CN106543088B - 一类sirt2蛋白抑制剂及其在制药中的用途 - Google Patents
一类sirt2蛋白抑制剂及其在制药中的用途 Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：其中，X选自等；R1选自芳基、杂芳基、取代芳基、取代杂芳基或R2选自R3选自卤素、C1～C4烷基或C1～C4烷氧基。本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择。
Description
技术领域
本发明属于化合物药物领域，具体涉及一类新型SIRT2蛋白抑制剂及其在制药中的用途。
背景技术
蛋白翻译后的可逆乙酰化修饰是蛋白功能调控的重要手段之一。组蛋白乙酰基转移酶 (HAT)可催化底物组蛋白或非组蛋白赖氨酸残基的乙酰化修饰，与此相反，组蛋白去乙酰转移酶(HDAC)可催化相应底物蛋白赖氨酸残基的去乙酰化作用，以上乙酰化/去乙酰化蛋白翻译后修饰共同调控着体内多种蛋白的功能从而参与了基因表达、细胞周期进程等重要生理过程。截止目前共研究发现18种HDAC，按照其催化机制分为两类，即Zn2+ 依赖型组蛋白去乙酰化酶(HDAC1-11)和NAD+依赖型组蛋白去乙酰化酶(Sirtuin1-7, SIRT1-7)。SIRT从细菌到人类具有高度保守性，并存在于多种组织和器官中，如肝脏、心脏、脑和胰腺等。SIRT1-7因其位于不同的亚细胞结构和作用于不完全相同的底物蛋白从而具有各异的生理功能。
在SIRT1-7当中SIRT2主要位于细胞质中，同时研究发现SIRT2可不断穿梭于细胞核和细胞质中，因此，其可催化组蛋白及α-tubulin、P53、p65、FOXO1等非组蛋白赖氨酸残基的去乙酰化作用从而调控基因的表达，微管的稳定和细胞周期进程等。由于SIRT2 参与诸多重要的生物学过程，近些年研究发现SIRT2的异常表达与多种疾病包括神经退行性疾病(帕金森、阿尔兹海默病、亨廷顿等)、肿瘤(肺癌、乳腺癌、肝癌等)等密切相关，因此，SIRT2被认为是这些疾病的潜在治疗靶点。
鉴于此，开发新型选择性高活性SIRT2抑制剂是目前药物研究的一个热点，受到国内外学者、研究机构和医药公司的高度关注。
截止目前已有大量新型SIRT2抑制剂相继被报道，其中包括Sirtinol(IC50＝46uM)、 Salermide(IC50＝25μM)、EX-527(IC50＝20μM)、AK-7(IC50＝15.5μM)、AGK2(IC50＝3.5μM) 等，它们对SIRT2蛋白的抑制活性及选择性各异，且仅极少数抑制剂表现出了一定的体内抗肿瘤或神经退行性疾病的效果，除此之外几乎暂无SIRT2的抑制剂用于相关疾病治疗的临床研究。
因此，开发真正体内外有效的SIRT2抑制剂用于相关疾病的治疗仍然是十分迫切的任务，特别是，现有SIRT2抑制剂的数量仍然较少，难以满足广大患者的需求，需要发明一类新的沉默信息调节因子2相关蛋白的抑制剂，为广大患者提供更多的用药选择。
发明内容
本发明的目的在于提供一类新的具有药用价值的N-(3,4-取代苯基)-2-(取代硫基)乙酰胺类化合物：式Ⅰ所示的化合物。
本发明提供的式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：
其中，
X选自
R1选自芳基、杂芳基、取代芳基、取代杂芳基或所述取代芳基和取代杂芳基的取代基，分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、 卤素、羟基、巯基、醚基、酯基、氨基或硝基；
R1a、R1b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、芳基、杂芳基或C3～C6环烷基；
R2选自
R2a～R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基；
R3选自卤素、C1～C4烷基或C1～C4烷氧基。
进一步的，
R1中，所述芳基为苯基或萘基，所述的杂芳基为吡啶基、呋喃基、噻吩基、喹啉基、吲唑基或喹啉基，所述取代芳基和取代杂芳基的取代基分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、
R1a、R1b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、C3～C6环烷基、苯基或噻吩基。
进一步的，R2中，R2a、R2c、R2f分别独立地选自羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基，R2b、R2d、R2e分别为H。
进一步的，所述的化合物为：
本发明还提供了一种制备上述化合物的方法，
当R2为时，它包括以下步骤：
①、化合物A与化合物B反应，得到化合物C；
其中，
化合物A与化合物B的摩尔比为1：0.5～2；
X选自
R1选自芳基、杂芳基、取代芳基、取代杂芳基或所述取代芳基和取代杂芳基的取代基，分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、 卤素、羟基、巯基、醚基、酯基、氨基或硝基；
R1a、R1b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、芳基、杂芳基或C3～C6环烷基；
Z选自卤素或羟基；
②、化合物C与化合物D反应，得到化合物Ⅰa；
其中，
化合物C与化合物D的摩尔比为1：0.5～2；
R2a～R2c分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基。
本发明还提供了一种制备上述化合物的方法，
当R2为时，它包括以下步骤：
①、化合物A与化合物B反应，得到化合物C；
其中，
化合物A与化合物B的摩尔比为1：0.5～2；
X选自
R1选自芳基、杂芳基、取代芳基、取代杂芳基或所述取代芳基和取代杂芳基的取代基，分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、 卤素、羟基、巯基、醚基、酯基、氨基或硝基；
R1a、R1b分别独立地选自C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基、芳基、杂芳基或C3～C6环烷基；
Z选自卤素或羟基；
②、化合物C与化合物E反应，得到化合物Ⅰb；
其中，
化合物C与化合物E的摩尔比为1：0.5～2；
R2d～R2f分别独立地选自H、羟基、卤素、C1～C4烷基、C1～C4烷氧基、C1～C4卤代烷基或苯基。
本发明还提供了上述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
本发明还提供了上述的化合物或其药学上可接受的盐、晶型、溶剂合物在制备治疗和 /或预防肿瘤的药物中的用途。
进一步的，所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
本发明还提供了一种治疗和/或预防肿瘤的药物组合物，它是以上述的化合物或其药学上可接受的盐、晶型、溶剂合物为活性成分，加上药学上常用的辅料制备得到的制剂。
本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～Cb烷基表明任何包含“a”至“b”个碳原子的烷基。因此，例如，C1～C4烷基是指包含1～4个碳原子的烷基，换句话说，C1～C4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然属于本发明保护的范围。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明化合物5的1H NMR图。
图2为本发明化合物5的13C NMR图。
图3为本发明化合物21的1H NMR图。
图4为本发明化合物21的13C NMR图。
图5为本发明化合物28的1H NMR图。
图6为本发明化合物28的13C NMR图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、N-(3-苄基苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物1)的合成
首先，将LiAlH4(10mmol,379.5mg)加入到反应瓶中后置于0℃下约15min后，将AlCl3(10mmol,1333mg)的乙醚(15ml)溶液滴加到反应中，混合液在0℃搅拌5min。接着将间氨基二苯甲酮(1a,1mmol,197.2mg)的乙醚(15ml)溶液滴加到反应中，并将反应移至室温反应3h,经TLC检测反应完全后，反应液先用6M HCl稀释，后用饱和NaHCO3中和，水层经乙酸乙酯(20ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得中间体1b。
然后，将中间体1b(1mmol,183mg)和溴乙酸(1.2mmol,166.8mg)溶于DCM(16ml)中，并置于0℃搅拌溶解后，在0℃下依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,1.2mmol,230.4mg),1-羟基苯并三唑(HOBT,1.2mmol,162mg),N,N-二异丙基乙胺(DIEA,2mmol,331μl),加毕，将反应移至室温搅拌反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得中间体1c。
再将化合物4,6-二甲基-2-巯基嘧啶(1.2mmol,168.2mg)溶于DMF(3ml)中，室温条件下加入叔丁醇钾(2mmol,224.4mg)并在室温下搅拌反应30min后将化合物1c(1mmol,302mg) 溶于DMF(1ml)中缓慢加入到反应中，室温搅拌反应4-5h后，经TLC检测反应完全后，往反应中加入冰水(40ml)，并用乙酸乙酯萃取(20ml×3。最后有机层经无水MgSO4干燥，浓缩后经柱层析得到化合物1(168mg,三步总产率38％)。
化合物1的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.17(s,1H),7.43-7.41(m,2H),7.31-7.27(m,2H),7.24-7.19(m,4H),7.00-6.94(m,2H),4.01(s,2H),3.91 (s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,142.3,141.5,139.6,129.2,129.1,128.8,125.5,124.2,119.9,117.4,116.5,41.6,35.9,23.8ppm。
实施例2、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氨基)苯基)乙酰胺(化合物2)的合成
首先，将间硝基苯胺(2mmol,276.3mg)、苯硼酸(1mmol,121.9mg)、 NiCl2.6H2O(0.2mmol,47.5mg)、2,2-二联吡啶(0.2mmol,31.2mg)和1,5-二氮杂二环[5.4.0]十一-5-烯(DBU,2mmol,304.4mg)溶于乙腈(10ml)中，并于室温搅拌反应28h，经TLC检测反应完全后向反应液中加入乙酸乙酯(10ml)和水(10ml)，水层经乙酸乙酯(10ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得中间体2b。
然后，将2b(0.2mmol,42mg)溶于EtOH(2ml)/H2O(1ml)中，加入NH4Cl(0.1mmol,5.4mg) 和Fe(1mmol,56mg)后于80℃反应30min，经TLC检测反应完全后趁热过滤除去不溶物质，接着加入NaHCO3调节pH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得中间体2c。
最后，利用中间体2c按照目标化合物1的合成方法合成目标化合物2，四步总产率26％。
化合物2的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.12(s,1H),8.18(s,1H),7.46(s,1H),7.24(t,J＝8.0Hz,2H),7.14(t,J＝8.0Hz,1H),7.08(d,J＝7.6Hz,2H), 7.01(d,J＝8.8Hz,1H),6.98(s,1H),6.83(t,J＝7.2Hz,1H),6.74(dd,J＝1.6Hz,J＝5.6Hz,1H), 4.02(s,2H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.2,140.8, 135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,36.0,23.8ppm。
实施例3、2-((4-甲基-6-羰基-1,6-二氢嘧啶-2-基)硫代)-N-(3-(苯胺基)苯基)乙酰胺(化合物3)的合成
首先，利用2c中间体与溴乙酸按照1c的合成方法合成3a，再利用3a与原料甲基硫脲嘧啶按照化合物1的合成方法合成目标化化合物3，两产率45％。
化合物3的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ12.56(br s, 1H),10.16(s,1H),8.20(s,1H),7.46(s,1H),7.24(t,J＝8.0Hz,2H),7.15(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,2H),7.01(d,J＝8.0Hz,1H),6.84(t,J＝7.6Hz,1H),6.75(dd,J＝1.6Hz,J＝7.6Hz,2H),6.01(br s,1H),4.06(s,2H),2.15(s,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.5,167.1,160.5，150.2,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1, 118.5,116.5,35.9,22.6ppm。
实施例4、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氧基)苯基)乙酰胺(化合物4)的合成
利用化合物4a,按照目标化合物1的合成方法合成化合物4，两步总产率为58％。
化合物4的1H NMR和13C NMR数据如下：1H NMR(400MHz,CDCl3):δ9.60(s,1H), 7.35(t,J＝8.0Hz,2H),7.27-7.25(m,2H),7.14(t,J＝7.2Hz,1H),7.09(s,1H),7.03(d,J＝7.6Hz,2H),6.82(s,1H),6.76-6.73(m,1H),3.88(s,2H),2.46(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.3,167.0,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1, 118.5,116.5,36.0,23.8ppm。
实施例5、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯硫基)苯基)乙酰胺(化合物5)的合成
首先，向反应瓶中加入间碘苯胺(5a,2mmol,438mg)、CuSO4.5H2O(0.1mmol,25mg)、KOH(10mmol,561mg)和DMSO(4ml)/H2O(0.4ml),接着加入1,2-乙二硫醇(2mmol,180μl) 并于100-110℃反应8h，然后将反应液冷却至室温后，将碘苯(2.6mmol,530.4mg)溶于 DMF(2ml)中后加入到反应中，于120℃继续反应18h。经TLC检测反应完全后，将反应冷却至室温，加入水和乙酸乙酯，经乙酸乙酯(10ml×3)萃取，合并有机相，无水Na2SO4干燥，浓缩，柱层析得中间体5b。
利用5b按照化合物1的合成方法合成目标化合物5，三步总产率46％。
化合物5的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.32(s,1H),7.92(s,1H),7.61(s,1H),7.52(d,J＝8.0Hz,1H),7.46-7.30(m,6H),7.02(d,J＝8.0Hz,1H), 6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.4,167.2,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,35.9,23.8 ppm。
实施例6、N-(3-苯甲酰苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物6)的合成
目标化合物6的合成按照化合物1的合成方法获得，两步总产率46％。
化合物6的1H NMR和13C NMR数据如下：1H NMR(400MHz,CDCl3):δ9.84(s,1H), 8.02(t,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,2H),7.66(s,1H),7.62(t,J＝7.2Hz,1H),7.52-7.43(m,4H),6.85(s,1H),3.91(s,2H),2.50(s,6H)ppm；13C NMR(100MHz,DMSO):δ196.0, 169.7,167.4,139.6,138.0,137.5,133.1,130.0,129.6,129.0,124.9,123.5,120.6,116.5,35.9,23.8ppm。
实施例7、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(羟基(苯基)甲基)苯基)乙酰胺(化合物7) 的合成
首先，将LiAlH4(5mmol,189.8mg)加入到反应瓶中，置于0℃下搅拌15min后将AlCl3(5mmol,666.7mg)的乙醚(8ml)溶液滴加到反应后，将混合液在0℃搅拌5min。接着将间氨基二苯甲酮(6a,1mmol,197.2mg)的乙醚(8ml)溶液滴加到反应中，然后将反应移至室温反应3h,经TLC检测反应完全后，将反应液先用6M HCl稀释，再用饱和NaHCO3中和，水层经乙酸乙酯(10ml×3)萃取，合并有机层，无水Na2SO4干燥，浓缩，柱层析得到化合物中间体7a。
最后利用7a按照目标化合物1的合成方法获得化合物7，三步总产率35％。
化合物7的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.20(s,1H),7.57(s,1H),7.47(d,J＝8.0Hz,1H),7.36(d,J＝7.6Hz,2H),7.30(t,J＝7.6Hz,2H),7.20(q, J＝8.0Hz,J＝8.0Hz,2H),7.07(d,J＝7.6Hz,1H),6.97(s,1H),5.90(d,J＝4.0Hz,1H),5.65(d, J＝4.0Hz,1H),4.01(s,2H),2.31(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4, 166.9,146.9,146.0,139.3,128.8,128.5,127.2,125.7,121.8,118.1,117.6,116.5,74.7,35.9, 23.8ppm。
实施例8、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-苯乙基)苯基)乙酰胺(化合物8)的合成
首先，将间硝基苯乙酮(8a,1mmol,165mg)和对甲基苯磺酰肼(1mmol,185mg)溶于10ml二氧六环中，并于80℃反应1.5小时，经TLC检测反应完全后，减压蒸馏得8b 粗产品；然后加入对甲氧基苯硼酸(1.5mmol,227mg)，K2CO3(1.5mmol)和15ml二氧六环后于110℃回流反应5小时，经TLC检测反应完全后，减压蒸馏除去溶剂后加入水和乙酸乙酯萃取(10ml×3),合并有机层，无水Na2SO4干燥，浓缩，柱层析得到化合物中间体8c；
利用8c按照化合物2的合成方法合成目标化合物8，五步总产率23％。
化合物8的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.18(s,1H),7.42(d,J＝7.6Hz,2H),7.30-7.28(m,2H),7.24-7.19(m,4H),7.00-6.94(m,2H),4.01(s,2H), 3.93(t,J＝7.6Hz,1H),3.87(s,3H),2.32(s,6H),1.58(d,J＝7.6Hz,3H)ppm；13C NMR(100 MHz,DMSO):δ169.8,167.4,166.9,142.3,141.5,139.6,129.2,129.1,128.8,125.5,124.2, 119.9,117.4,116.5,56.3,41.6,35.9,23.8,20.6ppm。
实施例9、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(甲基(苯基)氨基)苯基)乙酰胺(化合物9)的合成
首先，将原料2b(1.0当量)溶于DMF中用NaH(0.5当量)催化脱氢后与碘甲烷反应获得中间体9a，利用9a，按照化合物2的合成方法合成目标化合物9，四步总产率19％。
化合物9的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.13(s,1H),7.45(s,1H),7.23(t,J＝8.0Hz,2H),7.12(t,J＝8.0Hz,1H),7.06(d,J＝7.6Hz,2H),7.01(d, J＝8.8Hz,1H),6.98(s,1H),6.83(t,J＝7.2Hz,1H),6.74(dd,J＝1.6Hz,J＝5.6Hz,1H),4.02(s, 2H),3.02(s,3H),2.35(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,140.5, 135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,42.5,35.9,23.8ppm。
实施例10、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯亚磺酰基)苯基)乙酰胺(化合物10)的合成
利用化合物5b按照化合物1c的合成方法合成中间体10a,接着将10a(590mg,1.85mmol)用DCM(10mL)溶解，0℃搅拌下加入间氯过氧苯甲酸(335mg,1.94mmol)，室温反应45min，经TLC检测反应完全后减压除去多余的溶剂，柱层析得白色中间体10b。然后，利用中间体10b按照化合物1的合成方法合成目标化合物10，四步总产率32％。
化合物10的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.32(s, 1H),7.92(s,1H),7.61(s,1H),7.52(d,J＝8.0Hz,1H),7.46-7.30(m,6H),7.02(d,J＝8.0Hz,1H),6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.7,167.4,167.2,140.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,35.9,23.8 ppm。
实施例11、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯磺酰基)苯基)乙酰胺(化合物11)的合成
将化合物10a(590mg,1.85mmol)用DCM(10mL)溶解，0℃搅拌下加入间氯过氧苯甲酸(956mg,5.54mmol)，室温反应3h，经TLC检测反应完全后减压除去多余的溶剂，柱层析得白色中间体11a。利用11a按照目标化合物1的合成方法合成目标化合物11。两步总产率51％。
化合物11的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.33(s, 1H),7.98(s,1H),7.60(s,1H),7.55(d,J＝8.0Hz,1H),7.46-7.31(m,6H),7.02(d,J＝8.0Hz,1H),6.96(s,1H),4.02(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.2,142.5,135.9,134.9,131.4,130.3,130.1,128.0,125.7,121.1,118.5,116.5,36.0,23.8 ppm。
实施例12、N-(3-(苄胺基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物12)的合成
上述中间体12b的合成利用12a按照1b的合成方法合成，接着利用12b按照目标化合物1的合成方法合成中间体12c。
然后，将苯甲醛(0.374mmol,39.6mg)和化合物12c(0.34mmol,98.1mg)溶于DCM(6ml) 中，再将二氢吡啶酯(0.477mmol,120.1mg)加入，最后滴入三氟乙酸(0.17mmol,12.7μl)并置于45℃回流反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得目标化合物12，三步反应总产率为29％。
化合物12的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ9.93(s,1H),7.35-7.29(m,4H),7.22(t,J＝6.8Hz,1H),6.97-6.91(m,3H),6.75(d,J＝8.0Hz,1H),6.32-6.27 (m,2H),4.23(d,J＝6.0Hz,2H),3.99(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2, 112.7,48.0,36.0,23.8ppm。
实施例13、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((噻吩-2-基甲基)氨基)苯基)乙酰胺(化合物 13)的合成
利用重要中间体12c与2-噻吩甲醛按照化合物12的合成方法获得目标化合物13，产率68％。
化合物13的1H NMR数据如下：1H NMR(400MHz,DMSO):δ9.95(s,1H),7.36(dd, J＝0.8Hz,J＝4.0Hz,1H),7.03(d,J＝2.4Hz,1H),6.99-6.95(m,4H),6.77(d,J＝8.8Hz,1H),6.35-6.31(m,2H),4.41(d,J＝6.4Hz,2H),4.00(s,2H),2.34(s,6H)ppm。
实施例14、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((1-苯乙基)氨基)苯基)乙酰胺(化合物14) 的合成
利用重要中间体12c与苯乙酮按照化合物12的合成方法获得目标化合物14，产率53％。
化合物14的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ9.92(s,1H),7.35-7.29(m,4H),7.22(t,J＝7.2Hz,1H),6.97-6.91(m,3H),6.75(d,J＝7.2Hz,1H),6.32-6.27 (m,2H),4.20(m,1H),3.99(s,2H),2.33(s,6H),1.38(d,J＝6.0Hz,3H)ppm；13C NMR(100 MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0, 116.5,116.2,112.7,48.0,36.0,23.8ppm。
实施例15、N-(3-(苯氧基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物15)的合成
首先，将间氨基苯酚(15a,0.5mmol，54.6mg)溶于二氯甲烷(5ml)中，加入三乙胺(1.5mmol,208μl)，后加入醋酸酐(0.55mmol,51.9μl)并在室温下反应过夜。经TLC检测反应完全，减压浓缩，柱层析得化合物15b。
接着，将化合物15b(0.54mmol,81.6mg)和叔丁醇钾(0.81mmol,90.9mg)溶于DMF(5ml) 中，在室温下搅拌反应30min后将苄溴(0.59mmol,70.6μl)缓慢加入，且在室温反应过夜。经TLC检测反应完全，加入适量水，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得中间体15c。
然后，将化合物15c(0.26mmol,63.2mg)溶于甲醇(2ml)中，加入二氯亚砜(0.64mmol,45.3μl)，回流搅拌反应3h。经TLC检测反应完全，加入饱和NaHCO3溶液，调pH至碱性，减压除去甲醇，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得重要中间体15d。
最后利用15d按照化合物1的合成方法合成目标化合物15，五步总产率18％。
化合物15的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.22(s, 1H),7.46-7.33(m,6H),7.21(d,J＝8.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.98(s,1H),6.72(dd, J＝2.4Hz,J＝5.6Hz,1H),5.07(s,2H),4.04(s,2H),2.34(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.7,149.3,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5, 116.2,112.7,48.0,36.0,23.8ppm。
实施例16、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((苯胺基)甲基)苯基)乙酰胺(化合物16)的合成
将间硝基苯甲醛(16a,2mmol,302.2mg)和苯胺(2.2mmol,201μl)溶于DCM(16ml)中，接着将二氢吡啶酯(2.8mmol,708.4mg)加入，最后滴入三氟乙酸(1mmol,74.6μl)并置于45℃回流反应过夜。经TLC检测反应完全后减压除去多余的溶剂，柱层析得到还原胺化产物16b。将还原胺化产物16b(1.89mmol,427mg)溶于乙醇(10ml)和水(5ml)的混合溶剂后加入铁粉 (9.44mmol,528.4mg)和NH4Cl(0.945mmol,50.6mg)至反应中并置于80℃回流反应30min，经TLC检测反应完全后过滤除去不溶物质，加入NaHCO3调节pH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得目标化合物16，四步总产率45％。
化合物16的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.21(s, 1H),7.55(s,1H),7.48(d,J＝8.4Hz,1H),7.25(t,J＝8.0Hz,1H),7.06-7.01(m,3H),6.96(s,1H),6.55-6.49(m,3H),6.24(d,J＝6.0Hz,1H),4.22(d,J＝6.0Hz,2H),4.02(s,2H),2.32(s, 6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,47.0,35.9,23.8ppm。
实施例17、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(((4-甲氧基苯基)氨基)甲基)苯基)乙酰胺 (化合物17)的合成
利用16a将苯胺换做4-甲氧基苯胺，按照化合物16的合成方法合成目标化合物17，四步总产率46％。
化合物17的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.23(s, 1H),7.54(s,1H),7.46(d,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,1H),7.06-7.00(m,3H),6.96(s,1H),6.55-6.49(m,3H),6.24(d,J＝6.0Hz,1H),4.22(d,J＝6.0Hz,2H),4.02(s,2H),3.83(s, 1H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9,149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,47.0,58.0,35.9,23.8ppm。
实施例18、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(((3-(三氟甲基)苯基)氨基)甲基)苯基)乙酰胺(化合物18)的合成
使用16a和间三氟甲基苯胺，按照化合物16的合成方法合成目标化合物18，四步总产率38％。
化合物18的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.22(s, 1H),7.56(s,1H),7.50(d,J＝8.0Hz,1H),7.29-7.22(m,2H),7.06(d,J＝7.6Hz,1H),6.96(s,1H),6.84(s,1H),6.79(t,J＝7.6Hz,3H),4.29(d,J＝6.0Hz,2H),4.02(s,2H),2.31(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.5,166.9,146.9,146.1,139.3,133.3,129.3,128.8,128.5,127.2,125.7,121.8,119.4,118.1,117.6,116.5,74.7,35.9,23.8ppm。
实施例19、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-(苯胺基)乙基)苯基)乙酰胺(化合物19) 的合成
将间乙酰氨基苯乙酮(19a,2mmol,354.4mg)和苯胺(2.4mmol,219.2μl)溶于甲苯(30ml) 中，随后加入NaHCO3(10mmol,840mg)和适量的分子筛并置于120℃回流反应过夜。经 TLC检测反应完全后过滤除去不溶物质，减压浓缩，柱层析得亚胺化合物19b。
然后，将化合物19b溶于DCM(5ml)中，再加入催化量的DMF(0.2mmol,384μl)，反应液置于0℃，并在0℃下加入HSiCl3(2mmol,200μl)的DCM(5ml)溶液，加毕于0℃反应过夜。经TLC检测反应完全后加入适量水淬灭多余的HSiCl3，室温搅拌10min后用 NaHCO3调pH至碱性，减压除去DCM，水层经乙酸乙酯萃取，浓缩，柱层析得到亚胺还原产物19c。
接着将上步亚胺还原产物(19c,0.5mmol,127mg)溶于甲醇(2ml)中，加入二氯亚砜(1.2mmol,87μl)，65℃回流反应3-4h。经TLC检测反应完全后加入适量饱和NaHCO3调 pH至碱性，减压除去甲醇，水层经乙酸乙酯萃取，浓缩，柱层析得到重要中间体19d。最后利用19d,按照化合物1的合成方法合成目标化合物19；五步总产率为28％。
化合物19的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.19(s, 1H),7.56(s,1H),7.43(d,J＝8.0Hz,1H),7.23(t,J＝7.6Hz,1H),7.07(d,J＝7.6Hz,1H), 6.99-6.95(m,3H),6.48-6.44(m,3H),6.13(d,J＝6.0Hz,1H),4.40-4.34(m,1H),4.02(s,2H),2.32(s,6H),1.40(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.8149.1,141.6,139.6,129.3,129.1,122.6,118.2,118.0,116.5,116.2,112.7,55.8,35.9,23.8, 21.0ppm。
实施例20、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(1-((3-(三氟甲基)苯基)氨基)乙基)苯基)乙酰胺(化合物20)的合成
使用19a和间三氟甲基苯胺，按照化合物19的合成方法合成目标化合物20，五步总产率30％。
化合物20的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.20(s, 1H),7.57(s,1H),7.45(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.18(t,J＝8.0Hz,1H),7.08(d, J＝7.6Hz,1H),6.95(s,1H),6.80(s,1H),6.76-6.66(m,3H),4.49-4.42(m,1H),4.01(s,2H), 2.31(s,6H),1.42(d,J＝6.8Hz,3H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,166.9, 146.9,146.0,139.3,133.3,129.9,128.8,128.5,127.2,125.7,121.8,118.6,118.1,117.6,116.5, 74.7,35.9,23.8ppm。
实施例21、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-(苯氧甲基)苯基)乙酰胺(化合物21)的合成
首先，将苯酚(1.0当量)溶于DMF中，加入K2CO3(3.0当量)，后将间硝基苄溴的 DMF溶液加入到反应液中，室温搅拌反应过夜。经TLC检测反应完全后加入适量水，水层经乙酸乙酯萃取，合并有机相，无水Na2SO4干燥，浓缩后经柱层析得亲核取代产物21b。
然后，将21b(1mmol,229mg)溶于乙醇(3ml)和水(1.5ml)的混合溶剂中，加入NH4Cl(0.5mmol,26.8mg)，和Fe(5mmol,280mg)，于80℃反应30min，经TLC检测反应完全后趁热过滤除去不溶物质，再加入NaHCO3调节pH至碱性，减压除去乙醇，水层经乙酸乙酯萃取，浓缩，柱层析得到重要中间体21c。最后利用21c按照化合物1的合成方法合成目标化合物21，四步总产率35％。
化合物21的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.29(s, 1H),7.69(s,1H),7.54(d,J＝8.4Hz,1H),7.35-7.28(m,3H),7.14(d,J＝7.6Hz,1H),7.01-6.93(m,4H),5.08(s,2H),4.04(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8, 167.4,167.1,158.7,139.7,138.3,130.0,129.3,122.9,121.2,119.0,118.5,116.5,115.2,69.5,35.9,23.8ppm。
实施例22、N-(3-((4-乙酰氨基苯氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物22)的合成
使用对乙酰氨基酚替换苯酚，按照化合物21的合成方法合成目标化合物22，四步产率为28％。
化合物22的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.29(s, 1H),9.78(s,1H),7.68(s,1H),7.54(d,J＝8.0Hz,1H),7.48(d,J＝8.8Hz,2H),7.32(t,J＝7.6Hz,1H),7.12(d,J＝7.6Hz,2H),6.97(s,1H),6.93(d,J＝8.8Hz,2H),5.04(s,2H),4.05(s,2H), 2.34(s,6H),2.01(s,3H),ppm；13C NMR(100MHz,DMSO):δ169.8,168.0,167.4,167.1,158.7,139.7,138.3,130.0,129.3,122.9,121.2,119.0,118.5,116.5,115.2,69.5,35.9,23.8, 22.9ppm。
实施例23、N-(3-((3-乙酰氨基苯氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物23)的合成
使用间乙酰氨基酚替换苯酚，按照化合物21的合成方法合成目标化合物23，四步产率为29％。
化合物23的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.30(s, 1H),9.92(s,1H),7.68(s,1H),7.56(d,J＝7.6Hz,1H),7.37-7.32(m,2H),7.20(t,J＝7.6Hz,1H),7.12(t,J＝7.6Hz,2H),6.98(s,1H),6.69(d,J＝7.6Hz,1H),5.05(s,2H),4.05(s,2H),2.34(s,6H),2.04(s,3H),ppm；13C NMR(100MHz,DMSO):δ169.8,168.0,167.4,167.1,154.1,139.8,138.3,134.6,129.4,128.0,127.6,127.0,126.7,125.9,125.5,122.7,122.0,120.7, 119.0,118.7,118.3,116.5,106.3,69.8,36.0,23.8,22.9ppm。
实施例24、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((萘基-1-氧基)甲基)苯基)乙酰胺(化合物 24)的合成
使用1-萘酚，按照化合物21的合成方法合成目标化合物24，四步产率为33％。
化合物24的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.33(s, 1H),8.24(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.81(s,1H),7.61(d,J＝8.0Hz,1H), 7.58-7.49(m,3H),7.45-7.36(m,2H),7.24(d,J＝7.6Hz,1H),7.06(d,J＝7.6Hz,1H),6.95(s,1H),5.30(s,2H),4.06(s,2H),2.33(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,154.1,139.8,138.3,134.6,129.4,128.0,127.0,126.7,125.9,125.5,122.7,122.0,120.7, 119.0,118.3,116.5,106.3,69.8,36.0,23.8ppm。
实施例25、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((萘基-2-氧基)甲基)苯基)乙酰胺(化合物 25)的合成
使用2-萘酚，按照化合物21的合成方法合成目标化合物25，四步产率为35％。
化合物25的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.31(s, 1H),7.87-7.77(m,4H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.42(s,1H),7.36(t, J＝8.0Hz,2H),7.26-7.20(m,2H),6.96(s,1H),5.22(s,2H),4.06(s,2H),2.33(s,6H)ppm；13CNMR(100MHz,DMSO):δ169.8,167.4,167.1,156.7,139.7,138.1,134.7,129.9,129.4,129.1,128.0,127.2,125.9,124.1,123.0,119.2,119.1,118.7,116.5,107.8,69.7,36.0,23.8 ppm。
实施例26、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((喹啉基-8-氧基)甲基)苯基)乙酰胺(化合物 26)的合成
使用8-羟基喹啉，按照化合物21的合成方法合成目标化合物26，四步产率为25％。
化合物26的1H NMR数据如下：1H NMR(400MHz,DMSO):δ10.32(s,1H),8.80(dd, J＝1.6Hz,J＝4.0Hz,1H),8.33(dd,J＝1.6Hz,J＝8.0Hz,1H),7.76(s,1H),7.61-7.54(m,2H),7.53-7.48(m,2H),7.37(t,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,2H),6.96(s,1H),5.30(s,2H), 4.05(s,2H),2.32(s,6H)ppm。
实施例27、N-(4-((3-(2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺)苄基)氧基)苯基)噻吩-2-甲酰胺 (化合物27)的合成
将中间体22a(1.0mmol,286mg)溶解于5ml甲醇中，然后滴加0.5ml二氯亚砜后回流0.5小时，然后减压蒸馏出去溶剂后，加入NaHCO3调节pH为7-8后，加入水和乙酸乙酯萃取，有机层经Na2SO4干燥后，旋转蒸发仪旋除溶剂后，与噻吩-2-甲酰氯缩合后，硝基经铁粉还原，得中间体27b；
利用27b按照化合物1的合成方法合成目标化合物27，五步总产率为28％。
化合物27的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.30(s, 1H),10.13(s,1H),7.99(d,J＝3.2Hz,1H),7.84(dd,J＝0.8Hz,J＝4.0Hz,1H),7.71(s,1H),7.63(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,1H),7.34(t,J＝8.0Hz,1H),7.22(t,J＝8.0Hz,1H), 7.14(d,J＝8.0Hz,1H),7.02-6.97(m,3H),5.08(s,2H),4.06(s,2H),2.36(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,160.0,155.1,140.7,139.7,138.3,132.4,132.0,129.2,128.5,122.9,122.5,119.0,118.5,116.5,115.3,69.8,36.0,23.8ppm。
实施例28、N-(3((4-(环丙磺酰胺基)苯氧基)甲基)苯基-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺(化合物28)的合成
利用27a和环丙磺酰氯，按照化合物27的合成方法合成目标化合物28，四步总产率29％。
化合物28的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.30(s, 1H),9.38(s,1H),7.70(s,1H),7.54(d,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.18(d,J＝8.8Hz,2H),7.14(d,J＝7.6Hz,1H),6.98(s,1H),7.00-6.97(m,3H),5.06(s,2H),4.05(s,2H),2.50-2.47(m,1H),2.34(s,6H),0.91-0.86(m,4H),ppm；13C NMR(100MHz,DMSO):δ 169.8,167.4,167.1,156.0,139.6,138.2,131.5,129.3,124.2,122.9 119.0,118.6,116.5,115.7, 69.8,36.3,36.0,23.8,5.3ppm。
实施例29、2-((4,6-二甲基嘧啶-2-基)硫代)-N-(3-((4-(苯基磺酰胺基)苯氧基)甲基)苯基)乙酰胺(化合物29)的合成
利用27a和苯磺酰氯，按照化合物27的合成方法合成目标化合物29，四步总产率30％。
化合物29的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ10.28(s, 1H),9.95(s,1H),7.70(d,J＝7.2Hz,2H),7.65(s,1H),7.61(t,J＝7.2Hz,1H),7.56-7.52(m,3H),7.31(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,1H),6.99(s,1H),6.97(d,J＝2.8Hz,2H),6.89(s, 1H),6.87(s,1H),4.98(s,2H),4.04(s,2H),2.36(s,6H)ppm；13C NMR(100MHz,DMSO):δ 169.8,167.4,167.1,156.0,139.9,139.6,138.1,133.2,130.8,129.6,129.3,127.1,123.8,122.9, 119.0,118.6,116.5,115.7,69.8,35.9,23.8ppm。
实施例30、N-(3(((1H-吲唑-5-基)氧基)甲基)苯基)-2-((4,6-二甲基嘧啶-2-基)硫代)乙酰胺 (化合物30)的合成
将化合物30a(400mg,2.99mmol)用5mL DMF溶解，搅拌下加入K2CO3(3.19g,23.1mmol),将混合液冷至0℃，将间硝基苄溴(1g,4.62mmol)用5mL DMF溶解，缓慢滴加到化合物30a的混合液中，0℃下反应2h后室温反应3h,TLC监测反应完全，反应液加水，用EA提取，饱和NaCl洗涤，干燥浓缩得粗品，经柱层析纯化(DCM)得30b纯品420mg，收率52％。
接着，将化合物30b(200mg,0.74mmol)用4mL乙醇溶解，加入2mL H2O，室温搅拌下加入NH4Cl(20mg,0.37mmol)，铁粉(151mg,3.70mmol)，80℃回流30min。趁热过滤，滤饼用乙醇洗涤，将滤液浓缩，加水，EA提取，饱和NaCl洗涤，干燥浓缩得粗品 173mg，为淡黄色固体(化合物30c)，不经纯化直接投下一步。
再将化合物30c(170mg,0.71mmol)、8(108mg,0.78mmol)加入反应瓶，用8mL DCM溶解，0℃搅拌下加入EDCI(164mg,0.85mmol)，HOBt(125mg,0.85mmol)，DIEA (235μL,1.42mmol)，然后室温下反应过夜，将反应液旋干，经柱层析 (PE:EA＝3:1→PE:EA＝1:1)得30d纯品131mg，收率51％。
最后，将化合物30d(130mg,0.36mmol)用2mLDMF溶解，室温搅拌下加入t-BuOK(48mg,0.43mmol)，室温活化30min,然后将10(73mg,0.43mmol)用2mL DMF溶解后滴加入巯基咪唑的混合液中，室温反应过夜，加水，用EA提取，饱和NaCl洗涤，干燥浓缩得粗品，经柱层析(PE:EA＝3:1→PE:EA＝1:1)得淡黄色固体(化合物30)105mg，收率 71.9％。
化合物30的1H NMR和13C NMR数据如下：1H NMR(400MHz,DMSO):δ12.93(s, 1H),10.30(s,1H),7.95(s,1H),7.73(s,1H),7.55(d,J＝8.0Hz,1H),7.47(d,J＝8.8Hz,1H),7.34(t,J＝8.0Hz,1H),7.26(s,1H),7.17(d,J＝8.0Hz,1H),7.08(dd,J＝8.8Hz,J＝2.0Hz,1H), 6.96(s,1H),5.11(s,2H),4.05(s,2H),2.32(s,6H)ppm；13C NMR(100MHz,DMSO):δ169.8,167.4,167.1,153.2,139.7,138.5,136.3,133.3,129.3,123.5,122.9,118.9,118.8,118.5, 116.5,111.6,101.9,70.1,36.0,23.8ppm。
实施例31、化合物31的合成
利用5-氨基-2-氟苯酚(31a,0.5mmol,65mg)按照化合物15的合成方法合成目标化合物31，五步总产率26％。
化合物31的1H NMR和LC-MS数据如下：1H NMR(400MHz,DMSO):δ10.21(s,1H),7.44-7.30(m,6H),7.22(d,J＝8.4Hz,1H),7.13(d,J＝8.4Hz,1H),7.11(s,1H),6.98(s,1H), 5.06(s,2H),4.03(s,2H),2.34(s,6H)ppm；LC-MS m/z:398.1[M+H]+。
实施例32、化合物32的合成
利用5-氨基-2-甲基苯酚(32a,0.5mmol,62mg)按照化合物15的合成方法合成目标化合物32，五步总产率27％。
化合物32的1H NMR和LC-MS数据如下：1H NMR(400MHz,DMSO):δ10.22(s,1H),7.45-7.31(m,6H),7.24(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),7.10(s,1H),6.99(s,1H), 5.05(s,2H),4.03(s,2H),2.34(s,6H)，2.08(s,3H)ppm；LC-MS m/z:394.2[M+H]+。
实施例33、本发明化合物对体外SIRT2蛋白的抑制活性
测试方法如下：
(1)实验材料：
购买于美国BPS Bioscience公司的SIRT2酶(产品编号：50013)；美国PerkinElmer公司的384孔板(产品编号：6007279)；Sigma公司的阳性对照产品Suramin(产品编号：S2671)。
(2)实验方法：
首先，制备三羟甲氨基甲烷缓冲液；然后，将所有受试化合物及阳性对照化合物Suramin 溶解于100％的DMSO中配制成不同浓度的测试溶液并转移至测试孔板中；随后将SIRT2酶溶于缓冲溶液中配制酶溶液；同时利用烟酰胺腺嘌呤核苷酸(NAD+)和乙酰化的底物肽溶解于缓冲溶液中配制成底物缓冲溶液；接着在测试孔板中分别加入10μL酶溶液或空白对照缓冲溶液后将测试孔板置于室温孵化15分钟；再向每孔中加入10μL底物缓冲液反应4小时；反应完毕后向每孔中加入胰蛋白酶溶液反应1.5小时；最后使用Synergy MX酶标仪在激发光为360nM和460nM发射光波长处测试以上反应液的发光强度，从而确定化合物对SIRT2的抑制活性。
(3)实验结果：
通过以上实验方法，测试了本发明化合物针对SIRT2的抑制活性，具体的化合物在5μM、50μM浓度下的抑制活性及部分化合物对SIRT2的半数抑制有效浓度(IC50)见表1，其中“-”表示未测。
表1.本发明化合物对SIRT2的抑制活性(Inh％)
| 化合物 | Inh％@5μM | Inh％@50μM | IC<sub>50</sub>(μM) |
| 1 | 75 | 98 | 0.65 |
| 2 | 61 | 95 | 1.12 |
| 3 | 16 | 27 | - |
| 4 | 49 | 92 | - |
| 5 | 27 | 50 | - |
| 6 | 40 | 89 | - |
| 7 | 18 | 78 | - |
| 8 | 76 | 98 | 0.52 |
| 9 | 65 | 95 | 1.05 |
| 10 | 46 | 68 | - |
| 11 | 35 | 60 | - |
| 12 | 64 | 95 | 0.98 |
| 13 | 60 | 93 | 1.25 |
| 14 | 68 | 96 | 0.95 |
| 15 | 59 | 92 | - |
| 16 | 49 | 90 | - |
| 17 | 45 | 93 | - |
| 18 | 42 | 89 | - |
| 19 | 71 | 95 | 0.62 |
| 20 | 69 | 89 | 0.89 |
| 21 | 67 | 94 | 0.96 |
| 22 | 62 | 92 | - |
| 23 | 68 | 99 | - |
| 24 | 42 | 79 | - |
| 25 | 59 | 84 | - |
| 26 | 41 | 86 | - |
| 27 | 98 | 99 | 0.042 |
| 28 | 67 | 95 | - |
| 29 | 73 | 87 | - |
| 30 | 57 | 91 | - |
| 31 | 67 | 93 | - |
| 32 | 58 | 90 | - |
| 阳性对照Suramin | 46 | 78 | 8.3 |
上述结果表明，本发明化合物对SIRT2具有良好的抑制活性，可以用于制备沉默信息调节因子2相关蛋白的抑制剂。
实施例34、本发明化合物对多种肿瘤细胞株的增殖的抑制效果
(1)实验材料：
主要试剂：RPMI-1640、胎牛血清、胰酶等购自Gibco BRL公司(InvitrogenCorporation，USA)，IMDM培养基购自ATCC(American Type Culture Collection)。四甲基偶氮唑盐 (MTT)、二甲基亚砜(DMSO)为Sigma公司(USA)产品。人肝癌细胞系(HUH7),人肝癌细胞系(SMMC7721)，肝母细胞瘤细胞系(HepG2),人乳腺癌细胞系(MCF-7)，人肺癌细胞系(NCI-H460),人肺癌细胞系(A549),人胰腺癌细胞系(MIAPACA)，人早幼粒白血病细胞系(HL60),人慢性髓系白血病细胞系(K562),人前列腺癌细胞(DU-145)等均购于美国ATCC(American type culture collection)，由本实验室保存。
(2)实验方法：
用完全细胞培养液调整细胞浓度为1～2×104个/mL的细胞悬液，接种于96孔板，每孔200μl细胞悬液，培养过夜。次日，吸弃上清(悬浮细胞离心后吸取上清)，然后分别用梯度浓度的受试化合物处理细胞。同时设不含药物的阴性对照组和等体积的溶剂对照组，DMSO浓度为0.1％，每个剂量组设3个复孔，在37℃，5％CO2条件下培养。72小时后，每孔加入浓度为5mg/mL的MTT试剂20μl，再培养2-4h后，弃上清，每孔再加入DMSO 150μL，振荡混匀15min，用酶标仪(λ＝570nm)测定吸光度(A)值(A值与活细胞数成正比)，取其平均值。相对细胞增殖抑制率＝(阴性对照组A570-实验组A570) /阴性对照组A 570×100％。实验至少重复3次。实验数据用均数表示，数据统计资料采用 t检验，P<0.05为差异有统计学意义。以下各化合物对细胞增殖抑制作用均用IC50或抑制率表示。
(3)实验结果：
采用以上方法，测试了本发明化合物1、13、19、20、21对人肝癌细胞系(HUH7),人肝癌细胞系(SMMC7721)，肝母细胞瘤细胞系(HepG2),人乳腺癌细胞系(MCF-7)，人肺癌细胞系(NCI-H460),人肺癌细胞系(A549),人胰腺癌细胞系(MIAPACA)，人早幼粒白血病细胞系(HL60),人慢性髓系白血病细胞系(K562),人前列腺癌细胞(DU-145)等进行了增殖抑制活性测试，具体的为化合物在50μM、100μM浓度下的抑制活性，见表2。
表2、本发明化合物对不同肿瘤细胞株的增殖抑制活性(Inh％)
上述结果表明，本发明化合物对肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌和白血病的细胞增殖，具有很好的抑制作用，可以用于制备治疗和/或预防肿瘤的药物。
综上所述，本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。
Claims (7)
1.下述的化合物或其药学上可接受的盐：
2.一种制备权利要求1所述化合物的方法，其特征在于：
当化合物为1、2、5-32时，它包括以下步骤：
、化合物A与化合物B反应，得到化合物C；
其中，
化合物A与化合物B的摩尔比为1：0.5～2；
、化合物C与化合物D反应，得到化合物Ⅰa；
其中，
化合物C与化合物D的摩尔比为1：0.5～2；
X、R1、R2a、R2b、R2c、R3均为化合物1、2、5-32中相应位置的基团；
Z为卤素或羟基。
3.一种制备权利要求1所述化合物的方法，其特征在于：
当化合物为3时，它包括以下步骤：
、化合物A与化合物B反应，得到化合物C；
其中，
化合物A与化合物B的摩尔比为1：0.5～2；
、化合物C与化合物E反应，得到化合物3；
其中，
化合物C与化合物E的摩尔比为1：0.5～2。
4.权利要求1所述的化合物或其药学上可接受的盐在制备沉默信息调节因子2相关蛋白的抑制剂中的用途。
5.权利要求1所述的化合物或其药学上可接受的盐在制备治疗和/或预防肿瘤的药物中的用途。
6.根据权利要求5所述的用途，其特征在于：所述的肿瘤为肝癌、肝母细胞瘤、乳腺癌、肺癌、胰腺癌、前列腺癌或白血病。
7.一种治疗和/或预防肿瘤的药物组合物，其特征在于：它是以权利要求1所述的化合物或其药学上可接受的盐为活性成分，加上药学上常用的辅料制备得到的制剂。
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