WO2016095581A1 - 一种新型烟酰胺磷酸核糖转移酶抑制剂及其合成方法与应用 - Google Patents

一种新型烟酰胺磷酸核糖转移酶抑制剂及其合成方法与应用 Download PDF

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WO2016095581A1
WO2016095581A1 PCT/CN2015/090572 CN2015090572W WO2016095581A1 WO 2016095581 A1 WO2016095581 A1 WO 2016095581A1 CN 2015090572 W CN2015090572 W CN 2015090572W WO 2016095581 A1 WO2016095581 A1 WO 2016095581A1
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蒋晟
涂正超
郑多
秦东光
白进红
覃筱楚
姚毅武
刘洋汉
邱亚涛
陈家轩
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中国科学院广州生物医药与健康研究院
深圳大学
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
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    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

提供了一种如式I所示的烟酰胺磷酸核糖转移酶抑制剂，其制备方法及其应用。其合成原料便宜，路线简洁，操作简单，适于工业生产，且得到的化合物具有抗肿瘤活性，有望被开发为抗肿瘤药物。

Description

一种新型烟酰胺磷酸核糖转移酶抑制剂及其合成方法与应用 技术领域：
本发明涉及医药技术领域，具体涉及一种新型烟酰胺磷酸核糖转移酶抑制剂及其合成方法与应用。
背景技术：
烟酰胺磷酸核糖转移酶(Nampt)是哺乳动物烟酰胺腺嘌呤二核苷酸(NAD)合成途径的限速酶，调控着细胞内NAD水平。NAD是生命体内很多酶的辅酶，在许多细胞生理过程中发挥着重要作用。肿瘤细胞为了维持高增殖速率，需要更多的能量，更多的NAD依赖性的酶。因此肿瘤细胞就需要合成和补充更多的NAD,对细胞内NAD水平的依赖比正常细胞更强。另外研究表明Nampt还有促血管生成活性，支持着一些肿瘤细胞的生长。这些研究使得Nampt成为近年来抗癌药研究中一个非常有吸引力的靶标，Nampt抑制剂可以被用于肿瘤化疗。
目前已有三个Nampt抑制剂处于临床研究阶段，分别是FK866,CHS828和GMX1777。临床试验表明，上述三个药的不良反应比较相似，主要表现为血小板减少症和胃肠道毒性反应。三个化合物均为纳摩尔级别的细胞毒化合物，在体外及体内实验中均有较好的抗肿瘤活性。但是目前报道的一期临床研究结果并没有达到预期的肿瘤抑制效果，一般需要和其他抗肿瘤药物联用，尤其是和DNA损伤药物联用可能会发挥更好的治疗效果。
Figure PCTCN2015090572-appb-000001
烟酰胺磷酸核糖转移酶(Nampt)是一个非常优秀的抗肿瘤靶标，但目前为止只有三个Nampt抑制剂处于临床研究阶段，而且临床试验表明这三个抑制剂都有很多不足，迫切需要药物化学家设计合成更多新颖的Nampt抑制剂来满足学术研究和实际临床应用的需求。在此，我们运用计算机辅助药物设计手段，设计合成了一系列结构新颖的Nampt抑制剂。
发明内容：
本发明的目的是提供一种新型烟酰胺磷酸核糖转移酶抑制剂及其合成方法与应用。
本发明是通过以下技术方案予以实现的：
一种新型烟酰胺磷酸核糖转移酶抑制剂，其结构式如I所示的化合物或其药学上可接受的盐：
Figure PCTCN2015090572-appb-000002
其中，R1选自取代或非取代的芳香环或芳香杂环，所述取代基选自卤素，烷基，卤代烷基或烷氧基；
R2选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、烷氧羰基、苄基、羟乙基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
R3选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
R4选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
R5选自-(CH2)n1-,或脂杂链或烯键-(CHCH)n2-或杂环或芳环,所述脂杂链选自-Y(CH2)n3-或-Y-CH2-NH-CH2-CH2-,其中n1为1-10的整数；n2为1-3的整数,n3为1-10的整数,Y选自NH或O；
n为1–5的整数；
m为0–6的整数。
所述芳香环选自苯基，苯并呋喃基，苯并噻吩基，吲哚基，喹啉基，异喹啉基中的任一种，优选为吲哚基。
R2优选自氢、烷氧羰基、烷基、苄基、羟乙基。
R3优选自氢。
R4优选自氢。
n优选为1。
所述的烟酰胺磷酸核糖转移酶抑制剂，优选为如下化合物：
Figure PCTCN2015090572-appb-000003
Figure PCTCN2015090572-appb-000004
Figure PCTCN2015090572-appb-000005
Figure PCTCN2015090572-appb-000006
所述的式I所示的烟酰胺磷酸核糖转移酶小分子抑制剂的制备方法，其合成路线如下：
Figure PCTCN2015090572-appb-000007
特别地，当n为1，m也为1，R3选自氢，R4选自氢，R1选自取代的芳香环时，反应式如下：
Figure PCTCN2015090572-appb-000008
其中R2和R5的含义如前所述。
合成具体描述如下：
a、芳香醇1经过羟基磺酰化后被叠氮化钠亲核进攻，磺酰基离去，叠氮基再发生Staudinger还原反应得到中间体胺2；
b、中间体胺2跟羧酸3在EDCI、HOBt、三乙胺存在下室温下发生缩合反应得到化合物4，所述中 间体胺2、羧酸3、EDCI、HOBt、三乙胺的摩尔比为1～3:1:1～3:1～3:1～3；
c、化合物4在摩尔浓度为3mol/L的稀HCl溶液中,室温下反应12小时后，调节PH值到7，得到醛5；
d、醛5与胺6在氰基硼氢化钠，醋酸作用下室温还原胺化得到中间体7；醛5、胺6、氰基硼氢化钠、醋酸的摩尔比为1:1～3:1～3:1～3；
e、中间体7与卤代烃在碱性条件下室温到80℃发生亲核取代反应，得到目标化合物；中间体7、卤代烃、碱的摩尔比为1:1～3:1～3:1～3。
所述的EDCI是指1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，HOBt是指1-羟基苯并三唑。
所述的药学上可接受的盐为与以下酸形成的盐：盐酸，硫酸，磷酸，氢溴酸，硝酸，对甲苯磺酸等。
本发明还保护式I所示的化合物在制备预防和/或治疗与烟酰胺磷酸核糖转移酶活性失控有关疾病的药物中的应用。
本发明具有的有益效果如下：本发明开发了一类新型的Nampt酶小分子抑制剂，其合成原料便宜，路线简洁，操作简单，适于工业生产，且化合物具有优秀的抗肿瘤活性，有望被开发为新的抗肿瘤药物。
具体实施方式：
以下是对本发明的进一步说明，而不是对本发明的限制。
实施例1：
Figure PCTCN2015090572-appb-000009
将化合物9(408mg,1mmol)溶于无水DCM中，0℃下加入三乙胺(0.4mL,3mmol)，然后缓慢滴加甲磺酰氯(0.12mL,1.5mmol)，待滴加完毕反应一小时后，加入饱和碳酸氢钠溶液淬灭反应，加入DCM稀释后，依次用饱和碳酸氢钠，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩得粗品直接用于下一步反应。
将上一步得到的粗品溶于DMF中，加入叠氮化钠(195mg,3mmol)，80℃下反应2小时后冷却至室温，减压旋掉DMF,加入乙醚萃取，有机相用饱和氯化铵，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩得粗品直接用于下一步反应。
将上一步得到的粗品溶于THF中，加入三苯基膦(393mg,1.5mmol)，水(0.1mL,6mmol)，升温至60℃搅拌4小时后冷却至室温，浓缩柱层析得到黄色液体化合物10(297mg,73％)。
1H NMR(500MHz,CDCl3):δ7.34(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),5.36(s,1H),3,32(s,6H),2.67(t,J＝7.0Hz,2H),2.61(t,J＝7.5Hz,2H),1.66-1.59(m,2H),1.49-1.43(m,2H),1.36-1.33(m,2H)ppm.13C NMR(125MHz,CDCl3):δ142.9,135.4,128.1,126.5,103.3,52.7,42.1,35.5,33.6,31.2,26.4ppm.
实施例2：
Figure PCTCN2015090572-appb-000010
将化合物10(18mg,0.12mmol)溶于DMF中，然后依次加入EDCI(38mg,0.2mmol),HOBt(20mg,0.15mmol)，TEA(0.03mL,0.2mmol)，最后加入化合物3(41mg,0.1mmol),反应在室温下搅拌5小时后，旋蒸除去溶剂，然后用乙酸乙酯萃取，有机相依次用饱和碳酸氢钠，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩柱层析得到黄色固体化合物11(46mg,86％)。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.55-8.53(m,1H),7.77-7.73(m,1H),7.58(d,J＝16.0Hz,1H),7.33(d,J＝8.0Hz,2H),7.30-7.16(m,1H),7.15(d,J＝8.0Hz,2H),6.45(d,J＝16.0Hz,1H),5.98(s,1H),5.33(s,1H),3,39-3.32(m,2H),3.31(s,6H),2.60(t,J＝8.0Hz,2H),1.67-1.55(m,4H),1.41-1.35(m,2H)ppm.MS(ESI,m/z):369(M++1).
实施例3：
Figure PCTCN2015090572-appb-000011
将化合物11(40mg,0.07mmol)溶于乙酸乙酯中，然后缓慢滴加3mol/L HCl(0.1mL,0.3mmol),室温下反应12小时后，滴加饱和碳酸氢钠溶液调节反应液PH值到7，加入乙酸乙酯稀释，有机相依次用饱和碳酸氢钠，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩柱层析得到化合物12(28mg,90％)。1H NMR(400MHz,CDCl3):δ9.94(s,1H),8.71(d,J＝0.8Hz,1H),8.54-8.53(m,1H),7.78-7.73(m,3H),7.58(d,J＝15.6Hz,1H),7.31-7.27(m,2H),6.47(d,J＝15.6Hz,1H),6.08(s,1H),3.40-3.35(m,2H),2.68(t,J＝8.0Hz,2H),1.71-1.57(m,4H),1.43-1.37(m,2H)ppm.13C NMR(125MHz,CDCl3):δ191.9,165.1,150.2,149.9,149.0,137.1,134.4,134.3,130.7,129.9,129.0,123.7,122.9,39.6,35.9,30.5,29.4,26.4ppm.
实施例4：
Figure PCTCN2015090572-appb-000012
将化合物6(色胺,2.4g,15mmol)溶于甲醇中，加入化合物12(2.3g,12mmol),氰基硼氢化钠(1.6g,25mmol)，醋酸(0.72g,12mmol)，在室温下搅拌反应2小时后，旋蒸出去溶剂，然后用乙酸乙酯萃取，有机相依次用饱和氯化铵，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩柱层析得到黄色液体为化合物13(2.6g,65％)。1H NMR(400MHz,CD3OD):δ8.67(s,1H),8.49(d,J＝4.9Hz,1H),8.01(dd,J＝8.2,1.9Hz,1H),7.63–7.21(m,8H),7.16–6.93(m,3H),6.73(d,J＝15.9Hz,1H),4.07(s,2H),3.21(t,J＝7.6Hz,2H),3.12(t,J＝7.5Hz,2H),2.69(t,J＝7.7Hz,2H),1.98–1.76(m,4H)ppm.13C NMR(125MHz,CD3OD):δ167.7,150.7,149.7,144.1,138.3,137.4,136.2,132.9,131.6,130.8,130.2,128.2,125.5,124.8,124.0,122.7,119.9,118.9,112.50,110.8,52.2,40.1,33.8,32.0,24.0,23.7ppm.MS(ESI,m/z):439(M++1).
实施例5：
Figure PCTCN2015090572-appb-000013
把化合物13(22mg,0.05mmol)溶于乙腈中，加入碳酸钾(14mg,0.1mmol)，碘甲烷(4μL,0.06mmol)，室温下反应8小时后，旋蒸除去溶剂，然后用乙酸乙酯萃取，有机相依次用饱和碳酸氢钠，饱和食盐水洗涤，然后无水硫酸镁干燥，过滤，浓缩柱层析得到黄色固体为化合物14(13mg,56％)。
1H NMR(400MHz,CD3OD):δ8.69(d,J＝2.1Hz,1H),8.49(d,J＝4.9Hz,1H),8.00(dd,J＝8.1,2.0Hz,1H),7.53(d,J＝15.8Hz,1H),7.48–7.37(m,2H),7.34–7.14(m,5H),7.12–6.86(m,3H),6.71(d,J＝15.8Hz,1H),3.60(s,2H),3.42–3.31(m,2H),2.96(dd,J＝10.3,6.1Hz,2H),2.74-2.66(m,4H),2.33(s,3H),1.92-1.85(m,2H)ppm.13C NMR(125MHz,CD3OD):δ170.2,153.2,152.2,144.8,140.7,139.9,138.7,138.6,135.4,133.5,131.9,131.2,128.0,127.3,125.6,124.8,122.0,121.8,116.2,114.7,65.1,61.3,44.9,42.8,36.4,34.7, 26.2ppm.MS(ESI,m/z):453(M++1).
实施例6：
Figure PCTCN2015090572-appb-000014
化合物15的合成参考实施例5化合物14的合成，得到黄色固体(19mg,82％)。
1H NMR(400MHz,CD3OD):δ8.68(s,1H),8.49(d,J＝4.8Hz,1H),8.02(d,J＝7.9Hz,1H),7.53(d,J＝15.8Hz,1H),7.44(dd,J＝7.9,5.2Hz,1H),7.41–7.20(m,6H),7.06(d,J＝6.1Hz,2H),6.97(t,J＝7.5Hz,1H),6.74(d,J＝15.8Hz,1H),4.05(s,2H),3.41–3.31(m,2H),3.14–2.93(m,6H),2.71(t,J＝7.7Hz,2H),1.94-1.85(m,2H),1.27(t,J＝7.2Hz,3H)ppm.13C NMR(125MHz,CD3OD):δ167.7,150.7,149.7,143.9,138.2,137.4,136.2,132.9,131.6,130.0,128.3,125.5,124.8,123.7,122.6,119.8,119.0,112.4,111.6,58.1,53.8,40.2,33.9,32.1,22.1,10.3ppm.MS(ESI,m/z):467(M++1).
实施例7：
Figure PCTCN2015090572-appb-000015
化合物16的参考实施例5化合物14的合成，得到黄色固体(12mg,50％)。
1H NMR(400MHz,CD3OD):δ8.70(s,1H),8.50(d,J＝4.9Hz,1H),8.02(d,J＝7.9Hz,1H),7.54(d,J＝15.9Hz,1H),7.45(dd,J＝7.9,5.1Hz,1H),7.33(dd,J＝21.4,7.8Hz,4H),7.22(d,J＝7.6Hz,2H),7.10–6.90(m,3H),6.72(d,J＝15.7Hz,1H),3.81(s,2H),3.35-3.31(m,2H),3.01–2.93(m,2H),2.87(dd,J＝9.8,5.5Hz,2H),2.68(dt,J＝15.5,8.3Hz,4H),1.93-1.86(m,2H),1.67-1.59(m,2H),0.92(t,J＝7.3Hz,3H)ppm.13C NMR(125MHz,CD3OD):δ166.3,149.2,148.2,141.1,136.7,135.9,134.8,131.5,129.5,129.4,128.1,127.1,124.1,123.4,121.8,120.8,118.1,117.7,111.9,110.8,57.6,55.3,53.7,38.8,32.4,30.7,21.6,18.9,10.6ppm.MS(ESI,m/z):481(M++1).
实施例8：
Figure PCTCN2015090572-appb-000016
化合物17的合成参考实施例5化合物14的合成，得到黄色固体(18mg,75％)。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.55(d,J＝4.7Hz,1H),8.34(s,1H),7.75(d,J＝8.0Hz,1H),7.59(d,J＝15.6Hz,1H),7.45(d,J＝7.9Hz,1H),7.36–7.23(m,2H),7.21-7.02(m,6H),6.89(s,1H),6.41(d,J＝15.6Hz,1H),5.89(br,1H),3.69(s,2H),3.59–3.49(m,2H),3.40(q,J＝6.7Hz,2H),2.94(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H),2.74(t,J＝5.4Hz,2H),2.66(t,J＝7.6Hz,2H),1.90(dd,J＝14.9,7.5Hz,2H)ppm.13C NMR(125MHz,CDCl3):δ165.2,150.2,149.0,140.2,137.2,136.3,134.4,130.7,129.2,128.4,127.4,123.7,122.9,122.8,121.8,121.6,119.1,118.6,113.9,111.2,58.5,58.2,55.3,54.0,39.4,32.9,30.9,23.1ppm.MS(ESI,m/z):483(M++1).
实施例9：
Figure PCTCN2015090572-appb-000017
化合物18的合成参考实施例5化合物14的合成，得到黄色固体(22mg,85％)。
1H NMR(400MHz,CD3OD):δ8.68(s,1H),8.48(d,J＝4.9Hz,1H),7.98(d,J＝8.0Hz,1H),7.53(d,J＝15.8Hz,1H),7.41(dd,J＝7.9,5.1Hz,1H),7.37–7.09(m,11H),7.02(t,J＝7.6Hz,1H),6.93–6.81(m,2H),6.70(d,J＝15.9Hz,1H),3.64(s,2H),3.60(s,2H),3.41–3.31(m,2H),2.91(t,J＝7.8Hz,2H),2.73-2.64(m,4H),1.91-1.84(m,2H)ppm.13C NMR(125MHz,CD3OD):δ167.7,150.7,149.6,141.5,140.9,138.4,138.1,137.4,136.2,132.8,130.2,130.1,129.3,129.2,128.8,127.9,125.5,124.8,123.0,122.1,119.4,119.3,114.4,112.1,59.4,59.1,55.2,40.3,33.9,32.2,23.9ppm.MS(ESI,m/z):529(M++1).
实施例10：
Figure PCTCN2015090572-appb-000018
化合物19的合成参考实施例5化合物14的合成，得到黄色固体(12mg,52％)。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.56(d,J＝4.7Hz,1H),8.16–8.01(m,1H),7.75(d,J＝8.1Hz,1H),7.59(d,J＝15.8Hz,1H),7.45(d,J＝7.9Hz,1H),7.31(t,J＝7.9Hz,4H),7.19–7.00(m,4H),6.92(s,1H),6.37(d,J＝15.6Hz,1H),5.63(br,1H),3.63(s,2H),3.42(q,J＝6.9Hz,2H),3.11–3.00(m,1H),2.89–2.79(m,2H),2.78–2.61(m,4H),1.92(t,J＝7.3Hz,2H),1.05(d,J＝6.5Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ165.1,150.3,149.1,137.3,136.2,134.3,130.6,128.8,128.1,127.6,126.4,123.6,122.7,121.7,121.5,118.9,118.8,110.9,53.9,50.5,39.5,32.9,31.1,25.1,18.2ppm.MS(ESI,m/z):481(M++1).
实施例11：
Figure PCTCN2015090572-appb-000019
化合物20的合成参考实施例5化合物14的合成，得到黄色固体(10mg,42％)。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.55(d,J＝4.7Hz,1H),8.10(s,1H),7.76(d,J＝8.0Hz,1H),7.65(d,J＝15.7Hz,1H),7.54(d,J＝7.9Hz,1H),7.40–6.84(m,8H),6.47(d,J＝15.6Hz,1H),6.09(d,J＝23.0Hz,1H),5.08-4.92(m,1H),4.54(d,J＝5.7Hz,2H),4.40(d,J＝13.7Hz,2H),3.47(s,2H),2.94(s,2H),1.25(d,J＝6.2Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ164.9,150.4,149.1,142.6,137.8,136.9,136.3,134.3,130.6,128.3,128.1,127.8,127.4,123.6,122.5,121.9,121.8,119.3,118.6,111.2,68.7,50.5,47.2,43.6,22.20,18.2ppm.MS(ESI,m/z):453(M++1)
实施例12：
Figure PCTCN2015090572-appb-000020
化合物21的合成参考实施例5化合物14的合成，得到黄色固体(32mg,80％)。
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.56(d,J＝4.7Hz,1H),7.87(d,J＝8.2Hz,1H),7.77(d,J＝7.8Hz,1H),7.60(d,J＝15.7Hz,1H),7.47–6.97(m,10H),6.43(d,J＝15.5Hz,1H),5.73(br,1H),3.60(s,2H),3.38(q,J＝6.7Hz,2H),3.35-3.21(m,1H),2.74(s,4H),2.59(q,J＝7.4Hz,2H),1.79–1.48(m,4H),1.46–1.26(m,2H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.2,150.5,149.3,140.9,138.6,137.4,135.4,134.4,134.0,131.3,130.9,128.6,128.3,124.9,123.8,123.3,123.0,121.7,119.9,113.3,54.2,50.3,49.4, 40.3,39.9,35.5,31.2,29.6,26.6,18.2ppm.MS(ESI,m/z):509(M++1).
实施例13：
Figure PCTCN2015090572-appb-000021
化合物22的的合成参考实施例5化合物14的合成,得到黄色固体(32mg,59％)。
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.55(s,1H),8.32(s,1H),7.76(d,J＝8.0Hz,1H),7.59(d,J＝15.7Hz,1H),7.48–7.23(m,5H),7.21–7.00(m,4H),6.93(s,1H),6.44(d,J＝15.6Hz,1H),5.88(br,1H),3.78(s,2H),3.34(q,J＝6.8Hz,2H),3.25-3.18(m,1H),2.87-2.83(m,4H),2.59(t,J＝7.6Hz,2H),1.79–1.43(m,4H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.1,150.0,148.8,141.8,137.1,136.2,134.6,130.9,130.8,130.7,129.2,128.4,127.4,123.7,123.0,121.8,121.7,119.1,118.7,111.2,54.2,51.3,50.3,39.8,35.5,31.2,29.5,29.1,28.9,26.8,24.2,17.9ppm.MS(ESI,m/z):537(M++1).
实施例14：
Figure PCTCN2015090572-appb-000022
化合物23的合成参考实施例5化合物14的合成，得到黄色固体(32mg,69％)。
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.65(s,1H),8.36(s,1H),7.79(d,J＝8.0Hz,1H),7.61(d,J＝15.7Hz,1H),7.53–7.27(m,5H),7.23–7.03(m,4H),6.96(s,1H),6.46(d,J＝15.6Hz,1H),5.89(br,1H),4.37(brs,1H),3.79(s,2H),3.38(q,J＝6.8Hz,2H),3.25(m,1H),2.97-2.83(m,6H),2.59(t,J＝7.6Hz,2H),1.61(t,J＝7.4Hz,2H),1.51(t,J＝7.2Hz,2H),1.31-1.24(m,6H),1.14(d,J＝6.5Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ165.5,150.7,149.5,140.8,138.7,137.2,135.6,134.7,134.2,131.5,130.8,128.8,128.5,124.7,123.5,123.1,122.9,121.6,119.7,113.5,54.3,50.6,49.7,46.5,40.3,39.9,35.5,31.2,26.6,18.2ppm.MS(ESI,m/z):510(M++1).
实施例15：
Figure PCTCN2015090572-appb-000023
化合物24的合成参考实施例5化合物14的合成，得到黄色固体(32mg,55％)。
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.62(s,1H),8.33(s,1H),7.76(d,J＝8.0Hz,1H),7.58(d,J＝15.7Hz,1H),7.51–7.23(m,5H),7.20–7.00(m,4H),6.93(s,1H),6.45(d,J＝15.6Hz,1H),5.88(br,1H),4.36(brs,1H),3.78(s,2H),3.36(q,J＝6.8Hz,2H),3.24(m,1H),2.96-2.82(m,6H),2.58(t,J＝7.6Hz,2H),1.60(t,J＝7.4Hz,2H),1.50(t,J＝7.2Hz,2H),1.30-1.22(m,6H),1.13(d,J＝6.5Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ165.3,150.6,149.1,140.5,138.6,137.0,135.3,134.6,134.0,131.3,130.5,128.5,128.0,124.5,123.6,123.0,122.8,121.3,119.5,113.1,54.1,50.3,49.5,46.2,40.1,39.7,35.2,31.0,26.2,18.0ppm.MS(ESI,m/z):511(M++1).
实施例16：
Figure PCTCN2015090572-appb-000024
化合物25的合成参考实施例5化合物14的合成,得到黄色固体(32mg,30％)。
1H NMR(400MHz,CDCl3):δ8.78(s,1H),8.67(s,1H),8.38(s,1H),7.76(d,J＝8.0Hz,1H),7.65(d,J＝15.7Hz,1H),7.56–7.29(m,5H),7.28–7.06(m,4H),6.98(s,1H),6.48(d,J＝15.6Hz,1H),5.86(br,1H),4.36(brs,1H),4.31(s,2H),3.78(s,2H),3.35(q,J＝6.8Hz,2H),3.22(m,1H),2.94-2.80(m,2H),2.57(t,J＝7.6Hz,2H),1.63(t,J＝7.4Hz,2H),1.51(t,J＝7.2Hz,2H),1.14(d,J＝6.5Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ165.7,150.6,149.8,140.9,138.9,137.6,135.8,134.9,134.3,131.7,130.9,128.9,128.3,124.5,123.3,123.0,122.8,121.2,119.3,113.1,54.1,50.3,49.5,46.3,40.1,39.9,18.2ppm.MS(ESI,m/z):511(M++1).
实施例17：
Figure PCTCN2015090572-appb-000025
化合物26的合成参考实施例5化合物14的合成，得到黄色固体(20mg,20％)。
1H NMR(400MHz,CDCl3):δ8.77(s,1H),8.63(s,1H),8.36(s,1H),7.78(d,J＝8.0Hz,1H),7.67(d,J＝15.7Hz,1H),7.59–7.31(m,5H),7.29–7.09(m,4H),6.97(s,1H),6.49(d,J＝15.6Hz,1H),5.88(br,1H),5.19(s,2H),4.39(brs,1H),3.78(s,2H),3.10(t,J＝6.8Hz,2H),2.86(t,J＝7.0Hz,2H),2.59(t,J＝7.6Hz,2H),2.51(m,2H),2.48(m,1H),1.19(d,J＝6.5Hz,6H)ppm.13C NMR(125MHz,CDCl3):δ165.8,150.5,149.9,140.7,138.6,137.8,135.9,134.8,134.6,131.8,130.8,128.7,128.2,124.6,123.5,123.1,122.9,121.5,119.6,113.2,54.5,54.1,49.9,46.6,40.5,40.9,18.6ppm.MS(ESI,m/z):512(M++1).
实施例18：
Figure PCTCN2015090572-appb-000026
化合物27的合成参考实施例5化合物14的合成，得到黄色固体(50mg,50％)。
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.56(d,J＝4.7Hz,1H),7.87(d,J＝8.2Hz,1H),7.77(d,J＝7.8Hz,1H),7.60(d,J＝15.7Hz,1H),7.47–6.97(m,10H),6.43(d,J＝15.5Hz,1H),5.73(br,1H),3.60(s,2H),3.38(q,J＝6.7Hz,2H),3.35-3.21(m,1H),2.74(s,4H),1.79–1.48(m,4H),1.46–1.26(m,2H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.2,150.5,149.3,140.9,138.6,137.4,135.4,134.4,134.0,131.3,130.9,128.6,128.3,124.9,123.8,123.3,123.0,121.7,119.9,113.3,54.2,50.3,49.4,39.9,35.5,31.2,29.6,26.6,18.2ppm.MS(ESI,m/z):496(M++1).
实施例19：
Figure PCTCN2015090572-appb-000027
化合物28的合成参考实施例5化合物14的合成，得到黄色固体(40mg,40％)。
1H NMR(400MHz,CDCl3):δ8.75(d,J＝8.0Hz,2H),7.89(d,J＝8.0Hz,2H),7.77(d,J＝7.8Hz,1H),7.60(d,J＝15.7Hz,1H),7.47–6.97(m,8H),6.43(d,J＝15.5Hz,1H),5.73(br,1H),3.60(s,2H),3.38(q,J＝6.7Hz,2H),3.35-3.21(m,1H),2.74(s,4H),1.79–1.48(m,4H),1.46–1.26(m,2H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.3,150.6,149.6,140.7,138.7,137.6,135.3,134.2,134.1,131.3,130.9,128.6,128.3,124.9,123.8,123.3,123.0,121.7,119.9,113.3,54.2,50.3,49.4,39.9,35.5,31.2,29.6,26.6,18.2ppm.MS(ESI,m/z):496(M++1).
实施例20：
Figure PCTCN2015090572-appb-000028
化合物29的合成参考实施例5化合物14的合成，得到黄色固体(50％)。
1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.63(d,J＝5.6Hz,1H),8.57(d,J＝4.7Hz,1H),7.89(d,J＝8.6Hz,1H),7.78(d,J＝7.8Hz,1H),7.62(d,J＝15.8Hz,1H),7.47–6.97(m,7H),6.46(d,J＝15.6Hz,1H),5.72(br,1H),3.62(s,2H),3.36(t,J＝6.8Hz,2H),3.30(m,1H),2.75(t,J＝7.2Hz,2H),2.63(t,J＝7.4Hz,2H),2.56(t,J＝7.0Hz,2H),1.81-1.49(m,4H),1.43(m,2H),1.06(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ165.3,162.3,150.7,149.6,141.9,138.8,137.5,135.6,134.2,131.5,130.7,128.9,128.6,124.8,123.9,123.6,123.1,121.9,119.6,113.0,54.1,50.5,49.6,40.6,39.9,35.7,31.3,29.7,26.8,18.5ppm.MS(ESI,m/z):510(M++1).
实施例21：
Figure PCTCN2015090572-appb-000029
化合物30的合成参考实施例5化合物14的合成，得到黄色固体(46％)。
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.62(d,J＝5.7Hz,1H),8.55(d,J＝4.8Hz,1H),7.87(d,J＝8.5Hz,1H),7.76(d,J＝7.9Hz,1H),7.61(d,J＝15.6Hz,1H),7.46–6.96(m,7H),6.48(d,J＝15.6Hz,1H),5.70(br,1H),3.62(s,2H),3.33(t,J＝6.6Hz,2H),3.31(m,1H),2.73(t,J＝7.0Hz,2H),2.64(t,J＝7.2Hz,2H),2.57(t,J＝7.0Hz,2H),1.80-1.45(m,6H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.2,162.4,150.8,149.9,141.8,138.6,137.8,135.7,134.5,131.3,130.6,128.7,128.3,124.3,123.6,123.3,123.0,121.8,119.8,113.1,54.0,50.8,49.8,40.8,39.7,35.9,31.2,29.8,26.9,18.6ppm.MS(ESI,m/z):510(M++1).
实施例25：
Figure PCTCN2015090572-appb-000030
化合物31的合成参考实施例5化合物14的合成，得到黄色固体(66％)。
1H NMR(400MHz,CDCl3):δ8.62(s,1H),8.46(d,J＝4.6Hz,1H),7.78(d,J＝7.6Hz,1H),7.56(d,J＝15.6Hz,1H),7.43–6.99(m,10H),6.46(d,J＝15.6Hz,1H),3.60(s,2H),3.13(t,J＝6.2Hz,2H),3.01(m,1H),2.72(t,J＝6.8Hz,2H),2.65(t,J＝7.0Hz,2H),2.55(t,J＝5.8Hz,2H),1.65-1.30(m,6H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.7,150.6,149.8,142.7,139.6,137.8,136.7,133.8,133.0,129.0,128.7,128.0,127.8,126.0,124.9,123.8,57.9,52.9,51.5,40.4,36.0,34.3,31.1,30.1,26.7,18.5ppm.MS(ESI,m/z):470(M++1).
实施例26：
Figure PCTCN2015090572-appb-000031
化合物32的合成参考实施例5化合物14的合成,得到黄色固体(60％)。
1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.47(d,J＝4.6Hz,1H),7.79(d,J＝7.8Hz,1H),7.55(d,J＝15.6Hz,1H),7.33–6.92(m,9H),6.85(d,J＝15.6Hz,1H),3.62(s,2H),3.03(t,J＝6.2Hz,2H),2.99(m,1H),2.75(t,J＝6.7Hz,2H),2.65(t,J＝6.8Hz,2H),2.55(t,J＝5.9Hz,2H),1.62-1.30(m,6H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.7,160.3,150.0,149.6,144.0,137.2,133.7,132.8,132.6,129.4,128.7,128.1,127.9,127.6,124.9,124.3,123.8,115.4,57.9,52.9,51.5,40.4,36.0,31.1,30.1,26.5,23.4,18.8ppm.MS(ESI,m/z):488(M++1).
实施例27：
Figure PCTCN2015090572-appb-000032
化合物33的合成参考实施例5化合物14的合成,得到黄色固体(63％)。
1H NMR(400MHz,CDCl3):δ8.62(s,1H),8.45(d,J＝4.8Hz,1H),7.79(d,J＝7.6Hz,1H),7.56(d,J＝15.6Hz,1H),7.38–6.91(m,9H),6.84(d,J＝15.6Hz,1H),3.63(s,2H),3.02(t,J＝6.2Hz,2H),2.98(m,1H),2.73(t,J＝6.7Hz,2H),2.65(t,J＝6.8Hz,2H),2.54(t,J＝5.9Hz,2H),1.60-1.31(m,6H),1.04(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.5,162.8,150.1,149.5,144.1,137.1,133.6,132.9,132.5,129.3,128.8,128.3,127.9,127.5,124.8,124.2,123.7,115.5,57.8,52.8,51.6,40.5,36.1,31.2,30.0,26.6,23.5,18.7ppm. MS(ESI,m/z):488(M++1).
实施例28：
Figure PCTCN2015090572-appb-000033
化合物34的合成参考实施例5化合物14的合成,得到黄色固体(53％)。
1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.48(d,J＝4.8Hz,1H),7.80(d,J＝7.5Hz,1H),7.55(d,J＝15.6Hz,1H),7.40–7.00(m,9H),6.86(d,J＝15.6Hz,1H),3.64(s,2H),3.05(t,J＝6.3Hz,2H),2.99(m,1H),2.75(t,J＝6.8Hz,2H),2.69(t,J＝6.8Hz,2H),2.55(t,J＝5.9Hz,2H),1.65-1.31(m,6H),1.06(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.7,150.1,149.6,144.0,137.2,133.7,133.4,132.8,132.6,132.0,128.8,128.1,126.6,125.1,124.9,123.8,118.0,57.9,51.5,40.3,36.2,31.1,30.1,26.5,18.6ppm.MS(ESI,m/z):577(M++1).
实施例29：
Figure PCTCN2015090572-appb-000034
化合物35的合成参考实施例5化合物14的合成得到黄色固体(58％)。
1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.47(d,J＝4.7Hz,1H),7.80(d,J＝7.6Hz,1H),7.55(d,J＝15.6Hz,1H),7.33–6.97(m,9H),6.83(d,J＝15.6Hz,1H),3.64(s,2H),3.03(t,J＝6.3Hz,2H),2.99(m,1H),2.75(t,J＝6.7Hz,2H),2.67(t,J＝6.8Hz,2H),2.56(t,J＝5.9Hz,2H),1.62-1.30(m,6H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.7,160.1,150.0,149.6,144.0,137.2,135.1,133.7,132.8,132.6,129.4,128.7,127.9,124.9,123.8,115.4,57.9,52.9,51.7,40.4,36.0,31.0,30.1,26.4,18.6ppm.MS(ESI,m/z):488(M++1).
实施例30：
Figure PCTCN2015090572-appb-000035
化合物36的合成参考实施例5化合物14的合成,得到黄色固体(68％)。
1H NMR(400MHz,CDCl3):δ8.61(s,1H),8.45(d,J＝4.5Hz,1H),7.76(d,J＝7.2Hz,1H),7.53(d,J＝15.6Hz,1H),7.33–6.97(m,7H),6.82(d,J＝15.6Hz,1H),6.77–6.72(m,2H),3.73(s,3H),3.60(s,2H),3.00(t,J＝6.2Hz,2H),2.97(m,1H),2.73(t,J＝6.8Hz,2H),2.65(t,J＝6.8Hz,2H),2.55(t,J＝5.9Hz,2H),1.60-1.30(m,6H),1.03(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.6,157.3,150.0,149.6,144.1,137.2,133.8,132.8,132.6,128.8128.7,127.9,127.0,125.8,124.9,123.8,121.0,114.2,57.8,56.2,53.2,51.5,40.3,36.0,31.1,30.0,26.5,24.3,18.9ppm.MS(ESI,m/z):500(M++1).
实施例31：
Figure PCTCN2015090572-appb-000036
化合物37的合成参考实施例5化合物14的合成,得到黄色固体(62％)。
1H NMR(400MHz,CDCl3):δ8.62(s,1H),8.58(s,1H),8.57(d,J＝5.6Hz,1H),8.46(d,J＝4.5Hz,1H),7.78(d,J＝7.2Hz,1H),7.69(d,J＝7.0Hz,1H),7.55(d,J＝15.2Hz,1H),7.33–7.00(m,6H),6.85(d,J＝15.3Hz,1H),3.63(s,2H),3.01(t,J＝6.0Hz,2H),2.98(m,1H),2.72(t,J＝6.8Hz,2H),2.65(t,J＝6.8Hz,2H),2.55(t,J＝5.8Hz,2H),1.60-1.30(m,6H),1.05(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ166.8,150.1,149.6,148.5,147.0,144.2,139.4,137.2,133.7,133.5,132.9,132.6,128.7,127.9,124.9,123.8,123.4,57.9,52.9,51.6,40.4,36.0,34.3,31.1,30.0,26.5,18.8ppm.MS(ESI,m/z):471(M++1).
实施例32：
Figure PCTCN2015090572-appb-000037
化合物38的合成参考实施例5化合物14的合成,得到黄色固体(53％)。
1H NMR(400MHz,CDCl3):δ8.62(s,1H),8.58(s,1H),8.57(d,J＝5.6Hz,1H),8.46(d,J＝4.5Hz,1H),7.78(d,J＝7.2Hz,1H),7.69(d,J＝7.0Hz,1H),7.55(d,J＝15.2Hz,1H),7.33–7.00(m,6H),6.85(d,J＝15.3Hz,1H),3.63(s,2H),3.01(t,J＝6.0Hz,2H),2.98(m,1H),2.72(t,J＝6.8Hz,2H),2.65(t,J＝6.8Hz,2H),2.55(t,J＝5.8Hz,2H),1.60-1.30(m,6H),1.05(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ166.8,150.1,149.6,148.5,147.0,144.2,139.4,137.2,133.7,133.5,132.9,132.6,128.7,127.9,124.9,123.8,123.4,57.9,52.9, 51.6,40.4,36.0,34.3,31.1,30.0,26.5,18.8ppm.MS(ESI,m/z):471(M++1).
实施例33：
Figure PCTCN2015090572-appb-000038
化合物39的合成参考实施例5化合物14的合成,得到黄色固体(53％)。
1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.59(d,J＝4.8Hz,1H),8.47(d,J＝5.0Hz,1H),7.78(d,J＝7.2Hz,1H),7.55(d,J＝15.6Hz,1H),7.32–7.00(m,7H),6.86(d,J＝15.6Hz,1H),3.63(s,2H),3.01(t,J＝6.2Hz,2H),2.98(m,1H),2.76(t,J＝6.8Hz,2H),2.67(t,J＝6.6Hz,2H),2.57(t,J＝5.8Hz,2H),1.60-1.30(m,6H),1.05(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ166.8,150.1,149.6,149.3,148.8,144.0,137.2,133.7,132.8,132.6,128.7,127.9,124.9,123.8,123.1,57.9,52.9,51.5,40.5,36.0,34.3,31.1,30.2,26.1,18.6ppm.MS(ESI,m/z):472(M++1).
实施例34：
Figure PCTCN2015090572-appb-000039
化合物40的合成参考实施例5化合物14的合成,得到黄色固体(51％)。
1H NMR(400MHz,CDCl3):δ8.71(d,J＝5.8Hz,2H),8.63(d,J＝6.2Hz,1H),7.53(d,J＝15.2Hz,1H),7.51(d,J＝5.8Hz,2H),7.15(d,J＝15.2Hz,1H),7.12(d,J＝6.2Hz,1H),7.01(d,J＝7.2Hz,2H),7.00(d,J＝7.2Hz,2H),3.61(s,2H),3.02(t,J＝5.3Hz,2H),2.97(m,1H),2.73(t,J＝6.9Hz,2H),2.67(t,J＝6.9Hz,2H),2.53(t,J＝5.6Hz,2H),1.60-1.31(m,6H),1.03(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ172.2,166.7,157.0,149.7,144.5,143.7,137.2,132.8,128.7,127.9,125.5,120.7,118.0,57.9,52.9,51.5,40.5,36.1,33.2,31.0,30.1,26.2,18.5ppm.MS(ESI,m/z):471(M++1).
实施例35：
Figure PCTCN2015090572-appb-000040
化合物41的合成参考实施例5化合物14的合成,得到黄色固体(61％)。
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.55(d,J＝4.7Hz,1H),7.86(d,J＝8.2Hz,1H),7.76(d,J＝7.8Hz,1H),7.60(d,J＝15.7Hz,1H),7.48–6.98(m,10H),6.46(d,J＝15.5Hz,1H),5.75(br,1H),3.39(q,J＝6.7Hz,2H),3.21(m,1H),2.74(s,4H),2.70(d,J＝6.8Hz,2H),2.61(d,J＝6.8Hz,2H),2.59(q,J＝7.4Hz,2H),1.79–1.48(m,4H),1.46–1.26(m,2H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.3,150.5,149.2,140.9,138.7,137.3,135.5,134.2,134.1,131.3,130.9,128.7,128.2,124.8,123.7,123.2,123.0,121.8,119.8,113.2,54.5,50.2,49.3,40.2,39.8,35.2,31.3,29.3,26.3,18.5ppm.MS(ESI,m/z):523(M++1).
实施例36：
Figure PCTCN2015090572-appb-000041
化合物42的合成参考实施例5化合物14的合成,得到黄色固体(60％)。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.55(d,J＝4.7Hz,1H),7.86(d,J＝8.2Hz,1H),7.76(d,J＝7.8Hz,1H),7.61(d,J＝15.7Hz,1H),7.48–6.99(m,10H),6.46(d,J＝15.5Hz,1H),3.69(s,3H),3.60(s,2H),3.37(q,J＝6.7Hz,2H),3.36-3.22(m,1H),2.75(s,4H),2.59(q,J＝7.4Hz,2H),1.79–1.49(m,4H),1.48–1.27(m,2H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ165.2,150.5,149.3,140.9,138.6,137.4,135.4,134.5,134.0,131.3,130.9,128.6,128.3,124.9,123.8,123.3,123.0,121.7,119.9,113.3,54.2,50.3,49.4,42.6,40.3,39.9,35.5,31.2,29.6,26.6,18.2ppm.MS(ESI,m/z):523(M++1).
实施例37：
Figure PCTCN2015090572-appb-000042
化合物43的合成参考实施例5化合物14的合成,得到黄色固体(56％)。
1H NMR(400MHz,CDCl3):δ8.88(s,1H),8.70(s,1H),8.53(d,J＝4.7Hz,1H),7.85(d,J＝8.2Hz,1H),7.73(d,J＝7.8Hz,1H),7.60(d,J＝15.6Hz,1H),7.47–7.00(m,9H),6.49(d,J＝15.5Hz,1H),3.61(s,2H),3.36(q,J＝6.7Hz,2H),3.30(m,1H),2.77(s,4H),2.59(q,J＝7.6Hz,2H),2.39(s,3H),1.78–1.49(m,4H),1.49–1.29(m,2H),1.04(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ165.3,150.2,149.1,140.8,138.7,137.5,135.3,134.5,134.01,131.3,130.8,128.6,128.2,124.8,123.7,123.2,123.1,121.6,119.8,113.4,54.3,50.2, 49.3,40.2,39.8,35.6,31.2,29.5,26.7,18.2,12.9ppm.MS(ESI,m/z):523(M++1).
实施例38：
Figure PCTCN2015090572-appb-000043
化合物44的合成参考实施例5化合物14的合成,得到黄色固体(59％)。
1H NMR(400MHz,CDCl3):δ8.89(s,1H),8.68(s,1H),8.55(d,J＝4.7Hz,1H),7.86(d,J＝8.2Hz,1H),7.76(d,J＝7.8Hz,1H),7.62(d,J＝15.6Hz,1H),7.47–6.90(m,9H),6.52(d,J＝15.5Hz,1H),3.62(s,2H),3.35(q,J＝6.7Hz,2H),3.29(m,1H),2.78(s,4H),2.58(q,J＝7.6Hz,2H),2.39(s,3H),1.77–1.49(m,4H),1.40(m,2H),1.35(s,12H),1.04(d,J＝6.6Hz,6H).13C NMR(125MHz,CDCl3):δ165.5,150.3,149.1,140.9,138.7,137.5,135.2,134.6,134.1,131.5,130.8,128.7,128.2,124.8,123.7,123.2,123.0,121.6,119.8,113.4,57.9,54.3,51.5,40.5,36.0,32.9,32.3,31.0,29.7,22.5,18.6ppm.MS(ESI,m/z):565(M++1).
实施例39：
Figure PCTCN2015090572-appb-000044
化合物45的合成参考实施例5化合物14的合成,得到黄色固体(48％)。
1H NMR(400MHz,CDCl3):δ8.66(s,1H),8.49(d,J＝4.8Hz,1H),7.81(d,J＝7.5Hz,1H),7.57(d,J＝15.6Hz,1H),7.41–7.02(m,9H),6.85(d,J＝15.6Hz,1H),3.63(s,2H),3.03(t,J＝6.3Hz,2H),2.99(m,1H),2.73(t,J＝6.8Hz,2H),2.69(t,J＝6.8Hz,2H),2.56(t,J＝5.9Hz,2H),1.65-1.32(m,6H),1.05(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.7,150.0,149.6,144.0,139.8,137.2,133.7,133.4,132.8,132.6,128.7,127.9,127.8,124.9,124.6,124.2,123.8,122.9,116.3,114.6,111.4,110.9,57.9,54.0,51.5,40.5,36.2,31.1,30.1,28.0,26.5,18.9ppm.MS(ESI,m/z):577(M++1).
实施例40：
Figure PCTCN2015090572-appb-000045
化合物46的合成参考实施例5化合物14的合成，得到黄色固体(51％)。
1H NMR(400MHz,CDCl3):δ8.69(s,1H),8.48(d,J＝4.8Hz,1H),7.80(d,J＝7.5Hz,1H),7.58(d,J＝15.6Hz,1H),7.41–7.01(m,9H),6.86(d,J＝15.6Hz,1H),3.60(s,2H),3.01(t,J＝6.2Hz,2H),2.98(m,1H),2.75(t,J＝6.6Hz,2H),2.68(t,J＝6.8Hz,2H),2.57(t,J＝5.8Hz,2H),1.66-1.33(m,6H),1.06(d,J＝6.5Hz,6H).13C NMR(125MHz,CDCl3):δ166.8,150.0,149.6,144.0,137.2,136.8,133.7,132.8,132.6,130.8,128.7,127.9,124.9,124.2,123.8,122.9,122.1,119.3,116.7,110.9,107.4,57.9,54.0,51.5,40.6,36.0,31.1,30.1,28.0,26.6,18.8ppm.MS(ESI,m/z):577(M++1).
实施例41：酶活性实验
具体方法步骤：
1)配制缓冲液1,包括:10X NAMPT缓冲液10μL,10X Nicotinamide 10μL,10X PRPP 10μL,10X ATP10μL,NMNAT1酶2μL,加dH2O 48μL使体积达到90μL。
2)配制缓冲液2,包括:50X WST-1 2μL，50X ADH 2μL，50X Diaphorase 2μL，10X EtOH 10μL，加dH2O 4μL使体积达到20μL。
3)在微孔板中每孔加入90μL缓冲液1，接着加入2μL 50X的化合物，空白对照组加入2μL DMSO，阳性药对照组加入2μL FK866(1mM)。
4)每孔加入2μL recombinant NAMPT起始酶反应，充分混匀后在30℃孵育60min。
5)反应完成后加入20μL的缓冲液2显色，动态检测反应5-35min的450nm处吸收值。
表1：化合物1-36对Nampt酶活性(IC50，nM)
Figure PCTCN2015090572-appb-000046
Figure PCTCN2015090572-appb-000047
由表1可知，化合物21-30,41-46对Nampt的抑制活性优于FK866。
实施例42化合物对癌细胞活性的测定
化合物癌细胞抑制活性数据用CCK8方法来检测。所使用的癌细胞系MCF-7(人乳腺癌细胞)、BGC-823(人胃癌细胞)、K562(人慢性粒细胞白血病细胞)、U937(人组织细胞淋巴瘤细胞)。具体实验 步骤如下：
(1)收集对数生长期细胞，调整细胞悬液浓度，在96孔板中每孔加入100ul细胞悬液。每孔细胞数量约为7000个，在5％CO2，37℃孵育过夜至细胞完全贴壁。
(2)设置药物浓度梯度，每个浓度梯度设置3个复孔，将药物稀释到对应培养基中至所需终浓度，吸出96孔板中原有培养基，加入配好的含所需终浓度药物的培养基100ul，在5％CO2，37℃孵育。并同时设置空白组(只含100ul培养基，不含细胞，后续处理与其他各孔相同)与对照组(含有细胞与培养基)。
(3)药物处理至72小时时每孔加入3ul CCK8溶液，继续培养3小时。
(4)然后用酶标仪检测450nm光吸收强度。
(5)计算抑制率：抑制率＝1-(加药组OD值-空白组OD值)/(对照组OD值-空白组OD值)＝(对照组OD值-加药组OD值)/(对照组OD值-空白组的OD值)
(6)按上述实验步骤重复三次，得出三次抑制率的平均值，利用IC50计算器算出药物的IC50值。
化合物1-36按照MTT法对MCF-7、U937、BGC823、K562癌细胞系的半数致死量测试结果列于下表2中：
表2化合物1-36的细胞活性(IC50,nM)
Figure PCTCN2015090572-appb-000048
Figure PCTCN2015090572-appb-000049
由表2可以看出，化合物21—46对MCF-7(人乳腺癌细胞)具有优秀的抗肿瘤活性，化合物19、21-30,36，38-43，45-46对K562(人慢性粒细胞白血病细胞)具有优秀的抗肿瘤活性，化合物21-24,41-46对U937(人组织细胞淋巴瘤细胞)具有优秀的抗肿瘤活性，化合物21-24,27,32-34，36-46对BGC-823(人胃癌细胞)具有优秀的抗肿瘤活性，这些化合物有望被开发成为新的抗肿瘤药物。

Claims (7)

  1. 一种烟酰胺磷酸核糖转移酶抑制剂，其特征在于，其结构式如I所示的化合物或其药学上可接受的盐：
    Figure PCTCN2015090572-appb-100001
    其中，R1选自取代或非取代的芳香环或芳香杂环，所述取代基选自卤素，烷基，卤代烷基或烷氧基；
    R2选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、烷氧羰基、苄基、羟乙基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
    R3选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
    R4选自氢、卤素、苯基、取代苯基、烷基、卤代烷基、烷氧基、氨基、硝基或氰基，所述取代基选自卤素、烷基、卤代烷基、烷氧基、氨基、硝基或氰基；
    R5选自-(CH2)n1-,或脂杂链或烯键-(CHCH)n2-或杂环或芳环,所述脂杂链选自-Y(CH2)n3-或-Y-CH2-NH-CH2-CH2-,其中n1为1-10的整数；n2为1-3的整数,n3为1-10的整数,Y选自NH或O；
    n为1–5的整数；
    m为0–6的整数。
  2. 根据权利要求1所述的烟酰胺磷酸核糖转移酶抑制剂，其特征在于，所述芳香环选自苯基，苯并呋喃基，苯并噻吩基，吲哚基，喹啉基，异喹啉基中的任一种。
  3. 根据权利要求1或2所述的烟酰胺磷酸核糖转移酶抑制剂，其特征在于，所述R2选自氢、烷氧羰基、烷基、苄基、羟乙基；R3选自氢；R4选自氢；n为1。
  4. 根据权利要求1所述的烟酰胺磷酸核糖转移酶抑制剂，其特征在于，选自如下化合物：
    Figure PCTCN2015090572-appb-100002
    Figure PCTCN2015090572-appb-100003
    Figure PCTCN2015090572-appb-100004
    Figure PCTCN2015090572-appb-100005
    Figure PCTCN2015090572-appb-100006
  5. 一种权利要求1所述的烟酰胺磷酸核糖转移酶抑制剂的制备方法，其特征在于，制备反应式如下：
    Figure PCTCN2015090572-appb-100007
    其中m、n、R1-R5的含义如权利要求1所述。
  6. 根据权利要求5所述的烟酰胺磷酸核糖转移酶抑制剂的制备方法，其特征在于，当n为1，m为1，R3选自氢，R4选自氢，R1选自取代的芳香环，制备反应式如下：
    Figure PCTCN2015090572-appb-100008
    其中R2和R5的含义如权利要求1所述。
  7. 权利要求1所述的烟酰胺磷酸核糖转移酶抑制剂的应用，其特征在于，所述的烟酰胺磷酸核糖转移酶抑制剂在制备预防和/或治疗与烟酰胺磷酸核糖转移酶活性失控有关疾病的药物中的应用。
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