CN108135871B - 阻断疾病的泛素化-蛋白酶体系统的胺萘醌化合物及医药组合物 - Google Patents
阻断疾病的泛素化-蛋白酶体系统的胺萘醌化合物及医药组合物 Download PDFInfo
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- CN108135871B CN108135871B CN201580081988.1A CN201580081988A CN108135871B CN 108135871 B CN108135871 B CN 108135871B CN 201580081988 A CN201580081988 A CN 201580081988A CN 108135871 B CN108135871 B CN 108135871B
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及用于阻断疾病的泛素化‑蛋白酶体系统的具有低细胞毒性的新颖化合物。因此,这些化合物可用于治疗包括(但不限于)癌症、神经退化疾病、发炎病症、自体免疫病症及代谢失调的病症。
Description
技术领域
本发明涉及鉴别用于治疗病症的新药物目标。具体而言,本发明涉及用于阻断疾病的泛素化-蛋白酶体系统的具有低细胞毒性的新药物目标。
背景技术
癌症是体内细胞生长失控的疾病。大多数目前癌症治疗方法对人体造成严重一般毒性。辐射及化学疗法对宿主均具有有害效应,引起显著发病率及死亡率。因此,业内需要治疗癌症及预防肿瘤生长的非侵入性且无毒的方法。然而,癌症无法有效治愈。因此,业内需要研发有效治疗癌症但具有低细胞毒性的化合物。
发炎是保护哺乳动物免受侵入病原体影响的机制。然而,尽管短暂发炎对保护哺乳动物免受感染而言是必要的,但不受控发炎造成组织损坏且是许多病患的根本病因。发炎通常是通过抗原结合至T细胞抗原受体起始。通过T细胞的抗原结合起始钙经由钙离子通道(例如Ca2+释放活化型Ca2+通道(CRAC))流入细胞中。钙离子流入又起始信号传导级联从而引起这些细胞的活化及特征在于细胞介素产生的发炎反应。过度产生除IL-2以外的促炎性细胞介素亦已与许多自体免疫疾病相关。因此,业内持续需要克服目前用于治疗或预防发炎病症、过敏病症及自体免疫病症的药物的缺点中的一或多者的新药。
蛋白酶体是细胞调控特定蛋白质的浓度及降解错误折迭蛋白质的主要机制的一部分。蛋白酶体是所有真核细胞共有的大的环形或圆柱形多组份复合物。蛋白酶体是大的多亚单位蛋白酶复合物,其位于细胞核及胞质液中,其选择性地降解细胞内蛋白质。蛋白酶体在参与细胞循环、增殖及细胞凋亡的许多蛋白质的降解中起主要作用。其具有至少三种不同的肽链内切酶活性,这些活性包括水解疏水性、碱性及酸性氨基酸残基的羧基侧上的肽键。蛋白酶体藉助其蛋白质降解活性已参与若干重要细胞功能,包括DNA修复、细胞循环进展、信号转导、转录及抗原呈递。
蛋白酶体抑制代表癌症治疗的重要的新策略。US 7,442,830、US 8,003,819及US8,058,262涉及可用作蛋白酶体抑制剂的硼酸及硼酸酯化合物。US 8,389,564提供用于治疗及/或改善疾病或病况(例如癌症、微生物疾病及/或发炎)的嗜盐放线菌酰胺(salinosporamide)。WO 2010/005534提供作为蛋白酶体的抑制剂具有活性的化合物。
然而,业内持续需要蛋白酶体的新颖及/或有所改良的抑制剂。
发明内容
本发明的一个态样是提供具有下式(I)的化合物:
或其互变异构物、立体异构物或镜像异构物,或其溶剂合物、前药或医药上可接受的盐。
本发明的另一态样是提供含有式(I)化合物的医药组合物。
另一态样是提供抑制ITCH E3连接酶的方法,其包含向细胞或个体投与式(I)化合物。
再一态样是提供治疗癌症的方法,其包含向细胞或个体投与式(I)化合物。
再一态样是提供治疗自体免疫病症的方法,其包含向细胞或个体投与式(I)化合物。
图式简单说明
图1显示本发明的MPT0L056有效阻断ITCH自泛素化。
图2显示MPT0L056在0.5μm及5μm的浓度下阻断ITCH的活体内自泛素化。
图3显示MPT0L056在人类PRMI8226多发性骨髓瘤异种移植物模型中的抗癌活性。
图4显示MPT0L056并未显著影响动物体重。
图5显示MPT0L056在人类MDA-MB-231乳腺癌异种移植物模型中的抗癌活性。
图6显示MPT0L056并未显著影响动物体重。
图7显示MPT0L056在人类A2780卵巢腺癌异种移植物模型中的抗癌活性。
图8显示MPT0L056并未显著影响动物体重。
图9显示研究中的个别肿瘤生长曲线。
图10显示研究中的个别动物体重变化。
图11显示研究中小鼠的个别终点时间。
图12显示TMU-HCT-116-e0001研究中的中值肿瘤生长。
图13显示MPT0L056对鼠类RAW264.7巨噬细胞中的IL-6产生的效应。
图14显示MPT0L056对人类RAFLS(类风湿性关节炎纤维母细胞样滑膜细胞)细胞中的IL-6产生的效应。
图15显示佐剂诱导的关节炎(AIA)模型中使用微CT扫描MPT0L056抑制关节炎的发生。
图16显示MPT0L056展现爪肿胀的显著减轻。
图17显示利用MPT0L056治疗可在AIA模型中预防骨矿物质密度(BMD)及骨矿物质含量(BMC)损失。
具体实施方式
本发明涉及用于阻断疾病的泛素化-蛋白酶体系统的具有低细胞毒性的新颖化合物。因此,这些化合物可用于治疗包括(但不限于)癌症、发炎病症及自体免疫病症的病症。
定义及术语
本文中未明确定义的术语应根据熟习此项技术者根据揭示内容及上下文会给予的含义来理解。然而,除非指定相反含义,否则如说明书中所用的以下术语具有根据以下惯例所指示的含义。
术语“一(a及an)”是指一或多个。
术语“疾病”及“病症”在本文中可互换使用。
术语“治疗(treatment及treating)”涵盖预防性(即防御性)或治疗性(即治愈性及/或姑息性)治疗。因此,术语“治疗(treatment及treating)”包含对已发生所述病况、具体而言呈显性形式的患者的治疗性治疗。治疗性治疗可是对症治疗以便减轻具体适应症的症状,或病因治疗以便逆转或部分地逆转适应症的病况或停止或减慢疾病的进展。因此,本发明的化合物、组合物及方法可用作(例如)经一段时间的治疗性治疗以及用于长期疗法。另外,术语“治疗(treatment及treating)”包含防御性治疗,即治疗具有发生上文所提及病况的风险的患者,由此降低所述风险。
术语“治疗有效量”意指本发明化合物(i)治疗或预防特定疾病或病况,(ii)减弱、改善或消除特定疾病或病况的一或多种症状,或(iii)预防或延迟本文所述特定疾病或病况的一或多种症状发作的量。
如本文所用术语“经取代”意指,指定原子、基团或部分上的任何一或多个氢经选自指示基团者替代,前提是不超过所述原子的正常化合价,且所述取代产生可接受的稳定化合物。
术语“医药上可接受的”在本文中用以指那些在合理医学判断范围内适用于与人类及动物组织接触且无过大毒性、刺激性、过敏反应或其他问题或并发症且与合理益处/风险比相称的化合物、材料、组合物及/或剂型。
如本文所用“医药上可接受的盐”是指所揭示化合物的衍生物,其中通过制备其酸式或碱式盐来改质母体化合物。医药上可接受的盐的实例包括(但不限于)碱性残基(例如胺、吡啶、嘧啶及喹唑啉)的无机酸盐或有机酸盐;酸性残基(例如羧酸)的碱性盐或有机盐;及诸如此类。
如本文所用术语“立体异构物”是仅在其原子在空间中的定向上不同的个别分子的所有异构物的一般术语。其包括镜像异构物及不为彼此的镜像且具有超过一个手性中心的化合物的异构物(非镜像异构物)。
术语“手性中心”是指四个不同基团所附接的碳原子。
术语“镜像异构物(enantiomer及enantiomeric)”是指在其镜像上无法迭加且因此具有光学活性的分子,其中镜像异构物使偏振光的平面在一个方向上旋转且其镜像化合物使偏振光的平面在相反方向上旋转。
术语“外消旋”是指光学无活性的等份镜像异构物的混合物。
术语“拆分”是指分子的两种镜像异构物形式中的一者的分离或浓集或空乏。
如本文所使用,卤基或卤素是指氟基、氯基、溴基或碘基。
如本文所用术语“烷基”是指含有指定数量碳原子的直链或具支链烃链。举例而言,“C1-C6烷基”是选自具有1至6个碳原子的直链及具支链非环烃。代表性直链C1-C6烷基包括-甲基、-乙基、-正丙基、-正丁基、-正戊基及-正己基。代表性具支链C1-C6烷基包括-异丙基、-第二丁基、-异丁基、-第三丁基、-异戊基、-新戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、3-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基及3,3-二甲基丁基。
如本文所用术语“烯基”是指含有指定数量碳原子及一或多个双键的直链或具支链烃链。举例而言,“C2-C6烯基”选自具有2至6个碳原子且包括至少一个碳-碳双键的直链及具支链非环烃。代表性直链及具支链C2-C6烯基包括-乙烯基、-烯丙基、-1-丁烯基、-2-丁烯基、-异丁烯基、-1-戊烯基、-2-戊烯基、-3-甲基-1-丁烯基、-2-甲基-2-丁烯基、-2,3-二甲基-2-丁烯基、-1-己烯基、2-己烯基及3-己烯基。
如本文所用术语“炔基”是指含有指定数量碳原子及一或多个三键的直链或具支链链烃链。举例而言,“C2-C6炔基”选自具有2至6个碳原子且包括至少一个碳-碳三键的直链及具支链非环烃。代表性直链及具支链C2-C6炔基包括-乙炔基、-丙炔基、-1-丁炔基、-2-丁炔基、-1-戊炔基、-2-戊炔基、-3-甲基-1-丁炔基、-4-戊炔基、-1-己炔基、-2-己炔基及-5-己炔基。
术语“C1-n-伸烷基”(其中n是1至n的整数)在单独或与另一基团组合时表示含有1至n个碳原子的非环直链或具支链二价烷基。举例而言,术语C1-4-伸烷基包括--(CH2)--、--(CH2--CH2)--、--(CH(CH3))--、--(CH2--CH2--CH2)--、--(C(CH3)2)--、--(CH(CH2CH3))--、--(CH(CH3)--CH2)--、--(CH2--CH(CH3))--、--(CH2--CH2--CH2--CH2)--、--(CH2--CH2--CH(CH3))--、--(CH(CH3)--CH2--CH2)--、--(CH2--CH(CH3)--CH2)--、--(CH2--C(CH3)2)--、--(C(CH3)2--CH2)--、--(CH(CH3)--CH(CH3))--、--(CH2--CH(CH2CH3))--、--(CH(CH2CH3)--CH2)--、--(CH(CH2CH2CH3))-、--(CHCH(CH3)2)--及--C(CH3)(CH2CH3)--。
如本文所用,“环烷基”是指选自C3-C12环烷基的基团,且较佳地C3-8环烷基。典型环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基及环壬基。
如本文所用,术语“杂环基”是指含有1至4个各自选自O、S及N的杂原子的基团,其中每一杂环基团在其环系统中具有4至10个原子,且其中所述基团的环不含两个毗邻的O或S原子。典型杂环基的实例是吡咯啶基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫吡喃基、六氢吡啶基、环丁砜基、吗啉基、硫吗啉基、噻恶烷基、六氢吡嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高六氢吡啶基、氧杂环庚基、硫杂环庚基、氧氮基、二氮基、硫氮基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二恶烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、二氢喹唑啉基、吡唑啶基、咪唑啉基、咪唑啶基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基及喹嗪基。
如本文所用术语“烷氧基”是指含有指定数量碳原子的直链或具支链烷氧基。举例而言,C1-6烷氧基意指含有至少1个且至多6个碳原子的直链或具支链烷氧基。如本文所用“烷氧基”的实例包括(但不限于)甲氧基、乙氧基、丙氧基、丙-2-氧基、丁氧基、丁-2-氧基、2-甲基丙-1-氧基、2-甲基丙-2-氧基、戊氧基及己基氧基。附接点可在氧或碳原子上。
如本文所用术语“烷硫基”(亦称为烷基硫基)是指在烷基中的任一键处经由硫原子结合至分子的剩余部分的直链或具支链烷基(较佳地具有1至6个碳原子,例如1至4个碳原子(C1-C6-烷硫基)。C1-C4-烷硫基的实例包括甲硫基、乙基硫基、正丙基硫基、异丙基硫基、正丁基硫基、第二丁基硫基、异丁基硫基及第三丁基硫基。C1-C6-烷硫基的实例除针对C1-C4-烷硫基所提及的那些以外包括1-戊基硫基、2-戊基硫基及3-戊基硫基、1-己基硫基、2-己基硫基及3-己基硫基及其位置异构物。
如本文所用术语“烷氧基烷基”是指基团-alk1-O-alk2,其中alk1是烷基或烯基,且alk2是烷基或烯基。
如本文所用术语“烷基胺基”是指基团--NRR′,其中R是烷基且R′是氢或烷基。
如本文所用,“芳基”是指选自C6-14芳基的基团,尤其C6-10芳基。典型C6-14芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、联苯、苯蒽基(biphenylenyl)及茀基。
如本文所用,“杂芳基”是指具有5至14个环原子、在环状阵列中共有6个、10个或14个π电子且含有碳原子及1个、2个或3个氧、氮及/或硫杂原子的基团。杂芳基的实例包括吲唑基、呋喃基、噻吩基、吡咯基、咪唑基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、吡啶基、嗒嗪基、嘧啶基、吡嗪基、四唑基、三嗪基、氮基、氧氮呯基、吗啉基、硫氮基、二氮基、噻唑啉基、苯并咪唑基、苯并恶唑基、咪唑并吡啶基、苯并恶嗪基、苯并噻嗪基、苯并噻吩基、恶唑并吡啶基、苯并呋喃基、喹啉基、喹唑啉基、喹喏啉基、苯并噻唑基、邻苯二甲酰亚胺基、苯并呋喃基、苯并二氮基、吲哚基、二氢茚基、氮杂吲唑基、去氮嘌呤基及异吲哚基。
如本文所用术语“胺基(amino或amino group)”是指--NH2。
如本文所用术语“视情况经取代”是指未经取代或经一或多个取代基取代的基团。举例而言,倘若基团C1-C6烷基、C2-C6烯基、C2-C6炔基、--O--C1-C6烷基、--O--C2-C6烯基及--O--C2-C5炔基是作为视情况经取代提及,则其可经取代或可不经取代。倘若经取代,则其可经选自由以下各项组成的群的基团取代:卤基、卤基(C1-6)烷基、(卤基)2(C1-6)烷基、(卤基)3(C1-6)烷基、芳基、杂芳基、环烷基、杂环烷基、C1-6烷基、C2-6烯基、C2-6炔基、芳基(C1-6)烷基、芳基(C2-6)烯基、芳基(C2-6)炔基、环烷基(C1-6)烷基、杂环(C1-6)烷基、羟基(C1-6)烷基、胺基(C1-6)烷基、羧基(C1-6)烷基、烷氧基(C1-6)烷基、硝基、胺基、脲基、氰基、烷基羰基胺基、羟基、硫醇、烷基羰基氧基、迭氮基、烷氧基、羧基、胺基羰基及C1-6烷硫醇。较佳可选取代基包括卤基、卤基(C1-6)烷基、(卤基)2(C1-6)烷基、(卤基)3(C1-6)烷基、羟基(C1-6)烷基、胺基(C1-6)烷基、羟基、硝基、C1-6烷基、C1-6烷氧基及胺基。可选取代基的较佳数量为1、2或3。
本发明化合物或其互变异构物或立体异构物或其溶剂合物、前药或医药上可接受的盐
在一态样中,本发明提供具有下式(I)的化合物:
其中
R1是卤素、C1-10烷基、C2-10烯基、C2-10炔基、NH2、NO2、OH或CN;
每一R2相同或不同,代表H、C1-10烷基、C2-10烯基、C2-10炔基、NH2、NO2、C1-10烷基氧基、C1-10烷硫基、C1-10烷基胺基、C1-10烷基氧基C1-10烷基、OH或CN、C6-10芳基或具有1至3个选自由N、O及S组成的群的杂原子的C5-7杂环;
R3是H、C1-10烷基、C2-10烯基、C2-10炔基、NH2、NO2、OH或CN;
当Y是-N-时,R4是H、C1-10烷基、C2-10烯基、C2-10炔基、NH2、NO2、OH或CN,或当Y是-C-时,R4连同其所附接的碳原子及R5形成具有0至3个选自O、N及S的杂原子的C5-7杂环或具有0至3个选自O、N及S的杂原子的杂稠合二环;
R5为不存在、OH、C3-10环烷基、C6-10芳基、具有0至3个选自O、N及S的杂原子的C5-7杂环或具有0至3个选自O、N及S的杂原子的C10-12稠合杂环,环烷基、芳基、杂环及稠合杂环中的每一者未经取代或经以下各项中的一至三者取代:OH;卤素;NH2;NO2、CN、C1-10烷基;C2-10烯基;C2-10炔基;C1-10烷基氧基;具有1至3个选自由N、O及S组成的群的杂原子的C5-10杂芳基,其未经取代或经C1-10烷基、C2-10烯基、C2-10炔基、OH、卤素、CN、NH2或NO2取代;-S(O)2-苯基,其中所述苯基未经取代或经卤素、OH、CN、NH2、NO2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷基氧基取代;-C(O)NHOH;-C(O)NH2;-C(O)-苯基,其中苯基未经取代或经1至5个选自由OH、卤素、CN、NH2、NO2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷基氧基组成的群的相同或不同取代基取代;-C(O)NRaRb;NHS(O)2苯基,其中苯基视情况经OH、卤素、CN、NH2、NO2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷基氧基取代;C1-10伸烷基-杂芳基;-S(O)2-杂芳基;-S(O)2-杂环;-S(O)2N(H)-杂芳基;-伸烷基-N(H)-杂芳基;杂环,其未经取代或经C1-10烷基取代;且
Ra及Rb相同或不同,独立地代表H;OH;烷基;烯基;炔基;烷基氧基;环烷基;杂环基;伸烷基胺基;伸烷基-N-(烷基)2;芳基,其未经取代或经OH、卤素、CN、NH2、NO2、烷基、烯基、炔基、烷基氧基或杂芳基取代;杂芳基,其未经取代或经OH、卤素、CN、NH2、NO2、烷基、烯基、炔基或烷基氧基取代;伸烷基-杂芳基;或伸烷基-杂环基,其未经取代或经烷基取代;
X是-C(O)-、-S(O)2-或-NH-C(O)-;
Y是-C-或-N-;
m是0至3的整数;且
n为0至7的整数;
或其互变异构物、立体异构物或镜像异构物或其溶剂合物、前药或医药上可接受的盐。
在式(I)的一些实施例中,m是0;R1是卤素;n是1至4的任一整数;R3是H;X是-C(O)-;Y是-N-;R4是H;且R5是OH;C3-8环烷基;苯基,其未经取代或经一至三个选自OH、CN、卤素、NH2或C1-4烷基六氢吡嗪基的相同或不同的取代基取代;C1-6烷基六氢吡嗪基;C1-6烷基吡啶基;C1-6烷基吡咯啶基;吡啶基;嘧啶基;吡嗪基;六氢吡嗪基;吡咯啶基;噻唑基;苯并咪唑基;吡唑基;吲唑基;吡唑基;喹啉基;吲哚基;C1-4吲哚基;吲唑基;氮杂吲哚基;氮杂吲唑基;去氮嘌呤基;二氢茚基;吗啉酰基或C1-4烷基吗啉酰基,其中的每一者未经取代或经一个、两个或三个选自OH、CN、卤素或NH2的基团取代。
在式(I)的一些实施例中,m是0;R1是卤素;n是1至2的任一整数;R3是H;X是-C(O);Y是-N-;R4是H;且R5是OH;C3-8环烷基;吡啶基;苯基,其经经NH2、卤素、OH、CN或C1-4烷基六氢吡嗪基中的一至三者取代;嘧啶基,其未经取代或经NO2、NH2或C1-4烷基取代;吡嗪基,其未经取代或经NO2、NH2或C1-4烷基取代;噻唑基,其未经取代或经NO2、NH2或C1-4烷基取代;苯并咪唑基,其未经取代或经NO2、NH2或C1-4烷基取代;吡唑基,其未经取代或经NO2、NH2或C1-4烷基取代;吲唑基,其未经取代或经NO2、NH2或C1-4烷基取代;噻唑基,其未经取代或经NO2、NH2或C1-4烷基取代;喹啉基,其未经取代或经NO2、NH2或C1-4烷基取代;吲哚基,其未经取代或经NO2、NH2或C1-4烷基取代;吲唑基,其未经取代或经NO2、NH2或C1-4烷基取代;氮杂吲唑基,其未经取代或经NO2、NH2或C1-4烷基取代;去氮嘌呤基,其未经取代或经NO2、NH2或C1-4烷基取代;二氢茚基,其未经取代或经NO2、NH2或C1-4烷基取代;或吗啉酰基,其未经取代或经NO2、NH2或C1-4烷基取代。
在式(I)的一些实施例中,m是0;n是0;X是-C(O);Y是-N-;R1是卤素或C1-4烷基;R3是H;R4是H或C1-4烷基;且R5是吡啶基、吡嗪基或嘧啶基。
在式(I)的一些实施例中,m是0;n是0;X是-C(O);Y是-N-;R1是卤素;R3是H;R4是H;且R5是吡啶基、吡嗪基、或嘧啶基。
在式(I)的一些实施例中,m是0;n是0;X是-NHC(O)-;Y是-C-;R1是卤素或C1-4烷基;R3是H;且R4连同其所附接的碳原子及R5一起形成具有0至3个选自O的杂原子的C5-7杂环。较佳地,稠合C5-7杂环是吡啶基。
在式(I)的一些实施例中,m是0;n是0;X是S(O)2;Y是-N-;R1是卤素或C1-4烷基;R3是H;且R4连同其所附接的氮原子及R5形成稠合二环。较佳地,稠合二环是吲哚基或氮杂吲哚基。
在式(I)的一些实施例中,这些化合物包括(但不限于)以下化合物:
本文所揭示的本发明亦涵盖所揭示化合物的前药。前药视为在活体内释放活性式(I)化合物的任何共价键结的载剂。前药的非限制性实例包括式(I)化合物的酯,且这些可通过使这些化合物与酸酐(例如琥珀酸酐)反应来制备。
本文所揭示的本发明亦涵盖所揭示化合物的医药上可接受的盐。在一个实施例中,本发明包括所揭示化合物的任何及所有无毒的医药上可接受的盐,包含无机及有机酸加成盐及碱盐。本发明的医药上可接受的盐可通过习用化学方法自含有碱性或酸性部分的母体化合物来合成。通常,这些盐可通过使这些化合物的游离酸或碱形式与足量的适当碱或酸于水或有机稀释剂(如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。举例而言,这些盐包括乙酸盐、抗坏血酸盐、苯磺酸盐(benzenesulfonate)、苯甲酸盐、苯磺酸盐(besylate)、碳酸氢盐、酒石酸氢盐、溴化物/氢溴酸盐、乙二胺四乙酸钙/乙二胺四乙酸盐、右旋樟脑磺酸盐、碳酸盐、氯化物/盐酸盐、柠檬酸盐、乙二磺酸盐、乙烷二磺酸盐、依托酸盐(estolate)、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、麸胺酸盐、乙醇酸盐、乙醇酰基对胺基苯砷酸盐、己基间苯二酚盐、哈胺(hydrabamine)、羟基马来酸盐、羟基萘甲酸盐、碘化物、异硫代羟酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、苦杏仁酸盐、甲烷磺酸盐、甲磺酸盐、甲基溴、甲基硝酸盐、甲基硫酸盐、黏酸盐、萘磺酸盐、硝酸盐、草酸盐、双羟萘酸盐、泛酸盐、苯基乙酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、丙酸盐、柳酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、磺酰胺、硫酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘化物、铵、苄星青霉素(benzathine)、氯普鲁卡因(chloroprocaine)、胆碱、二乙醇胺、乙二胺、葡甲胺及普鲁卡因。其他医药上可接受的盐可利用金属(如铝、钙、锂、镁、钾、钠、锌及诸如此类)的阳离子形成。(参见Pharmaceutical salts,Birge,S.M.等人,J.Pharm.Sci.,(1977),66,1-19)。
本文所揭示的本发明亦涵盖所揭示化合物的溶剂合物。一种类型的溶剂合物是水合物。溶剂合物通常不显著有助于化合物的生理活性或毒性且因此可用作药理学等效物。
本文所揭示的本发明亦涵盖所揭示化合物的互变异构物及异构物。给定化学式或名称应涵盖互变异构物及所有立体、光学及几何异构物(例如镜像异构物、非镜像异构物、E/Z异构物等)及其外消旋物,以及不同比例的分离镜像异构物的混合物、非镜像异构物的混合物或前述任一形式的混合物(倘若存在这些异构物及镜像异构物),以及其盐(包括医药上可接受的盐)及其溶剂合物(例如水合物),包括游离化合物的溶剂合物或所述化合物的盐的溶剂合物。
本发明化合物的制备
可鉴于本发明使用熟习此项技术者已知的方法制备本发明化合物。举例而言,可如以下方案中所显示制备本发明的较佳化合物:
方案1
*试剂及条件
(a)4-胺基甲基苯甲酸,TEA,EtOH,回流
(b)EDC,HCl,HOBt,NMM,DMF,NH2OTHP,r.t.然后10%TFA(aq.),MeOH,r.t.,对于1
(c)经取代胺,HBTU,DIPEA,DMF,r.t.,对于2-5,9-26,28-42
方案2
*试剂及条件
(a)4-(胺基甲基)-N-(吡啶-2-基)苯甲酰胺,EtOH,回流
方案3
*试剂及条件
(a)i.Boc2O,NaOH,H2O,THF,rt,
ii.吡啶,DMF,草酰氯,rt然后经取代胺,吡啶,rt
(b)TFA,r.t.然后96,回流。
方案4
*试剂及条件
(a)i.4-硝基苯甲酰氯,pyr,CH2Cl2,r.t.然后碘化烷基,NaH,DMF,r.t.ii.10%Pd/C,MeOH,H2,r.t.,对于104-105
(b)经取代的1,4-萘醌,EtOH,回流,对于51-53
(c)Pd(PPh3)4,EtOH,甲苯,K2CO3(aq.),异丙基硼酸,对于56
方案5
*试剂及条件
(a)4-硝基苯甲酰氯,pyr,CH2Cl2,r.t.然后10%Pd/C,MeOH,H2,r.t。
(b)96,EtOH,回流
方案6
*试剂及条件
(a)4-硝基苯甲酰氯,pyr,CH2Cl2,r.t.然后10%Pd/C,MeOH,H2,r.t。
(b)96,EtOH,回流
方案7
*试剂及条件
(a)SOCl2,CH2CI2,4-硝基苯胺,r.t.然后10%Pd/C,MeOH,H2,r.t。
(b)96,EtOH,回流
方案8
*试剂及条件
(a)NaH,4-硝基苯磺酰氯,DMF,r.t.,对于119
(b)NaH,4-硝基苯磺酰氯,DMF,r.t.然后Fe粉末,NH4Cl,IPA,H2O,回流,对于120
(c)Fe粉末,NH4Cl,IPA,H2O,回流然后96,EtOH,回流,对于62
(d)96,EtOH,回流,对于63
(e)98,EtOh,回流然后Pd(PPh3)4,甲苯,EtOH,K2CO3(aq.),异丙基硼酸,对于64
方案9
*试剂及条件
(a)NaH,4-硝基苯磺酰氯,DMF,r.t,对于122
(b)3-硝基苯亚磺酰氯,吡啶,50℃,对于123
(c)10%Pd/C,H2,MeOH,r.t.然后经取代的1,4-萘醌,EtOH,回流,对于65-66
(d)Fe粉末,NH4Cl,IPA/H2O,回流然后96,EtOH,回流,对于67
方案10
*试剂及条件
(a)经取代的苄基氯或磺酰氯,甲苯,回流
(b)Fe粉末,NH4Cl,IPA/H2O,回流然后96,EtOH,回流
本发明的医药组合物及治疗方法
本发明的化合物及组合物可抑制PCTK1、ROCK2、CSNK1D、JNK1、JNK3、RIOK2及DYRK1B,表明本发明化合物是治疗及/或预防肿瘤疾病、神经退化疾病、自体免疫及发炎性疾病及/或代谢失调的潜在靶标。
PCTK1属蛋白激酶的丝胺酸/苏胺酸家族的cdc2/cdkx子家族。Cdc2 p34对于脊椎动物细胞中G2至M的转变而言是必需的。基因产物的潜在作用是控制神经突过度生长(Graeser R、Gannon J、Poon RY、Dubois T、Aitken A、Hunt T.(2002)Regulation of theCDK-related protein kinase PCTAIRE-1 and its possible role in neuriteoutgrowth in Neuro-2A cells.J.Cell.Sci.,115:3479-90)。
ROCK2属丝胺酸/苏胺酸激酶的AGC(PKA/PKG/PKC)家族。其通过作用于细胞骨架主要参与调控细胞的形状及移动。最近研究已显示ROCK信号传导在许多疾病(包括糖尿病、神经退化疾病(例如帕金森氏病(Parkinson’s disease)及肌肉萎缩性脊髓侧索硬化症)、肺高血压及癌症)中起重要作用(L,FrankT等人(2012)Inhibition of rho kinaseenhances survival of dopaminergic neurons and attenuates axonal loss in amouse model of Parkinson′s disease.Brain,135(11):3355-70;Lin Yao,SurabhiChandra,Haroldo A.Toque,Anil Bhatta,Modesto Rojas,Ruth B.Caldwell,R.WilliamCaldwell,(2013)Prevention of diabetes-induced arginase activation andvascular dysfunction by Rho kinase(ROCK)knockout.Cardiovascular Research,97,509-519;Ferrer,Isidre;Mohan,Pooja;Chen,Helen;Castellsague,Joan;Gómez-Baldó,Laia;Carmona,Marga;Garcia,Nadia;Aguilar,Helena;Jiang,Jihong;Skowron,Margaretha;Nellist,Mark;Ampuero,Israel;Russi,Antonio;Lázaro,Conxi;Maxwell,ChristopherA;Pujana,MiguelAngel.(2014).Tubers from patients with tuberoussclerosis complex are characterized by changes in microtubule biology throughROCK2 signalling.The Journal of Pathology,233(3):247-57;及Kim-Ann Saal,JanC.Koch,Lars Tatenhorst,Eva M.Szego″,ViniciusToledo Ribas,Uwe Michel,MathiasLarsPaul Lingor.(201.5)AAV.shRNA-mediated downregulation ofROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced modelsof Parkinson′s disease in vitro and in vivo.Neurobiology of Disease,(73):150-162)。
CSNK1D是调控多种细胞过程(包括DNA复制及修复)的必需丝胺酸/苏胺酸-蛋白激酶。经编码蛋白质亦可参与调控细胞凋亡、昼夜节律、微管动力学、染色体分离及p53介导的对生长的效应。最近研究亦已鉴别出在CK1δ基因的突变与家族性偏头痛及进阶睡眠阶段之间的关联。亦已发现CK1δ磷酸化Tau且中断其与微管的结合且可促成AD的退化及其他失智症(Lee H,Chen R,Lee Y,Yoo S,Lee C.(2009)Essential roles of CKI and CKI in themammalian circadian clock.PNAS,106(50):21359-64;及BiswasA,Mukherjee S,Das S,Shields D,Chow CW,Maitra U.(2011)Opposing action of casein kinase l andcalcineurin in nucleo-cytoplasmic shuttling of mammalian translationinitiation factor eIF6.Journal of Biological Chemistry,286(4):3129-38)。
c-Jun N-末端激酶(JNK)属促分裂原活化的蛋白激酶(MAPK)家族,且响应应力刺激(例如细胞介素、ROS、UV辐照、热休克及渗透性休克),且促成发炎反应。其亦在T细胞分化及细胞凋亡路径中起作用。已发现JNK1通过磷酸化及活化泛蛋白连接酶Itch来调控Jun蛋白质转换。JNK1对于CD4辅助T(TH)细胞的正常活化及分化成为TH1及TH2效应细胞而言是必需的。JNK1/JNK2发现于所有细胞及组织中,而JNK3主要发现于脑中,但亦发现于心脏及罩丸中(Lufen Chang,Hideaki Kamata,Giovanni Solinas,Jun-Li Luo,Shin Maeda,K.Venuprasad,Yun-Cai Liu,Michael Karin.(2006)The E3 Ubiquitin Ligase ItchCouples JNK Activation to TNFα-induced Cell Death by Inducing c-FLIPLTurnover.Cell,124(3):601-13;Bode AM,Dong Z.(2007)The Functional Contrarietyof JNK.Mol.Carcinog.46(8):591-8;Eun Kyung Kim,Eui-Ju Choi.(2010)Pathologicalroles of MAPK signaling pathways in human diseases.Biochimica et BiophysicaActa.1802:396-405)。
RIOK2是丝胺酸/苏胺酸-蛋白激酶且在核糖体生源说中起重要作用(Liu T,DengM,Li J,TongX,Wei Q,Ye X.(2011)Phosphorylation of right open reading frame 2(Rio2)protein kinase by polo-like kinase 1 regulates mitotic progression.JBiol Chem,286(42):36352-60;及Read RD,Fenton TR,Gomez GG,Wykosky J,VandenbergSR,Babic I,Iwanami A,Yang H,Cavenee WK,Mischel PS,Furnari FB,Thomas JB.(2013)A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinasesmediate cell proliferation and survival through TORC2-Akt signaling inglioblastoma.PLoS Genet,9(2):e1003253)。
DYRK1B主要发现于肌肉及罩丸中且参与细胞核功能的调控。经编码蛋白质参与细胞循环的调控。此基因的表达在肿瘤细胞中可能有所变化,且发现此基因的突变造成腹部肥胖症-代谢症候群3(Ali R.Keramati,M.D.,Mohsen Fathzadeh,Ph.D.,Gwang-Woong Go,Ph.D.,Rajvir Singh,Ph.D.,Murim Choi,Ph.D.,Saeed Faramarzi,M.D.,Shrikant Mane,Ph.D.,Mohammad Kasaei,M.D.,Kazem Sarajzadeh-Fard,M.D.,John Hwa,M.D.,Ph.D.,Kenneth K.Kidd,Ph.D.,Mohammad A.Babaee Bigi,M.D.,Reza Malekzadeh,M.D.,AdallatHosseinian,M.D.,Masoud Babaei,M.D.,Richard P.Lifton,M.D.,Ph.D.及Arya Mani,M.D.(2014)A Form of the Metabolic Syndrome Associated with Mutations inDYRK1B.N Engl J Med,370:1909-1919)。
因此,本发明化合物是治疗及/或预防肿瘤疾病、神经退化疾病、发炎性疾病及/或代谢失调的潜在靶标。在一些实施例中,肿瘤疾病包括(但不限于)良性肿瘤及癌症。在一些实施例中,神经退化疾病包括(但不限于)ALS、帕金森氏病、阿兹海默氏病(Alzheimer’sdisease)及杭丁顿氏症(Huntington’s disease)。在一些实施例中,自体免疫及发炎性疾病包括(但不限于)胰岛素依赖性糖尿病(IDDM)、糖尿病、多发性硬化、实验自体免疫脑脊髓炎、急性弥漫性脑脊髓炎、关节炎、类风湿性关节炎、实验自体免疫关节炎、重症肌无力、甲状腺炎、桥本氏病(Hashimoto′s disease)、原发性黏液水肿、甲状腺毒症、恶性贫血、自体免疫萎缩性胃炎、艾迪生氏病(Addison′s disease)、早熟绝经、男性不育、幼年糖尿病、古巴士德氏症候群(goodpasture′s syndrome)、寻常天疱疮、类天疱疮、交感性眼炎、晶状体源性眼色素层炎、自体免疫溶血性贫血、特发性白血球减少症、原发性胆汁性肝硬化、活动性慢性肝炎Hb.sub.s-ve、隐源性硬化、溃疡性结肠炎、薛格连氏症候群(Sjogren′ssyndrome)、硬皮症、华格纳氏肉芽肿(Wegener′s granulomatosis)、多发性肌炎/皮肌炎、盘状LE、全身性红斑狼疮、克隆氏病(chron′s disease)、牛皮癣、关节黏连性脊椎炎、抗磷脂抗体症候群、再生不良性贫血、自体免疫肝炎、腹部疾病、格雷夫斯氏病(graves′disease)、格林-巴利症候群(guillain-barre syndrome,GBS)、特发性血小板减少紫斑症、斜视眼阵挛肌阵挛症候群(OMS)、视神经炎、沃德氏甲状腺炎(ORd′s thyroiditis)、天疱疮、多发性关节炎、原发性胆汁性肝硬化、赖特尔氏症候群(Reiter′s syndrome)、高安氏(Takayasu′s)、颞动脉炎、温抗体型自体免疫溶血性贫血、华格纳氏肉芽肿、普秃(alopeciauniversalis)、白塞氏病(behcet′s disease)、恰加斯氏病(chagas′disease)、慢性疲劳症候群、自主神经机能障碍、子宫内膜异位症、化脓性汗腺炎、间质性膀胱炎、神经性肌强直、类肉瘤病、硬皮症、溃疡性结肠炎、白斑病、阴唇痛症、发炎皮肤疾病、过敏接触性皮肤炎、幽门螺旋杆菌性胃炎(H.pylory gastritis)、慢性鼻发炎性疾病、动脉硬化及移植物抗宿主病。在一些实施例中,代谢失调包括(但不限于)糖尿病、高血压、胆固醇、甘油三酯含量升高、空腹血糖异常及胰岛素抗性。
本发明化合物是以有效治疗特定病症的量存于组合物中,所述特定病症包括癌症、帕金森氏病、阿兹海默氏病及杭丁顿氏症、再狭窄、发炎、类风湿性关节炎、发炎病症、由发炎引起的组织损伤、过度增殖疾病、严重或关节炎牛皮癣、肌肉消耗性疾病、慢性传染病、异常免疫反应、涉及易损斑块的病况、与缺血性病况相关的损伤及病毒感染及增殖。
本发明化合物可以不存在任何其他组份的化学原料的形式投与哺乳动物。所述化合物较佳地作为含有所述化合物以及适宜医药上可接受的载剂的医药组合物的一部分投与。此一载剂可选自医药上可接受的赋形剂、稀释剂及辅助物。
本发明范围内的医药组合物包括本发明化合物与医药上可接受的载剂组合的所有组合物。在较佳实施例中,所述化合物是以有效达成其预期治疗目的的量存于组合物中。尽管个别需求可能有所变化,但熟习此项技术者可确定每一化合物的有效量的最佳范围。通常,可将化合物每天以约5mg/kg哺乳动物体重至约100mg/kg哺乳动物体重的剂量,或等效量的其医药上可接受的盐、前药或溶剂合物经口投与哺乳动物(例如人类),以治疗、预防或改善特定病症。投与哺乳动物的本发明化合物的有用经口剂量为约5mg/kg哺乳动物体重至约100mg/kg哺乳动物体重,或等效量的其医药上可接受的盐、前药或溶剂合物。对于肌内注射,剂量通常为经口剂量的约一半。
单位口服剂量可包含约5mg至约100mg且较佳地约5mg至约100mg化合物。单位剂量可(例如)作为一或多个锭剂或胶囊每天投与一或多次,每一锭剂或胶囊含有约0.01mg至约50mg化合物,或等效量的其医药上可接受的盐、前药或溶剂合物。
本发明化合物可与一或多种第二治疗剂、特定而言适于治疗及/或预防先前所提出病况及疾病的治疗剂组合使用。
举例而言,在癌症治疗中,所述第二治疗剂可为有丝分裂抑制剂(例如紫杉烷(taxane)(较佳地太平洋紫杉醇(paclitaxel)或多西他赛(docetaxel))、长春花生物碱(vinca alkaloid)(较佳地,长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)或长春瑞滨(vinorelbine))或灭必治(vepesid);蒽环抗生素(例如多柔比星(doxorubicin)、道诺霉素(daunorubicin)、泛艾霉素(epirubicin)、伊达比星(idarubicin)、戊柔比星(valrubicin)或米托蒽醌(mitoxantrone));核苷类似物(例如吉西他滨(gemcitabine));EGFR抑制剂(例如吉非替尼(gefitinib)或厄洛替尼(erlotinib));叶酸抗代谢物(例如甲氧苄啶(trimethoprim)、乙胺嘧啶(pyrimethamine)或培美曲塞(pemetrexed));顺铂(cisplatin)或卡铂(carboplatin)。所述第二治疗剂的实例包括(但不限于)他莫昔芬(tamoxifen)、紫杉醇(taxol)、长春碱、依托泊苷(etoposide)(VP-16)、阿德力霉素(adriamycin)、5-氟尿嘧啶(5FU)、喜树碱(camptothecin)、放线菌素-D(actinomycin-D)、丝裂霉素C(mitomycin C)、考布他汀(combretastatin)、更特定而言多西他赛(克癌易(taxotere))、顺铂(CDDP)、环磷酰胺、多柔比星、胺甲喋呤(methotrexate)、太平洋紫杉醇及长春新碱及其衍生物及前药。
其他有用的第二治疗剂包括干扰DNA复制、有丝分裂、染色体分离及/或微管蛋白活性的化合物。这些化合物包括阿德力霉素(亦称为多柔比星)、依托泊苷、维拉帕米(verapamil)、鬼臼毒素(podophyllotoxin)、考布他汀及诸如此类。亦可使用中断多核苷酸前体的合成及保真度的药剂。尤其可用已经历广泛测试且易于获得的药剂。因此,诸如5-氟尿嘧啶(5-FU)等药剂为肿瘤组织优先使用,使得此药剂尤其可用于靶向赘瘤细胞。
术语“血管生成”是指通常在组织或器官中生成新血管。在正常生理条件下,人类或动物仅在特定受限情形下经历血管生成。不受控(持续及/或不受调控)的血管生成与各种疾病状态相关,且在肿瘤发展及转移期间发生。因此,亦可使用抗血管生成剂作为第二抗癌剂。其他第二抗癌剂包括(但不限于)烷基化剂,例如环磷酰胺、依地福新(edelfosine)、雌氮芥(estramustine)及美法仑(melphalan);抗代谢物,例如氟尿嘧啶、胺甲喋呤、巯嘌呤、UFT、替加氟(tegafur)、尿嘧啶及阿糖胞苷;抗肿瘤博来霉素(anti-tumor Bleomycin)、道诺霉素、多柔比星及泛艾霉素;抗生素,例如丝裂霉素及米托蒽醌;拓朴异构酶,例如喜树碱、伊立替康(irinotecan)、依托泊苷、托泊替康(topotecan);紫杉烷多西他赛、太平洋紫杉醇、长春花生物碱、长春碱、长春新碱、顺铂及奥曲肽(octreotide)。
亦可使用组织蛋白去乙酰酶抑制剂(HDAC抑制剂)作为第二治疗剂。实例包括(但不限于)羟肟酸(或异羟肟酸)(例如曲古抑菌素A(trichostatin A))、环状四肽(例如妥泊辛B(trapoxin B))及酯肽、苯甲酰胺、亲电子酮及脂肪酸化合物(例如苯基丁酸盐及丙戊酸)。
举例而言,在发炎治疗中,所述第二治疗剂包括(但不限于)皮质类固醇、润滑剂、角质溶解剂、维生素D3衍生物、PUVA及蒽酚、β2-激动剂及皮质类固醇。
举例而言,在自体免疫疾病治疗中,所述第二治疗剂包括(但不限于)免疫抑制剂、NSAID、COX-2抑制剂、生物制剂、非类固醇钙调神经磷酸酶抑制剂、类固醇消炎剂、5-胺基柳酸、DMARD、硫酸羟氯喹、发炎调节剂、干扰B细胞作用的药剂及青霉胺(penicillamine)。
熟习此项技术者熟知医药上可接受的载剂及稀释剂。对于调配为液体溶液的组合物而言,可接受的载剂及/或稀释剂包括盐水及无菌水,且可视情况包括抗氧化剂、缓冲剂、抑菌剂及其他常用添加剂。亦可将组合物调配为丸剂、胶囊、粒剂或锭剂,其除本发明化合物外亦含有稀释剂、分散剂及表面活性剂、黏合剂及润滑剂。熟习此项技术者可另外以适当方式并根据所接受实践来本发明化合物,这些接受实践是(例如)揭示于Remington′sPharmaceutical Sciences,Gennaro编辑,Mack Publishing Co.,Easton,Pa.1990中的那些。
在一态样中,本发明提供治疗个体的与泛素化-蛋白酶体系统阻断相关的疾病的方法,其包含向个体投与有效量的本发明化合物。所述疾病包括(但不限于)癌症及如上文所论述的相关病况。因此,首先,本发明提供治疗个体的癌症的方法,其包含向个体投与有效量的本发明化合物。所述方法包括以足以治疗病况的量向个体投与本发明化合物。举例而言,所述癌症包括(但不限于)由以下各项组成的群:神经胚细胞瘤;肺癌;胆管癌;非小细胞肺癌;肝细胞癌;头颈部鳞状细胞癌;鳞状细胞子宫颈癌;淋巴瘤;鼻咽癌;胃癌(gastriccancer);结肠癌;子宫颈癌;胆囊癌;前列腺癌;乳癌;罩丸生殖细胞瘤;结肠直肠癌;神经胶质瘤;甲状腺癌;基底细胞癌;胃肠基质癌;肝母细胞瘤;子宫内膜癌;卵巢癌;胰脏癌;肾细胞癌症、卡波西氏肉瘤(Kaposi′s sarcoma)、慢性白血病、肉瘤、直肠癌、喉癌、黑色素瘤、结肠癌、膀胱癌、肥胖细胞瘤、乳癌、乳腺癌、咽部鳞状细胞癌、罩丸癌、胃肠癌症或胃癌(stomach cancer)及尿路上皮癌。
在另一态样中,本发明提供治疗发炎病症及自体免疫病症及如上文所论述的相关病况的方法。这些方法包括以足以治疗病况的量向个体投与本发明化合物。较佳地,所述病症是再狭窄、发炎、类风湿性关节炎、由发炎引起的组织损伤、过度增殖疾病、严重或关节炎牛皮癣、肌肉消耗性疾病、慢性传染病、异常免疫反应、涉及易损斑块的病况、与缺血性病况相关的损伤及病毒感染及增殖。
每天施用的通式(I)化合物的剂量范围通常为5mg/kg患者体重至100mg/kg患者体重,较佳地5mg/kg患者体重至100mg/kg患者体重。每一剂量单位可便捷地含有5mg至100mg本发明化合物。
当然,实际治疗有效量或治疗剂量将取决于熟习此项技术者已知的因素,例如患者的年龄及体重、投与途径及疾病严重度。在任一情形下,组合物将基于患者的独特病况以容许递送治疗有效量的剂量及方式来投与。
对于经口投与而言,本发明的适宜医药组合物包括粉剂、粒剂、丸剂、锭剂、菱形锭、咀嚼剂、凝胶及胶囊以及液体、糖浆、悬浮液、酏剂及乳液。这些组合物亦可包括抗氧化剂、矫味剂、防腐剂、悬浮剂、增稠剂及乳化剂、着色剂、矫味剂及其他医药上可接受的添加剂。用于经口投与的调配物可经调配为立即释放或修饰释放,其中修饰释放包括延迟、持续、脉冲、控制、靶向及程式化释放。
对于非经肠投与,经由静脉内、动脉内、腹膜内、肌内、皮下或其他注射或输注将本发明化合物直接投与至血流中、至肌肉中或至内部器官中。可以除本发明化合物以外可含有缓冲剂、抗氧化剂、抑菌剂、盐、碳水化合物及通常用于这些溶液中的其他添加剂的水性注射溶液来制备非经肠调配物。非经肠投与可为立即释放或修饰释放(例如注射式或植入式储库)。
本发明化合物亦可经局部、经皮(内)或经皮投与皮肤或黏膜。典型调配物包括凝胶、水凝胶、洗剂、溶液、乳霜、软膏剂、敷料、发泡体、皮肤贴剂、薄片、植入物及微乳液。亦可经由吸入或经鼻内投与例如利用干粉剂、气溶胶喷雾剂或作为滴剂投与本发明化合物。投与本发明化合物的其他途径包括阴道内及直肠投与(藉助栓剂、子宫托或灌肠剂)及经眼及经耳投与。
生物学分析
ITCH自泛素化的阻断
使用本发明的MPT0L056测试ITCH自泛素化的阻断。结果显示本发明的MPT0L056可有效阻断ITCH自泛素华(Lys依赖性)(参见图1:活体外分析及图2:活体内分析)。[活体外分析参考:Scialpi F、Malatesta M、Peschiaroli A、Rossi M、Melino G及BernassolaF.Itch self-polyubiquitylation occurs through lysine-63linkages.BiochemPharmacol.2008年12月1日;76(11):1515-21。活体内分析参考:Chang L、Kamata H、Solinas G、Luo JL、Maeda S、Venuprasad K、Liu YC及Karin M.The E3 ubiquitin ligaseitch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L)turnover.Cell.2006年2月10日;124(3):601-13]。
蛋白激酶分析(蛋白激酶组(Kinome)分析)。
使本发明化合物经受蛋白激酶分析。结果显示MPT0L056与PCTK1、ROCK2、CSNK1D、JNK1、JNK3、RIOK2及DYRK1B的Kd值分别>10μM、580nM、2μM、4.2μM、430nM、6.6μM及1.4μM,表明本发明化合物是治疗及/或预防肿瘤疾病、神经退化疾病、自体免疫及发炎性疾病及/或代谢失调的潜在靶标。
使本发明的MPT0L056经受生长抑制分析。
将细胞接种于96孔塑胶板中并使其暴露于MPT0L056达48小时。使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物分析来评价细胞存活率。生长抑制表示为药物处理的细胞对DMSO处理的对照细胞中存活细胞的百分比。
细胞类型 | GI<sub>50</sub>(M) | 细胞类型 | GI<sub>50</sub>(M) |
正常细胞 | 黑色素瘤 | ||
肝细胞 | 3.0×10<sup>-5</sup> | SK-MEL-5 | 2.1×10<sup>-7</sup> |
HUVEC | 1.6×10<sup>-5</sup> | B细胞白血病 | |
NHDF | 6.3×10<sup>-6</sup> | REH | 2.8×10<sup>-6</sup> |
胰脏癌 | Ramos | 8.9×10<sup>-7</sup> | |
AsPC1 | 4.6×10<sup>-6</sup> | T细胞淋巴瘤 | |
BxPC3 | 1.2×10<sup>-6</sup> | H33HJ-JA1 | 1.8×10<sup>-6</sup> |
结肠直肠癌 | 肺癌 | ||
HT-29 | 3.8×10<sup>-6</sup> | A549 | >5×10<sup>-6</sup> |
HCT-116 | 4.3×10<sup>-6</sup> | NCI-H460 | 2.9×10<sup>-6</sup> |
乳癌 | PC-6 | 1.8×10<sup>-6</sup> | |
MCF-7 | 9.0×10<sup>-7</sup> | 卵巢癌 | |
MDA-MB-231 | 2.9×10<sup>-6</sup> | OVCAR4 | 1.4×10<sup>-6</sup> |
ZR-75 | >5×10<sup>-6</sup> | OVCAR3 | 1.9×10<sup>-6</sup> |
头颈癌 | 前列腺癌 | ||
KB | 4.0×10<sup>-6</sup> | PC-3 | 2.5×10<sup>-6</sup> |
皮肤癌 | 脑癌 | ||
A431 | 1.2×10<sup>-6</sup> | U-87MG | 2.5×10<sup>-6</sup> |
胃癌 | T98 | 5.7×10<sup>-6</sup> | |
KATO III | 2.4×10<sup>-6</sup> | 白血病 | |
肝癌 | MOLT4 | 4.0×10<sup>-6</sup> | |
Hep 3B | 1.4×10<sup>-6</sup> | HL-60 | 1.6×10<sup>-6</sup> |
HepG2 | 3.6×10<sup>-6</sup> | K562 | 1.7×10<sup>-6</sup> |
肾癌 | |||
A-498 | 3.5×10<sup>-6</sup> | ||
ACHN | 2.7×10<sup>-6</sup> |
使本发明化合物经受生长抑制分析。
在雌性裸鼠中对MPT0L056抵抗人类RPMI8226多发性骨髓瘤的评估
将MPT0L056经口(1.0%羧甲基纤维素(CMC)及0.5%吐温80(Tween80))给予已植入PRMI8226多发性骨髓瘤细胞系(1.0×107个细胞于悬浮液中)的8周龄雌性裸鼠。第1天的平均肿瘤大小为约85mm3;当对照组中的平均肿瘤体积达到400mm3时研究结束。肿瘤大小(mm3)计算为:
其中w=肿瘤的宽度(mm)且l=肿瘤的长度(mm)。可基于1mg等于1mm3肿瘤体积的假设来估计肿瘤重量。研究设计如下(文本表1)来绘示。
文本表1.研究设计
根据表1中的方案实施TMU-RPMI8226-e0001研究。42天研究利用五组具有经确立人类PRMI8226多发性骨髓瘤且在D1具有约85mm3的平均体积的小鼠(n=6)。每一治疗组的肿瘤生长曲线及动物体重变化分别显示于图1及图2中。图1显示MPT0L056,其是每天一次以50mg/kg及25mg/kg以p.o.方式进行投与并保持42天。基于司徒登氏t测试(Student’s t-test)分析,MPT0L05650mg/kg(P<0.001)及25mg/kg(P<0.001)产生显著抗肿瘤活性。六只小鼠中的两只显示在两个剂量组中完全消退(CR)(图3)。另外,阳性对照SAHA亦显示抗肿瘤活性(P<0.001)且六只小鼠中的一只显示在每天一次100mg/kg下完全消退。(图3)。然而,所有经测试剂量下的体重皆未发生显著变化(图4)。MPT0L056显示在人类RPMI8226多发性骨髓瘤异种移植物模型中具有显著抗肿瘤活性,而无显著体重损失。
在雌性裸鼠中对MPT0L056抵抗人类MDA-MB-231乳癌的评估
将MPT0L056经口(1.0%羧甲基纤维素(CMC)及0.5%吐温80(Tween80))给予已植入人类MDA-MB-231乳房细胞系(1.0×107个细胞于悬浮液中)的8周龄雌性裸鼠。第1天的平均肿瘤大小为约250mm3;当对照组中的平均肿瘤体积达到2,000mm3时研究结束。肿瘤大小(mm3)计算为:
其中w=肿瘤的宽度(mm)且l=肿瘤的长度(mm)。可基于1mg等于1mm3肿瘤体积的假设来估计肿瘤重量。研究设计是如下(文本表2)来绘示。
文本表2.研究设计
根据表2中的方案实施TMU-MDA-MB-231-e0002研究。此研究利用五组具有经确立人类MDA-MB-231乳腺癌且在D1具有约250mm3的平均体积的小鼠(n=7只至8只)。每一治疗组的肿瘤生长曲线及动物体重变化分别显示于图5及图6中。图5显示MPT0L056,其是每天一次以100mg/kg、50mg/kg及25mg/kg以p.o.方式进行投与并保持10天。基于司徒登氏t测试分析,MPT0L056 100mg/kg(P<0.01)及50mg/kg(P<0.01)产生显著抗肿瘤活性。然而,MPT0L056在25mg/kg下并未显著表达肿瘤生长延迟(图5)。另外,参考组硼替佐米并未显示抗肿瘤活性(P>0.05)(图5)。然而,在所有经测试剂量下体重皆未发生显著变化(图6)。
在雌性裸鼠中对MPT0L056抵抗人类A2780卵巢癌的评估
将MPT0L056经口(1.0%羧甲基纤维素(CMC)及0.5%吐温80(Tween80))给予已植入人类A2780细胞系(1.0×107个细胞于悬浮液中)的8周龄雌性裸鼠。第1天的平均肿瘤大小为约150mm3;当对照组中的平均肿瘤体积达到4,000mm3时研究结束。肿瘤大小(mm3)计算为:
其中w=肿瘤的宽度(mm)且l=肿瘤的长度(mm)。可基于1mg等于1mm3肿瘤体积的假设来估计肿瘤重量。研究设计是如下(文本表3)来绘示。
文本表3.研究设计
根据表3中的方案实施TMU-A2780-e0001研究。此研究利用五组具有经确立人类2780卵巢腺癌且在D1具有约150mm3的平均体积的小鼠(n=5只至6只)。每一治疗组的肿瘤生长曲线及动物体重变化分别显示于图7及图8中。图7显示MPT0L056,其是每天一次以100mg/kg及200mg/kg以p.o.方式进行投与直至结束。基于司徒登氏t测试分析,MPT0L056200mg/kg(P<0.01)产生显著抗肿瘤活性,但50mg/kg(P>0.05)未产生显著抗肿瘤活性。另外,参考组硼替佐米(P<0.05)及阳性对照顺铂(P<0.01)显示抗肿瘤活性(图7)。然而,在所有经测试剂量下体重皆未发生显著变化(图8)。
在裸鼠中对单独MPT0L056及其与HDAC抑制剂MPT0E028的组合抵抗人类HCT116结肠直肠腺癌的评估
使用MPT0L056评估抵抗HCT116人类结肠直肠腺癌的活性。将MPT0L056以50mg/kg及100mg/kg经口(于D5W中的1.0%羧甲基纤维素(CMC)及0.5%吐温80(Tween80))给予已植入HCT116结肠直肠癌细胞系(1.0×107个细胞于悬浮液中)的8周龄雌性裸鼠。第1天的平均肿瘤大小为约160mm3;当经约59天在对照组中的平均肿瘤体积达到1,000mm3时研究结束。肿瘤大小(mm3)计算为:
其中w=肿瘤的宽度(mm)且1=肿瘤的长度(mm)。可基于1mg等于1mm3肿瘤体积的假设来估计肿瘤重量。然而,MPT0E028是在1.0%CMC及0.5%吐温80中经口(p.o.)投与且是以每日25mg/kg的剂量给予直至时间表结束。另外,硼替佐米是在D5W中以静脉内(i.v.)方式投与且是以每周1mg/kg的剂量给予直至排定方案结束。研究设计是如下(文本表4)来绘示。
文本表4.研究设计
当肿瘤达到1,000mm3的预定终点大小时,对每一只动物实施安乐死。通过以下等式计算每一只小鼠的终点时间(TTE):
其中TTE是以天数表示,终点体积是以mm3表示,b是截距,且m是通过log转变的肿瘤生长数据集的线性回归获得的直线的斜率。数据集包括超过研究终点体积的第一观察值及在即将到达终点体积之前的3个连续观察值。经计算TTE通常小于针对肿瘤大小对动物实施安乐死的日期。在研究结束时对未达到终点的动物实施安乐死,且将TTE值赋以等于最后日期(59天)。将分类为死于治疗相关性(TR)原因或非治疗相关性转移(NTRm)原因的动物赋以等于死亡日期的TTE值。将分类为死于非治疗相关性(NTR)原因的动物排除在TTE计算之外。
根据肿瘤生长延迟(TGD)测定治疗效能,所述肿瘤生长延迟定义为治疗组相比于对照组的中值TTE的增加:
TGD=T-C,
是以天数或以对照组的中值TTE的百分比表示:
其中:
T=治疗组的中值TTE,
C=对照组1的中值TTE。
亦根据最后一天在研究中剩余的动物的肿瘤体积且根据消退反应的数量来测定治疗效能。MTV(n)是定义为在D59剩余的n数量只动物的中值肿瘤体积,这些动物的肿瘤尚未到达终点体积。
治疗可使得动物的肿瘤部分地消退(PR)或完全消退(CR)。PR指示对于研究过程期间的三个连续量测值而言肿瘤体积为其D1体积的50%或更少,且对于所述三个量测值中的一或多者而言等于或大于50mm3。CR指示对于研究过程期间的三个连续量测值而言肿瘤体积小于50mm3。另外在研究结束时将具有CR的动物分类为无肿瘤存活者(TFS)。
在前五天每日对动物进行称重,然后每周两次称重直至完成研究。通常针对任何药物相关性不利副作用的明显体征检验小鼠。癌症药物的MTD的可接受毒性定义为在测试期间群组平均BW损失为20%或更少,且在10只动物中TR死亡不超过一个。若在给药时段期间或在最后剂量的10天内根据临床体征及/或验尸或根据未知原因证明具有治疗副作用,则将死亡分类为TR。若证明死亡与治疗副作用不相关,则将死亡分类为NTR。若验尸指示其可能因侵入及/或转移由肿瘤播散引起,则将死亡分类为NTRm。
使用对数秩测试来测定两个群组的TTE值间的差异的统计显著性,任何NTR死亡除外。利用Windows的Prism 3.03(GraphPad)实施统计及图形分析。在P=0.05下执行双尾统计分析。卡普兰-迈耶图(Kaplan-Meier plot)显示研究中剩余动物的百分比对时间。卡普兰-迈耶图使用与对数秩测试相同的数据集。肿瘤生长曲线显示群组中值肿瘤体积在log尺度上随时间变化。当动物由于肿瘤大小或TR死亡退出研究时,针对所述动物报告的最终肿瘤体积包括在内且所述数据用于计算随后时间点时的中值。因此,曲线显示的最后中值肿瘤体积显示可能与MTV不同,所述MTV是在最后一天在研究中剩余的小鼠的中值肿瘤体积(不包括所有具有已到达终点的肿瘤者)。若群组中发生一例以上TR死亡,则在第二例TR死亡前的最后量测的时间截断肿瘤生长曲线。当群组中超过50%的可评价动物中的肿瘤已生长至终点体积时,亦截断肿瘤生长曲线。
所述59天研究利用具有在D1的平均体积为约160mm3的经确立HCT116人类结肠直肠腺癌细胞的八组小鼠(n=7只至8只)。表5概述治疗反应及统计结果。来自对数秩分析的完全统计分析数据显示于表6中。每一治疗组的个别肿瘤生长曲线及个别动物体重变化分别显示于图9及图10中。图11在散布图中显示每一治疗组中个别小鼠的TTE值。每一组的中值肿瘤生长及卡普兰-迈耶曲线分别包括在图12的上部及下部面板中。
在对照小鼠中人类HCT116结肠直肠腺癌的生长
第1组小鼠接受媒剂且用作所有治疗组的对照。对照小鼠中的所有肿瘤皆生长至1,000mm3终点体积(图9)。第1组小鼠的中值TTE为22.7天(表6)。
人类HCT116结肠直肠腺癌对MPT0E028的反应
每天一次以25mg/kg p.o.投与MPT0E028(第2组)至结束产生40.5天的中值TTE,此对应于17.8天的T-C及78的TGD%。基于对数秩分析,MPT0E028产生显著抗肿瘤活性(P=0.0197,对数秩测试,表5及6)。在研究结束时三只小鼠的中值肿瘤体积(MTV)为454mm3。此研究中存在两只PR小鼠及两只CR小鼠。然而,在所述研究期间有一只小鼠显示无肿瘤存活者(TFS)。
人类HCT116结肠直肠腺癌对硼替佐米的反应
每周一次以1.0mg/kg i.v.投与硼替佐米(第3组)至结束产生38.9天的中值TTE,此对应于16.2天的T-C及71的TGD%。基于对数秩分析,硼替佐米产生显著抗肿瘤活性(P=0.0389,对数秩测试,表5及6)。在研究结束时一只小鼠的中值肿瘤体积(MTV)为683mm3。在此研究中存在一只PR小鼠及两只CR小鼠。
人类HCT116结肠直肠腺癌对MPT0L056的反应
每天一次以100mg/kg及50mg/kg p.o.投与MPT0L056(第4组及第5组)至终点分别产生48.5天及30.0天的中值TTE,对于100mg/kg及50mg/kg治疗组(第4组及第5组)对应于25.8天及7.3天的T-C及114及32的TGD%。基于对数秩分析,在100mg/kg下而非50mg/kg(P=0.2087)下的MPT0L056产生显著抗肿瘤活性(P=0.0033,对数秩测试,表3及4)。在研究结束时中值肿瘤体积(MTV)对于100mg/kg治疗组中的三只小鼠为160mm3且对于50mg/kg治疗组中的一只小鼠为975mm3。在100mg/kg治疗组中存在四只PR小鼠及一只CR小鼠,且在50mg/kg治疗组中存在一只PR小鼠及两只CR小鼠。然而,在100mg/kg治疗研究期间有一只小鼠显示无肿瘤存活者(TFS)。
人类HCT116结肠直肠腺癌对硼替佐米与MPT0E028的组合的反应
每周一次以1.0mg/kg i.v.投与硼替佐米(第6组)至终点与每天一次以25g/kgp.o.投与MPT0E028至终点组合,分别产生38.4天的中值TTE,此对应于15.7天的T-C及69的TGD%。基于对数秩分析,1.0mg/kg下的硼替佐米与MPT0E028组合并未产生显著协同的抗肿瘤活性效应(表5及6)。在研究结束时一只小鼠的中值肿瘤体积(MTV)为0mm3。此研究中存在一只PR小鼠及一只CR小鼠。然而,在所述研究期间亦有一只小鼠显示无肿瘤存活者(TFS)。
人类HCT116结肠直肠腺癌对MPT0L056与MPT0E028的组合的反应
每天一次以100及50mg/kg p.o.投与MPT0L056(第7组及第8组)至终点与每天一次以25mg/kg p.o.投与MPT0E028至终点组合,分别产生34.0天及45.3天的中值TTE,对于100mg/kg及50mg/kg治疗组(第7组及第8组)对应于11.3天及22.6天的T-C及50及100的TGD%。基于对数秩分析,50mg/kg(P=0.0096)下而非100mg/kg(P=0.4348)的MPT0L056与MPT0E028组合产生显著协同的抗肿瘤活性效应(表5及6)。然而,在50mg/kg治疗组中存在一只PR小鼠及三只CR小鼠。
表6
在鼠类RAW264.7巨噬细胞中MPT0L056对IL-6产生的效应
细胞培养.RAW264.7小鼠巨噬细胞是购自Bioresource Collection andResearch Center且将这些细胞在37℃下在5%CO2/95%空气中分别在90%汉姆氏F-12(Ham’s F-12)或达尔伯克氏改良伊戈尔培养基(Dulbecco’s modified Eagle medium)(均含有10%热去活化的胎牛血清(FBS)(Invitrogen Life Technologies,Carlsbad,CA)及1%青霉素/链霉素(Biological Industries,Israel))中培养。
IL-6测定.为测定MPT0L056对自LPS刺激的细胞产生细胞介素IL-6的效应,平铺RAW 264.7细胞(1×106)并将其在MPT0L056存在或不存在下预处理1h,且然后在37℃下利用LPS(25ng/mL)刺激24h。收集上清液并通过ELISA套组量测细胞介素IL-6的浓度。结果显示于图13中。图13显示在鼠类RAW264.7巨噬细胞中MPT0L056抑制IL-6产生(IC50值为1.21μM)。
MPT0L056对人类RAFLS(类风湿性关节炎纤维母细胞样滑膜细胞)细胞中的IL-6产生的效应
细胞培养.使来自Cell Application Inc.(San Diego,CA,USA)的人类类风湿性关节炎纤维母细胞样滑膜细胞(RAFLS)在来自同一供应商的滑膜细胞生长培养基中生长。
IL-6测定.利用各个浓度的MPT0L056将RA-FLS(2.5×104)处理24h,然后收集培养基并使用商业ELISA套组分析IL-6。结果显示于图14中。如图14中所显示,在人类类风湿性关节炎纤维母细胞样滑膜细胞中MPT0L056抑制IL-6产生(IC50值为7.26μM)。
在佐剂诱导的关节炎(AIA)模型中MPT0L056抑制关节炎的发生
活体内佐剂诱导的关节炎(AIA)模型.获得五周龄雄性路易斯大鼠(Lewis rat)。通过将热杀死的乳酪分枝杆菌(Mycobacterium butyricum)(Difco)以3mg/mL悬浮于矿物油中来制备完全弗氏佐剂(Complete Freund’s adjuvant,CFA)。通过在第0天将100μL CFA乳液真皮内注射至右后爪的基部诱导CFA诱导的关节炎。自第2天至第21天通过胃管灌食法给予MPT0L056(25mg/kg,po,qd)、硼替佐米(1mg/kg,ip,qwk)、阳性对照吲哚美辛(indomethacin)(1mg/kg,po,qwk)或媒剂。在第0天、第2天、第6天、第9天、第13天、第17天及第21天,对动物实施称重且使用数位器官充满度量测器(Diagnostic&ResearchInstruments Co.Ltd)量测两个后爪体积。在第21天,使用活体内微CT扫描仪(Skyscan1176,Bruker Corp.,Kontich,Belgium)以18μm解析度及180°扫描以及0.8o/影像的旋转步长、300msec积分时间、70keV光子能量及350μA电流实施爪的微电脑断层摄影(微CT)。结果显示于图15及16中。如图15中所显示,在佐剂诱导的关节炎中MPT0L056抑制关节炎的发生。图16显示MPT0L056显著减轻爪肿胀。
在AIA模型中利用MPT0L056处理来预防骨矿物质密度(BMD)及骨矿物质含量(BMC)损失
在所界定的距跗骨12mm至跟骨末端范围内的骨区域中实施体积骨矿物质密度(BMD)及骨体积(BV)的量化。通过BV及BMD的产物阐述骨矿物质含量(BMC)。结果显示于图17中。图17显示利用MPT0L056处理可预防骨矿物质密度(BMD)及骨矿物质含量(BMC)损失。
实例
实例1 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)苯甲酸(97)
将2,3-二氯-1,4-萘醌(0.49g,2.18mmol)、4-胺基甲基苯甲酸(0.30g,1.98mmol)及TEA(1ml)的混合物溶解于EtOH(10ml)中并搅拌并回流过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状97(0.36g,53.20%)。1H-NMR(500MHz,DMSO-d6):δ5.01(d,J=7.0Hz,2H),7.39(d,J=8.5Hz,2H),7.75(m,1H),7.81(m,1H),7.88(d,J=8.0Hz,2H),7.96(d,J=7.5Hz,2H),8.05(t,J=6.5Hz,1H)。
实例2 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-羟基苯甲酰胺(1)
将97(0.36g,1.05mmol)、EDC.HCl(0.30g,1.58mmol)、HOBt(0.17g,1.26mmol)、NMM(0.28ml,2.52mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加邻-(四氢-2H-吡喃-2-基)羟基胺(0.15g,1.26mmol),并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.45)上的急骤管柱纯化残余物,以获得油状产物。然后将油状产物溶解于MeOH(3ml)中并在室温下添加10%TFA(aq.)(3ml)并将混合物搅拌过夜。将H2O添加至反应中以产生沈淀物。过滤残余物且不经进一步纯化,以得到红色固体状1(0.24g,98.93%)。1H-NMR(500MHz,DMSO-d6):δ4.98(s,2H),7.35(d,J=8.5Hz,2H),7.68(d,J=8.5Hz,2H),7.73(m,1H),7.81(m,1H),7.96(m,2H),8.03(s,1H)。
实例3 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-2-基)苯甲酰胺(2)
将97(0.25g,0.73mmol)、EDC.HCl(0.21g,1.10mmol)、HOBt(0.12g,0.88mmol)、NMM(0.19ml,1.75mmol)及DMF(2.0ml)的混合物搅拌一会儿,然后在室温下向其中添加2-胺基吡啶(0.08g,0.88mmol)并将混合物搅拌过夜。通过在硅胶(二氯甲烷∶甲醇=30∶1,Rf=0.50)上的急骤管柱纯化残余物,以得到红色固体状2(0.04g,13.11%)。1H-NMR(300MHz,CDCl3):δ5.15(d,J=6.6Hz,2H),6.33(s,1H),7.08-7.12(m,1H),7.49(d,J=8.4Hz,2H),7.67(m,1H),7.77(m,2H),7.97(d,J=8.4Hz,2H),8.08(m,1H),8.18(m,1H),8.33(m,1H),8.40(d,J=8.4Hz,1H),8.59(br,1H)。
实例4 N-(2-胺基苯基)-4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)苯甲酰胺(3)
将97(0.25g,0.73mmol)、EDC.HCl(0.21g,1.10mmol)、HOBt(0.12g,0.88mmol)、NMM(0.19ml,1.75mmol)及DMF(2.0ml)的混合物搅拌一会儿,然后在室温下向其中添加邻-苯二胺(0.08g,0.88mmol)并将混合物搅拌过夜。通过在硅胶(二氯甲烷∶甲醇=30∶1,Rf=0.50)上的急骤管柱纯化残余物,以得到红色固体状3(0.06g,19.03%)。1H-NMR(300MHz,DMSO-d6):δ4.86(s,2H),5.03(s,2H),6.57(t,J=7.8Hz,1H),6.75(d,J=6.6Hz,1H),6.95(t,J=7.8Hz,1H),7.14(d,J=6.6Hz,1H),7.42(d,J=7.8Hz,2H),7.74(t,J=7.2Hz,1H),7.82(t,J=7.2Hz,1H),7.95(m,4H),8.10(br,1H),9.59(s,1H)。
实例5 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-3-基)苯甲酰胺(4)
将97(0.10g,0.29mmol)、HBTU(0.11g,0.29mmol)、DIPEA(0.06ml,0.35mmol)及DMF(1.0ml)的混合物搅拌一会儿,然后向其中添加3-胺基吡啶(0.03g,0.35mmol)。将反应物在室温下搅拌16h。过滤残余物且不经进一步纯化,以得到4(0.08g,66.02%)。1H NMR(300MHz,DMSO-d6):δ5.03(d,J=7.2Hz,2H),7.37(q,J=4.8Hz,1H),7.46(d,J=8.1Hz,2H),7.74-7.82(m,2H),7.91(d,J=8.1Hz,2H),7.95-7.98(m,2H),8.13-8.17(m,2H),8.27-8.29(m,1H),10.42(s,1H)。
实例6 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-4-基)苯甲酰胺(5)
将97(0.10g,0.29mmol)、HBTU(0.11g,0.29mmol)、DIPEA(0.06ml,0.35mmol)及DMF(1.0ml)的混合物搅拌一会儿,然后向其中添加4-胺基吡啶(0.03g,0.35mmol)。将反应物在室温下搅拌16h。过滤残余物且不经进一步纯化,以得到5(0.08g,66.02%)。1H NMR(300MHz,DMSO-d6):δ5.03(d,J=7.2Hz,2H),7.37(d,J=8.4Hz,2H),7.73-7.76(m,3H),7.79-7.84(m,1H),7.90(d,J=8.4Hz,2H),7.95-7.98(m,2H),8.08-8.13(m,1H),8.43-8.45(m,2H),10.53(s,1H)。
实例7 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(3-氟苯基)苯甲酰胺(9)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加3-氟苯胺(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.30)上的急骤管柱纯化残余物,以得到红色固体状9(0.04g,10.45%)。1H-NMR(300MHz,DMSO-d6):δ5.03(s,2H),6.92(m,1H),7.36(m,1H),7.45(d,J=8.1Hz,2H),7.52(m,1H),7.72(m,2H),7.80(m,1H),7.88(d,J=8.4Hz,2H),7.97(m,2H),8.11(br,1H),10.37(s,1H)。
实例8 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(4-氟苯基)苯甲酰胺(10)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-氟苯胺(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.35)上的急骤管柱纯化残余物,以得到红色固体状10(0.02g,5.23%)。1H-NMR(300MHz,DMSO-d6):δ5.02(s,2H),7.16(t,J=9.0Hz,2H),7.43(d,J=8.1Hz,2H),7.75(m,3H),7.82(m,1H),7.88(d,J=8.4Hz,2H),7.97(m,2H),8.08(br,1H),10.24(s,1H)。
实例9 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-苯基苯甲酰胺(11)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加苯胺(0.12g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状11(0.28g,76.33%)。1H-NMR(300MHz,DMSO-d6):δ5.02(s,2H),7.07(t,J=7.5Hz,1H),7.32(d,J=7.5Hz,2H),7.44(d,J=8.4Hz,2H),7.75(m,3H),7.83(m,1H),7.88(d,J=8.4Hz,2H),7.97(m,2H),8.10(br,1H),10.18(s,1H)。
实例10 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(2-氟苯基)苯甲酰胺(12)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-氟苯胺(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.25)上的急骤管柱纯化残余物,以得到红色固体状12(0.02g,5.23%)。1H-NMR(300MHz,DMSO-d6):δ5.03(s,2H),7.23(m,3H),7.44(d,J=8.1Hz,2H),7.56(t,J=7.5Hz,1H),7.74(m,1H),7.80(m,1H),7.91(d,J=8.1Hz,2H),7.97(m,2H),8.10(br,1H),10.05(s,1H)。
实例11 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(噻唑-2-基)苯甲酰胺(13)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-胺基噻唑(0.13g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状13(0.15g,40.21%)。1H-NMR(300MHz,DMSO-d6):δ5.03(d,J=7.2Hz,2H),7.26(d,J=3.6Hz,1H),7.45(d,J=8.4Hz,2H),7.53(d,J=3.6Hz,1H),7.75(m,1H),7.82(m,1H),7.97(m,2H),8.04(d,J=8.4Hz,2H),8.10(t,J=7.5Hz,1H),12.55(s,1H)。
实例12 N-(1H-苯并[d]咪唑-2-基)-4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)苯甲酰胺(14)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-胺基苯并咪唑(0.18g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状14(0.27g,67.16%)。1H-NMR(300MHz,DMSO-d6):δ5.03(d,J=6.9Hz,2H),7.11(m,2H),7.43(d,J=9.0Hz,4H),7.74(m,1H),7.82(m,1H),7.96(d,J=5.7Hz,2H),8.07(d,J=8.4Hz,3H),12.22(s,1H)。
实例13 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(4-羟基苯基)苯甲酰胺(15)
将97(0.15g,0.44mmol)、HBTU(0.25g,0.66mmol)、DIPEA(0.11ml,0.66mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-胺基酚(0.07g,0.66mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.30)上的急骤管柱纯化残余物,以得到15(0.02g,10.50%)as a brown solid。1H-NMR(300MHz,DMSO-d6):δ5.01(d,J=6.3Hz,2H),6.70(d,J=9.0Hz,2H),7.41(d,J=8.4Hz,2H),7.48(d,J=8.7Hz,2H),7.74(m,1H),7.80(m,1H),7.85(d,J=8.4Hz,2H),7.98(m,2H),8.09(br,1H),9.25(br,1H),9.95(s,1H)。
实例14 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(3-乙炔基苯基)苯甲酰胺(16)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后向其中添加3-乙炔基苯胺(0.15g,1.32mmol)在室温下并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶4,Rf=0.25)上的急骤管柱纯化残余物,以得到红色固体状16(0.12g,30.93%)。1H-NMR(300MHz,DMSO-d6):δ4.17(s,1H),5.03(s,2H),7.18(d,J=7.5Hz,1H),7.34(t,J=8.1Hz,1H),7.45(d,J=8.4Hz,2H),7.87(m,8H),8.11(br,1H),10.27(s,1H)。
实例15 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(2-氟-4-碘苯基)苯甲酰胺(17)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-氟-4-碘苯胺(0.31g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.45)上的急骤管柱纯化残余物,以得到红色固体状17(0.02g,4.05%)。1H-NMR(300MHz,CDCl3):δ5.03(d,J=6.9Hz,2H),7.41(m,3H),7.56(m,1H),7.73(m,1H),7.81(m,1H),7.90(d,J=8.4Hz,2H),7.96(m,2H),8.10(m,1H),10.09(s,1H)。
实例16 N-(1H-苯并[d]咪唑-5-基)-4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)苯甲酰胺(18)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基苯并咪唑(0.18g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状18(0.26g,64.67%)。1H-NMR(300MHz,DMSO-d6):δ5.03(d,J=7.2Hz,2H),7.43-7.48(m,3H),7.54(d,J=8.7Hz,1H),7.72-7.77(m,1H),7.80-7.85(m,1H),7.91(d,J=8.4Hz,2H),7.96-7.99(m,2H),8.09-8.15(m,2H),8.20(s,1H),10.20(s,1H)。
实例17 2-(4-(3-胺基-1H-吡唑-1-羰基)苄基胺基)-3-氯萘-1,4-二酮(19)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加3-胺基吡唑(0.11g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状19(0.17g,47.49%)。1H-NMR(300MHz,DMSO-d6):δ5.03(s,2H),5.64(s,2H),5.99(d,J=3.0Hz,1H),7.42(d,J=8.4Hz,2H),7.71-7.77(m,1H),7.79-7.85(m,1H),7.92-7.98(m,4H),8.11(s,1H),8.15(d,J=3.0Hz,1H)。
实例18 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-环丙基苯甲酰胺(20)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加环丙胺(0.09ml,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状20(0.12g,35.81%)。1H-NMR(300MHz,DMSO-d6):δ0.52-0.55(m,2H),0.63-0.69(m,2H),2.77-2.83(m,1H),4.98(s,2H),7.34(d,J=8.4Hz,2H),7.72-7.75(m,3H),7.82(t,J=7.5Hz,1H),7.96(d,J=7.8Hz,2H),8.05(s,1H),8.36(d,J=4.2Hz,1H)。
实例19 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-环戊基苯甲酰胺(21)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加环戊基胺(0.13ml,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状21(0.25g,69.48%)。1H-NMR(300MHz,DMSO-d6):δ1.50-1.56(m,4H),1.66(br,2H),1.80-1.89(m,2H),4.15-4.22(m,1H),4.98(s,2H),7.35(d,J=8.4Hz,2H),7.71-7.84(m,4H),7.96(d,J=7.8,2H),8.06(s,1H),8.19(d,J=7.2Hz,1H)。
实例20 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲唑-5-基)苯甲酰胺(22)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基吲唑(0.18g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状22(0.20g,49.74%)。1H-NMR(300MHz,DMSO-d6):δ5.04(d,J=7.2Hz,2H),7.43-7.51(m,3H),7.59-7.62(m,1H),7.72-7.77(m,1H),7.80-7.85(m,1H),7.90-7.99(m,4H),8.03(s,1H),8.13(t,J=7.2Hz,1H),8.21(s,1H),10.20(s,1H),12.99(s,1H)。
实例21 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(5-甲基噻唑-2-基)苯甲酰胺(23)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-胺基-5-甲基噻唑(0.15g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状23(0.38g,98.61%)。1H-NMR(300MHz,DMSO-d6):δ2.36(s,3H),5.03(d,J=7.2Hz,2H),7.20(s,1H),7.45(d,J=8.1Hz,2H),7.72-7.78(m,1H),7.80-7.85(m,1H),7.50-7.99(m,2H),8.03(d,J=8.1Hz,2H),8.10(t,J=8.1Hz,1H),12.21(br,1H)。
实例22 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(5-甲基-3H-吡唑-3-基)苯甲酰胺(24)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加3-胺基-5-甲基吡唑(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶9,Rf=0.20)上的急骤管柱纯化残余物,以得到红色固体状24(0.05g,13.50%)。1H-NMR(300MHz,CDCl3):δ5.14(d,J=6.3Hz,2H),5.34(s,1H),5.60(br,2H),6.29(br,1H),7.44(d,J=8.4Hz,2H),7.64-7.68(m,1H),7.73-7.78(m,1H),8.07(d,J=7.8Hz,1H),8.12(d,J=8.4Hz,2H),8.17(d,J=6.3Hz,1H)。
实例23 2-(4-(3-胺基-5-甲基-1H-吡唑-1-羰基)苄基胺基)-3-氯萘-1,4-二酮(25)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加3-胺基-5-甲基吡唑(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶4,Rf=0.25)上的急骤管柱纯化残余物,以得到红色固体状25(0.04g,10.80%)。1H-NMR(300MHz,DMSO-d6):δ2.49(s,3H),5.03(s,2H),5.44(s,2H),5.78(s,1H),7.38(d,J=8.4Hz,2H),7.73-7.86(m,4H),7.98(d,J=7.8Hz,2H),8.10(s,1H)。
实例24 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(3-硝基吡啶-4-基)苯甲酰胺(26)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-胺基-3-硝基吡啶(0.18g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.25)上的急骤管柱纯化残余物,以得到红色固体状26(0.06g,14.73%)。1H-NMR(300MHz,DMSO-d6):δ5.05(d,J=6.9Hz,2H),7.52(d,J=8.4Hz,2H),7.72-7.78(m,1H),7.80-7.86(m,1H),7.92(d,J=8.4Hz,2H),7.96-8.00(m,4H),8.13(t,J=6.9Hz,1H),8.76(d,J=5.7Hz,1H),9.12(s,1H),11.07(s,1H)。
实例26 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-6-基)苯甲酰胺(28)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加6-胺基喹啉(0.19g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.20)上的急骤管柱纯化残余物,以得到红色固体状28(0.11g,26.72%)。1H-NMR(300MHz,DMSO-d6):δ5.04(s,2H),7.46-7.49(m,3H),7.72-7.77(m,1H),7.80-7.85(m,1H),7.94-8.00(m,6H),8.12(br,1H),8.30(d,J=8.7Hz,1H),8.51(s,1H),8.78-8.80(m,1H),10.52(s,1H)。
实例27 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-8-基)苯甲酰胺(29)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加8-胺基喹啉(0.19g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状29(0.15g,36.43%)。1H-NMR(300MHz,DMSO-d6):δ5.07(d,J=6.9Hz,2H),7.55(d,J=8.4Hz,2H),7.62-7.69(m,2H),7.72-7.78(m,2H),7.81-7.84(m,1H),7.86-8.02(m,4H),8.14(t,J=6.6Hz,1H),8.44-8.47(m,1H),8.70-8.73(m,1H),8.94-8.95(m,1H),10.62(s,1H)。
实例28 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-3-基)苯甲酰胺(30)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加3-胺基喹啉(0.19g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.43)上的急骤管柱纯化残余物,以得到红色固体状30(0.10g,24.29%)。1H-NMR(300MHz,DMSO-d6):δ5.05(s,2H),7.49(d,J=8.4Hz,2H),7.55-7.60(m,1H),7.63-7.68(m,1H),7.72-7.85(m,2H),7.93-7.99(m,6H),8.11(br,1H),8.82(s,1H),9.12(s,1H),10.66(br,1H)。
实例29 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-5-基)苯甲酰胺(31)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基喹啉(0.13g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.20)上的急骤管柱纯化残余物,以得到红色固体状31(0.10g,24.29%)。1H-NMR(300MHz,DMSO-d6):δ5.06(s,2H),7.47-7.53(m,3H),7.68(d,J=6.9Hz,1H),7.73-7.83(m,3H),7.92-8.05(m,5H),8.14(s,1H),8.37(d,J=8.7Hz,1H),8.91(s,1H),10.48(s,1H)。
实例30 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(2-甲基喹啉-4-基)苯甲酰胺(32)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加2-甲基喹啉-4-胺(0.21 g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.13)上的急骤管柱纯化残余物,以得到红色固体状32(0.22g,51.87%)。1H-NMR(300MHz,DMSO-d6):δ2.65(s,3H),5.07(d,J=6.9Hz,2H),7.49-7.52(m,3H),7.70-7.76(m,2H),7.78-7.86(m,2H),7.91-7.80(m,3H),8.03(d,J=8.4Hz,2H),8.13-8.18(m,2H),10.54(s,1H)。
实例31 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲哚-5-基)苯甲酰胺(33)
将97(0.26g,0.76mmol)、HBTU(0.43g,1.13mmol)、DIPEA(0.20ml,1.13mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基吲哚(0.15g,1.13mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=2∶3,Rf=0.35)上的急骤管柱纯化残余物,以得到红色固体状33(0.03g,8.66%)。1H-NMR(300MHz,DMSO-d6):δ5.04(d,J=6.6Hz,2H),6.39(s,1H),7.30-7.38(m,3H),7.44(d,J=8.1Hz,2H),7.73-7.78(m,1H),7.81-7.86(m,1H),7.91(d,J=8.4Hz,2H),7.96-8.00(m,3H),8.11(s,1H),10.02(s,1H),11.01(s,1H)。
实例32 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(2-甲基-1H-吲哚-5-基)苯甲酰胺(34)
将97(0.26g,0.76mmol)、HBTU(0.43g,1.13mmol)、DIPEA(0.20ml,1.13mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基2-甲基吲哚(0.17g,1.13mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.13)上的急骤管柱纯化残余物,以得到红色固体状34(0.08g,22.40%)。1H-NMR(300MHz,DMSO-d6):δ2.36(s,3H),5.03(s,2H),6.08(s,1H),7.18-7.28(m,2H),7.43(d,J=8.4Hz,2H),7.73-7.86(m,3H),7.90(d,J=8.1Hz,2H),7.95-8.00(m,2H),8.11(br,1H),9.96(s,1H),10.82(s,1H)。
实例33 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲哚-7-基)苯甲酰胺(35)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加7-胺基吲哚(0.17g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.13)上的急骤管柱纯化残余物,以得到红色固体状35(0.02g,4.99%)。1H-NMR(300MHz,DMSO-d6):δ5.04(s,2H),6.44(s,1H),6.97(t,J=7.8Hz,1H),7.30-7.33(m,2H),7.39(d,J=7.8Hz,1H),7.46(d,J=8.1Hz,2H),7.72-7.78(m,1H),7.80-7.86(m,1H),7.86-7.99(m,4H),8.12(br,1H),10.05(s,1H),10.86(s,1H)。
实例34 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲哚-4-基)苯甲酰胺(36)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-胺基吲哚(0.17g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.45)上的急骤管柱纯化残余物,以得到红色固体状36(0.30g,74.78%)。1H-NMR(300MHz,DMSO-d6):δ5.04(s,2H),6.56(s,1H),7.04(t,J=7.8Hz,1H),7.20(d,J=1.5Hz,1H),7.27(t,J=3.0Hz,1H),7.35(d,J=7.2Hz,1H),7.44(d,J=8.4Hz,2H),7.72-7.77(m,1H),7.80-7.85(m,1H),7.93-7.99(m,4H),8.11(br,1H),9.99(s,1H),11.10(s,1H)。
实例35 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(4-(4-乙基六氢吡嗪-1-基)苯基)苯甲酰胺(37)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-(4-乙基六氢吡嗪-1-基)苯胺(0.27g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状37(0.40g,85.92%)。1H-NMR(300MHz,DMSO-d6):δ1.01(t,J=7.2Hz,3H),2.34(q,J=7.2Hz,2H),3.07(br,4H),5.01(s,2H),6.89(d,J=9.0Hz,2H),7.41(d,J=8.1Hz,2H),7.56(d,J=9.0Hz,2H),7.74(t,J=8.1Hz,1H),7.77-7.88(m,3H),7.95-7.98(m,2H),8.09(s,1H),9.98(s,1H)。
实例36 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲唑-6-基)苯甲酰胺(38)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加6-胺基吲唑(0.18g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状38(0.13g,37.94%)。1H-NMR(300MHz,DMSO-d6):δ5.05(s,2H),7.36(d,J=8.4Hz,1H),7.46(d,J=8.1Hz,2H),7.68(d,J=8.7Hz,1H),7.75(t,J=6.9Hz,1H),7.83(t,J=6.9Hz,1H),7.92(d,J=8.1Hz,2H),7.97-7.98(m,3H),8.12(br,1H),8.24(s,1H),10.32(s,1H),12.94(s,1H)。
实例37 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺(39)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基-7-氮杂吲哚(0.18g,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状39(0.31g,77.10%)。1H-NMR(300MHz,DMSO-d6):δ5.05(d,J=7.2Hz,2H),6.44(s,1H),7.45-7.47(m,3H),7.76(t,J=8.1Hz,1H),7.84(t,J=7.8Hz,1H),7.93-8.00(m,4H),8.12(br,1H),8.31(s,1H),8.44(s,1H),10.23(s,1H),11.57(s,1H)。
实例38 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吡唑并[3,4-b]吡啶-5-基)苯甲酰胺(40)
将97(0.28g,0.82mmol)、HBTU(0.47g,1.23mmol)、DIPEA(0.21ml,1.23mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加5-胺基-7-氮杂吲唑(0.12g,0.90mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.18)上的急骤管柱纯化残余物,以得到红色固体状40(0.09g,23.97%)。1H-NMR(300MHz,DMSO-d6):δ5.05(s,2H),7.48(d,J=8.4Hz,2H),7.73-7.78(m,1H),7.81-7.86(m,1H),7.94-8.00(m,4H),8.14(s,2H),8.60(d,J=2.4Hz,1H),8.73(d,J=2.1Hz,1H),10.44(s,1H),13.59(br,1H)。
实例39 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)苯甲酰胺(41)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.23ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加6-胺基-9-甲基-7-去氮嘌呤(0.20g,1.32mmol)并将混合物搅拌过夜。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.45)上的急骤管柱纯化残余物,以得到红色固体状41(0.07g,16.86%)。1H-NMR(300MHz,DMSO-d6):δ3.81(s,3H),5.05(d,J=7.2Hz,2H),6.61(d,J=3.6Hz,1H),7.44-7.47(m,3H),7.72-7.78(m,1H),7.81-7.86(m,1H),7.95-8.04(m,4H),8.12(t,J=7.5Hz,1H),8.57(s,1H),11.00(s,1H)。
实例40 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(2,3-二氢-1H-茚-4-基)苯甲酰胺(42)
将97(0.30g,0.88mmol)、HBTU(0.50g,1.32mmol)、DIPEA(0.13ml,1.32mmol)及DMF(2.5ml)的混合物搅拌一会儿,然后在室温下向其中添加4-胺基茚烷(0.24ml,1.32mmol)并将混合物搅拌过夜。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状42(0.33g,82.07%)。1H-NMR(300MHz,DMSO-d6):δ1.89-1.98(m,2H),2.81(t,J=7.5Hz,2H),2.88(t,J=7.5Hz,2H),5.02(d,J=7.2Hz,2H),7.05-7.13(m,2H),7.22(d,J=7.5Hz,1H),7.42(d,J=8.1Hz,2H),7.71-7.76(m,1H),7.79-7.85(m,1H),7.89(d,J=8.4Hz,2H),7.95-7.98(m,2H),8.10(t,J=7.5Hz,1H),9.82(s,1H)。
实例48 4-(((3-溴-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-2-基)苯甲酰胺(6)
搅拌2,3-二溴-1,4-萘醌(0.31g,0.97mmol)、4-(胺基甲基)-N-(吡啶-2-基)苯甲酰胺(0.20g,0.88mmol)及EtOH(10ml)的混合物并使其回流过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.20)上的急骤管柱纯化残余物,以得到红色固体状6(0.13g,31.95%)。1H-NMR(300MHz,DMSO-d6):δ5.05(d,J=7.2Hz,2H),7.14(m,1H),7.41(d,J=8.1Hz,2H),7.73(t,J=7.5Hz,1H),7.81(m,2H),7.97(m,5H),8.15(d,J=8.1Hz,1H),8.36(d,J=4.8Hz,1H),10.69(s,1H)。
实例49 4-(嘧啶-4-基胺甲酰基)苄基胺基甲酸第三丁基酯(100)
在0℃下将4-(胺基甲基)苯甲酸(5.0g,32.95mmol)缓慢添加至于H2O(62.5ml)及THF(25ml)中的相应氢氧化钠(1.45g,36.25毫莫耳)及二碳酸二-第三丁基酯(7.95g,36.25mmol)中。使反应混合物升温至室温,并再继续搅拌18h。蒸发溶液以得到残余物。向残余物中添加DMF(0.36mL)、吡啶(18mL)、草酰氯(6.24ml)及甲苯(144ml)并将混合物在rt下搅拌6hr。过滤溶液,用甲苯洗涤,并蒸发滤液以得到残余物。向残余物中添加吡啶(112mL),并添加4-胺基嘧啶(3.74g,39.4mmol)并将混合物在室温下搅拌16hr。蒸发溶液以得到残余物,通过在硅胶(EtOAc∶正己烷=2∶3)上的急骤管柱对其进行纯化,以得到100(3.03g,28.00%)。1H NMR(300MHz,CDCl3):δ1.48(s,3H),4.41(d,J=6.0Hz,2H),5.02(brs,1H),7.45(d,J=8.4Hz,2H),7.91(d,J=8.1Hz,2H),8.33-8.36(m,1H),8.69(d,J=5.7Hz,1H),8.72(brs,1H),8.88(s,1H)。
实例50 4-(吡嗪-2-基胺甲酰基)苄基胺基甲酸第三丁基酯(101)
在0℃下将4-(胺基甲基)苯甲酸(5.0g,32.95mmol)缓慢添加至于H2O(62.5ml)及THF(25mL)中的相应氢氧化钠(1.45g,36.25mmol)及二碳酸二-第三丁基酯(7.95g,36.25mmol)中。使反应混合物升温至室温,并再继续搅拌18h。蒸发溶液以得到残余物。向残余物中添加DMF(0.36ml)、吡啶(18ml)、草酰氯(6.24ml)及甲苯(144ml)并将混合物在室温下搅拌6hr。过滤溶液,用甲苯洗涤,并蒸发滤液以得到残余物。向残余物中添加吡啶(112ml),并添加2-胺基吡嗪(3.74g,39.4mmol)并将混合物在rt下搅拌16hr。通过在硅胶(EtOAc∶正己烷=2∶3)上的急骤管柱纯化残余物,以得到101(3.90g,36.05%)。1H NMR(300MHz,DMSO-d6):δ1.44(s,3H),4.37(d,J=5.4Hz,2H),4.98(brs,1H),7.41(d,J=8.4Hz,2H),7.88(d,J=8.4Hz,2H),8.23-8.25(m,1H),8.34-8.36(m,1H),8.54(s,1H),9.67(s,1H)。
实例51 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(嘧啶-4-基)苯甲酰胺(7)
将2,3-二氯-1,4-萘醌(0.25g,1.10mmol)及100(0.28g,1.23mmol)及乙醇(10ml)的混合物回流16h。过滤反应混合物洗涤。过滤残余物且不经进一步纯化,以得到红色固体状7(0.08g,17.36%)。1H NMR(300MHz,DMSO-d6):δ5.04(d,J=6.6Hz,2H),7.45(d,J=8.1Hz,2H),7.72-7.85(m,2H),7.97-7.99(m,4H),8.11(m,1H),8.19(d,J=4.5Hz,1H),8.70(d,J=5.4Hz,1H),8.93(s,1H),11.18(s,1H)。
实例52 4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡嗪-2-基)苯甲酰胺(8)
将2,3-二氯-1,4-萘醌(1.19g,5.26mmol)及101(1.5g,6.57mmol)及乙醇(20ml)的混合物回流16h。过滤反应混合物并洗涤。过滤残余物且不经进一步纯化,以得到红色固体状8(0.48g,21.79%)。1H NMR(300MHz,DMSO-d6):δ5.04(d,J=7.2Hz,2H),7.45(d,J=8.4Hz,2H),7.74-7.85(m,2H),7.95-8.01(m,4H),8.11(t,J=6.9Hz,1H),8.40(d,J=2.4Hz,1H),8.44-8.46(m,1H),9.39(d,J=1.5Hz,1H),11.04(s,1H)。
实例53 4-胺基-N-(吡啶-2-基)苯甲酰胺(103)
将2-胺基吡啶(0.50g,5.31mmol)、4-硝基苯甲酰氯(1.04g,5.58mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。用水淬灭反应并利用二氯甲烷(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.75)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将浅黄色固体状物溶解于MeOH(5ml)中并在室温下添加10%Pd/C作为触媒并将混合物在H2下搅拌过夜。经由硅藻土过滤10%Pd/C并自滤液去除溶剂,以得到油状产物。过滤残余物且不经进一步纯化,以得到黄色产物形式的103(0.70g,61.82%)。1H-NMR(500MHz,CDCl3):δ4.06(s,2H),6.71(d,J=8.5Hz,2H),7.03(m,1H),7.73(m,1H),7.76(d,J=8.5Hz,2H),8.28(d,J=4.0Hz,1H),8.36(d,J=8.5Hz,1H),8.44(br,1H)。
实例54 4-胺基-N-甲基-N-(吡啶-2-基)苯甲酰胺(104)
将2-胺基吡啶(0.50g,5.31mmol)、4-硝基苯甲酰氯(1.04g,5.58mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。用水淬灭反应并利用二氯甲烷(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.75)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将所述浅黄色固体状物溶解于DMF(2ml)中并在室温下添加60%NaH(0.07g,3.09mmol)并将混合物搅拌10min。添加碘甲烷(0.26ml,4.12mmol)并将混合物在室温下搅拌过夜。将水添加至残余物中以产生沈淀物。过滤反应物,以获得沈淀物且不经进一步纯化。将产物溶解于IPA/H2O(10ml)中并添加NH4Cl(0.10g,1.86mmol)及Fe粉末(0.16g,2.79mmol)并搅拌混合物并使其回流1h。经由硅藻土过滤Fe粉末并自滤液去除溶剂,以获得油状产物。过滤残余物且不经进一步纯化,以得到白色产物形式的104(0.21g,44.07%)。1H-NMR(500MHz,CDCl3):δ3.83(s,3H),3.89(s,2H),6.41(t,J=7.0Hz,1H),6.66(d,J=8.5Hz,2H),7.44(m,1H),7.45(m,1H),8.12(d,J=9.0Hz,2H),8.25(d,J=9.0Hz,1H)。
实例55 4-胺基-N-乙基-N-(吡啶-2-基)苯甲酰胺(105)
将2-胺基吡啶(0.50g,5.31mmol)、4-硝基苯甲酰氯(1.04g,5.58mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。用水淬灭反应并利用二氯甲烷(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.75)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将所述浅黄色固体状物溶解于DMF(2ml)中并在室温下添加60%NaH(0.07g,3.09mmol)并将混合物搅拌10min。添加碘乙烷(0.33ml,4.12mmol)并将混合物在室温下搅拌过夜。将水添加至残余物中以产生沈淀物。过滤反应物,以获得沈淀物且不经进一步纯化。将产物溶解于MeOH(5ml)中并添加10%Pd/C作为触媒并将混合物在H2下搅拌过夜。经由硅藻土过滤10%Pd/C并自滤液去除溶剂,以获得油状产物。通过在硅胶(二氯甲烷∶甲醇=9∶1,Rf=0.40)上的急骤管柱纯化残余物,以得到黄色产物形式的105(0.21g,40.59%)。1H-NMR(500MHz,CDCl3):δ1.49(t,J=7.5Hz,3H),3.89(s,2H),4.34(q,J=7.5Hz,2H),6.43(m,1H),6.66(d,J=8.5Hz,2H),7.43(m,1H),7.48(m,1H),8.10(d,J=8.5Hz,2H),8.26(d,J=9.0Hz,1H)。
实例56 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡啶-2-基)苯甲酰胺(50)
将103(0.30g,1.41mmol)及2,3-二氯-1,4-萘醌(0.35g,1.55mmol)的混合物溶解于EtOH(20ml)中并搅拌混合物并使其回流3天。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状50(0.03g,5.27%)。1H-NMR(500MHz,DMSO-d6):δ7.15(m,3H),7.81(t,J=8.0Hz,2H),7.87(t,J=8.0Hz,1H),7.97(d,J=8.5Hz,2H),8.04(d,J=7.5Hz,2H),8.16(d,J=8.5Hz,1H),8.36(d,J=4.5Hz,1H),9.46(s,1H),10.63(s,1H)。
实例57 4-((3-溴-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡啶-2-基)苯甲酰胺(51)
将103(0.35g,1.64mmol)及2,3-二溴-1,4-萘醌(0.57g,1.80mmol)的混合物溶解于EtOH(15ml)中并搅拌混合物并使其回流4天。通过抽吸过滤来过滤残余物并通过乙酸乙酯洗涤,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状51(0.03g,4.08%)。1H-NMR(500MHz,CDCl3):δ7.07-7.10(m,1H),7.16(d,J=8.5Hz,2H),7.76(m,4H),7.93(d,J=8.0Hz,2H),8.14(d,J=7.5Hz,1H),8.22(d,J=7.5Hz,1H),8.31(d,J=4.5Hz,1H),8.38(d,J=8.5Hz,1H),8.55(br,1H)。
实例58 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-甲基-N-(吡啶-2-基)苯甲酰胺(52)
将104(0.24g,1.06mmol)及2,3-二氯-1,4-萘醌(0.27g,1.17mmol)的混合物溶解于EtOH(15m))中并搅拌混合物并使其回流3天。通过抽吸过滤来过滤残余物,以得到红色产物。通过在硅胶(二氯甲烷∶甲醇=9∶1,Rf=0.50)上的急骤管柱纯化残余物,以得到红色固体状52(0.08g,18.06%)。1H-NMR(500MHz,DMSO-d6):δ3.85(s,3H),6.70(m,1H),7.10(d,J=8.5Hz,2H),7.70(m,1H),7.80(t,J=7.5Hz,1H),7.86(m,1H),8.03(d,J=8.0Hz,2H),8.09(d,J=8.5Hz,2H),8.11(m,1H),8.27(d,J=9.0Hz,1H),9.42(s,1H)。
实例59 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-乙基-N-(吡啶-2-基)苯甲酰胺(53)
将105(0.25g,0.92mmol)及2,3-二氯-1,4-萘醌(0.23g,1.01mmol)的混合物溶解于EtOH(15ml)中并搅拌混合物并使其回流4天。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状53(0.18g,45.30%)。1H-NMR(500MHz,CDCl3):δ1.53(m,3H),4.41(d,J=6.5Hz,2H),6.55(s,1H),7.08(d,J=8.5Hz,2H),7.57(m,2H),7.70(m,1H),7.77(m,2H),8.13(d,J=7.5Hz,1H),8.20(d,J=9.0Hz,1H),8.27(d,J=7.5Hz,2H),8.38(d,J=9.0Hz,1H)。
实例60 4-((3-异丙基-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡啶-2-基)苯甲酰胺(56)
将51(0.29g,0.86mmol)的混合物溶解于EtOH(3.3ml)及甲苯(6.5ml)中并添加Pd(PPh3)4(0.08g,0.07mmol)、2M K2CO3(aq.)(1ml)及异丙基硼酸(0.07g,0.78mmol)。经由硅藻土过滤反应物并自滤液去除溶剂,以得到油状产物。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.33)上的急骤管柱纯化残余物,以得到红色产物形式的56(0.03g,11.22%)。1H-NMR(300MHz,CDCl3):δ1.29(d,J=6.6Hz,6H),2.69(五重峰,J=6.9Hz,1H),7.09(m,3H),7.22(s,1H),7.67(m,1H),7.75(m,2H),7.91(d,J=8.7Hz,2H),8.09(m,2H),8.31(m,1H),8.37(m,1H),8.54(s,1H)。
实例61 4-胺基-N-(吡嗪-2-基)苯甲酰胺(108)
将2-胺基吡嗪(0.50g,5.26mmol)、4-硝基苯甲酰氯(1.02g,5.52mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。添加水以产生沈淀物,以得到黄色产物。将产物溶解于IPA/H2O(10ml)及NH4Cl(0.78g,14.61mmol)中并添加Fe粉末(0.54g,9.74mmol)并搅拌混合物并使其回流1h。经由硅藻土过滤Fe粉末并自滤液去除溶剂,以得到油状产物。过滤残余物且不经进一步纯化,以得到白色产物形式的108(0.37g,33.14%)。1H-NMR(500MHz,CD3OD+CDCl3):δ6.60(d,J=8.5Hz,2H),7.66(d,J=8.5Hz,2H),8.18(s,2H),9.49(s,1H)。
实例62 4-胺基-N-(嘧啶-2-基)苯甲酰胺(109)
将2-胺基嘧啶(0.50g,5.26mmol)、4-硝基苯甲酰氯(1.02g,5.52mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。添加水以产生沈淀物,以得到黄色产物。将产物溶解于IPA/H2O(10ml)中并添加NH4Cl(0.78g,14.61mmol)及Fe粉末(0.54g,9.74mmol)并搅拌混合物并使其回流1h。经由硅藻土过滤Fe粉末并自滤液去除溶剂,以得到油状产物。过滤残余物且不经进一步纯化,以得到白色产物形式的109(1.04g,50.88%)。1H-NMR(500MHz,CD3OD+CDCl3):δ6.58(d,J=8.5Hz,2H),6.95(t,J=4.5Hz,1H),7.66(d,J=8.5Hz,2H),8.50(d,J=5.0Hz,2H)。
实例63 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡嗪-2-基)苯甲酰胺(54)
将108(0.15g,0.70mmol)及2,3-二氯-1,4-萘醌(0.17g,0.77mmol)的混合物溶解于EtOH(15ml)中。搅拌反应物并使其回流过夜。通过抽吸过滤来过滤残余物并通过乙酸乙酯、二氯甲烷及甲醇洗涤,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状54(0.16g,56.46%)。1H-NMR(300MHz,DMSO-d6):δ7.19(d,J=8.7Hz,2H),7.86(m,2H),8.01(d,J=9.0Hz,2H),8.06(m,2H),8.43(m,2H),9.41(s,1H),9.53(s,1H),11.01(s,1H)。
实例64 4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(嘧啶-2-基)苯甲酰胺(55)
将109(0.30g,1.40mmol)及2,3-二氯-1,4-萘醌(0.35g,1.54mmol)的混合物溶解于EtOH(15ml)中并搅拌混合物并使其回流3天。通过在硅胶(二氯甲烷∶甲醇=9∶1,Rf=0.55)上的急骤管柱纯化残余物,以得到红色固体状55(0.14g,24.70%)。1H-NMR(300MHz,DMSO-d6):δ7.17(d,J=7.8Hz,2H),7.84(m,2H),8.03(m,4H),8.39(d,J=2.4Hz,1H),8.46(m,1H),9.40(d,J=1.5Hz,1H),9.52(br,1H),10.98(s,1H)。
实例65 3-胺基-N-(吡啶-2-基)苯甲酰胺(110)
将2-胺基吡啶(0.50g,5.31mmol)、3-硝基苯甲酰氯(1.04g,5.58mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。用水淬灭反应并利用乙酸乙酯(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.60)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将所述浅黄色固体状物溶解于MeOH(5ml)中并在室温下添加10%Pd/C作为触媒并将混合物在H2下搅拌过夜。经由硅藻土过滤10%Pd/C并自滤液去除溶剂,以得到油状产物。通过在硅胶(乙酸乙酯∶正己烷=2∶1,Rf=0.38)上的急骤管柱纯化残余物,以得到白色产物形式的110(0.25g,83.31%)。1H-NMR(500MHz,CDCl3):δ3.85(s,2H),6.86(d,J=8.5Hz,1H),7.07(m,1H),7.25(m,3H),7.75(m,1H),8.30(d,J=4.5Hz,1H),8.37(d,J=8.5Hz,1H),8.53(br,1H)。
实例66 3-胺基-N-(嘧啶-2-基)苯甲酰胺(111)
将2-胺基嘧啶(0.50g,5.26mmol)、3-硝基苯甲酰氯(1.02g,5.52mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。用水淬灭反应并利用二氯甲烷(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(二氯甲烷∶甲醇=9∶1,Rf=0.48)上的急骤管柱纯化残余物,以得到浅黄色固体状物。将产物溶解于IPA/H2O(10ml)中并添加NH4Cl(0.54g,10.08mmol)及Fe粉末(0.84g,15.12mmol)并搅拌混合物并使其回流1h。经由硅藻土过滤Fe粉末并自滤液去除溶剂,以得到油状产物。过滤残余物且不经进一步纯化,以得到白色产物形式的111(0.99g,87.64%)。1H-NMR(300MHz,CDCl3):δ3.89(s,2H),6.86(m,1H),7.05(t,J=4.8Hz,1H),7.27(m,3H),8.66(d,J=5.1Hz,3H)。
实例67 3-胺基-N-(吡嗪-2-基)苯甲酰胺(112)
将2-胺基吡嗪(0.50g,5.26mmol)、3-硝基苯甲酰氯(1.02g,5.52mmol)、吡啶(1ml)及二氯甲烷(5ml)的混合物在室温下搅拌过夜。添加水以产生沈淀物。过滤残余物且不经进一步纯化,以得到浅黄色固体状物。将产物溶解于IPA/H2O(10ml)中并添加NH4Cl(0.53g,9.82mmol)及Fe粉末(0.82g,14.73mmol)并搅拌混合物并使其回流1h。经由硅藻土过滤Fe粉末并自滤液去除溶剂,以得到油状产物。过滤残余物且不经进一步纯化,以得到白色产物形式的112(1.02g,90.63%)。1H-NMR(300MHz,CDCl3):δ3.88(s,2H),6.88(m,1H),7.25(m,3H),8.26(q,J=1.5Hz,1H),8.37(d,J=2.4Hz,1H),8.48(s,1H),9.70(d,J=1.5Hz,1H)。
实例68 3-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡啶-2-基)苯甲酰胺(57)
将110(0.59g,2.77mmol)及2,3-二氯-1,4-萘醌(0.69g,3.05mmol)的混合物溶解于EtOH(15ml)中并搅拌混合物并使其回流2天。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状57(0.67g,59.90%)。1H-NMR(500MHz,CDCl3+DMSO-d6):δ6.93(m,2H),7.07(t,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.46(s,1H),7.60(d,J=8.0Hz,1H),7.70(m,3H),8.00(d,J=5.0Hz,1H),8.03(d,J=9.0Hz,1H),8.45(s,1H)。
实例69 3-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(嘧啶-2-基)苯甲酰胺(58)
将111(0.35g,1.63mmol)及2,3-二氯-1,4-萘醌(0.41g,1.79mmol)的混合物溶解于EtOH(15ml)中并搅拌混合物并使其回流3天。通过在硅胶(二氯甲烷∶甲醇=9∶1,Rf=0.48)上的急骤管柱纯化残余物,以得到红色固体状58(0.04g,7.06%)。1H-NMR(300MHz,DMSO-d6):δ7.24(t,J=4.8Hz,1H),7.35(m,1H),7.44(t,J=8.1Hz,1H),7.72(m,2H),7.84(m,2H),8.04(m,2H),8.71(d,J=4.8Hz,2H),9.42(s,1H),10.90(s,1H)。
实例70 3-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡嗪-2-基)苯甲酰胺(59)
将112(0.25g,1.17mmol)及2,3-二氯-1,4-萘醌(0.29g,1.29mmol)的混合物溶解于EtOH(15m))中并搅拌混合物并使其回流过夜。通过抽吸过滤来过滤残余物且不经进一步纯化,以得到红色固体状59(0.24g,50.67%)。1H-NMR(300MHz,DMSO-d6):δ7.37(m,1H),7.46(t,J=7.8Hz,1H),7.80(m,3H),7.87(m,1H),8.04(m,2H),8.40(d,J=2.7Hz,1H),8.45(m,1H),9.39(d,J=1.5Hz,1H),10.99(s,1H)。
实例71 N-(4-胺基苯基)吡啶酰胺(115)
搅拌吡啶甲酸(0.50g,4.06mmol)、亚硫酰氯(0.88ml,12.18mmol)及二氯甲烷(5ml)的混合物并使其回流3h。然后向反应物中添加溶解于CH2Cl2(5ml)中的4-硝基苯胺(0.56g,4.06mmol)并搅拌混合物并使其回流过夜。用水淬灭反应并利用乙酸乙酯(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.40)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将所述浅黄色固体状物溶解于MeOH(5ml)中并在室温下添加10%Pd/C作为触媒并将混合物在H2下搅拌过夜。经由硅藻土过滤10%Pd/C并自滤液去除溶剂,以得到黄色产物。过滤残余物且不经进一步纯化,以得到黄色固体状115(0.36g,41.64%)。1H-NMR(500MHz,CD3OD):δ6.75(m,2H),7.48(m,2H),7.55(m,1H),7.97(m,1H),8.16(d,J=2.0Hz,1H)。
实例72 N-(4-胺基苯基)异烟碱酰胺(116)
搅拌异烟碱酰氯(0.50g,2.81mmol)、碳酸铯(1.83g,5.62mmol)、乙腈(10ml)的混合物并使其回流过夜。然后添加4-硝基苯胺(0.19g,1.41mmol),并将混合物在室温下搅拌过夜。用水淬灭反应并利用乙酸乙酯(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=3∶1,Rf=0.25)上的急骤管柱纯化残余物,以得到浅黄色固体状物。然后将所述浅黄色固体状物溶解于MeOH(5ml)中并在室温下添加10%Pd/C作为触媒并将混合物在H2下搅拌过夜。经由硅藻土过滤10%Pd/C并自滤液去除溶剂,以得到黄色产物。过滤残余物且不经进一步纯化,以得到黄色固体状116(0.10g,35.29%)。1H-NMR(500MHz,CD3OD):δ6.74(d,J=9.0Hz,2H),7.39(d,J=8.5Hz,2H),7.85(d,J=6.0Hz,2H),8.70(d,J=6.0Hz,2H)。
实例73 N-(4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)苯基)吡啶酰胺(60)
在微波下在150℃下将110(0.10g,0.47mmol)及2,3-二氯-1,4-萘醌(0.11g,0.49mmol)的混合物溶解于EtOH(2ml)中并保持2min。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.50)上的急骤管柱纯化残余物,以得到红色固体状60(0.01g,3.54%)。1H-NMR(500MHz,DMSO-d6):δ7.13(d,J=8.5Hz,2H),7.67(m,1H),7.79(m,1H),7.86(m,3H),8.03(m,2H),8.06(m,1H),8.15(d,J=7.5Hz,1H),8.74(d,J=4.5Hz,1H),9.29(s,1H),10.65(s,1H)。
实例74 N-(4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)苯基)异烟碱酰胺(61)
在微波下在150℃下将116(0.10g,0.47mmol)及2,3-二氯-1,4-萘醌(0.11g,0.49mmol)的混合物溶解于EtOH(2ml)中并保持2min。通过在硅胶(乙酸乙酯∶正己烷=3∶1,Rf=0.25)上的急骤管柱纯化残余物,以得到红色固体状61(0.01g,5.27%)。1H-NMR(500MHz,DMSO-d6):δ7.14(d,J=8.5Hz,2H),7.71(d,J=9.0Hz,2H),7.80(t,J=8.0Hz,1H),7.87(m,3H),8.03(m,2H),8.78(d,J=5.5Hz,2H),9.32(s,1H),10.50(s,1H)。
实例75 1-((4-硝基苯基)磺酰基)-1H-吲哚(119)
将吲哚(0.75g,6.40mmol)的混合物溶解于DMF(3ml)中并添加NaH(0.38g,9.60mmol)及4-硝基苯磺酰氯(2.13g,9.60mmol)并将混合物在室温下搅拌过夜。添加水以产生沈淀物。通过抽吸过滤来过滤残余物且不经进一步纯化,以得到白色产物,以得到黄色产物形式的119(0.78g,40.31%)。1H-NMR(300MHz,CDCl3):δ6.72(d,J=2.7Hz,1H),7.31(m,2H),7.55(m,2H),8.00(m,3H),8.25(d,J=2.4Hz,2H)。
实例76 4-((1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)苯胺(120)
将7-氮杂吲哚(1.00g,8.46mmol)的混合物溶解于DMF(3ml)中并添加NaH(0.51g,12.69mmol)并添加4-硝基苯磺酰氯(2.81g,12.69mmol)并将混合物在室温下搅拌过夜。添加水以产生沈淀物。通过抽吸过滤来过滤残余物,以得到白色产物。将产物溶解于IPA/H2O(70ml)中并添加NH4Cl(0.75g,14.16mmol)及Fe粉末(1.18g,21.24mmol)并搅拌混合物并使其回流1h。过滤反应物以经由硅藻土去除Fe粉末且通过在硅胶(乙酸乙酯∶正己烷=1∶4,Rf=0.08)上的急骤管柱纯化残余物,以得到黄色产物形式的120(1.13g,48.83%)。1H-NMR(300MHz,CDCl3):δ4.15(s,2H),6.54(d,J=3.9Hz,1H),6.60(d,J=8.7Hz,2H),7.15(m,1H),7.17(d,J=3.9Hz,1H),7.82(m,1H),7.96(d,J=8.7Hz,2H),8.41(m,1H)。
实例77 2-((4-((1H-吲哚-1-基)磺酰基)苯基)胺基)-3-氯萘-1,4-二酮(62)
将119的混合物溶解于IPA/H2O(30ml)中并添加NH4Cl(0.32g,5.96mmol)及Fe粉末(0.50g,8.94mmol)并搅拌混合物并使其回流1 h。过滤反应物以经由硅藻土去除Fe粉末且通过在硅胶(乙酸乙酯∶正己烷=1∶4,Rf=0.08)上的急骤管柱纯化残余物,以得到黄色产物。然后将残余物溶解于EtOH(15ml)中并添加2,3-二氯-1,4-萘醌(0.70g,3.07mmol)并搅拌混合物并使其回流3天。通过抽吸过滤来过滤残余物,以得到红色产物。通过在硅胶(乙酸乙酯∶正己烷=1∶4,Rf=0.18)上的急骤管柱纯化残余物,以得到红色固体状62(0.20g,15.49%)。1H-NMR(300MHz,CDCl3):δ6.67(m,1H),6.97(d,J=8.7Hz,2H),7.24(m,1H),7.31(m,1H),7.56(m,3H),7.75(m,2H),7.82(m,2H),7.97(m,1H),8.10(m,1H),8.18(m,1H)。
实例78 2-((4-((1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)苯基)胺基)-3-氯萘-1,4-二酮(63)
将120(1.20g,4.39mmol)及2,3-二氯-1,4-萘醌(1.10g,4.83mmol)的混合物溶解于EtOH(20ml)中并搅拌混合物并使其回流4天。通过抽吸过滤来过滤残余物,以得到红色产物。过滤残余物且不经进一步纯化,以得到红色固体状63(0.63g,30.94%)。1H-NMR(300MHz,DMSO-d6):δ6.81(d,J=3.9Hz,1H),7.18(d,J=9.0Hz,2H),7.29(m,1H),7.83(m,3H),8.03(m,5H),8.34(d,J=1.5Hz,1H),9.55(s,1H)。
实例79 2-((4-((1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)苯基)胺基)-3-异丙基萘-1,4-二酮(64)
将120(0.30g,1.10mmol)及2,3-二溴-1,4-萘醌(0.38g,1.21mmol)的混合物溶解于EtOH(20ml)中并搅拌混合物并使其回流4天。通过抽吸过滤来过滤残余物,以得到红色产物。然后将残余物溶解于EtOH(1.5ml)及甲苯(3ml)中并添加Pd(PPh3)4(0.02g,0.02mmol)、2M K2CO3(aq.)(0.3ml)及异丙基硼酸(0.02g,0.24mmol)。经由硅藻土过滤反应物并自滤液去除溶剂,以得到油状产物。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.55)上的急骤管柱纯化残余物,以得到红色产物形式的64(0.03g,5.78%)。1H-NMR(300MHz,CDCl3):δ1.23(d,J=6.6Hz,6H),2.56(五重峰,J=6.9Hz,1H),6.58(d,J=3.9Hz,1H),6.97(d,J=9.0Hz,2H),7.06(s,1H),7.17(m,1H),7.68(m,3H),7.84(m,1H),8.06(m,2H),8.13(d,J=9.0Hz,2H),8.41(m,1H)。
实例80 1-((4-硝基苯基)磺酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶(122)
将7-氮杂吲哚啉(0.50g,4.16mmol)的混合物溶解于DMF(5ml)中并添加NaH(0.25g,6.24mmol)并添加4-硝基苯磺酰氯(0.92g,4.16mmol)并将混合物在室温下搅拌0.5h。用水淬灭反应并利用乙酸乙酯(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.26)上的急骤管柱纯化残余物,以得到黄色固体状122(0.21g,16.53%)。1H-NMR(500MHz,CDCl3):δ3.09(t,J=8.5Hz,2H),4.10(t,J=8.5Hz,2H),6.85-6.87(m,1H),7.39(d,J=9.0Hz,1H),8.13(s,1H),8.30-8.35(m,4H)。
实例81 1-((3-硝基苯基)磺酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶(123)
将7-氮杂吲哚啉(0.20g,1.66mmol)的混合物溶解于吡啶(1.5ml)中并添加3-硝基苯磺酰氯(0.55g,2.49mmol)并将混合物在50℃下搅拌过夜。利用3N HCl(aq.)淬灭反应并利用乙酸乙酯(30ml*3)执行萃取。收集有机层并经无水MgSO4干燥并在真空中浓缩,以得到黄色产物。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.26)上的急骤管柱纯化残余物,以得到橙色固体状123(0.30g,59.19%)。1H-NMR(500MHz,CDCl3+CD3OD):δ2.95(t,J=8.0Hz,2H),3.92(t,J=8.5Hz,2H),6.77(s,1H),7.35(s,1H),7.58(t,J=8.0Hz,1H),7.90(d,J=5.5Hz,1H),8.24(s,1H),8.73(s,1H)。
实例82 2-氯-3-((4-((2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)苯基)胺基)萘-1,4-二酮(65)
将122(0.20g,0.66mmol)的混合物溶解于MeOH(10ml)中并添加10%Pd/C作为触媒并将混合物在H2下搅拌1h。过滤10%Pd/C并自滤液去除溶剂。过滤残余物且不经进一步纯化且将其溶解于EtOH(15ml)中,然后添加2,3-二氯-1,4-萘醌(0.15g,0.66mmol)。将反应物回流2天。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.33)上的急骤管柱纯化残余物,以得到红色固体状65(0.02g,6.50%)。1H-NMR(500MHz,CDCl3):δ3.07(t,J=8.5Hz,2H),4.08(t,J=9.0Hz,2H),6.82-6.84(m,1H),7.05(d,J=8.5Hz,1H),7.37(d,J=7.5Hz,1H),7.65(d,J=8.5Hz,2H),7.81-7.83(m,2H),7.95-7.97(m,1H),8.08-8.19(m,2H),8.28(d,J=8.5Hz,2H)。
实例83 2-溴-3-((4-((2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)苯基)胺基)萘-1,4-二酮(66)
将122(0.14g,0.46mmol)的混合物溶解于MeOH(15ml)中并添加10%Pd/C作为触媒并将混合物在H2下搅拌1h。过滤10%Pd/C并自滤液去除溶剂。过滤残余物且不经进一步纯化并将其溶解于EtOH(15ml)中,然后添加2,3-二溴-1,4-萘醌(0.15g,0.46mmol)。将反应物回流2天。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.33)上的急骤管柱纯化残余物,以得到红色固体状66(0.02g,8.52%)。1H-NMR(500MHz,CDCl3):δ3.07(t,J=8.5Hz,2H),4.07(t,J=8.5Hz,2H),6.54(s,1H),6.83-6.85(m,1H),7.34-7.38(m,3H),7.68-7.71(m,2H),7.78(t,J=7.5Hz,1H),8.10-8.13(m,2H),8.17(d,J=8.5Hz,2H)。
实例84 2-氯-3-((3-((2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)磺酰基)-苯基)胺基)萘-1,4-二酮(67)
将123(0.50g,1.64mmol)的混合物溶解于IPA/H2O(16.4ml)中并添加Fe粉末(0.27g,4.92mmol)及NH4Cl(0.18g,3.28mmol)。搅拌反应物并使其回流2h。通过乙酸乙酯(30ml*3)萃取残余物且不经进一步纯化,以得到产物。将产物溶解于EtOH(15ml)中,然后添加2,3-二氯-1,4-萘醌(0.37g,1.64mmol)。将反应物回流2天。通过在硅胶(乙酸乙酯∶正己烷=1∶1,Rf=0.33)上的急骤管柱纯化残余物,以得到红色固体状67(0.03g,3.93%)。1HNMR(300MHz,DMSO-d6):δ3.02(t,J=8.7Hz,2H),4.01(t,J=8.1Hz,2H),6.80(t,J=6.6Hz,1H),7.20(d,J=6.9Hz,1H),7.34-7.42(m,2H),7.66-7.76(m,3H),7.81(d,J=7.5Hz,1H),7.99(d,J=5.4Hz,1H),8.05(d,J=6.3Hz,1H),8.11(d,J=6.0Hz,1H)。
实例85 N-(3-硝基苄基)吡啶-2-胺(124)
将2-胺基吡啶(1.1g,11.66毫莫耳)及3-硝基苄基氯(1.0g,5.83mmol)的混合物溶解于甲苯(30mL)中。搅拌反应物并使其在N2下回流过夜。用饱和NaHCO3(aq.)及饱和NaCl(aq.)洗涤残余物且然后加以处理。过滤产物且不经进一步纯化,以得到124(1.50g,56.12%)。1H NMR(300MHz,CDCl3):δ4.66(d,J=6.0Hz,2H),5.01(brs,1H),6.39(d,J=8.4Hz,1H),6.60-6.65(m,1H),7.39-7.44(m,1H),7.49(t,J=7.8Hz,1H),7.70(d,J=8.1Hz,1H),8.09-8.12(m,2H),8.22(s,1H)。
实例86 N-(4-硝基苄基)吡啶-2-胺(125)
将2-胺基吡啶(0.18g,1.91mmol)的混合物溶解于甲苯(3ml)中并添加4-硝基苄基溴(0.21g,0.96mmol)并搅拌混合物并使其回流过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.20)上的急骤管柱纯化残余物,以得到浅黄色固体状125(0.12g,54.53%)。1H NMR(300MHz,CDCl3):δ4.67(d,J=6.0Hz,2H),5.00(s,1H),6.37(d,J=8.4Hz,1H),6.61-6.65(m,1H),7.38-7.44(m,1H),7.51(d,J=8.7Hz,2H),8.09-8.11(m,1H),8.18(d,J=8.7Hz,2H)。
实例87 3-硝基-N-(吡啶-2-基)苯磺酰胺(126)
将2-胺基吡啶(0.18g,1.91mmol)的混合物溶解于甲苯(3ml)中并添加3-硝基苯磺酰氯(0.47g,2.10mmol)并搅拌混合物并使其回流过夜。通过在硅胶(乙酸乙酯∶正己烷=1∶2,Rf=0.20)上的急骤管柱纯化残余物,以得到白色固体状126(0.23g,43.12%)。1H NMR(500MHz,CD3OD):δ6.89(t,J=7.0Hz,1H),7.33(d,J=9.0Hz,1H),7.79(t,J=8.0Hz,2H),7.92(d,J=5.5Hz,1H),8.31(d,J=7.5Hz,1H),8.40(d,J=8.0Hz,1H),8.73(s,1H)。
实例88 2-氯-3-((3-((吡啶-2-基胺基)甲基)苯基)胺基)萘-1,4-二酮(68)
将124(0.44g,1.92mmol)、Fe粉末(0.32g,5.76mmol)及氯化铵(0.21g,3.84mmol)的混合物溶解于IPA(15.2ml)及H2O(3.8ml)中并搅拌混合物并使其回流2hr。过滤反应混合物,并用二氯甲烷萃取,洗涤并加以处理。向残余物中添加乙醇(3ml)及2,3-二氯-1,4-萘醌(0.19g,0.83mmol)并将混合物回流过夜。蒸发溶液以得到残余物,通过在硅胶(EtOAc∶正己烷=2∶3)上的急骤管柱对其进行纯化,以得到68(0.05g,15.45%)。1H NMR(300MHz,CDCl3)∶δ4.54(d,J=3.6Hz,2H),4.91(brs,1H),6.38(d,J=4.8Hz,1H),6.58-6.61(m,1H),6.98(d,J=4.5Hz,1H),7.07(s,1H),7.20-7.26(m,1H),7.33-7.36(m,1H),7.38-7.42(m,1H),7.66-7.70(m,2H),7.77(t,J=4.5Hz,1H),8.09-8.12(m,2H),8.19(d,J=4.5Hz,1H)。
实例89 2-氯-3-((4-((吡啶-2-基胺基)甲基)苯基)胺基)萘-1,4-二酮(69)
将125(0.50g,2.18mmol)、Fe粉末(0.37g,6.54mmol)及氯化铵(0.23g,4.36mmol)的混合物溶解于IPA(17.4ml)及H2O(4.4ml)中并搅拌混合物并使其回流2hr。过滤反应混合物,并利用二氯甲烷萃取,洗涤并加以处理。向残余物中添加乙醇(3ml)及2,3-二氯-1,4-萘醌(0.49g,2.18mmol)并将混合物回流过夜。通过在硅胶(EtOAc∶正己烷=2∶3)上的急骤管柱纯化残余物,以得到69(0.05g,5.88%)。1H NMR(300MHz,CDCl3):δ4.54(d,J=3.6Hz,2H),4.88(brs,1H),6.38(d,J=4.8Hz,1H),6.59-6.62(m,1H),7.05(d,J=5.1Hz,2H),7.34(d,J=5.1Hz,2H),7.40-7.42(m,1H),7.65(s,1H),7.67-7.70(m,1H),7.75-7.78(m,1H),8.11-8.12(m,2H),8.18-8.20(d,J=3.9Hz,1H)。
实例90 3-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)-N-(吡啶-2-基)苯磺酰胺(70)
将125(0.50g,1.79mmol)、Fe粉末(0.30g,5.37mmol)及氯化铵(0.19g,3.58mmol)的混合物溶解于IPA(14.3ml)及H2O(3.6ml)中并搅拌混合物并使其回流2hr。过滤反应混合物,并利用二氯甲烷萃取,洗涤并加以处理。向残余物中添加乙醇(3m))及2,3-二氯-1,4-萘醌(0.41g,1.79mmol)并将混合物回流过夜。通过在硅胶(EtOAc∶正己烷=2∶3)上的急骤管柱纯化残余物,以得到70(0.10g,12.70%)。1H NMR(300MHz,DMSO-d6):δ6.84(d,J=6.6Hz,1H),7.14(d,J=8.7Hz,1H),7.25-7.29(m,1H),7.46(t,J=8.1Hz,1H),7.40-7.57(m,2H),7.72-7.66(m,1H),7.82-7.88(m,2H),7.95(d,J=4.8Hz,1H),8.00-8.04(m,2H)。
Claims (15)
2.如权利要求1之化合物,其中m是0;R1是Cl或Br;n是1;R3是H;X是C(O);R4是H;且R5是苯基,其未经取代或经一至三个选自卤素或NH2之相同或不同取代基取代;吡啶基;吡嗪基;噻唑基;苯并咪唑基;吲唑基;喹啉基或吲哚基,其中之每一者未经取代或经一个、两个或三个选自卤素或NH2之基团取代。
3.如权利要求1之化合物,其中m是0;R1是Cl或Br;n是1;R3是H;X是C(O);R4是H;且R5是吡啶基;苯基,其经卤素取代;吡嗪基,其未经取代或经NH2或C1-4烷基取代;噻唑基,其未经取代或经C1-4烷基取代;苯并咪唑基;吲唑基,其未经取代或经C1-4烷基取代;喹啉基,其未经取代或经C1-4烷基取代;或吲哚基,其未经取代或经C1-4烷基取代。
4.一种化合物,其是选自:
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡嗪-2-基)苯甲酰胺;
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-2-基)苯甲酰胺;
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(吡啶-3-基)苯甲酰胺;
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(4-氟苯基)苯甲酰胺;
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-苯基苯甲酰胺;
4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)-N-(噻唑-2-基)苯甲酰胺;
N-(1H-苯并[d]咪唑-2-基)-4-(((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基)胺基)甲基)苯甲酰胺;
N-(1H-苯并[d]咪唑-5-基)-4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)苯甲酰胺;
2-(4-(3-胺基-1H-吡唑-1-羰基)苄基胺基)-3-氯萘-1,4-二酮;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲唑-5-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(5-甲基噻唑-2-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(5-甲基-3H-吡唑-3-基)苯甲酰胺;
2-(4-(3-胺基-5-甲基-1H-吡唑-1-羰基)苄基胺基)-3-氯萘-1,4-二酮;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(3-硝基吡啶-4-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-6-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-8-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-3-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(喹啉-5-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(2-甲基喹啉-4-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲哚-5-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(2-甲基-1H-吲哚-5-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲哚-4-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吲唑-6-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺;
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(1H-吡唑并[3,4-b]吡啶-5-基)苯甲酰胺;和
4-((3-氯-1,4-二侧氧基-1,4-二氢萘-2-基胺基)甲基)-N-(7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)苯甲酰胺;
或其医药上可接受的盐。
6.一种医药组合物,其包含如权利要求1的化合物及医药上可接受的载剂。
7.如权利要求6的医药组合物,其进一步包含第二治疗剂。
8.如权利要求7的医药组合物,其中所述第二治疗剂是有丝分裂抑制剂、长春花生物碱(vinca alkaloid)、灭必治(vepesid)、蒽环抗生素、核苷类似物、EGFR抑制剂、叶酸抗代谢物、顺铂(cisplatin)、卡铂(carboplatin)或HDAC抑制剂。
9.如权利要求8的医药组合物,其中所述有丝分裂抑制剂是紫杉烷(taxane);长春花生物碱(vinca alkaloid)是长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)或长春瑞滨(vinorelbine);蒽环抗生素是多柔比星(doxorubicin)、道诺霉素(daunorubicin)、泛艾霉素(epirubicin)、伊达比星(idarubicin)、戊柔比星(valrubicin)或米托蒽醌(mitoxantrone);核苷类似物是吉西他滨(gemcitabine);EGFR抑制剂是吉非替尼(gefitinib)或厄洛替尼(erlotinib);叶酸抗代谢物是甲氧苄啶(trimethoprim)、乙胺嘧啶(pyrimethamine)或培美曲塞(pemetrexed)。
10.如权利要求9的医药组合物,其中所述紫杉烷是太平洋紫杉醇(paclitaxel)或多西他赛(docetaxel)。
11.如权利要求7的医药组合物,其中所述第二治疗剂是皮质类固醇、角质溶解剂、维生素D3衍生物、PUVA及蒽酚、β2-激动剂、皮质类固醇、免疫抑制剂、NSAID、COX-2抑制剂、生物制剂、非类固醇钙调神经磷酸酶抑制剂、类固醇消炎剂、5-胺基柳酸、DMARD、硫酸羟氯喹、发炎调节剂、干扰B细胞作用的药剂或青霉胺(penicillamine)。
12.一种如权利要求1的化合物作为制备治疗肿瘤疾病的药剂的用途。
13.如权利要求12的用途,其中所述肿瘤疾病是良性肿瘤或癌症。
14.如权利要求13的用途,其中所述癌症是选自由以下各项组成的群:肺癌、肝癌、头颈癌、T细胞淋巴瘤、胃癌、前列腺癌、乳癌、结肠直肠癌、卵巢癌、胰脏癌、肾癌、白血病、黑色素瘤、皮肤癌、脑癌及多发性骨髓瘤。
15.一种如权利要求1的化合物作为制备治疗关节炎的药剂的用途。
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Kai Xu等.Design and synthesis of naphthoquinone derivatives as antiproliferative agents and 20S proteasome inhibitors.《Bioorganic & Medicinal Chemistry Letters》.2012,1940-1951. * |
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US10577328B2 (en) | 2020-03-03 |
TW201716372A (zh) | 2017-05-16 |
JP2018529639A (ja) | 2018-10-11 |
EP3324954B1 (en) | 2022-03-09 |
CA2992981C (en) | 2023-10-17 |
WO2017014788A1 (en) | 2017-01-26 |
US20200148643A1 (en) | 2020-05-14 |
TWI690506B (zh) | 2020-04-11 |
EP3324954A4 (en) | 2019-03-06 |
AU2015402778B2 (en) | 2020-10-29 |
AU2015402778A2 (en) | 2019-09-19 |
US11919858B2 (en) | 2024-03-05 |
DK3324954T3 (da) | 2022-05-02 |
CN108135871A (zh) | 2018-06-08 |
US20180319749A1 (en) | 2018-11-08 |
NZ739867A (en) | 2023-06-30 |
ES2917526T3 (es) | 2022-07-08 |
JP6820313B2 (ja) | 2021-01-27 |
CA2992981A1 (en) | 2017-01-26 |
AU2015402778A1 (en) | 2018-03-08 |
EP3324954A1 (en) | 2018-05-30 |
BR112018001317A2 (pt) | 2018-09-11 |
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