CN115368306A - 含四氢异喹啉类结构的hdac抑制剂、组合物及其用途 - Google Patents
含四氢异喹啉类结构的hdac抑制剂、组合物及其用途 Download PDFInfo
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- CN115368306A CN115368306A CN202210901388.7A CN202210901388A CN115368306A CN 115368306 A CN115368306 A CN 115368306A CN 202210901388 A CN202210901388 A CN 202210901388A CN 115368306 A CN115368306 A CN 115368306A
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- China
- Prior art keywords
- hdac
- compound
- hdac inhibitor
- inhibitor
- tetrahydroisoquinoline
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- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 35
- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 35
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 9
- 239000003112 inhibitor Substances 0.000 title claims description 14
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims abstract description 31
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims abstract description 27
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
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- 102100022537 Histone deacetylase 6 Human genes 0.000 claims description 21
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 claims description 20
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
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- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 8
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Abstract
本发明属于医药化学领域，具体公开了一类含四氢异喹啉类结构的HDAC抑制剂、组合物及其用途，所述HDAC抑制剂为式(I)或式(II)通式所示的基于四氢异喹啉类结构的化合物或其药学上可接受的盐或氘代物。本发明还公开了包含该类HDAC抑制剂的药物组合物。所述HDAC抑制剂用于制备抗肿瘤、神经退行性疾病、自身免疫性疾病或病毒感染药物的用途。本发明制备的四氢异喹啉类结构的HDAC抑制剂均具有HDAC抑制活性，经药效学实验表明，本发明所涉及的药物可用作肿瘤、神经退行性疾病、自身免疫性疾病或病毒感染等的治疗药物。
Description
技术领域
本发明属于医药化学领域，具体涉及一类含四氢异喹啉类结构的HDAC抑制剂、组合物及其用途。
背景技术
组蛋白去乙酰化酶(Histone deacetylase，HDACs)是参与基因表达的表观遗传调控的关键酶，能够促进组蛋白N末端赖氨酸残基去乙酰化，然后核心组蛋白通过静电作用与DNA紧密结合，阻滞蛋白质复合物进入启动子结合位点，最终导致基因沉默，包括肿瘤抑制基因。在HDACs的四类亚型中，I类HDA Cs的失调与肿瘤细胞的发生发展有关(Pflieger M,et al.Novelα,β-unsaturate d hydroxamic acid derivatives overcome cisplatinresistanc.Bioorg Med Chem,2019,24(19):0968-0896.)。研究证实，I类HDACs亚型在多种恶性肿瘤中都呈高表达，如：乳腺癌、胰腺癌、胃癌、结肠癌、前列腺癌、肺癌、宫颈癌、血癌等(Witt O,et al.HDAC family:What are the cancer relevant targets？.Canc er Lett,2009,277(1):0-21；Tashima T,et al.Design and synthesis of novel and highly-active pan-histone deacetylase(pan-HDAC)inhibitors.Bioorg Med Chem,2014,22(14):3720-3731.)。研究表明，HDACs在肿瘤发生过程中起重要作用，主要包括：促进肿瘤细胞增殖和侵袭；促进肿瘤细胞血管生成；增强癌细胞对化疗和放疗的抵抗力；抑制肿瘤细胞的分化和凋亡。已经证明HDACs抑制剂能够诱导细胞凋亡，分化和细胞周期停滞以及抑制细胞迁移。因此，通过抑制HDACs可以达到治疗癌症的目的。(Chen X,et al.Design,synthesis and biol ogical evaluation of novel isoindolinone derivatives aspotent histone deacetylase inhibitors.EurJ Med Chem,2019,168:110-122.)。
II类HDACs中的HDAC6，基于其独特的结构和底物特异性，在多种疾病治疗过程中发挥功能，例如肿瘤、神经退行性疾病(如阿尔兹海默症)、慢性疾病(如炎症)、自身免疫性疾病或病毒感染(Leonhardt M,et al.Design and biological evaluation oftetrahydro-β-carboline derivatives as highly potent histone deacetylase 6(HDAC6)inhibitors.Eur J Med Chem,2018,152:329-357.)。研究表明，HDAC6的异常表达可通过微管蛋白、HSP90和泛素蛋白参与肿瘤的发生、发展和转移在内的多种癌症相关机制(Yang Penghui.HDAC6:Physiological function and its selective inhibitors forcancer treatment.Drug Discoveries Ther,2013,7(6):233-242.)。
目前，已被FDA批准用于临床的HDACs抑制剂主要为广谱HDACs抑制剂，包括Vorinostat(SAHA)，Romidepsin(FK-228)，Belinostat(PXD-101)和Panobinostat(LBH-589)。但这些非选择性或部分选择性HDACi通常会导致不良反应，如疲劳，恶心/呕吐和心脏毒性，故需集中于研究同种型选择性抑制剂。其已经是当今研究的热点，其中HDAC6选择性抑制剂的研究备受关注，但尚未有药物上市，仅ACY-1215处于临床研究中。事实上，HDAC6抑制剂比Pan-HDAC抑制剂(如SAHA)和HDAC1-3选择性抑制剂(如Romidepsin)具有更少的副作用，并且可能对正常细胞没有细胞毒性。已有研究证明抑制HDAC6不仅可以产生抗增殖作用，还可以产生抗抑郁和免疫抑制作用，具有潜在的治疗应用。
四氢异喹啉是最丰富的化学骨架之一，它存在于各种抗肿瘤药物的分子结构中，天然和合成的四氢异喹啉生物碱具有多种药理学性质，包括抗癌、抗抑郁、抗血栓、抗炎、抗病毒等。然而迄今，基于四氢异喹啉母核发现的HDAC抑制剂的报道较少。
发明内容
针对现有技术的不足，本发明提供了一类含四氢异喹啉类结构的HDAC抑制剂、组合物及其用途。
本发明的技术方案如下：
一类含四氢异喹啉类结构的HDAC抑制剂，所述HDAC抑制剂为式(I)–(II)所示的基于四氢异喹啉类结构的化合物或其药学上可接受的盐或氘代物：
其中，通式(I)中R1＝H或-OCH3，X是(CH2)n1或至少被1个R2取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基；
通式(II)中R1＝H或-OCH3，Z是C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基、或
而V是至少被1个R3取代的C6-14芳基、C5-14芳杂基；W是至少被1个R4取代的C5-14芳杂基；
n1＝1-9；R2、R3、R4分别独立地选自氢、卤素、羟基、氨甲酰基、氰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基等；
进一步方案，所述通式(I)–(II)所示的基于四氢异喹啉类结构的化合物选自以下化合物：
进一步方案，所述HDAC抑制剂为选择性的HDAC6抑制剂，所述选择性的HDAC6抑制剂为如下列通式(I)所示的四氢异喹啉类结构的化合物或其药学上可接受的盐或氘代物，
其中，(I)中R1＝-OCH3，X是至少被1个R2取代的C6-14芳基、C5-14芳杂基；R2独立地选自氢、卤素、羟基、氨甲酰基、氰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基等。
本发明还提供一种适于口服或其他方式给予哺乳动物的HDAC抑制剂的药物组合物，包括上述的HDAC抑制剂以及一种或多种药用载体或赋形剂。
进一步方案，所述HDAC抑制剂药物组合物还包括至少一种其它治疗剂。
所述HDAC抑制剂药物组合物的剂型为临床或药学上可接受的任一剂型。
本发明还提供了所述HDAC抑制剂在制备预防或治疗与HDAC活性异常表达相关的疾病的药物中的应用，所述与HDAC活性异常表达相关的疾病包括：癌症、神经退行性疾病、自身免疫性疾病或病毒感染等。
另外，本发明还提供一种HDAC抑制剂药物组合物在制备预防或治疗与HDAC活性异常表达相关的疾病的药物的应用，所述与HDAC活性异常表达相关的疾病包括：癌症、神经退行性疾病、自身免疫性疾病或病毒感染等。
本发明化合物的用药剂量为1mg-1000mg/天，也可根据病情的轻重或剂型的不同而确定。
除非另外定义，文本中使用的全部科技术语具有与权利要求主题所属领域的技术人员通常理解相同的含义。
其中“卤素”指氟、氯、溴或碘；
“C6-14芳基”是指6-10个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。其非限制性实例有：苯环、萘环、蒽环；
“C5-14芳杂基”是指5-14个环原子的非全碳单环或稠合多环基团，具有完全共轭的π电子系统。其非限制性实例有：嘧啶、吡啶、喹啉、吡咯、吡喃、咪唑、噻吩、呋喃、噻唑、嘌呤、吲哚；
“C7-12芳烷基”是指含7-12个碳原子的芳基上连有烷基的基团；
“C6-12芳杂烷基”是指含6-12个碳原子的芳杂基上连有烷基的基团；
“C1-6烷基”指1到6个碳原子的烷基；
“C1-6烷氧基”指1-6个碳原子的烷烃中一个氢原子被氧原子取代。如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基、异戊基-1-氧基、正己氧基和(2-甲基丁基)-1-氧基等；
“C2-6不饱和脂链烃基”指含有双键或者三键的碳原子数为2-6个的直链或者支链的烯基或者炔基。不饱和脂链烃基的非限制性实例有：乙烯基、1-丙烯基、乙炔基、丙炔基等。
本发明的化合物或其药学上可接受的盐或氘代物具有同样的功效且无毒，其中药学上可接受的盐是上述通式(I)和(II)的盐，其中药学上可接受的盐包括阳离子盐(钠盐、钾盐、钙盐、镁盐、铵盐等)和阴离子盐(磷酸盐、硫酸盐、硝酸盐、丙酸盐、羟基乙酸盐、枸橼酸盐、甲磺酸盐、苯甲磺酸盐、马来酸盐、富马酸盐或酒石酸盐)；氘代物指有机化合物分子中的氢被它的同位素氘(D)取代后的化合物。
“药物载体”是指药学领域常规的药物载体，例如典型的固体载体：淀粉、蔗糖、凝胶、甲基纤维素、聚乙烯吡咯烷酮、滑石粉、高龄土、碳酸钙等；液体载体：水、甘油、乙二醇、聚乙二醇300、甘油羟脂肪酸酯等。本发明的化合物的药物载体是本领域熟练技术人员所熟知的，熟练技术人员可根据制剂、给药方式等因素取舍。
“药学上可接受的任一剂型”适用于通过任何方便的或者其他适当的途径给药，如给药方式不局限于经皮、肌肉/皮下/静脉注射、鼻吸入、粘膜线路(口腔粘膜、直肠和肠粘膜等)和口服途径，给药的各种制剂包括固体制剂(如片剂、丸剂)、半固体制剂(如软膏剂、栓剂)、液体制剂(如注射剂、洗剂)以及气体制剂(如气雾剂、喷雾剂)等。这些制剂可由药剂学领域中已知的任何方法制备。例如，通过将活性成分与载体结合或与赋形剂混合的方法。
“治疗剂”选自免疫调节/治疗药物、DNA损伤化学治疗剂、蛋白酶体抑制剂、抗雄激素受体、抗逆转录病毒药物、逆转录酶抑制剂、化学治疗药物和免疫抑制剂等中的一种或多种组合。
本发明的有益效果：
本发明的HDAC抑制剂为具有HDAC抑制活性的四氢异喹啉衍生物或其药学上可接受的盐或氘代物。四氢异喹啉天然小分子化合物是一种广泛存在于罂粟科、毛茛科等植物中的生物碱，是最丰富的化学骨架之一，存在于各种抗肿瘤药物的分子结构中。通过多次实验证实，本发明制备的四氢异喹啉衍生物大多数具有较好的HDAC抑制活性，其中一部分化合物对HDAC1或/和HDAC6具有强抑制作用。部分化合物不仅对HDAC1具有较强的抑制作用，而且具有显著的抗肿瘤细胞增殖活性。另有部分化合物在高强度抑制HDAC6的同时，还表现出良好的HDAC6选择性抑制活性。药效学实验表明，本发明所涉及的化合物可用作肿瘤、神经退行性疾病、自身免疫性疾病或病毒感染的治疗药物。
具体实施方式
以化合物1、7(路线I)、化合物19、26(路线II)为例，本发明的化合物制备方法如下：
另外，化合物2-6、8-18参考路线I制备；化合物20-25、27-32参考路线II制备。需要指出的是，以下包含的特定实施例是为了对本发明做进一步的举例说明，不应被理解为对本发明范围的限制。此外，应对此了解清楚的是，本领域的技术人员可以对下述步骤作各种改动或修改以提高收率，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。
路线I中：a为EDC·HCl(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)，HOBt(1-羟基苯并三氮唑),TEA(三乙胺)，DCM(二氯甲烷)，rt(室温)；
b为ethyl 2-bromoacetate(溴乙酸乙酯)，K2CO3(碳酸钾)，KI(碘化钾)，DMF(N,N-二甲基甲酰胺)，110℃；
c为NH2OK(羟胺钾)，CH3OH(甲醇)，rt。
路线II中，a为K2CO3，KI，DMF，110℃；
b为CF3COOH(三氟乙酸)，DCM，rt；
c为EDC·HCl，HOBt,TEA，DCM，rt；
d为NH2OK，CH3OH，rt。
实施例1：
(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟乙酰胺(化合物1)的合成，具体步骤如下：
(1)、(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-羟基苯基)丙-2-烯-1-酮(中间体35)的合成
在圆底烧瓶中加入对羟基肉桂酸34(1.3g，8mmmol，1eq)，以DCM溶解(50mL)，依次加入EDC·HCl(2.3g，12mmol,1.5eq)、HOBt(1.6g，12mmol,1.5eq)，加入完毕后，室温反应1h。再加入6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐33(1.84g，8mmol，1eq)，TEA(3.33mL，24mmol，3eq)，继续反应过夜。反应液依次用饱和NaHCO3溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析得白色固体2.25g。
(2)、(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸乙酯(中间体36)的合成
在三口烧瓶中依次加入中间体35(0.3g，1mmol，1eq)，K2CO3(0.35g，2.5mmol，2.5eq)，以DMF(15mL)溶解，110℃下回流反应0.5h，继续加入溴乙酸乙酯(0.155mL，1.4mmol，1.4eq)、KI(0.02g，0.12mmol，0.1eq)，反应搅拌过夜。反应用大量水洗(150mL)，DCM萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析得白色固体0.32g。
(3)、(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟乙酰胺(化合物1)的合成
NH2OK甲醇溶液的制备：称取KOH(2g,35.7mmol,1.5eq)置于圆底烧瓶中，甲醇(5mL)溶解；称取NH2OH·HCl(1.65g,23.8mmol,1eq)置于三颈瓶中，甲醇(8.5mL)溶解；冰浴下，将KOH甲醇溶液滴加至NH2OH·HCl甲醇溶液中，N2保护下反应1h，抽滤，滤液待用。
在圆底烧瓶中，依次加入中间体36(0.1g，0.23mmol，1eq)、NH2OK甲醇溶液(3mL)，室温反应4h。用1N的HCl溶液调pH＝7，有固体析出，抽滤，滤饼水洗，干燥，经硅胶柱层析得白色固体0.07g。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
核磁共振氢谱结果为：1H NMR(400MHz,DMSO-d6):δ10.97(s,1H),9.03(s,1H),7.70(d,J＝7.8Hz,2H),7.63(d,J＝7.5Hz,1H),7.51-7.46(m,1H),7.24-7.14(m,1H),6.99(d,J＝7.1Hz,2H),6.82(s,1H),6.76(s,1H),4.53(s,2H),3.87(s,2H),3.72(s,6H),3.63(t,J＝13.8Hz,2H),2.80-2.65(m,2H)；电喷雾质谱(ESI-MS)结果为:413.17[M+H]+。
实施例2：
(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基乙酰胺(化合物7)的合成
(1)、(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-羟基-3-甲氧基苯基)丙-2-烯-1-酮(中间体38)的合成
中间体38参考实施例1步骤(1)制备,仅将对羟基肉桂酸替换为4-羟基-3甲氧基肉桂酸。
(2)、(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)乙酸酯(中间体39)的合成
中间体39参考实施例1步骤(2)制备。
(3)、(E)-2-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基乙酰胺(化合物7)的合成
化合物7参考实施例1中步骤(3)制备。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.77(s,1H),9.01(s,1H),7.48(d,J＝15.3Hz,1H),7.41(s,1H),7.23(s,1H),7.19(d,J＝15.3Hz,1H),6.94(d,J＝8.3Hz,1H),6.82(d,J＝10.6Hz,1H),6.77(s,1H),4.82(s,1H),4.65(s,1H),4.47(s,2H),3.86(s,3H),3.74(s,3H),3.73(s,3H),3.31(s,2H),2.84-2.70(m,2H)；ESI-MS:443.10[M+H]+。
实施例3：
(E)-N-羟基-2-(2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)乙酰胺(化合物19)的合成
(1)、6-(2-乙氧基-2-氧基乙氧基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(中间体41)的合成
在三口烧瓶中依次加入中间体40(1.0g，4.01mmol，1eq)，K2CO3(1.39g，10.03mmol，2.5eq)，以DMF(18mL)溶解，90℃下回流反应0.5h，继续加入溴乙酸乙酯(0.67mL，6.02mmol，1.5eq)、KI(0.33g，2.01mmol，0.1eq)，反应搅拌过夜。向反应液倾入大量水(180mL)，用DCM萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色油状物0.86g。
(2)、2-((1,2,3,4-四氢异喹啉-6-基)氧基)乙酸乙酯(中间体42)的合成
在圆底烧瓶中加入中间体41(2.4g，7.16mmol，1eq)，以DCM溶解(8.5mL)，在冰浴下滴入CF3COOH(2.13mL，28.62mmol，4eq)，滴加完毕转移至室温反应4h。反应液减压浓缩，经硅胶柱层析得黄色油状物1.65g。
(3)、(E)-2-((2-(3-(4-甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)乙酸乙酯(中间体44)的合成
在圆底烧瓶中加入4-甲氧基肉桂酸43(1.16g，6.54mmmol，1eq)，以DCM溶解(20mL)，依次加入EDC·HCl(1.88g，9.81mmol,1.5eq)、HOBt(1.33g，9.84mmol,1.5eq)，加入完毕后，室温反应0.5h.再加入中间体42(1.85g，7.84mmol，1.2eq)，三乙胺(2.7mL，19.62mmol，3eq)，继续反应10h。反应液依次用饱和NaHCO3溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色油状物1.37g。
(4)、(E)-N-羟基-2-((2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)乙酰胺(化合物19)的合成
化合物19参考实施例1中步骤(3)制备。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.81(s,1H),8.96(s,1H),7.69(d,J＝8.8Hz,2H),7.48(d,J＝15.3Hz,1H),7.21-7.11(m,2H),6.99-6.93(m,2H),6.86-6.74(m,2H),4.82(s,1H),4.64(s,1H),4.43(s,2H),3.90-3.72(m,5H,OCH3),2.90-2.72(m,2H)；ESI-MS:383.16[M+H]+。
实施例4：
2-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)-N-羟基乙酰胺(化合物26)的合成
(1)、6-(2-乙氧基-2-氧基乙氧基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(中间体41)的合成
在三口烧瓶中依次加入中间体40(1.0g，4.01mmol，1eq)，K2CO3(1.39g，10.03mmol，2.5eq)，以DMF(18mL)溶解，90℃下回流反应0.5h，继续加入溴乙酸乙酯(0.67mL，6.02mmol，1.5eq)、KI(0.33g，2.01mmol，0.1eq)，反应搅拌过夜。反应用大量水(180mL)，用DCM萃取，饱和食盐水洗涤，DCM萃取，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析得黄色油状物0.86g。
(2)、2-((1,2,3,4-四氢异喹啉-6-基)氧基)乙酸乙酯(中间体42)的合成
在圆底烧瓶中加入中间体41(2.4g，7.16mmol，1eq)，以DCM溶解(8.5mL)，在冰浴下滴入CF3COOH(2.13mL，28.62mmol，4eq)，滴加完毕转移至室温反应4h。反应液减压浓缩，经硅胶柱层析得黄色油状物1.65g。
(3)、2-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)乙酸乙酯(中间体46)的合成
中间体46参考实施例3的步骤(3)制备，仅将4-甲氧基肉桂酸替换为肉桂酸。
(4)、2-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)-N-羟基乙酰胺(化合物26)的合成
化合物26参考实施例3的步骤(4)制备。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.77(s,1H),9.17(s,1H),7.71(s,2H),7.52(s,2H),7.51(d,J＝8.5Hz,1H),7.46(s,1H),7.36(s,1H),7.22(s,1H),7.04(s,1H),6.81(d,J＝7.0Hz,1H),5.23(s,2H),4.81(s,1H),4.63(s,1H),3.63(s,J＝11.6Hz,2H),2.80(d,J＝30.9Hz,2H)；ESI-MS:353.14[M+H]+。
实施例5：
(E)-4-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟基丁酰胺(化合物2)的合成
化合物2参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为4-溴丁酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),8.72(s,1H),7.68(d,J＝7.5Hz,2H),7.48(d,J＝15.2Hz,1H),7.18(d,J＝15.2Hz,1H),6.96(d,J＝7.9Hz,2H),6.82(s,1H),6.76(s,1H),4.81(s,1H),4.63(s,1H),4.00(t,J＝5.8Hz,2H),3.72(s,6H),3.32(s,2H),2.79-2.67(m,2H)，2.13(t,J＝7.0Hz,2H)，1.97-1.92(m,2H)；ESI-MS:441.20[M+H]+。
实施例6：
(E)-5-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟基戊酰胺(化合物3)的合成
化合物3参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为5-溴戊酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):10.38(s,1H),8.70(s,1H),7.68(d,J＝8.3Hz,2H),7.48(d,J＝15.3Hz,1H),7.18(d,J＝15.3Hz,1H),6.96(d,J＝8.6Hz,2H),6.82(s,1H),6.76(s,1H),4.81(s,1H),4.64(s,1H),4.02(t,J＝5.9Hz,2H),3.94-3.84(m,2H),3.73(d,J＝2.7Hz,6H),2.81-2.72(m,2H),2.02(t,J＝7.0Hz,2H),1.71-1.63(m,4H)；ESI-MS:455.20[M+H]+。
实施例7：
(E)-6-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟基己酰胺(化合物4)的合成
化合物4参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为6-溴己酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.35(d,J＝10.6Hz,1H),8.67(d,J＝8.9Hz,1H),7.68(d,J＝8.3Hz,2H),7.48(d,J＝15.3Hz,1H),7.18(d,J＝15.3Hz,1H),6.96(d,J＝8.7Hz,2H),6.82(s,1H),6.76(s,1H),4.81(s,1H),4.63(s,1H),4.00(t,J＝6.4Hz,2H),3.73(d,J＝2.8Hz,6H),3.34(s,2H),2.80-2.67(m,2H),1.97(t,J＝7.3Hz,2H),1.74-1.70(m,2H),1.58-1.53(m,2H),1.41-1.38(m,2H)；ESI-MS:469.23[M+H]+。
实施例8：
(E)-7-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟基庚酰胺(化合物5)的合成
化合物5参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为7-溴庚酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),8.71(s,1H),7.67(d,J＝7.9Hz,2H),7.47(d,J＝15.2Hz,1H),7.17(d,J＝15.2Hz,1H),6.95(d,J＝8.1Hz,2H),6.81(s,1H),6.75(s,1H),4.81(s,1H),4.63(s,1H),4.99(t,J＝6.2Hz,2H),3.87(d,J＝12Hz,2H),3.72(s,6H),2.81-2.70(m,2H),1.97(t,J＝7.1Hz,2H),1.72-1.68(m,2H),1.53-1.49(m,2H),1.40-1.36(m,2H),1.31-1.26(m,2H)；ESI-MS:505.23[M+Na]+。
实施例9：
(E)-8-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)-N-羟基辛酰胺(化合物6)的合成
化合物6参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为8-溴辛酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ8.39(s,1H),7.68(d,J＝8.2Hz,2H),7.48(d,J＝15.3Hz,1H),7.18(d,J＝15.3Hz,1H),6.96(d,J＝8.6Hz,2H),6.82(s,1H),6.76(s,1H),4.81(s,1H),4.64(s,1H),4.00(t,J＝6.5Hz,2H),3.88(t,J＝11.5Hz,2H),3.73(d,J＝2.7Hz,6H),2.81-2.66(m,2H),1.95(t,J＝7.3Hz,2H),1.68(dd,J＝14.3Hz,J＝6.7Hz,2H),1.50(dd,J＝14.4Hz,J＝7.3Hz,2H),1.43-1.36(m,2H),1.31(d,J＝8.2Hz,2H),1.27(d,J＝7.5Hz,2H)；ESI-MS:497.20[M+H]+。
实施例10：
(E)-4-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基丁酰胺(化合物8)的合成
化合物8参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为4-溴丁酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),8.71(s,1H),7.48(d,J＝15.3Hz,1H),7.39(s,1H),7.23(d,J＝8.1Hz,1H),7.17(d,J＝15.3Hz,1H),6.97(d,J＝8.3Hz,1H),6.82(s,1H),6.77(s,1H),4.82(s,1H),4.64(s,1H),4.00(t,J＝6.3Hz,2H),3.85(s,3H),3.73(d,J＝2.5Hz,6H),3.31(s,2H),2.82-2.72(m,2H),2.13(t,J＝7.4Hz,2H),1.97-1.93(m,2H)；ESI-MS:471.30[M+H]+。
实施例11：
(E)-5-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基戊酰胺(化合物9)的合成
化合物9参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为5-溴戊酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),8.71(s,1H),7.51(d,J＝14.5Hz,1H),7.45(s,1H),7.39(d,J＝5.4Hz,1H),7.22(d,J＝7.4Hz,1H),7.00(d,J＝14.5Hz,1H),6.82(s,1H),6.77(s,1H),4.82(s,1H),4.64(s,1H),4.01-3.97(m,2H),3.84(s,3H),3.73(d,J＝2.4Hz,6H),3.34(s,2H),2.82-2.72(m,2H),2.02(t,J＝6.9Hz,2H),1.68(dd,J＝12.9Hz,J＝6.3Hz,4H)；ESI-MS:485.00[M+H]+。
实施例12：
(E)-6-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基己酰胺(化合物10)的合成
化合物10参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为6-溴己酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),8.68(s,1H),7.51(d,J＝14.8Hz,1H),7.46(s,1H),7.34(d,J＝10.6Hz,1H),7.22(d,J＝8.3Hz,1H),7.00(d,J＝14.8Hz,1H),6.80(s,1H),6.77(s,1H),4.82(s,1H),4.64(s,1H),4.01-3.96(m,2H),3.84(s,3H),3.78-3.72(m,6H),3.31(s,2H),2.75-2.66(m,2H),1.98(t,J＝7.3Hz,2H),1.74-1.69(m,2H),1.59-1.54(m,2H),1.41-1.36(m,2H)；ESI-MS:521.40[M+Na]+。
实施例13：
(E)-7-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基庚酰胺(化合物11)的合成
化合物11参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为7-溴庚酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.34(s,1H),8.67(s,1H),7.50(d,J＝13.8Hz,1H),7.45(s,1H),7.36(d,J＝5.0Hz,1H),7.22(d,J＝7.6Hz,1H),6.98(d,J＝13.8Hz,1H),6.82(s,1H),6.76(s,1H),4.82(s,1H),4.63(s,1H),4.00-3.96(m,2H),3.81(s,3H),3.74(d,J＝14.0Hz,6H),3.32-3.30(m,2H),2.73-2.62(m,2H),1.95(t,J＝6.7Hz,2H),1.73-1.68(m,2H),1.53-1.49(m,2H),1.40-1.37(m,2H),1.30(s,2H)；ESI-MS:535.24[M+Na]+。
实施例14：
(E)-8-(4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)-N-羟基辛酰胺(化合物12)的合成
化合物12参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为8-溴辛酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.34(s,1H),8.66(s,1H),7.52-7.47(m,H),7.41(s,1H),7.36(d,J＝6.7Hz,1H),7.21(d,J＝6.3Hz,1H),6.98-6.95(m,1H),6.82(s,1H),6.76(s,1H),4.82(s,1H),4.63(s,1H),4.01-3.97(m,2H),3.87(s,3H),3.80(d,J＝5.7Hz,6H),3.68(s,2H),2.78-2.66(m,2H),1.94(t,J＝6.8Hz,2H),1.70(s,2H),1.57(s,2H),1.51-1.47(m,2H),1.40(s,4H)；ESI-MS:527.27[M+H]+。
实施例15：
(E)-4-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)甲基)-N-羟基苯甲酰胺(化合物13)的合成
化合物13参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为4-氯甲基苯甲酸甲酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ7.94(d,J＝8.1Hz,2H),7.70(d,J＝8.5Hz,2H),7.52(d,J＝8.5Hz,2H),7.49-7.44(m,1H),7.23-7.16(m,1H),7.08(s,1H),7.05(s,1H),6.81(d,J＝10.4Hz,2H),6.76(s,1H),5.23(s,2H),4.81(s,1H),4.63(s,1H),3.73(d,J＝2.8Hz,6H),,3.48(s,2H)2.80-2.72(m,2H)；ESI-MS:489.20[M+H]+。
实施例16：
(E)-5-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)甲基)-N-羟基呋喃-2-甲酰胺(化合物14)的合成
化合物14参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为5-(氯甲基)呋喃-2-羧酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ11.21(s,1H),9.12(s,1H),7.71(d,J＝7.8Hz,2H),7.64(d,J＝8.6Hz,1H),7.49(d,J＝16.0Hz,1H),7.37(d,J＝14.4Hz,1H),7.21(d,J＝16.0Hz,1H),7.09(s,1H),7.04(s,1H),6.83(d,J＝7.7Hz,1H),6.74(d,J＝8.5Hz,1H),6.62-6.40(m,1H),5.16(d,J＝10.3Hz,2H),4.81(s,1H),4.63(s,1H),3.74(d,J＝16.6Hz,6H),3.67-3.57(m,2H),2.79-2.67(m,2H)；ESI-MS:477.16[M-H]-。
实施例17：
(E)-5-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)苯氧基)甲基)-N-羟基噻吩-2-甲酰胺(化合物15)的合成
化合物15参考实施例1制备，仅将步骤(2)中溴乙酸乙酯替换为5-溴甲基噻吩-2-羧酸甲酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ11.27(s,1H),9.17(s,1H),7.71(d,J＝7.5Hz,1H),7.51(d,J＝6.3Hz,2H),7.42-7.32(m,1H),7.19(d,J＝11Hz,1H),7.08-7.04(m,1H),7.00(s,1H),6.80(d,J＝11.4Hz,2H),6.76(s,1H),5.38(d,J＝8.9Hz,2H),4.81(s,1H),4.63(s,1H),3.72(s,6H),3.68-3.54(m,2H),2.80-2.67(m,2H)；ESI-MS:493.14[M-H]-。
实施例18：
(E)-4-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)甲基)-N-羟基苯甲酰胺(化合物16)的合成
化合物16参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为4-氯甲基苯甲酸甲酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ11.28(s,1H),9.14(s,1H),7.78(d,J＝7.4Hz,2H),7.51(d,J＝7.3Hz,2H),7.48-7.44(m,1H),7.42(s,1H),7.22(d,J＝7.4Hz,1H),7.07-7.00(m,1H),6.88(s,1H),6.82(s,1H),6.76(s,1H),5.19(s,2H),4.82(s,1H),4.64(s,1H),3.86(s,3H),3.73(s,6H),3.49(s,2H),2.81-2.67(m,2H)；ESI-MS:541.10[M+Na]+。
实施例19：
(E)-5-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)甲基)-N-羟基呋喃-2-甲酰胺(化合物17)的合成
化合物17参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为5-(氯甲基)呋喃-2-羧酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):11.26(s,1H),9.14(s,1H),7.48(d,J＝16.2Hz,1H),7.40(d,J＝3.4Hz,1H),7.36(s,1H),7.24(d,J＝8.4Hz,1H),7.14(d,J＝16.2Hz,1H),7.07(s,1H),6.78(d,J＝11.3Hz,1H),6.72(s,1H),6.60-6.44(m,1H),5.11(s,2H),4.83(s,1H),4.64(s,1H),3.83(s,3H),3.74(d,J＝14.2Hz,6H),3.64(d,J＝11.6Hz,2H),2.81-2.67(m,2H)；ESI-MS:531.17[M+Na]+。
实施例20：
(E)-5-((4-(3-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-氧代丙-1-烯-1-基)-2-甲氧基苯氧基)甲基)-N-羟基噻吩-2-甲酰胺(化合物18)的合成
化合物18参考实施例2制备，仅将步骤(2)中溴乙酸乙酯替换为5-(溴甲基)噻吩-2-羧酸甲酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ11.27(s,1H),9.15(s,1H),7.63(s,1H),7.53-7.49(m,1H),7.46(s,1H),7.41(d,J＝6.3Hz,1H),7.24(d,J＝4.6Hz,1H),7.21-7.18(m,1H),7.11(s,1H),6.81(d,J＝7.0Hz,1H),6.76(s,1H),5.33(s,2H),4.82(s,1H),4.64(s,1H),3.85(s,3H),3.73(s,6H),3.66-3.54(m,2H),2.81-2.67(m,2H)；ESI-MS:525.16[M+H]+。
实施例21：
(E)-N-羟基-6-(2-(3-(4-(4-甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)己酰胺(化合物20)的合成
化合物20参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为6-溴己酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.36(s,1H),8.67(s,1H),7.72-7.66(m,2H),7.48(d,J＝15.4Hz,1H),7.17(d,J＝15.3Hz,1H),7.11(d,J＝8.6Hz,1H),6.96(d,J＝8.8Hz,2H),6.80-6.72(m,2H),4.81(s,1H),4.62(s,1H),3.96-3.83(m,3H),3.79(s,3H),3.77-3.71(m,1H),2.89-2.74(m,2H),1.96(t,J＝7.3Hz,2H),1.73-1.63(m,2H),1.58-1.49(m,2H),1.42-1.33(m,2H)；ESI-MS:438.21[M+H]+。
实施例22：
(E)-N-羟基-7-(2-(3-(4-(4-甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)庚酰胺(化合物21)的合成
化合物21参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为7-溴庚酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.34(s,1H),8.65(s,1H),7.72-7.66(m,2H),7.48(d,J＝15.3Hz,1H),7.17(d,J＝15.3Hz,1H),7.11(d,J＝8.6Hz,1H),6.99-6.94(m,2H),6.80-6.73(m,2H),4.81(s,1H),4.62(s,1H),3.94-3.86(m,3H),3.79(s,3H),3.77-3.69(m,1H),2.88-2.74(m,2H),1.94(t,J＝7.3Hz,2H),1.72-1.63(m,2H),1.55-1.46(m,2H),1.42-1.34(m,2H),1.32-1.24(m,2H)；ESI-MS:452.23[M+H]+。
实施例23：
(E)-N-羟基-8-((2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)辛酰胺(化合物22)的合成
化合物22参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为8-溴辛酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ10.33(s,1H),8.65(s,1H),7.69(d,J＝8.7Hz,2H),7.48(d,J＝15.3Hz,1H),7.17(d,J＝15.3Hz,1H),7.11(d,J＝8.6Hz,1H),6.96(d,J＝8.8Hz,2H),6.79-6.72(m,2H),4.81(s,1H),4.62(s,1H),3.95-3.86(m,3Hr),3.79(s,3H),3.75-3.68(m,1H),2.89-2.72(m,2H),1.94(t,J＝7.3Hz,2H),1.72-1.63(m,2H),1.52-1.44(m,2H),1.41-1.26(m,6H)；ESI-MS:466.24[M+H]+。
实施例24：
(E)-N-羟基-2-((2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)嘧啶-5-羧酰胺(化合物23)的合成
化合物23参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为2-(溴甲基)嘧啶-5-羧酸乙酯。将制备得到的白色固体进行核磁共振氢谱和质谱检测，其结果如下：
1H NMR(400MHz,DMSO-d6):δ11.51(s,1H),9.38(s,1H),9.07(s,2H),7.68(d,J＝8.4Hz,2H),7.48(d,J＝15.3Hz,1H),7.16(d,J＝15.3Hz,1H),7.11(d,J＝8.5Hz,1H),7.01-6.92(d,J＝8.8Hz,2H),6.82(s,2H),5.32(s,2H),4.81(s,1H),4.62(s,1H),3.91-3.83(m,1H),3.79(s,3H,),3.76-3.68(m,1H),2.88-2.71(m,2H)；ESI-MS:460.20[M+H]+。
实施例25：
(E)-N-羟基-1-((2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)-1H-吲哚-6-羧酰胺(化合物24)的合成
化合物24参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为1-(溴甲基)-1H-吲哚-6-羧酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:497.21[M+H]+
实施例26：
(E)-N-羟基-5-((2-(3-(4-(甲氧基苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)噻吩-2-羧酰胺(化合物25)的合成
化合物25参考实施例3制备，仅将步骤(1)中溴乙酸乙酯替换为5-(溴甲基)噻吩-2-羧酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:464.16[M+H]+。
实施例27：
6-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)-N-羟基己酰胺(化合物27)的合成
化合物27参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为6-溴己酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:408.21[M+H]+。
实施例28：
7-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)-N-羟基庚酰胺(28)的合成
化合物28参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为7-溴庚酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:422.24[M+H]+。
实施例29：
8-((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)-N-羟基辛酰胺(29)的合成
化合物29参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为8-溴辛酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:436.23[M+H]+。
实施例30：
2-(((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)-N-羟基嘧啶-5-羧酰胺(化合物30)的合成
化合物30参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为2-(溴甲基)嘧啶-5-羧酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:430.18[M+H]+。
实施例31：
1-(((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)-N-羟基-1H-吲哚-6-羧酰胺(化合物31)的合成
化合物31参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为1-(溴甲基)-1H-吲哚-6-羧酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:467.20[M+H]+。实施例32：
5-(((2-肉桂酰基-1,2,3,4-四氢异喹啉-6-基)氧基)甲基)-N-羟基噻吩-2-羧酰胺(化合物32)的合成
化合物32参考实施例4制备，仅将步骤(1)中溴乙酸乙酯替换为5-(溴甲基)噻吩-2-羧酸乙酯。
将制备得到的白色固体进行质谱检测，其ESI-MS结果为:434.13[M+H]+。测试例1：本发明化合物的HDAC1酶抑制活性
本实施例以上市广谱HDACs抑制剂SAHA为阳性对照，采用Peptide HDAC ActivityAssay评价本发明化合物和SAHA的HDAC1酶抑制活性。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，但本发明化合物不限于具有以下有益效果。
HDAC1酶抑制活性的测试步骤为：配制待测化合物的二甲基亚砜(DMSO)溶液，并按试剂盒说明依次配制缓冲液、酶溶液以及相应的底物/胰蛋白酶混合溶液；将梯度浓度的化合物溶液、酶溶液、底物/胰蛋白酶混合溶液分别加入到384孔板中以配制催化反应体系(设无化合物对照、无酶对照孔)；室温孵育一定时间，离心后，采用Synergy酶标仪连续读取荧光信号值，并选取线性反应段得到斜率(slope)，进而计算各浓度下的抑制率，IC50由GraphPad Prism 5软件拟合得到。
表1：部分化合物对HDAC1酶的抑制活性
| Cpd. | HDAC1(IC<sub>50</sub>) |
| 3 | +++ |
| 4 | +++ |
| 5 | +++++ |
| 6 | +++++ |
| 10 | +++ |
| 11 | +++++ |
| 12 | +++ |
| SAHA | ++++ |
上表中：“+++++”代表0-12nM；“++++”代表12-20nM；“+++”代表20-100nM；“++”代表100-1000nM。
由表1中数据可知，所列举化合物均呈现出显著的HDAC1抑制活性，部分化合物抑酶活性与SAHA相当或优于SAHA。本专利中实施例1-32中的所有化合物1-32均表现出一定HDAC1酶抑制活性，表1中仅是示例性列举一些活性突出的化合物。
测试例2：本发明化合物的抗肿瘤细胞增殖活性
本实施例以SAHA为阳性对照，采用MTT法评价本发明化合物和SAHA对肺癌细胞株A549及结肠癌细胞株HCT116(所述肺癌细胞株A549及结肠癌细胞株HCT116来源于AmericAnTissue Culture Collection,Manassas,VA,USA)的抗增殖活性。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，但本发明化合物不限于具有以下有益效果。
抗肿瘤细胞增殖活性的测试步骤为：消化收集肿瘤细胞，以一定密度接种于96孔培养板，置于培养箱(37℃，5％CO2)中，直至细胞90％融合后，用无血清培养基孵育2h使细胞同步化。随后，弃去上清，分别加入含有各不同浓度的化合物的RPMI 1640培养基孵育72h，孵育结束前4h，每孔加入MTT溶液。孵育结束后，离心，弃去各孔上清液，每孔加入微量DMSO，细胞振荡仪上振荡10min，待结晶物充分溶解后用酶标仪于570nm波长下测定OD值，计算抑制率，GI50值由GraphPad Prism 6软件拟合得到。
表2：化合物的抗肿瘤细胞增殖活性
| Cpd. | A549(GI<sub>50</sub>) | HCT116(GI<sub>50</sub>) |
| 4 | ++ | ++ |
| 5 | ++ | ++ |
| 6 | ++ | ++ |
| 11 | ++ | ++ |
| 12 | +++ | +++ |
| 35 | ++ | ++ |
| 38 | + | + |
| SAHA | ++ | +++ |
上表中：“++++”代表＜0.1μM；“+++”代表0.1-1.0μM；“++”代表1.0-5.0μM；“+”代表5.0-20μM。
由表2中数据可知，所列举化合物均呈现出显著的抗肿瘤细胞增殖活性，抗增殖活性与SAHA相当。本专利中实施例1-32中的所有化合物1-32均表现出抗肿瘤细胞增殖活性，表1中仅是示例性列举一些抗肿瘤细胞增殖活性突出的化合物。
测试例3：本发明化合物的HDAC6选择性
文献表明，通过HDAC1、HDAC6酶抑制活性的测试可反映化合物对HDAC亚型抑制的选择性(Yu CW,et al.Quinazolin-2,4-dione-Based Hydroxamic Acids as SelectiveHistone Deacetylase-6 Inhibitors for Treatment of Non-Small Cell LungCancer.J Med Chem,2019,62(2):857-874.)
化合物对HDAC6抑制活性的测试方法参考HDAC1抑制活性的测试方法，仅在测试相应酶抑制活性时更换催化反应体系底物。
以下通过本发明部分化合物对HDAC1和HDAC6的抑制活性数据，进一步阐述其对HDAC1和HDAC6的选择性。不应理解为本发明仅以下化合物具有对HDAC6的选择性。
表3：化合物对HDAC6的抑制活性
上表中：“++++”代表0-10nM；“+++”代表10-100nM；“++”代表100-1000nM；“+”代表1000-10000nM。
由表3知，符合通式(I)的化合物16、17对HDAC6具有显著的抑酶活性，而对HDAC1的抑制活性则相对较弱，故为选择性的HDAC6抑制剂。化合物5、11相对于化合物16、17具有显著的HDAC1、HDAC6抑制活性。与广谱HDACs抑制剂SAHA相比，本发明化合物16、17在显著抑制相应HDAC亚型的同时，有利于降低SAHA对所有HDAC亚型抑制所产生的毒性。
综上，本发明制备的一类含有四氢异喹啉结构的HDACs抑制剂表现出低毒、高效、强选择性的特点，具有良好的应用前景。
Claims (10)
1.一类含四氢异喹啉类结构的HDAC抑制剂，其特征在于：所述HDAC抑制剂为式(I)–(II)所示的基于四氢异喹啉类结构的化合物或其药学上可接受的盐或氘代物：
如下列通式(I)–(II)所示:
上式中，R1＝H或-OCH3，X是(CH2)n1或至少被1个R2取代的C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基；
Z是C6-14芳基、C5-14芳杂基、C7-12芳烷基、C6-12芳杂烷基或
而V是至少被1个R3取代的C6-14芳基、C5-14芳杂基；
W是至少被1个R4取代的C5-14芳杂基；
n1＝1-9；R2、R3、R4分别包括氢、卤素、羟基、氨甲酰基、氰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基中一种。
2.根据权利要求1所述的一类含四氢异喹啉类结构的HDAC抑制剂，其特征在于：所述HDAC抑制剂选自以下任一化合物或其药学上可接受的盐或氘代物：
3.根据权利要求1所述的一类含四氢异喹啉类结构的HDAC抑制剂，其特征在于：所述HDAC抑制剂为选择性的HDAC6抑制剂，所述选择性的HDAC6抑制剂为通式(I)所示的四氢异喹啉类结构的化合物或其药学上可接受的盐或氘代物。
其中，通式(I)中R1＝-OCH3，X是至少被1个R2取代的C6-14芳基、C5-14芳杂基；R2包括氢、卤素、羟基、氨甲酰基、氰基、C1-6烷基、C1-6烷氧基、C2-6不饱和脂链烃基中一种。
4.一种含四氢异喹啉类结构的HDAC抑制剂的药物组合物，其特征在于，包括权利要求1-3任一项所述的HDAC抑制剂以及一种或多种药用载体或赋形剂。
5.根据权利要求4所述的一种含四氢异喹啉类结构的HDAC抑制剂的药物组合物，其特征在于：还包括至少一种治疗剂；所述HDAC抑制剂组合物的剂型为临床或药学上可接受的任一剂型。
6.一类如权利要求1-3任一项所述的HDAC抑制剂在制备与HDAC活性异常表达相关的疾病的药物中的应用。
7.根据权利要求6所述的与HDAC活性异常表达相关的疾病，包括：癌症、神经退行性疾病、自身免疫性疾病或病毒感染。
8.一类如权利要求4或5所述的药物组合物在制备与HDAC活性异常表达相关的疾病的药物中的应用。
9.根据权利要求8所述的与HDAC活性异常表达相关的疾病，包括：癌症、神经退行性疾病、自身免疫性疾病或病毒感染。
10.一种用于抑制HDAC的试剂盒，其特征在于，包含权利要求1-3任一项所述的HDAC抑制剂。
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