CN106938997A - N (4 substitution phenethyl) acetamides and application thereof - Google Patents

N (4 substitution phenethyl) acetamides and application thereof Download PDF

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CN106938997A
CN106938997A CN201710034898.8A CN201710034898A CN106938997A CN 106938997 A CN106938997 A CN 106938997A CN 201710034898 A CN201710034898 A CN 201710034898A CN 106938997 A CN106938997 A CN 106938997A
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amino
phenethyl
methyl
bases
pyrimidine
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CN106938997B (en
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朱进
黄瑾
陈文华
姚雪
凌大正
王曼炯
蒋华良
李剑
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to acetamides and application thereof.The invention discloses the novel N of a class formation (4 substitution phenethyl) amides compound.Show that such compound has enzyme inhibition activity to cysteine proteinase (FP 2) and dihyrofolate reductase (DHFR) by external activity test experiment.And kill malaria through external test result indicate that：Such compound is all inhibited to wild, resistance plasmodium.

Description

N- (4- replaces phenethyl) acetamides and application thereof
Technical field
The present invention relates to acetamides and application thereof, a more particularly to class N- (4- replaces phenethyl) ethanamide Compound and application thereof.
Background technology
Malaria is one of epidemic disease of most serious in the world.Have about 3,000,000,000 populations of more than 100 countries and regions by The threat of malaria, the annual malarial people in the whole world has 3.5~500,000,000, and the patient that malaria is died from every year is 150~2,700,000, wherein about Half is children, and the disadvantaged country in Africa and Asia occurs for 90% case.Mainly include in popular malaria area of China Hainan and 19, Yunnan etc. provinces and cities, the morbidity of autonomous region, about millions of people.Although current existing effective anti-malaria medicaments, malaria illness The death rate of person rises year by year, and main cause is that plasmodium adapts to limited antimalarial quickly, generate the serious resistance to the action of a drug.
Malaria control largely also relies on the prevention and treatment of chemicals.It is only a small number of over nearly more than 70 years Medicine is applied to clinic, and the strain of resistance to the action of a drug plasmodium increasingly increases.With biochemistry, molecular biology and molecular pharmacology etc. Continuing to develop for related discipline, discloses the effect in the Biochemical processes of many enzymes and acceptor in vivo, with life Play key enzyme in object, the development that new drug design has become New Drug Research is carried out as drug target Trend.The design of new antiplasmodial medicine is with a kind of cysteine protein played an important role in plasmodium life cycle Enzyme (falcipain) is target spot, and promote this evolution is people to this medicine of papain cysteine proteinase What thing target recognized deepens continuously.Plasmodium is used for the albumen of itself by digesting red blood cell as main origin of amino acid Matter is synthesized.It is known in the degradation process of hemoglobin, there are three kinds of plasmodium protease to play an important role.Wherein Plasmepain I and II belong to aspartic protease, falcipain category cysteine proteinases.Aspartic protease Inhibitor mainly acts on point valve protozoon and a red blood cell rupture；Cystatin mainly acts on protozoon nutrition Body, specifically acts on the first step that red blood cell is degraded in plasmodium life cycle, plasmodium is synthesized itself egg because lacking White free amino acid and it is dead.And clinically wide variety of antimalarial chloroquine then by suppressing the polymerization of free ferroheme, Plasmodium is set to be killed by a large amount of free radicals that free hemn discharges.
The mechanism that obvious cystatin kills plasmodium is different with chloroquine.Therefore cysteine egg is selected The target spot that white enzyme is studied as new antimalarial agent, it is expected to overcome the drug resistance problems of antimalarial agent.Cysteine proteinase be Mr about For 21,000~30,000 protein has highest hydrolysing activity at pH 4~6.5, and its active site has half Guang ammonia Sour residue, the cysteine proteinase of protozoon belongs to papain families.Known plasmodium cysteine proteinase has four Individual hypotype, falcipain-1, falcipain-2A, falcipain-2B, falcipain-3.Falcipain 1 is first Obtained plasmodium cysteine proteinase is expressed, its biological study shows, its asexual reproduction phases to plasmodium has no Influence, but the function of energy significant impact egg capsule.Falcipain-2A, falcipain-2B have 97% homology, amino 7 of acid sequence are different.Found by the monitoring of oligonucleotide probe, falcipain-2B mRNA expression ratio Falcipain-2A is low.But falcipain-2A and falcipain-2B plasmodium trophosome late period its expression time according to Bad property and peak value are very much like, and this shows that two kinds of different hypotypes have similar biological function.Falcipain-3 with Falcipain-2 has 66.6% homology in catalytic domain, but the stage that they are expressed is different.Falcipain-2 exists Vegetative stage reaches top, and falcipain-3 peaks in more ripe plasmodium phase table. Falcipain-3 crystal structure has not been reported.The falcipain-2 most study in this several hypotype, therefore its suppression The exploitation of preparation is also by more extensive concern.Except having inhibitory action to cysteine proteinase falcipain-2, to two Hydrogen folic acid reductase (dihydrofolatere ductase, DHFR) also has inhibitory action.
Dihyrofolate reductase (DHFR) is one of crucial enzyme in nucleic acid metabolism, is cancer, antimalarial, antibacterial drug therapy In main target enzyme, widely studied in recent years.Dihydrofolate reductase inhibitor can selectivity with dihydrofoilic acid also Protoenzyme is combined, and is suppressed its catalytic reduction activity, is prevented dihydrofoilic acid from being smoothly changed into tetrahydrofolic acid, and the latter becomes coenzyme F Afterwards, one carbon unit can be provided for the synthesis of the vivo biodistributions such as thymidine, purine, serine, methionine.If hindering folic acid metabolism Process, will disturb DNA and protein synthesis, ultimately results in cell death.Dihyrofolate reductase (DHFR) is almost present in Institute is zoic intracellular, one of main target enzyme in Field of Drug Discovery turns into antimalarial, anticancer, antibacterial drug therapy, In recent years because its extensive bioactivity receives much attention.
Therefore, growth, the breeding of plasmodium can be suppressed by suppressing falcipain-2 (FP-2) and DHFR, filtered out Potent FP-2＆DHFR double inhibitors treat malaria.
The content of the invention
The present inventor's design, N- (4- replaces phenethyl) the amide-type chemical combination for synthesizing class formation novelty of knowing clearly Thing.Show such compound to cysteine proteinase (falcipain-2) and dihydrofoilic acid by external activity test experiment Reductase (DHFR) has enzyme inhibition activity, and kills malaria in vitro test result indicate that such compound is former to wild, resistance malaria Worm is all inhibited.
It is an advantage of the invention to provide a kind of novel N- of structure (4- replaces phenethyl) amides compound.
N- (4- replace phenethyl) amides compound described in the present invention, be compound shown in Formulas I or its pharmaceutically Acceptable salt：
In Formulas I：R1Group shown in formula A or B (curve mark is substitution position, similarly hereinafter)：
R2For the C replaced by phenyl1~C4Straight or branched alkyl, C4~C13Cycloalkyl, heterocyclic radical or aromatic ring yl, Or the C of substitution4~C13Cycloalkyl, heterocyclic radical or aromatic ring yl；
Wherein, the hetero atom of the heterocyclic radical is nitrogen (N), oxygen (O) or/and sulphur (S), the substituted C4~C13Cycloalkanes The substituent of base, heterocyclic radical or aromatic ring yl is one or more kinds of in following groups (containing two kinds, similarly hereinafter)：
C1~C4Straight or branched alkyl, C1~C4Straight or branched alkoxyl, halogen (F, Cl, Br or I), hydroxyl (OH), ketone carbonylN is 1 or 2.
Another object of the present invention is to disclose a kind of purposes of above-mentioned N- (4- replaces phenethyl) amides compound. I.e.：Compound shown in Formulas I or its pharmaceutically acceptable salt preparing cysteine proteinase (falcipain-2) and two Application in hydrogen folic acid reductase (DHFR) inhibitor；And
Compound shown in Formulas I or its pharmaceutically acceptable salt prepare treatment malaria (particularly caused by plasmodium Malaria) medicine in application.
A further object of the invention is that there is provided a kind of method of compound shown in formula I.
Methods described comprises the following steps：
(1) by 4- nitro phenethylamine hydrochloridesWith carboxylic acid (R2COOH) react, formula II shownization The step of compound；
(2) compound shown in Formula II is through catalytic hydrogenating reduction, the step of obtaining compound shown in formula III；
(3) by guanidine nitrateReacted with ethoxy methylene malononitrile, obtain 2,4- di-amino-pyrimidine -5- nitriles The step of (compound shown in formula IV)；
(4) step of 2,4- di-amino-pyrimidine -5- formaldehyde (compound shown in Formula V) is prepared as 2,4- di-amino-pyrimidine -5- nitriles Suddenly；With,
(5) compound is reacted with compound shown in Formula V as shown in formula III, obtains the step of object (compound shown in Formulas I) Suddenly.
Wherein, R2Definition with it is described previously identical.
Brief description of the drawings
The test of Fig. 1 uv detection methods suppresses the principle schematic of the activity data of dihyrofolate reductase (DHFR)；
Fig. 2 are compound IA- 5 pairs of plasmodium falciparum 3D7C8 growth inhibitions curves (external)；
Fig. 3 compounds IA- 5 pairs of chloroquine resistance plasmodium falciparum Dd2 growth inhibitions curves (external).
Embodiment
In an optimal technical scheme of the invention, R1The group shown in formula A；R2For the C replaced by phenyl1~C4It is straight Chain or branched alkyl, furyl, thienyl, cyclohexyl, phenyl, pyridine radicals, naphthyl, fluorenyl, or substitution cyclohexyl, phenyl or Fluorenyl；
The substituent of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups：
C1~C4Straight or branched alkyl, C1~C4Straight or branched alkoxyl, halogen (F, Cl, Br or I), hydroxyl (OH), ketone carbonylN is 1 or 2.
R still more preferably2For benzyl, phenethyl, 2- furyls, 2- thienyls, cyclohexyl, phenyl, 2- pyridine radicals, Cyclohexyl, phenyl or the fluorenyl of 3- pyridine radicals, 2- naphthyls, fluorenyl, or substitution；
The substituent of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups：
Methoxyl group, the tert-butyl group, halogen (F, Cl, Br or I), hydroxyl (OH), ketone carbonylN is 1 or 2.
R still more preferably again2For benzyl, phenethyl, 4- tert-butylcyclohexyls, 2- fluoro-phenyls, 3- fluorophenyls, 4- Fluoro-phenyl, 3- methoxyl groups-phenyl, 4- methoxyl groups-phenyl, 3,4- dimethoxy-phenylfs, the bromo- phenyl of the fluoro- 4- of 2-, the fluoro- 4- of 2- Chloro- phenyl, 3,5- dimethoxy-phenylfs, 3- chloro-4-methoxies-phenyl,
In presently preferred technical scheme, R1The group shown in formula B；R2For substituted-phenyl；
The substituent of the substituted-phenyl is C1~C4Straight or branched alkoxyl orN is 1 or 2.
Still more preferably R2By methoxyl group orSubstituted-phenyl；
Still more preferably R again2For 3,4- dimethoxy-phenylfs or
The method of compound, specifically includes following steps shown in the formula I that the present invention is provided：
(1) by carboxylic acid (R2COOH) it is dissolved in lower addition 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne of dichloromethane stirring Diimmonium salt hydrochlorate and I-hydroxybenzotriazole, DIPEA, 4- dimethylaminos are added after reacting 1 hour at room temperature Pyridine, adds 4- nitro phenethylamine hydrochlorides, then reacts 24 hours at ambient temperature, stops reaction, adds water in reaction solution, It is extracted with ethyl acetate, concentrates, vacuum distillation removes solvent, residue washing, then is extracted with ethyl acetate, and organic phase is through silica gel Column chromatography is purified, and obtains compound shown in Formula II；
(2) compound shown in Formula II is dissolved in methanol, under stirring, adds 10% palladium-carbon catalyst and be passed through hydrogen (H2), React at room temperature at least 5 hours, filtering and concentration, residue obtain compound shown in formula III through silica gel column chromatography；
(3) guanidine nitrate is dissolved in caustic alcohol and ethanol, adds ethoxy methylene malononitrile and reacted under conditions of 5 DEG C 8h.Question response adds suitable quantity of water after terminating, and is extracted with ethyl acetate, saturated common salt washing organic phase, and concentration organic phase (steam by decompression Distillation solvent), residue silica gel column chromatography separating purification obtains 2,4- di-amino-pyrimidine -5- nitriles (compound shown in formula IV)；
(4) under Raney's nickel (catalyst) existence condition, compound and H as shown in formula IV2In room temperature reaction, 2,4- are obtained Di-amino-pyrimidine -5- formaldehyde (compound shown in Formula V)；
(5) compound shown in formula III and compound shown in Formula V are kept at least 24 hours in methanol in reflux state (as preparation R1Shown in formula A during the object of group, sodium cyanoborohydride is added in above-mentioned reaction system), suitable quantity of water is added, It is extracted with ethyl acetate, saturated common salt washing organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column layer Analysis is isolated and purified, and obtains object (compound shown in Formulas I).
The present invention is further elaborated below by embodiment, its purpose, which is only that, is best understood from present invention.Cause This, the cited case is not limited the scope of the invention.
Embodiment 1
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2,3- dihydrobenzos [b] [1,4] two Oxygen glutinous rehmannia -6- formamides are (marked as " IA- 1 " preparation)：
(1) N- (4- nitrophenethyls) -2,3- dihydrobenzos [b] [1,4] dioxin -6- formamide (shownization of Formula II -1 Compound) preparation：
1.80g (10mmol) Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are dissolved in 50ml dichloromethane, stirring is lower to add 3.8g (20mmol) 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, 2.7g (20mmol) I-hydroxybenzotriazole, React at room temperature and 3.3mL (20mmol) DIPEA is added after 1h, 0.122g (1mmol) DMAP, 2.03g (10mmol) 4- nitro phenethylamine hydrochlorides are added, 24h is reacted at ambient temperature, suitable quantity of water is added, acetic acid second is used Ester is extracted, saturated common salt washing organic phase, concentration organic phase (vacuum distillation removes solvent), and residue is separated pure with silica gel column chromatography (eluent is ethyl acetate for change：Petroleum ether=1:25, v/v) white solid (compound shown in Formula II -1), yield, are obtained 81%.
1H NMR (400MHz, DMSO) δ 8.42 (t, J=5.4Hz, 1H), 8.16 (d, J=8.6Hz, 2H), 7.52 (d, J =8.6Hz, 2H), 7.41-7.28 (m, 2H), 6.90 (d, J=8.1Hz, 1H), 4.27 (q, J=4.8Hz, 4H), 3.51 (dd, J =12.8,6.8Hz, 2H), 2.97 (t, J=7.0Hz, 2H)
(2) N- (4- aminobenzenes) -2,3- dihydrobenzos [b] [1,4] dioxin -6- formamide (chemical combination shown in formula III -1 Thing) preparation：
Compound shown in 1.64g (5mmol) Formula II -1 is dissolved in 5ml methanol, under stirring, 1.06g (10mmol) is added 10% palladium-carbon catalyst, with H2In room temperature reaction 5h, filtering and filtrate concentration, through silica gel column chromatography, (eluent is second to residue Acetoacetic ester：Petroleum ether=1:10, v/v) white solid (compound shown in formula III -1), yield 85%, are obtained.
1H NMR(400MHz,CDCl3) δ 7.26 (d, J=3.8Hz), 7.17 (d, J=8.2Hz), 7.02 (d, J= 7.7Hz), 6.85 (d, J=8.4Hz), 6.66 (d, J=7.7Hz), 6.02 (s), 4.27 (s), 3.62 (dd, J=12.7, 6.3Hz), 2.79 (t, J=6.6Hz)
(3) preparation of 2,4- di-amino-pyrimidines -5- nitriles (compound shown in formula IV)：
1.22g (10mmol) guanidine nitrate is dissolved in 50ml caustic alcohols and ethanol, 1.22g (10mmol) ethyoxyl is added sub- Methylmalononitrile reacts 8h under conditions of 5 DEG C, adds suitable quantity of water, is extracted with ethyl acetate, saturated common salt washing organic phase, dense Contracting organic phase (vacuum distillation removes solvent), with silica gel column chromatography separating purification, (eluent is methanol to residue：Dichloromethane=1: 30, v/v) white solid (compound shown in formula IV), yield 71%, are obtained.
1H NMR(400MHz,DMSO)δ8.16(s),7.11(s),6.97(s).
(4) preparation of 2,4- di-amino-pyrimidines -5- formaldehyde (compound shown in Formula V)：
Compound shown in 0.41g (2mmol) Formula V is dissolved in methanol, added in (the catalysis of 0.13g (2mmol) Raney's nickel Agent) and H2In room temperature reaction 24h, suitable quantity of water is added, is extracted with ethyl acetate, saturated common salt washing organic phase concentrates organic phase (vacuum distillation removes solvent), with silica gel column chromatography separating purification, (eluent is methanol to residue：Dichloromethane=1:30, v/v), Obtain white solid (compound shown in Formula V), yield 81%.
1H NMR (400MHz, DMSO) δ 9.45 (s, 1H), 8.31 (s, 1H), 7.66 (d, J=96.4Hz, 2H), 7.14 (d, J=31.3Hz, 2H)
(5)IAThe preparation of -1 (object)：
By compound, 0.126g shown in compound shown in 0.188g (1mmol) Formula V and 0.447g (1.5mmol) formula III -1 (2mmol) sodium cyanoborohydride, is kept for 24 hours in reflux state in 15mL methanol, adds suitable quantity of water, use ethyl acetate Extraction, saturated common salt washing organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column chromatography separating purification (eluent is methanol：Dichloromethane=1:10, v/v) white solid (I, is obtainedA- 1), yield 65%.
1H NMR (400MHz, DMSO) δ 8.33 (t, J=5.4Hz, 1H), 7.64 (s, 1H), 7.34 (dd, J=11.5, 1.9Hz, 2H), 6.91 (dd, J=10.8,8.3Hz, 3H), 6.52 (d, J=8.4Hz, 2H), 6.27 (s, 2H), 5.84 (s, 2H), 5.65 (d, J=5.7Hz, 1H), 4.41-4.16 (m, 4H), 3.88 (d, J=5.4Hz, 2H), 2.64 (dd, J=15.0, 7.2Hz,2H).
HRMS(EI)m/z calce C22H24N6O3(M+) 420.1910 (theoretical values), found (experiment value) 420.1911.
Embodiment 2
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) benzo [d] [1,3] Dloxole Alkane is (marked as " IA- 2 " preparation)：
Except 1,4- benzodioxanes -6- carboxylic acids in (1) the step of embodiment 1 are substituted for into dioxy between benzo [d] [1,3] Outside heterocycle cyclopentane carboxylic acid, remaining required raw material, reagent and preparation method be the same as Example 1 obtain white solid (IA- 2), yield 50%.
1H NMR (400MHz, DMSO) δ 8.35 (t, J=5.5Hz, 1H), 7.64 (s, 1H), 7.41 (dd, J=8.1, 1.7Hz, 1H), 7.36 (d, J=1.6Hz, 1H), 6.95 (dd, J=15.1,8.3Hz, 3H), 6.52 (d, J=8.4Hz, 2H), 6.46 (s, 1H), 6.08 (s, 2H), 6.03 (s, 2H), 5.68 (s, 1H), 3.89 (d, J=5.2Hz, 2H), 3.34 (s, 3H), 2.71–2.59(m,2H).
HRMS(EI)m/z calce C21H22N6O3(M+) 406.1753 (theoretical values), found 406.1753.
Embodiment 3
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3,4- dimethoxy benzenes (marked as “IA- 3 " preparation)：
Except 1,4- benzodioxanes -6- carboxylic acids in (1) the step of embodiment 1 are substituted for into 1,2- dimethoxybenzoic acids Outside, remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 3), yield 40%.
1H NMR (400MHz, DMSO) δ 8.39 (dd, J=12.5,7.1Hz, 1H), 7.64 (s, 1H), 7.49-7.39 (m, 2H), 7.00 (d, J=8.4Hz, 1H), 6.94 (d, J=8.4Hz, 2H), 6.53 (d, J=8.4Hz, 2H), 6.38 (s, 2H), 5.95 (s, 2H), 5.68 (t, J=5.5Hz, 1H), 3.90 (d, J=5.2Hz, 2H), 3.79 (d, J=2.3Hz, 6H), 2.72- 2.61(m,2H).
HRMS(EI)m/z calce C22H26N6O3(M+) 422.2066 (theoretical values), found 422.2067.
Embodiment 4
The bromo- N- of 4- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- fluorobenzamide (labels For " IA- 4 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for the bromo- 4- fluobenzoic acids of 2- in (1) the step of by embodiment 1, Remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 4), yield 40%.
1H NMR(400MHz,DMSO)δ8.38(s,1H),7.71–7.61(m,2H),7.56–7.45(m,2H),6.94 (d, J=8.3Hz, 2H), 6.53 (d, J=8.3Hz, 2H), 6.26 (s, 2H), 5.84 (s, 2H), 5.67 (s, 1H), 3.89 (s, 2H), 3.36 (d, J=5.9Hz, 2H), 2.69-2.59 (m, 2H)
HRMS(EI)m/z calce C20H20BrFN6O(M+) 458.0866 (theoretical values), found 458.0868.
Embodiment 5
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -4- fluorobenzamides are (marked as " IA- 5 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 4- fluobenzoic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 5), yield 39%.
1H NMR (400MHz, DMSO) δ 8.53 (t, J=5.5Hz, 1H), 7.89 (dd, J=8.9,5.5Hz, 2H), 7.64 (s, 1H), 7.28 (t, J=8.9Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 6.52 (d, J=8.4Hz, 2H), 6.24 (s, 2H), 5.85 (s, 2H), 5.66 (s, 1H), 3.89 (s, 2H), 3.37 (dd, J=14.5,6.2Hz, 3H), 2.70-2.60 (m, 2H).
HRMS(EI)m/z calce C20H21FN6O(M+) 380.1761 (theoretical values), found 380.1760.
Embodiment 6
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- fluorobenzamides are (marked as " IA- 6 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 2- fluobenzoic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 6), yield 46%.
1H NMR (400MHz, DMSO) δ 8.30 (s, 1H), 7.65 (s, 1H), 7.60-7.54 (m, 1H), 7.51 (dd, J= 12.7,6.4Hz, 1H), 7.27 (dd, J=12.9,5.6Hz, 2H), 6.95 (d, J=8.1Hz, 2H), 6.53 (d, J=8.2Hz, 2H), 6.34 (s, 2H), 5.99 (s, 2H), 5.68 (s, 1H), 3.90 (s, 3H), 3.37 (d, J=6.6Hz, 3H), 2.72-2.60 (m,2H).
HRMS(EI)m/z calce C20H21FN6O(M+) 380.1761 (theoretical values), found 380.1762.
Embodiment 7
The chloro- N- of 4- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- fluorobenzamide (labels For " IA- 7 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for the chloro- 3- fluobenzoic acids of 1- in (1) the step of by embodiment 1, Remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 7), yield 60%.
1H NMR (400MHz, DMSO) δ 8.38 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.58 (t, J=8.1Hz, 1H), 7.53 (dd, J=10.2,1.9Hz, 1H), 7.36 (dd, J=8.2,1.8Hz, 1H), 6.94 (d, J=8.4Hz, 2H), 6.53 (d, J=8.4Hz, 2H), 6.26 (s, 2H), 5.84 (s, 2H), 5.67 (s, 1H), 3.89 (s, 2H), 3.41-3.32 (m, 2H),2.69–2.59(m,2H).HRMS(EI)m/z calce C20H20ClFN6O(M+) 414.1371 (theoretical values), found 414.1370.
Embodiment 8
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3- fluorobenzamides are (marked as " IA- 8 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 3- fluobenzoic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 8), yield 45%.
1H NMR (400MHz, DMSO) δ 8.60 (t, J=5.4Hz, 1H), 7.67 (dd, J=16.0,8.3Hz, 2H), 7.61 (dd, J=9.6,2.0Hz, 1H), 7.51 (td, J=8.0,6.0Hz, 1H), 7.36 (td, J=8.2,2.3Hz, 1H), 6.94 (d, J=8.3Hz, 2H), 6.53 (d, J=8.4Hz, 2H), 6.18 (s, 2H), 5.78 (s, 2H), 5.65 (s, 1H), 3.89 (s, 2H), 3.38 (dd, J=14.1,6.4Hz, 2H), 2.74-2.59 (m, 2H) .HRMS (EI) m/z calce C20H21FN6O(M+) 380.1761 (theoretical values), found380.1761.
Embodiment 9
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -4- methoxy benzamides (marked as “IA- 9 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 4- methoxy benzoic acids in (1) the step of by embodiment 1, Remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 9), yield 60%.
1H NMR (400MHz, DMSO) δ 8.35 (t, J=5.5Hz, 1H), 7.80 (d, J=8.9Hz, 2H), 7.64 (s, 1H), 6.98 (d, J=8.9Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 6.52 (d, J=8.4Hz, 2H), 6.25 (s, 2H), 5.84 (s, 2H), 5.65 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 3.35 (dd, J=14.3,6.1Hz, 2H), 2.71- 2.60(m,2H).HRMS(EI)m/z calce C21H24N6O2(M+) 392.1961 (theoretical values), found 392.1963.
Embodiment 10
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3- methoxy benzamides (marked as “IA- 10 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 3- methoxy benzoic acids in (1) the step of by embodiment 1, Remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 10), yield 51%.
1H NMR (400MHz, DMSO) δ 8.49 (t, J=5.3Hz, 1H), 7.64 (s, 1H), 7.37 (dt, J=15.3, 7.8Hz, 3H), 7.07 (d, J=7.6Hz, 1H), 6.94 (d, J=8.3Hz, 2H), 6.53 (d, J=8.3Hz, 2H), 6.34 (s, 2H),5.92(s,2H),5.67(s,1H),3.89(s,2H),3.79(s,3H),3.41–3.31(m,2H),2.72–2.61(m, 2H).HRMS(EI)m/z calce C21H24N6O2(M+) 392.1961 (theoretical values), found 392.1961.
Embodiment 11
The chloro- N- of 3- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -4- methoxy benzamides (marked as " IA- 11 " preparation)：
Except 1,4- benzodioxanes -6- carboxylic acids in (1) the step of embodiment 1 are substituted for into 3- chlorine 4- methoxy benzoic acids Outside, remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 11), yield 41%.
1H NMR (400MHz, DMSO) δ 8.49 (t, J=5.3Hz, 1H), 7.91 (d, J=2.0Hz, 1H), 7.82 (d, J =8.6Hz, 1H), 7.65 (s, 1H), 7.22 (d, J=8.7Hz, 1H), 6.93 (d, J=8.2Hz, 2H), 6.52 (d, J= 8.2Hz, 2H), 6.21 (s, 2H), 5.81 (s, 2H), 5.66 (s, 1H), 3.91 (s, 3H), 3.89 (s, 2H), 3.36 (d, J= 6.7Hz,2H),2.69–2.61(m,2H).HRMS(EI)m/z calce C21H23ClN6O2(M+) 426.1571 (theoretical values), found 426.1572。
Embodiment 12
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3,5- dimethoxybenzarnides (mark Number be " IA- 12 " preparation)：
Except 1,4- benzodioxanes -6- carboxylic acids in (1) the step of embodiment 1 are substituted for into 3,5- dimethoxybenzoic acids Outside, remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 12), yield 33%.
1H NMR (400MHz, DMSO) δ 8.46 (t, J=5.6Hz, 1H), 7.64 (s, 1H), 6.97 (d, J=2.2Hz, 2H), 6.93 (d, J=8.3Hz, 2H), 6.62 (t, J=2.1Hz, 1H), 6.53 (d, J=8.4Hz, 2H), 6.22 (s, 2H), 5.81 (s, 2H), 5.66 (s, 1H), 3.89 (s, 2H), 3.77 (s, 6H), 3.35 (dd, J=14.1,6.1Hz, 2H), 2.69- 2.61(m,2H).HRMS(EI)m/z calce C22H26N6O3(M+) 422.2066 (theoretical values), found 422.2066.
Embodiment 13
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) picolinamide is (marked as " IA-13”) Preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 2- pyridine carboxylic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 13), yield 32%.
1H NMR (400MHz, DMSO) δ 8.72 (t, J=6.0Hz, 1H), 8.67-8.56 (m, 1H), 8.11-7.95 (m, 2H), 7.65 (s, 1H), 7.59 (ddd, J=7.2,4.8,1.5Hz, 1H), 6.94 (d, J=8.4Hz, 2H), 6.53 (d, J= 8.4Hz, 2H), 6.18 (s, 2H), 5.78 (s, 2H), 5.64 (s, 1H), 3.88 (s, 2H), 3.45 (dd, J=14.6,6.4Hz, 2H),2.78–2.60(m,2H).HRMS(EI)m/z calce C19H21N7O(M+) 363.1808 (theoretical values), found 363.1806。
Embodiment 14
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) niacinamide is (marked as " IA- 14 ") Prepare：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for acidum nicotinicum in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 14), yield 30%.
1H NMR (400MHz, DMSO) δ 8.97 (d, J=1.5Hz, 1H), 8.76-8.63 (m, 2H), 8.18-8.10 (m, 1H), 7.65 (s, 1H), 7.53-7.47 (m, 1H), 6.94 (d, J=8.4Hz, 2H), 6.53 (d, J=8.5Hz, 2H), 6.17 (s, 2H), 5.75 (s, 2H), 5.65 (t, J=6.0Hz, 1H), 3.88 (d, J=5.5Hz, 2H), 3.40 (dd, J=14.4, 6.2Hz, 3H), 2.67 (t, J=7.5Hz, 2H) .HRMS (EI) m/z calce C19H21N7O(M+) 363.1808 (theoretical values), found 363.1807。
Embodiment 15
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) furans -2- formamides are (marked as " IA- 15 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 2- furancarboxylic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 15), yield 40%.
1H NMR (400MHz, DMSO) δ 8.35 (t, J=5.6Hz, 1H), 7.80 (d, J=0.9Hz, 1H), 7.64 (s, 1H), 7.06 (d, J=3.4Hz, 1H), 6.92 (d, J=8.4Hz, 2H), 6.60 (dd, J=3.4,1.7Hz, 1H), 6.52 (d, J =8.4Hz, 2H), 6.37 (s, 2H), 5.96 (s, 2H), 5.67 (s, 1H), 3.89 (s, 2H), 3.33 (dd, J=14.5, 6.2Hz,2H),2.69–2.58(m,2H).HRMS(EI)m/z calce C18H20N6O2(M+) 352.1648 (theoretical values), found 352.1647。
Embodiment 16
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) thiophene-2-carboxamide derivatives are (marked as " IA- 16 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 2- thiophenic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 16), yield 43%.
1H NMR(400MHz,DMSO)δ8.53(s,1H),7.83–7.67(m,2H),7.64(s,1H),7.18–7.06 (m, 1H), 6.91 (dd, J=17.5,8.2Hz, 2H), 6.52 (d, J=7.8Hz, 2H), 6.43 (s, 2H), 6.01 (s, 2H), (m, 2H) .HRMS (EI) m/z of 5.68 (s, 1H), 3.89 (s, 2H), 3.34 (d, J=6.5Hz, 2H), 2.73-2.58 calce C18H20N6OS(M+) 368.1419 (theoretical values), found 368.1418.
Embodiment 17
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- naphthalenes are (marked as " IA- 17 " system) It is standby：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 2- naphthoic acids in (1) the step of by embodiment 1, remaining institute Raw material, reagent and preparation method be the same as Example 1 are needed, white solid (I is obtainedA- 17), yield 53%.
1H NMR (400MHz, DMSO) δ 8.68 (t, J=5.5Hz, 1H), 8.42 (s, 1H), 8.04-7.95 (m, 3H), 7.91 (dd, J=8.6,1.6Hz, 1H), 7.72-7.55 (m, 3H), 6.97 (d, J=8.3Hz, 2H), 6.54 (d, J=8.4Hz, 2H), 6.21 (s, 2H), 5.80 (s, 2H), 5.66 (s, 1H), 3.90 (s, 2H), 3.45 (d, J=6.2Hz, 2H), 2.77-2.68 (m,2H).HRMS(EI)m/z calce C24H24N6O(M+) 412.2012 (theoretical values), found 412.2014.
Embodiment 18
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3- hydrocinnamamides are (marked as " IA- 18 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 3- phenylpropionic acids in (1) the step of by embodiment 1, remaining Required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 18), yield 52%.
1H NMR (400MHz, DMSO) δ 7.83 (t, J=5.6Hz, 1H), 7.65 (s, 1H), 7.31-7.22 (m, 2H), 7.22-7.13 (m, 3H), 6.85 (d, J=8.4Hz, 2H), 6.50 (d, J=8.4Hz, 2H), 6.19 (s, 2H), 5.78 (s, 2H), 5.64 (s, 1H), 3.88 (s, 2H), 3.14 (dd, J=14.1,6.5Hz, 3H), 2.83-2.74 (m, 2H), 2.47 (s, 2H),2.38–2.29(m,2H).HRMS(EI)m/z calce C22H26N6O(M+) 390.2168 (theoretical values), found 390.2166。
Embodiment 19
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- phenyl acetamides are (marked as " IA- 19 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for phenylacetic acid in (1) the step of by embodiment 1, needed for remaining Raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 19), yield 43%.
1H NMR (400MHz, DMSO) δ 8.03 (s, 1H), 7.64 (s, 1H), 7.33-7.18 (m, 5H), 6.86 (d, J= 8.0Hz, 2H), 6.50 (d, J=8.1Hz, 2H), 6.37 (s, 2H), 5.95 (s, 2H), 5.68 (s, 1H), 3.89 (s, 3H), 3.37(s,2H),3.16–3.12(m,2H),2.54(m,2H).HRMS(EI)m/z calce C21H24N6O(M+)376.2012 (theoretical value), found376.2014.
Embodiment 20
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) oxygen-containing -9H- fluorenes -4- formamides of -9- (marked as " IA- 20 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 9-Fluorenone -4- formic acid in (1) the step of by embodiment 1, its Raw material, reagent and preparation method be the same as Example 1 needed for remaining, obtain white solid (IA- 20), yield 53%.
1H NMR (400MHz, DMSO) δ 8.76 (t, J=5.5Hz, 1H), 7.72-7.46 (m, 6H), 7.46-7.35 (m, 2H), 6.99 (d, J=8.4Hz, 2H), 6.54 (d, J=8.4Hz, 2H), 6.20 (s, 2H), 5.77 (d, J=8.7Hz, 2H), 5.70 (s, 1H), 3.89 (d, J=5.1Hz, 2H), 3.50 (dd, J=12.7,6.9Hz, 2H), 2.72 (t, J=7.1Hz, 2H) .HRMS(EI)m/z calce C27H24N6O2(M+) 464.1961 (theoretical values), found 464.1961.
Embodiment 21
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -9- hydroxyl -9H- fluorenes -4- formamides (marked as " IA- 21 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 9H- Fluorenone -4- formic acid in (1) the step of by embodiment 1, Remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 21), yield 46%.
1H NMR (400MHz, DMSO) δ 8.76 (t, J=5.5Hz, 1H), 7.72-7.46 (m, 6H), 7.46-7.35 (m, 2H), 6.99 (d, J=8.4Hz, 2H), 6.54 (d, J=8.4Hz, 2H), 6.20 (s, 2H), 5.77 (d, J=8.7Hz, 2H), 5.70 (s, 1H), 4.30 (s, 1H), 3.89 (d, J=5.1Hz, 2H), 3.50 (dd, J=12.7,6.9Hz, 2H), 2.72 (t, J =7.1Hz, 2H) .HRMS (EI) m/z calce C27H26N6O2(M+) 466.2117 (theoretical values), found 466.2118.
Embodiment 22
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -9H- fluorenes -9- formamides (marked as “IA- 22 " preparation)：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for 9- fluorenes formic acid in (1) the step of by embodiment 1, remaining institute Raw material, reagent and preparation method be the same as Example 1 are needed, white solid (I is obtainedA- 22), yield 53%.
1H NMR (400MHz, DMSO) δ 8.31 (t, J=5.4Hz, 1H), 7.86 (d, J=7.2Hz, 2H), 7.67 (s, 1H), 7.40 (t, J=7.3Hz, 4H), 7.29 (t, J=7.4Hz, 2H), 6.93 (d, J=8.3Hz, 2H), 6.54 (d, J= 8.4Hz, 2H), 6.24 (s, 2H), 5.83 (s, 2H), 5.72 (s, 1H), 4.75 (s, 1H), 3.91 (s, 2H), 3.28 (dd, J= 12.9,6.9Hz, 3H), 2.60 (t, J=7.0Hz, 2H) .HRMS (EI) m/z calce C27H26N6O(M+) 450.2168 (theories Value), found 450.2167.
Embodiment 23
N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) cyclopentane formamide is (marked as " IA- 23 ") preparation：
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acids are substituted for cyclohexyl formic acid in (1) the step of by embodiment 1, its Raw material, reagent and preparation method be the same as Example 1 needed for remaining, obtain white solid (IA- 23), yield 63%.
1H NMR (400MHz, DMSO) δ 7.70 (t, J=5.4Hz, 1H), 7.64 (s, 1H), 6.88 (d, J=8.2Hz, 2H), 6.51 (d, J=8.3Hz, 2H), 6.39 (s, 2H), 5.99 (s, 2H), 5.69 (s, 1H), 3.89 (s, 2H), 3.12 (dd, J =13.6,6.6Hz, 2H), 2.50-2.47 (m, 2H), 2.04 (t, J=11.2Hz, 1H), 1.66 (s, 3H), 1.36-1.25 (m, 2H),1.21–1.08(m,5H).HRMS(EI)m/z calce C20H28N6O(M+) 368.2325 (theoretical values), found 368.2325。
Embodiment 24
4- (tert-butyl group)-N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) hexamethylene -1- formyls Amine is (marked as " IA- 24 " preparation)：
Except 1,4- benzodioxanes -6- carboxylic acids in (1) the step of embodiment 1 are substituted for into 4- tert-butylcyclohexyl formic acid Outside, remaining required raw material, reagent and preparation method be the same as Example 1, obtain white solid (IA- 24), yield 43%.
1H NMR (400MHz, DMSO) δ 7.65 (dd, J=25.2,8.2Hz, 2H), 6.88 (dd, J=8.1,3.2Hz, 2H), 6.51 (d, J=8.2Hz, 2H), 6.26 (s, 2H), 5.86 (s, 2H), 5.66 (s, 1H), 3.88 (s, 2H), 3.12 (dd, J =13.6,6.9Hz, 2H), 2.51 (s, 2H), 2.03-1.97 (m, 1H), 1.74 (s, 2H), 1.46 (d, J=11.0Hz, 1H), 1.40-1.26 (m, 2H), 1.19 (dd, J=21.5,9.6Hz, 2H), 0.93 (s, 2H), 0.80 (d, J=13.1Hz, 9H) .HRMS (EI) m/z calce C24H36N6O (M+) 424.2951 (theoretical value), found 424.2950.
Embodiment 25
(E)-N- (4- (((2,4- dihydrobenzo -5- bases) methylene) amino) phenethyl) -2,3- dihydrobenzos [b] [1, 4] dioxin -6- formamides are (marked as " IB- 1 " preparation)：
By compound, 0.126g shown in compound shown in 0.188g (1mmol) Formula V and 0.447g (1.5mmol) formula III -1 (2mmol) sodium cyanoborohydride, is kept for 24 hours in reflux state in 15mL methanol, adds suitable quantity of water, use ethyl acetate Extraction, saturated common salt washing organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column chromatography separating purification (eluent is methanol：Dichloromethane=1:10, v/v) white solid (I, is obtainedB- 1), yield 78%.
1H NMR(400MHz,DMSO)δ8.77(s,1H),8.46–8.35(m,2H),8.15(s,1H),7.47–7.31 (m, 3H), 7.23 (d, J=8.4Hz, 2H), 7.14 (d, J=8.3Hz, 2H), 6.91 (d, J=8.2Hz, 1H), 6.68 (s, 2H), (t, J=7.3Hz, the 2H) .HRMS of 4.27 (q, J=4.8Hz, 4H), 3.44 (dd, J=13.6,6.6Hz, 2H), 2.82 (EI)m/z calce C22H22N6O3(M+) 418.1753 (theoretical values), found 418.1752.
Embodiment 26
(E)-N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3,4- dimethoxybenzoyls Amine is (marked as " IB- 2 " preparation)：
Isosorbide-5-Nitrae in (1) the step of embodiment 1-benzodioxane-6- carboxylic acids are substituted for 1,2- dimethoxybenzoic acids, Step (1)~(4) and embodiment 25 in embodiment 1 are repeated, white solid (I is obtainedB- 2), yield 43%.
1H NMR(400MHz,DMSO)δ8.76(s,2H),8.47–8.37(m,2H),8.15(s,1H),7.51–7.36 (m, 3H), 7.24 (d, J=8.4Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 7.01 (d, J=8.4Hz, 1H), 6.66 (s, 2H), (m, 2H) .HRMS (EI) m/z of 3.80 (d, J=1.2Hz, 6H), 3.51-3.41 (m, 2H), 2.88-2.79 calce C22H24N6O3(M+) 420.1910 (theoretical values), found 420.1910.
The structure list of the prepare compound of embodiment 1~26 is shown in Table 1..
Table 1.
Continued 1.
Embodiment 27
Suppression of the acetamides that the present invention is provided to cysteine proteinase (falcipain-2, FP-2) is lived Property data
The measure of FP-2 inhibitory activity：First by albumen FP-2 respectively with compound IA- 1~24 and compound IB- 1~2 After being incubated 30 minutes at room temperature, then start the measure of enzymatic activity.
Screening reaction is carried out in the orifice plate of BioTek Synergy2 ELIASAs 384, and reaction temperature is room temperature, and primary dcreening operation is determined Concentration is the inhibiting rate of 1 μM of compound, is substantially determined to be used to determine IC according to primary dcreening operation result50Required compound concentration gradient, 7 concentration gradients of each compound.Inhibiting rate is more than 40% during 10 μM of compound concentrations, is defined as effectively, determining the compound IC50；Inhibiting rate is less than 40% during 10 μM of compound concentrations, and it is invalid to be defined as.Test result is shown in Table the 2. (second that the present invention is provided Primary dcreening operation result of the amides compound to FP-2 inhibitory activity).
Table 2.
* E-64 is the inhibitor for the potent cysteine proteinase reported.
Embodiment 28
Inhibitory activity data of the acetamides that the present invention is provided to dihyrofolate reductase (DHFR).
The measure of DHFR inhibitory activity：The screening technique of use is uv detection method：Two can be catalyzed in the presence of NADPH Hydrogen folic acid (DHF) is reduced to tetrahydrofolic acid (THF), and NADPH has absworption peak at 340nm, therefore is examined with ultraviolet specrophotometer The absorbance (referring to accompanying drawing 1) surveyed at 340nm.The activity of enzyme is better, and absorbance is lower.
Specifically testing procedure is：By assay buffer [50 μM of TES (pH7.0), 1 μM of EDTA (pH8.0), 100M ADPH, 1mg/ml BSA, 75 μM of-ME] (190：L) with DHFRlysate (5：And testing compound (compound I l)A- 1~ 24 and compound IB- 1~2) be added in 5ml EP pipes in 4 DEG C be incubated 30 minutes, add DHF (100 μM) start reaction； OD340nm change is detected, it is 30 seconds to detect whole course of reaction；Using the DMSO of equivalent as negative control, PYR is positive right The speed declined according to, absorbance with the time is slower, shows that the inhibition of compound is better；Inhibiting rate during 10 μM of compound primary dcreening operations More than 50%, it is defined as effectively, and measure IC50Value.Test result is shown in Table the 3. (acetamides pair that the present invention is provided The primary dcreening operation result of DHFR inhibitory activity).
Table 3.
* PYR (pyrimethamine) is known PfDHFR potent inhibitors.
Embodiment 29
Compound IA- 5 couples of plasmodium falciparum 3D7C8 kill malaria EC in vitro50Data.
Plasmodium is cultivated：Plasmodium culture (contains NaHCO using RPMI3, HEPES, Albumax I, Hypoxanthine, Genaotamicin) complete medium (Complete Medium), in 37 DEG C of incubator (5%CO2, 5%O2) middle culture.
Compound plasmodium growth in vitro suppresses EC50Determine：100ul complete mediums are added in 96 orifice plates, first Appropriate compound is added in hole and 200ul is settled to complete medium so that compound IA- 5 final concentration of 10uM, it is blue or green Artemisin is 500nM, then carries out gradient dilution (11 concentration gradients) in 1/2 ratio, Artemsinin is as positive control, no Plus any compound is as negative control, plasmodium and compound are not added with as Experimental Background.100ul malaria is added per hole afterwards Protozoa culture thing (1%ring parasitemia, 4%HCT) is such that final HCT and parasitemia is 2% and 1%, changes The final concentration gradient of compound is 10uM.96 orifice plates are placed into 37 DEG C of incubator (5%CO after sample-adding is completed2, 5%O2) middle culture 72h.Culture adds 100ul Lysis Buffer (10x SYBR Green I, 0.5%v/v Triton per hole after completing X-100,0.5mg/ml saponin, 0.75%EDTA in Tris-Cl Buffer), after mixing, room temperature lucifuge is incubated 2h. With orifice plate fluorescence reading machine reading numerical values, (maximum excitation light/maximum receives light after incubation completion：485nm/535nm) according to Fluorescence readings calculates inhibiting rate, inhibiting rate=(negative control group-experimental group)/(negative control group-Experimental Background), according to difference The inhibiting rate of concentration draws growth inhibition curve and calculates EC by Graph Pad 650.Concrete outcome is shown in Fig. 2.
Embodiment 30
Compound IA- 5 couples of chloroquine resistance plasmodium falciparum Dd2 kill malaria EC in vitro50Data.
Plasmodium is cultivated：Chloroquine resistance plasmodium falciparum Dd2 cultures (contain NaHCO using RPMI3, HEPES, Albumax I, Hypoxanthine, Genaotamicin) complete medium (Complete Medium), in 37 DEG C of incubator (5%CO2, 5%O2) middle culture.
Compound chloroquine resistance plasmodium falciparum Dd2 growth in vitro suppresses EC50Determine：100ul complete mediums are added to In 96 orifice plates, appropriate compound is added in the first hole and 200ul is settled to complete medium so that compound IA- 5 Final concentration of 10uM, then carries out gradient dilution (11 concentration gradients) in 1/2 ratio, is not added with any compound as feminine gender Control, is not added with plasmodium and compound as Experimental Background.100ul plasmodium culture (1%ring is added per hole afterwards Parasitemia, 4%HCT) so that final HCT and parasitemia is 2% and 1%, the final concentration gradient of compound is 10uM.96 orifice plates are placed into 37 DEG C of incubator (5%CO after sample-adding is completed2, 5%O2) middle culture 72h.Culture is every after completing Hole adds 100ul Lysis Buffer (10x SYBR Green I, 0.5%v/v Triton X-100,0.5mg/ml Saponin, 0.75%EDTA in Tris-Cl Buffer), after mixing, room temperature lucifuge is incubated 2h.It is incubated after completing and uses (maximum excitation light/maximum receives light to orifice plate fluorescence reading machine reading numerical values：485nm/535nm) is calculated according to fluorescence readings and pressed down Rate processed, inhibiting rate=(negative control group-experimental group)/(negative control group-Experimental Background), is painted according to the inhibiting rate of various concentrations Growth inhibition curve processed simultaneously calculates EC by Graph Pad650.Concrete outcome is shown in Fig. 3.

Claims (10)

  1. It is compound shown in Formulas I or it is pharmaceutically acceptable 1. a kind of N- (4- replaces phenethyl) amides compound Salt：
    In Formulas I：R1The group shown in formula A or B：
    R2For the C replaced by phenyl1~C4Straight or branched alkyl, C4~C13Cycloalkyl, heterocyclic radical or aromatic ring yl, or take The C in generation4~C13Cycloalkyl, heterocyclic radical or aromatic ring yl；
    Wherein, the hetero atom of the heterocyclic radical is nitrogen, oxygen or/and sulphur, the substituted C4~C13Cycloalkyl, heterocyclic radical or virtue The substituent of ring group is one or more kinds of in following groups：
    C1~C4Straight or branched alkyl, C1~C4Straight or branched alkoxyl, halogen, hydroxyl, ketone carbonyl orN is 1 Or 2.
  2. 2. N- (4- replaces phenethyl) amides compound as claimed in claim 1, it is characterised in that wherein, R1For formula A institutes Show group；R2For the C replaced by phenyl1~C4Straight or branched alkyl, furyl, thienyl, cyclohexyl, phenyl, pyridine Cyclohexyl, phenyl or the fluorenyl of base, naphthyl, fluorenyl, or substitution；
    The substituent of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups：
    C1~C4Straight or branched alkyl, C1~C4Straight or branched alkoxyl, halogen, hydroxyl, ketone carbonyl orN is 1 Or 2.
  3. 3. N- (4- replaces phenethyl) amides compound as claimed in claim 2, it is characterised in that wherein, R2For benzyl, The ring of phenethyl, 2- furyls, 2- thienyls, cyclohexyl, phenyl, 2- pyridine radicals, 3- pyridine radicals, 2- naphthyls, fluorenyl, or substitution Hexyl, phenyl or fluorenyl；
    The substituent of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups：
    Methoxyl group, the tert-butyl group, halogen, hydroxyl, ketone carbonyl orN is 1 or 2.
  4. 4. N- (4- replaces phenethyl) amides compound as claimed in claim 3, it is characterised in that wherein R2For benzyl, benzene Ethyl, 4- tert-butylcyclohexyls, 2- fluoro-phenyls, 3- fluorophenyls, 4- fluoro-phenyls, 3- methoxyl groups-phenyl, 4- methoxyl groups-phenyl, 3,4- dimethoxy-phenylfs, the bromo- phenyl of the fluoro- 4- of 2-, the chloro- phenyl of the fluoro- 4- of 2-, 3,5- dimethoxy-phenylfs, the chloro- 4- methoxies of 3- Base-phenyl,
  5. 5. N- (4- replaces phenethyl) amides compound as claimed in claim 4, it is characterised in that (4- replaces the N- Phenethyl) amides compound is a kind of in following compounds：
    N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2,3- dihydrobenzos [b] [1,4] dioxin - Dioxane between 6- formamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) benzo [d] [1,3] Pentane, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3,4- dimethoxy benzenes, the bromo- N- (4- of 4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- fluorobenzamides, N- (4- (((2,4- di-amino-pyrimidines - 5- yls) methyl) amino) phenethyl) -4- fluorobenzamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) benzene Ethyl) -2- fluorobenzamides, the chloro- N- of 4- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- fluorobenzene Formamide, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3- fluorobenzamides, N- (4- (((2, 4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -4- methoxy benzamides, N- (4- (((2,4- di-amino-pyrimidines - 5- yls) methyl) amino) phenethyl) -3- methoxy benzamides, the chloro- N- of 3- (4- (((2,4- di-amino-pyrimidine -5- bases) first Base) amino) phenethyl) -4- methoxy benzamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) benzene second Base) -3,5- dimethoxybenzarnides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) pyridine acyl Amine, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) niacinamide, N- (4- (((2,4- Diaminopyrimidines Pyridine -5- bases) methyl) amino) phenethyl) furans -2- formamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) Phenethyl) thiophene-2-carboxamide derivatives, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -2- naphthalenes, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3- hydrocinnamamides, N- (4- (((2,4- di-amino-pyrimidine -5- Base) methyl) amino) phenethyl) -2- phenyl acetamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) benzene second Base) oxygen-containing -9H- fluorenes -4- formamides of -9-, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -9- hydroxyls Base -9H- fluorenes -4- formamides, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -9H- fluorenes -9- formyls Amine, N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) cyclopentane formamide, or 4- (tert-butyl group)-N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) hexamethylene -1- formamides.
  6. 6. N- (4- replaces phenethyl) amides compound as claimed in claim 1, it is characterised in that wherein, R1For formula B institutes Show group；R2For substituted-phenyl；
    The substituent of the substituted-phenyl is C1~C4Straight or branched alkoxyl orN is 1 or 2.
  7. 7. N- (4- replaces phenethyl) amides compound as claimed in claim 6, it is characterised in that wherein, R2For by methoxy Base orSubstituted-phenyl.
  8. 8. N- (4- replaces phenethyl) amides compound as claimed in claim 7, it is characterised in that wherein, R2For 3,4- bis- Methoxyl group-phenyl or
  9. 9. N- (4- replaces phenethyl) amides compound as claimed in claim 8, it is characterised in that the ethanamide Compound is (E)-N- (4- (((2,4- dihydrobenzo -5- bases) methylene) amino) phenethyl) -2,3- dihydrobenzos [b] [1,4] Dioxin -6- formamides, or (E)-N- (4- (((2,4- di-amino-pyrimidine -5- bases) methyl) amino) phenethyl) -3,4- diformazans Oxybenzamide.
  10. 10. N- (4- replaces phenethyl) amides compound is preparing cysteine as described in any one in claim 1~9 Protease and dihydrofolate reductase inhibitor, or the application in the medicine for preparing treatment malaria as caused by plasmodium.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101565418A (en) * 2008-04-23 2009-10-28 华东理工大学 Amide derivative and purpose thereof
CN101591285A (en) * 2008-05-26 2009-12-02 华东理工大学 Propionamides compound and uses thereof
CN101591327A (en) * 2008-05-26 2009-12-02 华东理工大学 Benzene alkyl amides compound and uses thereof
CN101693028A (en) * 2009-10-21 2010-04-14 华东理工大学 Application of lithospermic acid ester compounds in preparation of medicines for treating malaria
CN102086166A (en) * 2009-12-03 2011-06-08 华东理工大学 3-methoxy-4-(N-substituted amino sulfonyl)fenalamide compounds and application thereof
CN103127095A (en) * 2011-11-23 2013-06-05 华东理工大学 Synthesis and application of dihydrothiophenone derivative as pfDHODH inhibitor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101565418A (en) * 2008-04-23 2009-10-28 华东理工大学 Amide derivative and purpose thereof
CN101591285A (en) * 2008-05-26 2009-12-02 华东理工大学 Propionamides compound and uses thereof
CN101591327A (en) * 2008-05-26 2009-12-02 华东理工大学 Benzene alkyl amides compound and uses thereof
CN101693028A (en) * 2009-10-21 2010-04-14 华东理工大学 Application of lithospermic acid ester compounds in preparation of medicines for treating malaria
CN102086166A (en) * 2009-12-03 2011-06-08 华东理工大学 3-methoxy-4-(N-substituted amino sulfonyl)fenalamide compounds and application thereof
CN103127095A (en) * 2011-11-23 2013-06-05 华东理工大学 Synthesis and application of dihydrothiophenone derivative as pfDHODH inhibitor

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