CN114685382B - 具有HDACs抑制活性的喹唑啉-4-胺衍生物及其制备方法与用途 - Google Patents
具有HDACs抑制活性的喹唑啉-4-胺衍生物及其制备方法与用途 Download PDFInfo
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- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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Abstract
本发明涉及药物化学领域，具体涉及一类具有HDACs抑制活性的喹唑啉‑4‑胺衍生物及其制备方法与用途。本发明设计并合成了一系列靶向HDACs的小分子抑制剂，所述小分子抑制剂能够抑制HDAC的酶学功能，并表现出了黑色素瘤、非小细胞肺癌、乳腺癌等癌症的治疗潜力；所述小分子具有显著的抗肿瘤细胞增殖活性，其效果与药物SAHA相当或更优于SAHA，可用于制备抗肿瘤药物，具有广阔的应用前景。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类具有HDACs抑制活性的喹唑啉-4-胺衍生物及其制备方法与用途。
背景技术
表观遗传调节因子或蛋白质功能障碍所引起的表观遗传改变会导致癌症、炎症、感染、神经退行性疾病等各种疾病的发生与发展，小分子药物通过靶向动态可逆的表观遗传修饰过程，可有效治疗这类功能障碍引起的疾病。表观遗传修饰中研究最为广泛的是组蛋白的乙酰化与去乙酰化，主要由组蛋白乙酰化转移酶(histone acetyltransferases,HATs)和组蛋白去乙酰化酶(histone deacetylases，HDACs)所催化，影响着染色质的组织形态及基因表达，对细胞稳态至关重要。
组蛋白去乙酰化酶(HDAC)参与了脱乙酰化和蛋白质泛素化等重要生命过程，对基因转录和蛋白质功能有着重要的调节作用。迄今为止，已有18种HDAC亚型被鉴定出，并根据其与酵母蛋白的同源性分为4类：ClassⅠ(HDAC1、2、3和8)、ClassⅡ(Ⅱa：HDAC4、5、7、9；Ⅱb：6和10)、ClassⅢ(SIRT 1-7)、ClassⅣ(HDAC11)，其中，ClassⅠ、Ⅱ和Ⅳ属于金属锌离子(Zn2 +)依赖性酶，ClassⅢ为NAD+依赖性酶。
HDACs的生物学功能异常与多种肿瘤的发生、发展密切相关，因此，HDACs作为肿瘤治疗的重要靶点引起了广泛关注。目前，多项研究成果表明，通过改变多种细胞蛋白的乙酰化状态，可提高p21和其他基因的表达水平诱导细胞凋亡，抑制肿瘤细胞增殖。迄今为止，伏立诺他(SAHA)、罗米地辛(FK-228)、贝利司他(PXD-101)和帕比司他(LBH-589)已获FDA批准用于治疗淋巴瘤(CL)、皮肤T细胞淋巴瘤(CTCL)、外周T细胞淋巴瘤(PTCL)和多发性骨髓瘤(MM)等，进一步证实了Zn2+依赖性酶可成为治疗肿瘤的有效靶点。综上所述，本领域迫切需要开发骨架新颖的靶向HDACs的小分子抑制剂，并用于相关疾病治疗。
发明内容
本发明的目的在于设计、合成并验证了一系列靶向HDACs的小分子抑制剂，表现出了通过抑制HDAC的酶学功能来达到治疗黑色素瘤、非小细胞肺癌、乳腺癌等癌症的巨大潜力。具体包括以下内容：
第一方面，本发明提供了一种如下式(I)或式(Ⅱ)所示的化合物，或其药学上可接受的盐、水合物、氘代物、前药；
其中，A1、A2、A3、A4各自独立选自CR'或N；R'选自H，C1-C6烷氧基、C1-C6烷氨基、C1-C6烷氧基羰基、取代或未取代的C1-C6酰氨基、以及取代或未取代的C1-C10烷基；
R选自H，C1-C6烷氧基、C1-C6烷氨基、C1-C6烷氧基羰基、取代或未取代的C1-C6酰氨基、以及取代或未取代的C1-C10烷基；
M选自CR”、NH、O或S；R”选自H、卤素、羰基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷氧基羰基、取代或未取代的C1-C6酰氨基、以及取代或未取代的C1-C10烷基；
Y选择(CH2)n、取代或未取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基；n大于等于0；
X选自取代或未取代的C6-C12的芳基或杂芳基、取代或未取代3-12元脂环或杂环基；
所述的取代是指基团上的一个或多个氢原子被选自下组的取代基取代：卤素原子、羰基、羧基、羟基、氨基、硝基、氰基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷氧基羰基、C1-C6酰氨基、取代或未取代的C1-C10烷基，取代或未取代的C6-C10芳基或五元或六元杂芳基，优选为C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；其中，所述的取代或未取代的C1-C10烷基，取代或未取代的C6-C10芳基或五元或六元杂芳基的取代基选自下组：卤素原子、羰基、羟基、羧基、C1-C6烷氧基羰基、氨基、C1-C6酰氨基、硝基、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基、C6-C10芳基或五元或六元杂芳基，优选为卤素原子、C1-C6烷氧基羰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基或苯基。
优选地，所述化合物的结构式如式(Ⅲ)所示：
优选地，所述M为NH，所述X为取代或未取代的苯基。
优选地，所述取代苯基选自烷基取代苯基、烷氧基取代苯基、卤素取代苯基、卤代烷基取代苯基。
优选地，所述取代苯基选自包括C1-4烷基取代苯基、甲氧基取代苯基、卤素取代苯基、三氟甲基取代苯基。
优选地，所述取代苯基为4-甲基取代苯基、4-乙基取代苯基、4-异丙基取代苯基、4-叔丁基取代苯基、4-甲氧基取代苯基、4-卤素取代苯基、4-三氟甲基取代苯基、3-甲基取代苯基、3-三氟甲基取代苯基、2,3-二甲基取代苯基、2,4-二氟取代苯基、4-溴-3-氟取代苯基、2,4,6-三甲基取代苯基。
优选地，所述化合物的结构式如式(Ⅳ)或式(Ⅴ)所示：
优选地，所述化合物的结构式如式(Ⅵ)-(Ⅷ)任一所示：
本发明所述化合物包括：N-羟基-4-(2-氧代-2-((4-(苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺、N-羟基-4-(2-氧代-2-((4-(对甲苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺、4-(2-((4-((4-乙基苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺、N-羟基-4-(2-((4-((4-异丙基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺、4-(2-((4-((4-(叔丁基)苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺、N-羟基-4-(2-((4-((4-甲氧基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺、4-(2-((4-((2,3-二甲基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺、4-(2-((4-((2,4,6-三甲基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺、N-羟基-4-(2-氧代-2-((4-(间甲苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺、4-(2-((4-((4-氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺、4-(2-((4-((4-氯苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺、4-(2-((4-((4-溴苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺、N-羟基-4-(2-((4-((4-碘苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺、N-羟基-4-(2-氧代-2-((4-((4-(三氟甲基)苯基)氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺、N-羟基-4-(2-氧代-2-((4-((3-(三氟甲基)苯基)氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺、4-(2-((4-((2,4-二氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺、4-(2-((4-((4-溴-3-氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺。
第二方面，本发明提供了上述第一方面所述的化合物，或其药学上可接受的盐、水合物、氘代物、前药在制备HDAC抑制剂药物中的应用。
第二方面，本发明提供了上述第一方面所述的化合物，或其药学上可接受的盐、水合物、氘代物、前药在制备治疗肿瘤、自身免疫性疾病、炎症、阿尔兹海默症药物中的应用。
优选地，所述肿瘤包括黑色素瘤、肺癌、乳腺癌、胃癌。
本发明提供了上述任一所述的化合物加入药学上可接受盐辅料制成药学上可接受的任一剂型。
优选地，所述剂型包括片剂、注射剂、颗粒剂、混悬剂。
本发明的有益效果是：本发明提供了一种喹唑啉-4-胺衍生物，所述喹唑啉-4-胺衍生物均具有HDAC抑制活性，其中所述化合物中大部分可高强度地抑制HDAC6和/或HDAC1，并呈现出显著的抗肿瘤细胞增殖活性；其他部分化合物在高强度抑制HDAC6的同时，呈现出优良的HDAC6选择性；药效学实验表明，本发明所涉及的化合物可用作肿瘤、自身免疫性疾病、炎症或阿尔兹海默症的治疗药物。
具体实施方式
以化合物1-17(路线I)、化合物18-20(路线II)为例，本发明的化合物制备方法如下：
需要指出的是，以下包含的特定实施例是为了举例说明，不应被理解为对本发明范围的限制。此外应理解，在阅读了本发明涉及的内容以后，本领域的技术人员可以对本发明作各种改动或修改，这种等价形式同样落于本申请所附权利要求书所限定的范围。
化合物1的合成路线如路线I所示：
路线I中：a为甲酰胺，甲酸铵，120℃；
b为：氯化亚砜，回流；
c为：苯胺，异丙醇，回流；
d为：氯化亚锡，甲醇，回流，N2保护；
e为：1)氯化亚砜，回流；2)甲醇；3)氢氧化锂，THF/H2O/MeOH，rt；
f为：EDCI(1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐)，HOBt(1-羟基苯并三唑)，DIPEA(N，N-二异丙基乙胺)，80℃；
g为：i)NH2OH·HCl，NaOH，MeOH，rt；ii)NaOH，MeOH，rt。
其他喹唑啉-4-胺衍生物类化合物(化合物2-17)按与实施例1类似的合成方法，用相应的起始原料进行制备，具体如路线II所示：
路线II中：f为：EDCI(1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐)，HOBt(1-羟基苯并三唑)，DIPEA(N，N-二异丙基乙胺)，80℃；
g为：i)NH2OH·HCl，NaOH，MeOH，rt；ii)NaOH，MeOH，rt。
实施例1 N-羟基-4-(2-氧代-2-((4-(苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺(1)的合成
第一步：向1000mL三口瓶加入2-氨基-5硝基苯甲酸(50g)，甲酰胺(123.6g)，甲酸铵(20g)，将反应液升温至120℃，搅拌15h，TLC监测至反应结束，冷却反应液至室温，将其倒入到1000mL水中，室温搅拌0.5h，抽滤，滤饼用水淋洗，50℃旋蒸后得黄色固体22约36g，收率约70％。
第二步：在100mL单口瓶中，加入路线Ⅰ中的化合物22(36g)，二氯亚砜(200mL)，DMF(2mL)，加热反应液至回流4h，反应液冷却至室温，减压旋蒸除去多余的二氯亚砜，用DCM拖带两次旋干，得22g路线Ⅰ中的化合物23(棕黑色粘稠固体)约22g，收率：56％。(不经纯化直接用于下一步)。
第三步：500mL烧瓶加入路线Ⅰ中的化合物23(8.0g)，并加入异丙醇(200mL)搅拌溶解，然后室温滴加苯胺(22.5g)，滴毕，加热反应液至回流，反应2h，反应液冷却至室温，抽滤，滤饼用异丙醇淋洗，得6.6g路线Ⅰ中的化合物24(黄色固体)，收率：65％。
第四步：500mL烧瓶中加入路线Ⅰ中的化合物24(6.6g)和MeOH(200mL)，搅拌，室温加入二水氯化亚锡(22.5g)，氮气保护，加热至回流反应3h，反应液冷却至室温，旋蒸除去甲醇，加水用1mol/L氢氧化钠调pH＝8-，分液，EA(200mL×4)萃取水相，合并有机相，饱和盐水洗一次，无水硫酸钠干燥后，减压旋干，再用PE：EA＝20：1打浆30min，抽滤，旋蒸45℃拉干得路线Ⅰ中的化合物25(黄色固体)约4.3g，收率：74％。
第五步：在500mL烧瓶中加入4-羧甲基苯甲酸(路线Ⅰ中的化合物26)，加入氯化亚砜升温至回流，搅拌2h，旋蒸除去氯化亚砜，向残渣中加入无水甲醇，室温反应3h，旋蒸除去多余甲醇。将所得粗品中间体加入到500mL烧瓶中，加入THF/H2O/EtOH(6/6/1，65mL)，待原料溶解后，加入氢氧化锂(2.75g)，搅拌反应液升温至60℃，反应8h，减压浓缩，残留物用水稀释，乙酸乙酯洗涤。将水层用2.5N盐酸调至pH＝5-6，用乙酸乙酯萃取。无水硫酸钠干燥乙酸乙酯层，减压除去溶剂，将粗品快速柱层析得路线Ⅰ中的化合物27(白色固体)约1.17g，收率：60％。
第六步：在100mL烧瓶中，加入中间体(路线Ⅰ中的化合物27)(1.0g)，EDCI(1.2g)，HOBt(0.84g)，DIPEA(1.8mL)，室温搅拌30min，向反应液中加入中间体(路线Ⅰ中的化合物25)(1.45g)，升温至80℃，反应16h，TLC检测发现已无中间体(路线Ⅰ中的化合物27)剩余，停止反应。冷却至室温后，加水100mL，乙酸乙酯萃取(40mL×3)，合并有机相，无水硫酸钠干燥，柱层析(展开剂：CH2Cl2：MeOH＝80：1)纯化，得路线Ⅰ中的化合物28约1.0g，产率50％。
第七步：0℃下将NaOH粉末(10.0eq)加入到NH2OH·HCl(盐酸羟胺)的甲醇溶液中，室温搅拌30min，过滤混合物，将滤液加入到路线Ⅰ中的化合物28(1.0g)的甲醇溶液(0.1M)中，在0℃下额外向反应液中加入NaOH粉末(4.0eq)并将混合物在室温下搅拌过夜，TLC检测发现已无路线Ⅰ中的化合物28剩余，反应结束。向反应液中加入水40mL，用1M HCl调至pH＝6-7，室温搅拌30min，抽滤，滤饼50℃减压旋干，得灰色固体，将其加入到甲醇溶液中，升温至回流搅拌20min，打浆，过滤得白色纯净产物固体化合物1约0.52g，收率：52％。1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),10.62(s,1H),9.79(s,1H),9.03(s,1H),8.71(s,1H),8.50(s,1H),7.93–7.85(m,1H),7.80–7.69(m,5H),7.46(d,J＝7.8Hz,2H),7.37(t,J＝7.7Hz,2H),7.11(t,J＝7.3Hz,1H),3.81(s,2H).13C NMR(151MHz,DMSO-d6)δ169.3,164.6,162.8,158.0,153.8,147.1,139.9,139.5,137.1,131.7,129.8,128.8,127.5,127.4,124.0,122.9,115.9,112.6,43.4.MS(ESI):412.3(M-H)-.
其它喹唑啉-4-胺衍生物(2-17)类化合物按与实施例1类似的合成方法，用相应的起始原料进行制备。
实施例2 N-羟基-4-(2-氧代-2-((4-(对甲苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺(2)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ10.82(d,J＝20.0Hz,2H),9.81(s,1H),8.83(d,J＝5.9Hz,1H),8.48(s,1H),7.96(d,J＝7.7Hz,3H),7.73(t,J＝9.2Hz,4H),7.47(dd,J＝12.2,7.9Hz,2H),7.18(dd,J＝8.6,2.8Hz,2H),3.88(s,2H),2.30(s,3H).13C NMR(151MHz,DMSO-d6)δ169.4,169.3,158.0,153.8,146.9,139.5,137.4,137.3,133.0,131.7,130.2,129.8,129.4,129.3,128.7,127.4,127.1,122.9,115.9,112.6,43.6,21.0.MS(ESI):426.3(M-H)-.
实施例3 4-(2-((4-((4-乙基苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺(3)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对乙基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.52(s,1H),11.22(d,J＝17.3Hz,2H),9.03(d,J＝2.2Hz,1H),8.81(s,1H),8.11(dd,J＝9.0,2.1Hz,1H),7.98(d,J＝9.0Hz,1H),7.80–7.63(m,2H),7.56–7.50(m,2H),7.50–7.45(m,2H),7.33–7.28(m,2H),2.65(q,J＝7.6Hz,2H),1.21(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ169.8,164.5,160.0,149.9,142.9,139.5,139.3,135.2,134.9,131.7,129.9,129.8,128.5,127.4,125.4,120.9,114.4,113.3,43.3,28.3,16.1.MS(ESI):442.4(M+H)+.
实施例4 N-羟基-4-(2-((4-((4-异丙基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺(4)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对异丙基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.55(s,1H),11.21(d,J＝15.0Hz,2H),9.03(d,J＝2.1Hz,1H),8.82(s,1H),8.12(ddd,J＝9.0,2.3,1.1Hz,1H),7.99(dt,J＝9.0,1.6Hz,1H),7.82–7.63(m,2H),7.55–7.50(m,2H),7.50–7.46(m,2H),7.39–7.27(m,2H),3.87(s,2H),2.94(p,J＝6.9Hz,1H),1.24(d,J＝6.9Hz,6H).13C NMR(151MHz,DMSO-d6)δ169.8,164.5,160.0,149.8,147.5,139.5,139.3,135.0,134.9,131.7,129.9,129.8,127.4,127.0,125.4,125.2,120.8,114.3,113.2,49.1,43.3,33.6,24.3.MS(ESI):456.3(M+H)+.
实施例5 4-(2-((4-((4-(叔丁基)苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺(5)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对叔丁基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.22(s,1H),10.80(s,1H),9.75(s,1H),9.04(s,1H),8.70(s,1H),8.46(s,1H),7.92(d,J＝8.8Hz,1H),7.74(d,J＝8.1Hz,3H),7.68(d,J＝8.2Hz,2H),7.47(d,J＝7.8Hz,2H),7.38(d,J＝8.2Hz,2H),3.82(s,2H),1.30(s,9H).13CNMR(151MHz,DMSO-d6)δ169.4,158.1,153.8,147.0,146.4,137.2,137.1,129.8,128.7,127.4,125.5,122.8,115.9,112.6,43.4,31.7.MS(ESI):470.8(M+H)+.
实施例6 N-羟基-4-(2-((4-((4-甲氧基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺(6)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对甲氧基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.74(s,1H),8.68(s,1H),8.43(s,1H),8.01–7.55(m,6H),7.42(s,2H),6.94(d,J＝6.4Hz,2H),3.76(s,5H).13C NMR(151MHz,DMSO-d6)δ169.4,158.1,156.1,153.9,146.9,137.0,132.7,129.6,128.7,127.2,124.8,115.8,114.0,55.7,43.4.MS(ESI):442.0(M-H)-.
实施例7 4-(2-((4-((2,3-二甲基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺(7)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和2,3-二甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.20(s,1H),10.55(s,1H),9.69(s,1H),9.04(s,1H),8.78–8.59(m,1H),8.30(s,1H),7.98–7.66(m,4H),7.46(d,J＝7.9Hz,2H),7.19–7.00(m,3H),3.79(s,2H),2.29(s,3H),2.01(s,3H).13C NMR(151MHz,DMSO-d6)δ169.2,164.5,159.3,154.3,146.9,139.5,137.9,137.5,136.9,134.1,131.7,129.7,128.7,128.1,127.4,127.2,125.9,125.8,115.4,112.8,43.4,20.6,14.9.MS(ESI):442.2(M+H)+.
实施例8 4-(2-((4-((2,4,6-三甲基苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺(8)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和2,4,6-三甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.19(s,1H),10.51(s,1H),9.41(s,1H),9.02(s,1H),8.66–8.63(m,1H),8.25(s,1H),7.83(dd,J＝9.0,2.2Hz,1H),7.73(t,J＝9.1Hz,3H),7.45(d,J＝7.9Hz,2H),6.94(s,2H),3.79(s,2H),2.27(s,3H),2.06(s,6H).13C NMR(151MHz,DMSO-d6)δ169.2,164.6,159.1,154.5,146.9,139.5,136.7,136.0,134.2,131.7,129.7,129.0,128.9,128.7,127.4,127.3,115.2,112.8,43.3,21.0,18.4.MS(ESI):454.4(M-H)-.
实施例9 N-羟基-4-(2-氧代-2-((4-(间甲苯基氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺(9)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和3-甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.51(s,1H),11.22(d,J＝18.9Hz,2H),9.04(d,J＝2.1Hz,1H),8.84(s,1H),8.12(dt,J＝9.0,2.1Hz,1H),7.99(dd,J＝9.0,1.5Hz,1H),7.74(d,J＝8.1Hz,2H),7.48(d,J＝8.0Hz,2H),7.43(d,J＝8.2Hz,2H),7.36(t,J＝7.5Hz,1H),7.15(d,J＝7.5Hz,1H),3.87(s,2H),2.35(s,3H).13C NMR(151MHz,DMSO-d6)δ169.8,164.5,160.0,149.9,139.5,139.3,138.6,137.2,135.3,131.7,129.9,129.8,129.1,127.8,127.4,125.9,122.6,121.0,114.4,113.2,43.3,21.5.MS(ESI):428.8(M+H)+.
实施例10 4-(2-((4-((4-氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺(10)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对氟苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.55(s,1H),11.22(d,J＝16.1Hz,2H),9.04(d,J＝2.1Hz,1H),8.84(s,1H),8.11(dd,J＝9.1,2.1Hz,1H),7.99(d,J＝9.0Hz,1H),7.74(d,J＝8.0Hz,2H),7.66(dd,J＝8.9,5.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.32(t,J＝8.8Hz,2H),3.87(s,2H).13C NMR(151MHz,DMSO-d6)δ169.8,164.5,161.5,160.1,159.9,150.0,139.5,139.3,135.5,133.6,131.7,129.9,129.8,127.7,127.6,127.4,121.1,116.1,115.9,114.4,113.1,43.3.MS(ESI):432.9(M+H)+.
实施例11 4-(2-((4-((4-氯苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺(11)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对氯苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.23(s,1H),10.90(s,1H),9.90(s,1H),9.02(s,1H),8.74(d,J＝2.2Hz,1H),8.52(s,1H),7.94(dd,J＝9.0,2.1Hz,1H),7.89–7.81(m,2H),7.75(dd,J＝17.5,8.4Hz,3H),7.47(d,J＝8.0Hz,2H),7.45–7.37(m,2H),3.83(s,2H).13C NMR(151MHz,DMSO-d6)δ169.42,157.84,153.54,147.08,138.94,137.37,129.78,128.80,128.68,127.46,127.38,124.27,115.91,112.4,43.3.MS(ESI):446.0(M-H)-.
实施例12 4-(2-((4-((4-溴苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺(12)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对溴苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ12.89(s,1H),10.59(s,1H),9.89(s,1H),8.71(s,1H),8.54(s,1H),8.00–7.74(m,6H),7.53(dd,J＝21.1,8.2Hz,4H),3.84(s,2H).13C NMR(151MHz,DMSO-d6)δ169.2,167.7,157.8,153.6,147.1,141.3,139.3,137.2,131.6,130.0,129.84,129.75,129.0,127.6,124.6,123.8,115.9,115.6,112.4,43.5.MS(ESI):492.0(M+H)+.
实施例13 N-羟基-4-(2-((4-((4-碘苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)苯甲酰胺(13)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对碘苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.49(s,1H),11.19(d,J＝36.5Hz,2H),9.03(d,J＝2.1Hz,1H),8.86(s,1H),8.11(dt,J＝9.2,2.4Hz,1H),7.99(dd,J＝9.0,2.3Hz,1H),7.87–7.78(m,2H),7.74(d,J＝8.0Hz,2H),7.54–7.37(m,4H),3.87(s,2H).13C NMR(151MHz,DMSO-d6)δ169.8,159.9,150.0,139.5,139.3,137.9,137.3,131.7,129.9,129.8,127.4,121.3,114.6,113.1,92.0,43.3.MS(ESI):538.3(M-H)-.
实施例14 N-羟基-4-(2-氧代-2-((4-((4-(三氟甲基)苯基)氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺(14)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和对三氟甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.85–11.57(m,1H),11.28(s,2H),9.09(d,J＝2.1Hz,1H),8.92(s,1H),8.17(dd,J＝9.1,2.1Hz,1H),8.05(d,J＝9.0Hz,1H),7.94(d,J＝8.3Hz,2H),7.85(d,J＝8.5Hz,2H),7.75(dd,J＝8.2,2.0Hz,2H),7.49(d,J＝8.2Hz,2H),3.89(s,2H).13CNMR(151MHz,DMSO-d6)δ169.9,164.5,160.2,149.9,141.2,139.6,139.3,135.9,131.7,130.1,129.8,127.4,126.9,126.6,126.4,126.32,126.30,126.27,125.6,123.7,121.4,114.7,113.0,43.3.MS(ESI):480.1(M-H)-.
实施例15 N-羟基-4-(2-氧代-2-((4-((3-(三氟甲基)苯基)氨基)喹唑啉-6-基)氨基)乙基)苯甲酰胺(15)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和3-三氟甲基苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.20(s,1H),10.61(s,1H),10.05(s,1H),9.02(s,1H),8.76(d,J＝2.2Hz,1H),8.59(s,1H),8.25(d,J＝2.3Hz,1H),8.23–8.14(m,1H),7.89(dd,J＝9.0,2.2Hz,1H),7.81(d,J＝8.9Hz,1H),7.74(d,J＝7.9Hz,2H),7.61(t,J＝8.0Hz,1H),7.45(dd,J＝15.6,7.8Hz,3H),3.81(s,2H).13C NMR(151MHz,DMSO-d6)δ169.4,164.6,157.8,153.5,147.2,140.8,139.4,137.4,131.7,130.0,129.8,129.7,129.5,129.0,127.7,127.4,126.2,125.6,123.8,120.0,118.6,118.6,115.9,112.2,43.4.MS(ESI):480.4(M-H)-.
实施例16 4-(2-((4-((2,4-二氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧代乙基)-N-羟基苯甲酰胺(16)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和2,4-二氟苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.51(s,1H),11.19(d,J＝34.2Hz,2H),9.05(q,J＝2.5Hz,1H),8.82(d,J＝4.3Hz,1H),8.10(ddd,J＝11.3,8.9,4.2Hz,1H),8.06–7.95(m,1H),7.74(d,J＝7.9Hz,2H),7.57(dt,J＝9.9,7.6Hz,1H),7.47(dd,J＝7.8,2.5Hz,2H),7.23(td,J＝8.6,2.8Hz,1H),3.87(d,J＝4.3Hz,2H).13C NMR(151MHz,DMSO-d6)δ169.9,164.5,150.4,139.5,139.3,131.7,130.4,130.0,129.8,127.4,114.1,112.7,112.4,112.2,105.5,105.3,105.2,43.3.MS(ESI):450.4(M+H)+.
实施例17 4-(2-((4-((4-溴-3-氟苯基)氨基)喹唑啉-6-基)氨基)-2-氧乙基)-N-羟基苯甲酰胺(17)的合成
按与实施例1类似的合成方法，除第三步中用相应的中间体23和4-溴-3-氟苯胺为原料进行制备，其他步骤同实施例1。
1H NMR(600MHz,DMSO-d6)δ11.57(s,1H),11.22(s,2H),9.05(d,J＝2.1Hz,1H),8.93(s,1H),8.14(dd,J＝9.1,2.1Hz,1H),8.03(d,J＝9.0Hz,1H),7.88–7.78(m,2H),7.74(d,J＝8.0Hz,2H),7.53(dd,J＝8.7,2.3Hz,1H),7.48(d,J＝8.1Hz,2H),3.88(s,2H).13CNMR(151MHz,DMSO-d6)δ169.9,164.5,160.0,159.1,157.4,150.0,139.6,139.2,138.7,138.6,135.9,133.7,131.7,130.1,129.8,127.4,122.5,122.5,121.4,114.7,113.6,113.4,112.9,105.4,105.3,43.3.MS(ESI):510.1(M+H)+.
实施例18 N-羟基-4-(2-氧代-2-(喹啉-6-基氨基)乙基)苯甲酰胺(18)的合成
第一步：在100mL烧瓶中，加入路线Ⅱ中化合物27(1.0g)，EDCI(1.2g)，HOBt(0.84g)，DIPEA(1.8mL)，室温搅拌30min，向反应液中加入路线Ⅱ中化合物29(891mg)，升温至80℃，反应16h，TLC检测发现已化合物27剩余，停止反应。冷却至室温后，加水100mL，乙酸乙酯萃取(40mL×3)水相，合并有机相，无水硫酸钠干燥，柱层析(展开剂：CH2Cl2:MeOH＝80:1)纯化，得路线Ⅱ中化合物30约890mg，产率54％。
第二步：0℃下将NaOH粉末(10eq)加入到NH2OH·HCl(盐酸羟胺)的甲醇溶液中，室温搅拌30min，过滤混合物，将滤液加入到哈何物30的甲醇溶液(0.1M)中，在0℃下额外向反应液中加入NaOH粉末(4.0eq)并将混合物在室温下搅拌过夜，TLC检测发现已无化合物30剩余，反应结束。向反应液中加入水40mL，用1M HCl调至pH＝6-7，室温搅拌30min，抽滤，滤饼50℃减压旋干，得灰色固体，将其加入到甲醇溶液中，升温至回流搅拌20min，打浆，过滤得白色纯净产物固体化合物18约450mg，收率：51％。1H NMR(600MHz,DMSO-d6)δ11.20(s,1H),10.55(s,1H),9.03(s,1H),8.78(dd,J＝4.1,1.7Hz,1H),8.37(d,J＝2.4Hz,1H),8.30–8.20(m,1H),7.98(d,J＝9.0Hz,1H),7.82(dd,J＝9.2,2.4Hz,1H),7.74(d,J＝7.9Hz,2H),7.53–7.37(m,3H),3.79(s,2H).13C NMR(151MHz,DMSO-d6)δ169.6,164.6,149.5,145.2,139.5,137.5,136.0,131.7,130.0,129.7,128.8,127.4,123.7,122.3,115.5,43.6.MS(ESI):320.2(M-H)-.
实施例19 N-羟基-4-(2-氧代-2-(喹喔啉-6-基氨基)乙基)苯甲酰胺(19)的合成
化合物19参考实施例18制备，仅将6-氨基喹啉替换为6-氨基喹喔啉。
1H NMR(600MHz,DMSO-d6)δ11.04(s,1H),8.87(d,J＝1.8Hz,1H),8.81(d,J＝1.8Hz,1H),8.54(d,J＝2.2Hz,1H),8.06–7.98(m,1H),7.77–7.65(m,5H),7.46(d,J＝7.9Hz,2H),3.85(s,2H).13C NMR(151MHz,DMSO-d6)δ170.1,167.8,167.4,146.4,144.4,143.5,140.9,139.6,132.2,132.1,132.0,131.9,130.0,129.7,129.2,129.1,124.2,115.9,46.5.MS(ESI):321.6(M-H)-.
实施例20 N-羟基-4-(2-(萘-2-基氨基)-2-氧代乙基)苯甲酰胺(20)的合成
化合物20参考实施例18制备，仅将6-氨基喹啉替换为2-氨基萘。
1H NMR(600MHz,DMSO-d6)δ11.19(s,1H),10.53(d,J＝3.6Hz,1H),8.30(d,J＝2.1Hz,1H),7.84(dd,J＝18.2,8.5Hz,2H),7.79(d,J＝8.2Hz,1H),7.76–7.70(m,2H),7.63(dt,J＝8.8,1.9Hz,1H),7.51–7.43(m,3H),7.39(ddd,J＝8.1,6.7,1.2Hz,1H),3.79(s,2H).13C NMR(151MHz,DMSO-d6)δ169.5,164.6,139.7,137.2,133.9,131.6,130.2,129.7,128.8,127.9,127.8,127.4,126.9,125.1,120.4,115.7,60.2,43.6.MS(ESI):319.5(M-H)-.
实施例21化合物的HDAC6和HDAC1酶抑制活性
本实施例以常用工具化合物Tubastatin A作为阳性对照，采用基于荧光的HDAC活性测定方法评价本发明化合物和Tubastatin A的HDAC1和HDAC6酶抑制活性。采用多功能酶标仪于激发波长365nm，发射波长450nm下测定荧光值，计算抑制率，IC50值由软件GraphPadPrism 5.01拟合得到。本发明的其他化合物与以下所列举的化合物有类似的有益效果，但不应将此理解为本发明化合物仅具有以下有益效果。
HDAC1/6酶抑制活性的测试步骤为：配制待测化合物的DMSO溶液，将一系列浓度梯度的目标化合物(5μL/孔)和酶(5μL/孔)加入到HDAC6缓冲液(40μL/孔，5μl FluorogenicHDAC6 substrate 3(200μM)+5μl BSA(1mg/mL)+30μl HDAC Assay Buffer)中37℃预孵育30min，然后每孔加入未稀释的2×HDAC显影剂50μL，将培养板在室温下孵育15min。使用SpectraMax i3在激发波长和发射波长分别为365和450nm时测量荧光强度。每组分别进行3次独立实验，由GraphPad Prism 5.01拟合得到各化合物对HDAC6酶抑制活性的IC50值(表1)；HDAC1酶抑制活性的测试步骤与HDAC6酶抑制活性测试类似。
表1化合物对HDAC1和HDAC6酶的抑制活性
由表1中数据可知，所列举化合物均呈现出显著的HDAC1和HDAC6酶抑制活性，并且抑酶活性与Tubastatin A相当或优于Tubastatin A。并且本发明所合成的化合物13，17等对HDAC6均有着一定的选择性抑制活性。
实施例22化合物的抗肿瘤细胞增殖活性
本实施例以Tubastatin A和SAHA为阳性对照，采用CCK-8法评价本发明化合物及Tubastatin A对黑色素瘤细胞株A375、肺癌细胞株A549及乳腺癌细胞株MCF-7和MDA-MB-231及胃癌细胞株SGC-7901的抗增殖活性。本发明中的其他化合物与以下所列化合物有类似的抗增殖效果，但不应局限理解为本发明化合物仅具有以下有益效果。
抗肿瘤细胞增殖活性的测试步骤为：消化收集对数生长期的肿瘤细胞，以105个/mL的细胞密度接种于96孔培养板中，每孔分别加入100μL，将培养板置于培养箱(37℃，5％CO2)中，约24h后吸去培养基，并分别用不同浓度的化合物溶液处理细胞。作用48h后，向培养板各孔中分别加入10μL的CCK-8，将培养板置于培养箱(37℃，5％CO2)中继续培养1-3h。最后采用多功能酶标仪于450nm波长下测定吸光度(OD)值，计算抑制率，IC50值由GraphPadPrism 5.01软件拟合得到。结果如表2所示。
表2化合物的抗肿瘤细胞增殖活性
由表2中数据可知，本发明所述化合物大部分呈现出显著的抗肿瘤细胞增殖活性，抗增殖活性与Tubastatin A相当或优于Tubastatin A。
综上所述，本发明制备的化合物将具有良好的应用前景。
Claims (5)
1.一种如下式(I)或式(Ⅲ)所示的化合物，或其药学上可接受的盐；
其中，所述式(I)化合物选自：
所述式(Ⅲ)化合物选自：
2.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述化合物的结构式如式(Ⅳ)或式(Ⅴ)所示：
3.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述化合物的结构式如式(Ⅵ)或(Ⅷ)所示：
4.如权利要求1-3任一所述的化合物，或其药学上可接受的盐在制备HDAC抑制剂药物中的应用。
5.一种HDAC抑制剂药物，所述HDAC抑制剂药物为由如权利要求1-3任一所述的化合物加入药学上可接受的辅料制成的药学上可接受的任一剂型。
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