CN108586482A - A kind of Diarylmiazines HIV-1 inhibitor of the ring containing triazole and its preparation method and application - Google Patents

A kind of Diarylmiazines HIV-1 inhibitor of the ring containing triazole and its preparation method and application Download PDF

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CN108586482A
CN108586482A CN201810347783.9A CN201810347783A CN108586482A CN 108586482 A CN108586482 A CN 108586482A CN 201810347783 A CN201810347783 A CN 201810347783A CN 108586482 A CN108586482 A CN 108586482A
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nitrine
hiv
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diarylmiazines
benzyl
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刘新泳
康东伟
展鹏
武高禅
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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Abstract

The present invention relates to 1 inhibitor of Diarylmiazines HIV of a kind of ring containing triazole and its preparation method and application.The compound has the structure of Formulas I.The invention further relates to the pharmaceutical compositions containing Formulas I structural compounds.Composition the present invention also provides above compound and containing one or more such compounds is preparing the application in treating and preventing human immunodeficiency virus (HIV) drug.

Description

A kind of Diarylmiazines HIV-1 inhibitor of the ring containing triazole and preparation method thereof And application
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to the two of a kind of ring containing triazole Arylpyrimidines HIV-1 inhibitor and its preparation method and application.
Background technology
AIDS be also known as Immune Deficiency Syndrome (Acquired Immunodeficiency Syndrome, AIDS), it is to endanger pole caused by being infected by human immunodeficiency virus (human immunodeficiency virus, HIV) Big infectious disease.After the infected is infected, immunity of organism barrier would generally in turn be easy to suffer from by more serious destruction each Kind opportunistic infections and tumour and itself chronic disease.Thus AIDS becomes one of higher chronic illness of current case fatality rate.
HIV-1 reverse transcriptase (reverse transcriptase, RT) has key in the replicative cycle of the virus Effect, become anti-HIV-1 medicines research and development important target spot.The inhibitor for acting on RT is broadly divided into ucleosides reverse Transcriptase inhibitors (Nucleoside Reverse Transcriptase Inhibitors, NRTIs) and non-nucleoside reverse Transcriptase inhibitors (Non-nucleoside Reverse Transcriptase inhibitors, NNRTIs).Wherein, NNRTIs is the efficient anti-reverse transcription disease of current treatment AIDS due to the plurality of advantages such as its activity is high, selectivity is strong, toxicity is low Malicious therapy (HAART) important component.But drug resistance, toxic side effect and the medicine generation that NNRTIs occurs in clinical treatment The problem of kinetic property difference limits its clinical application to a certain extent.Therefore, it is anti-that new and effective low toxicity, wide spectrum are researched and developed Drug resistance and novel NNRTI with good pharmacokinetic property be current anti-AIDS drug research important directions it One.
Invention content
In view of the deficiencies of the prior art, the present invention provides a kind of Diarylmiazines HIV-1 of ring containing triazole to inhibit Agent and preparation method thereof, the active ingredients result as HIV-1 inhibitor and its application the present invention also provides above compound.
Technical scheme is as follows：
1. the Diarylmiazines HIV-1 inhibitor of the ring containing triazole
A kind of the Diarylmiazines HIV-1 inhibitor or its pharmaceutically acceptable salt of the ring containing triazole have general formula Structure shown in I：
Wherein,
X is：O or MH；
R is：CH3, CN or CH=CHCN；
R1For：Phenyl or pyridyl group；Or halogen, SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、 NHCH3、OH、 COOH、CH2OH、CO2Me、OCH3、NHCOCH3Substituted phenyl；Substituent group is o-, m-, contraposition is monosubstituted or polysubstituted；Or CONR2；
Wherein, R2For：Phenyl；Or halogen, SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、 OH、COOH、 CH2OH、CO2Me、OCH3、NHCOCH3Substituted phenyl；Substituent group is o-, m-, contraposition is monosubstituted or polysubstituted；Five-ring heterocycles, Hexa-member heterocycle.
According to currently preferred, the Diarylmiazines HIV-1 inhibitor of the ring containing triazole is one of following compounds：
Heretofore described " pharmaceutically acceptable salt " refers to the salt of compound in reliable medicine range of value Class is suitable for being in contact without unsuitable toxicity, stimulation and allergic reaction etc. with people or compared with the tissue of lower animal, has suitable Rational income and risk ratio, typically water or oil are soluble or dispersible, and are effectively used for its expected use On the way.It is that can do expected purposes herein including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts And it is compatible with the chemical property of compound of formula I.The list of suitable salt referring to S.M.Birge etc., J.Pharm.Sci., 1977,66,1-19 pages.
2. the preparation method of the Diarylmiazines HIV-1 inhibitor of the ring containing triazole
The preparation method of the Diarylmiazines HIV-1 inhibitor of the ring containing triazole, step include：Replaced with 2,4- dichloros Thieno [3,2-d] pyrimidine 1 be initial feed, first in n,N-Dimethylformamide solution with fortified phenol or aniline Nucleo philic substitution reaction generates intermediate 2；Then during intermediate 2 is generated with N-Boc-4- amino piperidine nucleo philic substitution reactions Mesosome 3, and then slough Boc in trifluoroacetic acid and protect to obtain intermediate 4.Then 4 react generation key intermediate with propargyl bromide 5, and then be obtained by the reaction with nitrine-end alkynes cycloaddition reaction (CuAAC Click) of azide substitution base generation monovalence copper catalysis Target product compound of formula I.Synthetic route is as follows：
Reagent and condition:(i) fortified phenol or aniline, n,N-Dimethylformamide, potassium carbonate, room temperature；(ii)N-Boc- 4- amino piperidines, n,N-Dimethylformamide, potassium carbonate, 110 DEG C；(iii) dichloromethane, trifluoroacetic acid, room temperature；(iv) bromine Propine, n,N-Dimethylformamide, potassium carbonate, room temperature；(v) vitamine C sodium, cupric sulfate pentahydrate, n,N-Dimethylformamide, Water, azide substitution base, 50 DEG C；
X、R、R1Shown in above-mentioned general formula I；
The fortified phenol or aniline be：Mesitylene phenol, 2,6- dimethyl -4- cyanophenols, 2,6- dimethyl - 4- (E)-vinyl phenol, trimethyl aniline, 2,6- dimethyl -4- cyano-anilines, 2,6- dimethyl -4- (E)-cyanogen Base vinyl aniline；
The azide substitution base is：O-chlorobenzyl nitrine, m-chloro benzyl azide, p-chlorobenzyl nitrine, adjacent bromobenzyl are folded Nitrogen, bromobenzyl nitrine, to bromobenzyl nitrine, adjacent luorobenzyl nitrine, luorobenzyl nitrine, to luorobenzyl nitrine, 2,4- difluoros Benzyl azide, 3,4- difluorobenzyls nitrine, o-cyanobenzyl nitrine, cyanobenzyls nitrine, to cyanobenzyls nitrine, adjacent nitre Base benzyl azide, nitrobenzyl nitrine, to nitrobenzyl nitrine, O-methoxy benzyl azide, meta-methoxy benzyl azide, To methoxy-benzyl nitrine, to methanesulfonylbenzyl nitrine, methanesulfonylbenzyl nitrine, adjacent methanesulfonylbenzyl nitrine, right Sulfoamido benzyl azide, sulfoamido benzyl azide, adjacent sulfoamido benzyl azide, to formamido benzyl azide, Formamido benzyl azide, adjacent formamido benzyl azide benzyl, 2- azidos -1- (pyrrolidin-1-yl) second -1- ketone, 2- nitrine Base-N- cyclopropyl-acetamides, 2- azido -1- morpholine -1- ketone.
Room temperature of the present invention is 20-30 DEG C.
3. Anti-HIV-1 Active and the application of the Diarylmiazines HIV-1 inhibitor of the ring containing triazole
The present invention has carried out carefully the Diarylmiazines derivatives of the part ring containing triazole synthesized according to the method described above Anti-HIV-1 (the III of born of the same parents' levelB), the screening active ingredients of double medicament-resistant mutation strain RES056 (K103N/Y181C), with nevirapine (NVP) and etravirine (ETV) is positive control.
Activity Results are as shown in table 1, and most compounds show extremely strong anti-HIV-1 IIIB activity, and EC50 values are in range Between 3.28-10.4nM, it is much better than positive drug NVP (EC50=163nM).Wherein, compound A7 (EC50=3.28 NM) and A9 (EC50=4.38nM) shows best anti-HIV-1 IIIB activity, is better than latest generation marketed drug ETV (EC50=5.1nM).And A7 (CC50>210 μM, SI>And A9 (CC50 64103)>212 μM, SI>48544) it all has extremely low Cytotoxicity shows high selectivity.
The Diarylmiazines HIV-1 inhibitor of the ring containing triazole of the present invention can be used as non-nucleoside HIV-1 inhibitor Using.Specifically, being used to prepare anti-AIDS drug as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition includes the Diarylmiazines HIV-1 inhibitor of the ring containing triazole of the present invention With one or more pharmaceutically acceptable carriers or excipient.
The present invention provides the Diarylmiazines HIV-1 inhibitor of the completely new ring containing triazole of structure and its preparation sides Method, the present invention also provides compound Anti-HIV-1 Active the selection result and its first Applications in antiviral field.By Experiment proves that the Diarylmiazines derivatives of the ring of the invention containing triazole can be used as HIV-1 inhibitor and apply and have very High application value.Specifically, being used to prepare anti-AIDS drug as HIV-1 inhibitor.
Specific implementation mode
Contribute to understand the present invention by following embodiments, but present disclosure cannot be limited.
Involved synthetic route is as follows in embodiment：
Embodiment 1：4- ((2- chlorothiophenes simultaneously [3,2-d] pyrimidine-4-yl) oxygroup) -3,5- xylylic acid nitriles (6) preparation
Claim disubstituted-4-hydroxy -3,5- dimethyl cyanophenyl (1.5g, 10mmol) and potassium carbonate (1.7g, 12mmol) in 30mL's It in DMF, is stirred at room temperature 15 minutes, 2,4- dichloro-thiophenes are then added, and simultaneously [3,2-d] pyrimidine 1 (1.9g, 10mmol) continues room temperature Stirring 2h (TLC detection reactions finish).It has waited for that a large amount of white solids generate, 100mL ice water is slowly added thereto, filtered, very Sky is dry, and intermediate 6 is recrystallized to obtain in ethyl alcohol.White solid, yield 93.8%, 258-260 DEG C of fusing point.ESI-MS: m/z 316.3[M+1]+.C15H10ClN3OS(315.02).
Embodiment 2：3,5- dimethyl -4- ((2- (piperidin-4-yl amino) thieno [3,2-d] pyrimidine-4-yl) oxygroup) The preparation of benzonitrile (8)
Successively by 6 (0.95g, 3.17mmol), N-Boc-4- amino piperidines (0.83g, 3.80mmol) and potassium carbonate (0.87 G, 6.33mmol) it is added in the DMF of 20mL, then it is heated to reflux 10h (TLC detections).Wait for that reaction is cooled to room temperature, slowly Reaction solution is added drop-wise in 50mL water, there are a large amount of yellow solids to generate.It is filtered after standing 30min, is dried in vacuo to obtain crude product.Claim It takes the crude product (1.26g, 2.53mmol) to be dissolved in 4mL dichloromethane, 2.22mL trifluoroacetic acids (30mmol), room temperature item is added 3-5h (TLC detections) is stirred under part.Then it is 9 to adjust reaction solution PH with the sodium bicarbonate solution of saturation, dichloromethane extraction (3 × 5mL), saturated nacl aqueous solution washing, organic layer is dried with anhydrous sodium sulfate.Then rapid column chromatography detaches to obtain intermediate 8.White solid, yield 84.2%, fusing point：114-116℃.1H NMR(400MHz, DMSO-d6,ppm)δ:8.20 (d, J= 5.4Hz,1H),7.72(s,1H),7.26(s,1H),6.92(s,1H),3.78(s,1H), 2.89(s,2H),2.12(s,6H), 1.74-1.78(m,2H),1.23-1.28(m,4H).ESI-MS:m/z 380.5[M+1]+. C20H21N5OS(379.15).
Embodiment 3：3,5- dimethyl -4- ((2- ((1- (propyl- 2- alkynes -1- bases) piperidin-4-yl) amino) thieno [3,2- D] pyrimidine-4-yl) oxygroup) and benzonitrile (9) preparation
Intermediate 8 (0.5mmol, 0.19g) is weighed in 5mL DMF, then sequentially add Anhydrous potassium carbonate (1.0mmol, 0.14g) with propargyl bromide (0.6mmol, 0.07g), react under room temperature (TLC detection reactions finish).After the reaction was complete, Saturated salt solution 20mL is added into reaction solution, ethyl acetate washs (3 × 15mL), and organic layer is dried with anhydrous sodium sulfate, mistake Filter, concentration.Rapid column chromatography detaches, and target compound 9 is then recrystallized to give in ethyl acetate-light petrol.1H NMR (400MHz,DMSO-d6) δ 8.20 (d, J=5.3Hz, 1H, C6-thienopyrimidine-H),7.72(s,2H, C3,C5- Ph-H),7.27(s,1H,C7-thienopyrimidine-H),6.88(s,1H,NH),3.69(s,1H),3.22(s,2H, N- CH2),3.13(s,1H,CH≡),2.74(s,2H),2.12(s,6H),1.90–1.30(m,6H).13C NMR(100MHz, DMSO-d6)δ162.4,160.5,153.4,133.2,132.9,123.7,119.0,109.0,75.9,51.3,46.6,31.5, 16.2. ESI-MS:m/z 418.5[M+1]+.C23H23N5OS(417.16).
Embodiment 4：The preparation of target compound A1-A10
9 (0.5mmol) and different azide substitution bases (0.6mmol) are added to DMF/H2O mixed solvents (v/v=1: In 1,10mL).Then vitamine C sodium (0.1mmol) aqueous solution and matter of the fresh configuration of 1M are added into this mixed solution Measure the CuSO that score is 7.5%4·5H2The aqueous solution of O (0.1mmol).It is heated to 50 DEG C and stirs 4-12h (TLC detections).Instead The a large amount of precipitations of generation are answered, filter cake is washed with water in filtering, dry.Then target product is recrystallized to give in methanol solution A1-A10。
4- ((2- ((1- ((1- (2- cyanobenzyls) -1H-1,2,3- triazole-4-yls) methyl) piperidin-4-yl) amino) thiophenes Pheno simultaneously [3,2-d] pyrimidine -4- bases) oxygroup) -3,5- xylylic acid nitriles (A1)
White solid, yield 92%, 149-151 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6- thienopyrimidine-H), 8.08 (s, 1H, triazol-H), 7.92 (dd, J=7.7,1.4Hz, 1H,C3- Ph '-H), 7.73 (d, J=1.5Hz, 1H, C5-Ph’-H),7.72(s,2H,C3,C5-Ph”-H),7.60–7.55(m, 1H,C6- Ph '-H), 7.36 (d, J=7.8Hz, 1H, C4-Ph’-H),7.26–7.25(m,1H,C7-thienopyrimidine- H),6.88(s,1H,NH),5.80(s, 2H,triazol-CH2),3.71(s,1H),3.56(s,2H,N-CH2),2.80(s, 2H),2.11(s,6H),1.72-1.53(m,3H), 1.45–1.39(m,3H).13C NMR(100MHz,DMSO-d6)δ162.4, 153.4,139.4,134.3,133.8,133.2, 133.0,129.8,129.6,124.9,119.0,117.4,111.6, 109.0,52.9,52.3,51.4,39.6,31.5,16.2.ESI-MS: m/z 576.6[M+1]+.C31H29N9OS(575.22).
4- ((2- ((1- ((1- (4- cyanobenzyls) -1H-1,2,3- triazole-4-yls) methyl) piperidin-4-yl) amino) thiophenes Pheno simultaneously [3,2-d] pyrimidine -4- bases) oxygroup) -3,5- xylylic acid nitriles (A2)
White solid, yield 90%, 140-142 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.3Hz, 1H,C6- thienopyrimidine-H), 8.13 (s, 1H, triazol-H), 7.86 (d, J=8.0Hz, 2H, C3, C5-Ph’-H),7.72(s, 2H,C3,C5- Ph "-H), 7.44 (d, J=7.5Hz, 2H, C2,C6-Ph’-H),7.27(s,1H,C7- thienopyrimidine-H), 6.87(s,1H,NH),5.73(s,2H,triazol-CH2),3.72–3.71(s,1H), 3.54(s,2H,N-CH2),2.79(s,2H), 2.11(s,6H),1.91–1.57(m,4H),1.45–1.39(s,2H).13C NMR(100MHz,DMSO-d6)δ162.4, 153.4,139.4,134.3,133.8,133.2,133.0,129.8,129.6, 124.9,119.0,117.4,111.6,109.0,52.9,52.3, 51.4,39.6,31.5,16.2.ESI-MS:m/z 576.6 [M+1]+.C31H29N9OS(575.22).
3,5- dimethyl-((2- ((1- ((1- (2- nitrobenzyls) -1H-1,2,3- triazole-4-yls) methyl) piperidines -4- Base) amino) thieno [3,2-d] pyrimidine-4-yl) oxygroup) benzonitrile (A3)
White solid, yield 93%, 155-157 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.21 (d, J= 5.4Hz, 1H,C6-thienopyrimidine-H),8.19–8.17(m,1H),8.01(s,1H,triazol-H),7.72(s, 2H, C3,C5-Ph”-H),7.62–7.55(m,2H),7.32–7.31(m,2H),7.26–7.24(m,1H, C7- thienopyrimidine-H),6.88(s,1H,NH),5.80(s,2H,triazol-CH2),3.70(s,1H),3.52(s, 2H, N-CH2),2.80(s,2H),2.11(s,6H),1.85-1.60(m,4H),1.42–1.31(m,2H).13C NMR (100MHz, DMSO-d6)δ162.4,153.4,139.7,134.3,133.8,133.2,133.0,129.8,124.9, 119.0,117.4,111.6, 109.0,52.9,52.3,51.3,39.6,31.5,16.2.ESI-MS:m/z 596.4[M+1 ]+.C30H29N9O3S(595.21).
3,5- dimethyl-((2- ((1- ((1- (2- methylbenzyls) -1H-1,2,3- triazole-4-yls) methyl) piperidines -4- Base) amino) thieno [3,2-d] pyrimidine-4-yl) oxygroup) benzonitrile (A4)
White solid, yield 88%, 114-116 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6-thienopyrimidine-H),7.91(s,1H,triazol-H),7.71(s,2H,C3,C5-Ph”-H), 7.28-7.18 (m, 4H), 7.05 (d, J=7.4Hz, 1H), 6.87 (s, 1H, NH), 5.58 (s, 2H, triazol-CH2), 3.68(s,1H),3.52(s,2H, N-CH2),2.77(s,2H),2.30(s,3H),2.11(s,6H),1.90–1.39(m, 6H).13C NMR(100MHz, DMSO-d6)δ162.4,153.4,136.6,134.8,133.2,130.8,128.9,128.7, 126.7,124.9,119.0,117.4, 111.6,109.0,53.0,52.3,51.3,39.6,31.5,19.1,16.2.ESI- MS:m/z 565.6[M+1]+.C31H32N8OS (564.24).
3,5- dimethyl-((2- ((1- ((1- (4- methylbenzyls) -1H-1,2,3- triazole-4-yls) methyl) piperidines -4- Base) amino) thieno [3,2-d] pyrimidine-4-yl) oxygroup) benzonitrile (A5)
White solid, yield 84%, 112-114 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6-thienopyrimidine-H),7.98(s,1H,triazol-H),7.71(s,2H,C3,C5-Ph”-H), 7.25–7.12(m, 5H),6.87(s,1H,NH),5.51(s,2H,triazol-CH2),3.68(s,1H),3.50(s,2H,N- CH2),2.76(s,2H), 2.28(s,3H),2.11(s,6H),1.87–1.62(m,3H),1.50–1.39(m,3H).13C NMR (100MHz, DMSO-d6)δ162.4,153.4,139.4,137.8,134.3,133.6,133.2,129.7,128.3, 124.9,119.0,117.8, 109.0,52.9,52.3,31.5,21.1,16.2.ESI-MS:m/z 565.6[M+1]+ .C31H32N8OS(564.24).
4- ((4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxies) thieno [3,2-d] pyrimidine -2-base) amino) piperazines Pyridine -1- bases) methyl) -1H-1,2,3- triazol-1-yls) methyl) benzsulfamide (A6)
White solid, yield 93%, 186-188 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6- thienopyrimidine-H), 8.07 (s, 1H, triazol-H), 7.82 (d, J=8.2Hz, 2H, C3, C5-Ph’-H),7.72(s, 2H,C3,C5- Ph "-H), 7.46 (d, J=8.0Hz, 2H, C2,C6-Ph’-H),7.38(s,2H, SO2NH2),7.26(s,1H, C7-thienopyrimidine-H),6.87(s,1H,NH),5.67(s,2H,triazol- CH2),3.69(s,1H),3.52(s,2H, N-CH2),2.76(s,2H),2.11(s,6H),1.89–1.52(m,4H),1.46– 1.22(m,2H).13C NMR(100MHz, DMSO-d6)δ162.4,153.4,144.5,144.2,140.4,139.4,133.2, 133.0,129.8,128.7,126.5,124.5, 119.0,117.6,112.1,109.0,53.1,52.5,52.4,39.6, 31.6,16.2.ESI-MS:m/z 530.5[M+1]+. C30H31N9O3S2(629.20).
4- ((4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxies) thieno [3,2-d] pyrimidine -2-base) amino) piperazines Pyridine -1- bases) methyl) -1H-1,2,3- triazol-1-yls) methyl) benzamide (A7)
White solid, yield 91%, 200-202 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6- thienopyrimidine-H), 8.05 (s, 1H, triazol-H), 7.86 (d, J=8.0Hz, 2H, C2, C6-Ph’-H),7.71(s, 2H,C3,C5-Ph”-H),7.40(s,1H,CONH2), 7.34 (d, J=8.0Hz, 2H, C3,C5- Ph’-H),7.27(s,1H, C7-thienopyrimidine-H),6.87(s,1H,NH),5.63(s,2H,triazol-CH2), 3.69(s,1H),3.51(s,2H, N-CH2),2.77(s,2H),2.11(s,6H),1.91–1.72(m,3H),1.51–1.23 (m,3H).13C NMR(100MHz, DMSO-d6)δ167.8,165.4,162.8,153.1,144.5,139.7,134.4, 133.2,133.0,128.3,128.0,126.1, 124.4,119.0,117.1,112.5,109.8,53.12,52.7,52.4, 39.6,31.6,16.2.ESI-MS:m/z 594.6[M+1]+. C31H31N9O2S(593.23).
2- (4- ((4- ((4- (4- cyano -2,6- dimethyl phenoxies) thieno [3,2-d] pyrimidine -2-base) amino) piperazines Pyridine -1- bases) methyl) -1H-1,2,3- triazol-1-yls)-N- (4- (methyl sulphonyl) phenyl) acetamide (A8)
White solid, yield 93%, 173-175 DEG C of fusing point.1H NMR(400MHz,DMSO-d6)δ10.93(s,1H, ), CONH 8.20 (d, J=5.4Hz, 1H, C6-thienopyrimidine-H),8.00(s,1H,triazol-H),7.90(d,J =8.7 Hz, 2H, C3,C5- Ph '-H), 7.82 (d, J=8.7Hz, 2H, C2,C6-Ph’-H),7.72(s,2H,C3,C5-Ph”- H),7.28(s, 1H,C7-thienopyrimidine-H),6.88(s,1H,NH),5.38(s,2H,triazol-CH2), 3.62–3.48(m,3H),3.18 (s,3H),2.85–2.82(m,2H),2.11(s,6H),1.91–1.55(m,4H),1.43– 1.17(m,2H).13C NMR(100 MHz,DMSO-d6)δ165.7,162.4,153.4,143.3,140.3,139.8,135.6, 133.2,128.8,126.5,124.5, 119.5,117.1,112.5,109.8,52.6,52.3,44.2,39.4,31.6, 16.2.ESI-MS:m/z 672.3[M+1]+. C32H33N9O4S2(671.21).
3,5- dimethyl -4- ((2- ((1- ((1- (2- morpholino -2- oxoethyls) -1H-1,2,3- triazole-4-yls) first Base) piperidin-4-yl) amino) thieno [3,2-d] pyrimidine-4-yl) oxygroup) benzonitrile (A9)
White solid, yield 93%, 228-230 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6-thienopyrimidine-H),7.84(s,1H,triazol-H),7.72(s,2H,C3,C5-Ph”-H), 7.27(s,1H, C7-thienopyrimidine-H),6.87(s,1H,NH),5.44(s,2H,triazol-CH2),3.64(d, J=4.8Hz, 2H), 3.59-3.52 (t, J=4.9Hz, 3H), 3.53 (d, J=5.2Hz, 4H), 3.46 (d, J=4.8Hz, 2H),2.79(s,2H),2.11(s, 6H),1.90–1.51(m,4H),1.47–1.23(m,2H).13C NMR(100MHz, DMSO-d6)δ165.0,162.3, 153.7,143.3,140.3,139.8,135.6,133.2,125.8,117.5,112.1, 109.6,66.4,66.3,53.1,52.3,50.9, 45.1,42.3,31.6,16.2.ESI-MS:m/z 588.5[M+1]+ .C29H33N9O3S(587.24).
3,5- dimethyl -4- ((2- ((1- ((1- (2- oxos -2- (pyrrolidin-1-yl) ethyl) -1H-1,2,3- triazoles - 4- yls) methyl) piperidines -4- bases) amino) thieno [3,2-d] pyrimidine-4-yl) methyl) benzonitrile (A10)
White solid, yield 91%, 219-221 DEG C of fusing point.1H NMR(400MHz,DMSO-d6) δ 8.20 (d, J= 5.4Hz, 1H,C6-thienopyrimidine-H),7.84(s,1H,triazol-H),7.72(s,2H,C3,C5-Ph”-H), 7.27(s,1H, C7-thienopyrimidine-H),6.87(s,1H,NH),5.31(s,2H,triazol-CH2),3.69(s, 1H), 3.52 (t, J=6.8 Hz, 4H), 3.51-3.47 (s, 2H, N-CH2),3.40–3.24(m,4H),2.79(s,2H), 2.11(s,6H),2.02–1.62(m, 4H),1.53–1.39(s,2H).13C NMR(100MHz,DMSO-d6)δ164.2, 162.1,153.0,143.6,140.1, 139.5,135.6,133.2,133.0,125.7,119.0,53.0,52.3,51.6, 46.2,45.5,39.6,31.6,26.0,24.1,16.2. ESI-MS:m/z 572.5[M+1]+.C29H33N9O2S(571.25).
Embodiment 5：The external HIV-resistant activity test experiments of target compound
Test philosophy：
The screening of Compound ira vitro HIV-resistant activity uses mtt assay.MTT full name are bromination -3- (4,5- dimethyl -2- thiazoles Base) -2,5- diphenyltetrazoliumbromide nitrogen, it can be used for detecting the survival and growth of cell.Testing principle is：MTT can be with cell living Interior succinate dehydrogenase combines the bluish violet crystallization first a ceremonial jade-ladle, used in libation for being reduced to water-insoluble to be deposited in cell, and dead cell has no this Function.Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, and detecting its absorbance (A) value at 540nm with microplate reader can be with The indirectly quantity of reflection living cells.Within the scope of certain cell number, it is directly proportional to cell number that MTT crystallizes the amount to be formed.
Since lesion can occur for (5-7 days) within a certain period of time for the MT-4 cells of HIV infection, to HIV infection The compound solution to be detected of debita spissitudo is added in MT-4 cell suspensions, through after a period of time after the culture of (5-7 days), With MTT assay MT-4 cell viabilities, drug concentration EC of 50% cell of protection from cytopathy is obtained50, simultaneously Make the concentration C C of the 50% cell generation lesion for being uninfected by HIV to target compound50, calculate selection coefficient S I (SI= CC50/EC50)。
Test material and method：
(1)HIV-1(IIIB), HIV-2 (ROD) strain, HIV-1 double-mutant strains RES056：It is cured by Belgian Univ Louvain Rega research institutes of institute provide.
(2) MT-4 cells：It is provided by Belgian Rega research institutes of medical college of Univ Louvain.
(3)MTT：Purchased from Sigma Co., USA.
(4) sample treatment：Sample is dissolved in DMSO and is made into debita spissitudo before use, is used in combination distilled water to make 5 times and dilutes, each 5 Dilution.
(5) positive control drug：Nevirapine (NVP) and etravirine (ETV).
(6) test method：It is added in HIV infection MT-4 cell suspensions after sample dilution, uses after a period of time MTT colorimetric method for determining cell viabilities calculate EC with absorbance (A) value being recorded in microplate reader under 540nm50, CC50With And SI.
(7) MTT colorimetric methods：After sample solution culture for a period of time is added, MTT solution (5mg/mL) 20 μ is added to every hole L continues after cultivating several hours, abandons dyeing liquor, and 150 μ L DMSO are added to every hole, is measured under 540nm in microplate reader Absorbance (A) value.
Experimental method：
50 μ L contain 1 × 10496 porocyte culture plates are added in MT-4 cell culture fluids, and -1 (III of 20 μ L infected by HIV is addedB, it is single Mutant strain or double-mutant strain) or HIV-2 (ROD) MT-4 cell suspensions or blank cultures, waiting for for various concentration is added It surveys compound or positive control medicine solution, each concentration sets 3 multiple holes.Cell is in 5%CO2Atmosphere is cultivated 5 days at 37 DEG C, 20mL (5mg/mL) MTT solution is added to every hole, continues culture 2 hours, DMSO is then added, measures reaction solution in 540nm The trap at place calculates the cell proliferation rate P% under compound various concentration.Blank and positive drug control group are set simultaneously, by Concentration (EC needed for the cytopathy that this cell for calculating compound protection 50% is induced from HIV50), make 50% to be uninfected by HIV Cell occur lesion concentration (CC50).Select the calculating of index：SI=CC50/EC50。
Carry out cell to the Diarylmiazines derivatives of part ring containing triazole of synthesis according to above-mentioned experimental method Horizontal anti-HIV-1 (IIIB) and double-mutant strain RES056 (K103N/Y181C) screening active ingredients, Activity Results such as 1 institute of table Show.
Diarylmiazines class compound HIV-resistant activity, toxicity and the selection index of 1. part ring containing triazole of table
aEC50:Inhibit 50% virus infection of compound concentration or protection of the cause cell mutation effect of 50% virus induction Cell from cytopathy compound concentration.
bCC50：Make 50% cell for being uninfected by HIV that the concentration of lesion occur.
cSI:Select coefficient, CC50/EC50Ratio.

Claims (5)

1. the Diarylmiazines HIV-1 inhibitor or its pharmaceutically acceptable salt, feature of a kind of ring containing triazole exist In with structure shown in general formula I：
Wherein,
X is：O or MH；
R is：CH3, CN or CH=CHCN；
R1For：Phenyl or pyridyl group；Or halogen, SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、COOH、 CH2OH、CO2Me、OCH3、NHCOCH3Substituted phenyl；Substituent group is o-, m-, contraposition is monosubstituted or polysubstituted；Or CONR2；
Wherein, R2For：Phenyl；Or halogen, SO2NH2、SO2CH3、CONH2、NO2、CN、NH2、CF3、NHCH3、OH、COOH、CH2OH、 CO2Me、OCH3、NHCOCH3Substituted phenyl；Substituent group is o-, m-, contraposition is monosubstituted or polysubstituted；It is five-ring heterocycles, hexa-atomic miscellaneous Ring.
2. the Diarylmiazines HIV-1 inhibitor of the ring containing triazole as described in claim 1, which is characterized in that be following One of compound：
3. the preparation method of the Diarylmiazines HIV-1 inhibitor of the ring containing triazole as described in claim 1, step packet It includes：With thieno [3,2-d] pyrimidine 1 of 2,4- dichloros substitution for initial feed, first in n,N-Dimethylformamide solution Intermediate 2 is generated with fortified phenol or aniline nucleo philic substitution reaction；Then intermediate 2 and N-Boc-4- amino piperidines are through nucleophilic Substitution reaction generates intermediate 3, and then sloughs Boc in trifluoroacetic acid and protect to obtain intermediate 4；Then 4 react with propargyl bromide Key intermediate 5 is generated, and then nitrine-end alkynes cycloaddition reaction (CuAAC of monovalence copper catalysis occurs with azide substitution base Click target product compound of formula I) is obtained by the reaction；Synthetic route is as follows：
Reagent and condition:(i) fortified phenol or aniline, n,N-Dimethylformamide, potassium carbonate, room temperature；(ii) N-Boc-4- ammonia Phenylpiperidines, n,N-Dimethylformamide, potassium carbonate, 110 DEG C；(iii) dichloromethane, trifluoroacetic acid, room temperature；(iv) propargyl bromide, N,N-Dimethylformamide, potassium carbonate, room temperature；(v) vitamine C sodium, cupric sulfate pentahydrate, n,N-Dimethylformamide, water, nitrine Substituent group, 50 DEG C；
X、R、R1Shown in claim 1 formula of I；
The fortified phenol or aniline be：Mesitylene phenol, 2,6- dimethyl -4- cyanophenols, 2,6- dimethyl -4- (E)-vinyl phenol, trimethyl aniline, 2,6- dimethyl -4- cyano-anilines, 2,6- dimethyl -4- (E)-cyano second Alkenyl aniline；
The azide substitution base is：O-chlorobenzyl nitrine, m-chloro benzyl azide, p-chlorobenzyl nitrine, adjacent bromobenzyl nitrine, Bromobenzyl nitrine, to bromobenzyl nitrine, adjacent luorobenzyl nitrine, luorobenzyl nitrine, folded to luorobenzyl nitrine, 2,4- difluorobenzyls Nitrogen, o-cyanobenzyl nitrine, cyanobenzyls nitrine, is folded cyanobenzyls nitrine, adjacent nitro benzyl 3,4- difluorobenzyls nitrine Nitrogen, nitrobenzyl nitrine, to nitrobenzyl nitrine, O-methoxy benzyl azide, meta-methoxy benzyl azide, to methoxybenzyl Base nitrine, to methanesulfonylbenzyl nitrine, methanesulfonylbenzyl nitrine, adjacent methanesulfonylbenzyl nitrine, to sulfoamido benzyl Base nitrine, sulfoamido benzyl azide, adjacent sulfoamido benzyl azide, to formamido benzyl azide, formamido benzyl Base nitrine, adjacent formamido benzyl azide benzyl, 2- azidos -1- (pyrrolidin-1-yl) second -1- ketone, 2- azido-N- cyclopropyl Acetamide, 2- azido -1- morpholine -1- ketone.
4. the Diarylmiazines HIV-1 inhibitor of the ring containing triazole as described in right wants 1 or 2 is preparing anti-AIDS drug In application.
5. a kind of anti-AIDS pharmaceutical composition, including right want the Diarylmiazines HIV- of the ring containing triazole described in 1 or 2 1 inhibitor and one or more pharmaceutically acceptable carriers or excipient.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369623A (en) * 2018-12-14 2019-02-22 山东大学 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof
CN110066273A (en) * 2019-06-05 2019-07-30 山东大学 A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and the preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926829A (en) * 2015-06-08 2015-09-23 山东大学 Thieno miazines derivatives and preparation method and application thereof
CN106117242A (en) * 2016-06-27 2016-11-16 山东大学 Tetrahydric thiapyran miazines derivative and preparation method and application
CN104530078B (en) * 2015-01-27 2017-03-22 山东大学 Thieno [3, 2-d] pyrimidine derivative and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530078B (en) * 2015-01-27 2017-03-22 山东大学 Thieno [3, 2-d] pyrimidine derivative and preparation method and application thereof
CN104926829A (en) * 2015-06-08 2015-09-23 山东大学 Thieno miazines derivatives and preparation method and application thereof
CN106117242A (en) * 2016-06-27 2016-11-16 山东大学 Tetrahydric thiapyran miazines derivative and preparation method and application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369623A (en) * 2018-12-14 2019-02-22 山东大学 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof
CN110066273A (en) * 2019-06-05 2019-07-30 山东大学 A kind of single arylpyrimidines HIV-1 reverse transcriptase inhibitor of the ring containing triazole and the preparation method and application thereof

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