CN104211682A - pyridine compounds and applications thereof - Google Patents
pyridine compounds and applications thereof Download PDFInfo
- Publication number
- CN104211682A CN104211682A CN201310253646.6A CN201310253646A CN104211682A CN 104211682 A CN104211682 A CN 104211682A CN 201310253646 A CN201310253646 A CN 201310253646A CN 104211682 A CN104211682 A CN 104211682A
- Authority
- CN
- China
- Prior art keywords
- pyridine
- fluorophenyl
- semicarbazone
- oxygen base
- triazole
- Prior art date
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- 0 CC(C)=CC*N=I Chemical compound CC(C)=CC*N=I 0.000 description 13
- JWAWEQBUZOGIBZ-UHFFFAOYSA-N C[n]1nncc1 Chemical compound C[n]1nncc1 JWAWEQBUZOGIBZ-UHFFFAOYSA-N 0.000 description 1
- AGQOIYCTCOEHGR-UHFFFAOYSA-N Cc1cc[n][o]1 Chemical compound Cc1cc[n][o]1 AGQOIYCTCOEHGR-UHFFFAOYSA-N 0.000 description 1
- LBBKWEDRPDGXPM-UHFFFAOYSA-N Cc1ccn[s]1 Chemical compound Cc1ccn[s]1 LBBKWEDRPDGXPM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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 invention relates to pyridine compounds represented by the formula I, pharmaceutically acceptable salts, hydrates, or prodrugs thereof; wherein the substituents K, Q, Ar, and Y are defined in the description. The invention also relates to the C-Raf and VEGFR-2 kinase inhibiting functions of the compounds represented by the formula I, and further relates to the applications of the compounds, the pharmaceutically acceptable salts, hydrates, or prodrugs thereof in preparation of drugs for treating diseases caused by abnormal high expression of C-Raf and VEGFR-2 kinases, and especially in preparation of drugs for treating and/or preventing cancers.
Description
Technical field
The present invention relates to new pyridine compounds and their and pharmacy acceptable salt thereof, hydrate or its prodrug, their preparation method and the pharmaceutical composition that contains described compound.The invention still further relates to this compounds and pharmacy acceptable salt thereof, hydrate or its prodrug in preparation treatment due to the purposes in the medicine of C-Raf and VEGFR-2 kinases disease that overexpression causes, particularly treat and/or prevent the purposes in the medicine of cancer in preparation.
Background technology
Malignant tumour is a kind of disease of serious harm human life health, and along with the variation of the extraneous factors such as environmental pollution, global pathogenesis of cancer number rises year by year.Just because of this, to the research of tumour mechanism and methods for the treatment of thereof also more and more extensively and profoundly.
In recent years, along with the develop rapidly of oncobiology and related discipline, the primary process of some cell carcinogenesis such as signal transduction, apoptotic induction in malignant cell is illustrated just gradually, there is great change in antitumor drug research and development theory thus, research and development focus is transferred to the new type antineoplastic medicine for signal transduction pathway in tumour cell from conventional cell poison class medicine, the point of penetration that makes tumor pharmacother by cell levels excessively to molecular level.New type antineoplastic medicine is for the difference between normal cell and tumour cell, and selectively acting is in the relevant specific kinases of tumour cell differentiation and proliferation, has the advantages such as efficient, low toxicity, high specificity.Therefore, the research of targeting antineoplastic medicine thing has become the important directions of current antitumor drug research and development.
At present, in the molecular targeted type antitumor drug of discovery, kinases inhibitor is a class of known most study.Protein kinase, due to sudden change or rearrangement, can cause signal transduction process obstacle or occur extremely, causing Growth of Cells, differentiation, metabolism and biological behaviour abnormal, thereby can bringing out kinds of tumors.This Signal Transduction Pathways of Ras/Raf/MEK/ERK is extensively present in eukaryote.Raf, as a crucial kinases in this path, can amplify signal cascade by a series of phosphorylations, thereby regulates cellular activity.Once this path generation overexpression, the acceleration of cell proliferation and the prolongation of cells survival phase can be led oncogenic formation.Raf kinases is divided into three hypotypes, A-Raf, B-Raf and C-Raf.Wherein, C-Raf expresses in most people body tissue, and be not the function of adjustable cellular activity by Ras/Raf/MEK/ERK path, studies show that its abnormal activation in the noumenal tumour of multiple rich blood vessel, as kidney, liver cancer and nonsmall-cell lung cancer etc., by reducing the generation that this kinase whose activity can inhibition tumor cell.VEGFR(Vascular endothelial growth factor receptor) be a member in receptor tyrosine family, the generation of new vessel has been played to crucial effect.The multiple physiology of human body and pathologic process have all related to new vessel generation and have comprised fetal development, menstrual cycle, wound healing, tumour, rheumatic arthritis and diabetic retinopathy etc.This receptor is mainly divided into three hypotypes, VEGFR-1, VEGFR-2 and VEGFR-3.Wherein, VEGFR-2 is topmost functional receptor.VEGFR-2 has another name called kinases insert district acceptor (kinase domain receptor, KDR), and its encoding gene is positioned at 4q12, and 1356 amino acid of having encoded are that a part amount is the transmembrane glycoprotein of 230kD.VEGFR-2 with receptors bind after, there is autophosphorylation in the tyrosine site of its born of the same parents' inner segment, the tyrosine residues of phosphorylation amplifies signal cascade, thereby regulates the Metabolic activity of cell.Research shows, the expression of VEGFR in the most tumors tissues such as cancer of the stomach, colon, rectum, ovary, mammary cancer obviously increased, and this also becomes one of important target of cancer therapy drug exploitation.
Make great progress for the research of target inhibitor in recent years.Sorafenib, many target spots of being ratified by FDA as first kinase inhibitor, produces good restraining effect by suppressing Raf, VEGFR and the kinase whose activity of PDGFR to tumour, has been approved for the treatment of metastatic renal cell carcinoma and liver cancer at present.Cabozantinib all shows significant inhibition activity to the kinases such as c-Met, VEGFR-2, the treatment for thyroid carcinoma by FDA approval.In addition, also have many micromolecular inhibitors to be in the clinical study stage, as foretinib, BMS-777607 etc.
Target inhibitor in active testing or clinical study stage has various structures type, wherein contain the compound of pyridine structure in to the active testing of various human tumor cell line, show good inhibition proliferation function, C-Raf and VEGFR-2 kinases have all been had to higher inhibition activity simultaneously.
The inventor, on the basis of reference, has designed and synthesized a series of new pyridine derivatives.Through external activity screening, show that this compounds has good anti-tumor activity and to C-Raf and the kinase whose dual restraining activities of VEGFR-2.
Summary of the invention:
The present invention relates to compound and pharmacy acceptable salt, hydrate or the prodrug of formula I, wherein,
Y is H, halogen;
K is O, S;
Ar is (C
6-C
10) aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains 1-3 heteroatoms that is selected from N, O or S, and the optional 1-3 of Ar identical or different R
1replace;
Each Q is respectively independently selected from C, C-Z, N-Z, N, O and S, and condition is N atom 0-4, and O and S atom 0-1, and N, O are 0 when different with S atom number;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, C
1-C
6alkylamidoalkyl, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, by 1-2 (C
1-C
6) alkyl replace formamyl, (C
1-C
3) alkylenedioxy group, allyl group;
Z is independently selected from H, (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl,
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl;
Or R
2and R
3form 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms being connected with them, described heterocyclic radical and heteroaryl except with R
2and R
3outside the nitrogen-atoms connecting, optionally contain 1-4 heteroatoms that is selected from N, O and S, except R
2and R
3outside the nitrogen-atoms connecting, described heterocyclic radical optionally comprises 1-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are optionally by 1-3 identical or different R
4replace;
R
4for (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl;
N is the integer between 0-6;
represent substituting group junction.
The present invention preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of formula I, wherein,
Y is halogen;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, (C
1-C
3) alkylenedioxy group, allyl group.
The present invention particularly preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of formula I, wherein,
Y is halogen;
be selected from:
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, (C
1-C
6) alkyl sulphonyl, allyl group.
The present invention also particularly preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of formula I, wherein,
Y is F, and the position of substitution is at the ortho position of O;
K is O;
be selected from:
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, (C
1-C
6) alkyl sulphonyl, allyl group;
The present invention also particularly preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of general formula I, wherein,
Y is F, and the position of substitution is at the ortho position of O;
K is O;
be selected from:
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, and the optional 1-3 of Ar identical or different R1 replaces;
R1 is H, hydroxyl, halogen, nitro, amino, cyano group, (C1-C6) alkyl, (C2-C6) thiazolinyl, (C2-C6) alkynyl, (C1-C6) alkoxyl group, optionally by (C1-C6) alkyl of hydroxyl, amino or halo or (C1-C6) alkoxyl group, the amino, (C1-C6) alkyl sulphonyl, the allyl group that are replaced by 1-2 (C1-C6) alkyl;
Each Z is independently selected from H, (C
1-C
6) alkyl,
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
3) alkyl;
Or R
2and R
3form piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl together with the nitrogen-atoms connecting with them;
N is 1,2,3.
The present invention very particularly preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of general formula I, wherein,
Y is F, and the position of substitution is at the ortho position of O;
K is O;
be selected from:
Ar is phenyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for halogen, hydroxyl, nitro, cyano group, trifluoromethyl, trifluoromethoxy, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, allyl group, dimethylamino, methylsulfonyl;
Each Z is independently selected from H, (C
1-C
3) alkyl,
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
3) alkyl;
Or R
2and R
3form piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl together with the nitrogen-atoms connecting with them;
N is 1,2 or 3.
The present invention more particularly preferably relates to compound and pharmacy acceptable salt, hydrate or the prodrug of general formula I, wherein,
Y is F, and the position of substitution is at the ortho position of O;
K is O;
Ar is phenyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for halogen, hydroxyl, nitro, cyano group, trifluoromethyl, trifluoromethoxy, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, allyl group, dimethylamino, methylsulfonyl;
Each Z is independently selected from H, (C
1-C
3) alkyl,
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
3) alkyl;
Or R
2and R
3form piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl together with the nitrogen-atoms connecting with them;
N is 1,2,3.
Preferably following compound of the compound of general formula I of the present invention and pharmacy acceptable salt thereof, hydrate or prodrug, but these compounds do not mean that any limitation of the invention:
(E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone;
(E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-chlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-dimethoxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-Trimethoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-methoxy-4-hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dibromine-4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-TMB) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-nitrobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-bromobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the chloro-4-fluorobenzaldehyde of 2-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone;
(E)-N
1-[4-[2-[4-[3-(dimethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-(morpholinyl propyl group)-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-(morpholinyl propyl group)-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[3-(diethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) thiosemicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) thiosemicarbazone.
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,5-dimethoxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-dimethoxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-Trimethoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-methoxy-4-hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxyl-3,5-dimethoxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(bromo-4 hydroxy benzaldehydes of 3,5-bis-) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-TMB) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-nitrobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-cyanobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-nitrobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-nitrobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-tri hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(Benzaldehyde,2-hydroxy) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-fluorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-fluorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-bromobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 difluorobenzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-difluorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-trifluoro-methoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-allyl group-Benzaldehyde,2-hydroxy) semicarbazone.
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(thiophene-2-formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(pyridine-3-formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-difluoro-methoxy phenyl aldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-difluoromethyl phenyl aldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-methyl propionate benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-methylsulfonyl phenyl aldehyde) semicarbazone;
(E)-N
1-[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-fluorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base] phenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone;
The compound of general formula I of the present invention and pharmacy acceptable salt thereof, hydrate or prodrug are more preferably following compound, but these compounds do not mean that any limitation of the invention:
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-nitrobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-bromobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the chloro-4-fluorobenzaldehyde of 2-) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone;
(E)-N
1-[4-[2-[4-[3-(dimethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[3-(diethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) thiosemicarbazone;
(E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) thiosemicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-allyl group-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-N
1-[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone;
(E)-N
1-[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base] phenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone.
And according to some usual methods in field under the present invention, the pyridine derivatives of formula of I of the present invention can generate pharmacy acceptable salt with acid.Pharmaceutically acceptable additive salt comprises mineral acid and organic acid addition salt, with the salt of following sour addition be particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, oxalic acid, tartrate, phenylformic acid etc.
In addition, the present invention also comprises the prodrug of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of formula I, they self may have weak activity and even there is no activity, but after administration, under physiological condition, (for example, by metabolism, solvolysis or other mode) is converted to corresponding biologically active form.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine generation; " alkyl " refers to the alkyl of straight or branched; " cycloalkyl " refers to and replaces or unsubstituted cycloalkyl; " aryl " refers to unsubstituted or is connected with substituent phenyl or naphthyl; " heteroaryl " refers to the ring-type system that contains one or more N of being selected from, O, the heteroatomic monocycle of S or many rings, ring-type system is aromaticity, as imidazolyl, pyridyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrryl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, benzimidazolyl-and benzoxazolyl etc.
We have found that the compounds of this invention is external and have had a growth inhibitory activity to tumor cell, therefore, it can be as preparing the medicine that treat and/or prevent cancer, as cancer and leukemia, the neuroblastoma etc. of mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate gland, bladder, uterus, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, Tiroidina, esophagus.
By the pernicious glioblastoma cells U87MG activity test of vitro inhibition lung carcinoma cell H460, colon cancer cell HT-29, gastric carcinoma cells MKN-45 and Liver cancer cell SMMC-7721, human breast cancer cell MDA-MB-231 and people, the compounds of this invention has remarkable restraining effect to lung carcinoma cell, colon cancer cell and stomach cancer cell, mammary cancer liver cancer and pernicious glioblastoma multiforme etc., is used in particular for preparing the medicine that treats and/or prevents lung cancer, colorectal carcinoma, cancer of the stomach and mammary cancer.
By C-Raf and the test of VEGFR-2 enzymic activity are found, the compounds of this invention has significant inhibition C-Raf and VEGFR-2 kinases dual restraining activities, lung carcinoma cell, colon cancer cell, cancer of the stomach and mammary cancer etc. to C-Raf and VEGFR-2 high expression level have stronger restraining effect, are used in particular for preparing the medicine that treats and/or prevents lung cancer.
Active compound of the present invention or its pharmacologically acceptable salt can be used as unique antitumor drug and use separately, or can combine use with the antitumor drug now having gone on the market (as platinum medicine cis-platinum, camptothecine irinotecan, vinca alkaloids medicine nvelbine, Deoxyribose cytidine class medicine gemcitabine, etoposide, taxol etc.).Combination therapy realizes by each being treated to component while, order or separating administration.
The compounds of this invention and preparation method thereof is further illustrated and illustrated to the embodiment hereinafter providing and preparation example.Should be appreciated that the scope of following example and preparation example and limit the scope of the invention never in any form, unlisted heterocycle
the method that can know according to organic chemistry filed those of ordinary skill of synthetic method prepare.
The preparation of formula I derivative of the present invention is summarized and described to synthetic route (route 1) below, prepared by the method that all raw materials are all modes by describing in these schematic diagram, know by organic chemistry filed those of ordinary skill or commercially available.All final derivatives of the present invention are all the methods by describing in these schematic diagram or prepare by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.Whole variable factors of applying in these schematic diagram are as definition below or as the definition in claim.
According to formula I derivative of the present invention, all can according to the method for route 1 by corresponding intermediate A and aldehyde in Virahol, add the glacial acetic acid of catalytic amount, the about 5h that refluxes, makes by condensation reaction.Wherein, the Q in compound, Y, K and Ar are as defined in claim.
When
for
time, the preparation method of intermediate A-1 is shown in route 2:
When
for
z is
time, route 3 is shown in the preparation of intermediate A-2 and A-3:
When
for
route 4 is shown in the preparation of intermediate A-4:
When
for
z is H, (C
1-C
3) when alkyl, route 5 is shown in the preparation of intermediate A-5:
When
for
time, route 6 is shown in the preparation of intermediate A-6:
In above 6 routes, substituting group Q, X, Y and the K of all intermediates are as defined in claim.
Embodiment:
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra of compound is measured with Bruker ARX-300, and mass spectrum is measured with Agilent1100LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1:
Chloro-pyridine-the 2-of steps A 4-methyl-formiate (2)
Under room temperature, by 150g (1.22mol) pyridine-2-formic acid, 20.1g (0.197mol) Sodium Bromide adds in 200ml chlorobenzene, stirs 10min, and reaction solution rises to 50 DEG C, slowly add 355ml (4.88mol) sulfur oxychloride, stir 30min, be warming up to back flow reaction 20h, steaming desolventizes, obtaining the chloro-pyridine-2-of intermediate 14-formyl chloride, is yellow oil.Intermediate 1 is added in 500ml toluene, control 0～5 DEG C of temperature and drip 100ml anhydrous methanol, drip and finish, 15 DEG C of stirring reaction 1.5h.Suction filtration, filter cake adds in unsaturated carbonate potassium solution, and dichloromethane extraction (3 × 400ml) merges organic layer, washing, anhydrous sodium sulfate drying, steaming desolventizes, and is dried to obtain yellow solid 150g, yield 72.1%.
Step B4-(the fluoro-4-nitro-phenoxy group of 2-)-pyridine-2-methyl-formiate (3)
20g (0.17mol) intermediate 2 and 27g (0.175mol) 2-fluoro-4-nitrophenol are dissolved in the chlorobenzene that 300ml is dry to back flow reaction 13h.Steaming removes chlorobenzene and obtains oily matter, add 500ml methylene dichloride to dissolve, wash (3 × 300ml) with unsaturated carbonate potassium solution, steaming removes organic layer and obtains brown solid, and crude product adds 300ml dehydrated alcohol, be warming up to return stirring 30min, reaction solution naturally cools to room temperature, leaves standstill crystallization, suction filtration, filtration cakes torrefaction obtains light yellow solid 15.2g, yield 44.5%.
Step C4-(the fluoro-4-nitro-phenoxy group of 2-)-pyridine-2-carboxamide (4)
By 10g (0.034mol) intermediate 3,30ml ammoniacal liquor adds in 50ml acetone, back flow reaction 2h.Steam except most of solvent, in system, add 100ml water, stir 30min, suction filtration, filtration cakes torrefaction obtains off-white color solid 7.3g, yield 73.2%.
Step D N-[(dimethylamino) methylene radical]-4-(the fluoro-4-nitrophenoxy of 2-) picolinamide (5)
Under room temperature, 6.3g (0.022mol) intermediate 4 is added in 50ml methylene dichloride, under stirring, add 5.5g (0.046mol) DMF dimethylacetal (DMF-DMA), be warming up to back flow reaction 2h.Steaming desolventizes, and reaction system adds 70ml ether, stirs 1h, suction filtration, and filtration cakes torrefaction obtains yellow solid 5.3g, yield 73.6%.
Step e 4-(fluoro-4 nitro-phenoxies of 2-)-2-(4H-1,2,4 triazoles-3-yl)-pyridine (6)
5g (0.015mol) intermediate 5 is added in 30ml Glacial acetic acid, be cooled to 10 DEG C, under stirring, add 1.88g (0.03mol) hydrazine hydrate, be warming up to 90 DEG C of stirring reaction 3h.Steam except most of solvent, reaction solution adds 70ml water, stirs 30min, and suction filtration, adds filter cake in 100ml ether, stirs 30min, suction filtration, and filtration cakes torrefaction obtains white solid 3g, yield 50.9%.
The fluoro-4-[2-of step F 3-(4H-1,2,4 triazoles-3-yl)-pyridine-4-oxygen base]-aniline (7)
2.5g (0.008mol) intermediate 6 is added in 50ml dehydrated alcohol, under room temperature, add 0.25gPd/C (10%), pass into hydrogen, stirring reaction 4h.Suction filtration, steams except filtrate, obtains white solid 1.75g, yield 77.8%.
The fluoro-4-[2-of step G[3-(4H-1,2,4 triazoles-3-yl)-pyridine-4-oxygen base]-phenyl]-phenyl carbamate (8)
2.3g (0.008mol) intermediate 7 is dissolved in 20ml acetone, adds 1.52g (0.011mol) salt of wormwood, be cooled to 0 DEG C, drip 1.59g (0.01mol) phenyl chloroformate, drip and finish, room temperature reaction 2h.In system, add 20ml water, dichloromethane extraction (3 × 50ml), merges organic layer, and steaming desolventizes, and filtration cakes torrefaction obtains white solid 2.86g, yield 86.3%.
Step H N-(4-(2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base)-3-fluorophenyl) Urea,amino-(A-1)
3g intermediate 8 is dissolved in 20ml dioxane, adds 6ml hydrazine hydrate, is warming up to back flow reaction 2h.Naturally cooling, leaves standstill crystallization, suction filtration, and a small amount of ether drip washing for filter cake, suction filtration, filtration cakes torrefaction obtains white solid 2.15g, yield 85%.
Step I (E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone (embodiment 1)
0.2g (0.61mmol) A-1 and 0.078g (0.73mmol) phenyl aldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 5h.Suction filtration, a small amount of Virahol drip washing for filter cake, is dried to obtain 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 and implements 3 compound for raw material and different aldehyde carry out condensation reaction.
Embodiment 2 (E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-chlorobenzaldehyde) semicarbazone
ESI-MS?m/z:452.1[M+H]
+
Embodiment 3 (E)-N
1-[4-[2-(4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:485.1[M+H]
+
Step J4-(the fluoro-4-nitro-phenoxy group of 2-)-pyridine-2-formyl hydrazine (9)
By 15g (0.051mol) intermediate 3,150ml hydrazine hydrate adds in 150ml acetonitrile, room temperature reaction 2h.Steam except partial solvent, reaction solution adds 200ml water, dichloromethane extraction (3 × 400ml), and steaming desolventizes, and is dried to obtain white solid 12.3g, and yield is 82%.
Step K N'-[4-(the fluoro-4-nitrophenoxy of 2-) pyridine-2-formyl radical]-N, N-dimethyl methyl hydrazone group amine (10)
12g (0.041mol) intermediate 9 is added in 60ml methylene dichloride, under stirring, add 9.78g (0.08mol) DMF dimethylacetal (DMF-DMA), be warming up to back flow reaction 2h.Steaming desolventizes, and reaction system adds 70ml ether, stirs 1h, suction filtration, and filtration cakes torrefaction obtains yellow solid 7.7g, yield 75.8%.
Step L2-[3-[4-(the fluoro-4-nitrophenoxy of 2-) pyridine-2-yl]-4H-1,2,4-triazole-4-yl]-N, N-dimethyl amine (11)
17.5g (0.05mol) intermediate 10 is added in 45ml Glacial acetic acid, be cooled to 10 DEG C, add 8.9g (0.1mol) N under stirring, N-dimethyl-ethylenediamine, is warming up to 90 DEG C of stirring reaction 3h.Steam except most of solvent, reaction solution adds 70ml water, stirs 30min, and suction filtration, adds filter cake in 100ml ether, stirs 30min, suction filtration, and filtration cakes torrefaction obtains yellow look solid 6.6g, yield 35.2%.
Step M4-[2-[4-(2-dimethylin-ethyl)-4H-1,2,4-triazole-3-yl]-pyridine-4-oxygen base] the fluoro-aniline of-3-(12)
5g (0.013mol) intermediate 11 is added in the ethanol of 60ml90%, add 0.048g (0.004mol) gac, 0.54g (0.002mol) ferric sesquichloride, stirring at room temperature 0.5h, 60 DEG C drip 8.13g (0.13mol) hydrazine hydrate, drip to finish to be warming up to back flow reaction 3h.Hot suction filtration, a small amount of hot ethanol drip washing for filter cake, steaming desolventizes, and is cooled to room temperature, adds 100ml ether in system, stirs 2h, suction filtration, filtration cakes torrefaction obtains white solid 2.18g, yield 47.5%.
Step N[4-[2-[4-(2-dimethylin-ethyl)-4H-1,2,4-triazole-3-yl]-pyridine-4-oxygen base] the fluoro-phenyl of-3-]-phenyl carbamate (13)
3.5 (0.01mol) intermediate 12 is dissolved in 25ml acetone, adds 1.79g (0.013mol) salt of wormwood, be cooled to 0 DEG C, drip 1.92g (0.012mol) phenyl chloroformate, drip and finish, room temperature reaction 2h.Reaction solution adds 20ml water, and dichloromethane extraction (3 × 50ml) merges organic layer, and steaming desolventizes, and is dried to obtain white solid 3.72g, yield 78.6%.
Step O N-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl] Urea,amino-(A-2)
3g (6.5mol) intermediate 13 is dissolved in 20ml dioxane, adds 6ml hydrazine hydrate, is warming up to back flow reaction 2h.System naturally cooling, leaves standstill crystallization, suction filtration, and a small amount of ether drip washing for filter cake, is dried to obtain white solid 2.17g, yield 83.5%.
Step P (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone (embodiment 4)
0.2g (0.5mmol) A-2 and 0.1g (0.6mmol) 2,3 dichloro benzaldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 5h.Suction filtration, a small amount of Virahol drip washing for filter cake, obtains white solid 0.2g, yield 71.6%.
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, taking different substituents intermediate A-2 as raw material and various aldehyde carry out condensation reaction and prepare the compound of embodiment 5-31.
Embodiment 5 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-dimethoxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-tri hydroxybenzaldehyde) semicarbazone
ESI-MS?m/z:536.3[M+H]
+
Embodiment 10 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-Dihydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-Trimethoxybenzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-methoxy-4-hydroxybenzaldehyde) semicarbazone
ESI-MS?m/z:535.3[M+H]
+
Embodiment 15 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dibromine-4-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-TMB) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-nitrobenzaldehyde) semicarbazone
ESI-MS?m/z:533.3[M+H]
+
Embodiment 22 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-bromobenzaldehyde) semicarbazone
ESI-MS?m/z:567.1[M+H]
+
Embodiment 23 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
ESI-MS?m/z:557.2[M+H]
+
Embodiment 25 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the chloro-4-fluorobenzaldehyde of 2-) semicarbazone
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)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone
ESI-MS?m/z:555.3[M+H]
+
Embodiment 27 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-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)-N
1-[4-[2-[4-[2-(dimethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone
ESI-MS?m/z:571.2[M+H]
+
Embodiment 29N
1-[the fluoro-4-[2-[4-of 3-(morpholinyl propyl group)-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base] phenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone
ESI-MS?m/z:613.2[M+H]
+
Embodiment 30N
1-[the fluoro-4-[2-[4-of 3-(morpholinyl propyl group)-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base] phenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:613.3[M+H]
+
Embodiment 31 (E)-N
1-[4-[2-[4-[2-(diethylamino) propyl group]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:599.2M+H]
+
Step Q2-[3-[4-(the fluoro-4-isothiocyanic acid of 2-phenoxy group) pyridine-2-yl]-4H-1,2,4-triazole-4-yl]-N, N-dimethyl amine (14)
Under room temperature, 5g (14.6mmol) intermediate 12 is dissolved in 60mL methylene dichloride, adds 10mL saturated sodium bicarbonate aqueous solution.0 DEG C splashes into 2g (17.5mmol) thiophosgene, drips and finishes, and stirring at room temperature 5h, separates organic phase, anhydrous sodium sulfate drying, and evaporate to dryness obtains yellow oily liquid 4.1g, yield 73.2%.
Step R N-(4-(2-(4-(2-(dimethylamino) ethyl)-4H-1,2,4-triazole-3-yl) pyridine-4-oxygen base)-3-fluorophenyl) thiosemicarbazide (A-3)
Under room temperature, 3.5g (9.1mmol) intermediate 14 is dissolved in 40mL methylene dichloride, adds 17mL80% hydrazine hydrate, stir 10h.Separate organic layer, washing (3 × 20mL), anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, is dried to obtain yellow solid 2.1g, yield 55.7%.
Step S (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) thiosemicarbazone (embodiment 32)
Under room temperature, 0.2g (0.48mmol) A-3 and 0.07g (0.58mmol) 2,3 dichloro benzaldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 6h.Suction filtration, a small amount of Virahol drip washing for filter cake, filtration cakes torrefaction obtains yellow solid 0.16g, yield 57.6%.
ESI-MS?m/z:572.2[M+H]
+
According to the method for embodiment 32, carry out condensation reaction and prepare the compound of embodiment 33 as raw material and 2,4 dichloro benzene formaldehyde taking intermediate A-3.
Embodiment 33 (E)-N
1-[4-[2-[4-[2-(dimethylamino) ethyl]-4H-1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) thiosemicarbazone;
ESI-MS?m/z:572.1[M+H]
+
The chloro-pyridine-2-carboxamide of step T4-(15)
20g (0.17mol) intermediate 2 is added in 500ml water, add 100ml ammoniacal liquor, stirring at room temperature 5h, suction filtration, filtration cakes torrefaction obtains white solid 15.7g, and yield is 85.8%.
Chloro-pyridine-the 2-of step U4-amine (16)
Under ice bath, 35.2g (0.22mol) bromine is splashed in NaOH solution (2.5N, 322ml), drip to finish and add 28.6g (0.18mol) intermediate 4, stirring at room temperature 1h, 80 DEG C of reaction 4h, putting into calm leaving standstill, suction filtration.Filter cake dissolves with 1NHCl, and insolubles suction filtration, with saturated NaOH tune PH to 13, is separated out solid, suction filtration, and filtration cakes torrefaction obtains white solid 11g, and yield is 47.6%.
Step V4-(the fluoro-4-nitro-phenoxy group of 2-)-pyridine-2-amine (17)
Under room temperature, 10g (0.078mol) intermediate 16 and 18.4g (0.12mol) 2-fluoro-4-nitrophenol are added in chlorobenzene to back flow reaction 23h, solvent evaporated, in system, add 500ml methylene dichloride, saturated potassium carbonate is washed (3 × 300ml), evaporated under reduced pressure solvent, etc. gray solid, add 200ml ether, stir 2h, suction filtration, after filtration cakes torrefaction, obtain gray solid 13.1g, yield 67.3%.
Step W4-(the fluoro-4-nitrophenoxy of 2-)-2-(1H-TETRAZOLE-1-yl) pyridine (18)
Under room temperature, 8g (0.032mol) intermediate 17 and 23.8g (0.16mol) triethyl orthoformate are added in 50ml Glacial acetic acid, back flow reaction 1h, adds 6.2g (0.096mol) sodiumazide, back flow reaction 3h.Reaction solution is poured in 200ml water, stirred 20min, suction filtration, filter cake ether drip washing, obtains off-white color solid 5.1g, yield 52.7% after being dried.。
Step X4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluoroaniline (19)
5g (0.017mol) intermediate 18 is added in the ethanol of 60ml90%, add 0.059g (0.005mol) gac, 0.68g (0.003mol) ferric sesquichloride, stirring at room temperature 0.5h, 60 DEG C drip 10.63g (0.17mol) hydrazine hydrate, drip to finish to be warming up to back flow reaction 3h.The hot suction filtration of reaction solution, a small amount of hot ethanol drip washing for filter cake, steaming desolventizes, and is cooled to room temperature, adds 100ml water in system, stirs 20min, suction filtration, filtration cakes torrefaction obtains white solid 3.54g, yield 76.6%.
Step Y phenyl [4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base] the fluoro-phenyl of-3-] phenyl carbamate (20)
3.5g (0.013mol) intermediate 19 is dissolved in 25ml acetone, adds 2.33g (0.017mol) salt of wormwood, be cooled to 0 DEG C, drip 2.44g (0.016mol) phenyl chloroformate, drip and finish, room temperature reaction 2h.Reaction solution adds 30ml water, and dichloromethane extraction (3 × 50ml) merges organic layer, and steaming desolventizes, and obtains white solid 3.86g, yield 75.7%.
Step Z N-(4-(2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base)-3-fluorophenyl) Urea,amino-(A-4)
3g (7.7mmol) intermediate 20 is dissolved in 20ml dioxane, adds 6ml hydrazine hydrate, is warming up to back flow reaction 2h.Reaction solution naturally cooling, leaves standstill crystallization, suction filtration, and a small amount of ether drip washing for filter cake, is dried to obtain white solid 2.16g, yield 85.7%.
Steps A
1(E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone (embodiment 34)
0.2g (0.60mmol) intermediate A-4 and 0.13g (0.72mmol) 2,3 dichloro benzaldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 6h.Suction filtration, a small amount of Virahol drip washing for filter cake, is dried to obtain 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, carry out condensation reaction and prepare the compound of embodiment 35-75 as raw material and different aldehyde taking intermediate A-4.
Embodiment 35 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,5-dimethoxy benzaldehyde) semicarbazone
ESI-MS?m/z:493.2[M-H]
-
Embodiment 39 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone
ESI-MS?m/z:479.1[M-H]
-
Embodiment 40 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-tri hydroxybenzaldehyde) semicarbazone
ESI-MS?m/z:482.2[M-H]
-
Embodiment 41 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-Dihydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-dimethoxy benzaldehyde) contracting is 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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-Trimethoxybenzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-methoxy-4-hydroxybenzaldehyde) contracting is 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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-hydroxyl-3,5-dimethoxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(bromo-4 hydroxy benzaldehydes of 3,5-bis-) semicarbazone
ESI-MS?m/z:604.8[M-H]
-
Embodiment 48 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3,4-TMB) semicarbazone
ESI-MS?m/z:509.1[M-H]
-
Embodiment 50 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-hydroxy benzaldehyde) semicarbazone
ESI-MS?m/z:449.2[M-H]
-
Embodiment 51 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-nitrobenzaldehyde) semicarbazone
ESI-MS?m/z:478.2[M-H]
-
Embodiment 53 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,6-dichlorobenzaldehyde) semicarbazone;
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-cyanobenzaldehyde) semicarbazone
ESI-MS?m/z:458.4[M-H]
-
Embodiment 55 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4-Dihydroxy benzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-nitrobenzaldehyde) semicarbazone
ESI-MS?m/z:478.3[M-H]
-
Embodiment 57 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-nitrobenzaldehyde) semicarbazone
ESI-MS?m/z:478.4[M-H]
-
Embodiment 58 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4,5-tri hydroxybenzaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(Benzaldehyde,2-hydroxy) semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2-fluorobenzaldehyde) semicarbazone
ESI-MS?m/z:451.2[M-H]
-
Embodiment 63 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-fluorobenzaldehyde) semicarbazone
ESI-MS?m/z:451.3[M-H]
-
Embodiment 64 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-bromobenzaldehyde) semicarbazone
ESI-MS?m/z:512.1[M-H]
-
Embodiment 65 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 difluorobenzene formaldehyde) contracting is amino;
ESI-MS?m/z:469.2[M-H]
-
Embodiment 66 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3,4-difluorobenzaldehyde) semicarbazone
ESI-MS?m/z:469.3[M-H]
-
Embodiment 67 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-trifluoro-methoxybenzaldehyde) semicarbazone
ESI-MS?m/z:517.2[M-H]
-
Embodiment 68 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-allyl group-Benzaldehyde,2-hydroxy) semicarbazone
ESI-MS?m/z:472.8[M-H]
-
Embodiment 69 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-benzaldehyde semicarbazone
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)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2 thiophene carboxaldehyde) semicarbazone
ESI-MS?m/z:493.2[M-H]
-
Embodiment 71 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-pyridylaldehyde) semicarbazone
ESI-MS?m/z:488.1[M-H]
-
Embodiment 72 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-difluoro-methoxy phenyl aldehyde) semicarbazone
ESI-MS?m/z:553.2[M-H]
-
Embodiment 73 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-difluoromethyl phenyl aldehyde) semicarbazone
ESI-MS?m/z:537.3[M-H]
-
Embodiment 74 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(3-propionyloxy phenyl aldehyde) semicarbazone
ESI-MS?m/z:559.3[M-H]
-
Embodiment 75 (E)-N
1-[4-[2-(1H-TETRAZOLE-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-methylsulfonyl phenyl aldehyde) semicarbazone
ESI-MS?m/z:565.3[M-H]
-
Step B
12-[4-(the fluoro-4-nitrophenoxy of 2-) pyridine-2-yl]-1,3,4-oxadiazoles (21)
Under room temperature, 2.92g intermediate 9 (0.01mmol) is dissolved in 30ml phosphorus oxychloride, adds 0.92g (002mol) formic acid, be warming up to back flow reaction 6h.Concentrating under reduced pressure falls most of solvent, and reaction solution is slowly poured in 200ml frozen water, and dichloromethane extraction (3 × 300ml) merges organic layer, and steaming desolventizes, and is dried to obtain white solid 1.58g, yield 52.3%.
Step C
14-[2-(1,3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluoroaniline (22)
5.1g (0.017mol) intermediate 21 is added in the ethanol of 50ml90%, under room temperature, add 0.5gPd/C (10%), pass into hydrogen, stirring reaction 4h.Suction filtration, steams except filtrate, in system, adds 100ml water, stirs 30min, suction filtration, and filtration cakes torrefaction obtains white solid 2.91g, yield 62.3%.
Step D
1phenyl 4-[2-(1,3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorine phenyl carbamate (23)
2.72g (0.01mol) intermediate 22 is dissolved in 30ml acetone, adds 2.07g (0.015mol) salt of wormwood, be cooled to 0 DEG C, drip 2.02g (0.013mol) phenyl chloroformate, drip and finish, room temperature reaction 1.5h.Reaction solution adds 35ml water, and dichloromethane extraction (3 × 70ml) merges organic layer, and steaming desolventizes, and obtains white solid 2.79g, yield 68.5%.
Step e
1n-[4-[2-(1,3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorophenyl] Urea,amino-(A-5)
1.96g (5mmol) intermediate 23 is dissolved in 15ml dioxane, adds 2ml hydrazine hydrate, is warming up to back flow reaction 3h.Reaction solution naturally cooling, leaves standstill crystallization, suction filtration, and a small amount of ether drip washing for filter cake, is dried to obtain white solid 0.87g, yield 52.7%.
Step F
1(E)-N
1-[4-[2-(1,3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone (embodiment 76)
0.2g (0.60mmol) A-5 and 0.13g (0.72mmol) 2,3 dichloro benzaldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 5h.Suction filtration, a small amount of Virahol drip washing for filter cake, is dried to obtain yellow solid 0.15g, yield 52.6%.
ESI-MS?m/z:487.2[M+H]
+
According to the method for embodiment 76, carry out condensation reaction and prepare the compound of embodiment 77-79 as raw material and the aldehyde of different replacements taking intermediate A-5.
Embodiment 77 (E)-N
1-[4-[2-(1,3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:487.3[M+H]
+
Embodiment 78 (E)-N
1-[4-[2-(5-methyl isophthalic acid, 3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone
ESI-MS?m/z:501.2[M+H]
+
Embodiment 79 (E)-N
1-[4-[2-(5-methyl isophthalic acid, 3,4-oxadiazoles-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:501.1[M+H]
+
Step G
14-(the fluoro-4-nitrophenoxy of 2-) pyridine-2-thioformamide (24)
Under room temperature, 5.54g intermediate 4 (0.02mol) is added in 30ml tetrahydrofuran (THF), add 4.44g thiophosphoric anhydride (0.02mol), back flow reaction 6h.Evaporated under reduced pressure solvent adds 100ml water in system, dichloromethane extraction (3 × 150ml), and steaming desolventizes, and is dried to obtain faint yellow solid 5.02g, yield 85.3%.
Step H
12-[4-(the fluoro-4-nitrophenoxy of 2-) pyridine-2-yl] thiazole (25)
Under room temperature, 2.93g intermediate 24 (0.01mol) is added in 20ml methyl alcohol, add 1.22g bromoacetaldehyde (0.01mol), back flow reaction 3h.Evaporated under reduced pressure solvent adds 50ml ether in system, stirs 30min, suction filtration, and filtration cakes torrefaction obtains yellow solid 1.94g, yield 61.2%.
Step I
1the fluoro-4-[2-of 3-(thiazole-2-yl) pyridine-4-oxygen base] aniline (26)
3.17g (0.01mol) intermediate 25 is added in 30ml dehydrated alcohol, under room temperature, add 0.3gPd/C (10%), pass into hydrogen, stirring reaction 5h.Steam except most of solvent, leave standstill 30min, suction filtration, filtration cakes torrefaction obtains white solid 1.63g, yield 56.7%.
Step J
1phenyl 4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorine phenyl carbamate (27)
Under ice bath, 2.82g (0.01mol) intermediate 26 is dissolved in 25ml acetone, adds 2.07g (0.015mol) salt of wormwood, drip 2.02g (0.013mol) phenyl chloroformate, drip and finish, room temperature reaction 3h.Suction filtration, washing filter cake, is dried to obtain white solid 2.52g, yield 61.9%.
Step K
1n-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl] Urea,amino-(A-6)
2.04g (5mmol) intermediate 27 is dissolved in 10ml dioxane, adds 2ml hydrazine hydrate, is warming up to 90 DEG C of reaction 3h.Reaction solution naturally cooling, leaves standstill crystallization, suction filtration, and a small amount of ether drip washing for filter cake, is dried to obtain white solid 1.23g, yield 71.3%.
Step L
1(E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,3 dichloro benzaldehyde) semicarbazone (embodiment 80)
0.17g (0.50mmol) A-6 and 0.11g (0.6mmol) 2,3 dichloro benzaldehyde are added in 2mL Virahol, add 1 glacial acetic acid, backflow 3h.Suction filtration, a small amount of Virahol drip washing for filter cake, is dried to obtain yellow solid 0.11g, yield 43.1%.
ESI-MS?m/z:502.1[M+H]
+
According to the method for embodiment 80, carry out condensation reaction and prepare the compound of embodiment 81-84 as raw material and the aldehyde of different replacements taking intermediate A-6.
Embodiment 81 (E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(2,4 dichloro benzene formaldehyde) semicarbazone
ESI-MS?m/z:502.0[M+H]
+
Embodiment 82 (E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-fluorobenzaldehyde) semicarbazone
ESI-MS?m/z:452.2[M+H]
+
Embodiment 83 (E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone
ESI-MS?m/z:468.1[M+H]
+
Embodiment 84 (E)-N
1-[4-[2-(thiazol-2-yl) pyridine-4-oxygen base] phenyl]-N
4-(4-chlorobenzaldehyde) semicarbazone;
ESI-MS?m/z:450.2[M+H]
+
The antitumor activity of product of the present invention
Extracorporeal anti-tumor cytoactive
To carried out the screening active ingredients of vitro inhibition lung carcinoma cell H460, colon cancer cell HT-29, gastric carcinoma cells MKN-45 and Liver cancer cell SMMC-7721 and human breast cancer cell MDA-MB-231 according to the quinoline derivatives of above formula I of the present invention.
(1) cell recovery and go down to posterity 2-3 time stable after, it is digested bottom culturing bottle with trypsin solution (0.25%).After cell dissociation buffer is poured in centrifuge tube, add afterwards nutrient solution to stop digestion.By centrifuge tube centrifugal 10min under 800r/min, after abandoning supernatant, add 5mL nutrient solution, piping and druming mixes cell, and absorption 10 μ L cell suspensions add in cell counting count board to be counted, and adjusting cell concn is 10
4individual/hole.In 96 orifice plates, except A1 hole is that blank well does not add extracellular, all the other all add 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, then add appropriate nutrient solution, make sample dissolution become 2mg/mL liquid, be then 20,4,0.8,0.16,0.032 μ g/mL by diluted sample in 24 orifice plates.
Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment larger, only and be blank cell hole use.96 orifice plates are put into incubator and cultivate 72h.
(3) will in 96 orifice plates, be with medicine nutrient solution to discard, with phosphate buffer solution (PBS) by cell rinse twice, in every hole, add MTT (0.5mg/mL) 100 μ L to put into after incubator 4h, discard MTT solution, add dimethyl sulfoxide (DMSO) 100 μ L.On magnetic force vibrator, vibration is fully dissolved survivaling cell and MTT reaction product formazan, puts into microplate reader measurement result.Can obtain medicine IC by Bliss method
50value.
Inhibition lung carcinoma cell H460, colon cancer cell HT-29, gastric carcinoma cells MKN-45 and Liver cancer cell SMMC-7721 and the human breast cancer cell MDA-MB-231 activity of compound the results are shown in Table 1.
Table 1
C-Raf and the test of VEGFR-2 kinase activity
The test that is used for measuring C-Raf and VEGFR-2 kinase activity is based on enzyme linked immunosorbent assay (ELISA).Concrete operations are:
Under room temperature, on the coated plate of 0.25mg/mL PGT, by embodiment compound, 50pM C-Raf/VEGFR-2 and 5 μ M ATP (25mM MOPS, pH7.4,5mM MgCl in test damping fluid
2, 0.5raM MnCl
2, 100 μ M sodium orthovanadates, 0.01%Triton X-100,1mM DTT, last DMSO concentration 1% (v/v)) and incubation 20min.Remove by flushing reaction mixture is also puted together horseradish peroxidase (HRP) Tyrosine O-phosphate monoclonal antibody specific (PY20) detection phosphorylation polymeric substrates with 0.2 μ g/mL.Add after 1M phosphoric acid color development stopping the color of the substrate (TMB) developing the color by spectrophotometric standard measure in 450nm place.Embodiment compound to C-Raf and the kinase whose inhibition data of VEGFR-2 in table 2 and table 3.
Table 2
Table 3
Can clearly be seen that from above-mentioned test-results, the compound of the claimed formula I of the present invention, has good anti tumor activity in vitro, quite or the antitumor drug cis-platinum that is better than having gone on the market.
The compound of formula of I of the present invention can be used separately, but normally give with pharmaceutical carrier mixture, the selection of described pharmaceutical carrier will be according to required route of administration and standard drug practice, use respectively the various pharmaceutical dosage forms of this compounds below, the for example preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, illustrates its new application in pharmacy field.
Embodiment 85: tablet
With the compound that contains compound in claim 1 (taking embodiment 12 compounds as example) 10g, after adding auxiliary material 20g and mix according to the general pressed disc method of pharmaceutics, be pressed into 100, every heavy 300mg.
Embodiment 86: capsule
With the compound that contains compound in claim 1 (taking embodiment 36 compounds as example) 10g, after auxiliary material 20g being mixed according to the requirement of pharmaceutics capsule, pack Capsules into, the heavy 300mg of each capsule.
Embodiment 87: injection
With the compound that contains compound in claim 1 (taking embodiment 1 compound as example) 10g, according to pharmaceutics ordinary method, carry out charcoal absorption, after 0.65 μ m filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, every dress 2mL, filling 100 bottles altogether.
Embodiment 88: aerosol
With the compound that contains compound in claim 1 (taking embodiment 22 compounds as example) 10g, after dissolving with appropriate propylene glycol, add after distilled water and other spoke material, make the settled solution of 500mL and get final product.
Embodiment 89: suppository
With the compound that contains compound in claim 1 (taking embodiment 19 compounds as example) 10g, add glycerine appropriate it porphyrize, after grinding well, add the glycogelatin having melted, to grind evenly, impouring has been coated with in the model of lubricant, makes 50 of suppositorys
Embodiment 90: film
With the compound that contains compound in claim 1 (taking embodiment 13 compounds as example) 10g, polyvinyl alcohol, medicinal glycerin, water etc. are stirred to expansion post-heating to be dissolved, 80 eye mesh screens filter, again embodiment 18 compounds are joined to stirring and dissolving in filtrate, 100 of film applicator maskings.
Embodiment 91: pill
With the compound that contains compound in claim 1 (taking embodiment 17 compounds as example) 10g, after mixing with matrix 50g heat fused such as gelatin, splash in cryogenic liquid paraffin, make altogether dripping pill 1000 balls.
Embodiment 92: externally-applied liniment
With the compound that contains compound in claim 1 (taking embodiment 31 compounds as example) 10g, according to auxiliary material 2.5g mixed grindings such as conventional dose method and emulsifying agents, then adding distil water makes to 200mL.
Embodiment 93: ointment
With the compound that contains compound in claim 1 (taking embodiment 47 compounds as example) 10g, after porphyrize, grind well and make with oleaginous base 500g such as Vaseline.
Although described the present invention by particular, amendment and equivalent variations are obvious for being proficient in the technician in this field, and within they are included in the scope of the invention.
Claims (12)
1. general formula
icompound and pharmacy acceptable salt, hydrate or prodrug,
Wherein,
Y is H, halogen;
K is O, S;
Ar is (C
6-C
10) aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains 1-3 heteroatoms that is selected from N, O or S, and the optional 1-3 of Ar identical or different R
1replace;
Each Q is respectively independently selected from C, C-Z, N-Z, N, O and S, and condition is N atom 0-4, and O and S atom 0-1, and N, O are 0 when different with S atom number;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, C
1-C
6alkylamidoalkyl, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, by 1-2 (C
1-C
6) alkyl replace formamyl, (C
1-C
3) alkylenedioxy group, allyl group;
Z is independently selected from H, (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl,
,
;
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl;
Or R
2and R
3form 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms being connected with them, described heterocyclic radical and heteroaryl except with R
2and R
3outside the nitrogen-atoms connecting, optionally contain 1-4 heteroatoms that is selected from N, O and S, except R
2and R
3outside the nitrogen-atoms connecting, described heterocyclic radical optionally comprises 1-2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl are optionally by 1-3 identical or different R
4replace;
R
4for (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl;
N is the integer between 0-6.
2. the general formula of claim 1
icompound and pharmacy acceptable salt, hydrate or prodrug, wherein,
Y is halogen;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6. alkyl acyl, formamyl, (C
1-C
3) alkylenedioxy group, allyl group.
3. the general formula of claim 2
icompound and pharmacy acceptable salt, hydrate or prodrug, wherein,
Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolyl, indyl, pyridyl, furyl, thienyl, pyrryl, pyrimidyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for H, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group, by 1-2 (C
1-C
6) alkyl replace amino, (C
1-C
6) alkyl sulphonyl, allyl group.
4. the general formula of claim 3
icompound and pharmacy acceptable salt, hydrate or prodrug,
Wherein,
Y is F, and the position of substitution is at the ortho position of O;
K is O.
5. the compound of the general formula I of claim 4 and pharmacy acceptable salt thereof, hydrate or prodrug, wherein,
Each Z is independently selected from H, (C
1-C
6) alkyl,
;
R
2, R
3identical or different, respectively independently selected from H, (C
1-C
3) alkyl;
Or R
2and R
3form piperidino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 4-methyl isophthalic acid-piperidyl, 1-pyrrolidyl together with the nitrogen-atoms connecting with them;
N is 1,2 or 3.
6. the compound of the general formula I of claim 5 and pharmacy acceptable salt thereof, hydrate or prodrug, wherein,
Each Z is independently selected from H, (C
1-C
3) alkyl,
;
Ar is phenyl, and the optional 1-3 of Ar identical or different R
1replace;
R
1for halogen, hydroxyl, nitro, cyano group, trifluoromethyl, trifluoromethoxy, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, allyl group, dimethylamino, methylsulfonyl.
7. the compound of the general formula I of claim 6 and pharmacy acceptable salt thereof, hydrate or prodrug, wherein,
。
8. the general formula of claim 1
icompound and pharmacy acceptable salt, hydrate or prodrug:
(E)-
n 1 -[4-[2-(4
h -1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -benzaldehyde semicarbazone;
(E)-
n 1 -[4-[2-(4
h -1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-chlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(4
h -1,2,4-triazole-3-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4-dimethoxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4,5-Trimethoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-methoxy-4-hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-dibromine-4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3,4-TMB) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-nitrobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-bromobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-chlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the chloro-4-fluorobenzaldehyde of 2-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -benzaldehyde semicarbazone;
(E)-
n 1 -[4-[2-[4-[3-(dimethylamino) propyl group]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-(morpholinyl propyl group)-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-(morpholinyl propyl group)-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[3-(diethylamino) propyl group]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) thiosemicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) thiosemicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,5-dimethoxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4-dimethoxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4,5-Trimethoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-methoxy-4-hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-hydroxyl-3,5-dimethoxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(bromo-4 hydroxy benzaldehydes of 3,5-bis-) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3,4-TMB) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-nitrobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-cyanobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4-Dihydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-nitrobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-nitrobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4,5-tri hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-fluorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-fluorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-bromobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 difluorobenzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,4-difluorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-trifluoro-methoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-allyl group-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -benzaldehyde semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(thiophene-2-formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(pyridine-3-formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-difluoro-methoxy phenyl aldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-difluoromethyl phenyl aldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-methyl propionate benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-methylsulfonyl phenyl aldehyde) semicarbazone;
(E)-
n 1 -[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-fluorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-chlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base] phenyl]-
n 4 -(4-chlorobenzaldehyde) semicarbazone.
9. the general formula of claim 1
icompound and pharmacy acceptable salt, hydrate or prodrug:
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3,4-tri hydroxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -[benzo [d] [1,3] two is disliked luxuriant phenyl aldehyde] semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-di-t-butyl-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-nitrobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-bromobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(4-chlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the chloro-4-fluorobenzaldehyde of 2-) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -benzaldehyde semicarbazone;
(E)-
n 1 -[4-[2-[4-[3-(dimethylamino) propyl group]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[3-(diethylamino) propyl group]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) thiosemicarbazone;
(E)-
n 1 -[4-[2-[4-[2-(dimethylamino) ethyl]-4
h -1,2,4-triazole-3-yl] pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) thiosemicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the fluoro-4-hydroxy benzaldehyde of 3-) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-hydroxyl-4-methoxybenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3,5-dimethyl-4-hydroxy benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(the bromo-4-hydroxy benzaldehyde of 3-) semicarbazone
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,6-dichlorobenzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2-hydroxyl-1-naphthalene Formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(1
h -tetrazolium-1-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(3-allyl group-Benzaldehyde,2-hydroxy) semicarbazone;
(E)-
n 1 -[4-2-(1,3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,3 dichloro benzaldehyde) semicarbazone;
(E)-
n 1 -[4-2-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) pyridine-4-oxygen base]-3-fluorophenyl]-
n 4 -(2,4 dichloro benzene formaldehyde) semicarbazone;
(E)-
n 1 -[4-[2-(thiazol-2-yl) pyridine-4-oxygen base] phenyl]-
n 4 -(4-chlorobenzaldehyde) semicarbazone.
10. a medicinal compositions, comprise in claim 1-9 any one compound and pharmacy acceptable salt, hydrate or prodrug as activeconstituents and pharmaceutically acceptable vehicle.
The compound of any one and pharmacy acceptable salt, hydrate or prodrug or composition claimed in claim 9 purposes in the medicine for the preparation of prevention or the treatment disease relevant with VEGFR-2 kinase inhibitor with C-Raf in 11. claim 1-9.
In 12. claim 1-9, the compound of any one and pharmacy acceptable salt, hydrate or prodrug or composition claimed in claim 9 treat and/or prevent the application in the medicine of lung cancer, liver cancer, cancer of the stomach, colorectal cancer, mammary cancer, pernicious glioblastoma multiforme, bladder cancer, prostate cancer, ovarian cancer and the esophageal carcinoma etc. in preparation.
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| CN107056810A (en) * | 2017-02-09 | 2017-08-18 | 广东省中医院 | A kind of preparation method of Carbostyril carboxylic acid derivatives |
| CN108329258A (en) * | 2018-04-09 | 2018-07-27 | 辽宁大学 | The 4- phenoxypyridines analog derivatives of the structure containing semicarbazones and its application |
| CN112225731A (en) * | 2019-06-27 | 2021-01-15 | 中山大学 | FAP alpha specific recognition methylene blue derivative with tumor diagnosis and treatment functions and preparation method and application thereof |
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| WO2007002584A1 (en) * | 2005-06-27 | 2007-01-04 | Bristol-Myers Squibb Company | Linear urea mimics antagonists of p2y1 receptor useful in the treatment of thrombotic conditions |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107056810A (en) * | 2017-02-09 | 2017-08-18 | 广东省中医院 | A kind of preparation method of Carbostyril carboxylic acid derivatives |
| CN107056810B (en) * | 2017-02-09 | 2019-04-26 | 广东省中医院 | A kind of preparation method of Carbostyril carboxylic acid derivatives |
| CN108329258A (en) * | 2018-04-09 | 2018-07-27 | 辽宁大学 | The 4- phenoxypyridines analog derivatives of the structure containing semicarbazones and its application |
| CN108329258B (en) * | 2018-04-09 | 2021-04-13 | 辽宁大学 | Semicarbazone structure-containing 4-phenoxypyridine derivative and application thereof |
| CN112225731A (en) * | 2019-06-27 | 2021-01-15 | 中山大学 | FAP alpha specific recognition methylene blue derivative with tumor diagnosis and treatment functions and preparation method and application thereof |
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