CN105017139A - Preparation and application of 3,4-disubstituted-6-phenethyl pyridinone HIV-1 reverse transcriptase inhibitor - Google Patents

Preparation and application of 3,4-disubstituted-6-phenethyl pyridinone HIV-1 reverse transcriptase inhibitor Download PDF

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CN105017139A
CN105017139A CN201410154784.3A CN201410154784A CN105017139A CN 105017139 A CN105017139 A CN 105017139A CN 201410154784 A CN201410154784 A CN 201410154784A CN 105017139 A CN105017139 A CN 105017139A
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styroyl
pyridone
compound
nmr
aryl
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刘俊义
王孝伟
曹源源
张志丽
郭莹
田超
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Peking University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention relates to an application of a 3,4-disubstituted-6-phenethyl pyridinone HIV-1 reverse transcriptase inhibitor and a pharmaceutical composition containing the compound used as drugs for treating Aids and antiviral drugs. Each group in the formula is as defined in the specification. Meanwhile, the invention also relates to a preparation method of the compound. In the general formula I, R1 is i-Pr, N, N-dimethyl, Br and I; R2 is a phenyl group, p-methylphenyl, a cyclohexyl group, a cyclopentyl group and 2-methylcyclohexyl; and X is oxygen atom, sulphur atom and nitrogen atom.

Description

3,4-bis-replaces preparation and the application thereof of-6-styroyl pyridinone HIV1-RT inhibitor
1. technical field
The application relates to 3,4-bis-replace-6-styroyl pyridinone HIV1-RT inhibitor and containing described compound pharmaceutical composition as treatment AIDS-treating medicine and antiviral in application, in formula, the definition of each group as is described in the claims, also relates to the preparation method of this compounds simultaneously.
2. background technology
Acquired immune deficiency syndrome (AIDS), also known as acquired immune deficiency syndrome (AIDS) (AIDS), is the CD4 caused owing to infecting human immunodeficiency virus (HIV) +t lymphocyte Progressive symmetric erythrokeratodermia reduces and immune deficiency, often with the clinical syndrome that a kind of mortality ratio of the inflammatory diseases of organa parenchymatosum, neurological disorder and malignant tumour is high, causes serious threat to the health of the mankind and existence.Because HIV is the virus that a kind of variability is very strong, Long-term taking medicine and the research and development of problem to AIDS-treating medicine such as the resistance produced and crossing drug resistant bring certain difficulty.Therefore, the low-cost inverase that research and development have a high-efficiency low-toxicity of autonomous property right is the very urgent and important problem of in face of the Chinese government and scientist one of pendulum.
According to virus of AIDS replicative cycle, reversed transcriptive enzyme, proteolytic enzyme and intergrase have become the important target spot of development anti-AIDS drug.Wherein, non-nucleoside reverse transcriptase inhibitor with its various structures, efficient, low toxicity and with the characteristic such as the synergy of other drug and receiving much concern.Non-nucleoside reverse transcriptase inhibitor is the compound that a group has nothing to do with nucleosides, the diverse specificity of chemical structure suppresses HIV1-RT.It is combined by noncompetitive highly can suppress HIV-1 virus.Because its action site is not or not Binding Capacity district, therefore can not have an impact to the DNA polymerase activity of host cell, therefore toxicity is very little, has very high antiviral selectivity index.Pyridinone anti-HIV-1 reverse transcriptase inhibitors has showed stronger anti-cross resistance, has become the emphasis of domestic and international drug research.
The application relates to non-nucleoside reverse transcriptase inhibitor 6-styroyl-2 (1H)-pyridone for lead compound, according to bioisosterism and hydrogen bond action scheduling theory, have devised the recruit of a class dependency structure, make it have efficient inhibit activities to HIV1-RT.
3. summary of the invention
The object of this invention is to provide new pyridine ketone HIV1-RT inhibitor as the application in treatment AIDS-treating medicine and antiviral and the preparation method of this compounds.
According to the correlation theory of medicinal design, with non-nucleoside HIV1-RT inhibitor 6-styroyl-2 (1H)-pyridone for primer, sec.-propyl is used respectively by 3, N, N-dimethyl and halogen group replace, and investigate electrical effect and stereoeffect to the impact suppressing reverse transcriptase activity.Use phenol respectively by 4, the group such as thiophenol and aniline replaces, and has investigated the impact of heteroatomic change on activity.Meanwhile, 4 saturated alicyclic rings are contrasted with aromatic nucleus.
By 3, the change of 4 bit substituents, have studied the structure activity relationship of this pyridine compounds for HIV1-RT.Relate to further the application as HIV1-RT inhibitor of the reverse transcriptase activity evaluation of compound and this compounds.
According to one embodiment of the invention, the present invention relates to general formula I analog derivative:
General formula I
Wherein, R 1for i-Pr, N, N-dimethyl, Br, I;
R 2for phenyl, p-aminomethyl phenyl, cyclohexyl, cyclopentyl, 2-methylcyclohexyl;
X is Sauerstoffatom, sulphur atom, nitrogen-atoms.
Compound concrete in compound of Formula I: 4-phenyl sulphur-3-N, N-dimethyl-6-styroyl-2 (1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl sulphur-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-phenyl sulphur-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone, 4-phenyl sulphur-6-styroyl-3-sec.-propyl-2 (1H)-pyridone, 4-phenyl oxygen-6-styroyl-3-sec.-propyl-2 (1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl oxygen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-phenyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone.
Part of compounds of the present invention can be prepared according to following synthetic route, will contribute to understanding the present invention, but do not limit content of the present invention by following reaction formula.
Route 1
Route 2
Route 3
Route 4
4. embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.If no special instructions, in following embodiment, " being spin-dried for solvent " refers generally to " using Rotary Evaporators solvent evaporated under water pump reduced pressure ".
Embodiment 1: the preparation (compound 1) of isopropylidene malonate
52g (0.5mol) propanedioic acid is dissolved in 60ml (0.6mol) diacetyl oxide, the 1.5ml vitriol oil is added under frozen water cooling and stirring, the acetone of 40ml (0.55mol) is dripped after 10min, after continuing to stir 15min under condition of ice bath, make it rise to normal temperature, mixture is placed in refrigerator overnight, decompress filter obtains white solid, recrystallization in acetone-frozen water, yield 72.2%.Mp:95 ~ 96 DEG C (literature value 94 ~ 95 DEG C).
The preparation (compound 2) of embodiment 2:3-oxo-4-phenylpentanoic acid ethyl ester
5.45g (37.81mmol) isopropylidene malonate is added in 100ml round-bottomed flask, 70ml methylene dichloride, 6.2ml pyridine, drips 7ml (52.93mmol) phenylpropyl alcohol acyl chlorides after frozen water cooling 15min, after continuing cooling 1h, stirred overnight at room temperature.The reaction solution 10%HCl aqueous solution (50ml × 2) washs, washing (50ml), anhydrous Na 2sO 4dry.Filter, the lower evaporate to dryness of decompression obtains reddish black solid, and solid adds 100ml dehydrated alcohol, reflux 4h, is spin-dried for solvent, sherwood oil: ethyl acetate=50: 1 purifying obtains compound 2, pale yellow oily liquid body, yield 56.75%.
1H NMR(400MHz，CDCl 3)：δppm7.17-7.29(m，5H，aryl)，4.16(q，2H，OCH 2CH 3)，3.41(s，2H，COCH 2CO)，2.85-2.92(m，4H，CH 2CH 2Ph)，1.25(t，3H，OCH 2CH 3).
The preparation (compound 3) of embodiment 3:4-hydroxyl-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
Add 2M methanolic ammonia solution 61ml (60.68mmol) in 3-oxo-4-phenylpentanoic acid ethyl ester 5g (24.27mmol), return line upper end adds that balloon is airtight, and reflux 6h is spin-dried for solvent for subsequent use.
In 40ml dehydrated alcohol, add 1.2g sodium Metal 99.5, cool after reacting completely, drip 7.4ml (48.8mmol) diethyl malonate, solution turned cloudy, reflux 2h, after cooling, ethanolic soln after dropping 3-oxo-4-phenylpentanoic acid second ester aminolysis, reflux 3d, there is a large amount of white precipitate, after solution cooling, in impouring 1N HCl, occur a large amount of solid, filtered on buchner funnel, ethyl acetate washs to obtain target product, is white solid, reclaims raw material.Yield 33%.
1H NMR(400MHz，DMSO-d 6)：δppm12.58(s，1H，OH)，11.51(s，1H，NH)，7.18-7.31(m，5H，aryl)，5.81(s，1H，C-5-H)，4.26(q，2H，OCH 2CH 3)，2.86-2.90(m，2H，CH 2CH 2-Ph)，2.69-2.73(m，2H，CH 2CH 2-Ph)，1.26(t，3H，OCH 2CH 3)；
13C NMR(101MHz，DMSO-d 6)：δppm172.82(COOEt)，170.57(C-4)，161.14(C-2).154.97(C-6)，140.68，128.78，126.61(aryl)，98.53(C-3)，97.52(C-5)，61.09(OCH 2CH 3)，34.54(CH 2CH 2-Ph)，34.09(CH 2CH 2-Ph)，14.58(OCH 2CH 3).
The preparation (compound 4) of the chloro-6-styroyl-2 of embodiment 4:4-(1H)-pyridone-3-carboxylic acid, ethyl ester
4.7g (16.3mmol) 4-hydroxyl-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 3) is added in 100ml round-bottomed flask, in 50ml anhydrous acetonitrile, 14.9g (65.2mmol) benzyltriethylammoinium chloride, 6.7ml (71.9mmol) phosphorus oxychloride, stirring at normal temperature 24h, solution decompression is spin-dried for, add 10ml frozen water, separate out a large amount of white solid, filtered on buchner funnel, ethyl alcohol recrystallization, drying obtains target product, for white solid, yield 80%, fusing point 147-149 DEG C.
MS(ESI)m/z：306.35[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.64(s，1H，NH)，7.21-7.35(m，5H，aryl)，6.19(s，1H，C-5-H)，4.37-4.43(q，2H，OCH 2CH 3)，2.98-3.03(m，2H，CH 2CH 2-Ph)，2.85-2.90(m，2H，CH 2CH 2-Ph)，1.31-1.35(t，3H，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm163.98(COOEt)，162.43(C-2)，150.79(C-4)，146.37，128.59，128.50，126.53(aryl)，139.70(C-6)，121.66(C-3)，107.64(C-5)，61.90(OCH 2CH 3)，35.48(CH 2CH 2-Ph)，34.99(CH 2CH 2-Ph)，14.11(OCH 2CH 3).
The preparation (compound 5) of the chloro-6-styroyl-2 of embodiment 5:4-(1H)-pyridone
The chloro-6-styroyl-2 of 5g (16.4mmol) 4-(1H)-pyridone-3-carboxylic acid, ethyl ester (compound 4) is added, 20ml2N HCl, reflux 2 days in 50ml round-bottomed flask, after having reacted, cooling, adds appropriate sodium carbonate, separates out a large amount of white solid, filtered on buchner funnel, ethyl alcohol recrystallization, drying obtains target product, is white solid, yield 72%, fusing point 147-149 DEG C.
MS(ESI)m/z：234.27[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.34(s，1H，NH)，7.23-7.34(m，5H，aryl)，6.48-6.50(d，1H，C-3-H)，6.08-6.10(d，1H，C-5-H)，3.00-3.05(m，2H，CH 2CH 2-Ph)，2.87-2.92(m，2H，CH 2CH 2-Ph)； 13C NMR(101MHz，CDCl 3)：δppm165.28(C-2)，149.66(C-4)，148.96，128.57，128.49，126.48(aryl)，139.78(C-6)，116.06(C-3)，107.43(C-5)，35.01(CH 2CH 2-Ph)，34.80(CH 2CH 2-Ph).
The preparation (compound 6a) of embodiment 6:4-benzene sulfydryl-6-styroyl-2 (1H)-pyridone
The chloro-6-styroyl-2 of 2.8g (12.0mmol) 4-(1H)-pyridone (compound 5) is added in 50ml round-bottomed flask, 1.3ml (13.0mmol) thiophenol, 20ml ethanol, after stirring, dropwise add 1ml triethylamine, reflux is after 2 days, and cooling, reduces pressure and be spin-dried for solvent, column chromatography for separation obtains target product, for white solid, yield 65%, fusing point 180-182 DEG C.
MS(ESI)m/z：308.54[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.97(s，1H，NH)，7.17-7.54(m，10H，aryl)，5.91(s，1H，C-3-H)，5.84(s，1H，C-5-H)，2.94-2.98(t，2H，CH 2CH 2-Ph)，2.79-2.83(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm164.77(C-2)，156.66(C-4)，147.82，135.53，129.89，128.53，128.46，126.30，116.05，110.60(aryl)，140.04(C-6)，107.31(C-3)，104.38(C-5)，34.84(CH 2CH 2-Ph)，34.64(CH 2CH 2-Ph).
4-is to the preparation (compound 6b) of methylbenzene sulfydryl-6-styroyl-2 (1H)-pyridone
Use as above example 6 method, with to methylbenzene phenyl-sulfhydrate for reactant obtains compound 6b, be white solid, yield 62%, fusing point 104-106 DEG C.
MS(ESI)m/z：322.42[M+H] +，344.43[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm12.96(s，1H，NH)，7.17-7，42(m，10H，aryl)，5.87(s，1H，C-3-H)，5.83(s，1H，C-5-H)，2.93-2.97(t，2H，CH 2CH 2-Ph)，2.78-2.82(t，2H，CH 2CH 2-Ph)，2.43(s，3H，CH 3-Ph)；
13C NMR(101MHz，CDCl 3)：δppm164.82(C-2)，157.20(C-4)，147.70，140.10，135.60，130.67，128.54，128.43，126.26，125.00(aryl)，140.25(C-6)，110.31(C-3)，104.18(C-5)，34.76(CH 2CH 2-Ph)，34.62(CH 2CH 2-Ph)，21.35(CH 3-Ph).
The preparation (compound 7a) of the iodo-6-styroyl-2 of embodiment 7:4-phenyl sulphur-3-(1H)-pyridone
After 0.61g (2mmol) 4-benzene sulfydryl-6-styroyl-2 (1H)-pyridone (compound 6a) is dissolved in 10ml anhydrous tetrahydro furan, add 0.47g (2.1mmol) NIS, after lucifuge stirring at normal temperature 12h, be spin-dried for solvent, column chromatography for separation obtains target compound 7a, for white solid, yield 91%, fusing point 225-227 DEG C.
HRMS(ESI)m/z：434.0071[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm11.85(s，lH，NH)，7.01-7.57(m，10H，aryl)，5.06(s，1H，C-5-H)，2.66-2.68(t，2H，CH 2CH 2-Ph)，2.52-2.57(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm159.90(C-4)，158.29(C-2)，153.39，140.33，135.66，130.73，130.62，130.33，128.73，126.57(aryl)，148.02(C-6)，107.17(C-5)，102.16(C-3)，34.12(CH 2CH 2-Ph)，34.07(CH 2CH 2-Ph).
The preparation (compound 7b) of the iodo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone
Use as above example 7 method, obtaining compound 7b to methylbenzene sulfydryl-6-styroyl-2 (1H)-pyridone (compound 6b) for reactant with 4-, is white solid, yield 92%, fusing point 216-218 DEG C.
HRMS(ESI)m/z：448.0224[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.11(s，1H，NH)，7.20-7.42(m，10H，aryl)，5.32(s，1H，C-5-H)，2.88-2.92(t，2H，CH 2CH 2-Ph)，2.69-2.73(t，2H，CH 2CH 2-Ph)，2.46(s，3H，Ph-CH 3)；
13C NMR(101MHz，CDCl 3)：δppm161.86(C-4)，161.35(C-2)，147.55，140.04，135.70，130.78，128.71，128.41，126.93(aryl)，140.60(C-6)，126.24(C-5)，103.93(C-3)，35.31(CH 2CH 2-Ph)，34.99(CH 2CH 2-Ph)，21.49(Ph-CH 3).
The preparation (compound 8a) of the bromo-6-styroyl-2 of embodiment 8:4-phenyl sulphur-3-(1H)-pyridone
After 0.61g (2mmol) 4-benzene sulfydryl-6-styroyl-2 (1H)-pyridone (compound 6a) is dissolved in 10ml anhydrous tetrahydro furan, add 0.37g (2.1mmol) NBS, after lucifuge stirring at normal temperature 12h, be spin-dried for solvent, column chromatography for separation obtains target compound 8a, for white solid, yield 95%, fusing point 204-207 DEG C.
HRMS(ESI)m/z：386.0204[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.04(s，1H，NH)，7.18-7.55(m，10H，aryl)，5.32(s，1H，C-5-H)，2.86-2.90(t，2H，CH 2CH 2-Ph)，2.69-2.73(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm160.41(C-2)，156.30(C-4)，146.45，135.88，130.75，130.22，129.95，129.36，128.64，128.53(aryl)，139.91(C-6)，126.26(C-5)，103.73(C-3)，35.38(CH 2CH 2-Ph)，34.95(CH 2CH 2-Ph).
The preparation (compound 8b) of the bromo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone
Use as above example 8 method, obtaining compound 8b to methylbenzene sulfydryl-6-styroyl-2 (1H)-pyridone (compound 6b) for reactant with 4-, is white solid, yield 96%, fusing point 209-211 DEG C.
HRMS(ESI)m/z：400.0370[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm7.18-7.41(m，10H，aryl)，5.33(s，1H，C-5-H)，2.86-2.90(t，2H，CH 2CH 2-Ph)，2.69-2.73(t，2H，CH 2CH 2-Ph)，2.46(s，3H，Ph-CH 3)；
13C NMR(101MHz，CDCl 3)：δppm160.19(C-2)，156.98(C-4)，146.26，139.84，135.84，130.77，128.60，128.43，126.29(aryl)，140.68(C-6)，125.62(C-5)，103.84(C-3)，35.25(CH 2CH 2-Ph)，34.87(CH 2CH 2-Ph)，21.46(Ph-CH 3).
The preparation (compound 9a) of embodiment 9:4-phenyl nitrogen-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
The chloro-6-styroyl-2 of 3.9g (13.0mmol) 4-(1H)-pyridone-3-carboxylic acid, ethyl ester (compound 4) and 1ml (13.5mmol) aniline is added in 10ml ethanol, after stirring, dropwise add 1ml triethylamine, reflux 2 days, after cooling, be spin-dried for solvent.Column chromatography for separation obtains compound 9a, is white solid, yield 73%, fusing point 190-192 DEG C.
MS(ESI)m/z：385.48[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm10.88(s，1H，NH)，7.05-7.37(m，10H，aryl)，5.70(s，1H，C-5-H)，4.31-4.37(m，2H，OCH 2CH 3)，3.86(s，1H，Ph-NH)，2.98-3.03(t，2H，CH 2CH 2-Ph)，2.78-2.82(t，2H，CH 2CH 2-Ph)，1.30-1.34(t，3H，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm170.20(COOEt)，164.39(C-4)，159.43(C-2)，151.86，140.03，129.44，128.54，128.44，126.27，125.99，125.37(aryl)，138.23(C-6)，125.26(C-5)，94.72(C-3)，60.46(COOCH 2CH 3)，35.16(CH 2CH 2-Ph)，34.13(CH 2CH 2-Ph)，14.34(COOCH 2CH 3).
The preparation (compound 9b) of 4-cyclohexyl nitrogen-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
Use as above example 9 method, being that reactant obtains compound 9b with hexahydroaniline, is white solid, yield 75%, fusing point 213-215 DEG C.
MS(ESI)m/z：369.45[M+H] +，391.38[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm11.93(s，1H，NH)，9.36-9.37(d，1H，cyclohexyl-NH)，7.17-7.30(m，5H，aryl)，5.44(s，1H，C-5-H)，4.25-4.31(m，2H，OCH 2CH 3)，3.26-3.28(m，1H，NH-CH)，3.02-3.06(t，2H，CH 2CH 2-Ph)，2.83-2.87(t，2H，CH 2CH 2-Ph)，1.26-1.86(m，13H，COOCH 2CH 3，cyclohexyl)；
13C NMR(101MHz，CDCl 3)：δppm170.44(C-4)，164.40(COOEt)，159.74(C-2)，151.52，128.53，128.40，126.25(aryl)，140.20(C-6)，93.23(C-5)，91.54(C-3)，59.95(COOCH 2CH 3)，51.05，32.78，25.50，24.44(cyclohexyl)，35.07(CH 2CH 2-Ph)，34.15(CH 2CH 2-Ph)，14.38(COOCH 2CH 3).
The preparation (compound 9c) of 4-cyclopentyl nitrogen-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
Use as above example 9 method, being that reactant obtains compound 9c with cyclopentamine, is white solid, yield 76%, fusing point 190-192 DEG C.
MS(ESI)m/z：355.70[M+H] +，377.64[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm12.04(s，1H，NH)，9.35-9.37(d，1H，cyclohexyl-NH)，7.19-7.30(m，5H，aryl)，5.51(s，1H，C-5-H)，4.24-4.30(m，2H，OCH 2CH 3)，3.75-3.80(m，1H，NH-CH)，3.03-3.07(t，2H，CH 2CH 2-Ph)，2.84-2.88(t，2H，CH 2CH 2-Ph)，1.48-1.97(m，8H，cyclohexyl)，1.25-1.29(t，3H，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm170.41(C-4)，164.28(COOEt)，160.28(C-2)，151.63，128.51，128.41，126.26(aryl)，140.20(C-6)，93.7l(C-5)，91.62(C-3)，59.97(COOCH 2CH 3)，54.03，33.56，23.93(cyclopentyl)，35.12(CH 2CH 2-Ph)，34.14(CH 2CH 2-Ph)，14.36(COOCH 2CH 3).
The preparation (compound 9d) of 4-o-Methylcyclohexylamine base-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
Using as above example 9 method, with 2-methyl cyclohexylamine for reactant obtains compound 9d, is white solid, yield 70%, fusing point 177-180 DEG C.
MS(ESI)m/z：383.46[M+H] +，405.47[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm12.11(s，1H，NH)，9.33-9.35(d，1H，cyclohexyl-NH)，7.17-7.28(m，5H，aryl)，5.41-5.46(d，1H，C-5-H)，4.24-4.32(m，2H，OCH 2CH 3)，3.48-3.52(m，1H，NH-CH)，3.03-3.07(t，2H，CH 2CH 2-Ph)，2.83-2.87(t，2H，CH 2CH 2-Ph)，0.87-1.85(m，16H，cyclohexyl，cyclohexyl-CH 3，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm170.55(C-4)，164.51(COOEt)，160.34(C-2)，140.27，128.55，128.37，126.22(aryl)，151.50(C-6)，93.18(C-5)，91.36(C-3)，59.89(COOCH 2CH 3)，57.86，53.00，38.44，33.22，25.48，25.18，19.42(cycIopentyl，cyclopentyl-CH 3)，35.07(CH 2CH 2-Ph)，34.15(CH 2CH 2-Ph)，14.37(COOCH 2CH 3).
The preparation (compound 10a) of embodiment 10:4-anilino-6-styroyl-2 (1H)-pyridone
5.0g (16.4mmol) 4-anilino-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 9a) is added in 10ml2N HCl, reflux 2 days, after having reacted, cooling, adding appropriate sodium carbonate regulates reaction solution pH value to be about 7, separate out white solid, filter, ethyl alcohol recrystallization, obtain compound 10a, for white solid, yield 70%, fusing point 268-270 DEG C.
MS(ESI)m/z：291.26[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm10.91(s，1H，NH)，8.60(s，1H，Ph-NH)，7.01-7.34(m，10H，aryl)，5.70(s，1H，C-3-H)，5.52(s，1H，C-5-H)，2.85-2.89(t，2H，CH 2CH 2-Ph)，2.62-2.66(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm164.75(C-2)，154.15(C-4)，148.45，141.14，129.65，128.85，128.78，126.52，123.28，121.57(aryl)，140.74(C-6)，97.14(C-5)，92.50(C-3)，34.77(CH 2CH 2-Ph)，34.56(CH 2CH 2-Ph).
The preparation (compound 10b) of 4-cyclohexylamino-6-styroyl-2 (1H)-pyridone
Use as above example 10 method, obtaining compound 10b with 4-cyclohexylamino-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 9b) for reactant, is white solid, yield 72%, fusing point 290-292 DEG C.
MS(ESI)m/z：297.25[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm10.37(s，1H，NH)，7.16-7.30(m，5H，aryl)，6.22-6.25(d，1H，cyclohexyl-NH)，5.48(s，1H，C-5-H)，4.94(s，1H，C-3-H)，3.08-3.10(m，1H，NH-CH)，2.80-2.85(t，2H，CH 2CH 2-Ph)，2.52-2.57(t，2H，CH 2CH 2-Ph)，1.07-1.85(m，10H，cyclohexyl)；
13C NMR(101MHz，DMSO-d 6)：δppm156.31(C-4)，147.14(C-2)，141.22，128.66，126.38，113.32(aryl)，128.72(C-6)，102.49(C-5)，96.10(C-3)，50.54，32.56，25.82，24.88(cyclohexyl)，34.79(CH 2CH 2-Ph)，34.59(CH 2CH 2-Ph).
The preparation (compound 10c) of 4-cyclopentamine base-6-styroyl-2 (1H)-pyridone
Use as above example 10 method, obtaining compound 10c with 4-cyclopentamine base-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 9c) for reactant, is white solid, yield 75%, fusing point 143-145 DEG C.
MS(ESI)m/z：283.26[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm10.39(s，1H，NH)，7.17-7.31(m，5H，aryl)，6.35-6.37(d，1H，cyclopentyl-NH)，5.48(s，1H，C-5-H)，4.94(s，1H，C-3-H)，3.51-3.64(m，1H，NH-CH)，2.81-2.85(t，2H，CH 2CH 2-Ph)，2.53-2.58(t，2H，CH 2CH 2-Ph)，1.22-1.90(m，8H，cyclopentyl)；
13C NMR(101MHz，DMSO-d 6)：δppm164.70(C-4)，156.74(C-2)，141.30，128.77，126.48(aryl)，146.99(C-6)，96.82(C-5)，89.07(C-3)，53.31，32.64，24.12(cyclopentyl)，34.69(CH 2CH 2-Ph)，34.49(CH 2CH 2-Ph).
The preparation (compound 10d) of 4-o-Methylcyclohexylamine base-6-styroyl-2 (1H)-pyridone
Use as above example 10 method, with 4-o-Methylcyclohexylamine base-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 9d)
For reactant obtains compound 10d, be white solid, yield 65%, fusing point 233-236 DEG C.
MS(ESI)m/z：311.30[M+H] +，333.29[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm12.01(s，1H，NH)，7.20-7.31(m，5H，aryl)，5.42(s，1H，C-5-H)，5.33(s，1H，C-3-H)，3.95-3.97(d，1H，cyclohexyl-NH)，3.46(m，1H，NH-CH)，2.98-3.02(t，2H，CH 2CH 2-Ph)，2.77-2.81(t，2H，CH 2CH 2-Ph)，0.87-2.08(m，13H，cyclohexyl，cyclohexyl-CH 3)；
13C NMR(101MHz，CDCl 3)：δppm166.48(C-4)，156.86(C-2)，147.79，128.63，128.38，126.14(aryl)，140.57(C-6)，97.65(C-5)，89.71(C-3)，57.28，52.52，38.77，32.98，25.65，25.30，19.32(cyclohexyl，cyclohexyl-CH 3)，34.92(CH 2CH 2-Ph)，34.54(CH 2CH 2-Ph).
The preparation (compound 11a) of the iodo-6-styroyl-2 of 4-phenyl nitrogen-3-(1H)-pyridone
Use as above example 7 method, obtaining compound 11a with 4-anilino-6-styroyl-2 (1H)-pyridone (compound 10a) for reactant, is white solid, yield 92%, fusing point 212-214 DEG C.
HRMS(ESI)m/z：417.0459[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm11.36(s，1H，NH)，7.53(s，1H，Ph-NH)，7.01-7.33(m，10H，aryl)，5.56(s，1H，C-5-H)，2.79-2.83(t，2H，CH 2CH 2-Ph)，2.59-2.63(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm161.82(C-4)，154.95(C-2)，148.14，140.18，129.59，128.90，128.73，126.49，124.56，123.75(aryl)，140.78(C-6)，95.26(C-5)，71.22(C-3)，34.57(CH 2CH 2-Ph)，34.35(CH 2CH 2-Ph).
The preparation (compound 11b) of the iodo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone
Use as above example 7 method, obtaining compound 11b with 4-cyclohexylamino-6-styroyl-2 (1H)-pyridone (compound 10b) for reactant, is yellow solid, yield 93%, fusing point 156-158 DEG C.
HRMS(ESI)m/z：423.0928[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.41-12.44(s，1H，NH)，7.20-7.37(m，5H，aryl)，5.50(s，1H，C-5-H)，4.92-4.94(d，1H，cyclohexyl-NH)，3.28-3.30(m，1H，NH-CH)，2.99-3.04(t，2H，CH 2CH 2-Ph)，2.84-2.88(t，2H，CH 2CH 2-Ph)，O.86-1.93(m，10H，cyclohexyl)；
13C NMR(101MHz，CDCl 3)：δppm155.89(C-4)，148.68(C-2)，140.50，128.42，126.18，111.32(aryl)，128.83(C-6)，93.71(C-5)，51.71(C-3)，35.63(CH 2CH 2-Ph)，35.29(CH 2CH 2-Ph)，33.21，29.71，25.47，24.55(cyclohexyl).
The preparation (compound 11c) of the iodo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone
Use as above example 7 method, obtaining compound 11c with 4-cyclopentamine base-6-styroyl-2 (1H)-pyridone (compound 10c) for reactant, is yellow solid, yield 91%, fusing point 191-193 DEG C.
HRMS(ESI)m/z：409.0764[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.80(s，1H，NH)，7.21-7.42(m，5H，aryl)，5.59(s，1H，C-5-H)，4.94-4.96(d，1H，cyclopentyl-NH)，3.80-3.88(m，1H，NH-CH)，3.02-3.07(m，2H，CH2CH2-Ph)，2.85-2.89(m，2H，CH 2CH 2-Ph)，1.48-2.07(m，8H，cyclopentyl)；
13C NMR(101MHz，CDCl 3)：δppm162.96(C-4)，156.41(C-2)，148.88，128.90，128.41，126.15(aryl)，140.67(C-6)，93.81(C-5)，66.97(C-3)，54.72，33.79，23.82(cyclopentyl)，35.84(CH 2CH 2-Ph)，35.48(CH 2CH 2-Ph).
The preparation (compound 11d) of the iodo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone
Use as above example 7 method, obtaining compound 11d with 4-o-Methylcyclohexylamine base-6-styroyl-2 (1H)-pyridone (compound 10d) for reactant, is yellow oil, yield 95%.
HRMS(ESI)m./z：437.1086[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.77(s，1H，NH)，7.18-7.40(m，5H，aryl)，5.48-5.53(d，1H，C-5-H)，4.81-4.83(d，1H，cyclohexyl-NH)，3.55-3.56(m，lH，NH-CH)，3.02-3.06(t，2H，CH 2CH 2-Ph)，2.86-2.92(t，2H，CH 2CH 2-Ph)，0.90-1.95(m，13H，cyclohexyl，cyclohexyl-CH 3)；
13C NMR(101MHz，CDCl 3)：δppm162.96(C-4)，156.35(C-2)，148.90，140.66，128.91，128.39(aryl)，148.78(C-6)，126.13(C-5)，93.54(C-3)，67.00，58.51，53.48，38.89，25.50，25.30，19.44(cyclohexyl，cyclohexyl-CH 3)，35.75(CH 2CH 2-Ph)，35.39(CH 2CH 2-Ph).
The preparation (compound 12a) of the bromo-6-styroyl-2 of EXAMPLE l l:4-phenyl nitrogen-3-(1H)-pyridone
The preparation (compound 10a) of 0.58g (2mmol) 4-anilino-6-styroyl-2 (1H)-pyridone is dissolved in 10ml anhydrous tetrahydro furan, 0.37gNBS (2.1mmol) is added in reaction solution on a small quantity in batches, after normal temperature lucifuge stirs 12h, be spin-dried for solvent, column chromatography for separation obtains target compound 12a, for white solid, yield 95%, fusing point 188-190 DEG C.
HRMS(ESI)m/z：369.0599[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.06(s，1H，NH)，7.10-7.42(m，10H，aryl)，6.71(s，1H，Ph-NH)，5.84(s，1H，C-5-H)，3.00-3.04(t，2H，CH 2CH 2-Ph)，2.81-2.85(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm162.06(C-2)，151.83(C-4)，147.73，140.43，129.60，128.83，128.43，126.17，125.62，124.28(aryl)，138.50(C-6)，95.11(C-5)，91.89(C-3)，35.73(CH 2CH 2-Ph)，35.24(CH 2CH 2-Ph).
The preparation (compound 12b) of the bromo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone
Use as above example 11 method, with 4-cyclohexylamino-6-styroyl-2 (1H)-pyridone (compound 10b) for reactant, obtaining compound 12b, is yellow oil, yield 92%.
HRMS(ESI)m/z：375.1068[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.49(s，1H，NH)，7.20-7.31(m，5H，aryl)，5.58(s，1H，C-5-H)，5.01-5.02(m，1H，cyclohexyl-NH)，3.24-3.26(m，1H，NH-CH)，3.01-3.05(t，2H，CH 2CH 2-Ph)，2.87-2.91(t，2H，CH 2CH 2-Ph)，1.21-1.92(m，10H，cyclohexyl)；
13C NMR(101MHz，CDCl 3)：δppm160.72(C-2)，153.13(C-4)，147.74，128.72，128.47，126.28(aryl)，140.21(C-6)，94.73(C-5)，89.17(C-3)，51.55，33.18，25.40，24.59(cyclohexyl)，35.47(CH 2CH 2-Ph)，35.07(CH 2CH 2-Ph).
The preparation (compound 12c) of the bromo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone
Use as above example 11 method, obtaining compound 12c with 4-cyclopentamine base-6-styroyl-2 (1H)-pyridone (compound 10c) for reactant, is white solid, yield 91%, fusing point 178-180 DEG C.
HRMS(ESI)m/z：361.0903[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.80(s，1H，NH)，7.20-7.39(m，5H，aryl)，5.63(s，1H，C-5-H)，4.95-4.97(d，1H，cyclopentyl-NH)，3.77-3.83(m，1H，NH-CH)，3.01-3.05(m，2H，CH 2CH 2-Ph)，2.84-2.88(m，2H，CH 2CH 2-Ph)，1.46-2.05(m，8H，cyclopemyl)；
13C NMR(101MHz，CDCl 3)：δppm161.44(C-2)，153.47(C-4)，147.80，128.81，128.41，126.16(aryl)，140.60(C-6)，94.21(C-5)，89.53(C-3)，54.41，33.79，23.82(cyclopentyl)，35.86(CH 2CH 2-Ph)，35.38(CH 2CH 2-Ph).
The preparation (compound 12d) of the bromo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone
Use as above example 11 method, obtaining compound 12d with 4-o-Methylcyclohexylamine base-6-styroyl-2 (1H)-pyridone (compound 10d) for reactant, is yellow oil, yield 96%.
HRMS(ESI)m/z：389.1225[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.73(s，1H，NH)，7.20-7.38(m，5H，aryl)，5.54(s，1H，C-5-H)，4.81-4.84(d，1H，cyclohexyl-NH)，3.52-3.53(m，1H，NH-CH)，3.01-3.05(t，2H，CH 2CH 2-Ph)，2.84-2.88(t，2H，CH 2CH 2-Ph)，0.91-1.94(m，13H，cyclohexyl，cyclohexyl-CH 3)；
13C NMR(101MHz，CDCl 3)：δppm161.43(C-2)，153.47(C-4)，147.67，128.85，128.40，126.15(aryl)，140.61(C-6)，93.89(C-5)，89.44(C-3)，58.14，38.93，34.38，33.90，25.52，25.33，19.39(cyclohexyl，cyclohexyl-CH 3)，35.83(CH 2CH 2-Ph)，35.33(CH 2CH 2-Ph).
The preparation (compound 13) of 4-hydroxyl-6-styroyl-2 (1H)-pyridone
Use as above example 10 method, obtaining compound 13 with 4-hydroxyl-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 3) for reactant, is white solid, yield 73%, fusing point 272-274 DEG C.
MS(ESI)m/z：214.18[M-H] -；
1H NMR(400MHz，DMSO-d 6)：δppm11.23(s，1H，NH)，10.52(s，1H，OH)，7.16-7.30(m，5H，aryl)，5.65(s，1H，C-3-H)，5.40(s，1H，C-5-H)，2.83-2.88(t，2H，CH 2CH 2-Ph)，2.63-2.68(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm168.12(C-4)，165.46(C-2)，149.66，128.81，128.76，126.53(aryl)，141.07(C-6)，98.44(C-5)，96.63(C-3)，34.52(CH 2CH 2-Ph).
The preparation (compound 14) of the iodo-6-styroyl-2 of embodiment 12:4-phenyl oxygen-3-(1H)-pyridone
2.74g (10mmol) two chloroiodobenzone and 1.0g (9.1mmol) sodium carbonate are joined in 40ml water, for subsequent use after stirring at room temperature half an hour.Preparation (compound 13) and 1.0g (9.1mmol) sodium carbonate of 2g (9mmol) 4-hydroxyl-6-styroyl-2 (1H)-pyridone is added in this solution, stirring at room temperature is after 1 hour, filtration obtains white solid, wash with water, vacuum-drying is for subsequent use.
Joined by white solid in 20ml DMF, reflux, after 2 hours, is spin-dried for solvent, and column chromatography for separation obtains compound 14, is white solid, yield 95%, fusing point 200-202 DEG C.
HRMS(ESI)m/z：418.0307[M+H] +；
1H NMR(400MHz，DMSO-d 6)：δppm11.97(s，1H，NH)，6.95-7.44(m，10H，aryl)，5.45(s，1H，C-5-H)，2.77-2.81(t，2H，CH 2CH 2-Ph)，2.64-2.66(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm166.81(C-4)，162.80(C-2)，154.39，150.54，130.69，128.84，128.73，126.56，125.42，119.96(aryl)，140.54(C-6)，97.24(C-5)，76.73(C-3)，34.57(CH 2CH 2-Ph)，34.30(CH 2CH 2-Ph).
The preparation (compound 15) of 4-benzene sulfydryl-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
Use as above example 9 method, being that reactant obtains compound 15 with thiophenol, is white solid, yield 83%, fusing point 178-180 DEG C.
MS(ESI)m/z：380.68[M+H] +，402.63[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm13.23(s，1H，NH)，7.10-7.49(m，10H，aryl)，5.45(s，1H，C-5-H)，4.36-4.42(m，2H，OCH 2CH 3)，2.84-2.88(t，2H，CH 2CH 2-Ph)，2.69-2.73(t，2H，CH 2CH 2-Ph)，1.31-1.35(t，3H，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm165.83(C-4)，162.07(COOEt)，158.21(C-2)，149.91，135.52，129.98，129.86，129.78，128.43，126.29(aryl)，139.80(C-6)，115.27(C-3)，104.51(C-5)，61.41(COOCH 2CH 3)，35.23(CH 2CH 2-Ph)，34.40(CH 2CH 2-Ph)，14.23(COOCH 2CH 3).
The preparation (compound 16) of embodiment 13:4-benzene sulfydryl-3-hydroxyl sec.-propyl-6-styroyl-2 (1H)-pyridone
0.80g (2.1mmol) 4-benzene sulfydryl-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 15) adds in 20ml THF, be cooled to-78 DEG C, syringe adds 3M methyUithium solution 7ml (21.0mmol), continues to stir 1h, stirs 2h under ice-water bath, stirring at room temperature 3h, after having reacted, add 2ml water termination reaction, add 1N HCl to pH value neutrality, extraction into ethyl acetate, saturated NaHC0 after organic phase merges 3washing, saturated NaCl washing, anhydrous Na SO 4drying, column chromatography for separation obtains yellow solid 16, yield 70%, fusing point 126-129 DEG C.
MS(ESI)m/z：364.47[M-H] -；
1H NMR(400MHz，CDCl 3)：δppm13.11(s，1H，NH)，7.07-7.45(m，10H，aryl)，5.59(s，1H，C-5-H)，5.46(s，1H，OH)，2.82-2.91(m，2H，CH 2CH 2-Ph)，2.64-2.71(m，2H，CH 2CH 2-Ph)，2.06，1.81(s，6H，COH(CH 3) 2)；
13C NMR(101MHz，CDCl 3)：δppm151.16(C-2)，144.21(C-4)，139.81，135.19，134.97，129.75，129.60，129.39，128.44，128.37(aryl)，135.59(C-6)，126.30(C-3)，107.77(C-5)，60.39(COH(CH 3) 2)，34.56(CH 2CH 2-Ph)，34.37(CH 2CH 2-Ph)，29.91，21.04(COH(CH 3) 2).
The preparation (compound 17) of embodiment 14:4-benzene sulfydryl-6-styroyl-3-alkene sec.-propyl-2 (1H)-pyridone
0.073g (0.2mmol) 4-benzene sulfydryl-3-hydroxyl sec.-propyl-6-styroyl-2 (1H)-pyridone (compound 16) is dissolved in the anhydrous THF of 30ml, and frozen water cooling 15min, syringe adds 0.1ml SOCl 2, room temperature reaction spends the night.After decompression is spin-dried for THF, add methylene dichloride 50ml, the saturated NaHCO of organic phase 3washing, saturated NaCl washing, anhydrous Na SO 4drying, column chromatography for separation obtains compound 17, is white solid, yield 70%, fusing point 183-185 DEG C.
MS(ESI)m/z：348.61[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm7.18-7.49(m，10H，aryl)，5.46，5.48(s，2H，CH 3C＝CH 2)，5.11(s，1H，C-5-H)，2.86-2.90(m，2H，CH 2CH 2-Ph)，2.66-2.70(m，2H，CH 2CH 2-Ph)，2.13(s，3H，CH 3C＝CH 2)；
13C NMR(101MHz，CDCl 3)：δppm162.12(C-2)，157.63(C-4)，151.68(CH 3C＝CH 2)，145.80，140.21，135.22，131.00，129.60，129.31，128.53，128.37(aryl)，140.32(C-6)，126.23(C-3)，118.47(CH 3C＝CH 2)，104.11(C-5)，35.40(CH 2CH 2-Ph)，34.87(CH 2CH 2-Ph)，21.56(CH 3C＝CH 2).
The preparation (compound 18) of embodiment 15:4-phenyl sulphur-6-styroyl-3-sec.-propyl-2 (1H)-pyridone
0.03g (0.086mmol) 4-benzene sulfydryl-6-styroyl-3-alkene sec.-propyl-2 (1H)-pyridone (compound 17) is dissolved in the mixed solution of 5ml methylene dichloride and 5ml anhydrous methanol, add 10mg10%Pd/C, hydrogenation instrument is used to pass into hydrogen, reaction 2d, filters, is spin-dried for, methylene dichloride: methyl alcohol=100: 1 normal pressure post is separated, obtaining compound 18 is white solid, yield 80%, fusing point 138-140 DEG C.
HRMS(ESI)m/z：350.1563[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm7.17-7.46(m，10H，aryl)，5.47(s，1H，C-5-H)，3.41-3.45(s，1H，CH(CH 3) 2)，2.89-2.93(m，2H，CH 2CH 2-Ph)，2.65-2.69(m，2H，CH 2CH 2-Ph)，1.42-1.44(d，6H，CH(CH 3) 2)；
13C NMR(101MHz，CDCl 3)：δppm163.32(C-2)，149.45(C-4)，144.52，134.48，131.63，129.75，129.52，128.82，128.47，128.37(aryl)，140.43(C-6)，126.17(C-3)，104.97(C-5)，34.94(CH 2CH 2-Ph)，34.86(CH 2CH 2-Ph)，29.79(CH(CH 3) 2)，19.29(CH(CH 3) 2).
The preparation (compound 19) of embodiment 16:4-phenylol-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester
The chloro-6-styroyl-2 of 0.2g (0.66mmol) 4-(1H)-pyridone-3-carboxylic acid, ethyl ester (compound 4) is added in 15ml dry DMF, 0.1g (1mmol) phenol, 0.14g (1mmol) salt of wormwood, stir, reflux 8h, after having reacted, cooling, be spin-dried for solvent, add appropriate 1N HCl, extraction into ethyl acetate, collect organic phase, dry, filter, column chromatography for separation obtains compound 19, is white solid, yield 89%, fusing point 182-184 DEG C.
MS(ESI)m/z：364.35[M+H] +，386.29[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm13.40(s，1H，NH)，7.02-7.42(m，10H，aryl)，5.53(s，1H，C-5-H)，4.32-4.38(m，2H，OCH 2CH 3)，2.93-2.97(m，2H，CH 2CH 2-Ph)，2.78-2.83(t，2H，CH 2CH 2-Ph)，1.26-1.30(t，3H，OCH 2CH 3)；
13C NMR(101MHz，CDCl 3)：δppm165.87(C-4)，164.66(COOEt)，164.24(C-2)，153.91，139.87，128.55，128.47，126.30，125.43(aryl)，130.00(C-6)，120.67(C-3)，97.48(C-5)，61.33(COOCH 2CH 3)，35.72(CH 2CH 2-Ph)，34.83(CH 2CH 2-Ph)，14.17(COOCH 2CH 3).
The preparation (compound 20) of 4-phenylol-3-hydroxyl sec.-propyl-6-styroyl-2 (1H)-pyridone
Use as above example 13 method, obtaining compound 20 with 4-phenylol-6-styroyl-2 (1H)-pyridone-3-carboxylic acid, ethyl ester (compound 19) for reactant, is white solid, yield 71%, fusing point 168-170 DEG C.
MS(ESI)m/z：348.40[M-H] -；
1H NMR(400MHz，CDCl 3)：δppm13.35(s，1H，NH)，8.00(s，1H，OH)，6.90-7.40(m，10H，aryl)，5.59(s，1H，C-5-H)，2.97-3.01(m，2H，CH 2CH 2-Ph)，2.80-2.84(m，2H，CH 2CH 2-Ph)，1.70(s，6H，COH(CH 3) 2)；
13C NMR(101MHz，CDCl 3)：δppm167.62(C-2)，162.73(C-4)，154.53，139.60，130.08，128.55，128.52，126.36，124.60，119.90(aryl)，147.29(C-6)，119.65(C-3)，101.02(C-5)，72.47(COH(CH 3) 2)，34.74(CH 2CH 2-Ph)，30.26(COH(CH 3) 2).
The preparation (compound 21) of embodiment 17:4-phenylol-6-styroyl-3-alkene sec.-propyl-2 (1H)-pyridone
0.04g (0.1mmol) 4-phenylol-3-hydroxyl sec.-propyl-6-styroyl-2 (1H)-pyridone (compound 20) is dissolved in 10ml acetic anhydride, reflux 1h, after cooling, add appropriate water, extraction into ethyl acetate, collect organic phase, drying, filters, and product at reduced pressure post is separated and obtains compound 21, for colorless oil, yield 80%.
MS(ESI)m/z：332.47[M+H] +，354.48[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm6.97-7.41(m，10H，aryl)，6.32(s，1H，C-5-H)，5.33，5.07(s，2H，CH 3C＝CH 2)，2.91-2.98(m，4H，CH 2CH 2-Ph)，2.07(s，3H，CH 3C＝CH 2)；
13C NMR(101MHz，CDCl 3)：δppm171.11(C-2)，169.12(C-4)，159.92(CH 3C＝CH 2)，164.26，154.67，136.55，130.10，128.47，128.32，125.93，125.08(aryl)，120.30(C-3)，117.80(CH 3C＝CH 2)，109.43(C-5)，39.53(CH 2CH 2-Ph)，35.52(CH 2CH 2-Ph)，21.03(CH 3C＝CH 2).
The preparation (compound 22) of 4-phenyl oxygen-6-styroyl-3-sec.-propyl-2 (1H)-pyridone
Use as above example 15 method, with 4-phenylol-6-styroyl-3-alkene sec.-propyl-2 (1H)-pyridone (compound 21) for reactant, obtaining compound 22, is white solid, yield 99%, fusing point 189-191C.
HRMS(ESI)m/z：334.1802[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm13.28(s，1H，NH)，6.95-7.40(m，10H，aryl)，5.58(s，1H，C-5-H)，3.53-3.61(s，1H，CH(CH 3) 2)，2.99-3.04(m，2H，CH 2CH 2-Ph)，2.78-2.82(m，2H，CH 2CH 2-Ph)，1.37-1.39(d，6H，HC(CH 3) 2)；
13C NMR(101MHz，CDCl 3)：δppm166.59(C-2)，163.17(C-4)，155.54，146.61，129.85，128.58，128.40，126.19，123.91，121.39(aryl)，140.52(C-6)，119.28(C-3)，99.53(C-5)，35.41(CH 2CH 2-Ph)，35.19(CH 2CH 2-Ph)，24.54(CH(CH 3) 2)，20.23(CH(CH 3) 2).
The preparation (compound 23) of embodiment 18:4-hydroxyl-3-nitro-6-styroyl-2 (1H)-pyridone
1.0g (4.7mmol) 4-hydroxyl-6-styroyl-2 (1H)-pyridone (compound 13) is added in 20ml Glacial acetic acid, stirring in 80 DEG C of oil baths makes it dissolve, careful dropping 0.2ml (5mmol) nitrosonitric acid, after reaction 5min, pours into reaction solution in frozen water, separate out a large amount of yellow solid, filter, dry compound 23 is yellow solid, yield 75%, fusing point 244-245 DEG C.
MS(ESI)m/z：259.32[M-H] -；
1H NMR(400MHz，DMSO-d 6)：δppm11.91(s，1H，NH)，7.18-7.32(m，5H，aryl)，5.82(s，1H，C-5-H)，2.84-2.89(t，2H，CH 2CH 2-Ph)，2.69-2.74(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，DMSO-d 6)：δppm161.98(C-4)，157.26(C-2)，152.50，128.82，126.68(aryl)，140.59(C-6)，125.98(C-3)，97.39(C-5)，34.59(CH 2CH 2-Ph)，34.26(CH 2CH 2-Ph).
The preparation (compound 24) of embodiment 19:2,4-dimethyl methyl perester radical-3-nitro-6-styroyl pyridone
1g (3.8mmol) 4-hydroxyl-3-nitro-6-styroyl-2 (1H)-pyridone (compound 23) and 1.5ml (19.0mmol) Methanesulfonyl chloride is added in 10ml methylene dichloride, after stirring at normal temperature is even, carefully add 1ml triethylamine, reaction 12h, be spin-dried for solvent, column chromatography for separation obtains compound 24, is yellow solid, yield 85%, fusing point 133-135 DEG C.
MS(ESI)m/z：417.35[M+H] +，439.29[M+Na] +，455.30[M+K] +；
1H NMR(400MHz，CDCl 3)：δppm7.16-7.33(m，6H，aryl，C-5-H)，3.51，3.32(s，6H，(SO 3CH 3) 2)，3.18-3.23(t，2H，CH 2CH 2-Ph)，3.08-3.12(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm164.54(C-6)，149.87(C-2)，148.94(C-4)，139.62，128.71，128.38(aryl)，126.56(C-3)，115.52(C-5)，41.72，34.62((SO 3CH 3) 2)，39.52(CH 2CH 2-Ph)，39.48(CH 2CH 2-Ph).
The preparation (compound 25) of embodiment 20:4-benzene sulfydryl-2-methylsulphonic acid ester group-3-nitro-6-styroyl pyridone
0.2g (0.5mmol) 2 is added in 10ml methylene dichloride, 4-dimethyl methyl perester radical-3-nitro-6-styroyl pyridone (compound 24) and 1ml triethylamine, stirring at normal temperature is even, slow dropping 0.06ml (0.5mmol) thiophenol, reaction 12h, is spin-dried for solvent, column chromatography for separation obtains compound 25, for yellow solid, yield 72%, fusing point 160-162 DEG C.
MS(ESI)m/z：431.39[M+H] +，453.34[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm7.01-7.56(m，10H，aryl)，6.32(s，1H，C-5-H)，3.52(s，3H，SO 3CH 3)，2.88-2.94(t，4H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm161.20(C-6)，151.16(C-2)，148.94，130.90，130.48，128.55，128.33，127.81，126.32(aryl)，139.87(C-3)，135.63(C-4)，119.66(C-5)，41.67(SO 3CH 3)，39.05(CH 2CH 2-Ph)，34.53(CH 2CH 2-Ph).
The preparation (compound 26) of embodiment 21:4-benzene sulfydryl-3-nitro-6-styroyl-2 (1H)-pyridone
23.0mg (1.0mmol) sodium joins in 10ml methyl alcohol, after sodium all dissolves, 0.04g (0.1mmol) 4-benzene sulfydryl-2-methylsulphonic acid ester group-3-nitro-6-styroyl pyridone (compound 25) is added in reaction solution, after heating reflux reaction 1h, cooling, is spin-dried for solvent, column chromatography for separation obtains compound 26, for yellow solid, yield 70%, fusing point 213-215 DEG C.
MS(ESI)m/z：353.40[M+H] +，375.41[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm13.23(s，1H，NH)，7.10-7.56(m，10H，aryl)，5.44(s，1H，C-5-H)，2.85-2.89(t，2H，CH 2CH 2-Ph)，2.72-2.76(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm157.44(C-2)，156.43(C-4)，151.18，135.77，130.81，130.23，128.62，128.48，126.53(aryl，C-3)，139.07(C-6)，104.12(C-5)，35.54(CH 2CH 2-Ph)，34.50(CH 2CH 2-Ph).
The preparation (compound 27) of 4-benzene sulfydryl-3-amino-6-styroyl-2 (1H)-pyridone
Use as above example 15 method, with 4-benzene sulfydryl-3-nitro-6-styroyl-2 (1H)-pyridone (compound 26) for reactant, obtaining compound 27, is yellow solid, yield 75%, fusing point 130-133 DEG C.
MS(ESI)m/z：323.49[M+H] +，345.43[M+Na] +；
1H NMR(400MHz，CDCl 3)：δppm12.50(s，1H，NH)，7.19-7.32(m，10H，aryl)，5.93(s，1H，C-5-H)，2.95-2.99(t，2H，CH 2CH 2-Ph)，2.77-2.81(t，2H，CH 2CH 2-Ph)，1.28(s，2H，NH 2)； 13C NMR(101MHz，CDCl 3)：δppm144.41(C-2)，140.56，133.44，129.29，128.48，128.44，126.83，126.19，118.57(aryl，C-3)，136.32(C-6)，133.79(C-4)，109.89(C-5)，35.31(CH 2CH 2-Ph)，34.62(CH 2CH 2-Ph).
The preparation (compound 28) of embodiment 22:4-phenyl sulphur-3-N, N-dimethyl-6-styroyl-2 (1H)-pyridone
0.04g (0.12mmol) 4-benzene sulfydryl-3-amino-6-styroyl-2 (1H)-pyridone is added in 10ml acetonitrile
(compound 27) and formalin (37%, 1.2mmol).In reaction solution, add sodium cyanoborohydride (0.36mmol, 0.023g) in batches, after stirring at room temperature 15min, slowly drip Glacial acetic acid (1ml), after room temperature reaction 2h, add appropriate 10% wet chemical, CH 2cl 2extraction, collects organic phase, dry, filters, and product at reduced pressure post is separated and obtains compound 28, is yellow solid, yield 80%, fusing point 194-196 DEG C.
HRMS(ESI)m/z：351.1523[M+H] +；
1H NMR(400MHz，CDCl 3)：δppm12.93(s，1H，NH)，7.18-7.52(m，10H，aryl)，5.28(s，1H，C-5-H)，2.90-2.94(t，2H，CH 2CH 2-Ph)，2.87(s，6H，N(CH 3) 2)，2.67-2.71(t，2H，CH 2CH 2-Ph)；
13C NMR(101MHz，CDCl 3)：δppm162.05(C-2)，153.49，140.40，131.98，131.21，129.49，129.24，128.47，128.38(aryl)，144.67(C-6)，135.76(C-3)，126.20(C-4)，102.69(C-5)，41.81，29.71(N(CH 3) 2)，35.08(CH 2CH 2-Ph)，34.93(CH 2CH 2-Ph).
Embodiment 23: the evaluated biological activity of synthesized compound being carried out to HIV1-RT
One experimental principle
1. reversed transcriptive enzyme:
Reversed transcriptive enzyme take single stranded RNA as the archaeal dna polymerase of template, synthetic dsdna.Multifunctional enzyme, have respectively with RNA or DNA for templated synthesis polysaccharase and ribonuclease H activity.
2. Nucleotide microwell plate is covalently cross-linked
Making nucleic acid molecular hybridization is divided into solid-phase hybridization and solution hybridization two type by environment.Solid-phase hybridization to participate in a cDNA chip of reaction on solid support, and another nucleic acid reaction chain is free in the solution.This experiment is using the oligo (dT) as primer 155 ' end phosphorylation after there is covalent cross-linking with the surface of the 96 amino plates in holes of NUNC company, thus reaction is carried out on solid support.
CovaLink tMnH: be that a kind of surface at polystyrene is with NH 2the microwell plate of group.At micropore surface approximately containing 10 14individual NH 2group/cm 2, proteins and peptides can be held by C or N end is attached on microwell plate, can be incorporated into microwell plate on the surface, whole reaction is carried out on solid support after 5 ' end phosphorylation of Nucleotide.
3. reaction principle:
With oligo (dT) 15for primer, and poly A (mRNA3 ' hold polyadenylic acid) be template, dTTP and biotin labeled dUTP is substrate, under the effect of reversed transcriptive enzyme, mixes synthetic DNA.Streptavidin (SA) specific binding that biotin labeled dUTP and alkaline phospholipase (ALP) mark, and color reaction can be there is with the alkaline phospholipase of streptavidin conjugation and PNPP, according to the size of absorbancy, the reactive behavior of reversed transcriptive enzyme can be judged at 405nm.
Two materials and methods
2.1 materials and instrument
HIV1-RT HIV-1RT is genetically engineered recombinase; AMV reversed transcriptive enzyme (AMV-RT) is provided by SIGMA company; Trisodium phosphonoformate hexahydrate (PFA, by Jiangsu, the honest pharmaceutical Co. Ltd that becomes a fine day produces, lot number: 0406012); Nevirapine (NVP, Shanghai Di Sainuo pharmaceutical Co. Ltd, lot number: DH027-4-0409016).Oligo (dT) 15(the oligomerization thymidine of 5 ' terminal phosphate, precious biotechnology company limited synthesizes by Dalian); 96 hole enzyme plates (CovaLinkNH, NUNC company of Denmark); Biotin-11-dUTP (biotin labeled Deoxycytidine triphosphate, Shen, Shanghai friend), other reagent is import reagent.Microplate reader (Bio-Rad, BenchmarkPlus, USA).
2.2 experimental technique
2.2.1Oligo (dT) 15bag is by the preparation of plate
By Oligo (dT) 15be dissolved in the hydrochloride buffer of the 1-methyl-imidazoles of 100mM (pH7.4), add in 96 hole enzyme plates, mix with water-soluble carbodiimide, react 4 hours in 50 DEG C of water-baths, reaction terminates rear washing lotion (50mmol/LTris-HCl, pH7.5) wash three times, remove unconjugated Oligo (dT) 15, by bag by after 96 orifice plates put 4 DEG C of preservations.
2.2.2HIV-1RT Activity determination
Reactive system cumulative volume is 100ul, containing 50mmol/L Tris-HCl, and pH8.3,3mmol/L MgCl 275mmol/LKCl, 5mmol/L DTT, 0.13mg/ml BSA (bSA), 10ug/ml poly (A), 0.75 μM of biotin-11-dUTP, 1.5 μMs of dTTP and appropriate enzyme, 37 DEG C of water-baths 1 hour, with washing lotion (50mmol/L Tris-HCl, pH7.5,0.15mol/L NaCl, 0.05mmol/L MgCl 2, 0.02%Tween20) and wash three times, remove unconjugated free substrate; Every hole adds 100ul1%BSA, and room temperature closes 30 minutes, stops the non-specific binding of vitamin H and streptavidin albumen, washes plate; Every hole adds the SA-ALP diluent (100ng/ml) of 50 μ l, and 37 DEG C of water-baths 1 hour, wash plate; Every hole adds 50 μ 1PNPP (1mg/ml, pH=9.5), 37 DEG C of water-baths 30 minutes; Every hole adds NaOH termination reaction O.5mol/L, and microplate reader measures 405nn wavelength place A value, to determine the activity of HIV-1RT; Not enzyme-added negative control is set simultaneously, experiment with computing hole A value/negative hole A value (P/N value).
Three experimental results
Can be found out by upper table experimental result, C 3specific activity C when position is sec.-propyl 3position is iodine, bromine, the dimethylated activity of N, N-will be got well.R 2for aromatic ring is better than the activity of cycloaliphatic ring.R 2for six-ring is better than pentacyclic activity.Work as R 22 by methyl substituted time, activity significantly improves.Work as R 2contraposition by methyl substituted time, activity improves.Time X is different heteroatoms, activity relationship is that Sauerstoffatom is better than nitrogen-atoms and is better than sulphur atom.In two series compounds of gained, the structure effect through related locus is optimized, and obtains active best compound 22.In above-claimed cpd, compound 11d, 12d, 14,18, the specific activity nevirapine (NVP) of 22 these five compounds exceeds 7-60 doubly.The structure activity relationship of this compounds can be furtherd investigate, to synthesize the compound of active higher anti-HIV-1 reversed transcriptive enzyme.

Claims (5)

1. compound of Formula I
Wherein, R 1for i-Pr, N, N-dimethyl, Br, I;
R 2for phenyl, p-aminomethyl phenyl, cyclohexyl, cyclopentyl, 2-methylcyclohexyl;
X is Sauerstoffatom, sulphur atom, nitrogen-atoms.
2. compound of Formula I according to claim 1, its particular compound is:
4-phenyl sulphur-3-N, N-dimethyl-6-styroyl-2 (1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl sulphur-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-phenyl sulphur-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-(4 '-aminomethyl phenyl sulphur)-3-(1H)-pyridone, 4-phenyl sulphur-6-styroyl-3-sec.-propyl-2 (1H)-pyridone, 4-phenyl oxygen-6-styroyl-3-sec.-propyl-2 (1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl oxygen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-(2 '-methylcyclohexyl nitrogen)-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-cyclopentyl nitrogen-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-phenyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-phenyl nitrogen-3-(1H)-pyridone, the bromo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone, the iodo-6-styroyl-2 of 4-cyclohexyl nitrogen-3-(1H)-pyridone.
3. the compound of synthesis described in claim 1 and 2 can be prepared according to following synthetic route, will contribute to understanding the present invention, but do not limit content of the present invention by following reaction formula:
4. pharmaceutical composition, it contains compound according to any one of claim 1 or 2 and at least one pharmaceutically acceptable carrier.
5. compound described in claim 1 or 2 is preparing the application in inverase.
CN201410154784.3A 2014-04-18 2014-04-18 Preparation and application of 3,4-disubstituted-6-phenethyl pyridinone HIV-1 reverse transcriptase inhibitor Pending CN105017139A (en)

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Publication number Priority date Publication date Assignee Title
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CN108264507B (en) * 2016-12-30 2021-02-23 北京大学 Preparation method and application of 6-phenethyl-4-hydroxy-2 (1H) -pyridone-3-formamide derivative

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