CN103483272B - Between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application - Google Patents

Between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application Download PDF

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CN103483272B
CN103483272B CN201310456775.5A CN201310456775A CN103483272B CN 103483272 B CN103483272 B CN 103483272B CN 201310456775 A CN201310456775 A CN 201310456775A CN 103483272 B CN103483272 B CN 103483272B
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pyrimidine
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CN103483272A (en
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刘新泳
李潇
展鹏
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Shandong University
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    • 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
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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

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Abstract

The present invention relates to a kind of as shown in formula I between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and pharmacy acceptable salt, ester or prodrug, its preparation method and containing this compounds one or more composition preparation treatment and prevention human immunodeficiency virus (HIV) infection medicine in application.

Description

Between two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application
Technical field
The present invention relates to a kind of derivative and preparation method thereof and application, between being specifically related to, two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative and preparation method thereof and application, belong to medical art.
Background technology
The acquired immune deficiency syndrome (AIDS) (acquired immune deficiency syndrome (AIDS), AIDS) caused is infected, one of great communicable disease being still harm humans life and health at present by human immunodeficiency virus (HIV).The application of existing anti-AIDS drug and highly active antiretroviral therapy (HAART) although enforcement effectively can delay the process of the state of an illness, but also exist and easily produce the problems such as resistance, dosage be large and expensive, therefore the research and development of novel anti-AIDS drug are very urgent.Noncompetitive non-nucleoside reverse transcriptase inhibitor (Non-nucleoside reverse transcriptase inhibitors, NNRTIs) is efficient because of it, the advantage of low toxicity has become the important component part of HAART.Such medicine gone on the market at present has 5 (nevirapine, delavirdine, efavirine, etravirine, rilpivirine).But because the amino acid of NNRTIs binding site is easily undergone mutation, cause the generation of resistance strain and spread, the clinical potency of such medicine is reduced rapidly.Therefore, the important directions that the anti-AIDS new drug that can overcome the new texture of existing pharmaceutical problems is the research of current anti-AIDS drug is found.(see 1. " anti-AIDS drug research ", Liu Xinyong edits, People's Health Publisher, Beijing, 2006,12. 2. Zhan P, Chen X, Li D, Fang Z, De Clercq E, Liu X.Med Res Rev.2013Jun; 33Suppl1:E1-E72.)
DAPY compounds (Diarylprimidines, diaryl pyrimidine) is that a class is novel, the HIV-1NNRTI of Effective Anti resistance.Wherein etravirine (etravirine, TMC125,2008) and rilpivirine (TMC278,2011) are widely used clinical as non-nucleoside reverse transcriptase inhibitor of new generation.They all have great inhibit activities (nM) to wild-type and several drug resistance virus strain (as K103N, Y181C, K103N/Y181C etc.).Particularly the active and overriding resistance strain activity of the against wild type hiv-1 of the rilpivirine of FDA in 2011 approval listing all increases than etravirine, and has long-acting advantage.Therefore, with DAPY compounds for template, carry out structural modification widely, to finding that high-efficiency broad spectrum overriding resistance, bioavailability are good and to have the novel inverase of independent intellectual property right significant.
Summary of the invention
According to the deficiencies in the prior art, the invention provides two aromatic hydrocarbons between one-polysubstituted pyrimidine analog derivative or its pharmacy acceptable salt, ester or prodrug.The present invention also provides the preparation method of above-claimed cpd and screening active ingredients result and application.
One, two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative:
Of the present invention two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative or its pharmacy acceptable salt, ester or prodrug, general structure I is as follows:
Wherein,
R 1, R 2be-H, halogen ,-NO independently of one another 2,-NH 2,-NHR ,-N (R) 2,-NHCOCH 3,-NHCOCF 3,-CN ,-OH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-COOH ,-SO 3h ,-CONH 2,-CONHR ' or-COOR ',
Or, R 1and R 2-OCH can be formed together 2o-;
R 3and R 4be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-SO 3h or-COOR ';
R 5for-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', CHO, to be selected from the heteroatomic quinary heteroaryl of N, O, S containing 1-3, and optionally replace with aldehyde radical, ketone group, cyano group, the undersaturated cyanogen of α, β, alkene, alkynes, aldehyde radical or ketone group on its ring structure;
R 6for-CN ,-CH=CH 2,-C ≡ CH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3h ,-C ≡ CR ' or-CH=CHR ';
X is-NH-,-O-,-S-,-CH 2-, CHOH-,-CHOR-,-NR-or-NCOR-;
Wherein R is C 1-4alkyl; R ' is H or C 1-6alkyl.
Preferably, formula I ＇ compound structure general formula of the present invention is as follows:
Wherein, R 1, R 3, R 4, R 5with general structure I.
More preferred, generalformulaⅰcompound is one of compound of having structure:
The preparation method of two, two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative or its pharmacologically acceptable salt
The preparation of two aromatic hydrocarbons between the present invention-polysubstituted pyrimidine analog derivative with the pyrimidine ring of two halogen substiuted for starting raw material, with substituted aryl amine and Ar 1-NH 2condensation obtains intermediate (IV), then between nucleophilic substitution reaction obtains two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative (I);
Synthetic route is as follows:
Reagent and condition: (i) triethylamine, tetrahydrofuran (THF), 0 DEG C; (ii) salt of wormwood, NN-dimethyl formamide, 60 DEG C.
Wherein, R 1, R 2, R 3, R 4, R 5, R 6and described in the same formula I of the definition of X.
Preferably, the preparation method of two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative,
With 5-nitro-2,4-dichloro pyrimidine (II) for starting raw material, obtain intermediate (IV) with to cyano-aniline (III) condensation under the alkaline condition of triethylamine; Then, (I a), then obtains target product (I b, I c, I d) through reduction hydrogenation, acylation reaction successively to obtain target product from the phenol (V) of different replacement through nucleophilic substitution reaction;
Synthetic route is as follows:
Reagent and condition: (i) triethylamine, tetrahydrofuran (THF), 0 DEG C; (ii) salt of wormwood, DMF, 60 DEG C; (iii) hydrogen, palladium carbon; (iv) tindichloride and hydrate, ethanol; (v) triethylamine, trifluoromethanesulfanhydride anhydride, methylene dichloride, 0 DEG C; (vi) triethylamine, Acetyl Chloride 98Min., 0 DEG C.
Wherein R 3, R 4, R 5the same formula I of definition described in.
The phenol (V) of described replacement is 4-cyano group-2,6-xylenol, 2,4,6-front three phenol, 2,4,6-Trichlorophenols, 2,4,6-tribromophenols, bromo-2, the 6-xylenols of 4-, 2,6-chlorophenesic acid or 4-aldehyde radical-2,6-xylenol.
Three, the application of two aromatic hydrocarbons between formula I of the present invention-poly-substituted miazines derivatives quasi-compound
Two aromatic hydrocarbons between formula I of the present invention-poly-substituted miazines derivatives quasi-compound demonstrates significant antiviral activity and higher selectivity in the test cell line (MT-4 cell) suppressing HIV to copy.Therefore, the present invention also provides:
Two aromatic hydrocarbons between the formula I-application of poly-substituted miazines derivatives quasi-compound in the medicine preparing AntiHIV1 RT activity.
A kind of inverase composition, comprises compound of the present invention or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
The compounds of this invention both can itself also can the form of its pharmacy acceptable salt or solvate use.The pharmacy acceptable salt of generalformulaⅰcompound comprises the conventional salt formed with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases.The example of suitable acid salt comprises with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, Hydrogen bromide, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxy-benzoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc. formed.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, N-methyl by and the salt that formed such as PROCAINE HCL, PHARMA GRADE.When relating to the compounds of this invention herein, comprise compound of Formula I and pharmacy acceptable salt thereof or solvate.
According to the present invention, type I compound of the present invention can become pharmaceutical composition with Conventional pharmaceutical carriers or vehicle group.This pharmaceutical composition is by oral or parenteral administration.Pharmaceutical composition of the present invention can be prepared into various formulation by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension, granule or injection etc., oral administration or parenteral administration.
Inventor herein is on the basis to DAPY compounds structure activity relationship and molecular simulation further investigation, according to bioisostere medicinal design principle, 1 the N C of pyrimidine ring in TMC125 is replaced and introduces other multifarious nitrogen-containing groups, build can and HIV1-RT (RT) formed more strong hydrogen bonding effect novel between two aromatic hydrocarbons-polysubstituted pyrimidine heterocyclic system.Have employed the high reactivity substituting group of DAPY class inhibitor in new ring C-4 position simultaneously, C-2 position then chooses that DAPY compounds is dissimilar, the new substituting group of different structure to instruct the various structures sex modification extending π-electron system (inquiring into spacing and aromaticity), and inquire into itself and conservative amino acid Trp229, Phe227 interaction to the material impact of anti-drug resistance.External AntiHIV1 RT activity viral activity assay has all been carried out to novel the two aromatic hydrocarbons-polysubstituted pyrimidine derivative of synthesis.It is active that result shows that nearly all compound is all provided with good against wild type hiv-1, and part of compounds shows good inhibit activities to the strain of HIV-1 (K103N/Y181C) mutated viruses.But also found that two compounds also have certain inhibit activities to HIV-2 virus strain unexpectedly.And in the vitro inhibition HIV1-RT activity test carried out the good compound of cytoactive, its reversed transcriptive enzyme inhibit activities is better than contrast medicine TMC125 or suitable with it, demonstrate the action target spot of this compounds thus.Therefore, two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative has larger Development volue.Compound of the present invention carries out new structural modification and further investigation contributes to developing the inverase made new advances.
Embodiment
Contribute to understanding the present invention by following embodiment, but content of the present invention can not be limited.
The preparation of embodiment 1:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-Cyano-phenoxy)-5-nitro-pyrimidine (I a-1)
2, the chloro-5-nitro-pyrimidine (II) of 4-bis-(0.39g, under tetrahydrofuran solution (15mL) ice bath magnetic agitation 2mmol), slowly drip the tetrahydrofuran solution (15mL) of 4-aminophenyl acetonitrile (III) and triethylamine.This reaction keeps 0 DEG C to stir after 3 hours and transfers room temperature to, and TLC monitors reaction process, after question response is complete, remove solvent under reduced pressure, add 20mL water, dichloromethane extraction 3 times, organic phase anhydrous sodium sulfate drying, filters, and concentrates and obtains key intermediate IV through flash column chromatography.Yellow solid, productive rate 65.0%, MS (ESI): m/z276.2 (M+1), 278.2 (M+3), C 11h 6clN 5o 2(275.65).
By intermediate IV 0.15g (0.5mmol), 0.15g salt of wormwood (1.0mmol) and 0.096g2,6-dimethyl-4-cyano-phenol (0.6mmol) is dissolved in 10mL N, in dinethylformamide, magnetic agitation, 60 DEG C of oil baths react 5 hours, solvent is removed under reduced pressure after TLC monitoring reacts completely, add 20mL water, extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying, filter, concentrate and obtain target product I a-1 through flash column chromatography, yellow solid, yield: 62.2%.mp:226-230 DEG C. 1hNMR (400MHz, DMSO-d 6, ppm) and δ: 10.50 (s, 1H, NH), 9.31 (s, 1H, C 6-pyrimidine-H), 7.53 (m, 6H, Ph-H, Ph '-H), 2.19 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 164.69 (C 2-pyrimidine), 160.27 (C 4-pyrimidine), 154.60 (C 1-Ph '-N), 153.09 (C 6-pyrimidine), 140.08 (C 1-Ph-O), 133.13 (2 × C), 132.75 (2 × C), 132.35 (2 × C), 124.99,121.61 (2 × CN), 118.11 (2 × C), 110.33,109.00,16.31 (2 × CH 3) .ESI-MS:m/z387.4 (M+1), 404.5 (M+18), C 20h 14n 6o 3[386.11].
The preparation of embodiment 2:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-Cyano-phenoxy)-5-aminopyrimidine (I b-1)
By 0.5g N-(4 '-cyano-phenyl)-2-(2 ' obtained by aforesaid method, 6 '-dimethyl-4 '-Cyano-phenoxy)-5-nitro-pyrimidine (I a-1) (1.2mmol) and 0.1g palladium carbon (10%) is placed in 100ml round-bottomed flask, adds ethanol 30mL wherein.Pass into hydrogen after this reaction system is vacuumized 3 times, and keep hydrogen in whole reaction process excessive, after reaction 15h, reaction solution decompress filter is also concentrated.Concentrated solution petroleum ether, again decompress filter, filter cake is dry in atmosphere, obtains target compound I b-1.White solid, yield: 70.4%.mp:218-221 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 8.93 (s, 1H, NH), 7.72 (s, 3H, C 6-pyrimidine-H, Ph-H), 7.63 (d, 2H, J=8.80Hz, 2H, Ph '-H), 7.56 (d, 2H, J=8.80Hz, 2H, Ph '-H), 4.93 (s, 2H, NH 2), 2.08 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 155.66 (C 2-pyrimidine), 154.96 (C 4-pyrimidine), 150.36 (C 1-Ph '-N), 144.51 (C 6-pyrimidine), 141.55 (C 1-Ph-O), 133.30 (2 × C), 133.09 (2 × C), 132.95 (2 × C), 125.71,119.72,119.58 (2 × CN), 119.24,107.99,103.77,16.28 (2 × CH 3) .ESI-MS:m/z357.4 (M+1), 474.4 (M+18) C 20h 16n 6o [356.14].
The preparation of embodiment 3:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-Cyano-phenoxy)-5-trifluoroacetyl yl pyrimidines (I c-1)
By 0.2g N-(4 '-cyano-phenyl)-2-(2 ' that top method is obtained, 6 '-dimethyl-4 '-Cyano-phenoxy)-5-aminopyrimidine (I b-1) (0.5mmol) and triethylamine (1.0mmol) tetrahydrofuran solution (15mL) ice bath magnetic agitation under, slow dropping trifluoroacetic anhydride (0.6mmol), keep this thermotonus 5 hours, solvent is removed under reduced pressure after TLC monitoring reacts completely, add 20mL water, extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying, filter, concentrate and obtain target product I c-1 through flash column chromatography.White solid, yield: 56.5%.mp:255-257 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.25 (s, 1H, C 6-pyrimidine-H), 8.18 (d, J=8.44Hz, 2H, Ph '-H), 7.94 (d, J=8.44Hz, 2H, Ph '-H), 7.67 (s, 2H, Ph-H), 2.13 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 161.82 (C 2-pyrimidine), 155.38 (C 4-pyrimidine), 153.50 (C 1-Ph-O), 153.37 (C 6-pyrimidine), 142.33 (C 1-Ph '-N), 141.94,135.64,133.84 (2 × C), 132.71 (2 × C), 132.43 (2 × C), 128.73,128.31 (2 × CN), 118.53,117.2,114.88,109.83,16.41 (2 × CH 3) .ESI-MS:m/z435.5 (C 22h 17f 2n 6o 2 +), C 22h 15f 3n 6o 2[452.12].
The preparation of embodiment 4:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-Cyano-phenoxy)-5-ethanoyl pyrimidine (I d-1)
By 0.2g N-(4 '-cyano-phenyl)-2-(2 ' that top method is obtained, 6 '-dimethyl-4 '-Cyano-phenoxy)-5-aminopyrimidine (I b-1) (0.5mmol) and triethylamine (1.0mmol) tetrahydrofuran solution (15mL) ice bath magnetic agitation under, slow dropping Acetyl Chloride 98Min. (0.6mmol), keep this thermotonus 5 hours, solvent is removed under reduced pressure after TLC monitoring reacts completely, add 20mL water, extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying, filter, concentrate and obtain target product I d-1 through flash column chromatography.White solid, yield: 54.2%.mp:278-282 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.42 (s, 1H, NH), 9.22 (s, 1H, C6-pyrimidine-H), 8.17 (s, 1H, NH), 7.74 (s, 2H, Ph-H), 7.64 (s, 4H, Ph '-H), 2.10 (s, 6H, 2 × CH 3), 2.09 (s, 3H, CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 170.26 (C=O), 160.65 (C 2-pyrimidine), 156.80 (C 4-pyrimidine), 156.80 (C 1-Ph-O), 155.83 (C 6-pyrimidine), 154.31 (C 1-Ph '-N), 143.59,133.08 (3 × C), 133.01 (2 × C), 120.67 (2 × C), 119.50 (2 × CN), 119.09,115.07,108.53,104.83,23.84,16.21 (2 × CH 3) .ESI-MS:m/z399.3 (M+1), 416.5 (M+18), C 22h 18n 6o 2[398.15].
The preparation of embodiment 5:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-nitro-pyrimidine (I a-2)
Working method is with the preparation of embodiment 1 I a-1, and difference uses 2，4，6-trimethyl phenol.Products therefrom is yellow crystals, yield: 65.8%.mp:185-189 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.44 (s, 1H, NH), 9.34 (s, 1H, C 6-pyrimidine-H), 7.40 (s, 4H, Ph '-H), 6.99 (s, 2H, Ph-H), 2.40 (s, 3H, CH 3), 2.07 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 165.70 (C 2-pyrimidine), 160.41 (C 4-pyrimidine), 154.37 (C 6-pyrimidine), 147.91 (C 1-Ph '-N), 140.52 (C 1-Ph-O), 135.83,132.99 (2 × C), 129.69 (2 × C), 129.56 (2 × C), 124.39,121.77,121.37,118.47,108.21,20.89 (CH 3), 16.24 (2 × CH 3) .ESI-MS:m/z376.4 (M+1), C 20h 17n 5o 3[375.13].
The preparation of embodiment 6:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-aminopyrimidine (I b-2)
Working method is with the preparation of embodiment 2 I b-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-nitro-pyrimidine (I a-2).Products therefrom is white solid, yield: 75.5%.mp:207-209 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 8.99 (s, 1H, NH), 7.72 (s, 1H, C 6-pyrimidine-H), 7.68 (d, 2H, J=8.84Hz, Ph '-H), 7.49 (d, 2H, J=8.84Hz, 2H, Ph '-H), 6.94 (s, 2H, Ph-H), 4.90 (s, 2H, NH2), 2.30 (s, 3H, CH 3), 1.98 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 156.55 (C 2-pyrimidine), 150.30 (C 4-pyrimidine), 148.93 (C 1-Ph '-N), 144.83 (C 6-pyrimidine), 142.02 (C 1-Ph-O), 133.94,125.03,132.97 (2 × C), 130.53 (2 × C), 129.39 (2 × C), 125.03,119.52 (2 × C), 103.39,20.80 (CH 3), 16.28 (2 × CH 3) .ESI-MS:m/z346.3 (M+1), C 20h 19n 5o [345.16].
The preparation of embodiment 7:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-trifluoroacetyl yl pyrimidines (I c-2)
Working method is with the preparation of embodiment 3 I c-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-aminopyrimidine (I b-2).Products therefrom is white solid, yield: 52.2%.mp:204-208 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.21 (s, 1H, C 6-pyrimidine-H), 8.18 (d, J=8.40Hz, 2H, Ph '-H), 7.94 (d, J=8.40Hz, 2H, Ph '-H), 6.91 (s, 2H, Ph-H), 2.24 (s, 3H, CH 3), 1.97 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 162.37 (C 2-pyrimidine), 162.34 (C 4-pyrimidine), 156.09 (C 6-pyrimidine), 153.31 (C 1-Ph '-N), 148.25 (C 1-Ph-O), 136.71,134,71,134.23 (2 × C), 130.00 (2 × C), 129.75 (2 × C), 129.58,128.71,119.82,118.37,117.11,113.81,20.79 (CH 3), 16.45 (2 × CH 3) .ESI-MS:m/z424.4 (C 22h 20f 2n 5o 2 +), C 22h 18f 3n 5o 2[441.14].
The preparation of embodiment 8:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-ethanoyl pyrimidine (I d-2)
Working method is with embodiment 4 I d-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-trimethyl-phenoxy)-5-aminopyrimidine (I b-2).Products therefrom is white crystal, yield: 49.9%.mp:222-226 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 8.62 (s, 1H, NH), 8.35 (s, 1H, C 6-pyrimidine-H), 8.20 (s, 1H, NH), 7.39 (dd, J 1=32.00Hz, J 2=8.40Hz, 4H, Ph '-H), 6.93 (s, 2H, Ph-H), 2.35 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.07 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 171.13 (C=O), 161.89 (C 2-pyrimidine), 155.60 (C 4-pyrimidine), 153.46 (C 1-Ph-O), 148.04 (C 6-pyrimidine), 142.74 (C 1-Ph '-N), 135.09,132.78 (2 × C), 130.23 (2 × C), 129.32 (2 × C), 119.92 (2 × C), 119.23,113.58,105.50,42.26 (CH 3), 23.61,16.37 (2 × CH 3) .ESI-MS:m/z388.4 (M+1), C 20h 15n 5o 4[387.17].
The preparation of embodiment 9:N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-nitro-pyrimidine (I a-3)
Working method is with the preparation of embodiment 1 I a-1, and difference is use 2,4,6-Trichlorophenol.Products therefrom is yellow crystals, yield: 66.9%.mp:150-153 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.54 (s, 1H, NH), 9.29 (s, 1H, C 6-pyrimidine-H), 7.89 (s, 2H, Ph-H), 7.70 (d, J=8.68Hz, 2H, Ph '-H), 7.53 (d, J=8.68Hz, 2H, Ph '-H). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 164.16 (C 2-pyrimidine), 160.28 (C 4-pyrimidine), 154.55 (C 6-pyrimidine), 144.33 (C 1-Ph '-N), 141.64 (C 1-Ph-O), 139.95 (2 × C), 129.73,128.83 (2 × C), 128.83,122.11,121.71,121.61 (2 × C), 118.21,109.08.ESI-MS:m/z436.3 (M+1), 438.3 (M+3), 440.4 (M+5), C 17h 8cl 3n 5o 3[434.97].
The preparation of embodiment 10:N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-aminopyrimidine (I b-3)
By 0.5g N-(4 '-cyano-phenyl)-2-(2 ' obtained by top method, 4 '-6 '-three chloro-phenoxy groups)-5-nitro-pyrimidine (I a-3) (1.1mmol) and 1.3g (5.5mmol) two water and tindichloride be placed in 100ml round-bottomed flask, adds ethanol 30mL wherein.This reaction solution room temperature reaction 10 hours, after TLC monitoring reacts completely, removes solvent under reduced pressure, adds 20mL water, extraction into ethyl acetate 3 times, organic phase anhydrous sodium sulfate drying, filter, concentrate and obtain I b-3 through flash column chromatography.Products therefrom is white solid, yield: 56.9%.mp:150-153 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.01 (s, 1H, NH), 7.87 (s, 2H, Ph-H), 7.74 (s, 1H, C 6-pyrimidine-H), 7.65 (m, 4H, Ph '-H), 5.00 (s, 2H, NH). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 154.92 (C 2-pyrimidine), 150.21 (C 4-pyrimidine), 145.78 (C 6-pyrimidine), 144.34 (C 1-Ph '-N), 141.33 (C 1-Ph-O), 133.10 (2 × C), 130.68,130.26 (2 × C), 129.29 (2 × C), 126.32,119.81 (2 × C), 119.65,104.05.ESI-MS:m/z406.4 (M+1), 408.4 (M+3), 410.4 (M+5), C 17h 10cl 3n 5o [405.00].
The preparation of embodiment 11:N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-trifluoroacetyl yl pyrimidines (I c-3)
Working method is with the preparation of embodiment 3 I c-1, and difference uses N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-aminopyrimidine (I b-3).Products therefrom is brown oil solid, yield: 41.2%. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.45 (s, 1H, NH), 10.14 (s, 1H, NH), 9.58 (s, 1H, C 6-pyrimidine-H), 7.40 (s, 4H, Ph '-H), 7.30 (s, 2H, Ph-H). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 160.73 (C 2-pyrimidine), 156.07 (C 4-pyrimidine), 153.28 (C 6-pyrimidine), 144.89 (C 1-Ph '-N), 142.85 (C 1-Ph-O), 136.51,134.26 (2 × C), 131.53,129.74 (2 × C), 129.64 (2 × C), 129.46 (2 × C), 118.32,116.99,114.28,113.97.ESI-MS:m/z484.2 (C 19h 11cl 3f 2n 5o 2 +), 586.2 (C 19h 11cl 3f 2n 5o 2 ++ 2), C 19h 9cl 3f 3n 5o 2[500.98]. the preparation of embodiment 12:N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-ethanoyl pyrimidine (I d-3)
Working method is with the preparation of embodiment 4 I d-1, and difference uses N-(4 '-cyano-phenyl)-2-(the chloro-phenoxy group of 2 ', 4 '-6 '-three)-5-aminopyrimidine (I b-3).Products therefrom is white solid, yield: 40.5%. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.40 (s, 1H, NH), 8.29 (s, 1H, NH), 8.20 (s, 1H, C 6-pyrimidine-H), and 7.90 (s, 2H, Ph-H) 7.63 (m, 4H, Ph '-H), 2.09 (s, 3H, CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 170.29 (C=O), 160.01 (C 2-pyrimidine), 156.83 (C 4-pyrimidine), 155.90 (C 1-Ph-O), 145.20 (C 6-pyrimidine), 143.36 (C 1-Ph '-N), 133.04 (2 × C), 131.29,129.92 (2 × C), 128.99 (2 × C), 121.03 (2 × C), 119.44,115.66,105.16,23.84 (CH 3) .ESI-MS:m/z448.2 (M+1), 450.2 (M+3), 452.3 (M+5), C 19h 12c l3n 5o 2[447.01].
The preparation of embodiment 13:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-nitro-pyrimidine (I a-4)
Working method is with embodiment 1 I a-1, and difference is use 2,4,6-tribromophenol.Products therefrom is yellow crystals, yield: 66.4%.mp:183-187 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.52 (s, 1H, NH), 9.31 (s, 1H, C 6-pyrimidine-H), 8.12 (s, 2H, Ph-H), 7.67 (d, J=8.60Hz, 2H, Ph '-H), 7.15 (d, J=8.40Hz, 2H, Ph '-H). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 163.32 (C 2-pyrimidine), 160.54 (C 4-pyrimidine), 154.56 (C 6-pyrimidine), 147.03 (C 1-Ph '-N), 141.08 (C 1-Ph-O), 135.43 (2 × C), 132.87 (2 × C), 126.67,124.42 (2 × C), 120.32,118.99,118.79 (2 × C), 107.94.ESI-MS:m/z568.1 (M+1), 570.1 (M+3), 572.1 (M+5), C 17h 8br 3n 5o 3[566.82].
The preparation of embodiment 14:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-aminopyrimidine (I b-4)
Working method is prepared with embodiment 10 I b-3, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-nitro-pyrimidine (I a-4).Products therefrom is white crystal, yield: 55.8%.mp:160-164 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 8.98 (s, 1H, NH), 8.09 (s, 2H, Ph-H), 7.74 (s, 1H, C 6-pyrimidine-H), 7.63 (dd, J 1=18.24Hz, J 2=8.96Hz, 4H, Ph '-H), 4.97 (s, 2H, NH). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 154.84 (C 2-pyrimidine), 150.08 (C 4-pyrimidine), 148.30 (C 6-pyrimidine), 144.38 (C 1-Ph '-N), 141.41 (C 1-Ph-O), 135.23 (2 × C), 133.09 (2 × C), 126.18,119.95 (2 × C), 119.75 (2 × C), 119.68,118.93,103.94.ESI-MS:m/z538.1 (M+1), 540.1 (M+3), 542.0 (M+5), 544.1 (M+7), C 17h 10br 3n 5o [536.84].
The preparation of embodiment 15:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-trifluoroacetyl yl pyrimidines (I c-4)
Working method is with the preparation of embodiment 3 I c-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-aminopyrimidine (I b-4).Products therefrom is brown oil solid, yield: 40.7%. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.42 (s, 1H, NH), 9.21 (s, 1H, C 6-pyrimidine-H), 8.38 (s, 2H, Ph-H), 7.97 (d, J=8.60Hz, 2H, Ph '-H), 7.05 (d, J=8.40Hz, 2H, Ph '-H). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 164.32 (C 2-pyrimidine), 163.44 (C 4-pyrimidine), 158.55 (C 6-pyrimidine), 150.66,148.13 (C 1-Ph '-N), 146.08 (C 1-Ph-O), 136.45 (2 × C), 132.89 (2 × C), 127.77,125.32 (2 × C), 122.42,119.97,118.71 (2 × C), 110.21,107.95.ESI-MS:m/z538.0 (C 17h 11br 3n 5o +), 540.0 (C 17h 10br 3n 5o ++ 2), 633.8 (M+1), 636.0 (M+3), 637.8 (M+5), C 19h 9br 3f 3n 5o 2[632.83].
The preparation of embodiment 16:N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-ethanoyl pyrimidine (I d-4)
Working method is with the preparation of embodiment 4 I d-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 4 '-6 '-tribroimo-phenoxy)-5-aminopyrimidine (I b-4).Products therefrom is white crystal, yield: 45.6%.mp:178-180 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.39 (s, 1H, NH), 9.27 (s, 1H, NH), 8.20 (s, 1H, C 6-pyrimidine-H), 8.12 (s, 2H, Ph-H), 7.61 (s, 4H, Ph '-H), 2.09 (s, 3H, CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 170.26 (C=O), 159.93 (C 2-pyrimidine), 156.68 (C 4-pyrimidine), 155.96 (C 1-Ph-O), 147.78 (C 6-pyrimidine), 143.41 (C 1-Ph '-N), 135.33 (2 × C), 133.02 (2 × C), 120.93 (2 × C), 119.54 (2 × C), 119.50,119.45,115.10,105.06,23.85 (CH 3) .ESI-MS:m/z579.9 (M+1), 582.0 (M+3), 583.9 (M+5), 586.0 (M+7), C 19h 12br 3n 5o 2[578.85].
The preparation of embodiment 17:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-nitro-pyrimidine (I a-5)
Working method is with the preparation of embodiment 1 I a-1, and difference is use 2,6-dimethyl-4-bromophenol.Products therefrom is yellow crystals, yield: 70.0%.mp:190-195 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.44 (s, 1H, NH), 9.35 (s, 1H, C 6-pyrimidine-H), 7.49 (d, J=8.68Hz, 2H, Ph-H), 7.39 (d, J=8.68Hz, 2H, Ph '-H), 7.26 (s, 2H, Ph '-H), 2.12 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 165.25 (C 2-pyrimidine), 160.44 (C 4-pyrimidine), 154.37 (C 6-pyrimidine), 149.17 (C 1-Ph '-N), 140.27 (C 1-Ph-O), 133.12 (2 × C), 132.99,132.50,131.75 (2 × C), 124.67,121.43 (2 × C), 119.16,118.29,108.71,16.17 (2 × CH 3) .ESI-MS:m/z440.4 (M+1), 442.4 (M+3), C 19h 14brN 5o 3[439.03].
The preparation of embodiment 18:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-aminopyrimidine (I b-5)
Working method is with the preparation of embodiment 10 I b-3, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-nitro-pyrimidine (I a-5).Products therefrom is white solid, yield: 55.8%.mp:160-164 DEG C. 1hNMR (400MHz, DMSO-d 6, ppm) and δ: 8.88 (s, 1H, NH), 7.73 (s, 1H, C 6-pyrimidine-H), 7.64 (d, J=8.88Hz, 2H, Ph '-H), 7.53 (d, J=8.88Hz, 2H, Ph '-H), 7.26 (s, 2H, Ph-H), 4.87 (s, 2H, NH 2), 2.02 (s, 6H, CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 156.09 (C 2-pyrimidine), 150.32 (C 4-pyrimidine), 150.03 (C 6-pyrimidine), 144.65 (C 1-Ph '-N), 141.92 (C 1-Ph-O), 133.49 (2 × C), 130.30 (2 × C), 128.91,128.29 (2 × C), 125.31,119.73,119.57 (2 × C), 103.62,16.83 (2 × CH 3) .410.4 (M+1), 412.4 (M+3), C 19h 16brN 5o [409.05].
The preparation of embodiment 19:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-trifluoroacetyl yl pyrimidines (I c-5)
Working method is with the preparation of embodiment 3 I c-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-aminopyrimidine (I b-5).Products therefrom is brown oil solid, yield: 50.6%. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.34 (s, 1H, NH), 10.11 (s, 1H, NH), 9.25 (s, 1H, C 6-pyrimidine-H), 7.60 (d, J=8.68Hz, 2H, Ph-H), 7.48 (d, J=8.68Hz, 2H, Ph '-H), 7.34 (s, 2H, Ph-H), 2.32 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 166.26 (C 2-pyrimidine), 161.14 (C 4-pyrimidine), 155.35 (C 6-pyrimidine), 150.67,148.27 (C 1-Ph '-N), 147.28 (C 1-Ph-O), 133.32 (2 × C), 132.09,132.51,130.85 (2 × C), 125.66,124.47 (2 × C), 119.36,118.00,110.22,109.71,16.74 (2 × CH 3) .ESI-MS:m/z588.3 (C 21h 17brF 2n 5o 2 +), 590.3 (C 21h 17brF 2n 5o 2 ++ 2), C 21h 15brF 3n 5o 2[505.04].
The preparation of embodiment 20:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-ethanoyl pyrimidine (I d-5)
Working method is with the preparation of embodiment 4 I d-5, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromo-phenoxy group)-5-aminopyrimidine (I b-5).Products therefrom is white crystal, yield: 59.7%.mp:145-148 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.36 (s, 1H, NH), 9.14 (s, 1H, NH), 8.16 (s, 1H, C 6-pyrimidine-H), 7.63 (dd, J 1=24.92Hz, J 2=8.92Hz, 4H, Ph '-H), 7.29 (s, 2H, Ph-H), 2.09 (s, 3H, CH 3), 2.05 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 170.29 (C=O), 161.06 (C 2-pyrimidine), 156.73 (C 4-pyrimidine), 156.02 (C 1-Ph-O), 149.50 (C 6-pyrimidine), 143.74 (C 1-Ph '-N), 133.17 (2 × C), 132.96 (2 × C), 129.42,128.56 (2 × C), 120.59 (2 × C), 119.55,114.72,104.62,23.85 (CH 3), 16.33 (2 × CH 3) .ESI-MS:m/z452.3 (M+1), 454.3 (M+3), C 21h 18brN 5o 2[451.06].
The preparation of embodiment 21:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-two chloro-4 '-phenoxy group)-5-nitro-pyrimidine (I a-6)
Working method is with the preparation of embodiment 1 I a-1, and difference is use 2,6-chlorophenesic acid.Products therefrom is yellow crystals, yield: 62.2%.mp:193-196 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.45 (s, 1H, NH), 9.30 (s, 1H, C 6-pyrimidine-H), 7.60 (s, 4H, Ph '-H), 7.32 (t, J=8.48Hz, 1H, C 4-Ph-H), 6.85 (d, J=8.52Hz, 2H, Ph-H) 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 164.54 (C 2-pyrimidine), 160.76 (C 4-pyrimidine), 154.59 (C 6-pyrimidine), 139.95 (C 1-Ph '-N), 133.17 (4 × C), 133.00,125.67,122.69 (4 × C), 121.84,118.29,109.25.ESI-MS:m/z402.4 (M+1), 404.4 (M+3), C 17h 9cl 2n 5o 3[401.01].
The preparation of embodiment 22:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-chloro-phenoxy group)-5-aminopyrimidine (I b-6)
Working method is with the preparation of embodiment 10 I b-3, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-two chloro-4 '-phenoxy group)-5-nitro-pyrimidine (I a-6).Products therefrom is white solid, yield: 78.2%.mp:114-117 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 8.95 (s, 1H, NH), 7.76 (s, 1H, C 6-pyrimidine-H), 7.64 (m, 6H, Ph-H, Ph '-H), 7.41 (t, 1H, J=8.80Hz, C 4-Ph-H), 4.96 (s, 2H, NH 2). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 155.11 (C 2-pyrimidine), 150.04 (C 4-pyrimidine), 146.36 (C 1-Ph '-N), 144.51 (C 6-pyrimidine), 141.34 (C 1-Ph-O), 133.08 (2 × C), 129.64 (2 × C), 129.33 (2 × C), 127.68,126.21,119.73,119.56 (2 × C), 103.75.ESI-MS:m/z372.2 (M+1), 374.2 (M+3), 376.3 (M+5), 378.3 (M+7), C 17h 11cl 2n 5o [371.03].
The preparation of embodiment 23:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-chloro-phenoxy group)-5-trifluoroacetyl yl pyrimidines (I c-6)
Working method is with the preparation of embodiment 3 I c-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-chloro-phenoxy group)-5-aminopyrimidine (I b-6).Products therefrom is brown oil solid, yield: 58.3%.mp:203-209 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.09 (s, 1H, C 6-pyrimidine-H), 7.91 (d, J=8.60Hz, 2H, Ph '-H), 7.64 (d, J=8.60Hz, 2H, Ph '-H), 7.41 (d, J=8.08Hz, 2H, Ph-H), 7.21 (t, J=8.08Hz, 1H, C 4-Ph-H). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 161.51 (C 2-pyrimidine), 155.05 (C 4-pyrimidine), 153.45 (C 6-pyrimidine), 145.59 (C 1-Ph-O), 142.24 (C 1-Ph '-N), 135.72,133.70 (2 × C), 129.16 (2 × C), 128.52 (2 × C), 127.09 (2 × C), 128.31 (2 × CN), 119.26,117.36,114.61.ESI-MS:m/z450.2 (C 19h 12cl 2f 2n 5o 2 ++ 1), 452.2 (C 19h 12cl 2f 2n 5o 2 ++ 2), C 19h 10cl 2f 3n 5o 2[467.02].
The preparation of embodiment 24:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-chloro-phenoxy group)-5-ethanoyl pyrimidine (I d-6)
Working method is with the preparation of embodiment 4 I d-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-chloro-phenoxy group)-5-aminopyrimidine (I b-6).Products therefrom is white solid, yield: 60.7%.mp:158-162 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 9.38 (s, 1H, NH), 9.22 (s, 1H, NH), 8.20 (s, 1H, C 6-pyrimidine-H), 7.67 (d, J=8.0Hz, 2H, Ph-H), 7.59 (s, 4H, Ph '-H), 7.44 (t, J=8.40Hz, 1H, C 4-Ph-H), 2.09 (s, 3H, CH3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 170.33 (C=O), 160.28 (C 2-pyrimidine), 156.79 (C 4-pyrimidine), 156.06 (C 1-Ph-O), 145.77 (C 6-pyrimidine), 143.45 (C 1-Ph '-N), 133.09 (2 × C), 129.76 (2 × C), 128.98 (2 × C), 128.23,120.66 (2 × C), 119.49,115.43,104.93,23.86 (CH 3) .ESI-MS:m/z414.3 (M+1), 416.3 (M+3), C 19h 13cl 2n 5o 2[413.04].
The preparation of embodiment 25:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-aldehyde radical-phenoxy group)-5-nitro-pyrimidine (I a-7)
Working method is with the preparation of embodiment 1 I a-1, and difference is use 2,6-dimethyl-4-aldehyde radical-phenol.Products therefrom is yellow crystals, yield: 66.9%.mp:171-173 DEG C. 1h NMR (400MHz, DMSO-d 6, ppm) and δ: 10.46 (s, 1H, NH), 10.01 (s, 1H, CHO), 9.29 (s, 1H, C 6-pyrimidine-H), 7.76 (s, 2H, Ph-H), 7.64 (s, 4H, Ph '-H), 2.15 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 192.68 (H-C=O), 164.27 (C 2-pyrimidine), 160.45 (C 4-pyrimidine), 154.84 (C 1-Ph-O), 154.54 (C 6-pyrimidine), 141.39 (C 1-Ph '-N), 134.44,132.58 (2 × C), 131.81 (2 × C), 130.56 (2 × C), 126.28,125.12,123.65 (2 × C), 119.02,16.31 (2 × CH 3) .ESI-MS:m/z390.3 (M+1), 407.5 (M+17), C 20h 15n 5o 4[389.11].
The preparation of embodiment 26:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromal base-phenoxy group)-5-aminopyrimidine (I b-7)
Working method is with the preparation of embodiment 2 I b-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-aldehyde radical-phenoxy group)-5-nitro-pyrimidine (I a-7).Products therefrom is white solid, yield: 78.2%.mp:293-297 DEG C. 1hNMR (400MHz, DMSO-d 6, ppm) and δ: 10.02 (s, 1H, CHO), 9.17 (s, 1H, NH), 7.79 (m, 3H, C 6-pyrimidine-H, Ph '-H), 7.68 (d, 2H, J=8.80Hz, Ph-H), 7.48 (d, 2H, J=8.80Hz, Ph-H), 5.07 (s, 2H, NH 2). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 192.81 (CHO), 156.10 (C 2-pyrimidine), 155.76 (C 4-pyrimidine), 150.26 (C 1-Ph '-N), 144.68 (C 6-pyrimidine), 141.47 (C 1-Ph-O), 133.59,133.00 (2 × C), 132.48 (2 × C), 132.29,130.45 (2 × C) 125.75,126.21,119.73,119.75 (2 × C), 103.56.ESI-MS:m/z360.4 (M+1), 382.5 (M+23), C 20h 17n 5o 2[359.14].
The preparation of embodiment 27:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-aldehyde radical-phenoxy group)-5-trifluoroacetyl yl pyrimidines (I c-7)
Working method is with the preparation of embodiment 3 I b-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromal base-phenoxy group)-5-aminopyrimidine (I b-7).Products therefrom is white solid, yield: 54.4%.m p: 179-183 DEG C. 1hNMR (400MHz, DMSO-d 6, ppm) and δ: 9.94 (s, 1H, H-C=O), 9.13 (s, 1H, C 6-pyrimidine-H), and 8.47 (b, 1H, NH) 7.93 (d, J=8.44Hz, 2H, Ph '-H), 7.67 (s, 2H, Ph-H), 2.18 (s, 6H, 2 × CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 192.27 (CHO), 161.82 (C 2-pyrimidine), 154.07 (C 4-pyrimidine), 153.47 (C 6-pyrimidine), 135.47 (C 1-Ph-O), 133.86 (2 × C), 133.83 (4 × C), 131.89 (2 × C), 130.74 (2 × C), 128.40,128.26 (2 × C), 117.16,114.61,16.51 (2 × CH 3) .ESI-MS:m/z438.4 (C 22h 18f 2n 5o 3 +), C 22h 16f 3n 5o 3[455.12].
The preparation of embodiment 28:N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-aldehyde radical-phenoxy group)-5-ethanoyl pyrimidine (I d-7)
Working method is with the preparation of embodiment 4 I d-1, and difference uses N-(4 '-cyano-phenyl)-2-(2 ', 6 '-dimethyl-4 '-bromal base-phenoxy group)-5-aminopyrimidine (I b-7).Products therefrom is white solid, yield: 53.3%.mp:167-170 DEG C. 1hNMR (400MHz, DMSO-d 6, ppm) and δ: 10.00 (s, 1H, NH), 9.94 (s, 1H, NH), 9.81 (s, 1H, CHO), 9.23 (s, 1H, C 6-pyrimidine-H), 7.45 (s, 2H, Ph-H), 7.64 (s, 4H, Ph '-H), 2.15 (s, 6H, 2 × CH3), 2.00 (s, 3H, CH 3). 13c-NMR (100MHz, DMSO-d 6, ppm) and δ: 193.88 (H-C=O), 166.37 (C 2-pyrimidine), 161.44 (C 4-pyrimidine), 160.34 (C 1-Ph-O), 155.20 (C 6-pyrimidine), 144.29 (C 1-Ph '-N), 135.46,133.58 (2 × C), 132.51 (2 × C), 131.66 (2 × C), 127.28,125.14,122.25 (2 × C), 120.22,20.35 (CH 3), 16.31 (2 × CH 3) .ESI-MS:m/z402.3 (M+1), 424.4 (M+23), C 22h 19n 5o 3[401.15].
Embodiment 29: HIV (human immunodeficiency virus)-resistant activity experiment (MT-4 cell model)
See 1. Pauwels R, et al.J.Virol.Methods.1988,20,309. 2. Pannecouque C, et al.NatProtocols2008,3,427.
Terminological interpretation:
MT-4 cell: people's acute lymphoblastic leukemia cell.
MTT analytical method: MTT is 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, trade(brand)name: tetrazolium bromide.
Nevirapine: anti-AIDS marketed drug nevirapine.
AZT: anti-AIDS marketed drug zidovudine.
3TC: anti-AIDS marketed drug lamivudine.
Efavirenz: anti-AIDS marketed drug efavirenz.
Delavirdine: anti-AIDS marketed drug Delavirdine.
DMSO: dimethyl sulfoxide (DMSO).
Test philosophy
Due to HIV MT-4 cell within a certain period of time (5-7 days) can pathology be there is; therefore in the MT-4 cell suspension of HIV, add the compound solution to be detected of proper concn; through after a while (5-7 days) cultivation after; with MTT assay MT-4 cell viability, obtain protection 50% cell and avoid cytopathic drug level (EC 50) activity of the AntiHIV1 RT activity of target compound can be drawn.Obtain the concentration (CC that target compound makes the cell generation pathology of 50% non-infected by HIV simultaneously 50), calculate choosing coefficient (selectivity index, SI=CC 50/ EC 50).
MTT analytical method principle: MTT and bromination-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazoliumbromide nitrogen, can combine with succinodehydrogenase in the cell of living, and not react with dead cell.Current mtt assay is a kind of method of analyzing enzyme of quick, succinct reflection cell viability.
Test material and method
(1) HIV-1 (IIIB), HIV-2 (ROD) strain, the two sudden change of HIV-1 (K103N/Y181C) persister RES056: provided by microbiological inhibitory institute of Rega research institute of Belgian Leuven university.
(2) MT-4 cell: provided by microbiological inhibitory institute of Rega research institute of Belgian Leuven university.
(3) MTT: purchased from American Sigma company.
(4) sample preparation: sample is dissolved in DMSO before use and is made into proper concn, and do 5 times of dilutions with distilled water, each 5 extent of dilution.
(5) positive control drug: Nevirapine (NVP), AZT, DDC, Efavirenz (EFV), Delavirdine (DLV).
(6) testing method: join in HIV MT-4 cell suspension after diluted sample, through using MTT colorimetric method for determining cell viability after a period of time, in microplate reader, recording absorbancy (A) value at 590 nm, calculating EC 50, CC 50and SI.
(7) MTT staining: after adding sample cultivation for some time, then MTT solution (5mg/mL) 20 μ L is added to every hole, continue to cultivate some hours, abandon staining fluid, and add 150 μ LDMSO to every hole, fully mix, in microplate reader, record absorbancy at 590 nm.
Concrete operations are as follows: dilute after compound DMSO or water dissolution, by 3 × 10 with phosphate buffered saline buffer 5the compound solution of MT-4 cell and 100 μ L different concns is at 37 DEG C of common preincubate 1h.Then in this mixture, add the viral dilution liquid of 100 μ L proper concns, cell is hatched 1h in 37 DEG C.After washing three times, cell be suspended in again respectively containing or do not contain in the culture medium of compound.Then by cell at 5%CO 2in environment, at 37 DEG C, hatch 7 days again, and in metainfective 3rd day with containing or not supplementing original fluid containing the culture medium of compound.The all repetitive operations twice of often kind of culture condition.Reverse optical microscope is all used to monitor every day to the cytopathic effect of virus.In general, usually within the 5th day after virus infection, cytopathy can be there is in viral dilution liquid used in this experiment.Drug inhibition concentration produces 50% restraining effect with drug on viral cytopathic effect and simultaneously to the concentration (EC of cell without direct toxicity 50) represent.It is emphasized that when compound water soluble is poor, when needing could dissolve with DMSO, DMSO volume by volume concentration, generally can lower than 10% (DMSO ultimate density in MT-4 cell culture medium be less than 2%) relative to water.Because DMSO can affect test compounds antiviral activity, the antiviral activity contrast blank assay containing same concentrations DMSO solution also should be carried out by parallel running.In addition, DMSO ultimate density (1/1000) copies desired concn well below affecting HIV-1 in MT-4 cell.
In Vitro Anti HIV-1 (IIIB), HIV-2 (ROD) and HIV-1 two sudden change RES056 persister screening active ingredients data of target compound are provided by microbiological inhibitory institute of Rega research institute of Belgian Leuven university, all activity datas all record through at least twice independence, parallel experiment, the results are shown in Table 1.
Table 1 compound AntiHIV1 RT activity -1 (IIIB, RES056) and HIV -the activity of 2 (ROD) and cytotoxicity
Embodiment 30: anti-reverse transcription enzymic activity test experiments
This experiment adopts chromatmetry reverse transcriptase activity determination experiment, use test kit Reverse Transcriptase Assay, colorimetric Version13.0 is purchased from Roche Holding Ag, and TMC125 selected by positive control medicine.(see 1. Hofman, A.D. & Banapour, B. & Levy, J.A. (1985) Virology147,326 – 335. 2. Ukkonen, P.et al. (1988) Eur.J.Clin.Microbiol. & Infect.Dis.7,518 – 523.)
Test philosophy
Chromatmetry reverse transcriptase activity measures and uses template/primer-oligomerization thing poly (A) × oligo (dT) as starting raw material, and with the Nucleotide of digoxin and biotin labeled Nucleotide replacement radio isotope [3H]-or [32P]-mark, these are advantage parts of this method.Synthesized by the DNA that goes out be the important parameter measuring reverse transcriptase activity, to detect and quantitative DNA employs the ELISA measuring method of following sandwich style: biotin labeled DNA the surface of the micro-edition module (MP) of antibiotin streptocin can combine with bag quilt.In an ensuing step, the DigiTAb being polymerized peroxidase needs to be attached on the DNA of digoxigenin labeled.Finally, the substrate 2,2-adding peroxidase joins nitrogen-two (3-ethyl-benzothiazole-6-sulfonic acid) di-ammonium salts (ABTS), makes them decompose under the katalysis of enzyme, produces the product with obvious color.Measured the microplate absorbance being loaded with sample by microplate reader, this absorbance presents direct association with the activity of reversed transcriptive enzyme, can obtain the inhibition concentration of compound to reversed transcriptive enzyme by formulae discovery.
Testing method
(1) first configure various working solution, and the appropriate DMSO of sample is dissolved, and be diluted to 5 concentration gradients with lysis buffer.In the reaction tubes that each are different, 4 – 6ng Recombinant HIV-1-RT lysis buffer (20 μ l/well) is diluted.Meanwhile, preparation only has lysis buffer and does not have the negative control group of RT.Then each retort add 20 μ l contain different concns test buffered soln and the 20 μ l reactant mixed solutions of sample, under 37 degrees Celsius, hatch one hour.
(2) prepare micro-edition enough module, be fixedly mounted in framework according to direction.The sample of hatching (60 μ l) is transferred in the hole of microplate, with plastic film covering well after second time 37 degrees Celsius hatch one hour.
Removed by solution, every hole washing lotion carefully rinses 5 times, often all over 250 μ l, retains 30 seconds.Every hole adds 200 μ l anti-digoxin-peroxidase polymkeric substance, and by microplate plastic film covering, well rear third time hatches one hour under 37 degrees Celsius.
(3) removed by solution, every hole washing lotion carefully rinses 5 times, often all over 250 μ l, retains 30 seconds.Every hole adds 200 μ lABTS solution, hatches under 15-25 degree Celsius, until green color occurs and enough passes through photometric detection (being generally 10-30 minute).
(4) be loaded with the absorbance of sample at wavelength 405nm place by microplate reader mensuration, the inhibition concentration of compound to reversed transcriptive enzyme can be obtained by following formulae discovery.
Inhibiting rate %=(positive control fluorescence intensity-fluorescent intensity)/(positive control fluorescence intensity-background fluorescence intensity) × 100% carries out linear regression, and bring inhibiting rate into linear equation, the concentration C of trying to achieve is IC 50, unit is (μ g/mL), then to be converted into μM according to compound molecular weight, and this experiment have chosen two best representative compound of two cytoactives, and positive control drug etravirine (ETV), and experimental result is in table 2.
Table 2 representation compound is to HIV1-RT inhibit activities
Above-mentioned experimental result shows: the compound with formula I of the present invention is the HIV-1 inhibitor that a class has novel texture skeleton, the inhibit activities of multiple compounds against wild type HIV-1 is wherein had to be in nanomolar range, to multidrug resistant disease strain, there is medium inhibit activities equally, especially the activity of compoundsⅰb-1 is suitable with the anti-AIDS drug etravirine (ETV) of widespread use clinically at present, has the prospect of research and development further.In addition, the present invention is also surprised to find that I c-3 and I c-5, two compounds also have certain inhibit activities to HIV-2, can be used as lead compound and does further research and discussion.Therefore, the compound that the present invention relates to very likely produces strong inhibit activities to the strain of HIV drug-resistant viral, has the potentiality developing into a class brand new anti-HIV new medicament.

Claims (7)

1. there is two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative or pharmacy acceptable salt between general formula (I):
Wherein,
R 1, R 2be-H, halogen ,-NO independently of one another 2,-NH 2,-NHR ,-N (R) 2,-NHCOCH 3,-NHCOCF 3;
R 3and R 4be halogen, C independently of one another 1-6alkyl;
R 5for-CN, halogen, C 1-6alkyl, CHO;
R 6for-CN;
X is-NH-,-O-;
Wherein R is C 1-4alkyl.
2. compound as claimed in claim 1, is characterized in that the structure with following general formula I ＇:
Wherein, R 1, R 3, R 4, R 5described in general structure I.
3. compound as claimed in claim 1 or 2, is characterized in that one of the compound for having structure:
4. the preparation method of compound as claimed in claim 1, is characterized in that with the pyrimidine ring of two halogen substiuted for starting raw material, with substituted aryl amine and Ar 1-NH 2condensation obtains intermediate (IV), then between nucleophilic substitution reaction obtains two aromatic hydrocarbons-polysubstituted pyrimidine analog derivative (I);
Synthetic route is as follows:
Reagent and condition: (i) triethylamine, tetrahydrofuran (THF), 0 DEG C; (ii) salt of wormwood, DMF, 60 DEG C;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6and described in the same formula I of the definition of X.
5. the preparation method of compound as claimed in claim 2, it is characterized in that with 5-nitro-2,4-dichloro pyrimidine (II) is starting raw material, obtains intermediate (IV) with to cyano-aniline (III) condensation under the alkaline condition of triethylamine; Then, obtain target product (Ia) from the phenol (V) of different replacement through nucleophilic substitution reaction, then obtain target product (Ib, Ic, Id) through reduction hydrogenation, acylation reaction successively;
Synthetic route is as follows:
Reagent and condition: (i) triethylamine, tetrahydrofuran (THF), 0 DEG C; (ii) salt of wormwood, DMF, 60 DEG C; (iii) hydrogen, palladium carbon; (iv) tindichloride dihydrate, ethanol; (v) triethylamine, trifluoromethanesulfanhydride anhydride, methylene dichloride, 0 DEG C; (vi) triethylamine, Acetyl Chloride 98Min., 0 DEG C;
Wherein R 3, R 4, R 5the same general formula I of definition described in;
The phenol (V) of described replacement is 4-cyano group-2,6-xylenol, 2,4,6-front three phenol, 2,4,6-Trichlorophenols, 2,4,6-tribromophenols, bromo-2, the 6-xylenols of 4-, 2,6-chlorophenesic acid, 4-aldehyde radical-2,6-xylenol.
6. an inverase composition, comprises compound described in any one of claim 1-3 or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
7. the application of compound in the medicine preparing AntiHIV1 RT activity described in any one of claim 1-3.
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