- epoxides) Phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 56mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.12(s,1H,-NHCO-),9.24(s,1H,-NHCO-),9.03(s,1H,-NHCO-),8.47(d,1H,ArH),8.13(d, 1H,ArH),7.69~7.72(m,2H,ArH),7.60(d,2H,ArH),7.38~7.24(m,6H,ArH),7.20~7.13(m, 3H,ArH),5.52(s,1H,-NH-),3.99(s,1H,-CH2-).MS(FAB)（M++1=557）
Embodiment 25.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (base is pitched to methylbenzyl) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
Enter and replace 2- butanone with p-tolyl aldehyde, carried out with reference to the operation of embodiment 3, obtained target compound is white Color solid 170mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.07(s,1H,-NHCO-),9.23(s,1H,- NHCO-),9.02(s,1H,-NHCO-),8.61(s,1H,-N=CH-),8.59(d,1H,ArH),8.12(d,1H,ArH),7.69 ~7.59(m,6H,ArH),7.48(d,1H,ArH),7.27(d,2H,ArH),7.23~7.20(m,3H,ArH),2.35(s,3H,- CH3).MS(FAB)（M++1=569）
Embodiment 26.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 60mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.06(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.47(d,1H,ArH),8.12(d, 1H,ArH),7.69~7.64(m,2H,ArH),7.60(d,2H,ArH),7.33(d,1H,ArH),7.27(d,2H,ArH),7.24 (d,2H,ArH),7.09~7.10(m,5H,ArH),5.40(s,1H,-NH-),3.93(s,1H,-CH2-),2.68(s,3H,- CH3).MS(FAB)（M++1=571）.
Embodiment 27.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- benzene ethidine) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
2- butanone is replaced with acetophenone, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 204mg。1H NMR(300MHz,DMSO-d6):δ(ppm):11.08(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.02 (s,1H,-NHCO-),8.61(d,1H,ArH),8.12(d,1H,ArH),7.86(q,2H,ArH),7.69~7.58(m,4H, ArH),7.49(d,1H,ArH),7.46~7.44(m,3H,ArH),7.26~7.20(m,3H,ArH),2.39(s,3H,-CH3) .MS(FAB)（M++1=569）.
Embodiment 28.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- phenethyls) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain colorless solid 65mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 9.84(d,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.43(d,1H,ArH),8.13(d, 1H,ArH),7.71~7.64(m,2H,ArH),7.59(d,2H,ArH),7.38(d,2H,ArH),7.33~7.28(m,3H, ArH),7.24~7.11(m,4H,ArH),5.30(t,1H,-NH-),4.22(m,1H,-CH<),1.28(d,3H,-CH3).MS (FAB)（M++1=571）.
Embodiment 29.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to dimethylamino benzal) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with paradime thylaminobenzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is Yellow solid 243mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.81(s,1H,-NHCO-),9.23(s,1H,- NHCO-),9.02(s,1H,-NHCO-),8.57(d,1H,ArH),8.47(s,1H,-N=CH-),8.12(d,1H,ArH),7.69 ~7.60(m,4H,ArH),7.52(d,2H,ArH),7.46(d,1H,ArH),7.46~7.44(m,3H,ArH),6.76(d,2H, ArH),2.98(s,6H,-CH3×2).MS(FAB)（M++1=598）.
Embodiment 30.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzhydrylidene) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with benzophenone, is carried out with reference to the operation of embodiment 3, obtained target compound is white solid 130mg。1H NMR(300MHz,DMSO-d6):δ(ppm):10.81(s,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01 (s,1H,-NHCO-),8.28(d,1H,ArH),8.12(d,1H,ArH),7.70~7.54(m,9H,ArH),7.47~7.42(m, 6H,ArH),7.18(d,2H,ArH),7.13~7.10(m,1H,ArH).MS(FAB)（M++1=631）.
Embodiment 31.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- (3,4- dimethoxy phenyls) ethylidene) Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 3,4- dimethoxy-acetophenones, is carried out with reference to the operation of embodiment 3, obtained target compound For white solid 150mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.02(s,1H,-NHCO-),9.24(s,1H,- NHCO-), 9.03 (s, 1H ,-NHCO-), 8.60 (d, 1H, ArH), 8.13 (d, 1H, ArH), 7.69 ~ 7.60 (m, 4H, ArH), 7.49~7.47(m,2H,ArH),7.43~7.39(m,1H,ArH),7.23~7.20(m,3H,ArH),7.02(d,1H,ArH), 3.81(s,6H,-CH3× 2), 2.36 (s, 3H ,-CH3).MS(FAB)（M++1=629）.
Embodiment 32.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- (3,4- dimethoxy phenyls) ethyl) Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain colorless solid 50mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 9.83(d,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.44(d,1H,ArH),8.12(d, 1H, ArH), 7.72 ~ 7.64 (m, 2H, ArH), 7.59 (d, 2H, ArH), 7.33 (d, 1H, ArH), 7.17 (d, 2H, ArH), 7.12 (q,1H,ArH),7.01(s,1H,ArH),6.85(s,2H,ArH),5.24(t,1H,-NH-),4.12(t,1H,-CH<),3.73 (d,6H,-CH3× 2), 1.25 (d, 3H ,-CH3).MS(FAB)（M++1=631）.
Embodiment 33.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (adjacent benzyl chloride fork) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with o-chlorobenzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is solid for white Body 206mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.53(s,1H,-NHCO-),9.26(s,1H,-NHCO-), 9.10(s,1H,-N=CH-),9.05(s,1H,-NHCO-),8.61(d,1H,ArH),8.14(d,1H,ArH),8.03~8.00 (m,1H,ArH),7.69~7.61(m,4H,ArH),7.55~7.41(m,4H,ArH),7.25~7.11(m,3H,ArH).MS (FAB)（M++1=589）.
Embodiment 34.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (o-chlorobenzyl) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain colorless solid 80mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.20(d,1H,-NHCO-),9.23(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.48(d,1H,ArH),8.12(d, 1H,ArH),7.74~7.58(m,5H,ArH),7.42~7.39(m,1H,ArH),7.32(d,1H,ArH),7.30~7.24(m, 2H,ArH),7.19~7.13(m,3H,ArH),5.64(dd,1H,-NH-),4.11(d,2H,-CH2-).MS(FAB)（M++1= 591）.
Embodiment 35.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,4- dihydroxies benzal) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 3,4- 4-dihydroxy benzaldehydes, is carried out with reference to the operation of embodiment 3, obtained target compound is White solid 165mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.89(s,1H,-NHCO-),9.39(s,1H, ArOH),9.29(s,1H,ArOH),9.23(s,1H,-NHCO-),9.02(s,1H,-NHCO-),8.58(d,1H,ArH),8.44 (s, 1H ,-N=CH-), 8.13 (d, 1H, ArH), 7.69 ~ 7.60 (m, 4H, ArH), 7.46 (d, 1H, ArH), 7.23 ~ 7.20 (m, 4H, ArH), 6.90 (dd, 1H, ArH), 6.78 (d, 1H, ArH) .MS (FAB)（M++1=587）.
Embodiment 36.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (acrinyls of 3,4- bis-) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 75mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.03(s,1H,-NHCO-),9.22(s,1H,-NHCO-),9.01(s,1H,-NHCO-),8.81(s,1H,ArOH),8.75 (s, 1H, ArOH), 8.47 (d, 1H, ArH), 8.12 (d, 1H, ArH), 7.74 ~ 7.64 (m, 2H, ArH), 7.97 (d, 2H, ArH), 7.34 (d, 1H, ArH), 7.18 (d, 2H, ArH), 7.15 ~ 7.13 (m, 1H, ArH), 6.75 (d, 1H, ArH), 6.65 (d, 1H, ArH),6.59(d,1H,ArH),5.20(bs,1H,-NH-),3.85(bs,2H,-CH2-).MS(FAB)（M++1=589）.
Embodiment 37.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with parahydroxyben-zaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is white Solid 160mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.92(s,1H,-NHCO-),9.94(s,1H,ArOH), 9.23(s,1H,-NHCO-),9.02(s,1H,-NHCO-),8.58(d,1H,ArH),8.52(s,1H,-N=CH-),8.13(d, 1H,ArH),7.69~7.60(m,4H,ArH),7.54(d,2H,ArH),7.47(d,1H,J=2.4Hz,ArH),7.23~7.20 (m,3H,ArH),6.84(d,2H,ArH).MS(FAB)（M++1=571）.
Embodiment 38.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to acrinyl) hydrazines carbonyl) pyridine -4- Epoxide) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 68mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.05(s,1H,-NHCO-),9.33(s,1H,ArOH),9.23(s,1H,-NHCO-),9.00(s,1H,-NHCO-),8.47 (d,1H,ArH),8.12(d,1H,ArH),7.74~7.64(m,3H,ArH),7.59(d,2H,ArH),7.33(d,1H,ArH), 7.19~7.13(m,4H,ArH),6.71(d,2H,ArH),5.26(bs,1H,-NH-),3.84(bs,2H,-CH2-).MS(FAB) （M++1=573）.
Embodiment 39.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to fluoroform benzal) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with p-trifluoromethyl benzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is White solid 155mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.36(s,1H,-NHCO-),9.23(s,1H,- NHCO-),9.02(s,1H,-NHCO-),8.74(s,1H,-N=CH-),8.61(d,1H,ArH),8.13(d,1H,ArH),7.92 (d,2H,ArH),7.82(d,2H,ArH),7.69~7.61(m,4H,ArH),7.50(d,1H,ArH),7.25~7.21(m,3H, ArH).MS(FAB)（M++1=623）.
Embodiment 40.1- (2,4- difluorophenyl) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 2,4- difluoroanilines, with reference to real The operation for applying example 3 is carried out, and obtained target compound is white solid 105mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 6.82-6.85(d,2H,ArH),7.03-7.09(t,1H,ArH),7.19-7.22(m,3H,ArH),7.28-7.7.36(m,1H, ArH),7.46-7.47(m,1H,ArH),7.52-7.61(m,4H,ArH),8.05-8.13(m,1H,ArH),8.47-8.58(m, 3H,=CH-,ArH,ph-NH-CO),9.18(s,1H,ph-NH-CO),9.94(s,1H,ph-NH-CO)MS(FAB)（M++1= 504）.
Embodiment 41.1- (2,4- difluorophenyl) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) benzene Base) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 2,4- difluoroanilines, with reference to real The operation for applying example 3 is carried out, and obtained target compound is white solid 102mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 2.34(s,3H,-CH3),7.04-7.08(m,1H,ArH),7.19-7.35(m,6H,ArH),7.48-7.49(d,1H,ArH), 7.58-7.60(m,4H,ArH),8.06-8.12(m,1H,ArH),8.54-8.60(m,3H,=CH-,ArH,ph-NH-CO), 9.17(s,1H,ph-NH-CO),9.95(s,1H,ph-NH-CO).MS(FAB)（M++1=502）.
Embodiment 42.1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with the chloro- 4- methylanilines of 3-, is joined Operation according to embodiment 3 is carried out, and obtained target compound is white solid 121mg.1H NMR(300MHz,DMSO-d6):δ (ppm):2.26(s,3H,-CH3),6.82-6.84(d,2H,ArH),7.18-7.26(m,5H,ArH),7.46-7.47(d,1H, ArH),7.52-7.60(m,4H,ArH),7.70((s,1H,ArH),8.52(s,1H,=CH-),8.56-8.58(d,1H,ArH), 8.82(s,1H,ph-OH),8.87(s,1H,ph-NH-CO),9.94(s,1H,ph-NH-CO),11.91(s,1H,ph-NH- CO).MS(FAB)（M++1=516）.
Embodiment 43.1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with the chloro- 4- methylanilines of 3-, is joined Operation according to embodiment 3 is carried out, and obtained target compound is white solid 115mg.1H NMR(400MHz,DMSO-d6):δ (ppm):2.26(s,3H,-CH3),2.34(s,3H,-CH3),7.18-7.28(m,7H,ArH),7.48(s,1H,ArH),7.58- 7.60(d,4H,ArH),7.70(s,1H,ArH),8.57-8.59(d,1H,ArH),8.61(s,1H,=CH-),8.81(s,1H, ph-NH-CO),8.87(s,1H,ph-NH-CO),12,06(s,1H,ph-NH-CO).MS(FAB)（M++1=514）.
Embodiment 44.1- (2,4- difluorophenyl) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) Urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 2,4- difluoroanilines, with reference to real The operation for applying example 3 is carried out, and obtained target compound is white solid 103mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 2.26(s,3H,-CH3),3.93(s,2H,N-CH2-),5.39(s,1H,-NH-),7.03-7.17(m,6H,ArH),7.23- 7.25(d,2H,ArH),7.29-7.32(m,2H,ArH),7.56-7.58(d,2H,ArH),8.05-8.11(m,1H,ArH), 8.45-8.46(d,1H,ArH),8.53(s,1H,ph-NH-CO),9.16(s,1H,ph-NH-CO),10.05(s,1H,ph-NH- CO).MS(FAB)（M++1=504）.
Embodiment 45.1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 100mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 2.26(s,3H,-CH3),3.84(s,2H,N-CH2-),5.26(s,1H,-NH-),6.67-6.69(d,2H,ArH),7.13- 7.26(m,7H,ArH),7.33(s,1H,ArH),7.56-7.58(d,2H,ArH),7.70((s,1H,ArH),8.45-8.47 (d,1H,ArH),8.82(s,1H,ph-OH),8.86(s,1H,ph-NH-CO),9.26(s,1H,ph-NH-CO),10.03- 10.04(d,1H,ph-NH-CO).MS(FAB)（M++1=518）.
Embodiment 46.1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) benzene Base) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 101mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 2.26(s,6H,-CH3),3.93(s,2H,-N-CH2-),5.39(s,1H,-NH-),7.09-7.16(m,5H,ArH),7.23- 7.25(m,4H,ArH),7.34-7.35(d,1H,ArH),7.56-7.59(d,2H,ArH),7.69(s,1H,ArH),8.44- 8.46(d,1H,ArH),9.63-9.65(d,2H,ph-NH-CO-NH-ph),10.04(s,1H,ph-NH-CO).MS(FAB)（M+ +1=516）.
Embodiment 47.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methoxy carbonyl benzal) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
With 2- butanone is replaced to methoxycarbonyl group benzaldehyde, carried out with reference to the operation of embodiment 3, obtained target compound is White solid 150mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.34(s,1H,-CONH),9.28(s,1H,- HNCO-),9.07(s,1H,-CONH-),8.72(s,1H,-N=CH-),8.61(d,1H,ArH),8.13(s,1H,ArH),8.04 (d,2H,ArH),7.84(d,2H,ArH),7.69~7.61(m,4H,ArH),7.49(d,1H,ArH),7.23~7.16(m,3H, ArH),3.88(s,3H,-COOCH3-);MS(FAB)（M++1=612）.
Embodiment 48.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methoxy carbonyl benzyl) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 101mg.1H NMR(300MHz,CD3COCD3):δ(ppm): 9.56(brs,1H,-CONH-),8.67(s,1H,-HNCO-),8.49(s,1H,-CONH-),8.40(d,1H,ArH),8.16 (s,1H,ArH),7.94(d,2H,ArH),7.76~7.73(m,1H,ArH),7.67(d,2H,ArH),7.56~7.49(m,4H, ArH),7.14(d,2H,ArH),7.07~7.04(m,1H,ArH),5.41(brs,1H,-CONHNH-),4.172(s,2H,- CONHNHCH2 -),3.85(s,3H,-COOCH3 -);MS(FAB)（M++1=614）.
Embodiment 49.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to benzyl chloride) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with 4-chloro-benzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is solid for white Body 153mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.22(s,1H,-CONHN=),9.24(s,1H,-HNCONH-), 9.03(s,1H,-HNCONH-),8.65(s,1H,-N=CH-),8.60(d,1H,ArH),8.13(s,1H,ArH),7.73(d, 2H,ArH),7.66~7.61(m,4H,ArH),7.53(d,2H,ArH),7.49(d,1H,ArH),7.23~7.20(m,3H, ArH);MS(FAB)（M++1=588）.
Embodiment 50.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to benzyl chloride) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 140mg.1H NMR(300MHz,CD3COCD3):δ(ppm): 9.54(brs,1H,-CONHNH-),8.77(s,1H,-HNCONH-),8.58(s,1H,-HNCONH-),8.40(d,1H,ArH), 8.16(d,1H,ArH),7.76~7.73(m,1H,ArH),7.67(d,2H,ArH),7.55~7.50(m,2H,ArH),7.43(d, 2H,ArH),7.33(d,2H,ArH),7.14(d,2H,ArH), 7.15 ~ 7.04 (m, 1H, ArH), 5.34 (brs, 1H ,- CONHNH-), 4.08 (s, 2H-CONHNHCH2 -);MS(FAB)（M++1=600）.
Embodiment 51.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to cyanobenzene) pyridine -4- Epoxide) phenyl) urea
With 2- butanone is replaced to cyanobenzaldehyde, carried out with reference to the operation of embodiment 3, obtained target compound is white Solid 151mg.1H NMR(300MHz,DMSO-d6):δ(ppm):12.39(s,1H,-CONHN=),9.23(s,1H,-HNCO-), 9.02(s,1H,-HNCO-),8.71(s,1H,-N=CH-),8.60(d,1H,ArH),8.13(s,1H,ArH),7.90(m,4H, ArH),7.63~7.60(m,4H,ArH),7.50(s,1H,ArH),,7.23~7.20(m,3H,ArH);MS(FAB)（M++1= 579）.
Embodiment 52.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to cyanobenzene) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 141mg.1H NMR(300MHz,CD3COCD3):δ(ppm): 9.62(brs,1H,-CONH-),8.68(s,1H,-CONH-),8.50(s,1H,-CONH-),8.40(d,1H,ArH),8.16 (d,1H,ArH),7.76~7.62(m,7H,ArH),7.55~7.49(m,2H,ArH),7.13(d,2H,ArH),7.07~7.04 (m,1H,ArH),5.49(brs,1H,-CONH-),4.21(s,2H,-CONHNHCH2-);MS(FAB)（M++1=581）.
Embodiment 53.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to carboxylic benzal) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with p -carboxybenzaldehyde, is carried out with reference to the operation of embodiment 3, obtained target compound is white Solid 155mg.1H NMR(300MHz,DMSO-d6):δ(ppm):13.08(s,1H,-COOH),12.29(s,1H,-CONHN=), 9.25(s,1H,-CONH-),9.04(s,1H,-CONH-),8.70(s,1H,-N=CH-),8.59(brs,1H,ArH),8.12 (s,1H,ArH),8.00(d,2H,ArH),7.81(brs,2H,ArH),7.62(m,4H,ArH),7.49(s,1H,ArH),7.21 (m,3H,ArH);MS(FAB)（M++1=598）.
Embodiment 54.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3- hydroxyl -4- methoxyl groups benzal) hydrazine carbonyls Base) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 3- hydroxyls -4-methoxybenzaldehyde, is carried out with reference to the operation of embodiment 3, obtained targeted Compound is white solid 158mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.96(s,1H,-CONHN=),9.33(s, 1H,ArOH),9.24(s,1H,-CONH-),9.03(s,1H,-CONH-),8.59(d,1H,ArH),8.50(s,1H,-N= CH-),8.14(d,1H,ArH),7.70~7.61(m,4H,ArH),7.48(d,1H,ArH),7.28~7.20(m,4H,ArH), 7.03~6.96(m,2H,ArH),3.81(s,3H,-OCH3);MS(FAB)（M++1=600）.
Embodiment 55.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2-（3- hydroxyl -4- methoxy-benzyls）Hydrazine carbonyl Base) pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 138mg.1H NMR(300MHz,CD3COCD3):δ(ppm): 9.53(s,1H,-CONH-),8.68(s,1H,-CONH-),8.50(s,1H,-CONH-),8.41(d,1H,ArH),8.16 (brs,1H,ArH),7.75(d,1H,ArH),7.66(d,2H,ArH),7.54~7.49(m,3H,ArH),7.15(d,2H, ArH),7.08~7.06(m,1H,ArH),6.91(d,1H,ArH),6.90~6.79(m,2H,ArH),5.18(brs,1H,- CONH-),3.95(s,2H,-CONHNHCH2-),3.79(s,3H,-OCH3);MS(FAB)（M++1=602）.
Embodiment 56.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,5- di-t-butyl -4- hydroxyls benzal) Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 4- hydroxyl -3,5- di-t-butyls benzaldehyde, is carried out with reference to the operation of embodiment 3, obtained mesh Mark compound is white solid 152mg.1HNMR(300MHz,DMSO-d6):δ(ppm):11.88(s,1H,-CONHN=),9.24 (s,1H,-CONH-),9.03(s,1H,-CONH-),8.59(d,1H,ArH),8.54(s,1H,=CH-),8.14(s,1H, ArOH),7.68~7.61(m,4H,ArH),7.47~7.45(m,4H,ArH),7.23~7.20(m,3H,ArH),1.42(s, 18H,-C(CH3)3);MS(FAB)（M++1=682）.
Embodiment 57.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,5- di-tert-butyl-4-hydroxyl benzyl) Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 136mg.1H NMR(300MHz,CD3COCD3):δ(ppm): 9.55(brs,1H,-CONH-),8.78(s,1H,-CONH-),8.59(s,1H,-CONH-),8.44(d,1H,ArH),8.17 (s,1H,ArH),7.74(d,1H,ArH),7.66(d,2H,ArH),7.53~7.51(m,2H,ArH),7.22~7.08(m,5H, ArH),5.96(s,1H,ArOH),5.49(d,1H,-CONH-),3.96(s,2H,-CONHNHCH2-),1.39(s,18H,-C (CH3)3);MS(FAB)（M++1=684）.
Embodiment 58.1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (4- carboxymethoxyls benzal) hydrazine carbonyl) pyrroles Pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with 4- carboxymethoxyl benzaldehydes, is carried out with reference to the operation of embodiment 3, obtained target compound is White solid 146mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.99(s,1H,-CONHN=),9.59(s,1H,- CONH-),9.36(s,1H,-CONH-),8.58(s,2H,-N=CH-,ArH),8.15(s,1H,ArH),7.70~7.60(m,6H, ArH),7.48(d,1H,ArH),7.21~7.19(m,3H,ArH),7.00(d,2H,ArH),4.70(s,2H,-OCH2CO-);MS (FAB)（M++1=628）.
Embodiment 59.1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- trifluoromethylbenzenes of 4- are replaced with the chloro- 5- 5-trifluoromethylanilines of 2- Amine, carried out with reference to the operation of embodiment 3, obtained target compound is white solid 146mg.1H NMR(300MHz,DMSO- d6):δ(ppm):2.33(s,3H,-CH3),7.21-7.27(dd,4H,ArH),7.37-7.39(d,1H,ArH),7.48(s,1H, ArH),7.58-7.63(t,3H,ArH),7.71-7.74(d,1H,ArH),8.57-8.60(m,3H,ArH),8.64((s,1H,- CH=),9.72(s,1H,-NHCO-),12.06(s,2H,-NHCO-);MS(FAB)（M++1=568）.
Embodiment 60.1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 146mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 2.25(s,3H,-CH3),3.93(s,2H,Ar-CH2-),5.37-5.39(d,1H,-CH2NH-),7.08-7.15(m,6H, ArH),7.34-7.37(d,2H,ArH),7.58-7.61(d,2H,ArH),7.69-7.72(d,1H,ArH),8.44-8.46(d, 1H,ArH),8.63(s,2H,-NHCO-,ArH),9.70(s,1H,-NHCO-),10.04-10.06(d,1H,J=6Hz,- NHCO-).MS(FAB)（M++1=570）.
Embodiment 61.1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- trifluoromethylbenzenes of 4- are replaced with the chloro- 5- 5-trifluoromethylanilines of 2- Amine, carried out with reference to the operation of embodiment 3, obtained target compound is white solid 156mg.1H NMR(300MHz,DMSO- d6):δ(ppm):6.83-6.85(d,2H,ArH),7.22-7.24(d,1H,ArH),7.38-7.40(d,1H,ArH),7.48 (s,2H,ArH),7.53-7.55(d,2H,ArH),7.62-7.64(d,2H,ArH),7.73-7.75(d,1H,ArH),8.52- 8.57(d,1H,ArH),8.57-8.59(d,1H,-CH=),8.65(s,2H,ArH),9.73(s,1H,-OH),9.94(s,1H,- NHCO-),11.92(s,2H,-NHCO-).MS(FAB)（M++1=570）.
Embodiment 62.1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 146mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 3.83(s,2H,-CH2-), 5.24 (brs, 1H ,-CH2NH-),6.53-6.69(m,2H,ArH),7.12-7.26(m,5H,ArH), 7.33-7.38(m,2H,ArH),7.58-7.61(d,2H,ArH),7.70-7.72(d,1H,ArH),8.45-8.47(d,1H, ArH),8.64(s,2H,,ArH,-NHCO-),9.27(s,1H,-NHCO-),9.71(s,1H,ArOH)10.03-10.05(d, 1H,-NHCO-).MS(FAB)（M++1=572）.
Embodiment 63.1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with the chloro- 3- nitroanilines of 4-, is joined Operation according to embodiment 3 is carried out, and obtained target compound is white solid 151mg.1H NMR(300MHz,DMSO-d6):δ (ppm):2.35(s,3H,CH3),7.21-7.29(dd,5H,ArH),7.48-7.49(d,1H,ArH),7.59-7.67(m,5H, ArH),8.33(s,1H,ArH),8.58-8.61(m,2H,ArH),9.09(s,1H,=CH-),9.35(s,1H,-NHCO-), 12.08(s,2H,-NHCO-).MS(FAB)（M++1=545）.
Embodiment 64.1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) benzene Base) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 146mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 2.22(s,3H,CH3),3.92-3.98(m,2H,-CH2-),7.01-7.17(m,6H,ArH),7.22-7.34(m,1H,ArH), 7.57-7.65(m,4H,ArH),8.31(s,2H,ArH),8.44-8.54(m,1H,ArH),9.15(s,1H,ArH),9.43(s, 1H,-NHCO-),10.05(s,1H,-NHCO-),11.21(s,1H,-NHCO-).MS(FAB)（M++1=547）.
Embodiment 65.1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with the chloro- 3- nitroanilines of 4-, is joined Operation according to embodiment 3 is carried out, and obtained target compound is white solid 149mg.1H NMR(300MHz,DMSO-d6):δ (ppm):6.82-6.85(d,2H,ArH),7.20-7.23(d,3H,ArH),7.46-7.47(d,1H,ArH),7.52-7.55 (d,2H,ArH),7.60-7.63(d,2H,ArH),7.67(s,2H,ArH),8.32(s,1H,ArH),8.53(s,1H,-CH=), 8.57-8.59(d,1H,ArH),9.08(s,1H,-NHCO-),9.34(s,1H,-NHCO-),9.94(s,1H,ArOH),11.92 (s,1H,-NHCO-).MS(FAB)（M++1=547）.
Embodiment 66.1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 140mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 3.85(s,2H,-CH2-),5.28(s,1H,-CH2NH-),6.52-6.71(m,3H,ArH),7.07-7.40(m,6H,ArH), 7.57-7.69(m,4H,ArH),8.33(s,1H,ArH),9.70(s,1H,ArOH),10.13(s,1H,-NHCO-),11.13 (s,2H,-NHCO-).MS(FAB)（M++1=549）.
Embodiment 67.1- (4- chlorphenyls) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 4- chloroanilines, with reference to embodiment 3 operation is carried out, and obtained target compound is white solid 156mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 11.91(s,1H,-CONH-),9.94(s,1H,Ph-OH),8.87(s,2H,-CONH-),8.57(d,1H,ArH),8.52(s, 1H,=CH),7.59(d,2H,ArH),7.55~7.47(m,5H,ArH),7.34(d,2H,ArH),7.21~7.16(m,3H, ArH),6.84(d,2H,ArH);MS(FAB)（M++1=502）.
Embodiment 68.1- (4- chlorphenyls) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 4- chloroanilines, with reference to embodiment 3 operation is carried out, and obtained target compound is white solid 150mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 12.07(s,1H,-CONH-),8.88(s,2H,-CONH-),8.61(s,1H,=CH),8.58(d,1H,ArH),7.61~7.57 (m,4H,ArH),7.52~7.50(m,3H,ArH),7.34(d,2H,ArH),7.27(d,2H,ArH),7.19~7.16(m,3H, ArH),2.35(s,3H,Ph-CH3);MS(FAB)（M++1=500）.
Embodiment 69.1- (4- chlorphenyls) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 141mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.06(d,1H,-CONH-),9.48(s,2H,-CONH-),8.46(d,1H,ArH),7.60(d,2H,ArH),7.53(d,2H, ArH),7.34-7.31(m,3H,ArH),7.24(d,2H,ArH),7.16-7.10(m,5H,ArH),5.40(m,1H,- CONHNHCH2-),3.94(d,2H,-NHCH2-),2.27(s,3H,-CH3);MS(FAB)（M++1=502）.
Embodiment 70.1- (4- chlorphenyls) -3- (4- (2- (2- (but-2-ene fork) hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
2- butanone is replaced with but-2-ene aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 4- chloroanilines, with reference to embodiment 3 Operation is carried out, and obtained target compound is white solid 165mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.83 (s,1H,-CONH-),8.87(s,2H,-CONH-),8.55(d,1H,=CH),8.22(d,1H,ArH),7.60~7.49(m,4H, ArH),7.43(d,1H,ArH),7.33(d,2H,ArH),7.20~7.15(m,3H,ArH),6.30~6.14(m,2H,=CH), 1.86(d,3H,=CH-CH3);MS(FAB)（M++1=450）.
Embodiment 71.1- (4- chlorphenyls) -3- (4- (2- (2-（3- allyls are pitched）Hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
2- butanone is replaced with 3- allyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 4- chloroanilines, with reference to embodiment 3 operation is carried out, and obtained target compound is white solid 156mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 12.09(s,1H,-CONH-),8.88(s,2H,-CONH-),8.58(d,1H,ArH),8.43(d,1H,=CH),7.65-7.59 (m,4H,ArH),7.46-6.98(m,13H,ArH,=CH);MS(FAB)（M++1=512）.
Embodiment 72.1- (3- aminomethyl phenyls) -3- (4- (2- (2-（To hydroxyl benzal）Hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
2- butanone is replaced with parahydroxyben-zaldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 3- methylanilines, with reference to implementation The operation of example 3 is carried out, and obtained target compound is white solid 145mg.1H NMR(400MHz,DMSO-d6):δ(ppm): 11.92(s,1H,-CONH-),9.94(s,1H,Ph-OH),8.82(s,1H,-CONH-),8.64(s,1H,-CONH-),8.57 (d,1H,ArH),8.53(s,1H,=CH),7.61~7.53(m,3H,ArH),7.47(d,1H,ArH)7.31~7.14(m,6H, ArH),6.85~6.79(m,3H,ArH),2.29(s,3H,Ph-CH3);MS(FAB)（M++1=482）.
Embodiment 73.1- (3- aminomethyl phenyls) -3- (4- (2- (2-（Methylbenzyl is pitched）Hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 3- methylanilines, with reference to implementation The operation of example 3 is carried out, and obtained target compound is white solid 156mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 12.07(s,1H,-CONH-),8.82(s,1H,-CONH-),8.64(s,1H,-CONH-),8.61(s,1H,=CH),8.58(d, 1H,ArH),7.61~7.59(m,4H,ArH),7.49(d,1H,ArH),7.31~7.14(m,8H,ArH),6.80(d,1H, ArH),2.35(s,3H,Ph-CH3),2.29(s,3H,Ph-CH3);MS(FAB)（M++1=480）.
Embodiment 74.1- (3- aminomethyl phenyls) -3- (4- (2- (2-（To methylbenzyl）Hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
Carried out with reference to the operation of embodiment 4, obtain white solid 146mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 10.05(s,1H,-CONH-),9.57(s,1H,-CONH-),9.31(s,1H,-CONH-),8.45(d,1H,ArH),7.59(d, 2H,ArH),7.35(d,1H,ArH),7.30-7.23(m,4H,ArH),7.18~7.10(m,6H,ArH),6.78(d,1H, ArH),5.52~5.41(brs,1H,-CONHNHCH2-),3.94(brs,2H,-NHCH2-),2.27(brs,6H,Ph-CH3),MS (FAB)（M++1=482）.
Embodiment 75.1- (3- aminomethyl phenyls) -3- (4- (2- (2- (but-2-ene fork) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
2- butanone is replaced with but-2-ene aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 3- methylanilines, with reference to embodiment 3 Operation carry out, obtained target compound is white solid 149mg.1H NMR(300MHz,DMSO-d6):δ(ppm):11.83 (s,1H,-CONH-),8.81(s,1H,-CONH-),8.64(s,1H,-CONH-),8.55(d,1H,ArH),8.22(d,1H,= CH),7.59(d,2H,ArH),7.44(d,1H,ArH),7.32~7.14(m,6H,ArH),6.79(m,1H,=CH),6.30~ 6.14(m,2H,=CH),2.29(s,3H,Ph-CH3),1.86(d,3H,=CHCH3);MS(FAB)（M++1=430）.
Embodiment 76.1- (3- aminomethyl phenyls) -3- (4- (2- (2-（3- allyls are pitched）Hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
2- butanone is replaced with 3- allyl aldehyde, the chloro- 3- 5-trifluoromethylanilines of 4- are replaced with 3- methylanilines, with reference to implementation The operation of example 3 is carried out, and obtained target compound is white solid 156mg.1H NMR(300MHz,DMSO-d6):δ(ppm): 12.09(s,1H,-CONH-),8.82(s,1H,-CONH-),8.65(s,1H,-CONH-),8.58(d,1H,ArH),8.43(d, 1H,=CH),7.65-7.58(m,4H,ArH),7.53-6.98(m,13H,ArH,=CH);MS(FAB)（M++1=492）.
Embodiment 77.1- (4- methyl -3- sulfamoyl phenyls) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- Epoxide) phenyl) urea
2- butanone is replaced with p-tolyl aldehyde, the chloro- 3- trifluoromethylbenzenes of 4- are replaced with 4- methyl -3- sulfanoyl anilines Amine, carried out with reference to the operation of embodiment 3, obtained target compound is white solid 156mg.1HNMR(DMSO-d6 300MHz),δ(ppm):2.34(s,3H,-CH3),2.52(s,3H,-CH3),7.13-7.59(m,13H,ArH),8.04(s,1H, ArH),8.60(m,2H,-CONH-,=CH-),8.84(s,1H,-CONH-),8.99(s,1H,-CONH-),12.07(s,2H,- SO2NH2).MS(FAB)（M++1=559）.
Pharmacological activity
External activity is evaluated：
Mtt assay determines tumor cell survival
Concentration is configured to after the cell of exponential phase is digested with pancreatin as 0.8 ~ 2 × 104Cell/ml cell liquid, 96 orifice plates are inoculated in by 1000/hole, add 100 μ l per hole.Next day addition medicine containing various concentrations and coordinative solvent compare new Fresh culture medium, add 100 μ l per hole（DMSO final concentrations<0.5%）, set 5~7 dosage groups per medicine, every group at least set three it is parallel Hole, after 37 DEG C are continued to cultivate 120hr, supernatant is abandoned, the MTT containing 0.5mg/ml of 100 μ l Fresh serum-free training is added per hole Base is supported, continues to cultivate 4hr, abandons culture supernatant, 200 μ l DMSO dissolving MTT first hairpin precipitations are added per hole, are vibrated with microoscillator Mix, OD value (OD) is determined under the conditions of reference wavelength 450nm, Detection wavelength 570nm with MK3 types ELIASA, with solvent The tumour cell of control treatment is control group, calculates inhibiting rate of the medicine to tumour cell with formula below, and press middle efficacious prescriptions journey Calculate IC50：
MTT the selection results（IC50μM）

Claims (17)

1. Formulas I and the pyridine -2- hydrazide derivatives shown in II, its officinal salt；
In formula, R1Selected from following structural
Wherein X and Y is independently selected from hydrogen, chlorine, fluorine, bromine, trifluoromethyl, methyl, methoxyl group, dimethylamino, cyano group, nitre Base, methylamino, mesyl, sulfamoyl, hydroxyl, amino；
Wherein n is selected from 1,2,3；
R2And R3It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, positive penta Base, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, isopentene group, carboxymethyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, expoxy propane base, epoxy butane base, epoxypentane base, epoxy Hexyl, nafoxidine base, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxyl methyl, methoxycarbonyl methyl, ethoxy Methyl, ethoxycarbonyl methyl, the third oxygen methyl, the third oxygen formyl methyl, fourth oxygen methyl, aminomethyl, first carbamoylmethyl, diformazan ammonia Methyl, second aminomethyl, second carbamoylmethyl, the third aminomethyl, fourth aminomethyl, dimethylamino acrylic, methoxvpropenvl, benzene Base, difluorophenyl, chlorophenyl, bromo phenyl, fluorine chlorophenyl, fluorine bromo phenyl, bromine chlorophenyl, aminomethyl phenyl, trifluoro Aminomethyl phenyl, hydroxy phenyl, dimethylamino phenyl, Dimethoxyphenyl, dihydroxy phenyl, cyano-phenyl, Carboxvmethoxv benzene Base, methoxycarbonyl phenyl, methoxyl group hydroxy phenyl, carboxyl phenyl, di-t-butyl hydroxy phenyl, naphthyl, furyl, butyrolactone Base, pyrrole radicals, oxo-pyrrolidine base, thienyl, thiazolyl, halo thiazole base, methyl thiazolium oxazolyl, imidazole radicals, pyridine radicals, halo Pyridine radicals, picolyl, pyrimidine radicals, a chlorophenylmethyl, p-aminophenyl methyl, picolyl；R2And R3It can connect during selected from alkyl C3-6 ring is connected into, including：When Y is hydrogen atom, R2And R3It is asynchronously first Base；For II formulas, R2And R3It is asynchronously hydrogen.
2. compound according to claim 1：It is characterized in that：
Wherein X and Y is independently selected from hydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, methoxyl group, dimethylamino, cyano group, nitre Base, methylamino, mesyl, sulfamoyl；
Wherein n is selected from 1,2,3.
R2And R3It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, positive penta Base, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, isopentene group, carboxymethyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, epoxy butane base, epoxypentane base, cyclohexene oxide groups, tetrahydrochysene Pyrrole radicals, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxycarbonyl methyl, ethoxycarbonyl methyl, the third oxygen methyl, first Aminomethyl, first carbamoylmethyl, dimethyl aminomethyl, second aminomethyl, second carbamoylmethyl, dimethylamino acrylic, methoxy propyl Alkenyl, phenyl, difluorophenyl, chlorophenyl, fluorine chlorophenyl, aminomethyl phenyl, trifluoromethyl, hydroxy phenyl, diformazan ammonia Base phenyl, Dimethoxyphenyl, dihydroxy phenyl, cyano-phenyl, 3- hydroxyl -4- methoxyphenyls, carboxy-- methoxyphenyl, first Oxygen formylphenyl, 3- methoxyl group -4- hydroxy phenyls, carboxyl phenyl, 3,5- di-tert-butyl-hydroxy phenyls, furyl, butyrolactone Base, pyrrole radicals, oxo-pyrrolidine base, thienyl, thiazolyl, halo thiazole base, methyl thiazolium oxazolyl, imidazole radicals, pyridine radicals, halo Pyridine radicals, picolyl, pyrimidine radicals, a chlorophenylmethyl, p-aminophenyl methyl, picolyl；R2And R3It can connect during selected from alkyl C3-6 ring is connected into, including：When Y is hydrogen atom, R2And R3It is asynchronously first Base；For II formulas, R2And R3It is asynchronously hydrogen.
3. compound according to claim 2：It is characterized in that：
Wherein X and Y is independently selected from hydrogen, chlorine, bromine, fluorine, trifluoromethyl, methyl, methoxyl group, dimethylamino, cyano group, nitre Base, methylamino, mesyl, sulfamoyl；
Wherein n is selected from 1,2,3.
R2And R3It is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, positive penta Base, isopentyl, neopentyl, vinyl, styryl, acrylic, pi-allyl, cyclobutenyl, pentenyl, isopentene group, carboxymethyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, epoxy butane base, epoxypentane base, cyclohexene oxide groups, tetrahydrochysene Pyrrole radicals, piperidyl, pyrazinyl, piperazinyl, methyl piperazine base, methoxycarbonyl methyl, ethoxycarbonyl methyl, the third oxygen methyl, first Carbamoylmethyl, dimethyl aminomethyl, second carbamoylmethyl, dimethylamino acrylic, phenyl, a fluorophenyl, rubigan are adjacent Chlorphenyl, chlorphenyl fluorine, p-methylphenyl, o-methyl-phenyl, p-trifluoromethyl phenyl, m-trifluoromethylphenyl, to hydroxyl Base phenyl, a hydroxy phenyl, to dimethylamino phenyl, m-dimethyl amino phenyl, 3,4- Dimethoxyphenyls, 3,4- dihydroxy benzenes Base, to cyano-phenyl, a cyano-phenyl, to carboxyl phenyl, 3,5- di-tert-butyl-hydroxy phenyls, 3- hydroxyl -4- methoxybenzenes Base, to (Carboxvmethoxv) phenyl, to methoxycarbonyl phenyl, furyl, butyrolactone base, pyrrole radicals, oxo-pyrrolidine base, thiophene Base, thiazolyl, chloro-thiazole base, fluoro thiazolyl, methyl thiazolium oxazolyl, imidazole radicals, pyridine radicals, chloro-pyridine base, picoline Base, pyrimidine radicals, a chlorophenylmethyl, p-aminophenyl methyl, picolyl；R2And R3C3-6 ring can be connected into during selected from alkyl, is wrapped Include：When Y is hydrogen atom, R2And R3It is asynchronously methyl；For II formulas, R2 And R3It is asynchronously hydrogen.
4. compound according to claim 1, described compound is selected from：
(E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (butyl- 2- pitches base) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (cyclopentylidene base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
(E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (2- methyl propylidene base) hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (amyl- 3- pitches base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
(E) -3- (the adjacent pyridine hydrazides fork bases of 4- (4- (3- (the chloro- 3- trifluoromethyls of 4-) urea groups) phenoxy group)) ethyl butyrate
(E) -1- (4- (2- (2- (butane) hydrazines carbonyl) pyridine -4- epoxides) phenyl) -3- (the chloro- 3- trifluoromethyls of 4-) urea
(E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (the methene base of ring penta) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (sec- butyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (amyl- 3- yls) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
(E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (furans -2- methenes base) hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (isobutyl group) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (normal-butyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (cyclopenta) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (methyl cyclopentane) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (methene base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
(E) -1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (ethidine) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (ethyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (furfuryl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (the fluoro- 4- of 2- (2- (2- (propyl- 2- pitches base) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (the fluoro- 4- of 2- (2- (2- (isopropyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) Urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzal base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (base is pitched to methylbenzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- phenylethylidenes) hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- phenylethyls) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to dimethylamino benzal base) hydrazine carbonyl) pyridine -4- epoxides) Phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (benzhydrylidene base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- (3,4- dimethoxy phenyls) ethidine) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (1- (3,4- dimethoxy phenyls) ethyl) hydrazine carbonyl) pyridine -4- Epoxide) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (adjacent benzyl chloride fork base) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (o-chlorobenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,4- dihydroxy benzals base) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (acrinyls of 3,4- bis-) hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to acrinyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to fluoroform benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
1- (2,4- difluorophenyl) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (2,4- difluorophenyl) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (2,4- difluorophenyl) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 4- aminomethyl phenyls of 3-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methoxy carbonyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) Urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to methoxy carbonyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to benzyl chloride) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to benzyl chloride) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to cyanobenzene) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to cyanobenzene) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (to carboxylic benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3- hydroxyl -4- methoxyl groups benzal) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3- hydroxyl -4- methoxy-benzyls) hydrazine carbonyl) pyridine -4- oxygen Base) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,5- di-t-butyl -4- hydroxyls benzal) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (3,5- di-tert-butyl-4-hydroxyl benzyl) hydrazine carbonyl) pyridine - 4- epoxides) phenyl) urea
1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (2- (4- carboxymethoxyls benzal) hydrazine carbonyl) pyridine -4- epoxides) benzene Base) urea
1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 5- trifluoromethyls of 2-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (the chloro- 3- nitrobenzophenones of 4-) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (to hydroxyl benzyl) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (but-2-ene fork) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- chlorphenyls) -3- (4- (2- (2- (benzene allylidene) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (3- aminomethyl phenyls) -3- (4- (2- (2- (to hydroxyl benzal) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (3- aminomethyl phenyls) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
1- (3- aminomethyl phenyls) -3- (4- (2- (2- (to methylbenzyl) hydrazines carbonyl) pyridine -4- epoxides) phenyl) urea
1- (3- aminomethyl phenyls) -3- (4- (2- (2- (but-2-ene fork) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (3- aminomethyl phenyls) -3- (4- (2- (2- (benzene allylidene) hydrazine carbonyl) pyridine -4- epoxides) phenyl) urea
1- (4- methyl -3- sulfamoyl phenyls) -3- (4- (2- (2- (pitches) hydrazine carbonyl to methylbenzyl) pyridine -4- epoxides) phenyl) urea
。
5. the compound according to claim 1, it is characterised in that described officinal salt is selected from：Hydrochloride, hydrobromate, phosphorus Hydrochlorate, sulfate, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino-acid salt, matrimony vine acid Salt, maleate, tartrate, fumarate, citrate, lactate；Sodium salt, sylvite, calcium salt, magnesium salts, lithium salts, ammonium salt and The salt of the organic base of physiologically acceptable cation, the organic base that can provide physiologically acceptable cation can be provided Salt include：Methylamine salt, dimethylamine salt, front three amine salt, piperidinium salt, alkylbenzyldimethylasaltsum saltsum and three (2- ethoxys) amine salt.
6. preparing the method for the compound of claim 1, comprise the following steps：
1) route 1
2) route 2
3) route 3
4) route 4
5) route 5
。
7. according to the preparation method of claim 6 route 1, it is characterised in that with hydrazides 1 be raw material in step (a), with common Method is condensed to yield hydrazide derivatives 2 with ketone or aldehyde carbonyl groups；In step (b), to R1H is under alkaline environment by hydrazides 2 Chlorine substituted ether obtain compound 3 or compound of Formula I, then reduced in step (c) and provide compound 4 or formula II compounds.
8. according to the preparation method of claim 6 route 2, it is characterised in that it is raw material with hydrazide derivatives 2 in step (a), With para hydroxybenzene amine under alkaline environment by obtaining compound 5 to the chlorine substituted ether in hydrazides 2, then can in step (b) Pass through the chloro- 3- 5-trifluoromethylanilines condensation generation urea derivatives 6 of CDI and 4-；Also can be with the chloro- 3- trifluoromethyls isocyanic acids of 4- Ester obtains urea derivative 6 by nucleophilic addition；Also nucleophilic can be crossed with the chloro- 3- trifluoromethyls phenylamino formic acid 4- nitro phenyl esters of 4- Substitution reaction obtains urea derivative 6；Reduced again in step (c) and provide compound 7.
9. according to the preparation method of claim 6 route 3, it is characterised in that it is raw material with ester 8 or acyl chlorides 9 in step (a), with The reaction of alkyl hydrazine 10 obtains hydrazide derivatives 11；In step (b), the fluoro- PAPs of 3- are under alkaline environment by hydrazides Chlorine substituted ether in derivative 11 obtains compound 12；In step (c), compound 12 can pass through CDI and the chloro- 3- fluoroforms of 4- Base aniline condensation generates urea derivative 13；Also can be obtained with the chloro- 3- trifluoromethylbenzenes based isocyanates of 4- by nucleophilic addition To urea derivative 13；Also nucleophilic substitution can be crossed with the chloro- 3- trifluoromethyls phenylamino formic acid 4- nitro phenyl esters of 4- and obtains urea derivative Thing 13.
10. according to the preparation method of claim 6 route 4, it is characterised in that in step (a), the fluoro- PAPs of 3- and 4- Chloro- 3- 5-trifluoromethylanilines and CDI condensation generation urea derivative 15；Also can lead to the chloro- 3- trifluoromethylbenzenes based isocyanates of 4- Cross nucleophilic addition and obtain urea derivative 15；Also nucleophilic can be passed through with the chloro- 3- trifluoromethyls phenylamino formic acid -4- nitro phenyl esters of 4- Substitution reaction obtains urea derivative 15；In step (b), urea derivative 15 is under alkaline environment by chlorine in hydrazide derivatives 11 Nucleophilic displacement of fluorine be etherified to obtain compound 17；Also step (c) can be first passed through under alkaline environment by chlorine in ester compounds 8 Nucleophilic displacement of fluorine is etherified to obtain compound 16, then obtains compound 17 by step (d) and the reaction of alkyl hydrazine 10.
11. according to the preparation method of claim 6 route 5, it is characterised in that it is raw material with N- methyl nitrosoureas 18 in the route, Etherification product 19 first is obtained with para hydroxybenzene amine or derivatives thereof reaction under alkaline environment, then basic hydrolysis acid amides 19 obtains To carboxylic acid 20, then esterification generation compound 21, the chloro- 3- 5-trifluoromethylanilines condensation generation urea derivatives of CDI and 4- can be passed through 22；Also urea derivative 22 can be obtained by nucleophilic addition with 4- chloro- 3- trifluoromethylbenzenes based isocyanates；Also can be with 4- Chloro- 3- trifluoromethyls phenylamino formic acid -4- nitros phenyl ester obtains urea derivative 22 by nucleophilic substitution；Then urea derivative 22 Hydrazides 23 is obtained with hydrazine reaction, then itself and ketone or aldehyde carbonyl groups condensation are readily available hydrazide derivatives 24 with common method, Then reduced and provide compound 25.
A kind of 12. composition of medicine, it is characterised in that the acceptable carrier of compound and galenic pharmacy containing claim 1.
13. application of the compound of claim 1 in the medicine for preventing and treating the disease relevant with protein kinase is prepared.
14. application of the compound of claim 1 in the medicine for preventing and treating the disease relevant with EGFR-TK is prepared.
15. application of the compound of claim 1 in the medicine for preventing and treating the disease relevant with Raf kinases is prepared.
16. application according to claim 15, it is characterised in that the disease relevant with Raf kinases is tumour, is immunized and loses Adjust, sacred disease.
17. application according to claim 16, it is characterised in that described tumor disease is liver cancer, kidney, lung cancer, cancer of pancreas, Colorectal cancer, carcinoma of urinary bladder and breast cancer, oophoroma, squamous cell carcinoma, glioma, incidence cancer.
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Citations (2)

* 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
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 (2)

* 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
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

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