CN104761568B - One class Fourth Ring Nai Bing oxazole derivatives and preparation method thereof - Google Patents

One class Fourth Ring Nai Bing oxazole derivatives and preparation method thereof Download PDF

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CN104761568B
CN104761568B CN201410002643.XA CN201410002643A CN104761568B CN 104761568 B CN104761568 B CN 104761568B CN 201410002643 A CN201410002643 A CN 201410002643A CN 104761568 B CN104761568 B CN 104761568B
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alkyl
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nmr
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CN104761568A (en
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张翱
缪泽鸿
王美凝
宋姗姗
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Shanghai Institute of Materia Medica of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of novel tetracyclic Nai Bing oxazole analog derivatives, it has below formula（I）Shown structure：

Description

One class Fourth Ring Nai Bing oxazole derivatives and preparation method thereof
Technical field
The present invention relates to organic chemistry and medicinal chemistry art, and in particular to a kind of novel tetracyclic Nai Bing oxazole analog derivatives And preparation method thereof.
Background technology
Benzoxazole, Nai Bing oxazoles are widely present in various active natural products and synthetic molecules structure as advantage skeleton In.With the multiple biological activities such as antibacterium, antimycotic, AntiHIV1 RT activity, antitumor.
In recent years, scientist has found that some contain benzoxazole, the other biological activity of Nai Bing oxazole molecule of the skeleton successively again Compound.Gonz á lez in 1999 et al. reports compound pseudopteroxazol can suppress tuberculosis bacteria growth (Rodr í guez,A.D.；Ramire,C.；Rodríguez,I.I.；González,E.Org.Lett.1999,1,527)；Shin in 2013 Et al. report compound Herqueioxazole have to aureus sortase A enzymes significant inhibitory activity (Julianti, E.；Lee,J.；Liao,L.；Park,W.；Park,S.；Oh,D.；Oh,K.；Shin,J.Org.Lett.2013,15,1286). However, the synthetic method of existing Nai Bing oxazole analog derivatives is relatively complicated, combined coefficient is not high, limits such compound Using.
The content of the invention
In order to solve the above-mentioned technical problem, it is an object of the present invention to provide a kind of novel tetracyclic Nai Bing oxazoles class derivative Thing.This kind of compound can suppress cell propagation growth, with potential antitumor, antibacterial etc. as DNA break reagent Bioactivity.
It is a further object to provide a kind of simple and easy to do, combined coefficient it is high prepare the Fourth Ring Nai Bing oxazoles The method of analog derivative, this method is the cascade reaction participated in using hydrocarbon activation come the method for innovative synthesis.
A further object of the present invention also resides in the application that above-claimed cpd breeds growth inhibitor as cell, and in system Application in standby antineoplastic.
In order to which with realizing above-mentioned mesh, the invention provides a kind of novel tetracyclic Nai Bing oxazole analog derivatives, it has as follows Structure shown in logical formula (I)：
Wherein,
X is O or S.
Y is O or S.
Z is C or N.
R1And R2It is not simultaneously independently but not hydrogen, is separately halogen atom, hydroxyl, C1-C6Alkoxy, ammonia Base, C1-C6Alkylamino, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Acylamino-, substituted or unsubstituted C1-C10Alkyl, substitution or Unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, preferably C1-C6Alkoxy carbonyl, C1-C6Acylamino-, substitution or not Substituted C1-C10Alkyl, substituted or unsubstituted phenyl；Or, R1And R2It can connect to form substituted or unsubstituted C6-C10 Aryl or five yuan or six membered heteroaryl, preferably substituted or unsubstituted phenyl；Wherein, substituent be selected from halogen atom, hydroxyl, Carboxyl, C1-C6Alkoxy carbonyl, amino, C1-C6Acylamino-, nitro, C1-C10Alkyl, halo C1-C10Alkyl, C1-C10Alcoxyl Base, C1-C6Alkylamino, C6-C10Aryl or five yuan or six membered heteroaryl, preferably halogen atom, carboxyl, C1-C6Alkoxy, C1- C6Alkyl or halo C1-C6Alkyl.
R3And R4It is separately hydrogen, halogen atom, C1-C6Alkoxy, C1-C6Alkylamino, C1-C6Alkoxy carbonyl, C1-C6Acylamino-, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, Preferably H, C1-C6Alkoxy carbonyl, C1-C6Acylamino-, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxy or C1-C6Alkane Amino；Or, R3And R4It can connect to form substituted or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl, preferably take Generation or unsubstituted phenyl；Wherein, substituent is selected from halogen atom, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, amino, C1-C6 Acylamino-, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkylamino, C6-C10Aryl or five yuan Or six membered heteroaryl, preferably halogen atom, C1-C6Alkoxy carbonyl, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxy Or phenyl.
R5And R7It is separately hydrogen, halogen atom, substitution or unsubstituted C1-C6Alkoxy, C1-C6Alkylamino, C1-C6 Alkoxy carbonyl, C1-C6Acylamino-, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C6-C10Aryl or five yuan or Six membered heteroaryl, preferably H, substitution or unsubstituted C1-C6Alkoxy, C1-C6Acylamino-, substituted or unsubstituted C1-C10Alkane Base, substituted or unsubstituted C6-C10Aryl；Wherein, substituent is selected from halogen atom, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, Amino, C1-C6Acylamino-, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C3-C6Cycloalkyl, 3 to 6 yuan of oxa-s or azepine Cycloaliphatic ring, C1-C6Alkoxy, C1-C6Alkylamino, C6-C10Aryl or five yuan or six membered heteroaryl, preferably halogen atom, C1-C6 Alkoxy carbonyl, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxy or phenyl.
R6For hydrogen, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted alkenyl, halo C1-C6Alkyl, substitution or Unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted C3-C6Oxa- or azacycloalkyl；Wherein, substituent is selected from halogen original Son, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Alkyl carbonyl epoxide, monosubstituted, disubstituted or unsubstituted amino, C1-C6Acyl Amino, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C3-C6Cycloalkyl, C3-C6Oxa- or azepine cycloaliphatic ring, C1-C6Alkane Epoxide, C1-C6Alkylamino, C6-C10Aryl or five yuan or six membered heteroaryl, wherein, substituent is selected from C1-C6Alkyl, C1-C6Carbonyl Base, C1-C6Alkoxy carbonyl.
It is highly preferred that in logical formula (I)：
X is O.
Y is O.
Z is N.
R1And R2It is separately substituted or unsubstituted C1-C6Alkyl or phenyl, C6-C10Aryl or five yuan or hexa-atomic Heteroaryl；Wherein, substituent is selected from halogen atom, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, amino, C1-C6Acylamino-, nitre Base, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkylamino.
R3And R4It is separately H, halogen atom, C1-C6Alkoxy carbonyl, C1-C6Alkyl, C1-C6Alkoxy or C1- C6Alkylamino；Or, R3And R4It can connect to form naphthalene nucleus.
R5And R7It is separately H, halogen atom, C1-C6Alkoxy carbonyl, substituted or unsubstituted C1-C6Alkyl or Phenyl, substitution or unsubstituted C1-C6Alkoxy or C1-C6Alkylamino；Wherein, substituent is selected from halogen atom, hydroxyl, amino, C6- C10Aryl or five yuan or six membered heteroaryl.
R6For hydrogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted alkenyl；Substituent be selected from halogen atom, Hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, C1-C6Alkyl carbonyl epoxide, monosubstituted, disubstituted or unsubstituted amino, C1-C6Acyl ammonia Base, nitro, cyano group, C1-C6Alkyl, halo C1-C6Alkyl, C3-C6Cycloalkyl, C3-C6Oxa- or azepine cycloaliphatic ring, C1-C6Alcoxyl Base, C1-C6Alkylamino, C6-C10Aryl or five yuan or six membered heteroaryl；Wherein, substituent is selected from C1-C6Alkyl, C1-C6Carbonyl, C1-C6Alkoxy carbonyl.
In the present invention, make and being defined as below：
The halogen atom refers to F, Cl, Br or I.
The C1-C10Alkyl refers to the straight or branched alkyl on main chain with 1 to 10 carbon atom, term " C1-C6 Alkyl " has similar implication.For example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, Base etc..
The C1-C10Alkoxy refers to the straight or branched alkoxyl on main chain with 1 to 10 carbon atom, term “C1-C6Alkoxy " has similar implication.Such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy.
The halo C1-C10Alkyl refers to the C replaced with one or more halogen atoms1-C10Alkyl, term " halo C1-C6Alkyl " has similar implication.Such as trifluoromethyl.
The C3-C10Cycloalkyl refers to the fatty carbocylic radical with 3 to 10 carbon atoms, including monocyclic and ring, bridge Ring, loop coil etc., such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, adamantyl etc..
The C1-C6Alkoxy carbonyl refers to the alkoxy carbonyl with 1 to 6 carbon atom, such as methoxycarbonyl, Ethoxy carbonyl etc..
The C1-C6Alkyl carbonyl epoxide refers to the alkyl carbonyl epoxide with 1 to 6 carbon atom, such as acetoxyl group.
The C1-C6Acylamino- refers to the carbonylamino with 1 to 6 carbon atom, such as acetylamino, propionamido, Butyrylamino etc..
The C6-C10Aryl refers to the armaticity carbocylic radical on ring with 6 to 10 carbon atoms, for example, phenyl, naphthyl Deng.
Described five yuan or six membered heteroaryl refer to have at least one in N, O and S on ring heteroatomic five First or hexa-atomic armaticity ring group, such as thiophene ring group, thiazole ring group, pyrazoles ring group, imidazoles ring group, pyridine ring group, pyrazine ring group, Pyrimidine ring group etc..
The C3-C6Cycloaliphatic ring refers to the fatty carbocyclic ring with 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, ring penta Alkane, hexamethylene.
The C3-C6Oxa- or the fatty cycloalkyl of azepine refer to having at least one miscellaneous in N, O and S on ring The cycloaliphatic ring containing 3 to 6 atoms of atom, such as nafoxidine, morpholine, piperazine, piperidines etc..
Most preferably, the compound shown in logical formula (I) of the invention is selected from following compounds：
The present invention provides the preparation method of compound shown in logical formula (I), and it is synthesized by following route：
2- substituted-aminos quinones is activated into the cascade reaction participated in formation target compound with substitution alkynes by C-H (I), reaction equation is as follows：
Here 5 of quinone are activated with metallic catalyst Rh, oxidant Cu (OAc) is added2.H2O, additive A gSbF6, Synthesis is reacted in solvent t-AmOH.
The present invention also provides above-mentioned novel tetracyclic Nai Bing oxazoles analog derivatives as the application of cytostatic agent, and Application in antineoplastic is prepared.
The present invention takes polysubstituted method, replaces quinone as the substrate of reaction by the use of amino, is participated in hydrocarbon activation The method innovation of cascade reaction synthesized some in the past be difficult to build Fourth Ring Nai Bing oxazole analog derivative skeletons, synthesis side Method is simple and easy to do, efficiency high, for significant deeper into hydrocarbon priming reaction, cascade reaction is recognized.The inventive method The product of gained has no document report, belongs to new compound, the Fourth Ring Nai Bing oxazoles analog derivatives of synthesis and traditional DNA break Agent structure is similar, can suppress cell propagation growth, with the bioactivity such as antibacterium, antimycotic, AntiHIV1 RT activity, antitumor.
Embodiment
Following examples are intended to illustrate rather than limit the scope of the present invention.
Unless otherwise indicated, the preparation used in the present invention and method of testing and equipment etc. is sides conventional in the art Method and equipment.Agents useful for same is that analysis is pure or chemical pure.
Embodiment 1.
The preparation of 2- substituted-amino quinones substrates refers to Khodade, V.S.；Dharmaraja,A.T.； Chakrapani,H.Bioorg.Med.Chem.Lett.2012,22,3766。
Weigh 86mg (0.4mmol) 2- n-propylamine base -1,4- naphthoquinones, 107mg (0.6mmol) dibenzenyl, 12mg (0.02mmol)[Rh(Cp*)Cl2]2(Cp*=pentamethylcyclopentadienes), 12mg (0.04mmol) AgSbF6And 160mg (0.8mmol)Cu(OAc)2.H2O is added in round bottom reaction bulb, is dissolved with 2mL t-AmOH, and 6h is heated at 120 DEG C and has been reacted Into.10mL water is added, is extracted with ethyl acetate three times (5mL x 3), merges organic phase, uses saturated common salt water washing, anhydrous sulphur Sour sodium is dried, and removes solvent, the isolated 113mg light yellow solid Compounds 1 of silica gel column chromatography, yield 73% under reduced pressure；25mg Light yellow solid Compound 29, yield 14%.
Compound 1：
1H NMR(300MHz,CDCl3) δ 7.60 (d, J=8.4Hz, 1H), 7.33 (m, 5H), 7.20 (m, 7H), 6.49 (d, J=7.4Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 1.50 (t, J=7.6Hz, 3H)；13C NMR(126MHz,CDCl3)δ 168.2,150.0(2),140.7,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.7,128.6, 127.7,127.6,120.6,120.1,116.3,116.1,115.8,98.5,22.4,11.1；EI-MS(m/z)389(M+)； HRMS C27H19NO2[M+], calculated value：389.1416, measured value：389.1418.
Compound 29：
1H NMR (300MHz, CDCl3) δ 7.65 (d, J=8.3Hz, 1H), 7.35 (m, 5H), 7.23 (m, 7H), 6.55 (d, J=7.5Hz, 1H), 6.18 (q, J=6.7Hz, 1H), 2.19 (s, 3H), 1.80 (d, J=6.7Hz, 3H)；13C NMR (126MHz,CDCl3)δ170.0,164.0,150.4,150.1,140.9,138.2,135.2,133.9,133.2,131.1, 129.2129.0,128.9,128.6,127.7(2),121.2,120.3,116.4,116.3,98.7,65.4,21.0,18.6； EI-MS(m/z)447(M+)；HRMS C29H21NO4 [M+], calculated value：447.1471, measured value：447.1473.
Embodiment 2.
In addition to replacing dibenzenyl with two p-methylphenyl acetylene, prepared according to the method for embodiment 1 110mg light yellow solid Compounds 2, yield 66%.27mg light yellow solid Compounds 30, yield 14%.
Compound 2：
1H NMR(400MHz,CDCl3) δ 7.62 (d, J=8.3Hz, 1H), 7.27 (m, 5H), 7.17 (m, 3H), 7.03 (d, J=8.1Hz, 2H), 6.53 (m, 1H), 3.06 (q, J=7.6Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 1.53 (t, J= 7.6Hz,3H)；13C NMR(101MHz,CDCl3)δ168.1,150.0,149.9,140.5,138.5,138.4,137.1, 133.5,132.3,131.2,130.9,129.8,128.8,128.6,128.4,120.5,120.0,115.8,115.6,98.3, 22.3,21.3(2),11.1；EI-MS(m/z)417(M+),HRMS C29H23NO2[M+], calculated value：417.1729, measured value： 417.1728.
Compound 30：
1H NMR(300MHz,CDCl3) δ 7.63 (dd, J=8.3,0.9Hz, 1H), 7.29 (dd, J=8.2,7.5Hz, 1H), 7.16 (m, 7H), 7.00 (d, J=7.9Hz, 2H), 6.54 (dd, J=7.4,0.9Hz, 1H), 6.18 (q, J=6.7Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 1.80 (d, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3) δ170.0,163.9,150.4150.0,140.8,138.5,138.1,137.2,133.5,132.2,131.1,130.8, 129.9,128.9,128.8,128.4,121.1,120.2,116.2,116.1,115.6,98.4,65.4,21.3(2),21.0, 18.6；EI-MS(m/z)475(M+),HRMS C31H25NO4[M+], calculated value：475.1784, measured value：475.1778.
Embodiment 3.
In addition to replacing dibenzenyl with two rubigan acetylene, 117mg is prepared according to the method for embodiment 1 Light yellow solid Compound 3, yield 64%.
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.4Hz, 1H), 7.36 (d, J=8.3Hz, 2H), 7.24 (m, 2H), 7.18 (m, 4H), 7.14 (m, 2H), 6.43 (d, J=7.4Hz, 1H), 3.02 (q, J=7.6Hz, 2H), 1.49 (t, J= 7.6Hz,3H)；13C NMR(101MHz,CDCl3)δ168.3,149.5,149.1,140.7,138.6,134.7,133.8, 133.5,132.4,132.1,130.2,129.6,128.6,128.1,120.3,120.0,116.6,115.7,115.5,98.7, 22.3,11.1；EI-MS(m/z)457(M+),HRMS C27H17NO2Cl2[M+], calculated value：457.0636, measured value： 457.0633.
Embodiment 4.
In addition to replacing dibenzenyl with two p-fluorophenyl acetylene, 102mg is prepared according to the method for embodiment 1 Light yellow solid Compound 4, yield 60%；25mg light yellow solid Compounds 31, yield 13%.
Compound 4：
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.1Hz, 1H), 7.27 (m, 3H), 7.18 (d, J=5.5Hz, 2H), 7.14 (s, 1H), 7.08 (t, J=8.2Hz, 2H), 6.88 (t, J=8.5Hz, 2H), 6.45 (d, J=7.2Hz, 1H), 3.02 (q, J=7.5Hz, 2H), 1.49 (t, J=7.5Hz, 3H)；13C NMR(126MHz,CDCl3)δ167.8,163.0, 162.7,161.1,160.8,149.2,148.9,140.2,138.2,132.4,132.3(2),130.5(3),130.4,129.5 (2),128.2,119.9,119.6,116.0,115.9,115.8,115.1,114.8,114.5,114.3,98.2,21.9, 10.6；EI-MS(m/z)425(M+),HRMS C27H17NF2O2[M+], calculated value：425.1227, measured value：425.1226.
Compound 31：
1H NMR(300MHz,CDCl3) δ 7.66 (d, J=8.4Hz, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.20 (m, 3H), 7.08 (t, J=8.6Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 6.50 (d, J=7.4Hz, 1H), 6.17 (q, J= 6.7Hz, 1H), 2.18 (s, 3H), 1.80 (d, J=6.8Hz, 3H)；13C NMR(101MHz,CDCl3)δ170.0,164.1, 163.8,163.5,161.3,161.0,150.0,149.4,140.9,138.1,132.8,132.7,131.0,130.9, 129.8,128.9,120.9,120.2,116.6,116.5,116.3,116.2,115.2,115.0,114.8,98.8,65.4, 21.0,18.6；EI-MS(m/z)483(M+),HRMS C29H19NF2O4[M+], calculated value：483.1282, measured value： 483.1278.
Embodiment 5.
In addition to replacing dibenzenyl with two pairs of ethylphenyl acetylene, prepared according to the method for embodiment 1 109mg light yellow solid Compounds 5, yield 61%.
1H NMR(300MHz,CDCl3) δ 7.58 (d, J=7.8Hz, 1H), 7.25 (m, 4H), 7.19 (s, 1H), 7.15 (d, J=5.9Hz, 3H), 7.01 (d, J=8.2Hz, 2H), 6.50 (d, J=7.0Hz, 1H), 3.02 (q, J=7.6Hz, 2H), 2.68 (q, J=7.6Hz, 2H), 2.57 (q, J=7.6Hz, 2H), 1.49 (t, J=7.6Hz, 3H), 1.28 (t, J=7.6Hz, 3H), 1.17 (t, J=7.6Hz, 3H)；13C NMR(101MHz,CDCl3)δ168.1,150.0,149.9,144.7,143.5,138.5, 133.6,132.5,131.4,130.9,128.8,128.7,128.6,127.2,120.5,120.1,115.8,115.7,98.3, 28.6(2),22.3,15.4,15.2,11.1；EI-MS(m/z)445(M+),HRMS C31H27NO2[M+], calculated value： 445.2042, measured value：445.2040.
Embodiment 6.
In addition to replacing dibenzenyl with di-p-methoxy phenylacetylene, prepared according to the method for embodiment 1 86mg light yellow solid Compounds 6, yield 48%.
1H NMR(300MHz,CDCl3) δ 7.57 (d, J=8.3Hz, 1H), 7.25 (m, 3H), 7.15 (d, J=9.0Hz, 3H), 6.92 (d, J=8.6Hz, 2H), 6.71 (d, J=8.8Hz, 2H), 6.49 (d, J=7.4Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.02 (q, J=7.6Hz, 2H), 1.49 (t, J=7.6Hz, 3H)；13C NMR(101MHz,CDCl3)δ 168.1,159.5,158.8,150.0,149.8,140.5,138.5,133.7,132.2,130.3,128.7,127.6, 126.5,120.4,120.0,115.7,115.4,114.7,114.6,113.1,98.2,55.2(2),22.3,11.1；EI-MS (m/z)449(M+),HRMS C29H23NO4[M+], calculated value：449.1627, measured value：449.1631.
Embodiment 7.
In addition to replacing dibenzenyl with two p-trifluoromethyl phenyl acetylene, it is prepared into according to the method for embodiment 1 To 149mg light yellow solid Compounds 7, yield 71%.
1H NMR(400MHz,CDCl3) δ 7.70 (d, J=8.1Hz, 3H), 7.50 (d, J=8.3Hz, 2H), 7.42 (d, J =8.2Hz, 4H), 7.32 (t, J=7.9Hz, 1H), 7.21 (s, 1H), 6.45 (d, J=7.3Hz, 1H), 3.07 (q, J= 7.6Hz, 2H), 1.54 (t, J=7.6Hz, 3H)；13C NMR(126MHz,CDCl3)δ168.5,149.4,149.0,140.8, 138.7,137.0,132.0,131.5,130.8,130.5,130.4 130.1,129.2,128.6,126.4,126.3,124.9 (2),122.9,122.6,120.4,120.1,117.1,116.4,116.0,99.1,22.3,11.1；EI-MS(m/z)525(M+),HRMS C29H17NF6O2[M+], calculated value：525.1163, measured value：525.1159.
Embodiment 8.
In addition to replacing dibenzenyl with dithienyl acetylene, 83mg is prepared according to the method for embodiment 1 shallow Yellow solid compound 8, yield 52%.
1H NMR(300MHz,CDCl3) δ 7.59 (t, J=5.6Hz, 2H), 7.26 (m, 3H), 7.19 (s, 2H), 7.07 (d, J=2.6Hz, 1H), 6.94 (m, 1H), 6.48 (d, J=7.3Hz, 1H), 3.02 (q, J=7.6Hz, 2H), 1.49 (t, J= 7.6Hz,3H)；13C NMR(101MHz,CDCl3)δ168.2,149.1,146.8,140.8,138.5,135.6,135.2, 133.5,129.9,128.8,128.7,128.4,128.3,128.2,126.7,119.8,119.7,116.2,116.1, 107.2,98.8,22.3,11.1；EI-MS(m/z)401(M+),HRMS C23H15NO2S2[M+], calculated value：401.0544, actual measurement Value：401.0536.
Embodiment 9.
In addition to replacing dibenzenyl with diη-propyl acetylene, 86mg is prepared according to the method for embodiment 1 shallow Yellow solid compound 9, yield 67%；44mg light yellow solid Compounds 32, yield 29%.
Compound 9：
1H NMR(300MHz,CDCl3) δ 7.55 (d, J=8.3Hz, 1H), 7.36 (m, 1H), 6.99 (s, 1H), 6.79 (d, J=7.3Hz, 1H), 2.99 (q, J=7.6Hz, 2H), 2.40 (m, 4H), 1.70 (m, 2H), 1.56 (m, 2H), 1.46 (t, J= 7.6Hz, 3H), 1.01 (td, J=7.3,1.5Hz, 6H)；13C NMR(126MHz,CDCl3)δ167.9,152.9,150.0, 140.3,138.3,132.1,128.7,120.8,120.2,114.9,112.6,110.6,97.7,32.7,28.4,22.3, 21.3,21.1,14.3,13.9,11.1；EI-MS(m/z)321(M+),HRMS C21H23NO2[M+], calculated value：321.1729, Measured value：321.1727.
Compound 32：
1H NMR(300MHz,CDCl3) δ 7.60 (d, J=8.3Hz, 1H), 7.40 (t, J=7.9Hz, 1H), 7.02 (s, 1H), 6.84 (d, J=7.4Hz, 1H), 6.15 (q, J=6.7Hz, 1H), 2.40 (m, 4H), 2.17 (s, 3H), 1.78 (d, J= 6.7Hz, 3H), 1.71 (m, 2H), 1.56 (m, 2H), 1.01 (t, J=7.3Hz, 6H)；13C NMR(126MHz,CDCl3)δ 170.0,163.7,153.0,150.4,140.5,137.9,132.1,128.9,121.3,120.4,115.2,113.2, 110.6,97.8,65.4,32.6,28.4,21.2,21.0(2),18.6,14.3,13.9；EI-MS(m/z)379(M+),HRMS C23H25NO2[M+], calculated value：379.1784, measured value：379.1791.
Embodiment 10.
In addition to replacing dibenzenyl with phenyl n-butyl-acetylene, 93mg is prepared according to the method for embodiment 1 Light yellow solid Compound 10, yield 63%；46mg light yellow solid Compounds 33, yield 27%.
Compound 10：
1H NMR(300MHz,CDCl3) δ 7.64 (d, J=8.3Hz, 1H), 7.55 (m, 2H), 7.44 (m, 4H), 7.06 (s, 1H), 6.93 (d, J=7.3Hz, 1H), 3.01 (q, J=7.6Hz, 2H), 2.42 (m, 2H), 1.59 (m, 2H), 1.48 (t, J= 7.6Hz, 3H), 1.33 (m, 2H), 0.86 (t, J=7.3Hz, 3H)；13C NMR(126MHz,CDCl3)δ168.1,150.6, 150.0,140.5,138.5,134.8,131.8,129.0,128.9,128.7,128.3,120.9,120.2,115.9, 113.7,112.8,98.2,30.3,26.8,22.8,22.3,13.8,11.1；EI-MS(m/z)369(M+),HRMS C25H23NO2 [M+], calculated value：369.1729, measured value：369.1723.
Compound 33：
1H NMR(300MHz,CDCl3) δ 7.69 (d, J=8.3Hz, 1H), 7.56 (m, 2H), 7.46 (m, 4H), 7.08 (s, 1H), 6.98 (d, J=7.4Hz, 1H), 6.17 (q, J=6.7Hz, 1H), 2.43 (m, 2H), 2.18 (s, 3H), 1.79 (d, J= 6.7Hz, 3H), 1.58 (m, 2H), 1.33 (m, 2H), 0.86 (t, J=7.3Hz, 3H)；13C NMR(101MHz,CDCl3)δ 170.0,163.9,150.6,150.4,140.7,138.0,134.6,131.8,129.1,128.9,128.4,121.5, 120.3,116.1,114.3,112.8,98.3,65.4,30.3,26.8,22.8,21.1,18.6,13.8；EI-MS(m/z)427 (M+),HRMS C27H25NO4[M+], calculated value：427.1784, measured value：427.1767.
Embodiment 11 and 12.
In addition to replacing dibenzenyl with methyl n-propyl acetylene, 45mg is prepared according to the method for embodiment 1 Light yellow solid Compound 11 (yield 38%) and 43mg light yellow solid Compounds 12 (yield 37%).
Compound 11：
1H NMR(300MHz,CDCl3) δ 7.57 (dd, J=8.3,0.7Hz, 1H), 7.39 (m, 1H), 7.02 (s, 1H), 6.75 (d, J=6.6Hz, 1H), 3.00 (q, J=7.6Hz, 2H), 2.44 (m, 2H), 1.94 (s, 3H), 1.72 (m, 2H), 1.47 (t, J=7.6Hz, 3H), 1.00 (t, J=7.4Hz, 3H)；13C NMR(126MHz,CDCl3)δ167.9,152.5,150.0, 140.3,138.4,133.0,128.8,120.3,119.9,115.1,112.5,106.1,97.8,32.9,22.4,21.1, 13.8,12.3,11.2；EI-MS(m/z)293(M+),HRMS C19H19NO2[M+], calculated value：293.1416, measured value： 293.1416.
Compound 12：
1H NMR(400MHz,CDCl3) δ 7.58 (d, J=8.2Hz, 1H), 7.40 (m, 1H), 7.03 (s, 1H), 6.81 (d, J=7.3Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 2.41 (m, 2H), 2.16 (s, 3H), 1.60 (m, 2H), 1.51 (t, J= 7.6Hz, 3H), 1.04 (t, J=7.4Hz, 3H)；13C NMR(126MHz,CDCl3)δ167.9,149.9,149.4,140.4, 138.3,132.0,128.7,120.8,120.2,114.9,112.3,110.6,97.8,28.6,22.3,20.8,17.1, 14.2,11.1；EI-MS(m/z)293(M+),HRMS C19H19NO2[M+], calculated value：293.1416, measured value：293.1415.
Embodiment 13.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- n-butyl amines base-Isosorbide-5-Nitrae naphthoquinones, according to the method for embodiment 1 Prepare 97mg light yellow solid Compounds 13, yield 60%；50mg light yellow solid Compounds 34, yield 27%.
Compound 13：
1H NMR(300MHz,CDCl3) δ 7.60 (d, J=8.4Hz, 1H), 7.32 (m, 5H), 7.23 (m, 6H), 7.18 (s, 1H), 6.49 (d, J=7.4Hz, 1H), 2.97 (t, J=7.5Hz, 2H), 1.98 (m, 2H), 1.08 (t, J=7.4Hz, 3H)；13C NMR(101MHz,CDCl3)δ167.2,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1, 129.1,129.0,128.7,128.6,127.7,127.6,120.6,120.1,116.3,116.2,115.8,98.5,30.7, 20.5,13.9；EI-MS(m/z)403(M+),HRMS C28H21NO2[M+], calculated value：403.1572, measured value：403.1563.
Compound 34：
1H NMR(300MHz,CDCl3) δ 7.65 (dd, J=8.4,0.9Hz, 1H), 7.32 (m, 6H), 7.22 (m, 6H), 6.54 (dd, J=7.4,0.9Hz, 1H), 6.00 (t, J=6.8Hz, 1H), 2.18 (m, 5H), 1.05 (t, J=7.4Hz, 3H)；13C NMR(126MHz,CDCl3)δ170.2,163.5,150.3,150.1,140.8,138.2,135.2,133.9,133.2, 131.1,129.2,129.0,128.9,128.6,127.7(2),121.1,120.3,116.4(2),116.3,98.7,70.2, 26.3,20.9,9.5；EI-MS(m/z)461(M+),HRMS C30H23NO4[M+], calculated value：461.1627, measured value： 461.1622.
Embodiment 14.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- pentylamines base-Isosorbide-5-Nitrae naphthoquinones, according to the method for embodiment 1 Prepare 105mg light yellow solid Compounds 14, yield 63%；40mg light yellow solid Compounds 35, yield 21%.
Compound 14：
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.3Hz, 1H), 7.28 (m, 12H), 6.49 (d, J=7.4Hz, 1H), 2.99 (t, J=7.6Hz, 2H), 1.92 (m, 2H), 1.49 (m, 2H), 0.99 (t, J=7.3Hz, 3H)；13C NMR (101MHz,CDCl3)δ167.4,150.0,149.9,140.6,138.6,135.3,134.0,133.1,131.1,129.1, 128.9,128.6,128.5,127.7,127.6,120.5,120.1,116.2,116.1,115.7,98.5,29.1,28.5, 22.3,13.7；EI-MS(m/z)417(M+),HRMS C29H23NO2[M+], calculated value：417.1729, measured value：417.1735.
Compound 35：
1H NMR(400MHz,CDCl3) δ 7.69 (d, J=8.3Hz, 1H), 7.37 (m, 6H), 7.25 (m, 6H), 6.58 (d, J=7.4Hz, 1H), 6.11 (t, J=6.9Hz, 1H), 2.23 (s, 3H), 2.17 (m, 2H), 1.51 (m, 2H), 1.03 (t, J= 7.4Hz,3H)；13C NMR(101MHz,CDCl3)δ170.2,163.7,150.3,150.0,140.7,138.1,135.1, 133.9,133.1,131.1,129.1,129.0,128.8,128.6,127.7(2),121.0,120.2,116.4,116.3, 116.2,98.7,68.8,35.0,20.9,18.4,13.6；EI-MS(m/z)475(M+),HRMS C31H25NO4[M+], calculate Value：475.1784, measured value：475.1784.
Embodiment 15.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- isoamylaminos-Isosorbide-5-Nitrae naphthoquinones, according to the method for embodiment 1 Prepare 90mg light yellow solid Compounds 15, yield 54%；30mg light yellow solid Compounds 36, yield 16%.
Compound 15：
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.4Hz, 1H), 7.33 (m, 5H), 7.25 (m, 3H), 7.18 (m, 4H), 6.50 (d, J=7.4Hz, 1H), 2.87 (d, J=7.2Hz, 2H), 2.35 (m, 1H), 1.07 (d, J=6.7Hz, 6H)；13C NMR(126MHz,CDCl3)δ166.7,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1, 129.1,129.0,128.6,128.5,127.7,127.6,120.6,120.1,116.2(2),115.7,98.5,37.7, 27.7,22.5；EI-MS(m/z)417(M+),HRMS C29H23NO2[M+], calculated value：417.1729, measured value：417.1721.
Compound 36：
1H NMR(400MHz,CDCl3) δ 7.67 (d, J=8.3Hz, 1H), 7.34 (m, 6H), 7.23 (m, 6H), 6.56 (d, J=7.3Hz, 1H), 5.84 (d, J=6.8Hz, 1H), 2.52 (m, 1H), 2.23 (s, 3H), 1.10 (d, J=6.8Hz, 3H), 1.04 (d, J=6.8Hz, 3H)；13C NMR(101MHz,CDCl3)δ170.3,163.3,150.3,150.0,140.6,138.2, 135.2,133.9,133.1,131.1,129.1,129.0,128.8,128.6,127.7,127.6,121.0,120.2, 116.4,116.3,116.2,98.7,73.7,31.9,20.8,18.3,18.0；EI-MS(m/z)475(M+),HRMS C31H25NO4[M+], calculated value：475.1784, measured value：475.1790.
Embodiment 16.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with the just own amino-Isosorbide-5-Nitrae naphthoquinones of 2-, according to the method for embodiment 1 Prepare 116mg light yellow solid Compounds 16, yield 67%；33mg light yellow solid Compounds 37, yield 17%.
Compound 16：
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.3Hz, 1H), 7.26 (m, 12H), 6.49 (d, J=7.3Hz, 1H), 2.98 (t, J=7.7Hz, 2H), 1.94 (m, 2H), 1.42 (d, J=3.2Hz, 4H), 0.93 (t, J=6.6Hz, 3H)；13C NMR(126MHz,CDCl3)δ167.4,150.0,149.9,140.6,138.6,135.3,134.0,133.2,131.1, 129.1,129.0,128.6,128.5,127.7,127.6,120.5,120.1,116.2,116.1,115.7,98.5,31.4, 28.8,26.7,22.3,13.9；EI-MS(m/z)431(M+),HRMS C30H25NO2[M+], calculated value：431.1885, actual measurement Value：431.1894.
Compound 37：
1H NMR(300MHz,CDCl3) δ 7.65 (d, J=8.1Hz, 1H), 7.28 (m, 12H), 6.54 (d, J=7.1Hz, 1H), 6.05 (t, J=6.9Hz, 1H), 2.19 (s, 3H), 2.15 (m, 2H), 1.39 (m, 4H), 0.91 (t, J=6.9Hz, 3H) ；13C NMR(126MHz,CDCl3)δ170.2,163.7,150.3,150.0,140.7,138.2,135.2,133.9,133.2, 131.1,129.1,129.0,128.8,128.6,127.7(2),121.1,120.3,116.4,116.3,116.2,98.7, 69.0,32.7,27.1,22.3,20.9,13.9；EI-MS(m/z)489(M+),HRMS C32H27NO4[M+], calculated value： 489.1940, measured value：489.1948.
Embodiment 17.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- (3- phenyl) the third amino-Isosorbide-5-Nitrae naphthoquinones, according to embodiment 1 Method prepare 141mg light yellow solid Compounds 17.Yield 76%.
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=8.3Hz, 1H), 7.28 (m, 17H), 6.51 (d, J=7.3Hz, 1H),3.29(m,4H)；13C NMR(101MHz,CDCl3)δ166.3,150.0,140.6,140.2,138.5,135.2, 134.0,133.2,131.1,129.1,128.9,128.7,128.6,128.5,128.3,127.7,127.6,126.5, 120.6,120.1,116.2,116.1,115.8,98.5,33.1,30.7；EI-MS(m/z)465(M+),HRMS C33H23NO2[M+], calculated value：465.1729, measured value：465.1728.
Embodiment 18.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- i-butylaminos-Isosorbide-5-Nitrae naphthoquinones, according to the method for embodiment 1 Prepare 153mg light yellow solid Compounds 18, yield 95%.
1H NMR(400MHz,CDCl3) δ 7.66 (d, J=8.3Hz, 1H), 7.40 (m, 3H), 7.34 (m, 2H), 7.29 (m, 3H), 7.23 (m, 4H), 6.54 (d, J=7.3Hz, 1H), 3.35 (hept, J=7.0Hz, 1H), 1.55 (d, J=7.0Hz, 6H)；13C NMR(126MHz,CDCl3)δ171.4,150.0,149.9,140.6,138.5,135.3,134.1,133.2, 131.1,129.1,129.0,128.6(2),127.7,127.6,120.6,120.2,116.3,116.2,115.8,98.6, 29.1,20.6；EI-MS(m/z)403(M+),HRMS C28H21NO2[M+], calculated value：403.1572, measured value：403.1566.
Embodiment 19.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with new penta amino of 2--Isosorbide-5-Nitrae naphthoquinones, according to the method for embodiment 1 Prepare 123mg light yellow solid Compounds 19, yield 74%.
1H NMR(400MHz,CDCl3) δ 7.67 (d, J=8.2Hz, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 7.29 (m, 3H), 7.22 (m, 4H), 6.54 (d, J=7.3Hz, 1H), 1.58 (s, 9H)；13C NMR(126MHz,CDCl3)δ173.6, 150.0,149.9,140.6,138.5,135.4,134.1,133.2,131.2,129.1,129.0,128.6(2),127.7, 127.6,120.6,120.2,116.3,116.2,115.7,98.7,34.4,28.7；EI-MS(m/z)417(M+),HRMS C29H23NO2[M+], calculated value：417.1729, measured value：417.1728.
Embodiment 20.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- cyclopropyl methylamino-Isosorbide-5-Nitrae naphthoquinones, according to embodiment 1 Method prepares 149mg light yellow solid Compounds 20, yield 93%.
1H NMR(400MHz,CDCl3) δ 7.60 (d, J=8.3Hz, 1H), 7.39 (m, 3H), 7.34 (m, 2H), 7.28 (m, 3H), 7.21 (m, 3H), 7.14 (s, 1H), 6.51 (d, J=7.3Hz, 1H), 2.30 (m, 1H), 1.35 (m, 2H), 1.23 (m, 2H)；13C NMR(126MHz,CDCl3)δ168.6,150.0,140.2,138.9,135.3,134.1,133.2,131.1, 129.1,129.0,128.6,128.5,127.7,127.6,120.3,119.9,116.3,116.0,115.5,98.3,9.6, 9.3；EI-MS(m/z)401(M+),HRMS C28H19NO2[M+], calculated value：401.1416, measured value：401.1414.
Embodiment 21.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- adamantyls methylamino-Isosorbide-5-Nitrae naphthoquinones, according to embodiment 1 Method prepare 127mg light yellow solid Compounds 21, yield 64%.
1H NMR(400MHz,CDCl3) δ 7.66 (d, J=8.3Hz, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 7.29 (m, 3H), 7.22 (m, 4H), 6.52 (d, J=7.3Hz, 1H), 2.26 (d, J=2.7Hz, 6H), 2.19 (s, 3H), 1.88 (t, J= 2.8Hz,6H)；13C NMR(101MHz,CDCl3)δ173.1,150.0,149.8,140.3,138.4,135.3,134.0, 133.1,131.1,129.1,129.0,128.5,127.7,127.6,120.5,120.1,116.2,115.6,98.6,40.4, 36.5,36.3,28.0；EI-MS(m/z)495(M+),HRMS C35H29NO2[M+], calculated value：495.2198, measured value： 495.2197.
Embodiment 22.
Except replaced with the naphthoquinones of 2-N-Boc-N- methyl-prop diaminourea methylamino -1,4 2- n-propylamines base -1,4- naphthoquinones with Outside, 93mg light yellow solid Compounds 22, yield 45% are prepared according to the method for embodiment 1.
1H NMR(400MHz,CDCl3) δ 7.65 (d, J=8.3Hz, 1H), 7.39 (m, 3H), 7.34 (m, 2H), 7.29 (m, 3H), 7.23 (m, 3H), 7.19 (s, 1H), 6.55 (d, J=7.4Hz, 1H), 3.81 (t, J=6.8Hz, 2H), 3.24 (s, 2H), 2.93 (d, J=20.9Hz, 3H), 1.43 (d, J=25.7Hz, 9H)；13C NMR(126MHz,CDCl3)δ164.6,155.4, 150.1,150.0,140.8,138.6,135.3,134.0,133.2,131.1,129.1,129.0,128.8,128.6,127.7 (2),120.7,120.2,116.3,116.2,116.0,98.5,79.8,47.0,34.4,29.7,28.4；EI-MS(m/z)518 (M+),HRMS C33H30N2O4[M+], calculated value：518.2206, measured value：518.2205.
Embodiment 23.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- (2- THP trtrahydropyranyls) ethylamino-Isosorbide-5-Nitrae naphthoquinones, according to The method of embodiment 1 prepares 151mg light yellow solid Compounds 23, yield 82%；29mg light yellow solid Compounds 38, Yield 14%.
Compound 23：
1H NMR(300MHz,CDCl3) δ 7.61 (d, J=7.7Hz, 1H), 7.36 (m, 3H), 7.30 (m, 3H), 7.22 (m, 5H), 7.15 (s, 1H), 6.51 (d, J=6.9Hz, 1H), 3.98 (dd, J=11.4,3.0Hz, 2H), 3.44 (td, J=11.7, 1.6Hz, 2H), 2.94 (d, J=7.1Hz, 2H), 2.25 (m, 1H), 1.74 (d, J=11.3Hz, 2H), 1.50 (ddd, J= 25.2,12.3,4.4Hz,2H)；13C NMR(126MHz,CDCl3)δ167.0,151.5,142.1,140.0,136.7,135.4, 134.6,132.5,130.6,130.4,130.2,130.0,129.2,129.1,122.1,121.5,117.7,117.6, 117.3,99.9,69.2,37.4,35.5,34.3；EI-MS(m/z)459(M+),HRMS C31H25NO3[M+], calculated value： 459.1834, measured value：459.1833.
Compound 38：
1H NMR(300MHz,CDCl3) δ 7.65 (dd, J=8.3,0.8Hz, 1H), 7.28 (m, 12H), 6.55 (dd, J= 7.4,0.7Hz, 1H), 5.88 (d, J=7.2Hz, 1H), 4.00 (t, J=11.1Hz, 2H), 3.42 (t, J=11.7Hz, 2H), 2.45 (m, 1H), 2.20 (s, 3H), 1.77 (d, J=12.0Hz, 1H), 1.60 (m, 2H), 1.50 (d, J=11.4Hz, 1H)；13C NMR(126MHz,CDCl3)δ171.6,163.9,151.8,151.5,142.1,139.6,136.6,135.3,134.6, 132.5,130.6,130.4(2),130.1,129.2,129.1,122.6 121.7 117.9,117.7,100.1,73.7, 68.9,68.7,40.0,30.0,29.7,22.2；EI-MS(m/z)517(M+),HRMS C33H27NO5[M+], calculated value： 517.1889, measured value：517.1890.
Embodiment 24.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 8- methoxyl group -2- n-propylamines base-Isosorbide-5-Nitrae naphthoquinones, according to implementation The method of example 1 prepares 78mg light yellow solid Compounds 24, yield 47%；10mg light yellow solid Compounds 39, yield 5%.
Compound 24：
1H NMR(300MHz,CDCl3) δ 7.29 (m, 8H), 7.17 (m, 3H), 6.67 (d, J=8.2Hz, 1H), 6.42 (d, J=8.1Hz, 1H), 3.98 (s, 3H), 3.05 (q, J=7.6Hz, 2H), 1.50 (t, J=7.5Hz, 3H)；13C NMR (126MHz,CDCl3)δ168.6,151.1,150.0,147.6,139.9,139.6,135.6,134.1,131.1,129.1, 128.8,128.2,127.7,127.6,125.8,122.0,116.3,116.2,113.0,107.2,99.9,55.9,22.3, 11.1；EI-MS(m/z)419(M+),HRMS C28H21NO3[M+], calculated value：419.1521, measured value：419.1521.
Compound 39：
1H NMR 300MHz,CDCl3) δ 7.36 (m, 3H), 7.27 (m, 5H), 7.17 (m, 3H), 6.70 (d, J=8.3Hz, 1H), 6.47 (d, J=8.2Hz, 1H), 6.20 (q, J=6.7Hz, 1H), 3.98 (s, 3H), 2.19 (s, 3H), 1.81 (d, J= 6.7Hz,3H)；13C NMR(126MHz,CDCl3)δ170.1,164.3,151.3,150.4,147.6,140.1,139.1, 135.5,134.0,131.1,129.1,128.8,128.3,127.7,127.6,125.7,122.5,117.0,116.2, 113.1,107.5,100.0,65.5,55.9,21.1,18.6；EI-MS(m/z)477(M+),HRMS C30H23NO5[M+], calculate Value：477.1576, measured value：477.1577.
Embodiment 25.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 8- benzyloxy -2- n-propylamines base-Isosorbide-5-Nitrae naphthoquinones, according to implementation The method of example 1 prepares 91mg light yellow solid Compounds 25, yield 46%；18mg light yellow solid Compounds 40, yield 8%.
Compound 25：
1H NMR(300MHz,CDCl3) δ 7.64 (d, J=7.3Hz, 2H), 7.39 (m, 6H), 7.29 (m, 2H), 7.24 (m, 2H), 7.19 (m, 4H), 6.75 (d, J=8.2Hz, 1H), 6.41 (d, J=8.2Hz, 1H), 5.24 (s, 2H), 3.04 (q, J= 7.5Hz, 2H), 1.49 (t, J=7.6Hz, 3H)；13C NMR(126MHz,CDCl3)δ168.4,150.0(2),147.8, 140.0,139.6,137.0,135.6,134.1,131.1,129.1,128.8,128.5,128.3,127.8,127.7, 127.6,126.9,126.1,122.0,116.2,113.4,108.7,99.9,70.3,22.4,11.0；EI-MS(m/z)495(M+),HRMS C34H25NO3[M+], calculated value：495.1834, measured value：495.1839.
Compound 40：
1H NMR(400MHz,CDCl3) δ 7.68 (d, J=7.3Hz, 2H), 7.46 (t, J=7.5Hz, 2H), 7.40 (m, 4H), 7.33 (m, 2H), 7.30 (d, J=1.6Hz, 1H), 7.28 (d, J=1.3Hz, 1H), 7.26 (s, 1H), 7.22 (m, 3H), 6.83 (d, J=8.2Hz, 1H), 6.52 (d, J=8.2Hz, 1H), 6.24 (q, J=6.7Hz, 1H), 5.27 (s, 2H), 2.13 (s, 3H), 1.82 (d, J=6.8Hz, 3H)；13C NMR(126MHz,CDCl3)δ169.5,163.7,149.9,149.6, 147.3,139.7,138.7,136.4,135.0,133.5,130.6,128.6,128.3,128.0,127.8,127.3, 127.2,127.1,126.3,125.5,122.1,116.4,115.7,112.9,108.4,99.5,69.7,65.1,20.5, 18.0；EI-MS(m/z)553(M+),HRMS C36H27NO5[M+], calculated value：553.1889, measured value：553.1891.
Embodiment 26.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- n-propylamines base-Isosorbide-5-Nitrae anthraquinone, according to the method for embodiment 1 Prepare 151mg light yellow solid Compounds 26, yield 86%.
1H NMR(300MHz,CDCl3) δ 8.19 (s, 1H), 7.79 (d, J=8.1Hz, 1H), 7.27 (m, 3H), 7.22 (m, 6H), 7.16 (m, 2H), 7.05 (m, 2H), 6.77 (ddd, J=9.2,6.5,1.3Hz, 1H), 3.06 (q, J=7.6Hz, 2H), 1.52 (t, J=7.6Hz, 3H)；13C NMR(126MHz,CDCl3)δ167.8,153.2,150.8,140.3,138.9,137.3, 134.6(2),131.4,129.3,128.9,128.6,128.3,127.7,127.4,126.9,126.0,123.7,122.9, 121.3,118.8,117.5,115.9,96.5,22.4,11.3；EI-MS(m/z)439(M+),HRMS C31H21NO2[M+], meter Calculation value：439.1572, measured value：439.1570.
Embodiment 27.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- methyl -3- cyclopropyl methylamino-Isosorbide-5-Nitrae naphthoquinones, according to reality The method for applying example 1 prepares 113mg light yellow solid Compounds 27, yield 70%.
1H NMR(300MHz,CDCl3) δ 7.57 (d, J=8.4Hz, 1H), 7.36 (m, 5H), 7.26 (d, J=8.5Hz, 2H), 7.19 (m, 4H), 6.45 (d, J=7.3Hz, 1H), 3.04 (q, J=7.6Hz, 2H), 2.57 (s, 3H), 1.49 (t, J= 7.6Hz,3H)；13C NMR(126MHz,CDCl3)δ167.6,149.5,146.2,139.9,138.8,135.5,134.3, 132.7,131.1,129.1,128.7,128.3,127.6,127.5,127.4,120.3,118.1,116.1,116.0, 115.6,108.1,22.4,11.4,9.9；EI-MS(m/z)403(M+),HRMS C28H21NO2[M+], calculated value：403.1572, Measured value：403.1573.
Embodiment 28.
In addition to replacing 2- n-propylamines base -1,4-naphthoquinone with 2- phenyl -3- cyclopropyl methylamino-Isosorbide-5-Nitrae naphthoquinones, according to reality The method for applying example 1 prepares 167mg light yellow solid Compounds 28, yield 89%.
1H NMR(300MHz,CDCl3) δ 7.87 (d, J=8.0Hz, 2H), 7.65 (d, J=8.3Hz, 1H), 7.48 (t, J =7.7Hz, 2H), 7.38 (m, 4H), 7.27 (m, 3H), 7.19 (d, J=7.9Hz, 2H), 7.10 (m, 3H), 6.52 (d, J= 7.4Hz, 1H), 3.03 (q, J=7.6Hz, 2H), 1.47 (t, J=7.5Hz, 3H)；13C NMR(101MHz,CDCl3)δ167.8, 149.4,145.5,140.6,137.8,135.5,133.7,133.6,133.0,131.1,130.6,129.3,128.8, 128.4,128.0,127.7,127.5,127.4,120.6,119.4,116.4,116.2,116.1,112.6,22.5,11.5； EI-MS(m/z)465(M+),HRMS C33H23NO2[M+], calculated value：4658.1729, measured value：465.1727.
Illustrate that biology of the compound by the invention in terms of cell breeds growth inhibition is living below by pharmacological evaluation Property.
Using KB, KB/VCR and A549 cell, compound processing 72h is separately added into, with the propagation of srb assay detection compound (this experiment uses method of testing and equipment for method and apparatus conventional in the art, institute for growth inhibition effect and its degree It is that analysis is pure or chemical pure with reagent, cell used is same experiments conventional commercial cell).
Using srb assay, with tanshinone-I (Tan-I) for positive control, preliminary assessment compound is to KB, KB/VCR and A549 The inhibited proliferation of cell, the results are shown in Table 1.Compound uses 20 μM of highest final concentration, processing cell 72 hours in experiment.
Inhibited proliferation of the compound of table 1. to KB, KB/VCR and A549 cell
Above example is enumerated only as the example of embodiment of the present invention, does not constitute any limit to the present invention System, it will be appreciated by those skilled in the art that the modification in the range of without departing from the essence of the present invention and design each falls within the present invention Protection domain.

Claims (8)

1. a kind of Fourth Ring Nai Bing oxazole analog derivatives, it has the structure shown in below formula (I)：
Wherein,
X is O；
Y is O；
Z is N；
R1And R2It is separately substituted or unsubstituted C6-C10Aryl or five yuan or six membered heteroaryl；Wherein, substituent is selected From halogen atom, hydroxyl, carboxyl, C1-C6Alkoxy carbonyl, amino, C1-C6Acylamino-, nitro, C1-C10Alkyl, halo C1-C10 Alkyl, C1-C10Alkoxy, C1-C6Alkylamino, C6-C10Aryl or five yuan or six membered heteroaryl；
R3And R4It is separately hydrogen, or, R3And R4It can connect to form C6-C10Aryl or five yuan or six membered heteroaryl；
R5And R7It is separately hydrogen, C1-C6Alkoxy, C1-C10Alkyl, C6-C10Aryl or five yuan or six membered heteroaryl；
R6For substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C3-C10Cycloalkyl；Wherein, substituent is selected from C1-C6 Alkyl carbonyl epoxide, monosubstituted, disubstituted or unsubstituted amino, C3-C6Oxa fatty ring, wherein, the substituent of the amino is selected from C1-C6Alkyl, C1-C6Alkoxy carbonyl.
2. Fourth Ring Nai Bing oxazole analog derivatives as claimed in claim 1, it is characterised in that：
R1And R2It is separately substituted or unsubstituted phenyl；Wherein, substituent is selected from halogen atom, carboxyl, C1-C6Alcoxyl Base, C1-C6Alkyl or halo C1-C6Alkyl.
3. Fourth Ring Nai Bing oxazole analog derivatives as claimed in claim 1, it is characterised in that：
R3And R4It is separately H；Or, R3And R4It can connect to form phenyl.
4. a kind of Fourth Ring Nai Bing oxazole analog derivatives, it is characterised in that the derivative is selected from one of following structural formula Compound：
5. a kind of method for preparing derivative as claimed in claim 1, it is synthesized by following route：
2- substituted-aminos quinones is activated into the cascade reaction participated in formation target compound (I) with substitution alkynes by C-H, Reaction equation is as follows：
Wherein, 5 of quinones are activated with metallic catalyst Rh, and add oxidant Cu (OAc)2.H2O and additive AgSbF6, synthesis is reacted in solvent t-AmOH.
6. a kind of method that method according to claim 5 prepares compound as claimed in claim 4, its reaction equation For：
7. the answering in the medicine as cytostatic agent is prepared of the Fourth Ring Nai Bing oxazoles analog derivatives described in claim 1 With.
8. application of the Fourth Ring Nai Bing oxazole analog derivatives in antineoplastic is prepared described in claim 1.
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A FACILE SYNTHESIS OF NOVEL HETEROPOLYCYCLIC PYRAZINES AND OXAZOLES AND MECHANISTIC STUDIES OF 2，3-DIHYDROBENZO[de]CHROMENE-7，8-DIONE WITH AMINES;Hua-pei Jian,等;《Heterocycles》;20080229;第75卷(第7期);1773-1778 *

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