CN114149341B - 芳氧环己基酰胺类ampk激动剂及其制备方法和医药用途 - Google Patents

芳氧环己基酰胺类ampk激动剂及其制备方法和医药用途 Download PDF

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CN114149341B
CN114149341B CN202111494656.XA CN202111494656A CN114149341B CN 114149341 B CN114149341 B CN 114149341B CN 202111494656 A CN202111494656 A CN 202111494656A CN 114149341 B CN114149341 B CN 114149341B
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戴量
王倩
刘耐欣
孙更
温小安
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Abstract

本发明公开了芳氧环己基酰胺类AMPK激动剂及其制备方法和医药用途，该AMPK激动剂具体如式(I)所示的芳氧环己基酰胺类化合物或其药学上可接受的盐或酯或溶剂化物。本发明具有AMPK激动活性的芳氧环己基酰胺类化合物，在细胞水平对AMPK具有显著的激动活性，可在体内有效地激活AMPK信号通路，因而可用于制备预防或治疗AMPK介导的多种疾病的药物。

Description

芳氧环己基酰胺类AMPK激动剂及其制备方法和医药用途
技术领域
本发明涉及生物医药领域，具体涉及一种具有AMPK激动作用的芳氧环己基酰胺类化合物及其制备方法和作为AMPK激动剂的医药用途。
背景技术
AMPK(腺苷酸活化蛋白激酶)是调控机体能量代谢及炎症反应的关键激酶，其磷酸化激活可克服胰岛素抵抗、降血糖、降血脂(通过抑制脂肪酸及胆固醇的合成)、抗炎、抗凋亡、抗纤维化、促进线粒体合成、增强线粒体的氧化代谢、抗衰老和抗肿瘤等(Physiol.Rev.2009,89,1025)。越来越多的证据表明，AMPK功能异常与多种疾病的发生发展密切相关。例如AMPK介导的代谢性疾病和心脑血管疾病：胰岛素抵抗、代谢综合征、1型或2型糖尿病、高脂血症、肥胖症、动脉粥样硬化、心肌缺血、非酒精性脂肪肝等和AMPK介导的炎症疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病或病原体感染所致的继发性疾病等(J.Med.Chem.,2015,58,2；Nature 2013,493,346；Experimental Neurology 2017,298,31；Biochemical Pharmacology,2010,80,170；Current Drug Targets,2016,17,908；Nat.Rev.Drug.Discov.,2019,DOI:10.1038/s41573-019-0019-2；J.Biol.Chem.2020,295,12279–12289)。
文献报道AMPK激动剂可预防和治疗多种AMPK介导的疾病。临床上广泛应用的二甲双胍(J.Clin.lnvestig,2001,108,1167-1174)和小檗碱(doi:10.1007/978-3-319-41334-1_2.)被认为主要是通过间接激活AMPK而发挥降血糖、抗炎等药理活性。然而基于AMPK直接激动的药物研发工作却无实质性进展。目前研制的新型AMPK激动剂主要存在以下问题：(1)活性强且生物利用度高的线粒体复合物I抑制剂(如R118)虽然可通过增加AMP/ATP的比值来强效激活的AMPK，但不可避免地会带来乳酸中毒的风险(doi:10.1002/cpt.178)；(2)AMP模拟物(如AICAR)通过直接结合AMPK亚基而激活AMPK，选择性差，导致脱靶副作用(J ClinPharmacol 1991,31:342–347)；(3)作用于该位点的AMPK-β亚基激动剂(如MK-8722)可能会导致心肌肥厚副作用。综上所述，临床上亟需开发活性高、毒副作用小的新型AMPK激动剂。
发明内容
发明目的：针对现有技术存在的问题，本发明提供一种具有AMPK激动活性的芳氧环己基酰胺类化合物，该类化合物在体内外水平均对AMPK具有显著的激动活性，因而可用于制备预防或治疗AMPK介导的多种疾病的药物。
本发明还提供所述芳氧环己基酰胺类化合物的制备方法和作为AMPK激动剂的医药用途。
本发明基于一类新型AMPK间接激动剂AdipoRon(通过激活脂联素受体来间接激活AMPK)进行结构改造时，意外地发现了一系列结构类型新颖且强效的新型AMPK激动剂，且其AMPK激动活性显著地优于公认的AMPK激动剂MK-8722。
技术方案：为了实现上述目的，本发明提供通式(I)芳氧环己基酰胺类化合物、其药学上可接受的盐或酯或溶剂化物：
其中R1、R2、R3、R4、R5各自独立地选自：H、卤素、羟基、C1-C4烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、杂芳基、取代的杂芳基、稠环芳基、或取代的稠环芳基；
R6、R7各自独立地选自：H、C1-C4烷基；
X、Y各自独立地选自碳原子或氮原子；
n＝0，1，2或3。
其中，所述芳氧环己基酰胺类化合物、其药学上可接受的盐或酯或溶剂化物：构型或为顺式或为反式。
在某些更优选的实施方案中，所述化合物或其药学上可接受的盐或酯或溶剂化合物选自如下任一所示：
本发明的化合物也可作为药用盐。该盐可为下列酸中的至少一种的酸盐：半乳糖二酸、D-葡糖醛酸、甘油磷酸、马尿酸、羟乙磺酸、乳糖酸、马来酸、1,5-萘二磺酸、萘-2-磺酸、新戊酸、对苯二甲酸、硫氰酸、胆酸、正十二烷基硫酸、苯磺酸、柠檬酸、D-葡萄糖，乙醇酸、乳酸、苹果酸、丙二酸、扁桃酸、磷酸、丙酸、盐酸、硫酸、酒石酸、琥珀酸、甲酸、氢碘酸、氢溴酸、甲烷磺酸、烟酸、硝酸、乳清酸、草酸、苦味酸、L-焦谷氨酸、糖精酸、水杨酸、龙胆酸、对甲苯磺酸、戊酸、棕榈酸、葵二酸、硬脂酸、月桂酸、乙酸、己二酸、碳酸、4-苯磺酸、乙烷二磺酸、乙基琥珀酸、富马酸、3-羟基萘-2-甲酸、1-羟基萘-2-甲酸、油酸、十一碳烯酸、抗坏血酸、樟脑酸、樟脑磺酸、二氯乙酸、乙烷磺酸。另一方面，该盐也可以是本发明的化合物与金属(包括钠、钾、钙等)离子或药学上可接受的胺(包括乙二胺、氨丁三醇等)或铵离子形成的盐。
本发明所述的化合物、其药学上可接受的盐或酯或溶剂化物的制备方法，包括如下反应路线：
合成路线
本发明所述化合物、其药学上可接受的盐或酯或溶剂化物在制备AMPK激动剂中的应用。
具体地，所述化合物或其药学上可接受的盐或酯或溶剂化物通过激活AMPK信号通路在制备AMPK激动剂中的应用。具体地，通过增强AMPK激动活性在制备AMPK激动剂中的应用。
本发明所述化合物、其药学上可接受的盐或酯或溶剂化物在制备预防或治疗AMPK介导的疾病的药物中的用途。
其中，所述AMPK介导的疾病包括代谢性疾病、心脑血管疾病、炎症疾病、自身免疫性疾病、器官纤维化疾病、神经退行性疾病、病原体感染所致的继发性疾病、线粒体功能障碍或紊乱疾病或肿瘤。
其中，所述AMPK介导的疾病，如代谢性疾病和心脑血管疾病，包括：如胰岛素抵抗、代谢综合征、1型或2型糖尿病、高脂血症、肥胖症、动脉粥样硬化、心肌缺血、心肌梗死、心律失常、冠心病、高血压、心衰、心肌肥大、心肌炎、糖尿病并发症(包括糖尿病心肌病、糖尿病肾病、视网膜病变、神经病变和糖尿病溃疡等)、非酒精性脂肪肝、非酒精性脂肪性肝炎、酒精性脂肪肝、肝硬化、痛风、中风或脑梗死等。
其中，所述AMPK介导的疾病，如炎症疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病或病原体感染所致的继发性疾病，包括：肺炎、哮喘、慢性阻塞性肺病、慢性支气管炎、肺气肿、闭塞性细支气管炎、特发性肺纤维化、囊性纤维化肺病、过敏性鼻炎、炎性肠病(如克罗恩病和溃疡性结肠炎)、多囊肾病、多囊卵巢综合征(PCOS)、白塞氏病、系统性红斑狼疮、类风湿关节炎、脊椎关节炎、骨关节炎、滑膜炎、肌腱炎、血栓闭塞性脉管炎、静脉炎、间歇性跛行、瘢痕瘤、银屑病、鱼鳞癣、大疱性类天疱疮、皮炎、接触性皮炎、胰腺炎、慢性肾炎、膀胱炎、脑膜炎、胃炎、败血症、坏疽性脓皮症、葡萄膜炎、帕金森病、阿尔茨海默病、α-共核蛋白病、抑郁症、多发性硬化症、肌萎缩侧索硬化病、纤维肌痛综合症、神经痛、唐氏综合征、哈勒沃登-施帕病、亨廷顿舞蹈病或威尔逊病等。
其中，所述AMPK介导的疾病，如线粒体功能障碍和紊乱疾病，包括：肌无力、肌阵挛、运动不耐受、卡恩斯-赛尔综合征、慢性疲乏综合征、利氏综合征、线粒体肌病-脑病-高乳酸血症、中风综合征或中风样发作。同样，本发明的化合物也可用于治疗肌肉营养不良状态，例如，杜氏肌营养不良、贝壳肌营养不良或弗立德希氏共济失调。
其中，所述AMPK介导的疾病，如肿瘤，包括：骨癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞系白血病、慢性淋巴细胞系白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、血管瘤、肉芽瘤、黄瘤、脑膜肉瘤、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性成胶质细胞瘤、少突神经胶质细胞瘤、神经鞘瘤、成视网膜细胞瘤、纤维神经瘤、肉瘤、食道癌、胃癌、胰腺癌、大肠癌、结肠癌、直肠癌、肾癌、前列腺癌、淋巴癌、睾丸癌、间质细胞癌、肺癌、肝癌、皮肤癌、恶性黑素瘤或基底细胞癌等。
本发明所述预防或治疗AMPK介导的疾病的药物组合物，其包含如式(I)所述的化合物、其药学上可接受的盐或酯或溶剂化合物作为活性成分和药学上可接受的辅料。可任意混合的辅料根据剂型、给药形式等可以改变。
优选的，所述药物组合物为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
本发明基于一类新型AMPK间接激动剂AdipoRon(通过激活脂联素受体来间接激活AMPK)进行结构改造时，意外地发现了一系列结构类型新颖且强效的新型AMPK激动剂，且其AMPK激动活性显著地优于公认的AMPK激动剂MK-8722。
有益效果：与现有技术相比，本发明具有如下优点：
(1)本发明的芳氧环己基酰胺类化合物在体内外水平均对AMPK具有显著的激动活性；
(2)本发明的芳氧环己基酰胺类化合物通过激活AMPK信号通路，可用于制备预防或治疗AMPK介导的多种疾病的药物。
(3)本发明的芳氧环己基酰胺类化合物在制备过程中具有原料便宜易得、制备路线简单等优点，同时制备的化合物具有较好的成药性。
附图说明
图1为部分化合物的对C2C12细胞中AMPK磷酸化水平的影响；
图2为部分化合物的对C2C12细胞中AMPK磷酸化水平的影响；
图3为部分化合物的对C2C12细胞中AMPK磷酸化水平的影响；
图4为部分化合物的对C2C12细胞中AMPK磷酸化水平的影响；
图5为不同浓度的25对C2C12细胞AMPK和ACC磷酸化水平的影响；
图6为化合物25在不同时间段对C57BL/J6雄鼠的心脏AMPK磷酸化情况。
具体实施方式
以下通过实施例对本发明做进一步的说明。
实施例1
反式-N-(4-(4-溴苯氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物1)
中间体A3的合成
将异丁酸甲酯(A1，12.91g,126.6mmol)溶于干燥的四氢呋喃(85mL)，氮气保护，降温至-78℃，加入浓度为2mol/L的二异丙基氨基锂(LDA)的四氢呋喃/正庚烷混合溶液(66.5mL,133mmol)，-78℃条件下搅拌2h。加入1,3-二溴丙烷(A2，25.56g，126.6mmol)，保持-78℃继续搅拌1h,自然升温至室温，搅拌过夜。蒸除溶剂，加水(130mL)，用2N盐酸将pH调节至3，再加入乙酸乙酯(130mL)，摇匀，分层，分液，水相再用乙酸乙酯萃取(130mL×2)，合并有机相。分别用0.25N盐酸(50mL)、水(50mL)和饱和氯化钠水溶液(50mL)洗涤，有机相用无水硫酸钠干燥。蒸除乙酸乙酯后，残余物经减压蒸馏得A3(无色油状物，18.6g，收率66％)。
中间体A5的合成
2,5-二甲基苯酚(A4，366mg,2.5mmol)和A3(558mg,2.5mmol)溶于乙腈(7.5mL)，加入碳酸钾(691mg,5mmol)，70℃加热10h。过滤，减压浓缩，加乙酸乙酯(10mL)溶解，水洗(5mL)，饱和氯化钠水溶液洗(5mL)，无水Na2SO4干燥，减压浓缩后，残余物经柱层析(石油醚/乙酸乙酯＝20:1)纯化，得A5(无色油状物，639mg，收率88％)。
中间体A6的合成
A5(617mg,2.13mmol)置于反应瓶中，加甲醇(6.5mL)和水(6.5mL)，再加入NaOH(213mg,5.32mmol)，80℃加热10h。蒸除甲醇，2N盐酸调节pH至2，有固体析出，过滤，滤饼水洗(5mL×3)，刮下固体，减压干燥得A6(白色固体，235mg，收率40％)。
中间体A8的合成
A6(12.515g,50mmol)和1-羟基苯并三氮唑(HOBT)(8.1g,60mmol)溶于二氯甲烷(150mL)，加入三乙胺(17.7g,175mmol)，搅拌均匀后，分批加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI·HCl,11.5g,60mmol),室温搅拌40分钟后，再加入反式-4-氨基环己醇(A7,6.912g，60mmol)，室温条件搅拌过夜。减压蒸除溶剂，加饱和碳酸氢钠水溶液(100mL)，二氯甲烷萃取(50mL×3)，合并有机相，有机相用饱和碳酸氢钠水溶液(20mL)洗，饱和氯化钠水溶液(20mL)洗，无水硫酸钠干燥。减压蒸除溶剂，残余物在乙酸乙酯和石油醚的混合溶剂中重结晶，得A8(白色蓬松固体，10.408g，收率60％)。
化合物1的合成
取A8(140mg，0.4mmol)溶于干燥的N,N-二甲基甲酰胺(DMF)(2mL)，冰浴冷却，加入氢化钠(NaH)(含量60％，表面覆盖矿物油，50mg,1.25mmol)，室温搅拌1h，加入4-溴氟苯(A9，91mg，0.52mmol)，60℃加热3h。将反应液倒入水(20mL)中，乙酸乙酯萃取(10mL×3)，合并有机相，水洗(8mL×2)，饱和氯化钠水溶液洗(8mL)，无水硫酸钠干燥。减压蒸除溶剂，残余物经柱层析(洗脱剂：石油醚/乙酸乙酯＝5:1)纯化，得化合物1(白色固体，70mg，收率35％)。
1H NMR(300MHz,DMSO-d6)δ7.41(d,J＝8.9Hz,2H),7.15(d,J＝7.5Hz,1H),6.98(d,J＝7.4Hz,1H),6.91(d,J＝8.9Hz,2H),6.69(s,1H),6.62(d,J＝7.4Hz,1H),4.28–4.15(m,1H),3.94–3.83(m,2H),3.68–3.53(m,1H),2.24(s,3H),2.09(s,3H),2.07–1.99(m,2H),1.81–1.68(m,2H),1.66–1.52(m,4H),1.48–1.28(m,4H),1.09(s,6H)；MS(ESI):m/z 502.2[M+H]+.
实施例2
反式-N-(4-(4-氰基苯氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物2)
参照实施例1的方法，将A9替换为对氟苯腈，得化合物2(白色固体，98mg，收率73％)。1H NMR(300MHz,DMSO-d6)δ7.73(d,J＝8.7Hz,2H),7.18(d,J＝7.6Hz,1H),7.11(d,J＝8.7Hz,2H),6.98(d,J＝7.4Hz,1H),6.69(s,1H),6.62(d,J＝7.4Hz,1H),4.46–4.33(m,1H),3.95–3.84(m,2H),3.69–3.55(m,1H),2.24(s,3H),2.09(s,3H),2.08–2.01(m,2H),1.83–1.70(m,2H),1.66–1.54(m,4H),1.52–1.33(m,4H),1.09(s,6H)；MS(ESI):m/z 471.3[M+Na]+.
实施例3
反式-N-(4-(4-(甲基磺酰基)苯氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基-戊酰胺(化合物3)
参照实施例1的方法，将A9替换为对氟苯甲砜，得化合物3(白色固体，127mg，收率84％)。1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.21–7.17(m,1H),7.15(d,J＝8.6Hz,2H),6.98(d,J＝7.4Hz,1H),6.69(s,1H),6.62(d,J＝7.4Hz,1H),4.47–4.32(m,1H),3.96–3.83(m,2H),3.71–3.54(m,1H),3.14(s,3H),2.24(s,3H),2.15–2.00(m,5H),1.87–1.71(m,2H),1.68–1.53(m,4H),1.53–1.34(m,4H),1.10(s,6H)；MS(ESI):m/z 524.3[M+Na]+.
实施例4
反式-N-(4-(吡嗪-2-基氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物4)
参照实施例1的方法，将A9替换为2-氟吡嗪，得化合物4(白色固体，72mg，收率56％)。1H NMR(300MHz,DMSO-d6)δ8.24(s,1H),8.21–8.15(m,2H),7.16(d,J＝7.8Hz,1H),6.98(d,J＝7.5Hz,1H),6.69(s,1H),6.62(d,J＝7.5Hz,1H),4.97–4.81(m,1H),3.96–3.82(m,2H),3.74–3.57(m,1H),2.24(s,3H),2.15–2.02(m,5H),1.83–1.71(m,2H),1.67–1.54(m,4H),1.53–1.34(m,4H),1.09(s,6H)；MS(ESI):m/z 448.3[M+Na]+.
实施例5
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物5)
参照实施例1的方法，将A9替换为2-氯-5-氟吡啶，得化合物5(白色固体，130mg，收率71％)。1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2.8Hz,1H),7.50(dd,J＝8.8,2.9Hz,1H),7.40(d,J＝8.8Hz,1H),7.15(d,J＝7.6Hz,1H),6.98(d,J＝7.5Hz,1H),6.69(s,1H),6.62(d,J＝7.5Hz,1H),4.37–4.27(m,1H),3.93–3.84(m,2H),3.67–3.55(m,1H),2.24(s,3H),2.09(s,3H),2.08–2.03(m,2H),1.81–1.71(m,2H),1.63–1.56(m,4H),1.47–1.35(m,4H),1.09(s,6H)；HRMS(ESI):m/z calculated for C26H35ClN2O3[M+Na]+481.2228,found481.2230.
实施例6
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物6)
参照实施例1的方法，将A9替换为3-氯-5-氟吡啶，得化合物6(淡黄色固体，86mg，收率：62％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.5Hz,1H),8.19(d,J＝2.0Hz,1H),7.63(dd,J＝2.5,2.0Hz,1H),7.17(d,J＝7.7Hz,1H),6.98(d,J＝7.5Hz,1H),6.69(s,1H),6.62(d,J＝7.5Hz,1H),4.48–4.33(m,1H),3.95–3.83(m,2H),3.69–3.53(m,1H),2.24(s,3H),2.09(s,3H),2.08–2.00(m,2H),1.83–1.70(m,2H),1.65–1.54(m,4H),1.51–1.33(m,4H),1.09(s,6H)；MS(ESI):m/z 481.3[M+Na]+.
实施例7
反式-N-(4-((6-氰基吡啶-3-基)氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物7)
参照实施例1的方法，将A9替换为2-氰基-5-氟吡啶，制得化合物7(白色固体，88mg，收率65％)。1H NMR(300MHz,DMSO-d6)δ8.41(d,J＝2.7Hz,1H),7.96(d,J＝8.7Hz,1H),7.62(dd,J＝8.7,2.8Hz,1H),7.19(d,J＝7.7Hz,1H),6.97(d,J＝7.4Hz,1H),6.68(s,1H),6.61(d,J＝7.5Hz,1H),4.55–4.41(m,1H),3.94–3.80(m,2H),3.69–3.54(m,1H),2.23(s,3H),2.15–1.99(m,5H),1.82–1.68(m,2H),1.65–1.53(m,4H),1.52–1.34(m,4H),1.08(s,6H)；MS(ESI):m/z 472.3[M+Na]+.
实施例8
反式-N-(4-((5-氟吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物8)
参照实施例1的方法，将A1替换为对氯苯酚，A9替换为3,5-二氟吡啶，得化合物8(白色固体，102mg，收率76％)。1H NMR(300MHz,DMSO-d6)δ8.20–8.16(m,1H),8.15(d,J＝2.2Hz,1H),7.49(ddd,J＝11.1,2.2,2.0Hz,1H),7.31(d,J＝8.9Hz,2H),7.20(d,J＝7.4Hz,1H),6.93(d,J＝8.9Hz,2H),4.44–4.32(m,1H),3.97–3.86(m,2H),3.67–3.53(m,1H),2.15–2.00(m,2H),1.81–1.68(m,2H),1.63–1.51(m,4H),1.50–1.34(m,4H),1.08(s,6H)；MS(ESI):m/z 449.2[M+H]+.
实施例9
反式-N-(4-((5-溴吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物9)
参照实施例1的方法，将A1替换为对氯苯酚，A9替换为5-溴-3-氟吡啶，得化合物9(白色固体，92mg,收率60％)。1H NMR(300MHz,DMSO-d6)δ8.28(d,J＝2.4Hz,1H),8.26(d,J＝1.6Hz,1H),7.75(dd,J＝2.4,1.6Hz,1H),7.31(d,J＝8.8Hz,2H),7.18(d,J＝7.4Hz,1H),6.93(d,J＝8.8Hz,2H),4.46–4.36(m,1H),3.96–3.86(m,2H),3.66–3.53(m,1H),2.12–2.00(m,2H),1.81–1.69(m,2H),1.62–1.53(m,4H),1.49–1.33(m,4H),1.08(s,6H)；MS(ESI):m/z531.2[M+Na]+.
实施例10
反式-N-(4-((5-氰基吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物10)
参照实施例1的方法，将A1替换为对氯苯酚，A9替换为3-氰基-5-氟吡啶，得化合物10(白色固体，61mg，收率45％)。1H NMR(300MHz,DMSO-d6)δ8.59–8.54(m,2H),8.03(dd,J＝2.6,1.7Hz,1H),7.31(d,J＝9.0Hz,2H),7.21(d,J＝7.6Hz,1H),6.93(d,J＝9.0Hz,2H),4.49–4.37(m,1H),3.96–3.87(m,2H),3.66–3.54(m,1H),2.15–2.01(m,2H),1.81–1.69(m,2H),1.61–1.53(m,4H),1.51–1.34(m,4H),1.09(s,6H)；MS(ESI):m/z 478.2[M+Na]+.
实施例11
反式-N-(4-(4-氰基苯氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物11)
中间体A11的合成
取反式-4-氨基环己醇(A7，576mg，5mmol)溶于干燥的DMF(20mL)，冷却至0℃，分批加入NaH(含量60％，表面覆盖矿物油，600mg，15mmol)，加完后室温搅拌1h。再加入4-氟苯甲腈(A10，727mg，6mmol)，60℃条件下搅拌3h。冷却至0℃，加水(10mL)淬灭反应，再倒入额外的水中(190mL)，乙酸乙酯萃取(50mL×4)，合并有机相，水(20mL)洗，饱和氯化钠水溶液洗(20mL)，无水硫酸钠干燥，减压浓缩后，残余物经柱层析(二氯甲烷/甲醇＝15:1，之后，二氯甲烷/甲醇/三乙胺＝40:2:1)得A11(浅黄色固体，938mg，收率87％)。
化合物11的合成
将A6(0.3mmol)溶于二氯甲烷(5mL)中，冰水浴冷却，加入草酰氯(0.6mmol)，再加DMF(10μL)，自然升温至室温，搅拌1h。蒸除溶剂和草酰氯，重新加入二氯甲烷(5mL)，再次冰水浴冷却，加入三乙胺(0.6mmol)后加入A11(0.3mmol)，自然升温至室温，搅拌过夜。蒸干溶剂，向残余物中加入饱和NaHCO3水溶液(10mL)，再加入乙酸乙酯(10mL)，分液。水相用乙酸乙酯萃取(10mL×2)，合并有机相，饱和NaHCO3水溶液洗(5mL)，水洗(5mL)，饱和氯化钠水溶液洗(5mL)，无水Na2SO4干燥，过滤，将滤液蒸干，残余物经柱层析(石油醚/乙酸乙酯＝2:1)纯化，得化合物11(白色固体，120mg，收率88％)。1H NMR(300MHz,DMSO-d6)δ7.73(d,J＝8.7Hz,2H),7.31(d,J＝8.9Hz,2H),7.19(d,J＝7.9Hz,1H),7.11(d,J＝8.7Hz,2H),6.93(d,J＝8.9Hz,2H),4.47–4.32(m,1H),3.97–3.85(m,2H),3.69–3.54(m,1H),2.14–1.99(m,2H),1.82–1.67(m,2H),1.62–1.52(m,4H),1.52–1.32(m,4H),1.08(s,6H)；HRMS(ESI):m/zcalculated for C26H32ClN2O3[M+H]+455.2096,found 455.2096.
实施例12
反式-N-(4-(吡啶-3-基氧基)环己基)-5-(2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(化合物12)
参照实施例11的方法，将A10替换为3-氟吡啶，制得化合物12(白色固体，109mg，收率86％)。1H NMR(300MHz,DMSO-d6)δ8.27(d,J＝2.5Hz,1H),8.14(d,J＝4.2Hz,1H),7.40(d,J＝8.3Hz,1H),7.30(dd,J＝8.3,4.5Hz,1H),7.16(d,J＝7.6Hz,1H),6.98(d,J＝7.4Hz,1H),6.69(s,1H),6.62(d,J＝7.4Hz,1H),4.39–4.23(m,1H),3.96–3.82(m,2H),3.70–3.53(m,1H),2.24(s,3H),2.09(s,3H),2.08–2.01(m,2H),1.83–1.70(m,2H),1.65–1.53(m,4H),1.50–1.32(m,4H),1.09(s,6H)；MS(ESI):m/z 425.3[M+H]+.
实施例13
反式-N-(4-(4-(甲基磺酰基)苯氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基-戊酰胺(化合物13)
中间体A12的合成
参照实施例1的方法，将A4替换为4-氯苯酚，得到中间体5-(4-氯苯氧基)-2,2-二甲基戊酸(A12，白色固体，5.84g，收率81％)。
中间体A13的合成
参照实施例11的方法，将A10替换为4-氟苯甲砜，得到中间体反式-4-(4-(甲基磺酰基)苯氧基)环己烷-1-胺(A13，黄色固体，1554mg，收率68％)。
化合物13的合成
参照实施例11的方法，以A12和A13为原料，制得化合物13(白色固体，135mg，收率89％)。1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.8Hz,2H),7.31(d,J＝8.9Hz,2H),7.20–7.12(m,3H),6.93(d,J＝8.9Hz,2H),4.46–4.34(m,1H),3.96–3.87(m,2H),3.68–3.55(m,1H),3.14(s,3H),2.14–2.02(m,2H),1.82–1.69(m,2H),1.62–1.52(m,4H),1.51–1.35(m,4H),1.08(s,6H)；HRMS(ESI):m/z calculated for C26H34ClNO5S[M+Na]+530.1738,found530.1734.
实施例14
反式-N-(4-(4-(甲基磺酰基)苯氧基)环己基)-2-(4-氯苯氧基)-2-甲基-丙酰胺(化合物14)
参照实施例11的方法，以2-(4-氯苯氧基)-2-甲基丙酸为原料，将A10替换为4-氟苯甲砜，制得化合物14(白色固体，123mg，收率88％)。1H NMR(300MHz,DMSO-d6)δ7.93(d,J＝8.0Hz,1H),7.80(d,J＝8.7Hz,2H),7.33(d,J＝8.8Hz,2H),7.15(d,J＝8.7Hz,2H),6.87(d,J＝8.8Hz,2H),4.46–4.30(m,1H),3.77–3.60(m,1H),3.14(s,3H),2.15–1.99(m,2H),1.84–1.68(m,2H),1.55–1.33(m,10H)；13C NMR(75MHz,CDCl3)δ173.93,162.02,152.94,132.31,129.70,129.39,128.63,122.47,115.97,81.92,75.33,47.31,44.95,30.17,29.98,25.13；HRMS(ESI):m/z calculated for C23H29ClNO5S[M+H]+466.1450,found 466.1452.
实施例15
顺式-N-(4-(4-氰基苯氧基)环己基)-5-(4-氟苯氧基)-2,2-二甲基戊酰胺(化合物15)
中间体B5的合成
将A7(5759mg,50mmol)、N-乙氧羰基邻苯二甲酰亚胺(B1,10960mg,50mmol)置于反应瓶中，加水110mL，降温至0℃，分批加入K2CO3(13820mg,100mmol)，恢复至室温，搅拌过夜。过滤，滤饼水洗(30mL×3)。将过滤得到得固体用乙醇(190mL)溶解，加水(380mL)，静置1h，析出固体，过滤，滤饼用乙醇/水(1:2)混合溶剂(20mL×3)洗，室温自然干燥一夜，再在45℃减压干燥1h，得B2(白色固体，5371mg，收率44％)。
取B2(1472mg，6mmol)、4-氰基苯酚(B3,858mg，7.2mmol)和三苯基膦(2518mg，9.6mmol)溶于四氢呋喃(25mL)，N2氛围下滴加DIAD(1941mg，9.6mmol)的四氢呋喃溶液(5mL)，室温搅拌过夜。蒸干溶剂，残余物经柱层析(洗脱剂：石油醚/乙酸乙酯/三乙胺＝20:5:1)得B4粗品(白色固体，1093mg)。
将上述所有B4粗品，溶于乙醇(15mL)/二氯甲烷(5mL)的混合溶剂，加入水合肼(98％,445μL,9.1mmol)，室温搅拌2天。过滤，蒸干滤液，重新加入二氯甲烷(30mL)，再过滤除去不溶物，水洗(7mL×3)，弃去该水相。有机相用0.5N盐酸萃取(10mL×3)，合并水相，水相用2N NaOH水溶液调pH至12，二氯甲烷萃取(10mL×4)，合并有机相，有机相用水洗(8mL×2)，饱和氯化钠水溶液洗(8mL)，无水硫酸钠干燥，蒸除二氯甲烷后得B5(淡黄色固体，122mg，两步收率9％)。
中间体A14的合成
参照实施例1的方法，将A4替换为4-氟苯酚，得到中间体5-(4-氟苯氧基)-2,2-二甲基戊酸(A14，白色固体，3.62g，收率55％)。
化合物15的合成
参照实施例11的方法，以B5和A14为原料，制得化合物15(白色固体，86mg，收率78％)。1H NMR(300MHz,DMSO-d6)δ7.75(d,J＝8.8Hz,2H),7.19(d,J＝7.7Hz,1H),7.14–7.01(m,4H),6.95–6.84(m,2H),4.73–4.64(m,1H),3.94–3.83(m,2H),3.76–3.62(m,1H),1.97–1.85(m,2H),1.71–1.45(m,10H),1.08(s,6H)；HRMS(ESI):m/z calculated for C26H32FN2O3[M+H]+439.2392,found 439.2390.
实施例16
反式-N-(4-(吡啶-3-基氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基-戊酰胺(化合物16)
参照实施例11的方法，以A12为原料，将A10替换为3-氟吡啶，制得化合物16(白色固体，96mg，收率74％)。1H NMR(300MHz,DMSO-d6)δ8.27(d,J＝2.4Hz,1H),8.14(d,J＝4.1Hz,1H),7.40(d,J＝8.3Hz,1H),7.35–7.25(m,3H),7.17(d,J＝7.7Hz,1H),6.93(d,J＝8.8Hz,2H),4.37–4.26(m,1H),3.96–3.85(m,2H),3.68–3.54(m,1H),2.13–2.00(m,2H),1.81–1.69(m,2H),1.62–1.52(m,4H),1.49–1.33(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.80,157.66,154.00,142.37,139.31,129.44,125.66,124.01,123.02,115.94,75.81,68.51,47.50,41.88,37.50,30.53,30.28,25.64,24.97；HRMS(ESI):m/zcalculated for C24H32ClN2O3[M+H]+431.2096,found 431.2097.
实施例17
反式-N-(4-(吡嗪-2-基氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基-戊酰胺(化合物17)
参照实施例11的方法，以A12为原料，将A10替换为2-氟吡嗪，制得化合物17(白色固体，84mg，收率65％)。1H NMR(300MHz,DMSO-d6)δ8.24(s,1H),8.21–8.15(m,2H),7.31(d,J＝8.8Hz,2H),7.17(d,J＝7.8Hz,1H),6.93(d,J＝8.8Hz,2H),4.95–4.82(m,1H),3.96–3.86(m,2H),3.70–3.57(m,1H),2.15–2.04(m,2H),1.81–1.70(m,2H),1.61–1.52(m,4H),1.52–1.32(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.78,159.86,157.69,140.50,136.59,136.43,129.43,125.66,115.93,73.37,68.54,47.57,41.87,37.53,30.77,30.14,25.64,24.99；HRMS(ESI):m/z calculated for C23H30Cl2N3O3[M+Cl]-466.1670,found 466.1670.
实施例18
反式-N-(4-((4-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物18)
参照实施例11的方法，以A12为原料，将A10替换为3-氟-4-氯吡啶，制得化合物18(白色固体，55mg，收率39％)。1H NMR(300MHz,DMSO-d6)δ8.53(s,1H),8.15(d,J＝5.1Hz,1H),7.53(d,J＝5.1Hz,1H),7.30(d,J＝8.9Hz,2H),7.17(d,J＝7.6Hz,1H),6.93(d,J＝8.9Hz,2H),4.51–4.40(m,1H),3.95–3.86(m,2H),3.69–3.55(m,1H),2.15–2.04(m,2H),1.81–1.70(m,2H),1.62–1.52(m,4H),1.52–1.33(m,4H),1.08(s,6H)；MS(ESI):m/z 465.2[M+H]+.
实施例19
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物19)
参照实施例11的方法，以A12为原料，将A10替换为2-氯-5-氟吡啶，制得化合物19(白色固体，111mg，收率79％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.8Hz,1H),7.51(dd,J＝8.7,3.0Hz,1H),7.40(d,J＝8.7Hz,1H),7.31(d,J＝8.8Hz,2H),7.17(d,J＝7.6Hz,1H),6.92(d,J＝8.8Hz,2H),4.40–4.25(m,1H),3.96–3.85(m,2H),3.67–3.53(m,1H),2.14–1.97(m,2H),1.83–1.67(m,2H),1.62–1.51(m,4H),1.50–1.30(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.82,157.65,153.24,142.76,138.15,129.45,126.62,125.68,124.62,115.94,76.40,68.49,47.43,41.89,37.50,30.45,30.18,25.64,24.97；HRMS(ESI):m/zcalculated for C24H31Cl2N2O3[M+H]+465.1706,found 465.1703.
实施例20
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-4-(4-氯苯氧基)-2,2-二甲基丁酰胺(化合物20)
中间体A15的合成
参照实施例1的方法，将A2替换为1,2-二溴乙烷，A4替换为4-氯苯酚，得中间体4-(4-氯苯氧基)-2,2-二甲基丁酸(A15，白色固体，1123mg,收率96％)。
中间体A16的合成
参照实施例11的方法，将A10替换为2-氯-5-氟吡啶，得中间体反式-4-((6-氯吡啶-3-基)氧基)环己烷-1-胺(A16，淡黄色固体，1554mg，收率68％)。
化合物20的合成
参照实施例11的方法，以A15和A16为原料，制得化合物20(白色固体，116mg，收率86％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.9Hz,1H),7.52(dd,J＝8.8,3.0Hz,1H),7.40(d,J＝8.8Hz,1H),7.34–7.24(m,3H),6.92(d,J＝8.8Hz,2H),4.40–4.27(m,1H),3.92(t,J＝7.1Hz,2H),3.69–3.56(m,1H),2.13–2.01(m,2H),1.93(t,J＝7.1Hz,2H),1.83–1.71(m,2H),1.51–1.33(m,4H),1.14(s,6H)；13C NMR(75MHz,CDCl3)δ176.52,157.39,153.17,142.68,138.07,129.45,126.54,125.69,124.63,115.79,76.22,65.51,47.46,41.16,39.66,30.38,30.10,26.17；HRMS(ESI):m/z calculated for C23H28Cl3N2O3[M+Cl]-485.1171,found 485.1172.
实施例21
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-3-(4-氯苯氧基)-2,2-二甲基丙酰胺(化合物21)
中间体C4的合成
取C1(2571mg,20mmol)和3-羟基-2,2-二甲基丙酸甲酯(C2，2643mg,20mmol)和三苯基膦(6820mg,26mmol)溶于干燥的四氢呋喃，N2保护，再加入偶氮二甲酸二乙酯(4528mg,26mmol)，室温搅拌过夜。蒸除四氢呋喃，加入过量甲基叔丁基醚进行溶解，滤去不溶的白色固体，滤液浓缩后，残余物经柱层析(洗脱剂：石油醚/二氯甲烷＝3:1之后，石油醚/乙酸乙酯＝10:1)纯化得中间体3-(4-氯苯氧基)-2,2-二甲基丙酸甲酯(C3，淡黄色油状物，3151mg，收率65％)。
将上述所得中间体C3(3105mg,12.8mmol)，置于反应瓶中，加入甲醇(15mL)和水(15mL)，再加入氢氧化钠(1280mg,32mmol)，80℃加热4h。蒸除甲醇，用2N盐酸调节pH至2，析出白色固体，过滤，水洗(5mL×3)，减压干燥，得C4(白色固体，2858mg，收率98％)。
化合物21的合成
参照实施例11的方法，以C4和A16为原料，制得化合物21(白色固体，106mg，收率81％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.7Hz,1H),7.51(dd,J＝8.7,2.9Hz,1H),7.40(d,J＝8.7Hz,1H),7.35–7.24(m,3H),6.93(d,J＝8.8Hz,2H),4.39–4.27(m,1H),3.93(s,2H),3.69–3.55(m,1H),2.12–1.99(m,2H),1.82–1.68(m,2H),1.50–1.32(m,4H),1.18(s,6H)；13C NMR(75MHz,CDCl3)δ175.29,157.23,153.24,142.75,138.17,129.62,126.60,126.48,124.61,116.05,76.26,75.18,47.32,42.83,30.20,29.97,22.87；HRMS(ESI):m/zcalculated for C22H27Cl2N2O3[M+H]+437.1393,found 437.1398.
实施例22
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-2-(4-氯苯氧基)-2-甲基丙酰胺(化合物22)
参照实施例11的方法，以2-(4-氯苯氧基)-2-甲基丙酸和A16为原料，制得化合物22(白色固体，110mg，收率87％)。1H NMR(300MHz,DMSO-d6)δ8.10(d,J＝2.9Hz,1H),7.91(d,J＝8.0Hz,1H),7.50(dd,J＝8.8,3.0Hz,1H),7.38(d,J＝8.8Hz,1H),7.32(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),4.37–4.22(m,1H),3.75–3.58(m,1H),2.12–1.96(m,2H),1.81–1.66(m,2H),1.51–1.33(m,10H)；HRMS(ESI):m/z calculated for C21H25Cl2N2O3[M+H]+423.1237,found 423.1232.
实施例23
顺式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物23)
参照实施例11的方法，以A12为原料，将A7替换为顺式-4-氨基环己醇，A10替换为2-氯-5-氟吡啶，制得化合物23(白色固体，75mg，收率60％)。1HNMR(300MHz,DMSO-d6)δ8.10(d,J＝2.8Hz,1H),7.50(dd,J＝8.7,3.0Hz,1H),7.42(d,J＝8.7Hz,1H),7.28(d,J＝8.9Hz,2H),7.18(d,J＝7.8Hz,1H),6.91(d,J＝8.9Hz,2H),4.67–4.57(m,1H),3.96–3.85(m,2H),3.74–3.62(m,1H),1.97–1.82(m,2H),1.70–1.42(m,10H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.67,157.69,153.03,142.67,138.63,129.42,126.01,125.64,124.60,115.92,72.52,68.52,47.03,41.88,37.54,28.40,27.34,25.63,25.00；HRMS(ESI):m/zcalculatedfor C24H30Cl2N2NaO3[M+Na]+487.1526,found 487.1524.
实施例24
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-N,2,2-三甲基戊酰胺(化合物24)
中间体D4的合成
室温下，将氢化铝锂(1520mg,40mmol)悬浮于四氢呋喃(50mL)中，分批加入反式-(-4-羟基环己基)氨基甲酸叔丁酯(D1，2153mg,10mmol)，66℃加热回流2h。冷却至0℃，依次加入水(1.5mL)、15％NaOH水溶液(1.5mL)、水(3mL)以淬灭反应。过滤，滤液减压浓缩后，加二氯甲烷(10mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液蒸干后，得D2(淡黄色固体，1080mg,收率84％)。
取D2(323mg,2.5mmol)和2-氯-5-氟吡啶(D3,329mg,2.5mmol)，60℃条件下搅拌3h。冷却至0℃，加水(50mL)淬灭反应，再倒入额外的水中(100mL)，乙酸乙酯萃取(30mL×4)，合并有机相，水(20mL)洗，饱和氯化钠水溶液洗(20mL)，无水硫酸钠干燥，减压浓缩后，残余物经柱层析(二氯甲烷/甲醇＝15:1，之后，二氯甲烷/甲醇/三乙胺＝40:2:1)得D4(橘黄色蜡状固体，287mg,收率48％)。
化合物24的合成
参照实施例11的方法，以A12和D4为原料，制得化合物24(白色固体，58mg，收率40％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.8Hz,1H),7.51(dd,J＝8.7,3.0Hz,1H),7.42(d,J＝8.8Hz,1H),7.31(d,J＝8.9Hz,2H),6.92(d,J＝8.8Hz,2H),4.47–4.32(m,1H),4.24–4.03(m,1H),3.95(t,J＝5.5Hz,2H),2.78(s,3H),2.17–2.03(m,2H),1.85–1.65(m,4H),1.65–1.38(m,6H),1.20(s,6H)；13C NMR(75MHz,CDCl3)δ176.29,173.82,157.65,153.24,142.82,138.22,129.45,126.56,125.64,124.62,115.85,76.67,68.46,54.34,42.82,37.62,31.03,30.29,27.47,27.14,25.30；HRMS(ESI):m/z calculated forC25H32Cl2N2NaO3[M+Na]+501.1682,found 501.1685.
实施例25
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物25)
参照实施例11的方法，以A12为原料，将A10替换为3-氯-5-氟吡啶，制得化合物25(白色固体，322mg，收率86％)。1H NMR(300MHz,DMSO-d6)δ8.26(d,J＝2.3Hz,1H),8.19(d,J＝1.7Hz,1H),7.64(dd,J＝2.3,1.7Hz,1H),7.31(d,J＝8.9Hz,2H),7.19(d,J＝7.5Hz,1H),6.93(d,J＝8.9Hz,2H),4.47–4.34(m,1H),3.97–3.85(m,2H),3.67–3.52(m,1H),2.13–1.99(m,2H),1.82–1.67(m,2H),1.62–1.52(m,4H),1.50–1.33(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.82,157.65,154.29,141.02,137.28,132.08,129.45,125.68,122.69,115.94,76.24,68.49,47.40,41.89,37.50,30.45,30.15,25.64,24.96；HRMS(ESI):m/zcalculated for C24H31Cl2N2O3[M+H]+465.1706,found 465.1704.
实施例26
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-4-(4-氯苯氧基)-2,2-二甲基丁酰胺(化合物26)
参照实施例11的方法，以A15为原料，将A10替换为3-氯-5-氟吡啶，制得化合物26(白色固体，110mg，收率81％)。1H NMR(300MHz,DMSO-d6)δ8.28–8.23(m,1H),8.21–8.16(m,1H),7.67–7.60(m,1H),7.31(d,J＝8.9Hz,2H),7.28–7.23(m,1H),6.92(d,J＝8.8Hz,2H),4.49–4.36(m,1H),3.92(t,J＝7.2Hz,2H),3.69–3.54(m,1H),2.15–2.00(m,2H),1.93(t,J＝7.2Hz,2H),1.84–1.69(m,2H),1.53–1.33(m,4H),1.15(s,6H)；MS(ESI):m/z 473.2[M+Na]+.
实施例27
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-3-(4-氯苯氧基)-2,2-二甲基丙酰胺(化合物27)
参照实施例11的方法，以C4为原料，将A10替换为3-氯-5-氟吡啶，制得化合物27(白色固体，91mg，收率69％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.3Hz,1H),8.18(d,J＝1.6Hz,1H),7.64(dd,J＝2.3Hz,1.6Hz,1H),7.31(d,J＝8.9Hz,2H),7.27(d,J＝8.1Hz,1H),6.93(d,J＝8.9Hz,2H),4.47–4.35(m,1H),3.94(s,2H),3.70–3.54(m,1H),2.13–1.99(m,2H),1.83–1.69(m,2H),1.52–1.32(m,4H),1.18(s,6H)；MS(ESI):m/z 459.2[M+Na]+.
实施例28
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-2-(4-氯苯氧基)-2-甲基丙酰胺(化合物28)
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参照实施例11的方法，以2-(4-氯苯氧基)-2-甲基丙酸为原料，将A10替换为3-氯-5-氟吡啶，制得化合物28(白色固体，111mg，收率87％)。1H NMR(300MHz,DMSO-d6)δ8.23(d,J＝2.3Hz,1H),8.17(d,J＝1.7Hz,1H),7.90(d,J＝7.8Hz,1H),7.63(dd,J＝2.3,1.7Hz,1H),7.32(d,J＝8.9Hz,2H),6.87(d,J＝8.9Hz,2H),4.44–4.32(m,1H),3.74–3.58(m,1H),2.14–1.97(m,2H),1.83–1.67(m,2H),1.53–1.33(m,10H)；MS(ESI):m/z 445.1[M+Na]+.
实施例29
顺式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-2,2-二甲基戊酰胺(化合物29)
参照实施例11的方法，以A12为原料，将A7替换为顺式-4-氨基环己醇，A10替换为3-氯-5-氟吡啶，制得化合物29(白色固体，98mg，收率70％)。1HNMR(300MHz,DMSO-d6)δ8.25(d,J＝2.4Hz,1H),8.20(d,J＝1.7Hz,1H),7.60(dd,J＝2.4,1.7Hz,1H),7.27(d,J＝8.9Hz,2H),7.19(d,J＝7.7Hz,1H),6.91(d,J＝8.9Hz,2H),4.72–4.66(m,1H),3.96–3.86(m,2H),3.74–3.63(m,1H),1.98–1.84(m,2H),1.71–1.45(m,10H),1.09(s,6H).MS(ESI):m/z 487.2[M+Na]+.
实施例30
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-N,2,2-三甲基戊酰胺(化合物30)
参照实施例24的方法，将D3替换为3-氯-5-氟吡啶，制得化合物30(白色固体，102mg，收率71％)。1H NMR(300MHz,DMSO-d6)δ8.24(d,J＝2.2Hz,1H),8.19(d,J＝1.9Hz,1H),7.63(dd,J＝2.2,1.9Hz,1H),7.30(d,J＝8.8Hz,2H),6.92(d,J＝8.9Hz,2H),4.52–4.39(m,1H),4.21–4.07(m,1H),3.95(t,J＝5.5Hz,2H),2.78(s,3H),2.17–2.04(m,2H),1.86–1.66(m,4H),1.66–1.40(m,6H),1.20(s,6H)；MS(ESI):m/z 501.2[M+Na]+.
实施例31
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氯苯氧基)-戊酰胺(化合物31)
中间体A17的合成
参照实施例1的方法，将A4替换为4-氯苯酚，A3替换为5-溴戊酸甲酯，得中间体5-(4-氯苯氧基)戊酸(A17，白色固体，753mg，收率95％)。
中间体A18的合成
参照实施例11的方法，将A10替换为3-氯-5-氟吡啶，得中间体反式-4-((5-氯吡啶-3-基)氧基)环己烷-1-胺(A18，黄色蜡状固体，877mg，收率39％)。
化合物31的合成
参照实施例11的方法，以A17和A18为原料，制得化合物31(白色固体，42mg，收率32％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.4Hz,1H),8.18(d,J＝1.8Hz,1H),7.75(d,J＝7.5Hz,1H),7.66(dd,J＝2.4,1.8Hz,1H),7.31(d,J＝9.0Hz,2H),6.94(d,J＝9.0Hz,2H),4.53–4.41(m,1H),3.95(t,J＝5.8Hz,2H),3.64–3.51(m,1H),2.11(t,J＝6.8Hz,2H),2.08–2.00(m,2H),1.87–1.76(m,2H),1.74–1.58(m,4H),1.51–1.24(m,4H)；MS(ESI):m/z 459.2[M+Na]+.
实施例32
顺式-4-((4-(5-(4-氯苯氧基)-2,2-二甲基戊酰胺基)环己基)氧基)苯甲酸酯(化合物32)
参照实施例11的方法，以A12为原料，将A7替换为顺式-4-氨基环己醇，A10替换为4-羟基苯甲酸甲酯，制得化合物32(白色固体，159mg，收率93％)。1H NMR(300MHz,DMSO-d6)δ7.88(d,J＝8.7Hz,2H),7.27(d,J＝8.9Hz,2H),7.20(d,J＝7.6Hz,1H),7.01(d,J＝8.7Hz,2H),6.91(d,J＝8.9Hz,2H),4.69–4.60(m,1H),3.97–3.85(m,2H),3.76–3.62(m,1H),2.01–1.85(m,2H),1.71–1.44(m,10H),1.09(s,6H)；HRMS(ESI):m/z calculated for C26H33ClNO5[M+H]+474.2042,found 474.2048.
实施例33
顺式-4-((4-(5-(4-氯苯氧基)-2,2-二甲基戊酰胺基)环己基)氧基)苯甲酸(化合物33)
取化合物32(136mg,0.28mmol)置于反应瓶中，加入四氢呋喃(3mL)、甲醇(1mL)、水(3mL)，再加入氢氧化锂一水合物(59mg,1.4mmol)，室温搅拌40h。蒸除四氢呋喃和甲醇，加水(2mL)，2N盐酸调pH值到2，析出白色固体，过滤，滤饼用水洗(2mL×3)，再用乙醚洗(8mL)，干燥后得化合物33(白色固体，103mg，收率78％)。1H NMR(300MHz,DMSO-d6)δ12.57(s,1H),7.88(d,J＝8.7Hz,2H),7.27(d,J＝8.9Hz,2H),7.20(d,J＝7.6Hz,1H),7.01(d,J＝8.7Hz,2H),6.91(d,J＝8.9Hz,2H),4.69–4.60(m,1H),3.97–3.85(m,2H),3.76–3.62(m,1H),2.01–1.85(m,2H),1.71–1.44(m,10H),1.09(s,6H)；HRMS(ESI):m/z calculated for C26H33ClNO5[M+H]+474.2042,found 474.2048.
实施例34
反式-N-(4-(4-氰基苯氧基)环己基)-5-(4-氟苯氧基)-2,2-二甲基戊酰胺(化合物34)
参照实施例11的方法，以A14为原料，制得化合物34(白色固体，107mg，收率81％)。1HNMR(300MHz,DMSO-d6)δ7.73(d,J＝8.8Hz,2H),7.18(d,J＝7.8Hz,1H),7.14–7.05(m,4H),6.96–6.86(m,2H),4.46–4.31(m,1H),3.93–3.83(m,2H),3.67–3.55(m,1H),2.14–1.99(m,2H),1.81–1.69(m,2H),1.62–1.52(m,4H),1.51–1.33(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.88,161.23,158.94,155.79,155.17,134.13,119.30,116.26,116.05,115.75,115.71,115.60,103.93,75.45,68.86,47.45,41.90,37.51,30.45,30.13,25.63,25.07；HRMS(ESI):m/z calculated for C26H32FN2O3[M+H]+439.2391,found 439.2393.
实施例35
反式-N-(4-(4-氰基苯氧基)环己基)-2-(4-氟苯氧基)-2-甲基丙酰胺(化合物35)
中间体A19的合成
参照实施例1的方法，将A4替换为4-氟苯酚，A3替换为2-溴异丁酸甲酯，得中间体A19(白色固体，10.37g，收率95％)。
化合物35的合成
参照实施例11的方法，以A19和A11为原料，制得化合物35(白色固体，80mg，收率58％)。1H NMR(300MHz,DMSO-d6)δ7.91(d,J＝8.0Hz,1H),7.72(d,J＝8.7Hz,2H),7.17–7.05(m,4H),6.96–6.86(m,2H),4.45–4.31(m,1H),3.76–3.60(m,1H),2.13–1.99(m,2H),1.84–1.70(m,2H),1.56–1.41(m,4H),1.39(s,6H)；13C NMR(75MHz,CDCl3)δ174.17,161.20,160.69,157.48,150.15,134.15,123.13,123.02,119.30,116.25,116.07,115.77,103.96,82.00,75.27,47.28,30.24,30.02,25.07；HRMS(ESI):m/z calculated for C23H26FN2O3[M+H]+397.1922,found 397.1933.
实施例36
顺式-5-(4-氯苯氧基)-2,2-二甲基-N-(4-(4-(甲基磺酰基)苯氧基)环己基)戊酰胺(化合物36)
中间体B6的合成
参照实施例15的方法，将B3替换为4-羟基苯甲砜，制的中间体顺式-4-(4-(甲基磺酰基)苯氧基)环己-1-胺(B6，油状物，38mg，收率13％)。
化合物36的合成
参照实施例11的方法，以A12和B6为原料，制得化合物36(白色固体，36mg，收率62％)。1H NMR(300MHz,DMSO-d6)δ7.83(d,J＝8.7Hz,2H),7.28(d,J＝8.8Hz,2H),7.20(d,J＝7.7Hz,1H),7.15(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),4.75–4.65(m,1H),3.97–3.84(m,2H),3.76–3.62(m,1H),3.15(s,3H),2.01–1.86(m,2H),1.74–1.44(m,10H),1.08(s,6H)；HRMS(ESI):m/z calculated for C26H34ClNNaO5S[M+Na]+530.1738,found530.1736.
实施例37
反式-N-(4-(4-(甲基磺酰基)苯氧基)环己基)-5-(4-氟苯氧基)-2,2-二甲基-戊酰胺(化合物37)
参照实施例11的方法，以A14为原料，将A10替换为4-氟苯甲砜，制得化合物37(白色固体，115mg，收率78％)。1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.22–7.06(m,5H),6.96–6.87(m,2H),4.46–4.34(m,1H),3.94–3.84(m,2H),3.68–3.55(m,1H),3.15(s,3H),2.14–2.03(m,2H),1.83–1.70(m,2H),1.61–1.53(m,4H),1.51–1.36(m,4H),1.09(s,6H)；13C NMR(75MHz,CDCl3)δ176.87,162.07,158.92,155.77,155.16,132.28,129.70,116.05,115.97,115.75,115.68,115.58,75.54,68.85,47.43,44.97,41.89,37.50,30.44,30.12,25.63,25.06；MS(ESI):m/z 514.3[M+Na]+.
实施例38
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(4-氟苯氧基)-2,2-二甲基戊酰胺(化合物38)
参照实施例11的方法，以A14和A16为原料，制得化合物38(白色蜡状固体，116mg，收率86％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.9Hz,1H),7.51(dd,J＝8.7,3.0Hz,1H),7.40(d,J＝8.7Hz,1H),7.17(d,J＝7.6Hz,1H),7.13–7.05(m,2H),6.95–6.86(m,2H),4.39–4.27(m,1H),3.93–3.83(m,2H),3.67–3.53(m,1H),2.12–1.99(m,2H),1.81–1.68(m,2H),1.61–1.51(m,4H),1.49–1.32(m,4H),1.08(s,6H)；MS(ESI):m/z 471.2[M+Na]+.
实施例39
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氟苯氧基)-2,2-二甲基戊酰胺(化合物39)
参照实施例11的方法，以A14和A18为原料，制得化合物39(白色固体，126mg，收率70％)。1H NMR(300MHz,DMSO-d6)δ8.26(d,J＝2.1Hz,1H),8.22–8.15(m,1H),7.67–7.60(m,1H),7.19(d,J＝7.7Hz,1H),7.15–7.04(m,2H),6.96–6.86(m,2H),4.50–4.32(m,1H),3.97–3.81(m,2H),3.68–3.52(m,1H),2.16–1.97(m,2H),1.83–1.67(m,2H),1.64–1.51(m,4H),1.51–1.33(m,4H),1.08(s,6H)；HRMS(ESI):m/z calculated for C24H31ClFN2O3[M+H]+449.2002,found 449.2003.
实施例40
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氯-3-氟苯氧基)-2,2-二甲基戊酰胺(化合物40)
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中间体A20的合成
参照实施例1方法，将A4替换为4-氯-3-氟苯酚，得中间体5-(4-氯＝-3-氟苯氧基)-2,2-二甲基戊酸(A20白色固体，235mg，收率40％)。
化合物40的合成
参照实施例11方法，以A20和A18为原料，制得化合物40(白色固体，128mg，收率88％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.4Hz,1H),8.19(d,J＝1.7Hz,1H),7.63(dd,J＝2.4,1.7Hz,1H),7.45(dd,J＝8.9,8.9Hz,1H),7.19(d,J＝7.7Hz,1H),7.02(dd,J＝11.6,2.7Hz,1H),6.85–6.75(m,1H),4.47–4.34(m,1H),4.00–3.89(m,2H),3.66–3.53(m,1H),2.13–1.99(m,2H),1.80–1.68(m,2H),1.62–1.52(m,4H),1.50–1.33(m,4H),1.08(s,6H)；MS(ESI):m/z 505.2[M+Na]+.
实施例41
反式-N-(4-(4-氰基苯氧基)环己基)-5-(2,4-二氟苯氧基)-2,2-二甲基戊酰胺(化合物41)
中间体A21的合成
参照实施例1的方法，将A4替换为2,4-二氟苯酚，得中间体5-(2,4-二氟苯氧基)-2,2-二甲基戊酸(A21，白色固体，5.73g，收率80％)。
化合物41的合成
参照实施例11的方法，以A21和A11为原料制得化合物41(白色固体，100mg，收率73％)。1H NMR(300MHz,DMSO-d6)δ7.74(d,J＝8.8Hz,2H),7.33–7.13(m,3H),7.11(d,J＝8.8Hz,2H),7.05–6.93(m,1H),4.46–4.32(m,1H),4.04–3.91(m,2H),3.69–3.53(m,1H),2.13–1.99(m,2H),1.83–1.68(m,2H),1.63–1.52(m,4H),1.51–1.32(m,4H),1.08(s,6H)；HRMS(ESI):m/z calculated for C26H31F2N2O3[M+H]+457.2297,found 457.2298.
实施例42
反式-N-(4-(4-(甲基磺酰基)苯氧基)环己基)-5-(2,4-二氟苯氧基)-2,2-二甲基-戊酰胺(化合物42)
参照实施例11的方法，以A21为原料，将A10替换为4-氟苯甲砜，制得化合物42(胶状物，123mg，收率80％)。1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.8Hz,2H),7.32–7.10(m,5H),7.05–6.94(m,1H),4.47–4.33(m,1H),4.05–3.91(m,2H),3.68–3.55(m,1H),3.14(s,3H),2.15–2.02(m,2H),1.83–1.70(m,2H),1.64–1.53(m,4H),1.51–1.34(m,4H),1.09(s,6H)；HRMS(ESI):m/zcalculated for C26H34F2NO5S[M+H]+510.2120,found 510.2128.
实施例43
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(2,4-二氟苯氧基)-2,2-二甲基戊酰胺(化合物43)
参照实施例11的方法，以A21和A16为原料，制得化合物43(白色固体，118mg，收率84％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝2.9Hz,1H),7.51(dd,J＝8.8,3.0Hz,1H),7.40(d,J＝8.7Hz,1H),7.31–7.20(m,1H),7.20–7.10(m,2H),7.04–6.94(m,1H),4.39–4.26(m,1H),4.03–3.91(m,2H),3.67–3.52(m,1H),2.13–1.98(m,2H),1.81–1.67(m,2H),1.63–1.51(m,4H),1.49–1.31(m,4H),1.08(s,6H)；HRMS(ESI):m/z calculated for C24H30ClF2N2O3[M+H]+467.1908,found 467.1907.
实施例44
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(2,4-二氟苯氧基)-2,2-二甲基戊酰胺(化合物44)
参照实施例11的方法，以A21和AA18为原料，A10替换为3-氯-5-氟吡啶，制得化合物44(胶状固体，101mg，收率72％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.5Hz,1H),8.19(d,J＝1.9Hz,1H),7.63(dd,J＝2.5,1.9Hz,1H),7.32–7.10(m,3H),7.04–6.94(m,1H),4.47–4.34(m,1H),4.02–3.93(m,2H),3.67–3.51(m,1H),2.16–1.98(m,2H),1.82–1.67(m,2H),1.63–1.52(m,4H),1.50–1.33(m,4H),1.08(s,6H)；HRMS(ESI):m/z calculated forC24H30ClF2N2O3[M+H]+467.1908,found 467.1908.
实施例45
反式-N-(4-((6-氯吡啶-3-基)氧基)环己基)-5-(4-氰基苯氧基)-2,2-二甲基戊酰胺(化合物45)
中间体A22的合成
参照实施例1的方法，将A4替换为4-羟基苯甲腈,制的中间体A22(白色固体，2657mg，收率89％)。
化合物45的合成
参照实施例11的方法，以A22和A16为原料，制得化合物45(白色蜡状固体，111mg，收率81％)。1H NMR(300MHz,DMSO-d6)δ8.11(d,J＝3.0Hz,1H),7.75(d,J＝8.7Hz,2H),7.51(dd,J＝8.7,3.0Hz,1H),7.40(d,J＝8.8Hz,1H),7.17(d,J＝7.8Hz,1H),7.07(d,J＝8.7Hz,2H),4.38–4.27(m,1H),4.07–3.96(m,2H),3.67–3.53(m,1H),2.12–1.98(m,2H),1.81–1.68(m,2H),1.66–1.51(m,4H),1.49–1.31(m,4H),1.08(s,6H)；13C NMR(75MHz,CDCl3)δ176.73,162.38,153.23,142.78,138.10,134.09,126.66,124.63,119.30,115.31,104.04,76.38,68.63,47.46,41.85,37.43,30.46,30.18,25.60,24.82；HRMS(ESI):m/z calculated forC25H31ClN3O3[M+H]+456.2048,found 456.2053.
实施例46
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-氰基苯氧基)-2,2-二甲基戊酰胺(化合物46)
参照实施例11的方法，以A22和AA18为原料，制得化合物46(白色固体，101mg，收率74％)。1H NMR(300MHz,DMSO-d6)δ8.26(d,J＝2.4Hz,1H),8.19(d,J＝1.8Hz,1H),7.75(d,J＝8.8Hz,2H),7.63(dd,J＝2.4,1.8Hz,1H),7.19(d,J＝7.7Hz,1H),7.08(d,J＝8.9Hz,2H),4.46–4.35(m,1H),4.01(t,J＝5.3Hz,2H),3.66–3.53(m,1H),2.12–2.01(m,2H),1.80–1.69(m,2H),1.64–1.54(m,4H),1.50–1.33(m,4H),1.09(s,6H)；MS(ESI):m/z 478.2[M+Na]+.
实施例47
反式-N-(4-((5-氯吡啶-3-基)氧基)环己基)-5-(4-(甲基磺酰基)苯氧基)-2,2-二甲基戊酰胺(化合物47)
中间体A23的合成
参照实施例1的方法，将A4替换为4-羟基苯甲砜，得到中间体A23(白色固体，1479mg，收率90％)。
化合物47的合成
参照实施例11的方法，以A23和A18为原料，制得化合物47(白色固体，129mg，收率84％)。1H NMR(300MHz,DMSO-d6)δ8.25(d,J＝2.4Hz,1H),8.18(d,J＝1.8Hz,1H),7.83(d,J＝8.8Hz,2H),7.64(dd,J＝2.4,1.8Hz,1H),7.19(d,J＝7.6Hz,1H),7.13(d,J＝8.9Hz,2H),4.48–4.34(m,1H),4.03(t,J＝5.3Hz,2H),3.67–3.53(m,1H),3.14(s,3H),2.13–2.00(m,2H),1.81–1.70(m,2H),1.66–1.53(m,4H),1.51–1.33(m,4H),1.09(s,6H)；MS(ESI):m/z509.3[M+H]+.
实施例48
化合物促进C2C12细胞AMPK(Thr172)磷酸化激活能力的测试
将小鼠骨骼肌C2C12细胞(购自中国科学院上海细胞库)铺板于12孔板中，用含10％牛血清的培养基促进细胞生长至密为80～90％，更换含2.0％马血清的培养基，每日更换培养基，诱导细胞分化。已分化的C2C12饥饿8-12小时后，将受试化合物(按终浓度10μM)添加于12孔板中，0.1％DMSO组设为阴性对照，MK-8722(按终浓度10μM)组设为阳性对照。给药2h后，丢弃培养基，预冷的PBS洗涤2次，每孔加入150μL的裂解液，收集裂解液。采用Western Blot技术检测AMPK磷酸化情况，然后进行灰度扫描，阴性对照组pAMPK/AMPK的比值定义为1，受试化合物pAMPK/AMPK的比值为阴性对照组的相对比值。pAMPK/AMPK的比值反映化合物促进AMPK磷酸化激活的能力。该数值越大，表明化合物的AMPK激动活性越强，实验结果见表1。
表1.化合物促进C2C12细胞AMPK磷酸化激活的能力
实验结果如表1和图1-5表明，本发明的化合物具有显著的AMPK激动活性。例如，化合物7、8、9、14、20、23、25、38、42、43和45显著增强AMPK的磷酸化水平，且活性优于公认的AMPK直接激动剂MK-8722。这表明本发明的化合物是明确的AMPK激动剂并且是具有且具有剂量依赖关系的AMPK激动剂。
实施例49
体内AMPK激动活性评价
灌胃给予C57BL/6J小鼠化合物25 30mg/kg，分别在一小时和两小时后检测其心脏组织的AMPK磷酸化情况，结果如图6所示。实验结果表明，化合物25可以显著增强小鼠心脏AMPK磷酸化情况。以上结果表明，本发明化合物可用体内有效的激活AMPK，提示着本发明化合物可以用于治疗代谢性疾病和心脑血管疾病。
实施例50
片剂的制备
将化合物25(1g)与乳糖(23g)和微晶纤维素(5.7g)用混合机混合。用滚轴压紧机将所得混合物压制成型，值得薄片状压制物料。用锤式粉碎机将所述薄片状压制物料研磨成粉，使所得粉状物料通过20目筛过筛。将一份轻质二氧化硅(0.3g)和硬脂酸镁(0.3g)加入到已过筛的物料中，并混合。所得混合产物用制片机压片，制备片剂。
实施例51
明胶胶囊剂的制备
将化合物25(1g)与微晶纤维素(0.35g)和乳糖(0.15g)用水制粒，然后将该颗粒与铰链羧甲基纤维素钠(0.04g)和硬脂酸镁(0.01g)混合。所得混合产物填充明胶胶囊，制备明胶胶囊剂。
此外，可以根据药典2015版常规制剂法，将化合物1～47赋予不同的药物辅料制成胶囊剂、散剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等。

Claims (7)

1.一种化合物或其药学上可接受的盐，其特征在于，所述化合物选自如下任一所示：
2.一种权利要求1所述的化合物或其药学上可接受的盐在制备AMPK激动剂中的应用。
3.根据权利要求2所述的应用，其特征在于，所述化合物或其药学上可接受的盐通过激活AMPK信号通路在制备AMPK激动剂中的应用。
4.一种权利要求1所述的化合物或其药学上可接受的盐在制备预防或治疗AMPK介导的疾病的药物中的用途。
5.根据权利要求4所述的用途，其特征在于，所述AMPK介导的疾病包括代谢性疾病、心脑血管疾病、炎症疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病、病原体感染所致的继发性疾病、线粒体功能障碍或紊乱疾病或肿瘤。
6.一种预防或治疗AMPK介导的疾病的药物组合物，其包含如权利要求1所述的化合物、其药学上可接受的盐作为活性成分和药学上可接受的辅料。
7.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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