CN106831605A - A kind of substituted diaryl pyridine derivatives and preparation method and application - Google Patents

A kind of substituted diaryl pyridine derivatives and preparation method and application Download PDF

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CN106831605A
CN106831605A CN201710112835.XA CN201710112835A CN106831605A CN 106831605 A CN106831605 A CN 106831605A CN 201710112835 A CN201710112835 A CN 201710112835A CN 106831605 A CN106831605 A CN 106831605A
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substituted
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dmf
potassium carbonate
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CN106831605B (en
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刘新泳
周忠霞
展鹏
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Shandong University
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    • 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
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a kind of diaryl pyrimidine derivative and its preparation method and application.The substituted diaryl pyrimidine derivatives or its pharmaceutically acceptable salt or prodrug, with the structure shown in below formula I or II, the application in treating and preventing human immunodeficiency virus (HIV) medicine is being prepared present invention additionally comprises the preparation method of substituted diaryl pyrimidine derivatives and the composition containing one or more such compounds.

Description

A kind of substituted diaryl pyridine derivatives and preparation method and application
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of substituted diaryl pyridine derivatives, the present invention is also related to And the application of preparation method and its anti human immune deficiency virus (HIV) inhibitor of this analog derivative.
Background technology
AIDS (AIDS) is a kind of disease for destroying human immune system and serious harm human life and health, by infecting Inhibition of HIV causes.In anti-AIDS drug, HIV-1 non-nucleoside reverse transcriptase inhibitors (Non-nucleoside Reverse Transcriptase Inhibitors, NNRTIs) sent out the advantages of its strong selectivity, high activity, hypotoxicity Wave key effect.But due to the variability of HIV-1 viruses, frequently occur a disaster of the antibody-resistant bacterium as clinical treatment Topic.Additionally, NNRTIs occurs in clinical drug therapy, and drug resistance is poor, toxic and side effect is strong and pharmacokinetics is poor asks Topic limits its clinical practice to a certain extent.Therefore, exploitation anti-drug resistance strong new and effective low toxicity, pharmacokinetics The good NNRTIs of matter is the focus and vital task of current AIDS research.
DAPY (Diarylpyrimidines) inhibitor is the newfound structure of a class with good flexible NNRTIs, it has inhibitory activity very high to wild type and the HIV-1 of mutation viruses.The part of compounds pair for having synthesized at present The activity of mutant strain reaches nanomolar range, and has two medicines --- etravirine etrivirine (TMC-125) and a sharp Wei Woods rilpivirine (TMC-278) has been listed.They have suppression very high as the NNRTIs of a new generation to various persisters System activity, but relatively low water-soluble and poor permeable membrane causes, and its bioavilability is low, oral dose is increased, and causes malicious secondary work With and the problems such as crossing drug resistant.For example, etravirine needs to be administered for multiple daily, and along with serious cutaneous anaphylaxis. Rilpivirine medicine increases for property, but still suffers from the poison such as depression, insomnia, ARDS, headache and fash Side effect, limits its extensive use.Therefore, efficient, wide spectrum overriding resistance is researched and developed and with good pharmacokinetic property NNRTIs is one of key areas of preceding anti-AIDS drug research.
The content of the invention
The present invention is in view of the shortcomings of the prior art, there is provided a kind of substituted diaryl pyridine derivatives and preparation method thereof, Present invention also offers the Anti-HIV-1 Active the selection result of substituted diaryl pyridine derivatives and its in antiviral field Using.
Technical scheme is as follows：
1. substituted diaryl pyridine derivatives
A kind of substituted diaryl pyridine derivatives involved in the present invention, or its pharmaceutically acceptable salt, ester or preceding Medicine, with the structure shown in below formula I or II：
Wherein,
X is O or NH；
N=0 or 1；
R1For：Alkynyl or alkenyl that side is directly connected with phenyl ring, its opposite side are cyclopropyl, phenyl ring, substituted benzene ring, take For naphthalene nucleus, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substituted hexa-atomic and five-ring heterocycles, various take The hexa-atomic and hexa-member heterocycle in generation, various substituted five yuan and five-ring heterocycles, various substituted benzo five-membered heterocycles or various substitutions Benzo hexa-member heterocycle and various different lengths hydrocarbon chain structure；
R2, R3It is independently each：H, halogen, cyano group, C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, trifluoromethyl, Amino or hydroxyl vinyl；
R4For：Substituted benzene ring, substitution naphthalene nucleus, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substitutions Hexa-atomic and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, various substituted Benzo five-membered heterocycle or various substituted benzo hexa-member heterocycles.
According to currently preferred,
R1It is the phenyl ring with general formula III or IV, cyclopropyl, monosubstituted phenyl ring, disubstituted phenyl ring, unsubstituted phenyl ring or pyrrole Pyridine ring, substituted pyridines ring, hydrocarbon chain；
Wherein,
R5It is H2NC6H4、HOOCC6H4、C5NH4、C3H5、OH、C6H5、CONHC6H4Or F3CC6H4；
R6It is C6H5Or CH3C6H4。
According to currently preferred,
R4It is the substituted benzene ring with formula V；
Wherein, R7It is SO2NH2、CONH2Or CN.
Heretofore described " pharmaceutically acceptable salt " refers to the salt of compound in reliable medicine range of value Class is suitable to be in contact and without unsuitable toxicity, stimulation and allergic reaction etc. with people or compared with the tissue of lower animal, with suitable Rational income/risk ratio, typically water or oil are solvable or dispersible, and are effectively used for its expected purposes. Including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts, be herein can do expected purposes and with Formulas I, the chemical property of II compounds are compatible.The list of suitable salt referring to S.M.Birge etc., J.Pharm.Sci., 1977, 66,1-19 pages.
Heretofore described " prodrug " refers to pharmaceutically acceptable derivates, so as to the biology obtained by these derivatives Transformation product is the active medicine as defined in Formulas I, II compounds.
According to the present invention it is further preferred that the substituted diaryl pyridine derivatives shown in formula I or II are with One of compound of row formula：
Wherein, R2、R3、R4、R5、R6With shown in above-mentioned formula I or II.
According to the present invention it is further preferred that the substituted diaryl pyridine derivatives shown in formula I or II are followingization One of compound：
2. the synthetic route and preparation method of substituted diaryl pyridine derivatives
The preparation method of substituted diaryl pyridine derivatives, step is as follows：With compound 1 as initiation material, with 4- ammonia Base cyanophenyl carries out frit reaction in 180 DEG C, and intermediate 2 and the POCl3 of generation flow back under the conditions of 100 DEG C and generate intermediate 3；Raw material 4 makees catalyst in cuprous iodide and double (triphenylphosphine) palladium chlorides, triethylamine do under conditions of alkali with alkynyl substituted Yuan coupled reaction of intermediate Fa Sheng obtain the midbody compound 5 of alkynyl substituted, additionally, raw material 4 is under the conditions of palladium There is the intermediate 5 that He Ke reactions obtain alkenyl substitution with the intermediate that alkenyl replaces；Intermediate 3 makees molten with intermediate 5 in DMF Target product I obtained and substitution reaction in agent, the alkalescence condition of potassium carbonate there is；In addition, with intermediate 6 as initiation material and intermediate 5 are dissolved in DMF reacts obtain intermediate 7 at room temperature, and then intermediate 7 is in DMF With the reaction of N-Boc-4- amino piperidines and then under the conditions of trifluoroacetic acid, de- Boc radical protections generate key intermediate 9；Finally Under conditions of this key intermediate 9 does alkali in DMF solution with potassium carbonate, reacted with the fragrant halogen of various substitutions Generation target product II；
Synthetic route is as follows：
Reagent and condition：a：4- aminobenzonitriles, 180 DEG C, fusion method, 8h；b：POCl3,0.5h；c：Intermediate 5, carbon Sour potassium, DMF, 100 DEG C, 10h；d：(i) substitutedphenylethynyl, bi triphenyl phosphorus palladium chloride, cuprous iodide, Fortified phenol, triethylamine, tetrahydrofuran, 60 DEG C, 10h；(ii) substituted phenylethylene, palladium, Tol3Iodo- 2, the 6- dimethyl of P, 4- Phenol, caustic alcohol, DMA, 60 DEG C, 10h；e：Substitutedphenylethynyl, potassium carbonate, DMF, room Temperature；f：N-Boc-4- amino piperidines, potassium carbonate, DMF, 120 DEG C, 12h；g：Trifluoroacetic acid, dichloromethane, Room temperature, 5h；h：The fragrant halogen of substitution, potassium carbonate, DMF, room temperature.
R1、R2、R3、R4, n is with shown in above-mentioned formula I or II.
According to currently preferred, the preparation method of substituted diaryl pyridine derivatives, comprise the following steps that：
(1) in reaction bulb, nitrogen protection is warming up to 180 DEG C of reaction 8h to the p-aminophenyl nitrile of precise initiation material 1；Instead After answering completely, reactant is dissolved with acetonitrile, filter cake is washed in ultrasonically treated, filtering with acetonitrile, and solid is dried to obtain intermediate compound The crude product of thing 2；
(2) intermediate 2 accurately is weighed, is dissolved in POCl3, nitrogen protection, 100 DEG C of backflow 0.5h；After reaction terminates, Cooling reaction solution, reaction solution is slowly added dropwise in clean frozen water POCl3 is quenched, and after being stirred vigorously, filtering, precipitation is used Water dissolves, NaOH adjusts pH to be equal to 7, filters again, dry yellow solid；Acetone recrystallization, separates out solid and is centre The sterling of body 3；
(3) precise initiation material 4 is dissolved in tetrahydrofuran, sequentially adds acetylenic substitution base, double (triphenylphosphine) dichloros Change palladium, cuprous iodide, triethylamine, nitrogen protection, 60 DEG C of backflow 10h；After reaction terminates, reaction solution is filtered with diatomite, it is molten Liquid is extracted with saturated nacl aqueous solution, and filtrate mixes sample after being evaporated, post separation obtains intermediate 5；When raw material is that alkenes replace base, will Itself and intermediate 4, palladium, Tol3P, monoethanolamine are dissolved in DMA, are warming up to 60 DEG C of reaction 10h；Reaction knot Shu Hou, solvent under reduced pressure is evaporated, and intermediate 5 is obtained with ethyl acetate/petroleum ether system post separation；
(4) accurate intermediate 3, intermediate 5 and the potassium carbonate of weighing is dissolved in DMF, 100 DEG C of reaction 10h；After reaction terminates, mistake Filter, filtrate is evaporated, and post separation obtains target product I after recrystallization from ethyl acetate/petroleum ether；
(5) accurately weighing intermediate 6, intermediate 5 and potassium carbonate is dissolved in DMF, room temperature reaction 10h；After reaction terminates, mistake Filter, evaporated under reduced pressure, post separation obtains intermediate 7；
(6) to N-Boc-4- amino piperidines, potassium carbonate is added in the DMF solution of intermediate 7, heat up To 120 DEG C of reaction 12h；After reaction cooling, frozen water is added dropwise to reaction solution, suspension is filtrated to get the crude product of intermediate 8；
(7) intermediate 8 for obtaining upper step is dissolved in dichloromethane, is slowly added dropwise trifluoroacetic acid, and 5h, reaction knot is stirred at room temperature Shu Houyong saturated sodium bicarbonates adjust pH to 10, and dichloromethane extraction dries the isolated intermediate 9 of rear pillar；
(8) key intermediate 9 and the fragrant halogen of substitution are dissolved in DMF, add potassium carbonate, be stirred at room temperature Night；Reaction terminates, mixed liquor evaporated under reduced pressure, is extracted with ethyl acetate three times, three organic layers of saturated common salt water washing, dries, Filtering is evaporated, post separation, and target product II is obtained after recrystallization from ethyl acetate/petroleum ether.
Room temperature of the present invention refers to 20-30 DEG C.
3. the anti-HIV-1 wild strain of substituted diaryl pyridine derivatives and mutant strain activity and application
Part substituted diaryl pyridine derivatives to synthesizing according to the method described above have carried out the anti-HIV-1 of cellular level (IIIB), single medicament-resistant mutation strain L100I, K103N, Y181C, Y188L and double medicament-resistant mutations strain RES056 (K103N/ Y181C), the screening active ingredients of F227L/V106A.Additionally, the compound of synthesis has also carried out the test of reverse transcriptase level；Wherein As shown in table 1, substituted diaryl pyridine derivatives have significant Anti-HIV-1 Active, and all chemical combination to HIV-resistant activity result The EC of thing50Value all reaches nanomole or sub- nanomolar range, wherein having 8 compounds (IA-1-3, IA-1-4, IA-1-5, IA-1- 6th, IA-1-8) to wild strain activity up to units nanomole level；And compound has to persister (E138K, K103N, L100I) There is significant inhibitory action (table 2), part of compounds reaches nanomolar range.Therefore substituted diaryl pyridine derivatives have Further the value of research and development, can be used as the lead compound of anti-HIV-1.
Substituted diaryl pyridine derivatives of the invention can be used as non-nucleoside HIV-1 inhibitor applications.Specifically, It is used to prepare anti-AIDS drug as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition, including substituted diaryl pyridine derivatives of the invention and one or more Pharmaceutically acceptable carrier or excipient.
The invention provides the brand-new substituted diaryl pyridine derivatives of structure, its preparation method, its Anti-HIV-1 Active The selection result and its first Application in antiviral field.Test proves that, substituted diaryl miazines of the invention spreads out Biology can be as the application of HIV-1 inhibitor and with application value very high.Specifically, it is used to make as HIV-1 inhibitor Standby anti-AIDS drug.
Specific embodiment
Contribute to understand the present invention by following examples, but present disclosure can not be limited.
Involved synthetic route is as follows in embodiment：
Synthetic route one：
Synthetic route two：
Embodiment 1：The preparation of intermediate 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile
The preparation of 4- ((4- oxo -1,6- dihydro-pyrimidin -2- bases) amino) benzonitrile (2)
Weigh 2- (methyl mercapto) pyrimidine -4 (3H) -one (3g, 21mmol) and 4- anthranilo nitriles (2.99g, 25mmol) in 50mL round-bottomed flasks, nitrogen protection, are slowly warmed up to 180 DEG C, react 8h.After reaction cooling, add 20mL acetonitriles ultrasonically treated, Filtering, filter cake is washed with acetonitrile, and TLC detections obtain faint yellow solid as 4- without 4- anthranilo nitriles residual, dry cake ((4- oxo -1,6- dihydro-pyrimidin -2- bases) amino) benzonitrile, yield 73.6%, ESI-MS:m/z 213.3[M+H]+, C11H8N4O(212.12).
The preparation of intermediate 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile
4- ((4- oxo -1,6- dihydro-pyrimidin -2- bases) amino) benzonitrile (0.80g, 3.8mmol) accurately is weighed, is added 5mL POCl3s, 100 DEG C are stirred at reflux 0.5h.After reaction cooling, mixture is slowly dropped in 50mL mixture of ice and water, Fierce stirring, filtering, the filter cake for obtaining is re-dissolved in water, is filtered again after adjusting pH to 7 with NaOH, is dried to obtain yellow Solid is 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile.Yield：71.3%；1H NMR(400MHz,DMSO-d6)δ10.58 (s, 1H), 8.55 (d, J=5.2Hz, 1H, C6-pyrimidine-H), 7.87 (dd, 4H, Ph-H), 7.13 (d, J=5.2Hz, 1H,C6-pyrimidine-H)；EI-MS:231.2[M+H]+,C11H7ClN4(230.04).
Embodiment 2：The preparation of target compound
The preparation of 4- ((3- aminophenyls) acetenyl) -2,6- xylenols
Weigh 3- amino phenylacetylene (0.1g, 0.85mmol), iodo- 2, the 6- xylenols (0.254g, 1.0mmol) of 4-, Bi triphenyl phosphorus palladium chloride (0.0359g, 0.51mmol), cuprous iodide (0.0195g, 1.0mmol), triethylamine (0.06g, Anhydrous tetrahydro furan 0.6mol) is dissolved in, reaction solution after 60 DEG C of reaction 10h, TLC detection reactions terminate, is used diatom by nitrogen protection Soil filtering, evaporated under reduced pressure, to addition 30mL ethyl acetate in remaining substrate, the saturated common salt aqueous solution is washed 3 times, each 10mL, Divide and take organic layer, anhydrous sodium sulfate drying, filtering, concentration.The isolated intermediate 4- of rapid column chromatography ((3- aminophenyls) second Alkynyl) -2,6- xylenols.
The preparation of 4- ((4- (4- ((3- aminophenyls) acetenyl) -2,6- dimethyl phenoxies) pyrimidine -2-base) amino)
4- ((3- aminophenyls) acetenyl) -2,6- xylenols (0.05g, 0.21mmol) are weighed, ((4- chlorine is phonetic for 4- Pyridine -2- bases) amino) benzonitrile (0.049g, 0.21mmol), potassium carbonate (0.035g, 0.25mmol) is dissolved in N, N- dimethyl methyls Acid amides, 100 DEG C of reaction 10h.Reaction terminates, evaporated under reduced pressure solvent, then to addition 30mL ethyl acetate, saturation in remaining substrate Common salt aqueous solution is washed 3 times, each 10mL, is divided and is taken organic layer, anhydrous sodium sulfate drying, filtering, concentration.Rapid column chromatography is separated Target compound is obtained, and then target compound IA-1-1 is recrystallized to give in ethyl acetate-light petrol system.
Product is yellow powder, yield：70%, fusing point：180-183℃.
1HNMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.48 (d, J=5.7Hz, 1H, C6-pyrimidine- ), H 7.63 (d, J=8.5Hz, 2H, Ph-H), 7.51 (d, J=8.8Hz, 2H, Ph-H), 7.42 (s, 2H, Ph-H), 7.07 (t, J =7.8Hz, Ph-H), 6.76 (t, J=1.9Hz, 1H, Ph-H), 6.70 (dt, J=7.5,1.2Hz, 1H, Ph-H), 6.60- 6.67 (m, 2H, C5-pyrimidine-H, Ph-H), 5.26 (s, 2H, NH2), 2.09 (s, 6H, 2CH3)；13C NMR(100MHz, DMSO)δ168.83,160.85,159.64,150.19,149.30,145.05,133.05,132.14,131.68,129.69, 122.96,120.50,119.85,119.32,118.75,116.63,115.09,102.99,99.37,90.37,87.83, 16.30；ESI-MS:432.5[M+H]+.C27H21N5O(431.50).
Operate ibid, except that using 4- ((4- hydroxyl -3,5- 3,5-dimethylphenyls) acetenyl) benzoic acid.
Product is pale yellow powder, yield：67%, fusing point:273-281℃.
1H NMR(400MHz,DMSO-d6)δ13.10(s,1H,carbonyl-H),10.16(s,1H,NH),8.49(d,J =5.7Hz, 1H, C6-pyrimidine-H), 7.99 (d, 2H, Ph-H), 7.69 (d, 2H, Ph-H), 7.62 (d, J=8.5Hz, 2H, Ph-H), 7.51 (m, 4H, Ph-H), 6.66 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.10 (s, 6H, 2CH3) ；13C NMR(100MHz,DMSO)δ168.77,167.15,160.90,159.62,150.76,145.02,133.04,132.44, 131.94,131.06,130.06,127.09,119.84,119.68,118.74,103.01,99.37,91.96,88.73, 16.31；ESI-MS:459.4[M-H]﹣.C28H20N4O3(460.49).
Operate ibid, except that using 2,6- dimethyl -4- (pyridin-3-yl acetenyl) phenol.
Product is white crystal, yield：89%, fusing point：220-223℃.
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H, NH), 8.78 (dd, J=2.2,0.9Hz, 1H, ), pyridine-H 8.61 (dd, J=4.9,1.7Hz, 1H, pyridine-H), 8.49 (d, J=5.6Hz, 1H, C6- ), pyrimidine-H 8.00 (dt, J=7.9,1.9Hz, 1H, pyridine-H), 7.61 (d, J=8.6Hz, 2H, Ph-H), 7.46-7.54 (m, 5H, Ph-H, pyridine-H), 6.67 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.10 (s, 6H, 2CH3)；13C NMR(100MHz,DMSO)δ168.76,160.92,159.62,152.04,150.76,149.48, 145.01,138.96,133.05,132.40,131.91,124.13,119.90,119.84,119.59,118.75,103.01, 99.37,92.28,86.25,16.31；ESI-MS:418.5[M+H]+.C26H19N5O(417.47).
Operate ibid, except that using 2,6- dimethyl -4- (pyridine -2- ethyl-acetylenes base) phenol.
Product is white crystal, yield：86%, fusing point：213-216℃.
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.63 (dd, J=4.9,1.8,1.0Hz, 1H, ), pyridine-H 8.49 (d, J=5.7Hz, 1H, C6-pyrimidine-H), 7.87 (td, J=7.8,1.8Hz, 1H, ), pyridine-H 7.66 (dt, J=7.8,1.1Hz, 1H, pyridine-H), 7.62 (d, J=8.6Hz, 2H, Ph-H), 7.51 (m, 4H, Ph-H), 7.43 (m, 1H, pyridine-H), 6.67 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.11 (s, 6H,2CH3)；13C NMR(100MHz,DMSO)δ168.76,160.91,159.62,150.91,150.66,145.02, 142.80,137.28,133.05,132.58,131.96,127.75,123.98,119.83,119.30,118.73,103.01, 99.40,89.13,88.34,16.32；ESI-MS:418.6[M+H]+.C26H19N5O(417.47).
Operate ibid, except that using (cyclopropyl acethlene base) -2,6- xylenols
Product is white crystal, yield：79%, fusing point：227-229℃.
1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6- ), pyrimidine-H 7.62 (s, 2H, Ph-H), 7.53 (m, 4H, Ph-H), 6.65 (d, J=5.6Hz, 1H, C5- pyrimidine-H),2.03(s,6H,2CH3)；0.92(m,1H,CH),0.85(m,2H,CH2),0.75(m,2H,CH2)；13C NMR(100MHz,DMSO)δ168.63,160.89,159.56,150.09,145.03,137.63,133.79,133.02, 119.85,118.73,102.97,99.38,91.06,16.00,13.41,0.52；ESI-MS:381.5[M+H]+.C24H20N4O (380.45).
Operate ibid, except that using 4- (4- hydroxyl butyl- 1- alkynes -1- bases) -2,6- xylenols
Product is yellow crystals, yield：49%, fusing point：181-183℃.
1H NMR(400MHz,DMSO-d6) δ 10.13 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6- ), pyrimidine-H 7.60 (d, J=8.6Hz, 2H, Ph-H), 7.49 (d, J=8.8Hz, 2H, Ph-H), 7.27 (s, 2H, Ph- ), H 6.62 (d, J=5.6Hz, 1H, C6-pyrimidine-H), 4.91 (t, J=5.6Hz, 1H ,-OH), 3.62 (q, J= 6.7Hz,2H,CH2), 2.58 (t, J=6.9Hz, 2H, CH2),2.04(s,6H,2CH3)；13C NMR(100MHz,DMSO)δ 168.83,160.82,159.62,149.72,145.03,133.03,132.14,131.38,121.12,119.84,118.71, 102.96,99.32,88.49,80.99,60.35,23.76,16.26；ESI-MS:385.5[M+1]+,402.5[M+NH3]+ .C23H20N4O2(384.22).
Operate ibid, except that using 2,6- dimethyl -4- (phenylene-ethynylene) phenol.
Product is pale yellow powder, yield：53% fusing point：198-201℃.
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H, NH), 8.48 (d, J=5.6Hz, 1H, C6- Pyrimidine-H), 7.55-7.66 (m, 4H, Ph-H), 7.51 (d, J=8.7Hz, 2H, Ph-H), 7.45 (d, J=5.9Hz, 5H, Ph-H), 6.66 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.09 (s, 6H, 2CH3)；13C NMR(100MHz, DMSO)δ168.80,160.89,159.63,150.42,145.03,137.64,133.79,133.04,132.25,131.78, 129.26,122.74,120.17,119.84,118.75,103.00,99.36,89.41,89.26,16.30；ESI-MS: 417.5[M+1]+.C27H20N4O(416.48).
Operate ibid, except that using N- (3- ((4- hydroxyl -3,5- 3,5-dimethylphenyls) acetenyl) phenyl) acetyl Amine.
Product is pale yellow powder, yield：41%, fusing point：251-252℃.
1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H, NH), 10.06 (s, 1H, NH), 8.48 (d, J=5.6Hz, 1H, C6-pyrimidine-H), 7.91 (t, J=1.8Hz, 1H, Ph-H), 7.63 (d, J=8.6Hz, 2H, Ph-H), 7.47- 7.57 (m, 5H, Ph-H), 7.36 (t, J=7.9Hz, 1H, Ph-H), 7.23 (dt, J=7.6,1.3Hz, 1H, Ph-H), 6.65 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.09 (s, 6H, 2CH3),2.07(s,3H,CH3)；13C NMR(100MHz, DMSO)δ169.03,168.81,160.86,159.64,150.42,145.03,140.07,133.06,132.28,131.77, 129.69,126.45,123.00,121.84,120.09,119.84,118.75,103.00,99.38,89.40,88.99, 24.52,16.30；ESI-MS:474.4[M+H]+,496.5[M+Na]+.C29H23N5O2(473.54).
Operate ibid, except that using 4- ((4- aminophenyls) acetenyl) -2,6- xylenols.
Product is brown ceramic powder, yield：63% fusing point：195-198℃.
H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.47 (d, J=5.6Hz, 1H, C6- ), pyrimidine-H 7.62 (d, J=8.6Hz, 2H, Ph-H), 7.51 (d, J=8.9Hz, 2H, Ph-H), 7.35 (s, 2H, Ph- ), H 7.22 (d, J=8.5Hz, 2H, Ph-H), 6.58 (d, J=8.5Hz, 2H, Ph-H), 6.63 (d, J=5.7Hz, 1H, C5- pyrimidine-H),5.59(s,2H,NH2),2.07(s,6H,2CH3)；13C NMR(100MHz,DMSO)δ168.89, 160.82,159.64,149.92,149.63,145.05,133.04,133.00,131.71,131.49,121.37,119.85, 118.74,114.16,108.67,102.97,99.33,91.34,86.35,16.30；ESI-MS:432.6[M+H]+ .C27H21N5O(431.50).
Embodiment 3：The preparation of target compound
The preparation of 2,6- dimethyl -4- styrylphenols
Weigh styrene (0.177g, 1.5mmol), iodo- 2, the 6- xylenols (0.248g, 1.0mmol) of 4-, palladium (0.0224g, 0.1mmol), Tol3P (0.091g, 0.3mmol), caustic alcohol (0.184g, 2.3mmol) in two-neck bottle, nitrogen DMA is added dropwise with constant pressure funnel under guard mode, 60 DEG C are warming up to, 10h is reacted, after reaction terminates, steams Dry solvent, quick post separation obtains the crude product of intermediate 5.
(E) -4- ((4- (2,6- dimethyl -4- styryls phenoxy group) pyrimidine -2-base) amino) benzonitrile
Operate with the preparation of IB-1-1, except that using 2,6- dimethyl -4- styrylphenols.
Product is white crystal, yield：38%, fusing point；222-224℃.
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.47 (d, J=5.6Hz, 1H, C6- ), pyrimidine-H 7.69-7.59 (m, 4H, Ph-H), 7.47 (d, J=8.4Hz, 4H, Ph-H), 7.40 (m, 2H, J= 16Hz,tran-CH2=CH2-), 7.32-7.25 (m, 3H, Ph-H), 6.63 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.10 (s, 6H, 2CH3)；13C NMR(100MHz,DMSO)δ169.08,160.71,159.69,149.45,149.33, 145.09,138.24,137.47,135.32,135.22,134.81,133.03,131.06,131.02,129.79,129.08, 128.96,128.81,127.99,127.40,127.30,127.20,127.16,126.84,124.21,119.83,118.73, 102.90,99.34,21.50,21.31,16.60,15.99；ESI-MS:419.3[M+H]+.C27H22N4O(418.50).
Operate ibid, except that using 2,6- dimethyl -4- (4- methyl styrenes base) phenol.
Product is light yellow crystal, yield：43% fusing point：212-214℃.
1H NMR (400MHz, DMSO-d6) δ 10.15 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6- Pyrimidine-H), 7.71-7.58 (m, 5H, Ph-H), 7.47 (d, J=7.7Hz, 5H), 7.40 (m, 2H, J=16Hz, tran-CH2=CH2-), 7.33-7.23 (m, 3H), 6.63 (d, J=5.7Hz, 1H, C5-pyrimidine-H), 2.11 (s, 6H, 2CH3)；13C NMR(100MHz,DMSO)δ169.07,160.73,159.69,149.49,145.09,137.58,135.16, 133.79,133.04,131.07,129.20,128.88,128.18,128.07,127.35,126.90,119.82,118.74, 102.90,99.36,16.60,15.99；ESI-MS:433.5[M+H]+.C28H24N4O(432.53).
Embodiment 4：The preparation of target compound
The system of (4- ((3- aminophenyls) acetenyl) -2,6- dimethyl phenoxies)-N- (piperidin-4-yl) pyrimidine -2- amine It is standby
Weigh Compound 2,4- dichloro pyrimidines (50.0mmol), 4- ((3- aminophenyls) acetenyl) -2,6- dimethyl benzenes Phenol (50.0mmol) in 10mL DMF, Anhydrous potassium carbonate (60.0mmol), under room temperature condition stir 10h (TLC detection reacted Finish).The isolated target compound of rapid column chromatography, and then crude product is recrystallized to obtain in ethyl acetate-light petrol system.Obtain Crude product (0.3g, 0.86mmol), N-Boc-4- amino piperidines (0.21g, 1.0mmol) and potassium carbonate (0.15g, 1.7mmol) In the DMF of 10mL, then it is heated to reflux 12 hours.Question response is cooled to after room temperature, at leisure will be anti- Answer drop to be added in the 20mL aqueous solution, stir, there are a large amount of solids to generate.Filtering, dry crude product 4- ((4- (4- ((3- aminobenzenes Base) acetenyl) -2,6- dimethyl phenoxies) pyrimidine -2-base) amino) piperidines -1- t-butyl formates.Weigh the crude product (0.60g, 1.5mmol) is dissolved in 5mL dichloromethane, and trifluoroacetic acid (0.74mL, 10mmol) is then added thereto at leisure, Stirred under room temperature condition 5 hours (TLC detection reactions are finished).To 10mL water is added in reaction solution, with the sodium bicarbonate water of saturation It is 10 that solution adjusts PH, dichloromethane extraction (3 × 5mL), and saturated aqueous common salt washing divides and takes organic layer, anhydrous sodium sulfate drying.So After carry out the isolated white solid of rapid column chromatography as compound (4- ((3- aminophenyls) acetenyl) -2,6- dimethyl Phenoxy group)-N- (piperidin-4-yl) pyrimidine -2- amine.
3- (4- ((4- (4- ((3- aminophenyls) acetenyl) -2,6- dimethyl phenoxies) pyrimidine -2-base) amino) piperazines Pyridine -1- bases) preparation
Weigh Compound 4- ((3- aminophenyls) acetenyl) -2,6- dimethyl phenoxies)-N- (piperidin-4-yl) pyrimidine - 2- amine (0.48mmol) adds Anhydrous potassium carbonate (0.13g, 0.96mmol) in 10mL DMF after stirring and dissolving under room temperature condition With the benzyl chloride or bromobenzyl (0.58mmol) of substitution, 12h is stirred under room temperature condition (TLC detection reactions are finished).Evaporated under reduced pressure solvent 30mL ethyl acetate, the saturated common salt aqueous solution is added to wash in backward remaining substrate 3 times, each 10mL divides and takes organic layer, anhydrous Sodium sulphate is dried, filtering, concentration.The isolated target compound of rapid column chromatography, and then in ethyl acetate-light petrol system It is recrystallized to give target compound IA-1-1.
Product is light yellow crystal, yield：43% fusing point：113-115℃.
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H,-NH2),7.89(s,1H,-NH2),7.48-6.94(m,8H, C6-pyrimidine-H,Ph-H),6.79-6.51(m,3H,Ph-H,C5-pyrimidine-H),6.15(s,1H,NH),5.24 (s,2H,NH2),3.53-3.92(m,4H,piperidine-H),2.86-2.63(m,1H,piperidine-H),2.07(s, 6H,2CH3),1.23(s,4H,piperidine-H),0.93-0.74(m,1H,piperidine-H).13C NMR(100MHz, DMSO)δ168.71,151.23,149.27,135.39,131.62,129.66,129.22,122.98,120.07,119.25, 117.98,116.56,60.22,48.22,29.48,22.56,21.23,16.37,14.56；ESI-MS:533.5[M+H]+ .C32H32N6O2(532.65).
Operate ibid, except that using 4- methylsulfonyl bromobenzyls.
Product is light yellow crystal, yield：43% fusing point：159-161℃.
1H NMR (400MHz, DMSO-d6) δ 8.15 (d, J=5.5Hz, 1H, C6-pyrimidine-H), 7.75 (s, 2H, Ph-H),7.43(s,2H,Ph-H),7.30(s,2H,Ph-H),7.29(s,2H,-SO2NH2), 7.06 (t, J=7.8Hz, 1H, Ph- ), H 6.72 (s, 1H, NH), 6.70-6.56 (m, 2H, Ph-H), 6.13 (d, J=5.5Hz, 1H, C5-pyrimidine-H), 5.25 (s,2H,NH2),3.69(s,1H,piperidine-H),3.37-3.59(m,2H,piperidine-H),2.55-2.87(m,2H, piperidine-H),2.04(s,6H,2CH3),1.2-1.8(m,6H,piperidine-H)；13C NMR(100MHz,DMSO)δ 168.78,149.30,131.61,129.69,129.40,126.04,123.04,120.06,119.24,116.57,115.01,95.61, 94.00,90.11,61.98,52.66,31.50,22.57,16.34；ESI-MS:583.4[M+H]+.C32H34N6O3S(582.72).
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 (trade names：Tetrazolium bromide), can be used to detect the survival and growth of cell.Cleaning Principle is：MTT Can be combined with intracellular succinate dehydrogenase living be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation 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 its extinction at 590 nm is detected with ELIASA Degree (A) value can indirectly reflect the quantity of living cells.In the range of certain cell number, MTT crystallizes the amount and cell to be formed Number is directly proportional.
Due to the MT-4 cells of HIV, (5-7 days) can occur lesion within a certain period of time, therefore to the MT- of HIV In 4 cell suspensions add debita spissitudo compound solution to be detected, through the culture of (5-7 days) after a while after, use MTT Assay MT-4 cell viabilities, obtain protecting 50% cell from the drug concentration (EC of cytopathy50) mesh can be drawn Mark the activity of the AntiHIV1 RT activity of compound.Obtaining target compound simultaneously makes 50% cell for being uninfected by HIV that the concentration of lesion to occur (CC50), calculate selection coefficient (selectivity index, SI=CC50/EC50)。
Test material and method：
(1)HIV-1(IIIB), HIV-2 (ROD) strain, various HIV-1 persisters：By Belgian medical college of Univ Louvain Rega research institutes provide.
(2) MT-4 cells：There 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, and makees 5 times of dilutions, each 5 with distilled water Dilution factor.
(5) positive control drug：NVP (NVP), efavirenz (EFV), etravirine (TMC125), Zidovudine (AZT), Delavirdine (DLV), rilpivirine (TMC278).
(6) method of testing：It is added to after Sample Dilution in HIV MT-4 cell suspensions, through using MTT after a period of time Colorimetric method for determining cell viability, with absorbance (A) value for being recorded in ELIASA at 590 nm, calculates EC50、CC50And SI.
(7) MTT colorimetric methods：After adding sample solution culture for a period of time, MTT solution (5mg/mL) 20 μ is added to every hole L, after continuing to cultivate some hours, abandons dyeing liquor, and adds 150 μ L DMSO to every hole, is sufficiently mixed, and is determined with ELIASA Absorbance (A) value under 590nm.
Experimental technique：
In 96 porocyte culture plates, 50 μ L are added to contain 1 × 104MT-4 cell culture fluids, then it is separately added into 20 μ L infection HIV-1(IIIBOr RES056) or HIV-2 (ROD) MT-4 cell suspensions (every milliliter contain 100 times of CCID50) or blank Culture medium (toxicity test), is subsequently adding the testing compound solution or positive control medicine of various concentrations, and each concentration sets 3 multiple holes of meter.Then cell is in 5%CO2Atmosphere, cultivates 5 days at 37 DEG C, to adding 20 μ L (5mg/mL) MTT solution in each hole, Continue to cultivate 2 hours, be subsequently adding DMSO, trap of the reaction solution at 540nm is determined using ELIASA, calculate compound not With the cell proliferation rate P% under concentration.Blank and drug control group and positive drug control group are set simultaneously, compound is thus calculated Concentration (EC needed for the cytopathy that the cell of protection 50% is induced from HIV50).Select the calculating of index：SI=CC50/EC50。
The part substituted diaryl pyridine derivatives for synthesizing have been carried out with the anti-of cellular level according to above-mentioned experimental technique HIV-1(IIIB), the activity sieve of single mutation strain K103N, Y181C, Y188L and double-mutant strain RES056 (K103N/Y181C) Choosing, Activity Results are as shown in Table 1 and Table 2.
The inhibitory activity and cytotoxicity (MT-4 cells) of the anti-HIV-1 (IIIB) of the part substituted diaryl pyridine derivatives of table 1
Note：aEC50:The MT-4 cells of 50% infected by HIV -1 are protected from the compound concentration of cytopathy；bCC50:Make There is the compound concentration of lesion in 50% cell for being uninfected by HIV-1；cSelectivity factor:CC50/EC50Ratio；TMC278、 NVP, EFV, ETV, DLV represent marketed drug rilpivirine, NVP, Sustiva, etravirine and Delavirdine respectively.
Inhibitory activity (MT-4 cell) of the part of compounds of table 2 to HIV resistance strains
Note：aEC50:The MT-4 cells of 50% infected by HIV -1 are protected from the compound concentration of cytopathy；TMC278、 NVP, EFV, ETV, DLV represent marketed drug rilpivirine, NVP, Sustiva, etravirine and Delavirdine respectively.
Conclusion：
By Tables 1 and 2 as can be seen that substituted diaryl pyrimidine derivatives of the invention are a series of left wings contains alkynyl and bone The novel non-nucleoside HIV-1 inhibitor of frame, it shows preferable anti-HIV-1 wild strain and mutant strain activity.Portion big absolutely Differentiation compound suppresses the EC of wild strain and mutant strain50Value reaching nanomole rank, wherein, the activity of compound IA-1-3 is particularly It is prominent, its EC to HIV-1 wild strains50It is worth for 0.003 μM with latest generation medicine etravirine (ETV) quite, its cell toxicant Property (CC50=3.476 μM) it is relatively low, it is 1.58 times of etravirine, the selectivity index to HIV-1 wild strains is 1010, is higher than Etravirine.Additionally, compound IIA-1-3 also shows preferable inhibitory activity to mutant strain, therefore, substituted diaryl is phonetic Piperidine derivatives have the value of further research and development, can be used as the lead compound of anti-HIV-1.

Claims (9)

1. a kind of substituted diaryl pyridine derivatives, or its pharmaceutically acceptable salt, ester or prodrug, with below formula I Or the structure shown in II：
Wherein,
X is O or NH；
N=0 or 1；
R1For：Alkynyl or alkenyl that side is directly connected with phenyl ring, its opposite side are cyclopropyl, phenyl ring, substituted benzene ring, substitution naphthalene It is ring, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substituted hexa-atomic and five-ring heterocycles, various substituted Hexa-atomic and hexa-member heterocycle, various substituted five yuan and five-ring heterocycles, various substituted benzo five-membered heterocycles or various substituted benzene And the hydrocarbon chain structure of hexa-member heterocycle and various different lengths；
R2, R3It is independently each：H, halogen, cyano group, C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, trifluoromethyl, amino Or hydroxyl vinyl；
R4For：Substituted benzene ring, substitution naphthalene nucleus, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substituted six Unit and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, various substituted benzos Five-ring heterocycles or various substituted benzo hexa-member heterocycles.
2. substituted diaryl pyridine derivatives as claimed in claim 1, it is characterised in that R1It is with general formula III or IV Phenyl ring, cyclopropyl, monosubstituted phenyl ring, disubstituted phenyl ring, unsubstituted phenyl ring or pyridine ring, substituted pyridines ring, hydrocarbon chain；
Wherein,
R5It is H2NC6H4、HOOCC6H4、C5NH4、C3H5、OH、C6H5、CONHC6H4Or F3CC6H4；
R6It is C6H5Or CH3C6H4。
3. substituted diaryl pyridine derivatives as claimed in claim 1, it is characterised in that R4It is the substituted benzene with formula V Ring；
Wherein, R7It is SO2NH2、CONH2Or CN.
4. substituted diaryl pyridine derivatives as claimed in claim 1, it is characterised in that be the chemical combination with general formula One of thing：
Wherein, R2、R3、R4With described in claim 1, R5、R6With described in claim 2.
5. substituted diaryl pyridine derivatives as claimed in claim 4, it is characterised in that be the chemical combination with general formula One of thing：
6. the preparation method of substituted diaryl pyridine derivatives as claimed in claim 1, it is characterised in that with compound 1 It is initiation material, frit reaction is carried out in 180 DEG C with 4- aminobenzonitriles, the intermediate 2 and POCl3 of generation is in 100 DEG C of conditions Lower backflow generation intermediate 3；Raw material 4 makees catalyst in cuprous iodide and double (triphenylphosphine) palladium chlorides, and triethylamine does alkali Under the conditions of the midbody compound 5 of alkynyl substituted is obtained with Yuan coupled reaction of intermediate Fa Sheng of alkynyl substituted, additionally, raw material There is the intermediate 5 that He Ke reactions obtain alkenyl substitution in 4 intermediates replaced with alkenyl under the conditions of palladium；Intermediate 3 with Intermediate 5 makees solvent in DMF, and the alkalescence condition of potassium carbonate occurs substitution reaction and obtains target product I；In addition, being with intermediate 6 Initiation material and intermediate 5 are dissolved in DMF and react at room temperature and obtain intermediate 7, and then intermediate 7 is in N, With the reaction of N-Boc-4- amino piperidines and then under the conditions of trifluoroacetic acid, de- Boc radical protections are generated in dinethylformamide Key intermediate 9；Under conditions of last this key intermediate 9 does alkali in DMF solution with potassium carbonate, with The various fragrant halogen reaction generation target product II of substitution；
Synthetic route is as follows：
Reagent and condition：a：4- aminobenzonitriles, 180 DEG C, fusion method, 8h；b：POCl3,0.5h；c：Intermediate 5, potassium carbonate, DMF, 100 DEG C, 10h；d：(i) substitutedphenylethynyl, bi triphenyl phosphorus palladium chloride, cuprous iodide, substituted benzene Phenol, triethylamine, tetrahydrofuran, 60 DEG C, 10h；(ii) substituted phenylethylene, palladium, Tol3Iodo- 2, the 6- xylenols of P, 4-, Caustic alcohol, DMA, 60 DEG C, 10h；e：Substitutedphenylethynyl, potassium carbonate, DMF, room temperature；f： N-Boc-4- amino piperidines, potassium carbonate, DMF, 120 DEG C, 12h；g：Trifluoroacetic acid, dichloromethane, room temperature, 5h；h：The fragrant halogen of substitution, potassium carbonate, DMF, room temperature；
R1、R2、R3、R4, n is with shown in claim 1 formula I or II.
7. the preparation method of substituted diaryl pyridine derivatives as claimed in claim 6, it is characterised in that step is as follows：
(1) in reaction bulb, nitrogen protection is warming up to 180 DEG C of reaction 8h to the p-aminophenyl nitrile of precise initiation material 1；React Quan Hou, reactant is dissolved with acetonitrile, and filter cake is washed in ultrasonically treated, filtering with acetonitrile, and solid is dried to obtain midbody compound 2 Crude product；
(2) intermediate 2 accurately is weighed, is dissolved in POCl3, nitrogen protection, 100 DEG C of backflow 0.5h；After reaction terminates, cooling Reaction solution, reaction solution is slowly added dropwise in clean frozen water POCl3 is quenched, after being stirred vigorously, filtering, and precipitation is with water-soluble Solution, NaOH adjusts pH to be equal to 7, filters again, dry yellow solid；Acetone recrystallization, separates out solid and is intermediate 3 Sterling；
(3) precise initiation material 4 is dissolved in tetrahydrofuran, sequentially add acetylenic substitution base, double (triphenylphosphine) palladium chlorides, Cuprous iodide, triethylamine, nitrogen protection, 60 DEG C of backflow 10h；After reaction terminates, reaction solution is filtered with diatomite, solution is used full And sodium chloride solution, filtrate mixes sample after being evaporated, post separation obtains intermediate 5；When raw material is that alkenes replace base, by it with Mesosome 4, palladium, Tol3P, monoethanolamine are dissolved in DMA, are warming up to 60 DEG C of reaction 10h；It is molten after reaction terminates Agent evaporated under reduced pressure, intermediate 5 is obtained with ethyl acetate/petroleum ether system post separation；
(4) accurate intermediate 3, intermediate 5 and the potassium carbonate of weighing is dissolved in DMF, 100 DEG C of reaction 10h；After reaction terminates, filtering, filter Liquid is evaporated, post separation, and target product I is obtained after recrystallization from ethyl acetate/petroleum ether；
(5) accurately weighing intermediate 6, intermediate 5 and potassium carbonate is dissolved in DMF, room temperature reaction 10h；After reaction terminates, filtering subtracts Pressure is evaporated, and post separation obtains intermediate 7；
(6) to N-Boc-4- amino piperidines, potassium carbonate is added in the DMF solution of intermediate 7,120 are warming up to DEG C reaction 12h；After reaction cooling, frozen water is added dropwise to reaction solution, suspension is filtrated to get the crude product of intermediate 8；
(7) intermediate 8 for obtaining upper step is dissolved in dichloromethane, is slowly added dropwise trifluoroacetic acid, 5h is stirred at room temperature, after reaction terminates PH to 10 is adjusted with saturated sodium bicarbonate, dichloromethane extraction dries the isolated intermediate 9 of rear pillar；
(8) key intermediate 9 and the fragrant halogen of substitution are dissolved in DMF, add potassium carbonate, be stirred overnight at room temperature；Instead Should terminate, mixed liquor evaporated under reduced pressure, be extracted with ethyl acetate three times, three organic layers of saturated common salt water washing are dried, and cross filtration Dry, post separation obtains target product II after recrystallization from ethyl acetate/petroleum ether.
8. one kind compound as described in claim any one of 1-5 is preparing treatment and prevention human immunodeficiency virus (HIV) medicine Application in thing.
9. it is a kind of treat and prevent human immunodeficiency virus pharmaceutical composition, comprising chemical combination described in claim any one of 1-5 Thing and one or more pharmaceutically acceptable carrier or excipient.
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