CN104211682B - Pyridine compounds and their and application thereof - Google Patents
Pyridine compounds and their and application thereof Download PDFInfo
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- CN104211682B CN104211682B CN201310253646.6A CN201310253646A CN104211682B CN 104211682 B CN104211682 B CN 104211682B CN 201310253646 A CN201310253646 A CN 201310253646A CN 104211682 B CN104211682 B CN 104211682B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D405/14—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 three or more hetero rings
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- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to the pyridine derivatives shown in formula I and their pharmaceutically acceptable salts, hydrate or prodrug, wherein substitution base K, Q, Ar, Y have the implication for providing in the description.Compound the invention further relates to formula I has the effect for suppressing the kinases of C Raf and VEGFR 2, and further relate to the purposes of such compound and its pharmaceutically acceptable salt, hydrate or prodrug in medicine of the treatment due to the kinases overexpression diseases caused of C Raf and VEGFR 2 is prepared, the particularly purposes in the medicine for the treatment of and/or pre- anti-cancer is prepared.
Description
Technical field
The present invention relates to new pyridine compounds and their and its pharmaceutically acceptable salt, hydrate or its prodrug, they
Preparation method and the pharmaceutical composition containing the compound.The invention further relates to such compound and its pharmaceutically acceptable
Salt, hydrate or its prodrug preparing treatment due to the medicine of C-Raf and VEGFR-2 kinases overexpression diseases caused
In purposes, particularly prepare treatment and/or pre- anti-cancer medicine in purposes.
Background technology
Malignant tumour is a kind of disease of serious harm human life and health, with the change of the extraneous factors such as environmental pollution
Change, global pathogenesis of cancer number rises year by year.Just because of this, to the research of elaboration of tumour mechanism and its treatment method
More and more extensively and profoundly.
In recent years, developing rapidly with oncobiology and related discipline, it is signal transduction in malignant cell, thin
The basic process of some cell carcinogenesis such as the induction of born of the same parents' apoptosis is just gradually elucidated with, and thus antineoplastic research and development theory there occurs
Great change, research and development focus from conventional cell poison class medicine be transferred to in tumour cell signal transduction pathway it is new
Antineoplastic, makes the point of penetration of tumor pharmacother by cellular level excessively to molecular level.New type antineoplastic medicine is directed to
Difference between normal cell and tumour cell, selectively acting has in the related specific kinases of tumor cell differentiation propagation
Efficiently, the advantages of low toxicity, high specificity.Therefore, the research of targeting antineoplastic medicine thing has turned into current antineoplastic research
The important directions of exploitation.
At present, kinases inhibitor is a class of known most study in the molecular targeted type antineoplastic of discovery.
Protein kinase can cause signal transduction process obstacle or exception occur due to being mutated or resetting, and cause cell growth, differentiation, generation
Thank with biological behaviour exception, thus kinds of tumors can be induced.Ras/Raf/MEK/ERK this Signal Transduction Pathways are widely present in very
In core biology.Raf can be amplified signal cascade by a series of phosphorylations as a Key kinases in the path,
So as to adjust cellular activity.Once the path is over-expressed, the acceleration of cell propagation can be led with the extension of cells survival phase
Oncogenic formation.Raf kinases is divided into three hypotypes, A-Raf, B-Raf and C-Raf.Wherein, C-Raf is in most of human body groups
Knit middle expression, and be not the function of adjustable cellular activity by Ras/Raf/MEK/ERK paths, research display its in various richnesses
Abnormal activation in the entity tumor of blood vessel, such as kidney, liver cancer and non-small cell lung cancer, can by the activity for reducing the kinases
To suppress the generation of tumour cell.VEGFR（Vascular endothelial growth factor receptor）It is acceptor
A member in tyrosine family, the generation to new vessels serves the effect of key.Various physiology and pathologic process of human body
Being directed to new vessels generation includes embryonic development, menstrual cycle, wound healing, tumour, rheumatic arthritis and diabetes
PVR etc..This receptor is broadly divided into three hypotypes, VEGFR-1, VEGFR-2 and VEGFR-3.Wherein, VEGFR-2 is most
Main functional receptor.VEGFR-2 also known as kinase insert domain receptor (kinase domain receptor, KDR), its coding base
Because being located at 4q12,1356 amino acid are encoded, be the transmembrane glycoprotein that a molecular weight is 230kD.VEGFR-2 with acceptor knot
After conjunction, the tyrosine site of its intracellular section there occurs autophosphorylation, and the tyrosine residue of phosphorylation amplifies signal cascade, so that
Adjust the metabolic activity of cell.Research shows that VEGFR is in the most tumors tissue such as stomach cancer, colon, rectum, ovary, breast cancer
Expression substantially increase, this also becomes one of important target of cancer therapy drug exploitation.
Research for targeted inhibition agent in recent years makes great progress.Sorafenib, as first by FDA
The Mutiple Targets kinase inhibitor of approval, good suppression is produced by the Activity on Tumor for suppressing Raf, VEGFR and PDGFR kinases
Make and use, the treatment of metastatic renal cell carcinoma and liver cancer has been approved at present.Cabozantinib swashs to c-Met, VEGFR-2 etc.
Enzyme shows significant inhibitory activity, ratifies the treatment for thyroid cancer by FDA.In addition, also many small molecule suppressions
Preparation is in clinical investigation phase, such as foretinib, BMS-777607.
Targeted inhibition agent in active testing or clinical investigation phase has various structures type, wherein containing pyridine knot
The compound of structure shows good Inhibit proliferaton effect, while right in the active testing of various human tumor cell lines
C-Raf and VEGFR-2 kinases is respectively provided with inhibitory activity higher.
The present inventor has designed and synthesized a series of new pyridine derivatives on the basis of bibliography.By body
Outer screening active ingredients, show that such compound has good antitumor activity and the double inhibition to C-Raf and VEGFR-2 kinases
Activity.
The content of the invention：
The present invention relates to compound and its pharmaceutically acceptable salt, the hydrate or prodrug of formula I, wherein,
Y is H, halogen；
K is O, S；
Ar is (C6-C10) aryl, 5-10 unit's heteroaryls, wherein, the heteroaryl contains the miscellaneous original of 1-3 selected from N, O or S
Son, and the optional 1-3 of Ar identical or different R1Substitution；
Each Q is separately selected from C, C-Z, N-Z, N, O and S, and condition is N atoms 0-4, and O and S atom 0-1 is individual, and
It is 0 when N, O are different with S atom number；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-
C6) alkoxy, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxy, by 1-2 (C1-C6) alkyl
Substituted amino, C1-C6Alkylamidoalkyl, free, into salt, esterification and amidated carboxyl, (C1-C6) alkyl Asia sulphur
Acyl group, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, by 1-2 (C1-C6) alkyl-substituted amino
Formoxyl, (C1-C3) alkylenedioxy group, pi-allyl；
Z is independently selected from H, (C1-C6) alkyl, (C3-C8) cycloalkyl,
R2、R3It is identical or different, separately selected from H, (C1-C6) alkyl, (C3-C8) cycloalkyl；
Or R2And R35-10 circle heterocycles base or 5-10 unit's heteroaryls, the heterocycle are formed with the nitrogen-atoms being connected with them
Base and heteroaryl except with R2And R3Outside the nitrogen-atoms of connection, optionally containing the 1-4 hetero atom selected from N, O and S, except R2With
R3Outside the nitrogen-atoms for being connected, the heterocyclic radical optionally includes 1-2 carbon-carbon double bond or three key, and the heterocyclic radical and heteroaryl are appointed
Select by 1-3 identical or different R4Substitution；
R4It is (C1-C6) alkyl, (C3-C7) cycloalkyl；
N is the integer between 0-6；
Represent substitution base junction.
Present invention is preferably related to compound and its pharmaceutically acceptable salt, the hydrate or prodrug of formula I, wherein,
Y is halogen；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-
C6) alkoxy, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxy, by 1-2 (C1-C6) alkyl
Substituted amino, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl,
(C1-C3) alkylenedioxy group, pi-allyl.
It is specifically preferred according to the invention to be related to compound and its pharmaceutically acceptable salt, the hydrate or prodrug of formula I, its
In,
Y is halogen；
It is selected from：
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridine radicals, furyl, thienyl, pyrrole
Cough up base, pyrimidine radicals, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-
C6) alkoxy, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxy, by 1-2 (C1-C6) alkyl
Substituted amino, (C1-C6) alkyl sulphonyl, pi-allyl.
The present invention it is also particularly that and be related to compound and its pharmaceutically acceptable salt, the hydrate or prodrug of formula I, its
In,
Y is F, and the position of substitution is at the ortho position of O；
K is O；
It is selected from：
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridine radicals, furyl, thienyl, pyrrole
Cough up base, pyrimidine radicals, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-
C6) alkoxy, optionally by the (C of hydroxyl, amino or halo1-C6) alkyl or (C1-C6) alkoxy, by 1-2 (C1-C6) alkyl
Substituted amino, (C1-C6) alkyl sulphonyl, pi-allyl;
The present invention it is also particularly that and be related to compounds of formula I and its pharmaceutically acceptable salt, hydrate or prodrug, its
In,
Y is F, and the position of substitution is at the ortho position of O；
K is O；
It is selected from：
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridine radicals, furyl, thienyl, pyrrole
Cough up base, pyrimidine radicals, and the optional 1-3 of Ar identical or different R1 substitution；
R1 be H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl,
(C1-C6) alkoxy, optionally by (C1-C6) alkyl of hydroxyl, amino or halo or (C1-C6) alkoxy, by 1-2 (C1-
C6) alkyl-substituted amino, (C1-C6) alkyl sulphonyl, pi-allyl;
Each Z is independently selected from H, (C1-C6) alkyl,
R2、R3It is identical or different, separately selected from H, (C1-C3) alkyl；
Or R2And R31- piperidyls, 4- morpholinyls, 4- methyl isophthalic acids-piperazine are formed together with the nitrogen-atoms being connected with them
Base, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls；
N is 1,2,3.
The present invention is very particularly preferably related to compounds of formula I and its pharmaceutically acceptable salt, hydrate or prodrug,
Wherein,
Y is F, and the position of substitution is at the ortho position of O；
K is O；
It is selected from：
Ar is phenyl, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is halogen, hydroxyl, nitro, cyano group, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy,
Pi-allyl, dimethylamino, mesyl;
Each Z is independently selected from H, (C1-C3) alkyl,
R2、R3It is identical or different, separately selected from H, (C1-C3) alkyl；
Or R2And R31- piperidyls, 4- morpholinyls, 4- methyl isophthalic acids-piperazine are formed together with the nitrogen-atoms being connected with them
Base, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls；
N is 1,2 or 3.
The present invention is more particularly preferably related to compounds of formula I and its pharmaceutically acceptable salt, hydrate or prodrug,
Wherein,
Y is F, and the position of substitution is at the ortho position of O；
K is O；
For
Ar is phenyl, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is halogen, hydroxyl, nitro, cyano group, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy,
Pi-allyl, dimethylamino, mesyl;
Each Z is independently selected from H, (C1-C3) alkyl,
R2、R3It is identical or different, separately selected from H, (C1-C3) alkyl；
Or R2And R31- piperidyls, 4- morpholinyls, 4- methyl isophthalic acids-piperazine are formed together with the nitrogen-atoms being connected with them
Base, 4- methyl isophthalic acids-piperidyl, 1- pyrrolidinyls；
N is 1,2,3.
Compounds of formula I of the present invention and its pharmaceutically acceptable salt, hydrate or prodrug preferably following compound, but
These compounds are not meant to any limitation of the invention：
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde contracting ammonia
Base urea；
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- chlorobenzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4- dimethoxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3- hydroxyls -4-methoxybenzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3,4- tri hydroxybenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,4- 4-dihydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (TMB) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3-methoxy-4-hydroxybenzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,5- dibromine-4-hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3,4- TMBs) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- [benzo [d] [1,3] two dislikes luxuriant benzaldehyde] semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,5- di-t-butyls-Benzaldehyde,2-hydroxy) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3- bromobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (4- chlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the chloro- 4- fluorobenzaldehydes of 2-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- [4- [3- (dimethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorobenzene
Base]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorobenzene
Base]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [3- (diethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) thiosemicarbazones.
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy benzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzenes first of 3-
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,5- dimethoxy benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyl -4- methoxyl groups
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- trihydroxy benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- dihydroxy benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dimethoxy benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxyls
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- trimethoxy-benzenes
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy-3-methoxies
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxyl -3,5- diformazans
Epoxide benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (bromo- 4 hydroxy benzenes of 3,5- bis-
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzenes first of 3-
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- trimethoxy-benzenes
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxy benzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- di-t-butyls -2-
Hydroxy benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- nitrobenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- cyanobenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dihydroxy benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- nitrobenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- nitrobenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- trihydroxy benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- [benzo [d] [1,3] two is disliked
Luxuriant benzaldehyde] semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (Benzaldehyde,2-hydroxy) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- fluorobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- bromobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 difluorobenzene formaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- difluorobenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- trifluomethoxybenzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- pi-allyl -2- hydroxyls
Benzaldehyde) semicarbazones.
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (thiophene -2-formaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (pyridine -3- formaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- difluoromethoxy phenyl first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- benzal fluoride first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- methyl propionates Ji Benjia
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- mesyl benzene first
Aldehyde) semicarbazones；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3- dichloro-benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene first
Aldehyde) semicarbazones；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,3-
Dichlorobenzaldehyde) semicarbazones；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,4-
Dichlorobenzaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzaldehydes) contracting amino
Urea；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- chlorobenzaldehydes) contracting amino
Urea；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones；
Compounds of formula I of the present invention and its pharmaceutically acceptable salt, hydrate or prodrug more preferably following chemical combination
Thing, but these compounds are not meant to any limitation of the invention：
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3,4- tri hydroxybenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- [benzo [d] [1,3] two dislikes luxuriant benzaldehyde] semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3,5- di-t-butyls-Benzaldehyde,2-hydroxy) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (3- bromobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (4- chlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (the chloro- 4- fluorobenzaldehydes of 2-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- [4- [3- (dimethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [3- (diethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzenes first of 3-
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyl -4- methoxyl groups
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxyls
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzenes first of 3-
Aldehyde) semicarbazones
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- pi-allyl -2- hydroxyls
Benzaldehyde) semicarbazones；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3- dichloro-benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) contracting ammonia
Base urea；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,4-
Dichlorobenzaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones.
And, according to some usual methods of the art, the pyridine derivatives of formula of of the present invention I can be with
With acid generation pharmaceutically acceptable salt.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, with following sour addition
Salt is particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, the sulphur of naphthalene two
Acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
Additionally, present invention additionally comprises the prodrug of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of formula I
Thing, their own may have weaker activity even without activity, but upon administration, (for example pass through in physiological conditions
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of straight or branched；" cycloalkyl "
It refer to substituted or unsubstituted cycloalkyl；" aryl " refers to unsubstituted or the phenyl or naphthyl for being connected with substitution base；" heteroaryl "
Refer to be selected from the heteroatomic monocyclic or polycyclic ring-type system of N, O, S containing one or more, ring-type system is armaticity, such as
Imidazole radicals, pyridine radicals, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrrole radicals, thiazolyl, benzene
Benzothiazolyl, oxazolyl, isoxazolyls, quinolyl, isoquinolyl, benzimidazolyl and benzoxazolyl etc..
It has been found that the compounds of this invention has in vitro suppresses tumor cell growth activity, therefore, it can serve as system
Standby treatment and/or the medicine of pre- anti-cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus,
Pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma etc..
Suppress lung carcinoma cell H460, colon cancer cell HT-29, gastric carcinoma cells MKN-45 and hepatoma cell strain by external
SMMC-7721, human breast cancer cell MDA-MB-231 and people's malignant glioblastoma cell U87MG activity tests, the present invention
Compound has notable to lung carcinoma cell, colon cancer cell and stomach cancer cell, breast cancer liver cancer and malignant glioblastoma etc.
Inhibitory action, it is especially useful in prepare the medicine for the treatment of and/or prevention lung cancer, colon cancer, stomach cancer and breast cancer.
Found by testing C-Raf and VEGFR-2 enzymatic activitys, the compounds of this invention have it is significant suppress C-Raf and
VEGFR-2 kinases dual restraining activities, lung carcinoma cell, colon cancer cell, stomach cancer and breast to C-Raf and VEGFR-2 expression high
Gland cancer etc. has stronger inhibitory action, it is especially useful in prepare the medicine for the treatment of and/or prevention lung cancer.
Reactive compound of the invention or its officinal salt can be used alone as unique antineoplastic, or can be with
With antineoplastic (such as platinum medicine cis-platinum, camptothecine Irinotecan, the vinca alkaloids medicine Novi for having listed
Sheet, deoxycytidine class medicine gemcitabine, etoposide, taxol etc.) it is used in combination.Therapeutic alliance is by by each treatment group
Point simultaneously, order or separate administration and realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the compounds of this invention and its preparation side
Method.It should be appreciated that the scope of following examples and preparation example limits the scope of the present invention, unlisted heterocycle never in any formSynthetic method can be prepared according to organic chemistry filed method well-known to the ordinarily skilled artisan.
Following synthetic route (route 1) is summarized and describes the preparation of the derivative of formula of the invention I, and all of raw material is all
Be prepared by way of described in these schematic diagrames, by organic chemistry filed method well-known to the ordinarily skilled artisan or
It is commercially available.The final derivative of whole of the invention is all by the method described in these schematic diagrames or by similar side
Prepared by method, these methods are organic chemistry fileds well-known to the ordinarily skilled artisan.The whole applied in these schematic diagrames is variable
Definition in the definition of factor following article or such as claim.
According to the derivative of formula of the invention I, all can according to the method for route 1 by corresponding intermediate A and aldehyde in isopropanol
In, the glacial acetic acid of catalytic amount is added, flow back about 5h, is obtained by condensation reaction.Wherein, Q, Y, K and the Ar in compound are as weighed
Defined in profit is required.
WhenForWhen, the preparation method of intermediate A -1 is shown in route 2：
WhenForZ isWhen, route 3 is shown in the preparation of intermediate A -2 and A-3：
WhenForRoute 4 is shown in the preparation of intermediate A -4：
WhenForZ is H, (C1-C3) alkyl when, route 5 is shown in the preparation of intermediate A -5：
WhenForWhen, route 6 is shown in the preparation of intermediate A -6：
Substitution base Q, X, Y and K of all intermediates be as defined in the claims in 6 routes of the above.
Specific embodiment：
Embodiment is intended to illustrate rather than limitation the scope of the present invention.The proton nmr spectra Bruker of compound
ARX-300 is determined, and mass spectrum is determined with Agilent1100LC/MSD；It is pure or chemical pure that agents useful for same is analysis.
Embodiment 1：
Chloro- pyridine -2- the methyl formates (2) of step A4-
At room temperature, by 150g (1.22mol) pyridine -2- formic acid, 20.1g (0.197mol) sodium bromide adds 200ml chlorobenzenes
In, 10min is stirred, reaction solution rises to 50 DEG C, is slowly added to 355ml (4.88mol) thionyl chloride, stirs 30min, is warming up to back
Stream reaction 20h, is evaporated off solvent, obtains the chloro- pyridine -2- formyl chlorides of intermediate 14-, is yellow oil.Intermediate 1 is added
In 500ml toluene, 0~5 DEG C of dropwise addition 100ml absolute methanol of control temperature, drop finishes, 15 DEG C of stirring reaction 1.5h.Suction filtration, filter cake adds
Enter in unsaturated carbonate potassium solution, dichloromethane extraction (3 × 400ml) merges organic layer, and washing, anhydrous sodium sulfate drying is evaporated off
Solvent, dry yellow solid 150g, yield 72.1%.
Step B4- (the fluoro- 4- nitro-phenoxies of 2-)-pyridine -2- methyl formates (3)
20g (0.17mol) intermediate 2 and 27g (0.175mol) 2- fluoro-4-nitrophenols are dissolved in the dry chlorine of 300ml
In benzene, back flow reaction 13h.Chlorobenzene is evaporated off and obtains grease, add the dissolving of 500ml dichloromethane, (3 are washed with unsaturated carbonate potassium solution
× 300ml), organic layer is evaporated off and obtains brown solid, crude product adds 300ml absolute ethyl alcohols, is warming up to and is refluxed 30min, reacts
Liquid naturally cools to room temperature, stands crystallization, and suction filtration, filtration cakes torrefaction obtains light yellow solid 15.2g, yield 44.5%.
Step C4- (the fluoro- 4- nitro-phenoxies of 2-)-pyridine-2-carboxamide (4)
10g (0.034mol) intermediate 3,30ml ammoniacal liquor are added in 50ml acetone, back flow reaction 2h.It is evaporated off most of molten
Agent, to 100ml water is added in system, stirs 30min, and suction filtration, filtration cakes torrefaction obtains off-white powder 7.3g, yield 73.2%.
Step D N- [(dimethylamino) methylene] -4- (the fluoro- 4-nitrophenoxys of 2-) picolinamide (5)
At room temperature, by the addition 50ml dichloromethane of 6.3g (0.022mol) intermediate 4, stirring is lower to add 5.5g
(0.046mol) DMF dimethylacetal (DMF-DMA), is warming up to back flow reaction 2h.Solvent is evaporated off, reacts
System adds 70ml ether, stirs 1h, and suction filtration, filtration cakes torrefaction obtains yellow solid 5.3g, yield 73.6%.
Step E4- (fluoro- 4 nitro-phenoxies of 2-) -2- (4H-1,2,4 triazole -3- bases)-pyridine (6)
By in the addition 30ml glacial acetic acid of 5g (0.015mol) intermediate 5,10 DEG C are cooled to, stirring is lower to add 1.88g
(0.03mol) hydrazine hydrate, is warming up to 90 DEG C of stirring reaction 3h.Most of solvent is evaporated off, reaction solution adds 70ml water, stirring
30min, suction filtration, by filter cake addition 100ml ether, stirs 30min, and suction filtration, filtration cakes torrefaction obtains white solid 3g, yield
50.9%。
The fluoro- 4- of step F3- [2- (4H-1,2,4 triazole -3- bases)-pyridine -4- epoxides]-aniline (7)
By in the addition 50ml absolute ethyl alcohols of 2.5g (0.008mol) intermediate 6,0.25gPd/C (10%) is added at room temperature, lead to
Enter hydrogen, stirring reaction 4h.Suction filtration, is evaporated off filtrate, obtains white solid 1.75g, yield 77.8%.
Step G [the fluoro- 4- of 3- [2- (4H-1,2,4 triazole -3- bases)-pyridine -4- epoxides]-phenyl]-phenyl carbamate
(8)
2.3g (0.008mol) intermediate 7 is dissolved in 20ml acetone, 1.52g (0.011mol) potassium carbonate, cooling is added
To 0 DEG C, 1.59g (0.01mol) phenyl chloroformate is added dropwise, drop finishes, room temperature reaction 2h.To addition 20ml water, dichloromethane in system
Alkane extracts (3 × 50ml), merges organic layer, and solvent is evaporated off, and filtration cakes torrefaction obtains white solid 2.86g, yield 86.3%.
Step H N- (4- (2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides) -3- fluorophenyls) semicarbazides (A-1)
3g intermediates 8 are dissolved in 20ml dioxane, add 6ml hydrazine hydrates, are warming up to back flow reaction 2h.Natural cooling,
Crystallization is stood, suction filtration, filter cake obtains white solid 2.15g, yield 85% with a small amount of ether drip washing, suction filtration, filtration cakes torrefaction.
Step I (E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde
Semicarbazones (embodiment 1)
0.2g (0.61mmol) A-1 and 0.078g (0.73mmol) benzaldehyde is added into 2mL isopropanols, adds 1 to drip
Glacial acetic acid, flow back 5h.Suction filtration, filter cake with a small amount of isopropanol drip washing, dry white solid 0.17g, yield 65.2%.
ESI-MS m/z:418.2[M+H]+
According to the method for embodiment 1, intermediate A -1 prepares embodiment 2 for raw material carries out condensation reaction from different aldehyde
With the compound for implementing 3.
Embodiment 2 (E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2-
Chlorobenzaldehyde) semicarbazones
ESI-MS m/z:452.1[M+H]+
Embodiment 3 (E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,
4- dichlorobenzaldehydes) semicarbazones
ESI-MS m/z:485.1[M+H]+
Step J4- (the fluoro- 4- nitro-phenoxies of 2-)-pyridine -2- formylhydrazines (9)
15g (0.051mol) intermediate 3,150ml hydrazine hydrates are added in 150ml acetonitriles, room temperature reaction 2h.Part is evaporated off
Solvent, reaction solution adds 200ml water, dichloromethane extraction (3 × 400ml) to be evaporated off solvent, dry white solid 12.3g, receives
Rate is 82%.
Step K N'- [4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- formoxyls]-N, N- dimethyl methyl hydrazone groups amine (10)
By in the addition 60ml dichloromethane of 12g (0.041mol) intermediate 9, stirring is lower to add 9.78g (0.08mol) N, N-
Dimethylformamide dimethyl acetal (DMF-DMA), is warming up to back flow reaction 2h.Solvent is evaporated off, reaction system adds 70ml second
Ether, stirs 1h, and suction filtration, filtration cakes torrefaction obtains yellow solid 7.7g, yield 75.8%.
Step L2- [3- [4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- bases] -4H-1,2,4- triazole-4-yls]-N, N- bis-
Methyl ethyl-amine (11)
By in the addition 45ml glacial acetic acid of 17.5g (0.05mol) intermediate 10,10 DEG C are cooled to, stirring is lower to add 8.9g
(0.1mol) N, N- dimethyl-ethylenediamines, are warming up to 90 DEG C of stirring reaction 3h.Most of solvent is evaporated off, reaction solution adds 70ml
Water, stirs 30min, and suction filtration, by filter cake addition 100ml ether, stirs 30min, and suction filtration, filtration cakes torrefaction obtains yellow color solid
6.6g, yield 35.2%.
Step M4- [2- [4- (2- dimethylamino-ethyls) -4H-1,2,4- triazole -3- bases]-pyridine -4- epoxides] -3- is fluoro-
Aniline (12)
By in the ethanol of the addition of 5g (0.013mol) intermediate 11 60ml90%, 0.048g (0.004mol) activated carbon is added,
0.54g (0.002mol) ferric sesquichloride, is stirred at room temperature 0.5h, and 60 DEG C of dropwise addition 8.13g (0.13mol) hydrazine hydrates drip complete being warming up to
Back flow reaction 3h.Hot suction filtration, filter cake is evaporated off solvent with a small amount of hot ethanol drip washing, is cooled to room temperature, and 100ml second is added in system
Ether, stirs 2h, and suction filtration, filtration cakes torrefaction obtains white solid 2.18g, yield 47.5%.
Step N [4- [2- [4- (2- dimethylamino-ethyls) -4H-1,2,4- triazole -3- bases]-pyridine -4- epoxides] -3-
Fluoro-phenyl]-phenyl carbamate (13)
3.5 (0.01mol) intermediates 12 are dissolved in 25ml acetone, 1.79g (0.013mol) potassium carbonate is added, is cooled to
0 DEG C, 1.92g (0.012mol) phenyl chloroformate is added dropwise, drop finishes, room temperature reaction 2h.Reaction solution adds 20ml water, dichloromethane extraction
Take (3 × 50ml), merge organic layer, be evaporated off solvent, dry white solid 3.72g, yield 78.6%.
Step O N- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -
3- fluorophenyls] semicarbazides (A-2)
3g (6.5mol) intermediate 13 is dissolved in 20ml dioxane, adds 6ml hydrazine hydrates, is warming up to back flow reaction 2h.
System natural cooling, stands crystallization, suction filtration, filter cake with a small amount of ether drip washing, dry white solid 2.17g, yield 83.5%.
Step P (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4-
Epoxide] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones (embodiment 4)
0.2g (0.5mmol) A-2 and 0.1g (0.6mmol) 2,3- dichlorobenzaldehydes are added into 2mL isopropanols, is added
1 drop glacial acetic acid, flow back 5h.Suction filtration, filter cake obtains white solid 0.2g, yield 71.6% with a small amount of isopropanol drip washing.
ESI-MS m/z:557.3[M+H]+；1H NMR(300MHz,DMSO)δ11.24(s,1H),9.34(s,1H),8.65
(s,1H),8.61(d,J=5.7Hz,1H),8.44–8.35(m,2H),7.90(dd,J=13.4,2.3Hz,1H),7.72–7.62
(m,2H),7.57(d,J=2.5Hz,1H),7.44(q,J=8.3Hz,2H),7.15(dd,J=5.7,2.5Hz,1H),4.63(t,J
=6.2Hz,2H),2.63(t,J=6.3Hz,2H),2.17(s,6H)
According to the method for embodiment 4, with different substituents intermediate A -2 for raw material carries out condensation reaction preparation with various aldehyde
Obtain the compound of embodiment 5-31.
Embodiment 5 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones
ESI-MS m/z:557.3[M+H]+；1H NMR(600MHz,DMSO)δ11.20(s,1H),9.35(s,1H),8.66
(s,1H),8.61(d,J=5.6Hz,1H),8.43(d,J=8.6Hz,1H),8.33(s,1H),7.89(d,J=13.1Hz,1H),
7.70(s,1H),7.63(d,J=8.7Hz,1H),7.57(s,1H),7.52(d,J=8.4Hz,1H),7.42(t,J=9.0Hz,
1H),7.16(d,J=3.4Hz,1H),4.68(s,2H),2.83(s,2H),2.32(s,6H)
Embodiment 6 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) semicarbazones
ESI-MS m/z:523.1[M+H]+；1H NMR(300MHz,DMSO)δ10.81(s,1H),10.28(s,1H),
9.19(s,1H),8.65(s,1H),8.61(d,J=5.4Hz,1H),7.94–7.84(m,3H),7.65(d,J=8.5Hz,1H),
7.56(s,1H),7.41(t,J=9.2Hz,1H),7.35(d,J=8.1Hz,1H),7.15(s,1H),6.98(t,J=8.6Hz,
1H),4.65(s,2H),2.69(s,2H),2.23(s,6H)
Embodiment 7 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,4- dimethoxy benzaldehydes) semicarbazones
ESI-MS m/z:549.1[M+H]+；1H NMR(300MHz,DMSO)δ10.70(s,1H),9.13(s,1H),8.63
(s,1H),8.60(d,J=5.7Hz,1H),8.25(s,1H),8.12(d,J=8.3Hz,1H),7.91(dd,J=13.5,2.3Hz,
1H),7.64(d,J=9.0Hz,1H),7.57(d,J=2.3Hz,1H),7.39(t,J=9.1Hz,1H),7.13(dd,J=5.7,
2.5Hz,1H),6.61(m,2H),4.62(t,J=6.3Hz,2H),3.86(s,3H),3.83(s,3H),2.59(t,J=6.3Hz,
2H),2.14(s,6H)
Embodiment 8 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyls -4-methoxybenzaldehyde) semicarbazones
ESI-MS m/z:535.3[M+H]+；1H NMR(300MHz,DMSO)δ10.69(s,1H),9.17(s,1H),9.06
(s,1H),8.62(m,2H),7.96–7.82(m,2H),7.63(d,J=8.1Hz,1H),7.56(s,1H),7.38(m,2H),
7.14(m,2H),6.96(d,J=8.2Hz,1H),4.63(t,2H),3.82(s,2H),2.64(s,2H),2.18(s,6H)
Embodiment 9 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,3,4- tri hydroxybenzaldehydes) semicarbazones
ESI-MS m/z:536.3[M+H]+
Embodiment 10 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3,4- 4-dihydroxy benzaldehydes) semicarbazones
ESI-MS m/z:521.3[M+H]+；1H NMR(300MHz,DMSO)δ10.57(s,1H),9.36(s,1H),9.10
(s,1H),8.59(s,1H),8.55(d,J=5.7Hz,2H),7.91–7.74(m,2H),7.61–7.49(m,2H),7.35(t,J
=9.0Hz,1H),7.24(s,1H),7.05(m,2H),6.74(d,J=7.9Hz,1H),4.57(t,J=6.7Hz,2H),2.53
(t,J=6.9Hz,2H),2.09(s,6H)
Embodiment 11 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy benzaldehydes) semicarbazones
ESI-MS m/z:505.2[M+H]+；1H NMR(300MHz,DMSO)δ10.68(s,1H),9.83(s,1H),9.13
(s,1H),8.68–8.54(m,2H),7.91(m,2H),7.73–7.61(m,3H),7.56(s,1H),7.39(t,J=9.0Hz,
1H),7.14(s,1H),6.82(d,J=7.9Hz,2H),4.62(t,J=6.0Hz,2H),2.59(t,J=5.9Hz,2H),2.14
(s,6H)
Embodiment 12 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxy benzaldehydes) semicarbazones
ESI-MS m/z:533.3[M+H]+；1H NMR(300MHz,DMSO)δ10.66(s,1H),9.12(s,1H),8.63
(m,2H),8.60(d,J=5.9Hz,1H),7.92(d,J=13.6Hz,1H),7.83(s,1H),7.65(d,J=8.4Hz,1H),
7.56(s,1H),7.44–7.36(m,3H),7.14(dd,J==6.0,3.1Hz,1H),4.62(t,J=6.3Hz,2H),2.59
(t,J=6.2Hz,2H),2.21(s,6H),2.14(s,6H)
Embodiment 13 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (TMB) semicarbazones
ESI-MS m/z:579.2[M+H]+；1H NMR(300MHz,DMSO)δ10.98(s,1H),9.30(s,1H),8.65
(m,2H),7.92(m,2H),7.70–7.38(m,3H),7.18(s,2H),4.63(s,2H),3.88(s,6H),3.71(s,
3H),2.59(s,2H),2.14(s,6H)
Embodiment 14 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3-methoxy-4-hydroxybenzaldehyde) semicarbazones
ESI-MS m/z:535.3[M+H]+
Embodiment 15 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3,5- dibromine-4-hydroxy benzaldehydes) semicarbazones
ESI-MS m/z:660.1[M+H]+；1H NMR(300MHz,DMSO)δ10.92(s,1H),9.33(s,1H),8.68
(s,1H),8.62(d,J=5.5Hz,1H),8.08(s,2H),7.91(d,J=13.2Hz,1H),7.84(s,1H),7.64(m,
3H),7.41(t,J=8.8Hz,1H),7.16(s,1H),4.71(t,J=6.6Hz,2H),2.91(t,J=6.6Hz,2H),2.38
(s,6H).
Embodiment 16 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) semicarbazones
ESI-MS m/z:583.3[M+H]+；1H NMR(300MHz,DMSO)δ10.76(s,1H),10.66(s,1H),
9.22(s,1H),8.69(s,1H),8.62(d,J=5.7Hz,1H),8.08(m,1H),7.90(m,2H),7.67–7.57(m,
3H),7.39(t,J=9.0Hz,1H),7.15(dd,J=5.7,2.4Hz,1H),7.02(d,J=8.4Hz,1H),4.73(t,J=
6.1Hz,2H),2.99(t,J=6.0Hz,2H),2.43(s,6H)
Embodiment 17 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,3,4- TMBs) semicarbazones
ESI-MS m/z:579.2[M+H]+；1H NMR(300MHz,DMSO)δ10.77(s,1H),9.16(s,1H),8.64
(s,1H),8.61(d,J=5.8Hz,1H),8.21(s,1H),8.01–7.83(m,2H),7.64(d,J=9.3Hz,1H),7.58
(s,1H),7.41(t,J=9.0Hz,1H),7.14(dd,J=5.4,2.4Hz,1H),6.91(d,J=8.9Hz,1H),4.63(t,J
=6.0Hz,2H),3.87(s,3H),3.85(s,3H),3.80(s,3H),2.60(t,J=6.3Hz,2H),2.15(s,6H)
Embodiment 18 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3- hydroxy benzaldehydes) semicarbazones
ESI-MS m/z:505.1[M+H]+；1H NMR(300MHz,DMSO)δ10.84(s,1H),9.68(s,1H),9.24
(s,1H),8.65(s,1H),8.62(d,J=5.6Hz,1H),7.90(m,2H),7.63(d,J=8.6Hz,1H),7.56(s,
1H),7.41(t,J=8.9Hz,1H),7.26(m,3H),7.16(d,J=3.1Hz,1H),6.83(d,J=5.9Hz,1H),4.64
(t,J=6.6Hz,2H),2.66(t,J=6.6Hz,2H),2.19(s,6H)
Embodiment 19 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- [benzo [d] [1,3] two dislikes luxuriant benzaldehyde] semicarbazones
ESI-MS m/z:533.3[M+H]+；1H NMR(300MHz,DMSO)δ10.75(s,1H),9.13(s,1H),8.58
(s,1H),8.56(d,J=5.6Hz,1H),7.86(m,2H),7.69(s,1H),7.60(d,J=8.8Hz,1H),7.51(s,
1H),7.36(t,J=8.5Hz,1H),7.09(d,J=5.9Hz,2H),6.91(d,J=7.1Hz,1H),6.04(s,2H),4.57
(t,J=6Hz,2H),2.53(t,J=5.9Hz,2H),2.08(s,6H)
Embodiment 20 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3,5- di-t-butyls-Benzaldehyde,2-hydroxy) semicarbazones
ESI-MS m/z:617.3[M+H]+；1H NMR(300MHz,DMSO)δ11.23(s,1H)10.63(s,1H),9.43
(s,1H),8.63(s,1H),8.60(d,J=5.7Hz,1H),8.25(s,1H),7.79(d,J=13.0Hz,1H),7.56(s,
1H),7.40(m,2H),7.28(s,1H),7.22(s,1H),7.13(dd,J=5.7,2.4Hz,1H),4.62(t,J=6.0Hz,
2H),2.61(t,J=6.2Hz,2H),2.16(s,6H),1.42(s,9H),1.29(s,9H)
Embodiment 21 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2- nitrobenzaldehydes) semicarbazones
ESI-MS m/z:533.3[M+H]+
Embodiment 22 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (3- bromobenzaldehydes) semicarbazones
ESI-MS m/z:567.1[M+H]+
Embodiment 23 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (4- chlorobenzaldehydes) semicarbazones
ESI-MS m/z:523.1[M+H]+；1H NMR(300MHz,DMSO)δ11.00(s,1H),9.28(s,1H),8.64
(s,1H),8.61(d,J=5.7Hz,1H),7.97(s,1H),7.94–7.88(m,3H),7.64(d,J=8.5Hz,1H),7.56
(d,J=2.2Hz,1H),7.50(d,J=8.4Hz,2H),7.42(t,J=9.1Hz,1H),7.15(dd,J=5.7,2.5Hz,1H),
4.62(t,J=6.0Hz,2H),2.59(t,J=6.2Hz,2H),2.14(s,6H)
Embodiment 24 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes) semicarbazones；
ESI-MS m/z:557.2[M+H]+
Embodiment 25 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (the chloro- 4- fluorobenzaldehydes of 2-) semicarbazones
ESI-MS m/z:541.1[M+H]+；1H NMR(300MHz,DMSO)δ11.10(s,1H),9.28(s,1H),8.59
(s,1H),8.56(d,J=5.7Hz,1H),8.46–8.38(m,1H),8.28(s,1H),7.84(dd,J=13.4,1.8Hz,
1H),7.58(d,J=8.5Hz,1H),7.53–7.45(m,2H),7.33(m,2H),7.10(dd,J=5.7,3.1Hz,1H),
4.58(t,J=6.0Hz,2H),2.57(t,J=6.1Hz,2H),2.11(s,6H)
Embodiment 26 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) semicarbazones
ESI-MS m/z:555.3[M+H]+
Embodiment 27 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- benzaldehyde semicarbazone
ESI-MS m/z:489.2[M+H]+；1H NMR(300MHz,DMSO)δ11.26(s,1H)9.55(s,1H),8.64
(s,1H),8.60(d,J=5.8Hz,1H),8.01(s,1H),7.91(dd,J=13.5,2.7Hz,1H),7.85(d,J=6.8Hz,
2H),7.62(d,J=9.3Hz,1H),7.55(d,J=2.4Hz,1H),7.47–7.37(m,4H),7.13(dd,J=5.7,
2.1Hz,1H),4.61(t,J=6.1Hz,2H),2.57(t,J=6.3Hz,2H).2.13(s,6H)
Embodiment 28 (E)-N1- [4- [2- [4- [2- (dimethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones
ESI-MS m/z:571.2[M+H]+
Embodiment 29N1- [the fluoro- 4- of 3- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- oxygen
Base] phenyl]-N4- (2,3 dichloro benzaldehyde) semicarbazones
ESI-MS m/z:613.2[M+H]+
Embodiment 30N1- [the fluoro- 4- of 3- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- oxygen
Base] phenyl]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones
ESI-MS m/z:613.3[M+H]+
Embodiment 31 (E)-N1- [4- [2- [4- [2- (diethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones
ESI-MS m/z:599.2M+H]+
Step Q2- [3- [4- (the fluoro- 4- isothiocyanic acids phenoxy groups of 2-) pyridine -2- bases] -4H-1,2,4- triazole-4-yls]-N,
N- dimethyl amines (14)
At room temperature, 5g (14.6mmol) intermediate 12 is dissolved in 60mL dichloromethane, adds 10mL saturated sodium bicarbonates
The aqueous solution.0 DEG C of instillation 2g (17.5mmol) thiophosgene, drop finishes, and 5h is stirred at room temperature, and separates organic phase, and anhydrous sodium sulfate drying is steamed
Do to obtain yellow oily liquid 4.1g, yield 73.2%.
Step R N- (4- (2- (4- (2- (dimethylamino) ethyl) -4H-1,2,4- triazole -3- bases) pyridine -4- epoxides) -
3- fluorophenyls) thiosemicarbazides (A-3)
At room temperature, 3.5g (9.1mmol) intermediate 14 is dissolved in 40mL dichloromethane, adds 17mL80% hydrazine hydrates, stirred
Mix 10h.Separate organic layer, wash (3 × 20mL), anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, dry yellow solid
2.1g, yield 55.7%.
Step S (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4-
Epoxide] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) thiosemicarbazones (embodiment 32)
At room temperature, 0.2g (0.48mmol) A-3 and 0.07g (0.58mmol) 2,3- dichlorobenzaldehydes are added different to 2mL
In propyl alcohol, 1 is added to drip glacial acetic acid, flow back 6h.Suction filtration, filter cake obtains yellow solid with a small amount of isopropanol drip washing, filtration cakes torrefaction
0.16g, yield 57.6%.
ESI-MS m/z:572.2[M+H]+
It is that raw material and 2,4- dichlorobenzaldehyde carry out condensation reaction preparation with intermediate A -3 according to the method for embodiment 32
Obtain the compound of embodiment 33.
Embodiment 33 (E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -
4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) thiosemicarbazones；
ESI-MS m/z:572.1[M+H]+
The chloro- pyridine-2-carboxamides of step T4- (15)
By in the addition 500ml water of 20g (0.17mol) intermediate 2,100ml ammoniacal liquor is added, 5h, suction filtration, filter cake is stirred at room temperature
Dry white solid 15.7g, yield is 85.8%.
Chloro- pyridine -2- the amine (16) of step U4-
Under ice bath, by 35.2g (0.22mol) bromine instillation NaOH solution (2.5N, 322ml), drop finishes addition 28.6g
(0.18mol) intermediate 4, is stirred at room temperature 1h, 80 DEG C of reaction 4h, is put into calm middle standing, suction filtration.Filter cake 1NHCl dissolves, no
Molten thing suction filtration, PH to 13 is adjusted with saturation NaOH, separates out solid, and suction filtration, filtration cakes torrefaction obtains white solid 11g, and yield is 47.6%.
Step V4- (the fluoro- 4- nitro-phenoxies of 2-)-pyridine -2- amine (17)
At room temperature, 10g (0.078mol) intermediate 16 and 18.4g (0.12mol) 2- fluoro-4-nitrophenols are added into chlorobenzene
In, back flow reaction 23h, solvent evaporated, to adding 500ml dichloromethane, saturated potassium carbonate to wash (3 × 300ml) in system, depressurizes
Solvent evaporated, etc. gray solid, adds 200ml ether, stirs 2h, and suction filtration obtains gray solid 13.1g, yield after filtration cakes torrefaction
67.3%。
Step W4- (the fluoro- 4-nitrophenoxys of 2-) -2- (1H-TETRAZOLE -1- bases) pyridine (18)
At room temperature, 8g (0.032mol) intermediate 17 and 23.8g (0.16mol) triethyl orthoformate are added into 50ml ice vinegar
In acid, back flow reaction 1h adds 6.2g (0.096mol) sodium azide, back flow reaction 3h.Reaction solution is poured into 200ml water,
Stirring 20min, suction filtration, filter cake ether drip washing obtains off-white powder 5.1g, yield 52.7% after drying..
Step X4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluoroanilines (19)
By in the ethanol of the addition of 5g (0.017mol) intermediate 18 60ml90%, 0.059g (0.005mol) activated carbon is added,
0.68g (0.003mol) ferric sesquichloride, is stirred at room temperature 0.5h, and 60 DEG C of dropwise addition 10.63g (0.17mol) hydrazine hydrates drip complete being warming up to
Back flow reaction 3h.The hot suction filtration of reaction solution, filter cake is evaporated off solvent with a small amount of hot ethanol drip washing, is cooled to room temperature, is added in system
100ml water, stirs 20min, and suction filtration, filtration cakes torrefaction obtains white solid 3.54g, yield 76.6%.
Step Y phenyl [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluoro-phenyls] phenyl carbamate (20)
3.5g (0.013mol) intermediate 19 is dissolved in 25ml acetone, 2.33g (0.017mol) potassium carbonate, cooling is added
To 0 DEG C, 2.44g (0.016mol) phenyl chloroformate is added dropwise, drop finishes, room temperature reaction 2h.Reaction solution adds 30ml water, dichloromethane
Extraction (3 × 50ml), merges organic layer, and solvent is evaporated off, and obtains white solid 3.86g, yield 75.7%.
Step Z N- (4- (2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides) -3- fluorophenyls) semicarbazides (A-4)
3g (7.7mmol) intermediate 20 is dissolved in 20ml dioxane, adds 6ml hydrazine hydrates, is warming up to back flow reaction 2h.
Reaction solution natural cooling, stands crystallization, suction filtration, filter cake with a small amount of ether drip washing, dry white solid 2.16g, yield
85.7%。
Step A1(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3- dichloro-benzenes
Formaldehyde) semicarbazones (embodiment 34)
0.2g (0.60mmol) intermediate As -4 and 0.13g (0.72mmol) 2,3 dichloro benzaldehyde are added to 2mL isopropyls
In alcohol, 1 is added to drip glacial acetic acid, flow back 6h.Suction filtration, filter cake with a small amount of isopropanol drip washing, dry yellow solid 0.19g, yield
63.8%。
ESI-MS m/z:484.8[M-H]-；1H NMR(300MHz,DMSO)δ11.23(s,1H),10.17(s,1H),
9.35(s,1H),8.56(d,J=5.8Hz,1H),8.41(s,1H),8.37(d,J=7.9Hz,1H),7.91(d,J=13.4Hz,
1H),7.72–7.62(m,2H),7.52(s,1H),7.45(t,J=8.0Hz,2H),7.21(d,J=3.7Hz,1H)
According to the method for embodiment 34, implementation is prepared for raw material carries out condensation reaction from different aldehyde with intermediate A -4
The compound of example 35-75.Embodiment 35 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-
(2,4 dichloro benzene formaldehyde) semicarbazones
ESI-MS m/z:486.7[M-H]-；1H NMR(300MHz,DMSO)δ11.19(s,1H),10.17(s,1H),
9.35(s,1H),8.56(d,J=5.8Hz,1H),8.42(d,J=8.5Hz,1H),8.34(s,1H),7.91(dd,J=13.3,
2.1Hz,1H),7.70(d,J=1.9Hz,1H),7.64(d,J=9.2Hz,1H),7.55–7.49(m,2H),7.45(t,J=
9.1Hz,1H),7.21(dd,J=5.8,2.0Hz,1H)
Embodiment 36 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy benzenes
Formaldehyde) semicarbazones
ESI-MS m/z:432.8[M-H]-；1H NMR(300MHz,DMSO)δ10.69(s,1H),10.17(s,1H),
9.82(s,1H),9.15(s,1H),8.55(d,J=5.8Hz,1H),7.94(dd,J=13.7,2.2Hz,1H),7.88(s,1H),
7.67(m,3H),7.52(d,J=2.2Hz,1H),7.42(t,J=9.1Hz,1H),7.20(dd,J=5.7,2.2Hz,1H),6.82
(d,J=8.6Hz,2H)
Embodiment 37 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- of 3-
Hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:450.7[M-H]-；1H NMR(300MHz,DMSO)δ:10.78(s,1H),10.23(s,1H),
10.16(s,1H),9.19(s,1H),8.56(d,J=5.8Hz,1H),7.94(dd,J=13.5,2.4Hz,1H),7.90–7.84
(m,2H),7.67(d,J=8.9Hz,1H),7.53(d,J=2.2Hz,1H),7.43(t,J=9.1Hz,1H),7.37(d,J=
8.4Hz,1H),7.20(dd,J=5.7,2.3Hz,1H),6.99(t,J=8.6Hz,1H)
Embodiment 38 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,5- diformazans
Epoxide benzaldehyde) semicarbazones
ESI-MS m/z:493.2[M-H]-
Embodiment 39 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyls-
4-methoxybenzaldehyde) semicarbazones
ESI-MS m/z:479.1[M-H]-
Embodiment 40 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- tri-
Hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:482.2[M-H]-
Embodiment 41 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- dihydroxies
Benzaldehyde) semicarbazones
ESI-MS m/z:448.8[M-H]-；1H NMR(300MHz,DMSO)δ10.60(s,1H),10.16(s,1H),
9.38(s,1H),9.14(s,1H),8.96(s,1H),8.55(d,J=5.8Hz,1H),7.92(dd,J=13.5,2.2Hz,1H),
7.82(s,1H),7.64(d,J=8.8Hz,1H),7.52(d,J=2.2Hz,1H),7.42(t,J=9.0Hz,1H),7.28(d,J=
1.7Hz,1H),7.20(dd,J=5.7,2.3Hz,1H),7.08(dd,J=8.2,1.7Hz,1H),6.79(d,J=8.1Hz,1H)
Embodiment 42 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- diformazans
Epoxide benzaldehyde) contracting amino
ESI-MS m/z:476.9[M-H]-；1H NMR(300MHz,DMSO)δ10.71(s,1H),10.16(s,1H),
9.15(s,1H),8.55(d,J=5.8Hz,1H),8.24(s,1H),8.12(d,J=8.4Hz,1H),7.93(dd,J=13.5,
2.4Hz,1H),7.65(d,J=8.9Hz,1H),7.52(d,J=2.2Hz,1H),7.42(t,J=9.1Hz,1H),7.19(dd,J=
5.7,2.3Hz,1H),6.61(d,J=8.4Hz,2H).3.85(s,3H),3.83(s,3H)
Embodiment 43 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- diformazans
Base -4- hydroxy benzaldehydes) semicarbazones
ESI-MS m/z:460.9[M-H]-.1H NMR(300MHz,DMSO)δ:10.65(s,1H),10.16(s,1H),
9.13(s,1H),8.62(s,1H),8.56(d,J=5.8Hz,1H),7.95(dd,J=13.4,2.1Hz,1H),7.84(s,1H),
7.67(d,J=8.9Hz,1H),7.52(d,J=2.0Hz,1H),7.47–7.39(m,3H),7.20(dd,J=5.7,2.1Hz,
1H),2.22(s,6H)
Embodiment 44 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- tri-
Methoxybenzaldehyde) semicarbazones
ESI-MS m/z:506.8[M-H]-；1H NMR(300MHz,DMSO)δ10.96(s,1H),10.18(s,1H),
9.30(s,1H),8.56(d,J=5.8Hz,1H),7.98–7.89(m,2H),7.64(d,J=8.9Hz,1H),7.51(d,J=
2.2Hz,1H),7.45(t,J=9.0Hz,1H),7.21(dd,J=5.7,2.2Hz,1H),7.16(s,2H),3.87(s,6H),
3.70(s,3H)
Embodiment 45 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxyls-
M-methoxybenzaldehyde) contracting amino
ESI-MS m/z:462.9[M-H]-；1H NMR(300MHz,DMSO)δ10.70(s,1H),10.15(s,1H),
9.37(s,1H),9.19(s,1H),8.55(d,J=5.8Hz,1H),7.94(dd,J=13.5,2.3Hz,1H),7.88(s,1H),
7.64(d,J=10.0Hz,1H),7.52(d,J=2.1Hz,1H),7.49(s,1H),7.42(t,J=9.0Hz,1H),7.19(m,
2H),6.82(d,J=8.1Hz,1H),3.87(s,3H)
Embodiment 46 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxyls-
3,5- dimethoxy benzaldehydes) semicarbazones
ESI-MS m/z:492.9[M-H]-；1H NMR(300MHz,DMSO)δ10.76(s,1H),10.13(s,1H),
9.20(s,1H),8.73(s,1H),8.51(d,J=5.7Hz,1H),7.90(d,J=13.5Hz,1H),7.83(s,1H),7.60
(d,J=9.3Hz,1H),7.47(s,1H),7.39(t,J=9.0Hz,1H),7.16(d,J=5.7Hz,1H),7.08(s,2H),
3.80(s,6H)
Embodiment 47 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- bis-
Bromo- 4 hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:604.8[M-H]-
Embodiment 48 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- of 3-
Hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:512.7[M-H]-；1H NMR(300MHz,DMSO)δ10.79(m,1H),10.65(m,1H),
10.17(m,1H),9.24(m,1H),8.56(m,1H),8.10(m,1H),7.93(dd,J=13.2,2.4Hz,1H),7.86(s,
1H),7.68–7.59(m,2H),7.52(d,J=2.4Hz,1H),7.48(t,J=9.0Hz,1H),7.20(dd,J=5.7,
2.25Hz,1H),7.02–6.96(d,J=8.4Hz,1H)
Embodiment 49 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- tri-
Methoxybenzaldehyde) semicarbazones
ESI-MS m/z:509.1[M-H]-
Embodiment 50 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxy benzenes
Formaldehyde) semicarbazones
ESI-MS m/z:449.2[M-H]-
Embodiment 51 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the uncles of 3,5- bis-
Butyl-2-hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:544.9[M-H]-；1H NMR(300MHz,DMSO)δ11.16(s,1H)10.58(s,1H),
10.11(s,1H),9.39(s,1H),8.50(d,J=5.8Hz,1H),8.21(s,1H),7.81–7.74(m,1H),7.48(d,J
=2.2Hz,1H),7.38(m,2H),7.24(d,J=2.1Hz,1H),7.19–7.13(m,2H),1.37(s,9H),1.24(s,
9H)
Embodiment 52 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- nitrobenzene
Formaldehyde) semicarbazones
ESI-MS m/z:478.2[M-H]-
Embodiment 53 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,6- dichloros
Benzaldehyde) semicarbazones；
ESI-MS m/z:484.7[M-H]-；1H NMR(300MHz,DMSO)δ11.26(s,1H),10.18(s,1H),
9.12(s,1H),8.55(d,J=5.8Hz,1H),8.17(s,1H),7.89(dd,J=13.4,2.2Hz,1H),7.57(m,3H),
7.52(d,J=2.1Hz,1H),7.43(m,2H),7.19(dd,J=5.8,2.2Hz,1H)
Embodiment 54 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- cyano group benzene
Formaldehyde) semicarbazones
ESI-MS m/z:458.4[M-H]-
Embodiment 55 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dihydroxies
Benzaldehyde) semicarbazones
ESI-MS m/z:448.9[M-H]-；1H NMR(300MHz,DMSO)δ10.58(s,1H),10.18(s,1H),
10.00(s,1H),9.73(s,1H),9.17(s,1H),8.56(d,J=5.7Hz,1H),8.19(s,1H),7.91(d,J=
13.6Hz,1H),7.76(d,J=8.6Hz,1H),7.62(d,J=9.4Hz,1H),7.53(s,1H),7.42(t,J=9.0Hz,
1H),7.25–7.17(m,1H),6.33(m,2H)
Embodiment 56 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- nitrobenzene
Formaldehyde) semicarbazones
ESI-MS m/z:478.3[M-H]-
Embodiment 57 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- nitrobenzene
Formaldehyde) semicarbazones
ESI-MS m/z:478.4[M-H]-
Embodiment 58 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- tri-
Hydroxy benzaldehyde) semicarbazones
ESI-MS m/z:464.7[M-H]-；1H NMR(300MHz,DMSO)δ10.57(s,1H),10.17(s,1H),
9.44(s,1H),9.20(s,1H),8.55(d,J=5.8Hz,1H),8.44(s,1H),8.17(s,1H),7.89(dd,J=
13.5,2.2Hz,1H),7.58(d,J=8.9Hz,1H),7.53(d,J=2.2Hz,1H),7.41(t,J=9.1Hz,1H),7.23–
7.13(m,2H),6.38(d,J=8.6Hz,1H)
Embodiment 59 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- [benzo [d]
[1,3] two dislike luxuriant benzaldehyde] semicarbazones
ESI-MS m/z:460.8[M-H]-；1H NMR(300MHz,DMSO)δ10.84(s,1H),10.20(s,1H),
9.23(s,1H),8.57(d,J=5.8Hz,1H),7.98-7.91(m,2H),7.77(s,1H),7.69(d,J=8.8Hz,1H),
7.54(d,J=1.6Hz,1H),7.46(t,J=9.1Hz,1H),7.22(d,J=3.7Hz,1H),7.16(d,J=8.2Hz,1H),
6.98(d,J=8.0Hz,1H),6.11(s,2H)
Embodiment 60 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyls-
1- naphthaldehydes) semicarbazones
ESI-MS m/z:482.9[M-H]-；1H NMR(300MHz,DMSO)δ10.78(s,1H),10.19(s,1H),
9.46(s,1H),9.01(s,1H),8.56(d,J=5.7Hz,1H),8.44(d,J=8.5Hz,1H),7.89(dd,J=9.1,
4.0Hz,3H),7.53(m,4H),7.41(m,2H),7.23(m,2H)
Embodiment 61 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxy benzenes
Formaldehyde) semicarbazones
ESI-MS m/z:432.9[M-H]-；1H NMR(300MHz,DMSO)δ10.74(s,1H),10.11(s,1H),
9.99(s,1H),9.18(s,1H),8.50(d,J=5.8Hz,1H),8.27(s,1H),7.93(d,J=6.9Hz,1H),7.87
(dd,J=13.5,2.4Hz,1H),7.58(d,J=10.0Hz,1H),7.48(d,J=2.2Hz,1H),7.38(t,J=9.0Hz,
1H),7.23–7.13(m,2H),6.88–6.79(m,2H)
Embodiment 62 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- fluorobenzene first
Aldehyde) semicarbazones
ESI-MS m/z:451.2[M-H]-
Embodiment 63 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzene first
Aldehyde) semicarbazones
ESI-MS m/z:451.3[M-H]-
Embodiment 64 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- bromobenzene first
Aldehyde) semicarbazones
ESI-MS m/z:512.1[M-H]-
Embodiment 65 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- difluoros
Benzaldehyde) contracting amino；
ESI-MS m/z:469.2[M-H]-
Embodiment 66 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- difluoros
Benzaldehyde) semicarbazones
ESI-MS m/z:469.3[M-H]-
Embodiment 67 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluoroforms
Epoxide benzaldehyde) semicarbazones
ESI-MS m/z:517.2[M-H]-
Embodiment 68 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- allyls
Base-Benzaldehyde,2-hydroxy) semicarbazones
ESI-MS m/z:472.8[M-H]-
Embodiment 69 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde contracts
Semicarbazides
ESI-MS m/z:417.0[M-H]-；1H NMR(300MHz,DMSO)δ:10.94(s,1H),10.19(s,1H),
9.26(s,1H),8.56(d,J=5.8Hz,1H),7.99(m,2H),7.90(m,3H),7.67(d,J=10.0Hz,1H),7.53
(d,J=2.2Hz,1H),7.44(m,3H),7.21(dd,J=5.8,2.3Hz,1H)
Embodiment 70 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- thiophene first
Aldehyde) semicarbazones
ESI-MS m/z:493.2[M-H]-
Embodiment 71 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- pyridine first
Aldehyde) semicarbazones
ESI-MS m/z:488.1[M-H]-
Embodiment 72 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- difluoro first
Epoxide benzaldehyde) semicarbazones
ESI-MS m/z:553.2[M-H]-
Embodiment 73 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- difluoro first
Benzaldehyde) semicarbazones
ESI-MS m/z:537.3[M-H]-
Embodiment 74 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- propionyl oxygen
Benzaldehyde) semicarbazones
ESI-MS m/z:559.3[M-H]-
Embodiment 75 (E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- methylsulfonyls
Benzaldehyde) semicarbazones
ESI-MS m/z:565.3[M-H]-
Step B12- [4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- bases] -1,3,4- oxadiazoles (21)
At room temperature, 2.92g intermediates 9 (0.01mmol) are dissolved in 30ml POCl3s, add 0.92g (002mol) first
Acid, is warming up to back flow reaction 6h.Be concentrated under reduced pressure most of solvent, and reaction solution is poured slowly into 200ml frozen water, dichloromethane extraction
Take (3 × 300ml), merge organic layer, be evaporated off solvent, dry white solid 1.58g, yield 52.3%.
Step C14- [2- (1,3,4- oxadiazoles -2- bases) pyridine -4- epoxides] -3- fluoroanilines (22)
By in the ethanol of the addition of 5.1g (0.017mol) intermediate 21 50ml90%, 0.5gPd/C (10%) is added at room temperature,
It is passed through hydrogen, stirring reaction 4h.Suction filtration, is evaporated off filtrate, to 100ml water is added in system, stirs 30min, suction filtration, filtration cakes torrefaction
Obtain white solid 2.91g, yield 62.3%.
Step D1Phenyl 4- [2- (1,3,4- oxadiazoles -2- bases) pyridine -4- epoxides] -3- fluorine phenyl carbamate (23)
2.72g (0.01mol) intermediate 22 is dissolved in 30ml acetone, 2.07g (0.015mol) potassium carbonate, cooling is added
To 0 DEG C, 2.02g (0.013mol) phenyl chloroformate is added dropwise, drop finishes, room temperature reaction 1.5h.Reaction solution adds 35ml water, dichloromethane
Alkane extracts (3 × 70ml), merges organic layer, and solvent is evaporated off, and obtains white solid 2.79g, yield 68.5%.
Step E1N- [4- [2- (1,3,4- oxadiazoles -2- bases) pyridine -4- epoxides] -3- fluorophenyls] semicarbazides (A-5)
1.96g (5mmol) intermediate 23 is dissolved in 15ml dioxane, adds 2ml hydrazine hydrates, is warming up to back flow reaction
3h.Reaction solution natural cooling, stands crystallization, suction filtration, filter cake with a small amount of ether drip washing, dry white solid 0.87g, yield
52.7%。
Step F1(E)-N1- [4- [2- (1,3,4- oxadiazoles -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,3-
Dichlorobenzaldehyde) semicarbazones (embodiment 76)
0.2g (0.60mmol) A-5 and 0.13g (0.72mmol) 2,3- dichlorobenzaldehydes are added into 2mL isopropanols,
1 is added to drip glacial acetic acid, flow back 5h.Suction filtration, filter cake with a small amount of isopropanol drip washing, dry yellow solid 0.15g, yield 52.6%.
ESI-MS m/z:487.2[M+H]+
According to the method for embodiment 76, it is prepared into for raw material carries out condensation reaction from different substituted aldehyde with intermediate A -5
To the compound of embodiment 77-79.
Embodiment 77 (E)-N1- [4- [2- (1,3,4- oxadiazoles -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4-(2,
4- dichlorobenzaldehydes) semicarbazones
ESI-MS m/z:487.3[M+H]+
Embodiment 78 (E)-N1- [4- [2- (5- Methyl-1,3,4-oxadiazole-2-2- bases) pyridine-4- epoxides]-3- fluorobenzene
Base]-N4- (2,3 dichloro benzaldehyde) semicarbazones
ESI-MS m/z:501.2[M+H]+
Embodiment 79 (E)-N1- [4- [2- (5- Methyl-1,3,4-oxadiazole-2-2- bases) pyridine-4- epoxides]-3- fluorobenzene
Base]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones
ESI-MS m/z:501.1[M+H]+
Step G14- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- thioformamides (24)
At room temperature, by 5.54g intermediates 4 (0.02mol) addition 30ml tetrahydrofurans, 4.44g phosphorus pentasulfides are added
(0.02mol), back flow reaction 6h.Evaporated under reduced pressure solvent, to addition 100ml water in system, dichloromethane extracts (3 × 150ml),
It is evaporated off solvent, dry faint yellow solid 5.02g, yield 85.3%.
Step H12- [4- (the fluoro- 4-nitrophenoxys of 2-) pyridine -2- bases] thiazole (25)
At room temperature, by 2.93g intermediates 24 (0.01mol) addition 20ml methyl alcohol, 1.22g bromoacetaldehydes are added
(0.01mol), back flow reaction 3h.Evaporated under reduced pressure solvent, to 50ml ether is added in system, stirs 30min, and suction filtration, filter cake is done
It is dry to obtain yellow solid 1.94g, yield 61.2%.
Step I1The fluoro- 4- of 3- [2- (thiazole -2-yl) pyridine -4- epoxides] aniline (26)
By in the addition 30ml absolute ethyl alcohols of 3.17g (0.01mol) intermediate 25,0.3gPd/C (10%) is added at room temperature, lead to
Enter hydrogen, stirring reaction 5h.Most of solvent is evaporated off, 30min is stood, suction filtration, filtration cakes torrefaction obtains white solid 1.63g, yield
56.7%。
Step J1Phenyl 4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorine phenyl carbamate (27)
Under ice bath, 2.82g (0.01mol) intermediate 26 is dissolved in 25ml acetone, adds 2.07g (0.015mol) carbonic acid
Potassium, is added dropwise 2.02g (0.013mol) phenyl chloroformate, and drop finishes, room temperature reaction 3h.Suction filtration, washes filter cake, dry white solid
2.52g, yield 61.9%.
Step K1N- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls] semicarbazides (A-6)
2.04g (5mmol) intermediate 27 is dissolved in 10ml dioxane, adds 2ml hydrazine hydrates, is warming up to 90 DEG C of reactions
3h.Reaction solution natural cooling, stands crystallization, suction filtration, filter cake with a small amount of ether drip washing, dry white solid 1.23g, yield
71.3%。
Step L1(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3- dichloro-benzenes first
Aldehyde) semicarbazones (embodiment 80)
0.17g (0.50mmol) A-6 and 0.11g (0.6mmol) 2,3- dichlorobenzaldehydes are added into 2mL isopropanols,
1 is added to drip glacial acetic acid, flow back 3h.Suction filtration, filter cake with a small amount of isopropanol drip washing, dry yellow solid 0.11g, yield 43.1%.
ESI-MS m/z:502.1[M+H]+
According to the method for embodiment 80, it is prepared into for raw material carries out condensation reaction from different substituted aldehyde with intermediate A -6
To the compound of embodiment 81-84.
Embodiment 81 (E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene
Formaldehyde) semicarbazones
ESI-MS m/z:502.0[M+H]+
Embodiment 82 (E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzaldehydes)
Semicarbazones
ESI-MS m/z:452.2[M+H]+
Embodiment 83 (E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- chlorobenzaldehydes)
Semicarbazones
ESI-MS m/z:468.1[M+H]+
Embodiment 84 (E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] phenyl]-N4- (4- chlorobenzaldehydes) contracting ammonia
Base urea；
ESI-MS m/z:450.2[M+H]+
The antitumor activity of product of the present invention
Extracorporeal anti-tumor cytoactive
Quinoline derivatives according to above formula of the invention I are carried out with external suppression lung carcinoma cell H460, colon cancer thin
The activity sieve of born of the same parents HT-29, gastric carcinoma cells MKN-45 and Liver cancer cell SMMC-7721 and human breast cancer cell MDA-MB-231
Choosing.
(1) cell recovery and pass on 2-3 times stabilization after, it is disappeared from blake bottle bottom with trypsin solution (0.25%)
Change is got off.After cell dissociation buffer is poured into centrifuge tube, nutrient solution is added to terminate digestion afterwards.By centrifuge tube in 800r/min
Lower centrifugation 10min, adds 5mL nutrient solutions after abandoning supernatant, piping and druming mixes cell, draws 10 μ L cell suspensions and adds cell
Counted in tally, adjustment cell concentration is 104Individual/hole.Except A1 holes for blank well is not added with extracellular in 96 orifice plates, remaining all adds
Enter 100 μ L cell suspensions.96 orifice plates are put into incubator and cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, appropriate nutrient solution is subsequently adding, sample is dissolved into 2mg/mL
Liquid, then in 24 orifice plates by Sample Dilution be 20,4,0.8,0.16,0.032 μ g/mL.
Each concentration add 3 holes, wherein around the row cell growing way of two row two it is affected by environment larger, only and be blanc cell
Hole uses.96 orifice plates are put into incubator and cultivate 72h.
(3) band medicine nutrient solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole
100 μ L of middle addition MTT (0.5mg/mL) are put into incubator after 4h, discard MTT solution, add the μ L of dimethyl sulfoxide (DMSO) 100.In magnetic
Vibration makes survivaling cell fully be dissolved with MTT product formazans on forced oscillation device, is put into measurement result in ELIASA.Pass through
Bliss methods can obtain medicine IC50Value.
The suppression lung carcinoma cell H460 of compound, colon cancer cell HT-29, gastric carcinoma cells MKN-45 and hepatoma cell strain
SMMC-7721 and human breast cancer cell MDA-MB-231 Activity Results are shown in Table 1.
Table 1
C-Raf and VEGFR-2 Kinase activity assays
Experiment for measuring C-Raf and VEGFR-2 kinase activities is based on EUSA (ELISA).Specifically
Operation is：
At room temperature, on the coated plates of 0.25mg/mL PGT, by embodiment compound, 50pM C-Raf/VEGFR-2 and 5
μM ATP (25mM MOPS, the pH7.4,5mM MgCl in buffer solution is tested2,0.5raM MnCl2, 100 μM of sodium orthovanadates,
0.01%Triton X-100,1mM DTT, last DMSO concentration 1% (v/v)) incubate 20min.By rinsing except dereaction mixes
Thing simultaneously detects phosphorus with the phosphotyrosine monoclonal antibody specific (PY20) that 0.2 μ g/mL are conjugated horseradish peroxidase (HRP)
Acidifying polymeric substrates.After adding 1M phosphoric acid color development stoppings, by the substrate of AAS quantitative chromogenic at 450nm
(TMB) color.Embodiment compound is shown in Table 2 and table 3 to the suppression data of C-Raf and VEGFR-2 kinases.
Table 2
Table 3
From above-mentioned result of the test it can be clearly seen that the compound of claimed formula I of the invention, with good
Anti tumor activity in vitro, quite or better than the antineoplastic cis-platinum for having listed.
The compound of formula of of the present invention I can be administered alone, but typically be given with pharmaceutical carrier mixture, described medicinal
The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various medicine agent of such compound
Type, such as tablet, capsule, injection, aerosol, suppository, film, pill, the preparation method of externally-applied liniment and ointment,
Illustrate its new opplication in pharmaceutical field.
Embodiment 85：Tablet
With compound (by taking the compound of the embodiment 12 as an example) 10g containing compound in claim 1, according to pharmacy one
As after pressed disc method adds auxiliary material 20g to mix, be pressed into 100, every weight 300mg.
Embodiment 86：Capsule
With compound (by taking the compound of the embodiment 36 as an example) 10g containing compound in claim 1, according to pharmacy glue
After the requirement of wafer mixes auxiliary material 20g, load Capsules, each capsule weight 300mg.
Embodiment 87：Injection
It is normal according to pharmacy with compound (by taking the compound of the embodiment 1 as an example) 10g containing compound in claim 1
Rule method, carries out charcoal absorption, through 0.65 μm of filtering with microporous membrane after, insert nitrogen pot and be made hydro-acupuncture preparation, every dress
2mL, altogether filling 100 bottles.
Embodiment 88：Aerosol
With compound (by taking the compound of the embodiment 22 as an example) 10g containing compound in claim 1, appropriate propane diols is used
After dissolving, after adding distilled water and other spoke material, the settled solution for being made 500mL is obtained final product.
Embodiment 89：Suppository
With compound (by taking the compound of the embodiment 19 as an example) 10g containing compound in claim 1, by finely ground addition
Appropriate glycerine, adds the glycerin gelatine for having melted after grinding well, grinding is uniform, is poured into the model for having applied lubricant, and suppository is obtained
50
Embodiment 90：Film
With compound (by taking the compound of the embodiment 13 as an example) 10g containing compound in claim 1, by polyvinyl alcohol,
Heating for dissolving after the stirring expansion such as medicinal glycerin, water, 80 mesh sieve net filtrations, then the compound of embodiment 18 is added in filtrate stirs
Mix dissolving, film applicator masking 100.
Embodiment 91：Pill
With compound (by taking the compound of the embodiment 17 as an example) 10g containing compound in claim 1, with the matrix such as gelatin
After 50g heating fusings are mixed, instill in cryogenic liquid paraffin, the ball of dripping pill 1000 is obtained altogether.
Embodiment 92：Externally-applied liniment
With compound (by taking the compound of the embodiment 31 as an example) 10g containing compound in claim 1, according to conventional dose
The auxiliary material 2.5g mixed grindings such as method and emulsifying agent, then add distilled water prepared to 200mL.
Embodiment 93：Ointment
With compound (by taking the compound of the embodiment 47 as an example) 10g containing compound in claim 1, it is finely ground after with all scholars
The oleaginous base such as woods 500g grinds well prepared.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field
Be will be apparent from for technical staff, and they are included within the scope of the invention.
Claims (12)
1. the compound and its pharmaceutically acceptable salt of formula I,
Wherein,
Y is halogen；
K is O；
Ar is phenyl or naphthyl, and the optional 1-3 of Ar identical or different R1Substitution；
Each Q is separately selected from C, C-Z, N-Z, N, O and S, and condition is N atoms 0-4, and O and S atom 0-1 is individual, and N, O
It is 0 when different with S atom number；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkane
Epoxide, C1-C6Alkylamidoalkyl, free, into salt, esterification and amidated carboxyl, (C1-C6) alkyl sulphinyl,
(C1-C6) alkyl sulphonyl, (C1-C6) alkyl acyl, carbamoyl, (C1-C3) alkylenedioxy group；
Z is independently selected from H, (C1-C6) alkyl, (C3-C8) cycloalkyl,
R2、R3It is identical or different, separately selected from H, (C1-C6) alkyl, (C3-C8) cycloalkyl；
Or R2And R3The nitrogen-atoms being connected with them forms 5-10 circle heterocycles base or 5-10 unit's heteroaryls, the heterocyclic radical and
Heteroaryl except with R2And R3Outside the nitrogen-atoms of connection, optionally containing the 1-4 hetero atom selected from N, O and S, except R2And R3Institute
Outside the nitrogen-atoms of connection, the heterocyclic radical optionally includes 1-2 carbon-carbon double bond or three key, the heterocyclic radical and heteroaryl optionally quilt
1-3 identical or different R4Substitution；
R4It is (C1-C6) alkyl, (C3-C7) cycloalkyl；
N is the integer between 0-6；
Represent substitution base junction.
2. the compound and its pharmaceutically acceptable salt of the formula I of claim 1, wherein,
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C2-C6) alkynyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl
Sulfonyl, (C1-C6) alkyl acyl, carbamoyl, (C1-C3) alkylenedioxy group, pi-allyl.
3. the compound and its pharmaceutically acceptable salt of the formula I of claim 2, wherein,
It is selected from：
Ar is phenyl, naphthyl, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is H, hydroxyl, halogen, nitro, amino, cyano group, (C2-C6) alkynyl, (C1-C6) alkyl sulphonyl, pi-allyl.
4. the compound and its pharmaceutically acceptable salt of the formula I of claim 3,
Wherein,
Y is F, and the position of substitution is at the ortho position of O.
5. the compounds of formula I and its pharmaceutically acceptable salt of claim 4, wherein,
Each Z is independently selected from H, (C1-C6) alkyl,
R2、R3It is identical or different, separately selected from H, (C1-C3) alkyl；
Or R2And R31- piperidyls, 4- morpholinyls, 4- methyl isophthalic acids-piperazinyl, 4- are formed together with the nitrogen-atoms being connected with them
Methyl isophthalic acid-piperidyl, 1- pyrrolidinyls；
N is 1,2 or 3.
6. the compounds of formula I and its pharmaceutically acceptable salt of claim 5, wherein,
Each Z is independently selected from H, (C1-C3) alkyl,
Ar is phenyl, and the optional 1-3 of Ar identical or different R1Substitution；
R1It is halogen, hydroxyl, nitro, cyano group, pi-allyl, mesyl.
7. the compounds of formula I and its pharmaceutically acceptable salt of claim 6, wherein,
8. following compound and its pharmaceutically acceptable salt：
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- chlorobenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (4H-1,2,4- triazole -3- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4- dimethoxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3- hydroxyls -4-methoxybenzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3,4- tri hydroxybenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,4- 4-dihydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,5- dimethyl -4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (TMB) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3-methoxy-4-hydroxybenzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,5- dibromine-4-hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3,4- TMBs) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- [benzo [d] [1,3] two dislikes luxuriant benzaldehyde] semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,5- di-t-butyls-Benzaldehyde,2-hydroxy) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3- bromobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,6- dichlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the chloro- 4- fluorobenzaldehydes of 2-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- [4- [3- (dimethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorophenyls] -
N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- (morpholinyl propyl group) -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorophenyls] -
N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [3- (diethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4- dichlorobenzaldehydes) thiosemicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,5- dimethoxy benzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyl -4- methoxybenzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- tri hydroxybenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- 4-dihydroxy benzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dimethoxy benzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxy benzenes
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- trimethoxy-benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxy 3-methoxybenzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- hydroxyl -3,5- dimethoxys
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4 hydroxy benzenes first of 3,5- bis-
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3,4- trimethoxy-benzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- di-t-butyl -2- hydroxyls
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- cyanobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- 4-dihydroxy benzaldehydes) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4,5- tri hydroxybenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- [benzo [d] [1,3] two dislikes luxuriant benzene
Formaldehyde] semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (Benzaldehyde,2-hydroxy) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- fluorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- bromobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 difluorobenzene formaldehyde) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,4- difluorobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- trifluoro-methoxybenzaldehydes)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- pi-allyl -2- hydroxy benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (thiophene -2-formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (pyridine -3- formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- difluoro-methoxies benzaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- difluoromethyls benzaldehyde) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- methyl propionates benzaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- methanesulfonylbenzaldehydes) contracts
Semicarbazides；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde)
Semicarbazones；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde)
Semicarbazones；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3- dichloros
Benzaldehyde) semicarbazones；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dichloros
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- fluorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (4- chlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones.
9. compounds of formula I and its pharmaceutically acceptable salt, the hydrate or prodrug of claim 1：
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4- dichlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3,4- tri hydroxybenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,5- dimethyl -4- hydroxy benzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- [benzo [d] [1,3] two dislikes luxuriant benzaldehyde] semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3,5- di-t-butyls-Benzaldehyde,2-hydroxy) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2- nitrobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (3- bromobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,6- dichlorobenzaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (the chloro- 4- fluorobenzaldehydes of 2-) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- benzaldehyde semicarbazone；
(E)-N1- [4- [2- [4- [3- (dimethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [3- (diethylamino) propyl group] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4 dichloro benzene formaldehyde) semicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,3 dichloro benzaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- [4- [2- (dimethylamino) ethyl] -4H-1,2,4- triazole -3- bases] pyridine -4- epoxides] -3- fluorine
Phenyl]-N4- (2,4 dichloro benzene formaldehyde) thiosemicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the fluoro- 4- hydroxy benzaldehydes of 3-) contracts
Semicarbazides；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- hydroxyl -4- methoxybenzene first
Aldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3,5- dimethyl -4- hydroxy benzenes
Formaldehyde) semicarbazones；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (the bromo- 4- hydroxy benzaldehydes of 3-) contracts
Semicarbazides
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,6- dichlorobenzaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2- hydroxyl-1-naphthalene Formaldehydes) contracting ammonia
Base urea；
(E)-N1- [4- [2- (1H-TETRAZOLE -1- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (3- pi-allyl -2- hydroxy benzenes first
Aldehyde) semicarbazones；
(E)-N1- [4-2- (1,3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde)
Semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,3 dichloro benzaldehyde) semicarbazones；
(E)-N1- [4-2- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyridine -4- epoxides] -3- fluorophenyls]-N4- (2,4- dichloros
Benzaldehyde) semicarbazones；
(E)-N1- [4- [2- (thiazol-2-yl) pyridine -4- epoxides] phenyl]-N4- (4- chlorobenzaldehydes) semicarbazones.
10. a kind of Pharmaceutical composition, the compound comprising any one in claim 1-9 and its pharmaceutically acceptable salt are made
It is active component and pharmaceutically acceptable excipient.
Group in 11. claim 1-9 described in the compound and its pharmaceutically acceptable salt or claim 10 of any one
Purposes of the compound in the medicine for being used for preventing or treat the disease relevant with C-Raf and VEGFR-2 kinase inhibitors is prepared.
Group in 12. claim 1-9 described in the compound and its pharmaceutically acceptable salt or claim 10 of any one
Compound is preparing treatment and/or prevention lung cancer, liver cancer, stomach cancer, colorectal cancer, breast cancer, malignant glioblastoma, bladder
Application in cancer, prostate cancer, oophoroma and oesophagus cancer drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102977014A (en) * | 2012-11-05 | 2013-03-20 | 沈阳药科大学 | New quinoline compounds and uses thereof |
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| CN102977014A (en) * | 2012-11-05 | 2013-03-20 | 沈阳药科大学 | New quinoline compounds and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| Syntheses and Antiproliferative Activities of Novel Diarylthiosemicarbazide Derivatives;ZHAI XIN et al.;《Chem. Res. Chin. Univ.》;20130116;第29卷(第1期);第62-66页 * |
| 四唑类化合物的合成及应用研究新进展;代玲玲等;《有机化学》;20130228;第33卷(第2期);第224-244页 * |
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