CN115466169B - 取代邻苯二酚醚类化合物及其制备方法和应用 - Google Patents

取代邻苯二酚醚类化合物及其制备方法和应用 Download PDF

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CN115466169B
CN115466169B CN202210484834.9A CN202210484834A CN115466169B CN 115466169 B CN115466169 B CN 115466169B CN 202210484834 A CN202210484834 A CN 202210484834A CN 115466169 B CN115466169 B CN 115466169B
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张翔
杨旭
董敏
尹大力
肖琼
田育林
杨虹
王永成
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Abstract

本发明属于医药技术领域，涉及取代邻苯二酚醚类化合物及其制备方法和应用。具体而言，本发明涉及一种通式(I)所示的化合物，其制备方法和其用于预防和/或治疗需要抑制磷酸二酯酶的任何疾病。

Description

取代邻苯二酚醚类化合物及其制备方法和应用
技术领域
本发明属于医药技术领域，涉及取代邻苯二酚醚类化合物及其制备方法和其在医药上的应用。具体而言，本发明涉及一种通式(I)所示的化合物，其制备方法和其用于预防和/或治疗需要抑制磷酸二酯酶的任何疾病。
背景技术
慢性阻塞性肺病(COPD)是一种呼吸系统常见慢性炎症性疾病，其特征是持续存在的呼吸系统炎性症状和气流受限，原因是气道和/或肺泡异常，通常与暴露于毒性颗粒和气体有关。COPD常见症状包括呼吸困难、咳嗽和咳痰等。2015年，全球估计有317万人死于慢性阻塞性肺病，占同年全世界所有死亡人数的5％；2016年，全球共有2.51亿例慢性阻塞性肺病病例；到2030年，COPD将会成为世界第三大死亡原因。治疗COPD一线药物主要是各种类型的支气管扩张剂，包括短效及长效β2激动剂、短效及长效抗胆碱能药物以及β2激动剂和抗胆碱能药物之间的联合使用、口服类药物甲基黄嘌呤和罗氟司特、糖皮质类药物和长效β2激动剂的联用，但尚未有临床证据表明，现有的药物治疗能够缓解COPD患者肺功能长期下降的趋势。因此，作为一种慢性炎症疾病，对COPD患者进行有效的抗炎治疗，应该可以减缓疾病的进程和恶化，并降低死亡率以及与COPD相关的合并症的发生。
环腺苷酸(cAMP)是细胞内重要的第二信使，主要通过激活PKA途径参与视觉传导、细胞的增殖分化、基因表达、炎症反应、细胞的凋亡和代谢等生理活动。细胞内cAMP水平的提升可以调控多种炎症介质，从而达到广谱抗炎的效果。cAMP在体内的平衡主要由腺苷酸环合酶(CA)和磷酸二酯酶(PDE)调控，CA催化ATP合成cAMP，PDEs促进cAMP降解为无活性的5’-AMP。因此，靶向抑制PDE的活性可以提升细胞内cAMP的水平，从而达到广谱抗炎的目的，其中PDE4是最主要的cAMP降解酶。罗氟司特是第一个选择性的PDE4抑制剂用于COPD治疗，起初它是由Nycomed公司开发，2010年，在欧洲和加拿大被批准用于严重慢性阻塞性肺病有频繁恶化加重患者的辅助治疗。然而由于剂量依赖的副作用，如恶心，呕吐等胃肠道不良反应，其严重性足以降低其依从性。越来越多的证据显示PDE4抑制剂由于作用于中枢系统PDE4引起的恶心呕吐等不良反应，已经很大程度上限制了该类药物在临床上的广泛使用。
发明内容
本发明涉及磷酸二酯酶的酶抑制剂邻苯二酚醚类似物及其制备方法和应用。具体而言，本发明涉及一种通式(I)所示的化合物，其制备方法和其用于预防和/或治疗需要抑制磷酸二酯酶的任何疾病。
具体的，本发明涉及通式(I)的邻苯二酚醚的衍生物，包括其立体异构体或药学上可接受的盐：
其中：
环A选自苯环、吡啶、哒嗪、嘧啶或吡嗪环，独立地任意地被R1取代；
每个R1相同或不同，各自独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；
或者当环A为苯环且被两个R1取代时，两个R1相邻，相邻的两个R1和与它们相连的苯环上的两个碳原子共同形成一个5-6元碳环、杂环、环酮基和杂环酮基，其可独立地任意地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；上述所述的杂环和杂环酮基中，杂原子为独立地任意地选自N，O，S，杂原子数为1或2；
上述所述R2选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；
R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；
R5选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；
y选自0，1，2或3；
n选自1，2，3，4或5；
对于通式(I)化合物,其中n选自1，2，3,4或5，环A为苯环，独立地任意地被R1取代，R1各自独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH)y-COOR5,巯基,氰基，硝基；或者被两个R1取代，两个R1相邻，相邻的两个R1和与它们相连的苯环上的两个碳原子共同形成一个5-6元碳环、杂环、环酮基和杂环酮基，其可独立地任意地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；上述所述的杂环和杂环酮基中，杂原子为独立地任意地选自N，O，S，杂原子数为1或2；R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基,R5任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3；
当环A为苯环，其中n是1时，R1优选位于取代苯乙基的间位或对位，R1独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；上述所述R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基,R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3；
对于通式(I)化合物，当环A为苯环，其中m是2时，优选两个R1相邻且相邻的两个R1和与它们相连的苯环上两个碳原子共同形成一个5-6元碳环，杂环，环酮基，杂环酮基，其可任选地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；5-6元环优选杂环，环酮基，杂环酮基；
对于上述的通式(I)化合物，当环A为苯环，其中m是3时，三个R1优选是处于相邻的位置，三个R1相同或不同，各自独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；上述所述R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3；
对于通式(I)化合物,其中n选自1,2,3或4，环A选自吡啶，哒嗪，嘧啶或吡嗪，独立地任意地被R1取代；R1选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基；上述所述R2选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；R5选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；y选自0，1，2或3；
对于通式(I)化合物,其中n选自1,2,3或4，环B为吡啶，哒嗪，嘧啶或吡嗪环，优选吡啶环和吡嗪环，独立地任意地被R1取代，R1各自独立地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基；R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3；
在本发明一个更优选的实施方案中，所述的通式(I)所示的化合物包括其立体异构体或药学上可接受的盐，当环A为苯环，其中n是1时，R1位于取代苯乙基的间位，R1选自-(CH2)y-COOR5或y是0或1，R5是氢；
在本发明一个更优选的实施方案中，所述的通式(I)所示的化合物包括其立体异构体或药学上可接受的盐，当环A为苯环，其中n是2时，两个R1相邻，且相邻的两个R1和与它们相连的两个碳原子共同形成一个5-6元碳环，杂环，环酮基和杂环酮基，其可任选地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；所述的5-6元环中，5元环是噻吩基，内酰胺环或可被羟基取代基取代的环酮基；6元环是哌嗪基，二氢吡啶基，吡嗪环或吡啶环；
在本发明一个更优选的实施方案中，所述的通式(I)所示的化合物包括其立体异构体或药学上可接受的盐，当其中环A是吡啶环时，独立地任选被R1取代，优选地被1个R1取代基取代，R1选自-(CH2)y-COOR5或y是0或1，R5是氢；
在本发明一个更优选的实施方案中，所述的通式(I)所示的化合物包括其立体异构体或药学上可接受的盐，当其中环A是吡嗪环，独立地任选被R1取代基取代，优选地被1个R1取代基取代，R1选自-(CH2)y-COOR5或y是0或1，R5是氢；
在本发明一个更优选的实施方案中，所述的通式(I)所示的化合物包括其立体异构体或药学上可接受的盐，当其中环A是吡啶环或吡嗪环，任选被R1取代基取代，优选地被1个R1取代基取代，R1选自-(CH2)y-COOR5或y是0或1，R5是氢，R1更优选地位于取代苯乙基的间位；
本发明提供通式(I)的化合物包括其立体异构体或药学上可接受的盐，是磷酸二酯酶的抑制剂，是用于制备药物的用途，所述药物用于预防和/或治疗其中需要抑制磷酸二酯酶的任何疾病。
研究发现通式(I)的化合物在nM范围内显出PDE4B1酶的体外抑制活性。
通式(I)的化合物可以根据本领域中已知的常规方法制备。可以使用的一些方法描述如下，并且不应该看作是限制可用于制备本发明化合物的合成方法的范围。
通式(I)的化合物的制备方法如下：
第一反应为式I-1的化合物在碱性条件下与维悌希盐反应，生成I-2化合物；
第二步反应式为I-2和I-3化合物在碱性条件下，催化剂存在下进行Heck反应，得到式I-4化合物；
第三步反应式为I-4化合物在催化剂条件下，还原得到I-5化合物；
在实施例中有特殊的目标化合物，其合成方法涉及到由I-5化合物通过官能团衍生化或其他合成方法而得到目标化合物，可根据后续的实施例中具体操作步骤进行说明，在此不再专门一一说明，仅做通用合成路线的详细说明。
提供碱性的条件包括但不限于三乙胺，叔丁醇钾或叔丁醇钠，氢氧化钠。
催化剂包括但不限于钯/碳、雷尼镍、四-三苯基膦钯、三(二亚苄基丙酮)二钯、醋酸钯。
所用溶剂包括但不限于：甲醇，乙醇，四氢呋喃，二氯甲烷，1，4-二氧六环，N,N-二甲基甲酰胺。
其中：
G为离去基团，选自卤素，羟基，优选溴；
环A如通式(I)中所定义。
本发明提供了通式(I)化合物包括其立体异构体或药学上可接受的盐、，是磷酸二酯酶的抑制剂，用于制备药物的用途，所述药物用于预防和/或治疗其中需要抑制磷酸二酯酶的任何疾病。
有益技术效果：本发明通过对邻苯二酚类化合物的精确结构修饰，获得了几个结构新颖的代表性化合物，体外酶学水平的测活，显示了较好的生物活性，酶学活性可达10nmol以下，具有良好的研究前景。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR的测定是用Mercury-400型和BrukerAVAVCE III 500型的核磁仪，测定溶剂是氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Thermo Exactive Orbitrap pus spectrometer(ESI-MS)质谱仪。
薄层层析硅胶板使用青岛GF254硅胶板，柱层析硅胶为青岛海洋300-400目硅胶。
本发明中的已知起始原料可按照已知方法自行合成，或可从市场上购买。
实施例中无特殊说明，反应均可在氩气氛或氮气氛下进行。
氩气氛或者氮气氛是指反应瓶连接一个约1L容积左右的氩气或者氮气球。
氢气氛是指反应瓶连接一个约1L容积左右的氢气球。
实施例中无特殊说明，反应温度为室温，为20230℃。
实施例中的反应进程的监测采用薄层色谱法的展开体系包括：A：二氯甲烷和甲醇体系，B:石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节，也可加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
制备2-(环丙基甲氧基)-1-(二氟甲氧基)-4-乙烯基苯(1-a)
将甲基三苯基碘化磷(33.4g,64mmol)、叔丁醇钾(9.3g,64mmol)置于三颈瓶中，加入无水THF(100mL)，氩气保护，室温反应1小时。将4-(二氟甲氧基)-3-(环丙基甲氧基)苯甲醛(7.7g,32mmol)溶于无水THF(20mL)，通过恒压滴液漏斗缓慢滴加进入反应液。滴加完毕，接着反应3小时。减压浓缩蒸去大部分THF，加入饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯萃取三次(3×50mL)，合并有机相，饱和氯化钠水溶液洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得无色透明油(1-a)，收率92％。
1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.2Hz,1H),6.99(d,J＝2.0Hz,1H),6.96(dd,J＝8.2,2.0Hz,1H),6.65(dd,J＝12,20Hz,1H),6.62(t,J＝76.0Hz,1H),5.68(dd,J＝17.5,0.8Hz,1H),5.25(dd,J＝10.8,0.8Hz,1H),3.89(d,J＝6.9Hz,2H),1.34-1.26(m,1H),0.68-0.63(m,2H),0.38-0.34(m,2H)；HRMS(ESI):m/z for C13H15F2O2(M+H)+241.1030.
实施例2
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)-2,6-二氟苯酚(1-b)
将1-a 100mg,0.42mmol)、4-溴-2,6-二氟苯酚(105mg,0.50mmol)、N,N-二异丙基乙胺(136mg,1.05mmol)、醋酸钯(10mg,0.042mmol)、三(邻甲基苯基)磷(26mg,0.084mmol)置于25mL单口瓶，加入无水DMF(10mL)，氩气保护，80℃反应18小时。待反应液冷却至室温，加水猝灭反应，乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得白色固体(1-b)，收率65％。
Mp:139-141℃；
1H NMR(400MHz,CDCl3)δ7.14(d,J＝8.3Hz,1H),7.06-7.02(m,4H),6.86(dd,J＝24.0，16.0Hz,2H),6.64(t,J＝75.5Hz,1H),5.07(s,1H),3.92(d,J＝6.9Hz,2H),1.35-1.28(m,1H),0.69-0.65(m,2H),0.40-0.36(m,2H)；HRMS(ESI):m/z for C19H15F4O3(M-H)-367.0920.
实施例3
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,6-二氟苯酚(1)
将1-b(130mg，0.35mmol)溶于甲醇(20mL)，加入钯碳(13mg)，氢气氛下室温反应过夜。硅藻土滤去钯碳，二氯甲烷洗硅藻土层，合并有机相。中压柱层析分离得白色固体(1)，收率77％。
Mp:130-132℃；
1H NMR(400MHz,CDCl3)δ7.06(d,J＝7.9Hz,1H),6.72-6.65(m,4H),6.59(t,J＝75.9Hz,1H),4.89(s,1H),3.82(d,J＝6.9Hz,2H),2.85-2.77(m,4H),1.30-1.20(m,1H),0.66-0.61(m,2H),0.36-0.32(m,2H)；HRMS(ESI):m/z for C19H17F4O3(M-H)-369.0973.
实施例4
制备(E)-3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯甲酸乙酯(2-a)
依次向封管里加入1-a(400mg,1.7mmol)、3-溴苯甲酸乙酯(381mg,1.7mmol)、Pd2(dba)3(16mg,0.017mmol)、HP(t-Bu)3BF4(20mg,0.068mmol)、DABCO(566mg,5.1mmol)，加入无水二氧六环(15mL)，氩气置换，旋紧塞子。90℃反应36小时。待反应液冷却至室温，加入饱和碳酸氢钠水溶液(10mL)猝灭反应。乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得白色固体(2-a)，收率65％。
Mp:110-112℃；
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.94(d,J＝7.7Hz,1H),7.66(d,J＝7.8Hz,1H),7.42(t,J＝7.7Hz,1H),7.18-7.00(m,5H),6.65(t,J＝75.6Hz,1H),4.41(q,J＝7.1Hz,2H),3.93(d,J＝6.9Hz,2H),1.42(t,J＝7.1Hz,3H),1.36-1.28(m,1H),0.69-0.65(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z for C22H23F2O4(M+H)+389.1541.
实施例5
制备(E)-3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯甲酸(2-b)
将2-a(200mg,0.5mmol)溶于THF/H2O(20mL)的混合溶剂，加入氢氧化钠(42mg,1.0mmol)，60℃反应10小时。待反应液冷却至室温，滴加2M盐酸调pH至4左右。乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得白色固体(2-b)，收率54％。
Mp:215-217℃；
1H NMR(400MHz,CDCl3)δ8.26(s,1H),8.02(d,J＝7.8Hz,1H),7.74(d,J＝7.8Hz,1H),7.48(t,J＝7.7Hz,1H),7.20-7.03(m,5H),6.65(t,J＝75.5Hz,1H),3.95(d,J＝6.9Hz,2H),1.37-1.30(m,1H),0.70-0.66(m,2H),0.41-0.37(m,2H)；13C NMR(100MHz,CDCl3)δ171.80,150.71,140.26(t,J＝3Hz),137.55,135.61,131.68,129.80,129.34,129.20,129.00,128.12,127.84,122.88,119.77,116.25(t,J＝258Hz),112.27,74.03,29.75,10.22,3.27；HRMS(ESI):m/z for C20H19F2O4(M+H)+361.1245.
实施例6
制备3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯甲酸(2)
将2-b(370mg,0.95mmol)溶于乙酸乙酯(20mL)，加入钯碳(40mg),氢气氛下室温反应过夜。硅藻土滤去钯碳，乙酸乙酯(2×10mL)洗硅藻土层，合并有机相。中压柱层析分离得无色透明油(2)，收率97％.
Mp:145-147℃；
1H NMR(400MHz,CDCl3)δ8.01-7.89(m,2H),7.93(s,1H),7.38(d,J＝4.6Hz,2H),7.07(d,J＝8.1Hz,1H),6.73(d,J＝8.4Hz,1H),6.70(s,1H),6.59(t,J＝75.7Hz,1H),3.80(d,J＝6.9Hz,2H),3.0-2.89(m,4H),1.28-1.21(m,1H),0.65-0.61(m,2H),0.34-0.33(m,2H)；13C NMR(100MHz,CDCl3)δ171.74,150.31,141.82,139.94,138.79(t,J＝3Hz),134.16,130.20,129.31,128.60,128.05,122.70,121.01,116.42(t,J＝258.3Hz),114.91,77.25,73.92,37.58,37.44,10.18,3.18；HRMS(ESI):m/z for C20H21F2O4(M+H)+363.1395.
实施例7
制备(E)-2-(3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯基)乙酸甲酯(3-a)
参照2-a的合成方法，3-溴苯乙酸甲酯为原料，得白色固体(3-a)，收率54％。
Mp:132-134℃；
1H NMR(400MHz,CDCl3)δ7.45-7.39(m,2H),7.32(t,J＝7.6Hz,1H),7.19(d,J＝7.5Hz,1H),7.14(d,J＝8.2Hz,1H),7.09(d,J＝2.0Hz,1H),7.06(dd,J＝8.2,2.0Hz,1H),7.03(d,J＝3.7Hz,2H),6.64(t,J＝75.6Hz,1H),3.93(d,J＝6.9Hz,2H),3.72(s,3H),3.65(s,2H),1.36-1.28(m,1H),0.70-0.65(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z forC22H23F2O4(M+H)+389.1541.
实施例8
制备2-(3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯基)乙酸甲酯(3-b)
参照2的合成方法，以3-a为原料，得无色透明油(3-b)，收率87％。
1H NMR(400MHz,CDCl3)δ7.25-7.21(m,1H),7.14-7.09(m,1H),7.08-7.04(m,3H),6.73(dd,J＝8.1,2.0Hz,1H),6.69(d,J＝2.0Hz,1H),6.60(t,J＝76.0Hz,1H),3.80(d,J＝6.9Hz,2H),3.70(s,3H),3.59(s,2H),2.88(s,4H),1.30-1.22(m,1H),0.65-0.61(m,2H),0.36-0.32(m,2H)；HRMS(ESI):m/z for C22H24F2O4Na(M+Na)+413.1523.
实施例9
制备2-(3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯基)乙酸(3)
参照2-b的合成方法，以3-b为原料，得无色透明油(3)，收率52％。
1H NMR(400MHz,CDCl3)δ7.26-7.22(m,1H),7.15-7.10(m,1H),7.10-7.07(m,2H),7.05(d,J＝8.1Hz,1H),6.72(dd,J＝8.1,2.0Hz,1H),6.68(d,J＝2.0Hz,1H),6.59(t,J＝76.0Hz,1H),3.79(d,J＝6.9Hz,2H),3.62(s,2H),2.92-2.83(m,4H),1.28-1.22(m,1H),0.64-0.60(m,2H),0.35-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ177.75,150.23,141.84,140.37,138.67(t,J＝3Hz),133.33,129.60,128.72,127.59,127.11,122.58,121.01,116.46(t,J＝257Hz),114.88,77.26,73.86,41.02,37.75,37.55,10.19,3.17；HRMS(ESI):m/z for C21H21F2O4(M-H)-375.1340.
实施例10
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯甲酸甲酯(4-a)
参照2-a的合成方法，4-溴苯甲酸甲酯为原料，得白色固体(4-a)，收率56％。
Mp:176-178℃；
1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.18-7.01(m,5H),6.65(t,J＝75.5Hz,1H),3.94(d,J＝7.5Hz,2H),3.93(s,3H),1.37-1.27(m,1H),0.70-0.65(m,2H),0.40-0.36(m,2H)；HRMS(ESI):m/z for C21H21F2O4(M+H)+375.1396.
实施例11
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯甲酸(4-b)
参照2的合成方法，以4-a为原料，得白色固体(4-b)，收率83％。
Mp:M 300℃；
1H NMR(400MHz,CDCl3)δ8.13(d,J＝8.5Hz,2H),7.63(d,J＝8.4Hz,2H),7.26-7.18(m,2H),7.18-7.07(m,3H),6.70(t,J＝76.0Hz,1H),3.99(d,J＝6.9Hz,2H),1.40-1.35(m,1H),0.82-0.66(m,2H),0.49-0.37(m,2H)；13C NMR(100MHz,DMSO-d6)δ167.53,150.57,141.78,140.11(t,J＝3Hz),135.73,130.62,130.27,130.01,128.24,126.90,121.71,120.24,117.20(t,J＝256Hz),112.57,73.49,10.49,3.51；HRMS(ESI):m/z for C20H19F2O4(M+H)+361.1243.
实施例12
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯甲酸(4)
将4-b(280mg,0.78mmol)溶于乙酸乙酯(20mL)，加入钯碳(30mg),氢气氛下室温反应过夜。硅藻土滤去钯碳，乙酸乙酯(2×10mL)洗硅藻土层，合并有机相。中压柱层析分离得白色固体(4)，收率64％。
Mp:210-212℃；
1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.4Hz,2H),7.26-7.24(m,2H),7.06(d,J＝8.1Hz,1H),6.72(dd,J＝8.1,2.0Hz,1H),6.67(d,J＝2.0Hz,1H),6.59(t,J＝75.7Hz,1H),3.79(d,J＝6.9Hz,2H),2.98(ddd,J＝8.6,6.3,2.0Hz,2H),2.91(ddd,J＝8.6,6.2,1.9Hz,2H),1.28-1.18(m,1H),0.65-0.60(m,2H),0.35-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ171.95,171.92,171.88,150.29,147.86,139.79,138.81(t,J＝3Hz),130.41,128.76,127.17,122.68,120.98,116.38(t,J＝258Hz),114.89,77.25,73.92,37.89,37.15,10.17,3.18；HRMS(ESI):m/z for C20H21F2O4(M+H)+363.1403.
实施例13
制备(E)-2-(4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯基)乙酸乙酯(5-a)
参照2-a的合成方法，4-溴苯乙酸乙酯为原料，得白色固体(5-a)，收率50％。
Mp:116-118℃；
1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.2Hz,2H),7.28(d,J＝8.2Hz,2H),7.14(d,J＝8.1Hz,1H),7.08(d,J＝1.9Hz,1H),7.07-7.04(m,1H),7.01(s,2H),6.64(t,J＝75.6Hz,1H),4.16(q,J＝7.1Hz,2H),3.93(d,J＝6.9Hz,2H),3.62(s,2H),1.35-1.30(m,1H),1.26(t,J＝7.1Hz,3H),0.71-0.64(m,2H),0.42-0.36(m,2H)；HRMS(ESI):m/z for C23H25F2O4(M+H)+403.1710.
实施例14
制备(E)-2-(4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯基)乙酸(5-b)
参照2-b的合成方法，以5-a为原料，得白色固体(5-b)，收率95％。
Mp:104-106℃；
1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.2Hz,2H),7.28(d,J＝8.0Hz 2H),7.14(d,J＝8.1Hz,1H),7.09-7.03(m,2H),7.01(s,2H),6.63(t,J＝75.6Hz,1H),3.93(d,J＝6.9Hz,2H),3.66(s,2H),1.35-1.28(m,1H),0.72-0.62(m,2H),0.43-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ177.27,150.66,140.01(t,J＝3Hz),136.24,136.03,132.77,129.81,128.61,127.91,126.80,122.84,119.62,116.28(t,J＝260.6Hz),112.15,74.01,40.70,29.74,10.22,3.25；HRMS(ESI):m/z for C21H21F2O4(M+H)+375.1406.
实施例15
制备2-(4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯基)乙酸(5)
参照2的合成方法，以5-b为原料，得白色固体(5)，收率76％。
Mp:170-172℃；
1H NMR(400MHz,CDCl3)δ7.31(s,1H),7.24(s,1H),7.19(s,1H),7.17(s,1H),7.11(d,J＝8.1Hz,1H),6.78(dd,J＝8.1,2.0Hz,1H),6.74(d,J＝2.0Hz,1H),6.64(t,J＝75.8Hz,1H),3.85(d,J＝6.9Hz,2H),3.68(s,2H),2.95-2.89(m,4H),1.35-1.25(m,1H),0.70-0.65(m,2H),0.40-0.36(m,2H)；13C NMR(100MHz,DMSO-d6)δ210.68,210.48,210.28,177.12,155.49,146.04,145.33,143.75,137.74,134.50,133.65,127.05,125.86,122.24(t,J＝256.7Hz),119.96,78.34,45.19,42.55,42.40,15.17,7.70；HRMS(ESI):m/z forC21H23F2O4(M+H)+377.1565.
实施例16
制备3-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-N-羟基苯甲酰胺(6)
将2(200mg,0.55mmol)和CDI(90mg,0.55mmol)溶于无水DMF(10mL)，室温反应2小时，加入盐酸羟胺(77mg,1.1mmol)，室温反应过夜。加水猝灭反应，乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得白色固体(6)，收率48％。
Mp:171-173℃；
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.98(s,1H),7.64(s,1H),7.57-7.50(m,1H),7.38-7.28(m,2H),7.02(d,J＝8.1Hz,1H),6.98(d,J＝1.9Hz,1H),6.96(t,J＝76.0Hz,1H),6.78(dd,J＝8.2,1.9Hz,1H),3.82(d,J＝6.9Hz,2H),2.93-2.79(m,4H),1.24-1.12(m,1H),0.55-0.51(m,2H),0.32-0.28(m,2H)；13C NMR(100MHz,DMSO-d6)δ164.76,150.17,142.10,140.61,138.33,133.25,131.68,128.71,127.50,124.82,121.61,120.90,117.32(t,J＝258.6Hz),115.20,73.29,37.33,37.03,10.47,3.45；HRMS(ESI):m/z forC20H22F2NO4(M+H)+378.1508.
实施例17
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)苯并[b]噻吩(7-a)
参照2-a的合成方法，以4-溴苯并[b]噻吩为原料，得白色固体(7-a)，收率67％。
Mp:100-102℃；
1H NMR(400MHz,CDCl3)δ7.82(dt,J＝8.1,0.9Hz,1H),7.65(dd,J＝5.5,0.9Hz,1H),7.61(dt,J＝7.5,0.8Hz,1H),7.54(d,J＝7.9Hz,1H),7.51(d,J＝2.7Hz,1H),7.36(t,J＝7.8Hz,1H),7.20-7.12(m,4H),6.66(t,J＝75.6Hz,1H),3.96(d,J＝6.9Hz,2H),1.37-1.31(m,1H),0.70-0.66(m,2H),0.42-0.38(m,2H)；HRMS(ESI):m/z for C21H19F2O2S(M+H)+373.1065.
实施例18
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)苯并[b]噻吩(7)
参照2的合成方法，以7-a为原料，得白色固体(7)，收率64％。
Mp:60-61℃；
1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.0Hz,1H),7.43(d,J＝5.6Hz,1H),7.33(dd,J＝5.5,0.9Hz,1H),7.29-7.23(m,1H),7.26(t,J＝8Hz,1H),7.11(d,J＝8.0Hz,1H),7.07(d,J＝8.1Hz,1H),6.77(dd,J＝8.0,2.0Hz,1H),6.60(d,J＝4.0Hz,1H),6.58(t,J＝76.0Hz,1H),3.71(d,J＝6.9Hz,2H),3.26-3.19(m,1H),3.02-2.95(m,2H),1.24-1.16(m,1H),0.64-0.59(m,2H),0.33-0.29(m,2H)；13C NMR(100MHz,CDCl3)δ150.24,140.42,140.01,138.75,138.68,136.25,126.04,124.36,124.07,122.69,121.58,120.96,120.54,116.42(t,J＝260Hz),114.98,77.24,73.86,36.90,35.95,10.15,3.17；HRMS(ESI):m/z for C21H21F2O2S(M+H)+375.1219.
实施例19
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吲哚-2-酮(8-a)
参照2-a的合成方法，4-溴吲哚酮为原料，得白色固体(8-a)，收率41％。
Mp:242-244℃；
1H NMR(400MHz,CDCl3)δ7.86(brs,1H),7.25(s,1H),7.24(d,J＝1.2Hz,1H),7.17(d,J＝8.1Hz,1H),7.11-7.06(m,2H),7.03(d,J＝16.4Hz,1H),6.93(d,J＝16.3Hz,1H),6.82-7.77(m,1H),6.65(t,J＝76.0Hz,1H),3.94(d,J＝6.9Hz,2H),3.64(s,2H),1.37-1.29(m,1H),0.70-0.65(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z for C21H20F2NO3(M+H)+372.1399.
实施例20
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)二氢吲哚-2-酮(8)
参照2的合成方法，以8-a为原料，得白色固体(8)，收率80％。
1H NMR(400MHz,CDCl3)δ7.93(brs,1H),7.16(t,J＝7.8Hz,1H),7.06(d,J＝8.1Hz,1H),6.84(d,J＝7.9Hz,1H),6.74-6.68(m,2H),6.63(d,J＝2.0Hz,1H),6.58(t,J＝76.0Hz,1H),3.78(d,J＝6.9Hz,2H),3.27(s,2H),2.99-2.69(m,4H),1.29-1.19(m,1H),0.65-0.60(m,2H),0.35-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ177.06,150.33,142.18,139.96,138.85(t,J＝3Hz),137.69,128.16,124.02,122.74,122.57,120.94,116.37(t,J＝257Hz),114.87,107.54,77.25,73.92,36.10,35.01,34.85,10.16,3.20；HRMS(ESI):m/zfor C21H22F2NO3(M+H)+374.1556.
实施例21
制备(E)-5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)喹啉(9-a)
参照2-a的合成方法，以5-溴喹啉为原料，得白色固体(9-a)，收率65％。
Mp:126-128℃；
1H NMR(400MHz,CDCl3)δ8.95(dd,J＝4.2,1.6Hz,1H),8.54(d,J＝8.5Hz,1H),8.08(d,J＝8.2Hz,1H),7.78(d,J＝8.0Hz,1H),7.75-7.67(m,2H),7.46(dd,J＝8.5,4.1Hz,1H),7.20(d,J＝8.6Hz,1H),7.17(d,J＝1.9Hz,1H),7.15(s,1H),7.10(d,J＝15.9Hz,1H),6.67(t,J＝75.5Hz,1H),3.96(d,J＝6.9Hz,2H),1.38-1.30(m,1H),0.70-0.66(m,2H),0.42-0.38(m,2H)；HRMS(ESI):m/z for C22H20F2NO2(M+H)+368.1451.
实施例22
制备5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)喹啉(9)
参照2的合成方法，以9-a为原料，得白色固体(9)，收率37％。
Mp:83-85℃；
1H NMR(400MHz,CDCl3)δ8.92(dd,J＝4.2,1.6Hz,1H),8.29(d,J＝8.6Hz,1H),8.00(d,J＝8.5Hz,1H),7.62(dd,J＝8.5,7.1Hz,1H),7.40(dd,J＝8.6,4.2Hz,1H),7.32(d,J＝7.1Hz,1H),7.07(d,J＝8.1Hz,1H),6.75(dd,J＝8.0,4.0Hz,1H),6.58(d,J＝2.1Hz,1H),6.58(t,J＝76.0Hz,1H),3.71(d,J＝6.8Hz,2H),3.39-3.31(m,2H),3.03-2.96(m,2H),1.22-1.16(m,1H),0.64-0.59(m,2H),0.33-0.29(m,2H)；13C NMR(100MHz,CDCl3)δ150.32,149.93,148.64,140.04,137.82,132.03,129.20,128.19,126.90,126.71,122.80,120.95,120.79,116.34(t,J＝260Hz),114.95,77.24,73.90,37.06,34.12,10.13,3.17；HRMS(ESI):m/z for C22H22F2NO2(M+H)+370.1614.
实施例23
制备5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-1,2,3,4-四氢喹啉(10)
参照2的合成方法，以9为原料，得白色固体(10)，收率44％。
Mp:124-126℃；
1H NMR(400MHz,CDCl3)δ7.07(d,J＝8.1Hz,1H),6.92(t,J＝7.7Hz,1H),6.76(d,J＝8.1Hz,1H),6.70(s,1H),6.59(t,J＝76.0Hz,1H),6.51(d,J＝7.4Hz,1H),6.37(d,J＝7.9Hz,1H),3.82(d,J＝6.9Hz,2H),3.25(t,J＝5.5Hz,2H),2.85-2.74(m,4H),2.63(t,J＝6.5Hz,2H),1.96-1.90(m,2H),1.31-1.21(m,1H),0.66-0.61(m,2H),0.37-0.33(m,2H)；13CNMR(100MHz,CDCl3)δ150.30,145.11,141.05,140.33,126.56,122.69,121.00,119.63,117.96,116.50,114.94,112.75,73.94,41.63,36.57,34.76,23.72,22.48,10.27,3.23；HRMS(ESI):m/z for C22H26F2NO2(M+H)+374.1925.
实施例24
制备(E)-7-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)-2,3-二氢-1H-茚-1-酮(11-a)
参照2-a的合成方法，以7-溴1-茚酮为原料，得白色固体(11-a)，收率66％。
Mp:149-151℃；
1H NMR(400MHz,CDCl3)δ8.39(d,J＝16.4Hz,1H),7.66(d,J＝7.7Hz,1H),7.53(t,J＝7.6Hz,1H),7.35(d,J＝7.5Hz,1H),7.21(d,J＝1.9Hz,1H),7.19-7.10(m,3H),6.65(t,J＝75.6Hz,1H),3.96(d,J＝6.9Hz,2H),3.26-2.99(m,2H),2.84-2.52(m,2H),1.37-1.27(m,1H),0.69-0.64(m,2H),0.41-0.38(m,2H)；HRMS(ESI):m/z for C22H21F2O3(M+H)+371.1445.
实施例25
制备7-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,3-二氢-1H-茚-1-酮(11)
参照2的合成方法，以11-a为原料，得白色固体(11)，收率80％。
Mp:82-84℃；
1H NMR(400MHz,CDCl3)δ7.44(t,J＝7.5Hz,1H),7.32(d,J＝7.7Hz,1H),7.05(d,J＝8.3Hz,2H),6.89(d,J＝2.0Hz,1H),6.80(dd,J＝8.1,2.0Hz,1H),6.59(t,J＝76.0Hz,1H),3.87(d,J＝6.9Hz,2H),3.33-3.26(m,2H),3.15-3.08(m,2H),2.86-2.79(m,2H),2.72-2.66(m,2H),1.32-1.24(m,1H),0.66-0.61(m,2H),0.38-0.34(m,2H).13C NMR(100MHz,CDCl3)δ207.66,156.45,150.26,142.36,140.84,138.62,138.58,134.15,128.46,124.65,122.47,121.15,116.50(t,J＝259.6Hz),114.91,77.25,73.79,37.15,36.88,34.20,25.49,10.24,3.17；HRMS(ESI):m/z for C22H23F2O3(M+H)+373.1595.
实施例26
制备7-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2-羟基-2,3-二氢-1H-茚-1-酮(12)
将11(100mg,0.27mmol)溶于甲醇(20mL)，加入KOH(165mg,3.0mmol)，0℃反应10分钟。加入PhI(OAc)2(104mg,0.32mmol)，0℃反应1小时，然后室温反应0.5小时。减压浓缩蒸干溶剂，残留物溶于乙酸乙酯(20mL)，饱和碳酸氢钠水溶液(20mL)洗有机相，减压浓缩蒸干乙酸乙酯。残留物溶于四氢呋喃(10mL)，加入6M盐酸(1mL)，室温反应0.5小时。饱和碳酸氢钠水溶液猝灭反应，乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得白色固体(12)，收率48％。
Mp:124-126℃；
1H NMR(400MHz,CDCl3)δ7.50(t,J＝7.5Hz,1H),7.30(d,J＝7.6Hz,1H),7.11(d,J＝7.5Hz,1H),7.05(d,J＝8.1Hz,1H),6.84(d,J＝2.0Hz,1H),6.77(d,J＝7.0Hz,1H),6.59(t,J＝76.0Hz,1H),4.46(dd,J＝8.0,5.3Hz,1H),3.86(d,J＝6.9Hz,2H),3.54(dd,J＝16.4,8.0Hz,1H),3.27(t,J＝8.0Hz,2H),2.98(dd,J＝16.4,5.3Hz,1H),2.94-2.85(m,2H),2.78(dt,J＝13.4,8.3Hz,1H),1.32-1.22(m,1H),0.66-0.61(m,2H),0.38-0.34(m,2H)；13CNMR(100MHz,CDCl3)δ206.71,151.58,150.30,142.83,140.39,135.35,131.23,129.00,124.65,122.55,121.12,116.44(t,J＝259.6Hz),114.92,77.24,74.50,73.84,37.10,34.95,34.11,10.23,3.19；HRMS(ESI):m/z for C22H23F2O4(M+H)+389.1552.
实施例27
制备(E)-6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)-2,3-二氢-1H-茚-1-酮(13-a)
参照2-a的合成方法，以6-溴1-茚酮为原料，得白色固体(13-a)，收率69％。
Mp:150-152℃；
1H NMR(400MHz,CDCl3)δ7.88(d,J＝1.7Hz,1H),7.71(dd,J＝8.0,1.8Hz,1H),7.47(d,J＝7.9Hz,1H),7.15(d,J＝8.1Hz,1H),7.13-7.02(m,4H),6.64(t,J＝75.6Hz,1H),3.94(d,J＝6.9Hz,2H),3.23-3.11(m,2H),2.78-2.68(m,2H),1.37-1.27(m,1H),0.70-0.65(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z for C22H21F2O3(M+H)+371.1445.
实施例28
制备6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,3-二氢-1H-茚-1-酮(13)
参照2的合成方法，以13-a为原料，得白色固体(13)，收率77％。
Mp:88-90℃；
1H NMR(400MHz,CDCl3)δ7.59(d,J＝1.6Hz,1H),7.39-7.34(m,2H),7.05(d,J＝8.6Hz,1H),6.73-6.69(m,2H),6.50(t,J＝76.0Hz,1H),3.81(d,J＝6.9Hz,2H),2.99-2.93(m,2H),2.91-2.85(m,2H),2.74-2.67(m,2H),1.28-1.22(m,1H),0.65-0.60(m,2H),0.35-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ207.13,153.19,150.33,140.78,139.95,138.79,137.40,135.39,126.56,123.13,122.66,120.99,116.41(t,J＝259.6Hz),114.89,73.93,37.51,37.37,36.60,25.52,10.19,3.18；HRMS(ESI):m/zfor C22H23F2O3(M+H)+373.1604.
实施例29
制备6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2-羟基-2,3-二氢-1H-茚-1-酮(14)
参照12的合成方法，以13为原料，得白色固体(14)，收率70％。
Mp:94-96℃；
1H NMR(400MHz,CDCl3)δ7.58(d,J＝1.7Hz,1H),7.45-7.33(m,2H),7.05(d,J＝8.6Hz,1H),6.70(d,J＝5.5Hz,2H),6.58(t,J＝76.0Hz,1H),4.56-4.50(m,1H),3.80(d,J＝6.9Hz,2H),3.54(dd,J＝16.4,7.7Hz,1H),3.03-2.83(m,6H),1.29-1.19(m,1H),0.65-0.61(m,2H),0.35-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ206.28,150.36,148.85,141.62,139.75,138.83,136.63,134.24,126.70,123.84,122.70,120.99,116.38(t,J＝257Hz),114.88,74.59,73.95,37.41,37.37,34.88,10.19,3.18；HRMS(ESI):m/z for C22H23F2O4(M+H)+389.1550.
实施例30
制备(E)-5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)-2,3-二氢-1H-茚-1-酮(15-a)
参照2-a的合成方法，以5-溴-1-茚酮为原料，得白色固体(15-a)，收率60％。
Mp:166-168℃；
1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.0Hz,1H),7.57(s,1H),7.51(d,J＝8.1Hz,1H),7.21-7.15(m,2H),7.12-7.04(m,3H),6.65(t,J＝75.4Hz,1H),3.94(d,J＝6.9Hz,2H),3.32-2.99(m,2H),2.96-2.55(m,2H),1.37-1.20(m,1H),0.70-0.65(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z for C22H21F2O3(M+H)+371.1447.
实施例31
制备5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,3-二氢-1H-茚-1-酮(15)
参照2的合成方法，以15-a为原料，得白色固体(15)，收率85％。
Mp:94-96℃；
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.8Hz,1H),7.23(s,1H),7.18(d,J＝7.9Hz,1H),7.06(d,J＝8.0Hz,1H),6.75-6.67(m,2H),6.59(t,J＝76.0Hz,1H),3.80(d,J＝6.9Hz,2H),3.13-3.06(m,2H),2.98(ddd,J＝8.8,6.3,2.0Hz,2H),2.90(ddd,J＝8.6,6.3,1.9Hz,2H),2.74-2.65(m,2H),1.28-1.20(m,1H),0.65-0.60(m,2H),0.34-0.30(m,2H)；13C NMR(100MHz,CDCl3)δ206.54,155.73,150.36,148.95,139.80,138.81,135.44,128.03,126.60,123.76,122.71,120.98,116.34(t,J＝257Hz),114.86,73.94,38.21,37.32,36.42,25.72,10.18,3.18；HRMS(ESI):m/z for C22H23F2O3(M+H)+373.1605.
实施例32
制备5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2-羟基-2,3-二氢-1H-茚-1-酮(16)
参照13-a的合成方法，以15为原料，得白色固体(16)，收率77％。
Mp:166-168℃；
1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.8Hz,1H),7.22(s,1H),7.20(d,J＝8.3Hz,1H),7.07(d,J＝8.0Hz,1H),6.74-6.67(m,2H),6.59(t,J＝76.0Hz,1H),4.52(dd,J＝7.8,4.8Hz,1H),3.80(d,J＝6.9Hz,2H),3.52(dd,J＝16.5,7.7Hz,1H),3.11-2.73(m,6H),1.28-1.18(m,1H),0.65-0.60(m,2H),0.34-0.31(m,2H)；13C NMR(100MHz,CDCl3)δ205.68,151.40,150.46,150.39,139.60,138.85,132.22,128.78,126.70,124.50,122.75,120.96,116.31(t,J＝259.6Hz),114.83,77.24,74.38,73.95,38.33,37.21,35.09,10.18,3.19；HRMS(ESI):m/z for C22H23F2O4(M+H)+389.1553.
实施例33
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,3-二氢-1H-茚-1-酮(17-a)
参照2-a的合成方法，以4-溴1-茚酮为原料，得白色固体(17-a)，收率65％。
Mp:150-152℃；
1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.6Hz,1H),7.70(d,J＝7.5Hz,1H),7.42(t,J＝7.6Hz,1H),7.20-7.07(m,5H),6.66(t,J＝75.5Hz,1H),3.95(d,J＝6.9Hz,2H),3.41-3.12(m,2H),2.89-2.52(m,2H),1.37-1.29(m,1H),0.70-0.66(m,2H),0.41-0.37(m,2H)；HRMS(ESI):m/z for C22H21F2O3(M+H)+371.1450.
实施例34
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2,3-二氢-1H-茚-1-酮(17)
参照2的合成方法，以17-a为原料，得白色固体(17)，收率86％。
Mp:98-100℃；
1H NMR(400MHz,CDCl3)δ7.63(d,J＝7.4Hz,1H),7.37(d,J＝7.3Hz,1H),7.32(t,J＝7.4Hz,1H),7.07(d,J＝8.1Hz,1H),6.71(d,J＝8.1Hz,1H),6.62(d,J＝1.9Hz,1H),6.59(t,J＝76.0Hz,1H),3.75(d,J＝6.9Hz,2H),3.02-2.83(m,6H),2.70-2.61(m,2H),1.25-1.17(m,1H),0.64-0.59(m,2H),0.33-0.30(m,2H)；13C NMR(100MHz,CDCl3)δ207.17,153.76,150.34,139.87,139.13,138.83,138.79,137.12,134.34,127.73,122.82,121.67,120.99,116.27(t,J＝259.6Hz),114.92,73.92,36.24,36.15,33.86,24.32,10.15,3.18；HRMS(ESI):m/z for C22H23F2O3(M+H)+373.1607.
实施例35
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)-2-羟基-2,3-二氢-1H-茚-1-酮(18)
参照12的合成方法，以17为原料，得白色固体(18)，收率67％。
Mp:128-130℃；
1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.4Hz,1H),7.42(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.07(d,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.9Hz,1H),6.60(d,J＝1.9Hz,1H),6.58(t,J＝76.0Hz,1H),4.46(d,J＝6.7Hz,1H),3.75(d,J＝6.9Hz,2H),3.37(dd,J＝16.4,7.5Hz,1H),3.00-2.91(m,2H),2.87(dt,J＝12.7,4.8Hz,3H),2.76-2.66(m,1H),1.25-1.17(m,1H),0.65-0.60(m,2H),0.34-0.30(m,2H)；13C NMR(100MHz,CDCl3)δ206.41,150.39,149.54,139.60,139.29,138.87,135.76,134.01,128.38,122.86,122.37,120.99,116.34(t,J＝260.6Hz),114.82,77.25,74.15,73.92,36.34,34.04,33.47,10.15,3.21；HRMS(ESI):m/z for C22H23F2O4(M+H)+389.1561.
实施例36
制备(E)-6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吡啶甲酸乙酯(19-a)
参照2-a的合成方法，以6-溴吡啶甲酸乙酯为原料，得无色透明油(19-a)，收率20％。
1H NMR(400MHz,CDCl3)δ7.98-7.94(m,1H),7.83-7.77(m,1H),7.66-7.61(m,1H),7.53(dd,J＝16.3,2.2Hz,1H),7.25–7.18(m,2H),7.17–7.08(m,2H),6.65(t,J＝75.5,1H),4.54-4.44(m,2H),3.95-3.87(m,2H),1.45(t,J＝7.1,2.4Hz,3H),1.35-1.24(m,1H),0.73-0.59(m,2H),0.39-0.37(m,2H)；13C NMR(101MHz,CDCl3)δ164.76,155.85,150.72,147.66,138.00,134.82,133.79,127.46,124.16,123.53,122.75,120.83,116.16,112.38,74.01,62.28,14.37,10.17,3.28；HRMS(ESI):m/z for C21H22F2NO4(M+H)+390.1531.
实施例37
制备6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶甲酸乙酯(19-b)
参照2的合成方法，以19-a为原料，得无色透明油(19-b)，收率82.43％。
1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.0Hz,1H),7.72-7.67(m,1H),7.23(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,1H),6.82-6.36(m,3H),4.48(q,J＝7.1Hz,2H),3.80(d,J＝8.0Hz,2H),3.29-2.95(m,4H),1.47-1.41(m,3H),1.27-1.23(m,1H),0.63-0.61(m,2H),0.34-0.32(m,2H)；13C NMR(101MHz,CDCl3)δ165.30,161.48,150.30,147.96,140.01,137.26,126.38,122.85,122.60,120.98,116.40,114.83,73.83,61.96,39.80,35.52,14.36,10.18,3.17；HRMS(ESI):m/z for C21H24F2NO4(M+H)+392.1681
实施例38
制备6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶甲酸(19)
参照2-b的合成方法，以19-b为原料，得白色固体(19)，收率71.81％。
Mp:55-60℃；
1H NMR(400MHz,CDCl3)δ8.07(dd,J＝7.7,1.0Hz,1H),7.84(t,J＝7.7Hz,1H),7.35(dd,J＝7.8,1.1Hz,1H),7.06(d,J＝8.7Hz,1H),6.73-6.71(m,2H),6.58(t,J＝75.5Hz,1H),3.81(d,J＝6.9Hz,2H),3.25-2.98(m,4H),1.28-1.23(m,1H),0.64-0.62(m,2H),0.46-0.27(m,2H)；13C NMR(101MHz,CDCl3)δ164.18,160.11,150.47,145.56,139.38,138.78,127.59,122.81,121.37,120.86,116.32,114.71,73.94,39.01,35.09,10.18,3.19；HRMS(ESI):m/z for C19H20F2NO4(M+H)+364.1362.
实施例39
制备(E)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吡啶甲酸甲酯(20-a)
在38ml封管中依次加入1-a(360mg,1.5mmol),4-溴吡啶甲酸甲酯(271mg,1.25mmol),醋酸钯(3mg,0.0125mmol),三(邻甲苯基膦)(16mg,0.05mmol),3ml三乙胺，氩气置换，旋紧塞子。100℃反应12小时。待反应液冷却至室温，加入纯净水(10mL)猝灭反应。乙酸乙酯萃取三次(3×20mL)，合并有机相，饱和氯化钠水溶液(20mL)洗有机相一次，分出有机相，无水硫酸钠干燥。中压柱层析分离得淡黄色固体(20-a)，收率6.57％。
Mp:179-181℃；
1H NMR(400MHz,CDCl3)δ8.71(d,J＝5.1Hz,1H),8.24(d,J＝1.7Hz,1H),7.56-7.48(m,1H),7.34(d,J＝16.2Hz,1H),7.18(d,J＝8.7Hz,1H),7.19-7.11(m,2H),6.99(d,J＝16.0Hz,1H),6.65(t,J＝75.5Hz,1H),4.04(s,3H),3.93(d,J＝6.9Hz,2H),1.40-1.25(m,1H),0.72-0.63(m,2H),0.47-0.33(m,2H)；13C NMR(101MHz,CDCl3)δ165.17,156.46,150.85,150.08,139.09,123.32,122.79,120.65,61.96,14.31,14.23,10.14,3.30；HRMS(ESI):m/z for C20H20F2NO4(M+H)+376.1345
实施例40
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶甲酸甲酯(20-b)
参照2的合成方法，以20-a为原料，得无色透明油(20-b)，收率92.31％。
1H NMR(400MHz,CDCl3)δ8.59(dd,J＝4.9,0.8Hz,1H),7.94(d,J＝1.7Hz,1H),7.21(dd,J＝4.9,1.7Hz,1H),7.05(d,J＝7.9Hz,1H),6.78-6.37(m,2H),6.57(t,J＝75.5Hz,1H),3.99(s,3H),3.78(d,J＝6.9Hz,2H),3.03-2.80(m,4H),1.30-1.17(m,1H),0.62-0.60(m,2H),0.32-0.31(m,2H)；13C NMR(101MHz,CDCl3)δ165.19,156.54,150.11,139.04,130.95,128.87,123.30,122.79,120.86,120.61,114.79,73.91,61.95,35.51,29.73,19.22,14.31,10.18,3.19；HRMS(ESI):m/z for C20H22F2NO4(M+H)+378.1510.
实施例41
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶甲酸(20)
参照2-b的合成方法，以20-b为原料，得白色固体(20)，收率39.60％。
Mp:123-126℃；
1H NMR(500MHz,CDCl3)δ8.55(s,1H),8.10(s,1H),7.34(s,1H),7.07(d,J＝8.4Hz,1H),6.70-6.69(m,2H),6.59(t,J＝75.5Hz,1H),3.82(d,J＝6.9Hz,2H),3.17-2.81(m,4H),1.33-1.19(m,1H),0.75-0.56(m,2H),0.36-0.33(m,2H)；13C NMR(101MHz,CDCl3)δ164.18,153.89,150.55,147.73,146.16,138.62,128.13,123.98,122.91,120.86,116.29,114.71,73.98,37.08,36.04,10.17,3.21；HRMS(ESI):m/z for C19H20F2NO4(M+H)+364.1340.
实施例42
制备(E)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)异烟酸乙酯(21-a)
参照20-a的合成方法，以2-溴异烟酸甲酯为原料，得无色透明油(21-a)，收率3.42％。
1H NMR(400MHz,CDCl3)δ8.72(dd,J＝5.1,0.9Hz,1H),7.94(s,1H),7.79-7.52(m,2H),7.20-7.07(m,4H),6.64(t,J＝75.5Hz,1H),4.44(dd,J＝8.9,7.1Hz,2H),3.92(d,J＝6.9Hz,2H),1.45-1.41(m,3H),1.36-1.24(m,1H),0.73-0.59(m,2H),0.42-0.22(m,2H)；13CNMR(101MHz,CDCl3)δ167.75,132.34,130.94,128.87,65.60,62.27,58.53,30.60,29.73,19.22,18.48,14.30,13.76,3.34.HRMS(ESI):m/z for C21H22F2NO4(M+H)+390.1510.
实施例43
制备(E)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)异烟酸乙酯(21-b)
参照20-b的合成方法，以21-a为原料，得无色透明油(21-b)，收率70％。
1H NMR(400MHz,CDCl3)δ8.70(d,J＝5.1Hz,1H),7.81-7.60(m,2H),7.15-6.31(m,4H),4.40(d,J＝7.1Hz,2H),3.81(d,J＝6.9Hz,2H),3.22-2.95(m,4H),1.40(t,J＝7.2Hz,3H),0.9-0.85(m,1H),0.67-0.58(m,2H),0.34-0.32(m,2H)；13C NMR(101MHz,CDCl3)δ165.57,152.18,150.49,149.48,147.57,138.87,127.30,125.47,122.88,120.90,114.75,73.95,53.06,37.03,36.18,10.17,3.19,1.05；HRMS(ESI):m/z for C21H24F2NO4(M+H)+392.1656.
实施例44
制备(E)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)异烟酸(21)
参照20的合成方法，以21-b为原料，得白色固体(21)，收率53.88％。
Mp:260-262℃；
1H NMR(400MHz,CDCl3)δ8.77(d,J＝5.1Hz,1H),7.80(d,J＝5.1Hz,1H),7.74(s,1H),7.04(d,J＝8.1Hz,1H),6.78-6.71(m,2H),6.56(t,J＝75.5Hz,1H),3.80(d,J＝6.9Hz,2H),3.21(t,J＝9.4,6.4Hz,2H),3.05(t,J＝9.4,6.4Hz,2H),0.88-0.85(m,1H),0.70-0.55(m,2H),0.41-0.27(m,2H)；13C NMR(101MHz,CDCl3)δ164.18,153.89,150.55,147.73,146.16,138.62,128.13,123.98,122.91,120.86,116.29,114.71,73.98,37.08,36.04,10.17,3.21；HRMS(ESI):m/z for C19H20F2NO4(M+H)+364.1340.
实施例45
制备(E)-5-(3-(环丙基甲氧基)-4-(2,2-二氟乙基)苯乙烯基)烟酸甲酸(22-a)
参照20-a的合成方法，以5-溴烟酸甲酯为原料，得白色固体(22-a)，收率5.34％。
Mp:138-140℃；
1H NMR(400MHz,Methanol-d4)δ9.0(s,1H),8.94(s,1H),8.74(s,1H),7.49-7.10(m,5H),6.77(t,J＝75.5Hz,1H),3.96(d,J＝6.8Hz,2H),1.35-1.25(m,1H),0.66-0.60(m,2H),0.4-0.36(m,2H)；13C NMR(101MHz,CDCl3)δ164.77,150.76,136.12,126.21,122.96,120.22,119.98,116.03,114.59,112.49,74.20,52.94,52.82,46.35,44.50,10.18,10.05,3.29,3.21；HRMS(ESI):m/z for C19H18F2NO4(M+H)+360.0757.
实施例46
制备(E)-5-(3-(环丙基甲氧基)-4-(2,2-二氟乙基)苯乙基)烟酸甲酸(22)
参照20-b的合成方法，以22-a为原料，得白色固体(22)，收率25％。
Mp:149-153℃；
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.66(s,1H),8.24(s,1H),7.08(d,J＝7.9Hz,1H),6.71-6.73(m,2H),6.59(t,J＝75.5Hz,1H),3.82(d,J＝7.0Hz,2H),3.10-2.84(m,4H),1.25(m,1H),0.71-0.50(m,2H),0.35-0.33(m,2H)；13C NMR(101MHz,CDCl3)δ167.89,151.78,150.50,147.77,139.05,138.98,138.64,137.27,122.87,121.00,116.42,114.85,73.96,36.93,34.68,10.18,3.19；HRMS(ESI):m/z for C19H20F2NO4(M+H)+364.1351.
实施例47
制备(E)-6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吡嗪-2-羧酸甲酯(23-a)
参照20-a的合成方法，以6-溴吡嗪-2-羧酸甲酯为原料，得无色透明油(23-a)，收率10.64％。
1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.92(s,1H),7.76(d,J＝16.2Hz,1H),7.27-7.18(m,4H),6.72(t,J＝75.5Hz,1H),4.11(s,3H),3.98(d,J＝6.9Hz,2H),1.45-1.31(m,1H),0.87-0.64(m,2H),0.45-0.41(m,2H)；13C NMR(101MHz,CDCl3)δ164.66,150.91,150.76,145.75,143.77,142.64,141.22,135.67,134.28,124.07,122.85,120.82,116.08,112.65,74.05,53.23,10.15,3.29；HRMS(ESI):m/z for C19H19F2N2O4(M+H)+377.1297.
实施例48
制备(E)-6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡嗪-2-羧酸甲酯(23-b)
将23-a(100mg,0.27mmol)溶于THF/H20为6:1(10mL)，加入钯碳(10mg),氢气氛下室温反应过夜。硅藻土滤去钯碳，乙酸乙酯(2×10mL)洗硅藻土层，合并有机相。中压柱层析分离得无色透明油(23-b)，收率30％.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.57(s,1H),7.10(d,J＝8.1Hz,1H),6.88-6.38(m,3H),4.09(s,3H),3.85(d,J＝6.9Hz,2H),3.32-3.04(m,4H),1.34-1.21(m,1H),0.74-0.57(m,2H),0.44-0.29(m,2H)；13C NMR(101MHz,CDCl3)δ164.70,156.35,150.47,147.54,143.76,142.59,139.11,122.80,120.93,116.32,114.76,73.90,53.19,37.05,35.09,10.17,3.19；HRMS(ESI):m/z for C19H21F2N2O4(M+H)+379.1453.
实施例49
制备(E)-6-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡嗪-2-羧酸甲酸(23)
参照20的合成方法，以23-b为原料，得白色固体(23)，收率93.33％。
Mp:99-102℃；
1H NMR(400MHz,CDCl3)δ9.28(s,1H),8.67(s,1H),7.18-6.32(m,4H),3.83(d,J＝6.9Hz,2H),3.28-3.01(m,4H),1.28-1.24(m,1H),0.72-0.61(m,2H),0.35-0.34(m,2H)；13CNMR(101MHz,CDCl3)δ163.21,155.18,150.65,148.75,143.24,140.19,138.57,122.99,120.83,116.25,114.66,74.00,36.45,34.73,30.35,10.18,3.21,1.05；HRMS(ESI):m/zfor C18H19F2N2O4(M+H)+365.1297.
实施例50
制备(E)-2-(苄氧基)-4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吡啶(24-a)
参照2-a的合成方法，以2-(苄氧基)-4-溴吡啶为原料，得淡黄色油状物(24-a)，收率为34.1％。
1H NMR(500MHz,Chloroform-d)δ8.19(d,J＝5.4Hz,1H),7.52(d,J＝7.0Hz,2H),7.38-7.36(m,2H),7.25-7.17(m,2H),7.15-7.08(m,2H),7.05(dd,J＝5.4,1.5Hz,1H),6.97-6.88(m,2H),6.70(t,J＝75.4Hz,1H),5.46(s,2H),3.97(d,J＝6.9Hz,2H),1.39-1.32(m,1H),0.77-0.65(m,2H),0.45-0.42(m,2H).13C NMR(125MHz,Chloroform-d)δ164.54,150.77,147.31,147.11,137.46,135.00,132.02,128.53,127.97,127.88,126.59,122.86,120.24,116.23,114.49,112.66,108.51,74.09,67.76,10.24,3.29.HRMS(ESI):m/z calcdfor C25H24F2NO3(M+H)+424.1735.
实施例51
制备4-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶-2-醇(24)
在50ml圆底烧瓶中依次加入24-a(60mg,0.14mmol)溶于甲醇(10mL)，加入钯碳(12mg),4滴甲酸，氢气氛下回流反应5小时。硅藻土滤去钯碳，乙酸乙酯(2×10mL)洗硅藻土层，合并有机相。中压柱层析分离得无色透明油(24)，收率25.26％.
1H NMR(500MHz,Chloroform-d)δ7.33-7.30(m,1H),7.10(d,J＝7.3Hz,1H),6.77-6.66(m,5H),3.88-3.86(m,2H),2.99-2.75(m,4H),1.36-1.23(m,1H),0.75-0.57(m,2H),0.38-0.36(m,2H).13C NMR(100MHz,Chloroform-d)δ165.51,156.59,150.44,139.22,134.00,122.77,120.89,118.25,116.36,114.71,108.64,73.94,37.29,35.28,10.19,3.19.HRMS(ESI):m/z calcd for C18H20F2NO3(M+H)+336.1401.
实施例52
制备(E)-2-(苄氧基)-5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙烯基)吡啶(25-a)
参照2-a的合成方法，以2-(苄氧基)-5-溴吡啶为原料，得无色油状物(25-a)，收率为28.41％。
1H NMR(500MHz,Chloroform-d)δ8.29(s,1H),7.86(dd,J＝8.7,2.4Hz,1H),7.51(d,J＝7.5Hz,2H),7.45-7.40(m,2H),7.38-7.35(m,1H),7.18(d,J＝8.2Hz,1H),7.13-7.06(m,2H),6.98(s,2H),6.89(d,J＝8.7Hz,1H),6.67(t,J＝75.6Hz,1H),5.47(s,2H),3.97(d,J＝6.9Hz,2H),1.42-1.29(m,1H),0.77-0.61(m,2H),0.44-0.41(m,2H).13C NMR(101MHz,Chloroform-d)δ162.76,150.23,145.37,139.51,136.72,135.46,135.05,128.05,127.53,127.47,126.61,126.11,124.74,122.34,118.99,115.87,111.50,111.05,73.48,67.44,9.75,2.77.HRMS(ESI):m/z calcd for C25H24F2NO3(M+H)+424.1720.
实施例53
制备5-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯乙基)吡啶-2-醇(25)
参照24的合成方法，以25-a为原料，得无色油状物(25)，收率为12.63％。
1H NMR(500MHz,Chloroform-d)δ7.40-7.34(m,1H),7.23-7.17(m,1H),7.10-7.09(m,1H),6.80-6.45(m,4H),3.86(d,J＝6.9Hz,2H),2.89-2.64(m,4H),1.31-1.26(m,1H),0.74-0.59(m,2H),0.39-0.36(m,2H).13C NMR(101MHz,Chloroform-d)δ164.17,150.43,143.68,139.23,132.61,122.76,120.98,120.40,119.65,118.94,116.36,114.82,73.94,36.68,33.35,10.19,3.20.HRMS(ESI):m/z calcd for C18H20F2NO3(M+H)+336.1401.
药理实验
测定酶学水平PDE4B1抑制活性
酶学水平的测试采用荧光偏振的方法，利用PDE4B1检测试剂盒(BPS公司)对所合成的化合物进行酶学水平活性评价。
实验步骤：
1.用PDE assay buffer将20μΜFAM-Cyclic-3′,5′-AMP稀释100倍至200nM，未使用完的原液请分装储存在-20℃；
2、将1M DTT按照1：500加入到200nM FAM-Cyclic-3′,5′-AMP稀释液中；
3、取25μL/孔FAM-Cyclic-3′,5′-AMP稀释液加入到测试板中，除了空白对照孔(Blank)；
4、加入45μL/孔PDE assay buffer到空白对照孔(Blank)中；加入20μL/孔PDEassay buffer到Substrate control孔中；
5、取5μL/孔化合物工作液到测试板相应的孔中；阳性对照孔(Positivecontrol)，Substrate control孔，空白对照(Blank)孔加入5μL/孔PDE assay buffer(10％DMSO)；
6、PDE4B1酶需要事先在冰上解冻，将完全解冻的酶用PDE assay buffer稀释到1pg/μL，取20μL/孔酶溶液加入到化合物孔和阳性对照孔(Positive control)中。未使用完的酶原液需要分装保存在-80℃
7、室温孵育1小时，此时化合物浓度为10μM，DMSO为1％；
8、用Binding Agent Diluent(cAMP)将Binding Agent按照1：100稀释备用；
9、结束孵育后，取100μL/孔Binding Agent稀释液加入到测试板中，室温，慢速振荡孵育30分钟；
10、结束孵育后，使用Envision进行FP检测，Excitation 480nm，Emission535nm；
11、计算化合物IC50
表1-代表性化合物的酶学水平数据：
。
测定细胞水平TNF-α释放抑制活性
采用基于电化学发光技术的Meso Scale Discovery(MSD)方法，评价化合物对LPS诱导的PBMC释放TNF-α的抑制活性。
实验步骤：
第一天：解冻PBMC
解冻PBMC，在37℃、5％CO2的培养箱中孵育。
第二天：接种细胞并添加测试化合物和LPS
1、以每孔2×105个细胞、100μL培养基的密度接种细胞；
2、对于待测化合物，最终测试浓度为:10000,3333,1111,370.33,123.44,41.15,13.72,4.57,1.52nM；
3、对于罗氟司特，最终测试浓度为:3000,1000,333.33,111.11,37.04,12.35,4.12,1.37,0.46nM；
4、向每个孔中添加LPS(终浓度为10ng/mL)；
5、将细胞在37℃、5％CO2培养箱中培养24小时。
第三天：人TNF-α检测
1、收集100μL/well的细胞上清液；
2、向每孔中添加50μL标准品或者样品，用粘性板密封，室温下摇动孵育2小时；
3、洗板3次；
4、每孔添加25μL/well的1X检测抗体溶液，用粘性板密封，并在室温下摇动孵育2小时；
5、洗板3次；
6每孔添加150μL/well的2X reader缓冲液，在MSD上读取数据。数据分析：
使用HC和LC进行测定稳健性检查：
HC:高对照组的平均信号值(Wells with LPS 10ng/mL and 0.1％DMSO)
LC:低对照组的平均信号值(3μM Roflumilast)
％inhibition
＝(SignalAve_HC-Signalcmpd)/(SignalAve_HC-SignalAve_LC)×100使用GraphPad Prism 8软件计算并绘制化合物的剂量效应图
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:Log of cpd concentration
Y:％inhibition
Top and Bottom:Plateaus in same units as Y
logIC50:same log units as X
HillSlope:Slope factor or Hill slope
表2-代表性化合物的细胞水平数据：
测定体外肝微粒体稳定性实验
实验步骤：
1.在238.5μL肝微粒体中加入1.5μL对照品/待测化合物工作溶液，轻轻混匀。
2. 37℃预孵育5分钟，加入60μL NADPH工作溶液开始反应。上下吹打混匀。在每个时间点：0min和30min，将50μL反应混合物移至300μL淬火溶液中。
3.对于没有NADPH的样品，加入60μL缓冲液。上下吹打混匀。在每个时间点：0min和30min，将50μL反应混合物移至300μL淬火溶液中。
4.剧烈涡旋约1分钟。在4℃下以4,000rpm的转速离心15分钟。
5.取出100μL的上清液并与100μL蒸馏水混合，用于LC-MS/MS分析。
表3-代表性化合物的肝微粒体稳定性数据：
(*：在30分钟的样品中未检测到峰，并且基于信号响应和噪声响应，相应的剩余量小于10％，因此报告了截止值。)。

Claims (11)

1.通式(I)所示的化合物、其立体异构体或药学上可接受的盐：
其中：
环A选自苯环、吡啶、哒嗪、嘧啶或吡嗪环，独立地任意地被R1取代；
每个R1相同或不同，各自独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；
或者当环A为苯环且被两个R1取代时，两个R1相邻，相邻的两个R1和与它们相连的苯环上的两个碳原子共同形成一个5-6元碳环、杂环、环酮基和杂环酮基，两个R1可独立地任意地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；上述所述的杂环和杂环酮基中，杂原子为独立地任意地选自N，O，S，杂原子数为1或2；
上述所述R2选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；
R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；
R5选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；y选自0，1，2或3；
n选自1，2，3，4或5。
2.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐，当环A为苯环，n是1时，R1独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；上述所述R2任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基,R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3。
3.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐，当环A为苯环，n是2时，两个R1相邻，且相邻的两个R1和与它们相连的两个碳原子共同形成一个5-6元碳环，杂环，环酮基，杂环酮基，两个R1可任选地被一个或多个氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基取代；所述的取代基中，R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y是0，1，2或3；所述的杂环和杂环酮基中杂原子为独立地任意地N，O,S，杂原子数为1或2。
4.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐，当环A为苯环，n是3时，R1独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；R2任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基,R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3。
5.根据权利要求2所述的化合物、其立体异构体或药学上可接受的盐，R1位于所连接苯环取代苯乙基的间位或对位，R1独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基；R2任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，
C3-C6环烷基，y是0，1，2或3。
6.根据权利要求4所述的化合物、其立体异构体或药学上可接受的盐，其中n是3，三个R1相邻，R1独立地任意地选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基,氰基，硝基；R2任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基,R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3。
7.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐,当环A选自吡啶，哒嗪，嘧啶或吡嗪，独立地任意地被R1取代，
R1选自-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基；上述所述R2选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基；y选自0，1，
2或3,n选自1，2，3或4。
8.根据权利要求7所述的化合物、其立体异构体或药学上可接受的盐,其中环A是吡啶环或者吡嗪环，独立地任意地被R1取代，R1选自氢，卤素，C1-C4直链或支链烷基，-OR2，-NR3R4，-(CH2)y-COOR5,巯基，氰基，硝基，上述所述R2独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R3和R4分别独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，R5独立地任意地选自氢，C1-C4直链或支链烷基，C1-C4杂烷基，C3-C6环烷基，y选自0，1，2或3，n选自1，2，3或4。
9.根据权利要求1的化合物、其立体异构体或药学上可接受的盐，其特征在于，所述的化合物选自如下化合物：
10.权利要求1-9任意一项所述的化合物、其立体异构体或药学上可接受的盐在制备磷酸二酯酶抑制剂中的应用。
11.权利要求1-9任意一项所述的化合物、其立体异构体或药学上可接受的盐在制备预防和/或治疗其中需要抑制磷酸二酯酶的任何疾病的药物中的应用。
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