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WO2018161476A1 - 一种酰胺类化合物及其制备方法和用途 - Google Patents

一种酰胺类化合物及其制备方法和用途 Download PDF

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WO2018161476A1
WO2018161476A1 PCT/CN2017/091212 CN2017091212W WO2018161476A1 WO 2018161476 A1 WO2018161476 A1 WO 2018161476A1 CN 2017091212 W CN2017091212 W CN 2017091212W WO 2018161476 A1 WO2018161476 A1 WO 2018161476A1
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aryl
alkyl
cycloalkyl
heteroaryl
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French (fr)
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袁其朋
谢瑞
邓炳华
李岩
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Beijing University of Chemical Technology
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Beijing University of Chemical Technology
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07C333/18—Esters of dithiocarbamic acids
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/21—Radicals derived from sulfur analogues of carbonic acid

Definitions

  • HDAC zinc ion-dependent metalloproteinase family-histone deacetylase
  • amide HDAC inhibitors are in clinical research. Among them, Tacedinaline (1, CI-994) shows certain inhibitory activity against HDAC and has a broad spectrum of antitumor activity, making it the first amide HDAC inhibition to enter clinical trials.
  • Agent, CI-994 is currently used in combination with gemcitabine in phase II clinical trials for patients with solid tumors such as non-small cell lung cancer and colon cancer.
  • Sedabamide (2, Chidamide, CS055) is an approved oral anti-acetylase inhibitor developed by Shenzhen Microcore Biotechnology Co., Ltd., and the approved indication is recurrent and refractory peripheral T-cell lymphoma.
  • Sidabenamine is in the clinical stage for the treatment of lung cancer, stomach cancer, liver cancer and breast cancer.
  • benzamide compounds such as MS-275 (3), and MGCD-0103 (4) is in the clinical stage.
  • Aminodithioformate is a class of compounds with a wide range of biological activities such as antioxidant, antibacterial, antiviral, and antitumor activities.
  • Brassinin (Compound 5 in the structure shown in the following figure) is a natural compound having an aminodithioformate structure extracted from Brassica juncea, and this compound was found to have excellent antitumor activity.
  • a series of derivatives of Brassinin (compounds 6, 7, 8 in the structure shown in the following figure) have been synthesized, and these derivatives also have excellent antitumor and antioxidant activities.
  • the above structural formula is a compound containing an aminodithioformate structure
  • the inventors of the present invention have creatively introduced a broadly biologically active aminodithioformate structure into the development of novel HDAC inhibitors, synthesized a series of novel skeletal structure amide compounds, and have HDAC inhibitory activity,
  • the anti-tumor activity in vitro the effect on the formation of monoclonal cells in tumor cells, the influence on tumor cell cycle and the effect on tumor cell apoptosis, the compounds in this patent showed more than the reference drugs CI994 and Chidamide (CS055).
  • MS275 has stronger antitumor activity and selectivity for HDAC enzymes.
  • the present invention relates to the design and synthesis of a class of compounds.
  • the present invention provides an amide compound which is more excellent in pharmacodynamic activity, a preparation method and use thereof. The reason why the present invention can solve the above problems is achieved by the following technical solutions:
  • A is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • Z is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • R 3 and R 4 each independently are selected from hydrogen, hydroxy, amino, thiol, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, hetero Aryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, alkyl, cycloalkyl, cycloalkylalkyl , alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocycle
  • the base, alkenyl, alkynyl group is optionally unsubstituted or substituted by one or more substituents, each independently selected from alkyl,
  • A is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkyne
  • the group is optionally unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino , hydroxy, mercapto, carboxy, alkoxy, cycloalkoxy, halogen, cyano, nitro, nitroso, sulfo;
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • X 1 , X 2 , X 3 , X 4 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, amino, hydroxy, decyl, carboxy, Alkoxy, cycloalkoxy, haloaryl, alkoxycarbonyl, halogen, cyano, nitro, nitroso, amido, thiocyano, isothiocyano, ureido, sulfo;
  • the compound is selected from the group consisting of compounds of formula IV:
  • R 1 and R 2 satisfy one of the following two conditions: (1) R 1 and R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl , arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl, alkenyl, alkynyl, above Alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, heterocycle And optionally substituted or substituted by one or more substituents each independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxy
  • a pharmaceutical composition comprising: the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, is provided.
  • a compound of the above formula I and a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial
  • a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial
  • antiviral and anti-oxidant drugs for use in the treatment or prevention of antitumor, anticancer, anti-inflammatory, antibacterial.
  • the tumor or cancer is selected from the group consisting of melanoma, gastric cancer, cervical cancer, ovarian cancer, liver cancer, lung cancer, nasopharyngeal cancer, colon cancer, rectal cancer, lymphoma, and blood cancer.
  • A, Z, R 1 , R 2 , R 3 , R 4 are the compounds of the first aspect of the invention as defined in formula I.
  • the base used in the reaction step (a) is selected from the group consisting of potassium phosphate, potassium carbonate, sodium phosphate, sodium carbonate, cesium carbonate, aluminum oxide, dipotassium hydrogen phosphate, and hydrogen phosphate.
  • the peptide condensing agent used is selected from the group consisting of: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrolidine hexafluorophosphate Phosphorus, N,N'-dicyclohexylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate.
  • alkyl group the following linear or branched groups may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers, n-heptyl and their respective isomers, n-octyl and its various isomers, n-decyl and Its various isomers.
  • cycloalkyl group the following groups may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl; and by two or more
  • the above-mentioned single ring is a fused ring, a bridged ring, or a spiro ring group formed by a common side and a common carbon atom.
  • alkenyl refers to a group formed in the case where one or more double bonds are present in the above alkyl group (except for a methyl group).
  • alkynyl refers to a group formed in the case where one or more triple bonds are present in the above alkyl group (except for a methyl group).
  • alkoxy refers to a group in which an oxygen atom is bonded to the above alkyl group and is bonded to the remainder of the molecule by a single bond of the oxygen atom, which encompasses various possible geometric isomers. With stereoisomeric groups.
  • alkoxy groups the following straight or branched groups may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, n-Butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and seven other isomers, n-hexyloxy and sixteen other isomers, n-heptyloxy and each Isomers, n-octyloxy groups, and various isomers, n-decyloxy groups, and various isomers.
  • aryl refers to an aromatic ring system consisting of at least 6 carbon atoms, which ring system may be monocyclic, bicyclic or polycyclic, wherein the bicyclic and polycyclic rings may be bonded by a single ring through a single bond. Formed in a fused manner.
  • aryl group the following groups may be mentioned: phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, pentenyl, heptyl, triphenylene, And tetraphenyl, penfenolyl, pentacene, tetra-p-phenylene, hephenenyl, hexaphenyl, decyl, trimethylene, heptendyl, heptaphenyl, egg phenyl, biphenyl Base, binaphthyl.
  • heteroaryl refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which ring system may be monocyclic, Bicyclic and polycyclic, wherein the bicyclic ring and the polycyclic ring may be formed by a single ring by a single bond connection or a condensed manner.
  • heteroaryl groups the following groups may be mentioned: oxazolyl, isoxazolyl, imidazolyl, furyl, fluorenyl, isodecyl, pyrrolyl, triazolyl, triazinyl , tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, Benzothiophenyl, benzofuranyl, oxazolyl, isoquinolyl, quinazolinyl, naphthyridinyl, fluorenyl, thiadiazolyl, pyridazinyl, phenazinyl, coumarinyl, Pyridopyridyl, pyridopyrida
  • heterocyclyl refers to a non-aromatic 3-18 membered ring system composed of a carbon atom and a hetero atom independently selected from N, O or S, which ring system may be monocyclic, bicyclic, Or a polycyclic ring, which may also be a fused ring, a bridged ring, a spiro ring, and may optionally contain one or more double bonds.
  • the heterocyclic group the following groups may be mentioned: acridinyl group, benzodioxanyl group, benzopyranyl group, benzohydropyranyl group, dioxolane group, decahydrogen Isoquinolyl, indanyl, porphyrin, isoindolyl, isochroman, morpholinyl, piperazinyl, 2-oxopiperrazinyl, octahydrofluorenyl , octahydroisodecyl, 4-piperidinone, dihydroquinolyl, dihydroisoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, 1-(diphenylmethyl) Piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl.
  • alkylcycloalkyl as used in the present invention means a cycloalkyl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein the cycloalkyl group and the alkyl group are as defined above.
  • arylalkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by an aryl group, wherein the aryl group and the alkyl group are as defined above.
  • alkylaryl as used in the present invention means an aryl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein the aryl group and the alkyl group are as defined above.
  • heteroarylalkyl refers to an alkyl group wherein one or more hydrogen atoms are independently substituted by a heteroaryl group, wherein said heteroaryl group and alkyl group are as defined above.
  • alkylheteroaryl refers to a heteroaryl group in which one or more hydrogen atoms are independently substituted by an alkyl group, wherein said heteroaryl group and alkyl group are as defined above.
  • alkylheterocyclyl as used in the present invention means a heterocyclic group wherein one or more hydrogen atoms are independently substituted by an alkyl group, wherein the heterocyclic group and the alkyl group are as defined above.
  • heterocyclylalkyl refers to an alkyl group in which one or more hydrogen atoms are independently substituted by a heterocyclic group, wherein the heterocyclic group and the alkyl group are as defined above.
  • Substituent means that the above substituent may be substituted by a single substituent, or the substituents may be freely combined to form a new substituent to participate in the substitution.
  • substituents the following groups may be mentioned: alkyl, cycloalkyl, aryl, alkylcycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, alkane Heteroaryl, heterocyclic, heterocyclylalkyl, alkylheterocyclyl, heterocyclylalkenyl, alkenylheterocyclyl, heterocyclylalkynyl, alkynylheterocyclyl, alkoxycarbonyl , haloaryl, cyanoaryl, alkoxycarbonylheteroaryl, haloheteroaryl, cyanoheteroaryl, haloarylalkyl, alkoxyarylalkyl, halo Aryl
  • Example 1 Synthesis of a part of the compounds in the present invention
  • Step (1) Weigh 1,3,3,4-tetrahydroisoquinoline 0.3 g (2.25 mmol), 4-bromomethylbenzoic acid 0.484 g (2.25 mmol), potassium phosphate 0.478 g (2.25 mmol), 30 ml of acetone was placed in a single-mouth round bottom flask with a volume of 100 ml, and magnetic stirring at room temperature After 30 minutes, 0.857 g (11.25 mmol) of carbon disulfide was added, and magnetic stirring was continued at room temperature, and the progress of the reaction was followed by a thin layer chromatography plate, and the final reaction completion time was 1 h. After the reaction was completed, the reaction system was spin-dried using a vacuum rotary evaporator.
  • Step (2) adding 15 ml of DMF (N,N-dimethylformamide) to the system after spin-drying in the step (1), and adding BOP (benzotriazol-1-yloxytri(dimethyl) Base amino)phosphonium hexafluorophosphate) 1.195g (2.70mmol), triethylamine 0.912g (9.00mmol), stirred at room temperature for 10min, then added o-phenylenediamine 0.292g (2.7mmol), continue magnetic stirring at room temperature, with thin The layer chromatography plate was used to track the progress of the reaction, and the final reaction time was 2 h.
  • DMF N,N-dimethylformamide
  • the compounds M102 to M134 were prepared in a similar manner to the compound M101 except that the starting material 1,2,3,4-tetrahydroisoquinoline in the step (1) was replaced with 1,2,3,4-tetrahydroquinoline ( 0.3 g, 2.25 mmol) (Compound M102); tetrahydropyrrole (0.16 g, 2.25 mmol) (Compound M103); 2-methylpiperidine (0.22 g, 2.25 mmol) (Compound M104); 4-methylpiperidine (0.22 g, 2.25 mmol) (Compound M105); 1-(Diphenylmethyl)piperazine (0.57 g, 2.25 mmol) (Compound M106); indoline (0.27 g, 2.25 mmol) (Compound M107) ; porphyrin-5-carboxylic acid methyl ester (0.40 g, 2.25 mmol) (compound M108); 5-chloroindoline (0.35 g, 2.25 mmol

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Abstract

一种酰胺类化合物及其制备方法和用途涉及药物化学领域。该化合物具有抑制癌细胞增殖的能力，达到治疗癌症的目的。尤其对抑制人皮肤黑色素瘤A375、人胃癌细胞MGC80-3、人宫颈癌细胞HeLa、人肝癌细胞SMMC7721、人肺癌细胞H1299、人结肠癌细胞HCT116具有优异的抑制癌细胞增殖的活性。该化合物具有下列通式I所示的结构,其中A、Z、R1、R2、R3和R4如本申请说明书中所定义。

Description

一种酰胺类化合物及其制备方法和用途 技术领域
本发明涉及一类酰胺类化合物及其制备方法和用途。
背景技术
寻找和发现有效的非细胞毒抗肿瘤药物是目前抗肿瘤药物化学研究的一个重点，近年来，一类锌离子依赖性金属蛋白酶家族-组蛋白去乙酰化酶(histone deacetylase，HDAC)成为抗肿瘤药物设计的新靶点。
组蛋白去乙酰化酶(histone deacetylase，HDAC)和组蛋白乙酰转移酶(histone acetyltransferase，HAT)为真核细胞中广泛存在的的一类相互拮抗的蛋白酶，它们共同调控着组蛋白末端氨基酸残基的乙酰化，使之处于平衡状态。组蛋白的乙酰化和去乙酰化修饰为调控基因转录的一种方式，组蛋白的乙酰化程度通过影响染色质的结构进而影响基因的表达。在肿瘤细胞中HDAC过量表达，从而抑制了某些抑癌基因的表达。大量文献表明抑制HDAC的活性能有效地抑制肿瘤细胞的生长、转移和和侵袭。HDAC抑制剂已成为重要的抗肿瘤作用的靶标，其中有一类具有苯甲酰胺结构的HDAC抑制剂具有良好的口服生物活性和抗肿瘤活性而受到人们的关注。
许多酰胺类HDAC抑制剂正处于临床研究阶段，其中Tacedinaline(1，CI-994)对HDAC显示出一定的抑制活性，具有广谱的抗肿瘤活性，成为第一个进入临床试验的酰胺类HDAC抑制剂，CI-994目前在Ⅱ期临床试验中与吉西他滨联用治疗非小细胞肺癌、结肠癌等实体瘤患者。西达本胺(2，Chidamide，CS055)是深圳微芯生物科技有限公司开发的已获准上市的组蛋白去乙酰化酶口服抑制剂，批准的适应症为复发及难治性外周T细胞淋巴瘤，西达本胺对肺癌，胃癌，肝癌，乳腺癌等的治疗正处于临床阶段。还有许多苯甲酰胺类化合物如MS-275(3)，MGCD-0103(4)正处于临床阶段。
Figure PCTCN2017091212-appb-000001
上面结构式是已上市或正处于临床研究的苯甲酰胺类化合物
氨基二硫代甲酸酯是一类具有广泛生物活性的化合物，如抗氧化、抗菌、抗病毒、抗肿瘤活性。Brassinin(下图中所示的结构中的化合物5)是从十字花科植物卷心菜中提取出来的具有氨基二硫代甲酸酯结构的天然化合物，此化合物被发现具有很好的抗肿瘤活性。Brassinin的一系列衍生物(下图中所示的结构中的化合物6、7、8)已被合成，这些衍生物同样具有很好的抗肿瘤、抗氧化活性。
Figure PCTCN2017091212-appb-000002
上面结构式是含有氨基二硫代甲酸酯结构的化合物
本专利发明人创造性地将具有广泛生物活性的氨基二硫代甲酸酯结构引入到新型HDAC抑制剂的开发中，合成了一系列新的骨架结构的酰胺类化合物，并对其HDAC抑制活性、体外抗肿瘤细胞活性、对肿瘤细胞单克隆形成影响、对肿瘤细胞周期影响以及对肿瘤细胞凋亡影响进行评价，本专利中的化合物显示出比参比药物CI994和西达本胺(Chidamide,CS055)以及MS275更强的抗肿瘤活性以及对HDAC酶的选择性。
发明内容
本发明涉及一类化合物的设计与合成，为了克服现有技术的上述不足，本发明提供一种药效活性更优异的酰胺类化合物及其制备方法和用途。本发明之所以能够解决上述问题乃是通过以下技术方案给予实现：
在本发明的第一方面，提供了具有通式I所示的化合物或其药学上可接受的盐或其溶剂合物或其前药分子：
Figure PCTCN2017091212-appb-000003
其中，
A选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
Z选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也可以是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
R3和R4各自独立地选氢、羟基、氨基、巯基、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、 磺基；
在本发明的第一方面的优先实施方式中，所述的化合物选自通式Ⅱ所示化合物：
Figure PCTCN2017091212-appb-000004
其中，
A选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
Z选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也可以是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的 取代基；
X1、X2、X3、X4各自独立地选自氢、烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基；
在本发明的第一方面的优先实施方式中，所述的化合物选自通式Ⅲ所示化合物：
Figure PCTCN2017091212-appb-000005
其中，
R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也可以是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
X1、X2、X3、X4各自独立地选自氢、烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基；
在本发明的第一方面的优先实施方式中，所述的化合物选自式Ⅳ所示化合物：
Figure PCTCN2017091212-appb-000006
其中，
R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也可以是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
在本发明的第一方面的最优选实施方式中，提供了以下具体化合物：
表1本发明合成其中一部分的化合物
Figure PCTCN2017091212-appb-000007
Figure PCTCN2017091212-appb-000008
Figure PCTCN2017091212-appb-000009
Figure PCTCN2017091212-appb-000010
Figure PCTCN2017091212-appb-000011
Figure PCTCN2017091212-appb-000012
在本发明的第二方面，提供一种药物组合物，所述药物组合物包含：本发明第一方面所述化合物或其药学上可接受的盐或其溶剂合物或其前药分子。
在本发明的第三方面，提供了上述通式Ⅰ化合物及其药学上可接受的盐或其溶剂合物或其前药分子在制备用于治疗或预防抗肿瘤、抗癌、抗炎、抗菌、抗病毒、抗氧化的药物方面的用途。
在本发明的第三方面的优选实施方式中，所述肿瘤或癌症选自于黑色素瘤、胃癌、宫颈癌、卵巢癌、肝癌、肺癌、鼻咽癌、结肠癌、直肠癌、淋巴癌、血癌、骨髓癌、脑癌、皮肤癌、骨癌、鼻咽癌、胰腺癌、肾癌、甲状腺癌、前列腺癌，膀胱癌、食管癌、乳腺癌。
在本发明的第四方面，提供制备上述通式Ⅰ化合物的方法，该方法包括如下步骤：
(a)将化合物1与化合物2与二硫化碳在碱存在下反应得到化合物3；
Figure PCTCN2017091212-appb-000013
(b)将化合物3与化合物4在肽缩合剂作用下反应得到化合物5
Figure PCTCN2017091212-appb-000014
其中A、Z、R1、R2、R3、R4为本发明的第一方面提供化合物的通式I中所定义。
在本发明的第四方面的优选实施方式中，反应步骤(a)使用的碱选自：磷酸钾、碳酸钾、磷酸钠、碳酸钠、碳酸铯、氧化铝、磷酸氢二钾、磷酸氢二钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢化钠、氢氧化钾、二乙胺、三乙胺、N-甲基吗啉、4-二甲氨基吡啶；和/或反应步骤(b)所用肽缩合剂选自:苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷、N,N'-二环己基碳二亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸。
附图说明
图1：化合物对肿瘤细胞单克隆形成能力的影响
具体实施方式
本发明中使用的术语“烷基”是指仅由碳原子和氢原子组成、且不具有不饱和度(例如双键、三键或环)的基团，其涵盖了各种可能的几何异构基团与立体异构基团。该基团通过单间与分子的其余部分向连。作为烷基的非限制性实例，可以列举以下直链或支链的基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体、正庚基及其各自异构体、正辛基及其各种异构体、正壬基及其各种异构体。
本发明中使用的术语“环烷基”是指至少3个碳原子组成的饱和非芳基环系，该环系可以是单环、双环、多环，也可以是稠环、桥环、螺环。作为环烷基的非限制性实例，可以列举以下基团：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基；以及由两个或多个上述单环通过公共边和公共碳原子形成的稠环、桥环、或螺环基团。
本发明中使用的术语“烯基”是指在上述烷基基团中(除甲基外)存在一个或多个双键的情况下所形成的基团。
本发明中使用的术语“炔基”是指在上述烷基基团中(除甲基外)存在一个或多个叁键的情况下所形成的基团。
本发明中使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举以下直连或支链的基团：甲氧基、乙氧基、正丙氧基、异丙氧基、 正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基以及另外七种异构体、正己氧基以及另外十六种异构体、正庚氧基以及各种异构体、正辛氧基以及各种异构体、正壬氧基以及各种异构体。
本发明中使用的术语“芳基”是指由至少6个碳原子组成的芳香环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为芳基的非限制性实例，可以列举以下基团：苯基、萘基、蒽基、菲基、茚基、芘基、苝基、戊搭烯基、庚搭烯基、三亚苯基、并四苯基、戊芬基、并五苯基、四邻亚苯基、己芬基、并六苯基、蔻基、三亚萘基、庚芬基、并七苯基、卵苯基、联苯基、联萘基。
本发明中使用的术语“杂芳基”是指具有一个或多个独立地选自N、O或S的杂原子的5-14元芳香族杂环环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的非限制性实例，可以列举以下基团：噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、咔唑基、异喹啉基、喹唑啉基、萘啶基、嘌呤基、噻二唑基、吲哚嗪基、吩嗪基、香豆素基、吡啶并吡啶基、吡啶并哒嗪基、咪唑并吡啶基、咪唑并哒嗪基；以及由上述杂芳基通过单键连接方式或稠合方式形成的基团。
本发明中使用的术语“杂环基”是指由碳原子和独立选自N、O或S的杂原子组成的非芳香族3-18元环系，该环系可以是单环、双环、或多环，也可以是稠环、桥环、螺环，并且可以任选地包含一个或多个双键。作为杂环基的非限制性实例，可以列举以下基团：吖啶基、苯并二氧杂环己基、苯并吡喃基、苯并二氢吡喃基、二氧戊环基、十氢异喹啉基、茚满基、吲哚啉基、异吲哚啉基、异苯并二氢吡喃基、吗啉基、哌嗪基、2-氧代哌嗪基、八氢吲哚基、八氢异吲哚基、4-哌啶酮基、二氢喹啉基、二氢异喹啉基、四氢喹啉基、四氢异喹啉基、1-(二苯基甲基)哌嗪基、四氢呋喃基、四氢吡喃基、四氢吡咯基、哌啶基。
本发明中使用的术语“环烷基烷基”是指一个或多个氢原子被环烷基独立取代的烷基，其中所述的环烷基和烷基如上文所定义。
本发明中使用的术语“烷基环烷基”是指一个或多个氢原子被烷基独立取代的环烷基，其中所述的环烷基和烷基如上文所定义。
本发明中使用的术语“芳基烷基”是指一个或多个氢原子被芳基独立取代的烷基，其中所述的芳基和烷基如上文所定义。
本发明中使用的术语“烷基芳基”是指一个或多个氢原子被烷基独立取代的芳基，其中所述的芳基和烷基如上文所定义。
本发明中使用的术语“杂芳基烷基”是指一个或多个氢原子被杂芳基独立取代的烷基，其中所述的杂芳基和烷基如上文所定义。
本发明中使用的术语“烷基杂芳基”是指一个或多个氢原子被烷基独立取代的杂芳基，其中所述的杂芳基和烷基如上文所定义。
本发明中使用的术语“烷基杂环基”是指一个或多个氢原子被烷基独立取代的杂环基，其中所述的杂环基和烷基如上文所定义。
本发明中使用的术语“杂环基烷基”是指一个或多个氢原子被杂环基独立取代的烷基，其中所述的杂环基和烷基如上文所定义。
本发明中使用的术语“卤素”或“卤代”是指氟、氯、溴或碘。
本发明中所叙述的“取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基”是指上述取代基可单独取代基参与取代，或取代基之间自由组合形成新的取代基参与取代。作为此类取代基的非限制性实例，可以列举以下基团：烷基、环烷基、芳基、烷基环烷基、环烷基烷基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、杂环基烯基、烯基杂环基、杂环基炔基、炔基杂环基、烷氧基羰基芳基、卤代芳基、氰基芳基、烷氧基羰基杂芳基、卤代杂芳基、氰基杂芳基、卤代芳基烷基、烷氧基芳基烷基、卤代杂芳基烷基、烷氧基杂芳基烷基、卤代杂芳基烯基、卤代杂芳基炔基、烷氧基杂芳基烯基、烷氧基杂芳基炔基。
通过以下的具体实施方式，对本发明的上述内容再作进一步的详细解释及展述，使本领域的普通技术人员能够更加容易地理解本发明，但不应该将此理解为本发明所述主题的范围仅限于以下的实例及限制本发明的任何或所有权利，更不应该背离本发明的精神。
实施例1：合成本发明中的一部分化合物
4-{[(2-氨基苯基)氨基]羰基}苄基3,4-二氢异喹啉-2(1H)-二硫代羧酸酯(M101)的制备。
步骤(1)：称量1,2,3,4-四氢异喹啉0.3g(2.25mmol)，4-溴甲基苯甲酸0.484g(2.25mmol)，磷酸钾0.478g(2.25mmol)，30ml丙酮置于容积为100ml的单口圆底烧瓶中，常温磁力搅拌 30分钟后，加入二硫化碳0.857g(11.25mmol)，继续常温磁力搅拌，用薄层层析板跟踪反应进度，最终反应完成时间为1h。反应完成后使用真空旋转蒸发仪将反应体系旋干。
步骤(2)：向步骤(1)中旋干后的体系中加入15ml DMF(N,N-二甲基甲酰胺)，加入BOP(苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐)1.195g(2.70mmol)，三乙胺0.912g(9.00mmol)，常温搅拌10min后加入邻苯二胺0.292g(2.7mmol)，继续常温磁力搅拌，用薄层层析板跟踪反应进度，最终反应时间为2h。反应完成后，向反应液中加入350ml乙酸乙酯萃取，倒入分液漏斗中，加入饱和碳酸钠水溶液洗3次，饱和氯化钠洗2次，有机相用无水硫镁干燥，过滤，旋蒸得固体，向固体中加入甲醇，过滤，用甲醇洗固体，用乙醚洗固体并抽干得固体，再经过柱层析纯化最终得灰白色固体0.62g，产率为：63.7％；mp150.8-152.1℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.95(d,J＝7.2Hz,2H),7.56(d,J＝7.3Hz,2H),7.26(m,5H),6.99(t,J＝6.9Hz,1H),6.80(d,J＝7.5Hz,1H),6.62(t,J＝6.8Hz,1H),5.20(m,2H),4.92(s,2H),4.70(s,2H),4.23(m,2H)2.99(m,2H)；13C NMR(400MHz,DMSO-d6):δ＝27.7,28.3,47.8,50.0,51.1,53.5,116.1,116.2,123.3,126.5,126.6,127.9,129.0,132.8,133.6,134.9,140.2,143.1,164.9,194.0ppm；C24H23N3OS2,MS(ES+)m/z:434.14(M+H)+.
化合物M102至M134的制备方法与化合物M101相似，只是将步骤(1)中的原料1,2,3,4-四氢异喹啉分别替换为1,2,3,4-四氢喹啉(0.3g，2.25mmol)(化合物M102)；四氢吡咯(0.16g，2.25mmol)(化合物M103)；2-甲基哌啶(0.22g，2.25mmol)(化合物M104)；4-甲基哌啶(0.22g，2.25mmol)(化合物M105)；1-(二苯基甲基)哌嗪(0.57g，2.25mmol)(化合物M106)；二氢吲哚(0.27g，2.25mmol)(化合物M107)；吲哚啉-5-羧酸甲酯(0.40g，2.25mmol)(化合物M108)；5-氯二氢吲哚(0.35g，2.25mmol)(化合物M109)；5-硝基二氢吲哚(0.37g，2.25mmol)(化合物M110)；6-硝基二氢吲哚(g，2.25mmol)(化合物M111)；二苄胺(0.44g，2.25mmol)(化合物M112)；1-甲基哌嗪(0.23g，2.25mmol)(化合物M113)；1-苯基哌嗪(0.37g，2.25mmol)(化合物M114)；1-(4-甲基苯基)哌嗪(0.40g，2.25mmol)(化合物M115)；1-(4-甲氧基苯基)哌嗪(0.43g，2.25mmol)(化合物M116)；1-(4-异氰基苯基)哌嗪(0.42g，2.25mmol)(化合物M117)；1-(4-氯苯基)哌嗪(0.44g，2.25mmol)(化合物M118)；1-(4-氟苯基)哌嗪(0.41g，2.25mmol)(化合物M119)；1-(2-氟苯基)哌嗪(0.41g，2.25mmol)(化合物M120)；1-环己基哌嗪(0.39g，2.25mmol)(化合物M121)；1-(4-吡啶基)哌嗪(0.37g，2.25mmol)(化合物M122)；1-(3-吡啶基)哌嗪(0.37g，2.25mmol)(化合物M123)；1-(2-嘧啶基)哌嗪(0.37g，2.25mmol)(化合物M124)；1-(2-吡嗪基)哌嗪(0.37g，2.25mmol)(化合物M125)；1-[(4-吡啶基)甲基]哌嗪(0.40g， 2.25mmol)(化合物M126)；1-[(3-吡啶基)甲基]哌嗪(0.40g，2.25mmol)(化合物M127)；1-[(2-吡啶基)甲基]哌嗪(0.40g，2.25mmol)(化合物M128)；1-苄基哌嗪(0.40g，2.25mmol)(化合物M129)；1-苯乙基哌嗪(0.43g，2.25mmol)(化合物M130)；N-甲基-N-(4-吡啶甲基)胺(0.27g，2.25mmol)(化合物M131)；N-甲基-N-(3-吡啶甲基)胺(化合物M132)；N-乙基-N-(4-吡啶甲基)胺(0.31g，2.25mmol)(化合物M133)；3-甲氨基吡啶(0.24g，2.25mmol)(化合物M134)。
化合物M102至M134的结构数据如下：
4-{[(2-氨基苯基)氨基]羰基}苄基3,4-二氢喹啉-1(2H)-二硫代羧酸酯(M102)
灰白色固体；产率78.5％；mp 200.7-201.8℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),7.92(d,J＝8.1Hz,2H),7.60(m,1H),7.50(d,J＝8.1Hz,2H),7.25(m,4H),6.98(t,J＝7.7Hz,1H),6.80(m,1H),6.61(t,J＝7.4Hz,1H),4.91(s,2H),4.59(s,2H),4.36(t,J＝6.4Hz,2H),2.70(t,J＝6.7Hz,2H),1.99(m,2H)；13C NMR(400MHz,DMSO-d6):δ＝23.0,25.5,40.7,51.9,116.0,116.1,123.2,125.7,126.0,126.4,126.6,127.5,127.9,128.7,129.0,133.6,134.5,139.6,139.7,143.1,164.9,196.7ppm；C24H23N3OS2,MS(ES+)m/z:434.13(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基吡咯烷-1-二硫代羧酸酯(M103)
灰白色固体；产率83.2％；mp 116.3-117.2℃；1H NMR(400MHz,DMSO-d6):δ＝9.64(s,1H),7.93(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,2H),7.18(d,J＝7.6Hz,1H),6.98(m,1H),6.80(m,1H),6.61(m,1H),4.97(m,2H),4.66(m,2H),3.81(t,J＝7.0Hz,2H),3.63(t,J＝6.8Hz,2H),2.03(m,2H),1.93(m,2H)；13C NMR(400MHz,DMSO-d6):δ＝8.54,23.7,25.6,45.6,50.5,55.2,116.1,123.3,126.5,127.9,128.8,133.5,140.7,143.0,164.9,190.1ppm；C19H21N3OS2,MS(ES+)m/z:372.12(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基2-甲基哌啶-1-二硫代羧酸酯(M104)
灰白色固体；产率79.3％；mp 106.3-108.4℃；1H NMR(400MHz,DMSO-d6):δ＝9.67(s,1H),7.95(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,2H),7.19(d,J＝7.5Hz,1H),6.98(m,1H),6.80(m,1H),6.61(m,1H),4.64(m,6H),3.07(m,2H),1.63(m,4H),1.20(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝8.46,18.0,25.2,29.6,45.4,54.1,116.1,123.1,126.5,127.9,129.0,133.5,140.2,143.0,165.0,193.6ppm；C21H25N3OS2,MS(ES+)m/z:400.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-甲基哌啶-1-二硫代羧酸酯(M105)
白色固体；产率48.1％；mp 154.7-155.9℃；1H NMR(400MHz,DMSO-d6):δ＝9.64(s,1H),7.93(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,2H),7.18(d,J＝7.6Hz,1H),6.98(m,1H),6.80(m,1H), 6.61(m,1H),5.28(m,1H),4.91(m,2H),4.64(m,2H),4.46(m,1H),3.26(m,2H),1.75(m,3H),1.11(m,2H),0.92(d,J＝6.2Hz,3H)；13C NMR(400MHz,DMSO-d6):δ＝21.0,30.0,33.2,33.7,50.1,51.5,116.1,123.2,126.5,127.9,128.9,133.5,140.3,143.1,164.9,193.1ppm；C21H25N3OS2,MS(ES+)m/z:400.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(二苯基甲基)哌嗪-1-二硫代羧酸酯(M106)
白色固体；产率86.2％；mp 135.7-136.3℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),7.93(d,J＝7.7Hz,2H),7.51(d,J＝7.8Hz,2H),7.45(d,J＝7.32Hz,4H),7.32(t,J＝7.32Hz,4H),7.21(m,3H),6.98(t,J＝7.1Hz,1H),6.80(d,J＝7.87Hz,1H),6.61(t,J＝7.3Hz,1H),4.91(s,2H),4.63(s,2H),4.40(s,1H),4.28(s,2H),3.95(s,2H),2.41(s,4H)；13C NMR(400MHz,DMSO-d6):δ＝14.0,20.7,50.9,74.1,116.0,116.2,123.2,126.4,126.6,127.0,127.6,127.8,128.6,129.0,133.6,140.0,142.1,143.0,164.9,194.2ppm；C32H32N4OS2,MS(ES+)m/z:553.20(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基二氢吲哚-1-二硫代羧酸酯(M107)
灰白色固体；产率59.4％；mp 162.9-163.5℃；1H NMR(400MHz,DMSO-d6):δ＝9.66(s,1H),7.97(d,J＝7.8Hz,2H),7.59(d,J＝8.0Hz,2H),7.38(d,J＝7.0Hz,1H),7.27(t,J＝7.5Hz,1H),7.20(d,J＝6.3Hz,2H),6.99(t,J＝7.3Hz,1H),6.80(d,J＝7.8Hz,1H),6.62(t,J＝7.3Hz,1H),4.93(s,2H),4.71(s,2H),4.49(m,2H),3.2(t,J＝7.8Hz,2H)；13C NMR(400MHz,DMSO-d6):δ＝27.0,116.1,116.2,117.9,123.3,125.5,125.7,126.4,126.5,126.7,127.7,127.9,129.1,129.4,133.6,135.4,139.8,143.1,165.0,190.2ppm；C23H21N3OS2,MS(ES+)m/z:420.12(M+H)+.
1-{[(4-{[(2-氨基苯基)氨基]羰基}苄基)硫代]硫羰基}二氢吲哚-5-羧酸甲酯(M108)
淡黄色固体；产率49.3％；mp 224.8-226.3℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),9.16(s,1H),7.92(m,4H),7.58(d,J＝8.2Hz,2H),7.18(d,J＝7.4Hz,1H),6.99(m,1H),6.80(t,1H),6.61(m,1H),4.94(s,2H),4.70(s,2H),4.54(t,J＝8.3Hz,2H),3.86(s,3H),3.27(t,J＝8.1Hz,2H)；13C NMR(400MHz,DMSO-d6):δ＝26.6,52.1,54.7,116.0,116.2,117.3,123.2,126.1,126.4,126.7,127.9,128.5,129.1,133.7,136.1,139.5,143.1,147.2,164.9,165.5,192.2ppm；C25H23N3O3S2,MS(ES+)m/z:478.12(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基5-氯二氢吲哚-1-二硫代羧酸酯(M109)
白色固体；产率79.1％；mp 179.2-181.9℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.96(d,J＝7.9Hz,2H),7.58(d,J＝7.9Hz,2H),7.45(s,1H),7.33(m,1H),7.19(d,J＝7.5Hz,1H),6.99(t,J＝7.5Hz,2H),6.80(d,J＝7.6Hz,1H),6.61(t,J＝7.5Hz,1H),4.92(s,2H),4.69(s,2H),4.50(t,J＝7.8Hz,2H),3.23(t,J＝7.8Hz,2H)；13C NMR(400MHz,DMSO-d6):δ＝26.9,54.0,116.1,116.2, 118.9,123.2,125.3,126.1,126.4,126.7,127.9,129.0,129.1,133.7,138.0,139.6,143.1,164.9,190.6ppm；C23H20ClN3OS2,MS(ES+)m/z:454.08(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基5-硝基二氢吲哚-1-二硫代羧酸酯(M110)
黄色固体；产率64.3％；mp 215.0-216.3℃；1H NMR(400MHz,DMSO-d6):δ＝9.66(s,1H),9.26(d,J＝8.2Hz,1H),8.23(m,2H),7.97(d,J＝7.6Hz,2H),7.59(d,J＝7.6Hz,2H),7.18(d,J＝7.4Hz,1H),6.99(t,J＝7.5Hz,1H),6.81(t,J＝7.5Hz,1H),6.62(t,J＝7.4Hz,1H),5.03(s,2H),4.71(s,2H),4.59(t,J＝8.1Hz,2H),3.32(t,J＝7.8Hz,2H)；13C NMR(400MHz,DMSO-d6):δ＝18.9,26.7,54.9,116.2,116.4,117.2,120.7,123.4,126.5,126.7,127.5,127.9,129.1,129.4,129.7,133.8,137.5,139.2,142.9,143.7,148.5,164.9,193.5ppm；C23H21N3OS2,MS(ES+)m/z:465.10(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基6-硝基二氢吲哚-1-二硫代羧酸酯(M111)
黄色固体；产率79.7％；mp 207.9-209.5℃；1H NMR(400MHz,DMSO-d6):δ＝10.05(s,1H),9.66(s,1H),8.08(m,1H),7.97(d,J＝7.9Hz,2H),7.60(t,J＝7.6Hz,3H),7.19(d,J＝7.6Hz,1H),6.99(t,J＝7.5Hz,1H),6.80(d,J＝7.6Hz,1H),6.61(t,J＝7.4Hz,1H),4.92(s,2H),4.71(s,2H),4.57(t,J＝8.1Hz,2H),3.35(m,2H)；13C NMR(400MHz,DMSO-d6):δ＝15.1,27.3,54.5,64.9,111.9,116.1,116.2,120.9,123.2,125.9,126.5,126.6,127.9,129.1,133.7,139.4,143.1,143.7,144.3,145.8,164.9,192.4ppm；C23H20N4O3S2,MS(ES+)m/z:465.10(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基二苄基二硫代氨基甲酸酯(M112)
灰色固体；产率84.2％；mp 161.9-163.1℃；1H NMR(400MHz,DMSO-d6):δ＝9.66(s,1H),7.95(d,J＝7.9Hz,2H),7.53(d,J＝8.1Hz,2H),7.35(m,8H),7.21(m,3H),6.99(m,1H),6.81(m,1H),6.62(m,1H),5.35(s,2H),5.02(s,2H),4.93(s,2H),4.70(s,2H)；13C NMR(400MHz,DMSO-d6):δ＝54.5,47.0,116.1,123.2,126.5,126.7,127.5,127.9,128.6,128.8,128.9,139.9,143.1,165.0,197.5ppm；C29H27N3OS2,MS(ES+)m/z:498.16(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-甲基哌嗪-1-二硫代羧酸酯(M113)
白色固体；产率59.1％；mp 271.3-273.5℃；1H NMR(400MHz,DMSO-d6):δ＝9.68(s,1H),7.94(d,J＝8.1Hz,2H),7.52(d,J＝8.1Hz,2H),7.18(d,J＝7.7Hz,1H),6.98(m,1H),6.79(m,1H),6.60(m,1H),4.92(s,2H),4.65(s,2H),4.25(s,2H),3.92(s,2H),2.40(m,4H),2.22(s,3H)；13CNMR(400MHz,DMSO-d6):δ＝45.1,49.6,51.1,54.0,116.1,123.3,126.5,127.9,128.9,133.6,140.1,143.1,164.9,194.3ppm；C20H24N4OS2,MS(ES+)m/z:401.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-苯基哌嗪-1-二硫代羧酸酯(M114)
白色固体；产率69.3％；mp 159.5-160.8℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H), 7.96(d,J＝7.7Hz,2H),7.56(d,J＝7.7Hz,2H),7.25(t,J＝7.6Hz,2H),7.20(d,J＝7.6Hz,1H),6.96(m,3H),6.81(m,2H),6.62(t,J＝7.6Hz,1H),4.93(s,2H),4.69(s,2H),4.40(s,2H),4.08(s,2H),3.30(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝47.5,49.3,50.7,115.4,116.0,116.2,119.2,123.2,126.4,126.6,127.9,129.0,133.6,140.0,143.0,149.9,164.9,194.4ppm；C25H26N4OS2,MS(ES+)m/z:463.16(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(4-甲基苯基)哌嗪-1-二硫代羧酸酯(M115)
白色固体；产率49.5％；mp 199.3-201.5℃；1H NMR(400MHz,DMSO-d6):δ＝9.64(s,1H),7.94(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.18(d,J＝7.5Hz,1H),7.06(d,J＝8.3Hz,2H),6.98(t,J＝7.5Hz,1H),6.87(d,J＝8.4Hz,2H),6.79(d,J＝7.7Hz,1H),6.61(t,J＝7.5Hz,1H),4.94(s,2H),4.68(s,2H),4.39(s,2H),4.08(s,2H),3.22(m,4H),2.2(s,3H)；13C NMR(400MHz,DMSO-d6):δ＝20.0,48.3,50.8,54.8,115.9,116.1,116.2,123.3,126.4,126.6,127.9,128.2,129.0,129.4,133.6,140.0,143.0,147.9,164.9,194.3ppm；C26H28N4OS2,MS(ES+)m/z:477.17(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(4-甲氧基苯基)哌嗪-1-二硫代羧酸酯(M116)
淡黄色固体；产率56.9％；mp 186.5-188.1℃；1H NMR(400MHz,DMSO-d6):δ＝9.66(s,1H),7.96(m,2H),7.56(d,J＝8.0Hz,2H),7.21(d,J＝7.5Hz,1H),6.89(m,6H),6.62(t,J＝7.4Hz,1H),4.92(s,2H),4.69(s,2H),4.41(s,2H),4.06(m,2H),3.70(s,3H),3.14(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝15.1,49.3,51.0,55.1,114.3,116.1,116.2,117.8,123.2,126.4,126.6,127.9,129.0,133.6,140.0,143.0,144.3,153.3,164.9,194.4ppm；C26H28N4O2S2,MS(ES+)m/z:493.17(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(4-氰基苯基)哌嗪-1-二硫代羧酸酯(M117)
淡黄色固体；产率68.3％；mp 216.4-218.0℃；1H NMR(400MHz,DMSO-d6):δ＝9.66(s,1H),7.96(d,J＝7.97Hz,2H),7.62(d,J＝8.7Hz,2H),7.56(d,J＝8.1Hz,2H),7.20(d,J＝7.6Hz,1H),6.97(m,3H),6.81(m,1H),6.62(t,J＝7.6Hz,1H),4.95(s,2H),4.69(s,2H),4.39(s,2H),4.09(s,2H),3.58(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝44.9,48.5,50.3,98.1,113.3,116.1,116.2,120.0,123.2,126.4,126.6,127.9,129.0,133.3,133.6,140.0,143.0,151.9,164.9,194.5ppm；C26H25N5OS2,MS(ES+)m/z:488.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(4-氯苯基)哌嗪-1-二硫代羧酸酯(M118)
白色固体；产率59.2％；mp 197.9-199.7℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.93(m,2H),7.53(d,J＝7.6Hz,2H),7.25(d,J＝8.8Hz,2H),7.17(d,J＝7.8Hz,1H),6.94(m,3H),6.78(d,J＝7.8Hz,1H),6.59(t,J＝7.4Hz,1H),4.91(s,2H),4.66(m,2H),4.38(s,2H),4.05(m,2H), 3.29(m,4H),2.49(s,1H)；13C NMR(400MHz,DMSO-d6):δ＝47.7,49.5,51.0,116.5,116.7,117.2,123.2,123.7,126.9,127.1,128.4,129.2,129.5,134.1,140.5,143.6,149.2,165.4,194.9ppm；C25H25ClN4OS2,MS(ES+)m/z:497.12(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(4-氟苯基)哌嗪-1-二硫代羧酸酯(M119)
白色固体；产率49.8％；mp 173.4-175.7℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.94(m,2H),7.55(d,J＝8.1Hz,2H),7.19(d,J＝7.6Hz,1H),7.09(m,2H),6.99(m,3H),6.80(m,1H),6.62(m,1H),4.92(s,2H),4.69(s,2H),4.40(s,2H),4.08(s,2H),3.23(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝48.5,49.3,50.8,115.3,116.1,116.2,117.4,123.2,126.5,127.9,129.0,133.6,140.1,143.1,146.9,155.1,157.5,165.0,194.5ppm；C25H25FN4OS2,MS(ES+)m/z:481.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(2-氟苯基)哌嗪-1-二硫代羧酸酯(M120)
白色固体；产率53.6％；mp 175.8-177.1℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.95(m,2H),7.55(d,J＝8.0Hz,2H),7.08(m,6H),6.80(d,J＝7.91Hz,1H),6.61(t,J＝7.62Hz,1H),4.92(s,2H),4.68(m,2H),4.43(s,2H),4.10(s,2H),3.37(s,3H),3.14(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝14.0,20.7,49.6,59.7,115.9,116.0,116.1,116.2,119.6,122.9,123.0,123.2,124.8,126.4,126.6,127.9,129.0,133.6,138.7,138.8,140.0,143.0,153.6,156.1,164.9,170.3,194.6ppm；C25H25FN4OS2,MS(ES+)m/z:481.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-环己基哌嗪-1-二硫代羧酸酯(M121)
白色固体；产率73.3％；mp 178.6-181.4℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.95(m,2H),7.54(d,J＝7.4Hz,2H),7.20(d,J＝7.3Hz,1H),6.99(t,J＝7.0Hz,1H),6.81(d,J＝7.7Hz,1H),6.62(t,J＝6.9Hz,1H),4.93(s,2H),4.66(m,2H),4.24(s,2H),3.89(s,2H),2.59(s,4H),2.30(m,1H),1.75(m,4H),1.19(m,6H)；13C NMR(400MHz,DMSO-d6):δ＝25.2,25.7,28.2,48.1,50.2,51.6,62.2,116.1,116.2,123.2,126.4,126.6,127.8,128.9,133.5,140.1,143.0,164.9,193.9ppm；C25H32N4OS2,MS(ES+)m/z:469.20(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-吡啶-4-基哌嗪-1-二硫代羧酸酯(M122)
淡黄色固体；产率91.5％；mp 139.8-141.5℃；1H NMR(400MHz,DMSO-d6):δ＝9.64(s,1H),8.20(d,J＝4.4Hz,2H),7.94(d,J＝7.4Hz,2H),7.54(d,J＝7.5Hz,2H),7.17(d,J＝7.5Hz,1H),6.97(m,1H),6.79(m,2H),6.60(d,J＝7.3Hz,1H),6.44(m,1H),4.90(s,2H),4.68(s,2H),4.38(s,2H),4.09(s,2H),3.58(s,4H)；13C NMR(400MHz,DMSO-d6):δ＝44.1,107.7,114.6,116.0,116.2,117.2,123.2,126.6,127.8,129.0,133.6,140.0,143.0,148.9,153.6ppm；C24H25N5OS2,MS(ES+) m/z:464.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-吡啶-3-基哌嗪-1-二硫代羧酸酯(M123)
白色固体；产率60.3％；mp 190.3-191.7℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),8.13(d,J＝4.0Hz,1H),7.92(d,J＝8.0Hz,2H),7.54(m,3H),7.16(d,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.79(m,2H),6.67(m,1H),6.59(t,J＝7.4Hz,1H),4.90(s,2H),4.67(s,2H),4.36(s,2H),4.04(s,2H),3.67(m,4H),3.34(s,1H),2.50(s,4H)；13C NMR(400MHz,DMSO-d6):δ＝44.0,107.4,113.7,116.5,116.6,123.6,126.9,127.1,128.3,129.5,134.1,138.1,140.5,143.6,148.0,158.6,165.4,194.9ppm；C24H25N5OS2,MS(ES+)m/z:464.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-嘧啶-2-基哌嗪-1-二硫代羧酸酯(M124)
白色固体；产率54.2％；mp 192.9-194.2℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),8.41(m,2H),7.95(d,J＝8.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.19(d,J＝7.6Hz,1H),6.99(m,1H),6.80(m,1H),6.69(t,J＝4.9Hz,1H),6.61(t,J＝7.4Hz,1H),4.92(s,2H),4.69(s,2H),4.37(s,2H),4.06(s,2H),3.89(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝42.5,49.2,50.7,110.6,116.0,116.2,123.2,126.4,126.6,127.9,129.0,133.1,140,0,143.0,157.9,160.8,164.9,194.5ppm；C23H24N6OS2,MS(ES+)m/z:465.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-吡嗪-2-基哌嗪-1-碳二硫代酸酯(M125)
白色固体；产率53.7％；mp 192.7-194.3℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),8.30(s,1H),8.11(s,1H),7.91(m,3H),7.53(d,J＝7.7Hz,2H),7.16(d,J＝7.3Hz,1H),6.97(t,J＝7.3Hz,1H),6.77(d,J＝7.7Hz,1H),6.59(t,J＝6.9Hz,1H),4.90(s,1H),4.67(m,2H),4.38(s,2H),4.07(m,2H),3.75(m,4H),3.33(s,4H)；13C NMR(400MHz,DMSO-d6):δ＝43.4,49.3,50.8,116.5,116.6,123.7,126.9,127.1,128.3,129.5,131.6,133.2,134.1,140.5,141.9,143.6,154.3,165.4,195.1ppm；C23H24N6OS2,MS(ES+)m/z:465.15(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(吡啶-4-基甲基)哌嗪-1-二硫代羧酸酯(M126)白色固体；产率49.2％；mp 174.5-176.3℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),8.54(m,2H),7.93(d,J＝8.1Hz,2H),7.53(d,J＝8.1Hz,2H),7.36(m,2H),7.18(d,J＝7.5Hz,1H),6.98(m,1H),6.79(m,1H),6.61(m,1H),4.92(s,2H),4.65(s,2H),4.29(s,2H),3.95(s,2H),3.58(s,2H),2.51(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝49.6,51.0,51.9,59.7,116.0,116.1,123.2,123.7,126.4,126.6,127.8,129.0,133.6,140.0,143.0,146.7,149.5,164.9,194.3ppm；C25H27N5OS2,MS(ES+)m/z:478.17(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(吡啶-3-基甲基)哌嗪-1-二硫代羧酸酯(M127)
白色固体；产率47.2％；mp 180.2-181.6℃；1H NMR(400MHz,DMSO-d6):δ＝9.64(s,1H),8.53(s,1H),8.50(m,1H),7.94(d,J＝7.9Hz,2H),7.74(m,1H),7.53(d,J＝8.1Hz,2H),7.38(m,1H),7.19(d,J＝7.6Hz,1H),6.99(t,J＝7.6Hz,1H),6.80(d,J＝7.7Hz,1H),6.61(t,J＝7.4Hz,1H),4.92(s,2H),4.65(s,2H),4.28(s,2H),3.93(s,2H),3.57(s,2H),2.49(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝49.6,51.0,51.8,58.3,116.0,116.2,123.2,123.4,126.4,126.6,127.8,128.9,132.9,133.6,136.6,140.0,143.0,148.4,150.0,164.9,194.2ppm；C25H27N5OS2,MS(ES+)m/z:478.17(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(吡啶-3-基甲基)哌嗪-1-二硫代羧酸酯(M128)
白色固体；产率42.5％；mp 169.2-170.8℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),8.50(d,J＝4.5Hz,1H),7.92(d,J＝7.8Hz,2H),7.77(t,J＝7.4Hz,1H),7.51(d,J＝7.8Hz,2H),7.46(d,J＝7.6Hz,1H),7.27(t,J＝6.4Hz,1H),6.16(d,J＝7.6Hz,1H),6.97(t,J＝7.6Hz,1H),6.78(d,J＝7.8Hz,1H),6.59(t,J＝7.4Hz,1H),4.91(s,2H),4.63(s,2H),4.27(s,2H),3.93(s,2H),3.65(s,2H)；13CNMR(400MHz,DMSO-d6):δ＝50.2,51.6,52.6,63.3,116.5,116.6,122.7,123.3,123.7,126.9,127.1,128.3,129.5,134.0,137.0,140.5,143.6,149.3,158.2,165.4,194.7ppm；C25H27N5OS2,MS(ES+)m/z:478.17(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-苄基哌嗪-1-二硫代羧酸酯(M129)
浅黄色固体；产率58.2％；mp 150.5-151.8℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(s,1H),7.95(d,J＝8.1Hz,2H),7.53(d,J＝8.1Hz,2H),7.34(m,5H),7.20(d,J＝7.5Hz,1H),6.99(m,1H),6.81(m,1H),6.62(t,J＝7.5Hz,1H),5.20(m,2H),4.94(s,2H),4.65(s,2H),4.28(s,2H),3.93(s,2H),3.54(s,2H),2.48(m,4H)；13C NMR(400MHz,DMSO-d6):δ＝15.2,49.7,51.1,51.9,61.2,64.9,116.1,116.2,123.3,126.5,126.6,127.1,127.9,128.2,128.9,129.0,133.6,140.1,143.1,165.0,194.1ppm；C26H28N4OS2,MS(ES+)m/z:477.18(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基4-(2-苯基乙基)哌嗪-1-二硫代羧酸酯(M130)
白色固体；产率40.6％；mp 166.1-167.9℃；1H NMR(400MHz,DMSO-d6):δ＝9.67(s,1H),7.96(s,2H),7.56(s,2H),7.27(m,6H),7.00(s,1H),6.82(s,1H),6.63(s,1H),4.94(s,2H),4.67(s,2H),4.28(s,2H),3.95(s,2H),2.77(s,2H),2.57(m,6H)；13C NMR(400MHz,DMSO-d6):δ＝32.5,49.6,51.1,52.0,58.8,116.0,116.1,123.2,125.8,126.4,126.6,127.8,128.2,128.6,128.9,133.5,140.1,143.0,164.9,194.1ppm；C27H30N4OS2,MS(ES+)m/z:491.19(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基甲基(吡啶-3-基甲基)二硫代氨基甲酸酯(M131)
白色固体；产率63.9％；mp 152.5-154.0℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(d, J＝9.1Hz,1H),8.56(d,J＝5.0Hz,2H),7.93(m,2H),7.52(m,2H),7.20(m,3H),6.98(t,J＝7.3Hz,1H),6.79(d,J＝7.8Hz,1H),6.61(t,J＝7.5Hz,1H),5.37(d,1H),5.14(s,1H),4.91(s,2H),4.65(d,J＝10.2Hz,2H),3.53(s,1H),3.39(s,2H),3.35(s,4H),2.51(s,1H)；13C NMR(400MHz,DMSO-d6):δ＝44.3,55.9,58.1,116.0,116.1,121.5,122.0,123.2,126.4,126.6,127.9,128.9,133.6,139.9,143.1,144.6,149.7,149.9,164.9ppm；C22H22N4OS2,MS(ES+)m/z:423.13(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基甲基(吡啶-3-基甲基)二硫代氨基甲酸酯(M132)
白色固体；产率72.5％；mp 148.9-150.2℃；1H NMR(400MHz,DMSO-d6):δ＝9.63(s,1H),8.51(m,2H),7.92(m,2H),7.71(m,2H),7.52(m,2H),7.40(m,1H),7.16(d,J＝7.3Hz,1H),6.97(t,J＝7.7Hz,1H),6.78(d,J＝7.8Hz,1H),6.59(t,J＝7.1Hz,1H),5.36(s,1H),5.12(s,1H),4.90(s,2H),4.65(s,2H),3.49(s,1H),3.34(m,7H)；13C NMR(400MHz,DMSO-d6):δ＝44.5,55.1,57.0,116.5,116.6,123.7,124.1,126.9,127.1,128.4,129.4,132.0,134.1,135.7,140.4,143.6,149.2,149.3,165.4,197.2ppm；C22H22N4OS2,MS(ES+)m/z:423.13(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基乙基(吡啶-4-基甲基)二硫代氨基甲酸酯(M133)
浅黄色固体；产率84.3％；mp 181.6-183.1℃；1H NMR(400MHz,DMSO-d6):δ＝9.65(m,1H),8.55(s,2H),7.94(m,2H),7.55(m,2H),7.22(m,3H),6.98(m,1H),6.80(m,1H),6.61(m,1H),5.21(m,2H),4.92(s,2H),4.64(m,2H),3.83(m,2H),1.23(m,3H)；13C NMR(400MHz,DMSO-d6):δ＝12.3,47.6,53.5,55.7,116.0,116.1,121.4,121.9,123.2,126.4,126.6,127.8,127.9,128.9,139.9,143.1,149.6,149.9,164.9,196.3ppm；C23H24N4OS2,MS(ES+)m/z:437.14(M+H)+.
4-{[(2-氨基苯基)氨基]羰基}苄基甲基(吡啶-3-基)二硫代氨基甲酸酯(M134)
浅黄色固体；产率69.2％；mp 185.2-186.7℃；1H NMR(400MHz,DMSO-d6):δ＝9.61(s,1H),8.63(m,2H),7.90(m,3H),7.56(m,1H),7.45(d,J＝7.8Hz,2H),7.16(d,J＝7.4Hz,1H),6.97(t,J＝7.0Hz,1H),6.78(d,J＝7.2Hz,1H),6.60(t,J＝7.0Hz,1H),4.89(s,2H),4.54(s,2H),3.74(s,3H),3.36(s,5H)；13C NMR(400MHz,DMSO-d6):δ＝15.1,64.8,116.0,116.1,123.2,124.5,126.4,126.6,127.8,128.9,133.6,135.0,139.8,143.0,148.0,149.7,164.9ppm；C21H20N4OS2,MS(ES+)m/z:409.11(M+H)+.
实施例2：化合物抗肿瘤细胞增殖实验
(1)实验细胞系，选用六种癌细胞：人皮肤黑色素瘤A375、人胃癌细胞MGC80-3、人宫颈癌细胞HeLa、人肝癌细胞SMMC7721、人肺癌细胞H1299、人结肠癌细胞HCT116。实验前，六种癌细胞被保藏在液氮中，首先取出癌细胞，在37摄氏度的水浴锅中使其快速 升温到37摄氏度，将细胞液离心去除上层冻存液，细胞用培养基重新悬浮后，转移到24mL细胞培养瓶中，每瓶加入6ml培养基于37摄氏度，含5％CO2的培养箱培养，(其中人皮肤黑色素瘤A375、人胃癌细胞MGC80-3、人宫颈癌细胞HeLa，在含10％胎牛血清的DMEM培养基中，用0.25％胰蛋白酶常规消化后传代培养。人肝癌细胞SMMC7721、人肺癌细胞H1299、人结肠癌细胞HCT116在含10％胎牛血清的RPMI-1640培养基中，用0.25％胰蛋白酶常规消化后传代培养。)等细胞生长达到培养瓶70％-80％左右时，先用PBS洗去培养基，用0.25％胰蛋白酶消化将细胞从培养瓶中脱落下来，加入新鲜培养基离心后，去除上层培养基，再加入新鲜培养基重悬后1：2～3传代。
(2)当细胞生长稳定后，将处于对数期的癌细胞用胰酶消化成单个细胞后，用新鲜培养基稀释到(3～4)×104个/ml的细胞密度，在96孔板中，每孔加入90μL的细胞液，在37摄氏度，含5％CO2的培养箱中培养12h，加药(把合成的化合物事先稀释到一系列不同的浓度，将不同浓度的化合物溶液加入到96孔板中，每个浓度重复3个复孔)，72小时后，96孔板中每孔加入10μL CCK-8溶液，再培养1小时后，用BIO-RAD酶标仪测定450nm波长处的吸光度值，通过Graphpad Prism 5软件拟合得到抑制曲线，最终得到IC50值。
表2：本发明所合成的化合物对三种不同癌细胞的抑制效果
Figure PCTCN2017091212-appb-000015
Figure PCTCN2017091212-appb-000016
表3：本发明所合成的化合物对六种不同癌细胞的抑制效果
Figure PCTCN2017091212-appb-000017
表2、表3的结果表明：本发明合成的含有氨基二硫代甲酸酯结构的酰胺类化合物对六种癌细胞均具有强的抑制活性，而且大部分化合物具有比参比药物更强的抗肿瘤效果，尤其对于人肝癌细胞，本专利中合成的含有氨基二硫代甲酸酯结构的酰胺类化合物M101、M122以及M133的药效强于参比药物西达本胺超过21倍，比参比药物MS275的药效强5倍。
实施例3：化合物对HDAC酶的抑制实验
使用瑞士
Figure PCTCN2017091212-appb-000018
Life Sciences公司生产的HDAC绿色荧光测试试剂盒(产品序号：BML-AK530)进行HeLa细胞核提取物的HDAC酶活性抑制实验，使用产品序号为BML-AK511的试剂盒进行HDAC1酶活性抑制实验，使用产品序号为BML-AK512的试剂盒进行HDAC2酶活性抑制实验，使用产品序号为BML-AK516的试剂盒进行HDAC6酶活性抑制实验。操作严格按照试剂盒说明书进行，15μL的HDAC酶与10μL的待测化合物充分混合，将底物和上述混合物在37摄氏度放置5分钟以使底物和酶获得相同的起始温度，然后每孔快速加入25μL底物，将整个96孔板放置于37摄氏度孵育30-60分钟，然后向每孔中加入50μL终止液。此后将96孔板放置常温10分钟，用酶标仪测荧光强度。得到不同浓度化合物对HDAC酶抑制率后，通过Graphpad Prism 5软件拟合得到抑制曲线，最终得到IC50值。
表4：本发明所合成的化合物对HDAC酶的抑制效果
Figure PCTCN2017091212-appb-000019
表4的结果表明：本发明合成的含有氨基二硫代甲酸酯结构的酰胺类化合物对HeLa细胞核提取物的HDAC、HDAC1和HDAC2具有强的抑制活性，其中化合物M122比参比药物西达本胺和CI994具有更强的HDAC1酶抑制效果，同时本发明合成的含有氨基二硫代甲酸酯结构的酰胺类化合物对HDAC6几乎没有抑制效果(IC50>40μM)，因此本发明合成的化合物具有更强的HDAC1和HDAC2酶的选择性抑制。
实施例4：化合物抗肿瘤细胞单克隆形成实验
取对数生长期的SMMC7721肝癌细胞铺于6孔板，每孔铺3000个细胞，立即用0.125μmol/L、1μmol/L和4μmol/L的CS055、MS275、M101、M104、M122和M133处理细胞，以DMSO处理组为空白对照，7天后，移去每孔的培养基，加入PBS(磷酸盐缓冲液)轻轻洗2遍，加入3.7％甲醛水溶液固定20min，再用PBS轻轻洗两遍，0.1％结晶紫水溶液染色30min，PBS洗3遍，观察实验结果并拍照。
由图1可看出本发明合成的化合物M101、M104、M122和M133比参比药物西达本胺 具有更强的抗肿瘤细胞单克隆形成的能力。
实施例5：化合物诱导肿瘤细胞凋亡实验
取对数生长期的SMMC7721肝癌细胞铺于6孔板，每孔铺16万个细胞，12h后加入CS055、MS275、M101、M122和M133(浓度为0.125μmol/L、1μmol/L和4μmol/L)处理细胞，以DMSO处理为对照组，72h后收集每孔的培养基，用胰酶消化收集各孔细胞，1000rpm离心5min，去除离心后的上清，再用PBS洗两遍，然后加入100μL1×binding buffer缓冲液，5μL of Alexa Fluor 488 annexin和1μL的碘化丙锭(100μg/ml)，避光室温孵育15min，以Alexa Fluor 488 annexin和碘化丙锭单染的组别作为对照组，样品用MoFlo XDP流式细胞仪检测。
诱导肿瘤细胞凋亡的结果显示：本发明合成的化合物M101、M104、M122和M133在4μmol/L浓度下能够分别诱导54.00％、75.74％、56.96％的SMMC7721肝癌细胞发生凋亡，而CS055(西达本胺)仅能诱导25.83％的SMMC7721肝癌细胞凋亡，MS275仅能诱导42.66％的SMMC7721肝癌凋亡。由此可见本发明所合成的化合物具有比参比药物西达本胺和CI994更强的诱导肿瘤细胞凋亡的能力。
实施例6：化合物阻断肿瘤细胞周期实验
取对数生长期的SMMC7721肝癌细胞铺于6孔板，每孔铺16万个细胞，12h后加入CS055、MS275、M101和M133(浓度为0.125μmol/L、1μmol/L和4μmol/L)处理细胞，以DMSO处理为对照组，72h后收集每孔的培养基，用胰酶消化收集各孔细胞，1000rpm离心5min，去除离心后的上清，再用PBS洗两遍，细胞用70％乙醇固定，PBS洗两遍，加入RNA酶37℃避光孵育30min，样品用MoFlo XDP流式细胞仪检测。
结果显示本发明合成的化合物能将SMMC7721肝癌细胞抑制在G2/M期，其中在4μmol/L浓度下M101和M133显著将癌细胞周期阻断在G2/M期(加DMSO处理的对照组癌细胞处于G2/M期的比例为14.14％，经过4μmol/L化合物M101或M133的处理后，处于G2/M期癌细胞的比例分别增加到28.31％和48.94％，而使用CS055或MS275处理后，SMMC7721肝癌细胞处于G2/M期的比例仅分别增加到18.05％和21.24％)

Claims (10)

  1. 一种药物，为式I所示的化合物或其药学上可接受的盐或其溶剂合物或其前药分子：
    Figure PCTCN2017091212-appb-100001
    其中，
    A选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
    Z选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
    R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，或者是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
    R3和R4各自独立地选氢、羟基、氨基、巯基、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基 烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基；
  2. 根据权利要求1所述的药物，其特征在于，化合物为式Ⅱ所示化合物：
    Figure PCTCN2017091212-appb-100002
    其中，
    A选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
    Z选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基，上述烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤素、氰基、硝基、亚硝基、磺基；
    R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫 烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也或者是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
    X1、X2、X3、X4各自独立地选自氢、烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基；
  3. 根据权利要求2所述的化合物或其药学上可接受的盐或其溶剂合物或其前药分子，其特征在于，选自式Ⅲ所示化合物：
    Figure PCTCN2017091212-appb-100003
    其中，
    R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也或者是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取 代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
    X1、X2、X3、X4各自独立地选自氢、烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基，烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基；
  4. 根据权利要求3所述的药物，其特征在于，化合物为式Ⅳ所示化合物：
    Figure PCTCN2017091212-appb-100004
    其中，
    R1和R2满足下述两种情形之一：(1)R1和R2各自独立地选自氢、烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，上述烷基、环烷基、环烷基烷基、烷基环烷基、芳基、芳基烷基、烷基芳基、杂芳基、杂芳基烷基、烷基杂芳基、杂环基、杂环基烷基、烷基杂环基、烯基、炔基，任选不取代或被一个或多个取代基所取代，所述取代基各自独立地选自烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、卤代芳基、烷氧基羰基、酰基氧基、酰胺基、脲基、烷基磺酰基、芳基磺酰基、卤代烷基、卤素、氰基、硝基、亚硝基、硫氰基、异硫氰基、硫烷基、磺基；或者(2)R1和R2连同二者所连接的N原子共同形成杂环基，所述杂环基为单环、双环或三环，也或者是稠环、桥环或螺环，所述杂环基只包含一个N原子或者除上述N原子外任选额外包含1个或2个或3个选自于N、S和O的杂原子，所述杂环基不取代或者任选被一个或多个取代基所取代，所述的取代基各自独立地选自于由烷基、环烷基、芳基、杂芳基、杂环基、烯基、炔基、氨基、羟基、巯基、羧基、烷氧基、环烷氧基、烷氧基羰基、卤素、氰基、硝基、亚硝基、酰胺基、硫氰基、异硫氰基、脲基、磺基单独作为取代基或自由组合所形成的取代基；
  5. 根据权利要求1至4任意一项所述的药物，其中所述的化合物选自:
    Figure PCTCN2017091212-appb-100005
    Figure PCTCN2017091212-appb-100006
    Figure PCTCN2017091212-appb-100007
    Figure PCTCN2017091212-appb-100008
    Figure PCTCN2017091212-appb-100009
  6. 一种药物组合物，所述药物组合物包含：权利要求1至5中任意一项所述的药物。
  7. 权利要求1至6中任一项所述的药物在制备用于治疗或预防抗肿瘤、抗癌、抗炎、抗菌、抗病毒、抗氧化的药物方面的用途。
  8. 如权利要求7所述的用途，所述肿瘤选自于黑色素瘤、癌症选自于胃癌、宫颈癌、卵巢癌、肝癌、肺癌、鼻咽癌、结肠癌、直肠癌、淋巴癌、血癌、骨髓癌、脑癌、皮肤癌、 骨癌、鼻咽癌、胰腺癌、肾癌、甲状腺癌、前列腺癌，膀胱癌、食管癌、乳腺癌。
  9. 如权利要求1至5所述药物的制备方法，其特征在于化合物的制备包括以下步骤：
    (a)将化合物1与化合物2与二硫化碳在碱存在下反应得到化合物3；
    Figure PCTCN2017091212-appb-100010
    (b)将化合物3与化合物4在肽缩合剂作用下反应得到化合物5
    Figure PCTCN2017091212-appb-100011
    其中A、Z、R1、R2、R3、R4如权利要求1中所定义。
  10. 如权利要求9所述的制备方法，其特征在于：
    反应步骤(a)使用的碱选自：磷酸钾、碳酸钾、磷酸钠、碳酸钠、碳酸铯、氧化铝、磷酸氢二钾、磷酸氢二钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢化钠、氢氧化钾、二乙胺、三乙胺、N-甲基吗啉、4-二甲氨基吡啶；
    反应步骤(b)所用肽缩合剂选自:
    苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、
    六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷、
    N,N'-二环己基碳二亚胺、
    O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸。
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