CN108530444A - A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage - Google Patents

A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage Download PDF

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CN108530444A
CN108530444A CN201810594278.4A CN201810594278A CN108530444A CN 108530444 A CN108530444 A CN 108530444A CN 201810594278 A CN201810594278 A CN 201810594278A CN 108530444 A CN108530444 A CN 108530444A
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alkyl
base
alkenyl
aryl
heteroaryl
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CN108530444B (en
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蒋晟
郝海平
郭长缨
吴筱星
姚和权
张阔军
邱亚涛
郑啸
陈东
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Yaokang Zhongtuo (Jiangsu) Pharmaceutical Technology Co.,Ltd.
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention discloses a kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usages, and in particular to a kind of furazan class compound or its pharmaceutically acceptable salt, solvate, prodrug, ester, racemic modification and isomers and pharmaceutical composition containing this kind of compound and these compounds or pharmaceutical composition application in preparation of anti-tumor drugs.The active fragment of IDO inhibitor and NAMPT inhibitor progress rational joint obtained the bis- target spot inhibitor of furazan class IDO/NAMPT by the present invention, one side double inhibition NAD+Biosynthesis, to show stronger tumors inhibition activity；The active inhibition of another aspect IDO can be effectively facilitated the proliferation of T cell, to enhance attacking ability of the body to tumour cell.This kind of bis- target spot inhibitor of furazan class IDO/NAMPT or its pharmaceutical composition have broad application prospects, and are expected to become antitumor drug.

Description

A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage
Technical field
The invention belongs to biotech drug fields, and in particular to furazan class compound shown in Formulas I or its is pharmaceutically acceptable Salt, solvate, prodrug, ester, racemic modification and isomers and pharmaceutical composition containing this kind of compound and these changes Close object or pharmaceutical composition application in preparation of anti-tumor drugs.
Background technology
Cancer is to perplex the major disease of human health, and research and development new type antineoplastic medicine is the great class of biomedicine field Topic and long-range mission.It is the one of the important signs that of cancer that numerous studies, which show cell metabolism extremely,.Two nucleoside of nicotinamide adenine Acid (nicotinamide adenine dinucleotide, abbreviation NAD+) it is substance indispensable in electron transfer process, It plays a significant role during energetic supersession and signal transduction.In addition, NAD+With its reduced-NAD H for remaining intracellular Reducing environment be of great significance to protect cells from the damage of oxidative stress.Therefore, intracellular NAD+Level be Determine the key factor of cell fate.Relative to normal cell, tumour cell have uncontrollable multiplication rate, quickly Metabolic rate and the oxidative stress dramatically increased, thus tumour cell is for NAD+Horizontal change is more sensitive.NAD+ The key enzyme of vivo biodistribution route of synthesis has become the important target spot of anticancer drug.NAD+Internal route of synthesis includes from the beginning closing At approach and salvage route.
Indoles amine -2,3- dioxygenase (Indoleamine-2,3-dioxygenase, abbreviation IDO) is a kind of containing ferrous blood The monomeric enzyme of red pigment, the wide expression in the Various Tissues of mammal, the high expression in kinds of tumor cells.IDO is internal First enzyme on tryptophan metabolic pathway and be rate-limiting enzyme, catalysis tryptophan is converted to N- formyl dogs by oxidation reaction Urinary ammonia acid, the latter, which hydrolyzes, generates kynurenine, and then enters kynurenine metabolic pathway and generate the metabolism such as quinolinic acid, kynurenic acid production Object.Wherein, quinolinic acid is NAD+The starting material of de novo synthesis.On the other hand, IDO expression is excessive, can result in part Tryptophan depletion, the metabolins such as kynurenine increase, it is suppressed that the proliferation of T cell, activating regulatory T cell in turn result in immune Tolerance, makes body that can not tumour cell is identified and be removed.Therefore, inhibit the activity of IDO that can effectively prevent tumour On the one hand the degradation of cell peripheral tryptophan inhibits NAD in tumour cell+De novo synthesis, on the other hand promote T cell Proliferation, to enhance attacking ability of the body to tumour cell.In addition, IDO inhibitor can also be shared with chemotherapeutics, drop The drug resistance of low tumour cell, to enhance the antitumor activity of conventional cytotoxic therapy.Taking IDO inhibitor simultaneously can also carry The effect of therapeutic vaccine of high cancer patient.Therefore, the research of IDO inhibitor has become the hot spot neck of tumour immunotherapy Domain.But there is presently no IDO inhibitors to list as drug, finding new and effective IDO inhibitor has important theory Meaning and application value.
NAD+Salvage route is using niacin, niacinamide or niacinamide ribose as starting material.Due to many NAD+Consumption Enzyme, such as poly- adenosine diphosphate-ribose polymerase (poly-ADP-ribose polymerase, abbreviation PARP) and deacetylation Enzyme (Sirtuins, abbreviation SIRT), can soon release niacinamide again, thus using niacinamide as the NAD of raw material+It remedies Route of synthesis is most economical, most important NAD+Biosynthesis pathway (Galli U.et al.J.Med.Chem.2013,22,56 (16):6279-96).And Nampt (nicotinamide phosphoribosyltransferase, Abbreviation NAMPT) it is to control niacinamide to NAD+The rate-limiting enzyme of conversion.It is vigorous in view of tumour cell abnormal energy metabolism, more need Want NAD+It quickly supplements in time, tumour cell becomes more dependent on NAMPT and then inhibits more sensitive to NAMPT.Therefore, NAMPT is considered as effective anticancer target spot, and NAMPT inhibitor has become the hot spot studied extensively.Currently, there are two NAMPT inhibitor Cs HS-828 and FK866 enter clinical experimental stage (Montecucco F.et al.Curr.Drug Targets.2013,1,14(6):637-43).But the clinical test results of the two compounds are unsatisfactory, patient's administration Significant therapeutic effect is not shown afterwards.Also, the pharmacokinetic property of the two compounds is bad, also shows bleeding Platelet reduces the dose-dependent toxicities such as disease and gastrointestinal tract toxic side effect.Therefore, the good NAMPT suppressions of structure novel, druggability Preparation needs further research and development.
A kind of IDO inhibitor, Chinese patent application are disclosed in Chinese patent application 201480028214.8 A kind of NAMPT inhibitor is disclosed in 201380036899.6, the two druggability is poor, therapeutic effect is single, and curative effect is weak, malicious secondary makees With big, and the active fragment of IDO inhibitor and NAMPT inhibitor progress rational joint has been obtained furazan class IDO/ by the present invention NAMPT bis- target spot inhibitor, one side double inhibition NAD+Biosynthesis, live to show stronger tumor suppression Property；The active inhibition of another aspect IDO can be effectively facilitated the proliferation of T cell, be attacked to tumour cell to enhance body Hit ability.This kind of bis- target spot inhibitor of furazan class IDO/NAMPT or its pharmaceutical composition have broad application prospects, and are expected into For antitumor drug.
Invention content
The present invention is directed to deficiency in the prior art, provides a kind of furazan class indoleamine 2,3-dioxygenase/niacinamide phosphoric acid core The double target spot inhibitor of sugared transferase, to solve the problems such as existing anticancer drug curative effect is weak, toxic side effect is larger.
In compound of the present invention, as any variable (such as R1, R2Deng) occur more than in any component primary, then it is every The definition of secondary appearance is independently of other definition occurred every time.Equally, the combination for allowing substituent group and variable, as long as this combination Compound is set to stablize.The line that loop system is included in from substituent group indicates that signified key may be connected on any annular atom that can replace. If loop system is polycyclic, it means that this key is connected only on any carbon atom appropriate of adjacent loops.It is appreciated that ability The those of ordinary skill in domain may be selected the compounds of this invention substituent group and substitution pattern and provide chemically stable and can lead to The method of art technology and following proposition is crossed from readily available raw material, is readily synthesized target compound.If substitution Base itself is exceeded a group substitution, it should be understood that as long as making stable structure, these groups can be in identical carbon atoms or different On carbon atom.
Described in the terms such as relational language " alkyl " " aryl " " heteroaryl " " halogen " used in this application and fields The general sense of term is without significantly different.
For example, term " alkyl " refers to 1-6 (C1-C6) carbon atom number linear chain or branched chain saturated hydrocarbyl.Representativeness saturation Alkyl includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, n-pentyl, tertiary butyl, neopentyl, just Hexyl, 2- methyl-1s-propyl, 2- methyl-2-propyls, 2-methyl-1-butene base, 3- methyl-1s-butyl, 2- methyl -3- butyl, 2- Methyl-1-pentene base, 3- methyl-1-pentenes base, 4- methyl-1-pentenes base, 2- methyl -2- amyls, 4- methyl -2- amyls.It should illustrate , when its carbon atom number is not particularly limited, only refer to the carbon atom number of the moieties wherein indicated, and do not include alkane Carbon atom number on the substituent group of base.
Term " heteroaryl " used in this application represent the stabilization for having 5-6 atom in ring monocycle or each ring in contain 5-6 The bicyclic carbocyclic of a atom, wherein at least one ring are aromatic rings and at least contain there are one and be independently selected from the miscellaneous original of O, N and S Son.Heteroaryl as defined in the range of this includes but not limited to：Imidazole radicals, thiazolyl, pyrazolyl, furyl, thienyl, oxazoles Base, furazanyl, isoxazolyls, triazolyl, tetrazole radical, pyrazinyl, pyridazinyl, pyriconyl, pyrimidine radicals, pyrrole radicals, benzo thiophene Oxazolyl, quinolyl, isoquinolyl, indyl, dihydro phthalazinyl, benzothienyl, indazolyl, benzofuraxan base, benzo Oxazolyl, phthalazinyl, Pyrazolopyridine base, pyrrolopyridinyl, tetrazolo pyridyl group, imidazolidine and pyridyl group, four Hydrogen Pyrazolopyridine base, thiazolopyridinyl, thiazolopyridinyl." heteroaryl " also is understood as including any containing nitrogen The N- oxide derivatives of heteroaryl.
Those skilled in the art should appreciate that following term or the meaning of abbreviation.
Term " pharmaceutically acceptable salt " refers to being suitable for and mammal especially people in scope of sound medical judgment Tissue contact and without excessive toxicity, stimulation, allergic reaction etc. and with rational benefit/risk than the salt that matches, such as amine, carboxylic acid It is known in the art with the medically acceptable salt of other type compounds.
Term " isomers " refers to two or more compounds that molecular composition is identical but structure is different with property.
Term " racemic modification " refers to a kind of equimolar mixture of tool active chiral molecules and its enantiomer, it is by revolving Light direction is opposite, the identical molecule mixed in equal amounts of optical activity forms, and optical activity is mutually supported because of these intermolecular effects Disappear, thus is optically inactive.
Term " solvate " refers to the mixture of compound and solvent composition, such as crystalline solid is a kind of solvate.
Term " prodrug " refers to by hydrolyzing in blood in vivo rapid conversion and generates the parent chemical combination with above-mentioned chemical formula The compound of object.
As will be appreciated by a person skilled in the art, " halogen " use herein includes chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl group, aryl, heteroaryl and heterocycle are unsubstituted or take Generation.For example, C1-C6Alkyl can be by the substitution such as morpholinyl, piperidyl of hydroxyl, halogen, alkoxy, alkylamino or heterocycle Base replaces.
The compounds of this invention can forming salt." salt " in the application refers to the acid salt formed with inorganic acid or organic acid, and The basic salt formed with inorganic base or organic base.In addition, when the compound have alkaline part (such as pyridine, imidazoles etc.) and When acidic moiety (such as carboxylic acid), amphoteric ion (" inner salt ") can be formed, and be also included in term used in this application " salt ".It can By conventional chemical processes can pharmaceutically connecing for the present invention is synthesized from containing the compounds of this invention of alkaline part or acidic moiety The salt received.In general, by ion-exchange chromatography or by free alkali and stoichiometric amount or it is excessive needed for salt form it is inorganic Or organic acid reaction in the combination of appropriate solvent or multi-solvents prepares the salt of alkali compounds.It is similar, by with it is appropriate Inorganic or organic base react the salt to form compound.It is preferred that medicinal, nontoxic, physiologically acceptable salt, but other salt Also it is available.
Exemplary nontoxic acid salt includes from inorganic acid, such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid etc. Salt, also include from organic acid, such as acetic acid, propionic acid, succinic acid, glycolic, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, Citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, phosphoglycerol, salicylic acid, P-aminobenzene sulfonic acid, fumaric acid, 2- acetoxy-benzoics, fumaric acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, grass The salt of the preparations such as acid, isethionic acid and trifluoroacetic acid.
Exemplary non-toxic base salts include the salt from inorganic base, such as aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium Salt, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc., also include the salt from organic base, the alkali include primary amine, secondary amine and The salt of tertiary amine, substituted amine include naturally occurring substitution amine, cyclic amine and deacidite, such as arginine, sweet tea Dish, caffeine, choline, N, N '-dibenzyl-ethylenediamins, diethylamine, 2- DEAE diethylaminoethanols, 2-dimethylaminoethanol, ammonia Base ethyl alcohol, ethanol amine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, gucosamine, Glucosamine, methyl glucose osamine, Histidine, lysine, isopropylamine, morpholine, piperidines, polyamines resin, procaine, purine, theobromine, triethylamine, trimethylamine, Tripropyl amine (TPA) and tromethamine etc..
Term " free form " is for " salt " form, it is intended that with Formulas I compound represented existing for salt-independent shape. Free form is in certain physical properties, and respectively salt form is more or less distinguished with its in the solubility such as in polar solvent, but It is that respectively free form is suitable with its in terms of other pharmacy for this hydrochlorate of purpose and alkali salt of invention.
To achieve the goals above, the present invention provides following technical solutions：
A kind of novel NAMPT and IDO double inhibitors, it is characterised in that：Its with furazan class compound shown in general formula I and its Pharmaceutically acceptable salt, solvate, prodrug, ester, racemic modification and isomers.General formula I is：
R in above-mentioned general formula I1For can be independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, sulfydryl, O- carboxyls, C- carboxyls, Sulfonic group, phosphate, phosphorous acidic group, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6It is naphthenic base, aryl, heteroaryl, miscellaneous Naphthenic base, C3-C6Naphthenic base-(C1-C6Alkyl), aryl (C1-C6Alkyl), heteroaryl (C1-C6Alkyl), Heterocyclylalkyl (C1-C6 Alkyl), C3-C6Naphthenic base-(C2-C6Alkenyl), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), Heterocyclylalkyl (C2-C6Alkene Base), C3-C6Naphthenic base-(C2-C6Alkynyl), aryl (C2-C6Alkynyl), heteroaryl (C2-C6Alkynyl), Heterocyclylalkyl (C2-C6Alkynes Base), (C3-C6Naphthenic base)-O- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkoxy), aryl-O- (CH2) q-, aryl-(C1- C6Alkoxy), heteroaryl-O- (CH2) q-, heteroarylalkoxy, Heterocyclylalkyl-O- (CH2) q-, Heterocyclylalkyl-(C1-C6Alcoxyl Base), (C3-C6Naphthenic base)-S- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkane sulfydryl), aryl-S- (CH2) q-, aryl-(C1- C6Alkane sulfydryl), heteroaryl-S- (CH2) q-, heteroaryl alkane sulfydryl, Heterocyclylalkyl-S- (CH2) q-, Heterocyclylalkyl-(C1-C6Alkane mercapto Base), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), (C3-C6Naphthenic base)-(C2-C6Alkenyl), Heterocyclylalkyl (C2-C6Alkene Base), C1-C6Alkoxy-(CH2)q-、C2-C6Alkenyl oxygroup (CH2)q-、C1-C6Alkane sulfydryl-(CH2)q-、C2-C6Alkenyl sulfydryl, halogen Generation (C1-C6Alkyl), halogenated (C2-C6Alkenyl), amino (C1-C6Alkyl), amino (C2-C6Alkenyl), hydroxyl (C1-C6Alkyl), hydroxyl Base (C2-C6Alkenyl), sulfydryl (C1-C6Alkyl), sulfydryl (C2-C6Alkenyl), cyano (C1-C6Alkyl), cyano (C2-C6Alkenyl), nitre Base (C1-C6Alkyl), nitro (C2-C6Alkenyl), O- carboxyls (C1-C6Alkyl), O- carboxyls (C2-C6Alkenyl), C- carboxyls (C1-C6Alkane Base), C- carboxyls (C2-C6Alkenyl), sulfonic group (C1-C6Alkyl), sulfonic group (C2-C6Alkenyl), phosphate (C1-C6Alkyl), phosphorous Acidic group (C1-C6Alkyl), phosphate (C2-C6Alkenyl), phosphorous acidic group (C2-C6Alkenyl), (C1-C6Alkylamino)-(C1-C6Alcoxyl Base), (C1-C6Alkylamino) oxygroup-(CH2)q、(C1-C6Alkane sulfydryl)-(C1-C6Alkoxy), (C1-C6Alkane sulfydryl) oxygroup- (CH2)q, halogenated (C1-C6Alkoxy)-(CH2)q, (halogenated C1-C6Alkyl)-O- (CH2)q, hydroxyl (C1-C6Alkoxy)- (CH2)q, (hydroxyl C1-C6Alkyl) oxygroup-(CH2)q, cyano (C1-C6Alkoxy)-(CH2)q, (cyano C1-C6Alkyl)-O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C=O) NRaRb、-(CH2)q-NRc(C=O) Rd、-(CH2)q-NRc(C=O) ORd、- (CH2)q(C=O)-(C1-C6Alkyl) ,-(CH2)q(C=O) aryl ,-(CH2)q(C=O) heteroaryl ,-(CH2)q(C= O)-(C3-C6Naphthenic base) ,-(CH2)q(C=O) O- (C1-C6Alkyl) ,-(CH2)q(C=O) O aryl ,-(CH2)q(C=O) S-(C1-C6Alkyl) ,-(CH2)q(C=O) S aryl ,-(CH2)q- O (C=O)-(C1-C6Alkyl) ,-(CH2)q- O (C=O) virtues Base ,-(CH2)q(S=O)2NRaRb、-(CH2)q-NRc(S=O) Rd、-(CH2)q(S=O)2(C1-C6Alkyl) ,-(CH2)q-(S =O)2Aryl ,-(CH2)q(S=O)2Heterocyclylalkyl ,-(CH2)q(S=O)2Heteroaryl ,-(CH2)q(S=O)2Alkyl halide Base ,-(CH2)q(S=O)-(C1-C6Alkyl) ,-(CH2)q(S=O) aryl ,-(CH2)q(S=O)-Heterocyclylalkyl ,- (CH2)q(S=O) heteroaryl ,-(CH2)q(S=O) halogenated alkyl and-(CH2)q(P=O) RcRdIn 1,2,3,4 It is a or 5；
Wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkane Base), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C1-C6Alkyl-NH- (C1-C6Alkyl)-, (C1-C6Alkyl)2-N-(C1-C6Alkane Base)-, C3-C6Naphthenic base, aryl, aryl-NH-, heteroaryl, Heterocyclylalkyl, C3-C6Naphthenic base-(C1-C6Alkyl), aryl (C1- C6Alkyl), heteroaryl (C1-C6Alkyl) and Heterocyclylalkyl (C1-C6Alkyl) or RaAnd RbWith shape together with the nitrogen-atoms that they are connected At 5 yuan or 6 membered heterocycloalkyls, wherein the Heterocyclylalkyl contains miscellaneous original that is one or more additional and being independently selected from N, O or S Son, RcAnd RdIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1- C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, aryl, heteroaryl and Heterocyclylalkyl；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl can independently with aryl, heteroaryl, C3-C6Naphthenic base or Heterocyclylalkyl is condensed；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl are unsubstituted or are optionally taken by single or multiple substituent groups Generation, the substituent group it is identical or different and independently selected from：Deuterium, halogen, nitro, amino, hydroxyl, cyano, sulfoamido, O- carboxylics Base, C- carboxyls, sulfydryl, oxo, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkane sulfydryl, halogenated (C1-C6Alkyl), hydroxyl (C1-C6 Alkyl), sulfydryl (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, heteroaryl, Heterocyclylalkyl ,-(CH2)qNRaRb、- (CH2)q(S=O)2NRaRb、-(CH2)q(C=O) NRaRb, wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, virtue One or several or R in base, heteroaryl and HeterocyclylalkylaAnd Rb5 yuan or 6 can be formed together with the nitrogen-atoms that they are connected Membered heterocycloalkyl, wherein the Heterocyclylalkyl contains hetero atom that is one or more additional and being independently selected from N, O or S；
L in general formula I is aryl, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group, Heterocyclylalkyl, C1-C8Alkyl, C2-C8Alkene Base, C2-C8Alkynyl, aryl-(C1-C6Alkyl), heteroaryl-(C1-C6Alkyl), (naphthenic base)-(C1-C6Alkyl) or (heterocycle alkane Base)-(C1-C6One or more of alkyl)；
The C1-C8Alkyl, C2-C8Alkenyl and C2-C8Alkynyl can not be by or by following group：- O- ,-S- ,-NH- ,-S (= O)2,-S (=O)-,-(C=O)-,-O (C=O)-,-(C=O) O- ,-O (C=O) O- ,-NH (C=O)-,-(C=O) NH- ,- S (C=O)-,-(C=O) S- ,-NH (C=O)2NH- ,-NH (C=S)2NH-, NH (C=O)2O- is separated 1 time, 2 times, 3 times or 4 It is secondary；
The C1-C8Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, aryl, heteroaryl, C3-C6Naphthenic base and Heterocyclylalkyl are not taken In generation, is replaced by single or multiple substituent groups, and the substituent group is independently selected from identical or differently：Halogen, nitro, amino, hydroxyl Base, cyano, sulfoamido, O- carboxyls, C- carboxyls, sulfydryl, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C2-C6Alkenyl oxygroup, C1-C6Alkane sulfydryl, C1-C6Alkylamino, halogenated (C1-C6Alkyl), hydroxyl (C1-C6Alkyl), sulfydryl (C1-C6 Alkyl), cyano (C1-C6Alkyl), nitro (C1-C6Alkyl), O- carboxyls (C1-C6Alkyl), C- carboxyls (C1-C6Alkyl), (C1-C6 Alkoxy)-(C1-C6Alkyl), (C1-C6Alkylamino)-(C1-C6Alkyl), (C1-C6Alkylamino)-(C1-C6Alkyl)-(C1-C6Alkane Oxygroup), (C1-C6Alkane sulfydryl)-(C1-C6Alkyl), (C1-C6Alkane sulfydryl)-(C1-C6Alkyl)-(C1-C6Alkoxy), amino (C1- C6Alkoxy), amino (C1-C6Alkoxy)-(C1-C6Alkyl), halogenated (C1-C6Alkoxy)-(C1-C6Alkyl), hydroxyl (C1-C6 Alkoxy)-(C1-C6Alkyl), cyano (C1-C6Alkoxy) (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, Heterocyclylalkyl One or more of with heteroaryl；
E in general formula I is O, S or N-C ≡ N；
X in general formula I is C0-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base or (CH2)nNH, wherein n are 0-4；
R in general formula I2For aryl, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group or Heterocyclylalkyl；
The aryl, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group or Heterocyclylalkyl are unsubstituted or optionally single Or multiple substituent group substitutions, the substituent group is identical or different and is independently selected from：Deuterium, halogen, nitro, cyano, hydroxyl, sulfydryl, O- carboxyls, C- carboxyls, sulfonic group, phosphate, phosphorous acidic group, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, Aryl, heteroaryl, Heterocyclylalkyl, C3-C 6Naphthenic base-(C1-C6Alkyl), aryl (C1-C6Alkyl), heteroaryl (C1-C6Alkyl), Heterocyclylalkyl (C1-C6Alkyl), C3-C6Naphthenic base-(C2-C6Alkenyl), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), it is miscellaneous Naphthenic base (C2-C6Alkenyl), C3-C6Naphthenic base-(C2-C6Alkynyl), aryl (C2-C6Alkynyl), heteroaryl (C2-C6Alkynyl), heterocycle Alkyl (C2-C6Alkynyl), (C3-C6Naphthenic base)-O- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkoxy), aryl-O- (CH2) Q-, aryl-(C1-C6Alkoxy), heteroaryl-O- (CH2) q-, heteroarylalkoxy, Heterocyclylalkyl-O- (CH2) q-, heterocycle alkane Base-(C1-C6Alkoxy), (C3-C6Naphthenic base)-S- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkane sulfydryl), aryl-S- (CH2) q-, aryl-(C1-C6Alkane sulfydryl), heteroaryl-S- (CH2) q-, heteroaryl alkane sulfydryl, Heterocyclylalkyl-S- (CH2) q-, miscellaneous Naphthenic base-(C1-C6Alkane sulfydryl), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), (C3-C6Naphthenic base)-(C2-C6Alkene Base), Heterocyclylalkyl (C2-C6Alkenyl), C1-C6Alkoxy-(CH2)q-、C2-C6Alkenyl oxygroup (CH2)q-、C1-C6Alkane sulfydryl- (CH2)q-、C2-C6Alkenyl sulfydryl, halogenated (C1-C6Alkyl), halogenated (C2-C6Alkenyl), amino (C1-C6Alkyl), amino (C2-C6 Alkenyl), hydroxyl (C1-C6Alkyl), hydroxyl (C2-C6Alkenyl), sulfydryl (C1-C6Alkyl), sulfydryl (C2-C6Alkenyl), cyano (C1-C6 Alkyl), cyano (C2-C6Alkenyl), nitro (C1-C6Alkyl), nitro (C2-C6Alkenyl), O- carboxyls (C1-C6Alkyl), O- carboxyls (C2-C6Alkenyl), C- carboxyls (C1-C6Alkyl), C- carboxyls (C2-C6Alkenyl), sulfonic group (C1-C6Alkyl), sulfonic group (C2-C6Alkene Base), phosphate (C1-C6Alkyl), phosphorous acidic group (C1-C6Alkyl), phosphate (C2-C6Alkenyl), phosphorous acidic group (C2-C6Alkenyl), (C1-C6Alkylamino)-(C1-C6Alkoxy), (C1-C6Alkylamino) oxygroup-(CH2)q、(C1-C6Alkane sulfydryl)-(C1-C6Alkoxy), (C1-C6Alkane sulfydryl) oxygroup-(CH2)q, halogenated (C1-C6Alkoxy)-(CH2)q, (halogenated C1-C6Alkyl)-O- (CH2)q, hydroxyl Base (C1-C6Alkoxy)-(CH2)q, (hydroxyl C1-C6Alkyl) oxygroup-(CH2)q, cyano (C1-C6Alkoxy)-(CH2)q, (cyanogen Base C1-C6Alkyl)-O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C=O) NRaRb、-(CH2)q-NRc(C=O) Rd、-(CH2)q- NRc(C=O) ORd、-(CH2)q(C=O)-(C1-C6Alkyl) ,-(CH2)q(C=O) aryl ,-(CH2)q(C=O) heteroaryl Base ,-(CH2)q(C=O)-(C3-C6Naphthenic base) ,-(CH2)q(C=O) O- (C1-C6Alkyl) ,-(CH2)q(C=O) O virtues Base ,-(CH2)q(C=O) S- (C1-C6Alkyl) ,-(CH2)q(C=O) S aryl ,-(CH2)q- O (C=O)-(C1-C6Alkyl) ,- (CH2)q- O (C=O) aryl ,-(CH2)q(S=O)2NRaRb、-(CH2)q-NRc(S=O) Rd、-(CH2)q(S=O)2(C1-C6 Alkyl) ,-(CH2)q(S=O)2Aryl ,-(CH2)q(S=O)2Heterocyclylalkyl ,-(CH2)q(S=O)2Heteroaryl ,-(CH2)q- (S=O)2Halogenated alkyl ,-(CH2)q(S=O)-(C1-C6Alkyl) ,-(CH2)q(S=O) aryl ,-(CH2)q(S=O)-is miscellaneous Naphthenic base ,-(CH2)q(S=O) heteroaryl ,-(CH2)q(S=O) halogenated alkyl and-(CH2)q(P=O) RcRd；
Wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkane Base), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C1-C6Alkyl-NH- (C1-C6Alkyl)-, (C1-C6Alkyl)2- N- (C1-C6 alkane Base)-, C3-C6Naphthenic base, aryl, aryl-NH-, heteroaryl, Heterocyclylalkyl, C3-C6Naphthenic base-(C1-C6Alkyl), aryl (C1- C6Alkyl), heteroaryl (C1-C6Alkyl), Heterocyclylalkyl (C1-C6Alkyl) or RaAnd RbThe nitrogen-atoms one that can be connected with them It rises and forms 5 yuan or 6 membered heterocycloalkyls, wherein the Heterocyclylalkyl contains one or more additional and is independently selected from N, O or S Hetero atom, RcAnd RdIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), it is halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, aryl, heteroaryl, Heterocyclylalkyl；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl can independently with aryl, heteroaryl, C3-C6Naphthenic base or Heterocyclylalkyl is condensed；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl are unsubstituted or are optionally taken by single or multiple substituent groups Generation, the substituent group it is identical or different and independently selected from：Deuterium, halogen, nitro, amino, hydroxyl, cyano, sulfoamido, O- carboxylics Base, C- carboxyls, sulfydryl, oxo, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkane sulfydryl, halogenated (C1-C6Alkyl), hydroxyl (C1-C6 Alkyl), sulfydryl (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, heteroaryl, Heterocyclylalkyl ,-(CH2)qNRaRb、- (CH2)q(S=O)2NRaRb、-(CH2)q(C=O) NRaRb, wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, virtue Base, heteroaryl, Heterocyclylalkyl or RaAnd Rb5 yuan or 6 membered heterocycloalkyls can be formed together with the nitrogen-atoms that they are connected, wherein The Heterocyclylalkyl contains hetero atom that is one or more additional and being independently selected from N, O or S.
R in general formula I2Preferably
Described is selected from compounds of formula I：
Or its pharmaceutical salts.
Described has furazan class compound and its pharmaceutically acceptable salt shown in general formula I, solvate, prodrug, disappears outside Rotation body and isomers can be applicable to indoles amine -2,3- dioxygenase inhibitors, Nampt inhibitor or Yin The preparation of diindyl amine -2,3- dioxygenases and Nampt double inhibitor.
The furazan class compound and its pharmaceutically acceptable salt, prodrug, stereoisomer or the furazan class chemical combination The pharmaceutical composition that object and its pharmaceutically acceptable salt, solvate, prodrug, racemic modification and isomers form can be applied to Treat the preparation of the drug of the mankind and the tumour excess proliferative disease of other mammals.
The furazan class compound and its pharmaceutically acceptable salt, prodrug, stereoisomer or the furazan class chemical combination Object and its pharmaceutically acceptable salt, solvate, prodrug, racemic modification and isomers and pharmaceutically acceptable carrier form Pharmaceutical composition can be applied to prevent or tumor preparation；The prevention or tumor include but not It is limited to cancer immunotherapy drug, cancer chemotherapeutic drug or targeting cancer therapy drug.
Further, the furazan class compound and its pharmaceutically acceptable salt, prodrug, stereoisomer and its medicine group Close object can be used for preventing or treat lymthoma, non-small cell lung cancer, Small Cell Lung Cancer, incidence cell cancer, glioma, at Nerve-cell tumor, lung squamous cancer, adenocarcinoma of lung, carcinoma of urinary bladder, gastric cancer, colon cancer, colorectal cancer, kidney, cholangiocarcinoma, gastric cancer, esophageal squamous cell carcinoma, Oophoroma, cancer of pancreas, breast cancer, prostate cancer, liver cancer, the cancer of the brain, melanoma, Huppert's disease, cutaneum carcinoma, epithelial cell The cancers such as cancer, leukaemia and cervical carcinoma are included in other separate tissues of tumour original site or the metastasis of organ.
The preparation method of above-mentioned novel NAMPT and IDO double inhibitors, it is characterised in that：Described has compounds of formula I Synthetic route it is as follows：
In some embodiments, the compound involved by the application and its pharmaceutically acceptable salt can with it is applying at present or Cytotoxin/cytostatics, estrogenic agents, androgen receptor modifier, retinoid-like in the development phase Receptor modulators, protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse at antiproliferative Transcriptase inhibitors, angiogenesis inhibitors, cell Proliferation and survival signaling inhibitor, the drug of interference cell cycle check and thin Born of the same parents' inducer of apoptosis, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/Soviet Union's ammonia Acid albumin inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibit Agent, topoisomerase enzyme inhibitor, histon deacetylase (HDAC) inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 families Protein inhibitor, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibit Agent, AKT inhibitor, cox 2 inhibitor, integrin retarding agent, P53 activator, VEGF antibody, PD-1 antibody, PD-L1 are anti- The combination therapies such as body, PD-L2 antibody, CTLA-4 antibody and EGF antibody increase its clinical effectiveness.
Compound and its pharmaceutically acceptable salt involved by the application can be according to following methods for treating but being not limited to down Row disease：
It is a kind of to utilize the pharmaceutical composition comprising the compound described herein with Formulas I structure and its pharmaceutically acceptable salt Come treat people or other mammals breast cancer method, treatable disease includes but is not limited to aggressive conduit Cancer, aggressive lobular carcinoma, carcinoma in situ and in situ lobular carcinoma.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the respiratory cancer of people or other mammals, treatable disease includes but is not limited to cellule Lung cancer, non-small cell lung cancer, bronchial adenocarcinoma and pleuropulinonary blastoma.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for the treatment of the cancer of the brain of people or other mammals, treatable disease includes but is not limited to brain stem and now Glioma, cerebellum and cerebral astrocytoma, ependymocytoma and neuroderm and pinealoma.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application Object is come the method for the treatment of female, male reproductive organ the tumour of people or other mammals；Its treatable male genital The tumour of official includes but is not limited to prostate and carcinoma of testis；The tumour of its treatable female reproductive organ includes but not office It is limited to cervical carcinoma, carcinoma of endometrium, oophoroma, carcinoma of vagina and carcinoma of vulva and intrauterine tumor.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the digestive system cancer of people or other mammals, treatable disease includes but is not limited to anus Cancer, colon cancer, colon straight way cancer, cancer of the esophagus, gastric cancer, cancer of pancreas, the carcinoma of the rectum, carcinoma of small intestine and glandula cancer.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application Object come the method for the treatment of the carcinoma of urethra of people or other mammals, treatable disease include but is not limited to carcinoma of urinary bladder, Carcinoma of penis, kidney, carcinoma of renal pelvis, carcinoma of ureter and carcinoma of urethra.
It is a kind of to utilize the pharmaceutical composition for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the cancer eye of people or other mammals, treatable disease includes but is not limited to intraocular melanoma And retinocytoma.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the liver cancer of people or other mammals, treatable disease includes but is not limited to hepatoma (with or without the hepatocellular carcinoma of fiberboard variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and mixed hepatocellular cholangiocarcinoma.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the cutaneum carcinoma of people or other mammals, treatable disease includes but is not limited to pinacocyte Cancer, Kaposi's sarcoma, malignant mela noma, Merck Schwann Cells cutaneum carcinoma and non-melanoma cell cancer.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application Object come the method for the treatment of the head and neck cancer of people or other mammals, treatable disease include but is not limited to larynx, hypopharynx, Nasopharynx, oropharyngeal cancer and lip and carcinoma of mouth.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the lymthoma of people or other mammals, treatable disease includes but is not limited to AIDS correlations Lymthoma, non-Hodgkin's lymphoma, skin T cell lymphoma, systemic T-cell lymthoma, hodgkin's lymphoma and maincenter god Through system lymphomas.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the sarcoma of people or other mammals, treatable disease includes but is not limited to soft tissue meat Tumor, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdomyosarcoma.
It is a kind of to utilize the pharmaceutical compositions for including the compound and its pharmaceutically acceptable salt with Formulas I structure involved by the application For object come the method for treating the leukaemia of people or other mammals, treatable disease includes but is not limited to Acute Meyloid Property leukaemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia and hairy cell are white Blood disease.Take mode and dosage range
According to standard pharmaceutical techniques, the compounds of this invention can individually or in pharmaceutical composition with pharmaceutically acceptable load Mammal, preferably people are given in body, auxiliary material or diluent combination.In orally available or subcutaneous, intramuscular injection, peritonaeum, vein, rectum and office Compound, lung, nasal cavity, parenteral is given at eyes by portion.
In one embodiment, when treating using Formulas I compound represented or control the patients such as cancer, taking dose is ranging from In oral 0.1~500 mg/day/kg body weight.Administering mode appropriate be daily single dose be administered or twice daily, three times, Four inferior multiple dosings are administered using slow release method.For large mammal, ranging from 0.1~1500 milli of preferred dose Gram/day/kg body weight.The patient for being 70 kilograms for average weight, dosage are 1~500 milligram.For some especially high work Property compound, adult patient's daily dosage can be down to 0.1 mg/day.
In one embodiment, when treating using the compound with structure shown in Formulas I or control the patients such as cancer, agent is taken Amount is ranging from intravenous injection 0.1~500 mg/day/kg body weight.Administering mode appropriate is daily single dose administration or every Day twice, three times, four inferior multiple dosings or be administered using slow release method.For large mammal, preferred dose range For 0.1~1500 mg/day/kg body weight.The patient for being 70 kilograms for average weight, dosage are 1~500 milligram.It is right In some special high-activity compounds, adult patient's daily dosage can be down to 0.1 mg/day.
Dosage form
The pharmaceutical composition that the present invention contains active constituent can be made into suitable for oral delivery form, for example, tablet, lozenge, pastille, Water or oil suspension, dispersible pulvis or granule, emulsion, hard capsule, soft capsule, syrup or tincture.It can be according to medicine Any known method prepares the expected oral composition for giving to give in compositions manufacturing field, and is pharmaceutically refined to provide And agreeable to the taste preparation, this composition contain one or more medicines selected from sweetener, flavoring agent, colorant and preservative Agent.
Tablet contains active constituent and the nontoxic pharmaceutically acceptable auxiliary material for being suitable for manufacturing tablet.These auxiliary materials can for Such as, inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulation agent (granulating) and disintegrant Such as microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cornstarch or alginic acid；Adhesive such as starch, gelatin, polyvinyl pyrrole Alkanone or Arabic gum；And lubricant such as magnesium stearate, stearic acid or talcum powder.Tablet can not be coated or pass through known technology Be coated to cover the disagreeable taste of drug or extend be disintegrated and absorb in the gastrointestinal tract and thus provide and last much longer Drug effect.For example, the raw material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose of water-soluble taste masking can be used, or Using time delay material such as ethyl cellulose, acetylbutyrylcellulose.Tabules can be 0.1 milli gram/piece, 0.2 milli gram/piece, 0.25 milli gram/piece, 0.5 milli gram/piece, 1 milli gram/piece, 2 milli gram/piece, 5 milli gram/piece, 10 milli gram/piece, 25 milli gram/piece, 50 milligrams/ Piece, 100 millis gram/piece and 250 millis gram/piece.Other dosage forms such as capsule etc. can make comparable amount reference.
The preparation being administered orally may be made as hard-gelatin capsules, and wherein active constituent is mixed in inert solid diluent, such as In calcium carbonate, sodium carbonate or white bole；Or Gelseal is made, wherein it is for example poly- to be mixed in water-solubility carrier for active constituent In ethylene glycol or oil medium such as peanut oil, atoleine or olive oil.Aqueous suspension contains and is suitable for manufacture aqueous suspension Auxiliary material mixing active material.This auxiliary material is suspending agent such as carmethose, methylcellulose, hydroxypropyl-methyl Cellulose, sodium alginate, polyvinylpyrrolidone or Arabic gum；This aqueous suspension can also contain one or more preservatives Such as ethyl-para-hydroxybenzoate or P-hydroxybenzoic acid n-propyl, one or more colorants, one or more flavoring agents, and One or more Sweetening agents such as sucrose, saccharin or aspartame.It can be by being suspended active constituent with vegetable oil such as, peanut In oil, sesame oil, coconut oil or olive oil, mineral oil such as atoleine prepares oil-based suspension.This oil-based suspension can contain There are thickener such as beeswax, solid paraffin or cetanol.
Sweetener described above and flavoring agent can be added and be suitble to oral preparation to provide, it can be by the way that antioxidant be added for example Butylated Hydroxyanisole or alpha-tocopherol store these compositions.
Dispersion powder or granule provide by be suitable for preparing aqueous suspension by addition water with dispersant or wetting agent, suspending agent and The active constituent of one or more preservative mixing.Dispersant or wetting agent and suspending agent appropriate by foregoing relate to example Sub- explanation.Also other auxiliary materials such as sweetener, flavoring agent and colorant may be present.These compositions can be by being added antioxidant Such as ascorbic acid and store.
The present composition can be made into the form of oil-in-water emulsion.Oil phase can be vegetable oil such as peanut oil or olive oil, or Or mixtures thereof mineral oil such as atoleine.Emulsifier appropriate can be naturally occurring phosphatide such as soybean lecithin and ester Class or the inclined fat such as dehydrated sorbitol mono-fatty acid ester mixed derived from aliphatic acid and hexitan, and the partial ester and alkylene oxide Condensation product such as Polysorbate 80.This emulsion can also contain sweetener, flavoring agent, antioxidant And preservative.
Sweetening agents such as glycerine, propylene glycol, sorbierite or sucrose can be used to prepare syrup and tincture.This preparation can also contain There are wetting agent, flavoring agent, colorant, antioxidant and preservative.
The present composition can be made into the aqueous solution of aseptic injection.Water, woods grignard can be used in acceptable carrier and solvent Liquid and isotonic sodium chlorrde solution.
This sterile injection agent may be made as the sterile injection oil-in-water microemulsion that active constituent is dissolved in oil phase.For example, Active constituent is dissolved in the mixture of soya-bean oil and lecithin, is then put into oil solution in the mixture of water and glycerine simultaneously first It handles and microemulsion is made.
This pharmaceutical composition can be made into for intramuscular or subcutaneous administration sterile injectable solution or oleagenous suspension form.It can According to known technology this suspension is prepared using the dispersant or wetting agent and suspending agent being mentioned above.Sterile injection system Agent may be made as the sterile injectable solution in nontoxic parenteral acceptable diluent or solvent or suspension, such as conduct Solution in 1,3 butylene glycol.In addition, conventional to use fixed oil as solvent or suspension medium.For this purpose, can be used Any nonirritant fixed oil includes the monoglyceride or diglyceride of synthesis.In addition, find to make in injectable formulation With aliphatic acid such as oleic acid.
Drug combination
Formulas I compound represented can be combined to the known other medicines for treating or improving similar symptom.It is former when administering drug combinations The administering mode and dosage for carrying out drug remain unchanged, and simultaneously, in advance or then take Formulas I compound represented.Shown in Formulas I Compound when being taken simultaneously with other one or more of drugs, it is preferable to use containing one or more of known drugs and formula simultaneously The pharmaceutical composition of compound shown in I.Drug combination be also included within overlapping period take formula compound with it is other a kind of or Several known drugs.When Formulas I compound represented is combined with other one or more of drugs, Formulas I compound represented Or dosage of the dosage of known drug when may be than their independent medications is relatively low.
The drug of drug combination can be carried out with Formulas I compound represented or active constituent includes but is not limited to：Cytotoxin/ Cytostatics, estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, antiproliferative, albumen Inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitor, Agiogenesis inhibition Agent, cell Proliferation and survival signaling inhibitor, the drug of interference cell cycle check and cell death inducer, cytotoxic drug Object, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl suppressions Preparation, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, group Albumen deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitors, MDM2 families egg White inhibitor, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitor, AKT inhibitor, COX-2 inhibit Agent, integrin retarding agent, P53 activator, VEGF antibody, PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, EGF antibody etc..
In one embodiment, the drug that drug combination can be carried out with Formulas I compound represented includes but is not limited to：Ah Ground interleukin, A Lun see acid, interferon, Ah Qu Nuoying, Allopurinol, allopurinol sodium, palonosetron hydrochloride, hemel, Amino glutethimide, Amifostine, Amrubicin, amphidine, arimidex, Dolasetron, aranesp, arglabin, three oxidations Two arsenic, A Nuoxin, U-18496, imuran, BCG vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate, Bei Sha Luo Ting, Bleomycin Sulphate, broxuridine, bortezomib, busulfan, calcitonin, A Laizuo monoclonal antibodies injection, capecitabine, Carboplatin, cis-platinum, Casodex, cefesone, Celmoleukin, daunorubicin, Chlorambucil, Cladribine, chlorine bend phosphoric acid, ring Phosphamide, arabinose born of the same parents' former times, Dacarbazine, actinomycin D, daunorubicin liposome, fill in rice give, fill in phosphoric acid rice give, valeric acid Estradiol, denileukin diftitox, Deslorelin, La Zuosheng, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, Ah mould Element, Dronabinol, chitosan complexes, draw step stand enzyme, epirubicin hydrochloride, aprepitant, Epi-ADM, Epoetin Alfa, Erythropoietin(EPO), eptalatin, Ergamisole, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinyloestradiol, hydroxyl Phosphoric acid, Etopophos, etoposide, Fadrozole, tamoxifen preparation, Filgrastim, Fei Leisi are replaced, floxuridine, Fluconazole, fluorine reach Draw shore, 5- fluorodeoxyuridines phosphate, 5 FU 5 fluorouracil, Fluoxymesterone, Flutamide, formestane, 1- β-D-arabinose Furans born of the same parents fill in the stearic phosphate of pyridine -5 ' -, Fotemustine, fulvestrant, the third clock globulin, gemcitabine, WAY-CMA 676, her horse For Buddhist nun, Gliadel, Goserelin, Graniseeron Hydrochloride, Histrelin and U.S. be new, hydrocortisone, red Type-hydroxynonyl adenine, hydroxycarbamide, for smooth different shellfish not monoclonal antibody, idarubicin, ifosfamide, interferon-' alpha ', interferon-' alpha ' 2, Interferon α-2 A, interferon α-2 B, interferon alfa-n1, Alferon N, interferon beta, interferon gamma -1a, interleukin 2, Intron A, Iressa, Irinotecan Kytril, sulfuric acid lentinan, Letrozole, formyl tetrahydrofolic acid, Leuprorelin, bright third Nafarelin acetate salt, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, Lonidamine, Dronabinol, Mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estriol, 6- sulfydryls Purine, mesna, amethopterin, amino-laevulic acid ester, Miltefosine, minocycline, mitomycin C, mitotane, rice support green onion Quinone, Trilostane, citric acid Evacet, Nedaplatin, Pegfilgrastim, oprelvekin, Neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Octreotide, hydrochloric acid Ao Danxi It is grand, remove his plug, prednisone sodium phosphate, Pei Men of hydrocortisone oral solution, oxaliplatin, taxol, Taxotere, kappa Winter enzyme, PEG-IFN alpha-2a, Pentostatin, Picibanil, hydrochloric acid Pi Luka product, adjoin it is soft than star, plicamycin, foretell pheno nurse sodium, Po Nimo Take charge of spit of fland, prednisone, Prednisolone Steaglate, premarin, the third kappa neat, epoetin, Raltitrexed, Libiee, According to for sour rhenium -186 of seeing, Mabthera, Redoxon-A, Romurtide, Salagen, sargramostim, Semustine, west Assistant mutters, Ao Buzuosheng, bluffs sodium methylprednisolone, is Paphos acid, streptozotocin, Metastron, levoid, tamoxifen, smooth Shu Luoxin, Ta Suonaming, tastolactone, taxotere, teceleukin, Temozolomide, Teniposide, testosterone propionate, first testis It is ketone, thioguanine, thio-tepa, thyrotropic hormone, acid of seeing for Shandong, topotecan, Toremifene, tositumomab, bent auspicious appropriate Pearl monoclonal antibody, Treosulfan, vitamin A acid, methopterin tablet, trimethyl melamine, Trimetrexate, acetic acid Triptorelin, pamoic acid Triptorelin, excellent fudding, uridine, valrubicin, Vesnarinone, vincaleukoblastinum, vincristine, Vindesine, vinorelbine, Wei Lu The sharp Qin, dextropine imine, Zinostatin stimalamer, ondansetron, Taxol-protein stabilization formulations, acolbifene, Affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, atamestane, atrasentan, Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, crisnatol, cyproterone acetate, gemcitabine, adriamycin-MTC, she class sees Acid, lanreotide, lasofoxifene, Miproxifene, minot bend acid esters, liposome MTP-PE, nafarelin, Nola Qu Te, taxol Polyglutamic acid esters, seocalcitol, Erlotinib, Paclitaxel liposome, tipifarnib, SAHA, Tirapazamine, Vapreotide, Vatalanib, Verteporfin, vinflunine or combination thereof.
Beneficial effects of the present invention are：Furazan class compound of the present invention is in vitro in active testing experiment to indoleamine 2, 3- dioxygenases and Nampt show significant inhibitory activity, can not only double inhibition NAD+ Biosynthesis is to inhibit growth and the proliferation of tumour cell, additionally it is possible to be effectively facilitated the proliferation of T cell to enhance body To the attacking ability of tumour cell, there is significant antitumor activity, be expected to become antitumor drug.
Specific implementation mode
In order to better illustrate the technology contents of the present invention, with reference to specific example, the present invention is further elaborated, but should Embodiment is not intended to limit protection scope of the present invention.
The synthetic route (synthesis of A series compounds) of compound shown in general formula I
Embodiment 1
(Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) second Base) imidazoles [1,2-a] pyridine -6- formamides preparation
(1) preparation of (Z) -4- amino-N '-hydroxy-n-(the bromo- 4- fluorophenyls of 3-) -1,2,5- oxadiazole -3- first miaows
At 0 DEG C, acetic acid (5Ml), hydrochloric acid (4N) (5mL), NaNO are instilled successively into compound 1 (5g, 34.96mmol)2 Water (5mL) solution of (2.42g, 34.96mmol) is warming up to room temperature reaction 18h, and ethyl acetate (25ml), layering, water phase is added It is extracted with ethyl acetate (2*25ml), merges organic phase, washed with saturated salt solution (25mL), anhydrous sodium sulfate drying is concentrated to give Intermediate 2 (4.5g).Under nitrogen protection, to the first of compound 2 (4.5g) and the bromo- 4- fluoroanilines (11.8g, 62.0mmol) of 3- NaHCO is added in alcohol (20ml) solution3Water (20ml) solution of (7.8g, 93.0mmol), 50 DEG C are reacted 12 hours, TLC detections The reaction was complete, concentration, and ethyl acetate (20mL), layering is added, and water phase is extracted with ethyl acetate (2*20mL), merges organic phase, It is washed with saturated salt solution (20mL), anhydrous sodium sulfate drying, concentration, column chromatography obtains (Z) -4- amino-N- (bromo- 3- fluorobenzene of 4- Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows (V-1) (7.32g, 75%).Its nuclear magnetic resonance spectroscopy is：1H NMR (400MHz,DMSO):δ 11.45 (s, 1H), 8.83 (s, 1H), 8.08 (dd, J=3.6,2.4Hz, 1H), 7.71 (m, 1H), 7.60 (t, J=8.8Hz, 1H), 6.59 (s, 2H) ppm.
(2) (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyl -1,2,5-1,2,5- oxadiazoles -3- The preparation of first miaow (II-1)
Compound V-1 (7g, 22.2mmol) is dissolved in tetrahydrofuran, Anhydrous potassium carbonate (9g, 6.66mmol), catalytic amount is added KI, be stirred at room temperature the lower tetrahydrofuran solution by N-Boc-2- chlorethamins (4.0g, 22.2mmol) be slowly dropped to it is above-mentioned molten In liquid, 6h is reacted at room temperature.After reaction, filter, filtrate concentration, column chromatography obtain compound intermediate compound (7.12g, 70%).Midbody compound (7.12g, 15.6mol) is dissolved in ethyl acetate (20ml), the ethyl acetate saturation of HCl is passed through Solution (10ml), reacts 8h at room temperature.After reaction, ethyl acetate extraction (30ml × 3) merges organic phase, saturation NaHCO3Solution washs (50ml), saturated common salt water washing (50ml), anhydrous sodium sulfate drying, concentration, and column chromatography obtains chemical combination Its nuclear magnetic resonance spectroscopy of object II-1 (5.03g, 90%) is：1H NMR(400MHz,DMSO):δ11.42(s,1H),8.85(s, 1H), 7.18 (t, J=8.8Hz, 1H), 7.10 (dd, J=3.2,2.8Hz, 1H), 6.76 (m, 1H), 6.05 (s, 1H), 3.22 (s,2H),2.76(s,2H)ppm.
(3) (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) Ethyl) imidazoles [1,2-a] pyridine -6- formamides preparation
Imidazoles [1,2-a] pyridine -6- carboxylic acids (50mg, 0.28mmol) are dissolved in DCM, sequentially add II-1 (100mg, 0.28mmol), EDCI (91mg, 0.48mmol), HOBt (47.25mg, 0.35mmol), triethylamine (0.07ml, 0.48mmol), It is stirred to react 5h at room temperature.After reaction, water (20ml) is added, ethyl acetate extracts (20ml × 3), merges organic phase, uses It is saturated NaHCO3Solution (10mL) washs, and saturated ammonium chloride solution (10mL) washing is washed (10mL), anhydrous sodium sulfate drying, Concentration, column chromatography obtain target compound (116mg, 85%).
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.23(s,1H),9.86(s,1H),8.74(s,1H), 8.34 (s, 1H), 7.67 (d, J=3.5Hz, 1H), 7.60 (m, 1H), 7.44 (s, 2H), 6.94 (m, 1H), 6.78 (m, 1H), 6.60(m,1H),6.05(s,1H),3.59-3.43(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.2,154.3,148.7,145.2,142.3,138.5, 134.2,131.3,119.7,118.6,116.2,113.8,110.7,48.3,35.2.
Its mass spectrum is：MS(EI,m/z):503(M++1).
Embodiment 2
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-3- Chlorine propylamine, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.83(s,1H), 8.44 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.65 (m, 1H), 7.46 (s, 2H), 6.93 (m, 1H), 6.76 (m, 1H), 6.64(m,1H),6.05(s,1H),3.35(m,2H),3.05(m,2H),1.93(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,1634.5,155.3,147.2,145.2,143.2, 138.4,134.2,129.3,119.7,117.2,113.2,110.6,42.1,41.2,27.8.
Its mass spectrum is：MS(EI,m/z):517(M++1).
Embodiment 3
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-4- Neoprene amine, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) butyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.83(s,1H),8.79(s,1H), 8.44 (s, 1H), 7.91 (d, J=3.5Hz, 1H), 7.71 (m, 1H), 7.37 (s, 2H), 6.86 (m, 1H), 6.78 (m, 1H), 6.56(m,1H),6.06(s,1H),3.25(m,2H),3.05(m,2H),1.50-1.48(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,163.5,155.2,153.3,148.7,147.2,145.2, 143.2,134.4,133.2,129.3,119.2,118.6,117.2,116.7,114.2,110.2,42.1,39.2,27.8, 26.1.
Its mass spectrum is：MS(EI,m/z):531(M++1).
Embodiment 4
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-5- Chlorine amylamine, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) amyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.89(s,1H), 8.31 (s, 1H), 7.78 (d, J=3.5Hz, 1H), 7.61 (m, 1H), 7.47 (s, 2H), 6.96 (m, 1H), 6.94 (m, 1H), 6.82(m,1H),6.62(m,1H),6.06(s,1H),3.25-3.20(m,4H),1.60-1.57(m,4H),1.32(s,2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.3,155.1,153.2,147.8,146.2,145.0, 143.4,134.7,133.2,129.2,118.7,117.6,113.2,108.6,42.1,39.2,31.2,29.8,23.1.
Its mass spectrum is：MS(EI,m/z):545(M++1).
Embodiment 5
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-6- Chlorine hexylamine, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) hexyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.79(s,1H), 8.41 (s, 1H), 7.81 (d, J=3.5Hz, 1H), 7.70 (m, 1H), 7.37 (s, 1H), 6.96 (m, 1H), 6.48 (m, 1H), 6.36(m,1H),3.32-3.27(m,4H),1.60-1.57(m,4H),1.32(s,2H),1.20(s,2H)ppm.
Its carbon is composed：δ 167.8,164.5,156.7,153.3,148.7,147.2,145.2,135.4,129.3,118.7, 117.2,115.2,107.6,42.1,41.2,30.5,27.8,26.2.
Its mass spectrum is：MS(EI,m/z):585(M++1).
Embodiment 6
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-7- Chlorine heptyl amice, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) heptyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.63(s,1H), 8.31 (s, 1H), 7.79 (d, J=3.7Hz, 1H), 7.65 (m, 1H), 7.47 (s, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.67(m,1H),6.05(s,1H),3.38-3.23(m,4H),1.63-1.59(m,4H),1.36-1.28(m,6H)ppm.
Its carbon is composed：13C NMR(400MHz,DMSO):δ165.8,163.5,154.8,152.3,147.8,145.2,143.2, 138.4,134.3,130.4,119.8,118.3,117.2,116.5,114.2,110.9,43.2,41.2,31.3,30.5, 27.8,26.2,23.5.
Its mass spectrum is：MS(EI,m/z):573(M++1).
Embodiment 7
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, (Z)-N- (2- ((4- (N- (4- fluorophenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) ethyl) obtained The structural formula of imidazoles [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.64(s,1H), 8.34 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 6.08(s,1H),3.56-3.42(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,157.3,152.9,147.3,145.2,138.5, 134.8,134.0,133.3,129.6,120.2,116.8,115.2,48.3,37.2.
Its mass spectrum is：MS(EI,m/z):425(M++1).
Embodiment 8
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- (4- fluorobenzene obtained Base)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.78(s,1H), 8.43 (s, 1H), 7.79 (d, J=3.6Hz, 1H), 7.65 (m, 1H), 7.45 (s, 2H), 6.87 (m, 2H), 6.54 (m, 2H), 6.05(s,1H),3.54(m,2H),3,18(m,2H),1.85(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.5,152.3,147.6,145.2,144.3,140.9, 138.2,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,46.3,45.2,29.8.
Its mass spectrum is：MS(EI,m/z):439(M++1).
Embodiment 9
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups- 2- fluoroanilines, (Z)-N- (2- ((4- (N- (4- methoxyl group -2- fluorophenyls)-N '-hydroxyl first miaows base) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.75(s,1H),8.76(s,1H), 8.67 (s, 1H), 7.71 (d, J=3.8Hz, 1H), 7.64 (m, 1H), 7.32 (s, 2H), 6.93 (m, 1H), 6.72 (m, 1H), 6.32(m,1H),6.05(s,1H),3.82(s,3H),3.44-3.34(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,164.5,159.3,153.6,149.2,147.9,145.1, 138.2,135.2,130.3,118.0,116.2,114.9,110.7,104.3,56.3,48.6,39.8.
Its mass spectrum is：MS(EI,m/z):455(M++1).
Embodiment 10
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups- 2- fluoroanilines, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- obtained (4- methoxyl group -2- fluorophenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyrrole The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.85(s,1H),8.79(s,1H), 8.63 (s, 1H), 7.61 (d, J=3.5Hz, 1H), 7.64 (m, 1H), 7.41 (s, 2H), 6.95 (m, 1H), 6.72 (m, 1H), 6.52(m,1H),6.07(s,1H),3.67(s,3H),3.34(m,2H),3.12(m,2H),1.75(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,159.3,153.2,149.0,147.2,145.9, 138.2,136.2,130.3,118.6,114.2,105.9,55.8,41.8,39.8,28.8.
Its mass spectrum is：MS(EI,m/z):469(M++1).
Embodiment 11
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (2- methoxies Base oxethyl) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) phenyl) first miaow base)-obtained 1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,1H),8.73(s,1H), 8.38(s,1H),7.89-7.84(m,3H),7.61(m,1H),7.55(s,2H),6.53(m,2H),6.05(s,1H),3.75 (s,3H),4.31(m,2H),3.79(m,2H),3.50(m,2H),3.43(m,3H),3.23(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,149.3,147.6,145.2,138.2, 135.2,130.3,128.0,116.3,115.2,114.7,76.3,69.8,57.5,46.7,39.2.
Its mass spectrum is：MS(EI,m/z):481(M++1).
Embodiment 12
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (2- methoxies Base oxethyl) aniline, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) miaow The structural formula of azoles [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.88(s,1H),8.68(s,1H), 8.34(s,1H),7.79-7.74(m,3H),7.51(m,1H),7.45(s,2H),6.54(m,2H),6.05(s,1H),4.34 (m,2H),3.85(s,3H),3.69(m,2H),3.52-3.44(m,5H),3.23(m,2H),1.83(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,149.3,147.6,145.2,138.2, 135.2,130.3,128.0,116.3,115.2,114.7,79.3,69.8,59.5,41.7,39.2,27.6.
Its mass spectrum is：MS(EI,m/z):495(M++1).
Embodiment 13
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3,5- diformazans Oxygroup aniline, (Z)-N- (2- ((4- (N- (3,5- dimethoxy)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.07(s,1H),9.88(s,1H),8.78(s,1H), 8.63 (s, 1H), 7.79 (d, J=3.5Hz, 1H), 7.65 (m, 1H), 7.48 (s, 2H), 6.12 (s, 2H), 6.07 (s, 1H), 5.86(s,1H),3.84(s,6H),3.52-3.46(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,159.3,152.0,148.1,147.3,146.2, 134.2,116.2,114.5,97.2,90.3,56.3,47.1,39.8.
Its mass spectrum is：MS(EI,m/z):467(M++1).
Embodiment 14
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3,5- diformazans Oxygroup aniline, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- obtained (3,5- dimethoxys)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- The structural formula of formamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.07(s,1H),9.78(s,1H),8.76(s,1H), 8.63 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.67 (m, 1H), 7.41 (m, 2H), 6.23 (s, 2H), 6.05 (s, 1H), 5.75(s,1H),3.84(s,6H),3.52(m,2H),3.20(m,2H),1.86(s,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.2,162.5,160.3,153.2,148.9,147.0,146.2, 136.2,117.2,113.5,98.2,92.3,46.3,39.8.
Its mass spectrum is：MS(EI,m/z):481(M++1).
Embodiment 15
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into the fluoro- 4- of 2- (4- pyridyl groups oxygroup) aniline, (Z)-N- (2- ((4- (N- (the fluoro- 4- of 2- (4- pyridin-2-yls oxygroup)-N '-hydroxyl first miaows obtained Base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.57(s,1H),9.82(s,1H),8.73(s,1H), 8.67 (s, 1H), 8.38 (d, J=6.5Hz, 2H), 7.78 (d, J=3.5Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 7.05 (m,2H),6.78(m,1H),6.61(m,1H),6.32(m,1H),6.05(s,1H),3.50-3.47(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,163.5,158.2,152.3,149.4,147.9,146.2, 145.0,136.2,134.2,132.5,123.4,118.8,116.3,115.4,114.5,110.2,102.3,48.1,37.8.
Its mass spectrum is：MS(EI,m/z):518(M++1).
Embodiment 16
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into the fluoro- 4- of 2- (4- pyridyl groups oxygroup) aniline, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- obtained (2- ((4- (N- (the fluoro- 4- of 2- (4- pyridin-2-yls oxygroup)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) The structural formula of imidazoles [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.59(s,1H),9.88(s,1H),8.89(s,1H), 8.63 (s, 1H), 8.41 (d, J=6.7Hz, 2H), 7.77 (d, J=3.7Hz, 1H), 7.63 (m, 1H), 7.45 (m, 2H), 7.05 (m,2H),6.83(m,1H),6.61(m,1H),6.34(m,1H),6.05(s,1H),3.54(m,2H),3.47(m,2H),1.78 (m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,159.2,152.3,148.4,147.9,147.3, 137.2,134.2,132.5,124.7,117.8,115.5,111.2,103.3,42.3,27.8.
Its mass spectrum is：MS(EI,m/z):532(M++1).
Embodiment 17
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (4- ammonia Base -3- fluorophenoxies) pyridine -2- amine, (Z)-N- (2- ((4- (N- (4- ((2-aminopyridine -4- bases) oxygroup) -2- fluorine obtained Phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.59(s,1H),9.88(s,1H),8.79(s,1H), 8.63(s,1H),7.83(m,1H),7.75(m,1H),7.65(m,2H),7.48(s,2H),6.83-6.80(m,2H),6.61 (m,1H),6.32(s,1H),6.05(s,1H),5.80(s,1H),3.50-3.43(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.7,163.6,158.2,152.3,148.4,148.0,146.3, 145.8,138.2,134.2,129.7,123.8,118.8,116.3,115.2,111.3,110.5,101.3,95.4,47.2, 39.8.
Its mass spectrum is：MS(EI,m/z):533(M++1).
Embodiment 18
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (4- ammonia Base -3- fluorophenoxies) pyridine -2- amine, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, obtained (Z)-N- (2- ((4- (N- (4- ((2-aminopyridine -4- bases) oxygroup) -2- fluorophenyls)-N '-hydroxyl first miaow) -1,2,5- Evil bis- Azoles -3- bases) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.56(s,1H),9.87(s,1H),8.86(s,1H), 8.63(s,1H),7.98(m,1H),7.79(m,1H),7.65(m,2H),7.45(s,2H),6.79-6.73(m,2H),6.51 (m,1H),6.42(s,1H),6.05(s,1H),5.76(s,1H),3.56(m,2H),3.43(m,2H),1.67(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.3,159.2,152.3,149.7,148.1,147.3, 146.8,145.2,138.6,134.8,134.0,130.7,123.8,117.9,116.8,115.2,114.3,110.3, 101.3,97.4,41.2,39.8,27.7.
Its mass spectrum is：MS(EI,m/z):547(M++1).
Embodiment 19
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method (1) step are replaced with into 4- (4- amino -3- Fluorophenoxy)-N- picoline amides, (Z)-N- (2- ((4- (N- (the fluoro- 4- of 2- ((2- (methylcarbamoyl) pyrroles obtained Pyridine -4- bases) oxygroup) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine - The structural formula of 6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.52(s,1H),9.88(s,1H),8.86(s,1H), 8.63 (m, 1H), 8.09-7.98 (m, 2H), 7.76 (d, J=3.5Hz, 1H), 7.63-7.60 (m, 2H), 7.53 (s, 2H), 6.82(m,1H),6.61(m,1H),6.32(m,1H),6.05(s,1H),3.51-3.42(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.7,164.6,163.1,160.2,158.2,152.4,151.5, 147.3,146.8,145.1,138.2,134.2,130.7,123.7,118.8,116.3,115.7,114.3,113.2, 110.3,109.4,48.2,39.8,26.3.
Its mass spectrum is：MS(EI,m/z):575(M++1).
Embodiment 20
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (4- ammonia Base -3- fluorophenoxies)-N- picoline amides, the N-Boc-2- chlorethamins in (2) step replace with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- (the fluoro- 4- of 2- ((2- (methylcarbamoyl) pyridin-4-yl) oxygroup) phenyl)-N '-hydroxyls obtained Base first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.53(s,1H),9.86(s,1H),8.88(s,1H), 8.64 (m, 1H), 8.09-7.98 (m, 2H), 7.71 (d, J=3.6Hz, 1H), 7.65-7.62 (m, 2H), 7.53 (s, 1H), 6.83(m,1H),6.56(m,1H),6.32(m,1H),6.05(s,1H),3.35(m,2H),3.15(m,2H),1.73(m,2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,164.8,163.1,158.2,158.2,152.4,149.5, 148.1,146.8,145.4,138.2,134.1,130.0,123.7,117.8,116.3,115.4,113.7,112.3, 109.4,42.2,39.2,28.8,26.3.
Its mass spectrum is：MS(EI,m/z):589(M++1).
Embodiment 21
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- cyclopenta Aniline, (Z)-N- (2- ((4- (N- (4- cyclopentyl phenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) ammonia obtained Base) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06 5(s,1H),9.87(s,1H),8.78(s, 1H), 8.61 (s, 1H), 7.79 (d, J=3.5Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.95 (m, 2H), 6.87 (m, 2H),6.05(s,1H),3.52-3.47(m,4H),2.75(m,1H),1.73-1.68(m,8H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,152.6,147.3,145.1,138.2,136.2, 134.3,130.5,127.2,116.0,115.8,114.3,48.3,45.2,39.8,34.5,25.1.
Its mass spectrum is：MS(EI,m/z):475(M++1).
Embodiment 22
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- cyclopenta N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- obtained by aniline (4- cyclopentyl phenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- The structural formula of formamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.89(s,1H), 8.61 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.53 (m, 1H), 7.48 (s, 2H), 6.95 (m, 2H), 6.87 (m, 2H), 6.05(s,1H),3.52(m,2H),3.22(m,2H),2.79(m,1H),1.93-1.68(m,10H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,147.3,138.6,137.2,134.8, 134.2,129.6,127.6,116.0,115.8,113.3,46.3,42.8,39.8,34.6,28.5,25.1.
Its mass spectrum is：MS(EI,m/z):489(M++1).
Embodiment 23
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls Aniline, (Z)-N- (2- ((4- (N- (4- isopropyl phenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) ammonia obtained Base) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.84(s,1H), 8.67 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.95 (m, 2H), 6.67 (m, 2H), 6.05 (s, 1H), 3.52-3.47 (m, 4H), 2.75 (m, 1H), 1.23 (d, J=6.5Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,152.3,147.6,145.2,138.2,134.3, 132.5,130.3,129.6,126.2,116.3,116.0,114.5,48.3,39.8,33.2,23.1.
Its mass spectrum is：MS(EI,m/z):449(M++1).
Embodiment 24
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- obtained by aniline (4- isopropyl phenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- The structural formula of formamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.16(s,1H),9.88(s,1H),8.89(s,1H), 8.66 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.53 (t, J=5.0Hz, 1H), 7.44 (s, 2H), 6.98 (m, 2H), 6.63 (m, 2H), 6.05 (s, 1H), 3.50 (m, 2H), 3.25 (m, 2H), 2.75 (m, 1H), 1.87 (m, 2H), 1.20 (d, J= 6.5Hz,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.9,163.5,152.3,148.6,147.1,138.7,138.0, 134.3,132.5,129.6,126.2,116.0,114.2,42.3,39.2,33.2,28.5,23.1.
Its mass spectrum is：MS(EI,m/z):463(M++1).
Embodiment 25
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3,5- diformazans Base aniline, (Z)-N- (2- ((4- (N- (2,5- 3,5-dimethylphenyl)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- obtained Base) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.85(s,1H), 8.53 (s, 1H), 7.71 (d, J=3.5Hz, 1H), 7.50 (t, J=4.6Hz, 1H), 7.48 (s, 2H), 6.85 (t, J= 5.6Hz,1H),6.57(s,2H),6.05(s,1H),3.50-3.45(m,4H),2.75(s,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.1,150.6,147.1,145.2,144.3,139.2, 138.2,134.3,132.5,120.7,117.3,116.5,114.3,49.3,39.7,21.1.
Its mass spectrum is：MS(EI,m/z):435(M++1).
Embodiment 26
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3,5- diformazans N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- (N- obtained by base aniline (2,5- 3,5-dimethylphenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine - The structural formula of 6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.77(s,1H), 8.63 (s, 1H), 7.78 (d, J=3.8Hz, 1H), 7.43 (t, J=4.6Hz, 1H), 7.32 (s, 2H), 6.88 (t, J= 5.8Hz,1H),6.53(m,2H),6.05(s,1H),3.45(m,2H),3.10(m,2H),2.78(s,6H),1.83(m,2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.2,164.1,149.6,148.0,146.2,143.7,138.7, 136.2,134.3,132.5,121.7,118.0,116.3,114.2,42.3,38.7,29.7,21.1.
Its mass spectrum is：MS(EI,m/z):449(M++1).
Embodiment 27
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into methyl -3 4-, 5- 5-trifluoromethylanilines, (Z)-N- (2- ((4- (N- (bis- trifluoromethyl of 4- methyl -2,5-)-N '-hydroxyl first miaows obtained Base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H), 8.73 (s, 1H), 8.61 (s, 1H), 7.77 (d, J=3.7Hz, 1H), 7.53 (t, J=4.6Hz, 1H), 7.43 (s, 2H), 7.03 (s,2H),6.05(s,1H),3.50-3.45(m,4H),2.18(s,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.1,150.6,148.1,145.3,142.5,136.2, 134.3,134.0,132.5,128.6,123.2,118.3,116.2,115.6,114.1,48.3,38.1,15.2.
Its mass spectrum is：MS(EI,m/z):557(M++1).
Embodiment 28
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into methyl -3 4-, N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- obtained by 5- 5-trifluoromethylanilines (2- ((4- (N- (two trifluoromethyls of 4- methyl -2,5-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) Propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.05(s,1H),9.78(s,1H),8.77(s,1H), 8.36 (s, 1H), 7.65 (d, J=3.7Hz, 1H), 7.49 (t, J=4.6Hz, 1H), 7.48 (s, 2H), 7.03 (s, 2H), 6.05 (s,1H),3.35(m,2H),3.10(m,2H),2.13(s,3H),1.78(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.2,152.3,147.6,145.0,142.1,138.2, 134.3,132.5,129.5,128.7,123.2,118.0,117.3,115.2,112.3,42.3,38.9,28.7,16.1.
Its mass spectrum is：MS(EI,m/z):571(M++1).
Embodiment 29
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1H- pyrroles Azoles -1- bases) aniline, (Z)-N- (2- ((4-N- (4- (1H- pyrazol-1-yls) phenyl-N '-hydroxyl first miaow) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.71 (d, J=3.7Hz, 1H), 7.53-7.46 (m, 5H), 6.80 (s, 2H), 6.46 (t, J=3.4Hz, 1H), 6.05 (s, 1H), 3.55-3.47 (m, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.1,152.3,147.3,145.5,141.2,138.6, 135.2,134.3,134.0,132.2,129.6,126.8,120.7,116.3,114.3,108.6,48.3,39.6.
Its mass spectrum is：MS(EI,m/z):473(M++1).
Embodiment 30
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1H- pyrroles Azoles -1- bases) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained ((4-N- (4- (1H- pyrazol-1-yls) phenyl-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2- A] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.93(s,1H), 8.52 (s, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.76 (d, J=3.7Hz, 1H), 7.53-7.46 (m, 5H), 6.68 (s, 2H), 6.42 (d, J=3.6Hz, 1H), 6.15 (s, 1H), 3.45 (m, 2H), 3.27 (m, 2H), 1.89 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.8,162.1,152.6,147.5,145.3,142.5,138.2, 135.3,134.5,133.2,130.7,128.6,126.7,123.2,118.3,116.6,109.0,42.9,39.8,26.1.
Its mass spectrum is：MS(EI,m/z):487(M++1).
Embodiment 31
Unique step is with embodiment：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ammonia Base-N- (furans -2- ylmethyls) aniline, (Z)-N- (2- ((4- (N- (4- ((furans -2- ylmethyls) carbamoyl) obtained Phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H), 8.79 (s, 1H), 7.79 (d, J=3.7Hz, 1H), 7.55-7.58 (m, 6H), 6.97 (m, 2H), 6.38-6.34 (m, 2H), 6.05(s,1H),4.85(s,1H),3.50-3.48(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.3,163.1,152.6,147.3,145.2,145.1, 143.5,142.1,141.0,138.6,134.8,134.0,129.6,118.6,116.3,113.2,110.5,109.3,48.3, 39.6,35.4.
Its mass spectrum is：MS(EI,m/z):530(M++1).
Embodiment 32
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- (furans -2- ylmethyls) aniline, N-Boc-3- chlorine propylamine is replaced with by the N-Boc-2- chlorethamins in (2) step, obtained (Z)-N- (2- ((4- (N- (4- ((furans -2- ylmethyls) carbamoyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- Evil bis- Azoles -3- bases) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H), 8.76 (s, 1H), 7.68 (d, J=4.0Hz, 1H), 7.56-7.52 (m, 6H), 6.93 (m, 2H), 6.37-6.35 (m, 2H), 6.08(s,1H),4.79(s,1H),3.35(m,2H),3.15(m,2H),1.75(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,153.2,147.1,145.3,143.6, 142.9,141.4,138.8,134.8,131.3,118.6,116.4,114.1,112.0,110.3,42.3,39.6,34.5, 25.4.
Its mass spectrum is：MS(EI,m/z):544(M++1).
Embodiment 33
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- Butyl benzamide, (Z)-N- obtained (2- ((4- (N- (4- (Butylcarbamoyl) phenyl)-N '-hydroxyl first miaow) -1,2, 5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H), 8.76 (s, 1H), 8.69 (s, 1H), 7.71 (d, J=4.0Hz, 1H), 7.55-7.52 (m, 5H), 6.97 (m, 2H), 6.08 (s, 1H),3.50(m,2H),3.32-3.30(m,4H),1.57(m,2H),1.32(m,2H),1.08(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,165.6,163.1,152.3,147.0,145.2,142.3, 138.7,133.9,132.3,129.2,126.2,119.6,115.1,114.3,48.3,38.7,32.1,20.1,15.4.
Its mass spectrum is：MS(EI,m/z):506(M++1).
Embodiment 34
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained by butyl benzamide ((4- (N- (4- (Butylcarbamoyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles The structural formula of [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.87(s,1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.78 (d, J=4.0Hz, 1H), 7.55-7.52 (m, 5H), 6.77 (m, 2H), 6.05 (s, 1H),3.35-3.32(m,4H),3.18(m,2H),3.18(m,2H),1.85(m,2H),1.58(m,2H),1.45(m,2H), 0.88(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.6,164.2,150.2,147.1,145.4,141.2, 137.7,134.9,134.0,131.3,126.2,118.6,116.3,114.1,42.3,39.3,32.2,28.7,19.1, 13.4.
Its mass spectrum is：MS(EI,m/z):520(M++1).
Embodiment 35
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- Ethyl benzamide, (Z)-N- obtained (2- ((4- (N- (4- (ethylaminocarbonyl) phenyl)-N '-hydroxyl first miaow) -1,2, 5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H), 8.78 (s, 1H), 8.41 (s, 1H), 7.79 (d, J=3.5Hz, 1H), 7.55-7.52 (m, 5H), 6.93 (m, 2H), 6.05 (s, 1H),3.50(m,2H),3.32-3.29(m,4H),1.07(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,165.6,163.1,152.3,148.0,146.5,141.3, 136.8,134.9,132.7,123.9,118.6,116.2,114.3,49.6,34.7,32.3,15.4.
Its mass spectrum is：MS(EI,m/z):478(M++1).
Embodiment 36
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained by ethyl benzamide ((4- (N- (4- (ethylaminocarbonyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles The structural formula of [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.83(s,1H), 8.79 (s, 1H), 8.46 (s, 1H), 7.89 (d, J=3.5Hz, 1H), 7.50-7.47 (m, 5H), 6.90 (m, 2H), 6.12 (s, 1H),3.35-3.28(m,4H),3.12(m,2H),1.87(m,2H),1.04(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.6,162.1,150.3,148.5,147.2,142.3, 138.8,134.7,130.8,124.2,117.6,116.4,113.4,42.6,39.8,34.7,23.3,14.8.
Its mass spectrum is：MS(EI,m/z):492(M++1).
Embodiment 37
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into amino -2 4-, 6- dimethyl-N -s (2- (piperidin-1-yl) benzamide, (Z)-N- (2- ((4- (N- (3,5- dimethyl -4- ((2- piperazines obtained Pyridine -1- bases) ethylaminocarbonyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1, 2-a] pyridine -6- formamides structural formula it is as follows:
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H), 8.74 (s, 1H), 8.61 (s, 1H), 7.81 (d, J=3.9Hz, 1H), 7.60 (t, J=4.9Hz, 1H), 7.48 (s, 2H), 6.93 (s,2H),6.05(s,1H),3.60(m,2H),3.50(m,2H),3.32(m,2H),2.60(m,2H),2.48(s,6H),2.32 (m,4H),1.47(m,4H),1.17(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,153.2,149.5,148.0,136.8, 134.9,132.7,128.8,116.5,114.3,113.4,56.2,53.4,49.6,39.2,37.7,25.3,24.6,15.4.
Its mass spectrum is：MS(EI,m/z):589(M++1).
Embodiment 38
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into amino -2 4-, (2- (piperidin-1-yl) benzamide, N-Boc-3- chlorine is replaced with by the N-Boc-2- chlorethamins in (2) step to 6- dimethyl-N -s Propylamine, (Z)-N- (2- ((4- (N- (3,5- dimethyl -4- ((2- piperidin-1-yls) propvlcarbamovl) phenyl)-obtained N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.19(s,1H),9.79(s,1H),8.98(s,1H), 8.78 (s, 1H), 8.67 (s, 1H), 7.77 (d, J=3.9Hz, 1H), 7.67 (m, 1H), 7.26 (s, 2H), 6.88 (s, 2H), 6.05(s,1H),3.60(m,2H),3.36(m,2H),3.12(m,2H),2.38(s,6H),2.22-2.20(m,6H),1.85 (m,2H),1.47(m,4H),1.27(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,152.3,147.5,147.0,146.5, 138.8,134.9,134.0,127.2,118.6,114.3,112.9,56.9,52.0,41.6,39.7,32.3,27.5,25.9, 22.4,15.4.
Its mass spectrum is：MS(EI,m/z):603(M++1).
Embodiment 39
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into amino -2 4-, 6- dimethyl-N -s (2- (morpholine -1- bases) benzamide, (Z)-N- (2- ((4- (N- (3,5- dimethyl -4- ((2- obtained Quinoline ethyl) carbamoyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.88(s,1H), 8.74 (s, 1H), 8.66 (s, 1H), 7.79 (d, J=3.9Hz, 1H), 7.60 (t, J=5.0Hz, 1H), 7.48 (s, 2H), 6.93 (s,2H),6.05(s,1H),3.60(m,2H),3.52-3.50(m,6H),3.42(m,2H),2.56(m,2H),2.48(s, 6H),2.32(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,165.6,164.1,152.2,147.5,147.0,145.3, 138.8,134.9,134.0,128.8,116.5,114.3,112.4,69.8,55.2,54.5,49.6,40.2,36.5,17.8.
Its mass spectrum is：MS(EI,m/z):591(M++1).
Embodiment 40
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into amino -2 4-, (2- (morpholine -1- bases) benzamide, N-Boc-3- chlorine is replaced with by the N-Boc-2- chlorethamins in (2) step to 6- dimethyl-N -s Propylamine, (Z)-N- (2- ((4- (N- (3,5- dimethyl -4- ((2- morpholines propyl) carbamoyl) phenyl)-N '-hydroxyls obtained Base first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.12(s,1H),9.88(s,1H),8.92(s,1H), 8.84 (s, 1H), 8.75 (s, 1H), 7.60 (d, J=4.2Hz, 1H), 7.67 (t, J=5.0Hz, 1H), 7.58 (s, 2H), 6.99 (s,2H),6.15(s,1H),3.60(m,2H),3.52(m,2H),3.42(m,2H),3.19(m,2H),2.59(m,2H),2.48 (s,6H),2.42(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.3,165.6,164.1,152.8,147.6,147.2,144.3, 138.5,133.9,132.7,129.8,127.4,116.5,115.3,113.4,66.8,53.2,52.5,41.6,38.2, 35.2,27.8,18.3.
Its mass spectrum is：MS(EI,m/z):605(M++1).
Embodiment 41
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- (diethylamino) propionamide, (Z)-N- (2- ((4- (N- (4- (3- (diethylamino) propionamido-) obtained Phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.88(s,1H), 8.74 (s, 1H), 8.61 (s, 1H), 7.81 (d, J=3.9Hz, 1H), 7.60 (t, J=4.9Hz, 1H), 7.48 (s, 2H), 6.93 (s,2H),6.05(s,1H),3.60(m,2H),3.50(m,2H),3.32(m,2H),2.60(m,2H),2.48(s,6H),2.32 (m,4H),1.47(m,4H),1.17(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,153.2,149.5,148.0,136.8, 134.9,132.7,128.8,116.5,114.3,113.4,56.2,53.4,49.6,39.2,37.7,25.3,24.6,15.4.
Its mass spectrum is：MS(EI,m/z):549(M++1).
Embodiment 42
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- (diethylamino) propionamide, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, are made (Z)-N- (2- ((4- (N- (4- (3- (diethylamino) propionamido-) phenyl)-N '-hydroxyl first the miaow) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.12(s,1H),9.88(s,1H),8.92(s,1H), 8.84 (s, 1H), 8.75 (s, 1H), 7.60 (d, J=4.2Hz, 1H), 7.67 (t, J=5.0Hz, 1H), 7.58 (s, 2H), 6.99 (s,2H),6.15(s,1H),3.60(m,2H),3.52(m,2H),3.42(m,2H),3.19(m,2H),2.59(m,2H),2.48 (s,6H),2.42(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.3,165.6,164.1,152.8,147.6,147.2,144.3, 138.5,133.9,132.7,129.8,127.4,116.5,115.3,113.4,66.8,53.2,52.5,41.6,38.2, 35.2,27.8,18.3.
Its mass spectrum is：MS(EI,m/z):563(M++1).
Embodiment 43
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) propionamide, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- propionamido-s phenyl) first miaow -1,2,5- oxadiazoles-obtained 3- yls) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.56(s,1H),10.16(s,1H),9.88(s,1H), 8.78 (s, 1H), 8.53 (s, 1H), 7.64 (d, J=3.9Hz, 1H), 7.50 (t, J=5.0Hz, 1H), 7.48 (s, 2H), 7.08 (d, J=4.9Hz, 2H), 6.77 (d, J=5.2Hz, 2H), 6.05 (s, 1H), 3.52-3.50 (m, 4H), 2.56 (m, 2H), 2.48 (s, 6H), 1.02 (t, J=2.8Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ170.3,165.6,163.1,153.8,147.5,145.3,138.3, 134.9,133.7,128.8,116.5,115.9,114.3,49.6,37.2,30.5,10.8.
Its mass spectrum is：MS(EI,m/z):478(M++1).
Embodiment 44
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) propionamide, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained ((4- (N '-hydroxy-ns-(4- propionamido-s phenyl) first miaow -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyrrole The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.62(s,1H),10.03(s,1H),9.79(s,1H), 8.92 (s, 1H), 8.64 (s, 1H), 7.68 (d, J=4.9Hz, 1H), 7.57 (t, J=5.3Hz, 1H), 7.58 (s, 2H), 7.02 (d, J=4.8Hz, 2H), 6.78 (d, J=5.2Hz, 2H), 6.15 (s, 1H), 3.60 (m, 2H), 3.45 (m, 2H), 3.12 (m, 2H), 2.48 (s, 2H), 1.67 (m, 2H), 1.72 (m, 2H), 1.12 (t, J=2.8Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ172.3,165.6,163.1,153.2,148.2,145.3,138.5, 134.9,133.7,129.8,128.4,122.4,116.5,116.3,115.3,66.8,41.6,39.2,35.2,30.6, 28.8,10.3.
Its mass spectrum is：MS(EI,m/z):492(M++1).
Embodiment 45
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- chlorobenzamides, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is (Z)-obtained N- (2- ((4- (3- chloro-benzoyl aminos) phenyl)-N '-hydroxyl first miaow -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles The structural formula of [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.56(s,1H),10.26(s,1H),9.89(s,1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.95-7.90 (m, 2H), 7.82 (d, J=3.9Hz, 1H), 7.79-7.70 (m, 3H), 7.48 (s, 2H), 7.40 (d, J=2.9Hz, 2H), 6.72 (d, J=4.9Hz, 2H), 6.13 (s, 1H), 3.42-3.40 (m, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.3,164.6,163.1,153.8,148.5,144.3,138.2, 138.9,135.7,134.2,133.2,132.7,130.9,127.8,125.4,121.3,116.9,116.0,114.3,49.6, 37.2.
Its mass spectrum is：MS(EI,m/z):560(M++1).
Embodiment 46
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- chlorobenzamides, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is (Z)-obtained N- (2- ((4- (3- chloro-benzoyl aminos) phenyl)-N '-hydroxyl first miaow -1,2,5- oxadiazole -3- bases) aminopropyl) imidazoles [1, 2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.43(s,1H),10.35(s,1H),9.88(s,1H), 8.76 (s, 1H), 8.53 (s, 1H), 7.95-7.90 (m, 2H), 7.82 (d, J=3.9Hz, 1H), 7.69-7.60 (m, 3H), 7.48 (s, 2H), 7.32 (d, J=2.3Hz, 2H), 6.78 (d, J=4.9Hz, 2H), 6.06 (s, 1H), 3.42 (m, 2H), 3.12 (m,2H)
ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.3,165.6,162.1,152.8,147.5,145.2,137.2, 138.9,135.7,134.2,133.2,131.3,129.9,127.8,124.4,122.3,116.9,116.3,114.3,49.6, 41.3,27.2.
Its mass spectrum is：MS(EI,m/z):574(M++1).
Embodiment 47
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- phenyl amino phenyl formamides, (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (3- phenylaminos) phenylpropyl alcohol acylamino-) obtained Phenyl) first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.49(s,1H),10.16(s,1H),9.88(s,1H), 8.74 (s, 1H), 8.67 (s, 1H), 8.23 (s, 2H), 7.98 (d, J=4.9Hz, 1H), 7.82 (d, J=3.9Hz, 1H), 7.69 (t, J=3.9Hz, 1H), 7.38-7.32 (m, 4H), 7.08-7.02 (m, 3H), 6.77 (d, J=5.9Hz, 2H), 6.03 (s, 1H),3.42-3.40(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.3,164.7,162.1,152.8,147.5,145.3,141.3, 139.2,138.0,134.7,134.2,133.2,132.7,131.9,129.8,126.7,124.4,122.3,120.7, 116.9,114.3,49.6,39.2.
Its mass spectrum is：MS(EI,m/z):633(M++1).
Embodiment 48
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -3- phenyl amino phenyl formamides, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is obtained (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (3- phenylaminos) phenylpropyl alcohol acylamino-) phenyl) first miaow) -1,2,5- oxadiazole -3- bases) Amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.49(s,1H),10.16(s,1H),9.88(s,1H), 8.74 (s, 1H), 8.36 (s, 1H), 8.30 (s, 2H), 7.98 (d, J=4.9Hz, 1H), 7.79 (d, J=3.9Hz, 1H), 7.65 (d, J=3.9Hz, 1H), 7.54 (t, J=3.9Hz, 1H), 7.48-7.42 (m, 7H), 7.08-7.02 (m, 3H), 6.77 (d, J =5.9Hz, 2H), 6.12 (s, 1H), 3.52 (m, 2H), 3.18 (m, 2H), 1.72 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.2,163.7,161.1,153.8,148.5,146.4,142.3, 140.0,138.2,135.7,134.6,133.2,131.9,130.9,127.8,125.7,124.4,121.3,119.7, 117.2,113.9,41.6,39.2,18.3.
Its mass spectrum is：MS(EI,m/z):647(M++1).
Embodiment 49
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -2- methoxyl acetamides, (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (2- methoxyl acetamides base) phenyl) obtained First miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),9.65(s,1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.79 (m, 1H), 7.60 (m, 1H), 7.48 (d, J=3.6Hz, 2H), 7.32 (d, J= 5.6Hz, 2H), 6.75 (d, J=5.6Hz, 2H), 6.04 (s, 1H), 4.20 (s, 2H), 3.45 (m, 4H), 3.20 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ169.2,165.3,163.5,152.2,147.9,145.9,138.4, 134.9,133.9,133.2,130.6,128.7,122.7,117.3,116.2,114.2,71.4,56.3,48.9,39.9.
Its mass spectrum is：MS(EI,m/z):494(M++H).
Embodiment 50
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -2- methoxyl acetamides, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is obtained (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (2- methoxyl acetamides base) phenyl) first miaow) -1,2,5- oxadiazole -3- bases) ammonia Base) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),9.65(s,1H), 8.67 (s, 1H), 8.34 (s, 1H), 7.79 (m, 1H), 7.60 (m, 1H), 7.48 (d, J=3.6Hz, 2H), 7.32 (d, J= 5.6Hz, 2H), 6.79 (d, J=5.6Hz, 2H), 6.04 (s, 1H), 4.30 (s, 2H), 3.40 (s, 3H), 3.32 (m, 2H), 3.18(m,2H),1.88(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ169.2,165.3,162.5,152.2,147.9,145.1,138.4, 134.9,133.9,133.2,130.6,128.7,122.7,117.3,116.2,114.2,71.9,57.3,41.9,38.9, 28.8.
Its mass spectrum is：MS(EI,m/z):508(M++H).
Embodiment 51
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -4- methoxy benzamides, (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (4- methoxy benzamides base) benzene obtained Base) first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),10.20(s,1H),9.87(s,1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.95 (d, J=6.4Hz, 2H), 7.79 (m, 1H), 7.60 (m, 1H), 7.45 (m, 4H), 7.05 (d, J=6.4Hz, 2H), 6.74 (d, J=6.4Hz, 2H), 6.04 (s, 1H), 3.80 (s, 3H), 3.45 (m, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,165.2,164.4,163.6,152.9,147.9,147.2, 145.6,138.4,134.9,133.9,130.2,128.6,127.7,126.5,126.7,117.9,116.3,115.2, 114.3,55.4,48.9,39.9.
Its mass spectrum is：MS(EI,m/z):556(M++H).
Embodiment 52
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into N- (4- amino Phenyl) -4- methoxy benzamides, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is obtained (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (4- methoxy benzamides base) phenyl) first miaow) -1,2,5- oxadiazole -3- bases) ammonia Base) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),10.20(s,1H),9.87(s,1H), 8.67 (s, 1H), 8.34 (s, 1H), 7.95 (d, J=6.4Hz, 2H), 7.79 (m, 1H), 7.60 (m, 1H), 7.45 (m, 4H), 7.05 (d, J=6.4Hz, 2H), 6.74 (d, J=6.4Hz, 2H), 6.04 (s, 1H), 3.80 (s, 3H), 3.35 (m, 2H), 3.15 (m,2H),1.83(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,165.1,164.4,163.6,153.9,148.2,147.2, 145.6,138.4,134.9,133.9,130.2,128.6,127.7,126.5,126.7,117.9,116.3,115.2, 114.3,55.9,41.9,39.9,28.1.
Its mass spectrum is：MS(EI,m/z):570(M++H).
Embodiment 53
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- thiophenyls Aniline, (Z)-N- (2- ((4-N '-hydroxy-ns-(4- (thiophenyl) phenyl) first miaow) -1,2,5- oxadiazole -3- bases) ammonia obtained Base) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.75(s,1H), 8.61(m,1H),7.79(m,1H),7.63(m,1H),7.45(m,7H),7.05(m,4H),6.08(s,1H),3.42(m,4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5, 135.2,134.8,134.0,132.0,131.3,129.8,128.6,127.3,125.6,116.6,115.4,114.9,48.4, 39.9.
Its mass spectrum is：MS(EI,m/z):515(M++H).
Embodiment 54
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- thiophenyls N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4-N '-hydroxyls obtained by aniline Base-N- (4- (thiophenyl) phenyl) first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- formyls The structural formula of amine is as follows:
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H), 8.34(m,1H),7.79(m,1H),7.63(m,1H),7.45(m,7H),7.05(m,4H),6.08(s,1H),3.40(m,2H), 3.18(m,2H),1.80(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.5,163.2,152.9,148.9,145.2,138.4,136.5, 135.6,134.8,134.2,132.0,131.1,129.8,128.6,127.3,125.6,116.6,115.4,114.2,41.4, 39.2,28.3.
Its mass spectrum is：MS(EI,m/z):529(M++H).
Embodiment 55
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- chlorine Phenyl) sulfenyl) aniline, (Z)-N- obtained (2- ((4-N- (4- ((4- chlorphenyls) sulphur) phenyl)-N ' hydroxy formamidines base) -1,2, 5- oxadiazole -3- bases) amino) ethyl) and imidazo [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.00(s,1H),9.89(s,1H),8.75(s,1H), 8.65 (m, 1H), 7.78 (m, 3H), 7.63 (m, 1H), 7.45 (d, J=4.8Hz, 2H), 7.19 (d, J=4.8Hz, 2H), 7.08 (m,4H),6.08(s,1H),3.42(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5, 135.1,134.3,133.2,132.8,130.8,130.0,129.8,128.6,125.3,116.6,115.4,114.9,48.4, 39.9.
Its mass spectrum is：MS(EI,m/z):549(M++H).
Embodiment 56
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- chlorine Phenyl) sulfenyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- obtained (2- ((4-N- (4- ((4- chlorphenyls) sulphur) phenyl)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) propyl) miaow Azoles is simultaneously
[1,2-a] pyridine -6- formamides it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.00(s,1H),9.89(s,1H),8.65(s,1H), 8.35 (m, 1H), 7.78 (m, 3H), 7.63 (m, 1H), 7.45 (d, J=4.8Hz, 2H), 7.19 (d, J=4.8Hz, 2H), 7.08 (m,4H),6.08(s,1H),3.42(m,2H),3.12(m,2H),1.82(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.9,145.2,138.7,136.5, 135.1,134.3,133.2,132.8,130.8,130.0,129.8,128.6,125.3,116.6,115.4,114.9,48.4, 39.9.
Its mass spectrum is：MS(EI,m/z):563(M++H).
Embodiment 57
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- diethylaminos Base aniline, (Z)-N- (2- ((4-N- (4- lignocaines) phenyl)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- obtained Base) amino) ethyl) and imidazo [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.87(s,1H),8.75(s,1H), 8.61 (m, 1H), 7.79 (m, 1H), 7.63 (m, 1H), 7.48 (d, J=4.8Hz, 2H), 6.69 (d, J=4.4Hz, 2H), 6.46 (d, J=4.4Hz, 2H), 6.02 (s, 1H), 3.42 (m, 8H), 1.29 (t, J=8.4Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,147.1,145.2,139.7,138.5, 135.2,134.8,130.7,128.6,127.0,117.0,116.3,114.8,113.6,48.4,47.6,38.4,13.9.
Its mass spectrum is：MS(EI,m/z):478(M++H).
Embodiment 58
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- diethylaminos N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4-N- obtained by base aniline (4- lignocaines) phenyl)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazo [1,2-a] pyrrole The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.87(s,1H),8.65(s,1H), 8.31 (m, 1H), 7.79 (m, 1H), 7.63 (m, 1H), 7.48 (d, J=4.8Hz, 2H), 6.63 (d, J=4.4Hz, 2H), 6.36 (d, J=4.4Hz, 2H), 6.02 (s, 1H), 3.42 (m, 6H), 3.12 (m, 2H), 1.82 (m, 6H), 1.19 (t, J=8.4Hz, 6H) its carbon of ppm. spectrum is：13C NMR(125MHz,DMSO):δ166.5,164.2,152.1,147.1,145.2,139.4, 137.5,135.2,134.8,131.7,128.6,127.0,117.0,116.3,114.8,113.6,48.4,41.6,39.4, 28.9,15.9.
Its mass spectrum is：MS(EI,m/z):492(M++H).
Embodiment 59
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- diformazan ammonia Base aniline, (Z)-N- (2- ((4-N- (4- dimethylaminos) phenyl)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- obtained Base) amino) ethyl) and imidazo [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),8.75(s,1H), 8.65 (m, 1H), 7.79 (m, 1H), 7.60 (m, 1H), 7.43 (d, J=4.4Hz, 2H), 6.75 (d, J=4.4Hz, 2H), 6.49 (d, J=4.4Hz, 2H), 6.03 (s, 1H), 3.42 (m, 4H), 3.09 (s, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,152.9,148.5,147.9,145.2,138.7, 135.2,134.8,131.3,127.3,117.6,116.6,114.4,113.9,48.4,41.4,39.9.
Its mass spectrum is：MS(EI,m/z):450(M++H).
Embodiment 60
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- diformazan ammonia N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4-N- obtained by base aniline (4- dimethylaminos) phenyl)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazo [1,2-a] pyrrole The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),8.65(s,1H), 8.35 (m, 1H), 7.73 (m, 1H), 7.60 (m, 1H), 7.45 (d, J=4.4Hz, 2H), 6.75 (d, J=4.4Hz, 2H), 6.46 (d, J=4.4Hz, 2H), 6.03 (s, 1H), 3.42 (m, 2H), 3.12 (m, 2H), 3.03 (s, 6H), 1.83 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.5,164.2,152.9,148.5,147.9,145.6,138.7, 135.2,134.2,131.3,125.3,117.6,116.6,114.4,113.9,41.9,41.2,39.9,28.5.
Its mass spectrum is：MS(EI,m/z):464(M++H).
Embodiment 61
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1- morpholines Base) aniline, (Z)-N- (2- ((4- (N- (4- morpholino phenyls)-N '-hydroxyl first miaows base) -1,2,5- diazole -3- bases) obtained Amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.86(s,1H),8.63(s,1H), 8.32 (s, 1H), 7.72 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.70 (m, 2H), 6.55 (m, 2H), 6.08 (s, 1H), 3.73 (t, J=8.0Hz, 4H), 3.48 (m, 4H), 3.10 (t, J=8.0Hz, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.7,163.6,157.2,152.9,147.1,145.2,138.6, 134.9,134.1,133.3,129.6,119.2,114.8,115.2,66.5,53.9,48.6,39.2.
Its mass spectrum is：MS(EI,m/z):492(M++H).
Embodiment 62
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1- morpholines Base) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- obtained (N- (4- morpholino phenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine - The structural formula of 6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),8.76(s,1H), 8.42 (s, 1H), 7.79 (d, J=3.6Hz, 1H), 7.64 (m, 1H), 7.48 (s, 2H), 6.80 (m, 2H), 6.54 (m, 2H), 6.05 (s, 1H), 3.75 (t, J=8.0Hz, 4H), 3.54 (m, 2H), 3.18 (m, 2H), 3.04 (t, J=8.0Hz, 4H), 1.85 (m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.9,164.5,152.4,147.6,145.3,144.1,140.9, 138.6,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,66.0,54.2,46.3, 45.2,29.8.
Its mass spectrum is：MS(EI,m/z):506(M++H).
Embodiment 63
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (4- methyl Piperazinyl) aniline, (Z)-N- obtained (2- ((4- (N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) phenyl) first miaow base) -1, 2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.09(s,1H),9.86(s,1H),8.43(s,1H), 8.13 (s, 1H), 7.71 (d, J=6.4Hz, 1H), 7.48 (m, 3H), 7.07 (m, 1H), 6.69 (m, 2H), 6.50 (m, 3H), 6.08 (s, 1H), 3.50-3.43 (m, 8H), 2.38 (t, J=6.4Hz, 4H), 2.21 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.5,148.9,147.9,145.3,140.1,136.5, 134.8,134.0,133.7,132.6,127.6,126.2,117.8,115.2,114.3,113.6,57.3,52.1,48.3, 46.5,39.2.
Its mass spectrum is：MS(EI,m/z):505(M++H).
Embodiment 64
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (4- methyl Piperazinyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained ((4- (N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) The structural formula of imidazoles [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.39(s,1H),9.88(s,1H),8.43(s,1H), 8.15 (s, 1H), 7.73 (d, J=6.4Hz, 1H), 7.48 (m, 3H), 7.09 (m, 1H), 6.69 (m, 2H), 6.53 (m, 3H), 6.08 (s, 1H), 3.49 (m, 8H), 2.38 (t, J=6.4Hz, 4H), 2.21 (s, 3H), 1.80 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.5,148.9,147.9,145.3,140.1,136.5, 134.8,134.0,133.7,132.6,127.6,126.2,117.8,115.2,114.3,113.6,57.3,52.1,48.3, 46.5,39.2,28.9.
Its mass spectrum is：MS(EI,m/z):519(M++H).
Embodiment 65
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1- piperazines Base) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (piperidin-1-yl) phenyl) first miaow base) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.49(s,1H),9.82(s,1H),8.42(s,1H), 8.11 (s, 1H), 7.71 (d, J=6.4Hz, 1H), 7.46 (m, 3H), 7.03 (m, 1H), 6.69 (m, 2H), 6.50 (m, 3H), 6.08(s,1H),3.47(m,8H),1.58(m,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.4,163.1,148.9,147.4,145.3,140.0,136.5, 134.5,134.3,133.7,132.2,127.1,126.1,117.6,115.2,114.1,113.6,54.2,48.3,39.2, 25.6,24.3.
Its mass spectrum is：MS(EI,m/z):490(M++H).
Embodiment 66
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1- piperazines Base) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- ((4- obtained (N '-hydroxy-ns-(4- (piperidin-1-yl) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] The structural formula of pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.39(s,1H),9.86(s,1H),8.45(s,1H), 8.17 (s, 1H), 7.73 (d, J=6.4Hz, 1H), 7.46 (m, 3H), 7.06-7.00 (m, 1H), 6.66 (m, 2H), 6.52 (m, 3H),6.08(s,1H),3.46(m,8H),1.75(m,8H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.6,163.5,148.7,147.4,145.3,140.5,136.1, 134.8,134.0,133.3,132.6,127.3,126.2,117.8,115.6,114.3,113.3,54.3,42.5,41.5, 28.8,25.5,24.2.
Its mass spectrum is：MS(EI,m/z):504(M++H).
Embodiment 67
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3- fluoroforms Base -4- (1- morpholinyls) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholinyls -3- (trifluoromethyl) phenyl) obtained First miaow base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.39(s,1H),9.86(s,1H),8.40(s,1H), 8.11 (s, 1H), 7.71 (d, J=6.4Hz, 1H), 7.45 (m, 3H), 7.02 (m, 2H), 6.49 (m, 3H), 6.01 (s, 1H), 3.70 (t, J=8.0Hz, 4H), 3.50 (m, 4H), 3.14 (t, J=8.0Hz, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.0,148.9,147.5,145.8,136.9,134.9, 134.6,134.3,133.9,133.2,132.2,126.6,125.2,120.8,115.9,115.1,114.5,113.8, 113.3,66.3,53.1,48.3,39.2.
Its mass spectrum is：MS(EI,m/z):560(M++H).
Embodiment 68
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3- fluoroforms Base -4- (1- morpholinyls) aniline, N-Boc-3- chlorine propylamine is replaced with by the N-Boc-2- chlorethamins in (2) step, obtained (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholinyls -3- (trifluoromethyl) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) Amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.43(s,1H),9.81(s,1H),8.41(s,1H), 8.13 (s, 1H), 7.72 (d, J=6.4Hz, 1H), 7.45 (m, 3H), 7.01 (m, 2H), 6.48 (m, 3H), 6.05 (s, 1H), 3.72 (t, J=8.0Hz, 4H), 3.35 (m, 2H), 3.14 (m, 6H), 1.85 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.4,163.3,148.5,147.7,145.3,136.9,135.4, 134.7,134.3,133.7,133.1,132.2,126.6,125.1,120.4,115.4,115.1,114.3 113.8, 113.0,66.0,53.4,42.9,41.3,29.2.
Its mass spectrum is：MS(EI,m/z):574(M++H).
Embodiment 69
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into the fluoro- 4- of 3- (N- ethyls-N '-(2- ethoxys) amino) aniline, (Z)-N- (2- ((4- (ethyl (ethoxy) amino) -3- fluorobenzene obtained Base-N '-hydroxyls-first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles [1,2-a] pyridine -6- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.36(s,1H),9.84(s,1H),8.41(s,1H), 8.12 (s, 1H), 7.73 (d, J=6.4Hz, 1H), 7.45 (m, 3H), 7.05 (m, 2H), 6.75 (s, 1H), 6.51 (m, 2H), 6.26 (m, 1H), 4.85 (s, 1H), 4.20 (t, J=7.2Hz, 2H), 3.73 (m, 2H), 3.45 (m, 6H), 1.21 (t, J= 8.0Hz,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.0,156.3,148.9,147.5,145.8,136.9, 135.4,134.9,134.2,133.8,132.9,127.6,126.2,116.8,115.9,114.1,112.5,105.3,61.3, 58.1,48.3,47.1,39.2,12.5.
Its mass spectrum is：MS(EI,m/z):512(M++H).
Embodiment 70
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into the fluoro- 4- of 3- (N- ethyls-N '-(2- ethoxys) amino) aniline, N-Boc-3- chlorine third is replaced with by the N-Boc-2- chlorethamins in (2) step Amine, (Z)-N- (2- ((4- (ethyl (ethoxy) amino) -3- fluorophenyls-N '-hydroxyl-first miaow base) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.46(s,1H),9.80(s,1H),8.44(s,1H), 8.16 (s, 1H), 7.71 (d, J=6.4Hz, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 6.75 (s, 1H), 6.53 (m, 2H), 6.26 (m, 1H), 4.82 (s, 1H), 4.23 (t, J=7.2Hz, 2H), 3.71 (m, 2H), 3.38 (m, 4H), 3.18 (m, 2H), 1.23 (t, J=8.0Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.0,163.5,156.3,148.3,147.2,145.8,136.9, 135.6,134.9,134.1,133.1,132.4,127.3,126.5,116.2,115.9,114.5,112.4,105.3,61.3, 58.6,48.3,47.8,39.2,28.3,12.2.
Its mass spectrum is：MS(EI,m/z):526(M++H).
Embodiment 71
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 2- methoxyl groups- 4- (2,6- dimethylated morpholinyl) aniline, (Z)-N- (2- ((4- (N- (4- (2,6- dimethylated morpholinyl) -2- methoxyl groups obtained Phenyl)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazoles [1,2-a] pyridine -6- formamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.59(s,1H),9.96(s,1H),8.41(s,1H), 8.11 (s, 1H), 7.71 (d, J=6.4Hz, 1H), 7.49 (m, 3H), 7.00 (m, 2H), 6.46 (m, 1H), 6.21 (m, 3H), 6.11 (m, 1H), 3.90 (s, 3H), 3.55 (m, 6H), 3.14 (m, 4H), 1.11 (d, J=6.4Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.0,148.8,148.3,147.2,145.6,140.9, 136.9,135.6,134.7,133.6,132.2,126.6,122.2,118.8,115.9,114.1,104.5,98.5,73.3, 68.9,55.1,48.3,39.2,19.7.
Its mass spectrum is：MS(EI,m/z):550(M++H).
Embodiment 72
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 2- methoxyl groups- 4- (2,6- dimethylated morpholinyl) aniline, N-Boc-3- chlorine propylamine is replaced with by the N-Boc-2- chlorethamins in (2) step, is made (Z)-N- (2- ((4- (N- (4- (2,6- dimethylated morpholinyls) -2- methoxyphenyls)-N '-hydroxyl first miaows base) -1,2,5- Evil Diazole -3- bases) amino) propyl) and imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.45(s,1H),9.94(s,1H),8.42(s,1H), 8.11 (s, 1H), 7.73 (d, J=6.4Hz, 1H), 7.39 (m, 3H), 7.06 (m, 2H), 6.46 (m, 1H), 6.21 (m, 3H), (6.11 m, 1H), 3.86 (s, 3H), 3.55 (m, 2H), 3.30 (m, 4H), 3.14 (m, 4H), 1.86 (m, 2H), 1.11 (d, J= 6.4Hz,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.2,163.3,148.5,148.2,147.7,145.6,140.9, 136.5,135.6,134.3,133.4,132.2,126.0,122.1,118.3,115.4,114.1,104.5,98.5,73.3, 68.9,55.0,42.3,41.3,28.4,19.3.
Its mass spectrum is：MS(EI,m/z):590(M++H).
Embodiment 73
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (3- hydroxyls Pyrroles -1- bases) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (3- hydroxypyrrole -1- bases) phenyl) first miaows obtained Base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.43(s,1H),9.89(s,1H),8.46(s,1H), 8.18 (s, 1H), 7.72 (d, J=6.4Hz, 1H), 7.45 (m, 3H), 7.01 (m, 2H), 6.65 (m, 2H), 6.49 (m, 3H), 6.05(s,1H),5.39(s,1H),3.69(m,1H),3.42(m,5H),3.15(m,3H),1.75(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.4,163.3,148.5,147.3,145.6,139.9,136.4, 135.4,134.2,133.3,132.7,127.6,126.1,118.4,116.4,114.6,113.3,71.8,65.0,49.4, 48.1,41.3,39.2.
Its mass spectrum is：MS(EI,m/z):492(M++H).
Embodiment 74
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (3- hydroxyls Pyrroles -1- bases) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- obtained (2- ((4- (N '-hydroxy-ns-(4- (3- hydroxypyrrole -1- bases) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) third Base) imidazoles [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.33(s,1H),9.99(s,1H),8.46(s,1H), 8.28 (s, 1H), 7.72 (d, J=6.4Hz, 1H), 7.55 (m, 3H), 7.11 (m, 2H), 6.65 (m, 2H), 6.54 (m, 3H), 6.15(s,1H),5.39(s,1H),3.69(m,1H),3.39(m,3H),3.15(m,5H),1.75(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.4,163.3,148.9,147.3,145.6,138.9,136.4, 135.4,134.5,133.1,130.7,127.6,125.1,116.4,115.4,113.6,111.3,71.8,65.0,49.4, 43.1,41.3,38.2,28.4.
Its mass spectrum is：MS(EI,m/z):506(M++H).
Embodiment 75
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (morpholines- 1- bases sulfonyl) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (morpholine -1- bases sulfonyl) phenyl) carbonamidines obtained Base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.64(s,1H), 8.34 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 6.08 (s, 1H), 3.64 (t, J=7.2Hz, 4H), 3.48 (m, 4H), 2.99 (t, J=7.2Hz, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5, 134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,65.7,48.9,47.1, 39.2.
Its mass spectrum is：MS(EI,m/z):556(M++H).
Embodiment 76
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((morpholines- 1- bases sulfonyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- obtained (2- ((4- (N '-hydroxy-ns-(4- (morpholine -1- bases sulfonyl) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) third Base) imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.62(s,1H), 8.31 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 6.08 (s, 1H), 3.69 (t, J=7.2Hz, 4H), 3.33 (m, 4H), 2.99 (t, J=7.2Hz, 4H), 1.80 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.9,162.5,149.3,147.9,144.3,140.2,136.5, 134.8,134.0,133.3,132.6,131.2,128.3,126.8,115.2,114.5,111.9,65.7,46.9,43.1, 41.3,29.2.
Its mass spectrum is：MS(EI,m/z):570(M++H).
Embodiment 77
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- (first Base piperazine -1- bases) sulfonyl) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) sulphurs obtained Acyl) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1,2-a] pyridine -6- base formamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.83(s,1H),8.64(s,1H), 8.30 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 6.08(s,1H),3.54(m,4H),3.08(m,4H),2.39(m,4H),2.09(s,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5, 134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,57.7,49.9,48.8, 48.1,46.7,39.2.
Its mass spectrum is：MS(EI,m/z):569(M++H).
Embodiment 78
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- (first Base piperazine -1- bases) sulfonyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, are made (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) sulphonyl) phenyl) carbonamidine base) -1,2,5- oxadiazoles - 3- yls) amino) propyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.83(s,1H),8.64(s,1H), 8.30 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 6.90 (m, 2H), 6.75 (m, 2H), 6.08(s,1H),3.34(m,2H),3.08(m,6H),2.39(m,4H),2.09(s,3H),1.88(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.3,141.2,136.5, 134.8,134.0,133.3,132.6,131.2,129.3,126.8,115.2,114.5,112.9,56.7,48.9,46.8, 43.1,42.7,29.2.
Its mass spectrum is：MS(EI,m/z):583(M++H).
Embodiment 79
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((uncles N- Butylsulfamoyl base) aniline, (Z)-N- (2- ((4- (N- tertiary butyls sulfamoyl) phenyl) carbonamidine base) -1,2,5- Evil obtained Diazole -3- bases) amino) ethyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.10(s,1H),9.77(s,1H),8.41(s,1H), 8.13 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.40 (m, 4H), 7.20 (m, 2H), 6.97 (m, 1H), 6.85 (m, 2H), 6.45(m,1H),6.08(s,1H),3.44(m,4H),1.29(s,9H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,164.5,148.3,147.9,145.3,142.2,136.5, 134.8,134.0,133.3,132.6,130.2,129.3,126.8,115.2,114.5,112.9,48.7,46.3,39.9, 29.2.
Its mass spectrum is：MS(EI,m/z):542(M++H).
Embodiment 80
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((uncles N- Butylsulfamoyl base) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is (Z)-obtained N- (2- ((4- (N- tertiary butyls sulfamoyl) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazo [1, 2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.10(s,1H),9.77(s,1H),8.44(s,1H), 8.13 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.40 (m, 4H), 7.20 (m, 2H), 7.07 (m, 1H), 6.80 (m, 2H), 6.45(m,1H),6.08(s,1H),3.25(m,4H),1.88(m,2H),1.29(s,9H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,164.5,148.3,147.9,145.3,142.2,136.5, 134.8,134.0,133.3,132.6,130.2,129.3,126.8,115.2,114.5,112.9,47.7,42.9,41.3, 29.7.
Its mass spectrum is：MS(EI,m/z):556(M++H).
Embodiment 81
With embodiment 1 difference lies in：By the bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step replace with 4- ((N- (2, 4- difluorophenyls) sulfamoyl) aniline, (Z)-N- (2- ((4- (N- (4- (2,4- difluorophenyl) sulfamoyl) benzene obtained Base) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) ethyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.97(s,1H),9.67(s,1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.47 (m, 5H), 7.08 (m, 1H), 6.76 (m, 3H), 6.55(m,2H),6.08(s,1H),3.54(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,160.2,154.3,148.3,147.9,145.3, 141.2,136.5,135.6,134.3,133.5,132.6,131.2,130.3,129.4,126.8,119.2,115.7, 114.5,112.9,111.3,105.8,48.9,39.2.
Its mass spectrum is：MS(EI,m/z):598(M++H).
Embodiment 82
With embodiment 1 difference lies in：By the bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step replace with 4- ((N- (2, 4- difluorophenyls) sulfamoyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, are made (Z)-N- (2- ((4- (N- (4- (2,4 difluorobenzene base) sulfamoyl) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) ammonia Base) propyl) imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.97(s,1H),9.63(s,1H), 8.41 (s, 1H), 8.10 (s, 1H), 7.72 (d, J=3.6Hz, 1H), 7.43 (m, 5H), 7.01 (m, 1H), 6.76 (m, 3H), 6.45(m,2H),6.08(s,1H),3.34(m,4H),1.86(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.5,160.2,154.3,149.3,147.9,146.3, 142.2,136.5,135.6,134.3,133.5,132.6,131.2,130.3,129.4,126.8,119.2,115.7, 114.5,112.9,111.3,105.8,43.9,41.4,29.2.
Its mass spectrum is：MS(EI,m/z):612(M++H).
Embodiment 83
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- (3- Methoxyl group pyrazine -2- bases) sulfamoyl) aniline, (Z)-N- (2- ((4-N '-hydroxyls-(N- (4- (3- methoxies obtained Base pyrazine -2- bases) sulfamoyl) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1, 2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,2H),9.97(s,1H),8.44(s,1H), 8.13 (s, 1H), 8.03 (m, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 6H), 7.08 (m, 1H), 6.79 (m, 2H), 6.45(m,1H),6.08(s,1H),4.04(s,3H),3.36(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,149.3,148.9,148.1,147.5,145.3, 141.2,136.5,135.4,134.5,133.3,132.6,131.9,131.3,130.5,129.3,126.8,115.8, 114.5,112.2,55.7,48.9,39.0.
Its mass spectrum is：MS(EI,m/z):594(M++H).
Embodiment 84
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- (3- Methoxyl group pyrazine -2- bases) sulfamoyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- Chlorine propylamine, (Z)-N- (2- ((4-N '-hydroxyls-(N- (4- (3- methoxyl group pyrazine -2- bases) sulfamoyl) benzene obtained Base) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) propyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,2H),9.97(s,1H),8.44(s,1H), 8.16 (s, 1H), 8.03 (m, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 6H), 7.08 (m, 1H), 6.79 (m, 2H), 6.45(m,1H),6.08(s,1H),4.04(s,3H),3.36(m,2H),3.16(m,2H),1.86(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,164.5,150.3,148.9,148.1,146.5,145.3, 142.2,136.5,135.4,134.5,133.3,132.6,131.9,131.3,130.5,129.3,127.8,115.8, 114.5,113.2,55.7,43.9,42.1,29.0.
Its mass spectrum is：MS(EI,m/z):608(M++H).
Embodiment 85
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- (2- Ethoxy) sulfamoyl) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (N- (2- hydroxyethyls) sulfonamides obtained Base) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1,2-a] pyridine -6- base formamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.45(s,1H), 8.14 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 3H), 7.32 (m, 3H), 6.99 (m, 1H), 6.85 (m, 2H), 6.45(m,1H),6.08(s,1H),4.85(s,1H),3.48(m,8H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.5,148.3,147.9,146.1,140.2,136.5, 135.4,134.7,134.1,133.3,132.6,130.2,126.9,115.2,114.5,112.9,60.7,48.9,45.1, 39.2.
Its mass spectrum is：MS(EI,m/z):530(M++H).
Embodiment 86
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- (2- Ethoxy) sulfamoyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it is obtained (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (N- (2- hydroxyethyls) sulfamoyl) phenyl) carbonamidine base) -1,2,5- oxadiazoles - 3- yls) amino) ethyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.97(s,1H),8.45(s,1H), 8.14 (s, 1H), 7.76 (d, J=3.6Hz, 1H), 7.54 (m, 3H), 7.32 (m, 3H), 6.99 (m, 1H), 6.85 (m, 2H), 6.45(m,1H),6.08(s,1H),4.65(s,1H),3.40(m,6H),3.13(m,2H),1.70(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.5,149.3,147.9,146.1,140.2,137.5, 136.4,135.4,134.1,133.3,132.6,130.2,126.9,115.2,114.5,112.9,60.1,45.9,43.1, 41.8,29.2.
Its mass spectrum is：MS(EI,m/z):544(M++H).
Embodiment 87
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- second Base-N- propyl) sulfamoyl) aniline, (Z)-N- (2- ((4- (N- (4- (N- ethyl-N- propylsulfamovs) benzene obtained Base)-N '-hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1,2-a] pyridine -6- base formamides Structural formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.45(s,1H), 8.10 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 5H), 6.99 (m, 1H), 6.75 (m, 2H), 6.45 (m, 1H), 6.08 (s, 1H), 3.45 (m, 4H), 3.18 (m, 4H), 1.58 (m, 4H), 1.18 (t, J=7.2Hz, 3H), 0.89 (t, J= 7.2Hz,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,164.5,149.3,147.9,146.1,141.2,136.5, 135.4,134.7,133.7,132.6,130.2,128.6,126.9,115.2,114.5,112.9,52.7,48.9,41.1, 39.2,21.1,12.9,11.3.
Its mass spectrum is：MS(EI,m/z):556(M++H).
Embodiment 88
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((N- second Base-N- propyl) sulfamoyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, are made (Z)-N- (2- ((4- (N- (4- (N- ethyl-N- propylsulfamovs) phenyl)-N '-hydroxy formamidines base) -1,2,5- Evil bis- Azoles -3- bases) amino) propyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.97(s,1H),8.55(s,1H), 8.19 (s, 1H), 7.77 (d, J=3.6Hz, 1H), 7.51 (m, 5H), 6.99 (m, 1H), 6.75 (m, 2H), 6.45 (m, 1H), 6.18 (s, 1H), 3.25 (m, 6H), 3.08 (m, 2H), 1.58 (m, 4H), 1.08 (t, J=7.2Hz, 3H), 0.83 (t, J= 7.2Hz,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ168.8,165.5,149.3,147.9,146.1,142.2,136.5, 135.4,134.7,133.7,132.6,130.2,128.0,126.9,115.2,114.5,110.9,52.7,43.9,41.1, 39.2,28.4,21.1,13.9,12.3.
Its mass spectrum is：MS(EI,m/z):570(M++H).
Embodiment 89
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- first Base sulfonyl) piperazine -1- bases) aniline, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (4- sulfonyloxy methyls) piperazine -1- obtained Base) phenyl) carbonamidine base) -1,2,5- oxadiazole -3- bases) amino) ethyl) imidazo [1,2-a] pyridine -6- base formamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.44(s,1H),9.87(s,1H),8.67(s,1H), 8.63 (s, 1H), 7.73 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (m, 2H), 6.69 (m, 2H), 6.50 (m, 2H), 6.08(s,1H),3.45(m,4H),3.28(m,4H),3.19(m,4H),2.87(s,3H),2.58(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,164.5,152.3,147.9,146.1,141.2,136.5, 134.7,133.7,130.2,128.6,117.2,114.5,113.9,52.7,48.9,41.1,39.2
Its mass spectrum is：MS(EI,m/z):569(M++H).
Embodiment 90
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- ((4- first Base sulfonyl) piperazine -1- bases) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, are made (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (4- sulfonyloxy methyls) piperazine -1- bases) phenyl) carbonamidine base) -1,2,5- oxadiazoles - 3- yls) amino) propyl) and imidazo [1,2-a] pyridine -6- base formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.44(s,1H),9.87(s,1H),8.67(s,1H), 8.63 (s, 1H), 7.73 (d, J=3.6Hz, 1H), 7.60 (m, 1H), 7.48 (m, 2H), 6.69 (m, 2H), 6.50 (m, 2H), 6.08(s,1H),3.35(m,2H),3.18-3.15(m,6H),2.87(s,3H),2.48(m,4H),1.78(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ165.8,163.2,152.5 147.9,145.1,139.5,138.7, 134.8,133.7,130.2,127.6,118.2,114.5,113.7,52.7,47.9,41.8,37.2,28.9.
Its mass spectrum is：MS(EI,m/z):583(M++H).
Embodiment 91
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (methyl sulphurs Acylamino-) aniline, (Z)-N- obtained (2- ((4- (N '-hydroxy-ns-(4- (sulfonyloxy methyl amino) phenyl) first miaow base) -1,2, 5- oxadiazole -3- bases) amino) ethyl) and imidazo [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),10.04(s,1H),9.87(s,1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 3H), 7.05 (m, 1H), 6.65 (d, J= 4.8Hz,2H),6.48(m,3H),6.08(s,1H),3.42(m,4H),3.25(s,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,163.2,148.9,147.4,145.3,136.4,135.2, 134.4,133.5,132.0,128.8,127.3,125.1,118.8,117.5,115.6,114.3,48.3,42.6,38.9.
Its mass spectrum is：MS(EI,m/z):500(M++H).
Embodiment 92
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (methyl sulphurs Acylamino-) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, (Z)-N- (2- obtained ((4- (N '-hydroxy-ns-(4- (sulfonyloxy methyl amino) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) imidazoles And the structural formula of [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.84(s,1H),10.04(s,1H),9.87(s,1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.52 (m, 3H), 7.05 (m, 1H), 6.65 (d, J= 4.8Hz,2H),6.54(m,3H),6.08(s,1H),3.38(m,2H),3.25(s,3H),3.13(m,1H),1.88(m,2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.5,164.2,149.9,147.4,145.3,136.4,135.2, 134.2,133.5,132.0,127.8,126.3,125.1,118.8,117.5,115.6,114.3,43.3,42.6,41.9, 29.6.
Its mass spectrum is：MS(EI,m/z):514(M++H).
Embodiment 93
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into cyano -3 4-, 5- dimethylanilines, (Z)-N- obtained (3- ((4- (N- (4- (cyano -3,5- 3,5-dimethylphenyl)-N '-hydroxyl first miaows base) -1, 2,5- oxadiazole -3- bases) amino) ethyl) and imidazo [1,2-a] pyridine -6- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.40(s,1H), 8.11 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.50 (m, 3H), 7.04 (m, 1H), 6.94 (s, 2H), 6.45 (d, J= 4.8Hz,2H),6.08(s,1H),3.47(m,4H),2.25(s,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,164.2,148.9,148.2,147.2,145.3,142.4, 136.6,135.2,134.4,133.5,132.0,126.8,117.8,115.6,114.3,113.4,107.5,48.3,39.6, 21.9.
Its mass spectrum is：MS(EI,m/z):460(M++H).
Embodiment 94
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into cyano -3 4-, N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, (Z)-N- (3- obtained by 5- dimethylanilines ((4- (N- (4- (cyano -3,5- 3,5-dimethylphenyls)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) miaow The structural formula of azoles simultaneously [1,2-a] pyridine -6- formamides is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.40(s,1H), 8.11 (s, 1H), 7.61 (d, J=3.6Hz, 1H), 7.40 (m, 3H), 7.01 (m, 1H), 6.94 (s, 2H), 6.35 (d, J= 4.8Hz,2H),6.08(s,1H),3.37(m,2H),3.17(m,2H),2.35(s,6H),1.87(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.5,164.2,149.7,148.2,147.2,145.8,142.4, 136.6,135.2,134.4,133.5,132.0,126.8,117.3,115.1,114.3,113.4,108.5,42.3,41.4, 29.6,21.9.
Its mass spectrum is：MS(EI,m/z):474(M++H).
Embodiment 95
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- aminobenzenes Acetic acid esters, ethyl (Z) -4- (N '-hydroxyls -4- ((2- (imidazoles [1,2-a] pyridine -6- formamidos) ethyl) amino)-obtained 1,2,5- oxadiazole -3- first miaow) benzoic ether structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.40(s,1H), 8.15 (s, 1H), 7.71 (d, J=3.6Hz, 1H), 7.48 (m, 5H), 7.03 (m, 1H), 6.67 (d, J=4.8Hz, 2H), 6.44 (m, 1H), 6.08 (s, 1H), 4.42 (q, J=9.6Hz, 2H), 3.35 (m, 4H), 1.32 (t, J=9.6Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.5,165.4,163.2,148.9,147.4,145.4,142.3, 136.4,135.2,134.5,133.4,132.5,130.0,126.8,120.5,117.3,115.1,114.8,60.6,48.3, 39.6,15.9.
Its mass spectrum is：MS(EI,m/z):479(M++H).
Embodiment 96
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- aminobenzenes N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, ethyl (Z) -4- (N '-hydroxyls obtained by acetic acid esters Base -4- ((2- (imidazoles [1,2-a] pyridine -6- formamidos) ethyl) amino) -1,2,5- oxadiazole -3- first miaow) benzoic ether Structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.43(s,1H), 8.15 (s, 1H), 7.73 (d, J=3.6Hz, 1H), 7.48 (m, 5H), 7.03 (m, 1H), 6.69 (d, J=4.8Hz, 2H), 6.54 (m, 1H), 6.08 (s, 1H), 4.42 (q, J=9.6Hz, 2H), 3.35 (m, 2H), 3.15 (m, 2H), 1.83 (m, 4H), 1.32 (t, J=9.6Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ168.5,166.4,163.1,148.9,147.4,145.4,141.3, 136.4,135.2,134.5,133.4,132.5,131.0,127.8,120.5,117.3,115.1,114.8,60.6,43.3, 42.6,29.4,15.9.
Its mass spectrum is：MS(EI,m/z):493(M++H).
Embodiment 97
With embodiment 1 difference lies in：Imidazoles [1,2-a] pyridine -6- carboxylic acids in synthetic method step the (3) step are replaced with Trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaow)-obtained 1,2,5- oxadiazole -3- bases) amino) ethyl) and -3- (pyridin-3-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.23(s,1H),9.86(s,1H),8.84(s,1H), 8.63 (dd, J=3.5,2.3Hz, 1H), 8.21 (s, 1H), 7.89 (m, 1H), 7.71 (d, J=3.5Hz, 1H), 7.35 (m, 1H),6.96(m,1H),6.87(m,1H),6.76(m,1H),6.46(m,1H),6.05(s,1H),3.59-3.43(m,4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.2,154.3,148.7,147.2,146.3,141.2, 135.5,133.2,131.3,29.6,126.2,123.8,118.7,117.5,114.2,108.6,48.3,35.2.
Its mass spectrum is：MS(EI,m/z):490(M++1).
Embodiment 98
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-3- Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (3- pyridyl groups) acrylic acid by chlorine propylamine, are made (E)-N- (2- ((4- ((Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) third Base) -3- (pyridin-3-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.83(s,1H), 8.23 (dd, J=3.5,2.4Hz, 1H), 8.11 (s, 1H), 7.90 (m, 1H), 7.71 (d, J=3.5Hz, 1H), 7.25 (m, 1H),6.76(m,1H),6.78(m,1H),6.76(m,1H),6.34(m,1H),6.05(s,1H),3.35(m,2H),3.05(m, 2H),1.93(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,164.5,153.3,148.7,147.2,145.2,143.2, 133.4,131.2,129.3,128.6,124.2,121.8,116.7,115.2,113.2,107.6,42.1,41.2,27.8.
Its mass spectrum is：MS(EI,m/z):504(M++1).
Embodiment 99
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with into trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- obtained (2- ((4- ((Z)-N- (4- fluorophenyls)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) -3- (pyridine -3- Base) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.84(s,1H), 8.63 (dd, J=3.5,2.3Hz, 1H), 8.41 (s, 1H), 7.89 (m, 1H), 7.71 (d, J=3.5Hz, 1H), 7.35 (m, 1H),6.86(m,1H),6.87(m,1H),6.53(m,1H),6.36(m,1H),6.08(s,1H),3.56-3.42(m,4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.5,153.3,148.9,147.3,146.2,140.9, 136.5,133.2,131.3,129.6,125.2,120.8,117.6,115.2,112.5,107.6,46.3,37.2.
Its mass spectrum is：MS(EI,m/z):412(M++1).
Embodiment 100
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, by imidazoles [1,2-a] pyridine-in (3) step 6- carboxylic acids replace with trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (4- fluorophenyls)-N '-obtained Hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) -3- (pyridin-3-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.78(s,1H), 8.53 (dd, J=3.0,2.3Hz, 1H), 8.41 (s, 1H), 7.79 (m, 1H), 7.51 (d, J=3.5Hz, 1H), 7.25 (m, 1H),6.75(m,1H),6.87(m,1H),6.54(m,1H),6.37(m,1H),6.05(s,1H),3.54-3.43(m,4H), 2.35(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.5,152.3,147.6,145.2,144.3,140.9, 138.2,135.2,133.3,128.0,125.2,122.7,118.3,114.2,112.5,110.6,46.3,45.2,29.8.
Its mass spectrum is：MS(EI,m/z):426(M++1).
Embodiment 101
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (3- pyridyl groups) acrylic acid by phenetidine, (E)-N- (2- ((4- ((Z)-N- (the fluoro- 4- methoxyphenyls of 2-)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) ammonia obtained Base) ethyl) -3- (pyridin-3-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.65(s,1H),8.78(s,1H), 8.63 (dd, J=3.2,2.4Hz, 1H), 8.41 (s, 1H), 7.88 (m, 1H), 7.77 (m, 2H), 7.61 (d, J=3.5Hz, 1H), 7.47 (t, J=3.3Hz, 1H), 6.45 (m, 2H), 6.32 (m, 1H), 6.05 (s, 1H), 4.34 (m, 2H), 3.72 (m, 2H),3.45(s,3H),3.35-3.23(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,163.5,149.3,148.1,146.2,136.6,134.8, 131.3,129.6,125.7,123.9,117.3,115.2,76.3,62.1,59.8,48.6,39.2.
Its mass spectrum is：MS(EI,m/z):468(M++1).
Embodiment 102
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, by the imidazoles in (3) step by phenetidine [1,2-a] pyridine -6- carboxylic acids replace with trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (2- obtained Fluoro- 4- methoxyphenyls)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) -3- (pyridin-3-yl) formamide Structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.88(s,1H),8.87(s,1H), 8.63 (dd, J=3.2,2.4Hz, 1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.87 (m, 2H), 7.71 (d, J=3.5Hz, 1H), 7.43 (t, J=3.4Hz, 1H), 6.65 (m, 2H), 6.42 (m, 1H), 6.05 (s, 1H), 4.31 (m, 2H), 3.73 (m, 2H),3.45(s,3H),3.35(m,2H),3.18(m,2H),1.78(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ168.8,164.5,148.2,147.8,145.3,136.6,133.8, 130.3,128.6,124.7,120.9,116.3,114.8,76.3,62.1,59.8,42.6,29.2.
Its mass spectrum is：MS(EI,m/z):482(M++1).
Embodiment 103
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (3- pyridyl groups) acrylic acid by aniline, obtained (E)-N- (2- ((4- ((Z)-N- (4- isopropyl phenyls)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) ethyl) -3- The structural formula of (pyridin-3-yl) formamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.87(s,1H),8.84(s,1H), 8.63 (dd, J=3.2,2.4Hz, 1H), 8.41 (s, 1H), 7.89 (m, 1H), 7.71 (d, J=3.5Hz, 1H), 7.55 (t, J= 4.5Hz, 1H), 6.95 (m, 2H), 6.67 (m, 2H), 6.41 (d, J=3.5Hz, 1H), 6.05 (s, 1H), 3.52-3.47 (m, 4H), 2.75 (m, 1H), 1.23 (d, J=6.5Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.5,149.6,148.2,146.1,136.2,134.3, 132.5,129.6,126.2,123.8,116.3,48.3,39.8,33.2,23.1.
Its mass spectrum is：MS(EI,m/z):436(M++1).
Embodiment 104
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine by aniline, by the imidazoles [1,2-a] in (3) step Pyridine -6- carboxylic acids replace with into trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (4- isopropyls obtained Base phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) and -3- (pyridin-3-yl) formamide structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.16(s,1H),9.88(s,1H),8.89(s,1H), 8.66 (dd, J=3.5,2.6Hz, 1H), 8.41 (s, 1H), 7.89 (m, 1H), 7.71 (d, J=3.5Hz, 1H), 7.53 (t, J= 5.0Hz, 1H), 6.98 (m, 2H), 6.63 (m, 2H), 6.41 (d, J=3.5Hz, 1H), 6.05 (s, 1H), 3.50 (m, 2H), 3.25 (m, 2H), 2.75 (m, 1H), 1.87 (m, 2H), 1.23 (d, J=6.5Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.9,163.5,149.6,148.2,147.1,136.2,134.3, 132.5,129.6,126.2,123.8,116.0,42.3,33.2,28.5,23.1.
Its mass spectrum is：MS(EI,m/z):436(M++1).
Embodiment 105
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1H- pyrroles Azoles -1- bases) aniline, imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with into trans- -3- (3- pyridyl groups) propylene Acid, (E)-N- (2- ((4- ((Z)-N- (4- (1H- pyrazol-1-yls) phenyl-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- obtained Base) amino) ethyl) and -3- (pyridin-3-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H), 8.63 (dd, J=3.6,2.5Hz, 1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.71 (d, J=3.7Hz, 1H), 7.53-7.46 (m, 4H), 6.80 (s, 2H), 6.46 (d, J=3.4Hz, 1H), 6.05 (s, 1H), 3.55-3.47 (m, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,163.1,149.6,148.1,147.3,141.5,136.6, 134.3,132.5,129.6,126.8,123.8,120.7,116.3,108.6,48.3,39.6.
Its mass spectrum is：MS(EI,m/z):460(M++1).
Embodiment 106
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (1H- pyrroles Azoles -1- bases) aniline, the N-Boc-2- chlorethamins in (2) step are substituted for N-Boc-3- chlorine propylamine, by the miaow in (3) step Azoles [1,2-a] pyridine -6- carboxylic acids are substituted for trans- -3- (3- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- obtained (4- (1H- pyrazol-1-yls) phenyl-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) -3- (pyridin-3-yl) first The structural formula of amide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.26(s,1H),9.89(s,1H),8.93(s,1H), 8.74 (dd, J=3.7,2.8Hz, 1H), 8.52 (s, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.71 (d, J=3.7Hz, 1H), 7.53-7.46 (m, 4H), 6.68 (s, 2H), 6.42 (d, J=3.6Hz, 1H), 6.15 (s, 1H), 3.45 (m, 2H), 3.27 (m,2H),1.89(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,164.1,150.6,149.5,148.3,147.0,142.5, 136.2,134.3,132.5,128.6,126.7,123.2,118.3,116.6,109.0,42.9,26.1.
Its mass spectrum is：MS(EI,m/z):474(M++1).
Embodiment 107
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (3- pyrroles by (furans -2- ylmethyls) benzamide Piperidinyl) acrylic acid, N- (furans -2- ylmethyls) -4- ((Z)-N '-hydroxyls-((2- ((E) -3- (pyridin-3-yl) propylene obtained Amide groups) ethyl) amino -1,2,5- oxadiazole -3- first miaow) and benzamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.88(s,1H),8.83(s,1H), 8.79 (s, 1H), 8.63 (dd, J=3.6,2.5Hz, 1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.71 (d, J =3.7Hz, 1H), 7.55-7.58 (m, 4H), 6.97 (m, 2H), 6.46 (d, J=3.4Hz, 1H), 6.38-6.34 (m, 2H), 6.05(s,1H),4.85(s,1H),3.50-3.48(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,166.3,163.1,149.6,148.1,147.3,145.2, 143.5,142.1,141.0,136.6,134.8,132.3,129.6,126.2,122.9,118.6,116.3,110.5,48.3, 39.6,35.4.
Its mass spectrum is：MS(EI,m/z):517(M++1).
Embodiment 108
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- (furans -2- ylmethyls) benzamide, N-Boc-3- chlorine propylamine is replaced with by the N-Boc-2- chlorethamins in (2) step, by (3) imidazoles in step [1,2-a] pyridine -6- carboxylic acids replace with trans- -3- (3- pyridyl groups) acrylic acid, N- (furans -2- obtained Ylmethyl) -4- ((Z)-N '-hydroxyls-((2- ((E) -3- (pyridin-3-yl) acrylamido) propyl) amino -1,2,5- Evil bis- Azoles -3- first miaow) benzamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H), 8.76 (s, 1H), 8.69 (dd, J=3.5,2.7Hz, 1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.88 (m, 1H), 7.71 (d, J =4.0Hz, 1H), 7.56-7.52 (m, 4H), 6.93 (m, 2H), 6.41 (d, J=3.5Hz, 1H), 6.37-6.35 (m, 2H), 6.08(s,1H),4.79(s,1H),3.35(m,2H),3.15(m,2H),1.75(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.6,163.1,149.1,148.1,147.1,145.3, 143.6,142.9,141.4,136.8,133.8,131.3,129.2,126.2,123.9,117.6,114.1,112.9, 112.0,42.3,37.6,25.4.
Its mass spectrum is：MS(EI,m/z):531(M++1).
Embodiment 109
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (3- pyridyl groups) propylene by butyl benzamide Acid, N- butyl -4- obtained ((Z)-N '-hydroxyls-((2- ((E) -3- (pyridin-3-yl) acrylamido) ethyl) amino -1, 2,5- oxadiazole -3- first miaow) benzamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.08(s,1H),9.76(s,1H),8.83(s,1H), 8.76 (s, 1H), 8.69 (dd, J=3.5,2.7Hz, 1H), 8.41 (s, 1H), 7.98 (m, 1H), 7.71 (d, J=4.0Hz, 1H), 7.55-7.52 (m, 3H), 6.97 (m, 2H), 6.46 (d, J=3.5Hz, 1H), 6.08 (s, 1H), 3.50-3.46 (m, 4H),3.32(m,2H),1.57(m,2H),1.32(m,2H),0.78(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.8,167.6,163.1,149.5,148.1,147.0,142.3, 136.7,133.9,132.3,129.2,126.2,124.9,119.6,115.1,48.3,38.7,20.1,15.4.
Its mass spectrum is：MS(EI,m/z):493(M++1).
Embodiment 110
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- amino-N- N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, by the miaow in (3) step by butyl benzamide Azoles [1,2-a] pyridine -6- carboxylic acids replace with trans- -3- (3- pyridyl groups) acrylic acid, N- butyl -4- ((Z)-N '-hydroxyls obtained Base-((2- ((E) -3- (pyridin-3-yl) acrylamido) propyl) amino -1,2,5- oxadiazole -3- first miaow) benzamide Structural formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.06(s,1H),9.86(s,1H),8.87(s,1H), 8.69 (s, 1H), 8.52 (dd, J=3.5,2.7Hz, 1H), 8.41 (s, 1H), 7.88 (m, 1H), 7.71 (d, J=4.0Hz, 1H), 7.55-7.52 (m, 3H), 6.77 (m, 2H), 6.36 (d, J=3.5Hz, 1H), 6.05 (s, 1H), 3.35-3.32 (m, 4H),3.18(m,2H),1.85(m,2H),1.58(m,2H),1.45(m,2H),0.88(m,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.8,165.6,164.2,149.5,148.2,147.1,143.4, 137.7,134.9,131.3,128.2,126.2,123.2,118.6,114.1,42.3,39.3,32.2,28.7,19.1, 13.4.
Its mass spectrum is：MS(EI,m/z):507(M++1).
Embodiment 111
With embodiment 1 difference lies in：Imidazoles [1,2-a] pyridine -6- carboxylic acids in synthetic method step the (3) step are replaced with Trans- -3- (4- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaow)-obtained 1,2,5- oxadiazole -3- bases) amino) ethyl) and -3- (pyridin-4-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.41 (s, 1H), 7.53 (d, J=3.2Hz, 2H), 7.32 (d, J=3.6Hz, 1H), 6.94 (m, 1H), 6.84 (s,3H),6.08(s,1H),3.47(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,164.2,155.9,149.2,147.2,144.3,142.4, 141.6,134.2,126.4,123.5,119.0,118.8,117.8,110.6,48.3,39.6.
Its mass spectrum is：MS(EI,m/z):490(M++H).
Embodiment 112
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-3- Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (4- pyridyl groups) acrylic acid by chlorine propylamine, are made (E)-N- (2- ((4- ((Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) third Base) -3- (pyridin-4-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.14 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.48 (s, 1H), 7.53 (d, J=3.2Hz, 2H), 7.32 (d, J=3.6Hz, 1H), 6.94 (m, 1H), 6.84 (s,3H),6.08(s,1H),3.35(m,2H),3.18(m,2H),1.85(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.5,164.2,156.9,149.2,147.2,144.3,142.4, 141.6,134.2,126.4,123.5,119.1,118.8,117.8,110.6,42.3,41.6,29.3.
Its mass spectrum is：MS(EI,m/z):504(M++H).
Embodiment 113
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3- fluoroforms Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (4- pyridyl groups) acrylic acid by base aniline, are made (E)-N- (2- ((4- ((Z)-N- (3- trifluoromethyls)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) second Base) -3- (pyridin-4-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.43 (s, 1H), 7.53 (d, J=3.2Hz, 2H), 7.32 (m, 3H), 6.99 (m, 1H), 6.74 (m, 2H), 6.04(s,1H),3.47(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.5,164.2,149.2,147.4,145.2,144.3,141.4, 134.6,131.2,129.4,126.5,124.0,123.8,120.8,119.6,115.8,48.8,39.6.
Its mass spectrum is：MS(EI,m/z):462(M++H).
Embodiment 114
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 3- fluoroforms N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine by base aniline, by the imidazoles [1,2- in (3) step A] pyridine -6- carboxylic acids are substituted for trans- -3- (4- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (3- trifluoros obtained Aminomethyl phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) and -3- (pyridin-4-yl) formamide structural formula It is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.43 (s, 1H), 7.55 (d, J=3.2Hz, 2H), 7.30 (m, 3H), 6.99 (m, 1H), 6.74 (m, 2H), 6.04(s,1H),3.37(m,2H),3.17(m,2H),1.85(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.1,164.2,149.2,147.4,145.1,144.3,141.0, 134.6,131.2,129.4,127.5,124.1,123.8,120.2,119.6,115.8,42.8,40.7,29.6.
Its mass spectrum is：MS(EI,m/z):476(M++H).
Embodiment 115
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with trans- -3- (4- pyridyl groups) acrylic acid by phenetidine, (E)-N- (2- ((4- ((Z)-N- (the fluoro- 4- methoxyphenyls of 2-)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) ammonia obtained Base) ethyl) -3- (pyridin-4-yl) formamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.41 (s, 1H), 7.81 (d, J=4.8Hz, 2H), 7.53 (d, J=3.2Hz, 2H), 7.32 (d, J=3.6Hz, 1H), 6.74 (d, J=3.6Hz, 1H), 6.54 (d, J=4.8Hz, 2H), 6.04 (s, 1H), 4.31 (t, J=8.4Hz, 2H), 3.74 (t, J=8.4Hz, 2H), 3.54 (m, 4H), 3.36 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.9,164.1,149.9,149.2,147.2,144.3,141.4, 134.6,129.2,126.4,123.5,116.0,115.8,72.8,69.6,59.6,48.3,39.6.
Its mass spectrum is：MS(EI,m/z):468(M++H).
Embodiment 116
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, by the imidazoles in (3) step by phenetidine [1,2-a] pyridine -6- carboxylic acids replace with trans- -3- (4- pyridyl groups) acrylic acid, (E)-N- (2- ((4- ((Z)-N- (2- obtained Fluoro- 4- methoxyphenyls)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) -3- (pyridin-4-yl) formamide Structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.70 (d, J= 3.2Hz, 2H), 8.41 (s, 1H), 7.82 (d, J=4.8Hz, 2H), 7.54 (d, J=3.2Hz, 2H), 7.31 (d, J=3.6Hz, 1H), 6.78 (d, J=3.6Hz, 1H), 6.54 (d, J=4.8Hz, 2H), 6.04 (s, 1H), 4.31 (t, J=8.4Hz, 2H), 3.74 (t, J=8.4Hz, 2H), 3.46 (s, 3H), 3.29 (m, 2H), 3.13 (m, 2H), 1.89 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ166.9,164.1,149.9,149.2,147.2,144.3,141.4, 134.6,129.2,126.4,123.5,116.0,115.8,73.8,69.2,58.6,42.3,40.6,28.4.
Its mass spectrum is：MS(EI,m/z):482(M++H).
Embodiment 117
With embodiment 1 difference lies in：Imidazoles [1,2-a] pyridine -6- carboxylic acids in synthetic method step the (3) step are replaced with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, (Z)-N- (2- ((4-N- (the bromo- 4- fluorophenyls of 3-)-N ' hydroxy formamidines base)-obtained 1,2,5- oxadiazole -3- bases) amino) ethyl) and -1H- pyrroles [3,2-c] pyridine-3-carboxamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H), 8.70 (s, 1H), 8.43 (m, 1H), 7.38 (d, J=5.2Hz, 1H), 6.87 (m, 3H), 6.64 (m, 1H), 6.02 (s, 1H), 3.48(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,155.8,148.6,147.9,147.2,142.6, 134.1,129.3,125.1,122.6,119.8,118.2,117.4,114.3,110.4,108.7,48.6,39.6.
Its mass spectrum is：MS(EI,m/z):503(M++H).
Embodiment 118
With embodiment 1 difference lies in：N-Boc-2- chlorethamins in synthetic method step the (2) step are replaced with into N-Boc-3- Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid by chlorine propylamine, system (the Z)-N- (2- ((4-N- (the bromo- 4- fluorophenyls of 3-)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) third obtained Base) -1H- pyrroles [3,2-c] pyridine-3-carboxamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H), 8.34 (m, 2H), 7.38 (d, J=5.2Hz, 1H), 6.87 (m, 3H), 6.64 (m, 1H), 6.02 (s, 1H), 3.48 (m, 2H), 3.13(m,2H),1.79(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,155.8,148.6,147.9,147.2,142.6, 134.1,129.3,125.1,122.6,119.8,118.2,117.4,114.3,110.4,108.7,41.6,39.6,28.6.
Its mass spectrum is：MS(EI,m/z):517(M++H).
Embodiment 119
With embodiment 1 uniquely difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid by base aniline, system (Z)-N- (2- ((4-N- (4- isopropyl phenyls)-N ' hydroxy formamidines the base) -1,2,5- oxadiazole -3- bases) amino) ethyl obtained) - The structural formula of 1H- pyrroles [3,2-c] pyridine-3-carboxamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H), 8.76 (s, 1H), 8.43 (d, J=5.2Hz, 1H), 7.38 (d, J=5.2Hz, 1H), 6.97 (d, J=5.6Hz, 2H), 6.84 (m, 1H), 6.67 (d, J=5.6Hz, 2H), 6.02 (s, 1H), 3.45 (m, 4H), 2.84 (m, 1H), 1.23 (d, J=9.6Hz, 6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,148.6,147.9,147.2,138.6,134.9, 134.1,129.3,126.1,125.6,122.8,116.2,114.4,108.7,48.6,39.6,33.2,23.6.
Its mass spectrum is：MS(EI,m/z):449(M++H).
Embodiment 120
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- isopropyls N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine by aniline, the imidazoles [1,2-a] during third is walked Pyridine -6- carboxylic acids replace with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, (Z)-N- (2- ((4-N- (4- cumenes obtained Base)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1H- pyrroles [3,2-c] pyridine-3-carboxamide Structural formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),9.49(m,2H), 8.76 (s, 1H), 8.53 (d, J=5.2Hz, 1H), 7.34 (d, J=5.2Hz, 1H), 6.97 (d, J=5.6Hz, 2H), 6.84 (m, 1H), 6.67 (d, J=5.6Hz, 2H), 6.02 (s, 1H), 3.35 (m, 2H), 3.12 (m, 2H), 2.84 (m, 1H), 1.75 (m, 2H), 1.23 (d, J=9.6Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,148.6,147.9,147.2,138.6,134.4, 133.5,129.3,126.4,125.6,122.8,116.2,114.4,108.7,41.6,39.2,33.2,28.5,23.6.
Its mass spectrum is：MS(EI,m/z):463(M++H).
Embodiment 121
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with into 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, it is (Z)-obtained N- (2- ((4-N- (4- fluorophenyls)-N ' hydroxy formamidines base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1H- pyrroles [3,2- C] pyridine-3-carboxamide structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H), 9.45(s,1H),8.64(s,1H),8.43(m,1H),7.46(m,1H),6.87(m,3H),6.75(m,2H),6.08(s,1H), 3.44(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,158.3,148.9,148.1,147.4,134.5, 133.4,129.7,125.7,122.6,120.2,116.6,114.9,108.9,48.9,39.2.
Its mass spectrum is：MS(EI,m/z):425(M++H).
Embodiment 122
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- fluoroanilines, N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, by imidazoles [1,2-a] pyridine-in (3) step 6- carboxylic acids replace with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, (Z)-N- (2- ((4- (N- (4- fluorophenyls)-N '-hydroxyls obtained Base first miaow) -1,2,5- oxadiazole -3- bases) amino) propyl) -1H- pyrroles [3,2-c] pyridine -3- acrylamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.10(s,1H),9.87(s,1H),9.60(s,1H), 9.43(s,1H),8.64(s,1H),8.42(m,1H),7.36(m,1H),6.87(m,3H),6.75(m,2H),6.12(s,1H), 3.28(m,4H),188(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.9,163.2,158.9,148.9,148.3,147.4,135.2, 133.4,129.7,125.7,122.4,120.2,116.6,114.2,108.9,41.9,39.5,28.2.
Its mass spectrum is：MS(EI,m/z):439(M++H).
Embodiment 123
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups Imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with 1H- pyrroles [3,2-c] pyridine -3- carboxylics by phenetidine Acid, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) phenyl) first miaow base) -1,2,5- Evil bis- obtained Azoles -3- bases) amino) ethyl) and -1H- pyrroles [3,2-c] pyridine -3- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H), 9.45(s,1H),8.64(s,1H),8.43(m,1H),7.76(m,2H),7.46(m,1H),6.87(m,1H),6.65(m,2H), 6.08 (s, 1H), 4.33 (t, J=6.8Hz, 2H), 3.73 (t, J=6.8Hz, 2H), 3.48 (m, 4H), 3.35 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.2,163.2,149.5,148.9,148.1,147.4,134.5, 130.4,129.3,125.7,122.6,116.6,114.9,113.9,108,72.4,69.6,58.2,48.9,39.5.
Its mass spectrum is：MS(EI,m/z):481(M++H).
Embodiment 124
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- methoxyl groups N-Boc-2- chlorethamins in (2) step are replaced with N-Boc-3- chlorine propylamine, by the imidazoles in (3) step by phenetidine [1,2-a] pyridine -6- carboxylic acids replace with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, (Z)-N- (2- ((4- (N '-hydroxyls obtained Base-N- (4- (2- methoxy ethoxies) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1H- pyrroles [3, 2-c] pyridine -3- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H), 9.45(s,1H),8.64(s,1H),8.43(m,1H),7.76(m,2H),7.46(m,1H),6.87(m,1H),6.65(m,2H), 6.08 (s, 1H), 4.33 (t, J=6.8Hz, 2H), 3.73 (t, J=6.8Hz, 2H), 3.39 (s, 3H), 3.21 (m, 4H), 1.81 (m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,163.2,149.5,148.4,148.1,147.4,134.0, 130.2,129.3,125.7,122.6,116.6,114.9,113.9,108,72.4,69.6,58.2,41.9,39.5,28.6.
Its mass spectrum is：MS(EI,m/z):494(M++H).
Embodiment 125
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (morpholines- 1- bases sulfonyl) aniline, imidazoles [1,2-a] pyridine -6- carboxylic acids in (3) step are replaced with into 1H- pyrroles [3,2-c] pyridine - 3- carboxylic acids, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholine -1- bases sulfonyl) phenyl) first miaow base) -1,2,5- Evil obtained Diazole -3- bases) amino) ethyl) and -1H- pyrroles [3,2-c] pyridine -3- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),9.60(s,1H), 9.45 (s, 1H), 8.44 (s, 1H), 8.35 (m, 1H), 7.56 (m, 3H), 6.80 (m, 3H), 6.04 (s, 1H), 4.63 (t, J= 7.2Hz, 4H), 3.44 (m, 4H), 2.93 (t, J=7.2Hz, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.0,163.2,148.5,147.8,147.4,140.5,134.4, 130.6,129.7,129.0,125.7,122.6,114.2,112.6,108.9,65.4,48.9,47.3,39.2.
Its mass spectrum is：MS(EI,m/z):456(M++H).
Embodiment 126
With embodiment 1 difference lies in：The bromo- 4- fluoroanilines of 3- in synthetic method step the (1) step are replaced with into 4- (morpholines- 1- bases sulfonyl) aniline, the N-Boc-2- chlorethamins in (2) step are replaced with into N-Boc-3- chlorine propylamine, it will be in (3) step Imidazoles [1,2-a] pyridine -6- carboxylic acids replace with 1H- pyrroles [3,2-c] pyridine-3-carboxylic acid, (Z)-N- (2- ((4- (N '-obtained Hydroxy-n-(4- morpholines sulfamoyl) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1H- pyrroles [3,2- C] pyridine -3- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.10(s,1H),9.87(s,1H),9.62(s,1H), 9.41 (s, 1H), 8.44 (s, 1H), 8.31 (m, 1H), 7.56 (m, 3H), 6.80 (m, 3H), 6.04 (s, 1H), 4.63 (t, J= 7.2Hz, 4H), 3.24 (m, 4H), 2.95 (t, J=7.2Hz, 4H), 1.86 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.2,163.2,148.8,147.9,147.0,140.5,134.4, 130.3,129.7,129.1,125.7,122.3,114.2,112.6,108.9,65.4,47.9,41.3,39.2,27.8.
Its mass spectrum is：MS(EI,m/z):570(M++H).
The synthetic route (synthetic route of B series compounds) of compound shown in general formula I
Embodiment 127
(Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyls -4- ((2- (3- (pyridin-3-yl methyl) urea) ethyl) amino) -1,2, 5- oxadiazole -3- first miaow preparation methods are as follows：
Triphosgene (148mg, 0.5mmol) is dissolved in dry toluene, at 0 DEG C, under nitrogen protection, by 3- aminomethyl-pyridines The toluene solution of (108mg, 1mmol) is added drop-wise in above-mentioned solution, then the toluene solution drop of triethylamine (0.27ml, 2mmol) It is added in above-mentioned solution；It is warming up to room temperature, reacts 2h；Then 70 DEG C of reaction 1h are warming up to, compound VII-1 crude products are obtained, Concentration is direct plungeed into and is reacted in next step.0 DEG C, under nitrogen protection, by the tetrahydrofuran solution of 3- (isocyanatomethyl)-pyridine (5mL) is slowly added drop-wise in the tetrahydrofuran solution (5mL) of compound II-1 (315mg, 1mmol), is warming up to room temperature reaction 16h, concentration are added water (10mL), add ethyl acetate (20mL), are layered, and water phase is extracted with ethyl acetate (2*10mL), close And organic phase, saturated salt solution (30mL) are washed, anhydrous sodium sulfate drying, concentration, column chromatography obtains object (246mg, 50%).Its Nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H),8.37(m, 1H),7.87(m,1H),7.37(m,1H),6.90(m,2H),6.74(m,1H),6.44(s,1H),6.02(s,2H),4.48(s, 2H), 3.43 (m, 4H) ppm. its carbon spectrums are：13C NMR(125MHz,DMSO):δ163.5,157.2,155.9,149.2, 148.1,147.2,143.3,136.4,135.6,134.2,123.4,119.5,118.8,117.8,110.6,48.3,45.9, 41.6. its mass spectrum is：MS(EI,m/z):493(M++H).
Embodiment 128
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows, (Z)-N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyls -4- ((2- (3- (pyridine -3- obtained Ylmethyl) urea) ethyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.63(s,1H), 8.37(m,1H),7.87(m,1H),7.37(m,1H),6.90(m,2H),6.74(m,1H),6.45(s,1H),6.02(s,2H), 4.48(s,2H),3.35(m,4H),1.85(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.7,155.9,149.2,148.1,146.2,143.3, 136.4,135.6,134.2,123.4,119.5,118.8,117.8,110.6,50.3,45.3,41.9,28.6.
Its mass spectrum is：MS(EI,m/z):507(M++H).
Embodiment 129
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (3,5- 3,5-dimethylphenyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- (3,5- 3,5-dimethylphenyl)-N '-hydroxyls -4- ((2- (3- (pyridines-obtained 3- ylmethyls) urea) ethyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37(m,1H),7.87(m,1H),7.37(m,1H),6.80(s,2H),6.54(s,1H),6.43(s,1H),6.02(s,2H), 4.48(s,2H),3.40(m,4H),2.26(s,6H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.2,147.7,147.2,144.3,139.4, 136.6,135.7,134.2,123.4,119.9,117.8,49.0,45.3,41.9,21.6.
Its mass spectrum is：MS(EI,m/z):425(M++H).
Embodiment 130
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (3,5- 3,5-dimethylphenyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- (3,5- 3,5-dimethylphenyl)-N '-hydroxyls -4- ((2- (3- (pyridines-obtained 3- ylmethyls) urea) propyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37(m,1H),7.87(m,1H),7.37(m,1H),6.80(s,2H),6.54(s,1H),6.43(s,1H),6.02(s,2H), 4.48(s,2H),3.36(m,4H),2.26(s,6H),1.86(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.2,147.7,147.2,144.3,139.4, 136.6,135.7,134.2,123.4,119.9,117.8,49.9,45.3,41.2,28.6,21.6.
Its mass spectrum is：MS(EI,m/z):439(M++H).
Embodiment 131
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxyls -4- ((2- (3- (pyridin-3-yl methyl) urea) ethyl) ammonia obtained Base)-N- (4- (trifluoromethyl) phenyl) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37 (m, 1H), 7.87 (m, 1H), 7.37 (m, 3H), 6.60 (d, J=6.4Hz, 2H), 6.44 (s, 1H), 6.02 (s, 2H), 4.48(s,2H),3.53(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.9,147.8,147.3,141.3,135.6, 134.9,134.3,126.4,125.5,124.8,123.8,116.6,48.3,45.9,41.6.
Its mass spectrum is：MS(EI,m/z):465(M++H).
Embodiment 132
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxyls -4- ((2- (3- (pyridin-3-yl methyl) urea) ethyl) ammonia obtained Base)-N- (4- (trifluoromethyl) phenyl) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37 (m, 1H), 7.89 (m, 1H), 7.37 (m, 3H), 6.60 (d, J=6.4Hz, 2H), 6.44 (s, 1H), 6.00 (s, 2H), 4.46(s,2H),3.38(m,4H),1.85(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.9,147.8,146.3,142.3,135.6, 134.9,134.3,126.4,125.5,124.8,123.4,116.6,50.3,45.9,41.6,28.9.
Its mass spectrum is：MS(EI,m/z):479(M++H).
Embodiment 133
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5-1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (morpholine -1- base sulphurs Acyl group) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (morpholine -1- base sulphonyl obtained Base) phenyl) -4- ((2- (3- pyridin-3-yls methyl) urea groups) ethyl) amino) and -1,2,5- oxadiazole -3- first miaows structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37 (m, 1H), 7.87 (m, 1H), 7.57 (d, J=5.6Hz, 2H), 7.30 (m, 1H), 6.83 (d, J=5.6Hz, 2H), 6.44 (s, 1H), 6.02 (s, 2H), 4.43 (s, 2H), 3.43 (m, 8H), 2.93 (t, J=8.8Hz, 4H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.7,147.4,146.9,140.3,136.4, 135.6,134.2,130.4,129.5,123.8,112.8,65.6,48.3,47.9,45.3,41.6.
Its mass spectrum is：MS(EI,m/z):546(M++H).
Embodiment 134
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5-1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (morpholine -1- base sulphurs Acyl group) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (morpholine sulfonyl) benzene obtained Base) -4- ((2- (3- pyridin-3-yls methyl) urea groups) propyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.37 (m, 1H), 7.87 (m, 1H), 7.57 (d, J=5.6Hz, 2H), 7.30 (m, 1H), 6.83 (d, J=5.6Hz, 2H), 6.44 (s, 1H), 6.02 (s, 2H), 4.43 (s, 2H), 3.69 (t, J=8.8Hz, 4H), 3.33 (m, 4H), 2.93 (t, J=8.8Hz, 4H),1.83(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,148.7,147.4,146.9,140.3,136.4, 135.6,134.2,130.4,129.5,123.8,112.8,65.6,50.3,47.9,45.3,41.6,29.6.
Its mass spectrum is：MS(EI,m/z):560(M++H).
Embodiment 135
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (2- hydroxyethyls) sulphonyl ammonia Base) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (2- hydroxyethyls) sulphonyl obtained Amino) phenyl) -4- ((2- (3- pyridin-3-yls methyl) urea groups) ethyl) amino) and -1,2,5- oxadiazole -3- first miaows structural formula It is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.33 (m, 1H), 7.87 (m, 1H), 7.37 (m, 2H), 7.17 (d, J=5.6Hz, 2H), 6.77 (d, J=5.6Hz, 2H), 6.44 (s,1H),6.02(s,2H),4.68(s,1H),4.48(s,2H),3.43(m,8H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,149.2,148.1,147.6,140.3,136.1, 135.6,134.8,134.2,130.4,123.5,112.8,61.8,48.6,45.8,45.2,41.6.
Its mass spectrum is：MS(EI,m/z):520(M++H).
Embodiment 136
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (2- hydroxyethyls) sulphonyl ammonia Base) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (2- hydroxyethyls) sulphonyl obtained Amino) phenyl) -4- ((2- (3- pyridin-3-yls methyl) urea groups) propyl) amino) and -1,2,5- oxadiazole -3- first miaows structural formula It is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.59(s,1H), 8.33 (m, 1H), 7.87 (m, 1H), 7.37 (m, 2H), 7.17 (d, J=5.6Hz, 2H), 6.77 (d, J=5.6Hz, 2H), 6.44 (s,1H),6.02(s,2H),4.68(s,1H),4.48(s,2H),3.40(m,8H),1.80(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.6,157.2,149.2,148.1,147.6,140.3,136.1, 135.6,134.8,134.0,130.1,123.5,112.8,61.1,50.6,45.8,45.2,41.6,29.3.
Its mass spectrum is：MS(EI,m/z):534(M++H).
Embodiment 137
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (4- methylpiperazine-1-yls) Phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) benzene obtained Base) -4- ((2- (3- pyridin-3-yls methyl) ghiourea group) ethyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,2H),8.59(s,1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.30 (m, 2H), 6.64 (d, J=5.6Hz, 2H), 6.44 (d, J=5.6Hz, 2H), 6.04 (s, 2H), 4.78 (s, 2H), 3.89 (m, 2H), 3.44 (m, 6H), 2.34 (t, J=9.6Hz, 4H), 2.29 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ183.5,162.2,148.9,147.2,146.5,139.6,136.2, 135.3,134.4,128.6,123.2,117.4,114.5,57.8,52.8,50.6,48.3,46.9,46.3.
Its mass spectrum is：MS(EI,m/z):511(M++H).
Embodiment 138
With embodiment 127 difference lies in：It is middle by (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (4- methyl piperazines -1- Base) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (4- methylpiperazine-1-yls) obtained Phenyl) -4- ((2- (3- pyridin-3-yls methyl) ghiourea group) propyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,2H),8.59(s,1H), 8.32 (m, 1H), 7.87 (m, 1H), 7.30 (m, 2H), 6.64 (d, J=5.6Hz, 2H), 6.44 (d, J=5.6Hz, 2H), 6.04 (s, 2H), 4.72 (s, 2H), 3.69 (m, 2H), 3.35 (m, 6H), 2.34 (t, J=9.6Hz, 4H), 2.21 (s, 3H), 1.91 (s,3H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ183.2,162.2,148.9,147.2,146.5,139.6,136.2, 135.3,134.4,128.6,123.2,117.4,114.5,57.8,52.8,50.6,46.3,44.9,42.3,29.4.
Its mass spectrum is：MS(EI,m/z):525(M++H).
Embodiment 139
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- methoxy ethoxies) benzene Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (2- methoxy ethoxies) phenyl)-obtained 4- ((2- (3- pyridin-3-yls methyl) ghiourea group) ethyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,2H),8.59(s,1H), 8.37 (m, 1H), 7.82 (m, 3H), 7.31 (m, 2H), 6.57 (d, J=5.6Hz, 2H), 6.04 (s, 1H), 4.78 (s, 2H), 4.36 (t, J=9.2Hz, 2H), 3.78 (m, 4H), 3.49 (m, 2H), 3.35 (s, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ183.5,163.5,149.2,148.9,147.8,146.5,136.2, 135.4,134.4,129.6,123.2,116.8,115.8,72.6,68.3,59.9,50.3,48.6,46.6.
Its mass spectrum is：MS(EI,m/z):487(M++H).
Embodiment 140
With embodiment 127 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- methoxy ethoxies) benzene Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N '-hydroxy-ns-(4- (2- methoxy ethoxies) phenyl)-obtained 4- ((2- (3- pyridin-3-yls methyl) ghiourea group) ethyl) amino) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.85(s,2H),8.54(s,1H), 8.37 (m, 1H), 7.82 (m, 3H), 7.31 (m, 2H), 6.57 (d, J=5.6Hz, 2H), 6.04 (s, 1H), 4.66 (s, 2H), 4.31 (t, J=9.2Hz, 2H), 3.65 (m, 4H), 3.35 (s, 3H), 3.30 (m, 2H), 1.86 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ183.5,163.5,149.2,148.9,147.8,146.5,136.2, 135.4,134.4,129.6,123.2,116.8,115.8,72.4,68.1,59.4,50.3,44.6,42.6,30.3.
Its mass spectrum is：MS(EI,m/z):501(M++H).
The synthetic route (synthetic route of C series compounds) of compound shown in general formula I
Embodiment 141
(Z)-N- (the bromo- 4- fluorophenyls of 3-) -4- ((2- ((E) -2- cyano -3- (pyridin-4-yl) guanidine radicals) ethyl) amino)-N ' - Hydroxyl -1,2,5-1, the preparation of 2,5- oxadiazole -3- first miaows are as follows：
At 0 DEG C, sodium hydrogen (1.53g, 63.83mmol) is added in DMF, by 4-aminopyridine (5g, 53.2mmol) and compound X (9.32g, 63.83mmol) is added sequentially in above-mentioned suspension, goes to room temperature reaction for 24 hours.After reaction, saturation chlorine is added Change ammonium salt solution to be quenched, NaHCO is added3Solution adjusts Ph to 8, CH2Cl2It extracts (50 × 3mL), merges organic phase, saturated salt solution Washing, concentration, column chromatography for separation obtain compound IX (9g, 90%).By compound IX (100mg, 0.52mmol) and compound II-1 (186mg, 0.52mmol) is dissolved in pyridine, and DMAP (6mg, 0.052mmol) is added, and is heated to 50 DEG C of reactions for 24 hours.Reaction After, it is spin-dried for removing solvent, column chromatography obtains target compound (104mg, 40%).Its nuclear magnetic resonance spectroscopy is：1H NMR (400MHz,DMSO):δ 11.04 (s, 1H), 9.87 (s, 1H), 8.89 (s, 1H), 8.47 (d, J=5.2Hz, 2H), 7.35 (d, J =5.2Hz, 2H), 6.90 (m, 2H), 6.72 (m, 1H), 6.02 (s, 1H), 3.78 (m, 2H), 3.43 (m, 2H), 2.47 (s, 1H) Ppm. its carbon spectrum is：13C NMR(125MHz,DMSO):δ163.5,158.2,155.9,154.8,149.2,147.1,142.2, 134.2,119.5,118.8,117.8,116.6,110.7,109.3,48.3,35.9. its mass spectrum is：MS(EI,m/z):503(M++H).
Embodiment 142
With embodiment 141 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows, (Z)-N- (the bromo- 4- fluorophenyls of 3-) -4- ((2- ((E) -2- cyano -3- (pyridines-obtained 4- yls) guanidine radicals) propyl) amino)-N '-hydroxyl -1,2,5-1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.00(s,1H),9.86(s,1H),8.82(s,1H), 8.45 (d, J=5.2Hz, 2H), 7.35 (d, J=5.2Hz, 2H), 6.90 (m, 2H), 6.72 (m, 1H), 6.06 (s, 1H), 3.58 (m,2H),3.33(m,2H),2.47(s,1H),1.80(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.1,157.2,155.9,154.1,149.2,146.1,140.2, 134.2,119.5,118.8,117.8,116.6,110.7,109.3,41.3,33.9,28.4.
Its mass spectrum is：MS(EI,m/z):517(M++H).
Embodiment 143
With embodiment 141 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N-4- ((2- ((E) -2- cyano -3- (pyridin-4-yl) guanidine radicals) second obtained Base) amino)-N '-hydroxy-ns-(4- (trifluoromethyl) phenyl) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H), 8.47 (m, 1H), 7.37 (m, 4H), 6.60 (d, J=5.2Hz, 2H), 6.04 (s, 1H), 3.78 (s, 2H), 3.43 (m, 2H), 2.48(s,1H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.5,155.2,150.8,147.2,141.3,134.4, 126.6,125.2,124.4,117.5,116.8,110.6,48.3,35.9.
Its mass spectrum is：MS(EI,m/z):475(M++H).
Embodiment 144
With embodiment 141 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N-4- ((2- ((E) -2- cyano -3- (pyridin-4-yl) guanidine radicals) third obtained Base) amino)-N '-hydroxy-ns-(4- (trifluoromethyl) phenyl) -1,2,5- oxadiazole -3- first miaows structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H), 8.45 (m, 1H), 7.37 (m, 4H), 6.62 (d, J=5.2Hz, 2H), 6.04 (s, 1H), 3.58 (s, 2H), 3.23 (m, 2H), 2.48(s,1H),1.83(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.4,157.5,154.2,150.8,147.2,142.3,134.4, 126.6,125.2,124.4,117.5,116.8,110.6,41.3,34.9,30.3.
Its mass spectrum is：MS(EI,m/z):489(M++H).
Embodiment 145
With embodiment 141 difference lies in：4-aminopyridine is replaced with into 3- aminopyridines, (Z)-N- (the bromo- 4- fluorine of 3- obtained Phenyl) -4- ((2- ((E) -2- cyano -3- (pyridin-3-yl) guanidine radicals) ethyl) amino)-N '-hydroxyl -1,2,5-1,2,5- Evil bis- The structural formula of azoles -3- first miaows is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H), 8.53(m,1H),8.13(m,1H),7.43(m,1H),7.17(m,1H),6.87(m,2H),6.64(m,1H),6.02(s,1H), 3.82(m,2H),3.48(m,2H),2.49(s,1H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.2,155.8,148.2,146.9,142.1,137.6, 135.6,134.3,132.1,127.6,119.8,118.2,117.4,116.5,110.8,48.6,37.6.
Its mass spectrum is：MS(EI,m/z):503(M++H).
Embodiment 146
With embodiment 141 difference lies in：4-aminopyridine is replaced with into 3- aminopyridines, by (Z) -4- ((2- aminoethyls) ammonia Base)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyl -1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- ammonia third Base) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (the bromo- 4- fluorine of 3- obtained Phenyl) -4- ((2- ((E) -2- cyano -3- (pyridin-3-yl) guanidine radicals) ethyl) amino)-N '-hydroxyl -1,2,5-1,2,5- Evil bis- The structural formula of azoles -3- first miaows is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H), 8.53(m,1H),8.13(m,1H),7.42(m,1H),7.15(m,1H),6.87(m,2H),6.64(m,1H),6.02(s,1H), 3.52(m,2H),3.28(m,2H),2.49(s,1H),1.82(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ164.5,158.2,155.2,148.1,146.3,142.7,137.2, 135.6,134.3,132.1,127.6,119.8,118.2,117.4,116.5,110.8,41.6,34.6,30.4.
Its mass spectrum is：MS(EI,m/z):517(M++H).
Embodiment 147
With embodiment 141 difference lies in：4-aminopyridine is replaced with into 3- aminopyridines, by (Z) -4- ((2- aminoethyls) ammonia Base)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyl -1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- ammonia second Base) amino)-N- (4- fluorophenyls)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z) -4- ((2- ((E) -2- cyanogen obtained Base -3- (pyridin-3-yl) guanidine radicals) ethyl) amino) and-N- (4- fluorophenyls)-N '-hydroxyl -1,2,5- oxadiazole -3- first miaows knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.79(s,1H), 8.50 (m, 1H), 8.13 (m, 1H), 7.33 (m, 1H), 7.17 (m, 1H), 6.97 (d, J=5.2Hz, 2H), 6.74 (d, J= 5.2Hz,2H),6.02(s,1H),3.82(m,2H),3.48(m,2H),2.49(s,1H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.2,157.8,148.2,146.9,138.6,135.6, 134.1,133.3,132.1,127.6,119.8,117.2,116.4,48.6,37.6.
Its mass spectrum is：MS(EI,m/z):425(M++H).
Embodiment 148
With embodiment 141 difference lies in：4-aminopyridine is replaced with into 3- aminopyridines, by (Z) -4- ((2- aminoethyls) ammonia Base)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyl -1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- ammonia third Base) amino)-N- (4- fluorophenyls)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z) -4- ((2- ((E) -2- cyanogen obtained Base -3- (pyridin-3-yl) guanidine radicals) propyl) amino) and-N- (4- fluorophenyls)-N '-hydroxyl -1,2,5- oxadiazole -3- first miaows knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.02(s,1H),9.84(s,1H),8.79(s,1H), 8.52 (m, 1H), 8.13 (m, 1H), 7.33 (m, 1H), 7.17 (m, 1H), 6.97 (d, J=5.2Hz, 2H), 6.74 (d, J= 5.2Hz,2H),6.02(s,1H),3.56(m,2H),3.38(m,2H),2.49(s,1H),1.88(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.2,157.8,148.2,146.9,138.6,135.6, 134.5,133.3,132.1,127.6,119.8,117.2,116.4,41.6,34.6,29.4.
Its mass spectrum is：MS(EI,m/z):439(M++H).
The synthetic route (synthetic method of D series compounds) of compound shown in general formula I
Embodiment 149
(Z)-N- (2- ((4- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaow) -1,2,5-1,2,5- oxadiazole -3- bases) amino) second Base) -2- (pyridin-3-yl) cyclopropane -1- formamides preparation, be as follows：
Under nitrogen protection, 3- bromopyridines (157g, 0.994mol), n-butyl acrylate (192g, 1.50mmol), Pd (OAc)2 (2.3g,10.2mmol,)、PPh3(5.2g,19.8mmol)、K2CO3(276g, 2.00mol) is added in DMF (200ml), is added Heat to 130 DEG C reaction 20h.It is cooled to room temperature, filters, water is added in filtrate concentration, and ethyl acetate extracts (500ml × 3), saturation Brine It, anhydrous sodium sulfate drying, concentration, column chromatography obtain compound 8 (160g).By compound 8 (70g, 0.34mol) It is dissolved in ethyl alcohol (150ml), potassium hydroxide (40g, 0.71mol) is dissolved in water (150ml), is added in above-mentioned solution, adds Heat reflux 3h.After reaction, Ph to 6.0, Precipitation are adjusted with 12M HCl, filtering collects filter cake, obtains compound 9 (50g, 98%).Compound 9 (50g, 0.34mol) and N, O- dimethyl hydroxylamine hydrochloride (65g, 0.67mol) are dissolved in dichloro In methane (1L), EDCI (127g, 0.66mol) and DMAP (80g, 0.65mol) are then sequentially added, is stirred to react at room temperature 2h.After reaction, water 200ml is added, dichloromethane extracts (1L × 2) extraction, merges organic phase, organic phase saturated common salt Water washing (500ml × 3), anhydrous sodium sulfate drying, concentration obtain 10 crude product 70g of compound.Trimethyl sulphur oxygen iodine (145g, It 0.67mol) is dissolved in DMSO (500ml), at 0 DEG C, sodium hydrogen (26g, 1.1mol) is added in above-mentioned solution.Room temperature is gone to, 1h is stirred, then compound 10 (66g, 0.34mol) is added in foregoing solution, the reaction was continued at room temperature 1h.Instead After answering, saturated ammonium chloride solution (400mL) is added and is quenched, ethyl acetate extracts (3 × 1L), merges organic phase, washing (3 × 500mL), anhydrous sodium sulfate drying concentrates, and column chromatography obtains yellow oily compound 11 (56g, 80%).By compound 11 (50g, 0.24mol) is dissolved in ethyl alcohol, and potassium hydroxide (40g, 0.71mol) is dissolved in water (100mL), above-mentioned solution is added to In, it is heated to reflux 3h, after reaction, water (300mL), dichloromethane (3 × 100mL) extraction, water phase 12M HCl tune is added Ph to 6.0 is saved, water phase is then concentrated to give solid, methanol is added into solid, filters away insoluble matter, filtrate concentration obtains To the faint yellow crude Compounds of 34g 12.Compound 12 (1.0g, 6.13mmol) is dissolved in anhydrous methylene chloride (5mL), is added Thionyl chloride (10mL, 138mmol), 1 drop DMF, is heated to 40 DEG C, reacts 5h.It is cooled to room temperature, is concentrated to give crude Compound 13(1.34g).Compound II-1 is dissolved in anhydrous DMF, triethylamine (1.0g, 10mmol) is added, by the chloride compounds of preparation 13 (0.18g, 0.99mmol) are dissolved in anhydrous DMF, are added drop-wise to II-1 (461.82mg, 1.29mmol), are reacted 4h at room temperature.Instead Liquid is answered to concentrate, column chromatography obtains target compound (149mg, 30%).
Synthetic method such as embodiment 1.Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H), 9.87(s,1H),8.37(m,2H),8.01(s,1H),7.58(m,1H),7.12(m,1H),6.74(m,3H),6.08(s,1H), 3.47 (m, 4H), 3.17 (m, 1H), 2.83 (m, 1H), 1.83 (m, 2H) ppm. its carbon spectrums are：13C NMR(125MHz,DMSO):δ 174.5,163.2,155.9,151.2,148.2,147.3,143.4,142.6,135.2,134.5,123.4,119.0, 118.8,117.8,110.6,48.3,39.6,27.8,25.2,16.4. its mass spectrum is：MS(EI,m/z):504(M++H).
Embodiment 150
With embodiment 149 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows) -1,2,5- obtained 1,2,5- oxadiazole -3- bases) amino) propyl) and -2- (pyridin-3-yl) cyclopropane -1- formamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.37(m,2H), 8.01(s,1H),7.52(m,1H),7.11(m,1H),6.75(m,3H),6.04(s,1H),3.37(m,2H),3.17(m,3H), 2.83(m,1H),1.83(m,4Hppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ174.5,163.2,155.9,151.2,148.2,147.3,143.4, 142.6,135.2,134.5,123.4,119.0,118.8,117.8,110.6,41.3,38.6,29.4,27.8,25.2, 17.4.
Its mass spectrum is：MS(EI,m/z):518(M++H).
Embodiment 151
With embodiment 149 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- methoxyethoxyphenyls) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) obtained Phenyl) first miaow base) -, 2,5- oxadiazole -3- bases) amino) ethyl) and -2- (pyridin-3-yl) cyclopropane -1- formamides structural formula It is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.38(m,2H), 8.08 (s, 1H), 7.73 (m, 3H), 7.22 (m, 1H), 6.54 (d, J=4.8Hz, 1H), 6.08 (s, 1H), 4.32 (t, J= 8.4Hz, 2H), 3.74 (t, J=8.4Hz, 2H), 3.54 (m, 4H), 3.36 (s, 3H), 3.13 (m, 1H), 2.86 (m, 1H), 1.89(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ174.5,164.1,150.9,149.7,149.2,148.5,147.2, 143.3,135.4,134.6,129.2,123.4,116.8,114.8,72.6,69.3,58.5,48.3,39.6,26.7,24.5, 17.8.
Its mass spectrum is：MS(EI,m/z):482(M++H).
Embodiment 152
With embodiment 149 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- methoxyethoxyphenyls) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) obtained Phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) ethyl) and -2- (pyridin-3-yl) cyclopropane -1- formamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.87(s,1H),8.38(m,2H), 8.08 (s, 1H), 7.70 (m, 3H), 7.22 (m, 1H), 6.54 (d, J=4.8Hz, 1H), 6.08 (s, 1H), 4.30 (t, J= 8.4Hz, 2H), 3.72 (t, J=8.4Hz, 2H), 3.42 (s, 3H), 3.34 (m, 2H), 3.18 (m, 3H), 2.79 (m, 1H), 1.84(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ174.5,164.1,150.9,149.7,149.2,148.5,147.2, 143.3,135.4,134.6,129.2,123.4,116.8,114.8,72.6,69.3,58.5,48.3,39.6,26.7,24.5, 17.8.
Its mass spectrum is：MS(EI,m/z):496(M++H).
The synthetic route (synthetic method of E series compounds) of compound shown in general formula I
Embodiment 153
(Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) second Base) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides preparation, be as follows：
Compound II-1 (1g, 2.79mmol) is dissolved in dry toluene, compound 14 (1.1g, 5.58mmol) is added to above-mentioned In solution, under nitrogen protection, 120 DEG C are warming up to, reacts 30min.It is cooled to room temperature, filters, filter cake is washed with toluene, changed Close object VIII-1 (1.3g, 90%).By compound 15 (114mg, 0.96mmol) and compound VIII-1 (500mg, It 0.96mmol) is dissolved in ethyl alcohol, is warming up to 90 DEG C, after reacting 2h, stop reaction.It is cooled to room temperature, concentrates, column chromatography obtains mesh Mark compound (193mg, 40%).Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87 (s,1H),8.65(s,1H),8.11(m,1H),7.19(m,1H),6.87(m,2H),6.65(m,1H),6.04(s,2H),5.20 (s, 2H), 4.45 (s, 2H), 3.36 (m, 4H) ppm. its carbon spectrums are：13C NMR(125MHz,DMSO):δ163.5,158.2, 155.3,150.9,148.1,147.4,146.6,142.5,134.5,133.4,124.7,119.7,118.6,117.2, 110.6,58.4,57.3,48.9,41.2. its mass spectrum is：MS(EI,m/z):505(M++H).
Embodiment 154
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N- (the bromo- 4- fluorophenyls of 3-)-N '-hydroxyl first miaows base)-obtained 1,2,5- oxadiazole -3- bases) amino) propyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.65(s,1H), 8.11(m,1H),7.19(m,1H),6.87(m,2H),6.65(m,1H),6.04(s,2H),5.20(s,2H),4.45(s,2H), 3.34(m,4H),1.84(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.2,158.2,154.3,150.9,148.1,147.2,146.6, 142.5,134.2,133.4,124.7,119.7,118.6,117.2,110.6,58.9,57.3,49.9,41.0,28.4.
Its mass spectrum is：MS(EI,m/z):519(M++H).
Embodiment 155
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- methoxyethoxyphenyls) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) obtained Phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- propylene The structural formula of amide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.60(s,1H), 8.11(m,1H),7.79(m,2H),7.19(m,1H),6.57(m,2H),6.05(s,2H),5.20(s,2H),4.45(s,2H), 4.33 (t, J=6.8Hz, 2H), 3.73 (t, J=6.8Hz, 2H), 3.48 (m, 4H), 3.35 (s, 3H) ppm
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,149.7,148.1,147.4,146.7, 134.5,133.4,129.7,124.7,116.6,115.2,72.4,69.5,59.4,58.1,57.3,48.7,41.2
Its mass spectrum is：MS(EI,m/z):482(M++H).
Embodiment 156
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- methoxyethoxyphenyls) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- (2- methoxy ethoxies) obtained Phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- propylene The structural formula of amide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.89(s,1H),8.60(s,1H), 8.11(m,1H),7.79(m,2H),7.19(m,1H),6.57(m,2H),6.05(s,2H),5.20(s,2H),4.45(s,2H), 4.33 (t, J=6.8Hz, 2H), 3.73 (t, J=6.8Hz, 2H), 3.42 (s, 3H), 3.32 (m, 4H), 1.82 (m, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.1,157.2,150.9,149.3,148.1,147.4,146.7, 134.5,133.0,128.7,124.7,116.6,115.2,72.4,69.5,59.4,58.1,57.3,50.4,41.7,28.7.
Its mass spectrum is：MS(EI,m/z):497(M++H).
Embodiment 157
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- obtained (2- ((4- (N- (4- trifluorophenyls)-N '-hydroxyl first miaows base) -1, 2,5- oxadiazole -3- bases) amino) ethyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.24(s,1H),9.84(s,1H),8.65(s,1H), 8.10 (m, 1H), 7.32 (d, J=4.8Hz, 2H), 7.19 (m, 1H), 6.67 (d, J=4.8Hz, 2H), 6.04 (s, 2H), 5.20 (s,2H),4.45(s,2H),3.56(m,4H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.2,151.3,147.9,147.1,146.4,141.5, 134.5,133.4,126.4,125.3,124.7,124.1,116.7,58.4,57.3,48.9,41.2.
Its mass spectrum is：MS(EI,m/z):477(M++H).
Embodiment 158
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- trifluoromethyls)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- obtained (2- ((4- (N- (4- trifluorophenyls)-N '-hydroxyl first miaows base) -1, 2,5- oxadiazole -3- bases) amino) propyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.84(s,1H),8.65(s,1H), 8.12 (m, 1H), 7.34 (d, J=4.8Hz, 2H), 7.19 (m, 1H), 6.67 (d, J=4.8Hz, 2H), 6.04 (s, 2H), 5.20 (s,2H),4.45(s,2H),3.33(m,4H),1.86(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,158.3,151.3,145.3,147.1,146.4,140.5, 134.5,133.4,127.4,125.3,124.7,123.1,116.7,58.4,57.3,50.9,41.2,29.5.
Its mass spectrum is：MS(EI,m/z):491(M++H).
Embodiment 159
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (ethyl carbamyl) benzene Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N- (4- (ethyl carbamyl) phenyl-obtained N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- third The structural formula for preparing acrylamide of acrylamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H), 8.45 (s, 1H), 8.11 (m, 1H), 7.54 (d, J=4.8Hz, 2H), 7.19 (m, 1H), 6.94 (d, J=4.8Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.46 (m, 4H), 3.28 (q, J=8.0Hz, 2H), 1.04 (t, J=8.0Hz, 3H) its carbon of ppm. spectrum is：13C NMR(125MHz,DMSO):δ167.5,163.5,158.2,150.3,147.9,147.2, 146.1,141.4,134.6,133.5,125.5,124.4,118.7,116.7,58.3,57.1,48.9,41.2,34.9, 15.6.
Its mass spectrum is：MS(EI,m/z):480(M++H).
Embodiment 160
With embodiment 153 difference lies in：It is middle by (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (ethyl carbamyl) Phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N- (4- (ethyl carbamyl) benzene obtained Base-N '-hydroxyl first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- The structural formula for preparing acrylamide of acrylamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H), 8.45 (s, 1H), 8.11 (m, 1H), 7.54 (d, J=4.8Hz, 2H), 7.19 (m, 1H), 6.94 (d, J=4.8Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.45 (m, 4H), 3.18 (q, J=8.0Hz, 2H), 1.85 (m, 2H), 1.04 (t, J=8.0Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.1,163.5,158.2,150.0,147.9,147.2,145.1, 141.4,134.6,133.5,125.5,123.4,118.7,116.7,58.3,57.1,50.9,41.2,34.9,28.0,15.6.
Its mass spectrum is：MS(EI,m/z):494(M++H).
Embodiment 161
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (N- (3,5- dimethyl -4- ((2- morpholines ethyl) carbamyl) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N- obtained (3,5- dimethyl -4- ((2- morpholines ethyl) carbamyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) Ethyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.85(s,1H), 8.65(s,1H),8.11(m,1H),7.19(m,1H),6.97(s,2H),6.04(s,2H),5.20(s,2H),4.45(s,2H), 3.56(m,6H),2.46(m,12H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.4,163.5,157.2,150.9,148.4,147.7,147.2, 146.6,137.5,134.5,133.4,127.6,124.7,113.7,66.9,58.4,57.3,55.6,54.7,48.9,41.2, 37.2,18.9.
Its mass spectrum is：MS(EI,m/z):593(M++H).
Embodiment 162
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (N- (3,5- dimethyl -4- ((2- morpholines ethyl) carbamyl) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N- obtained (3,5- dimethyl -4- ((2- morpholines ethyl) carbamyl) phenyl)-N '-hydroxyl first miaow) -1,2,5- oxadiazole -3- bases) amino) Propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.77(s,1H),8.83(s,1H), 8.65(s,1H),8.11(m,1H),7.19(m,1H),6.97(s,2H),6.08(s,2H),5.20(s,2H),4.45(s,2H), 3.56(m,6H),3.36(m,4H),2.46(m,12H),1.86(m,2H)ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ167.4,163.5,157.2,150.9,148.4,147.7,147.2, 146.6,137.5,134.5,133.4,127.6,124.7,113.7,66.9,58.4,57.3,55.4,54.3,50.7,41.9, 37.2,28.9,18.9.
Its mass spectrum is：MS(EI,m/z):607(M++H).
Embodiment 163
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- (3- (diethylamino) third Acylamino-) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (3- (diethylamino) third obtained Acylamino-) phenyl)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1,3- dihydro-2 h-pyrroles [3, 4-c] pyridine -2- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.84(s,1H),9.89(s,1H),9.80(s,1H), 8.65 (s, 1H), 8.11 (m, 1H), 7.34 (d, J=4.4Hz, 2H), 7.19 (m, 1H), 6.77 (d, J=4.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.76 (t, J=8.4Hz, 2H), 3.55 (m, 4H), 3.06 (q, J=8.8Hz, 4H), 2.55 (t, J=8.4Hz, 2H), 1.16 (t, J=8.8Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ173.4,163.5,157.2,150.9,148.4,147.2,146.6, 135.5,134.5,133.4,128.6,124.7,122.6,116.7,58.4,57.3,56.6,49.7,48.9,41.2,33.2, 13.9.
Its mass spectrum is：MS(EI,m/z):551(M++H).
Embodiment 164
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- (3- (diethylamino) third Acylamino-) phenyl)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (3- (diethylamino) third obtained Acylamino-) phenyl)-N '-hydroxyl first miaows base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3, 4-c] pyridine -2- acrylamides structural formula it is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.89(s,1H),9.40(s,1H), 8.65 (s, 1H), 8.11 (m, 1H), 7.34 (d, J=4.4Hz, 2H), 7.19 (m, 1H), 6.77 (d, J=4.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.76 (t, J=8.4Hz, 2H), 3.35 (m, 4H), 3.06 (q, J=8.8Hz, 4H), 2.55 (t, J=8.4Hz, 2H), 1.88 (m, 2H), 1.16 (t, J=8.8Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ173.4,163.5,157.2,150.9,148.4,147.2,146.6, 135.5,134.5,133.4,128.6,124.7,122.6,116.7,58.4,57.3,56.6,51.2,49.7,41.2,33.2, 13.3.
Its mass spectrum is：MS(EI,m/z):565(M++H).
Embodiment 165
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- propionamidos) phenyl)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- propionamidos phenyl) first miaows obtained Base -1,2,5- oxadiazole -3- bases) amino) ethyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structure Formula is as follows:
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),10.20(s,1H),9.87(s,1H), 8.65 (s, 1H), 8.11 (m, 1H), 7.35 (d, J=6.4Hz, 2H), 7.19 (m, 1H), 6.75 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.56 (m, 4H), 2.36 (q, J=8.4Hz, 2H), 1.36 (t, J=8.4Hz, 3H) its carbon of ppm. spectrum is：13C NMR(125MHz,DMSO):δ172.4,163.5,157.2,150.9,147.7,147.2, 146.6,134.5,133.4,132.6,128.6,124.7,122.5,116.7,58.4,57.3,48.9,41.2,30.2, 11.9.
Its mass spectrum is：MS(EI,m/z):480(M++H).
Embodiment 166
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- propionamidos) phenyl)-N ' - Hydroxyl -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- propionamido-s phenyl) first miaows obtained Base -1,2,5- oxadiazole -3- bases) amino) propyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.00(s,1H),10.20(s,1H),9.67(s,1H), 8.62 (s, 1H), 8.11 (m, 1H), 7.35 (d, J=6.4Hz, 2H), 7.19 (m, 1H), 6.73 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.36 (m, 4H), 2.34 (q, J=8.4Hz, 2H), 186 (m, 2H), 1.16 (t, J=8.4Hz, 3H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ173.4,162.5,158.2,151.9,147.7,147.2,146.6, 134.5,133.4,131.6,128.6,123.7,122.5,115.7,58.4,57.3,50.9,41.2,30.2,28.9,11.9.
Its mass spectrum is：MS(EI,m/z):494(M++H).
Embodiment 167
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- morpholine -1- bases sulfonyl) benzene Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholine -1- base sulphurs obtained Acyl group) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- The structural formula of acrylamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H), 8.11 (m, 1H), 7.55 (d, J=6.4Hz, 2H), 7.13 (m, 1H), 6.65 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.36 (m, 8H), 2.96 (t, J=8.4Hz, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6,140.5, 134.5,133.4,130.6,129.6,124.7,112.5,65.5,58.4,57.3,48.9,47.3,41.2.
Its mass spectrum is：MS(EI,m/z):558(M++H).
Embodiment 168
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- morpholine -1- bases sulfonyl) benzene Base)-N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholine sulfonamides obtained Base) phenyl) first miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- third The structural formula of acrylamide is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.65(s,1H), 8.10 (m, 1H), 7.45 (d, J=6.4Hz, 2H), 7.23 (m, 1H), 6.65 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.66 (t, J=8.4Hz, 4H) 3.36 (m, 4H), 2.96 (t, J=8.4Hz, 2H), 1.84 (m, 2H) its carbon of ppm. spectrum is：13C NMR(125MHz,DMSO):δ164.5,157.2,150.3,148.3,147.2,146.2, 140.5,134.5,133.4,131.6,129.6,123.7,111.5,65.5,58.4,57.3,50.9,47.3,41.2,28.5.
Its mass spectrum is：MS(EI,m/z):572(M++H).
Embodiment 169
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- morpholine -1- bases) phenyl) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholine -1- bases phenyl) first obtained Miaow base) -1,2,5- oxadiazole -3- bases) amino) ethyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.64(s,1H),9.87(s,1H),8.65(s,1H), 8.11 (m, 1H), 7.19 (m, 1H), 6.65 (d, J=6.4Hz, 2H), 6.45 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.76 (t, J=8.4Hz, 4H), 3.45 (m, 4H), 3.16 (t, J=8.4Hz, 2H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6,139.4, 134.5,133.4,128.6,124.7,117.5,113.7,66.5,58.4,57.3,53.3,48.9,41.2.
Its mass spectrum is：MS(EI,m/z):494(M++H).
Embodiment 170
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- morpholine -1- bases) phenyl) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- morpholine -1- bases phenyl) first obtained Miaow base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides knot Structure formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ10.54(s,1H),9.87(s,1H),8.65(s,1H), 8.11 (m, 1H), 7.19 (m, 1H), 6.63 (d, J=6.4Hz, 2H), 6.40 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.76 (t, J=8.4Hz, 4H), 3.35 (m, 4H), 3.16 (t, J=8.4Hz, 2H), 1.88 (m, 2H) its carbon of ppm. spectrum is：13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.7,147.2,146.6, 139.4,134.5,133.4,128.6,124.7,117.5,113.7,66.5,58.4,57.3,53.3,50.9,41.2,28.4.
Its mass spectrum is：MS(EI,m/z):508(M++H).
Embodiment 171
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminoethyls) amino)-N- (4- isopropyls) phenyl)-N '-hydroxyls Base -1,2,5- oxadiazole -3- first miaows, (Z)-N- obtained (2- ((4- (N '-hydroxy-ns-(4- isopropyl phenyls) first miaow base) -1, 2,5- oxadiazole -3- bases) amino) ethyl) and -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structural formula such as Under：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.04(s,1H),9.87(s,1H),8.65(s,1H), 8.11 (m, 1H), 7.19 (m, 1H), 6.95 (d, J=6.4Hz, 2H), 6.75 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.45 (s, 2H), 3.50 (m, 4H), 2.88 (m, 1H), 1.30 (d, J=8.4Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.5,157.2,150.9,147.9,147.2,146.6,138.4, 134.9,133.9,133.2,126.6,124.7,116.7,58.4,57.3,48.9,41.2,33.2,23.9.
Its mass spectrum is：MS(EI,m/z):451(M++H).
Embodiment 172
With embodiment 153 difference lies in：By (Z) -4- ((2- aminoethyls) amino)-N- (4- bromine-3-fluorophenyls)-N '-hydroxyls - 1,2,5- oxadiazole -3- first miaows (II-1) replace with (Z) -4- ((2- aminopropyls) amino)-N- (4- morpholine -1- bases) phenyl) - N '-hydroxyls -1,2,5- oxadiazole -3- first miaows, (Z)-N- (2- ((4- (N '-hydroxy-ns-(4- isopropyl phenyls) first miaows obtained Base) -1,2,5- oxadiazole -3- bases) amino) propyl) -1,3- dihydro-2 h-pyrroles [3,4-c] pyridine -2- acrylamides structure Formula is as follows：
Its nuclear magnetic resonance spectroscopy is：1H NMR(400MHz,DMSO):δ11.14(s,1H),9.87(s,1H),8.65(s,1H), 8.21 (m, 1H), 7.13 (m, 1H), 6.92 (d, J=6.4Hz, 2H), 6.65 (d, J=6.4Hz, 2H), 6.04 (s, 2H), 5.20 (s, 2H), 4.55 (s, 2H), 3.35 (m, 4H), 2.88 (m, 1H), 1.82 (m, 2H), 1.20 (d, J=8.4Hz, 6H) ppm.
Its carbon is composed：13C NMR(125MHz,DMSO):δ163.2,156.2,151.9,147.6,147.0,145.6,138.4, 134.9,133.9,133.2,126.6,124.7,116.7,58.4,57.3,50.2,41.5,33.5,28.4,23.1.
Its mass spectrum is：MS(EI,m/z):465(M++H).
Contrast test
The measurement of external enzyme inhibition activity
The assay method of IDO1 enzymatic activitys
Buffer solution (the PH of 15 μ l dibastic sodium phosphates is added in micropore plate hole first:7-8), 5 μ l are added and contain appropriate IDO-1 enzymes Heterocyclic urea compound prepared by reaction buffer and the present invention, mixing, after reacting at room temperature 3 hours, with PE companies Envision MultilabelReader multi-function microplate readers are detected 320nm wavelength absorbance values, according to absorption radiometer Inhibiting rate of the heterocyclic urea compound to enzyme reaction is calculated, carrying out analysis with GraphPad softwares calculates heterocyclic urea compound IC50 values.
The test method of NAMPT enzymatic activitys
(1) buffer solution 1 is prepared, including:10 μ L, 10X Nicotinamide of 10X NAMPT buffer solutions, 10 μ L, 10X PRPP 10 2 μ L of μ L, 10X ATP10 μ L, NMNAT1 enzyme, aggravating 48 μ L of water makes volume reach 90 μ L.
(2) buffer solution 2 is prepared, including:2 μ L, 50X ADH of 50X WST-1,2 μ L, 50X Diaphorase, 2 μ L, 10X EtOH 10 μ L, aggravating 4 μ L of water makes volume reach 20 μ L.
(3) 90 μ L buffer solutions 1 are added per hole in microwell plate, are subsequently added into the compound of 2 μ L 50X, 2 μ are added in blank control group 2 μ L FK866 (1mM) are added in L DMSO, positive drug control group.It is anti-that 2 μ L recombinant NAMPT starting enzymes are added per hole It answers, is incubated 60min after mixing well at 30 DEG C.The buffer solution 2 that 20 μ L are added after the completion of reaction develops the color, and dynamic detection reacts 5- Absorption value at the 450nm of 35min.
IDO1 the and NAMPT enzyme inhibition activity measurement results of each furazan class compound are as shown in table 1.
A:IC50<1nM；B:IC50=100nM-1 μM；C:IC50>1μM
Result can be seen that from table 1：Furazan class compound prepared by the present invention compared with positive control (INCB24360), With the significant activity for inhibiting listed IDO1 enzymes；Simultaneously compared with positive control (FK866), there is the suppression of significant NAMPT enzymes System activity.
It is provided for the embodiments of the invention heterocyclic urea compound and its Pharmaceutical composition and application above, has carried out detailed Jie It continues, principle and implementation of the present invention are described for specific case used herein, and the explanation of above example is only It is the method and its core concept for being used to help understand the present invention；Meanwhile for those of ordinary skill in the art, according to this hair Bright thought, there will be changes in the specific implementation manner and application range, in conclusion the content of the present specification should not manage Solution is limitation of the present invention.

Claims (11)

1. a kind of novel NAMPT and IDO double inhibitors, it is characterised in that：Its with furazan class compound shown in general formula I and Its pharmaceutically acceptable salt, solvate, prodrug, ester, racemic modification and isomers.General formula I is：
2. novel NAMPT and IDO double inhibitors according to claim 1, it is characterised in that：R in general formula I1For can be only It is vertical to be selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxyl, sulfydryl, O- carboxyls, C- carboxyls, sulfonic group, phosphate, phosphorous acidic group, C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Naphthenic base, aryl, heteroaryl, Heterocyclylalkyl, C3-C6Naphthenic base-(C1-C6Alkane Base), aryl (C1-C6Alkyl), heteroaryl (C1-C6Alkyl), Heterocyclylalkyl (C1-C6Alkyl), C3-C6Naphthenic base-(C2-C6Alkene Base), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), Heterocyclylalkyl (C2-C6Alkenyl), C3-C6Naphthenic base-(C2-C6Alkynes Base), aryl (C2-C6Alkynyl), heteroaryl (C2-C6Alkynyl), Heterocyclylalkyl (C2-C6Alkynyl), (C3-C6Naphthenic base)-O- (CH2) q-、(C3-C6Naphthenic base)-(C1-C6Alkoxy), aryl-O- (CH2) q-, aryl-(C1-C6Alkoxy), heteroaryl-O- (CH2) Q-, heteroarylalkoxy, Heterocyclylalkyl-O- (CH2) q-, Heterocyclylalkyl-(C1-C6Alkoxy), (C3-C6Naphthenic base)-S- (CH2) q-、(C3-C6Naphthenic base)-(C1-C6Alkane sulfydryl), aryl-S- (CH2) q-, aryl-(C1-C6Alkane sulfydryl), heteroaryl-S- (CH2) Q-, heteroaryl alkane sulfydryl, Heterocyclylalkyl-S- (CH2) q-, Heterocyclylalkyl-(C1-C6Alkane sulfydryl), aryl (C2-C6Alkenyl), heteroaryl Base (C2-C6Alkenyl), (C3-C6Naphthenic base)-(C2-C6Alkenyl), Heterocyclylalkyl (C2-C6Alkenyl), C1-C6Alkoxy-(CH2)q-、 C2-C6Alkenyl oxygroup (CH2)q-、C1-C6Alkane sulfydryl-(CH2)q-、C2-C6Alkenyl sulfydryl, halogenated (C1-C6Alkyl), halogenated (C2-C6 Alkenyl), amino (C1-C6Alkyl), amino (C2-C6Alkenyl), hydroxyl (C1-C6Alkyl), hydroxyl (C2-C6Alkenyl), sulfydryl (C1-C6 Alkyl), sulfydryl (C2-C6Alkenyl), cyano (C1-C6Alkyl), cyano (C2-C6Alkenyl), nitro (C1-C6Alkyl), nitro (C2-C6 Alkenyl), O- carboxyls (C1-C6Alkyl), O- carboxyls (C2-C6Alkenyl), C- carboxyls (C1-C6Alkyl), C- carboxyls (C2-C6Alkenyl), sulphur Acidic group (C1-C6Alkyl), sulfonic group (C2-C6Alkenyl), phosphate (C1-C6Alkyl), phosphorous acidic group (C1-C6Alkyl), phosphate (C2-C6Alkenyl), phosphorous acidic group (C2-C6Alkenyl), (C1-C6Alkylamino)-(C1-C6Alkoxy), (C1-C6Alkylamino) oxygroup- (CH2)q、(C1-C6Alkane sulfydryl)-(C1-C6Alkoxy), (C1-C6Alkane sulfydryl) oxygroup-(CH2)q, halogenated (C1-C6Alkoxy)- (CH2)q, (halogenated C1-C6Alkyl)-O- (CH2)q, hydroxyl (C1-C6Alkoxy)-(CH2)q, (hydroxyl C1-C6Alkyl) oxygroup- (CH2)q, cyano (C1-C6Alkoxy)-(CH2)q, (cyano C1-C6Alkyl)-O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C =O) NRaRb、-(CH2)q-NRc(C=O) Rd、-(CH2)q-NRc(C=O) ORd、-(CH2)q(C=O)-(C1-C6Alkyl) ,- (CH2)q(C=O) aryl ,-(CH2)q(C=O) heteroaryl ,-(CH2)q(C=O)-(C3-C6Naphthenic base) ,-(CH2)q(C= O)O-(C1-C6Alkyl) ,-(CH2)q(C=O) O aryl ,-(CH2)q(C=O) S- (C1-C6Alkyl) ,-(CH2)q(C=O) S Aryl ,-(CH2)q- O (C=O)-(C1-C6Alkyl) ,-(CH2)q- O (C=O) aryl ,-(CH2)q(S=O)2NRaRb、- (CH2)q-NRc(S=O) Rd、-(CH2)q(S=O)2(C1-C6Alkyl) ,-(CH2)q(S=O)2Aryl ,-(CH2)q(S=O)2- Heterocyclylalkyl ,-(CH2)q(S=O)2Heteroaryl ,-(CH2)q(S=O)2Halogenated alkyl ,-(CH2)q(S=O)-(C1-C6Alkane Base) ,-(CH2)q(S=O) aryl ,-(CH2)q(S=O)-Heterocyclylalkyl ,-(CH2)q(S=O) heteroaryl ,-(CH2)q(S= O) halogenated alkyl and-(CH2)q(P=O) RcRdIn 1,2,3,4 or 5；
Wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkane Base), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C1-C6Alkyl-NH- (C1-C6Alkyl)-, (C1-C6Alkyl)2-N-(C1-C6Alkane Base)-, C3-C6Naphthenic base, aryl, aryl-NH-, heteroaryl, Heterocyclylalkyl, C3-C6Naphthenic base-(C1-C6Alkyl), aryl (C1- C6Alkyl), heteroaryl (C1-C6Alkyl) and Heterocyclylalkyl (C1-C6Alkyl) or RaAnd RbWith shape together with the nitrogen-atoms that they are connected At 5 yuan or 6 membered heterocycloalkyls, wherein the Heterocyclylalkyl contains miscellaneous original that is one or more additional and being independently selected from N, O or S Son, RcAnd RdIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1- C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, aryl, heteroaryl and Heterocyclylalkyl；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl can independently with aryl, heteroaryl, C3-C6Naphthenic base is miscellaneous It is Cycloalkylfused；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl are unsubstituted or are optionally taken by single or multiple substituent groups Generation, the substituent group it is identical or different and independently selected from：Deuterium, halogen, nitro, amino, hydroxyl, cyano, sulfoamido, O- carboxylics Base, C- carboxyls, sulfydryl, oxo, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkane sulfydryl, halogenated (C1-C6Alkyl), hydroxyl (C1-C6 Alkyl), sulfydryl (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, heteroaryl, Heterocyclylalkyl ,-(CH2)qNRaRb、- (CH2)q(S=O)2NRaRb、-(CH2)q(C=O) NRaRb, wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, virtue One or several or R in base, heteroaryl and HeterocyclylalkylaAnd Rb5 yuan or 6 can be formed together with the nitrogen-atoms that they are connected Membered heterocycloalkyl, wherein the Heterocyclylalkyl contains hetero atom that is one or more additional and being independently selected from N, O or S.
3. novel NAMPT and IDO double inhibitors according to claim 1, it is characterised in that：L in general formula I is virtue Base, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group, Heterocyclylalkyl, C1-C8Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, aryl- (C1-C6Alkyl), heteroaryl-(C1-C6Alkyl), (naphthenic base)-(C1-C6Alkyl) or (Heterocyclylalkyl)-(C1-C6Alkyl) in It is one or more of；
The C1-C8Alkyl, C2-C8Alkenyl and C2-C8Alkynyl can not be by or by following group：- O- ,-S- ,-NH- ,-S (=O )2,-S (=O)-,-(C=O)-,-O (C=O)-,-(C=O) O- ,-O (C=O) O- ,-NH (C=O)-,-(C=O) NH- ,-S (C=O)-,-(C=O) S- ,-NH (C=O)2NH- ,-NH (C=S)2NH-, NH (C=O)2O- is separated 1 time, 2 times, 3 times or 4 times；
The C1-C8Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, aryl, heteroaryl, C3-C6Naphthenic base and Heterocyclylalkyl are not taken In generation, is replaced by single or multiple substituent groups, and the substituent group is independently selected from identical or differently：Halogen, nitro, amino, hydroxyl Base, cyano, sulfoamido, O- carboxyls, C- carboxyls, sulfydryl, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Alkoxy, C2-C6Alkenyl oxygroup, C1-C6Alkane sulfydryl, C1-C6Alkylamino, halogenated (C1-C6Alkyl), hydroxyl (C1-C6Alkyl), sulfydryl (C1-C6 Alkyl), cyano (C1-C6Alkyl), nitro (C1-C6Alkyl), O- carboxyls (C1-C6Alkyl), C- carboxyls (C1-C6Alkyl), (C1-C6 Alkoxy)-(C1-C6Alkyl), (C1-C6Alkylamino)-(C1-C6Alkyl), (C1-C6Alkylamino)-(C1-C6Alkyl)-(C1-C6Alkane Oxygroup), (C1-C6Alkane sulfydryl)-(C1-C6Alkyl), (C1-C6Alkane sulfydryl)-(C1-C6Alkyl)-(C1-C6Alkoxy), amino (C1- C6Alkoxy), amino (C1-C6Alkoxy)-(C1-C6Alkyl), halogenated (C1-C6Alkoxy)-(C1-C6Alkyl), hydroxyl (C1-C6 Alkoxy)-(C1-C6Alkyl), cyano (C1-C6Alkoxy) (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, Heterocyclylalkyl One or more of with heteroaryl；
E in general formula I is O, S or N-C ≡ N；
X in general formula I is C0-C4Alkyl, C2-C4Alkenyl, C3-C6Naphthenic base or (CH2)nNH, wherein n are 0-4.
4. novel NAMPT and IDO double inhibitors according to claim 1, it is characterised in that：R in general formula I2For virtue Base, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group or Heterocyclylalkyl；
The wherein aryl, heteroaryl, C3-C6Naphthenic base, C3-C6Cycloalkenyl group or Heterocyclylalkyl is unsubstituted or optionally coverlet A or multiple substituent group substitutions, the substituent group is identical or different and is independently selected from：Deuterium, halogen, nitro, cyano, hydroxyl, mercapto Base, O- carboxyls, C- carboxyls, sulfonic group, phosphate, phosphorous acidic group, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C6Cycloalkanes Base, aryl, heteroaryl, Heterocyclylalkyl, C3-C 6Naphthenic base-(C1-C6Alkyl), aryl (C1-C6Alkyl), heteroaryl (C1-C6Alkane Base), Heterocyclylalkyl (C1-C6Alkyl), C3-C6Naphthenic base-(C2-C6Alkenyl), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkene Base), Heterocyclylalkyl (C2-C6Alkenyl), C3-C6Naphthenic base-(C2-C6Alkynyl), aryl (C2-C6Alkynyl), heteroaryl (C2-C6Alkynes Base), Heterocyclylalkyl (C2-C6Alkynyl), (C3-C6Naphthenic base)-O- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkoxy), virtue Base-O- (CH2) q-, aryl-(C1-C6Alkoxy), heteroaryl-O- (CH2) q-, heteroarylalkoxy, Heterocyclylalkyl-O- (CH2) Q-, Heterocyclylalkyl-(C1-C6Alkoxy), (C3-C6Naphthenic base)-S- (CH2)q-、(C3-C6Naphthenic base)-(C1-C6Alkane sulfydryl), virtue Base-S- (CH2) q-, aryl-(C1-C6Alkane sulfydryl), heteroaryl-S- (CH2) q-, heteroaryl alkane sulfydryl, Heterocyclylalkyl-S- (CH2) Q-, Heterocyclylalkyl-(C1-C6Alkane sulfydryl), aryl (C2-C6Alkenyl), heteroaryl (C2-C6Alkenyl), (C3-C6Naphthenic base)-(C2-C6 Alkenyl), Heterocyclylalkyl (C2-C6Alkenyl), C1-C6Alkoxy-(CH2)q-、C2-C6Alkenyl oxygroup (CH2)q-、C1-C6Alkane sulfydryl- (CH2)q-、C2-C6Alkenyl sulfydryl, halogenated (C1-C6Alkyl), halogenated (C2-C6Alkenyl), amino (C1-C6Alkyl), amino (C2-C6 Alkenyl), hydroxyl (C1-C6Alkyl), hydroxyl (C2-C6Alkenyl), sulfydryl (C1-C6Alkyl), sulfydryl (C2-C6Alkenyl), cyano (C1-C6 Alkyl), cyano (C2-C6Alkenyl), nitro (C1-C6Alkyl), nitro (C2-C6Alkenyl), O- carboxyls (C1-C6Alkyl), O- carboxyls (C2-C6Alkenyl), C- carboxyls (C1-C6Alkyl), C- carboxyls (C2-C6Alkenyl), sulfonic group (C1-C6Alkyl), sulfonic group (C2-C6Alkene Base), phosphate (C1-C6Alkyl), phosphorous acidic group (C1-C6Alkyl), phosphate (C2-C6Alkenyl), phosphorous acidic group (C2-C6Alkenyl), (C1-C6Alkylamino)-(C1-C6Alkoxy), (C1-C6Alkylamino) oxygroup-(CH2)q、(C1-C6Alkane sulfydryl)-(C1-C6Alkoxy), (C1-C6Alkane sulfydryl) oxygroup-(CH2)q, halogenated (C1-C6Alkoxy)-(CH2)q, (halogenated C1-C6Alkyl)-O- (CH2)q, hydroxyl Base (C1-C6Alkoxy)-(CH2)q, (hydroxyl C1-C6Alkyl) oxygroup-(CH2)q, cyano (C1-C6Alkoxy)-(CH2)q, (cyanogen Base C1-C6Alkyl)-O- (CH2)q-、-(CH2)qNRaRb、-(CH2)q(C=O) NRaRb、-(CH2)q-NRc(C=O) Rd、-(CH2)q- NRc(C=O) ORd、-(CH2)q(C=O)-(C1-C6Alkyl) ,-(CH2)q(C=O) aryl ,-(CH2)q(C=O) heteroaryl Base ,-(CH2)q(C=O)-(C3-C6Naphthenic base) ,-(CH2)q(C=O) O- (C1-C6Alkyl) ,-(CH2)q(C=O) O virtues Base ,-(CH2)q(C=O) S- (C1-C6Alkyl) ,-(CH2)q(C=O) S aryl ,-(CH2)q- O (C=O)-(C1-C6Alkyl) ,- (CH2)q- O (C=O) aryl ,-(CH2)q(S=O)2NRaRb、-(CH2)q-NRc(S=O) Rd、-(CH2)q(S=O)2(C1-C6 Alkyl) ,-(CH2)q(S=O)2Aryl ,-(CH2)q(S=O)2Heterocyclylalkyl ,-(CH2)q(S=O)2Heteroaryl ,-(CH2)q- (S=O)2Halogenated alkyl ,-(CH2)q(S=O)-(C1-C6Alkyl) ,-(CH2)q(S=O) aryl ,-(CH2)q(S=O)-is miscellaneous Naphthenic base ,-(CH2)q(S=O) heteroaryl ,-(CH2)q(S=O) halogenated alkyl and-(CH2)q(P=O) RcRd；
Wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkane Base), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C1-C6Alkyl-NH- (C1-C6Alkyl)-, (C1-C6Alkyl)2- N- (C1-C6 alkane Base)-, C3-C6Naphthenic base, aryl, aryl-NH-, heteroaryl, Heterocyclylalkyl, C3-C6Naphthenic base-(C1-C6Alkyl), aryl (C1- C6Alkyl), heteroaryl (C1-C6Alkyl), Heterocyclylalkyl (C1-C6Alkyl) or RaAnd RbThe nitrogen-atoms one that can be connected with them It rises and forms 5 yuan or 6 membered heterocycloalkyls, wherein the Heterocyclylalkyl contains one or more additional and is independently selected from N, O or S Hetero atom, RcAnd RdIt is simultaneously or asynchronously hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), it is halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, aryl, heteroaryl, Heterocyclylalkyl；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl can independently with aryl, heteroaryl, C3-C6Naphthenic base is miscellaneous It is Cycloalkylfused；
The aryl, heteroaryl, C3-C6Naphthenic base, Heterocyclylalkyl are unsubstituted or are optionally taken by single or multiple substituent groups Generation, the substituent group it is identical or different and independently selected from：Deuterium, halogen, nitro, amino, hydroxyl, cyano, sulfoamido, O- carboxylics Base, C- carboxyls, sulfydryl, oxo, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkane sulfydryl, halogenated (C1-C6Alkyl), hydroxyl (C1-C6 Alkyl), sulfydryl (C1-C6Alkyl), C3-C6Naphthenic base, C6-C12Aryl, heteroaryl, Heterocyclylalkyl ,-(CH2)qNRaRb、- (CH2)q(S=O)2NRaRb、-(CH2)q(C=O) NRaRb, wherein q is 0-4, RaAnd RbIt is simultaneously or asynchronously hydrogen, C1-C6Alkane Base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl (C1-C6Alkyl), halogenated (C1-C6Alkyl), C1-C6Alkoxy, C3-C6Naphthenic base, virtue Base, heteroaryl, Heterocyclylalkyl or RaAnd Rb5 yuan or 6 membered heterocycloalkyls can be formed together with the nitrogen-atoms that they are connected, wherein The Heterocyclylalkyl contains hetero atom that is one or more additional and being independently selected from N, O or S.
5. novel NAMPT and IDO double inhibitors according to claim 4, it is characterised in that：The R2For
6. novel NAMPT and IDO double inhibitors according to claim 1, it is characterised in that：Chemical combination with general formula I Object is selected from：
Or its pharmaceutical salts.
7. novel NAMPT and IDO double inhibitors according to claim 1, it is characterised in that：Described has general formula I Shown in furazan class compound and its pharmaceutically acceptable salt, solvate, prodrug, racemic modification and isomers preparing Yin Diindyl amine -2,3- dioxygenase inhibitors and its Related product, Nampt inhibitor and its Related product or Application in indoles amine -2,3- dioxygenases and Nampt double inhibitor and its Related product.
8. novel NAMPT and IDO double inhibitors according to claim 7, it is characterised in that：The furazan class chemical combination Object and its pharmaceutically acceptable salt, prodrug, stereoisomer or the furazan class compound and its pharmaceutically acceptable The pharmaceutical composition that salt, solvate, prodrug, racemic modification and isomers form can be applied to the treatment mankind and other lactations The preparation of the drug of the tumour excess proliferative disease of animal.
9. novel NAMPT and IDO double inhibitors according to claim 7, it is characterised in that：The furazan class chemical combination Object and its pharmaceutically acceptable salt, prodrug, stereoisomer or the furazan class compound and its pharmaceutically acceptable The pharmaceutical composition that salt, solvate, prodrug, racemic modification and isomers are formed with pharmaceutically acceptable carrier can be applied to Prevention or the preparation of tumor；The prevention or tumor is cancer immunotherapy drug, cancer chemotherapy Drug or targeting cancer therapy drug.
10. the novel NAMPT and IDO double inhibitors according to claim 1-9, it is characterised in that：The furazan class Compound and its pharmaceutically acceptable salt, prodrug, stereoisomer and its pharmaceutical composition can be used for preventing or treat lymph Tumor, non-small cell lung cancer, Small Cell Lung Cancer, incidence cell cancer, glioma, neuroblastoma, lung squamous cancer, lung gland Cancer, carcinoma of urinary bladder, gastric cancer, colon cancer, colorectal cancer, kidney, cholangiocarcinoma, gastric cancer, esophageal squamous cell carcinoma, oophoroma, cancer of pancreas, breast cancer, The cancers such as prostate cancer, liver cancer, the cancer of the brain, melanoma, Huppert's disease, cutaneum carcinoma, cell carcinoma, leukaemia and cervical carcinoma Disease is included in other separate tissues of tumour original site or the metastasis of organ.
11. a kind of preparation method of novel NAMPT and IDO double inhibitors as described in claim 1-10, it is characterised in that： The synthetic route with compounds of formula I is as follows：
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109485646A (en) * 2018-12-12 2019-03-19 中国药科大学 A kind of benzothiazole quinones compound and its preparation method and application
CN111718310B (en) * 2019-08-19 2021-06-11 中国药科大学 Phenyl-substituted five-membered heterocyclic compound, and preparation method, application and pharmaceutical composition thereof
CN114539237A (en) * 2022-02-28 2022-05-27 中国药科大学 IDO inhibitor, preparation method, pharmaceutical composition and application
CN116283953A (en) * 2023-03-10 2023-06-23 沈阳药科大学 Indoline compound containing thiazole structure, and preparation method and application thereof
CN116444454A (en) * 2023-06-16 2023-07-18 中国医学科学院医药生物技术研究所 N-hydroxy amidine derivative, preparation method and application thereof, and tumor immunotherapy medicament

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106660974A (en) * 2015-03-31 2017-05-10 江苏恒瑞医药股份有限公司 Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals
CN107304191A (en) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 Indoleamine 2,3 dioxygenase inhibitors and preparation method and application
CN107709338A (en) * 2015-07-02 2018-02-16 葛兰素史克知识产权开发有限公司 Indoleamine 2, the inhibitor of 3 dioxygenases
CN107954999A (en) * 2016-10-17 2018-04-24 上海医药集团股份有限公司 Han oxadiazole rings compound, preparation method, intermediate, composition and application
CN107987031A (en) * 2017-12-01 2018-05-04 华东理工大学 1 nitrogen mustards inhibitor of one kind targeting indoles amine -2,3- dioxygenases and its preparation method and application
CN108003111A (en) * 2017-12-14 2018-05-08 华东理工大学 Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106660974A (en) * 2015-03-31 2017-05-10 江苏恒瑞医药股份有限公司 Sulfamyl-containing 1,2,5-oxadiazole derivative, preparation method therefor and use thereof in pharmaceuticals
CN107709338A (en) * 2015-07-02 2018-02-16 葛兰素史克知识产权开发有限公司 Indoleamine 2, the inhibitor of 3 dioxygenases
CN107304191A (en) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 Indoleamine 2,3 dioxygenase inhibitors and preparation method and application
CN107954999A (en) * 2016-10-17 2018-04-24 上海医药集团股份有限公司 Han oxadiazole rings compound, preparation method, intermediate, composition and application
CN107987031A (en) * 2017-12-01 2018-05-04 华东理工大学 1 nitrogen mustards inhibitor of one kind targeting indoles amine -2,3- dioxygenases and its preparation method and application
CN108003111A (en) * 2017-12-14 2018-05-08 华东理工大学 Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUN FANG: "《Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors》", 《ACS MEDICINAL CHEMISTRY LETTERS》 *
陈伟: "《基于HDAC的双靶点抑制剂合理设计、合成和生物活性评价》", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109485646A (en) * 2018-12-12 2019-03-19 中国药科大学 A kind of benzothiazole quinones compound and its preparation method and application
CN111718310B (en) * 2019-08-19 2021-06-11 中国药科大学 Phenyl-substituted five-membered heterocyclic compound, and preparation method, application and pharmaceutical composition thereof
CN114539237A (en) * 2022-02-28 2022-05-27 中国药科大学 IDO inhibitor, preparation method, pharmaceutical composition and application
CN116283953A (en) * 2023-03-10 2023-06-23 沈阳药科大学 Indoline compound containing thiazole structure, and preparation method and application thereof
CN116283953B (en) * 2023-03-10 2024-02-02 沈阳药科大学 Indoline compound containing thiazole structure, and preparation method and application thereof
CN116444454A (en) * 2023-06-16 2023-07-18 中国医学科学院医药生物技术研究所 N-hydroxy amidine derivative, preparation method and application thereof, and tumor immunotherapy medicament
CN116444454B (en) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-hydroxy amidine derivative, preparation method and application thereof, and tumor immunotherapy medicament

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