CN106938997B - N- (4- replaces phenethyl) acetamides and application thereof - Google Patents

N- (4- replaces phenethyl) acetamides and application thereof Download PDF

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CN106938997B
CN106938997B CN201710034898.8A CN201710034898A CN106938997B CN 106938997 B CN106938997 B CN 106938997B CN 201710034898 A CN201710034898 A CN 201710034898A CN 106938997 B CN106938997 B CN 106938997B
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phenethyl
phenyl
compound
replaces
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CN106938997A (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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  • 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 N- of a kind of structure novel (4- replaces phenethyl) amides compounds.Show that such compound has enzyme inhibition activity to cysteine proteinase (FP-2) and dihyrofolate reductase (DHFR) by external activity test experiment.And malaria is killed the results showed that such compound is to wild, drug resistance plasmodium is all inhibited in vitro.

Description

N- (4- replaces phenethyl) acetamides and application thereof
Technical field
The present invention relates to acetamides and application thereof, in particular to one kind N- (4- replaces phenethyl) ethanamides Compound and application thereof.
Background technique
Malaria is one of the epidemic disease of most serious in the world.Have about 3,000,000,000 populations of a countries and regions more than 100 by The threat of malaria, the annual malarial people in the whole world have 3.5~500,000,000, and the patient for dying of malaria every year is 150~2,700,000, wherein about Half is children, and the disadvantaged country in Africa and Asia occurs for 90% case.Prevalence malaria area, China mainly include 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, to produce serious drug resistance.
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 Drug is suitable for clinic, and drug resistance plasmodium strain is increasing.With biochemistry, molecular biology and molecular pharmacology etc. The continuous development of related discipline discloses the effect in the Biochemical processes of many enzymes and receptor in vivo, in life Play key enzyme in object, carries out the development that new drug design has become New Drug Research as drug target Trend.The design of novel antiplasmodial drug is with a kind of cysteine protein to play an important role in plasmodium life cycle Enzyme (falcipain) is target spot, and push this development process is people to this medicine of papain cysteine proteinase Object target understanding deepens continuously.Plasmodium is used for the albumen of itself as main origin of amino acid by digestion red blood cell Matter synthesis.It is known in the degradation process of hemoglobin, play an important role there are three types of plasmodium protease.Wherein Plasmepain I and II belong to aspartic protease, and falcipain belongs to cysteine proteinase.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, and plasmodium is made to synthesize itself egg because lacking White free amino acid and it is dead.And clinically widely applied antimalarial chloroquine then passes through the polymerization for inhibiting free ferroheme, The a large amount of free radicals kill for discharging plasmodium by the hemn that dissociated.
Obvious cystatin kills the mechanism and chloroquine difference of plasmodium.Therefore selection cysteine egg 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 It is 21,000~30,000 protein, there is highest hydrolysing activity at 4~6.5 pH, its active site has half Guang ammonia The cysteine proteinase of sour residue, protozoon belongs to papain families.Known plasmodium cysteine proteinase has four A hypotype, falcipain-1, falcipain-2A, falcipain-2B, falcipain-3.Falcipain 1 is first Obtained plasmodium cysteine proteinase is expressed, biological study shows that it has no the asexual reproduction phases of plasmodium It influences, but the function of energy significant impact egg capsule.Falcipain-2A, falcipain-2B have 97% homology, amino 7 of acid sequence are different.It is found by the monitoring of oligonucleotide probe, the expression ratio of falcipain-2B mRNA Falcipain-2A is low.However falcipain-2A and falcipain-2B plasmodium trophosome advanced stage its expression time according to Rely property and peak value very much like, this shows that two 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 the more mature plasmodium stage. The crystal structure of falcipain-3 has not been reported.The most study of falcipain-2 in these types of hypotype, therefore it presses down The exploitation of preparation is also by more extensive concern.In addition to having inhibiting effect to cysteine proteinase falcipain-2, to two Hydrogen folic acid reductase (dihydrofolatere ductase, DHFR) also has inhibiting effect.
Dihyrofolate reductase (DHFR) is one of enzyme crucial 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 combines, and inhibits its catalytic reduction activity, prevents dihydrofoilic acid from being smoothly changed into tetrahydrofolic acid, and the latter becomes coenzyme F Afterwards, it can be synthesized for vivo biodistributions such as thymidine, purine, serine, methionine and one carbon unit is provided.If hindering folic acid metabolism Process will interfere the synthesis of DNA and protein, eventually lead to cell death.Dihyrofolate reductase (DHFR) is almost present in Institute is zoic intracellular, has become one of antimalarial, anticancer, main target enzyme in antibacterial drug therapy in Field of Drug Discovery, In recent years because its extensive bioactivity receives much attention.
Therefore, growth, the breeding that can inhibit plasmodium by inhibiting falcipain-2 (FP-2) and DHFR, filter out Potent FP-2&DHFR double inhibitor treats malaria.
Summary of the invention
The present inventor's design, N- (4- replaces phenethyl) the amides chemical combination for having synthesized a kind of structure novel Object.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 the experimental results showed that such compound is to wild, drug resistance malaria is former Worm is all inhibited.
It is an advantage of the invention to provide a kind of N- of structure novel (4- replaces phenethyl) amides compounds.
N- described in the present invention (4- replace phenethyl) amides compound, be compound shown in Formulas I or its pharmaceutically Acceptable salt:
In Formulas I: R1For group shown in formula A or B (curve mark be replace position, similarly hereinafter):
R2For the C replaced by phenyl1~C4Linear or branched alkyl group, C4~C13Naphthenic base, heterocycle or aromatic ring yl, Or the C replaced4~C13Naphthenic base, heterocycle or aromatic ring yl；
Wherein, the hetero atom of the heterocycle is nitrogen (N), oxygen (O) or/and sulphur (S), the substituted C4~C13Cycloalkanes The substituent group of base, heterocycle or aromatic ring yl is one or more kinds of in following groups (containing two kinds, similarly hereinafter):
C1~C4Linear or branched alkyl group, 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, discloses a kind of purposes of above-mentioned N- (4- replaces phenethyl) amides compound. That is: compound shown in Formulas I or its pharmaceutically acceptable salt is 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 preparation treatment malaria (especially caused by plasmodium Malaria) drug in application.
A further object of the invention is, provides a kind of method of compound shown in preparation formula I.
Described method includes following steps:
(1) by 4- nitro phenethylamine hydrochlorideWith carboxylic acid (R2COOH it) reacts, preparation formula II shownization The step of closing object；
(2) the step of compound shown in Formula II is through catalytic hydrogenating reduction, obtains compound shown in formula III；
(3) by guanidine nitrateIt is reacted with ethoxy methylene malononitrile, obtains 2,4- di-amino-pyrimidine -5- nitrile 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- nitrile Suddenly；With,
(5) compound as shown in formula III is reacted with compound shown in Formula V, obtains the step of object (compound shown in Formulas I) Suddenly.
Wherein, R2Definition with it is described previously identical.
Detailed description of the invention
The test of Fig. 1 uv detection method inhibits the schematic illustration of the activity data of dihyrofolate reductase (DHFR)；
Fig. 2 is compound IA- 5 pairs of plasmodium falciparum 3D7C8 growth inhibition curves (external)；
Fig. 3 compound IA- 5 pairs of chloroquine resistance plasmodium falciparum Dd2 growth inhibition curves (external).
Specific embodiment
In an optimal technical scheme of the invention, R1For group shown in formula A；R2For the C replaced by phenyl1~C4It is straight Chain or branched alkyl, furyl, thienyl, cyclohexyl, phenyl, pyridyl group, naphthalene, fluorenyl, or replace cyclohexyl, phenyl or Fluorenyl；
The substituent group of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups:
C1~C4Linear or branched alkyl group, 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- furyl, 2- thienyl, cyclohexyl, phenyl, 2- pyridyl group, 3- pyridyl group, 2- naphthalene, fluorenyl, or the cyclohexyl, phenyl or the fluorenyl that replace；
The substituent group of the substituted cyclohexyl, phenyl or fluorenyl is one or more kinds of in following groups:
Methoxyl group, tert-butyl, halogen (F, Cl, Br or I), hydroxyl (OH), ketone carbonylN is 1 or 2.
R still more preferably again2For benzyl, phenethyl, 4- tert-butylcyclohexyl, 2- fluoro-phenyl, 3- fluorophenyl, 4- Fluoro-phenyl, 3- methoxyl group-phenyl, 4- methoxyl group-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-methoxy-phenyl,
In presently preferred technical solution, R1For group shown in formula B；R2For substituted-phenyl；
The substituent group 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-phenylf or
The method of compound shown in preparation formula I provided by the invention, specifically comprises the following steps:
(1) by carboxylic acid (R2COOH it) is dissolved in methylene chloride and is added with stirring 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne N,N-diisopropylethylamine, 4- dimethylamino is added after reacting 1 hour at room temperature in diimmonium salt hydrochlorate and I-hydroxybenzotriazole 4- nitro phenethylamine hydrochloride is added in pyridine, then reacts 24 hours at room temperature, stops reaction, adds water in reaction solution, It is extracted with ethyl acetate, is concentrated, vacuum distillation removes solvent, residue washing, then is extracted with ethyl acetate, and organic phase is through silica gel Column chromatographic purifying obtains compound shown in Formula II；
(2) compound shown in Formula II is dissolved in methanol, under stirring, 10% palladium-carbon catalyst is added and is passed through hydrogen (H2), It reacts 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 sodium ethoxide and ethyl alcohol, ethoxy methylene malononitrile is added and is reacted under conditions of 5 DEG C 8h.It to which suitable quantity of water is added after reaction, is extracted with ethyl acetate, saturated common salt washes 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- nitrile (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 compound shown in formula III and Formula V is kept at least 24 hours in methanol in reflux state (as preparation R1For group shown in formula A object when, in above-mentioned reaction system plus sodium cyanoborohydride), be added suitable quantity of water, It is extracted with ethyl acetate, saturated common salt washes organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column layer Analysis isolates and purifies, and obtains object (compound shown in Formulas I).
The present invention is further elaborated below by embodiment, purpose, which is only that, is best understood from the content of present invention.Cause This, the cited case does not limit the scope of the invention.
Embodiment 1
N- (4- (((2,4- di-amino-pyrimidine -5- base) methyl) amino) phenethyl) -2,3- dihydrobenzo [b] [1,4] two Oxygen glutinous rehmannia -6- formamide is (marked as " IA- 1 " preparation):
(1) N- (4- nitrophenethyl) -2,3- dihydrobenzo [b] [1,4] dioxin -6- formamide (- 1 shownization of Formula II Close object) preparation:
1.80g (10mmol) Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is dissolved in 50ml methylene chloride, is added with stirring 3.8g (20mmol) 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2.7g (20mmol) I-hydroxybenzotriazole, Addition 3.3mL (20mmol) n,N-diisopropylethylamine after reaction 1h at room temperature, 0.122g (1mmol) 4-dimethylaminopyridine, 2.03g (10mmol) 4- nitro phenethylamine hydrochloride is added, reacts at room temperature for 24 hours, adds suitable quantity of water, with acetic acid second Ester extraction, saturated common salt wash organic phase, concentration organic phase (vacuum distillation removes solvent), and residue silica gel column chromatography separates pure Change (eluent is ethyl acetate: petroleum ether=1:25, v/v), obtains white solid (compound shown in Formula II -1), yield 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- aminobenzene) -2,3- dihydrobenzo [b] [1,4] dioxin -6- formamide (chemical combination shown in formula III -1 Object) preparation:
Compound shown in 1.64g (5mmol) Formula II -1 is dissolved in 5ml methanol, under stirring, is added 1.06g (10mmol) 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), obtain white solid (compound shown in formula III -1), yield 85%.
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-pyrimidine -5- nitrile (compound shown in formula IV):
1.22g (10mmol) guanidine nitrate is dissolved in 50ml sodium ethoxide and ethyl alcohol, it is sub- that 1.22g (10mmol) ethyoxyl is added Methylmalononitrile reacts 8h under conditions of 5 DEG C, and suitable quantity of water is added, is extracted with ethyl acetate, and saturated common salt washes organic phase, dense Contracting organic phase (vacuum distillation remove solvent), residue with silica gel column chromatography separating purification (eluent is methanol: methylene chloride=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-pyrimidine -5- formaldehyde (compound shown in Formula V):
Compound shown in 0.41g (2mmol) Formula V is dissolved in methanol, is added in (the catalysis of 0.13g (2mmol) Raney's nickel Agent) and H2For 24 hours in room temperature reaction, suitable quantity of water is added, is extracted with ethyl acetate, saturated common salt washes organic phase, and organic phase is concentrated (vacuum distillation remove solvent), residue with silica gel column chromatography separating purification (eluent is methanol: methylene chloride=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 wash organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column chromatography separating purification (eluent is methanol: methylene chloride=1:10, v/v), obtains white solid (IA- 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- base) methyl) amino) phenethyl) benzo [d] [1,3] Dloxole Alkane is (marked as " IA- 2 " preparation):
Except 1,4- benzodioxane -6- carboxylic acid in (1) the step of embodiment 1 is substituted for dioxy between benzo [d] [1,3] Outside heterocycle cyclopentane carboxylic acid, remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -3,4- dimethoxy benzene (marked as “IA- 3 " preparation):
Except 1,4- benzodioxane -6- carboxylic acid in (1) the step of embodiment 1 is substituted for 1,2- dimethoxybenzoic acid Outside, remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -2- fluorobenzamide (label For " IA- 4 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for the bromo- 4- fluobenzoic acid of 2- in the step of by embodiment 1 (1), Remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -4- fluorobenzamide is (marked as " IA- 5 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 4- fluobenzoic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -2- fluorobenzamide is (marked as " IA- 6 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 2- fluobenzoic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -2- fluorobenzamide (label For " IA- 7 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for the chloro- 3- fluobenzoic acid of 1- in the step of by embodiment 1 (1), Remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -3- fluorobenzamide is (marked as " IA- 8 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 3- fluobenzoic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -4- methoxy benzamide (marked as “IA- 9 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 4- methoxy benzoic acid in the step of by embodiment 1 (1), Remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -3- methoxy benzamide (marked as “IA- 10 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 3- methoxy benzoic acid in the step of by embodiment 1 (1), Remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -4- methoxy benzamide (marked as " IA- 11 " preparation):
Except 1,4- benzodioxane -6- carboxylic acid in (1) the step of embodiment 1 is substituted for 3- chlorine 4- methoxy benzoic acid Outside, remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -3,5- dimethoxybenzarnide (mark Number be " IA- 12 " preparation):
Except 1,4- benzodioxane -6- carboxylic acid in (1) the step of embodiment 1 is substituted for 3,5- dimethoxybenzoic acid Outside, remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) picolinamide is (marked as " IA-13”) Preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 2- pyridine carboxylic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) niacinamide is (marked as " IA- 14 ") Preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for acidum nicotinicum in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) furans -2- formamide is (marked as " IA- 15 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 2- furancarboxylic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) thiophene-2-carboxamide derivatives are (marked as " IA- 16 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 2- thiophenic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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), 5.68 (s, 1H), 3.89 (s, 2H), 3.34 (d, J=6.5Hz, 2H), 2.73-2.58 (m, 2H) .HRMS (EI) m/z calce C18H20N6OS(M+) 368.1419 (theoretical values), found 368.1418.
Embodiment 17
N- (4- (((2,4- di-amino-pyrimidine -5- base) methyl) amino) phenethyl) -2- naphthalene is (marked as " IA- 17 " system) It is standby:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 2- naphthoic acid in the step of by embodiment 1 (1), remaining institute It needs raw material, reagent and the preparation method is the same as that of Example 1, obtain white solid (IA- 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- base) methyl) amino) phenethyl) -3- hydrocinnamamide is (marked as " IA- 18 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 3- phenylpropionic acid in the step of by embodiment 1 (1), remaining Required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -2- phenyl acetamide is (marked as " IA- 19 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for phenylacetic acid in the step of by embodiment 1 (1), needed for remaining Raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) oxygen-containing -9H- fluorenes -4- formamide of -9- (marked as " IA- 20 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 9-Fluorenone -4- formic acid in the step of by embodiment 1 (1), Raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -9- hydroxyl -9H- fluorenes -4- formamide (marked as " IA- 21 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 9H- Fluorenone -4- formic acid in the step of by embodiment 1 (1), Remaining required raw material, reagent and the preparation method is the same as that of 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- base) methyl) amino) phenethyl) -9H- fluorenes -9- formamide (marked as “IA- 22 " preparation):
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for 9- fluorenes formic acid in the step of by embodiment 1 (1), remaining institute It needs raw material, reagent and the preparation method is the same as that of Example 1, obtain white solid (IA- 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- base) methyl) amino) phenethyl) cyclopentane formamide is (marked as " IA- 23 ") preparation:
In addition to Isosorbide-5-Nitrae-benzodioxane -6- carboxylic acid is substituted for cyclohexyl formic acid in the step of by embodiment 1 (1), Raw material, reagent and the preparation method is the same as that of 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)-N- (4- (((2,4- di-amino-pyrimidine -5- base) methyl) amino) phenethyl) hexamethylene -1- formyl Amine is (marked as " IA- 24 " preparation):
Except 1,4- benzodioxane -6- carboxylic acid in (1) the step of embodiment 1 is substituted for 4- tert-butylcyclohexyl formic acid Outside, remaining required raw material, reagent and the preparation method is the same as that of 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- base) methylene) amino) phenethyl) -2,3- dihydrobenzo [b] [1, 4] dioxin -6- formamide is (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 wash organic phase, concentration organic phase (vacuum distillation removes solvent), residue silica gel column chromatography separating purification (eluent is methanol: methylene chloride=1:10, v/v), obtains white solid (IB- 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), 4.27 (q, J=4.8Hz, 4H), 3.44 (dd, J=13.6,6.6Hz, 2H), 2.82 (t, J=7.3Hz, 2H) .HRMS (EI)m/z calce C22H22N6O3(M+) 418.1753 (theoretical values), found 418.1752.
Embodiment 26
(E)-N- (4- (((2,4- di-amino-pyrimidine -5- base) methyl) amino) phenethyl) -3,4- dimethoxybenzoyl Amine is (marked as " IB- 2 " preparation):
Isosorbide-5-Nitrae in (1) the step of embodiment 1-benzodioxane-6- carboxylic acid is substituted for 1,2- dimethoxybenzoic acid, 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), 3.80 (d, J=1.2Hz, 6H), 3.51-3.41 (m, 2H), 2.88-2.79 (m, 2H) .HRMS (EI) m/z calce C22H24N6O3(M+) 420.1910 (theoretical values), found 420.1910.
The structure list of 6 prepare compound of Examples 1 to 2 is shown in Table 1..
Table 1.
Continued 1.
Embodiment 27
Acetamides provided by the invention are living to the inhibition of cysteine proteinase (falcipain-2, FP-2) Property data
The measurement of FP-2 inhibitory activity: first by albumen FP-2 respectively with compound IA- 1~24 and compound IB- 1~2 After being incubated for 30 minutes at room temperature, then start the measurement of enzymatic activity.
Screening reaction carries out in 384 orifice plate of BioTek Synergy2 microplate reader, and reaction temperature is room temperature, primary dcreening operation measurement The inhibiting rate for the compound that concentration is 1 μM is substantially determined for measuring IC according to primary dcreening operation result50Required compound concentration gradient, 7 concentration gradients of each compound.Inhibiting rate is greater than 40% when 10 μM of compound concentrations, is determined as effectively, measuring the compound IC50；For inhibiting rate less than 40%, it is invalid to be determined as when 10 μM of compound concentrations.Test result is shown in Table 2. (second provided by the invention Primary dcreening operation result of the amides compound to FP-2 inhibitory activity).
Table 2.
* E-64 is the inhibitor of reported potent cysteine proteinase.
Embodiment 28
Inhibitory activity data of the acetamides provided by the invention to dihyrofolate reductase (DHFR).
The measurement 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 absorption peak at 340nm, therefore is examined with ultraviolet specrophotometer Survey the absorbance (being detailed in attached drawing 1) at 340nm.The activity of enzyme is better, and absorbance is lower.
Specific testing procedure is: by assay buffer [50 μM of TES (pH7.0), 1 μM of EDTA (pH8.0), 100M ADPH, the BSA of 1mg/ml, 75 μM of-ME] (190:l) and DHFRlysate (5:l) and untested compound (compound IA- 1~ 24 and compound IB- 1~2) it is added in the EP pipe of 5ml and is incubated for 30 minutes in 4 DEG C, add DHF (100 μM) and start to react； The variation for detecting OD340nm, detecting entire reaction process is 30 seconds；Using the DMSO of equivalent as negative control, PYR is positive right According to the rate that absorbance declines at any time is slower, shows that the inhibitory effect of compound is better；Inhibiting rate when 10 μM of compound primary dcreening operations Greater than 50%, it is determined as effectively, and measure IC50Value.Test result is shown in Table 3. (acetamides pair provided by the invention The primary dcreening operation result of DHFR inhibitory activity).
Table 3.
* PYR (pyrimethamine) is known PfDHFR potent inhibitor.
Embodiment 29
Compound IA- 5 couples of plasmodium falciparum 3D7C8 kill malaria EC in vitro50Data.
Plasmodium culture: 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) in culture.
Compound plasmodium growth in vitro inhibits EC50Measurement: 100ul complete medium is added in 96 orifice plates, first Suitable compound is added in hole and is settled to 200ul with complete medium and makes compound IA- 5 final concentration of 10uM, it is green Artemisin is 500nM, then carries out gradient dilution (11 concentration gradients) in 1/2 ratio, Artemsinin is as positive control, no Add any compound as negative control, plasmodium and compound is not added as Experimental Background.The malaria of 100ul is added in every hole later Protozoa culture object (1%ring parasitemia, 4%HCT) makes final HCT and parasitemia be 2% and 1%, changes The final concentration gradient for closing object is 10uM.96 orifice plates are placed into 37 DEG C of incubator (5%CO after sample-adding is completed2, 5%O2) in culture 72h.After completing 100ul Lysis Buffer (10x SYBR Green I, 0.5%v/v Triton is added in every hole in culture X-100,0.5mg/ml saponin, 0.75%EDTA in Tris-Cl Buffer), after mixing, room temperature, which is protected from light, is incubated for 2h. Be incubated for complete after with orifice plate fluorescence reading machine reading numerical values (maximum excitation light/maximum receives light: 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 culture: chloroquine resistance plasmodium falciparum Dd2 culture (contains NaHCO using RPMI3, HEPES, Albumax I, Hypoxanthine, Genaotamicin) complete medium (Complete Medium), in 37 DEG C of incubator (5%CO2, 5%O2) in culture.
Compound chloroquine resistance plasmodium falciparum Dd2 growth in vitro inhibits EC50Measurement: 100ul complete medium is added to In 96 orifice plates, suitable compound is added in the first hole and is settled to 200ul with complete medium makes compound IA- 5 Then final concentration of 10uM carries out gradient dilution (11 concentration gradients) in 1/2 ratio, any compound is not added as negative Control, is not added plasmodium and compound as Experimental Background.Plasmodium culture (the 1%ring of 100ul is added in every hole later Parasitemia, 4%HCT) to make final HCT and parasitemia be 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) in cultivate 72h.Culture is every after completing 100ul Lysis Buffer (10x SYBR Green I, 0.5%v/v Triton X-100,0.5mg/ml is added in hole Saponin, 0.75%EDTA in Tris-Cl Buffer), after mixing, room temperature, which is protected from light, is incubated for 2h.It is incubated for after completing and uses (maximum excitation light/maximum receives light: 485nm/535nm) is calculated according to fluorescence readings and is pressed down orifice plate fluorescence reading machine reading numerical values Rate processed, inhibiting rate=(negative control group-experimental group)/(negative control group-Experimental Background), draws according to the inhibiting rate of various concentration Growth inhibition curve processed simultaneously calculates EC by Graph Pad650.Concrete outcome is shown in Fig. 3.

Claims (8)

1. a kind of N- (4- replaces phenethyl) amides compound, is compound shown in Formulas I or it is pharmaceutically acceptable Salt:
Wherein, R1For group shown in formula A: R2For benzyl, phenethyl, 2- furyl, 2- thienyl, phenyl, 2- pyridyl group, 3- pyrrole Piperidinyl, 2- naphthalene, fluorenyl, or the phenyl or fluorenyl that replace；
The substituent group of the substituted phenyl or fluorenyl is one or more kinds of in following groups:
Methoxyl group, tert-butyl, halogen, hydroxyl, oxo orN is 2；
Or,
R1For group shown in formula B: R2For by methoxyl group orSubstituted-phenyl；
2. N- (4- replaces phenethyl) amides compound as described in claim 1, which is characterized in that wherein, R1For formula A institute Show group；R2For benzyl, phenethyl, 2- fluoro-phenyl, 3- fluorophenyl, 4- fluoro-phenyl, 3- methoxyl group-phenyl, 4- methoxyl group-benzene Base, 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- of 3- Methoxyl group-phenyl,
3. N- (4- replaces phenethyl) amides compound as described in claim 1, which is characterized in that wherein, R1For formula B institute Show group；R2For 3,4- dimethoxy-phenylf or
4. a kind of N- (4- replaces phenethyl) amides compound, is compound shown in Formulas I or it is pharmaceutically acceptable Salt:
Wherein, R1For group shown in formula A, R2For 3- fluorophenyl, 4- fluoro-phenyl, 3- methoxyl group-phenyl, 3- chloro-4-methoxy-benzene Base or
5. a kind of N- (4- replaces phenethyl) amides compound, is compound shown in Formulas I or it is pharmaceutically acceptable Salt:
Wherein, R1For group shown in formula A, R2For 4- fluoro-phenyl:
6. N- (4- replaces phenethyl) amides compound is preparing dihyrofolate reductase suppression as described in claim 1,2 or 3 Application in preparation.
7. N- (4- replaces phenethyl) amides compound as claimed in claim 4 is preparing cysteine proteinase and dihydro Application in folic acid reductase inhibitor.
8. N- (4- replaces phenethyl) amides compound as claimed in claim 5 treats the malaria as caused by plasmodium in preparation Drug in application.
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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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