WO2015120730A1 - 脱氢硫胺[2,3-c]喹啉-12-酮衍生物及其制备方法和应用 - Google Patents

脱氢硫胺[2,3-c]喹啉-12-酮衍生物及其制备方法和应用 Download PDF

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WO2015120730A1
WO2015120730A1 PCT/CN2014/089182 CN2014089182W WO2015120730A1 WO 2015120730 A1 WO2015120730 A1 WO 2015120730A1 CN 2014089182 W CN2014089182 W CN 2014089182W WO 2015120730 A1 WO2015120730 A1 WO 2015120730A1
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quinolin
chloro
dehydrothieno
amino
group
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黄旭山
于大雄
陈宗志
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黄旭山
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • the invention relates to the technical field of cancer drugs, in particular to a dehydrothiamine [2,3-c]quinolin-12-one derivative, its anticancer activity application and evaluation.
  • telomere length In most organisms, the replication and maintenance of telomere length must be dependent on telomerase. Telomerase is a ribonuclease that is a complex of RNA and protein subunits. At present, some important telomerase subunits have been identified, including human telomerase reverse transcriptase (hTERT), which has reverse transcriptase activity, in terms of human telomerase composition. And a human telomerase RNA component as a template, and some proteins that bind to telomerase such as human telomerase-associated protein, p23, hsp90, hsp40, hsp70 Wait.
  • hTERT human telomerase reverse transcriptase
  • telomeres are gradually reduced as the number of cell divisions increases, which can be regarded as a mitotic clock for cells to calculate the number of divisions.
  • the telomere When the telomere is short to a certain extent, the cell will stop dividing and enter the aging stage, and the cell will stay at this stage for a period of time, and then go to death, this period is called the M1 phase (mortality stage1); if in the M1 phase, Mutations in the intratumoral tumor suppressor gene, such as p53 and Rb, cause cells to escape the aging phase and continue cell division, a period known as the M2 phase (mortality stage 2). During this period, due to the absence of telomerase activity, the telomere length will still be shortened. At this time, telomeres can not protect the integrity of the chromosome ends, which leads to chromosomal instability, and the cells cannot completely transmit the genetic information.
  • M2 M2 is also called crisis; most of the cells will die in M2 phase, only a few cells will survive due to the expression of telomerase activity, and this cell can be unrestricted and persistently divided. Become an undead cell (or cancer cell).
  • telomere length to prevent cells from entering replicative senescence, or to remove telomerase activity and inhibit its activity to limit the division of cancer cells, both of which can be cell-oriented and cancerous.
  • a drug capable of inhibiting telomerase activity does not affect the physiological state of normal cells when inhibiting telomerase activity.
  • this active inhibitory drug can attenuate the proliferation of cancer cells, so if telomerase activity inhibitors can be found, the development of cancer therapeutic drugs is highly promising through the discussion of anticancer mechanisms.
  • the cause of cancer is due to abnormal proliferation of DNA. Therefore, as long as you can selectively attack the DNA of cancer cells, I don't want to damage the DNA of normal cells, but it is very difficult to distinguish the DNA of normal cells from the DNA of cancer cells. Therefore, after discovering the difference in characteristics between normal cells and cancer cells, it is produced with specificity.
  • Target therapy combined with other chemotherapy or radiation therapy, can significantly reduce side effects and achieve better results, so target treatment is the current research direction to treat cancer. Because topoisomerase plays an indispensable role in DNA replication, it is the target of recent anti-cancer target treatment research.
  • Camptothecin is the first small molecule drug used to inhibit the first type of topoisomerase.
  • camptothecin has many disadvantages that make it impossible to use it in clinical practice, such as the lactate ring in the human body.
  • it is easy to be hydrolyzed into hydroxycarboxylate, which leads to easy binding to serum albumin in vivo and loses the effect of inhibiting the first type of topoisomerase;
  • the triple complex of camptothecin-TopI-DNA is not covalently linked Therefore, the structure is unstable; the water solubility of camptothecin is poor, resulting in poor bioavailability;
  • p-glycoprotein (MDR1, ABCB1) on the cell membrane is discharged from the pump to push the drug out of the cell; more importantly, some Tumor cells gradually develop resistance to camptothecin and its derivatives and adverse drug side effects, making even two more soluble water-soluble semi-synthetic drugs, even in the later stages of camptothecin, in AD 1996
  • topoisomerase activity inhibitors are very important in the development of cancer therapeutic drugs.
  • R is a group selected from the group consisting of the following substituents:
  • Iv a C 3-12 nitrogen-containing cycloalkyl group and a heterocyclic group containing from 1 to 3 heteroatoms selected from O, S and N, wherein the ortho, meta or para is more independently
  • substituents hydrogen group, (CH 2 ) n alkyl group, (CH 2 ) n hydroxyl group, (CH 2 ) n C 3-12 cycloalkyl group, (CH 2 ) n C 3-12 a nitrogen cycloalkyl group, a (CH 2 ) n benzene ring, an aldehyde group, and a (CH 2 ) n COC 3-12 nitrogen-containing cycloalkyl group; wherein 0 ⁇ n ⁇ 10;
  • R 1 is one of the following substituents: N(CH 3 ) 2 , C(NH 2 ) 2 , NH(CH 2 ) n H a linear alkyl group, a branched alkyl group, an alkyl group having an amine group, and an alkyl group having a hydroxyl group;
  • R 2 is one of the following substituents: a benzene ring, a C 3-12 cycloalkyl group and a heterocyclic group, containing from 1 to 3 a hetero atom selected from O, S and N, wherein the ortho, meta or para position is more independently selected from one of the following substituents: methoxy, amine, benzene, with C1-C3 Branched substituted alkyl, amine, nitro, hydroxy, and C 3-12 heterocycle; wherein the C 3-12 heterocycle contains from 1 to 3 heteroatoms selected from O, S, and N; Acceptable salts, stereoisomers, and mirror image isomers.
  • the substituent group i)-vi) is selected from the group consisting of chlorine, hydroxyl, methoxy, dimethylamino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4 -ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-benzylpiperazin-1-yl, 4-phenylpiperazin-1-yl, morpholine , thiomorpholino, piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-benzylpiperidin-1-yl, [1,4'-bipiperidinyl]-1'- , 4-(3-(piperidin-4-yl)propyl, pyrrolidin-1-yl, 2-oxopiperidin-1-yl, methylamino, ethylamino, propylamino, butyl Amino, isobutyl, pent-3-ylamin
  • the compound is selected from the group consisting of compounds 2-21 and N1-N34.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described above, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • Another object of the present invention is to provide a use of a compound as described above for the manufacture of a medicament useful for inhibiting the activity of a first type of topoisomerase.
  • Another object of the present invention is to provide a use of a compound as described above for the manufacture of a medicament useful for inhibiting the activity of a second type of topoisomerase.
  • Another object of the present invention is to provide a use of a compound as described above for the manufacture of a medicament useful for the treatment of cancer.
  • the cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colorectal cancer, central nervous cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.
  • Another object of the present invention is to provide a method of producing the above compound, the method comprising:
  • the dehydrothiamine [2,3-c]quinolin-12-one derivative of the present invention has the ability to significantly inhibit the growth of cancer cells, inhibit the activity of the first and second type topoisomerases, and thereby treat cancer and the like.
  • Figure 1 is a summary of the reaction of chemical synthesis of dehydrothiamine [2,3-c]quinolin-12-one derivatives
  • Figure 2 is a graph showing the effects of compounds 5, 7, 8, 16, 19 and CPT (camptothecin) at 25, 50 ⁇ M on the helix of DNA acting on the first type of topoisomerase (TOP I);
  • Figure 3 is a graph showing the effects of the compounds N2, N7, N8, N9, N14-N19, N25 and CPT at 50 ⁇ M on the unwinding of DNA acting on the first type of topoisomerase (TOP I);
  • Figure 4a-d shows the effect of compound 7, N7, N14, N15, N18, N19, N25 and CPT at 1-50 ⁇ M for the helix of DNA acting on the first type of topoisomerase (TOP I);
  • Figure 5 shows compounds 5, 7, 8, 16, 19 and VP-16 (etoposide, as a positive control) at 25, 50 ⁇ M, for the second type of topoisomerase (TOP II) DNA unwinding Effect;
  • Figure 6 is a graph showing the effects of the compounds N2, N7, N8, N9, N14-N19, N25 and VP-16 at 50 ⁇ M on the helicase of the second type of topoisomerase (TOP II) DNA;
  • Figures 7a-d show the effect of Compound 7, N7, N8, N14, N15, N18, N19, N25 and VP-16 at 1-50 ⁇ M for the unwinding of DNA acting on the second type of topoisomerase (TOP II).
  • treatment is meant to delay, ameliorate, reduce, or reverse a condition that is currently afflicting a patient with the condition or any condition associated with the condition and preventing the condition or any of its emerging symptoms.
  • pharmaceutically acceptable means that the substance or composition must be compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition of the present invention can be prepared into a composition suitable for use in the present invention by using the above-described Lactobacillus isolate and a pharmaceutically acceptable vehicle using techniques well known to those skilled in the art.
  • the dosage form comprises, but is not limited to, a solution, an emulsion, a suspension, a powder, a tablet, a pill, a lozenge, a tablet. (troche), chewing gum, slurries, and other dosage forms similar or suitable for use in the present invention.
  • the pharmaceutically acceptable carrier may comprise or be selected from the group consisting of: a solvent, an emulsifier, a suspending agent, a decomposer, a binding agent. ), excipient, stabilizing agent, chelating agent, diluent (diluent), gelling agent (gelling) Agent), preservative, lubricant, surfactant, and other carriers similar or suitable for use in the present invention.
  • a dissolution aid In the above composition, a dissolution aid, a buffer, a preservative, a coloring agent, a flavoring agent, a flavoring agent and the like which are usually used in the field of various preparations may be appropriately added as needed.
  • pharmaceutically acceptable excipient includes, but is not limited to, polymers, resins, plasticizers, fillers, lubricants, diluents, binders, disintegrants, solvents, cosolvents, surfactants, At least one of a preservative, a sweetener, a flavoring agent, a pharmaceutical grade dye or pigment, and a viscosity agent.
  • composition is a solid or liquid composition, the form, concentration and degree of purity of which is suitable for administration to a patient (such as a human or animal patient), which can be induced after administration. Want to change physiologically.
  • Pharmaceutical compositions are typically sterile and/or non-pyrogenic.
  • the present invention is exemplified by the following examples, but the present invention is not limited by the following examples.
  • the drugs and biomaterials used in the present invention are commercially available and are readily available. The following are merely examples of available channels.
  • Multiplicities are denoted as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintuplet), sext (sextet), sep (septet), m (multiplet), dd (doublet of doublet), Dt(doublet of triplet), td(triplet of doublet), qd(quartet of doublet) and br(broadened).
  • High resolution electrospray ionization HRESI: Finnigan MAT95S (Instrument Center, National Taiwan University).
  • X-ray single crystal diffraction Bruker Enraf-Nonius APEX II diffractometer (Department of Chemistry, National Taiwan Normal University). A typical procedure for the preparation of thiochromenoquinolones is indicated in the typical experiment and is described below ( Figure 1).
  • cytotoxic cell line PC-3 BCRC60122, Taiwan
  • DU-145 HTB-81 TM , ATCC, Rockville, MD
  • the above cells were cultured in RPMI-1640, 5% FBS (v/v), 100 U/mL penicillin and 50 mg/mL streptomycin.
  • Approximately 2 x 103 cells were cultured in 96-well plates at 5% CO 2 for 24 hours at 37 °C.
  • all compounds were dissolved in DMSO before the experiment, and pre-mixed in the same cell culture medium for drug administration, and adjusted to different concentrations (0.15, 0.5, 1.5, 5, 15 ⁇ ). ) Perform three replicate experiments.
  • the compounds N7, N8, N14, N15, N17 and N18 contain at least one nitrogen atom in the side branch, which shows superior cytotoxic activity compared to only a single hydroxyl group, an alkyl group or an aromatic ring.
  • Compounds 5, 7, 8, 16, 19, N2, N7, N8, N9, N14, N15, N16, N17, N18, N19 and N25 were screened for topoisomerase activity assays.
  • NCI National Cancer Research Center
  • 26 compound structures (2, 3, 4, 5, 6, 8, 10, 11, 12, 13, N1, N2, N6, N7, N9, N12, N13, N14, N16, N17, N19, N21, N25, N27, N30, N31), a poisoning test of 60 cancer cell lines against these 26 compounds.
  • 26 compounds were first subjected to a 10 ⁇ M poisoning test, and a poisoning test of 60 cancer cell lines was performed. After 48 hours, a cell survival test (Sulforhodamine B, SRB) was performed.
  • SRB cell survival test

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Abstract

本发明公开了一系列新颖脱氢硫胺[2,3-c]喹啉-12-酮衍生物，并进一步提供该些衍生物的制备方法及其应用，该应用包含将该类衍生物作为治疗癌症的医药组合物，且其应用包含该类衍生物具有明显抑制癌细胞生长的能力、抑制第一、二型拓朴异构酶的活性，进而治疗癌症等功效。

Description

脱氢硫胺[2,3-c]喹啉-12-酮衍生物及其制备方法和应用 技术领域
本发明涉及癌症药物技术领域，特别涉及脱氢硫胺[2,3-c]喹啉-12-酮衍生物、其抗癌活性应用及评估。
背景技术
在大多数的生物体中，端粒长度的复制与维持，必须依赖端粒酶(telomerase)。端粒酶为一种核糖核酸蛋白酶，是由RNA与蛋白质次单元组成的复合体。目前，部分重要的端粒酶次单元已被鉴定出来，就人类端粒酶组成而言，包括具反转录酶活性的人类的端粒酶反转录酶(human telomerase reverse transcriptase,hTERT)，以及作为模板的人类端粒酶RNA组成体(human telomerase RNA component)，和一些与端粒酶结合的蛋白如：人类端粒酶结合蛋白(human telomerase-associated protein)、p23、hsp90、hsp40、hsp70等。
许多研究指出，人类端粒酶活性仅存在一些具高度增生能力的细胞中，例如：生殖细胞(germ cell)、造血细胞、部分干细胞(stem cell)、大部分的不死细胞(immortalized cell)及绝大部分的肿瘤细胞。在一般体细胞中，由于不含有端粒酶活性，因此端粒会随细胞分裂次数的增加而逐渐减短，这可视为细胞计算分裂次数的指标(mitotic clock)。而当端粒短至一定程度时，细胞会停止分裂而进入老化阶段，且细胞会在此阶段停留一段时间，而后走向死亡，此时期称之为M1期(mortality stage1)；若于M1期，细胞内的抑制肿瘤基因(tumorsuppressor gene)发生突变，如p53和Rb，会促使细胞逃离老化阶段而继续进行细胞分裂，此时期称之为M2期(mortality stage2)。此时期因不具端粒酶活性的存在，因此端粒长度仍会缩短，而此时端粒无法保护染色体末端的完整性，进而导致染色体不稳定现象产生，细胞无法完整的将遗传讯息传递而逐渐死亡，因此M2期又称之为危机期(crisis)；大部分的细胞会于M2期死亡，仅有少数细胞会因端粒酶活性的表达而存活，此细胞可不受限制的持续性分裂，成为不死细胞(或癌细胞)。
因此一般认为：活化端粒酶，可维持端粒长度而避免细胞进入复制性衰老，或将端粒酶活性去除，抑制其活性，以限制癌细胞的分裂，两者可为细胞朝向不老及癌化发展的关键。综合上述，由于正常人类体细胞不具有端粒酶活性，因此，一个能够抑制端粒酶活性的药物，在对端粒酶产生抑制作用时，对正常细胞的生理状况并不会产生影响，相反地，此活性抑制药物却能减弱癌细胞的增生能力，所以若能找寻到端粒酶活性抑制剂，通过抗癌机转的探讨，朝癌症治疗药物发展是深具潜力的。
癌症起因是由于DNA的异常增殖。因此，只要可以选择性地攻击癌细胞的DNA即可， 不希望伤害到正常细胞的DNA，但要分辨正常细胞的DNA和癌细胞的DNA是很困难的，于是在发现正常细胞和癌细胞之间特性的差别后，便产了具有专一性的「标靶治疗」，此治疗结合其它化学疗法或是放射疗法时，能够大幅降低副作用而达到更好的疗效，故标靶治疗是现今热门的研究治疗癌症的方向。因为拓朴异构酶(topoisomerase)在DNA的复制过程中扮演不可或缺的角色，故为近年抗癌标靶治疗研究中的标的。
喜树碱是第一个小分子药物用于抑制第一型拓朴异构酶，可惜的是喜树碱有许多缺点导致无法于临床医疗上使用，例如内酯环(lactone ring)在人体内pH值环境下易水解变成羟基羧酸(hydroxycarboxylate)，导致易和体内血清白蛋白结合而失去药物抑制第一型拓朴异构酶的作用；camptothecin-TopI-DNA的三复合体因非以共价键连接故结构不稳定；喜树碱的水溶性不佳，导致生体可用率(bioavailability)不佳；细胞膜上的p-glycoprotein(MDR1,ABCB1)排出帮浦将药物推出至细胞外；更重要的是一些肿瘤细胞渐渐对喜树碱及其衍生物产生抗药性及不良的药物副作用，使得即使之后上市较喜树碱增加了许多水溶性的两个经由半合成(semi-synthetic)的药物，在公元1996年由美国食品药物管理局(FDA)核准于治疗卵巢癌的Topotecan
Figure PCTCN2014089182-appb-000001
及治疗结肠癌的Irinotecan
Figure PCTCN2014089182-appb-000002
面临临床治疗上的困境。因此，拓朴异构酶活性抑制剂于癌症治疗药物发展上是非常重要的。
发明内容
基于此，本发明的目的在于提供一种脱氢硫胺[2,3-c]喹啉-12-酮衍生物。
解决上述技术问题的具体技术方案如下：
一种式(I)化合物，
Figure PCTCN2014089182-appb-000003
其中R是选自下列取代基所组成的群组：
i)卤基、胺基、羟基及硫基；
ii)NH(CH2)nH的直链烷基、带有支链取代的烷基、具有一胺基取代的烷基支链、具有一羟基取代的烷基支链，其中1≤n≤10；
iii)O(CH2)nH、N(CH3)2、NH(CH2)nNH(CH2)nOH；其中1≤n≤10；
iv)C3-12含氮的环烷基及杂环基团，它含有从1至3个选自于O、S以及N的杂原子，其中邻位、间位或对位更可独立地选自下列取代基其中之一：氢基、(CH2)n烷基、(CH2)n羟基、 (CH2)nC3-12环烷基、(CH2)nC3-12含氮环烷基、(CH2)n苯环、醛基及(CH2)nCOC3-12含氮环烷基；其中0≤n≤10；
v)NH(CH2)nR1，0≤n≤10，R1是选自下列取代基其中之一：N(CH3)2，C(NH2)2，NH(CH2)nH的直链烷基、带有支链取代的烷基、具有一胺基取代的烷基支链、具有一羟基取代的烷基支链；
vi)NH(CH2)nR2，0≤n≤10，R2是选自下列取代基其中之一：苯环、C3-12环烷基及杂环基团，含有从1至3个选自于O、S以及N的杂原子，其中邻位、间位或对位更可独立地选自下列取代基其中之一：甲氧基、胺基、苯环、带有C1-C3支链取代的烷基、胺基、硝基、羟基及C3-12杂环；其中该C3-12杂环含有从1至3个选自于O、S以及N的杂原子；以及医药上可接受的盐、立体异构物及镜像异构物。
为达成前述发明目的，其中取代基群组i)-vi)是选自由氯、羟基、甲氧基、二甲氨基、哌嗪-1-基、4-甲基哌嗪-1-基、4-乙基哌嗪-1-基、4-(2-羟乙基)哌嗪-1-基、4-芐基哌嗪-1-基、4-苯基哌嗪-1-基、吗啉代、硫代吗啉代、哌啶-1-基、4-羟基哌啶-1-基、4-芐基哌啶-1-基、[1,4'-联哌啶]-1'-基、4-(3-(哌啶-4-基)丙基、吡咯烷-1-基、2-氧代哌啶-1-基、甲基氨基、乙基氨基、丙基氨基、丁基氨基、异丁基、戊-3-基氨基、(2-(二甲基氨基)乙基)氨基、(2-(二乙基氨基)乙基)氨基、2-乙醇氨基、3-丙醇氨基、5-戊醇氨基、(1-羟基丁烷-2-基)氨基、(4-甲基戊-2-基)氨基、(2-氨基乙基)氨基、(2-((2-羟乙基)氨基)乙基)氨基、(2-吗啉代乙基)氨基、(3-(二甲基氨基)丙基)氨基、(3-(二乙氨基)丙基)氨基、(3-((2-羟乙基)氨基)丙基)氨基、(2,3-二氢-1H-茚-2-基)氨基、环己基、(1-芐基哌啶-4-基)氨基、(噻吩-2-基甲基)氨基、(环己基甲基)氨基、芐基氨基、(吡啶-2-基甲基)氨基、(苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基、(2-甲氧芐基)氨基、(3,4-二甲氧基芐基)氨基、苯乙基氨基、(4-甲氧基苯乙基)氨基、(4-氨基苯乙基)氨基、胍及哌啶-1-基氨基所组成的群组。
为达成前述发明目的，其中该化合物是选自由下列所组成的群组：化合物2-21及N1-N34。
3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸、
6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮、
10-氯-6-羟基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-甲氧基-12H-脱氢硫*胺并[2,3-c]喹啉-12-酮、
10-氯-6-二甲氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-甲基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-乙基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-(2-羟乙基)哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉12-酮、
6-(4-芐基哌嗪-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-苯基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-硫代吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-羟基哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(4-芐基哌啶-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-([1,4'-联哌啶]-1'-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-(3-(哌啶-4-基)丙基)哌啶-1-基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(吡咯烷-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(2-氧代哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-甲基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-乙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-丙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(丁基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-异丁基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(戊-3-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-(二甲基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-(二乙基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(2-乙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(3-丙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(5-戊醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((1-羟基丁烷-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((4-甲基戊-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((2-氨基乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-((2-羟乙基)氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-吗啉代乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-(二甲基氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-(二乙氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-((2-羟乙基)氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2,3-二氢-1H-茚-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(环己基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((1-芐基哌啶-4-基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((噻吩-2-基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((环己基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(芐基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((吡啶-2-基甲基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-甲氧芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3,4-二甲氧基芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(苯乙基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((4-甲氧基苯乙基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((4-氨基苯乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
2-(10-氯-12-氧代-12H-脱氢硫胺并[2,3-c]喹啉-6-基)胍、
10-氯-6-(哌啶-1-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
以及其等的盐类。
本发明的另一目的在于提供一种医药组合物，包含治疗有效量的如前述的化合物，和至少一种医药上可接受载剂、稀释剂或赋形剂。
本发明的另一目的在于提供一种如前述的化合物的用途，其是用于制造可用于抑制第一型拓朴异构酶活性的医药品。
本发明的另一目的在于提供一种如前述的化合物的用途，其是用于制造可用于抑制第二型拓朴异构酶活性的医药品。
本发明的另一目的在于提供一种如前述的化合物的用途，其是用于制造可用于治疗癌症的医药品。
为达成前述发明目的，其中该癌症是选自白血病、非小细胞肺癌、大肠癌、中枢神经癌、黑色素瘤、卵巢癌、肾脏癌、前列腺癌及乳癌所组成。
本发明的另一目的是在于提供一种制造上述化合物的方法，该方法包含：
(1)将isatin、2-((4-chlorophenyl)thio)acetic acid及醋酸钠混合，于150℃反应1小时，将反应完的混合液冷却后加入醋酸得到沉淀物，再以醋酸、水、正己烷冲洗，得到化合物2(3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸)；
(2)取化合物2(3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸)溶于三氯氧磷150℃、48小时，冷却后将反应物倒入水中，过滤收集沉淀物置入10％碳酸氢钠溶液搅拌1小时，收集沉淀物后再以水冲洗，粗产物以二氯甲烷再结晶，得到化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)；
(3)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)溶于DMF，加入浓盐酸并回流六小时，之后逐滴加入浓盐酸并再回流12小时，反应物以真空脱水，再加入水，过滤后粗产物以乙醇清洗得到化合物4(10-氯-6-羟基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮)；
(4)于甲醇中的悬浮化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与甲醇钠回流16小时，冷却后移除溶剂，过滤后再以乙醇与正己烷清洗，得到化合物5(10-氯-6-甲氧基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮)；
(5)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与一适当二级胺与碳酸钠溶于DMSO或DMF，回流10小时，静置冷却后，反应物加入冰水中，过滤出沉淀物后，以水及甲醇清洗收集分别得到化合物6-21：
10-氯-6-二甲氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-甲基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-乙基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-(2-羟乙基)哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉12-酮、
6-(4-芐基哌嗪-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-苯基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-硫代吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-羟基哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(4-芐基哌啶-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-([1,4'-联哌啶]-1'-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(4-(3-(哌啶-4-基)丙基)哌啶-1-基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(吡咯烷-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、及
10-氯-6-(2-氧代哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮；
(6)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与一适当一级胺溶于DMSO，回流8小时，冷却后，反应物加入100mL水中。过滤出沉淀物后，以水及甲醇清洗收集分别得到化合物N1-N34：
10-氯-6-甲基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-乙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-丙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(丁基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-异丁基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(戊-3-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-(二甲基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-(二乙基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(2-乙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(3-丙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(5-戊醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((1-羟基丁烷-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((4-甲基戊-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((2-氨基乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-((2-羟乙基)氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-吗啉代乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-(二甲基氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-(二乙氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3-((2-羟乙基)氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2,3-二氢-1H-茚-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(环己基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((1-芐基哌啶-4-基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((噻吩-2-基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((环己基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
6-(芐基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((吡啶-2-基甲基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((2-甲氧芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((3,4-二甲氧基芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-(苯乙基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
10-氯-6-((4-甲氧基苯乙基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
6-((4-氨基苯乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
2-(10-氯-12-氧代-12H-脱氢硫胺并[2,3-c]喹啉-6-基)胍、及
10-氯-6-(哌啶-1-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮。
本发明所述的脱氢硫胺[2,3-c]喹啉-12-酮衍生物及其制备方法和应用具有以下优点和有益效果：
本发明所述脱氢硫胺[2,3-c]喹啉-12-酮衍生物具有明显抑制癌细胞生长的能力、抑制第一、二型拓朴异构酶的活性，进而治疗癌症等功效。
附图说明
图1为脱氢硫胺[2,3-c]喹啉-12-酮衍生物化学合成的反应概要；
图2为化合物5、7、8、16、19与CPT(喜树碱)于25、50μM，对于作用于第一型拓朴异构酶(TOP I)DNA解螺旋的效果；
图3为化合物N2、N7、N8、N9、N14-N19、N25与CPT于50μM，对于作用于第一型拓朴异构酶(TOP I)DNA解螺旋的效果；
图4a-d为化合物7、N7、N14、N15、N18、N19、N25与CPT于1-50μM，对于作用于第一型拓朴异构酶(TOP I)DNA解螺旋的效果；
图5为化合物5、7、8、16、19与VP-16(etoposide医百幸，作为正向对照组)于25、50μM，对于作用于第二型拓朴异构酶(TOP II)DNA解螺旋的效果；
图6为化合物N2、N7、N8、N9、N14-N19、N25与VP-16于50μM，对于作用于第二型拓朴异构酶(TOP II)DNA解螺旋的效果；
图7a-d为化合物7、N7、N8、N14、N15、N18、N19、N25与VP-16于1-50μM，对于作用于第二型拓朴异构酶(TOP II)DNA解螺旋的效果。
具体实施方式
本说明书中所述的所有技术性及科学术语，除非另外有所定义，皆为该所属领域具有通常技艺者可共同了解的意义。
术语“治疗”、“治疗中”及其类术语是指延缓、改善、减少或逆转目前正折磨着患者的该病症或该病症相关的任何症状的方法以及预防该病症或其任何正出现的症状的方法。
术语“药学上可接受”是指物质或组合物必须与调配物的其它成份兼容，且对患者无害。
本发明的组合物是可利用熟习此技艺者所详知的技术，将上述的乳杆菌分离株，与药学上可接受的载剂(pharmaceutically acceptable vehicle)，制备成适用本发明组合物的剂型。其中该剂形包含但不限于：溶液(solution)、乳剂(emulsion)、悬浮液(suspension)、粉末(powder)、锭剂(tablet)、丸剂(pill)、口含锭(lozenge)、片剂(troche)、口嚼胶(chewing gum)、胶囊(slurry)以及其它类似或适用本发明的剂型。
其中该药学上可接受的载剂可包含或多种选自于下列的试剂：溶剂(solvent)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizing agent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling  agent)、防腐剂(preservative)、润滑剂(lubricant)、表面活性剂(surfactant)，及其它类似或适用本发明的载剂。
上述组合物中，亦可视需要适宜地添加或多种以上制剂领域内通常使用的溶解补助剂、缓冲剂、保存剂、着色剂、香料、风味剂等。
术语“药学上可接受的赋形剂”，包括但不限于，聚合物、树脂、增塑剂、填料、润滑剂、稀释剂、黏合剂、崩解剂、溶剂、共溶剂、界面活性剂、防腐剂、甜味剂、调味剂、药学级的染料或颜料、及黏度剂至少一种。
术语“医药组成物(pharmaceutical composition)”为一种固体或液体组成物，其形式、浓度和纯度程度适合投予给病患(如人类或动物病患)，在投予之后，其可诱发所欲生理变化。医药组成物典型地为无菌及/或非发热性者(non-pyrogenic)。
本发明是以下面的实施例予以示范阐明，但本发明不受下述实施例所限制。本发明所用的药物、生物材料皆市售易于取得，下列仅为示例可取得的渠道。
所有反应通过涂有硅胶60F254的薄层色谱(TLC)监视。所有合成化合物的熔点是由Büchi B-545测定装置所测定。1H NMR：Varian GEMINI-300(300MHz)或Agilent400MR DD2(400MHz)；δ值单位为ppm，相对于四甲基硅烷(TMS)作为内部标准(0ppm)。Multiplicities记为s(singlet),d(doublet),t(triplet),q(quartet),quin(quintuplet),sext(sextet),sep(septet),m(multiplet),dd(doublet of doublet),dt(doublet of triplet),td(triplet of doublet),qd(quartet of doublet)与br(broadened)。High resolution electrospray ionization(HRESI):Finnigan MAT95S(仪器中心，国立台湾大学)。X-射线单晶衍射：Bruker Enraf-Nonius APEX II diffractometer(国立台湾师范大学化学系)。典型的实验中指出用于thiochromenoquinolones制备的一般程序，描述如下(图1)。
化学合成步骤通则
合成步骤通则A：合成化合物2。
将isatin(0.44g，2.99mmole)及2-((4-chlorophenyl)thio)acetic acid(0.70g,3.47mmol)及sodium acetate(0.05g)混合，于miniclave(150℃)反应1小时(thin-layer chromatography，TLC监控)。将反应完的混合液冷却后加入acetic acid(10mL)得到灰色沉淀物，醋酸、水、正己烷冲洗，可得到亮紫色化合物。
合成步骤通则B：合成化合物3。
取化合物2溶于三氯氧磷(5mL)150℃48小时。冷却后将反应物倒入0℃冰水，过滤收集绿色沉淀物置入10％碳酸氢钠溶液(50mL)剧烈搅拌1小时，收集沉淀物后再以水冲洗。粗产物以二氯甲烷再结晶，得到黄色产物化合物3。
合成步骤通则C：合成化合物4。
取化合物3(0.32g,0.96mmol)溶于DMF(20mL)，加入浓盐酸(3mL)并回流(refluxed)。六小时后，逐滴加入浓盐酸(6mL)并再回流12小时。反应物以真空脱水，再加入水20mL，过滤后粗产物以乙醇清洗得到黄色固体化合物4。
合成步骤通则D：合成化合物5。
于20mL甲醇中的悬浮化合物3(0.33g,1.0mmol)与甲醇钠(0.55g,10mmol)回流16小时。冷却后以旋转蒸发真空仪器移除溶剂，过滤后再以乙醇与正己烷清洗，得到白色固体化合物5。
合成步骤通则E：合成化合物6-21。
取化合物3(0.33g,1.0mmol)与一适当二级胺(1.1mmol)与碳酸钠(5mmol)溶于DMSO或DMF(20mL)，回流10小时(TLC监控)。静置冷却后，反应物加入100mL冰水中。过滤出沉淀物后，以水及甲醇清洗收集得到黄色固体。
合成步骤通则F：合成化合物N1-34。
取化合物3(0.33g,1.0mmol)与一适当一级胺(1.1mmol)溶于DMSO(30mL)，回流8小时(TLC监控)。冷却后，反应物加入100mL水中。过滤出沉淀物后，以水及甲醇清洗收集得到黄色固体。
以下将结合具体实施例对本发明做进一步说明。
实施例1
3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸(2)
3-((4-Chlorophenyl)thio)-2-hydroxyquinoline-4-carboxylic acid(TC-SCl)(2)
该纯化合物为灰色固体(产率86％)。(Rf＝0.5at EA:AcOH＝20:1).Mp306-308℃.1H NMR(300MHz,DMSO-d6):δ(ppm)7.26(3H,t,J＝7.6Hz,Ar-H),7.34(2H,d,J＝6.0Hz,Ar-H),7.39(1H,d,J＝8.0Hz,Ar-H),7.46(1H,d,J＝8.0Hz,Ar-H),7.62(1H,t,J＝8.0Hz,Ar-H),12.22(1H,s,-COOH).13C NMR(100MHz,DMSO-d6):δ(ppm)115.58,116.26,120.36,123.21,126.21,129.33,130.30,131.47,132.54,134.36,140.11,151.69,159.37,166.80(CO).HRMS(ESI)calcd for C16H10NO3SCl[M]+331.0070；found[M+H]+332.0147(100),[M+H+2]+334.0122(33)；found[M-H]-330.0002.
实施例2
6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮(3)
6,9-Dichloro-12H-thiochromeno[2,3-c]quinolin-12-one(3)
分离出黄色固体(产率90％)。(Rf＝0.50at CH2Cl2:n-hexane＝1:1).Mp259-261℃(CH2Cl2). 1H NMR(400MHz,CDCl3):δ(ppm)7.71(2H,m,Ar-H),7.77-7.85(2H,m,Ar-H),8.10-8.13(m,1H,Ar-H),8.60(t,1H,J＝1.2Hz,Ar-H),9.67-9.71(1H,m,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)124.87,126.28,127.85,129.17,129.39,129.93,130.31,131.20,131.90,133.01,133.09,133.38,134.43,145.27,146.61,180.64(CO).HRMS(ESI)calcdforC16H7NOSCl2[M]+330.9625；found[M+H]+331.9699(100),[M+H+2]+333.9672(67),[M+H+4]+335.9645(11).
实施例3
10-氯-6-羟基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(4)
10-Chloro-6-hydroxy-12H-thiochromeno[2,3-c]quinolin-12-one(4)
分离出黄色固体(产率95％)。(Rf＝0.40at EA).Mp>410℃.1H NMR(400MHz,DMSO-d6):δppm7.35(1H,td,J＝7.2,1.2Hz,Ar-H),7.47(1H,dd,J＝8.4,1.2Hz,Ar-H),7.59(1H,td,J＝7.2Hz,1.6Hz,Ar-H),7.89(1H,dd,J＝8.4Hz,2.4Hz,Ar-H),8.10(1H,d,J＝8.8Hz,Ar-H),8.38(1H,d,J＝2.4Hz,Ar-H),9.35(1H,dd,J＝8.4,2.4Hz,Ar-H),12.73(br,1H,-OH).13C NMR(75MHz,CDCl3):δ(ppm)116.61,117.52,123.65,126.82,128.44,130.22,130.49,130.54,132.52,133.00,133.42,135.09,136.27,138.90,158.70,180.38(CO).HRMS(ESI)m/z calcdfor C16H8NO2SCl[M]+:312.9964,found,314.0051.
实施例4
10-氯-6-甲氧基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(5)
10-Chloro-6-methoxy-12H-thiochromeno[2,3-c]quinolin-12-one(5)
分离出灰色固体(产率91％)。(Rf＝0.52at CH2Cl2:n-hexane＝1:1).Mp227-228℃.1HNMR(400MHz,CDCl3):δ(ppm)4.27(3H,s,-OCH3),7.60(1H,td,J＝7.6,1.2Hz,Ar-H),7.37(1H,d,J＝2.0Hz,Ar-H),7.70(1H,td,J＝7.6Hz,1.6Hz,Ar-H),7.94(1H,dd,J＝8.0Hz,1.2Hz,Ar-H),8.60(1H,d,J＝1.6Hz,Ar-H),9.64(1H,dd,J＝8.8Hz,1.2Hz,Ar-H).13CNMR(100MHz,CDCl3):δ(ppm)54.83(OCH3),122.91,126.23,126.54,126.76,127.66,127.95,129.23,129.50,130.54,132.49,133.48,133.85,143.82,156.06,180.47(CO).HRMS(ESI)m/z calcd for C17H10NO2SCl[M]+327.0121；found[M+H]+328.0203,[M+H+2]+330.0172.
实施例5
10-氯-6-二甲氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(6)
10-Chloro-6-dimethylamino-12H-thiochromeno[2,3-c]quinolin-12-one(6)
分离出黄色固体(产率85％)。(Rf＝0.45at CH2Cl2:n-hexane＝1:1).Mp194-195℃.1H  NMR(400MHz,CDCl3):δ(ppm)3.06(6H,s,-CH3),7.59-7.67(3H,m,Ar-H),7.71(1H,t,J＝7.2Hz,Ar-H),8.00(1H,d,J＝8.4Hz,Ar-H),8.59(1H,d,J＝1.2Hz,Ar-H),9.60(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)43.00,123.44,125.71,127.22,127.78128.47,129.07,129.37,130.59,130.67,132.23,132.46,133.61,134.36,144.84,158.32,181.52(CO).HRMS(ESI)calcd for C18H13N2OSCl[M]+340.0437；found[M+H]+341.0517(100),[M+H+2]+343.0501(33).
实施例6
10-氯-6-(哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(7)
10-Chloro-6-(piperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(7)
分离出黄色固体(产率69％)。(Rf＝0.12at EA:MeOH:ammonia water＝20:5:1).Mp211-213℃.1H NMR(400MHz,CDCl3):δ(ppm)3.20(4H,t,J＝4.8Hz,-CH2-),3.36(4H,t,J＝4.8Hz,-CH2-),7.60-7.66(3H,m,Ar-H),7.70(1H,td,J＝8.0,1.2Hz,Ar-H),7.99(1H,dd,J＝8.4,0.8Hz,Ar-H),8.56(1H,d,J＝2.0Hz,Ar-H),9.60(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)45.95,52.31,123.62,125.81,127.58,127.86,128.72,129.10,129.37,130.65,130.99,132.17,132.47,133.63,134.33,144.94,157.61,181.45(CO).HRMS(ESI)calcd for C20H16N3OSCl[M]+381.0703；found[M+H]+382.0783.
实施例7
10-氯-6-(4-甲基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(8)
10-Chloro-6-(4-methylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(8)
分离出黄绿色固体(产率80％)。(Rf＝0.24at EA:methanol＝5:1).Mp212-214℃.1H NMR(400MHz,CDCl3):δ(ppm)2.51(3H,s,-CH3),2.84(4H,br,-CH2-),3.50(4H,t,J＝4.5Hz,-CH2-),7.60-7.66(3H,m,Ar-H),7.68-7.72(1H,td,J＝8.1,1.5Hz,Ar-H),8.01(1H,dd,J＝8.1,1.5Hz,Ar-H),8.56(1H,d,J＝1.5Hz,Ar-H),9.60(1H,dd,J＝8.4,1.5Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)45.73,50.31,54.65,123.70,125.90,127.60,127.80,128.82,129.20,129.39,130.62,130.84,132.36,132.47,133.78,134.24,145.08,157.18,181.42(CO).HRMS(ESI)calcd for C21H18N3OSCl[M]+395.0859；found[M+H]+396.0926.
实施例8
10-氯-6-(4-乙基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(9)
10-Chloro-6-(4-ethylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(9)
分离出黄色固体(产率74％)。(Rf＝0.48at EA:MeOH＝10:1).Mp196-198℃.1H NMR (400MHz,CDCl3):δ(ppm)1.19(3H,t,J＝7.2Hz,-CH3),2.58(2H,q,J＝7.2Hz,-CH2-),2.78(4H,br,-CH2-),3.46(4H,t,J＝4.4Hz,-CH2-),7.61-7.66(3H,m,Ar-H),7.68-7.73(1H,td,J＝8.4,1.6Hz,Ar-H),8.01(1H,dd,J＝8.0,1.2Hz,Ar-H),8.59(1H,d,J＝4.0Hz,Ar-H),9.62(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)12.07,50.88,52.46,52.67,123.55,125.77,127.48,127.83,128.78,129.12,129.36,130.62,130.76,132.21,132.47,133.62,134.34,144.97,157.34,181.50(CO).HRMS(ESI)calcd for C22H20N3OSCl[M]+409.1016；found[M+H]+410.1069.
实施例9
10-氯-6-(4-(2-羟乙基)哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉12-酮(10)
10-Chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12one(10)
分离出黄绿色固体(产率60％)。(Rf＝0.37at EA:MeOH＝2:1).Mp211-213℃.1H NMR(400MHz,CDCl3):δ(ppm)2.74(2H,t,J＝5.2Hz,-CH2-),2.87(4H,t,J＝3.6Hz,-CH2-),3.45(4H,t,J＝3.6Hz,-CH2-),3.72(2H,t,J＝5.2Hz,-CH2O-),7.62-7.67(3H,m,Ar-H),7.72(1H,td,J＝7.2,1.6Hz,Ar-H),8.01(1H,dd,J＝8.4,1.2Hz,Ar-H),8.59(1H,d,J＝0.6Hz,Ar-H),9.62(1H,dd,J＝4.8,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)50.85,52.72,57.74,59.35,123.65,125.81,127.66,127.82,128.73,129.14,129.44,130.68,130.77,132.19,132.51,133.69,134.21,144.90,157.26,181.43(CO).HRMS(ESI)calcd for C22H20N3O2SCl[M]+425.0965；found[M+H]+426.1024.
实施例10
6-(4-芐基哌嗪-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(11)
6-(4-Benzylpiperazin-1-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(11)
分离出黄色固体(产率81％)。(Rf＝0.43at EA:n-hexane＝1:4).Mp191-193℃.1H NMR(400MHz,CDCl3):δ(ppm)2.78(4H,br,-CH2N-),3.43(4H,t,J＝4.85Hz,-NCH2-),3.68(2H,s,-CH2-),7.27-7.42(5H,m,Ar’-H),7.61-7.67(3H,m,Ar-H),7.71(1H,td,J＝7.6,1.6Hz,Ar-H),8.00(1H,dd,J＝8.4,1.2Hz,Ar-H),8.58(1H,d,J＝2.0Hz,Ar-H),9.61(1H,dd,J＝8.4,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)50.94,52.96,63.08,123.57,125.78,127.18,127.48,127.83,128.33,128.73,129.09,129.17,129.34,130.58,130.90,132.18,132.44,133.60,134.36,138.11,144.95,157.48,181.47(CO).HRMS(ESI)calcd for C27H22N3OSCl[M]+471.1172；found[M+H]+472.1241.
实施例11
10-氯-6-(4-苯基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(12)
10-Chloro-6-(4-phenylpiperazin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(12)
分离出黄色固体(产率77％)。(Rf＝0.73at EA:n-hexane＝1:4).Mp236-237℃.1H NMR(300MHz,CDCl3):δ(ppm)3.50-3.60(8H,m,-CH2-),6.94(1H,t,J＝7.2Hz,Ar’-H),7.04(2H,d,J＝8.4Hz,Ar’-H),7.33(2H,t,J＝7.5Hz,Ar’-H),7.63-7.67(3H,m,Ar-H),7.71(1H,t,J＝7.2Hz,Ar-H),8.02(1H,d,J＝7.2Hz,Ar-H),8.58(1H,s,Ar-H),9.63(1H,d,J＝8.1Hz,Ar-H).13C NMR(75MHz,CDCl3):δ(ppm)48.60,50.33,115.77,119.51,123.21,125.38,127.14,127.30,128.27,128.65,128.71,128.88,130.23,131.77,131.97,133.22,133.70,144.52,150.90,156.83,159.91,180.91(CO).HRMS(ESI)calcd for C26H20N3OSCl[M]+457.1016；found[M+H]+458.1095.
实施例12
10-氯-6-吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(13)
10-Chloro-6-morpholino-12H-thiochromeno[2,3-c]quinolin-12-one(13)
分离出黄色固体(产率70％)。(Rf＝0.42at CH2Cl2).Mp217-218℃.1H NMR(300MHz,CDCl3):δ(ppm)3.41(4H,t,J＝4.5Hz,-NCH2-),4.02(4H,t,J＝4.5Hz,-CH2O-),7.62-7.70(3H,m,Ar-H),7.73(1H,td,J＝7.5,1.5Hz,Ar-H),8.03(1H,dd,J＝8.4,1.5Hz,Ar-H),8.59(1H,dd,J＝2.1,0.6Hz,Ar-H),9.35(1H,dd,J＝8.7,1.8Hz,Ar-H).13C NMR(75MHz,CDCl3):δ(ppm)51.36,66.88,123.92,126.06,127.85,127.91,128.94,129.34,129.52,130.71,131.05,132.50,132.61,133.95,134.29,145.23,157.29,181.51(CO).HRMS(ESI)calcd for C20H15N2O2SCl[M]+382.8633；found[M+H]+383.0620.
实施例13
10-氯-6-硫代吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(14)
10-Chloro-6-thiomorpholino-12H-thiochromeno[2,3-c]quinolin-12-one(14)
分离出黄色固体(产率86％)。(Rf＝0.77at EA:n-hexane＝1:4).Mp219-220℃.1H NMR(300MHz,CDCl3):δ(ppm)2.98(4H,t,J＝4.8Hz,-NCH2-),3.64(4H,t,J＝5.1Hz,-SCH2-),7.62-7.84(3H,m,Ar-H),7.73(1H,td,J＝8.4,1.8Hz,Ar-H),8.06(1H,dd,J＝8.1,1.5Hz,Ar-H),8.57(1H,dd,J＝1.8,0.6Hz,Ar-H),9.61(1H,dd,J＝7.8,1.2Hz,Ar-H).13C NMR(75MHz,CDCl3):δ(ppm)27.06,52.64,114.95,123.23,125.40,127.27,127.31,128.30,128.68,128.87,130.55,131.81,131.96,133.29,133.70,144.93,157.43,180.86(CO).HRMS(ESI)m/z calcd for C20H15N2S2OCl+[M]+398.0314,found[M+H]+399.0420,[M+H+2]+401.0394.
实施例14
10-氯-6-(哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(15)
10-Chloro-6-(piperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(15)
分离出黄色固体(产率86％)。(Rf＝0.75at EA).Mp187-188℃.1H NMR(400MHz,CDCl3):δ(ppm)1.71-1.74(2H,m,-CH2-),1.88(4H,p,J＝4.5Hz,-CH2-),3.31(4H,t,J＝4.2Hz,-NCH2-),7.60-7.64(2H,m,Ar-H),7.61(1H,d,J＝6.3Hz,Ar-H),7.69(1H,td,J＝5.1,1.2Hz,Ar-H),7.99(1H,dd,J＝5.4,0.6Hz,Ar-H),8.58(1H,d,J＝1.5Hz,Ar-H),9.62(1H,dd,J＝6.3,0.6Hz,Ar-H)13C NMR(100MHz,CDCl3):δ(ppm)24.27,25.89,52.33,123.47,125.75,127.28,127.85,128.56,129.02,129.23,130.48,131.62,132.16,132.33,133.46,134.67,144.97,158.50,181.51(CO).HRMS(ESI)calcd for C21H17N2OSCl[M]+380.0750；found[M+H]+381.0816.
实施例15
10-氯-6-(4-羟基哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(16)
10-Chloro-6-(4-hydroxypiperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(16)
分离出黄灰色固体(产率84％)。(Rf＝0.4at EA:n-hexane＝1:1).Mp224-225℃.1H NMR(400MHz,CDCl3):δ(ppm)1.89(1H,td,J＝7.2,2.7Hz,piperidine-CHa),1.94(1H,td,J＝6.9,2.7Hz,piperidine-CHa),2.15-2.21(2H,m,piperidine-CHe),3.19(2H,td,J＝8.4,2.1Hz,piperidine-NCHa),3.60-3.65(2H,m,piperidine-NCHe),4.01(1H,sext,J＝3.0Hz,piperidine-CH),7.61-7.67(3H,m,Ar-H),7.71(1H,td,J＝6.3,1.2Hz,Ar-H),7.99(1H,dd,J＝6.3,0.6Hz,Ar-H),8.59(1H,dd,J＝1.5,0.6Hz,Ar-H),9.64(1H,dd,J＝6.3,0.6Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)34.49,48.90,67.80,123.62,125.82,127.54,127.88,128.64,129.11,129.36,130.61,131.29,132.20,132.47,133.63,134.43,144.91,157.83,181.47(CO).HRMS(ESI)calcd for C21H17N2OSCl[M]+396.0699；found[M+H]+397.0757.
实施例16
6-(4-芐基哌啶-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(17)
6-(4-Benzylpiperidin-1-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(17)
分离出黄色固体(产率90％)。(Rf＝0.57at CH2Cl2:n-hexane＝2:1).Mp184-185℃.1H NMR(400MHz,CDCl3):δ(ppm)1.67(2H,td,J＝9.3,3.0Hz,-CH2-),1.79-1.89(1H,m,-CH-),1.88(2H,d,J＝6.9Hz,piperidine-CH2),2.71(2H,d,J＝5.1Hz,piperidine-CH2),3.00(2H,td,J＝9.3,1.2Hz,-NCH2-),3.65(2H,d,J＝9.3Hz,-NCH2-),7.20-7.25(3H,m,Ar-H),7.31-7.33(2H,m, Ar-H),7.60-7.72(4H,m,Ar-H),7.98(1H,dd,J＝6.3,0.6Hz,Ar-H),8.59(1H,d,J＝1.8Hz,Ar-H),9.62(1H,dd,J＝6.6,0.6Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)32.21,37.88,43.30,51.64,123.52,125.79,125.99,127.36,127.87,128.61,129.09,129.17,129.29,130.55,131.49,132.22,132.41,133.54,134.62,140.46,144.98,147.04,158.25,181.55(CO).HRMS(ESI)calcd for C28H23N2OSCl[M]+471.0130；found[M+H]+471.1276.
实施例17
6-([1,4'-联哌啶]-1'-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(18)
6-([1,4'-Bipiperidin]-1'-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(18)
分离出黄色固体(产率92％)。(Rf＝0.15at EA:MeOH＝5:1).Mp187-189℃.1H NMR(400MHz,CDCl3):δ(ppm)1.50-1.52(2H,m,piperidine-H),1.66-1.67(3H,m,piperidine-H),1.86-1.98(2H,qd,J＝12.4,2.8Hz,piperidine-H),2.06(2H,d,J＝11.6Hz,piperidine-H),2.54(1H,t,J＝10.8Hz,piperidine-H),2.65(3H,br,piperidine-H),3.05(2H,t,J＝12Hz,piperidine-H),3.73(2H,d,J＝12.8Hz,piperidine-H),7.60-7.66(3H,m,Ar-H),7.70(1H,td,J＝8.0,1.2Hz,Ar-H),7.98(1H,d,J＝8.0Hz,Ar-H),8.58(1H,s,Ar-H),9.62(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)24.79,26.36,28.24,50.45,51.16,62.40,123.57,125.80,127.42,127.86,128.61,129.08,129.30,130.52,131.41,132.18,132.43,133.56,134.54,144.92,157.92,181.47(CO).HRMS(ESI)calcd forC26H26N3OSCl[M]+463.1485；found[M+H]+464.1593.
实施例18
10-氯-6-(4-(3-(哌啶-4-基)丙基)哌啶-1-基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(19)
10-Chloro-6-(4-(3-(piperidin-4-yl)propyl)piperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(19)
分离出黄色固体(产率76％)。(Rf＝0.13at CH2Cl2).Mp164-165℃.1H NMR(400MHz,CDCl3):δ(ppm)1.16(2H,qd,J＝11.6,3.2Hz,-CH2-),1.20-1.28(2H,m,-CH2-),1.36-1.39(4H,m,-CH2-),1.51-1.58(4H,m,-CH2-),1.70(2H,d,J＝13.6Hz,-CH2-),1.87(2H,d,J＝9.6Hz,-CH2-),2.43(1H,br,-NH),2.60(2H,td,J＝12.0,2.0Hz,-CH2-),2.99(2H,t,J＝11.2Hz,-CH2-),3.10(2H,d,J＝12Hz,-CH2-),3.64(2H,d,J＝12.4Hz,-CH2-),7.59-7.65(3H,m,Ar-H),7.68(1H,td,J＝8.0,1.2Hz,Ar-H),8.00(1H,dd,J＝11.2,1.2Hz,Ar-H),8.57(1H,d,J＝1.6Hz,Ar-H),9.61(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)23.66,32.40,33.24,35.73,36.08,36.86,37.38,46.58,51.76,123.49,125.79,127.30,127.84,128.57,129.05,129.26,130.49,131.55,132.17,132.36,133.50,134.64,144.98,158.34,181.50(CO).HRMS(ESI)calcd for  C29H32N3OSCl[M]+505.1955；found[M+H]+506.2004.
实施例19
10-氯-6-(吡咯烷-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(20)
10-Chloro-6-(pyrrolidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(20)
分离出黄色固体(产率86％)。(Rf＝0.56at CH2Cl2:n-hexane＝1:1).Mp170-171℃.1H NMR(300MHz,CDCl3):δ(ppm)2.05(4H,quin,J＝3.6Hz,-CH2-),3.76(4H,t,J＝6.9Hz,-NCH2-),7.50(1H,td,J＝7.2,1.5Hz,Ar-H),7.61(1H,d,J＝1.5Hz,Ar-H11),7.65(1H,td,J＝7.5,1.5Hz,Ar-H),7.88(1H,dd,J＝8.4,1.5Hz,Ar-H),8.54(1H,t,J＝1.5Hz,Ar-H),9.44(1H,dd,J＝8.7,1.5Hz,Ar-H).13C NMR(75MHz,CDCl3):δ(ppm)24.89,50.52,121.90,124.97,125.17,126.92,127.33,128.42,128.84,130.09,131.77,131.92,133.10,133.32,144.73,154.62,159.91,181.07(CO).HRMS(ESI)calcd for C20H15N2OSCl[M]+366.0594；found[M+H]+367.0659.
实施例20
10-氯-6-(2-氧代哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(21)
10-Chloro-6-(2-oxopiperidin-1-yl)-12H-thiochromeno[2,3-c]quinolin-12-one(21)
取化合物3(0.33g,1.0mmol)与piperidin-2-one(5.55mmol)与碳酸钠(5mmol)溶于DMF(15mL)，回流10小时(TLC监控)。静置10分钟冷却后，反应物加入100mL冰水中。过滤出沉淀物后，以水及甲醇清洗收集得到黄色固体。分离出黄色固体(产率89％)。Mp:258-261℃.1H NMR(400MHz,CDCl3):δppm.1.25(1H,d,J＝4.8Hz,piperidone-H),2.44(2H,quin,-CH2-),2.61(1H,s,piperidone-H),2.75(2H,t,J＝8.4Hz,-CH2-),4.11-4.14(2H,m,-CH2-),7.60-7.67(2H,m,Ar-H),7.78-7.81(2H,m,Ar-H),8.09-8.12(1H,m,Ar-H),8.60(1H,d,J＝2.0Hz,Ar-H),9.72-9.75(1H,m,Ar-H).13C NMR(100MHz,CDCl3):δppm.19.37,31.47,41.05,49.14,125.25,126.08,127.65,129.29,129.51,129.80,129.88,130.74,131.96,132.26,132.74,133.47,133.91,145.05,148.08,176.14,181.01.
实施例21
10-氯-6-甲基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N1)
10-Chloro-6-methylamino-12H-thiochromeno[2,3-c]quinolin-12-one(N1)
分离出黄色固体(产率92％)。(Rf＝0.65at CH2Cl2).Mp237-238℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.26(3H,d,J＝4.8Hz,-CH3),4.92(1H,d,J＝4.8Hz,-NH-),7.45(1H,td,J＝11.2,1.6Hz,Ar-H),7.58(1H,d,J＝8.4Hz,Ar-H),7.69-7.65(2H,m,Ar-H),7.86(1H,dd,J＝ 8.4,0.8Hz,Ar-H),8.56(1H,d,J＝1.6Hz,Ar-H),9.45(1H,dd,J＝8.4,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)29.38,120.73,123.68,124.65,125.87,127.18,127.49,129.38,129.51,129.62,131.04,132.50,132.53,134.14,145.64,151.21,180.96(CO).HRMS(ESI)m/z calcd for C17H11N2OSCl[M]+:326.0281,found[M+H]+:327.0356.
实施例22
10-氯-6-乙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N2)
10-Chloro-6-ethylamino-12H-thiochromeno[2,3-c]quinolin-12-one(N2)
分离出黄色固体(产率91％)。(Rf＝0.75at CH2Cl2).Mp204-205℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.41(3H,t,J＝7.2Hz,-CH3),3.75(2H,q,J＝1.6Hz,-CH2 -),4.81(1H,br,-NH-),7.44(1H,td,J＝8.4,1.6Hz,Ar-H),7.58-7.64(3H,m,Ar-H),7.83(1H,d,J＝8.4Hz,Ar-H),8.56(1H,d,J＝1.6Hz,Ar-H),9.44(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)14.79,37.28,120.70,123.50,124.58,125.84,127.18,127.47,129.39,129.47,129.66,131.08,132.50,132.53,134.12,145.67,150.55,181.00(CO).HRMS(ESI)m/z calcd for C18H13N2OSCl[M]+:340.0437,found[M+H]+:341.0493.
实施例23
10-氯-6-丙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N3)
10-Chloro-6-propylamino-12H-thiochromeno[2,3-c]quinolin-12-one(N3)
分离出黄色固体(产率85％)。(Rf＝0.82at CH2Cl2).Mp178-179℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.09(3H,t,J＝7.2Hz,-CH3),1.81(2H,sext,J＝7.2Hz,-CH2-),3.69(2H,q,J＝7.2Hz,-NCH2-),4.87(1H,br,-NH-),7.44(1H,td,J＝8.0,1.2Hz,Ar-H),7.58-7.64(3H,m,Ar-H),7.82(1H,d,J＝8.0Hz,Ar-H),8.56(1H,d,J＝1.2Hz,Ar-H),9.44(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)11.68,22.64,44.13,120.67,123.53,124.53,125.82,127.15,127.46,129.38,129.46,129.65,131.05,132.49,134.10,145.66,150.62,181.02(CO).HRMS(ESI)m/z calcd for C19H15N2OSCl[M]+:354.0594,found[M+H]+:355.0651.
实施例24
6-(丁基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N4)
6-(Butylamino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(N4)
分离出黄色固体(产率91％)。(Rf＝0.85at CH2Cl2).Mp147-149℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.03(3H,t,J＝7.2Hz,-CH3),1.53(2H,sext,J＝7.2Hz,-CH2-),1.76(2H, quin,J＝7.2Hz,-CH2-),3.71(2H,q,J＝6.8Hz,-NCH2-),4.83(1H,br,-NH-),7.43(1H,td,J＝7.6,1.2Hz,Ar-H),7.57-7.64(3H,m,Ar-H),7.82(1H,d,J＝8.4Hz,Ar-H),8.55(1H,d,J＝1.6Hz,Ar-H),9.43(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)13.97,20.36,31.54,42.12,120.67,123.53,124.52,125.84,127.16,127.46,129.38,129.46,129.65,131.05,132.48,132.52,134.11,145.68,150.62,181.00(CO).HRMS(ESI)m/z calcd for C20H17N2OSCl[M]+:368.0750,found[M+H]+:369.0846.
实施例25
10-氯-6-异丁基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N5)
10-Chloro-6-isobutylamino-12H-thiochromeno[2,3-c]quinolin-12-one(N5)
分离出黄色固体(产率61％)。(Rf＝0.85at CH2Cl2).Mp159-160℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.08(6H,d,J＝6.8Hz,-CH3),2.10(1H,sep,J＝6.8Hz,-CH-),3.56(2H,t,J＝6.4Hz,-CH2-),4.94(1H,br,-NH),7.44(1H,t,J＝7.2Hz,Ar-H),7.59-7.64(3H,m,Ar-H),7.82(1H,d,J＝8.4Hz,Ar-H),8.57(1H,dd,J＝2.0,0.8Hz,Ar-H),9.43(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)20.50,28.16,49.72,120.67,123.54,124.51,125.82,127.13,127.47,129.39,129.47,129.69,131.02,132.50,134.11,138.34,145.62,150.68,181.02(CO).HRMS(ESI)m/z calcd for C20H17N2OSCl[M]+:368.0750,found[M+H]+:369.0825.
实施例26
10-氯-6-(戊-3-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N6)
10-Chloro-6-(pentan-3-ylamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N6)
分离出黄色固体(产率65％)。(Rf＝0.87at CH2Cl2).Mp160-161℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)0.92(6H,t,J＝7.6Hz,-CH3),1.69(4H,quin,J＝6.0Hz,-CH2-),4.34(1H,sext,J＝7.2Hz,-CH-),6.58(1H,d,J＝8.0Hz,Ar-H),7.36(1H,t,J＝8.0Hz,Ar-H),7.58(1H,t,J＝8.0Hz,Ar-H),7.65(1H,d,J＝8.0Hz,Ar-H),7.90(1H,dd,J＝8.4,2.4Hz,Ar-H),8.01(1H,d,J＝8.4Hz,Ar-H),8.40(1H,d,J＝2.4Hz,Ar-H),9.34(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)11.21,26.86,54.41,120.16,123.92,125.13,125.81,127.05,128.49,129.02,129.37,129.73,132.17,132.55,133.22,133.29,145.69,151.64,180.85(CO).HRMS(ESI)m/z calcd for C21H19N2OSCl[M]+:382.0907,found[M+H]+:383.0994,[M-H]–:381.0851.
实施例27
10-氯-6-((2-(二甲基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N7)
10-Chloro-6-((2-(dimethylamino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N7)
分离出黄色固体(产率76％)。(Rf＝0.82at EA:MeOH:ammonia water＝10:5:1).Mp156-157℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)2.36(6H,s,-N(CH3)2),2.69(2H,t,J＝6.0Hz,-CH2N-),3.57(2H,q,J＝5.6Hz,-NCH2-),5.86(1H,br,-NH),7.44(1H,td,J＝8.0,1.6Hz,Ar-H),7.62(2H,td,J＝7.6,1.6Hz,Ar-H),7.65(1H,dd,J＝8.0,0.8Hz,Ar-H),7.82(1H,dd,J＝8.4,1.2Hz,Ar-H),8.58(1H,dd,J＝1.6,0.4Hz,Ar-H),9.46(1H,dd,J＝8.8,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)39.53,45.28,57.57,120.71,123.46,125.90,127.02,127.27,127.57,129.35,129.43,129.56,131.46,132.43,132.56,134.02,145.72,150.90,181.05.(CO).HRMS(ESI)m/z calcd for C20H18N3OSCl[M]+:383.0859,found[M+H]+:384.0925.
实施例28
10-氯-6-((2-(二乙基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N8)
10-Chloro-6-((2-(diethylamino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N8)
分离出黄色固体(产率86％)。(Rf＝0.8at EA:MeOH:ammonia water＝10:5:1).Mp152-153℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.13(6H,t,J＝7.2Hz,-CH3),2.64(4H,q,J＝6.8Hz,-NCH2-),2.82(2H,t,J＝6.0Hz,-CH2N-),3.70(2H,q,J＝5.2Hz,-NCH2-),6.08(1H,br,-NH-),7.43(1H,t,J＝7.2Hz,Ar-H),7.59-7.64(3H,m,Ar-H),7.81(1H,d,J＝8.4Hz,Ar-H),8.57(1H,d,J＝1.2Hz,Ar-H),9.45(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)12.34,39.52,46.81,50.89,120.64,124.25,124.34,125.89,126.96,127.63,129.32,129.41,129.53,131.49,132.37,132.55,133.98,145.79,150.96,181.06(CO).HRMS(ESI)m/z calcd for C22H22N3OSCl[M]+:411.1172,found[M+H]+:412.1262.
实施例29
10-氯-6-(2-乙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N9)
10-Chloro-6-(2-ethanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N9)
分离出黄色固体(产率77％)。(Rf＝0.65at EA).Mp190-192℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.93(2H,q,J＝4.4Hz,-NCH2-),4.00(2H,t,J＝4.4Hz,-CH2O-),4.23(1H,br,-OH),5.45(1H,br,-NH),7.48(1H,td,J＝8.0,1.6Hz,Ar-H),7.62-7.68(3H,m,Ar-H),7.81(1H,dd,J＝7.6,0.8Hz,Ar-H),8.58(1H,dd,J＝1.6,0.4Hz,Ar-H),9.45(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)45.88,63.59,120.97,123.67,125.12,125.92,126.60,127.50,129.48,129.83,130.15,130.91,132.55,132.69,134.35,144.65,151.32,180.87(CO).HRMS(ESI)m/z calcd for C18H13N2O2SCl[M]+:356.8260,found[M+H]+:357.0476,[M+H+2]+: 359.0455.
实施例30
10-氯-6-(3-丙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N10)
10-Chloro-6-(3-propanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N10)
分离出黄色固体(产率94％)。(Rf＝0.66at EA).Mp201-202℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.94(2H,p,J＝6.0Hz,-CH2-),3.72(2H,t,J＝5.2Hz,-NCH2-),3.93(2H,q,J＝6.0Hz,-CH2O-),4.41(1H,br,-OH),5.38(1H,t,J＝5.2Hz,-NH-),7.45(1H,td,J＝7.6,1.2Hz,Ar-H),7.58-7.65(3H,m,Ar-H),7.78(1H,dd,J＝8.4,0.8Hz,Ar-H),8.56(1H,dd,J＝2.0,0.4Hz,Ar-H),9.42(1H,dd,J＝8.4,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)33.23,38.94,59.25,120.72,123.44,124.84,125.94,126.32,127.45,129.44,129.92,130.11,130.84,132.49,132.64,134.31,144.83,151.33,180.88(CO).HRMS(ESI)m/z calcd for C19H15N2O2SCl[M]+:370.0543,found[M+H]+:371.0622.
实施例31
10-氯-6-(5-戊醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N11)
10-Chloro-6-(5-pentanolamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N11)
分离出黄色固体(产率91％)。(Rf＝0.7at EA).Mp158-160℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.40(1H,br,-OH),1.49-1.62(2H,m,-CH2-),1.71(2H,quin,-CH2-),1.83(2H,quin,-CH2-),3.74(4H,quin,-CH2-),4.91(1H,br,-NH),7.45(1H,td,J＝7.6,1.2Hz,Ar-H),7.59(3H,m,Ar-H),7.83(1H,d,J＝8.4Hz,Ar-H),8.57(1H,d,J＝1.2Hz,Ar-H),9.44(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)23.39,29.17,32.40,42.24,62.83,120.69,123.53,124.60,125.84,127.11,127.48,129.40,129.51,129.71,131.02,131.79,132.53,134.14,145.60,150.58,181.02(CO).HRMS(ESI)m/z calcd for C21H19N2O2SCl[M]+:398.0856,found[M+H]+:399.0914.
实施例32
10-氯-6-((1-羟基丁烷-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N12)
10-Chloro-6-((1-hydroxybutan-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N12)
分离出黄色固体(产率94％)。(Rf＝0.8at EA).Mp203-204℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.21(3H,t,J＝7.6Hz,-CH3),1.71-1.88(2H,m,-CH2-),3.79(1H,dd,J＝11.2,1.6Hz,-CH2-),3.99(1H,dd,J＝11.2,2.8Hz,-CH2-),4.34(1H,quin,J＝11.2Hz,-NCH-),4.59 (1H,br,-OH),5.02(1H,d,J＝6.0Hz,-NH-),7.44(1H,td,J＝8.0,1.2Hz,Ar-H),7.56(1H,d,J＝8.4Hz,Ar-H),7.59(1H,td,J＝7.6,1.2Hz,Ar-H),7.61(1H,d,J＝8.4Hz,Ar-H),7.74(1H,d,J＝8.4Hz,Ar-H),8.52(1H,d,J＝2.0Hz,Ar-H),9.40(1H,dd,J＝7.6,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)10.95,24.95,56.89,67.08,120.83,123.68,124.98,125.88,126.51,127.40,129.39,129.75,130.02,130.81,132.38,132.62,134.28,144.53,151.09,180.75(CO).HRMS(ESI)m/z calcd for C20H17N2O2SCl[M]+:384.0699,found[M+H]+:385.0790.
实施例33
10-氯-6-((4-甲基戊-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N13)
10-Chloro-6-((4-methylpentan-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N13)
分离出黄色固体(产率94％)。(Rf＝0.9at CH2Cl2).Mp176-177℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)0.98(3H,d,J＝6.8Hz,-CH3),1.03(3H,d,J＝6.8Hz,-CH3),1.35(3H,d,J＝6.4Hz,-CH3),1.45(1H,quin,J＝6.4Hz,-CH2-),1.66(1H,quin,J＝6.8Hz,-CH2-),1.80(1H,sep,J＝6.8Hz,-CH-),4.63(1H,br,-NH),4.63-4.66(1H,m,-CH-),7.43(1H,td,J＝7.6,1.2Hz,Ar-H),7.58-7.63(3H,m,Ar-H),7.81(1H,d,J＝8.4Hz,Ar-H),8.56(1H,d,J＝1.2Hz,Ar-H),9.43(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)21.38,22.87,22.92,25.40,45.73,46.80,120.55,123.42,124.36,125.80,127.21,127.44,129.38,129.71,131.08,132.47,132.52,134.07,145.76,150.01,181.05(CO).HRMS(ESI)m/z calcd for C22H19N2OSCl[M]+:396.1063,found[M+H]+:397.1142.
实施例34
6-((2-氨基乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N14)
6-((2-Aminoethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(N14)
分离出黄色固体(产率90％)。(Rf＝0.6at EA:MeOH:ammonia water＝10:5:1).Mp193-194℃(MeOH).1H NMR(400MHz,DMSO-d6):δ(ppm)2.90(2H,t,J＝6.0Hz,-CH2-),3.59(2H,t,J＝6.0Hz,-CH2-),7.36(1H,t,J＝8.0Hz,Ar-H),7.59(1H,t,J＝8.0Hz,Ar-H),7.66(1H,d,J＝8.0Hz,Ar-H),7.85(1H,d,J＝7.2Hz,Ar-H),7.96(1H,d,J＝8.8Hz,Ar-H),8.35(1H,br,Ar-H),9.32(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,DMSO-d6):δ(ppm)40.79,45.06,120.24,124.08,125.31,125.84,127.00,128.39,128.83,129.32,129.69,132.06,132.33,133.12,133.26,145.58,151.52,180.65(CO).HRMS(ESI)m/z calcd for C18H14N3OSCl[M]+:355.0546,found[M+H]+:356.0641.
实施例35
10-氯-6-((2-((2-羟乙基)氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N15)
10-Chloro-6-((2-((2-hydroxyethyl)amino)ethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-o ne(N15)
分离出黄色固体(产率58％)。(Rf＝0.63at EA:MeOH:ammonia water＝10:5:1).Mp141-143℃(MeOH).1H NMR(400MHz,DMSO-d6):δ(ppm)2.69(2H,t,J＝5.6Hz,-CH2-),2.90(2H,t,J＝6.0Hz,-CH2-),3.51(2H,t,J＝5.6Hz,-CH2-),3.65(2H,t,J＝6.0Hz,-CH2-),7.10(1H,br,-NH-),7.32(1H,t,J＝7.2Hz,Ar-H),7.55(1H,t,J＝7.2Hz,Ar-H),7.62(1H,d,J＝8.4Hz,Ar-H),7.76(1H,t,J＝7.2Hz,Ar-H),7.86(1H,d,J＝8.4Hz,Ar-H),8.25(1H,d,J＝2.0Hz,Ar-H),9.26(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,DMSO-d6):δ(ppm)41.90,48.16,51.80,60.72,120.13,123.96,125.14,125.81,126.94,128.26,128.65,129.16,129.60,131.82,132.11,132.96,133.19,145.50,151.35,180.45(CO).HRMS(ESI)m/z calcd for C20H18N3O2SCl[M]+:399.8938,found[M+H]+:400.0880.
实施例36
10-氯-6-((2-吗啉代乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N16)
10-Chloro-6-((2-morpholinoethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N16)
分离出黄色固体(产率87％)。(Rf＝0.48at EA).Mp189-190℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)2.63(4H,br,-CH2-),2.81(2H,br,-CH2-),3.81(6H,br,-CH2-),5.92(1H,br,-NH-),6.70(2H,d,J＝8.4Hz,Ar’-H),7.45(1H,td,J＝7.8,1.6Hz,Ar-H),7.60-7.64(3H,m,Ar-H),7.81(1H,d,J＝8.4Hz,Ar-H),8.57(1H,s,Ar-H),9.46(1H,dd,J＝8.8,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)38.28,53.31,56.52,67.13,120.73,123.94,124.58,125.91,127.01,127.56,129.37,129.49,129.64,131.27,132.47,132.54,134.10,145.66,150.76,180.99(CO).HRMS(ESI)m/z calcd for C22H20N3O2SCl[M]+:425.0965,found[M+H]+:426.1058,[M-H]-:424.0885.
实施例37
10-氯-6-((3-(二甲基氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N17)
10-Chloro-6-((3-(dimethylamino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N17)
分离出黄色固体(产率43％)。(Rf＝0.71at EA:MeOH:ammonia water＝10:5:1).Mp194-195℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.92(2H,quin,J＝6.0Hz,-CH2-),2.41 (6H,s,-N(CH3)2),2.60(2H,t,J＝5.6Hz,-CH2N-),3.81(2H,q,J＝5.6Hz,-NCH2-),7.95(1H,br,-NH),7.40(1H,td,J＝7.6,1.6Hz,Ar-H),7.56-7.63(4H,m,Ar-H),7.80(1H,d,J＝8.4Hz,Ar-H),8.57(1H,d,J＝2.4Hz,Ar-H),9.44(1H,dd,J＝7.6,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)24.83,43.64,45.68,59.72,120.46,123.97,124.56,125.84,126.83,127.54,129.32,129.48,131.84,132.29,132.56,133.86,146.01,151.27,181.14(CO).HRMS(ESI)m/z calcd for C21H20N3OSCl[M]+:397.1016,found[M+H]+:398.1072.
实施例38
10-氯-6-((3-(二乙氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N18)
10-Chloro-6-((3-(diethylamino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N18)
分离出黄色固体(产率70％)。(Rf＝0.68at EA:MeOH:ammonia water＝10:5:1).Mp142-143℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.15(6H,t,J＝6.8Hz,-CH3),1.91(2H,quin,J＝6.0Hz,-CH2-),2.66-2.72(6H,m,-NCH2-),3.81(2H,q,J＝4.8Hz,-NCH2-),7.40(1H,td,J＝7.2,1.2Hz,Ar-H),7.55-7.58(1H,dd,J＝8.4,3.6Hz,Ar-H),7.60-7.64(2H,m,Ar-H),7.81(1H,d,J＝8.0Hz,Ar-H),7.93(1H,br,Ar-H),8.58(1H,t,J＝2.0Hz,Ar-H),9.45(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)11.44,24.71,44.25,47.09,53.57,120.45,123.99,124.50,125.86,126.87,127.46,129.34,129.43,131.85,132.32,132.57,133.88,146.04,151.30,181.15(CO).HRMS(ESI)m/z calcd for C23H24N3SOCl[M]+:425.1329,found[M+H]+:426.1396,[M-H]–:424.1284.
实施例39
10-氯-6-((3-((2-羟乙基)氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N19)
10-Chloro-6-((3-((2-hydroxyethyl)amino)propyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N19)
分离出黄褐色固体(产率75％)。(Rf＝0.65at EA:MeOH:ammonia water＝10:5:1).Mp65-67℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.89(2H,quin,J＝6.0Hz,-CH2-),2.15(2H,br,-OH&-NH-),2.85(4H,quin,-CH2-),3.74(2H,t,J＝6.0Hz,-CH2-),3.80(2H,t,J＝5.2Hz,-CH2-),6.53(1H,br,-NH-),7.39(1H,td,J＝7.6,0.8Hz,Ar-H),7.44(1H,d,J＝8.8Hz,Ar-H),7.50(1H,dd,J＝8.4,2.4Hz,Ar-H),7.58(1H,td,J＝7.2,1.2Hz,Ar-H),7.76(1H,d,J＝8.0Hz,Ar-H),8.46(1H,d,J＝2.0Hz,Ar-H),9.39(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)28.37,42.23,48.74,51.65,61.42,120.48,123.99,124.22,125.85,126.88,127.42,129.13, 129.33,129.38,131.23,132.21,132.33,133.95,145.69,150.82,180.92(CO).HRMS(ESI)m/z calcd for C21H20N3O2SCl[M]+:413.0965,found[M+H]+:414.1053,[M+H+2]+:416.1037.
实施例40
10-氯-6-((2,3-二氢-1H-茚-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N20)
10-Chloro-6-((2,3-dihydro-1H-inden-2-yl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N20)
分离出黄褐色固体(产率65％)。(Rf＝0.7at CH2Cl2:n-hexane＝2:1).Mp251-252℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.02(1H,d,J＝5.2Hz,indane-H),3.06(1H,d,J＝5.2Hz,indane-H),3.59(1H,d,J＝7.2Hz,indane-H),3.63(1H,d,J＝7.2Hz,indane-H),5.10(1H,d,J＝6.8Hz,-NH),5.23(1H,q,J＝5.2Hz,indane-H),7.21-7.25(2H,m,Ar’-H),7.28-7.31(2H,m,Ar’-H),7.47(1H,td,J＝6.8,1.2Hz,Ar-H),7.58(1H,d,J＝8.4Hz,Ar-H),7.61-7.67(1H,td,J＝6.8,1.2Hz,Ar-H),7.87(1H,d,J＝7.6Hz,Ar-H),8.57(1H,d,J＝2.0Hz,Ar-H),9.46(1H,dd,J＝8.8,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)40.41,53.27,120.79,123.60,124.81,124.93,125.84,126.76,127.37,127.46,129.38,129.51,129.71,131.02,132.50,132.54,134.12,141.29,145.56,150.20,181.00(CO).HRMS(ESI)m/z calcd for C25H17N2OSCl[M]+:428.0750；found[M+H]+:429.0822.
实施例41
10-氯-6-(环己基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N21)
10-Chloro-6-(cyclohexylamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N21)
分离出黄褐色固体(产率91％)。(Rf＝0.7at CH2Cl2:n-hexane＝2:1).Mp196-197℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.25-1.40(4H,m,cyclohexylamine-CH2),1.49-1.60(2H,m,cyclohexylamine-CH2),1.70-1.74(2H,m,cyclohexylamine-CH2),1.79-1.84(2H,m,cyclohexylamine-CH2),2.21(2H,dd,J＝8.8,3.2Hz,cyclohexylamine-CH2),4.30(1H,sep,J＝3.6Hz,cyclohexylamine-CH),4.72(1H,d,J＝6.8Hz,-NH-),7.41(1H,t,J＝8.0Hz,Ar-H),7.51-62(3H,m,Ar-H),7.79(1H,d,J＝8.0Hz,Ar-H),8.51(1H,d,J＝1.6Hz,Ar-H),9.41(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)24.94,25.92,33.10,50.26,120.51,123.50,124.34,125.77,127.11,127.37,129.27,129.35,129.60,131.01,132.37,132.41,134.00,145.66,149.75,180.95(CO).HRMS(ESI)m/z calcd for C22H19N2OSCl[M]+:394.0907；found[M+H]+:395.0991.
实施例42
6-((1-芐基哌啶-4-基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N22)
6-((1-Benzylpiperidin-4-yl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(N22)
分离出黄褐色固体(产率62％)。(Rf＝0.77at EA).Mp194-196℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.62-1.72(2H,m,piperidine-H),2.24(2H,d,J＝13.2Hz,piperidine-H),2.32(2H,t,J＝11.2Hz,piperidine-H),2.92(2H,d,J＝11.6Hz,piperidine-H),3.59(2H,s,-CH2-),4.35(1H,sext,J＝6.4Hz,piperidine-CH),4.75(1H,d,J＝7.2Hz,-NH),7.26-7.30(1H,m,Ar’-H),7.36-7.38(4H,m,Ar’-H),7.44(1H,td,J＝7.6,0.8Hz,Ar-H),7.59-7.64(3H,m,Ar-H),7.80(1H,d,J＝7.6Hz,Ar-H),8.56(1H,d,J＝1.6Hz,Ar-H),9.43(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)32.26,48.63,52.35,63.22,120.63,123.47,124.57,125.81,127.07,127.12,127.47,128.25,129.21,129.35,129.44,129.74,130.99,132.46,132.52,134.10,138.37,145.57,149.76,181.00(CO).HRMS(ESI)m/z calcd for C28H24N3OSCl[M]+:485.1329；found[M+H]+:486.1379.
实施例43
10-氯-6-((噻吩-2-基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N23)
10-Chloro-6-((thiophen-2-ylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N23)
分离出黄褐色固体(产率78％)。(Rf＝0.7at CH2Cl2:n-hexane＝2:1).Mp178-180℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)5.07(1H,d,J＝5.2Hz,-NCH2-),5.17(1H,br,-NH-),7.00(1H,t,J＝4.4Hz,thiophene-H),7.16(1H,d,J＝3.2Hz,thiophene-H),7.25(1H,d,J＝0.8Hz,thiophene-H),7.47(1H,t,J＝8.0Hz,Ar-H),7.52(1H,d,J＝8.4Hz,Ar-H),7.58(1H,d,J＝8.4Hz,Ar-H),7.65(1H,t,J＝7.6Hz,Ar-H),7.89(1H,d,J＝8.0Hz,Ar-H),8.53(1H,s,Ar-H),9.46(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)41.14,121.06,123.58,125.05,125.47,125.89,126.47,126.73,127.29,127.45,129.33,129.57,129.71,130.94,132.39,132.51,134.12,141.36,145.20,149.82,180.80(CO).HRMS(ESI)m/z calcd for C21H13N2OS2Cl[M]+:408.0158；found[M+H]+:409.0251,[M-H]–:407.0085.
实施例44
10-氯-6-((环己基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N24)
10-Chloro-6-((cyclohexylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N24)
分离出黄褐色固体(产率79％)。(Rf＝0.7at CH2Cl2:n-hexane＝2:1).Mp165-166℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)1.07(1H,d,J＝11.2Hz,cyclohexyl-CH2),1.30 (1H,d,J＝11.2Hz,cyclohexyl-CH2),1.23(2H,q,J＝11.6Hz,cyclohexyl-CH2),1.31(2H,q,J＝11.6Hz,cyclohexyl-CH2),1.78-1.81(4H,m,cyclohexyl-CH2),1.90(2H,d,J＝12.4Hz,cyclohexyl-CH2),3.53(2H,t,J＝6.0Hz,-NCH2-),4.85(1H,br,-NH-),7.40(1H,t,J＝7.2Hz,Ar-H),7.51(1H,d,J＝8.8Hz,Ar-H),7.55(1H,d,J＝1.6Hz,Ar-H),7.60(1H,t,J＝8.0Hz,Ar-H),7.79(1H,d,J＝8.0Hz,Ar-H),8.50(1H,d,J＝1.2Hz,Ar-H),9.41(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)25.97,26.52,31.23,37.63,48.50,120.59,123.57,124.41,125.80,127.10,127.38,129.26,129.38,129.45,130.95,132.33,132.41,134.02,145.58,150.64,180.87(CO).HRMS(ESI)m/z calcd for C23H21N2OCl[M]+:408.1063；found[M+H]+:409.1115.
实施例45
6-(芐基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N25)
6-(Benzylamino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(N25)
分离出黄褐色固体(产率93％)。(Rf＝0.67at CH2Cl2:n-hexane＝2:1).Mp194-195℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)4.94(2H,d,J＝5.2Hz,-CH2-),5.16(1H,br,-NH-),7.33-7.51(6H,m,Ar-H),7.58-7.67(3H,m,Ar-H),7.87(1H,d,J＝8.0Hz,Ar-H),8.59(1H,d,J＝2.0Hz,Ar-H),9.47(1H,d,J＝8.0Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)37.63,120.98,123.54,124.89,125.87,127.26,127.50,127.63,128.24,128.79,129.43,129.57,129.85,131.02,132.58,134.18,138.82,145.48,150.33,181.00(CO).HRMS(ESI)m/z calcd for C23H15N2OSCl[M]+:402.0594；found[M+H]+:403.0692.
实施例46
10-氯-6-((吡啶-2-基甲基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮(N26)
10-Chloro-6-((pyridin-2-ylmethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N26)
分离出黄褐色固体(产率93％)。(Rf＝0.25at EA).Mp187-189℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)5.01(2H,d,J＝4.0Hz,-CH2-),6.79(1H,br,-NH-),7.24-7.28(1H,m,Ar’-H),7.45(2H,t,J＝7.2Hz,Ar’-H&Ar-H),7.61-7.67(3H,m,Ar-H),7.73(1H,td,J＝7.6,1.6Hz,Ar-H),7.86(1H,d,J＝8.4Hz,Ar-H),8.58(1H,d,J＝2.0Hz,Ar-H),8.67(1H,d,J＝4.8Hz,Ar’-H),9.47(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)46.74,120.81,122.37,124.19,124.61,125.93,127.04,127.60,129.33,129.44,129.60,131.40,132.46,132.52,134.03,136.94,145.62,148.94,150.43,156.58,181.00(CO).HRMS(ESI)m/z calcd for C22H14N3OSCl[M]+:403.0546；found[M+H]+:404.0615.
实施例47
6-((苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N27)
6-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-o ne(N27)
分离出黄褐色固体(产率90％)。(Rf＝0.88at EA).Mp205-206℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)4.82(2H,t,J＝5.2Hz,-NCH2-),5.08(1H,br,-NH-),5.97(2H,s,-OCH2O-),6.82(1H,d,J＝8.0Hz,Ar’-H),6.96(1H,d,J＝8.0Hz,Ar’-H),7.00(1H,d,J＝1.2Hz,Ar’-H),7.47(1H,td,J＝8.0,1.2Hz,Ar-H),7.57(1H,d,J＝8.8Hz,Ar-H),7.60-7.66(2H,m,Ar-H),7.86(1H,d,J＝8.0Hz,Ar-H),8.62(1H,d,J＝2.0Hz,Ar-H),9.46(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)46.30,101.10,108.40,108.85,120.95,121.58,123.52,124.88,125.86,127.23,127.46,129.39,129.56,129.76,130.98,132.48,132.55,132.61,134.15,145.42,147.07,147.92,150.21,180.93(CO).HRMS(ESI)m/z calcd for C24H15N2O3SCl[M]+:446.0492；found[M+H]+:447.0586,[M-H]–:445.0440.
实施例48
10-氯-6-((2-甲氧芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮(N28)
10-Chloro-6-((2-methoxybenzyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N28)
分离出黄褐色固体(产率82％)。(Rf＝0.65at CH2Cl2:n-hexane＝2:1).Mp223-224℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.95(3H,s,-OCH3),4.93(2H,d,J＝5.6Hz,-NCH2-),5.57(1H,t,J＝5.6Hz,-NH-),5.97(2H,s,-OCH2O-),6.94-7.00(2H,m,Ar’-H),7.30(1H,td,J＝8.0,2.0Hz,Ar’-H),7.45(1H,td,J＝8.0,1.6Hz,Ar’-H),7.51(1H,d,J＝7.2Hz,Ar’-H),7.59-7.66(3H,m,Ar-H),7.89(1H,dd,J＝8.4,1.2Hz,Ar-H),8.57(1H,dd,J＝2.0,0.8Hz,Ar-H),9.45(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)42.33,55.49,110.47,120.68,120.81,123.90,124.59,125.82,126.68,127.20,127.52,128.88,129.38,129.44,129.71,130.49,131.23,132.46,132.54,134.04,145.59,150.62,157.89,181.04(CO).HRMS(ESI)m/z calcd for C24H17N2O2SCl[M]+:432.0699；found[M+H]+:433.0783.
实施例49
10-氯-6-((3,4-二甲氧基芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮(N29)
10-Chloro-6-((3,4-dimethoxybenzyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N29)
分离出黄褐色固体(产率84％)。(Rf＝0.66at CH2Cl2:n-hexane＝2:1).Mp251-252℃ (MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.89(3H,s,-OCH3),3.90(3H,s,-OCH3),4.86(2H,d,J＝4.8Hz,-NCH2-),5.11(1H,t,J＝5.2Hz,-NH-),6.89(1H,d,J＝8.0Hz,Ar’-H),7.05(1H,dd,J＝8.0,2.0Hz,Ar’-H),7.08(1H,d,J＝2.0Hz,Ar’-H),7.48(1H,td,J＝7.6,1.2Hz,Ar-H),7.60(1H,dd,J＝8.4,0.4Hz,Ar-H),7.65(1H,dd,J＝8.4,1.5Hz,Ar-H),7.66(1H,td,J＝8.0,1.2Hz,Ar-H),7.88(1H,dd,J＝8.4,0.8Hz,Ar-H),8.59(1H,dd,J＝1.5,0.4Hz,Ar-H),9.48(1H,dd,J＝8.4,1.2Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)46.45,55.96,55.99,111.31,111.82,120.59,120.99,123.56,124.88,125.91,127.20,127.50,129.45,129.60,129.88,131.04,131.34,132.59,134.21,145.52,148.63,149.20,150.34,181.01(CO).HRMS(ESI)m/z calcd for C25H19N2O3SCl[M]+:462.0805；found[M+H]+:463.0900,[M-H]–:461.0754.
实施例50
10-氯-6-(苯乙基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N30)
10-Chloro-6-(phenethylamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N30)
分离出黄褐色固体(产率94％)。(Rf＝0.52at CH2Cl2:n-hexane＝2:1).Mp151-152℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.10(2H,t,J＝6.8Hz,-CH2-),3.98(2H,q,J＝6.4Hz,-NCH2-),4.91(1H,t,J＝4.8Hz,-NH-),7.27-7.39(5H,m,Ar’-H),7.45(1H,t,J＝8.0Hz,Ar-H),7.54(1H,d,J＝8.4Hz,Ar-H),7.59(1H,d,J＝1.2Hz,Ar-H),7.63(1H,t,J＝7.6Hz,Ar-H),7.85(1H,d,J＝8.4Hz,Ar-H),8.54(1H,d,J＝1.6Hz,Ar-H),9.44(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)35.33,43.52,120.77,123.66,124.69,125.85,126.56,127.23,127.50,128.73,128.94,129.33,129.48,129.50,131.03,132.54,134.08,139.30,145.57,150.36,180.94(CO).HRMS(ESI)m/z calcd for C24H17N2OSCl[M]+:416.9226；found[M+H]+:417.0857,[M+H+2]+:419.0834.
实施例51
10-氯-6-((4-甲氧基苯乙基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮(N31)
10-Chloro-6-((4-methoxyphenethyl)amino)-12H-thiochromeno[2,3-c]quinolin-12-one(N31)
分离出黄色固体(产率95％)。(Rf＝0.89at CH2Cl2).Mp214-215℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)3.03(2H,t,J＝6.8Hz,-CH2-),3.81(3H,s,-OCH3),3.94(2H,q,J＝6.4Hz,-NCH2-),4.90(1H,t,J＝4.8Hz,-NH-),6.90(2H,d,J＝8.4Hz,Ar’-H),7.23(2H,d,J＝8.4Hz,Ar’-H),7.45(1H,t,J＝7.6Hz,Ar-H),7.55(1H,d,J＝8.8Hz,Ar-H),7.59(1H,d,J＝2.0Hz,Ar-H),7.63(1H,t,J＝7.6Hz,Ar-H),7.85(1H,d,J＝8.0Hz,Ar-H),8.54(1H,d,J＝2.0Hz,Ar-H),9.44(1H,d,J＝8.8Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)34.39,43.68,55.31,114.13, 120.76,123.67,124.67,125.85,127.22,127.52,129.36,129.49,129.68,129.87,131.05,131.24,132.48,134.09,145.59,150.41,158.31,180.99(CO).HRMS(ESI)m/z calcd for C25H19N2O2SCl[M]+:446.0856；found[M+H]+:447.0938.
实施例52
6-((4-氨基苯乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N32)
6-((4-Aminophenethyl)amino)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one(N32)
分离出黄色固体(产率82％)。(Rf＝0.52at CH2Cl2).Mp208-210℃(MeOH).1H NMR(400MHz,CDCl3):δ(ppm)2.97(2H,t,J＝6.8Hz,-CH2-),3.63(2H,br,-NH2),3.91(2H,q,J＝6.4Hz,-NCH2-),4.91(1H,t,J＝4.8Hz,-NH-),6.70(2H,d,J＝8.4Hz,Ar’-H),7.09(2H,d,J＝8.0Hz,Ar’-H),7.44(1H,t,J＝7.6Hz,Ar-H),7.55(1H,d,J＝8.0Hz,Ar-H),7.60(1H,d,J＝8.4Hz,Ar-H),7.63(1H,t,J＝7.6Hz,Ar-H),7.84(1H,d,J＝8.0Hz,Ar-H),8.54(1H,d,J＝2.0Hz,Ar-H),9.44(1H,d,J＝8.4Hz,Ar-H).13C NMR(100MHz,CDCl3):δ(ppm)34.37,43.70,115.52,120.72,123.73,124.59,125.83,127.19,127.51,129.06,129.31,129.45,129.59,129.75,131.09,132.42,134.04,144.89,145.60,150.45,180.96(CO).HRMS(ESI)m/z calcd for C24H16N3OSCl[M]+:431.0859；found[M+H]+:432.0950.
实施例53
2-(10-氯-12-氧代-12H-脱氢硫胺并[2,3-c]喹啉-6-基)胍
2-(10-Chloro-12-oxo-12H-thiochromeno[2,3-c]quinolin-6-yl)guanidine(N33)
分离出黄色固体(产率85％)。Mp:370℃.1H NMR(400MHz,DMSO-d6):δppm.7.40(3H,td,J＝8.4,1.2Hz,Ar-H&-NH2),7.59(1H,td,J＝8.7,1.2Hz,Ar-H),7.59(1H,dd,J＝8.4,0.8Hz,Ar-H),7.83(1H,dd,J＝8.4,2.0Hz,Ar-H),7.95(1H,d,J＝8.8Hz,Ar-H),8.40(1H,d,J＝2.4Hz,Ar-H),9.49(1H,dd,J＝8.4,0.8Hz,Ar-H).13C NMR(100MHz,DMSO-d6):δppm.120.77,124.49,125.86,126.82,128.11,128.60,129.21,129.85,132.13,132.52,132.68,136.17,136.80,144.49,159.19,181.16.HRMS(ESI)calcd for C17H11N4OSCl[M]+354.0342；found[M+H]+355.0438.
实施例54
10-氯-6-(哌啶-1-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮(N34)
10-Chloro-6-(piperidin-1-ylamino)-12H-thiochromeno[2,3-c]quinolin-12-one(N34)
分离出黄色固体(产率60％)。Mp:180-181℃.1H NMR(400MHz,CDCl3):δppm1.72-1.74 (2H,m,-CH2-),1.89(4H,quin,J＝5.2Hz,-CH2-),3.32(4H,J＝4.8Hz,-CH2-),7.36(1H,tt,J＝8.7,2.1Hz,Ar-H10),7.47(1H,dd,J＝8.4,2.7Hz,Ar-H8),7.61-7.73(3H,m,Ar-H),8.00(1H,d,J＝8.0Hz,Ar-H),8.59(1H,d,J＝2.0Hz,Ar-H),9.63(1H,d,J＝8.8Hz,Ar-H).13CNMR(100MHz,CDCl3):δppm,24.28,25.91,52.36,123.49,125.77,127.32,127.90,128.59,129.06,129.27,130.51,131.66,132.18,132.39,133.49,134.70,144.98,158.53,181.58.
药理活性实验
在药理试验方面，将化学合成出的化合物结构2-21与N-1至N-34(共54种药物)，进行下列五个部份的药理活性试验：一、细胞存活分析(MTT assay)试验；二、第一型、第二型拓朴异构酶活性试验；三、细胞周期阻滞；四、细胞凋亡相关蛋白表现量；五、美国癌症研究中心(NCI)筛选出26个化合物结构，针对这26个化合物进行60种癌细胞株的毒杀试验。
实施例55细胞存活分析(MTT assay)试验
所有的合成化合物利用MTT比色法，分析化合物于PC-3(BCRC60122,Taiwan)与DU-145(HTB-81TM,ATCC,Rockville,MD)细胞株细胞毒性。上述细胞培养于RPMI-1640、5％FBS(v/v)、100U/mL青霉素与50mg/mL链霉素。于96孔盘培养约2x103个细胞，5％CO2于37℃24小时。为了测量体外细胞毒性，所有的化合物皆于实验前溶于DMSO，并预先混和在相同的细胞培养液中以利给药，并调整好不同的给药浓度(0.15、0.5、1.5、5、15μΜ)进行三重复实验。给药后72小时，100μL的MTT(1mg/mL)加入每个孔中，并在培养于37℃4小时。移除MTT溶液后，加入100μL的DMSO至每一孔中，再培养于37℃20分钟。以ELISA读取机侦测吸收光谱为560nm的数值。结果以至少三重复的平均值呈现，表1呈现IC50数值。
表1、利用MTT分析出脱氢硫胺[2,3-c]喹啉-12-酮衍生物的细胞毒性
Figure PCTCN2014089182-appb-000004
Figure PCTCN2014089182-appb-000005
Figure PCTCN2014089182-appb-000006
Figure PCTCN2014089182-appb-000007
aSD:标准差，所有实验皆至少三重复。
此外，相较于只有单一羟基、烷基或芳香环，化合物N7、N8、N14、N15、N17及N18含有至少一个氮原子在侧支链，显示具有较优异的细胞毒杀活性。化合物5、7、8、16、19、N2、N7、N8、N9、N14、N15、N16、N17、N18、N19及N25被筛选进行拓朴异构酶活性试验。
实施例56第一、二型拓朴异构酶活性试验
化合物5、7、8、16、19、N2、N7、N8、N9、N14、N15、N16、N17、N18、N19及N25以25μM或50μM以进行拓朴异构酶活性试验(图2-4)。
于第一型拓朴异构酶活性试验中，化合物7、N7、N14、N15、N17、N18与N25相较于喜树碱为更具有抑制效果，并进一步以五种不同浓度进行实验(图4a-d)。化合物7、N7、N14、N15、N17、N18与N25的IC50值分别为10、10、1、5、25、5与25μΜ(使用TopoGEN TG2005H、TG-2000H-1所测得)。
于第二型拓朴异构酶活性试验中(图5-7)，化合物7、N7、N8、N14、N15、N18与N19相较于喜树碱为更具有抑制效果，并进一步以五种不同浓度进行实验(图7a-d)。化合物7、N7、N8、N14、N15、N18与N19的IC50值分别为10、10、1、10、5、1与1μΜ(使用TopoGEN TG2005H、TG-2000H-1所测得)。
实施例57美国癌症研究中心(NCI)筛选
美国癌症研究中心(NCI)筛选出26个化合物结构(2、3、4、5、6、8、10、11、12、13、N1、N2、N6、N7、N9、N12、N13、N14、N16、N17、N19、N21、N25、N27、N30、N31)，针对这26个化合物进行60种癌细胞株的毒杀试验。第一阶段先进行26个化合物于10μM的毒杀试验，进行六十种癌细胞株的毒杀试验，作用48小时后进行细胞存活试验(Sulforhodamine B，SRB)。结果如表2-表4，以生长百分比(growthpercent)作为表示。
之后从中找出较具有毒杀潜力的化合物结构共5个：N2、N7、N14、N19与N25进行第二阶段五种浓度(0.01、0.1、1、10、100μM)的毒杀试验(表5)。
表2、化合物2、3、4、5、6、8、10、11、12、13的NCI数据
Figure PCTCN2014089182-appb-000008
Figure PCTCN2014089182-appb-000009
aNCI60种细胞体外药物筛选程序，各化合物的浓度为10-5M。
bN.T.＝No test。
表3、化合物N1、N2、N6、N7、N9、N12、N13、N14的NCI数据
Figure PCTCN2014089182-appb-000010
Figure PCTCN2014089182-appb-000011
Figure PCTCN2014089182-appb-000012
aNCI60种细胞体外药物筛选程序，各化合物的浓度为10-5M。
bN.T.＝No test。
表4、化合物N16、N17、N19、N21、N25、N27、N30、N31的NCI数据
Figure PCTCN2014089182-appb-000013
Figure PCTCN2014089182-appb-000014
Figure PCTCN2014089182-appb-000015
aNCI60种细胞体外药物筛选程序，各化合物的浓度为10-5M。
bN.T.＝No test。
表5、N2、N7、N14、N19、N25NCI的GI50、TGI、LC50数据
Figure PCTCN2014089182-appb-000016
Figure PCTCN2014089182-appb-000017
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (9)

  1. 一种式(I)化合物，
    Figure PCTCN2014089182-appb-100001
    其中R是选自下列取代基所组成的群组：
    i)卤基、胺基、羟基及硫基；
    ii)NH(CH2)nH的直链烷基、带有支链取代的烷基、具有一胺基取代的烷基支链、具有一羟基取代之烷基支链，其中1≤n≤10；
    iii)O(CH2)nH、N(CH3)2、NH(CH2)nNH(CH2)nOH；其中1≤n≤10；
    iv)C3-12含氮的环烷基及杂环基团，它含有从1至3个选自于O、S以及N的杂原子，其中邻位、间位或对位更可独立地选自下列取代基其中之一：氢基、(CH2)n烷基、(CH2)n羟基、(CH2)nC3-12环烷基、(CH2)nC3-12含氮环烷基、(CH2)n苯环、醛基及(CH2)nCOC3-12含氮环烷基；其中0≤n≤10；
    v)NH(CH2)nR1，0≤n≤10，R1是选自下列取代基其中之一：N(CH3)2，C(NH2)2，NH(CH2)nH的直链烷基、带有支链取代的烷基、具有一胺基取代的烷基支链、具有一羟基取代的烷基支链；
    vi)NH(CH2)nR2，0≤n≤10，R2是选自下列取代基其中之一：苯环、C3-12环烷基及杂环基团，含有从1至3个选自于O、S以及N的杂原子，其中邻位、间位或对位更可独立地选自下列取代基其中之一：甲氧基、胺基、苯环、带有C1-C3支链取代的烷基、胺基、硝基、羟基及C3-12杂环；其中该C3-12杂环含有从1至3个选自于O、S以及N的杂原子；以及
    医药上可接受的盐、立体异构物及镜像异构物。
  2. 根据权利要求1所述的化合物，其特征在于，其中取代基群组i)-vi)是选自由氯、羟基、甲氧基、二甲氨基、哌嗪-1-基、4-甲基哌嗪-1-基、4-乙基哌 嗪-1-基、4-(2-羟乙基)哌嗪-1-基、4-芐基哌嗪-1-基、4-苯基哌嗪-1-基、吗啉代、硫代吗啉代、哌啶-1-基、4-羟基哌啶-1-基、4-芐基哌啶-1-基、[1,4'-联哌啶]-1'-基、4-(3-(哌啶-4-基)丙基、吡咯烷-1-基、2-氧代哌啶-1-基、甲基氨基、乙基氨基、丙基氨基、丁基氨基、异丁基、戊-3-基氨基、(2-(二甲基氨基)乙基)氨基、(2-(二乙基氨基)乙基)氨基、2-乙醇氨基、3-丙醇氨基、5-戊醇氨基、(1-羟基丁烷-2-基)氨基、(4-甲基戊-2-基)氨基、(2-氨基乙基)氨基、(2-((2-羟乙基)氨基)乙基)氨基、(2-吗啉代乙基)氨基、(3-(二甲基氨基)丙基)氨基、(3-(二乙氨基)丙基)氨基、(3-((2-羟乙基)氨基)丙基)氨基、(2,3-二氢-1H-茚-2-基)氨基、环己基、(1-芐基哌啶-4-基)氨基、(噻吩-2-基甲基)氨基、(环己基甲基)氨基、芐基氨基、(吡啶-2-基甲基)氨基、(苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基、(2-甲氧芐基)氨基、(3,4-二甲氧基芐基)氨基、苯乙基氨基、(4-甲氧基苯乙基)氨基、(4-氨基苯乙基)氨基、胍及哌啶-1-基氨基所组成的群组。
  3. 根据权利要求1的化合物，其特征在于，其中该化合物是选自由下列所组成的群组：
    3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸、
    6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮、
    10-氯-6-羟基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-甲氧基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-二甲氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-甲基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-乙基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-(2-羟乙基)哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉12-酮、
    6-(4-芐基哌嗪-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-苯基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-硫代吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-羟基哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(4-芐基哌啶-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-([1,4'-联哌啶]-1'-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-(3-(哌啶-4-基)丙基)哌啶-1-基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(吡咯烷-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(2-氧代哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-甲基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-乙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-丙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(丁基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-异丁基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(戊-3-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-(二甲基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-(二乙基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(2-乙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(3-丙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(5-戊醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((1-羟基丁烷-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((4-甲基戊-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((2-氨基乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-((2-羟乙基)氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-吗啉代乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-(二甲基氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-(二乙氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-((2-羟乙基)氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2,3-二氢-1H-茚-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(环己基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((1-芐基哌啶-4-基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((噻吩-2-基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((环己基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(芐基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((吡啶-2-基甲基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-甲氧芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3,4-二甲氧基芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(苯乙基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((4-甲氧基苯乙基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((4-氨基苯乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    2-(10-氯-12-氧代-12H-脱氢硫胺并[2,3-c]喹啉-6-基)胍、
    10-氯-6-(哌啶-1-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    以及其等的盐类。
  4. 一种医药组合物，其特征在于，包含治疗有效量的如权利要求1所述的化合物，和至少一种医药上可接受载剂、稀释剂或赋形剂。
  5. 一种如权利要求1-4任一项所述的化合物的用途，其特征在于，其是用于制造可用于抑制第一型拓朴异构酶活性的医药品。
  6. 一种如权利要求1-4中任一项所述的化合物的用途，其特征在于，其是用于制造可用于抑制第二型拓朴异构酶活性的医药品。
  7. 一种如权利要求1-4中任一项所述的化合物的用途，其特征在于，其是用于制造可用于治疗癌症的医药品。
  8. 根据权利要求7所述的用途，其特征在于，其中该癌症是选自白血病、非小细胞肺癌、大肠癌、中枢神经癌、黑色素瘤、卵巢癌、肾脏癌、前列腺癌及乳癌所组成的群组。
  9. 一种制造如权利要求1所述的化合物的方法，其特征在于，该方法包含：
    (1)将isatin、2-((4-chlorophenyl)thio)aceticacid及醋酸钠混合，于150℃反应1小时，将反应完的混合液冷却后加入醋酸得到沉淀物，再以醋酸、水、正己烷冲洗，得到化合物2(3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸)；
    (2)取化合物2(3-((4-氯苯基)硫代)-2-羟基喹啉-4-羧酸)溶于三氯氧磷150℃、48小时，冷却后将反应物倒入水中，过滤收集沉淀物置入10％碳酸氢钠溶液搅拌1小时，收集沉淀物后再以水冲洗，粗产物以二氯甲烷再结晶，得到化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)；
    (3)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)溶于DMF，加入浓盐酸并回流六小时，之后逐滴加入浓盐酸并再回流12小时，反应物以真空脱水，再加入水，过滤后粗产物以乙醇清洗得到化合物4(10-氯-6-羟基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮)；
    (4)于甲醇中的悬浮化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与甲醇钠回流16小时，冷却后移除溶剂，过滤后再以乙醇与正己烷清洗，得到化合物5(10-氯-6-甲氧基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮)；
    (5)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与一适当二级胺与碳酸钠溶于DMSO或DMF，回流10小时，静置冷却后，反应物加入冰水中，过滤出沉淀物后，以水及甲醇清洗收集分别得到化合物6-21：
    10-氯-6-二甲氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-甲基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-乙基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-(2-羟乙基)哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉12-酮、
    6-(4-芐基哌嗪-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-苯基哌嗪-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-硫代吗啉代-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-羟基哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(4-芐基哌啶-1-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-([1,4'-联哌啶]-1'-基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(4-(3-(哌啶-4-基)丙基)哌啶-1-基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(吡咯烷-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、及
    10-氯-6-(2-氧代哌啶-1-基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮；
    (6)取化合物3(6,9-二氯-12H-脱氢硫胺[2,3-c]喹啉-12-酮)与一适当一级胺溶于DMSO，回流8小时，冷却后，反应物加入水中。过滤出沉淀物后，以水及甲醇清洗收集分别得到化合物N1-N34：
    10-氯-6-甲基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-乙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-丙基氨基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(丁基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-异丁基-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(戊-3-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-(二甲基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-(二乙基氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(2-乙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(3-丙醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(5-戊醇氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((1-羟基丁烷-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((4-甲基戊-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((2-氨基乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-((2-羟乙基)氨基)乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-吗啉代乙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-(二甲基氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-(二乙氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3-((2-羟乙基)氨基)丙基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2,3-二氢-1H-茚-2-基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(环己基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((1-芐基哌啶-4-基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((噻吩-2-基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((环己基甲基)氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-(芐基氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((吡啶-2-基甲基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((苯并[d][1,3]二氧杂环戊烯-5-基甲基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((2-甲氧芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((3,4-二甲氧基芐基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-(苯乙基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    10-氯-6-((4-甲氧基苯乙基)氨基)-12H–脱氢硫胺并[2,3-c]喹啉-12-酮、
    6-((4-氨基苯乙基)氨基)-10-氯-12H-脱氢硫胺并[2,3-c]喹啉-12-酮、
    2-(10-氯-12-氧代-12H-脱氢硫胺并[2,3-c]喹啉-6-基)胍、及
    10-氯-6-(哌啶-1-基氨基)-12H-脱氢硫胺并[2,3-c]喹啉-12-酮。
PCT/CN2014/089182 2014-02-14 2014-10-22 脱氢硫胺[2,3-c]喹啉-12-酮衍生物及其制备方法和应用 WO2015120730A1 (zh)

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