CN105198828A - 杂环蒽酮类组蛋白甲基转移酶抑制剂及其医药用途 - Google Patents
杂环蒽酮类组蛋白甲基转移酶抑制剂及其医药用途 Download PDFInfo
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- HLZNXZPTIFGKRE-UHFFFAOYSA-N CN(C)CCNc(cc(c1n[o]c(-c2c3cccc2)c11)N2CCCC2)c1C3=O Chemical compound CN(C)CCNc(cc(c1n[o]c(-c2c3cccc2)c11)N2CCCC2)c1C3=O HLZNXZPTIFGKRE-UHFFFAOYSA-N 0.000 description 1
- GJWWZYOTEYWODM-UHFFFAOYSA-N CN(C)CCNc(cc(c1n[o]c(-c2ccccc22)c11)N(CC3)CCN3c3ncccn3)c1C2=O Chemical compound CN(C)CCNc(cc(c1n[o]c(-c2ccccc22)c11)N(CC3)CCN3c3ncccn3)c1C2=O GJWWZYOTEYWODM-UHFFFAOYSA-N 0.000 description 1
- PGLCXSDFIXKVKF-UHFFFAOYSA-N O=C(c(cccc1)c1-c1c2c(c(Br)c3)n[o]1)c2c3Sc1ccccc1 Chemical compound O=C(c(cccc1)c1-c1c2c(c(Br)c3)n[o]1)c2c3Sc1ccccc1 PGLCXSDFIXKVKF-UHFFFAOYSA-N 0.000 description 1
- CFLCCLSHOUOYIN-UHFFFAOYSA-N O=C(c1ccccc1-c1c2c(c(N(CC3)CCN3c3ccccc3)c3)n[o]1)c2c3NCCN1CCCC1 Chemical compound O=C(c1ccccc1-c1c2c(c(N(CC3)CCN3c3ccccc3)c3)n[o]1)c2c3NCCN1CCCC1 CFLCCLSHOUOYIN-UHFFFAOYSA-N 0.000 description 1
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及药物化学领域,具体涉及一类杂环蒽酮类组蛋白甲基转移酶抑制剂(I)、其制备方法及其医药用途。药理学实验证明本发明化合物对组蛋白甲基转移酶从分子水平到细胞水平具有良好的抑制作用,对肿瘤细胞株具有良好的抗增殖活性,具有合理的成药性参数,如适合的解离常数(pKa)、脂水分布系数(LogD,pH=7.4)、水溶性及膜透过率。药代动力学的研究表明本发明化合物在大鼠体内分布较广,血浆清除率处在可接受的范围内,且具有较好的生物利用度。本发明化合物及其药物制剂可以用于治疗由于组蛋白甲基转移酶酶活性失调而导致的一系列疾病,例如,实体瘤,白血病、疟疾以及神经退行性等疾病。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类杂环蒽酮类组蛋白甲基转移酶抑制剂、其制备方法及其医药用途。
背景技术
组蛋白甲基化修饰是一种重要的表观遗传学调控方式,参与染色质构象的调控、基因的转录和表达。组蛋白的甲基化水平与多种原癌基因和肿瘤抑制基因密切相关,组蛋白的甲基化水平的异常使得这些原癌基因和肿瘤抑制基因非正常表达,可能会导致肿瘤的发生。因此,通过调节组蛋白的甲基化水平,某些重要基因得以转录,以达到***的目的。组蛋白甲基化调节蛋白已成为目前肿瘤药物研发领域最新、最热门的靶标。
组蛋白甲基转移酶主要的作用底物是组成核小体的组蛋白。在人体内,组蛋白末端的赖氨酸和精氨酸残基会被甲基化。组蛋白精氨酸甲基化是由两类甲基转移酶催化完成的:I类精氨酸甲基转移酶和II类精氨酸甲基转移酶。另一类组蛋白甲基转移酶主要作用于组蛋白的赖氨酸,称作组蛋白赖氨酸甲基转移酶(Lysinemethyltransferases,KMTs)。与其它的转录后修饰不同,组蛋白甲基化可以有二甲基化、三甲基化,因此,甲基化的进程更加复杂(MosammaparastN,ShiY.Reversalofhistonemethylation:biochemicalandmolecularmechanismsofhistonedemethylases[J].AnnuRevBiochem,2010,79:155-179.)组蛋白甲基转移酶能够利用辅因子S-腺苷甲硫氨酸(S-adenosylmethionine,SAM)作为甲基供体催化组蛋白N-端赖氨酸残基,使其增加1-3个甲基。到目前为止组蛋白赖氨酸的甲基化影响基因转录的具体机理尚未研究清楚,其更多的生物学功能有待进一步阐释。组蛋白赖氨酸甲基转移酶在众多生理过程中发挥着重要作用。例如,细胞的分化和发育,衰老过程的调节,基因组稳定性的控制,神经元功能的调节和肿瘤细胞的增殖。组蛋白甲基转移酶不仅可以作用于组蛋白,还可以使非组蛋白底物甲基化。与癌症相关的p53可以被KMTs甲基化。p53的373位赖氨酸甲基化后,减弱p53动态信号的传递,最终导致肿瘤细胞不可控的生长(WestLE,GozaniO.Regulationofp53functionbylysinemethylation[J].Epigenomics,2011,3(3):361-369)有研究表明,组蛋白甲基转移酶在结肠癌,肝癌,乳腺癌细胞中表达异常。此外,在白血病、***癌、肺癌和腮腺癌中都可观察到组蛋白甲基转移酶的过表达。
考虑到组蛋白甲基转移酶的重要功能,尤其是在肿瘤发生发展过程中起着至关重要的作用,因此将组蛋白甲基转移酶作为抗肿瘤靶标是非常有前景的。目前报道的组蛋白甲基转移酶抑制剂根据来源主要分为两大类:一类为天然产物类抑制剂,一般是从真菌中提取的抗生素类化合物。主要是毛壳素(chaetocin)类化合物,该类化合物包含有环二硫酮哌嗪类结构;另一类为人工设计合成的小分子抑制剂,目前报道的小分子抑制剂以SAM的类似物居多,另有苯并咪唑类,喹唑啉类化合物报道。
组蛋白甲基转移酶抑制剂根据作用方式的不同分为底物竞争性抑制剂和SAM竞争性抑制剂。到目前为止组蛋白甲基转移酶抑制剂的研究绝大多数处在临床前阶段。所以研发选择性的组蛋白甲基转移酶抑制剂,无论对学术研究还是对开发其临床应用的可能性都具有非常重大的意义。
发明内容
本发明涉及一类基于组蛋白甲基转移酶设计的杂环蒽酮类的衍生物,药理学实验证明本发明化合物对组蛋白甲基转移酶从分子水平到细胞水平具有良好的抑制作用,对肿瘤细胞株具有良好的抗增殖活性,具有合理的成药性参数,如适合的解离常数(pKa)、脂水分布系数(LogD,pH=7.4)、水溶性及膜透过率。药代动力学的研究表明本发明化合物在大鼠体内分布较广,血浆清除率处在可接受的范围内,且具有较好的生物利用度。本发明化合物及其药物制剂可以用于治疗由于组蛋白甲基转移酶酶活性失调而导致的一系列疾病,例如,实体瘤,白血病、疟疾以及神经退行性等疾病。
本发明涉及下列通式(I)的化合物
其中Ar代表
W代表C、N、O或S;
L代表C1-C6的碳链;
R1代表卤素、羟基、-NRaRb、硝酸酯基、硫氰基、C1-C6烷氧基、C2-C6不饱和烯氧基、C1-C6烷基酰氧基或取代的C6-C8苯基酰氧基,所述取代基是氢、卤素、甲氧基、硝基、羟基或NRaRb;
R2代表-NRaRb、被0-2个Z取代基取代的苯基、含有1-2个选自N、O或S的五元、六元饱和或不饱和杂环或者含有该不饱和杂环的苯并杂环,其中取代基Z基是卤素、氨基、羟基、硝基、氰基、羧基、C1-C6的烷基、C1-C6的烷氧基或C1-C6的烷基胺基;
Ra、Rb各自独立代表H、C1-C6烷基、C1-C6羟烷基或C1-C6烷酰基;或Ra、Rb连接形成含有1-2个N或O原子的5-6元杂环;
R3代表单、双或三取代,取代基为H、卤素、C1-C3烷氧基或C1-C3烷硫基。
Ar优选代表
R1优选代表-NRaRb,其中Ra、Rb各自独立地代表H、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、***啉基、哌嗪基、N-甲基哌嗪基、N-甲基高哌嗪基、N-乙基哌嗪基,N-丙基哌嗪基、N-异丙基哌嗪基、N-环戊基哌嗪基、N-环己基哌嗪基、N-苯基哌嗪基、N-苄基哌嗪基或N-嘧啶基哌嗪基。
R2优选代表-NRaRb,其中Ra、Rb各自独立地代表H、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、***啉基、哌嗪基、N-甲基哌嗪基、N-甲基高哌嗪基、N-乙基哌嗪基、N-丙基哌嗪基、N-异丙基哌嗪基、N-环戊基哌嗪基、N-环己基哌嗪基、N-苯基哌嗪基、N-苄基哌嗪基;或2-氟苯基、3-氟苯基、4-氟苯基,2,4-二氟苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲氧基苯基,2-氯苯基、3-氯苯基、4-氯苯基,2,4-二氯苯基或3-氟-4-氯苯基。
R3优选代表单、双或三取代基,取代基选自氢、氯、甲氧基或甲硫基。
更优选下列任一结构的化合物或其药学上可接受的盐:
通式(I)化合物及药学上可接受的盐或溶剂化物都包括在本发明范围内。
本发明化合物(I)可用下列方法制备:
首先适当的商业购买的原料1经过溴代得到中间体2,中间体2在AlCl3作用下和商业购买的各种发生取代反应得到中间体3,随后目标化合物由中间体3和商业网购买的各种R1发生取代反应得到。
通式(I)所述化合物及其中间体可以通过常见的分离方法进行纯化,如重结晶、柱层析等。
本发明还公开了一种药物组合,通式(I)化合物及其药学上可接受的盐或溶剂化物可以添加药学上可接受的载体制成常见的药物制剂,如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂,可以加入香料、甜味剂、液体或固体填充料或稀释剂等常用的药物辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物(I)临床所用剂量为0.01mg~1000mg/天,也可根据病情的轻重或剂型的不同偏离此范围。
下面是本发明化合物的部分药理学实验及结果,药理部分的化合物代号所对应的结构式等同于实施例部分的代号所对应的结构式:
一、对组蛋白甲基转移酶的抑制实验
材料试剂及仪器:384孔不透明黑板,BiotinylatedhistoneH3peptide、SAM与组蛋白甲基转移酶;特异性识别甲基化位点的一抗及相应的抗鼠微珠,Streptavidin偶联的微珠,AlphaScreenmicroplatereader酶标仪。
组蛋白甲基转移酶抑制活性测定方法:将BiotinylatedhistoneH3peptide、SAM与组蛋白甲基转移酶混合,同时加入不同浓度的通式(I)化合物,每个浓度做三个复孔,在室温下反应60分钟后,加入特异性识别甲基化位点的一抗及相应的抗鼠微珠,混匀后,室温孵育90分钟,最后加入Streptavidin偶联的微珠,混匀并孵育30分钟后,在PerkinElmer公司的AlphaScreenmicroplatereader酶标仪上检测相应的TR-FRET信号。
数据分析方法:a)计算每个样本的平均信号值;b)每个样本浓度的信号值减去背景信号值,c)计算每个样本的抑制率。
%抑制率=(A药物-A本底)/(A对照-A本底)×100%
用GraphpadPrism5软件处理,计算出化合物的IC50值
表1本发明代表化合物对组蛋白甲基转移酶的IC50
化合物编号 | %抑制率10μM | IC50(μM) |
CPUY074017 | 62.93 | 6.89±1.45 |
CPUY074018 | 69.21 | 3.87±1.92 |
CPUY074019 | 92.02 | 1.22±0.13 |
CPUY074020 | 91.52 | 2.18±0.013 |
CPUY074021 | 70.58 | 3.48±0.36 |
CPUY074022 | 70.01 | 4.57±0.64 |
CPUY074023 | 87.14 | 3.22±0.14 |
CPUY074024 | 63.92 | 3.96±0.54 |
CPUY074025 | 64.31 | 3.47±0.31 |
CPUY074026 | 81.51 | 3.75±0.24 |
CPUY074027 | 60.98 | 5.97±0.32 |
CPUY074028 | 63.69 | 4.84±0.38 |
CPUY074029 | 60.99 | 3.84±0.035 |
CPUY074030 | 79.01 | 1.87±0.19 |
CPUY074031 | 64.28 | 2.49±0.13 |
CPUY074032 | 72.21 | 2.68±0.089 |
CPUY074033 | 71.54 | 2.98±0.22 |
CPUY074034 | 49.03 | 13.4±0.16 |
CPUY074035 | 72.23 | 2.83±0.012 |
CPUY074036 | 65.05 | 4.96±0.15 |
CPUY074037 | 78.99 | 1.69±0.22 |
CPUY074038 | 39.21 | 19.05±0.17 |
CPUY074039 | 59.87 | 6.96±0.06 |
CPUY074040 | 50.26 | 5.01±0.19 |
CPUY074041 | 66.34 | 3.21±0.07 |
CPUY074042 | 39.08 | 12.89±0.16 |
CPUY074043 | 78.89 | 2.56±0.23 |
CPUY074044 | 80.96 | 1.89±0.10 |
CPUY074045 | 82.08 | 2.01±0.15 |
CPUY074046 | 66.34 | 3.21±0.07 |
二、对肿瘤细胞的体外抗增殖实验
测试本发明化合物对人类结肠癌细胞株HCT116,人类乳腺癌细胞株MCF7及人肝癌细胞(HepG2)的抗增殖活性。方法:共选用三种肿瘤细胞(HCT116,MCF7,HepG2)。将细胞接种于96孔的平板中(每孔约有4000-10000个细胞),24小时后,将不同浓度的化合物加入至细胞中,72小时后,各小孔中分别加入20μLMTT的PBS溶液(浓度为5mg/mL),于37℃孵育4小时,除去MTT,每个小孔中分别加入150μLDMSO(含量为100%),于570nm下检测(采用ThermoMultiskanSpectrum)。其中UNC0638是目前报道的酶活和细胞活都较好的小分子抑制剂,被广泛应用为阳性对照。
表2本发明代表化合物对不同肿瘤细胞株的抗增殖活性
三、在细胞内对组蛋白底物的甲基化水平影响实验
测试本发明化合物在人类乳腺癌细胞株MCF7中对组蛋白底物甲基化水平的影响。方法:蛋白免疫印迹WesternBlot。将细胞接种于细胞培养瓶中,于37℃,CO2含量5%的孵箱中培养24h后,将不同浓度的化合物加入至细胞中培养24小时后,收集细胞(2.5*105),使用细胞裂解液RIPA进行细胞破碎进行蛋白提取,BCA方法测定蛋白浓度,进行SDS-PAGE凝胶电泳,分别对目的条带进行一抗4℃过夜孵育,TBS缓冲液洗涤,二抗孵育,应用OdysseyInfraredImagingSystem进行目的蛋白的检测。
图1和图2分别代表化合物CPUY074017和CPUY074020对H3K9me2和H3K9me3甲基化水平的影响。
上述药理实验结果显示:本发明化合物对组蛋白甲基转移酶表现出显著的抑制作用,部分化合物的抑制活性(IC50)处于较低微摩尔水平。这对新型骨架的组蛋白甲基转移酶抑制剂的发现及其作用机制的研究都有重要意义。
本发明化合物对肿瘤细胞HCT116,MCF7和HepG2细胞具有较好的抗增殖活性,其中部分化合物的抗增殖活性甚至高于阳性对照UNC0638。
附图说明
图1是CPUY074017对H3K9me2和H3K9me3甲基化水平的影响
图2是CPUY074020对H3K9me2和H3K9me3甲基化水平的影响
具体实施方式
实施例1
3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮的制备
将6H-蒽[1,9-cd]异恶唑-6-酮(5g,22.60mmol)溶于AcOH(50mL)中,同时将溴(2.90mL,56.51mmol)的醋酸溶液滴加至反应液中,TLC检测,反应停止。将该反应液用饱和碳酸氢钠调至弱碱性,用二氯甲烷(3×50mL)萃取,有机层用无水硫酸钠干燥,旋干溶剂,柱层析分离得到黄色3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(7.26g,73%).m.p.247-248℃.1HNMR(300MHz,CDCl3):δ8.45(d,J=7.71Hz,1H,ArH),8.08(d,J=7.5Hz,1H,ArH),7.97(s,1H,ArH),7.82(t,J=7.23Hz,1H,ArH),7.72(t,J=7.35Hz,ArH).HRMS(ESI):calcdforC14H5Br2NO2[M+H]+377.8760,found377.8752.
实施例2
将不同取代的氨溶解在溶有无水氯化铝的二氯甲烷溶液中,实施例1化合物加入到该混合物中,于40℃搅拌12h,TLC检测,停止反应。将该反应液用水(2×30mL)萃取。有机层用无水硫酸钠干燥,旋干溶剂得到红色固体。
以下化合物(实施例3-11)均按照上述方法由实施例2经取代反应合成。
实施例3
3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和对甲氧基苯胺(0.19g,1.58mmol)按照实施例2方法合成。m.p.156-157℃.1HNMR(300MHz,CDCl3):δ11.32(s,1H,NH),8.58(d,J=7.23Hz,1H,ArH),8.18(d,J=7.23Hz,ArH),7.82(t,J=7.47Hz,1H,ArH),7.70(t,J=8.01Hz,1H,ArH),7.62(s,1H,ArH),7.30(d,J=8.79Hz,2H,ArH),7.05(d,J=8.85Hz,2H,ArH),3.91(s,3H,CH3).HRMS(ESI):calcdforC21H13BrN2O3[M+H]+421.0182,found421.0186.
实施例4
3-溴-5-((4-甲基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和对甲基苯胺(0.17g,1.58mmol)按照实施例2方法合成。m.p.197-198℃.1HNMR(300MHz,CDCl3):δ11.35(s,1H,NH),8.54(d,J=7.68Hz,1H,ArH),8.14(d,J=7.65Hz,1H,ArH),7.79(t,J=7.35Hz,1H,ArH),7.67(t,J=5.79Hz,2H,ArH),7.32(d,J=8.19Hz,2H,ArH),7.25(d,J=8.10Hz,2H,ArH),2.43(s,3H,CH3).HRMS(ESI):calcdforC21H13BrN2O2[M+H]+405.0233,found405.0229.
实施例5
4-((3-溴-6-氧--6H-蒽[1,9-cd]异恶唑-5-基)氨基)苯甲腈
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和对氰基苯胺(0.18g,1.58mmol)按照实施例2方法合成。m.p.179-180℃.1HNMR(300MHz,CDCl3):δ11.45(s,1H,NH),8.55(d,J=7.47Hz,1H,ArH),8.19(d,J=7.47Hz,1H,ArH),7.88-7.81(m,4H,ArH),7.74(d,J=8.37Hz,1H,ArH),7.49(d,J=8.55Hz,2H,ArH).HRMS(ESI):calcdforC21H10BrN3O2[M+H]+416.0027,found416.0031.
实施例6
3-溴-5-((4-氯苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和对氯苯胺(0.20g,1.58mmol)按照实施例2方法合成。m.p.189-190℃.1HNMR(300MHz,CDCl3):δ11.33(s,1H,NH),8.56(d,J=7.23Hz,1H,ArH),8.25(d,J=5.55Hz,1H,ArH),8.17(d,J=7.68Hz,1H,ArH),8.09(s,1H,ArH),7.85-7.77(m,2H,ArH),7.70(s,1H,ArH),7.51(d,J=8.46Hz,2H,ArH).HRMS(ESI):calcdforC20H10BrClN2O2[M+H]+424.9687,found424.9688.
实施例7
3-溴-5-((2-氟苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和邻氟苯胺(0.15mL,1.58mmol)按照实施例2方法合成。m.p.218-219℃.1HNMR(300MHz,CDCl3):δ11.16(s,1H,NH),8.57(d,J=7.71Hz,1H,ArH),8.17(d,J=7.77Hz,1H,ArH),7.85(t,J=7.53Hz,1H,ArH),7.72-7.68(m,1H,ArH),7.58(s,1H,ArH),7.51-7.46(m,1H,ArH),7.40-7.31(m,3H,ArH).HRMS(ESI):calcdforC20H10BrFN2O2[M+H]+408.9982,found408.9988.
实施例8
3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和1-(2-氨基乙基)吡咯(0.20mL,1.58mmol)按照实施例2方法合成。m.p.159-160℃.1HNMR(300MHz,CDCl3):δ9.99(s,1H,NH),8.56(d,J=8.01Hz,1H,ArH),8.12(d,J=7.77Hz,1H,ArH),7.66-7.61(m,2H,ArH),7.56(s,1H,ArH),3.74-3.67(m,2H,NHCH 2 ),2.92(t,J=6.48Hz,2H,CH2),2.68(s,4H,2CH2),1.92-1.83(m,4H,2CH2).HRMS(ESI):calcdforC20H18BrN3O2[M+H]+412.0655,found412.0650.
实施例9
3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和N,N-二甲基乙基氨(0.15ml,1.58mmol)按照实施例2方法合成。m.p.180-181℃.1HNMR(300MHz,CDCl3):δ9.94(s,1H,NH),8.48(d,J=7.56Hz,1H,ArH),8.06(d,J=7.41Hz,1H,ArH),7.70(t,J=7.11Hz,1H,ArH),7.57(t,J=7.38Hz,1H,ArH),7.46(s,1H,ArH),3.57(s,2H,NHCH 2 ),2.66(t,J=5.73Hz,2H,CH2),2.33(s,6H,2CH3).HRMS(ESI):calcdforC18H17BrN3O2[M+H]+386.0499,found386.0495.
实施例10
3-溴-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和1-(2-氨基乙基)哌啶(0.22mL,1.58mmol)按照实施例2方法合成。m.p.178-179℃.1HNMR(300MHz,CDCl3):δ10.00(s,1H,NH),8.52(d,J=7.68Hz,1H,ArH),8.11(d,J=7.26Hz,1H,ArH),7.76-7.64(m,5H,ArH),3.73(s,2H,NHCH 2 ),2.79-2.62(m,8H,4CH2),1.73-1.52(m,4H,2CH2).HRMS(ESI):calcdforC21H20BrN3O2[M+H]+426.0812,found416.0810.
实施例11
3-溴-5-((2-吡咯-1-基)丙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(0.10g,0.26mmol)和1-(2-氨基丙基)吡咯(0.15mL,1.58mmol)按照实施例2方法合成。m.p.177-178℃.1HNMR(300MHz,CDCl3):δ9.91(s,1H,NH),8.48(d,J=7.92Hz,1H,ArH),8.13(d,J=7.32Hz,1H,ArH),7.77(d,J=7.77Hz,1H,ArH),7.68-7.65(m,2H,ArH),3.86(t,J=6.48Hz,2H,NHCH 2 ),3.23(d,J=6.03Hz,2H,CH2),2.41-2.29(m,2H,CH2),2.18-2.14(m,4H,CH2CH2),1.44-1.36(m,4H,CH2CH2).HRMS(ESI):calcdforC21H20BrN3O2[M+H]+426.0812,found426.0806.
实施例12
将实施例3-14和各种取代的仲氨溶解于乙腈中,滴加三乙胺,于80℃下反应,TLC监测反应,2h后停止反应,反应液缓慢降至室温,然后于-15℃下静置1h,得到红色固体,抽滤并将滤饼用冷乙腈洗涤2-3次。
以下化合物均按照上述方法由实施例12经取代反应制得。
实施例13
3-(二甲基氨基)-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074002)
本品由3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例3,0.31g,0.73mmol)和N,N-二甲基氨(0.15g,1.82mmol)按照实施例12方法合成。m.p.190-191℃.1HNMR(300MHz,CDCl3):δ11.63(s,1H,NH),8.70(d,J=7.59Hz,1H,ArH),8.17(d,J=7.59Hz,1H,ArH),7.77-7.72(m,1H,ArH),7.64(t,J=1.20Hz,1H,ArH),7.35(d,J=8.82Hz,2H,ArH),6.99(d,J=8.85Hz,2H,ArH),5.85(s,1H,ArH),3.88(s,3H,OCH 3 ),3.40(s,6H,2NCH 3 ).HRMS(ESI):calcdforC23H19N3O3[M+H]+386.1499,found386.1503.
实施例14
3-(4-甲基哌嗪-1-基)-5-((4-甲基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074007)
本品由3-溴-5-((4-甲基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例4,0.32g,0.80mmol)和N-甲基哌嗪(0.16g,2.00mmol)按照实施例12方法合成。m.p.196-197℃.1HNMR(300MHz,CDCl3):δ11.73(s,1H,NH),8.61(d,J=7.80Hz,1H,ArH),8.16(d,J=7.71Hz,1H,ArH),7.73(t,J=7.26Hz,1H,ArH),7.63(t,J=7.11Hz,1H,ArH),7.27(s.5H,ArH),6.26(s,1H,ArH),3.91(s,4H,2CH2),2.62(t,J=4.23Hz,4H,2CH2),2.39(d,J=9.78Hz,6H,2CH3).HRMS(ESI):calcdforC26H24N4O2[M+H]+425.1972,found425.1971.
实施例15
4-((3-(二甲基氨基)-6-氧--6H-蒽[1,9-cd]异恶唑-5-基)氨基)苯甲腈(CPUY074009)
本品由4-((3-溴-6-氧--6H-蒽[1,9-cd]异恶唑-5-基)氨基)苯甲腈(实施例5,0.33g,0.80mmol)和N,N-二甲基氨(0.16g,2.00mmol)按照实施例12方法合成。m.p.190-191℃.1HNMR(300MHz,CDCl3):δ12.05(s,1H,NH),8.62(d,J=8.49Hz.1H,ArH),8.20(d,J=6.12Hz,1H,ArH),7.74(d,J=7.95Hz,4H,ArH),7.54(d,J=6.39Hz,2H,ArH),6.18(s,1H,ArH),3.54(s,6H,2NCH 3 ).HRMS(ESI):calcdforC23H16N4O2[M+H]+381.1346,found381.1342.
实施例16
3-(4-甲基哌嗪-1-基)-5-((4-氯苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074010)
本品由3-溴-5-((4-甲基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例6,0.32g,0.80mmol)和N-甲基哌嗪(0.16g,2.00mmol)按照实施例12方法合成。m.p.194-195℃.1HNMR(300MHz,CDCl3):δ11.72(s,1H,NH),8.60(d,J=7.95Hz,1H,ArH),8.16(d,J=7.59Hz,1H,ArH),7.78-7.72(m,1H,ArH),7.68-7.03(m,1H,ArH),7.44(d,J=8.70Hz,2H,ArH),7.34(d,J=8.67Hz,2H,ArH),6.21(s,1H,ArH),3.94(d,J=4.53,4H,2CH2),2.65(t,J=4.41Hz,4H,2CH2),2.40(s,3H,CH3).13CNMR(75MHz,CDCl3):δ176.23,153.05,147.84,146.27,136.48,132.84,130.65,130.48,129.27,127.73,127.38,124.91,123.89,121.51,96.20,94.20,76.98,76.55,76.13,54.08,48.17,45.54.HRMS(ESI):calcdforC25H21ClN4O2[M+H]+445.1426,found445.1422.
实施例17
3-(二甲基氨基)-5-((2-氟苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074011)
本品由3-溴-5-((4-甲基苯基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例7,0.34g,0.80mmol)和N,N-二甲基氨(0.16g,2.00mmol)按照实施例12方法合成。m.p.193-194℃.1HNMR(300MHz,CDCl3):δ11.64(s,1H,NH),8.65(d,J=7.77Hz,1H,ArH),8.14(d,J=7.68Hz,1H,ArH),7.72(t,J=6.78Hz,1H,ArH),7.63(t,J=7.20Hz,1H,ArH),7.57-7.52(m,1H,ArH),7.62-7.21(m,2H,ArH),5.81(s,1H,ArH),3.41(s,6H,2NCH 3 ).HRMS(ESI):calcdforC22H16FN3O2[M+H]+374.1299,found374.1300.
实施例18
3-(4-甲基哌嗪-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074017)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和N-甲基哌嗪(0.22g,2.00mmol)按照实施例12方法合成。m.p.176-177℃.1HNMR(300MHz,CDCl3):δ10.26(s,1H,NH),8.61(d,J=7.86Hz,1H,ArH),8.15(d,J=7.38Hz,1H,ArH),7.71(t,J=6.30Hz,1H,ArH),7.64(t,J=6.93Hz,1H,ArH),5.91(s,1H,ArH),3.99(t,J=4.45Hz,4H,2CH3),3.69-3.63(m,2H,CH2),2.91(t,J=6.99Hz,2H,CH2),2.66(d,J=2.44Hz,8H,4CH2),2.40(s,3H,CH3),1.84(d,J=3.15Hz,4H,2CH2).13CNMR(75MHz,CDCl3):δ175.16,155.95,153.42,147.69,146.24,133.18,129.84,127.28,127.19,123.65,121.24,95.21,93.45,54.65,54.08,53.94,48.13,45.56,41.93,23.07.HRMS(ESI):calcdforC25H29N5O2[M+H]+432.2394,found432.2401.
实施例19
3-(二甲基氨基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074018)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和N,N-二甲基氨(0.16g,2.00mmol)按照实施例12方法合成。m.p.176-177℃.1HNMR(300MHz,DMSO-d6):δ10.11(s,1H,NH),8.43(d,J=7.88Hz,1H,ArH),8.12(d,J=7.77Hz,1H,ArH),7.79-7.73(m,1H,ArH),7.67-7.61(m,1H,ArH),5.08(s,1H,ArH),3.44(s,6H,2CH3),2.77(t,J=6.27Hz,2H,CH2),2.55(s,4H,2CH2),1.72(s,4H,2CH2).HRMS(ESI):calcdforC22H24N4O2[M+H]+377.1972,found377.1976.
实施例20
3-(吡咯-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074019)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和吡咯烷(0.16mL,2.00mmol)按照实施例12方法合成。m.p.184-185℃.1HNMR(300MHz,DMSO-d6):δ10.08(t,J=5.07Hz,1H,NH),8.43(d,J=7.68Hz,1H,ArH),8.11(d,J=7.83Hz,1H,ArH),7.76(t,J=7.41Hz,1H,ArH),7.63(t,J=7.08Hz,1H,ArH),5.56(s,1H,ArH),4.02-3.55(m,6H,3CH3).HRMS(ESI):calcdforC24H26N4O2[M+H]+403.2129,found403.2132.
实施例21
3-(哌啶-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074020)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和哌啶(0.19mL,2.00mmol)按照实施例12方法合成。m.p.177-178℃.1HNMR(300MHz,CDCl3):δ10.28(s,1H,NH),8.62(d,J=8.01Hz,1H,ArH),8.16(d,J=7.65Hz,1H,ArH),7.71(t,J=7.26Hz,1H,ArH),7.62(t,J=7.14Hz,1H,ArH),5.88(s,1H,ArH),4.00(s,4H,2CH2),3.68(s,2H,CH2),2.93(t,J=15.9Hz,10H,5CH2).13CNMR(75MHz,CDCl3):δ174.75,156.41,153.36,147.97,146.25,133.26,129.70,127.23,127.11,123.59,121.23,118.63,95.01,92.36,54.68,53.97,49.87,45.17,41.88,25.22,23.77,23.07.HRMS(ESI):calcdforC25H28N4O2[M+H]+417.2285,found417.2277.
实施例22
3-(4-乙基哌嗪-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074021)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和N-乙基哌嗪(0.25mL,2.00mmol)按照实施例12方法合成。m.p.170-171℃.1HNMR(300MHz,DMSO-d6):δ10.14(t,J=5.34ArH,1H,NH),8.42(d,J=7.83Hz,1H,ArH),8.11(d,J=7.50Hz,1H,ArH),7.77(t,J=6.78Hz,1H,ArH),7.65(t,J=7.08Hz,1H,ArH),6.10(s,1H,ArH),3.98(s,4H,2CH2),3.69-3.63(m,2H,CH 2 CH3),2.76(t,J=6.09ArH,2H,CH2),2.57-2.48(m,8H,4CH2),2.43-2.36(m,2H,CH2),1.72(s,4H,2CH2),1.05(t,J=7.17ArH,3H,CH3).HRMS(ESI):calcdforC26H31N5O2[M+H]+446.2551,found446.2557.
实施例23
3-(4-(嘧啶-2-基)哌嗪-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074022)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和2-(哌嗪-1-基)嘧啶(0.33g,2.00mmol)按照实施例12方法合成。m.p.179-180℃.1HNMR(300MHz,DMSO-d6):δ10.13(t,J=5.01Hz,1H,NH),8.42(d,J=7.71Hz,2H,ArH),8.11(d,J=7.62Hz,1H,ArH),7.76(t,J=7.11Hz,1H,ArH),7.64(t,J=7.14Hz,1H,ArH),6.69(t,J=4.74Hz,1H,ArH),6.07(s,1H,ArH),4.08(d,J=2.76Hz,4H,2CH2),3.98(d,J=2.88Hz,4H,2CH2),3.68-3.63(m,2H,CH2),2.76(t,J=5.94Hz,2H,CH2),2.52(d,J=17.19Hz,4H,2CH2),1.72(s,4H,2CH2).13CNMR(75MHz,CDCl3):δ174.88,160.81,157.29,155.76,153.17,147.42,133.17,129.79,127.28,127.13,123.53,121.16,118.38,109.96,95.06,92.62,77.02,76.59,76.17,54.57,53.91,47.51,42.34,41.81,29.18,23.08.HRMS(ESI):calcdforC28H29N7O2[M+H]+496.2455,found496.2460.
实施例24
3-(4-苯基哌嗪-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074023)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和N-苯基哌嗪(0.31mL,2.00mmol)按照实施例12方法合成。m.p.166-167℃.1HNMR(300MHz,DMSO-d6):δ10.17-10.14(m,1H,NH),8.43(d,J=7.77Hz,1H,ArH),8.13(d,J=7.65Hz,1H,ArH),7.78(t,J=7.17Hz,1H,ArH),7.65(t,J=7.23Hz,1H,ArH),7.65(t,J=7.23Hz,1H,ArH),7.25(t,J=7.56Hz,2H,ArH),7.02(d,J=8.19Hz,2H,ArH),6.82(t,J=7.23Hz,1H,ArH),6.16(s,1H,ArH),4.14(s,4H,2CH2),3.70-3.66(m,2H,CH2),3.41(s,4H,2CH2),2.27(t,J=6.03Hz,2H,CH2),2.56(s,4H,2CH2),1.72(s,4H,2CH2).HRMS(ESI):calcdforC30H31N5O2[M+H]+494.2551,found494.2558.
实施例25
3-(4-甲基-1,4-二氮杂庚烷-1-基)-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074024)
本品由3-溴-5-((2-吡咯-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例8,0.33g,0.80mmol)和N-甲基高哌嗪(0.25mL,2.00mmol)按照实施例12方法合成。m.p.181-182℃.1HNMR(300MHz,DMSO-d6):δ10.12(t,J=5.13Hz,1H,NH),8.43(d,J=7.80Hz,1H,ArH),8.12(d,J=7.62Hz,1H,ArH),7.77(t,J=7.50Hz,1H,ArH),7.64(t,J=7.11Hz,1H,ArH),5.82(s,1H,ArH),4.15(brs,2H,CH2),3.94(brs,2H,CH2),3.66-3.61(m,2H,CH2),2.76(t,J=5.85Hz,2H,CH2),2.55-2.48(m,4H,2CH2),2.28(s,3H,CH3),2.01(brs,2H,CH3),1.72(s,4H,2CH2).HRMS(ESI):calcdforC26H31N5O2[M+H]+446.2551,found446.2558.
实施例26
3-(二甲基氨基)-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074025)
本品由3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例9,0.31g,0.80mmol)和N,N-二甲基氨(0.16g,2.00mmol)按照实施例12方法合成。m.p.193-194℃.1HNMR(300MHz,CDCl3):δ10.16(s,1H,NH),8.64(d,J=7.98Hz,1H,ArH),8.13(d,J=7.74Hz,1H,ArH),7.69(t,J=6.72Hz,1H,ArH),7.60(t,J=7.14Hz,1H,ArH),5.24(s,1H,ArH),3.50-3.44(m,2H,NHCH 2 CH2),3.32(s,6H,2NCH 3 ),2.71(t,J=6.66Hz,2H,CH2),2.38(s,6H,2NCH 3 ).13CNMR(75MHz,CDCl3):δ174.12,155.90,152.56,147.43,146.16,133.31,129.44,127.22,126.81,123.34,121.00,188.31,94.51,90.39,77.02,76.59,76.17,57.45,45.16,41.62,40.42.HRMS(ESI):calcdforC20H22N4O2[M+H]+351.1816,found351.1813.
实施例27
3-(哌啶-1-基)-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074026)
本品由3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例9,0.31g,0.80mmol)和哌啶(0.19mL,2.00mmol)按照实施例12方法合成。m.p.192-193℃.1HNMR(300MHz,DMSO-d6):δ10.11(t,J=5.13Hz,1H,NH),8.44(d,J=7.53Hz,1H,ArH),8.12(d,J=7.47Hz,1H,ArH),7.77(t,J=7.29Hz,1H,ArH),7.65(t,J=7.08Hz,1H,ArH),6.05(s,1H,ArH),3.99(s,4H,2CH2),3.66-3.60(m,2H,CH2),2.58(t,J=5.92Hz,2H,CH2),2.26(s,6H,2NCH 3 ),1.71(s,6H,3CH2).HRMS(ESI):calcdforC23H26N4O2[M+H]+391.2129,found391.2135.
实施例28
3-(吡咯-1-基)-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074027)
本品由3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例9,0.31g,0.80mmol)和吡咯烷(0.16mL,2.00mmol)按照实施例12方法合成。m.p.188-189℃.1HNMR(300MHz,CDCl3):δ10.20(s,1H,NH),8.65(d,J=7.80Hz,1H,ArH),8.14(d,J=7.71Hz,1H,ArH),7.69(t,J=7.44Hz,1H,ArH),7.60(t,J=7.32Hz,1H,ArH),5.32(brs,1H,ArH),3.51(s,4H,2CH2),2.72(t,J=5.40Hz,2H,CH2),2.38(s,6H,2NCH 3 ),2.10(s,6H,3CH2).HRMS(ESI):calcdforC22H24N4O2[M+H]+377.1972,found377.1974.
实施例29
3-(4-甲基哌嗪-1-基)-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074028)
本品由3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例9,0.31g,0.80mmol)和N-甲基哌嗪(0.22mL,2.00mmol)按照实施例12方法合成。m.p.181-182℃.1HNMR(300MHz,DMSO-d6):δ10.14(s,1H,NH),8.44(d,J=7.59Hz,1H,ArH),8.14(d,J=7.47Hz,1H,ArH),7.79(t,J=6.48Hz,1H,ArH),7.67(t,J=7.08Hz,1H,ArH),6.15(s,1H,ArH),3.99(s,4H,2CH2),3.69-3.63(m,2H,CH2),2.61-2.50(m,6H,3CH2),2.10(s,9H,3CH3).HRMS(ESI):calcdforC23H27N5O2[M+H]+406.2238,found406.2238.
实施例30
3-(4-(嘧啶-2-基)哌嗪-1-基)-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074029)
本品由3-溴-5-((二甲基氨基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例9,0.31g,0.80mmol)和2-(哌嗪-1-基)嘧啶(0.33g,2.00mmol)按照实施例12方法合成。m.p.195-196℃.1HNMR(300MHz,CDCl3):δ10.26(s,1H,NH),8.64(d,J=7.77Hz,1H,ArH),8.19(d,J=4.65Hz,2H,ArH),8.15(d,J=7.68Hz,1H,ArH),7.71(t,J=7.20Hz,1H,ArH),7.62(t,J=7.65Hz,1H,ArH),6.60(t,J=4.62Hz,1H,ArH),5.87(s,1H,ArH),4.11(s,8H,4CH2),3.62-3.56(m,2H,CH2),2.73(t,J=6.42Hz,2H,CH2),2.85(s,6H,2NCH 3 ).HRMS(ESI):calcdforC26H27N7O2[M+H]+470.2299,found470.2299.
实施例31
3-(4-甲基哌嗪-1-基)-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074030)
本品由3-溴-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例10,0.34g,0.80mmol)和N-甲基哌嗪(0.22mL,2.00mmol)按照实施例12方法合成。m.p.161-162℃.1HNMR(300MHz,CDCl3):δ10.23(s,1H,NH),8.62(d,J=8.04,1H,ArH),8.15(d,J=7.71Hz,1H,ArH),7.71(t,J=7.08Hz,1H,ArH),7.62(t,J=7.26Hz,1H,ArH),5.94(s,1H,ArH),4.02(t,J=4.68Hz,4H,2CH2),3.68-3.62(m,2H,CH2),2.76(t,J=6.90Hz,2H,CH2),2.67(t,J=4.86Hz,4H,2CH2),2.54(s,4H,2CH2),2.41(s,3H,CH3),1.67(t,J=5.19Hz,4H,2CH2),1.50(d,J=5.01Hz,2H,CH2).13CNMR(75MHz,CDCl3):δ175.59,156.01,146.32,133.21,129.90,127.32,127.26,123.67,121.29,95.60,93.68,76.99,76.57,76.14,57.38,54.40,48.18,45.58,40.33,29.21,25.46,23.75.HRMS(ESI):calcdforC26H31N5O2[M+H]+446.2551,found446.2558.
实施例32
3-(4-甲基-1,4-二氮杂庚烷-1-基)-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074031)
本品由3-溴-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例10,0.34g,0.80mmol)和N-甲基高哌嗪(0.25mL,2.00mmol)按照实施例12方法合成。m.p.174-175℃.1HNMR(300MHz,CDCl3):δ10.20(s,1H,NH),8.62(d,J=7.71Hz,1H,ArH),8.13(d,J=7.71Hz,1H,ArH),7.69(t,J=7.44Hz,1H,ArH),7.61(t,J=7.56Hz,1H,ArH),5.59(d,J=19.44Hz,1H,ArH),4.22(brs,2H,CH2),3.87(brs,2H,CH2),2.64(d,J=4.08Hz,2H,CH2),2.53(s,4H,2CH2),2.42(s,3H,CH3),2.14(s,2H,CH2),1.66(t,J=5.13Hz,4H,2CH2),1.49(d,J=4.80Hz,2H,CH2).HRMS(ESI):calcdforC27H33N5O2[M+H]+460.2707,found460.2707.
实施例33
3-(4-苯基哌嗪-1-基)-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074032)
本品由3-溴-5-((2-哌啶-1-基)乙基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例10,0.34g,0.80mmol)和4-苯基哌嗪(0.31mL,2.00mmol)按照实施例12方法合成。m.p.177-178℃.1HNMR(300MHz,CDCl3):δ10.25(s,1H,NH),8.63(d,J=7.83Hz,1H,ArH),8.16(d,J=7.53Hz,1H,ArH),7.74-7.69(m,1H,ArH),7.66-7.61(m,1H,ArH),7.37-7.28(m,2H,ArH),7.02-6.92(m,2H,ArH),6.03(s,1H,ArH),4.21(s,4H,2CH2),3.74(brs,2H,CH2),3.48(t,J=5.16Hz,4H,2CH2),2.82(s,2H,CH2),2.61(s,4H,2CH2),1.72(s,4H,2CH2),1.52(s,2H,CH2).HRMS(ESI):calcdforC31H33N5O2[M+H]+508.2707,found508.2708.
实施例34
3-(二甲基氨基)-5-((2-吡咯-1-基)丙基基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074033)
本品由3-溴-5-((2-吡咯-1-基)丙基基)氨基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例11,0.34g,0.80mmol)和N,N-二甲基氨(0.16g,2.00mmol)按照实施例12方法合成。m.p.185-186℃.1HNMR(300MHz,DMSO-d6):δ10.14(s,1H,NH),8.45(d,J=8.25Hz,1H,ArH),8.15(d,J=7.62Hz,ArH),7.80(t,J=7.23Hz,1H,ArH),7.67(t,J=6.63Hz,1H,ArH),5.76(s,1H,ArH),3.69(d,J=5.10Hz,2H,CH2),3.51(s,6H,3CH2),3.28(d,J=24.15Hz,6H,2CH3),2.09(d,J=10.86Hz,2H,CH2),1.94(s,4H,2CH2).HRMS(ESI):calcdforC23H26N4O2[M+H]+391.2129,found391.2134.
实施例35
3-溴-5-(2,4-二氟苯基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
将3,5-二溴-6H-蒽[1,9-cd]异恶唑-6-酮(实施例1,1g,2.43mmol)和(2,4-二氟苯基)硼酸(0.46g,2.91mmol)溶于THF(50mL)中,加入碳酸钠(0.52g,4.85mmol)和四三苯基膦钯(0.28g,0.24mmol),在N2保护下回流4h,TLC检测,停止反应。旋干,柱层析分离(PE:EA=50:1)得红色固体(0.86g,78.89%)。m.p.167-169℃.1HNMR(300MHz,CDCl3):δ8.34(d,J=7.71Hz,1H,ArH),7.89(d,J=7.5Hz,1H,ArH),7.75–7.70(m,2H,ArH),7.56–7.51(m,2H,ArH),7.07(t,J=7.23Hz,1H,ArH),6.74(t,J=7.35Hz,ArH).HRMS(ESI):calcdforC20H8BrF2NO2[M+H]+411.9779,found411.9800.
实施例36
3-(4-甲基哌嗪-1-基)-5-(2,4-二氟苯基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074034)的制备
本品由3-溴-5-(2,4-二氟苯基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例35,0.35g,0.80mmol)和N-甲基哌嗪(0.16g,2.00mmol)按照实施例12方法合成。m.p.197-198℃.1HNMR(300MHz,CDCl3):δ8.35(d,J=7.71Hz,1H,ArH),7.86(d,J=7.5Hz,1H,ArH),7.77–7.71(m,2H,ArH),7.52–7.48(m,2H,ArH),7.01(t,J=7.23Hz,1H,ArH),6.54(t,J=7.35Hz,ArH).3.92(d,J=4.53,4H,2CH2),2.55(t,J=4.41Hz,4H,2CH2),2.38(s,3H,CH3).HRMS(ESI):calcdforC25H19F2N3O2[M+H]+431.1445,found445.1442.
实施例37
3-溴-5-(4-甲氧基苯氧基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
将3-溴-5-羟基-6H-蒽[1,9-cd]异恶唑-6-酮(1g,3.16mmol)溶于30mLDMF中,加入K2CO3(0.22g,1.58mmol)和TBAB(0.51g,1.58mmol)于室温搅拌,加入4-甲氧基氯苯(0.54g,3.8mmol)升温至100℃反应8h,TLC检测,停止反应,将反应液倾入200mL水中,用稀盐酸调至pH=7,EA萃取,有机层用无水硫酸钠干燥,旋干,柱层析分离(PE:EA=50:1)得红色固体(0.98g,73.13%).m.p.167-169℃.1HNMR(300MHz,CDCl3):δ8.34(d,J=7.23Hz,1H,ArH),7.89(d,J=7.23Hz,ArH),7.70(t,J=7.47Hz,1H,ArH),7.51(t,J=8.01Hz,1H,ArH),7.49(s,1H,ArH),7.32(d,J=8.79Hz,2H,ArH),6.95(d,J=8.85Hz,2H,ArH),3.83(s,3H,CH3).HRMS(ESI):calcdforC21H12BrNO4[M+H]+422.0022,found422.0028.
实施例38
3-(4-甲基哌嗪-1-基)-5-(4-甲氧基苯氧基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074035)
本品由3-溴-5-((4-甲氧基苯氧基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例37,0.50g,1.18mmol)和N-甲基哌嗪(0.37mL,2.96mmol)按照实施例12方法合成。m.p.185-187℃.1HNMR(300MHz,CDCl3):δ8.35(d,J=7.47Hz,1H,ArH),7.96(d,J=7.65Hz,1H,ArH),7.73(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.48(t,J=8.73Hz,2H,ArH),7.23(d,J=8.82,2H,ArH),6.46(s,1H,ArH),3.88(t,J=1.74Hz,7H,2CH2andOCH 3 ),2.55(t,J=4.65Hz,4H,2CH2),2.53-2.42(m,2H,CH2),1.14(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H26N4O3[M+H]+442.1689,found455.1685.
实施例39
3-溴-5-(苯基巯基)-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由5-(苯基巯基)-6H-蒽[1,9-cd]异恶唑-6-酮(1g,3.04mmol)和液溴(0.23mL,4.55mmol)按照实施例1方法合成。m.p.167-169℃.1HNMR(300MHz,CDCl3):δ8.36(d,J=7.55Hz,1H,ArH),7.87(d,J=7.65Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.23Hz,1H,ArH),7.46(s,1H,ArH),7.41(d,J=8.73Hz,2H,ArH),7.25(t,J=8.82,2H,ArH),7.19(s,1H,ArH).HRMS(ESI):calcdforC20H10BrNO2S[M+H]+407.9615,found408.9595.
实施例40
3-(4-甲基哌嗪-1-基)-5-(苯基巯基)-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074036)的制备
本品由3-溴-5-(苯基巯基)-6H-蒽[1,9-cd]异恶唑-6-酮(实施例39,0.5g,1.22mmol)和N-甲基哌嗪(0.32mL,3.06mmol)按照实施例12方法合成。m.p.177-179℃.1HNMR(300MHz,CDCl3):δ8.36(d,J=7.55Hz,1H,ArH),7.87(d,J=7.65Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.46(t,J=8.73Hz,2H,ArH),7.41(d,J=8.82,2H,ArH),7.25(s,1H,ArH),2.65-2.55(m,4H,2CH2),2.45-2.36(m,4H,2CH2),1.14(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H26N4O3[M+H]+427.1354,found427.1388.
实施例41
3,5-二溴-7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品由7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮(1g,3.45mmol)和液溴(0.44mL,8.62mmol)按照实施例1方法合成。m.p.254-255℃.1HNMR(300MHz,CDCl3):δ8.10(s,1H,ArH),7.68(d,J=7.23Hz,1H,ArH),7.49(d,J=7.17Hz,1H,ArH).HRMS(ESI):calcdforC14H3Br2Cl2NO2[M+H]+445.7908,found445.7887.
实施例42
3-溴-5-((4-甲氧基苯基)氨基)-7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮的制备
本品有3,5-二溴-7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮(实施例41,0.5g,1.12mmol)和4-甲氧基苯胺(0.82g,6.70mmol)按照实施例2方法过程合成。m.p.164-166℃.1HNMR(300MHz,CDCl3):δ11.28(s,1H,NH),7.68(d,J=7.23Hz,1H,ArH),7.49(d,J=7.23Hz,ArH),7.55(d,J=7.47Hz,1H,ArH),7.02(d,J=8.01Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,CH3).HRMS(ESI):calcdforC21H11BrCl2N2O3[M+H]+488.9730,found488.9736.
实施例43
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮(CPUY074037)
本品由3-溴-5-((4-甲氧基苯基)氨基)-7,10-二氯-6H-蒽[1,9-cd]异恶唑-6-酮(实施例42,0.31g,065mmol)和N-甲基哌嗪(0.42mL,3.79mmol)按照实施例12方法合成。m.p.161-162℃.1HNMR(300MHz,CDCl3):δ11.28(s,1H,NH),7.69(d,J=7.23Hz,1H,ArH),7.50(d,J=7.23Hz,ArH),7.54(d,J=7.46Hz,1H,ArH),7.02(d,J=7.55Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,OCH3).2.58-2.50(m,4H,2CH2),2.45-2.37(m,4H,2CH2),1.15(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC26H22Cl2N4O3[M+H]+508.1069,found508.1039.
实施例44
3,5-二溴-二苯并[cd,g]-吲唑-6H-酮的制备
本品由二苯并[cd,g]-吲唑-6H-酮(1g,4.54mmol)和液溴(0.58mL,11.35mmol)按照实施例1方法合成。m.p.255-256℃.1HNMR(300MHz,CDCl3):δ13.70(S,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(S,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH).HRMS(ESI):calcdforC14H6Br2N2O[M+H]+376.8847,found376.8836.
实施例45
3-溴-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲唑-6H-酮的制备
本品有3,5-二溴-二苯并[cd,g]-吲唑-6H-酮(实施例44,0.5g,1.32mmol)和4-甲氧基苯胺(0.98g,7.94mmol)按照实施例2方法合成。m.p.168-170℃.1HNMR(300MHz,CDCl3):δ13.70(s,1H,NH),11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,CH3).HRMS(ESI):calcdforC21H14BrN3O2[M+H]+420.0269,found420.0249.
实施例46
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲唑-6H-酮(CPUY074038)
本品由3-溴-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲唑-6H-酮(实施例45,0.31g,0.74mmol)和N-甲基哌嗪(0.49mL,4.43mmol)按照实施例12方法合成。m.p.187-188℃.1HNMR(300MHz,CDCl3):δ13.70(s,1H,NH),11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,OCH3),2.54-2.49(m,4H,2CH2),2.45-2.32(m,4H,2CH2),1.14(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC26H25N5O2[M+H]+440.2008,found440.2042.
实施例47
3,5-二溴-10-甲氧基二苯并[cd,g]-吲唑-6H-酮的制备
本品由10-甲氧基二苯并[cd,g]-吲唑-6H-酮(1g,4.00mmol)和液溴(0.52mL,9.99mmol)按照实施例1方法合成。m.p.258-260℃.1HNMR(300MHz,CDCl3):δ13.70(s,1H,NH),8.10(s,1H,ArH),7.90(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.24(d,J=7.17Hz,1H,ArH),3.83(s,3H,OCH3).HRMS(ESI):calcdforC15H8Br2N2O2[M+H]+406.8953,found406.9832.
实施例48
3-溴-5-((4-甲氧基苯基)氨基)-10-甲氧基二苯并[cd,g]-吲唑-6H-酮的制备
本品有3,5-二溴-10-甲氧基二苯并[cd,g]-吲唑-6H-酮(实施例47,0.5g,1.23mmol)和4-甲氧基苯胺(0.91g,7.03mmol)按照实施例2方法合成。m.p.172-173℃.1HNMR(300MHz,CDCl3):δ13.70(s,1H,NH),11.30(s,1H,NH),8.10(s,1H,ArH),7.90(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.17Hz,1H,ArH),7.24(d,J=7.01Hz,1H,ArH),7.02(d,J=7.23Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,6H,2OCH3).HRMS(ESI):calcdforC22H16BrN3O3[M+H]+450.0375,found450.0355.
实施例49
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-10-甲氧基二苯并[cd,g]-吲唑-6H-酮(CPUY074039)的制备
本品由3-溴-5-((4-甲氧基苯基)氨基)-10-甲氧基二苯并[cd,g]-吲唑-6H-酮(实施例48,0.31g,0.69mmol)和N-甲基哌嗪(0.46mL,4.13mmol)按照实施例12方法合成。m.p.192-194℃.1HNMR(300MHz,CDCl3):δ13.70(s,1H,NH),11.30(s,1H,NH),8.10(s,1H,ArH),7.90(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.17Hz,1H,ArH),7.24(d,J=7.01Hz,1H,ArH),7.02(d,J=7.23Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,6H,2OCH3),2.54-2.49(m,4H,2CH2),2.45-2.32(m,4H,2CH2),1.14(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H27N5O3[M+H]+470.2114,found470.2147.
实施例50
3,5-二溴-二苯并[cd,g]-吲哚-6H-酮的制备
本品由二苯并[cd,g]-吲哚-6H-酮(1g,4.58mmol)和液溴(0.56mL,11.46mmol)按照实施例1方法合成。m.p.255-256℃.1HNMR(300MHz,CDCl3):δ8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),6.95(s,1H,CH),5.00(s,1H,NH).HRMS(ESI):calcdforC15H7Br2N2O[M+H]+375.8894,found375.8874.
实施例51
3-溴-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲哚-6H-酮的制备
本品有3,5-二溴-二苯并[cd,g]-吲哚-6H-酮(实施例50,0.5g,1.33mmol)和4-甲氧基苯胺(0.98g,7.96mmol)按照实施例2方法合成。m.p.169-170℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),6.95(S,1H,CH),5.00(S,1H,NH),3.85(s,3H,OCH3).HRMS(ESI):calcdforC22H15BrN2O2[M+H]+419.0317,found419.0296.
实施例52
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲哚-6H-酮(CPUY074040)
本品由3-溴-5-((4-甲氧基苯基)氨基)-二苯并[cd,g]-吲哚-6H-酮(实施例51,0.31g,0.74mmol)和N-甲基哌嗪(0.48mL,4.44mmol)按照实施例12方法合成。m.p.197-198℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),6.95(s,1H,CH),5.00(s,1H,NH),3.85(s,3H,OCH3),2.54-2.49(m,4H,2CH2),2.45-2.32(m,4H,2CH2),1.14(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H26N4O2[M+H]+439.2089,found439.2056.
实施例53
3,5-二溴-6H-蒽[1,9-cd]异噻唑-6-酮的制备
本品由6H-蒽[1,9-cd]异噻唑-6-酮(1g,4.21mmol)和液溴(0.54mL,10.54mmol)按照实施例1方法合成。m.p.250-252℃.1HNMR(300MHz,CDCl3):δ8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH).HRMS(ESI):calcdforC14H5Br2NOS[M+H]+393.8459,found394.8438.
实施例54
3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异噻唑-6-酮的制备
本品有3,5-二溴-6H-蒽[1,9-cd]异噻唑-6-酮(实施例53,0.5g,1.27mmol)和4-甲氧基苯胺(0.94g,7.59mmol)按照实施例2方法合成。m.p.170-171℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,OCH3).HRMS(ESI):calcdforC21H13BrN2O2S[M+H]+436.9881,found436.9861.
实施例55
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异噻唑-6-酮(CPUY074041)
本品由3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异噻唑-6-酮(实施例54,0.31g,0.71mmol)和N-甲基哌嗪(0.47mL,4.25mmol)按照实施例12方法合成。m.p.187-188℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,OCH3),2.55-2.38(m,4H,2CH2),2.43-2.31(m,4H,2CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC26H24N4O2S[M+H]+456.1620,found456.1654.
实施例56
10-甲硫基-3,5-二溴-6H-蒽[1,9-cd]异噻唑-6-酮的制备
本品由10-甲硫基-6H-蒽[1,9-cd]异噻唑-6-酮(1g,3.53mmol)和液溴(0.45mL,8.82mmol)按照实施例1方法合成。m.p.260-262℃.1HNMR(300MHz,CDCl3):δ8.14(d,1H,J=7.17Hz,ArH),8.10(s,1H,ArH),7.64(d,J=7.23Hz,1H,ArH),7.41(t,J=7.17Hz,1H,ArH),2.53(s,3H,SCH3).HRMS(ESI):calcdforC15H7Br2NOS2[M+H]+439.8336,found439.8315.
实施例57
3-溴-5-((4-甲氧基苯基)氨基)-10-甲硫基-6H-蒽[1,9-cd]异噻唑-6-酮的制备
本品有10-甲硫基-3,5-二溴-6H-蒽[1,9-cd]异噻唑-6-酮(实施例56,0.5g,1.13mmol)和4-甲氧基苯胺(0.84g,6.80mmol)按照实施例2方法合成。m.p.188-189℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.10(d,1H,J=7.23Hz,ArH),7.64(d,J=7.23Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.41(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,OCH3),2.53(s,3H,SCH3).HRMS(ESI):calcdforC22H15BrN2O2S2[M+H]+482.9758,found482.9738.
实施例58
10-甲硫基-3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异噻唑-6-酮(CPUY074042)的制备
本品由10-甲硫基-3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[1,9-cd]异噻唑-6-酮(实施例57,0.31g,0.64mmol)和N-甲基哌嗪(0.43mL,3.85mmol)按照实施例12方法合成。m.p.197-198℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.10(d,1H,J=7.23Hz,ArH),7.64(d,J=7.23Hz,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.41(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,OCH3),2.55-2.38(m,4H,2CH2),2.53(s,3H,SCH3),2.43-2.31(m,4H,2CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H26N4O2S2[M+H]+503.1497,found503.1531.
实施例59
3,5-二溴乙烯合蒽-6(1H)-酮的制备
本品由乙烯合蒽-6(1H)-酮(1g,4.58mmol)和液溴(0.57mL,11.45mmol)按照实施例1方法合成。m.p.244-246℃.1HNMR(300MHz,CDCl3):δ7.89(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),6.42(s,1H,CH),2.90(s,2H,CH2).HRMS(ESI):calcdforC16H9Br2O[M+H]+375.9020,found275.9000.
实施例60
3-溴-5-((4-甲氧基苯基)氨基)乙烯合蒽-6(1H)-酮的制备
3,5-二溴乙烯合蒽-6(1H)-酮(实施例59,0.5g,1.33mmol)和4-甲氧基苯胺(0.98g,7.98mmol)按照实施例2方法合成。m.p.168-169℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),7.89(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),6.74(d,J=7.17Hz,1H,ArH),6.42(s,1H,CH),6.33(d,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,OCH3),2.90(s,2H,CH2).HRMS(ESI):calcdforC23H17BrNO2[M+H]+419.0443,found419.0422.
实施例61
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)乙烯合蒽-6(1H)-酮(CPUY074043)
本品由3-溴-5-((4-甲氧基苯基)氨基)乙烯合蒽-6(1H)-酮(实施例60,0.31g,0.74mmol)和N-甲基哌嗪(0.49mL,4.45mmol)按照实施例12法合成。m.p.170-171℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),7.89(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),6.74(d,J=7.17Hz,1H,ArH),6.42(s,1H,CH),6.33(d,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.83(s,3H,OCH3),2.90(s,2H,CH2).2.55-2.38(m,4H,2CH2),2.43-2.31(m,4H,2CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC28H27N3O2[M+H]+438.2103,found438.2137.
实施例62
3,5-二溴-6H-蒽[9,1-bc]噻吩-6-酮的制备
本品由6H-蒽[9,1-bc]噻吩-6-酮(1g,4.23mmol)和液溴(0.54mL,10.58mmol)按照实施例1方法合成。m.p.259-260℃.1HNMR(300MHz,CDCl3):δ8.34(d,J=7.23Hz,1H,ArH),8.10(s,1H,ArH),7.89(d,1H,J=7.17Hz,ArH),7.70(t,J=7.23Hz,1H,ArH),7.61(s,1H,CH),7.51(t,J=7.17Hz,1H,ArH),7.61(s,1H,CH).HRMS(ESI):calcdforC15H6Br2OS[M+H]+392.8506,found392.8496.
实施例63
3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[9,1-bc]噻吩-6-酮的制备
本品由3,5-二溴-6H-蒽[9,1-bc]噻吩-6-酮(实施例62,0.5g,1.27mmol)和4-甲氧基苯胺(0.94g,7.61mmol)按照实施例2方法合成。m.p.167-168℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.61(s,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,OCH3)HRMS(ESI):calcdforC22H14BrNO2S[M+H]+435.9929,found435.9908.
实施例64
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)6H-蒽[9,1-bc]噻吩-6-酮(CPUY074044)
本品由3-溴-5-((4-甲氧基苯基)氨基)-6H-蒽[9,1-bc]噻吩-6-酮(实施例63,0.31g,0.71mmol)和N-甲基哌嗪(0.47mL,4.26mmol)按照实施例13方法合成。m.p.201-203℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),8.34(d,1H,J=7.23Hz,ArH),8.10(s,1H,ArH),7.89(d,J=7.23Hz,1H,ArH),7.70(t,J=7.17Hz,1H,ArH),7.61(s,1H,ArH),7.55(d,J=7.25Hz,1H,ArH),7.51(t,J=7.17Hz,1H,ArH),7.02(d,J=7.01Hz,1H,ArH),6.79(s,1H,ArH),3.85(s,3H,OCH3),2.55-2.38(m,4H,2CH2),2.43-2.31(m,4H,2CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H25N3O2S[M+H]+456.1667found456.1701.
实施例65
3,5-二溴甲萘酚[1,2,3-cd]吲哚-6(1H)-酮的制备
本品由甲萘酚[1,2,3-cd]吲哚-6(1H)-酮(1g,4.56mmol)和液溴(0.58mL,11.40mmol)按照实施例1方法合成。m.p.148-149℃.1HNMR(300MHz,CDCl3):δ7.94(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),2.00(s,2H,CH2).HRMS(ESI):calcdforC15H7Br2NO[M+H]+375.8894,found375.8896.
实施例66
3-溴-5-((4-甲氧基苯基)氨基)甲萘酚[1,2,3-cd]吲哚-6(1H)-酮的制备
本品由3,5-二溴甲萘酚[1,2,3-cd]吲哚-6(1H)-酮(实施例65,0.5g,1.33mmol)和4-甲氧基苯胺(0.98g,7.96mmol)按照实施例2方法合成。m.p.157-158℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),7.81(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),6.74(d,J=7.25Hz,1H,ArH),6.33(d,J=7.17Hz,1H,ArH),3.85(s,3H,OCH3),2.00(s,2H,CH2).HRMS(ESI):calcdforC22H15BrN2O2[M+H]+419.0317,found419.0296.
实施例67
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)甲萘酚[1,2,3-cd]吲哚-6(1H)-酮(CPUY074045)
本品由3-溴-5-((4-甲氧基苯基)氨基)甲萘酚[1,2,3-cd]吲哚-6(1H)-酮(实施例66,0.31g,0.74mmol)和N-甲基哌嗪(0.49mL,4.44mmol)按照实施例12方法合成。m.p.191-193℃.1HNMR(300MHz,CDCl3):δ11.30(s,1H,NH),7.81(s,1H,ArH),7.68(t,1H,J=7.17Hz,ArH),7.57(d,J=7.23Hz,1H,ArH),7.52(t,J=7.17Hz,1H,ArH),7.36(d,J=7.23Hz,1H,ArH),6.74(d,J=7.25Hz,1H,ArH),6.33(d,J=7.17Hz,1H,ArH),3.85(s,3H,OCH3),2.55-2.38(m,4H,2CH2),2.43-2.31(m,4H,2CH2),2.00(s,2H,CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC27H26N4O2[M+H]+439.2056found439.2089.
实施例68
3,5-二溴-6H-蒽[9,1-cd]异恶唑-6-酮的制备
本品由6H-蒽[9,1-cd]异恶唑-6-酮(1g,4.52mmol)和液溴(0.58mL,11.40mmol)按照实施例1方法合成。m.p.247-248℃.1HNMR(300MHz,CDCl3):δ8.45(d,J=7.71Hz,1H,ArH),8.08(d,J=7.5Hz,1H,ArH),7.97(s,1H,ArH),7.82(t,J=7.23Hz,1H,ArH),7.72(t,J=7.35Hz,ArH).HRMS(ESI):calcdforC14H5Br2NO2[M+H]+377.8760,found377.8752.
实施例69
3-溴-5-((4-甲氧基苯基)氨基)6H-蒽[9,1-cd]异恶唑-6-酮的制备
本品由3,5-二溴-6H-蒽[9,1-cd]异恶唑-6-酮(实施例68,0.10g,0.26mmol)和对甲氧基苯胺(0.19g,1.58mmol)按照实施例2方法合成。m.p.156-157℃.1HNMR(300MHz,CDCl3):δ11.32(s,1H,NH),8.58(d,J=7.23Hz,1H,ArH),8.18(d,J=7.23Hz,ArH),7.82(t,J=7.47Hz,1H,ArH),7.70(t,J=8.01Hz,1H,ArH),7.62(s,1H,ArH),7.30(d,J=8.79Hz,2H,ArH),7.05(d,J=8.85Hz,2H,ArH),3.91(s,3H,CH3).HRMS(ESI):calcdforC21H13BrN2O3[M+H]+421.0182,found421.0186.
实施例70
3-(4-甲基哌嗪-1-基)-5-((4-甲氧基苯基)氨基)6H-蒽[9,1-cd]异恶唑-6-酮(CPUY074046)
本品由3-溴-5-((4-甲氧基苯基)氨基)6H-蒽[9,1-cd]异恶唑-6-酮(实施例69,0.31g,0.73mmol)和N-甲基哌嗪(0.47mL,4.39mmol)按照实施例12方法合成。m.p.191-193℃.1HNMR(300MHz,CDCl3):δ11.32(s,1H,NH),8.58(d,J=7.23Hz,1H,ArH),8.18(d,J=7.23Hz,ArH),7.82(t,J=7.47Hz,1H,ArH),7.70(t,J=8.01Hz,1H,ArH),7.62(s,1H,ArH),7.30(d,J=8.79Hz,2H,ArH),7.05(d,J=8.85Hz,2H,ArH),3.91(s,3H,CH3),2.55-2.38(m,4H,2CH2),2.43-2.31(m,4H,2CH2),1.16(t,J=7.17Hz,3H,CH3).HRMS(ESI):calcdforC26H24N4O3[M+H]+441.1848found441.1882.
Claims (9)
1.通式(I)的化合物或其药学上可接受的盐:
其中Ar代表
W代表C、N、O或S;
L代表C1-C6的碳链;
R1代表卤素、羟基、-NRaRb、硝酸酯基、硫氰基、C1-C6烷氧基、C2-C6不饱和烯氧基、C1-C6烷基酰氧基或取代的C6-C8苯基酰氧基,所述取代基是氢、卤素、甲氧基、硝基、羟基或NRaRb;
R2代表-NRaRb、被0-2个Z取代基取代的苯基、含有1-2个选自N、O或S的五元、六元饱和或不饱和杂环或者含有该不饱和杂环的苯并杂环,其中取代基Z基是卤素、氨基、羟基、硝基、氰基、羧基、C1-C6的烷基、C1-C6的烷氧基或C1-C6的烷基胺基;
Ra、Rb各自独立代表H、C1-C6烷基、C1-C6羟烷基或C1-C6烷酰基;或Ra、Rb连接形成含有1-2个N或O原子的5-6元杂环;
R3代表单、双或三取代,取代基为H、卤素、C1-C3烷氧基或C1-C3烷硫基。
2.权利要求1的化合物或其药学上可接受的盐,其中Ar代表
3.权利要求1的化合物或其药学上可接受的盐,其中R1代表-NRaRb,Ra、Rb各自独立地代表H、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、***啉基、哌嗪基、N-甲基哌嗪基、N-甲基高哌嗪基、N-乙基哌嗪基,N-丙基哌嗪基、N-异丙基哌嗪基、N-环戊基哌嗪基、N-环己基哌嗪基、N-苯基哌嗪基、N-苄基哌嗪基或N-嘧啶基哌嗪基。
4.权利要求1的化合物或其药学上可接受的盐,其中R2代表-NRaRb,Ra、Rb各自独立地代表H、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、***啉基、哌嗪基、N-甲基哌嗪基、N-甲基高哌嗪基、N-乙基哌嗪基、N-丙基哌嗪基、N-异丙基哌嗪基、N-环戊基哌嗪基、N-环己基哌嗪基、N-苯基哌嗪基、N-苄基哌嗪基;或2-氟苯基、3-氟苯基、4-氟苯基,2,4-二氟苯基、4-甲基苯基、4-甲氧基苯基、4-三氟甲氧基苯基,2-氯苯基、3-氯苯基、4-氯苯基,2,4-二氯苯基或3-氟-4-氯苯基。
5.权利要求1的化合物或其药学上可接受的盐,其中R3代表单、双或三取代基,取代基选自氢、氯、甲氧基或甲硫基。
6.权利要求1的化合物或其药学上可接受的盐,是下列任一结构的化合物或其药学上可接受的盐:
7.一种药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
8.权利要求1的化合物或其药学上可接受的盐用于制备治疗组蛋白甲基转移酶活性失调而导致的疾病的药物的用途。
9.权利要求8的用途,其中组蛋白甲基转移酶失调而导致的疾病是肿瘤、白血病、神经***疾病或疟疾。
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Application publication date: 20151230 |