CN113402414A - 一种苯甲酸衍生物及其制法和药物用途 - Google Patents

一种苯甲酸衍生物及其制法和药物用途 Download PDF

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CN113402414A
CN113402414A CN202010188664.0A CN202010188664A CN113402414A CN 113402414 A CN113402414 A CN 113402414A CN 202010188664 A CN202010188664 A CN 202010188664A CN 113402414 A CN113402414 A CN 113402414A
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肖志艳
叶菲
王永成
杨亚军
田金英
张晓琳
候现新
姜楠
杨颖�
李雪晨
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Abstract

本发明公开了一种苯甲酸衍生物及其制法和药物用途，属于医药技术领域。具体公开了式(I)化合物所示的苯甲酸衍生物，及其生理上可接受的盐，所述化合物的制备方法和在制备URAT1抑制剂中的用途，含有所述化合物的药物制剂，以及所述化合物在制备预防和治疗与高尿酸血症相关疾病药物中的应用。

Description

一种苯甲酸衍生物及其制法和药物用途
技术领域
本发明属于医药技术领域，具体涉及通式I所示的苯甲酸衍生物，以及它们生理上可接受的盐；这些化合物的药物组合物、制备方法，以及这些化合物在制备尿酸盐转运蛋白1(urate transporter 1,URAT1)抑制剂中的用途，在制备预防或治疗URAT1相关疾病的药物中的应用。
背景技术
痛风是尿酸单钠盐在关节及外周组织中沉积析出所导致的炎性关节疾病。尿酸生成增加或(和)排泄减少所产生的高尿酸血症是痛风的直接诱因。痛风和高尿酸血症还与代谢综合症、高血压、糖尿病、心血管疾病等多种疾病密切相关。
持续性的高尿酸血症是痛风发作的直接诱因，降尿酸疗法(urate-loweringtherapy,ULT)是治疗高尿酸血症和慢性痛风的主要策略。目前降尿酸疗法主要分为三类：(1)抑制尿酸生成的黄嘌呤氧化酶(xanthine oxidase,XOD)抑制剂；(2)促进尿酸排泄的尿酸盐转运蛋白1(urate transporter 1,URAT1)抑制剂；(3)促进尿酸分解的尿酸酶(uricase)类抑制剂。高尿酸血症患者的发病机制约90％与尿酸排泄减少有关，而URAT1是经过临床验证的调控尿酸重吸收，促进尿酸排泄的重要靶点，所以通过URAT1抑制剂减少尿酸的重吸收是非常有前景的降尿酸疗法(ULT)。目前临床上应用的URAT1抑制剂主要有丙磺舒，苯溴马隆和雷西纳德。但丙磺舒和苯溴马隆存在耐受性差，毒副反应多的问题。2015年底上市的雷西纳德在临床上与XOD抑制剂别嘌呤醇联用治疗高尿酸血症和慢性痛风，但是其对URAT1的抑制活性偏弱，临床上使用剂量大(200mg/d)。
近年来，随着人们饮食结构的改变和人口老龄化的加速，痛风发病率在持续上升，已经成为一个不可忽视的全民健康问题。而目前临床上可用的治疗药物较少，而且各自存在不同的缺陷。因此，研究新型URAT1抑制具有重要的现实意义和市场前景。
发明内容
本发明旨在提供一种如通式I所示的苯甲酸衍生物，其具有高的URAT1抑制活性，可用于治疗高尿酸血症以及高尿酸血症引起的痛风等疾病。本发明解决的技术问题是提供一种式I所示的新型苯甲酸衍生物，其制备方法，药物组合物和在制备URAT1抑制剂中的用途，以及在制备预防或治疗与高尿酸血症有关的疾病中的用途。
为了解决本发明的技术问题，本发明采用如下技术方案：
本发明技术方案的第一方面是提供了一种由下述通式(I)表示的苯甲酸衍生物及其生理上可接受的盐,
Figure BDA0002415083690000011
其中，Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基、取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基；R1选自氢或卤素；L选自-XC(R2R3)2-或-(CH2)n-，其中X选自氧或硫原子，R2、R3独立选自氢或甲基，n选自0或1。
优选的化合物为通式IA所述的化合物及其在药学上可接受的盐，
Figure BDA0002415083690000021
其中，Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基；X选自氧原子或硫原子；R2、R3独立选自氢或甲基。
优选的化合物为通式IB所述的化合物及其药学上可接受的盐，
Figure BDA0002415083690000022
其中，Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基。。
优选的化合物为通式IC所述的化合物及其药学上可接受的盐，
Figure BDA0002415083690000023
其中，Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基。
以上通式中，所述的卤素选自氟、氯、溴、碘，所述的C1-C6烷基各自独立地选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基；所述的C3-C6环烷基各自独立的选自环丙基、环丁基、环戊基、环己基；所述的C1-C3烷氧基各自独立地选自甲氧基、乙氧基、丙氧基、异丙氧基。
更优选的化合物为下述的化合物及其生理上可接受的盐，其特征在于，所述的化合物选自：
Figure BDA0002415083690000024
Figure BDA0002415083690000031
Figure BDA0002415083690000041
Figure BDA0002415083690000051
Figure BDA0002415083690000061
本发明技术方案的第二方面在于提供了第一方面所述化合物的合成方法，包括以下步骤：
相应的酸在草酰氯活化下得到相应的酰氯，然后与胺类化合物发生酰化反应，得到中间体I-1，随后I-1在碱性条件下水解得到目标化合物I；
Figure BDA0002415083690000071
(1)式IA化合物的制备：相应的酚或硫酚类化合物与溴乙酸乙酯或2-溴-2-甲基丙酸乙酯在碳酸钾和碘化钾存在下发生亲核反应生成中间体IA-1,后者在碱性条件下水解得到中间体IA-2，后者在草酰氯活化下得到相应的酰氯，然后与氨基苯甲酸甲酯或其衍生物酰化反应，得到中间体IA-3，后者随后在碱性条件下水解得到目标化合物IA；
Figure BDA0002415083690000072
Ar、X、R2、R3的定义同本发明技术方案的第一方面所述；
(2)式IB化合物的制备：相应的苯乙酸或萘乙酸衍生物在草酰氯活化下得到相应的酰氯，然后与2-氨基苯甲酸甲酯发生酰化反应，得到中间体IB-1，随后IB-1在碱性条件下水解得到目标化合物IB；
Figure BDA0002415083690000073
Ar的定义同本发明技术方案的第一方面所述；
(3)式IC化合物的制备：相应的芳基甲酸类化合物在草酰氯活化下得到相应的酰氯，然后与氨基苯甲酸甲酯类化合物发生酰化反应得到中间体IC-1，随后IC-1在碱性条件下水解得到目标化合物；
Figure BDA0002415083690000074
Ar的定义同本发明技术方案的第一方面所述。
本发明技术方案的第三方面是提供一种药物组合物，其特征在于，所述的药物组合物含有有效剂量的本发明第一方面所述的任一苯甲酸衍生物及其生理上可接受的盐和在药学上可接受的载体或赋形剂。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
为了制成药剂，可将通式I化合物按已知方法与合适的制药载体物质、芳香剂、调味剂和颜料用已知的方法混合，并被制成片剂或包衣的片剂，或者将其与其它的附加物质悬浮或溶解在水或油中。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、胶囊剂、包衣剂，非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。
本发明技术方案的第四方面是提供了本发明的第一方面所述化合物及其生理上可接受的盐在制备URAT1抑制剂中的用途。
本发明技术方案的第四方面还提供了第一方面所述的苯甲酸衍生物及其生理上可接受的盐在制备预防或治疗URAT1相关疾病的药物中的应用。所述的URAT1相关疾病选自高尿酸血症、痛风。
药理学研究表明，本发明的通式I化合物具有抑制URAT1的活性，可有效降低体内的血尿酸水平，从而达到治疗的目的。
有益技术效果：
URAT1抑制剂是临床上使用的重要降尿酸药物。本发明涉及的化合物具有显著的URAT1抑制作用。其中，部分化合物与临床同类产品雷西纳德比较，体外抑制URAT1活性更强。
具体实施方式
以下结合实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
合成实验中所使用的试剂和溶剂均通过商业途径(包括但不限于毕得，伊诺凯，安耐吉，百灵威等)购买，未经处理直接使用。无水溶剂为商业购买的超干溶剂，溶剂的混合比例为体积比。所有反应监测均采用GF-254薄层硅胶板，柱层析分离采用200-300目硅胶。1H-NMR由Varian Mercury 400-MHz核磁共振仪采集获得，13C-NMR由Varian Mercury 400-MHz或500-MHz核磁共振仪采集获得。化学位移(δ)以百万分之一(ppm)给出，内标为TMS，偶合常数以赫兹(Hz)为单位。高分辨质谱数据由Exactive PlusTM LC/MSD Orbitrap(ThermoFisher Scientific)测试获得。化合物熔点由Yanaco显微熔点仪测定，温度计未校正。
实施例1：TM-1的制备
Figure BDA0002415083690000081
(1)中间体IA-1a的制备
Figure BDA0002415083690000082
将3,4-二甲氧基苯酚(1.54g,10mmol)，溴乙酸乙酯(2.00g,12mmol)，碳酸钾(2.07g,15mmol)，碘化钾(166mg,1.00mmol)依次加入30mL乙腈中，反应体系加热至80℃反应6h。TLC监测反应完全，将反应液用水缓慢淬灭，乙酸乙酯萃取三次，饱和盐水洗涤，有机相干燥浓缩得到中间体IA-1a，2.10g，收率：87％。1H NMR(400MHz,CDCl3)δ6.75(d,J＝8.8Hz,1H),6.61(d,J＝2.8Hz,1H),6.34(dd,J＝8.7,2.9Hz,1H),4.56(s,2H),4.26(q,J＝7.1Hz,2H),3.84(s,3H),3.82(s,3H),1.29(t,J＝7.1Hz,3H).
(2)中间体的IA-2a制备
Figure BDA0002415083690000083
将中间体IA-1a(2.10g,8.74mmol)加入30mL四氢呋喃-乙醇-水(2:2:1)的混合溶剂中，然后加入氢氧化钠(0.70g,17.48mmol)，室温搅拌反应2h。TLC监测反应完全，减压除去反应中大部分有机溶剂，然后加水稀释，用1N盐酸水溶液缓慢调节pH至3-4，析出固体，抽滤，干燥的白色固体IA-2a 1.6g，收率：86％。1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),6.83(d,J＝8.8Hz,1H),6.59(d,J＝2.9Hz,1H),6.38(dd,J＝8.8,2.9Hz,1H),4.59(s,2H),3.73(s,3H),3.68(s,3H)。
(3)中间体的IA-3a制备
Figure BDA0002415083690000091
将中间体IA-2a(255mg,1.20mmol)溶于10mL无水二氯甲烷(DCM)中，加入3滴DMF，然后缓慢滴加草酰氯(190mg,1.50mmol)，室温搅拌反应1h。减压浓缩除去反应溶剂和过量的草酰氯，再将其溶于10mL无水二氯甲烷中备用。将2-氨基苯甲酸甲酯(151mg,1.00mmol)溶解于无水二氯甲烷中，加入三乙胺(202mg,2.0mmol)，然后缓慢加入上述制备的酰氯，室温下反应2h。TLC监测反应完全，将反应液用50mL二氯甲烷稀释，然后用水洗涤，有机相用无水硫酸钠干燥,减压除去溶剂后，柱色谱分离(石油醚-乙酸乙酯10:1)得到中间体IA-3a180mg,收率:52％。1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.63(d,J＝8.5Hz,1H),8.01(dd,J＝1.6,8.0Hz,1H),7.66(m,1H),7.22(m,1H),6.90(d,J＝8.8Hz,1H),6.82(d,J＝2.8Hz,1H),6.59(dd,J＝2.9,8.8Hz,1H),4.69(s,2H),3.90(s,3H),3.78(s,3H),3.70(s,3H).
(4)目标物TM-1的制备
Figure BDA0002415083690000092
将中间体IA-3a(180mg,0.52mmol)加入30mL四氢呋喃-乙醇-水(2:2:1)的混合溶剂中，然后加入氢氧化钠(42mg,1.04mmol)，室温搅拌反应2h。TLC监测反应完全，减压除去反应中大部分有机溶剂，然后加水稀释，用1N盐酸水溶液缓慢调节pH至3-4，析出固体，抽滤，干燥的白色固体TM-1 120mg，收率：70％。mp:174-176℃；1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),12.09(s,1H),8.70(d,J＝8.1Hz,1H),8.02(dd,J＝1.5,7.9Hz,1H),7.67–7.59(m,1H),7.19(t,J＝7.6Hz,1H),6.88(d,J＝8.8Hz,1H),6.75(d,J＝2.8Hz,1H),6.57(dd,J＝2.8,8.8Hz,1H),4.68(s,2H),3.77(s,3H),3.69(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.24,167.44,151.66,149.66,143.92,140.11,134.28,131.34,123.07,119.51,116.28,112.65,105.05,101.22,68.04,56.04,55.62；HR-MS(ESI)m/z:Cald for C17H18O6N[M+H]+332.1129,found 332.1119。
实例2：TM-2的制备
Figure BDA0002415083690000093
合成方法与TM-1类似，不同之处在于第一步用3,4-二甲氧基苯硫酚替代3,4-二甲氧基苯酚，最后一步收率62％。白色固体，mp:127-129℃；1H NMR(400MHz,DMSO-d6)δ13.77(s,1H),11.98(s,1H),8.51(d,J＝8.4Hz,1H),7.99(d,J＝7.8Hz,1H),7.56(t,J＝7.8Hz,1H),7.14(t,J＝7.6Hz,1H),7.06(d,J＝1.7Hz,1H),7.00(dd,J＝1.9,8.3Hz,1H),6.90(d,J＝8.4Hz,1H),3.88(s,2H),3.70(s,3H),3.68(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.33,167.64,148.92,148.46,140.43,133.81,131.18,124.98,123.22(2C),122.85,119.55,114.38,112.38,55.51,55.46,40.36；HR-MS(ESI)m/z:Cald for C17H18O5NS[M+H]+348.0900,found 348.0891
实例3：TM-3的制备
Figure BDA0002415083690000101
合成方法与TM-1类似，不同之处在于第一步用芝麻酚替代3,4-二甲氧基苯酚，最后一步收率56％。白色固体，mp:221-223℃；1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),12.13(s,1H),8.73–8.65(m,1H),8.02(dd,J＝1.4,7.9Hz,1H),7.67–7.57(m,1H),7.19(t,J＝7.6Hz,1H),6.85(d,J＝8.5Hz,1H),6.78(d,J＝2.5Hz,1H),6.52(dd,J＝2.5,8.5Hz,1H),5.98(s,2H),4.65(s,2H)；HR-MS(ESI)m/z:Cald for C16H14O6N[M+H]+316.0816,found316.0818
实例4：TM-4的制备
Figure BDA0002415083690000102
合成方法与TM-1类似，不同之处在于第一步用芝麻酚替代3,4-二甲氧基苯酚，同时用2-溴-2-甲基丙酸乙酯替换溴乙酸乙酯，最后一步收率51％，白色固体。mp:159-162℃；1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),12.29(s,1H),8.68(dd,J＝1.0,8.5Hz,1H),8.02(dd,J＝1.6,7.9Hz,1H),7.63(ddd,J＝1.7,7.4,8.7Hz,1H),7.22–7.15(m,1H),6.82(d,J＝8.4Hz,1H),6.72(d,J＝2.4Hz,1H),6.52(dd,J＝2.4,8.4Hz,1H),6.00(s,2H),1.47(s,6H)；13C NMR(101MHz,DMSO-d6)δ173.19,169.35,148.64,147.51,143.29,140.50,134.22,131.26,122.90,119.39,116.45,113.92,107.78,104.13,101.34,81.79,24.66(2C)；HR-MS(ESI)m/z:Cald for C18H18O6N[M+H]+344.1129,found 344.1120。
实例5：TM-5的制备
Figure BDA0002415083690000103
合成方法与TM-1类似，不同之处在于第一步用4-甲氧基苯酚替代3,4-二甲氧基苯酚，最后一步收率51％，白色固体。mp:194-197℃；1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),12.19(s,1H),8.70(d,J＝9.3Hz,1H),8.02(dd,J＝1.6,7.9Hz,1H),7.67–7.59(m,1H),7.23–7.15(m,1H),7.07–6.98(m,2H),6.94–6.87(m,2H),4.66(s,2H),3.71(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.39,167.45,154.10,151.19,140.19,134.24,131.29,123.02,119.41,116.29,115.75(2C),114.69(2C),67.94,55.38；HR-MS(ESI)m/z:Cald forC16H16O5N[M+H]+302.1023,found 302.1016。
实例6：TM-6的制备
Figure BDA0002415083690000104
合成方法与TM-1类似，不同之处在于第三步用苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率76％，白色固体。mp:199-201℃；1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),12.18(s,1H),8.71(d,J＝9.7Hz,1H),8.02(d,J＝7.9Hz,1H),7.63(t,J＝7.8Hz,1H),7.35(t,J＝7.9Hz,2H),7.19(t,J＝7.6Hz,1H),7.09(d,J＝8.0Hz,2H),7.01(t,J＝7.3Hz,1H),4.73(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.41,167.22,157.11,140.19,134.33,131.31,129.64(2C),123.06,121.65,119.45,116.15,114.81(2C),67.23；HR-MS(ESI)m/z:Cald for C15H14O4N[M+H]+272.0917,found 272.0908。
实例7：TM-7的制备
Figure BDA0002415083690000111
合成方法与TM-1类似，不同之处在于第一步用苯硫酚替代3,4-二甲氧基苯酚，最后一步收率70％，白色固体。mp:163-164℃；1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),11.80(s,1H),8.50(d,J＝8.4Hz,1H),7.96(dd,J＝1.7,7.9Hz,1H),7.57(td,J＝1.7,8.0,8.7Hz,1H),7.38(dd,J＝1.4,8.3Hz,2H),7.34–7.28(m,2H),7.22–7.12(m,2H),4.00(s,2H)；HR-MS(ESI)m/z:Cald for C15H14O3NS[M+H]+288.0689,found 288.0681。
实例8：TM-8的制备
Figure BDA0002415083690000112
合成方法与TM-1类似，不同之处在于用4-吡啶巯基乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步调pH至5-6，收率65％，白色固体。mp:233-234℃；1HNMR(400MHz,DMSO-d6)δ11.73(s,1H),8.48(d,J＝8.2Hz,1H),8.39(d,J＝4.8Hz,2H),7.96(dd,J＝1.5,7.9Hz,1H),7.62–7.53(m,1H),7.32(d,J＝6.1Hz,2H),7.16(t,J＝8.0Hz,1H),4.18(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.28,166.61,149.14(2C),147.69,140.15(2C),134.07,131.21,123.34,120.71,120.16,117.21,35.42；HR-MS(ESI)m/z:Cald forC14H13O3N2S[M+H]+289.0641,found 289.0634。
实例9：TM-9的制备
Figure BDA0002415083690000113
合成方法与TM-1类似，不同之处在于第一步用4-甲基苯酚替代3,4-二甲氧基苯酚，最后一步收率82％，白色固体。mp:182-184℃；1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),12.18(s,1H),8.70(d,J＝8.3Hz,1H),8.02(dd,J＝1.6,8.0Hz,1H),7.67–7.58(m,1H),7.19(t,J＝7.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.98(d,J＝8.5Hz,2H),4.68(s,2H),2.24(s,3H)；13C NMR(101MHz,DMSO-d6)δ169.39,167.36,155.07,140.19,134.28,131.29,130.40,129.94(2C),123.03,119.41,116.20,114.63(2C),67.39,20.09；HR-MS(ESI)m/z:Cald forC16H16O4N[M+H]+286.1074,found 286.1068。
实例10：TM-10的制备
Figure BDA0002415083690000114
合成方法与TM-1类似，不同之处在于第一步用4-丙基苯酚替代3,4-二甲氧基苯酚，最后一步收率78％，白色固体。mp:152-155℃；1H NMR(400MHz,DMSO-d6)δ13.77(s,1H),12.16(s,1H),8.70(d,J＝8.4Hz,1H),8.02(dd,J＝1.4,7.9Hz,1H),7.67–7.58(m,1H),7.19(t,J＝7.6Hz,1H),7.15(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),4.69(s,2H),2.49(t,J＝7.2Hz,2H),1.61–1.48(m,2H),0.87(t,J＝7.3Hz,3H)；13C NMR(101MHz,DMSO-d6)δ169.39,167.36,155.24,140.19,135.27,134.32,131.30,129.34(2C),123.04,119.43,116.13,114.58(2C),67.62,36.37,24.26,13.58；HR-MS(ESI)m/z:Cald for C18H20O4N[M+H]+314.1387,found 314.1380。
实例11：TM-11的制备
Figure BDA0002415083690000121
合成方法与TM-1类似，不同之处在于第一步用4-异丙基苯酚替代3,4-二甲氧基苯酚，最后一步收率71％，白色固体。mp:157-160℃；1H NMR(400MHz,DMSO-d6)δ13.81(s,1H),12.18(s,1H),8.71(d,J＝8.3Hz,1H),8.02(d,J＝7.5Hz,1H),7.63(t,J＝8.5Hz,1H),7.20(d,J＝8.4Hz,3H),7.00(d,J＝8.6Hz,2H),4.69(s,2H),2.90–2.78(m,1H),1.17(d,J＝6.9Hz,6H)；13C NMR(101MHz,DMSO-d6)δ169.40,167.38,155.27,141.61,140.20,134.32,131.30,127.29(2C),123.05,119.42,116.14,114.64(2C),99.46,67.42,32.62,24.07(2C)；HR-MS(ESI)m/z:Cald for C18H20O4N[M+H]+314.1387,found 314.1380。
实例12：TM-12的制备
Figure BDA0002415083690000122
合成方法与TM-1类似，不同之处在于第一步用4-氟苯酚替代3,4-二甲氧基苯酚，最后一步收率77％，白色固体。mp:189-191℃；1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),10.26(s,1H),8.28(s,1H),7.87(d,J＝9.1Hz,1H),7.66(d,J＝7.1Hz,1H),7.45(s,1H),7.20–7.11(m,2H),7.07–6.99(m,2H),4.70(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O4NF[M+H]+290.0823,found 290.0816。
实例13：TM-13的制备
Figure BDA0002415083690000123
合成方法与TM-1类似，不同之处在于第一步用4-氟苯硫酚替代3,4-二甲氧基苯酚，最后一步收率77％，白色固体。mp:196-199℃；1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),10.35(s,1H),8.19(s,1H),7.79–7.73(m,1H),7.63(dt,J＝1.1,7.7Hz,1H),7.52–7.46(m,2H),7.43(t,J＝7.9Hz,1H),7.23–7.15(m,2H),3.82(s,2H)；HR-MS(ESI)m/z:Cald forC15H13O3NFS[M+H]+306.0595,found 306.0588。
实例14：TM-14的制备
Figure BDA0002415083690000124
合成方法与TM-1类似，不同之处在于第三步用4-氯苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率86％，白色固体。mp:222-224℃；1H NMR(400MHz,DMSO-d6)δ13.81(s,1H),12.16(s,1H),8.69(d,J＝8.4Hz,1H),8.02(dd,J＝1.5,7.9Hz,1H),7.68–7.59(m,1H),7.45–7.36(m,2H),7.19(t,J＝7.2Hz,1H),7.14–7.07(m,2H),4.75(s,2H).13C NMR(101MHz,DMSO-d6)δ169.47,166.86,155.97,140.14,134.35,131.31,129.43(2C),125.40,123.11,119.43,116.60(2C),116.15,67.52；HR-MS(ESI)m/z:Cald for C15H13O4NCl[M+H]+306.0528,found 306.0523。
实例15：TM-15的制备
Figure BDA0002415083690000125
合成方法与TM-1类似，不同之处在于第一步用4-氯苯硫酚替代3,4-二甲氧基苯酚，最后一步收率77％，白色固体。mp:168-170℃；1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.53–8.42(m,1H),7.96(dd,J＝1.6,7.9Hz,1H),7.58(ddd,J＝1.7,7.5,8.6Hz,1H),7.45–7.33(m,4H),7.21–7.12(m,1H),4.03(s,2H).13C NMR(101MHz,DMSO-d6)δ169.29,167.24,140.30,134.26,134.18,131.24,131.08,129.82(2C),129.19(2C),123.23,119.94,116.82；HR-MS(ESI)m/z:Cald for C15H13O3NClS[M+H]+322.0299,found 322.0291。
实例16：TM-16的制备
Figure BDA0002415083690000131
合成方法与TM-1类似，不同之处在于第三步用3-氯苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率82％，白色固体。mp:204-206℃；1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),12.16(s,1H),8.69(d,J＝8.2Hz,1H),8.03(dd,J＝1.5,7.9Hz,1H),7.68–7.59(m,1H),7.38(t,J＝8.2Hz,1H),7.21(d,J＝7.8Hz,1H),7.18(t,J＝2.0Hz,1H),7.12–7.03(m,2H),4.78(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O4NCl[M+H]+306.0528,found 306.0522。
实例17：TM-17的制备
Figure BDA0002415083690000132
合成方法与TM-1类似，不同之处在于第三步用2-氯苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率77％，白色固体。mp:167-170℃；1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),11.84(s,1H),8.69–8.62(m,1H),8.00(dd,J＝1.6,7.9Hz,1H),7.67–7.59(m,1H),7.48(dd,J＝1.6,7.9Hz,1H),7.35–7.27(m,1H),7.24–7.14(m,2H),7.03(td,J＝1.3,7.7Hz,1H),4.86(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.19,166.90,152.81,140.01,134.23,131.25,130.24,128.38,123.31,122.69,121.77,120.07,116.55,114.36,68.26；HR-MS(ESI)m/z:Cald for C15H13O4NCl[M+H]+306.0528,found306.0521。
实例18：TM-18的制备
Figure BDA0002415083690000133
合成方法与TM-1类似，不同之处在于第一步用3-苯酚替代3,4-二甲氧基苯酚，最后一步收率88％，白色固体。mp:151-153℃；1H NMR(400MHz,DMSO-d6)δ14.00(s,1H),12.45(s,1H),8.68(d,J＝8.2Hz,1H),8.03(d,J＝7.7Hz,1H),7.60(t,J＝7.6Hz,1H),7.30(d,J＝8.6Hz,2H),7.19(dd,J＝7.5,14.9Hz,2H),7.11(d,J＝8.5Hz,1H),4.76(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O4NBr[M+H]+350.0022,found 350.0025。
实例19：TM-19的制备
Figure BDA0002415083690000134
合成方法与TM-1类似，不同之处在于第三步用4-溴苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率85％，白色固体。mp:225-227℃；1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),12.15(s,1H),8.69(d,J＝8.2Hz,1H),8.02(dd,J＝1.6,8.0Hz,1H),7.67–7.59(m,1H),7.57–7.48(m,2H),7.19(t,J＝7.6Hz,1H),7.10–7.01(m,2H),4.74(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.47,166.83,156.42,140.14,134.35,132.32(2C),131.31,123.11,119.43,117.11(2C),116.14,113.16,67.45；HR-MS(ESI)m/z:Cald for C15H13O4NBr[M+H]+350.0022,found 350.0017。
实例20：TM-20的制备
Figure BDA0002415083690000141
合成方法与TM-1类似，不同之处在于第一步用2,4-二溴苯酚替代3,4-二甲氧基苯酚，最后一步收率88％，白色固体。mp:206-208℃；1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),12.23(s,1H),8.70(d,J＝8.4Hz,1H),8.04(d,J＝7.8Hz,1H),7.72(d,J＝8.0Hz,2H),7.65(t,J＝7.8Hz,1H),7.23(t,J＝7.6Hz,1H),7.13(t,J＝8.0Hz,1H),4.61(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.04,166.00,151.05,139.92,134.25,133.10(2C),131.26,128.15,123.30,119.78,117.57(2C),116.61,70.95；HR-MS(ESI)m/z:Cald for C15H12O4NBr2[M+H]+427.9128,found 427.9124。
实例21：TM-21的制备
Figure BDA0002415083690000142
合成方法与TM-1类似，不同之处在于第三步用4-氰基苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率85％，白色固体。mp:200-203℃；1H NMR(400MHz,DMSO-d6)δ13.85(s,1H),12.17(s,1H),8.67(d,J＝8.2Hz,1H),8.02(d,J＝7.8Hz,1H),7.86(d,J＝8.6Hz,2H),7.63(t,J＝7.7Hz,1H),7.24(d,J＝8.6Hz,2H),7.19(t,J＝7.4Hz,1H),4.86(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.51,166.35,160.42,140.09,134.36(2C),131.32,123.18,119.45(2C),118.90,116.23,115.93(2C),104.03,67.33；HR-MS(ESI)m/z:Cald for C16H13O4N2[M+H]+297.0870,found 297.0865。
实例22：TM-22的制备
Figure BDA0002415083690000143
合成方法与TM-1类似，不同之处在于第三步用4-三氟甲基基苯氧乙酸作为中间体IA-2与2-氨基苯甲酸甲酯进行酰化反应，最后一步收率78％，白色固体。mp:195-197℃；1HNMR(400MHz,DMSO-d6)δ13.86(s,1H),12.20(s,1H),8.69(d,J＝8.4Hz,1H),8.03(dd,J＝1.6,8.0Hz,1H),7.74(d,J＝8.7Hz,2H),7.68–7.59(m,1H),7.26(d,J＝8.6Hz,2H),7.23–7.15(m,1H),4.86(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.60,166.63,159.90,140.18,134.44,131.37,127.21(d,J＝3.8Hz,2C)),123.21,119.49,119.48,116.18,115.40(2C),99.50,67.36；HR-MS(ESI)m/z:Cald for C16H13O4NF3[M+H]+340.0791,found 340.0785。
实例23：TM-23的制备
Figure BDA0002415083690000144
合成方法与TM-1类似，不同之处在于第一步用3-三氟甲基苯酚替代3,4-二甲氧基苯酚，最后一步收率77％，白色固体。mp:231-234℃；1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),12.19(s,1H),8.69(d,J＝8.4Hz,1H),8.03(d,J＝7.6Hz,1H),7.67–7.55(m,2H),7.45–7.34(m,3H),7.19(t,J＝7.6Hz,1H),4.85(s,2H)；HR-MS(ESI)m/z:Cald for C16H13O4NF3[M+H]+340.0791,found 340.0792。
实例24：TM-24的制备
Figure BDA0002415083690000151
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，最后一步收率69％，白色固体。mp:200-202℃；1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),12.17(s,1H),8.78–8.71(m,1H),8.62(d,J＝9.7Hz,1H),8.04(dd,J＝1.6,7.9Hz,1H),7.91(dd,J＝2.1,7.3Hz,1H),7.70–7.62(m,1H),7.61–7.52(m,3H),7.44(t,J＝8.0Hz,1H),7.26–7.17(m,1H),7.06(d,J＝7.5Hz,1H),4.94(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.49,167.09,152.74,140.20,134.31,134.12,131.28,127.45,126.63,126.03,125.65,124.76,123.25,122.00,121.22,119.98,116.45,106.09,67.88；HR-MS(ESI)m/z:Cald for C19H16O4N[M+H]+322.1074,found 322.1060。
实例25：TM-25的制备
Figure BDA0002415083690000152
合成方法与TM-1类似，不同之处在于第一步用4-羟基喹啉替代3,4-二甲氧基苯酚，最后一步调pH至5-6，乙醇-水重结晶得白色固体，收率39％。mp:282-285℃；1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),11.49(s,1H),8.47(d,J＝8.3Hz,1H),8.19(d,J＝7.7Hz,1H),8.03(d,J＝7.8Hz,1H),7.95(d,J＝7.4Hz,1H),7.69(t,J＝7.6Hz,1H),7.59(t,J＝7.9Hz,1H),7.54(d,J＝8.6Hz,1H),7.38(t,J＝7.4Hz,1H),7.17(t,J＝7.5Hz,1H),6.14(d,J＝7.6Hz,1H),5.26(s,2H)；13C NMR(101MHz,DMSO-d6)δ176.72,169.43,166.18,145.38,140.51,139.99,134.23,132.31,131.18,126.56,125.79,123.53,123.42,120.08,116.89,116.31,109.50,55.52；HR-MS(ESI)m/z:Cald for C18H15O4N2[M+H]+323.1026,found323.1019。
实例26：TM-26的制备
Figure BDA0002415083690000153
合成方法与TM-1类似，不同之处在于第一步用1-萘硫酚替代3,4-二甲氧基苯酚，最后一步收率59％，白色固体。mp:185-188℃；1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),11.89(s,1H),8.47(d,J＝8.4Hz,1H),8.30(d,J＝8.0Hz,1H),7.95(d,J＝7.7Hz,2H),7.82(d,J＝8.2Hz,1H),7.65–7.52(m,4H),7.46(t,J＝7.7Hz,1H),7.13(t,J＝7.5Hz,1H),4.09(s,2H)；HR-MS(ESI)m/z:Cald for C19H16O3NS[M+H]+338.0845,found 338.0837。
实例27：TM-27的制备
Figure BDA0002415083690000154
合成方法与TM-1类似，不同之处在于第一步用1-萘硫酚替代3,4-二甲氧基苯酚，同时用2-溴-2-甲基丙酸乙酯替代溴乙酸乙酯，最后一步收率51％，白色固体。mp:154-156℃；1H NMR(400MHz,DMSO-d6)δ13.61(s,1H),11.68(s,1H),8.44(d,J＝8.4Hz,2H),8.00–7.91(m,2H),7.88(d,J＝8.0Hz,1H),7.70(d,J＝6.4Hz,1H),7.57–7.50(m,1H),7.47–7.39(m,2H),7.33(t,J＝7.6Hz,1H),7.11(t,J＝7.6Hz,1H),1.57(s,6H)；HR-MS(ESI)m/z:Caldfor C21H20O3NS[M+H]+366.1158,found 366.1151。
实例28：TM-28的制备
Figure BDA0002415083690000161
合成方法与TM-1类似，不同之处在于第一步用4-溴-1-萘酚替代3,4-二甲氧基苯酚，最后一步收率51％，白色固体。mp:204-206℃；1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),12.14(s,1H),8.72(d,J＝8.3Hz,1H),8.68(d,J＝8.3Hz,1H),8.11(d,J＝8.4Hz,1H),8.04(d,J＝7.0Hz,1H),7.80(d,J＝8.3Hz,1H),7.76(t,J＝7.5Hz,1H),7.72–7.62(m,2H),7.22(t,J＝7.6Hz,1H),7.03(d,J＝8.4Hz,1H),4.97(s,2H)；HR-MS(ESI)m/z:Cald forC19H15O4NBr[M+H]+400.0179,found 400.0183。
实例29：TM-29的制备
Figure BDA0002415083690000162
合成方法与TM-1类似，不同之处在于第一步用4-氯-1-萘酚替代3,4-二甲氧基苯酚，最后一步收率55％，白色固体。mp:194-196℃；1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),12.15(s,1H),8.73(d,J＝8.3Hz,1H),8.70(d,J＝8.3Hz,1H),8.15(d,J＝8.4Hz,1H),8.04(dd,J＝1.6,7.9Hz,1H),7.80–7.73(m,1H),7.72–7.64(m,2H),7.62(d,J＝8.4Hz,1H),7.25–7.19(m,1H),7.07(d,J＝8.4Hz,1H),4.96(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.51,166.73,152.09,140.15,134.30,131.26,130.47,128.19,126.67,126.13,125.83,123.57,123.25,122.92,122.75,119.93,116.43,106.54,68.05；HR-MS(ESI)m/z:Cald forC19H15O4NCl[M+H]+356.0684,found 356.0678。
实例30：TM-30的制备
Figure BDA0002415083690000163
合成方法与TM-1类似，不同之处在于第一步用4-氟-1-萘酚替代3,4-二甲氧基苯酚，最后一步收率56％，白色固体。mp:218-221℃；1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),12.15(s,1H),8.73(d,J＝8.2Hz,1H),8.65(d,J＝8.1Hz,1H),8.08–7.96(m,2H),7.74–7.61(m,3H),7.31–7.17(m,2H),7.01(dd,J＝3.9,8.5Hz,1H),4.93(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.49,166.90,153.86,149.04,140.17,134.30,131.27,127.38,126.84,124.54(d,J＝197.4Hz),123.23,122.38,119.93,119.76(d,J＝4.0Hz),116.41,109.05(d,J＝21.6Hz,2C),105.45(d,J＝8.1Hz),68.14；HR-MS(ESI)m/z:Cald for C19H15O4NF[M+H]+340.0980,found 340.0979。
实例31：TM-31的制备
Figure BDA0002415083690000171
合成方法与TM-1类似，不同之处在于第一步用4-甲氧基-1-萘酚替代3,4-二甲氧基苯酚，最后一步收率61％，白色固体。mp:209-212℃；1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),12.17(s,1H),8.75(d,J＝8.4Hz,1H),8.57(dd,J＝2.3,6.8Hz,1H),8.14(dd,J＝2.5,6.8Hz,1H),8.04(dd,J＝1.6,8.0Hz,1H),7.70–7.63(m,1H),7.63–7.54(m,2H),7.22(t,J＝7.6Hz,1H),6.97(d,J＝8.5Hz,1H),6.86(d,J＝8.5Hz,1H),4.87(s,2H),3.93(s,3H)；13CNMR(101MHz,DMSO-d6)δ169.51,167.36,149.46,146.58,140.26,134.35,131.31,126.27,126.11,125.55,125.48,123.22,121.98,121.39,119.92,116.36,105.80,103.57,68.12,55.64；HR-MS(ESI)m/z:Cald for C20H18O5N[M+H]+352.1179,found 352.1180。
实例32：TM-32的制备
Figure BDA0002415083690000172
合成方法与TM-1类似，不同之处在于第一步用2-萘酚替代3,4-二甲氧基苯酚，最后一步收率72％，白色固体。mp:239-241℃；1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.73(d,J＝7.8Hz,1H),8.03(dd,J＝1.6,7.9Hz,1H),7.92(d,J＝8.9Hz,1H),7.84(dd,J＝8.1,13.5Hz,2H),7.68–7.60(m,1H),7.54–7.46(m,1H),7.45(d,J＝2.5Hz,1H),7.43–7.33(m,2H),7.24–7.16(m,1H),4.87(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.60,167.22,155.00,140.29,134.48,134.13,131.47,129.70,129.04,127.69,127.00,126.76,124.25,123.25,119.56,118.54,116.34,107.61,67.34；HR-MS(ESI)m/z:Cald for C19H16O4N[M+H]+322.1074,found 322.1066。
实例33：TM-33的制备
Figure BDA0002415083690000173
合成方法与TM-1类似，不同之处在于第一步用2-萘硫酚替代3,4-二甲氧基苯酚，最后一步收率61％，白色固体。mp:167-169℃；1H NMR(400MHz,DMSO-d6)δ13.67(s,1H),11.86(s,1H),8.49(d,J＝8.3Hz,1H),7.95(dd,J＝1.5,7.9Hz,1H),7.92–7.88(m,1H),7.86(d,J＝8.9Hz,2H),7.79(d,J＝7.8Hz,1H),7.59–7.42(m,4H),7.17–7.09(m,1H),4.14(s,2H)；13C NMR(101MHz,DMSO-d6)δ169.19,167.29,140.26,133.98,133.26,132.67,131.31,131.09,128.57,127.63,126.93,126.81,126.22,125.90,125.69,123.01,119.84,116.77,37.90；HR-MS(ESI)m/z:Cald for C19H16O3NS[M+H]+338.0845,found 338.0839。
实例34：TM-34的制备
Figure BDA0002415083690000174
合成方法与TM-1类似，不同之处在于第一步用2-萘硫酚替代3,4-二甲氧基苯酚，同时用2-溴-2-甲基丙酸乙酯替换溴乙酸乙酯，最后一步收率66％，白色固体。mp:145-147℃；1H NMR(400MHz,DMSO-d6)δ13.66(s,1H),11.94(s,1H),8.54(d,J＝8.1Hz,1H),8.01(d,J＝6.4Hz,2H),7.89(d,J＝7.8Hz,1H),7.83(d,J＝8.5Hz,1H),7.76(d,J＝7.6Hz,1H),7.63–7.57(m,1H),7.56–7.48(m,2H),7.42(dd,J＝1.7,8.5Hz,1H),7.16(t,J＝7.6Hz,1H),1.58(s,6H)；13C NMR(101MHz,DMSO-d6)δ172.05,169.61,140.95,135.24,134.24,132.88,132.70,131.78,131.22,128.41,128.32,127.67,127.53,127.12,126.69,122.65,119.38,116.03,53.15,25.97(2C)；HR-MS(ESI)m/z:Cald for C21H20O3NS[M+H]+366.1158,found366.1150。
实例35：TM-35的制备
Figure BDA0002415083690000181
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用3-氨基苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率60％，白色固体。mp:215-217℃；1HNMR(400MHz,DMSO-d6)δ12.99(s,1H),10.42(s,1H),8.37–8.31(m,1H),8.30(s,1H),7.89(d,J＝5.3Hz,2H),7.67(d,J＝7.8Hz,1H),7.59–7.50(m,3H),7.50–7.38(m,2H),6.95(d,J＝7.6Hz,1H),4.94(s,2H)；13C NMR(101MHz,DMSO-d6)δ167.12,166.77,153.44,138.70,134.12,131.34,129.10,127.45,126.62,126.10,125.41(2C),124.89,123.89,122.00,120.69,120.50,105.55,67.55；HR-MS(ESI)m/z:Cald for C19H16O4N[M+H]+322.1074,found 322.1075。
实例36：TM-36的制备
Figure BDA0002415083690000182
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用4-氨基苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率71％，白色固体。mp:249-251℃；1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),10.56(s,1H),8.37–8.26(m,1H),7.96–7.85(m,3H),7.78(d,J＝8.7Hz,2H),7.60–7.48(m,3H),7.42(t,J＝7.9Hz,1H),6.94(d,J＝8.0Hz,1H),4.97(s,2H)；13C NMR(101MHz,DMSO-d6)δ166.93,153.41,142.49,134.09,130.40(2C),127.42,126.58,126.04,125.57,125.39(2C),124.86,121.89,120.68,118.90(2C),105.56,67.55；HR-MS(ESI)m/z:Cald for C19H16O4N[M+H]+322.1074,found322.1069。
实例37：TM-37的制备
Figure BDA0002415083690000183
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用2-氨基-4-氟苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率56％，白色固体。mp:175-178℃；1H NMR(400MHz,DMSO-d6)δ13.86(s,1H),12.37(s,1H),8.65–8.53(m,2H),8.12(dd,J＝6.9,8.8Hz,1H),7.94–7.87(m,1H),7.61–7.50(m,3H),7.44(t,J＝8.0Hz,1H),7.12–7.01(m,2H),4.96(s,2H)；HR-MS(ESI)m/z:Cald for C19H15O4NF[M+H]+340.0980,found 340.0974。
实例38：TM-38的制备
Figure BDA0002415083690000184
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用2-氨基-4-三氟甲基苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率51％，白色固体。mp:241-243℃；1H NMR(400MHz,DMSO-d6)δ14.30(s,1H),12.27(s,1H),9.12(s,1H),8.65–8.57(m,1H),8.24(d,J＝8.2Hz,1H),7.96–7.87(m,1H),7.62–7.52(m,4H),7.44(t,J＝8.0Hz,1H),7.08(d,J＝7.6Hz,1H),4.98(s,2H)；HR-MS(ESI)m/z:Cald for C20H15O4NF3[M+H]+390.0948,found 390.0942。
实例39：TM-39的制备
Figure BDA0002415083690000191
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用2-氨基-4-溴苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率58％，白色固体。mp:225-227℃；1H NMR(400MHz,DMSO-d6)δ14.04(s,1H),12.34(s,1H),8.98(d,J＝2.0Hz,1H),8.66–8.57(m,1H),7.96(d,J＝8.5Hz,1H),7.94–7.86(m,1H),7.60–7.51(m,3H),7.47–7.39(m,2H),7.06(d,J＝7.6Hz,1H),4.95(s,2H)；HR-MS(ESI)m/z:Cald for C19H15O4NBr[M+H]+400.0179,found 400.0183。
实例40：TM-40的制备
Figure BDA0002415083690000192
合成方法与TM-1类似，不同之处在于第一步用1-萘酚替代3,4-二甲氧基苯酚，第三步用2-氨基-4-氯苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率56％，白色固体。mp:164-167℃；1H NMR(400MHz,DMSO-d6)δ13.99(s,1H),12.28(s,1H),8.84(d,J＝2.2Hz,1H),8.65–8.56(m,1H),8.04(d,J＝8.6Hz,1H),7.95–7.87(m,1H),7.61–7.52(m,3H),7.44(t,J＝8.0Hz,1H),7.29(dd,J＝2.2,8.6Hz,1H),7.06(d,J＝7.6Hz,1H),4.96(s,2H)；13C NMR(101MHz,DMSO-d6)δ168.77,167.56,152.63,141.20,138.51,134.10,132.98,127.43,126.62,126.00,125.63,124.70,123.13,121.96,121.26,119.28,115.39,106.12,67.80；HR-MS(ESI)m/z:Cald for C19H15O4NCl[M+H]+356.0684,found 356.0677。
实例41：TM-41的制备
Figure BDA0002415083690000193
合成方法与TM-1类似，不同之处在于第一步用4-甲氧基-1-萘酚替代3,4-二甲氧基苯酚，第三步用2-氨基-4-氟苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率60％，白色固体。mp:178-181℃；1H NMR(400MHz,DMSO-d6)δ13.83(s,1H),12.34(s,1H),8.61–8.52(m,2H),8.17–8.07(m,2H),7.62–7.54(m,2H),7.07(td,J＝2.7,8.4Hz,1H),6.96(d,J＝8.5Hz,1H),6.85(d,J＝8.5Hz,1H),4.89(s,2H),3.92(s,3H)；HR-MS(ESI)m/z:Cald forC20H17O5NF[M+H]+370.1085,found 370.1086。
实例42：TM-42的制备
Figure BDA0002415083690000201
(1)中间体ID-1a的制备
Figure BDA0002415083690000202
将中间体1-萘氧乙酸(242mg,1.20mmol)溶于10mL无水二氯甲烷中，加入3滴DMF，然后缓慢滴加草酰氯(190mg,1.50mmol)，室温搅拌反应1h。减压浓缩除去反应溶剂和过量的草酰氯，再将其溶于10mL无水二氯甲烷中备用。将2-氨基苯腈(118mg,1.00mmol)溶解于无水二氯甲烷中，加入三乙胺(202mg,2.0mmol)，然后缓慢加入上述制备的酰氯，室温下反应2h。TLC监测反应完全，将反应液用50mL二氯甲烷稀释，然后水洗，有机相用无水硫酸钠干燥,减压除去溶剂后，柱色谱分离(石油醚-乙酸乙酯10∶1)得到白色固体ID-1a 160mg,收率:53％。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.43(d,J＝7.7Hz,1H),7.89(m,2H),7.75(m,2H),7.55(m,3H),7.43(m,2H),7.03(d,J＝7.7Hz,1H),4.99(s,2H)。
(2)目标化合物TM-42的制备
Figure BDA0002415083690000203
将中间体ID-1a(151mg,0.50mmol)，TMSN3(86mg,0.75mmol)，TBAF-3H2O(158mg,0.5mmol)依次加入10mL乙二醇二甲醚(DME)中，将反应体系加热至80℃反应12h。TLC监测反应完全，用50mL乙酸乙酯稀释反应液，1N盐酸溶液洗涤一次，饱和盐水洗涤一次，有机相浓缩干燥得粗品，然后用乙酸乙酯重结晶得到白色固体125mg，收率72％。mp:210-212℃；1HNMR(400MHz,DMSO-d6)δ17.09(s,1H),11.68(s,1H),8.93(d,J＝7.8Hz,1H),8.69(d,J＝8.4Hz,1H),8.02(d,J＝8.0Hz,1H),7.90(d,J＝7.2Hz,1H),7.69–7.52(m,4H),7.44(t,J＝8.0Hz,1H),7.38(t,J＝7.6Hz,1H),7.08(d,J＝7.6Hz,1H),4.98(s,2H)；13C NMR(101MHz,DMSO-d6)δ167.17,152.74,136.43,134.07,132.01,128.71,127.26,126.71,125.95(2C),125.81,124.80,124.38,122.69,121.69,121.16,112.54,105.95,67.68；HR-MS(ESI)m/z:Cald for C19H16O2N5[M+H]+346.1299,found 346.1292。
实例43：TM-43的制备
Figure BDA0002415083690000211
合成方法与TM-42类似，不同之处在于第一步用4-甲氧基-1-萘氧乙酸替代1-萘氧乙酸，最后一步收率75％，白色固体。mp:227-230℃；1H NMR(400MHz,DMSO-d6)δ17.11(brs,1H),11.70(s,1H),8.89(d,J＝8.1Hz,1H),8.71(dd,J＝0.8,8.5Hz,1H),8.13(d,J＝7.6Hz,1H),8.02(dd,J＝1.4,7.9Hz,1H),7.68–7.56(m,3H),7.38(td,J＝1.1,7.7Hz,1H),6.99(d,J＝8.5Hz,1H),6.85(d,J＝8.5Hz,1H),4.90(s,2H),3.93(s,3H)；HR-MS(ESI)m/z:Cald forC20H18O3N5[M+H]+376.1404,found 376.1403。
实例44：TM-44的制备
Figure BDA0002415083690000212
(1)中间体IB-1a的制备
Figure BDA0002415083690000213
将1-萘乙酸(223mg,1.20mmol)溶于10mL无水二氯甲烷中，加入3滴DMF，然后缓慢滴加草酰氯(190mg,1.50mmol)，室温搅拌反应1h。减压浓缩除去反应溶剂和过量的草酰氯，再将其溶于10mL无水二氯甲烷中备用。将2-氨基苯甲酸甲酯(151mg,1.00mmol)溶解于无水二氯甲烷中，加入三乙胺(202mg,2.00mmol)，然后缓慢加入上述制备的酰氯，室温下反应2h。TLC监测反应完全，将反应液用50mL二氯甲烷稀释，然后水洗一次，有机相用无水硫酸钠干燥,减压除去溶剂后，柱色谱分离(石油醚-乙酸乙酯10∶1)得到中间体IB-1a 190mg,收率:60％。1H NMR(400MHz,CDCl3)δ10.93(s,1H),8.69(d,J＝8.5Hz,1H),8.10(d,J＝8.3Hz,1H),7.88(m,3H),7.53(m,5H),7.02(m,1H),4.24(s,2H),3.71(s,3H)。
(2)目标化合物TM-44的制备
Figure BDA0002415083690000214
将化合物IB-1a(190mg,0.60mmol)加入10mL四氢呋喃-甲醇-水(2:2:1)的混合溶剂中，然后加入NaOH(48mg,1.20mmol)，室温反应2h。TLC监测反应完全，减压浓缩除去反应体系中大部分的有机溶剂，然后加水稀释，用1N盐酸缓慢调节pH至3-4，析出固体，抽滤，干燥得粗品，然后用乙醇-水体系重结晶得到白色固体120mg，收率66％。mp:175-178℃；1HNMR(400MHz,DMSO-d6)δ13.50(s,1H),11.15(s,1H),8.55(d,J＝8.4Hz,1H),8.05(d,J＝7.9Hz,1H),7.95(d,J＝7.4Hz,1H),7.92–7.85(m,2H),7.60(d,J＝6.7Hz,1H),7.58–7.48(m,4H),7.09(t,J＝8.0Hz,1H),4.25(s,2H)；13C NMR(101MHz,DMSO-D6)δ169.74,169.25,140.80,134.09,131.96,131.02,130.97,128.74,128.57,127.93,126.45,125.85,125.77,123.82,122.63,119.61,116.00,42.59；HR-MS(ESI)m/z:Cald for C19H16O3N[M+H]+306.1125,found 306.1119。
实例45：TM-45的制备
Figure BDA0002415083690000221
合成方法与TM-44类似，不同之处在于第一步用2-萘乙酸替代1-萘乙酸，最后一步收率76％，白色固体。mp:154-157℃；1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),11.21(s,1H),8.52(d,J＝8.5Hz,1H),7.95–7.86(m,5H),7.60–7.54(m,1H),7.54–7.47(m,3H),7.12(t,J＝7.5Hz,1H),3.94(s,2H)；HR-MS(ESI)m/z:Cald for C19H16O3N[M+H]+306.1125,found306.1126。
实例46：TM-46的制备
Figure BDA0002415083690000222
合成方法与TM-44类似，不同之处在于第一步用胡椒乙酸替代1-萘乙酸，最后一步收率68％，白色固体。mp:170-173℃；1H NMR(400MHz,DMSO-d6)δ13.57(s,1H),11.08(s,1H),8.52(dd,J＝1.0,8.5Hz,1H),7.94(dd,J＝1.6,7.9Hz,1H),7.56(ddd,J＝1.7,7.4,8.7Hz,1H),7.15–7.09(m,1H),6.93(d,J＝1.6Hz,1H),6.88(d,J＝7.9Hz,1H),6.82(dd,J＝1.6,8.0Hz,1H),6.00(s,2H),3.67(s,2H)；HR-MS(ESI)m/z:Cald for C16H14O5N[M+H]+300.0866,found 300.0870。
实例47：TM-47的制备
Figure BDA0002415083690000223
合成方法与TM-44类似，不同之处在于第一步用2-氯苯乙酸替代1-萘乙酸，最后一步收率77％，白色固体。mp:123-125℃；1H NMR(400MHz,DMSO-d6)δ13.62(s,1H),11.14(s,1H),8.55(dd,J＝1.0,8.5Hz,1H),7.94(dd,J＝1.6,7.9Hz,1H),7.60–7.55(m,1H),7.54–7.50(m,1H),7.50–7.46(m,1H),7.38–7.32(m,2H),7.16–7.10(m,1H),3.91(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O3NCl[M+H]+290.0578,found 290.0580。
实例48：TM-48的制备
Figure BDA0002415083690000224
合成方法与TM-44类似，不同之处在于第一步用3-氯苯乙酸替代1-萘乙酸，最后一步收率82％，白色固体。mp:139-140℃；1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),11.12(s,1H),8.48(d,J＝8.0Hz,1H),7.95(dd,J＝1.2,8.0Hz,1H),7.61–7.53(m,1H),7.45(s,1H),7.40–7.30(m,3H),7.17–7.10(m,1H),3.81(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O3NCl[M+H]+290.0578,found 290.0578。
实例49：TM-49的制备
Figure BDA0002415083690000231
合成方法与TM-44类似，不同之处在于第一步用4-氯苯乙酸替代1-萘乙酸，最后一步收率71％，白色固体。mp:175-176℃；1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),11.10(s,1H),8.48(dd,J＝1.1,8.5Hz,1H),7.94(dd,J＝1.7,7.9Hz,1H),7.57(ddd,J＝1.7,7.3,8.7Hz,1H),7.44–7.36(m,4H),7.16–7.11(m,1H),3.78(s,2H)；HR-MS(ESI)m/z:Cald forC15H13O3NCl[M+H]+290.0578,found 290.0578。
实例50：TM-50的制备
Figure BDA0002415083690000232
合成方法与TM-44类似，不同之处在于第一步用3-溴苯乙酸替代1-萘乙酸，最后一步收率79％，白色固体。mp:181-184℃；1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),11.13(s,1H),8.47(d,J＝8.7Hz,1H),7.95(dd,J＝1.7,7.9Hz,1H),7.61–7.54(m,2H),7.51–7.46(m,1H),7.37(d,J＝7.8Hz,1H),7.31(t,J＝7.7Hz,1H),7.17–7.11(m,1H),3.80(s,2H)；HR-MS(ESI)m/z:Cald for C15H13O3NBr[M+H]+334.0073,found 334.0074。
实例51：TM-51的制备
Figure BDA0002415083690000233
合成方法与TM-44类似，不同之处在于第一步用3-甲氧基苯乙酸替代1-萘乙酸，最后一步收率75％，白色固体。mp:116-118℃；1H NMR(400MHz,DMSO-d6)δ13.56(s,1H),11.12(s,1H),8.50(dd,J＝1.0,8.4Hz,1H),7.94(dd,J＝1.6,7.9Hz,1H),7.57(ddd,J＝1.7,7.4,8.7Hz,1H),7.26(t,J＝8.0Hz,1H),7.16–7.10(m,1H),6.95(t,J＝2.0Hz,1H),6.92(d,J＝7.6Hz,1H),6.87–6.82(m,1H),3.75(s,3H),3.72(s,2H)；HR-MS(ESI)m/z:Cald forC16H16O4N[M+H]+286.1074,found 286.1073。
实例52：TM-52的制备
Figure BDA0002415083690000234
合成方法与TM-44类似，不同之处在于第一步用3,4-二甲氧基苯乙酸替代1-萘乙酸，最后一步收率70％，白色固体。mp:132-135℃；1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),11.08(s,1H),8.53(d,J＝7.8Hz,1H),7.94(dd,J＝1.6,7.9Hz,1H),7.60–7.53(m,1H),7.12(t,J＝7.9Hz,1H),6.98(d,J＝1.8Hz,1H),6.91(d,J＝8.1Hz,1H),6.86(dd,J＝1.9,8.1Hz,1H),3.75(s,3H),3.73(s,3H),3.67(s,2H)；HR-MS(ESI)m/z:Cald for C17H18O5N[M+H]+316.1179,found 316.1181。
实例53：TM-53的制备
Figure BDA0002415083690000241
(1)中间体IC-1a的制备
Figure BDA0002415083690000242
将1-萘甲酸(206mg,1.20mmol)溶于10mL无水二氯甲烷中，加入3滴DMF，然后缓慢滴加草酰氯(190mg,1.50mmol)，室温搅拌反应1h。减压浓缩除去反应溶剂和过量的草酰氯，再将其溶于10mL无水二氯甲烷中备用。将2-氨基苯甲酸甲酯(151mg,1.00mmol)溶解于5mL无水二氯甲烷中，加入三乙胺(202mg,2.00mmol)，然后缓慢加入上述制备的酰氯，室温下反应2h。TLC监测反应完全，将反应液用50mL二氯甲烷稀释，然后水洗，有机相用无水硫酸钠干燥,减压除去溶剂后，柱色谱分离(石油醚-乙酸乙酯10∶1)得到中间体IC-1a 160mg,收率:52％。1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.46(d,J＝8.3Hz,1H),8.37(m,1H),8.14(d,J＝8.3Hz,1H),8.04(d,J＝7.8Hz,1H),7.98(dd,J＝1.6,7.9Hz,1H),7.90(d,J＝7.1Hz,1H),7.72(m,1H),7.65(m,3H),7.29(m,1H),3.82(s,3H)。
(2)目标化合物TM-53的制备
Figure BDA0002415083690000243
将化合物IC-1a(160mg,0.52mmol)加入10mL四氢呋喃-甲醇-水(2:2:1)的混合溶剂中，然后加入NaOH(42mg,1.04mmol)，室温反应2h。TLC监测反应完全，减压浓缩除去反应体系中大部分的有机溶剂，然后加水稀释，用1N盐酸溶液缓慢调节pH至3-4，析出固体，抽滤，干燥得粗品，然后用乙醇-水体系重结晶得到目标化合物107mg，收率71％。mp:203-205℃；1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),11.81(s,1H),8.73(d,J＝8.4Hz,1H),8.43–8.33(m,1H),8.13(d,J＝8.2Hz,1H),8.09–8.00(m,2H),7.91(d,J＝7.0Hz,1H),7.71(t,J＝7.8Hz,1H),7.68–7.56(m,3H),7.25(t,J＝7.6Hz,1H)；13C NMR(101MHz,DMSO-d6)δ169.58,166.89,140.77,134.16(2C),133.38,131.19,131.11,129.60,128.45,127.28,126.58,125.48,125.14,125.11,123.29,120.30,117.34；HR-MS(ESI)m/z:Cald for C18H14O3N[M+H]+292.0968,found 292.0967。
实例54：TM-54的制备
Figure BDA0002415083690000244
合成方法与TM-53类似，不同之处在于第一步用4-甲氧基-1-萘甲酸替代1-萘甲酸，最后一步收率66％，白色固体。mp:181-185℃；1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.75(d,J＝8.2Hz,1H),8.49(d,J＝8.3Hz,1H),8.25(d,J＝7.7Hz,1H),8.06(dd,J＝1.2,8.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.66–7.54(m,3H),7.17(t,J＝7.2Hz,1H),7.07(d,J＝8.1Hz,1H),4.04(s,3H)；HR-MS(ESI)m/z:Cald for C19H16O4N[M+H]+322.1074,found322.1075。
实例55：TM-55的制备
Figure BDA0002415083690000251
合成方法与TM-53类似，不同之处在于第一步用4-溴-1-萘甲酸替代1-萘甲酸，最后一步收率75％，白色固体。mp:252-253℃；1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),11.77(s,1H),8.64(d,J＝7.7Hz,1H),8.42(d,J＝7.8Hz,1H),8.28(d,J＝8.3Hz,1H),8.07–8.02(m,2H),7.83–7.68(m,4H),7.30–7.24(m,1H)；HR-MS(ESI)m/z:Cald for C18H13O3NBr[M+H]+370.0073,found 370.0075。
实例56：TM-56的制备
Figure BDA0002415083690000252
合成方法与TM-53类似，不同之处在于第一步用4-氟-1-萘甲酸替代1-萘甲酸，最后一步收率65％，白色固体。mp:166-169℃；1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),11.79(s,1H),8.67(d,J＝8.4Hz,1H),8.50–8.43(m,1H),8.20–8.15(m,1H),8.04(dd,J＝1.6,7.9Hz,1H),7.96(dd,J＝5.5,7.9Hz,1H),7.78–7.67(m,3H),7.50(dd,J＝8.0,10.5Hz,1H),7.30–7.22(m,1H)；HR-MS(ESI)m/z:Cald for C18H13O3NF[M+H]+310.0874,found 310.0875。
实例57：TM-57的制备
Figure BDA0002415083690000253
合成方法与TM-53类似，不同之处在于第一步用喹啉-4-羧酸替代1-萘甲酸，最后一步调pH至5-6，收率55％，白色固体。mp:245-247℃；1H NMR(400MHz,DMSO-d6)δ13.66(s,1H),11.83(s,1H),9.09(d,J＝4.2Hz,1H),8.57(d,J＝8.2Hz,1H),8.35(d,J＝8.5Hz,1H),8.15(d,J＝8.4Hz,1H),8.04(d,J＝7.8Hz,1H),7.90–7.80(m,2H),7.72(t,J＝7.6Hz,2H),7.30(t,J＝7.6Hz,1H)；13C NMR(101MHz,DMSO-d6)δ169.37,164.99,150.48,148.20,141.39,139.79,134.00,131.12,130.14,129.52,127.78,125.33,124.00,123.77,121.04,118.95,118.62；HR-MS(ESI)m/z:Cald for C17H13O3N2[M+H]+293.0921,found 293.0917。
实例58：TM-58的制备
Figure BDA0002415083690000261
合成方法与TM-53类似，不同之处在于第一步用6-氯喹啉-4-羧酸替代1-萘甲酸，最后一步调pH至5-6，收率51％，白色固体。mp:275-279℃；1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),11.97(s,1H),9.12(d,J＝4.2Hz,1H),8.51(d,J＝8.2Hz,1H),8.44(d,J＝2.1Hz,1H),8.17(d,J＝9.0Hz,1H),8.04(d,J＝7.6Hz,1H),7.94–7.87(m,2H),7.70(t,J＝7.8Hz,1H),7.30(t,J＝7.6Hz,1H)；HR-MS(ESI)m/z:Cald for C17H12O3N2Cl[M+H]+327.0531,found327.0534。
实例59：TM-59的制备
Figure BDA0002415083690000262
合成方法与TM-53类似，不同之处在于第一步用6-溴喹啉-4-羧酸替代1-萘甲酸，最后一步调pH至5-6，收率56％，白色固体。mp:267-269℃；1H NMR(400MHz,DMSO-d6)δ13.67(s,1H),11.84(s,1H),9.13(d,J＝4.4Hz,1H),8.59(d,J＝1.6Hz,1H),8.51(d,J＝8.2Hz,1H),8.09(d,J＝9.0Hz,1H),8.04(d,J＝7.7Hz,1H),8.00(dd,J＝1.8,9.0Hz,1H),7.91(d,J＝4.3Hz,1H),7.71(t,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H)；13C NMR(101MHz,DMSO-d6)δ169.28,164.45,151.13,146.86,140.17,139.54,133.92,133.25,131.71,131.06,127.52,125.07,124.17,121.36,121.13,119.92,119.03；HR-MS(ESI)m/z:Cald for C17H12O3N2Br[M+H]+371.0026,found 371.0020。
实例60：TM-60的制备
Figure BDA0002415083690000263
合成方法与TM-53类似，不同之处在于第一步用喹啉-4-羧酸替代1-萘甲酸，同时用3-氨基苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步调pH至5-6，收率59％，白色固体。mp:230-232℃；1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),10.96(s,1H),9.06(d,J＝4.3Hz,1H),8.47(s,1H),8.17(d,J＝8.4Hz,1H),8.13(d,J＝8.3Hz,1H),7.99(d,J＝9.0Hz,1H),7.89–7.82(m,1H),7.79–7.67(m,3H),7.53(t,J＝7.9Hz,1H)；13C NMR(101MHz,DMSO-d6)δ167.08,165.48,150.34,147.96,141.65,138.97,131.44,129.99,129.48,129.14,127.67,125.22,124.97,124.07,123.91,120.71,119.29；HR-MS(ESI)m/z:Cald for C17H13O3N2[M+H]+293.0921,found 293.0918。
实例61：TM-61的制备
Figure BDA0002415083690000264
合成方法与TM-53类似，不同之处在于第一步用苯并呋喃-2-甲酸替代1-萘甲酸，最后一步收率61％，白色固体。mp:195-198℃；1H NMR(400MHz,DMSO-d6)δ13.91(s,1H),12.53(s,1H),8.72(d,J＝8.3Hz,1H),8.08(dd,J＝1.3,7.9Hz,1H),7.83(d,J＝7.8Hz,1H),7.73(s,1H),7.68(t,J＝7.6Hz,2H),7.53(t,J＝7.8Hz,1H),7.39(t,J＝7.5Hz,1H),7.24(t,J＝7.6Hz,1H)；HR-MS(ESI)m/z:Cald for C16H12O4N[M+H]+282.0761,found 282.0756。
实例62：TM-62的制备
Figure BDA0002415083690000271
合成方法与TM-53类似，不同之处在于第一步用苯并噻吩-2-甲酸替代1-萘甲酸，最后一步收率55％，白色固体。mp:258-260℃；1H NMR(400MHz,DMSO-d6)δ13.91(s,1H),12.53(s,1H),8.63–8.56(m,1H),8.13–8.03(m,4H),7.71–7.62(m,1H),7.56–7.44(m,2H),7.23(t,J＝7.6Hz,1H)；HR-MS(ESI)m/z:Cald for C16H12O3NS[M+H]+298.0532,found298.0526。
实例63：TM-63的制备
Figure BDA0002415083690000272
合成方法与TM-53类似，不同之处在于第一步用喹啉-2-羧酸替代1-萘甲酸，最后一步调pH至5-6，收率61％，白色固体。mp:257-259℃；1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),13.43(s,1H),8.96–8.89(m,1H),8.65(d,J＝8.5Hz,1H),8.29(d,J＝8.5Hz,1H),8.13(d,J＝8.8Hz,2H),8.09(dd,J＝1.6,7.9Hz,1H),7.97–7.89(m,1H),7.82–7.74(m,1H),7.73–7.64(m,1H),7.24(t,J＝8.1Hz,1H)；HR-MS(ESI)m/z:Cald for C17H13O3N2[M+H]+293.0921,found 293.0915。
实例64：TM-64的制备
Figure BDA0002415083690000273
合成方法与TM-53类似，不同之处在于第一步用呋喃-2-羧酸替代1-萘甲酸，最后一步收率71％，白色固体。mp:193-195℃；1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),12.18(s,1H),8.67(d,J＝8.3Hz,1H),8.05(dd,J＝1.4,7.9Hz,1H),7.99(d,J＝0.8Hz,1H),7.70–7.59(m,1H),7.28(d,J＝3.4Hz,1H),7.20(t,J＝7.2Hz,1H),6.75(dd,J＝1.7,3.4Hz,1H)；HR-MS(ESI)m/z:Cald for C12H10O4N[M+H]+232.0604,found 232.0600。
实例65：TM-65的制备
Figure BDA0002415083690000274
合成方法与TM-53类似，不同之处在于第一步用噻吩-2-羧酸替代1-萘甲酸，最后一步收率77％，白色固体。mp:213-216℃；1H NMR(400MHz,DMSO-d6)δ13.84(s,1H),12.14(s,1H),8.58(d,J＝8.3Hz,1H),8.05(d,J＝7.8Hz,1H),7.94(d,J＝4.8Hz,1H),7.75(d,J＝3.4Hz,1H),7.65(t,J＝7.6Hz,1H),7.28(d,J＝4.4Hz,1H),7.20(t,J＝7.6Hz,1H)；13C NMR(101MHz,DMSO-d6)δ170.02,159.44,140.79,139.63,134.34,132.56,131.30,128.72,128.48,122.98,119.85,116.43；HR-MS(ESI)m/z:Cald for C12H10O3NS[M+H]+248.0376,found 248.0373。
实例66：TM-66的制备
Figure BDA0002415083690000281
合成方法与TM-53类似，不同之处在于第一步用喹啉-2-羧酸替代1-萘甲酸，同时用3-氨基苯甲酸甲酯替换2-氨基苯甲酸甲酯，最后一步收率81％，白色固体。mp:268-270℃；1HNMR(400MHz,DMSO-d6)δ13.06(s,1H),10.96(s,1H),8.68–8.60(m,2H),8.26(t,J＝9.1Hz,2H),8.21–8.16(m,1H),8.13(d,J＝7.9Hz,1H),7.97–7.89(m,1H),7.81–7.70(m,2H),7.53(t,J＝7.9Hz,1H)；13C NMR(101MHz,DMSO-d6)δ167.28,163.03,149.89,145.90,138.58,138.21(2C),131.62,130.68,129.35,128.94,128.42,128.14,124.80,124.41,121.16,118.78；HR-MS(ESI)m/z:Cald for C17H13O3N2[M+H]+293.0921,found 293.0913。
药理实验：
实验例1：目标化合物对hURAT1的体外的抑制活性
方法：
培养稳定表达hURAT1的HEK-293T细胞株(DMEM培养基+10％胎牛血清+500μg/mLG418+1％P/S)，将细胞接种到96孔细胞培养板中，培养12～24小时。化合物用DMSO配成10mM浓度的母液，再用缓冲液稀释成1mM，进一步进行4倍等比稀释。待96孔板中细胞培养贴壁后即可进行14C-尿酸在稳定表达hURAT1细胞中的吸收试验。每孔加入50微升相应化合物和0.1Ci/mL 14C-尿酸溶液，在37℃培养箱中孵育5分钟后，立即加入150微升冰冷的缓冲液以终止吸收。加入50微升/孔的裂解液到所有孔中，置于振荡器上以900rpm的速度振荡5分钟；加入150微升/孔的闪烁液Microsint40，以900rpm的速度振荡5分钟；采用MicroBetaTrilux(PerkinElmer公司生产)仪器测定放射活性，并通过XL-fit软件进行分析数据。
结果：
分别测定了上述化合物在浓度为10μM时对hURAT1的抑制率；测定并计算抑制活性较好的化合物的IC50值，结果如表1所示。
表1.化合物对hURAT1的抑制作用
Figure BDA0002415083690000291
ND:Not Determined，未测试。

Claims (11)

1.一种由下述通式I表示的化合物及其药学上可接受的盐，
Figure FDA0002415083680000011
其中，
Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基、取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基；
R1选自氢或卤素；
L选自-XC(R2 R3)2-或-(CH2)n-，其中X选自氧或硫原子，R2、R3独立选自氢或甲基，n选自0或1。
2.根据权利要求1所述的化合物及其药学上可接受的盐，其特征在于，所述的化合物是通式IA所示的化合物及其生理上可接受的盐：
Figure FDA0002415083680000012
其中，
Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基；
X选自氧原子或硫原子；
R2、R3独立选自氢或甲基。
3.根据权利要求1所述的化合物及其药学上可接受的盐，其特征在于，所述的化合物是通式IB所示的化合物及其生理上可接受的盐：
Figure FDA0002415083680000013
其中，
Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基。
4.根据权利要求1所述的化合物及其药学上可接受的盐，其特征在于，所述的化合物是通式IC所示的化合物及其生理上可接受的盐：
Figure FDA0002415083680000014
其中，
Ar选自取代或未取代的苯基、取代或未取代的萘基、取代或未取代的喹啉基，取代或未取代吡啶基、取代或未取代呋喃基、取代或未取代噻吩基、取代或未取代苯并呋喃基、取代或未取代苯并噻吩基，所述的取代基为单取代或多取代基团，其各自独立的选自卤素、C1-C6直链或支链烷基、C3-C6环烷基、C1-C3直链或支链烷氧基、三氟甲基、氰基、羟基、氨基、硝基。
5.根据权利要求1～4任一项所述的化合物及其药学上可接受的盐，其特征在于，所述的卤素选自氟、氯、溴、碘，所述的C1-C6烷基各自独立地选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基；所述的C3-C6环烷基各自独立的选自环丙基、环丁基、环戊基、环己基；所述的C1-C3烷氧基各自独立地选自甲氧基、乙氧基、丙氧基、异丙氧基。
6.具有如下结构的化合物及其生理上可接受的盐，其特征在于，所述化合物选自：
Figure FDA0002415083680000021
Figure FDA0002415083680000031
Figure FDA0002415083680000041
Figure FDA0002415083680000051
Figure FDA0002415083680000061
7.权利要求1～6任一项所述化合物的制备方法，其特征在于，包括以下步骤：
相应的酸在草酰氯活化下得到相应的酰氯，然后与胺类化合物发生酰化反应，得到中间体I-1，随后I-1在碱性条件下水解得到目标化合物I；
Figure FDA0002415083680000062
Ar、L、R1的定义同权利要求1～6任一项所述；
(1)式IA化合物的制备：相应的酚或硫酚类化合物与溴乙酸乙酯或2-溴-2-甲基丙酸乙酯在碳酸钾和碘化钾存在下发生亲核反应生成中间体IA-1,后者在碱性条件下水解得到中间体IA-2；IA-2在草酰氯活化下得到相应的酰氯，然后与氨基苯甲酸甲酯或其衍生物酰化反应，得到中间体IA-3，后者随后在碱性条件下水解得到目标化合物IA；
Figure FDA0002415083680000063
Ar、X、R2、R3的定义同权利要求1～5任一项所述；
(2)式IB化合物的制备：相应的苯乙酸或萘乙酸衍生物在草酰氯活化下得到相应的酰氯，然后与2-氨基苯甲酸甲酯发生酰化反应，得到中间体IB-1，随后IB-1在碱性条件下水解得到目标化合物IB；
Figure FDA0002415083680000071
Ar的定义同权利要求1～5任一项所述；
(3)式IC化合物的制备：相应的芳基甲酸类化合物在草酰氯活化下得到相应的酰氯，然后与氨基苯甲酸甲酯类化合物发生酰化反应得到中间体IC-1，随后IC-1在碱性条件下水解得到目标化合物；
Figure FDA0002415083680000072
Ar的定义同权利要求1～5任一项所述。
8.一种含有有效剂量的如权利要求1～6所述的任一化合物及其药学上可接受的盐及载体的药物组合物。
9.根据权利要求8所述的药物组合物，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、颗粒剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
10.权利要求1～6任一项所述的化合物及其药学上可接受的盐在制备预防和/或治疗尿酸盐转运蛋白1相关疾病的药物中的应用。
11.根据权利要求10所述的应用，其特征在于所述的尿酸盐转运蛋白1相关疾病选自高尿酸血症或痛风。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2088225A1 (en) * 1970-05-29 1972-01-07 Ugine Kuhlmann Substd salicylanilides - having antiuric props
GB1378618A (en) * 1972-04-15 1974-12-27 Microbial Chem Res Found N-2,4-dihydroxybenzoyl-4-aminosalicyclic acid
JPS5126839A (ja) * 1974-08-21 1976-03-05 Dainippon Pharmaceutical Co Benzuaniridojudotaino seizoho

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2088225A1 (en) * 1970-05-29 1972-01-07 Ugine Kuhlmann Substd salicylanilides - having antiuric props
GB1378618A (en) * 1972-04-15 1974-12-27 Microbial Chem Res Found N-2,4-dihydroxybenzoyl-4-aminosalicyclic acid
JPS5126839A (ja) * 1974-08-21 1976-03-05 Dainippon Pharmaceutical Co Benzuaniridojudotaino seizoho

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