WO2015120800A1 - 一类氮杂环化合物及其制备方法和用途 - Google Patents

一类氮杂环化合物及其制备方法和用途 Download PDF

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WO2015120800A1
WO2015120800A1 PCT/CN2015/072817 CN2015072817W WO2015120800A1 WO 2015120800 A1 WO2015120800 A1 WO 2015120800A1 CN 2015072817 W CN2015072817 W CN 2015072817W WO 2015120800 A1 WO2015120800 A1 WO 2015120800A1
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group
prodrug
hydrate
pharmaceutically acceptable
acceptable salt
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French (fr)
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吴勇
朱义
王一茜
海俐
李�杰
余永国
刘威加
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四川百利药业有限责任公司
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    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • 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
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    • 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
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    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to a compound, a preparation method and use thereof, in particular to a nitrogen heterocyclic compound, a preparation method thereof and use thereof.
  • Nitrogen heterocycles have a wide range of biological activities, such as antidepressants, vasodilators, cardiotonics, analgesics/anti-inflammatory drugs, antihypertensives, and as acaricides and herbicides in agriculture, as well as Inhibitors such as acetylcholinesterase, aldose reductase, monoamine oxidase, CDKs, COX-2, P38 MAP kinase, and the like.
  • Inhibitors such as acetylcholinesterase, aldose reductase, monoamine oxidase, CDKs, COX-2, P38 MAP kinase, and the like.
  • the patent document US 2007/0072866 A1 reports a class of nitrogen heterocyclic compounds whose structural formula is As a GSK-3 ⁇ inhibitor, it is used to treat metabolic diseases or neurodegenerative diseases and related diseases. Its parent ring is a pyridazinone.
  • the patents WO 03/059891 and WO 2005/007632 disclose nitrogen heterocyclic compounds for the treatment of diseases or conditions caused or aggravated by P38 MAP kinase activity and/or TNF activity dysregulation.
  • the pyridazinone compound in the above patent document has a structural formula of It can be used to treat inflammatory diseases, diabetes, Alzheimer's disease or cancer, in which R 4 is mainly aryl substituted, R 1 is mainly halogen, R 2 is a more type of substitution, and R 3 is only H Replace.
  • the parent ring of the compounds mentioned in this patent is also a pyridazinone.
  • Aventis has applied for a nitrogen heterocyclic derivative as a CDK2 inhibitor with a structure of Wherein X is C(O)NHR, NHC(O)R and a nitrogen-containing heterocycle, R 2 is H, and R 3 is an aromatic ring and a heterocyclic ring. Its parent ring is also a pyridazinone.
  • the nitrogen heterocyclic compounds disclosed in the patent documents CN101538245 and CN101537006 are mainly used for anti-hepatocarcinoma drugs, and the structure thereof is A class of compounds having 6-(3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one as the core is also a pyridazinone compound.
  • X is OH, SH, NH 2 , -ORa, -ORa, -OC(O)-Ra, -NRaRb, -NHC(O)Ra, -NHC(S)Ra, -SRa, -S(O) Ra, -SO 2 Ra, -NHSO 2 Ra, -SO 2 NRaRb, -O-SO 2 Ra, or -SO 2 -ORa;
  • R 1 is an electron withdrawing group
  • R 2 is halogen, substituted or unsubstituted C 1 -C 10 alkyl, -ORa, -OC(O)-Ra, -NRaRb, -NHC(O)Ra, -NHC(S)Ra, -SRa,- S(O)Ra, -SO 2 Ra, -NHSO 2 Ra, -SO 2 NRaRb, -O-SO 2 Ra, -SO 2 -ORa, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Or a substituted or unsubstituted heterocyclic group;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of: H, halogen, amino, CN, NO 2 , -C(O)Ra, -CH 2 Ra, -ORa, -OC(O )-Ra, -NRaRb, -NHC(O)Ra, -C(O)NRaRb, -NHC(S)Ra, -SRa, -S(O)Ra, -SO 2 Ra, -NHSO 2 Ra, -SO 2 NRaRb, -O-SO 2 Ra, -SO 2 -ORa, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heterocyclic group;
  • Ra, Rb are each independently selected from: H, halogen, unsubstituted or at least monosubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, heterocyclyl, aryl Or heteroaryl.
  • the electron withdrawing group in R 1 is selected from the group consisting of trifluoromethyl, difluoromethyl, cyano or trichloromethyl.
  • the substituent substituted in R 2 is selected from the group consisting of halogen, CN, NH 2 , NO 2 , -C(O)Ra, -CH 2 Ra, -O-Ra, -OC(O)-Ra, -NRaRb, -NHC(O)Ra, -C(O)NRaRb, -NHC(S)Ra, -SRa, -S(O)Ra, -SO 2 Ra, -NHSO 2 Ra, -SO 2 NRaRb, - O-SO 2 Ra, -SO 2 -ORa, aryl, heteroaryl or heterocyclic group.
  • the aryl group, heteroaryl group or heterocyclic group in the substituent is at least monosubstituted, and the substituent is selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen, a trifluoromethyl group.
  • Base difluoromethyl, trichloromethyl or hydroxy.
  • the aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic group.
  • heterocyclic ring comprising one or more heteroatoms selected from N, O or S; the heterocyclic group being a 3 to 10 membered non-aromatic mono- or polycyclic heterocyclic ring comprising one or more selected from N, O or The hetero atom of S.
  • the substituent substituted in the Ra, Rb is selected from the group consisting of halogen, hydroxy, heteroaryl, aryl, heterocyclic, C 1 -C 10 alkoxy, (C 1 -C 10 -alkane) Thio, -COOH, -COO-(C 1 -C 6 -alkyl), -CONH 2 , trifluoromethyl, CN, amino, (C 1 -C 10 -alkyl)amino or di (C) 1 -C 10 -alkyl)amino group.
  • the aryl group, heteroaryl group or heterocyclic group in the substituent is at least monosubstituted, and the substituent is selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen, a trifluoromethyl group.
  • Base difluoromethyl, trichloromethyl or hydroxy.
  • the aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system
  • the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring including one or more selected from the group consisting of N and O. Or a hetero atom of S
  • the heterocyclic group is a 3 to 10 membered non-aromatic mono- or polycyclic heterocyclic ring including one or more hetero atoms selected from N, O or S.
  • the substituent substituted in the R 3 , R 4 , R 5 , R 6 or R 7 is selected from the group consisting of halogen, hydroxy, heteroaryl, aryl, heterocyclic, C 1 -C 10 -alkane Oxyl, (C 1 -C 10 -alkyl)thio, -COOH, -COO-(C 1 -C 6 -alkyl), -CONH 2 , trifluoromethyl, CN, amino, (C 1 - C 10 -alkyl)amino or di(C 1 -C 10 -alkyl)amino.
  • the aryl, heteroaryl or heterocyclic substituent is at least monosubstituted, the substituent of which is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, trifluoromethyl, Difluoromethyl, trichloromethyl or hydroxy.
  • the aryl group in R 3 , R 4 , R 5 , R 6 or R 7 is a 5- to 10-membered aromatic mono- or bicyclic ring system;
  • the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring, wherein Including one or more heteroatoms selected from N, O or S;
  • the heterocyclic group is a 3 to 10 membered non-aromatic mono- or polycyclic heterocyclic ring including one or more heteroatoms selected from N, O or S .
  • Z is a halogen
  • A, B, D, E, F, X, R 3 and R 4 are as defined above.
  • Z is a halogen
  • A, B, D, E, F, X, R 3 and R 4 are as defined above.
  • Z is a halogen
  • A, B, D, E, F, X, R 3 and R 4 are as defined above.
  • Z is a halogen
  • A, B, D, E, F, X, R 3 and R 4 are as defined above.
  • a pharmaceutical composition comprising a nitrogen heterocyclic compound of the above formula (I) or a pharmaceutically acceptable salt, hydrate thereof and prodrug thereof.
  • the antitumor drug is an anti-hepatocarcinoma drug or an anti-cancer drug.
  • the pharmaceutically acceptable salts in the present invention include: mineral acids such as hydrochloride, hydrobromide, sulfate, phosphate, and the like, malate, fumarate, maleate, methanesulfonic acid, p-toluene Organic acid salts such as sulfonic acid, formate, phthalate, acetate, oxalate, succinate, tartrate, malonate, lactate, mandelate, and sodium salt, Potassium salt, barium salt, calcium salt, etc.
  • mineral acids such as hydrochloride, hydrobromide, sulfate, phosphate, and the like
  • malate fumarate, maleate
  • methanesulfonic acid p-toluene
  • Organic acid salts such as sulfonic acid, formate, phthalate, acetate, oxalate, succinate, tartrate, malonate, lactate, mandelate, and sodium salt, Potassium salt, barium salt, calcium salt,
  • a prodrug means that the drug obtained by chemical structural modification is inactive or less active in vitro, and is converted by the enzyme or non-enzymatic conversion in the body to contain the compound involved in the patent.
  • the beneficial effects of the present invention are that the present invention provides a series of new compounds, and the synthesis method is simple. Its anti-tumor effect Obvious.
  • Each compound was diluted by 6 concentration gradients at a 10-fold ratio, and an MTS experiment was performed 72 hours later to calculate the GI50 value.
  • a negative control group without DMSO only
  • a doxorubicin hydrochloride doxorubicin
  • Two positive concentrations were selected: 1 ⁇ M and 0.1 ⁇ M.
  • FetalBovineSerum Gibco, Invitrogen (Cat# 10437-036)
  • DMSO Dimethylsulfoxide
  • the ultra-clean workbench table was irradiated with ultraviolet rays for 30 minutes.
  • the water bath was preheated to 37 ° C and the freshly prepared medium was preheated in a water bath.
  • the frozen cells are taken out, and the frozen tube is quickly thawed into a preheated water bath and continuously shaken to rapidly melt the liquid in the tube.
  • the liquid in the cryotube was completely dissolved, and the outer wall of the frozen tube was wiped out with a 70% alcohol cotton ball. Pipette the cells in the cryotube and transfer to a 15 ml centrifuge tube while adding 5 ml of pre-warmed complete medium. Centrifuge at 500g for 3-5 minutes at low speed and aspirate the supernatant.
  • the medium required for cell culture and the ratio of cell passage are referred to the cell supplier cell culture instructions.
  • the cells were incubated in a 37 ° C / 5% CO 2 incubator until the cell monolayer was filled with the bottom of the well (96 well flat bottom plate), and 50 ⁇ l of a 2 ⁇ concentration gradient of the drug was added.
  • the cells can be added after the wall is attached, or two hours, or half a day. The method used in this study was to lay the cells and add the drug 6 hours later.
  • the compound cell growth inhibition rate (GI) (1-OD sample/OD negative) ⁇ 100%, wherein the OD sample is the OD value of the dosing hole or the positive control hole, and the OD negative is the undoped OD value ( That is, the cell control of the same concentration of DMSO treatment), using the Graphpad Prism 4.0 data processing software four-parameter logic fitting module to process the data calculation GI50 draw dose-effect curve.
  • the GI50 value indicates the concentration of the compound corresponding to 50% cell growth inhibition of the compound compared to no compound treatment.
  • the same generation of cells were used to inoculate the tumor cells in a good growth state in a suitable amount in a 96-well plate, and after 6 hours, the drug was added at a maximum concentration of 10 ⁇ M, and the concentration gradient was diluted 10-fold by 6 times, 2 duplicate wells.
  • a negative control group without DMSO only
  • a doxorubicin hydrochloride doxorubicin
  • Compound 19 has a good inhibitory effect on various types of tumor cells, especially for liver cancer and gastric cancer.
  • N/A indicates that this compound does not reach 50% of the highest inhibition rate of the cell within the range of detection, or has no inhibitory effect at all.
  • the invention is not limited to the specific embodiments described above.
  • the invention extends to any new feature or any new combination disclosed in this specification, as well as any novel method or process steps or any new combination disclosed.

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Abstract

提供一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其具有明显的抗肿瘤作用，同时还提供了氮杂环化合物的制备方法。

Description

一类氮杂环化合物及其制备方法和用途 技术领域
本发明涉及一种化合物及其制备方法和用途，特别涉及一类氮杂环化合物及其制备方法和用途。
背景技术
氮杂环类化合物具有广泛的生物活性，比如作为抗抑郁药、血管舒张药、强心药、止痛/抗炎药、抗高血压药及在农业上作为杀螨剂、除草剂，还有作为乙酰胆碱酯酶、醛糖还原酶、单胺氧化酶、CDKs、COX-2、P38MAP激酶的抑制剂等。
部分氮杂环类化合物显示了一定的抗肿瘤活性。专利文献US2007/0072866A1报道了一类氮杂环化合物，其结构式为
Figure PCTCN2015072817-appb-000001
作为GSK-3β抑制剂，用于治疗代谢疾病或神经退化疾病及相关疾病。其母环为哒嗪酮类。
专利文献WO03/059891及WO2005/007632公开了氮杂环化合物用于治疗因P38MAP激酶活性和/或TNF活性失调引起或加重的疾病或病症。上述专利文献中的哒嗪酮类化合物，结构式为
Figure PCTCN2015072817-appb-000002
可用于治疗炎性疾病、糖尿病、阿耳茨海默氏病或癌症，其中R4主要为芳基取代，R1为主要为卤素，R2为各类较多类型取代，R3仅为H取代。该专利中提到的化合物母环也为哒嗪酮类。
Aventis公司申请了一种氮杂环衍生物为CDK2抑制剂，其结构为
Figure PCTCN2015072817-appb-000003
其中X为C(O)NHR，NHC(O)R及含氮杂环，R2为H，R3为芳环及杂环。其母环亦为哒嗪酮类。
专利文献CN101538245、CN101537006中公开的氮杂环类化合物主要用于抗肝癌药物的用途，其结构为
Figure PCTCN2015072817-appb-000004
以6-(3-(三氟甲基)苯基)哒嗪-3(2H)-酮为母核的一类化合物，也属于哒嗪酮类化合物。
发明内容
本发明的目的在于，提供一类新的氮杂环化合物衍生物。同时，本发明还提供了氮杂环化合物衍生物的制备方法和用途。
为实现上述目的，本发明所采用的技术方案是：
结构如下的通式(Ⅰ)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药：
Figure PCTCN2015072817-appb-000005
其中，X为OH、SH、NH2、-ORa、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、或-SO2-ORa；
A为CR3或N；B为CR4或N；D为CR5或N；E为CR6或N；F为CR7或N；
R1为吸电子基团；
R2为卤素、取代或未取代的C1-C10烷基、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、取代或未取代的芳基、取代或未取代的杂芳基、或者取代或未取代的杂环基；
R3、R4、R5、R6、R7分别独立的选自：H、卤素、氨基、CN、NO2、-C(O)Ra、-CH2Ra、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-C(O)NRaRb、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、取代或未取代的芳基、取代或未取代的杂芳基、或者取代或未取代的杂环基；
Ra、Rb分别独立的选自：H、卤素、未取代或至少单取代的C1-C10烷基、C2-C10烯基、C2-C10炔基、杂环基、芳基或杂芳基。
作为优选方式，所述R1中吸电子基团选自三氟甲基、二氟甲基、氰基或三氯甲基。
作为优选方式，所述R2中取代的取代基选自卤素、CN、NH2、NO2、-C(O)Ra、-CH2Ra、-O-Ra、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-C(O)NRaRb、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、芳基、杂芳基或杂环基。
进一步优选，所述取代基中的芳基、杂芳基或杂环基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。作为优选方式，所述R2中，芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性
杂环，其中包括一个或者多个选自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
作为优选方式，所述Ra、Rb中取代的取代基选自选自卤素、羟基、杂芳基、芳基、杂环基、C1-C10烷氧基、(C1-C10-烷基)硫代、-COOH、-COO-(C1-C6-烷基)、-CONH2、三氟甲基、CN、氨基、(C1-C10-烷基)氨基或二(C1-C10-烷基)氨基。
进一步优选，所述取代基中的芳基、杂芳基或杂环基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。
作为优选方式，所述Ra、Rb中，芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性杂环，其中包括一个或者多个选自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
作为优选方式，所述R3、R4、R5、R6或R7中取代的取代基选自：卤素、羟基、杂芳基、芳基、杂环基、C1-C10-烷氧基、(C1-C10-烷基)硫代、-COOH、-COO-(C1-C6-烷基)、-CONH2、三氟甲基、CN、氨基、(C1-C10-烷基)氨基或二(C1-C10-烷基)氨基。
进一步优选，所述芳基、杂芳基或杂环基取代基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。
作为优选方式，所述R3、R4、R5、R6或R7中芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性杂环，其中包括一个或者多个选自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
上述化合物选自：
Figure PCTCN2015072817-appb-000006
Figure PCTCN2015072817-appb-000007
Figure PCTCN2015072817-appb-000008
通式(I)一类氮杂环化合物或其药学上可接受盐、水合物以及前药的制备方法，
方法1：
Figure PCTCN2015072817-appb-000009
其中，Z为卤素，A、B、D、E、F、X、R3、R4如上述所定义。
方法2：
Figure PCTCN2015072817-appb-000010
其中，Z为卤素，A、B、D、E、F、X、R3、R4如上述所定义。
方法3：
Figure PCTCN2015072817-appb-000011
其中，Z为卤素，A、B、D、E、F、X、R3、R4如上述所定义。
方法4：
Figure PCTCN2015072817-appb-000012
其中，Z为卤素，A、B、D、E、F、X、R3、R4如上述所定义。
包括上述通式(Ⅰ)一类氮杂环化合物或其药学上可接受的盐、水合物以及前药的药物组合物。
上述通式(Ⅰ)一类氮杂环化合物或其药学上可接受的盐、水合物以及前药在制备抗肿瘤药物中的用途。
作为优选方式，所述抗肿瘤药物为抗肝癌药物或抗胃癌药物。
本发明中药学上可接受的盐包括：盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等无机酸，以及苹果酸盐、富马酸盐、马来酸盐、甲磺酸、对甲苯磺酸、甲酸盐、领苯二甲酸盐、醋酸盐、草酸盐、琥珀酸盐、酒石酸盐、丙二酸盐、乳酸盐、扁桃酸盐等有机酸盐，以及钠盐、钾盐、钡盐、钙盐等。
前药，是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出含本专利中涉及的化合物。本发明的有益效果在于：本发明提供一系列新的化合物，合成方法简单。其抗肿瘤的作用明 显。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
实施例1化合物3的合成
Figure PCTCN2015072817-appb-000013
将10g(0.048mol)化合物1、8.4g(0.048mol)化合物2、3.36g(0.0048mol)二(三苯基磷)二氯化钯、250ml圆底烧瓶中，氩气置换三次，加入四氢呋喃(150ml)和水(10ml)，原料溶解，于外温70℃反应2h，反应完全后，减压旋去溶剂，干法过柱(PE：EA＝20:1)得到淡黄色固体8g。收率：65％。m.p.198-202℃。1HNMR(400MHz,DMSO-d6):δ＝12.67(br,1H),8.26(s,1H),8.24(s,1H),8.22(d,1H,J＝6.0),8.13(s,1H),7.576(t,1H,J＝10.0)。
实施例2化合物5的合成
Figure PCTCN2015072817-appb-000014
将0.22g Na溶于5ml甲醇中备用。称取0.1g 4a，加入新制甲醇钠溶液后，100℃封管反应至完全。将反应液倒入冰水中，稀盐酸调pH1左右，再用NaHCO3粉末调pH至5-6后，EA萃取3X，旋干干法拌样。PE：acetone 8:1柱层析即得0.052g黄色固体，收率49.5％。m.p.202-208℃。1HNMR(400MHz,DMSO-d6):δ＝12.59(br,1H),8.20(s,1H),8.16(s,1H),8.12(d,1H,J＝10.0),7.32(d,1H,J＝8.8),3.92(s,3H)。
实施例3化合物7的合成
Figure PCTCN2015072817-appb-000015
将500mg化合物1加入到5ml四氢吡咯中，封管下，于外温120℃反应8h，反应完全后，旋去溶剂，干法过柱，得到类白色固体448mg，收率72％。
将400mg(1.54mmol)化合物6、270mg(1.54mmol)化合物2、108mg(0.154mmol)二(三苯基磷)二氯化钯置10ml圆底烧瓶中，氩气置换三次，加入四氢呋喃(5ml)和水(1ml)，原料溶解，升温至70℃，搅拌回流2h。反应完全后，减压旋去溶剂，干法过柱(PE：EA＝20:1)得到淡黄色固体257mg。收率：54％。m.p.162-165℃。1HNMR(400MHz,DMSO-d6):δ＝8.09(s,1H),8.08(s,1H),8.07(s,1H),7.92(d,1H,J＝8.8),7.09(d,1H,J＝8.8),3.31(s,5H),1.893(s,3H)。
实施例4化合物9的合成
Figure PCTCN2015072817-appb-000016
合成方法同实施例3，得到淡黄色固体化合物9,两步总收率：42％。m.p.176-178℃。1HNMR(400MHz,DMSO-d6):δ＝12.64(br,1H),8.17(s,1H),8.12(s,1H),8.11(s,1H),8.08(s,1H),7.52(d,1H,J＝8.4),2.83(t,4H,J＝4.4),1.63(s,4H),1.52(d,2H,J＝4.4)。
实施例5化合物11的合成
Figure PCTCN2015072817-appb-000017
合成方法同实施例3，得到淡黄色固体化合物11，两步总收率：32％。1HNMR(400MHz,DMSO-d6):δ＝12.49(br,1H),8.19(s,1H),8.14(s,1H),8.125(s,1H),8.122(s,1H),7.59(d,1H,J＝8.4),3.70(t,4H,J＝8.0),2.88(s,4H)。
实施例6化合物13的合成
Figure PCTCN2015072817-appb-000018
合成方法同实施例3，得到淡黄色固体化合物13，两步总收率：24％。m.p.>250℃。1HNMR(400MHz,CDCl3):δ＝13.3(br,1H),8.12(s,1H),7.85(s,1H),7.60(d,1H,J＝8.4),7.45(s,1H),7.23(d,1H,J＝8.4),3.12(s,4H),2.69(s,4H)。
实施例7化合物14的合成
Figure PCTCN2015072817-appb-000019
将100mg化合物13用2ml3mol/L氯化氢甲醇溶液溶解后，减压旋去溶剂，即得到类白色固体14。m.p.>250℃。1HNMR(400MHz,DMSO-d6):δ＝14.0(br,1H),13.12(br,1H),8.65(s,1H),8.25(s,1H),8.11(d,1H,J＝8.4),7.88(s,1H),7.47(d,1H,J＝8.4),3.45(s,4H),2.97(s,4H)。
实施例8化合物15的合成
Figure PCTCN2015072817-appb-000020
将100mg化合物13用5ml甲醇溶解后，加入3当量的(Boc)2O，于室温下搅拌12h后，减压旋去溶剂，干法上样，过柱(PE：EA＝15:1)，得类白色固体110mg.收率：85％。m.p.>250℃。1HNMR(400MHz,CDCl3):δ＝13.0(br,1H),8.34(s,1H),8.05(s,1H),7.90(d,1H,J＝8.4),7.68(s,1H),7.37(d,1H,J＝8.4),3.58(s,4H),2.90(s,4H),1.49(s,9H)。
实施例9化合物17的合成
Figure PCTCN2015072817-appb-000021
合成方法同实施例3，得到淡黄色固体化合物17，两步总收率：29％。m.p.190-194℃。1HNMR(400MHz,CDCl3):δ＝12.64(br,1H),8.33(s,1H),8.06(s,1H),7.90(d,1H,J＝8.4),7.74(s,1H),7.43(d,1H,J＝8.8),5.746(brs.,2H),3.08(s,4H),2.67(s,4H),2.41(s,3H)。
实施例10化合物19的合成
Figure PCTCN2015072817-appb-000022
合成方法同实施例1，得到淡黄色固体化合物19，收率：75.2％。m.p.220-224℃。1HNMR(400MHz,DMSO-d6):δ＝12.75(br,1H),8.309(s,1H),8.304(s,1H),8.17(dd,1H,J＝2.4,8.4),8.13(d,1H,J＝0.8),7.76(d,1H,J＝8.8)。
实施例11化合物22的合成
Figure PCTCN2015072817-appb-000023
合成方法同实施例3，得到黄色固体化合物22，两步总收率：24.2％。m.p200℃碳化，1H-NMR(400MHz,DMSO-d6)δ:12.700(br,1H),8.286(s,1H),8.153(m,3H),7.372(d,1H,J＝9.2),3.698(t,4H,J＝4.4),3.014(t,4H,J＝4.4)。
实施例12化合物24的合成
Figure PCTCN2015072817-appb-000024
合成方法同实施例3，得到黄色固体化合物24，收率：64.8％。m.p194-196℃,1H-NMR(400MHz,DMSO-d6)δ:8.414(d,1H,J＝1.6),8.339(d,1H,J＝2.4),8.075(d,1H,J＝1.2),8.008(dd,1H,J＝2.0，8.4),7.201(d,1H,J＝8.8),4.807(br,2H),3.866(t,4H,J＝4.8),3.108(t,4H,J＝4.4)。
实施例13化合物27的合成
Figure PCTCN2015072817-appb-000025
合成方法同实施例3，得到淡黄色固体化合物27，两步总收率：34％。m.p：186～188℃,1H-NMR(CDCl3)δ:12.5～13.5(s,1H)；8.352(s,1H)；8.045(s,1H)；7.888(d,1H,J＝8.0)；7.708(s,1H)；7.283(d,1H,J＝6.8)；7.089(t,1H,J＝55.4)；3.873(t,2H)；3.025(m,2H)。
实施例14化合物31的合成
Figure PCTCN2015072817-appb-000026
将化合物28(200mg，0.823mmol)、化合物29(86.34mg，0.549mmol)和K2CO3(227.63mg，1.647mmol)加至25ml两颈瓶中，油泵除去瓶内气体并用氩气饱和后，针筒注入3mlTHF和1mlH2O，继而再用水泵除去瓶内气体并用氩气饱和。缓慢加入PdCl2(PPh3)2(38mg,0.0549mmol)，再用水泵除去瓶内气体并用氩气饱和。升温至70℃，搅拌回流2h。将反应液用乙酸乙酯萃取3次，合并有机层，无水Na2SO4干燥，浓缩。柱层析PE:EA＝100:1得120mg白色固体3，收率53％，m.p.76-78℃。
将30(120mg)加至5ml冰醋酸中，160℃封管搅拌反应2天。TLC监测反应完毕，将反应液倒入冰水中，乙酸乙酯萃取。有机层用饱和NaHCO3和饱和NaCl洗涤，无水Na2SO4干燥，浓缩，柱层析PE:EA＝1:2得60mg白色粉末31，收率53.6％。m.p.192-194℃。1HNMR(400MHz,CDCl3)δ13.00(s,1H),7.73(dd,1H,J＝2.4,9.2),7.63(d,1H,J＝6.4),7.60(s,1H),7.57(d,1H,J＝4.4),7.29(d,1H,J＝9.6),6.72(d,1H,J＝9.6)。
实施例15化合物33的合成
Figure PCTCN2015072817-appb-000027
合成方法同实施例14，两步总收率：13.6％。m.p.208℃炭化。1HNMR(400MHz,CDCl3)δ13.49(s,1H),7.77(dd,1H,J＝2.4,5.2),7.68(d,1H,J＝2.0),7.64(d,1H,J＝2.4),7.58(dd,1H,J＝2.0,8.4),7.42(d,1H,J＝8.0),6.72(d,1H,J＝9.6),3.86(t,4H,J＝4.4),2.96(t,4H,J＝4.0)。
实施例16化合物36的合成
Figure PCTCN2015072817-appb-000028
合成方法同实施例14，两步总收率：15.1％。m.p.220-222℃。1HNMR(400MHz,CDCl3)δ7.82(d,1H,J＝9.6Hz),7.71(s,1H),7.65(s,1H),7.545(d,1H,J＝6.8),7.396(d,1H,J＝8.4),6.788(d,1H,J＝9.6),2.80(s,6H)。
实施例17化合物39的合成
Figure PCTCN2015072817-appb-000029
合成方法同实施例14，两步总收率：11.4％。m.p.174-178℃。1HNMR(400MHz,CDCl3)δ12-14(br,1H),7.76(dd,1H,J＝2.4,9.6),7.56(s,1H),7.29(d,1H,J＝8.4),6.67(d,1H,J＝9.6),6.64(d,2H,J＝8.4),3.32(s,4H),2.04(s,4H)。
实施例18化合物42的合成
Figure PCTCN2015072817-appb-000030
合成方法同实施例14，得到白色固体，两步总收率：13.4％。m.p.220-222℃。1HNMR(400MHz,CDCl3)δ7.82(d,1H,J＝9.6),7.71(s,1H),7.65(s,1H),7.545(d,1H,J＝6.8),7.396(d,1H,J＝8.4),6.788(d,1H,J＝9.6),2.80(s,6H)。
实施例19化合物45的合成
Figure PCTCN2015072817-appb-000031
合成方法同实施例14，得到白色固体，两步总收率：14.1％。m.p.208-212℃。1HNMR(400MHz,CDCl3)：δ13-14(br,1H),7.76(dd,1H,J＝2.8,9.6),7.66(t,2H,J＝2.4),7.58(m,1H),6.71(d,1H,J＝9.6),3.13(s,4H),2.71(s,4H),2.54(s,3H)。
实施例20化合物48的合成
Figure PCTCN2015072817-appb-000032
合成方法同实施例14，得到白色固体，两步总收率：16.1％。m.p.>250℃。1HNMR(400MHz,CDCl3)：δ13.05(br,1H),8.18(d,1H,J＝9.6),7.90(s,1H),7.77(s,1H),7.65(d,1H,J＝8.0),7.43(d,1H,J＝8.4),7.07(d,1H,J＝9.6),3.58(s,4H),2.90(s,4H),2.19(2H,q，J＝7.2)，0.98(3H,t，J＝7.2)。
实施例21化合物49的合成
Figure PCTCN2015072817-appb-000033
将100mg化合物48溶解于5ml甲醇中，加入2当量三乙胺，4当量(Boc)2，于室温下搅拌5h，减压旋去溶剂，柱层析(PE：EA＝30:1)得白色固体94mg，收率：85％。m.p.222-225℃。1HNMR(400MHz,CDCl3)：δ7.88(d,1H,J＝9.6Hz),7.79(s,1H),7.69(s,1H),7.59(d,1H,J＝8.0),7.39(d,1H,J＝8.4),6.87(d,1H,J＝9.6),3.58(s,4H),2.90(s,4H),1.49(s,9H)。
实施例22化合物52的合成
Figure PCTCN2015072817-appb-000034
合成方法同实施例14，得到白色固体，两步总收率：10.1％。m.p.220-222℃。1HNMR(400MHz,CDCl3)：δ12-14(br,1H),7.75(d,1H,J＝8.8),7.61(s,2H),7.54(d,1H,J＝8.0),7.07(d,1H,J＝8.4),6.72(d,1H,J＝8.8),3.92(s,3H)。
实施例23化合物55的合成
Figure PCTCN2015072817-appb-000035
合成方法同实施例14，得到白色固体，两步总收率：17.1％。m.p.>250℃。1HNMR(400MHz,CDCl3)：δ13.5(br,2H),7.81(d,1H,J＝8.8),7.72(s,2H),7.61(d,1H,J＝8.0),7.27(d,1H,J＝8.4),6.89(d,1H,J＝8.8)。
实施例24化合物58的合成
Figure PCTCN2015072817-appb-000036
合成方法同实施例14，得到白色固体，两步总收率：15.6％。m.p.>250℃,1HNMR(400MHz,CDCl3)：δ12.31(br,1H),8.51(s,1H),7.51(m,2H),7.42(d,1H,J＝8.4),7.11(d,1H,J＝8.4),6.73(d,1H,J＝8.8),4.24(s,1H),3.20(s,1H),2.55(s,3H),2.04(m,2H),1.58(m,2H),1.54(m,1H),1.21(m,2H)。
实施例25化合物59的合成
Figure PCTCN2015072817-appb-000037
化合物41(100mg)、NaSCH3(128mg)、4ml无水DMF混合后，升温至100℃回流12h。将反应液倒入冰水，有固体析出，过滤得棕色固体。柱层析PE：EA＝100:1得类白色固体130mg，收率100％，m.p.80-84℃。1HNMR(400MHz,CDCl3)：δ8.66(d,1H,J＝2.0),7.77(d,1H,J＝2.0),7.68(m,2H),7.39(d,1H,J＝8.4),7.28(s,1H),2.80(s,6H),2.63(s,3H)。
实施例26化合物60的合成
Figure PCTCN2015072817-appb-000038
合成方法同实施例25，得到白色粉末，收率88.5％。m.p.166-170℃。1HNMR(400MHz,CDCl3)：δ8.62(d,1H,J＝2.0),7.68(m,2H),7.59(dd,1H,J＝2.0,8.4),7.26(m,1H),7.07(d,1H,J＝8.8),2.61(s,3H)。
实施例27化合物61的合成
Figure PCTCN2015072817-appb-000039
合成方法同实施例25，得到白色粉末，收率78.3％。m.p.98-102℃。1HNMR(400MHz,CDCl3)：δ8.65(s,1H),7.78(s,1H),7.63(m,2H),7.68(d,2H,J＝8.4),7.40(d,1H,J＝8.4),7.26(d,1H,J＝7.6),3.57(s,4H),2.90(s,4H),2.61(s,3H),1.48(s,9H)。实施例28化合物62的合成
Figure PCTCN2015072817-appb-000040
将100mg化合物58溶于5mlDCM后，加入1mlCF3COOH，室温搅拌，TLC监测反应完毕后，依次用饱和Na2CO3洗涤三次、brine洗涤一次，旋干即得棕黄固体130mg。柱层析DCM：MeOH＝20:1得黄色固体52mg，收率66.75％。m.p.230℃炭化。1HNMR(400MHz,CDCl3)：δ8.73(s,1H),8.09(d,1H,J＝8.0),7.97(m,2H),7.69(d,1H,J＝7.6),7.51(d,1H,J＝8.4),3.37(s,4H),3.30(s,4H),2.64(s,3H)。
实施例29化合物63的合成
Figure PCTCN2015072817-appb-000041
合成方法同实施例25，得到土黄色固体93mg，收率50％。m.p.92-96℃。1HNMR(400MHz,CDCl3)：δ8.60(s,1H),7.78(s,1H),7.63(m,2H),7.42(d,1H,J＝8.0),7.21(d,1H,J＝8.4),2.99(m,4H),2.57(m,4H),2.36(s,3H)。
实施例30化合物64的合成
Figure PCTCN2015072817-appb-000042
合成方法同实施例25，得到土黄色固体56mg，收率54.5％。1HNMR(400MHz,CDCl3)：δ8.47(s,1H),7.57(m,2H),7.48(d,1H,J＝8.4),7.02(d,1H,J＝8.4),6.84(d,1H,J＝8.8),4.12(s,1H),3.29(s,1H),2.64(s,3H),2.29(s,3H)，2.12(m,2H),1.45(m,2H),1.49(m,1H),1.25(m,2H)。
实施例31化合物65的合成
Figure PCTCN2015072817-appb-000043
冰浴下将52mg化合物59溶解于7mlDCM中，分批缓慢加入57.5mg间氯过氧苯甲酸，加毕移至室温搅拌6h。反应液用饱和Na2CO3洗涤3次，Brine洗涤1次，无水Na2SO4干燥，浓缩得白色固体30mg，收率52％，m.p.132-135℃。1HMNR(400MHz,CDCl3)：δ8.92(s,1H),8.16(d,1H,J＝8.0),8.102(dd,1H,J＝2.4,8.4),7.833(d,1H,J＝2.0),7.72(dd,1H,J＝2.0,8.4),7.39(d,1H,J＝8.8),3.27(s,3H),2.87(s,6H)。
实施例32化合物68的合成
Figure PCTCN2015072817-appb-000044
将化合物1(70mg)、化合物66(90.8mg)、Pd(OAc)2(4.1mg)、KF·2H2O(68.5mg)加至10ml圆底烧瓶，加入2ml MeOH后，微波回流反应20min。停止反应，旋干溶剂，柱层析PE：EA＝50:1得52mg白色粉末67。
将化合物67加至5ml冰醋酸中，130℃封管搅拌反应8h。TLC监测反应完毕后，将反应液倒入冰水中，乙酸乙酯萃取。有机层用饱和NaHCO3和饱和NaCl洗涤，无水Na2SO4干燥，浓缩，柱层析EA得32mg白色粉末68，收率35.4％。m.p.大于240℃。1HNMR(400MHz,DMSO)：δ12-13(br,1H),8.70(s,2H),8.02(s,2H),7.59(m,1H)。
实施例33化合物70的合成
Figure PCTCN2015072817-appb-000045
将化合物69(200mg，0.948mmol)、化合物1(237mg，1.138mmol)、Pd(AcO)2(11mg，0.0474mmol)、KF·H2O(178.47mg，1.896mmol)和甲醇混合后，升温至回流。TLC监测反应完全，干法拌样，柱层析PE:EA30:1得200mg无色液体，收率为63.4％。1HNMR(400MHz,CDCl3)：δ8.30(s,2H),7.52(d,1H,J＝7.6),7.34(m,1H),7.10(t,1H,J＝8.4)，1.56(s,18H)。
实施例34化合物71的合成
Figure PCTCN2015072817-appb-000046
将化合物70(120mg)溶于5mlDCM后，加入1ml三氟醋酸，室温搅拌至反应完全。反应液依次用饱和Na2CO33X、brine1X，干法拌样。柱层析DCM：甲醇300:1得白色固体，收率为48.2％，m.p.190-192℃。1HNMR(400MHz,CDCl3)：δ8.50(s,2H),7.68(d,1H,J＝8.4),7.64(m,1H),7.30(t,1H,J＝8.4),5.24(br,2H)。
实施例35化合物73的合成
Figure PCTCN2015072817-appb-000047
合成方法同实施例32，两步总收率23％。m.p.183-185℃。1HNMR(400MHz,DMSO-d6):δ：12.43(br,1H),8.54(s,2H),7.72(s,2H),7.39(m,1H),3.51(s,5H),1.93(s,3H)。
实施例36化合物75的合成
Figure PCTCN2015072817-appb-000048
合成方法同实施例32，两步总收率19.8％。m.p.174-178℃。1HNMR(400MHz,DMSO-d6):δ：12.23(br,1H)，8.50(s,2H),7.82(s,2H),7.39(m,1H)，2.93(t,4H,J＝4.4),1.73(s,4H),1.62(d,2H,J＝4.4)。
实施例37化合物77的合成
Figure PCTCN2015072817-appb-000049
合成方法同实施例32，两步总收率12.8％。m.p.165-168℃。1HNMR(400MHz,DMSO-d6):δ：12.23(br,1H)，8.60(s,2H),8.02(s,2H),7.49(m,1H)，2.89(s,6H)。
实施例38化合物80的合成
Figure PCTCN2015072817-appb-000050
先将0.12g化合物78、0.24g化合物79、碳酸钾0.427g与水6mL、二氧六环12mL混合后，绝氧操作，加入四三苯基膦钯0.0238g，避光于80℃下反应24h，TLC监控反应完全，向反应液中加入饱和碳酸氢钠30ml,再用EA萃取三次，合并有机相用饱和食盐水洗两次，干燥浓缩得棕色固体，过柱(PE:EA＝20:1,加1％三乙胺)，得淡黄色固体240mg。m.p.212-218℃。1HNMR(400MHz,CDCl3):δ8.87(s,1H),7.88(d,1H,J=8.4),7.74(m,1H),7.50(t,1H,J=8.4),5.74 (br,2H)。
实施例39化合物81的合成
Figure PCTCN2015072817-appb-000051
将500mg(1.92mmol)化合物3溶解于乙腈/水(2.5ml/2.5ml)中，分批缓慢加入NBS410mg(2.305mmol)，加毕，于0℃下搅拌反应搅拌反应4h。待反应完全后旋干溶剂，减压旋去溶剂，干法过柱，PE:EA＝20:1，得到淡黄色固体335mg，收率51.4％，m.p.217-223℃。1HNMR(400MHz,DMSO-d6):δ＝12.87(br,1H),8.36(s,1H),8.22(d,1H,J＝6.0),8.13(s,1H),7.576(t,1H,J＝10.0)。
实施例40化合物84的合成
Figure PCTCN2015072817-appb-000052
合成方法同实施例32，得类白色固体，两步总收率：21％.m.p223～228℃，1HNMR(400MHz,DMSO-d6):δ：12.73(br,1H)，8.58(s,2H),8.32(s,1H),7.99(s,1H)，3.23(t,4H,J＝4.8),2.43(s,4H),1.92(d,2H,J＝4.8)。
实施例41化合物87的合成
Figure PCTCN2015072817-appb-000053
合成方法同实施例32，得类白色固体，两步总收率10.9％，m.p214～218℃，1HNMR(400MHz,CDCl3)δ8.82(s,1H),7.92(s,1H),7.75(d,1H,J＝6.8),7.66(d,1H,J＝6.8),3.20(s,6H)。
实施例42化合物90的合成
Figure PCTCN2015072817-appb-000054
合成方法同实施例32，得类白色固体，两步总收率14.6％，m.p224～228℃，1HNMR(400MHz,CDCl3)：12.18(br,1H),8.87(s,1H),8.56(s,1H),8.12(d,1H,J＝10.0),7.24(d,1H,J＝10.0),3.79(t,4H,J＝4.8,N-CH2),3.52(t,4H,J＝4.8,O-CH2)。
实施例43化合物93的合成
Figure PCTCN2015072817-appb-000055
合成方法同实施例32，得类白色固体，两步总收率16.1％。m.p.200-206℃。1HNMR(400MHz,CDCl3):δ11.34(br,1H),7.92(d,1H,J＝9.6),7.71(s,1H),7.34(d,1H,J＝6.8),7.16(d,1H,J＝6.8),6.98(d,1H,J＝9.6),3.10(s,6H),2.11(s,1H)。
实施例44化合物94的合成
Figure PCTCN2015072817-appb-000056
合成方法同实施例38，得淡黄色固体，收率45%。m.p.>250℃。1HNMR(400MHz,CDCl3):δ13.89
(br,2H),8.21(d,1H,J＝8.8),7.82(d,1H,J＝8.8),7.61(d,1H,J＝8.0),7.27(d,1H,J＝8.0)。
实施例45化合物95的合成
Figure PCTCN2015072817-appb-000057
将100mg(0.3mmol)化合物80、36mg(0.3mmol)苯硼酸、碳酸钾127mg与水6mL、二氧六环12mL混合后，绝氧操作，加入四(三苯基膦)钯34mg(0.03mmol)，避光于80℃下反应24h，TLC监控反应完全，向反应液中加入饱和碳酸氢钠10ml,再用EA萃取三次，合并有机相用饱和食盐水洗两次，干燥浓缩得棕色固体，过柱(PE:EA＝20:1)，得淡黄色固体50mg，收率50％。m.p.172-178℃。1HNMR(400MHz,CDCl3):δ＝12.27(br,1H),8.27(s,1H),8.12(d,1H,J＝10.0),8.02(s,1H),7.87(dd,1H,J＝10.0),7.67(d,2H,J＝8.4),7.61(t,2H,J＝8.4),7.51(t,1H,J＝8.4)。
实施例46化合物97的合成
Figure PCTCN2015072817-appb-000058
合成方法同实施例1，得到淡黄色固体，收率45％。m.p.172-174℃。1HNMR(400MHz,CDCl3):δ13.45(br,1H),7.68(d,1H,J＝2.4),7.63(d,1H,J＝6.4),7.51(s,1H),7.31(d,1H,J＝9.6),6.79(d,1H,J＝9.6),2.45(s,3H)。
实施例47化合物100的合成
Figure PCTCN2015072817-appb-000059
合成方法同实施例32，得类白色固体，两步总收率9.1％。m.p.>250℃。1HNMR(400MHz,CDCl3):δ13.11(br,2H),8.21(s,1H),7.85(d,1H,J=8.8),7.62(s,1H),7.37(s,1H),6.98 (d,1H,J＝8.8),2.56(s,1H)。
实施例47：体外抗肿瘤活性实验
每个化合物按10倍比稀释6个浓度梯度，72小时后进行MTS实验，计算GI50值。实验同时设置阴性对照组(不加药仅含DMSO)和盐酸阿霉素(多柔比星)阳性对照组，阳性对照选择2个浓度：1μM和0.1μM。
1.材料
1.1细胞培养材料：
(1)RPMI1640:Gibco,Invitrogen(Cat#22400)
(2)FetalBovineSerum(FBS):Gibco,Invitrogen(Cat#10437-036)
(3)Penicilin-Streptomycin:Gibco,Invitrogen(Cat#10378)
(4)Trypsin-EDTA:Gibco,Invitrogen(Cat#GB25300-062)
(5)100mmTC-TreatedCultureDish:Corning(Cat#430167)
(6)96-wellTC-TreatedMicroplate:Corning(Cat#3599)
1.2细胞系
(1)QGY-7703细胞株(肝癌)
(2)Bel-7402细胞株(肝癌)
(3)SMMC-7721细胞株(肝癌)
(4)SNU-398细胞株(肝癌)
(5)SNU-449细胞株(肝癌)
(6)MGC803细胞株(胃癌)
(7)HS746T细胞株(胃癌)
(8)SK-OV3细胞株(卵巢癌)
(9)H460细胞株(肺癌)
(10)SK-Br3细胞株(乳腺癌)
1.3检测试剂CellProliferationKitI(MTS):Invitrogen(Cat#G5421)
1.4检测仪器
Flexstation3：MolecularDevices公司
a)其它试剂
Dimethylsulfoxide(DMSO):Sigma(Cat#D2650)
2.实验方法:
2.1细胞培养
2.1.1细胞复苏
实验前，超净工作台台面用紫外线照射30min。将水浴锅预热至37℃,将新鲜配制的培养基置于水浴锅预热。取出冻存的细胞，迅速将冻存管投入到已经预热的水浴锅中迅速解冻，并不断的摇动，使管中的液体迅速融化。约1-2min后冻存管内液体完全溶解，取出用含70％酒精棉球擦拭冻存管的外壁。吸取冻存管内细胞，转移至15ml离心管中，同时加入5ml预热完全培养基。500g低转速离心3-5分钟，吸弃上清液。向离心管内加入10ml培养液，轻柔吹打制成细胞悬液。通过台盼蓝染色细胞记数并进行活力测定后，将细胞悬液加入10-cm培养皿中，于含37℃/5％CO2培养箱中培养过夜。
2.1.2细胞培养与传代
细胞培养时所需的培养基以及细胞传代的比例参考细胞供货商细胞培养说明书。
2.1.3细胞冻存
配制新鲜的细胞冻存液(60％培养基，30％FBS，10％DMSO)。取对数生长期细胞，用0.05％胰酶消化，将贴壁细胞吹打至悬浮后移至15ml离心管中。1000g离心5min后吸弃上清，加入适量配制好的冻存培养液，用吸管轻轻吹打使细胞均匀并计数，调节冻存液中细胞的最终密度为1×106/ml。将细胞分装入冻存管中，每管1ml。用程序降温盒冻存细胞后移至-80℃保存。
2.2化合物处理
化合物用用含0.1％DMSO的完全培养基稀释10倍稀释，6个浓度。避光于4℃保存。
2.3MTS细胞活力测试方法
1)收集对数期细胞，调整细胞悬液浓度，每孔加入50μl细胞悬液,每孔细胞数为优化后数量,即4000个每孔。(边缘孔用无菌PBS填充）。
2)细胞在37℃/5％CO2培养箱孵育，至细胞单层铺满孔底(96孔平底板)，加入50μl的2Χ浓度梯度的药物。原则上细胞贴壁后即可加药，或两小时，或半天时间。本研究采用的方法是铺细胞，6h后加入药物。
3)细胞在37℃/5％CO2培养箱孵育，在24小时、48小时和72小时时用倒置显微镜进行观察。
4)加药72h后加入20μl MTS检测试剂。
5)37℃/5％CO2培养箱孵育1-4h
6)在酶标仪Flexstation3(Molecular Devices公司)测定OD490nm吸光值。
2.4数据分析
化合物细胞生长抑制率(Growth inhibition rate,GI)＝(1-OD样品/OD阴性)×100％，其中OD样品为加药孔或阳性对照孔OD值，OD阴性为不加药孔OD值(即同等浓度DMSO处理的细胞对照)，采用Graphpad Prism 4.0数据处理软件四参数逻辑拟合模块进行处理数据计算GI50绘制量效曲线。GI50值表示与未加化合物处理相比，化合物抑制50％细胞生长对应的化合物浓度。
3.实验结果
使用同一代次的细胞接种于将生长状态良好的肿瘤细胞按照适宜的量接种于96孔板中，6h后加药，药物按照最高浓度10μM，依次10倍稀释6个浓度梯度，2复孔，实验同时设置阴性对照组(不加药仅含DMSO)和盐酸阿霉素(多柔比星)阳性对照组，阳性对照选择2个浓度：1μM和0.1μM。
表1.化合物19对多种肿瘤细胞的GI50值
Figure PCTCN2015072817-appb-000060
Figure PCTCN2015072817-appb-000061
从上表中可以看出，化合物19对多种类型的肿瘤细胞均有较好的抑制作用，尤其是对肝癌以及胃癌的抑制作用最为明显。
表2.化合物对三种不同肝肿瘤细胞的GI50值汇总
注：N/A:表示这个化合物在检测的范围内对该细胞的最高抑制率没有达到50％，或者完全没有抑制作用。
上述实验结果证明：化合物的活性已经达到较高水平，本发明的化合物均有很显著的抗肿瘤活性。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的组合。

Claims (19)

  1. 结构如下的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药：
    Figure PCTCN2015072817-appb-100001
    其中，X为OH、SH、NH2、-ORa、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、或-SO2-ORa；
    A为CR3或N；B为CR4或N；D为CR5或N；E为CR6或N；F为CR7或N；
    R1为吸电子基团；
    R2为卤素、取代或未取代的C1-C10烷基、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、取代或未取代的芳基、取代或未取代的杂芳基、或者取代或未取代的杂环基；
    R3、R4、R5、R6、R7分别独立的选自：H、卤素、氨基、CN、NO2、-C(O)Ra、-CH2Ra、-ORa、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-C(O)NRaRb、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、取代或未取代的芳基、取代或未取代的杂芳基、或者取代或未取代的杂环基；
    Ra、Rb分别独立的选自：H、卤素、未取代或至少单取代的C1-C10烷基、C2-C10烯基、C2-C10炔基、杂环基、芳基或杂芳基。
  2. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述R1中吸电子基团选自三氟甲基、二氟甲基、氰基或三氯甲基。
  3. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述R2中取代的取代基选自卤素、CN、NH2、NO2、-C(O)Ra、-CH2Ra、-O-Ra、-O-C(O)-Ra、-NRaRb、-NHC(O)Ra、-C(O)NRaRb、-NHC(S)Ra、-SRa、-S(O)Ra、-SO2Ra、-NHSO2Ra、-SO2NRaRb、-O-SO2Ra、-SO2-ORa、芳基、杂芳基或杂环基。
  4. 根据权利要求3所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述芳基、杂芳基或杂环基取代基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。
  5. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述R2中，芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性杂环，其中包括一个或者多个选 自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
  6. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述Ra、Rb中取代的取代基选自选自卤素、羟基、杂芳基、芳基、杂环基、C1-C10烷氧基、(C1-C10-烷基)硫代、-COOH、-COO-(C1-C6-烷基)、-CONH2、三氟甲基、CN、氨基、(C1-C10-烷基)氨基或二(C1-C10-烷基)氨基。
  7. 根据权利要求6所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述芳基、杂芳基或杂环基取代基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。
  8. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述Ra、Rb中，芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性杂环，其中包括一个或者多个选自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
  9. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述R3、R4、R5、R6或R7中取代的取代基选自：卤素、羟基、杂芳基、芳基、杂环基、C1-C10-烷氧基、(C1-C10-烷基)硫代、-COOH、-COO-(C1-C6-烷基)、-CONH2、三氟甲基、CN、氨基、(C1-C10-烷基)氨基或二(C1-C10-烷基)氨基。
  10. 根据权利要求9所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述芳基、杂芳基或杂环基取代基至少被单取代，其取代基选自C1-C6烷基、C1-C6烷氧基、卤素、三氟甲基、二氟甲基、三氯甲基或羟基。
  11. 根据权利要求1所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于：所述R3、R4、R5、R6或R7中芳基为5至10元芳香性一或者二环体系；杂芳基为5至10元芳香性杂环，其中包括一个或者多个选自N、O或S的杂原子；杂环基为3至10元非芳香性一或多环杂环，其中包括一个或者多个选自N、O或S的杂原子。
  12. 根据权利要求1-11任一所述的通式(I)的一类氮杂环化合物或其药学上可接受的盐、水合物以及前药，其特征在于所述化合物选自：
    Figure PCTCN2015072817-appb-100002
    Figure PCTCN2015072817-appb-100003
  13. 根据权利要求1-11任一所述的通式(I)一类氮杂环化合物或其药学上可接受盐、水合物以及前药的制备方法，其特征在于包括以下步骤：
    Figure PCTCN2015072817-appb-100004
    其中，Z为卤素，A、B、D、E、F、X、R3、R4如权利要求1-11任一项所定义。
  14. 根据权利要求1-11任一所述的通式(I)一类氮杂环化合物或其药学上可接受盐、水合物以及前药的制备方法，其特征在于包括以下步骤：
    Figure PCTCN2015072817-appb-100005
    其中，Z为卤素，A、B、D、E、F、X、R3、R4如权利要求1-11任一项所定义。
  15. 根据权利要求1-11任一所述的通式(I)一类氮杂环化合物或其药学上可接受盐、水合物以及前药的制备方法，其特征在于包括以下步骤：
    Figure PCTCN2015072817-appb-100006
    其中，Z为卤素，A、B、D、E、F、X、R3、R4如权利要求1-8任一项所定义。
  16. 根据权利要求1-11任一所述的通式(I)一类氮杂环化合物或其药学上可接受盐、水合物以及前药的制备方法，其特征在于包括以下步骤：
    Figure PCTCN2015072817-appb-100007
    其中，Z为卤素，A、B、D、E、F、X、R3、R4如权利要求1-11任一项所定义。
  17. 包括权利要求1-12任一所述的通式(I)一类氮杂环化合物或其药学上可接受的盐、水合物以及前药的药物组合物。
  18. 根据权利要求1-12任一所述的通式(I)一类氮杂环化合物或其药学上可接受的盐、水合物以及前药在制备抗肿瘤药物中的用途。
  19. 1根据权利要求18所述的通式(I)一类氮杂环化合物或其药学上可接受的盐、水合物以及前药的用途，其特 征在于：所述抗肿瘤药物为抗肝癌药物或抗胃癌药物。
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