CN104109120B - N '-virtue acryloyl group neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes - Google Patents
N '-virtue acryloyl group neighbour's pyridine hydrazide derivatives and its preparation method and pharmaceutical composition and purposes Download PDFInfo
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- CN104109120B CN104109120B CN201310141950.1A CN201310141950A CN104109120B CN 104109120 B CN104109120 B CN 104109120B CN 201310141950 A CN201310141950 A CN 201310141950A CN 104109120 B CN104109120 B CN 104109120B
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- 0 C[C@](C1)C(OC(C=C(C(N*C(C=CC(C(C(C)(*)C(F)=C2F)F)=C2I=C)=O)=O)N)=CC=I)=CC=C1NC(NC1C=C(C(F)(F)F)C(Cl)=CC=C1)=O Chemical compound C[C@](C1)C(OC(C=C(C(N*C(C=CC(C(C(C)(*)C(F)=C2F)F)=C2I=C)=O)=O)N)=CC=I)=CC=C1NC(NC1C=C(C(F)(F)F)C(Cl)=CC=C1)=O 0.000 description 4
- CQXQMGCQLXGEJM-GIDUJCDVSA-N Cc(cc1)ccc1NC(Nc(cc1)ccc1Oc1ccnc(C(NNC(/C=C/c(cc2)ccc2Cl)=O)=O)c1)=O Chemical compound Cc(cc1)ccc1NC(Nc(cc1)ccc1Oc1ccnc(C(NNC(/C=C/c(cc2)ccc2Cl)=O)=O)c1)=O CQXQMGCQLXGEJM-GIDUJCDVSA-N 0.000 description 1
- AIBWFMYCJBEORA-VOTSOKGWSA-N NC(/C=C/C1CC=CCC1)=O Chemical compound NC(/C=C/C1CC=CCC1)=O AIBWFMYCJBEORA-VOTSOKGWSA-N 0.000 description 1
- QOCIQUAQLUDZHG-SNAWJCMRSA-N NC(/C=C/c1cccc(O)c1)=O Chemical compound NC(/C=C/c1cccc(O)c1)=O QOCIQUAQLUDZHG-SNAWJCMRSA-N 0.000 description 1
- HLUMBQNJCORIOD-KGVSQERTSA-N O=C(/C=C/c(cc1)ccc1Cl)NNC(c1nccc(OC(C=C2)=CCC2NC(Nc(c(F)c2)ccc2F)=O)c1)=O Chemical compound O=C(/C=C/c(cc1)ccc1Cl)NNC(c1nccc(OC(C=C2)=CCC2NC(Nc(c(F)c2)ccc2F)=O)c1)=O HLUMBQNJCORIOD-KGVSQERTSA-N 0.000 description 1
- UXWCXMKXQZEODL-CSKARUKUSA-N O=C(/C=C/c1ccc[s]1)NNC(c1cc(OC(CC2)=CC=C2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O Chemical compound O=C(/C=C/c1ccc[s]1)NNC(c1cc(OC(CC2)=CC=C2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O UXWCXMKXQZEODL-CSKARUKUSA-N 0.000 description 1
- ZEDYVTOJLLFFEN-NYYWCZLTSA-N O=C(/C=C/c1cccc(F)c1)NNC(c1cc(OC(CC2)=CC=C2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O Chemical compound O=C(/C=C/c1cccc(F)c1)NNC(c1cc(OC(CC2)=CC=C2NC(Nc(cc2C(F)(F)F)ccc2Cl)=O)ccn1)=O ZEDYVTOJLLFFEN-NYYWCZLTSA-N 0.000 description 1
Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses N ' virtues acryloyl group neighbour's pyridine hydrazide derivatives shown in Formulas I; its officinal salt; and preparation method thereof, the purposes of composition and such compound containing this one or more compound in terms for the treatment of disease related with protein kinase such as immune disorder and tumor disease.
Description
Invention field
The present invention relates to N '-virtues acryloyl group neighbour's pyridine hydrazide derivatives, officinal salts shown in Formulas I, and its prepare
Method, composition and such compound containing this one or more compound are treating disease related with protein kinase such as
Purposes in terms of immune disorder and tumor disease, belongs to pharmaceutical technology field.
Background of invention
Recent years greatly promotees due to the raising to enzyme and some other and the understanding of the relevant biomolecule of disease
Into the discovery or development of the new drug for the treatment of disease, protein kinase is exactly a kind of important one kind studied extensively, it is one
Large family, it is related with the intracellular various controls of signal transduction process.Due to they structure and catalysis conservative it
Be considered evolving from a common ancestral gene.Nearly all kinases is all containing there are one similar 250-300 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..Generally, protein kinase is turned by influencing a phosphoryl from a ribonucleoside triphosphote
It moves on to one and carrys out signal transduction in mediated cell with the relevant protein receptor of signal transduction pathway.These phosphorylated events, which are used as, divides
Sub switch adjusts the biological function of target protein, is finally excited and reacts to various extracellular and other stimulations.Kinases exists
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.Research shows that by blocking VEGFR and pdgf receptor in upstream, block Raf/MEK/ERK in downstream, it can
It reduces the angiogenesis of tumour simultaneously and inhibits the duplication of tumour cell, to hinder the growth of tumour.
Raf kinases is the protein product encoded by proto-oncogene raf, is made of 648 amino acid, molecular weight 70000
~74000D, contains 3 conserved regions in structure, respectively CR1 (61~194D), CR2 (254~269D), CR3 (335~
627D).CR1 is located at its molecule possessing amino, is 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 also close to aminoterminal, is 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 accesses
In a Key kinases, Raf can play its signal transduction adjustment effect by way of relying on or not depending on Ras.As Raf
The stream substrates of kinases, the MEK phosphorylated CREBs of activation, adjust various cell functions.Once excessive activation occurs for the access, then
Cell Proliferation is caused to accelerate to extend with the cells survival phase, so as to cause the generation of tumour.
Studies have shown that 80% or more oncogene and proto-oncogene are present in the cancer coding protein tyrosine kinase of people（PTK）
In, the generation and development of the various cancers of the mankind be it is related with the abnormal cell signal transduction of protein tyrosine kinase is come from,
One increase for being mainly characterized by tyrosine kinase activity of malignant cell.Therefore, inhibit the activation or blocking of tyrosine kinase
Its signal transduction path becomes the new way of control tumour.
Endothelial growth factor receptor (EGFR) is a kind of protein tyrosine kinase receptor (RTK), is located at No. 7 chromosome
The areas p13~q22, overall length 200kb are made of 28 exons, encode 1186 amino acid, glycoprotein molecule amount is about
170kDa 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 transmembrane domain and 1
Cytoplasmic domain with tyrosine kinase activity.Its intracellular region and erbB oncoprotein very high homologies.The activation of EGFR
The Receptor dimerization that can be induced by ligand, which acts on, to be realized.In ErbB receptor family, other than HER2, other members have it
Respective ligand, various ligands be by corresponding transmembrane protein precursor by proteolysis from, have 1 EGF sample
Structural domain.Ligand with EGFR specific bindings includes epidermal growth factor (EGF), transforming growth factor α (TGFα), two-way tune
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 to
Activate their cytoplasmic location.After the intracellular region tyrosine phosphorylation of ErbB2 and then second messenger's transduction is activated, passes through MAPK
The activation (adjusting 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 the transcription activators of STAT1, STATS3；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 the transcription activating of ATF, NF-kB, Ap-1, C-fos and C-Jun.These are all the growths that EGFR is mediated or carcinogenic
Basic downstream pathway.Abnormal EGFR activation mechanisms include the amplification of receptor itself, the overexpression of receptors ligand, Activating mutations with
And negativity adjusts the shortage of approach, therefore EGFR induced cancers are at least through 3 kinds of mechanism：The overexpression of EGFR ligands, EGFR's
Amplification or the mutation of EGFR activation.In this 3 kinds of mechanism, the mutation activation of EGFR is to lead to tumour cell aberrant biological behavior
Main factor.Certain mutation of EGFR gene can lead to the extension of receptor effect enhancing and duration.The proofs such as Lynch
Become isoreceptor and have no effect on the stability of receptor protein, found by the EGFR activation of Tyr1068 phosphorylation assay, wild type by
The activation 15min of body is lowered, and becomes the effect that isoreceptor shows 2 times than normal EGFR high, and is more than the continuous activation of 3h.
EGFR mutation do not have an impact the ability that tumour cell is combined with TKI (tyrosine kinase inhibitor).TKI is to those
The reason of causing EGFR to activate because of mutation, can be explained by oncogeneaddiction models.Pass through Ras.Raf-
MEK.ERK1/ERK2, PI3K.Akt, STAT3/STAT5 access, EGFR discontinuity heights activate downstream signal, start EGFR and adjust
Anti-apoptotic and survival signaling cause cancer cell to become dependent upon this signal to maintain its existence -- i.e. have oncogene (mutation
The feature that EG is relied on；After blocking EGFR signals using specificity T KI, its proliferative effects and output survival signaling will be eliminated,
Lead to death of neoplastic cells.Result, it is believed that the variation of signal transduction pathway is that the high sensitive basis of drug 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 by other RTK after EGFR inhibition.In oncogene relies on model,
The oncogene that cell carcinomas relies on can generate 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, and cancer cell is made to maintain growth and proliferation.Work as cancer
It is that existence significantly weakens rapidly first in crucial window phase 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) treats NSCLC patient, about 10% patient performance
Go out rapid and satisfied clinical effectiveness, further study show that there are EGFR genetic mutations for these patient's overwhelming majority.Current
Known gene mutation related with EGFR-TKI (endothelial growth factor receptor tyrosine kinase inhibitor) is confined to following several
Kind：G719X (18 exon), E746-A450 lack (19 exon), L858R (21 exon), L861Q (21 exon),
T790M (20 exon) and D770-N771 (20 exon).Wherein E746-A450 is lacked and the treatment of the mutation and TKI of L858R
It imitates highly relevant.The analysis result of Mitsudomi T, Yatabe 568 Patients with Non-small-cell Lung of Y couple：All non-small thin
About 90% EGFR genetic mutation concentrates in 19 or 21 exons in born of the same parents' patients with lung cancer, wherein the deletion mutation of 19 exons
And the patient of 21 point mutation in exon takes the effective percentage of EGFR-TKI and reaches 70% or more.Recent research prompt,
The slotting human nature mutation (D770-N771) of EGFR extron 20s can make receptor reduce by 100 times to the sensibility of EGFR-TKI, 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, is exactly that the threonine in 790 site of EGFR tyrosine kinase domains is replaced (T790M) by methionine in protein level, it is this
Mutation can make EGFR be in the state that is activated again, drug resistant the reason is that mutation causes so as to cause the acquired resistance of TKI
EGFR structures change, and make TKI is in connection steric effect occur.
There is the reason of research prompt KRAS mutation may be Gefitinib, Erlotinib initial drug-resistant.Helena
The TKI therapeutic effects that 1008 NSCLC patients are summarized in the Meta analyses of linardou, at 165 of generation K-ras mutation
In patient, 94% patient treats without significant reaction TKI.In general, KRAS and EGFR mutation NSCLC is excluded each other
There are notable differences in different tumors subtypes：EGFR mutation are mainly seen in non-smoker, and KRAS mutation is more often seen
It smokes relevant cancer.Because KRAS mutation always betides in the NSCLC with Wild type EGFR, it is difficult to differentiate between pair
EGFR-TKI insensitive is mutated because of KRAS mutation, or because of no 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
It is mainly distributed on vascular endothelial cell, candidate stem cell, macrophage and monocyte, it can be with VEGF-A, VEGF-B and P1GF
In conjunction with mainly related 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 proliferation increases vascular permeability
Property and new vascular generation effect mainly by conjunction with realizing compared with VEGFR-2 with activation VEGFR-2, VEGFR-l with
The affinity of VEGF is 10 times high, but the activity for adjusting endothelial cell is much lower, it may be possible to have 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, and lymphatic endothelium is regulated and controled
Growth.
Research shows that：When diameter of tumor is more than 2mm, it is useless to provide nutriment and excretion metabolism to need new vessels
Object.VEGF/VEGFR signal paths serve in tumor vascular generation it is key, can be by blocking or interfering VEGF/
VEGFR signal paths inhibit the new life of blood vessel, to reach the effect of growth for controlling tumour.With traditional cytotoxic drug phase
Than having prodigious advantage under normal physiological conditions by the antitumor drug of target of VEGF/VEGFR-2, angiogenesis only exists
It works in the physiological activities 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 is in direct contact with blood, make drug be more prone to reach action site pass through it is current right
The understanding of VEGF/VEGFR signal path mechanism of action can obtain following several possible inhibitor research directions：A. it utilizes
Monoclonal antibody inhibits VEGF or VEGFR, prevents it from specifically binding, disabling signal conduction.Gene can certainly be utilized
Technology inhibits their expression, weakens its activity.B. specific micromolecular inhibitor is designed, the extracellular VEGF knots of VEGFR are attached to
Region is closed, competitive antagonism VEGF can also be similarly the particular combination domain for being attached to VEGFR on VEGF, competitive antagonism
VEGFR.C. inhibit the intracellular kinase domain of VEGFR, the mainly binding site of ATP, competitively antagonism ATP, makes it that can not carry
For phosphate.D. inhibit the critical proteins of the VEGFR downstream signals of intracellular to consider the compliance of patient, can take orally small
Molecule inhibitor may have good foreground.
Platelet derived growth factor (platelet.derived growth factor, PDGF) is induction and promotion blood
Pipe formation acts on most strong, most single-minded one of angiogenesis factor.PDGF mainly by with pdgf receptor (PDGFR) combine, into
And activated protein kinase signal transduction pathway and play a role.PDGFR is made 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 molecular weight is about 180~190ku, belong to
In tyrosine kinase receptor (receptor tyrosine kinase, RTK) family.PDGFR is in tumour formation and development process
In also play an important role.The overexpression of PDGFR- β 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,
And it is closely related with the growth, transfer and prognosis of certain tumours.So PDGFR- β are an ideal neoplasm targeted therapies
Target.
Raf kinases and its Raf/MEK/ERK accesses of mediation have remarkable effect in tumour progression and transfer process, and
Include epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and platelet growth factor with many growth factors
(PDGF) etc. closely related.People have thought a variety of methods to adjust this access, including the farnesyl for inhibiting Ras albumen
Change, inhibits the expression of Rat "-I kinases (also referred to as C-RAF kinases), inhibits the activity of Raf kinases and MEK kinases.Above-mentioned method
It not only inhibits the signal transduction of ERK but also successfully inhibits the growth of xenograft tumours.In addition, existing evidence is shown, greatly
Partial tumors are not dominated by single signal conduction path, carry out inhibiting that bigger curative effect may be obtained for multiple target point.
Many diseases are that abnormal cell effect for causing with protein kinase mediated event is associated.These disease packets
It includes, but is not limited to, tumour, inflammation disease, immunological diseases, bone disease, metabolic disease, neurological disease, cardiovascular and cerebrovascular disease, hormone
Relevant disease etc..Consequently found that being very important as medicine with searching kinases inhibitor.Although many hairs
It is bright that very big contribution has been made to this field, but to improve medication effect, this field still is continuing to study.
Invention content
It is pharmaceutically acceptable the purpose of the present invention is to provide N '-virtues acryloyl group neighbour's pyridine hydrazide derivatives shown in general formula I
Salt.
Another object of the present invention is to provide the systems of N '-virtues acryloyl group neighbour's pyridine hydrazide derivatives shown in general formula I
Preparation Method.
It is still another object of the present invention to provide one kind to spread out containing the fragrant acryloyl group neighbour's pyridine hydrazides of N '-shown in general formula I
The pharmaceutical composition of biology.
Another object of the present invention is to provide such compound in anticancer, and in the drug of protein kinase related disorder
Purposes.
In order to complete the purpose of the present invention, following technical solution can be used：
The present invention is related to having structure N ' shown in general formula I-virtue acryloyl group neighbour's pyridine hydrazide derivatives：
Or its officinal salt, in formula:
A can be selected from hydrogen, halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, ethyoxyl, isopropoxy, fluoroform
Oxygroup, cyano, amino, methylamino, sulfonamido, methanesulfonamido, mesyl, sulfamoyl, carboxyl, ester group, acetyl group,
Aryl
A is more preferably from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, ethyoxyl,
Isopropoxy, trifluoromethoxy, cyano, amino, methylamino, sulfonamido, methanesulfonamido, mesyl, sulfamoyl, carboxylic
Base, ethoxycarbonyl, acetyl group；
A is more preferably from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropyl oxygen
Base, trifluoromethoxy, cyano, methylamino, sulfonamido, methanesulfonamido, mesyl, sulfamoyl, carboxyl, ethoxycarbonyl,
Acetyl group；
A is particularly preferably from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropyl oxygen
Base, trifluoromethoxy, cyano, methylamino, methanesulfonamido, mesyl, sulfamoyl, carboxyl, acetyl group；
A is most preferably from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoro methoxy
Base, cyano, methylamino, mesyl, sulfamoyl, carboxyl, acetyl group；
N is selected from the integer of 0-5；
X can be selected from hydrogen, halogen, methyl, trifluoromethyl；
X is more preferably from hydrogen, F, Cl, Br, methyl, trifluoromethyl；
X is more preferably from hydrogen, F, Cl, methyl, trifluoromethyl；
Ar can be selected from aromatic ring and hetero-aromatic ring substitution or do not replace；Substituent group is selected from halogen, the alkyl of C1-6, fluoroform
Base, hydroxyl, methoxyl group, trifluoromethoxy, cyano, amino, methylamino, sulfonamido, methanesulfonamido, mesyl, ammonia sulphur
Acyl group, carboxyl, ester group, acetyl group, acetoxyl group, aryl.
Ar is more preferably from benzene, pyridine, naphthalene, indoles, pyrroles, furans, thiophene, thiazole, benzo thiophene substitution or do not replace
Azoles, pyrazoles, benzopyrazoles, imidazoles, benzimidazole, pyrimidine, oxazoles, pyrazine, quinoline, quinazoline, phenthazine, carbazole, substituent group
Selected from halogen, the alkyl of C1-6, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, cyano, amino, methylamino, sulphonyl ammonia
Base, methanesulfonamido, mesyl, sulfamoyl, carboxyl, ester group, phenyl, acetyl group, acetoxyl group.
Ar is more preferably from benzene that is substitution or not replacing, pyridine, naphthalene, indoles, thiophene, thiazole, pyrroles, pyrazoles, furans, phonetic
Ding, oxazoles, pyrazine, substituent group are selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, trifluoromethyl, hydroxyl
Base, methoxyl group, trifluoromethoxy, cyano, amino, methylamino, sulfonamido, methanesulfonamido, mesyl, sulfamoyl,
Carboxyl, ester group, acetyl group, acetoxyl group, phenyl.
Ar is particularly preferably from benzene that is substitution or not replacing, pyridine, naphthalene, indoles, thiazole, thiophene, pyrroles, pyrazoles, furans, phonetic
Ding, oxazoles, pyrazine, substituent group be selected from F, Cl, Br, methyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group,
Trifluoromethoxy, cyano, amino, methylamino, sulfonamido, methanesulfonamido, mesyl, carboxyl, ester group, acetyl group, second
Acyloxy.
Ar is most preferably from benzene that is substituted or not replacing, pyridine, naphthalene, indoles, furans, thiazole, thiophene, pyrazoles, pyrimidine, pyrrole
Qin, oxazoles, substituent group be selected from F, Cl, Br, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy,
Cyano, amino, methylamino, methanesulfonamido, mesyl, carboxyl, carbomethoxy, acetyl group, acetoxyl group.
Pharmaceutically acceptable salt described in Formulas I includes different acid-addition salts, such as the sour addition of following inorganic acid or organic acid
Salt：Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid, tartaric acid, rich horse
Acid, citric acid, lactic acid.Conventional method preparation all can be used in all these salt within the scope of the present invention.
The invention also discloses the methods for preparing the compounds of this invention, including following route steps：Prepare claim 1
The method of the compound, includes the following steps：
Route 1
Step（a）In with hydrazides 1 be raw material, reacted and held very much with substituted acryloyl chloride or acid anhydrides or acid with common method
It is easy to get to N '-virtue propylene hydrazide derivatives 2.
Step（b）In can pass through CDI and substituted aniline condensation and generate urea derivative I;It also can be with substituted phenyl isocyanide
Acid esters obtains urea derivative I by nucleophilic addition；Also it can pass through nucleophilic displacement of fluorine with substituted phenylamino formic acid 4- nitro phenyl esters
Urea derivative I is obtained by the reaction.
Route 2
Step（a）In with hydrazides 1 be raw material, reacted with acyl chlorides or acid anhydrides or acid with common method and be readily available N '-
Fragrant propylene hydrazide derivatives 2.
Step（b）In, with para hydroxybenzene amine derivative by being obtained to the chlorine substituted ether in hydrazides 2 under alkaline environment
Compound 3.
Step（c）In can pass through CDI and substituted aniline condensation and generate urea derivative I;It also can be with substituted phenyl isocyanide
Acid esters obtains urea derivative I by nucleophilic addition；Also it can pass through nucleophilic displacement of fluorine with substituted phenylamino formic acid 4- nitro phenyl esters
Urea derivative I is obtained by the reaction.
Route 3
Step（a）In, it is raw material with ester 4 or acyl chlorides 5, bishydrazide derivative 2 is obtained by the reaction with N '-virtue propylene hydrazides 6.
Step（b）In, 4-aminophenol derivative is under alkaline environment by replacing ether to the chlorine in bishydrazide derivative 2
Change obtains compound 3.
Step（c）In can pass through CDI and substituted aniline condensation and generate urea derivative I;It also can be with substituted phenyl isocyanide
Acid esters obtains urea derivative I by nucleophilic addition；Also it can pass through nucleophilic displacement of fluorine with substituted phenylamino formic acid 4- nitro phenyl esters
Urea derivative I is obtained by the reaction.
Route 4
Step（a）In, phenolic compounds 7 is under alkaline environment by being obtained to the chlorine substituted ether in bishydrazide derivative 2
Urea derivative I.Step（b）In, ester compounds 8 are reacted with N '-virtue propylene hydrazides 6 is similarly obtained urea derivative I.
Route 5
The route is raw material with hydrazides 9, with common method by itself and fragrant acrylic acid derivative or acyl chlorides or anhydride reaction
It is readily available urea derivative I.
In addition, the starting material and intermediate in above-mentioned reaction are easy to get, or to those skilled in the art
It can be easy to synthesize with the conventional method in organic synthesis.
The invention further relates to the pharmaceutical compositions using the compounds of this invention as active ingredient.The pharmaceutical composition can basis
It is prepared by method well known in the art.It can be by by the compounds of this invention and one or more pharmaceutically acceptable solids or liquid
Excipient and/or adjuvant combine, and any dosage form 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 administration route 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）, suspension, injection（Including liquid drugs injection, powder-injection
And infusion）, 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 capsule, soft capsule, capsulae enterosolubilis）, granule, dissipate
Agent, pellet, dripping pill, suppository, film, patch, 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 tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including 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
Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate 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 double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, active ingredient the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It also can active ingredient the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrant, then is placed in hard capsule or soft capsule.It is used to prepare 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 injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure regulator is added.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 can also be added mannitol, glucose etc. and be used as proppant.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well 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 be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization
The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.01-100mg/Kg 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 of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other medicines, which exist, to act synergistically, its dosage should be adjusted according to actual conditions.
The compounds of this invention is multiple target point kinases inhibitor or its precursor, 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..Generally, albumen
Kinases is transferred to one and the relevant protein receptor of signal transduction pathway by influencing a phosphoryl from a ribonucleoside triphosphote
Carry out signal transduction in mediated cell.These phosphorylated events adjust the biological function of target protein as molecular switch, are finally swashed
Hair reacts 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 that by blocking in upstream
VEGFR and pdgf receptor block Raf/MEK/ERK in downstream, can reduce the angiogenesis of tumour simultaneously and inhibit tumour thin
The duplication of born of the same parents, to hinder the growth of tumour.The compounds of this invention has higher bioavilability, can be used for a variety of mankind and dislikes
The treatment of property tumour, including the tumor disease is liver cancer, gastric cancer, kidney, lung cancer, cancer of pancreas, colorectal cancer, carcinoma of urinary bladder and
Breast cancer, oophoroma, squamous cell carcinoma, glioma, leukaemia, incidence cancer.
Specific implementation mode
Invention is described further below with reference to embodiment, but is not limit the scope of the invention.
Determining instrument：NMR spectrum Vaariaan Mercury300 or 400 type Nuclear Magnetic Resonance.Mass spectrum is used
ZAD-2F and VG300 mass spectrographs.
Embodiment 1.1- (4- (2- (2-（3- rubigan acryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
N’-（3- rubigan acryloyl groups）The synthesis of -4- (p-aminophenyl oxygroup) pyridine -2- hydrazides
By 105mg（0.43mmol）Compound 4-（P-aminophenyl oxygroup）Pyridine -2- hydrazides is dissolved in 7mlTHF, is added
0.09mL（0.64mmol）TEA is added dropwise to THF solutions of the 2ml dissolved with 0.52mmol3- rubigan acryloyl chlorides, and flow back 4h
Afterwards, there is white solid generation, stop reaction, filtering, a small amount of tetrahydrofuran is washed, and is washed, and drying obtains N '-（3- rubigan
Acryloyl group）- 4- (p-aminophenyl oxygroup) pyridine -2- hydrazides, white solid 60mg.1H NMR(400MHz,DMSO-d6):
10.59(br,1H,-CONH2-),10.48(s,1H,-CONH-),8.52(d,1H,Ar-H),7.56(m,3H,Ar-H),7.49
(m,4H,Ar-H),6.88(d,2H,Ar-H),6.73(d,1H,-CH=CH-Ar),6.65(d,1H,Ar-H),5.19(s,2H,
Ar-NH2).MS(FAB):(M++1=409).
1-(4-(2-(2-（3- rubigan acryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (the chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
Method 1.
By 1.12g（6.9mmol）CDI is dissolved in the dichloromethane of 7mL dryings, and beginnings solution is white opacity, will be dissolved with
1.2g（6.2mmol）The 10mL dichloromethane solutions of the chloro- 3- 5-trifluoromethylanilines of 4-, instill in above-mentioned solution, solution gradually becomes
Clarification after 8h is stirred at room temperature, is added dissolved with 2.1mmol N '-（3- rubigan acryloyl groups）- 4- (p-aminophenyl oxygroup) pyrrole
The dichloromethane solution 5mL of pyridine -2- hydrazides after being heated to reflux 10h, stops reaction, and column chromatography separates object 0.21g.1H-
NMR(300MHz,DMSO-d6):δ(ppm):10.56(brs,2H,-CONH-),9.36(s,1H,-CONH-),9.14(s,1H,-
CONH-),8.58(d,1H,ArH),8.13(brs,1H,ArH), 7.69~7.49 (m, 9H, ArH,=CH),7.41(d,1H,
ArH), 7.24~7.19 (m, 3H, ArH), 6.76~6.71 (d, 1H ,=CH);MS(FAB)（M++1=630）.
Method 2.
By 200mg（0.43mmol）Compound 1- (the chloro- 3- trifluoromethyls of 4-) -3- (4- (2- (hydrazine carbonyl) pyridines -
4- oxygroups) phenyl) urea is dissolved in 7mlTHF, 0.09mL is added（0.64mmol）TEA is added dropwise to 2ml dissolved with 0.52mmol3- pairs
The THF solution of chlorphenyl acryloyl chloride flows back after 4h, there is a white solid generation, stops reaction, filtering, a small amount of tetrahydrofuran
It washes, washes, drying is similarly obtained 1- (4- (2- (2-（3- rubigan acryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea, white solid 60mg.
Embodiment 2.1- (4- (2- (2-（3- m-trifluoromethylphenyl acryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -
3- (the chloro- 3- trifluoromethyls of 4-) urea
3- rubigan acrylic acid is replaced using 3- m-trifluoromethylphenyl acrylic acid, is carried out with reference to the operation of embodiment 1,
It is white solid 175mg to obtain target compound.1H NMR(400MHz,DMSO-d6):10.65(m,2H,-CONH-),9.39
(s,1H,-CONH-),9.16(s,1H,-CONH-),8.57(d,1H,Ar-H),8.03(m,3H,Ar-H),7.61(m,7H,Ar-
H,=CH-Ph),7.40(s,1H,Ar-H),7.20(m,3H,Ar-H),6.86(d,1H,-COCH=).MS(FAB)（M++1=664）
Embodiment 3.1- (4- (2- (2-（3- adjacency pair dichlorophenyl acryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
3- rubigan acrylic acid is replaced using 3- adjacency pair dichlorophenyl acrylic acid, carries out, obtains with reference to the operation of embodiment 1
It is white solid 135mg to target compound.1H NMR(400MHz,DMSO-d6):10.64(br,2H,-CONH-),9.46(s,
1H,-CONH-),9.23(s,1H,-CONH-),8.56(d,1H,Ar-H),8.12(s,1H,Ar-H),7.87(m,1H,Ar-H),
7.72(m,3H,Ar-H,=CHPh),7.40(m,3H,Ar-H),7.40(m,3H,Ar-H),6.78(d,1H,-COCH=);MS
(FAB)（M++1=664）
Embodiment 4.1- (4- (2- (2-（3-（To methoxycarbonyl group phenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) benzene
Base) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（To methoxycarbonyl group phenyl）Acrylic acid replace 3- rubigan acrylic acid, with reference to embodiment 1 operation into
Row, it is white solid 145mg to obtain target compound.1H NMR(300MHz,DMSO-d6):10.67(s,1H,-CONH-),
10.51(br,1H,-CONH-),9.30(s,1H,-CONH-),9.08(s,1H,-CONH-),8.58(d,1H,Ar-H),8.12
(d,1H,Ar-H),7.99(m,2H,Ar-H),7.76(d,2H,Ar-H),7.63(m,5H,Ar-H,-CH=C-),7.41(d,1H,
Ar-H),7.22(m,3H,Ar-H),6.86(d,1H,-CH=C-),3.87(s,3H,-O-CH3).MS(FAB)（M++1=654）
Embodiment 5.1- (4- (2- (2-（3- phenylacryloyls）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (the chloro- 3- of 4-
Trifluoromethyl) urea
3- rubigan acrylic acid is replaced using 3- phenylacrylic acids, is carried out with reference to the operation of embodiment 1, obtains targeted
Conjunction object is white solid 115mg.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.63(brs,2H,-CONH-),9.35(s,
1H,-CONH-),9.12(s,1H,-CONH-),8.57(d,1H,ArH),8.13(s,1H,ArH),7.66-7.53(m,7H,
ArH,=CH),7.42(brs,4H,ArH),7.27-7.19(m,3H,ArH),6.76-6.71(d,1H,=CH);MS(FAB)（M++
1=596）
Embodiment 6.1- (4- (2- (2-（3-（Between hydroxy phenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（Between hydroxy phenyl）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
It is white solid 155mg to target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.62(s,1H,-CONH-),
9.66(s,1H,-CONH-),9.42(s,1H,-CONH-),9.19(s,1H,-CONH-),8.57(d,1H,ArH),8.13(s,
1H,ArH),7.69-7.41(m,6H,ArH,=CH),7.24-7.18(m,4H,ArH),7.04-6.98(m,2H,ArH),6.82-
6.80(d,1H,ArH),6.67-6.62(d,1H,=CH);MS(FAB)（M++1=612）
Embodiment 7.1- (4- (2- (2-（3-（The hydroxy phenyl between methoxyl group）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups)
Phenyl) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（The hydroxy phenyl between methoxyl group）Acrylic acid replaces 3- rubigan acrylic acid, with reference to the behaviour of embodiment 1
It carries out, it is white solid 155mg to obtain target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.59(brs,
2H,-CONH-),9.46(s,1H,-CONH-),9.23(s,1H,-CONH-),8.56(d,1H,ArH),8.13(s,1H,ArH),
7.69-7.60(m,5H,ArH),7.41-7.36(m,2H,ArH,=CH),7.21-7.18(m,3H,ArH),7.02-6.93(m,
2H,ArH),6.51-6.46(d,1H,=CH),3.80(s,3H,-CH3 );MS(FAB)（M++1=642）
Embodiment 8.1- (4- (2- (2-（3-（To hydroxyl m-methoxyphenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups)
Phenyl) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（To hydroxyl m-methoxyphenyl）Acrylic acid replaces 3- rubigan acrylic acid, with reference to the behaviour of embodiment 1
It carries out, it is white solid 125mg to obtain target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):9.45(s,1H,-
CONH-),9.22(s,1H,-CONH-),8.56(d,1H,ArH),8.13(s,1H,ArH),7.69-7.60(m,5H,ArH,),
7.46-7.36(m,2H,ArH=CH),7.21-7.16(m,4H,ArH),6.82-6.79(d,1H,ArH),6.56-6.51(d,
1H,=CH),3.81(s,3H,-CH3 );MS(FAB)（M++1=642）
Embodiment 9.1- (4- (2- (2-（3-（Between cyano-phenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（Between cyano-phenyl）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
It is white solid 155mg to target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):9.33(s,1H,-CONH-),
9.11(s,1H,-CONH-),8.58(d,1H,ArH),8.12-8.04(m,2H,ArH),7.97-7.84(m,2H,ArH),
7.72-7.55(m,6H,ArH,=CH),7.47(s,1H,ArH),7.21-7.19(m,3H,ArH),6.86-6.80(d,1H,=
CH);MS(FAB)（M++1=621）
Embodiment 10.1- (4- (2- (2-（3-（3,4- Dimethoxyphenyls）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) benzene
Base) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（3,4- Dimethoxyphenyls）Acrylic acid replaces 3- rubigan acrylic acid, with reference to the operation of embodiment 1
It carries out, it is white solid 115mg to obtain target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.58(s,1H,-
CONH-),10.32(s,1H,-CONH-),9.51(s,1H,-CONH-),9.27(s,1H,-CONH-),8.57(d,1H,ArH),
8.14(s,1H,ArH),7.71-7.61(m,4H,ArH),7.51-7.46(s,1H,=CH),7.41(d,1H,ArH),7.27-
7.16(m,5H,ArH),7.02-6.99(s,1H,ArH),6.65-6.60(d,1H,=CH),3.81-3.77(m,6H,-OCH3 );
MS(FAB)（M++1=656）
Embodiment 11.1- (4- (2- (2-（3-（3,4- difluorophenyls）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -
3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（3,4- difluorophenyls）Acrylic acid replaces 3- rubigan acrylic acid, is carried out with reference to the operation of embodiment 1,
It is white solid 145mg to obtain target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.58(brs,2H,-
CONH-),9.34(s,1H,-CONH-),9.12(s,1H,-CONH-),8.57(d,1H,ArH),8.12(s,1H,ArH),
7.72-7.40(m,9H,ArH),7.33-7.27(s,1H,=CH),7.21-7.18(d,2H,ArH),6.73-6.68(d,1H,=
CH),3.81-3.77(m,6H,-OCH3 );MS(FAB)（M++1=632）
Embodiment 12.1- (4- (2- (2-（3-（Furans -2）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
Utilize 3-（Furans -2）Acrylic acid replaces 3- rubigan acrylic acid, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 115mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.60(brs,1H,-CONH-),
10.40(brs,1H,-CONH-),9.41(s,1H,-CONH-),9.18(s,1H,-CONH-),8.57(d,1H,ArH),8.13
(s,1H,ArH),7.85-7.81(d,1H,ArH),7.72-7.60(m,4H,ArH),7.42-7.40(d,1H,ArH),7.37-
7.33(d,1H,=CH),7.20-7.18(m,3H,ArH),6.84(s,1H,ArH), 6.65~6.61 (d, 1H, ArH), 6.52~
6.43(d,1H,=CH);MS(FAB)（M++1=586）
Embodiment 13.1- (4- (2- (2-（3-（Furans -3）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
Utilize 3-（Furans -3）Acrylic acid replaces 3- rubigan acrylic acid, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 155mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.57(brs,1H,-CONH-),
10.32(brs,1H,-CONH-),9.44(s,1H,-CONH-),9.21(s,1H,-CONH-),8.57(d,1H,ArH),8.16-
8.06(m,2H,ArH),7.74-7.61(m,5H,ArH),7.47-7.40(m,2H,ArH,=CH),7.20-7.18(m,3H,
ArH),6.76(s,1H,ArH), 6.45~6.41 (d, 1H ,=CH);MS(FAB)（M++1=586）
Embodiment 14.1- (4- (2- (2-（3-（Thiophene -2）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
Utilize 3-（Thiophene -2）Acrylic acid replaces 3- rubigan acrylic acid, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 125mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.61(brs,1H,-CONH-),
10.38(brs,1H,-CONH-),9.34(s,1H,-CONH-),9.12(s,1H,-CONH-),8.57(d,1H,ArH),8.12
(s,1H,ArH),7.72-7.60(m,6H, ArH),7.44-7.40(m,2H,ArH,=CH),7.21-7.13(m,4H,ArH),
6.49-6.45(d,1H,=CH);MS(FAB)（M++1=602）
Embodiment 15.1- (4- (2- (2-（3-（Pyridine -3）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
Utilize 3-（Pyridine -3）Acrylic acid replaces 3- rubigan acrylic acid, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 145mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.66(s,1H,-CONH-),
10.48(s,1H,-CONH-),9.23(s,1H,-CONH-),9.02(s,1H,-CONH-),8.87-8.81(d,1H,ArH),
8.59-8.57(m,2H,ArH),8.16-8.12(m,1H,ArH),8.04(d,1H,ArH),7.75-7.58(m,5H,ArH,=
CH),7.47-7.41(m,2H, ArH),7.21-7.19(m,3H, ArH),6.86-6.82(d,1H,=CH);MS(FAB)（M++
1=597）
Embodiment 16.1- (4- (2- (2-（3-（P-methoxyphenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（P-methoxyphenyl）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
It is white solid 155mg to target compound.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.58(s,1H,-CONH-),
10.36(s,1H,-CONH-),9.47(s,1H,-CONH-),9.23(s,1H,-CONH-),8.57(d,1H,ArH),8.14(s,
1H,ArH),7.69-7.48(m,7H,ArH,=CH),7.41(s,1H,ArH),7.21-7.19(m,3H,ArH),7.00-6.98
(d,2H,ArH),6.61-6.57(d,1H,=CH),3.80(s,3H,-OCH3 );MS(FAB)（M++1=626）
Embodiment 17.1- (4- (2- (2-（3-（P-trifluoromethyl phenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) benzene
Base) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（P-trifluoromethyl phenyl）Acrylic acid replace 3- rubigan acrylic acid, with reference to embodiment 1 operation into
Row, it is white solid 165mg to obtain target compound.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.30(s,1H,-
CONH-),9.08(s,1H,-CONH-),8.57(d,1H,ArH),8.12(s,1H,ArH),7.94-7.92(d,1H,ArH),
7.82-7.78(m,4H,ArH),7.66-7.60(m,4H,ArH,=CH),7.42(s,1H,ArH),7.21-7.19(m,3H,
ArH),6.88-6.84(d,1H,=CH);MS(FAB)（M++1=664）
Embodiment 18.1- (4- (2- (2-（3-（Between chlorphenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（Between chlorphenyl）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
Target compound is white solid 155mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.57(brs,2H,-CONH-),
9.30(s,1H,-CONH-),9.08(s,1H,-CONH-),8.57(d,1H,ArH),8.13(s,1H,ArH),7.70-7.33
(m,9H,ArH,=CH),7.27-7.19(m,4H,ArH),6.79-6.75(d,1H,=CH);MS(FAB)（M++1=630）
Embodiment 19.1- (4- (2- (2-（3-（Between fluorophenyl）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（Between fluorophenyl）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
Target compound is white solid 145mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):10.60(brs,2H,-CONH-),
9.30(s,1H,-CONH-),9.08(s,1H,-CONH-),8.57(d,1H,ArH),8.13(s,1H,ArH),7.69-7.55
(m,6H,ArH),7.51-7.38(m,4H,ArH,=CH),7.21-7.19(m,3H,ArH),6.80-6.76(d,1H,=CH);MS
(FAB)（M++1=614）.
Embodiment 20.1- (4- (2- (2-（3-（P-hydroxybenzene）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（P-hydroxybenzene）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
It is white solid 115mg to target compound.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.56(brs,1H,-
CONH-),10.25(brs,1H,-CONH-),9.89(s,1H,Ph-OH),9.33(s,1H,-CONH-),9.14(s,1H,-
CONH-),8.57(d,1H,ArH),8.13(s,1H,ArH), 7.69~7.55 (m, 5H, ArH,=CH), 7.48~7.35 (m,
3H,ArH), 7.23~7.11 (m, 3H, ArH),6.82(d,2H,ArH), 6.54~6.49 (d, 1H ,=CH);MS(FAB)（M++1
=612）.
Embodiment 21.1- (4- (2- (2-（3-（To acetoxyl group m-methoxyphenyl）Acryloyl）Hydrazine carbonyl) pyridine -4-
Oxygroup) phenyl) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（To acetoxyl group m-methoxyphenyl）Acrylic acid replaces 3- rubigan acrylic acid, with reference to embodiment 1
Operation carry out, obtain target compound be white solid 125mg.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.61
(brs,2H,-CONH-),9.30(s,1H,-CONH-),9.08(s,1H,-CONH-),8.58(d,1H,ArH),8.12(brs,
1H,ArH), 7.69~7.52 (m, 5H, ArH,=CH), 7.44~7.38 (m, 2H, ArH), 7.24~7.13 (m, 5H, ArH),
6.76~6.71 (d, 1H ,=CH),3.83(s,3H,-OCH3 ),2.27(s,3H,-COCH3 );MS(FAB)（M++1=684）.
Embodiment 22.1- (4- (2- (2-（3-（Pentafluorophenyl group）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
Utilize 3-（Pentafluorophenyl group）Acrylic acid replaces 3- rubigan acrylic acid, carries out, obtains with reference to the operation of embodiment 1
Target compound is white solid 155mg.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.73(brs,2H,-CONH-),
9.38(s,1H,-CONH-),9.16(s,1H,-CONH-),8.58(d,1H,ArH),8.13(d,1H,ArH), 7.69~7.60
(m,4H,ArH,=CH), 7.45~7.39 (m, 2H, ArH), 7.23~7.19 (m, 3H, ArH), 7.03~6.98 (d, 1H ,=
CH);MS(FAB)（M++1=686）.
Embodiment 23.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (the chloro- 3- trifluoromethyls of 4-) urea
Utilize 4-（The fluorophenoxy between amino）Pyridine -2- hydrazides replaces 4-（P-aminophenyl oxygroup）Pyridine -2- hydrazides, ginseng
Operation according to embodiment 1 carries out, and it is white solid 125mg to obtain target compound.1H-NMR(400MHz,DMSO-d6):δ
(ppm):9.58(s,1H,-CONH-),8.79(s,1H,-CONH-),8.59(d,1H,ArH),8.19-8.12(m,2H,ArH),
7.74-7.72(d,1H,ArH),7.63(s,3H,ArH),7.50-7.45(m,4H,ArH,=CH),7.38-7.25(m,2H,
ArH),7.11-7.09(d,1H,ArH),6.75-6.71(d,1H,ArH);MS(FAB)（M++1=648）.
Embodiment 24.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (2,4- difluorophenyl) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 2,4- difluoroanilines, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 125mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.23(s,1H,-CONH-),8.58
(brs,2H,-CONH-,ArH),8.08(m,1H,ArH),7.74-7.72(d,1H,ArH),7.65-7.58(m,4H,ArH),
7.51-7.49(d,2H,ArH),7.41(s,1H,ArH),7.33-7.29(m,2H,ArH,=CH),7.21-7.19(d,2H,
ArH),7.23-7.16(m,5H,ArH),7.05(t,1H,ArH),6.75-6.71(d,1H,=CH);MS(FAB)（M++1=
564）.
Embodiment 25.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (the chloro- 4- aminomethyl phenyls of 3-) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using the chloro- 4- methylanilines of 3-, carries out, obtains with reference to the operation of embodiment 1
Target compound is white solid 135mg.1H-NMR(400MHz,DMSO-d6):δ(ppm):8.96(s,1H,-CONH-),
8.91(s,1H,-CONH-),8.57(d,1H,ArH),7.74-7.70(m,2H,ArH),7.65-7.63(d,1H,ArH),
7.60-7.58(d,2H, ArH),7.51-7.49(d,2H,ArH),7.41(s,1H,ArH),7.33-7.17(m,6H,ArH,=
CH),6.75-6.71(d,1H,=CH),2.26(s,3H,-CH3 );MS(FAB)（M++1=576）.
Embodiment 26.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (4- trifluoromethyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 4- 5-trifluoromethylanilines, carries out, obtains with reference to the operation of embodiment 1
Target compound is white solid 125mg.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.62(brs,2H,-CONH-),
9.29(s,1H,-CONH-),9.10(s,1H,-CONH-),8.57(d,1H,ArH),7.75-7.57(m,8H,ArH),7.51-
7.41(m,3H,ArH),7.34-7.29(d,1H,=CH),7.21-7.19(m,3H,ArH),6.76-6.71(d,1H, ArH);
MS(FAB)（M++1=596）.
Embodiment 27.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (4- chlorphenyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 4- chloroanilines, is carried out with reference to the operation of embodiment 1, obtains targeted
Conjunction object is white solid 145mg.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.55(brs,2H,-CONH-),8.97
(s,2H,-CONH-),8.57(d,1H,ArH),7.75-7.72(d,2H,ArH),7.66-7.58(m,3H,ArH),7.51-
7.48(m,4H,ArH),7.41(s,1H,ArH),7.34-7.28(m,3H,ArH,=CH),7.20-7.17(d,2H,ArH),
6.76-6.71(d,1H,ArH);MS(FAB)（M++1=562）.
Embodiment 28.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (3- aminomethyl phenyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using m-toluidine, is carried out with reference to the operation of embodiment 1, obtains target
Compound is white solid 135mg.1HNMR(300MHz,DMSO-d6):10.64(br,1H,-CONH-),10.41(br,1H,-
CONH-),8.82(s,1H,-CONH-),8.64(s,1H,-CONH-),8.57(s,1H,Ar-H),7.72(m,9H,Ar-H),
7.17(m,3H,Ar-H,-CH=CH-),6.71(m,4H,Ar-H,-CH=CH-),2.28(s,3H,-CH3);MS(FAB)（M++1=
542）.
Embodiment 29.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (4- ethoxyl phenenyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 4- phenetidines, is carried out with reference to the operation of embodiment 1, obtains mesh
Mark compound is white solid 125mg.1HNMR(300MHz,DMSO-d6):10.64(br,1H,-CONH-),10.41(br,
1H,-CONH-),8.76(s,1H,-CONH-),8.57(s,1H,-CONH-),8.51(s,1H,Ar-H),8.36(s,1H,Ar-
H),7.52(m,12H,Ar-H,-CH=CH-),7.17(m,3H,Ar-H,-CH=CH-),6.71(m,4H,Ar-H,-CH=CH-),
2.28(s,3H,-CH3);MS(FAB)（M++1=572）.
Embodiment 30.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (4- fluorophenyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 4- fluoroanilines, is carried out with reference to the operation of embodiment 1, obtains targeted
Conjunction object is white solid 132mg.1HNMR(300MHz,DMSO-d6):10.63(br,1H,-CONH-),10.40(br,1H,-
CONH-),8.84(s,1H,-CONH-),8.76(s,1H,-CONH-),8.57(d,1H,Ar-H),7.57(m,10H,Ar-H,-
CH=CH-),7.17(m,5H,Ar-H,),6.68(d,1H,-CH=CH-);MS(FAB)（M++1=546）.
Embodiment 31.1- (4- (2- (2-（3-（Rubigan）Acryloyl）Hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorobenzene
Base) -3- (3- bromophenyls) urea
The chloro- 3- 5-trifluoromethylanilines of 4- are replaced using 3- bromanilines, is carried out with reference to the operation of embodiment 1, obtains targeted
Conjunction object is white solid 132mg.1HNMR(300MHz,DMSO-d6):10.64(br,1H,-CONH-),10.41(br,1H,-
CONH-),8.93(s,2H,-CONH-),8.57(d,1H,-CONH-),7.86(s,1H,Ar-H),7.64(m,7H,Ar-H,-CH
=CH-),7.41(s,1H,Ar-H),7.21(m,6H,Ar-H),6.74(d,1H,-CH=CH-),2.28(s,3H,-CH3);MS
(FAB)（M++1=606）.
Pharmacological activity
External activity is evaluated：
Mtt assay measures tumor cell survival
A concentration of 0.8~2 × 10 are configured to after the cell of exponential phase is digested with pancreatin4The cell liquid of cell/ml,
96 orifice plates are inoculated in by 1000/hole, add 100 μ l per hole.Next day addition drug containing various concentration and coordinative solvent compare new
Fresh culture medium adds 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
Supernatant is abandoned in hole after 37 DEG C are continued to cultivate 120hr, and the serum-free training of the MTT containing 0.5mg/ml of 100 μ l Fresh 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
Mixing measures OD value (OD), with solvent with MK3 types microplate reader under the conditions of reference wavelength 450nm, Detection wavelength 570nm
The tumour cell of control treatment is control group, calculates inhibiting rate of the drug to tumour cell with following formula, and press middle efficacious prescriptions journey
Calculate IC50：
MTT the selection results
MTT the selection results
Claims (17)
1. N '-virtues acryloyl group neighbour's pyridine hydrazide derivatives shown in Formulas I, officinal salt,
In formula:A is selected from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, ethyoxyl, isopropyl
Oxygroup, trifluoromethoxy, cyano, amino, methylamino, methanesulfonamido, mesyl, sulfamoyl, carboxyl, ethoxycarbonyl
Base, acetyl group；
N is selected from the integer of 0-5；
X is selected from hydrogen, F, Cl, Br, methyl, trifluoromethyl；
Ar be selected from substitution or do not replace benzene, pyridine, naphthalene, indoles, pyrroles, furans, thiophene, thiazole, benzothiazole, pyrazoles,
Benzopyrazoles, imidazoles, benzimidazole, pyrimidine, oxazoles, pyrazine, quinoline, quinazoline, phenthazine, carbazole, substituent group be selected from halogen,
Alkyl, trifluoromethyl, hydroxyl, methoxyl group, the trifluoromethoxy of C1-6, cyano, amino, methylamino, methanesulfonamido, methylsulfonyl
Base, sulfamoyl, carboxyl, methoxycarbonyl base, phenyl, acetyl group, acetoxyl group.
2. compound and its officinal salt according to claim 1, which is characterized in that
Wherein A be selected from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, three
Fluorine methoxyl group, cyano, methylamino, methanesulfonamido, mesyl, sulfamoyl, carboxyl, ethoxycarbonyl, acetyl group；
N is selected from the integer of 0-5；
X is selected from hydrogen, F, Cl, methyl, trifluoromethyl；
Ar be selected from substitution or do not replace benzene, pyridine, naphthalene, indoles, thiophene, thiazole, pyrroles, pyrazoles, furans, pyrimidine, oxazoles,
Pyrazine, substituent group are selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxy
Base, trifluoromethoxy, cyano, amino, methylamino, methanesulfonamido, mesyl, sulfamoyl, carboxyl, methoxycarbonyl base,
Acetyl group, acetoxyl group, phenyl.
3. compound and its officinal salt according to claim 2, which is characterized in that
Wherein A be selected from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, isopropoxy, three
Fluorine methoxyl group, cyano, methylamino, methanesulfonamido, mesyl, sulfamoyl, carboxyl, acetyl group；
N is selected from the integer of 0-5；
X is selected from hydrogen, F, Cl, methyl, trifluoromethyl；
Ar be selected from substitution or do not replace benzene, pyridine, naphthalene, indoles, thiazole, thiophene, pyrroles, pyrazoles, furans, pyrimidine, oxazoles,
Pyrazine, substituent group are selected from F, Cl, Br, methyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoro methoxy
Base, cyano, amino, methylamino, methanesulfonamido, mesyl, carboxyl, methoxycarbonyl base, acetyl group, acetoxyl group.
4. compound and its officinal salt according to claim 3, which is characterized in that
Wherein A be selected from hydrogen, fluorine, chlorine, bromine, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy,
Cyano, methylamino, mesyl, sulfamoyl, carboxyl, acetyl group；
N is selected from the integer of 0-5；
X is selected from hydrogen, F, Cl, methyl, trifluoromethyl；
Ar is selected from benzene, pyridine, naphthalene, indoles, furans, thiazole, thiophene, pyrazoles, pyrimidine, pyrazine, oxazoles substitution or do not replace,
Substituent group is selected from F, Cl, Br, methyl, isopropyl, tertiary butyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, cyano, ammonia
Base, methylamino, methanesulfonamido, mesyl, carboxyl, methoxycarbonyl base, acetyl group, acetoxyl group.
5. according to the compound and its officinal salt of any one of claim 1-4, the compound is selected from：
1- (4- (2- (2- (3- rubigan acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoromethyls of 4-
Phenyl) urea
1- (4- (2- (2- (3- m-trifluoromethylphenyls acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- of 4- tri-
Trifluoromethylphenyl) urea
1- (4- (2- (2- (3- adjacency pair dichlorophenyls acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
1- (4- (2- (2- (3- (to methoxycarbonyl group phenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- of 4-
Trifluoromethyl) urea
1- (4- (2- (2- (3- phenylacryloyls) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (the chloro- 3- trifluoromethyls of 4-)
Urea
1- (4- (2- (2- (3- (hydroxy phenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
1- (4- (2- (2- (3- (hydroxy phenyl between methoxyl group) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
1- (4- (2- (2- (3- (to hydroxyl m-methoxyphenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (4-
Chloro- 3- trifluoromethyls) urea
1- (4- (2- (2- (3- (cyano-phenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
(4- is chloro- by -3- by 1- (4- (2- (2- (3- (3,4- Dimethoxyphenyls) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl)
3- trifluoromethyls) urea
1- (4- (2- (2- (3- (3,4- difluorophenyls) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- of 4- tri-
Trifluoromethylphenyl) urea
1- (4- (2- (2- (3- (furans -2) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoromethyls of 4-
Phenyl) urea
1- (4- (2- (2- (3- (furans -3) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoromethyls of 4-
Phenyl) urea
1- (4- (2- (2- (3- (thiophene -2) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoromethyls of 4-
Phenyl) urea
1- (4- (2- (2- (3- (pyridine -3) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoromethyls of 4-
Phenyl) urea
1- (4- (2- (2- (3- (p-methoxyphenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
1- (4- (2- (2- (3- (p-trifluoromethyl phenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- of 4-
Trifluoromethyl) urea
1- (4- (2- (2- (3- (chlorphenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- fluoroforms of 4-
Base phenyl) urea
1- (4- (2- (2- (3- (fluorophenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- fluoroforms of 4-
Base phenyl) urea
1- (4- (2- (2- (3- (p-hydroxybenzene) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- trifluoros of 4-
Aminomethyl phenyl) urea
1- (4- (2- (2- (3- (to acetoxyl group m-methoxyphenyl) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3-
(the chloro- 3- trifluoromethyls of 4-) urea
1- (4- (2- (2- (3- (pentafluorophenyl group) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) phenyl) -3- (chloro- 3- fluoroforms of 4-
Base phenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (chloro- 3- of 4- tri-
Trifluoromethylphenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (2,4- difluoros
Phenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (chloro- 4- first of 3-
Base phenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (4- fluoroforms
Base phenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (4- chlorphenyls)
Urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (3- methylbenzenes
Base) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (4- ethyoxyls
Phenyl) urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (4- fluorophenyls)
Urea
1- (4- (2- (2- (3- (rubigan) acryloyl) hydrazine carbonyl) pyridine -4- oxygroups) -2- fluorophenyls) -3- (3- bromophenyls)
Urea
6. compound according to claim 1 and its officinal salt, which is characterized in that the officinal salt is selected from：Hydrochloride,
Hydrobromate, phosphate, sulfate, mesylate, tosilate, acetate, trifluoroacetate, salicylate, amino
Hydrochlorate, matrimony vine hydrochlorate, maleate, tartrate, fumarate, citrate, lactate.
7. prepare claim 1 described in compound method, in following 5 kinds of methods any one：Wherein, X, A, Ar, with
And the range of choice of n is equal to claim 1,
Route 1
Route 2
Route 3
Route 4
Route 5
8. preparation method according to claim 7, which is characterized in that step (a) is raw material with hydrazides 1 in route 1, is replaced with Ar
Acryloyl chloride or acid anhydrides or acid the fragrant propylene hydrazide derivatives of N ' -2 are obtained by the reaction；Pass through CDI and n (A) substitutions in step (b)
Aniline condensation generates urea derivative I；Or urea derivative is obtained by nucleophilic addition with the phenyl isocyanate of n (A) substitutions
Object I；Or urea derivative I is obtained by nucleophilic substitution with the phenylamino formic acid 4- nitros phenyl ester of n (A) substitutions, wherein X, A,
The range of choice of Ar and n is equal to claim 1.
9. preparation method according to claim 7, which is characterized in that step (a) is raw material with hydrazides 3 in route 2, is replaced with Ar
Acryloyl chloride or acid anhydrides or acid the fragrant acryloyl group hydrazine derivates of N ' -4 are obtained by the reaction；In step (b), replace to hydroxyl with adjacent X
Aniline, by obtaining compound 2 to the chlorine substituted ether in hydrazides 4, is taken in step (c) by CDI and n (A) under alkaline environment
The aniline condensation in generation generates urea derivative I；Or urea is obtained by nucleophilic addition with the phenyl isocyanate of n (A) substitutions
Derivative I；Or urea derivative I is obtained by nucleophilic substitution with the phenylamino formic acid 4- nitros phenyl ester of n (A) substitutions, wherein
X, the range of choice of A, Ar and n are equal to claim 1.
10. preparation method according to claim 7, which is characterized in that be original with ester 5 or acyl chlorides 6 in route 3 in step (a)
Bishydrazide derivative 4 is obtained by the reaction with N '-virtue propylene hydrazides 7 in material；In step (b), 3-X-4- amino-phenols are under alkaline environment
By obtaining compound 2 to the chlorine substituted ether in bishydrazide derivative 4；Pass through the aniline of CDI and n (A) substitutions in step (c)
Condensation generates urea derivative I；Or urea derivative I is obtained by nucleophilic addition with the phenyl isocyanate of n (A) substitutions；
Or with n (A) substitution phenylamino formic acid 4- nitros phenyl ester urea derivative I is obtained by nucleophilic substitution, wherein X, A, Ar,
And the range of choice of n is equal to claim 1.
11. preparation method according to claim 7, which is characterized in that in route 4 in step (a), phenolic compounds 8 is in alkaline ring
By obtaining urea derivative I to the chlorine substituted ether in bishydrazide derivative 4 under border；In step (b), ester compounds 9 and N '-virtues
The reaction of propylene hydrazides 7 is similarly obtained urea derivative I, wherein the range of choice of X, A, Ar and n are equal to claim 1.
12. preparation method according to claim 7, which is characterized in that with hydrazides 10 be raw material in route 5, itself and Ar are replaced
Acrylic acid or acyl chlorides or anhydride reaction obtain urea derivative I, wherein the range of choice of X, A, Ar and n are equal to claim
1。
13. a kind of composition of drug, which is characterized in that the compound containing any one of claim 1-6 and its pharmaceutically acceptable
Salt and the acceptable carrier of galenic pharmacy.
14. the compound and its officinal salt of any one of claim 1-6 are related with protein kinase in preparation prevention and treatment
Disease drug in application.
15. the compound and its officinal salt of any one of claim 1-6 have in preparation prevention and treatment with tyrosine kinase
Application in the drug of the disease of pass.
16. application according to claim 15, which is characterized in that the disease related with tyrosine kinase is tumour.
17. application according to claim 16, which is characterized in that the tumor disease is liver cancer, kidney, lung cancer, cancer of pancreas,
Gastric cancer, colorectal cancer, carcinoma of urinary bladder, breast cancer, oophoroma, squamous cell carcinoma, glioma, incidence cancer.
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| WO2004078128A2 (en) * | 2003-02-28 | 2004-09-16 | Bayer Pharmaceuticals Corporation | Substituted pyridine derivatives useful in the treatment of cancer and other disorders |
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| CN101381379A (en) * | 2003-04-25 | 2009-03-11 | 吉里德科学公司 | Kinase inhibitor phosphonate conjugates |
| WO2008115263A2 (en) * | 2007-03-20 | 2008-09-25 | Curis, Inc. | Raf kinase inhibitors containing a zinc binding moiety |
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