CN117137901A - Tgr5调节剂及其应用 - Google Patents

Tgr5调节剂及其应用 Download PDF

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CN117137901A
CN117137901A CN202310421546.3A CN202310421546A CN117137901A CN 117137901 A CN117137901 A CN 117137901A CN 202310421546 A CN202310421546 A CN 202310421546A CN 117137901 A CN117137901 A CN 117137901A
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alkyl
nmr
carboxylic acid
phenethylsulfamoyl
methyl
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焦宁
徐�明
孙金鹏
豆晓东
赵心怡
常天棋
杨帆
王佳星
吴襄
霍童雨
苏凌宇
刘雅萌
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Peking University
Peking University Third Hospital Peking University Third Clinical Medical College
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Abstract

本发明属于医药技术领域。特别地，本发明涉及可作为TGR5调节剂的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，及其医药用途，所述化合物的结构如式(I)所示。

Description

TGR5调节剂及其应用
技术领域
本发明属于医药技术领域。特别地，本发明涉及可作为TGR5调节剂的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式。本发明还涉及所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的制备方法以及医药用途。
背景技术
G蛋白偶联受体(G Protein-Coupled Receptors，GPCRs)，作为成药最多的靶点，占目前上市药物靶点的30％以上，针对其开发的小分子功能调控剂具有很高的成药潜力价值。
胆汁酸作为营养物质吸收的关键促溶剂，近些年来被发现在脂质代谢之外的机体活动中也起到了重要作用。TGR5(Takeda G Protein-coupled Receptor 5，TGR5)，又名GPBAR1、GPCR19、GPR131、BG37、M-BAR等是一种重要的胆汁酸G蛋白偶联受体，分别在2002年及2003年被Banyu制药和Takeda公司独立发现。TGR5基因包括993对碱基，编码由330个氨基酸组成的蛋白质。人TGR5基因位于染色体2q35，与牛、兔和啮齿类动物的基因同源性大于80％，显示了哺乳动物结构蛋白的保守性。TGR5在人体表达广泛，胆囊高表达，胃肠道、肝脏、脾脏、卵巢、胎盘、肺等中等表达，骨骼肌、棕色脂肪组织、大脑、皮肤等较低表达。与广泛分布相对应，TGR5受体调控多种生理过程，如能量代谢、免疫炎症反应、肝胆系统功能、胃肠道系统功能等。能量代谢方面，由于TGR5激活可促进肠道L细胞分泌GLP-1、GLP-2和PYY，从而促进血糖依赖的胰岛素分泌、抑制食欲、减缓胃肠排空并增加葡萄糖摄取利用；棕色脂肪组织和骨骼肌的TGR5激动可促进细胞代谢水平。免疫炎症方面，TGR5主要发挥炎症抑制作用，激动TGR5会降低促炎因子的分泌并抵抗氧化应激。Kupffer细胞和肝窦内皮细胞上TGR5激动可促进NO的释放，舒张血管；胆小管上皮细胞TGR5激动促进细胞增殖抑制凋亡。小鼠心脏衰竭模型上，TGR5激动可缓解心肌收缩受损及病理性增生。多样的调控作用使得TGR5成为治疗糖尿病(例如二型糖尿病)、代谢障碍、特应性皮炎、肝纤维化、肥胖症、心血管疾病等的高价值治疗靶点。
直到2020年，TGR5受体的三维结构才由山东大学孙金鹏等利用冷冻电镜技术解析，包括其与小分子配体P395、胆汁酸类似物INT777及下游Gs形成的两个复合结构。这为TGR5配体的发现和理性药物设计提供了基础。
由于激动TGR5具有较高的成药价值，其调控剂研究集中在激动剂方面。按照小分子化学结构类型，可以将TGR5激动剂分为三类：胆汁酸及其类似物、非胆汁酸甾体骨架类、非甾体骨架类。胆汁酸及其类似物包括初级(CA、CDCA、HCA)、次级(DCA、HDCA、LCA、UDCA)胆汁酸、合成胆汁酸类似物(INT777、INT767)等；非胆汁酸甾体骨架包括齐墩果酸衍生物、白桦脂酸衍生物、柠檬苦素衍生物、黄柏桐衍生物、诺米林衍生物等；非甾体骨架类包括联芳基酰胺衍生物、二苯基二磺酰胺衍生物、咪唑或1，2，4-三氮唑衍生物、苯氧吡啶/嘧啶酰胺衍生物、芳环并氮杂衍生物、2-芳基-3-氨基甲基喹啉衍生物、链型结构/多环联芳基酰胺衍生物、肟类结构、吡啶酰胺类结构、联四芳基衍生物等。
本领域技术人员仍然渴望一种新型结构的TGR5调节剂，可用于糖尿病、代谢障碍、特应性皮炎、肝纤维化、肥胖症、心血管疾病等TGR5相关疾病的研究和治疗。
发明内容
本申请的本发明人通过深入的研究和创造性的发现，得到了一系列可作为TGR5调节剂(例如激动剂)的化合物，所述化合物可用于预防或治疗与TGR5相关的疾病，由此提供了下述发明。
化合物的制药用途
在一个方面，本申请提供了化合物用于制备药物中的用途，所述药物用于预防或治疗与TGR5相关的疾病，所述化合物选自式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，
其中，
X1为砜、羰基、亚甲基，所述亚甲基基任选地被1或2个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基；
X2为CH＝CH、O或CH2-CH2；
R1为H、苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基，所述苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基或C2-C6炔基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基、卤代C1-C6烷基、卤代C1-C6烷氧基；
R2为H或C1-C6烷基，任选地，R2与X2形成呋喃环；任选地，所述呋喃环被C1-C6烷基所取代；
R3选自氢、苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯氧基、苯甲酰基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基、8-10元含氮螺杂环基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基或8-10元含氮螺杂环基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基、C1-C6烷酰基-苯基-C1-C6烷酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
R5选自：羟基、-O-R6、-NH-R7；R6、R7独立地选自C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、苯基；
n1、n2、n3各自独立地选自0、1、2、3、4、5、6；
任选地，与R1之间的任意一个或多个亚甲基上的碳被氧代。
在一些实施方案中，所述化合物具有如式(II)所示的结构，
其中，X1、R1、R3、R4、R5、R6、R7、n1、n3如上文所述；
R8为C1-C6烷基。
在一些实施方案中，R3选自苯基、萘基、喹啉基。
在一些实施方案中，R3为氢。
在一些实施方案中，X1为砜或亚甲基；
R1为苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3选自苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯氧基、苯甲酰基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基、C1-C6烷酰基-苯基-C1-C6烷酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为1或2。
在一些实施方案中，
X1为砜或亚甲基；
R1为苯基，所述苯基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3选自苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯甲酰基、苯氧基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为1；
R8为甲基。
在一些实施方案中，X1为砜或亚甲基；
R1为苯基或吡啶基，所述苯基或吡啶基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3为氢或苯基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为0或1；
R8为甲基；
R5为羟基或-NH-R7；R7选自C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、苯基；
任选地，与R1之间的任意一个亚甲基上的碳被氧代。
在一些实施方案中，X1为羰基或亚甲基，所述亚甲基基任选地被1或2个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基；
X2为CH＝CH或CH2-CH2；
R1为H、苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
R2为H；
R3为苯基，任选地，R3被一个或多个R4取代；
R4选自：二(C1-C6烷基)氨基、单或双C1-C6烷基取代的胺甲酰基；
n1选自0、1、2、3、4、5、6；
n2为0；
n3为0或1。
在一些实施方案中，所述化合物具有式(III)所示的结构，
其中，X1’为砜；
R1’选自H、苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基，所述苯基、5-6元杂芳基、5-6元环烷基或5-6元杂环基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基、卤代C1-C6烷基、卤代C1-C6烷氧基；
R3’选自任选被一个或多个R4取代的苯基；
R4’选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、哌嗪基、哌啶基、8-10元含氮螺杂环基；所述哌嗪基、哌啶基、8-10元含氮螺杂环基上的N任选被C1-C6烷氧羰基取代；
R5’为羟基；
R8’为C1-C6烷基；
n1’、n3’各自独立地选自0、1、2。
在一些实施方案中，所述化合物具有式(IV)所示的结构，
其中，X2为CH＝CH、O或CH2-CH2；
R2为H或C1-C6烷基，n2为0或1。
在一些实施方案中，所使用的化合物选自：
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在一些实施方案中，所述与TGR5相关的疾病选自：与TGR5相关的肝脏疾病、心血管疾病、消化系统疾病、神经系统疾病、内分泌系统疾病或皮肤或结缔组织疾病。
在一些实施方案中，所述与TGR5相关的疾病选自：代谢性疾病、肿瘤、炎性肠病相关疾病。
在一些实施方案中，所述与TGR5相关的疾病选自：与DNA/RNA病毒感染相关的疾病。
在一些实施方案中，所述与TGR5相关的疾病选自：动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、胆汁淤积性肝病、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、葡萄糖代谢障碍、高血糖、高脂血症(例如，高胆固醇血症)、胆石、肝硬化、胆汁淤积(例如肝内胆汁淤积)；
心肌梗塞/心肌梗死、心肌缺血、心肌缺血再灌注损伤相关疾病；
炎性肠病相关疾病，选自：溃疡性结肠炎、克罗恩病、未定型结肠炎、结肠炎相关结直肠癌；
肿瘤，选自：乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤；
肌萎缩性侧索硬化症、多发性硬化、囊性纤维化、哮喘。
治疗方法
本申请还提供了一种用于在受试者中预防或治疗与TGR5相关的疾病的方法，所述方法包括向有此需要的受试者施用有效量的如上所述的任意化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式。
所述与TGR5相关的疾病可以选自上文所述的疾病。
化合物
在一个方面，本申请提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物如具有如式(II)所示的结构，
其中，
X1为砜或亚甲基；
R1为苯基或吡啶基，所述苯基或吡啶基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3为氢或苯基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为0或1；
R8为甲基；
R5为羟基或-NH-R7；R7选自C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、苯基；
任选地，与R1之间的任意一个亚甲基上的碳被氧代。
在一个方面，本申请提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物具有如式(I)所示的结构，
其中，X1为羰基或亚甲基，所述亚甲基基任选地被1或2个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基；
X2为CH＝CH或CH2-CH2；
R1为H、苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
R2为H；
R3为苯基，任选地，R3被一个或多个R4取代；
R4选自：二(C1-C6烷基)氨基、单或双C1-C6烷基取代的胺甲酰基；
n1选自0、1、2、3、4、5、6；
n2为0；
n3为0或1。
在一个方面，本申请提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物具有式(III)所示的结构，
其中，X1’为砜；
R1’选自H、苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基，所述苯基、5-6元杂芳基、5-6元环烷基或5-6元杂环基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基、卤代C1-C6烷基、卤代C1-C6烷氧基；
R3’选自任选被一个或多个R4取代的苯基；
R4’选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、哌嗪基、哌啶基、8-10元含氮螺杂环基；所述哌嗪基、哌啶基、8-10元含氮螺杂环基上的N任选被C1-C6烷氧羰基取代；
R5’为羟基；
R8’为C1-C6烷基；
n1’、n3’各自独立地选自0、1、2。
在一个方面，本申请提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物具有式(IV)所示的结构，
其中，X2为CH＝CH、O或CH2-CH2；
R2为H或C1-C6烷基，n2为0或1。
在一些实施方案中，本发明的化合物选自：
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在一些实施方案中，所述的酯为化合物的乙酯。
药物组合物
本申请还提供了一种药物组合物，其包含本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式；任选地，所述药物组合物还包含药学上可接受的载体或赋形剂。
在本发明中，所述药物组合物可以是医学领域已知的任何形式。例如，所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)、吸入剂、喷雾剂等形式。优选剂型取决于预期的给药方式和治疗用途。
在某些实施方案中，所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式，可以以单位剂量形式存在于药物组合物中，以便于施用。
所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或者所述药物组合物，可以通过本领域已知的任何合适的方法来施用，包括但不限于，口服、直肠、肠胃外或局部给药。
一种示例性施用途径是口服给药。用于口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂、酏剂等。除活性化合物以外，液体剂型可含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂。除惰性稀释剂以外，口服给药的液体剂型也可包括助剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂等。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、锭剂、粉剂、颗粒剂等。除活性化合物以外，固体剂型可含有药学上可接受的惰性赋形剂或载体，例如填充剂、粘合剂、湿润剂、崩解剂、润滑剂及其混合物。
本发明的化合物或药物组合物也可通过非口服途径给药。
因此，另一种示例性的施用途径是肠胃外给药，例如，皮下注射、静脉注射、腹膜内注射、肌肉注射、胸骨内注射和注入。用于肠道外给药的剂型可以为注射制剂，包括注射液、注射用无菌粉末或注射用浓溶液。除活性化合物以外，注射剂型可含有药学上可接受的载体例如无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。
另一种示例性的施用途径是局部给药，例如经皮给药(如通过经皮贴剂或离子电渗装置给药)、眼内给药或者鼻内或吸入给药。用于经皮给药的剂型可以为局部凝胶剂、喷雾剂、软膏剂和霜剂。除活性化合物以外，局部剂型可含有能够提高该活性化合物通过皮肤或其它作用区域的吸收或渗透的成分。当本发明的化合物通过经皮装置给药时，给药将使用存储和多孔膜类型或者固体基质品种的贴剂完成。用于眼部局部给药的剂型可以为滴眼剂，其中本发明的化合物被溶于或者悬浮于适宜的载体中。对于鼻内给药或吸入给药来说，本发明的化合物以溶液剂或悬浮剂的形式从压力喷雾容器中被方便地递送，所述传递是通过患者压握或者泵送而进行的，或者是作为气溶胶喷雾剂制剂从压力容器或喷雾器中使用适宜的抛射剂而传递的。
另一种示例性的施用途径是直肠给药。用于直肠给药的剂型可以为栓剂。
此外，还可以使用药学领域已知的其它载体材料和给药方式。本发明的药物组合物可以通过任何公知的制药工艺制备，例如有效的制剂和给药方法。关于有效制剂和给药方法的上述考虑因素是本领域中公知的，并且描述于标准教科书中。药物的制剂描述在，例如，Hoover，John E.，Remington′s Pharmaceutical Sciences.Mack Publishing Co.，Easton，Pennsylvania，1975；Liberman等人编辑，Pharmaceutical Dosage Forms，MarcelDecker，New York，N.Y.，1980；以及Kibbe等人编辑，Handbook of PharmaceuticalExcipients(第3版)，American Pharmaceutical Association，Washington，1999。
在某些实施方案中，所述药物组合物含有本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的量为0.01-2000mg，优选为0.1-1000mg，更优选为1-800mg，更优选为10-600mg，特别优选为50-500mg。
本发明的药物组合物可以包括“治疗有效量”或“预防有效量”的如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式。“预防有效量”是指，足以预防，阻止，或延迟疾病的发生的量。“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。本领域技术人员理解，如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式的治疗有效量可根据如下因素发生变化：待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
在本发明中，可调整给药方案以获得最佳目的反应(例如治疗或预防反应)。例如，可以单次给药，可以在一段时间内多次给药，或者可以随治疗情况的紧急程度按比例减少或增加剂量。
本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的治疗或预防有效量的典型非极限范围是0.01～1000mg/kg，例如0.1～500mg/kg。应注意的是，剂量可随需要治疗的症状的类型和严重性不同而发生变化。此外，本领域技术人员理解，对于任一特定患者，特定的给药方案应根据患者需要和医生的专业评价而随时间调整；此处给出的剂量范围只用于举例说明目的，而不限定本发明药物组合物的使用或范围。
在某些实施方案中，所述药物组合物还可以包含另外的药学活性剂。
在某些实施方案中，在所述药物组合物中，本发明化合物与所述另外的药学活性剂作为分离的组分或混合的组分提供。因此，本发明化合物与所述另外的药学活性剂可以同时、分开或相继施用。
制备方法
化合物TZ-S14～TZ-S62、TZ-W7、TZ-R1～TZ-R7、TZ-R9～TZ-R27、TZ-D10～TZ-D11的合成路线见方案1.1。首先，邻羟基苯乙酮和溴乙酸乙酯在N,N-二甲基甲酰胺中回流环合生成中间体M1。中间体M1在氯仿中与氯磺酸反应得到中间体M2后，与2-苯基乙烷-1-胺缩合生成中间体M3。中间体M3与取代的苄溴亲核取代生成中间体M4、TZ-S8、M-R1～M-R7、M-R9～M-R27。M4在强碱作用下水解得到终产物TZ-S14～TZ-S62、TZ-W7、TZ-R1～TZ-R7、TZ-R9～TZ-R27、TZ-D10～TZ-D11。
方案1.1化合物TZ-S14～TZ-S62、TZ-W7、TZ-R1～TZ-R7、TZ-R9～TZ-
R27、TZ-D10～TZ-D11的合成路线。
示例性的试剂、反应条件和收率如下:
(a)溴乙酸乙酯,碳酸钾,N,N-二甲基甲酰胺,加热至回流,反应3h,收率:37％；
(b)氯磺酸,氯仿,0℃到室温,反应4h,收率:45％；
(c)取代胺,碳酸钾,无水二氯甲烷,反应3h,收率:87％；
(d)取代的苄溴,碳酸钾,二氯甲烷,加热至60℃,反应2-72h,收率:48-99％；
(e)氢氧化钠或氢氧化锂,乙醇/水＝4:1,加热至回流,反应1h,收率:34-99％.
作为一种实施方案，设计化合物TZ-S11、TZ-S76、TZ-S79、TZ-S86、TZ-S87、TZ-R8的合成路线见方案1.2。首先，4-硝基苯基哌嗪与取代的酰氯缩合生成中间体M5。中间体M5在锌粉盐酸中还原生成相应的氨基中间体M6。苯乙醛或苯乙胺与取代的苯甲胺或苯甲醛通过还原胺化生成中间体M7，或(2-碘乙基)苯与取代的苯胺或苯乙胺亲核取代生成中间体M7。中间体M7与中间体M2酰胺缩合生成中间体M8、M-R8后，在强碱作用下水解得到终产物TZ-S11、TZ-S76、TZ-S79、TZ-S86、TZ-S87、TZ-R8。
方案1.2化合物TZ-S11、TZ-S76、TZ-S79、TZ-S86、TZ-S87、TZ-R8的合成路线。
示例性的试剂、反应条件和收率如下:
(a)取代的酰氯,三乙胺,无水四氢呋喃,0℃至室温,反应10h,收率:87-93％；
(b)锌粉,浓盐酸,室温反应11h,收率:60-99％；
(c)取代苄胺或苯甲醛,氰基硼氢化钠,原甲酸三甲酯,甲醇,0℃至室温,反应10h,收率:44-94％；
(d)取代苯胺或苯乙胺,碳酸钾,乙腈,加热至60℃,反应24h,收率:6-82％；
(e)中间体M2,碳酸钾,二氯甲烷,加热至60℃,反应2-72h,收率:25-97％；
(f)氢氧化钠,乙醇/水＝4:1,加热至回流,反应1h,收率:38-99％.
设计化合物TZ-S96、TZ-S105的合成路线见方案1.3。首先，中间体M8-77和M8-87在三氟乙酸中脱去Boc保护基生成中间体M9。中间体M9与取代的酸酐、酰氯或羧酸缩合生成中间体9，或与卤代烃亲核取代生成中间体M10。中间体M10在强碱作用下水解得到终产物TZ-S89～TZ-S105。
方案1.3化合物TZ-S96、TZ-S105的合成路线。
示例性的试剂、反应条件和收率如下:
(a)三氟乙酸,二氯甲烷,室温反应2h,收率:98-99％；
(b)取代的酸酐,二异丙基乙胺,二甲氨基吡啶,无水二氯甲烷,0℃至室温,反应5h,或取代的酰氯,三乙胺,无水二氯甲烷,0℃至室温,反应5h,或取代的羧酸,碳二亚胺盐酸盐,羟基苯并三唑,二异丙基乙胺,二甲基氨基吡啶,无水二氯甲烷,室温反应24h,或卤代烃,碳酸钾,乙腈,加热至60℃,反应24h,收率:52-99％；
(c)氢氧化钠,乙醇/水＝4:1,加热至回流,反应1h,收率:28-89％.
术语定义
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
如本文中所使用的，术语“C1-C6烷基”是指含有1-6个碳原子的直链或支链烷烃去掉一个氢原子后得到的基团，优选的C1-C6烷基是C1-C4烷基，其具体实例包括但不限于：甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、叔丁基或异丁基。
如本文中所使用的，术语“卤素”包括氟、氯、溴和碘。
如本文中所使用的，术语“卤代”是指基团或化合物上的氢被一个或多个卤素原子取代，包括全卤代和部分卤代。
如本文中所使用的，术语“氧代(oxo)”是指基团或化合物上的碳原子、氮原子或硫原子形成C＝O、N＝O、S＝O或SO2。
如本文中所使用的，术语“烷氧基”是指，以烷基-O-方式形成的基团，实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、新戊氧基、或正己氧基。
如本文中所使用的，术语“C1-C6酰基”是指以H-(C＝O)-或者C1-C6烷基-(C＝O)-方式形成的基团，实例包括但不限于甲酰基、乙酰基、正丙酰基、正丁酰基、异丁酰基、正戊酰基、新戊酰基等。
如本文中所使用的，术语“5至6元单环杂芳基”是指含有5至6个环原子的具有芳香性的单环环状基团，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，同时包括环上的碳原子、氮原子和硫原子被氧代的情况。实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮、4-吡啶酮、嘧啶基等。
如本文中所使用的，术语“药学上可接受的盐”是指，(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐，并且包括但不限于，碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等；无机碱盐，如铵盐；有机碱盐，如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及，(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH2)与适当的无机或者有机阴离子(酸)形成的盐，并且包括但不限于，氢卤酸盐，如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等；无机酸盐，如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等；低级烷磺酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等；芳基磺酸盐，如苯磺酸盐、对苯磺酸盐等；有机酸盐，如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等；氨基酸盐，如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
如本文中所使用的，术语“药学上可接受的酯”是指，本发明所提供的化合物中存在的-COOH与适当的醇(例如甲醇或乙醇)形成的酯，或者本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。
如本文中所使用的，术语“溶剂合物”是指本发明化合物与溶剂分子缔合形成的物质。所述溶剂可以是有机溶剂(例如甲醇、乙醇、丙醇、乙腈等)，例如本发明化合物可以与乙醇形成乙醇化物。本发明化合物还可以与水形成水合物。
如本文中所使用的，术语“晶型”是指物质的晶体结构。物质在结晶时由于受各种因素影响，使分子内或分子间键合方式发生改变，致使分子或原子在晶格空间排列不同，形成不同的晶体结构。本发明化合物可以一种晶体结构存在，也可以多种晶体结构存在，即具有“多晶型”。本发明化合物可以不同的晶型存在。
如本文中所使用的，术语“立体异构体”包括构象异构体和构型异构体，其中所述构型异构体主要包括顺反异构体和旋光异构体。本发明化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，及其任何组合或任何混合物。例如单一对映异构体，单一非对映异构体或以上的混合物。当本发明化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。
如本文中所使用的，术语“前药”是指可在受试者体内通过例如氧化、还原、水解等反应转化成本发明的化合物。前药自身可或不可具有式(I)化合物的生物活性(例如，调节糖脂代谢活性，抗炎活性，抗氧化活性)。例如，包括羟基或羧基的式(I)化合物可以酯的形式给药，其在体内水解转化成羟基化合物或羧基化合物。类似地，包括氨基的式(I)化合物发生酰化、烷基化或磷酸化，以形成例如二十烷酰基氨基(Eicosanoylamino)、丙氨酰氨基、新戊酰氧甲基氨基的化合物给药。关于前体药物使用的进一步信息可以参见Pro-drugs asNovel Delivery Systems，Vol.14，ACS Symposium Series(T Higuchi and W Stella)和Bioreversible Carriers in Drug Design，Pergamon Press，1987(ed.E B Roche，American Pharmaceutical Association)。根据本发明的一些前体药物实例包括：(i)若式(I)化合物含有羧酸官能团(-COOH)，则包括它的酯，例如用(C1-C8)烷基代替氢；(ii)若式(I)化合物含有醇官能团(-OH)，则包括它的醚，例如用(C1-C6)烷酰氧基甲基代替氢；和(iii)若式(I)化合物含有伯或仲氨基官能团(-NH2或-NHR，其中R不为H)，则包括它的酰胺，例如用(C1-C10)烷酰基代替一个或两个氢。此外，某些式(I)化合物本身可以充当其他式(I)化合物的前体药物。
如本文中所使用的，术语“药学上可接受的载体或赋形剂”是指，在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995)，并且包括但不限于：崩解剂、粘合剂、表面活性剂、助流剂、润滑剂、pH调节剂、离子强度增强剂、维持渗透压的试剂、延迟吸收的试剂、稀释剂、抗氧化剂、着色剂、矫味剂、防腐剂、味道掩蔽剂等。
如本文中使用的，术语“受试者”是指哺乳动物，例如鼠、兔、犬，例如灵长类哺乳动物，例如猴、人。
如本文中使用的，术语“调节剂”是指可以直接或间接与靶标相互作用的分子。所述调节剂包括但不限于激动剂、部分激动剂、反向激动剂和拮抗剂。在本申请的一些实施方案中，调节剂是激动剂。
如本文所用的，术语“激动剂”是指与特定受体结合并且触发在细胞中的反应的分子。激动剂可以模仿与相同受体结合的内源性配体(诸如LPA、前列腺素、激素或神经递质)的作用。
如本文所用的，术语“拮抗剂”是指减弱、抑制或阻止另一种分子的作用或受体位点的活性的分子。拮抗剂包括但不限于竞争性拮抗剂、非竞争性拮抗剂、不竞争性拮抗剂、部分激动剂和反向激动剂。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。
除非特别指明，否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本领域技术人员知晓，实施例以举例方式描述本发明，且不意欲限制本发明所要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通过引用合并入本文。
化合物的合成和结构表征
MS的测定使用Agilent(ESI)质谱仪，生产商：Agilent,型号：Agilent 6120B制备高分辨质谱质谱采用PE SCLEX QSTAR光谱仪记录。
核磁氢谱和核磁碳谱采用用Bruker AVIII-400光谱仪记录。
薄层色谱法纯化采用的事研讨产的GF254(0.4-0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC),使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，溶剂的体积比根据化合物调节，但可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应温度为室温(20-30℃)。
实例中所使用的试剂购自Acros oRganmes，Aldrich Chemical Company或者百灵威化学等公司。
如本文中使用的缩写具有以下含义：
EA：乙酸乙酯；DCM：二氯甲烷；MeOH：甲醇；EtOH：乙醇；PE：石油醚；THF：四氢呋喃；DMF：N,N二甲基甲酰胺；AcCl：乙酰氯；Ac2O：乙酸酐；DMSO：二甲基亚砜；NaOH：氢氧化钠；LiOH：氢氧化锂。
实施例1
3-甲基-N-苯乙基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-甲酰胺(TZ-S8)
将苯乙胺(1mL)和碳酸钾(138mg,1.0mmol)溶于无水二氯甲烷(10mL)中，室温下滴加5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(302mg,1.0mmol)的无水二氯甲烷(20mL)溶液，室温搅拌4h，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(20mL)溶解，乙酸乙酯(20mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝10/1～1/1)得白色固体90mg，收率20％。1H NMR(400MHz,氯仿-d)δ8.10(d,J＝1.6Hz,1H),7.82(dd,J＝8.7,1.9Hz,1H),7.47(d,J＝8.7Hz,1H),7.34(dd,J＝8.9,5.8Hz,2H),7.30–7.14(m,6H),7.05(d,J＝6.5Hz,2H),6.72(t,J＝5.9Hz,1H),4.70(t,J＝6.2Hz,1H),3.74(q,J＝6.9Hz,2H),3.24(q,J＝6.8Hz,2H),2.96(t,J＝7.1Hz,2H),2.76(t,J＝6.9Hz,2H),2.61(s,3H).13C NMR(101MHz,氯仿-d)δ159.5,154.8,144.7,138.6,137.6,135.2,130.2,128.8,128.8,128.7,128.7,126.8,126.7,125.6,122.5,121.2,112.3,44.3,40.4,35.8,35.8,8.9.HRMS(ESI)[M+H]+理论值C26H27N2O4S:463.1692；实测值：463.1693.
实施例2
3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)
将3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(195mg,0.5mmol)，2-氟苄溴(189mg,1.0mmol)，碳酸钾(276mg,2.0mmol)溶于无水二氯甲烷(10mL)中，60℃搅拌过夜，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(20mL)溶解，二氯甲烷(20mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝20/1～2/1)得白色固体219mg，收率88％。1H NMR(400MHz,氯仿-d)δ8.10(s,1H),7.84(d,J＝8.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.44(t,J＝7.0Hz,1H),7.19(ddp,J＝28.7,21.6,7.4Hz,5H),7.00(dd,J＝12.4,8.1Hz,3H),4.50(s,2H),4.49–4.42(m,2H),3.44–3.36(m,2H),2.79–2.68(m,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ160.9(d,J＝247.5Hz,1C),159.9,155.8,142.9,138.1,135.4,131.2(d,J＝3.7Hz,1C),129.8(d,J＝8.2Hz,1C),129.4,128.7,128.5,126.5,126.2,125.6,124.5(d,J＝3.6Hz,1C),123.2(d,J＝14.2Hz,1C),121.5,115.4(d,J＝21.8Hz,1C),113.0,61.6,50.0,45.1(d,J＝3.8Hz,1C),35.2,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-118.62.HRMS(ESI)[M+H]+理论值C27H27NO5FS:496.1594；实测值：496.1595.
实施例3
3-甲基-5-(N-(2-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-16)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-溴苄溴，其余条件均一致。得白色固体267mg，收率96％。1HNMR(400MHz,氯仿-d)δ8.15(s,1H),7.88(d,J＝8.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.52(t,J＝7.5Hz,2H),7.29(t,J＝7.6Hz,1H),7.23–7.10(m,4H),7.01(d,J＝7.0Hz,2H),4.56(s,2H),4.47(q,J＝7.1Hz,2H),3.52–3.36(m,2H),2.76–2.65(m,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,143.0,138.0,135.5,135.3,132.8,130.5,129.4,129.4,128.7,128.5,127.8,126.5,126.2,125.6,123.3,121.6,113.1,61.6,51.8,50.5,35.2,14.4,9.4.HRMS(ESI)[M+H]+理论值C27H27NO5SBr:556.0793；实测值：556.0785.
实施例4
3-甲基-5-(N-(3-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-20)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为3-氟苄溴，其余条件均一致。得白色固体257mg，收率99％。1HNMR(400MHz,氯仿-d)δ8.15(s,1H),7.87(d,J＝8.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.27(q,J＝7.7Hz,1H),7.18(dt,J＝11.6,6.8Hz,3H),7.04(d,J＝7.7Hz,1H),6.97(t,J＝8.1Hz,4H),4.47(q,J＝7.1Hz,2H),4.38(s,2H),3.46–3.30(m,2H),2.74–2.64(m,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ163.0(d,J＝247.9Hz,1C),159.9,155.8,143.0,138.8(d,J＝7.1Hz,1C),138.1,135.4,130.2(d,J＝8.3Hz,1C),129.5,128.6,128.5,126.6,126.2,125.5,123.8(d,J＝2.9Hz,1C),121.5,115.2(d,J＝22.0Hz,1C),114.9(d,J＝21.2Hz,1C),113.1,61.6,51.7(d,J＝1.6Hz,1C),49.7,35.2,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-112.36.HRMS(ESI)[M+H]+理论值C27H27NO5FS:496.1594；实测值：496.1593.
实施例5
3-甲基-5-(N-(3-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-22)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为3-溴苄溴，其余条件均一致。得白色固体265mg，收率92％。1HNMR(400MHz,氯仿-d)δ8.12(s,1H),7.85(d,J＝8.7Hz,1H),7.63(d,J＝8.7Hz,1H),7.39(d,J＝7.0Hz,1H),7.31(s,1H),7.18(dq,J＝14.9,7.1Hz,5H),6.98(d,J＝7.0Hz,2H),4.48(q,J＝7.1Hz,2H),4.35(s,2H),3.48–3.26(m,2H),2.74–2.64(m,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,143.0,138.5,138.1,135.4,131.3,131.1,130.2,129.5,128.7,128.6,126.9,126.6,126.2,125.6,122.7,121.5,113.2,61.6,51.5,49.7,35.3,14.4,9.4.HRMS(ESI)[M+H]+理论值C27H27NO5SBr:556.0793；实测值：556.0792.
实施例6
3-甲基-5-(N-(3-硝基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-25)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为3-硝基苄溴，其余条件均一致。得白色固体259mg，收率99％。1H NMR(400MHz,氯仿-d)δ8.19(s,1H),8.05(d,J＝8.7Hz,2H),7.90(d,J＝8.7Hz,1H),7.64(dd,J＝15.4,8.2Hz,2H),7.46(t,J＝7.8Hz,1H),7.12(q,J＝10.2,8.3Hz,3H),6.95(d,J＝6.9Hz,2H),4.46(dd,J＝15.3,8.2Hz,4H),3.55–3.39(m,2H),2.81–2.67(m,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.7,155.8,148.2,143.0,138.9,137.9,134.8,134.2,129.6,129.5,128.5,128.5,126.5,126.2,125.4,122.8,122.7,121.6,113.1,61.5,51.5,50.0,35.1,14.3,9.3.HRMS(ESI)[M+H]+理论值C27H27N2O7S:523.1539；实测值：523.1531.
实施例7
3-甲基-5-(N-(4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-29)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-氯苄溴，其余条件均一致。得白色固体222mg，收率87％。1HNMR(400MHz,氯仿-d)δ8.12(s,1H),7.86(d,J＝8.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.30–7.23(m,2H),7.22–7.11(m,5H),6.95(d,J＝6.5Hz,2H),4.48(q,J＝7.1Hz,2H),4.34(s,2H),3.43–3.29(m,2H),2.69–2.62(m,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,143.0,138.1,135.4,134.7,133.8,129.7,129.5,128.8,128.6,128.6,126.6,126.2,125.5,121.5,113.1,61.6,51.6,49.6,35.2,14.4,9.4.HRMS(ESI)[M+H]+理论值C27H27NO5SCl:512.1298；实测值：512.1299.
实施例8
3-甲基-5-(N-(4-三氟甲基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-32)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-三氟甲基苄溴，其余条件均一致。得白色固体132mg，收率80％。1H NMR(400MHz,氯仿-d)δ8.19–8.12(m,1H),7.87(dd,J＝8.8,1.6Hz,1H),7.64(d,J＝8.8Hz,1H),7.55(d,J＝8.1Hz,2H),7.38(d,J＝8.0Hz,2H),7.16(t,J＝7.7Hz,3H),6.94(d,J＝6.5Hz,2H),4.48(q,J＝7.1Hz,2H),4.43(s,2H),3.48–3.32(m,2H),2.74–2.64(m,2H),2.60(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.8,155.8,143.1,140.4,138.0,135.2,129.5,128.6,128.6,128.5,126.6,126.1,125.6(d,J＝3.7Hz,1C),125.5,121.6,113.2,61.6,51.8,49.9,35.1,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-62.51.HRMS(ESI)[M+H]+理论值C28H27NO5F3S:546.1562；实测值：546.1567.
实施例9
3-甲基-5-(N-(4-(三氟甲硫基)苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-35)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-(三氟甲硫基)苄溴，其余条件均一致。得白色固体237mg，收率82％。1H NMR(400MHz,氯仿-d)δ8.15(d,J＝1.8Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.59(dd,J＝17.7,8.4Hz,3H),7.32(d,J＝8.1Hz,2H),7.22–7.08(m,3H),6.92(dd,J＝7.6,1.5Hz,2H),4.57–4.29(m,4H),3.47–3.31(m,2H),2.62(d,J＝25.5Hz,5H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.8,155.8,143.1,139.7,138.0,136.5,135.2,129.6(d,J＝309.4Hz,1C),129.5,129.3,128.6,128.5,126.6,126.2,125.5,123.8(d,J＝2.4Hz,1C),121.6,113.2,61.6,51.8,49.9,35.2,14.3,9.3.19F NMR(376MHz,氯仿-d)δ-42.65.
实施例10
3-甲基-5-(N-(4-异丙基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-36)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-异丙基苄溴，其余条件均一致。得白色固体234mg，收率90％。1H NMR(400MHz,氯仿-d)δ8.17(d,J＝1.9Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.62(d,J＝8.8Hz,1H),7.23–7.11(m,7H),6.96(d,J＝6.8Hz,2H),4.48(q,J＝7.1Hz,2H),4.39(s,2H),3.45–3.32(m,2H),2.89(hept,J＝6.8Hz,1H),2.74–2.64(m,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H),1.24(d,J＝6.9Hz,6H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,148.7,142.9,138.4,135.7,133.2,129.4,128.7,128.6,128.5,126.7,126.5,126.3,125.6,121.5,113.0,61.6,51.8,49.3,35.3,33.8,24.0,14.4,9.4.
实施例11
3-甲基-5-(N-(4-(叔丁基)苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-37)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-(叔丁基)苄溴，其余条件均一致。得白色固体236mg，收率89％。1H NMR(400MHz,氯仿-d)δ8.18(d,J＝1.9Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.62(d,J＝8.8Hz,1H),7.33(d,J＝8.4Hz,2H),7.23–7.11(m,5H),7.00–6.92(m,2H),4.48(q,J＝7.1Hz,2H),4.40(s,2H),3.50–3.26(m,2H),2.75–2.65(m,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H),1.31(s,9H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,151.0,142.9,138.4,135.7,132.9,129.4,128.7,128.5,128.3,126.5,126.3,125.6,125.6,121.6,113.0,61.6,51.7,49.3,35.3,34.6,31.4,14.4,9.4.
实施例12
3-甲基-5-(N-(4-乙酰基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-38)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-(乙酰基)苄溴，其余条件均一致。得白色固体256mg，收率98％。1H NMR(400MHz,氯仿-d)δ8.11(d,J＝1.9Hz,1H),7.95–7.76(m,3H),7.57(d,J＝8.7Hz,1H),7.33(d,J＝8.1Hz,2H),7.20–7.02(m,3H),6.97–6.84(m,2H),4.50–4.33(m,4H),3.42–3.28(m,2H),2.67–2.49(m,8H),1.40(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ198.8,159.9,155.8,142.9,142.2,138.0,136.3,135.1,129.4,128.8,128.6,128.5,128.4,126.5,126.2,125.5,121.5,113.2,61.6,51.9,49.9,35.1,26.5,14.3,9.4.HRMS(ESI)[M+H]+理论值C29H30NO6S:520.1794；实测值：520.1786.
实施例13
3-甲基-5-(N-(萘-1-基甲基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-43)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为1-(溴甲基)萘，其余条件均一致。得白色固体220mg，收率84％。1H NMR(400MHz,氯仿-d)δ8.28(d,J＝8.1Hz,1H),8.20(s,1H),7.95(d,J＝8.5Hz,1H),7.81(t,J＝6.7Hz,2H),7.62(d,J＝8.7Hz,1H),7.50(dt,J＝15.2,6.7Hz,2H),7.36(d,J＝8.8Hz,2H),7.08(d,J＝7.3Hz,3H),6.75(d,J＝6.7Hz,2H),4.80(s,2H),4.46(q,J＝6.9Hz,2H),3.40–3.10(m,2H),2.58(s,3H),2.46–2.29(m,2H),1.44(t,J＝7.0Hz,3H).13CNMR(101MHz,氯仿-d)δ159.9,155.9,143.0,138.3,134.5,133.9,132.0,130.9,129.5,129.4,128.7,128.6,128.4,127.9,126.8,126.5,126.4,126.2,125.6,125.0,124.0,121.7,113.1,61.6,51.4,49.9,35.7,14.4,9.4.HRMS(ESI)[M+H]+理论值C31H30NO5S:528.1845；实测值：528.1837.
实施例14
3-甲基-5-(N-(喹啉-8-基甲基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-44)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为8-(溴甲基)喹啉，其余条件均一致。得白色固体222mg，收率84％。1H NMR(400MHz,氯仿-d)δ8.83(d,J＝2.6Hz,1H),8.19–8.07(m,2H),7.95(d,J＝7.1Hz,1H),7.88(d,J＝10.3Hz,1H),7.71(d,J＝8.0Hz,1H),7.61–7.47(m,2H),7.36(dd,J＝8.2,4.2Hz,1H),7.11(dq,J＝14.2,7.0Hz,3H),6.94(d,J＝7.0Hz,2H),5.22(s,2H),4.46(q,J＝7.1Hz,2H),3.71–3.50(m,2H),2.91–2.66(m,2H),2.56(s,3H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.6,149.5,146.2,142.8,138.4,136.4,135.7,134.8,129.7,129.2,128.7,128.4,128.1,127.7,126.5,126.3,126.3,125.6,121.4,121.2,112.8,61.5,50.8,47.5,35.3,14.4,9.4.HRMS(ESI)[M+H]+理论值C30H29N2O5S:529.1797；实测值：529.1790.
实施例15
3-甲基-5-(N-(2,6-二氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-46)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2,6-二氟苄溴，其余条件均一致。得白色固体203mg，收率79％。1H NMR(400MHz,氯仿-d)δ8.15(d,J＝1.6Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.59(d,J＝8.8Hz,1H),7.31–7.21(m,3H),7.20–7.13(m,1H),7.12–7.05(m,2H),6.85(t,J＝7.9Hz,2H),4.56(s,2H),4.48(q,J＝7.1Hz,2H),3.49–3.35(m,2H),2.94–2.80(m,2H),2.61(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ161.8(dd,J＝251.5,7.8Hz,1C),159.9,155.8,142.9,138.3,135.2,130.5(t,J＝10.5Hz,1C),129.2,128.7(d,J＝20.6Hz,1C),126.4(d,J＝10.4Hz,1C),125.6,121.6,112.9,111.9,111.6(dd,J＝19.5,6.1Hz,1C),61.5,49.9,39.4(t,J＝2.9Hz,1C),35.5,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-112.91.HRMS(ESI)[M+H]+理论值C27H26NO5F2S:514.1500；实测值：514.1494.
实施例16
3-甲基-5-(N-(2-氟-6-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-47)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-氟-6-氯苄溴，其余条件均一致。得白色固体240mg，收率91％。1H NMR(400MHz,氯仿-d)δ8.16(d,J＝1.7Hz,1H),7.91(dd,J＝8.8,1.9Hz,1H),7.62(d,J＝8.8Hz,1H),7.25–7.13(m,5H),7.04–6.94(m,3H),4.63(s,2H),4.48(q,J＝7.1Hz,2H),3.40–3.28(m,2H),2.78–2.70(m,2H),2.62(s,3H),1.47(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ162.2(d,J＝252.6Hz,1C),159.9,155.8,142.9,138.3,136.3(d,J＝5.2.Hz,1C),134.9,130.5(d,J＝10.0Hz,1C),129.3,128.7,128.5,126.5,126.4,125.8(d,J＝3.4Hz,1C),125.6,121.7,121.5(d,J＝17.0Hz,1C),114.3(d,J＝22.8Hz,1C),112.9,61.6,50.1,43.6(d,J＝2.7Hz,1C),35.9,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-110.75.HRMS(ESI)[M+H]+理论值C27H26NO5FSCl:530.1204；实测值：530.1207.
实施例17
3-甲基-5-(N-(2,6-二甲基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-50)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2,6-二甲基苄溴，其余条件均一致。得白色固体122mg，收率80％。1H NMR(400MHz,氯仿-d)δ8.21–8.11(m,1H),7.93(dd,J＝8.7,1.6Hz,1H),7.67(d,J＝8.7Hz,1H),7.23–7.09(m,4H),7.04(d,J＝7.5Hz,2H),6.79(d,J＝6.8Hz,2H),4.48(q,J＝7.1Hz,2H),4.42(s,2H),3.15–3.04(m,2H),2.63(s,3H),2.55–2.45(m,2H),2.34(s,6H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,143.0,138.5,138.5,133.9,130.9,129.5,128.8,128.6,128.5,126.4,126.3,125.6,121.7,113.0,61.6,49.9,47.6,37.0,20.3,14.4,9.4.HRMS(ESI)[M+H]+理论值C29H32NO5S:506.2001；实测值：506.1993.
实施例18
3-甲基-5-(N-(2,4-二氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-51)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2,4-二氟苄溴，其余条件均一致。得白色固体252mg，收率98％。1H NMR(400MHz,氯仿-d)δ8.10(s,1H),7.83(d,J＝8.7Hz,1H),7.61(d,J＝8.8Hz,1H),7.44(q,J＝8.4Hz,1H),7.17(dq,J＝14.1,7.0Hz,3H),7.01(d,J＝6.9Hz,2H),6.85(t,J＝8.1Hz,1H),6.80–6.70(m,1H),4.47(dd,J＝15.5,8.3Hz,4H),3.46–3.33(m,2H),2.78–2.67(m,2H),2.60(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ163.0(dd,J＝250.8,12.2Hz,1C),160.8(dd,J＝249.8,11.9Hz,1C),159.9,155.8,143.0,138.0,135.3,132.1(dd,J＝9.7,5.4Hz,1C),129.4,128.6(d,J＝11.1Hz,1C),126.6,126.2,125.5,121.5,119.3(dd,J＝14.3,3.7Hz,1C),113.1,111.8(dd,J＝21.3,3.7Hz,1C),103.7(t,J＝25.6Hz,1C),61.6,50.0,44.8(d,J＝3.1Hz,1C),35.1,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-109.80,-114.40.HRMS(ESI)[M+H]+理论值C27H26NO5F2S:514.1500；实测值：514.1497.
实施例19
3-甲基-5-(N-(2-氟-4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-52)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-氟-4-氯苄溴，其余条件均一致。得白色固体252mg，收率95％。1H NMR(400MHz,氯仿-d)δ8.08(d,J＝1.5Hz,1H),7.83(dd,J＝8.8,1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.38(t,J＝8.2Hz,1H),7.17(dq,J＝14.3,7.1Hz,3H),7.11–7.06(m,1H),7.05–6.96(m,3H),4.54–4.38(m,4H),3.47–3.34(m,2H),2.80–2.66(m,2H),2.59(s,3H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ160.9(d,J＝250.9Hz,1C),159.8,155.8,143.0,137.9,135.2,134.6(d,J＝10.2Hz,1C),131.9(d,J＝4.6Hz,1C),129.4,128.6(d,J＝10.8Hz,1C),126.6,126.2,125.5,124.9(d,J＝3.5Hz,1C),122.1(d,J＝14.4Hz,1C),121.5,116.1(d,J＝25.5Hz,1C),113.1,61.6,50.2,44.9(d,J＝3.3Hz,1C),35.1,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-115.97.HRMS(ESI)[M+H]+理论值C27H26NO5FSCl:530.1204；实测值：530.1215.
实施例20
3-甲基-5-(N-(2-氟-4-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-53)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-氟-4-溴苄溴，其余条件均一致。得白色固体280mg，收率98％。1H NMR(400MHz,氯仿-d)δ8.07(d,J＝1.6Hz,1H),7.82(dd,J＝8.8,1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.31(t,J＝8.1Hz,1H),7.25–7.11(m,5H),7.05–6.97(m,2H),4.52–4.38(m,4H),3.45–3.36(m,2H),2.78–2.68(m,2H),2.59(s,3H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ160.5(d,J＝251.9Hz,1C),159.8,155.8,143.0,137.9,135.2,132.2(d,J＝4.4Hz,1C),129.4,128.6(d,J＝10.6Hz,1C),127.8(d,J＝3.5Hz,1C),126.6,126.1,125.5,122.6(d,J＝14.3Hz,1C),122.1(d,J＝9.5Hz,1C),121.5,119.0(d,J＝25.1Hz,1C),113.1,61.6,50.2,44.9(d,J＝3.5Hz,1C),35.1,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-115.76.HRMS(ESI)[M+H]+理论值C27H26NO5FSBr:574.0699；实测值：574.0704.
实施例21
3-甲基-5-(N-(2-氟-4-氰基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-54)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-氟-4-氰基苄溴，其余条件均一致。得白色固体230mg，收率92％。1H NMR(400MHz,氯仿-d)δ8.12(s,1H),7.84(d,J＝8.7Hz,1H),7.62(dd,J＝11.9,8.0Hz,2H),7.40(d,J＝8.0Hz,1H),7.28(d,J＝9.1Hz,1H),7.16(t,J＝8.0Hz,3H),6.99(d,J＝7.1Hz,2H),4.47(d,J＝9.5Hz,4H),3.43(t,J＝7.7Hz,2H),2.80–2.48(m,5H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9(d,J＝251.0Hz,1C),159.8,155.9,143.1,137.6,134.6,131.7(d,J＝4.3Hz,1C),129.8(d,J＝14.2Hz,1C),129.5,128.6,128.4(d,J＝3.4Hz,1C),126.7,126.1,125.4,121.6,119.0(d,J＝25.4Hz,1C),117.3(d,J＝2.4Hz,1C),113.3,113.1(d,J＝9.7Hz,1C),61.6,50.6,45.3(d,J＝3.4Hz,1C),35.0,14.3,9.1106-4.19F NMR(376MHz,氯仿-d)δ-115.58.HRMS(ESI)[M+H]+理论值C28H26N2O5FS:521.1546；实测值：521.1552.
实施例22
3-甲基-5-(N-(2-甲基-5-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-61)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2-甲基-5-氟苄溴，其余条件均一致。得白色固体134mg，收率87％。1H NMR(400MHz,氯仿-d)δ8.17(d,J＝1.6Hz,1H),7.90(dd,J＝8.8,1.8Hz,1H),7.65(d,J＝8.8Hz,1H),7.17(m,3H),7.09(dd,J＝8.2,5.8Hz,1H),6.99–6.84(m,4H),4.47(q,J＝7.1Hz,2H),4.34(s,2H),3.40–3.25(m,2H),2.61(d,J＝6.1Hz,5H),2.27(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ162.4,160.0,159.9,155.9,143.0,138.1,135.7(d,J＝6.8Hz,1C),134.7,132.5(d,J＝3.3Hz,1C),132.0(d,J＝7.7Hz,1C),129.5,128.6(d,J＝4.8Hz,1C),126.5,126.3,125.6,121.6,115.9(d,J＝22.2Hz,1C),114.6(d,J＝20.7Hz,1C),113.1,61.6,50.6,50.1,35.5,18.5,14.4,9.4.19F NMR(376MHz,氯仿-d)δ-116.96.HRMS(ESI)[M+H]+理论值C28H29NO5FS:510.1750；实测值：510.1758.
实施例23
3-甲基-5-(N-(2,6-二氟-4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-62)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为2,6-二氟-4-氯苄溴，其余条件均一致。得白色固体243mg，收率89％。1H NMR(400MHz,氯仿-d)δ8.09(d,J＝1.5Hz,1H),7.84(dd,J＝8.8,1.8Hz,1H),7.59(d,J＝8.8Hz,1H),7.25–7.12(m,3H),7.06(d,J＝6.9Hz,2H),6.83(d,J＝7.2Hz,2H),4.46(d,J＝7.2Hz,4H),3.48–3.32(m,2H),2.90–2.78(m,2H),2.59(s,3H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ161.5(dd,J＝254.1,9.4Hz,1C),159.8,155.8,143.0,138.1,135.5(t,J＝14.2Hz,1C),134.9,129.3,128.7,128.6,126.5,126.3,125.5,121.6,112.6(dd,J＝29.8,1.8Hz,1C),110.9(t,J＝18.9Hz,1C),61.6,50.2,39.5,35.4,14.4,9.3.19F NMR(376MHz,氯仿-d)δ-110.99.HRMS(ESI)[M+H]+理论值C27H25NO5F2SCl:548.1110；实测值：548.1105.
实施例24
3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)
将3-甲基-5-(氯磺酰基)苯并呋喃-2-羧酸乙酯(91mg,0.3mmol)，4-(4-(苯乙氨基)苄基)哌嗪-1-羧酸叔丁酯(118mg,0.3mmol)，碳酸钾(46mg,0.33mmol)溶于无水二氯甲烷(10mL)中，60℃搅拌过夜，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(10mL)溶解，二氯甲烷(20mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝10/1～5/1)得白色固体247mg，收率74％。1H NMR(400MHz,氯仿-d)δ7.83(d,J＝1.4Hz,1H),7.58(dd,J＝8.8,1.7Hz,1H),7.51(d,J＝8.8Hz,1H),7.26–7.11(m,5H),7.07(d,J＝7.0Hz,2H),6.96(d,J＝8.3Hz,2H),4.43(q,J＝7.1Hz,2H),3.84–3.71(m,2H),3.48(s,2H),3.42(t,J＝5.0Hz,4H),2.83–2.72(m,2H),2.49(s,3H),2.36(t,J＝5.0Hz,4H),1.43(d,J＝9.5Hz,12H).13C NMR(101MHz,氯仿-d)δ159.8,155.8,154.8,142.9,138.1,138.0,137.9,133.6,129.6,129.1,128.8,128.7,128.5,126.8,126.5,125.5,122.0,112.6,79.6,62.4,61.5,52.9,52.2,35.2,28.4,14.4,9.3.HRMS(ESI)[M+H]+理论值C36H44N3O7S:662.2900；实测值：662.2896.
实施例25
3-甲基-5-(N-(4-吗啉苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-79)
按照3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)所用方法，将4-(4-(苯乙氨基)苄基)哌嗪-1-羧酸叔丁酯替换为M7-79，其余条件均一致。得白色固体142mg，收率63％。1H NMR(400MHz,氯仿-d)δ8.23–8.04(m,1H),7.93–7.78(m,1H),7.60(d,J＝8.8Hz,1H),7.15(dq,J＝16.9,8.2,7.5Hz,5H),6.96(d,J＝7.1Hz,2H),6.81(d,J＝8.0Hz,2H),4.46(q,J＝7.0Hz,2H),4.32(s,2H),3.83(s,4H),3.43–3.28(m,2H),3.11(s,4H),2.74–2.53(m,5H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,155.7,150.9,142.9,138.5,135.8,129.6,129.3,128.7,128.5,126.9,126.4,126.3,125.6,121.5,115.5,113.0,66.8,61.5,51.5,49.2,49.1,35.3,14.4,9.4.HRMS(ESI)[M+H]+理论值C31H35N2O6S:563.2216；实测值：563.2211.
实施例26
3-甲基-5-(N-苯乙基-N-(4-苯氧基苄基)氨磺酰)苯并呋喃-2-羧酸乙酯(M8-86)
按照3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)所用方法，将4-(4-(苯乙氨基)苄基)哌嗪-1-羧酸叔丁酯替换为M7-86，其余条件均一致。得白色固体70mg，收率25％。1H NMR(400MHz,氯仿-d)δ8.16(d,J＝1.9Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.7Hz,1H),7.34(dd,J＝8.6,7.3Hz,2H),7.26–7.08(m,6H),7.03–6.91(m,6H),4.48(q,J＝7.1Hz,2H),4.38(s,2H),3.47–3.34(m,2H),2.75–2.66(m,2H),2.62(s,3H),1.46(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ159.9,157.2,156.9,155.8,143.0,138.3,135.6,130.6,130.0,129.8,129.4,128.7,128.5,126.5,126.2,125.6,123.6,121.5,119.0,118.8,113.1,61.6,51.6,49.4,35.3,14.4,9.4.
实施例27
3-甲基-5-(N-(2-(4-(叔丁氧羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-87)
按照3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)所用方法，将4-(4-(苯乙氨基)苄基)哌嗪-1-羧酸叔丁酯替换为4-(2-((苯乙胺基)甲基)苯基)哌嗪-1-羧酸叔丁酯，其余条件均一致。得白色固体250mg，收率75％。1H NMR(400MHz,氯仿-d)δ8.07(d,J＝1.5Hz,1H),7.80(dd,J＝8.8,1.8Hz,1H),7.55(d,J＝8.8Hz,1H),7.33(d,J＝7.7Hz,1H),7.23–7.16(m,1H),7.12–6.98(m,5H),6.88–6.78(m,2H),4.49(s,2H),4.39(q,J＝7.1Hz,2H),3.45(s,4H),3.29–3.20(m,2H),2.78–2.67(m,4H),2.53(d,J＝4.4Hz,5H),1.39(d,J＝9.6Hz,12H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,154.8,151.4,143.0,138.4,135.5,130.8,130.0,129.4,128.7,128.5,128.5,126.4,126.2,125.5,124.7,121.5,120.2,113.0,79.9,61.6,52.9,49.5,46.4,34.8,28.4,14.4,9.4.HRMS(ESI)[M+H]+理论值C36H44N3OS:662.2900；实测值：662.2896.
实施例28
3-甲基-5-(N-苯乙基-N-(2-(哌嗪-1-基)苯基)氨磺酰)苯并呋喃-2-羧酸乙酯(M9-1)
将4-(2-(((2-(乙氧基羰基)-3-甲基-N-苯乙基苯并呋喃)-5-磺酰胺基)苯基)哌嗪-1-羧酸叔丁酯(96mg,0.15mmol)，三氟乙酸(85.5mg,0.75mmol)加入二氯甲烷(5mL)中，室温搅拌2h，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(20mL)溶解，加入适量碳酸氢钠调pH至7～8，二氯甲烷(20mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(DCM/CH3OH＝15/1～10/1))得淡黄色固体85mg，收率99％。1H NMR(400MHz,氯仿-d)δ8.17(d,J＝1.5Hz,1H),7.91(dd,J＝8.8,1.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.34(dt,J＝8.5,4.5Hz,1H),7.23–7.13(m,4H),7.04(d,J＝4.1Hz,2H),6.97(d,J＝6.6Hz,2H),4.49(q,J＝7.1Hz,2H),4.17(s,1H),3.88(s,1H),3.26–2.75(m,8H),2.61(s,5H),1.47(t,J＝7.1Hz,3H),1.27(s,1H).13C NMR(101MHz,氯仿-d)δ159.9,155.8,151.5,143.0,138.4,136.3,133.6,130.7,129.3,129.3,128.6,128.4,126.8,126.4,125.6,124.0,122.6,122.0,112.9,61.6,51.1,34.7,29.7,14.4,9.4.HRMS(ESI)[M+H]+理论值C30H34N3O5S:548.2219；实测值：548.2230.
实施例29
3-甲基-5-(N-苯乙基-N-(2-(哌嗪-1-基)苄基)氨磺酰)苯并呋喃-2-羧酸乙酯(M9-2)
将5-(N-(2-(4-(叔丁氧羰基)哌嗪)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(1.981g,3.0mmol)溶于二氯甲烷(20mL)，加入三氟乙酸(1.337mL,18.0mmol)搅拌1h，TLC检测反应完全后，减压蒸馏除去溶剂，真空泵抽干，得到白色固体1.65g，产率98％。1H NMR(400MHz,氯仿-d)δ8.17(d,J＝2.0Hz,1H),7.90(dd,J＝8.7,2.0Hz,1H),7.67(d,J＝8.7Hz,1H),7.47–7.08(m,7H),6.98–6.86(m,2H),4.61–4.42(m,4H),3.83(d,J＝41.7Hz,2H),3.31(t,J＝8.1Hz,2H),2.61(d,J＝23.8Hz,5H),1.48(t,J＝7.1Hz,3H).13CNMR(101MHz,氯仿-d)δ159.9,155.8,143.0,138.3,135.3,131.0,130.2,129.5,129.0,128.5,128.5,126.5,126.2,125.5,121.5,120.8,113.1,61.6,49.4,47.1,47.1,45.2,35.0,14.4,9.4.
实施例30
3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸乙酯(M10-105)
将3-甲基-5-N-苯乙基-N-(2-(哌嗪-1-基)苄基)氨磺酰基)苯并呋喃-2-羧酸乙酯(202mg,0.36mmol)，苯甲酸(96mg,0.79mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(152mg,0.79mmol)，1-羟基苯并三唑(107mg,0.79mmol)，N,N-二异丙基乙胺(150mg,1.08mmol)，4-二甲氨基吡啶(5mg,0.04mmol)加入二氯甲烷(2mL)中，室温搅拌过夜后，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(10mL)溶解，二氯甲烷(10mL)萃取三次，有机相用饱和氯化钠水溶液洗，加无水硫酸钠干燥，粗品经柱层析分离(PE/EA＝8/1～6/1)得白色固体181mg，产率95％。1H NMR(400MHz,氯仿-d)δ8.18(d,J＝1.8Hz,1H),8.12(dd,J＝8.3,1.2Hz,1H),7.94–7.86(m,1H),7.66(d,J＝8.7Hz,1H),7.45(s,6H),7.22–7.10(m,5H),6.92(dd,J＝7.7,1.4Hz,2H),4.60(s,2H),4.50(q,J＝7.1Hz,2H),δ3.59(s,4H),3.38–3.29(m,2H),2.91(s,4H)2.63(s,5H),1.48(t,J＝7.1Hz,3H).13C NMR(101MHz,氯仿-d)δ170.6,159.9,155.8,150.9,143.0,138.3,135.6,135.3,133.5,130.9,130.2,130.1,129.8,129.4,129.0,128.6,128.5,128.4,127.1,126.5,126.2,125.5,125.0,121.5,120.5,113.1,61.6,49.5,46.9,35.0,14.4,9.4.
实施例31
3-甲基-5-(N-(4-硝基苯基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M-W7)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法，将2-氟苄溴替换为4-硝基苄溴，其余条件均一致。得黄色固体200mg，收率80％。M.p.>380℃(分解).1H NMR(400MHz,氯仿-d)δ8.18–8.13(m,3H),7.82(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.52(dt,J＝8.6,1.0Hz,2H),7.31–7.18(m,5H),4.38–4.30(m,4H),3.30(t,J＝6.3Hz,2H),2.86(tt,J＝6.4,1.0Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).13C NMR(101MHz,氯仿-d)δ161.5,157.8,147.4,143.9,141.8,138.0,132.8,130.3,128.9,128.8,127.5,126.6,126.2,125.0,123.8,120.5,113.7,60.6,50.9,47.5,35.0,14.3,10.0.
实施例32
3-甲基-5-(((2-(4-甲基哌嗪-1-基)苄基)(苯乙基)氨基)甲基)苯并呋喃-2-羧酸乙酯(M-D1)
按照3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸乙酯(M10-105)所用方法合成。1H NMR(400MHz,氯仿-d)δ7.52(d,J＝2.1Hz,1H),7.35(d,J＝8.5Hz,1H),7.29–7.19(m,6H),7.18–7.07(m,2H),6.98(ddd,J＝8.4,7.7,1.5Hz,1H),6.76(dd,J＝7.3,1.4Hz,1H),4.34(q,J＝6.4Hz,2H),3.73–3.66(m,4H),3.22–3.13(m,4H),2.92–2.82(m,4H),2.76(tt,J＝5.5,1.0Hz,2H),2.66–2.56(m,5H),2.29(s,3H),1.39(t,J＝6.3Hz,3H).13C NMR(101MHz,氯仿-d)δ161.5,154.7,150.6,143.6,139.7,134.6,129.7,128.9,128.8,128.6,128.0,127.4,127.4,126.6,124.5,121.1,120.8,117.4,112.9,60.6,58.7,56.9,56.7,53.5,50.1,45.3,33.6,14.3,10.2.
实施例33
(E)-3-(4-((2-(二甲基氨甲酰基)苯基)(2-(噻吩-2-基)乙基)氨甲酰基)苯基)丙酸乙酯(M-D2)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。1H NMR(400MHz,氯仿-d)δ7.94–7.88(m,2H),7.66–7.56(m,4H),7.51(dd,J＝7.8,1.5Hz,1H),7.34–7.27(m,1H),7.21–7.11(m,2H),6.93(dd,J＝6.2,5.3Hz,1H),6.69(dd,J＝6.1,1.7Hz,1H),6.42(d,J＝15.9Hz,1H),4.58(t,J＝5.5Hz,2H),4.18(q,J＝6.0Hz,2H),3.14(t,J＝5.5Hz,2H),3.01(s,6H),1.27(t,J＝6.1Hz,3H).13C NMR(101MHz,氯仿-d)δ171.1,169.8,168.1,145.2,142.0,141.3,137.4,136.0,130.5,129.0,128.8,128.6,127.2,126.6,125.5,125.5,125.5,123.9,118.2,60.7,47.1,36.4,30.7,14.2.
实施例34
3-(4-((2-(二甲基氨基)苄基)(3-苯丙基)氨甲酰基)苯基)丙酸乙酯(M-D3)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。1H NMR(400MHz,氯仿-d)δ7.61–7.55(m,2H),7.46(dt,J＝8.5,0.9Hz,2H),7.30–7.19(m,5H),7.17–7.10(m,2H),6.94–6.87(m,1H),6.76–6.70(m,1H),4.52(d,J＝0.9Hz,2H),4.13(q,J＝6.6Hz,2H),3.42–3.36(m,2H),2.92–2.85(m,8H),2.68–2.58(m,4H),1.87(tt,J＝8.5,6.2Hz,2H),1.24(t,J＝6.6Hz,3H).13C NMR(101MHz,氯仿-d)δ172.8,170.2,151.2,142.1,141.9,135.6,129.7,129.5,128.6,128.6,128.6,127.8,126.7,125.8,121.0,115.4,60.3,50.3,46.6,44.2,35.6,33.7,30.5,28.2,14.2.
实施例35
3-(4-(丁基(2-(二乙基氨基)苄基)氨甲酰基)苯基)丙酸乙酯(M-D4)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。1H NMR(400MHz,氯仿-d)δ7.61–7.55(m,2H),7.46(dt,J＝8.5,1.0Hz,2H),7.21–7.15(m,1H),7.10(td,J＝7.6,1.6Hz,1H),6.94–6.87(m,1H),6.66(dd,J＝7.5,1.5Hz,1H),4.55(d,J＝0.9Hz,2H),4.13(q,J＝6.6Hz,2H),3.43(q,J＝7.0Hz,4H),3.35(t,J＝6.3Hz,2H),2.88(ddt,J＝9.2,8.4,1.0Hz,2H),2.65–2.58(m,2H),1.60(p,J＝6.6Hz,2H),1.36(h,J＝7.3Hz,2H),1.24(t,J＝6.6Hz,3H),1.12(t,J＝7.0Hz,6H),0.94(t,J＝7.4Hz,3H).13C NMR(101MHz,氯仿-d)δ172.8,170.2,148.4,142.1,135.6,129.9,129.5,128.6,127.7,127.1,120.9,116.4,60.3,50.3,46.9,46.1,35.6,30.5,29.9,20.1,14.2,14.0,12.5.
实施例36
(E)-3-(4-(((2-(1H-吡唑-5-基)乙基)(4-(二甲基氨甲酰基)苯基)氨基)甲基)苯基)丙烯酸乙酯(M-D5)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。1H NMR(400MHz,氯仿-d)δ7.95(d,J＝3.1Hz,1H),7.61–7.54(m,3H),7.50–7.44(m,2H),7.27(dt,J＝8.4,1.0Hz,2H),6.90–6.84(m,2H),6.42(d,J＝16.0Hz,1H),6.30(d,J＝3.3Hz,1H),4.56(t,J＝1.0Hz,2H),4.18(q,J＝6.0Hz,2H),3.62(t,J＝5.2Hz,2H),3.00(s,6H),2.94(t,J＝5.2Hz,2H),1.27(t,J＝6.1Hz,3H).13C NMR(101MHz,氯仿-d)δ170.8,168.1,152.8,145.1,142.5,138.4,136.8,133.2,130.2,129.5,129.1,128.8,118.2,114.7,104.3,60.7,55.7,51.0,37.5,26.9,14.2.
实施例37
5-(N-(2-氯苄基)-N-(2-(4-特戊酰基哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-D6)
按照3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸乙酯(M10-105)所用方法合成。1H NMR(400MHz,氯仿-d)δ8.16(d,J＝2.3Hz,1H),7.82(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.1Hz,1H),7.44–7.39(m,1H),7.34(ddt,J＝6.9,3.0,1.0Hz,1H),7.30–7.22(m,2H),7.17–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.45(dd,J＝6.3,1.0Hz,4H),4.34(q,J＝6.4Hz,2H),3.69(dd,J＝5.3,2.6Hz,2H),3.63(dd,J＝5.3,2.6Hz,2H),3.20(dd,J＝5.3,2.6Hz,2H),3.09(dd,J＝5.4,2.7Hz,2H),2.60(s,3H),1.39(t,J＝6.3Hz,3H),1.22(s,9H).13C NMR(101MHz,氯仿-d)δ178.0,161.5,157.8,149.2,143.9,135.5,133.7,133.1,131.6,130.8,129.9,129.7,128.1,127.5(d,J＝3.8Hz),127.4,126.2,125.0,121.4,120.5,117.3,113.7,60.6,52.3,52.1,49.8,46.2,41.6,26.5,14.3,10.0.
实施例38
5-(N-(2-(4-异丁酰基哌嗪-1-基)苄基-N-(2-(3-甲基吡啶-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-D7)
按照3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸乙酯(M10-105)所用方法合成。1H NMR(400MHz,氯仿-d)δ8.32(dd,J＝4.1,1.9Hz,1H),8.16(d,J＝2.4Hz,1H),7.82(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.54(ddq,J＝7.6,1.5,0.8Hz,1H),7.18(dd,J＝7.7,4.0Hz,1H),7.16–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.40(d,J＝0.9Hz,2H),4.34(q,J＝6.4Hz,2H),3.70(dd,J＝6.5,3.8Hz,2H),3.64(dd,J＝6.5,3.8Hz,2H),3.45(t,J＝6.2Hz,2H),3.15(dd,J＝6.5,3.8Hz,2H),3.06(dd,J＝6.5,3.8Hz,2H),2.96(t,J＝6.3Hz,2H),2.82(hept,J＝7.3Hz,1H),2.60(s,3H),2.26(d,J＝0.7Hz,3H),1.39(t,J＝6.3Hz,3H),1.06(d,J＝7.3Hz,6H).13C NMR(101MHz,氯仿-d)δ176.2,161.5,157.8,154.8,149.1,146.5,143.9,137.4,132.8,131.3,130.7,127.5(d,J＝3.6Hz),127.1,126.2,125.0,121.7,121.4,120.5,117.3,113.7,60.6,50.7,50.0,46.3,44.7,32.7,30.2,18.7,18.0,14.3,10.0.
实施例39
3-甲基-5-(N-(3-吗啉苄基)-N-(2-氧代-苯基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-D8)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。1H NMR(400MHz,氯仿-d)δ8.16(d,J＝2.3Hz,1H),8.00–7.94(m,2H),7.82(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.60–7.48(m,3H),7.16(dd,J＝8.3,7.4Hz,1H),7.04–6.95(m,2H),6.82(tt,J＝2.2,1.0Hz,1H),4.44(t,J＝1.0Hz,2H),4.42(s,2H),4.34(q,J＝6.4Hz,2H),3.80(ddd,J＝9.5,6.2,3.5Hz,4H),3.23(ddd,J＝8.4,6.1,3.4Hz,4H),2.60(s,3H),1.39(t,J＝6.3Hz,3H).13C NMR(101MHz,氯仿-d)δ194.5,161.5,157.8,150.8,143.9,137.4,134.8,133.3,132.4,130.5,129.4,128.6,127.5,126.2,125.0,123.7,120.5,117.8,114.9,113.7,66.7,60.6,53.7,51.4,48.2,14.3,10.0.
实施例40
5-(N-(2-(4-(4-乙酰基苯甲酰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-D9)
按照3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸乙酯(M10-105)所用方法合成。1H NMR(400MHz,氯仿-d)δ8.16(d,J＝2.3Hz,1H),7.96–7.90(m,2H),7.85–7.75(m,3H),7.68(d,J＝9.1Hz,1H),7.31–7.20(m,5H),7.17–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.40(d,J＝0.9Hz,2H),4.34(q,J＝6.4Hz,2H),3.73(dd,J＝6.0,3.3Hz,2H),3.62(dd,J＝6.2,3.3Hz,2H),3.35–3.20(m,2H),3.10(td,J＝6.0,3.3Hz,4H),2.86(tt,J＝6.4,0.9Hz,2H),2.60(s,3H),2.56(s,3H),1.39(t,J＝6.3Hz,3H).13C NMR(101MHz,氯仿-d)δ197.4,170.2,161.5,157.8,149.1,143.9,141.0,138.9,138.0,132.8,130.7,129.7,128.9,128.8,128.1,127.5,127.5,127.1,126.6,126.2,125.0,121.4,120.5,117.3,113.7,60.6,50.7,49.9,47.2,47.0,35.0,26.4,14.3,10.0.
实施例41
3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)
将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(93mg,0.2mmol)，氢氧化钠(40mg,1.0mmol)溶于乙醇(8mL)和水(2mL)组成的混合溶液中，100℃搅拌1h，TLC检测反应完毕后，减压蒸馏除去溶剂，加水(10mL)溶解，用1M稀盐酸调节PH值为3.0，静止5h后，减压抽滤、干燥得白色固体90mg，收率96％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.80(d,J＝10.6Hz,1H),7.71(d,J＝8.7Hz,1H),7.43(t,J＝7.7Hz,1H),7.39–7.30(m,1H),7.25–7.11(m,5H),7.01(d,J＝6.9Hz,2H),4.47(s,2H),3.38–3.27(m,2H),2.63–2.54(m,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ162.8,160.9(d,J＝246.5Hz,1C),154.8,138.6,133.8,131.4(d,J＝3.9Hz,1C),130.9,130.3(d,J＝8.2Hz,1C),128.9,128.8,126.8,124.9(d,J＝3.3Hz,1C),124.5,124.2(d,J＝14.3Hz,1C),120.7,117.8,115.9,115.7,112.8,50.2,45.8(d,J＝3.3Hz,1C),34.9,9.5.19F NMR(376MHz,DMSO-d6)δ-117.84.HRMS(ESI)[M-H]-理论值C25H21NO5FS:466.1124；实测值：466.1128.
实施例42
3-甲基-5-(N-(2-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S16)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-16，其余条件均一致。得白色固体104mg，收率98％。M.p.170-171℃.1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝1.7Hz,1H),7.95(dd,J＝8.8,1.9Hz,1H),7.85(d,J＝8.8Hz,1H),7.61(d,J＝7.0Hz,1H),7.48(d,J＝6.3Hz,1H),7.37(t,J＝7.0Hz,1H),7.28–7.17(m,3H),7.14(t,J＝7.2Hz,1H),7.02(d,J＝8.2Hz,2H),4.50(s,2H),3.42–3.34(m,2H),2.58(s,5H).13C NMR(101MHz,DMSO)δ161.4,155.5,138.5,136.3,134.6,133.1,130.9,130.1,129.8,129.0,128.3,126.8,126.4,123.2,122.0,113.5,52.2,50.6,35.0,9.6.HRMS(ESI)[M-H]-理论值C25H21NO5SBr:526.0324；实测值：526.0331.
实施例43
3-甲基-5-(N-(3-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S20)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-20，其余条件均一致。得白色固体85mg，收率91％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.80(d,J＝8.7Hz,1H),7.72(d,J＝8.7Hz,1H),7.44–7.34(m,1H),7.19(d,J＝7.4Hz,3H),7.12(dt,J＝9.0,6.5Hz,3H),7.00(d,J＝6.9Hz,2H),4.42(s,2H),3.37–3.28(m,2H),2.61–2.54(m,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ163.1,162.6(d,J＝244.6Hz,1C),154.7,152.0,140.8(d,J＝7.2Hz,1C),138.7,133.8,131.1,130.8(d,J＝8.4Hz,1C),129.0,128.8,126.7,124.6(d,J＝2.6Hz,1C),124.2,120.6,116.9,115.2(d,J＝21.7Hz,1C),114.7(d,J＝21.0Hz,1C),112.7,51.3,50.1,40.4,34.7,9.5.19F NMR(376MHz,DMSO-d6)δ-113.23.HRMS(ESI)[M-H]-理论值C25H21NO5FS:466.1124；实测值：466.1127.
实施例44
3-甲基-5-(N-(3-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S22)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-22，其余条件均一致。得白色固体93mg，收率99％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.81(d,J＝8.7Hz,1H),7.72(d,J＝8.7Hz,1H),7.50–7.43(m,2H),7.38–7.27(m,2H),7.20(t,J＝7.2Hz,2H),7.14(dd,J＝8.7,5.8Hz,1H),7.01(d,J＝6.9Hz,2H),4.41(s,2H),3.37–3.28(m,2H),2.62–2.54(m,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ162.5,154.8,140.6,138.7,133.9,131.3,131.0,131.0,130.8,129.0,128.8,127.6,126.8,124.5,122.1,120.7,112.8,51.1,50.2,34.8,9.5.HRMS(ESI)[M-H]-理论值C25H21NO5SBr:526.0324；实测值：526.0326.
实施例45
3-甲基-5-(N-(3-硝基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S25)
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按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-25，氢氧化钠替换为氢氧化锂，其余条件均一致。得白色固体51mg，收率52％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.31(d,J＝1.5Hz,1H),8.16–8.06(m,2H),7.96(dd,J＝8.8,1.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.78(d,J＝7.7Hz,1H),7.62(t,J＝7.9Hz,1H),7.23–7.06(m,3H),7.01(d,J＝6.9Hz,2H),4.57(s,2H),3.52–3.34(m,2H),2.61(d,J＝21.9Hz,5H).13C NMR(101MHz,DMSO-d6)δ161.2,155.6,148.2,144.0,140.2,138.5,135.0,134.8,130.3,129.7,129.0,128.7,126.7,125.1,123.0,122.8,122.2,113.6,51.2,50.5,34.8,9.5.HRMS(ESI)[M-H]-理论值C25H21N2O7S:493.1069；实测值：493.1065.
实施例46
3-甲基-5-(N-(4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S29)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-29，其余条件均一致。得白色固体89mg，收率92％。M.p.172-173℃.1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.93(d,J＝8.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.37(q,J＝8.5Hz,4H),7.19(t,J＝7.3Hz,2H),7.13(t,J＝7.2Hz,1H),7.01(d,J＝7.1Hz,2H),4.42(s,2H),3.41–3.26(m,2H),2.58(d,J＝4.6Hz,5H).13C NMR(101MHz,DMSO-d6)δ161.3,155.5,144.4,138.6,136.6,135.1,132.6,130.5,129.7,129.0,128.9,128.8,126.7,126.5,124.6,122.0,113.5,51.1,50.1,34.8,9.5.HRMS(ESI)[M-H]-理论值C25H21NO5SCl:482.0829；实测值：482.0829.
实施例47
3-甲基-5-(N-(4-(三氟甲基)苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S32)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-32，其余条件均一致。得白色固体72mg，收率70％。M.p.>192 -193℃.1H NMR(400MHz,DMSO-d6)δ8.33–8.19(m,1H),7.94(dd,J＝8.7,1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.68(d,J＝7.9Hz,2H),7.55(d,J＝7.9Hz,2H),7.14(dq,J＝14.1,7.3Hz,3H),7.00(d,J＝7.3Hz,2H),4.53(s,2H),3.37(t,J＝7.8Hz,2H),2.59(d,J＝10.2Hz,5H).13C NMR(101MHz,DMSO-d6)δ161.6,155.4,145.2,142.7,138.6,134.7,129.9,129.2,129.0,128.7,126.7,126.2,126.1,125.7(d,J＝3.7Hz,1C),123.5(d,J＝34.9Hz,1C),121.9,113.4,51.5,50.5,34.8,9.5.19F NMR(376MHz,DMSO-d6)δ-60.94.HRMS(ESI)[M-H]-理论值C26H21NO5SF3:516.1093；实测值：516.1096.
实施例48
3-甲基-5-(N-(4-(三氟甲硫基)苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S35)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-35，其余条件均一致。得白色固体192mg，收率70％。M.p.165 -166℃.1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.92(dd,J＝8.7,1.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.70(d,J＝7.9Hz,2H),7.51(d,J＝7.9Hz,2H),7.17(dt,J＝13.7,6.9Hz,3H),7.00(d,J＝7.2Hz,2H),4.50(s,2H),3.36(t,J＝7.9Hz,2H),2.65–2.54(m,5H).13C NMR(101MHz,DMSO-d6)δ161.7,155.4,141.8,138.6,136.7,134.5,131.6,130.0,130.0,129.0,128.7,128.5,126.7,126.0,122.3,121.8,113.3,51.4,50.5,34.9,9.5.19F NMR(376MHz,DMSO-d6)δ-42.23.HRMS(ESI)[M-H]-理论值C26H21F3NO5S2:548.0819；实测值：548.0805.
实施例49
3-甲基-5-(N-(4-异丙基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S36)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-36，其余条件均一致。得白色固体220mg，收率88％。M.p.206-207℃.1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.26(d,J＝1.9Hz,1H),7.93(dd,J＝8.8,1.9Hz,1H),7.84(d,J＝8.8Hz,1H),7.19(dq,J＝16.2,9.2,8.7Hz,7H),7.02–6.94(m,2H),4.38(s,2H),3.34–3.27(m,2H),2.85(h,J＝6.8Hz,1H),2.58(s,5H),1.17(d,J＝6.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.1,155.5,148.3,143.8,138.8,135.5,134.5,129.6,129.0,128.8,128.8,126.8,126.7,126.6,125.2,122.0,113.5,51.4,49.6,34.8,33.6,24.3,9.6.HRMS(ESI)[M-H]-理论值C28H28NO5S:490.1694；实测值：490.1684.
实施例50
3-甲基-5-(N-(4-叔丁基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S37)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-37，其余条件均一致。得白色固体212mg，收率84％。M.p.206-207℃.1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.97–7.77(m,2H),7.34(d,J＝8.0Hz,2H),7.18(ddd,J＝22.9,15.8,7.5Hz,5H),6.97(d,J＝6.6Hz,2H),4.39(s,2H),3.36–3.27(m,2H),2.58(s,5H),1.25(s,9H).13C NMR(101MHz,DMSO)δ161.4,155.4,150.5,138.8,135.4,134.1,129.7,129.0,128.7,128.5,126.7,126.4,125.6,124.5,121.9,113.4,107.1,51.3,49.6,34.8,34.7,31.6,9.6.HRMS(ESI)[M-H]-理论值C29H30NO5S:504.1850；实测值：504.1838.
实施例51
3-甲基-5-(N-(4-乙酰基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S38)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-38，其余条件均一致。得白色固体48mg，收率49％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),8.28(d,J＝1.9Hz,1H),8.00–7.80(m,4H),7.47(d,J＝8.0Hz,2H),7.21–7.09(m,3H),7.05–6.98(m,2H),4.52(s,2H),3.40–3.31(m,2H),2.57(t,J＝5.6Hz,8H).13C NMR(101MHz,DMSO-d6)δ197.9,161.1,155.6,143.7,143.1,138.6,136.5,135.1,129.6,129.0,128.8,128.8,128.7,126.7,126.7,125.3,122.1,113.6,51.6,50.3,34.8,27.2,9.5.HRMS(ESI)[M-H]-理论值C27H24NO6S:490.1324；实测值：490.1322.
实施例52
3-甲基-5-(N-(萘-2-基甲基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S43)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-43，其余条件均一致。得白色固体94mg，收率89％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.48–8.30(m,2H),8.06(dd,J＝8.7,1.9Hz,1H),8.01–7.86(m,3H),7.67–7.53(m,3H),7.49(t,J＝7.6Hz,1H),7.09(dq,J＝14.0,7.1Hz,3H),6.86–6.70(m,2H),4.86(s,2H),3.24(t,J＝8.2Hz,2H),2.60(s,3H),2.22(t,J＝8.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ161.4,155.6,144.4,138.5,134.3,133.9,132.0,131.9,129.8,129.3,129.0,128.8,128.7,128.4,126.9,126.8,126.7,126.5,125.7,124.3,122.2,113.5,51.1,49.9,35.3,9.6.HRMS(ESI)[M-H]-理论值C29H24NO5S:498.1375；实测值：498.1376.
实施例53
3-甲基-5-(N-(喹啉-8-基甲基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S44)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-44，其余条件均一致。得白色固体103mg，收率99％。M.p.190-191℃.1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.36(d,J＝7.9Hz,1H),8.20(s,1H),7.91(t,J＝9.1Hz,2H),7.80(d,J＝5.6Hz,2H),7.68–7.48(m,2H),7.12(dd,J＝15.3,6.9Hz,3H),6.95(d,J＝7.0Hz,2H),5.10(s,2H),3.60–3.38(m,2H),2.73–2.60(m,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,155.4,150.2,145.8,143.6,138.7,137.2,135.4,135.0,129.8,129.4,129.0,128.7,128.2,126.8,126.7,125.2,122.0,121.9,113.4,50.8,47.7,35.1,9.5.HRMS(ESI)[M-H]-理论值C28H23N2O5S:499.1328；实测值：499.1321.
实施例54
3-甲基-5-(N-(2,6-二氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S46)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-46，其余条件均一致。得白色固体89mg，收率92％。M.p.180-181.1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝1.9Hz,1H),7.85(dd,J＝8.8,1.9Hz,1H),7.78(d,J＝8.8Hz,1H),7.40(ddd,J＝15.0,8.5,6.6Hz,1H),7.24(t,J＝7.3Hz,2H),7.16(ddd,J＝7.3,5.1,1.3Hz,1H),7.12–7.00(m,4H),4.49(s,2H),3.37–3.26(m,2H),2.72–2.63(m,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ162.0,161.6(dd,J＝249.6,8.0Hz,1C),155.3,146.0,134.4,131.5(t,J＝10.6Hz,1C),129.9,128.9,128.9,126.8,125.9,122.8,121.5,113.2,112.5,112.2(dd,J＝18.9,12.0Hz,1C),112.1(d,J＝25.1Hz,1C),50.4,35.2,9.5.19F NMR(376MHz,DMSO-d6)δ-113.36.HRMS(ESI)[M-H]-理论值C25H20NO5F2S:484.1030；实测值：484.1036.
实施例55
3-甲基-5-(N-(2-氟-6-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S47)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-47，其余条件均一致。得白色固体93mg，收率94％。M.p.195-196.1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.9Hz,1H),7.92(dd,J＝8.8,2.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.39(td,J＝8.2,6.1Hz,1H),7.30(d,J＝8.0Hz,1H),7.26–7.12(m,4H),6.98(d,J＝7.0Hz,2H),4.55(s,2H),3.35–3.23(m,2H),2.56(s,5H).13C NMR(101MHz,DMSO-d6)δ162.1(d,J＝250.9Hz,1C),161.2,155.5,143.9,138.5,135.6(d,J＝5.3Hz,1C),134.5,131.6(d,J＝10.0Hz,1C),129.5,128.9(d,J＝2.2Hz,1C),126.8,126.7,126.3(d,J＝3.1Hz,1C),125.0,122.0,121.8(d,J＝16.9Hz,1C),115.2(d,J＝22.6Hz,1C),113.5,50.5,44.3(d,J＝1.9Hz,1C),35.7,9.5.19F NMR(376MHz,DMSO-d6)δ-111.00.HRMS(ESI)[M-H]-理论值C25H20NO5FSCl:500.0735；实测值：500.0743.
实施例56
3-甲基-5-(N-(2,6-二甲基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S50)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-50，其余条件均一致。得白色固体62mg，收率65％。M.p.211-212℃.1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.22(s,1H),7.96(d,J＝8.7Hz,1H),7.86(d,J＝8.7Hz,1H),7.15(dt,J＝14.1,6.9Hz,4H),7.02(d,J＝7.4Hz,2H),6.77(d,J＝7.0Hz,2H),4.37(s,2H),3.15–2.98(m,2H),2.58(s,3H),2.41–2.31(m,2H),2.26(s,6H).13C NMR(101MHz,DMSO-d6)δ161.2,155.6,143.7,138.6,133.8,131.6,129.6,128.9,128.8,128.8,128.6,126.8,126.7,125.2,122.2,113.5,49.9,47.9,40.4,36.6,20.2,9.6.HRMS(ESI)[M-H]-理论值C27H26NO5S:476.1532；实测值：476.1533.
实施例57
3-甲基-5-(N-(2,4-二氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S51)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-51，其余条件均一致。得白色固体92mg，收率95％。M.p.155-156℃.1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝1.9Hz,1H),7.87(dd,J＝8.7,2.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.47(q,J＝8.5Hz,1H),7.28–7.11(m,4H),7.11–6.99(m,3H),4.44(s,2H),3.41–3.28(m,2H),2.58(d,J＝20.0Hz,5H).13C NMR(101MHz,DMSO-d6)δ162.1,155.2,138.6,134.4,132.7(dd,J＝9.7,5.1Hz,1C),130.2,129.0,128.8,126.8,125.7,121.7(d,J＝2.8Hz,1C),121.4,120.6(dd,J＝14.8,3.7Hz,1C),113.2,112.0(dd,J＝21.1,3.2Hz,1C),104.3(t,J＝26.2Hz,1C),50.3,45.5(d,J＝1.4Hz,1C),35.0,9.5.19F NMR(376MHz,DMSO-d6)δ-110.70,-113.08.HRMS(ESI)[M-H]-理论值C25H20NO5SF2:484.1030；实测值：484.1037.
实施例58
3-甲基-5-(N-(2-氟-4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S52)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-52，其余条件均一致。得白色固体90mg，收率90％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝1.9Hz,1H),7.79(dd,J＝8.6,2.0Hz,1H),7.71(d,J＝8.7Hz,1H),7.44(t,J＝8.3Hz,1H),7.37(dd,J＝10.0,2.1Hz,1H),7.26(dd,J＝8.3,2.1Hz,1H),7.24–7.11(m,3H),7.03(d,J＝6.9Hz,2H),4.43(s,2H),3.39–3.28(m,2H),2.67–2.58(m,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ163.1,160.6(d,J＝250.7Hz,1C),154.7,151.5,138.6,133.7,133.6,132.6(d,J＝4.8Hz,1C),131.0,129.0,128.8,126.8,125.1(d,J＝3.5Hz,1C),124.4,123.7(d,J＝14.4Hz,1C),120.6,117.3,116.4(d,J＝25.5Hz,1C),112.8,50.4,45.5(d,J＝2.2Hz,1C),34.9,9.5.19F NMR(376MHz,DMSO-d6)δ-114.61.HRMS(ESI)[M-H]-理论值C25H20NO5FSCl:500.0735；实测值：500.0736.
实施例59
3-甲基-5-(N-(2-氟-4-溴苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S53)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-53，其余条件均一致。得白色固体98mg，收率90％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝1.9Hz,1H),7.79(dd,J＝8.7,2.0Hz,1H),7.71(d,J＝8.7Hz,1H),7.53–7.46(m,1H),7.38(d,J＝5.0Hz,2H),7.26–7.11(m,3H),7.03(d,J＝6.7Hz,2H),4.42(s,2H),3.38–3.28(m,2H),2.67–2.58(m,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ163.1,160.6(d,J＝251.6Hz,1C),154.7,151.8,138.6,133.5,132.9(d,J＝4.7Hz,1C),131.0,129.0,128.8,128.1(d,J＝3.4Hz,1C),126.8,124.3,124.2(d,J＝14.4Hz,1C),121.6(d,J＝9.7Hz,1C),120.6,119.2(d,J＝25.0Hz,1C),117.1,112.8,50.4,45.6(d,J＝1.7Hz,1C),34.9,9.5.19F NMR(376MHz,DMSO-d6)δ-114.52.HRMS(ESI)[M-H]-理论值C25H20NO5FSBr:544.0230；实测值：544.0230.
实施例60
3-甲基-5-(N-(2-氟-4-氰基苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S54)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-54，其余条件均一致。得白色固体89mg，收率91％。M.p.233 -234℃.1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.23(s,1H),8.12–7.76(m,3H),7.66(dd,J＝25.0,9.7Hz,2H),7.50(d,J＝8.9Hz,1H),7.17(dd,J＝19.8,5.5Hz,3H),7.04(d,J＝7.3Hz,2H),4.53(s,2H),3.50–3.29(m,2H),2.81–2.53(m,5H).13C NMR(101MHz,DMSO-d6)δ166.6,161.2,160.4(d,J＝247.2Hz,1C),155.6,143.9,138.5,136.4(d,J＝6.8Hz,1C),134.9,131.1(d,J＝4.2Hz,1C),129.6,129.0,128.8,127.5(d,J＝14.8Hz,1C),126.8,126.7,125.1,123.9(d,J＝6.1Hz,1C),122.1,114.8(d,J＝23.0Hz,1C),113.5,50.5,45.8(d,J＝1.8Hz,1C),35.0,9.5.19F NMR(376MHz,DMSO-d6)δ-117.31.HRMS(ESI)[M-H]-理论值C26H20N2O5FS:509.1188；实测值：509.1185.
实施例61
3-甲基-5-(N-(2-甲基-5-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S61)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-61，其余条件均一致。得白色固体72mg，收率75％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.0Hz,1H),7.89(dd,J＝8.7,2.0Hz,1H),7.79(d,J＝8.7Hz,1H),7.28–7.09(m,5H),7.02(td,J＝8.5,2.9Hz,1H),6.95(d,J＝6.8Hz,2H),4.37(s,2H),3.37–3.22(m,2H),2.56(s,3H),2.46(d,J＝7.7Hz,2H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ162.5,161.0(d,J＝242.1Hz,1C),155.0,138.6,137.6(d,J＝6.9Hz,1C),133.6,133.0(d,J＝2.8Hz,1C),132.2(d,J＝7.9Hz,1C),130.7,128.8(d,J＝9.0Hz,1C),126.7,125.1,121.2,115.9(d,J＝22.3Hz,1C),114.4(d,J＝20.8Hz,1C),113.0,50.5,50.2,35.1,18.4,9.5.19F NMR(376MHz,DMSO-d6)δ-117.53.HRMS(ESI)[M-H]-理论值C26H23NO5SF:480.1281；实测值：480.1284.
实施例62
3-甲基-5-(N-(2,6-二氟-4-氯苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S62)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M4-62，其余条件均一致。得白色固体102mg，收率98％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝1.9Hz,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.81(d,J＝8.8Hz,1H),7.24(t,J＝7.7Hz,4H),7.17(t,J＝7.3Hz,1H),7.09(d,J＝7.0Hz,2H),4.43(s,2H),3.42–3.32(m,2H),2.77–2.69(m,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.4(dd,J＝252.4,9.9Hz,1C),161.2,155.5,144.1,138.6,134.7(t,J＝14.2Hz,1C),134.7,129.5,129.0,128.9,126.8,126.5,124.7,121.7,113.4,113.2(d,J＝29.6Hz,1C),111.8(t,J＝19.3Hz,1C),50.8,35.3,9.5.19F NMR(376MHz,DMSO-d6)δ-111.06.HRMS(ESI)[M-H]-理论值C25H19NO5F2SCl:518.0641；实测值：518.0642.
实施例63
3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸(TZ-S76)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M8-76，其余条件均一致。得白色固体185mg，收率97％。M.p.234-235℃.1H NMR(400MHz,DMSO-d6)δ7.77(d,J＝1.9Hz,1H),7.73(d,J＝8.7Hz,1H),7.51(dd,J＝8.7,1.9Hz,1H),7.24(dd,J＝13.8,7.7Hz,4H),7.18(d,J＝7.1Hz,1H),7.11(d,J＝7.1Hz,2H),6.99(d,J＝8.2Hz,2H),3.81(t,J＝7.3Hz,2H),3.49(s,2H),3.32(t,J＝5.1Hz,4H),2.64(t,J＝7.3Hz,2H),2.46(s,3H),2.30(t,J＝4.9Hz,4H),1.38(s,9H).13C NMR(101MHz,DMSO-d6)δ162.0,155.3,154.3,147.5,138.7,138.0,137.9,132.7,130.0,129.8,129.2,128.8,128.7,126.7,125.8,121.6,121.1,112.8,79.2,61.7,52.7,51.5,34.7,28.5,9.3.HRMS(ESI)[M-H]-理论值C34H38N3O7S:632.2430；实测值：632.2432.
实施例64
3-甲基-5-(N-(4-(4-吗啉苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸(TZ-S79)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M8-79，其余条件均一致。得白色固体73mg，收率68％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.27–8.13(m,1H),7.91(dd,J＝8.8,1.6Hz,1H),7.82(d,J＝8.8Hz,1H),7.16(dq,J＝15.5,7.1Hz,5H),7.00(d,J＝7.0Hz,2H),6.87(d,J＝8.5Hz,2H),4.32(s,2H),3.76–3.67(m,4H),3.34–3.24(m,2H),3.12–3.00(m,4H),2.55(d,J＝10.5Hz,5H).13C NMR(101MHz,DMSO)δ161.4,155.4,151.0,138.8,135.6,129.8,129.6,129.0,128.8,127.1,126.7,126.4,121.8,115.3,113.4,66.5,51.2,49.4,48.7,34.9,9.6.HRMS(ESI)[M-H]-理论值C29H29N2O6S:533.1746；实测值：533.1737.
实施例65
3-甲基-5-(N-(4-苯甲酰苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸(TZ-S86)
按照5-(N-苄基-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸所用方法，将5-(N-苄基-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯替换为3-甲基-5-(N-(4-苯甲酰基苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯，其余条件均一致。得白色固体70mg，收率63％。M.p.192-193℃.1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.30(d,J＝1.9Hz,1H),7.97(dd,J＝8.8,2.0Hz,1H),7.86(d,J＝8.7Hz,1H),7.69(d,J＝8.0Hz,5H),7.60–7.48(m,4H),7.19(t,J＝7.3Hz,2H),7.13(t,J＝7.2Hz,1H),7.08–6.99(m,2H),4.55(s,2H),3.41(t,J＝7.9Hz,2H),2.64(t,J＝7.9Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ195.8,161.1,155.6,143.8,142.6,138.7,137.5,136.6,135.1,133.1,130.3,130.0,129.6,129.0,129.0,128.8,128.6,126.7,126.7,125.3,122.2,113.6,51.6,50.4,34.8,9.6.HRMS(ESI)[M-H]-理论值C32H26NO6S:552.1481；实测值：552.1484.
实施例66
3-甲基-5-(N-(2-(4-(叔丁氧羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸(TZ-S87)
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按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M8-87，其余条件均一致。得白色固体144mg，收率75％。M.p.158-159℃.1H NMR(400MHz,DMSO-d6)δ8.29(d,J＝1.9Hz,1H),7.97(dd,J＝8.8,1.9Hz,1H),7.87(d,J＝8.8Hz,1H),7.42(d,J＝7.0Hz,1H),7.30(t,J＝7.6Hz,1H),7.23–7.09(m,5H),6.95(d,J＝7.0Hz,2H),4.53(s,2H),3.41(s,4H),3.33–3.23(m,2H),2.78(t,J＝4.8Hz,4H),2.61(s,3H),2.56–2.52(m,2H),1.43(s,9H).13C NMR(101MHz,DMSO-d6)δ161.6,155.4,154.4,151.7,138.8,135.0,131.6,129.9,128.8,128.8,126.7,126.3,124.4,121.7,120.6,113.3,79.4,52.8,49.9,46.8,34.5,28.5,9.5.HRMS(ESI)[M-H]-理论值C34H38N3O7S:632.2430；实测值：632.2423.
实施例67
3-甲基-5-(N-(2-(4-苯甲酰哌嗪-1-基)苄基)-N-苯乙氨磺酰)苯并呋喃-2-羧酸(TZ-S105)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M10-105，其余条件均一致。得白色固体133mg，收率78％。Mp163-164℃.1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.8Hz,1H),7.93–7.76(m,2H),7.51–7.36(m,6H),7.28(t,J＝8.1Hz,1H),7.14(dt,J＝25.5,7.5Hz,5H),6.92(d,J＝7.0Hz,2H),4.53(s,2H),3.56(d,J＝124.8Hz,4H),3.30–3.20(m,2H),2.82(s,4H),2.59–2.47(m,5H).13C NMR(101MHz,DMSO-d6)δ169.5,162.8,155.0,151.5,149.0,138.8,136.3,134.3,131.7,130.5,130.0,129.9,129.7,128.9,128.8,128.8,127.4,126.7,125.2,124.5,121.1,120.7,119.9,113.0,52.8,49.9,46.9,34.5,9.5.HRMS(ESI)[M-H]-理论值C36H34N3O6S:636.2174；实测值：636.2177.
实施例68
3-甲基-5-(N-(4-硝基苯基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-W7)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-W7，其余条件均一致。得白色固体100mg，收率96％。M.p.>380℃(分解).1H NMR(400MHz,DMSO-d6)δ8.19–8.12(m,3H),7.83(dd,J＝9.3,2.3Hz,1H),7.68(d,J＝9.3Hz,1H),7.52(dt,J＝8.6,1.0Hz,2H),7.33–7.17(m,5H),4.34(t,J＝0.9Hz,2H),3.30(t,J＝6.3Hz,2H),2.86(tt,J＝6.4,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,158.0,147.4,143.1,141.8,138.0,132.8,130.3,128.9,128.8,127.5,126.6,125.6,125.0,123.8,120.5,113.8,50.9,47.5,35.0,10.0.
实施例69
3-甲基-5-(((2-(4-甲基哌嗪-1-基)苄基)(苯乙基)氨基)甲基)苯并呋喃-2-羧酸(TZ-D1)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ7.52(d,J＝2.1Hz,1H),7.35(d,J＝8.5Hz,1H),7.31–7.19(m,6H),7.19–7.07(m,2H),6.98(ddd,J＝8.4,7.7,1.5Hz,1H),6.76(dd,J＝7.3,1.4Hz,1H),3.71(s,2H),3.68(d,J＝1.1Hz,2H),3.22–3.13(m,4H),2.92–2.82(m,4H),2.76(tt,J＝5.6,1.0Hz,2H),2.64–2.56(m,5H),2.29(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,154.8,150.6,142.3,139.7,134.6,129.7,128.8,128.6,128.6,128.0,127.4,127.4,126.6,124.4,121.1,120.8,117.4,112.9,58.7,56.9,56.7,53.5,50.1,45.3,33.6,10.2.
实施例70
(E)-3-(4-((2-(二甲基氨甲酰基)苯基)(2-(噻吩-2-基)乙基)氨甲酰基)苯基)丙酸(TZ-D2)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ7.94–7.88(m,2H),7.81–7.74(m,1H),7.67–7.62(m,2H),7.61–7.57(m,2H),7.51(dd,J＝7.8,1.5Hz,1H),7.34–7.27(m,1H),7.19(dd,J＝5.3,1.6Hz,1H),6.93(dd,J＝6.2,5.3Hz,1H),6.69(dd,J＝6.1,1.7Hz,1H),6.46(d,J＝16.5Hz,1H),4.58(t,J＝5.5Hz,2H),3.14(t,J＝5.5Hz,2H),3.01(s,6H).13C NMR(101MHz,DMSO-d6)δ171.1,170.0,169.8,143.7,142.0,141.3,137.3,136.0,130.5,129.0,128.8,128.6,127.2,126.6,125.5,125.5,125.5,123.9,119.6,47.1,36.4,30.7.
实施例71
3-(4-((2-(二甲基氨基)苄基)(3-苯丙基)氨甲酰基)苯基)丙酸(TZ-D3)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ7.61–7.55(m,2H),7.46(dt,J＝8.5,1.0Hz,2H),7.30–7.17(m,5H),7.17–7.10(m,2H),6.94–6.87(m,1H),6.76–6.70(m,1H),4.52(d,J＝0.9Hz,2H),3.39(t,J＝6.1Hz,2H),2.89(s,6H),2.82(tq,J＝8.6,0.8Hz,2H),2.68–2.59(m,4H),1.87(tt,J＝8.5,6.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ177.1,170.2,151.2,142.1,141.9,135.6,129.7,129.5,128.6,128.6,128.6,127.8,126.7,125.8,121.0,115.4,50.3,46.6,44.2,35.7,33.7,30.6,28.2.
实施例72
3-(4-(丁基(2-(二乙基氨基)苄基)氨甲酰基)苯基)丙酸(TZ-D4)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ7.61–7.55(m,2H),7.46(dt,J＝8.5,1.0Hz,2H),7.21–7.15(m,1H),7.10(td,J＝7.6,1.6Hz,1H),6.94–6.87(m,1H),6.66(dd,J＝7.5,1.5Hz,1H),4.55(d,J＝1.0Hz,2H),3.43(q,J＝7.0Hz,4H),3.35(t,J＝6.3Hz,2H),2.82(tq,J＝8.6,0.8Hz,2H),2.61(td,J＝8.7,0.8Hz,2H),1.60(p,J＝6.6Hz,2H),1.36(h,J＝7.3Hz,2H),1.12(t,J＝7.0Hz,6H),0.94(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ177.1,170.2,148.4,142.1,135.6,129.9,129.5,128.6,127.7,127.1,120.9,116.4,50.3,46.9,46.1,35.7,30.6,29.9,20.1,14.0,12.5.
实施例73
(E)-3-(4-(((2-(1H-吡唑-5-基)乙基)(4-(二甲基氨甲酰基)苯基)氨基)甲基)苯基)丙烯酸(TZ-D5)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝3.1Hz,1H),7.70–7.64(m,1H),7.62–7.56(m,2H),7.50–7.44(m,2H),7.27(dt,J＝8.4,0.9Hz,2H),6.90–6.84(m,2H),6.46(d,J＝16.5Hz,1H),6.30(d,J＝3.3Hz,1H),4.56(t,J＝1.0Hz,2H),3.62(t,J＝5.2Hz,2H),3.00(s,6H),2.94(t,J＝5.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ170.8,170.0,152.8,143.5,142.5,138.4,136.8,133.1,130.2,129.5,129.1,128.8,119.6,114.7,104.3,55.7,51.0,37.5,26.9.
实施例74
5-(N-(2-氯苄基)-N-(2-(4-特戊酰基哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D6)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.3Hz,1H),7.83(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.44–7.39(m,1H),7.34(ddt,J＝6.9,3.0,1.0Hz,1H),7.30–7.23(m,2H),7.17–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.45(dd,J＝6.3,1.0Hz,4H),3.69(dd,J＝5.3,2.6Hz,2H),3.63(dd,J＝5.3,2.6Hz,2H),3.20(dd,J＝5.3,2.6Hz,2H),3.09(dd,J＝5.4,2.7Hz,2H),2.58(s,3H),1.22(s,9H).13CNMR(101MHz,DMSO-d6)δ178.0,165.0,158.0,149.2,143.1,135.5,133.7,133.1,131.6,130.8,129.9,129.7,128.1,127.5,127.5,127.4,125.6,125.0,121.4,120.5,117.3,113.8,52.3,52.1,49.8,46.2,41.6,26.5,10.0.
实施例75
5-(N-(2-(4-异丁酰基哌嗪-1-基)苄基-N-(2-(3-甲基吡啶-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D7)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.32(dd,J＝4.1,1.9Hz,1H),8.17(d,J＝2.3Hz,1H),7.83(dd,J＝9.2,2.3Hz,1H),7.68(d,J＝9.2Hz,1H),7.54(ddq,J＝7.7,1.5,0.8Hz,1H),7.18(dd,J＝7.7,4.0Hz,1H),7.16–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.40(d,J＝0.9Hz,2H),3.70(dd,J＝6.5,3.8Hz,2H),3.64(dd,J＝6.5,3.8Hz,2H),3.45(t,J＝6.2Hz,2H),3.15(dd,J＝6.5,3.8Hz,2H),3.06(dd,J＝6.5,3.8Hz,2H),2.96(t,J＝6.3Hz,2H),2.82(hept,J＝7.3Hz,1H),2.58(s,3H),2.26(d,J＝0.7Hz,3H),1.06(d,J＝7.3Hz,6H).13C NMR(101MHz,DMSO-d6)δ176.2,165.0,158.0,154.8,149.1,146.5,143.1,137.4,132.8,131.3,130.7,127.5,127.5,127.1,125.6,125.0,121.7,121.4,120.5,117.3,113.8,50.7,50.0,46.3,44.7,32.7,30.2,18.7,18.0,10.0.
实施例76
3-甲基-5-(N-(3-吗啉苄基)-N-(2-氧代-苯基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D8)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.3Hz,1H),8.00–7.94(m,2H),7.83(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.60–7.48(m,3H),7.16(dd,J＝8.3,7.4Hz,1H),7.04–6.95(m,2H),6.82(tt,J＝2.2,1.0Hz,1H),4.44(t,J＝1.0Hz,2H),4.42(s,2H),3.80(ddd,J＝8.4,6.1,3.4Hz,4H),3.23(ddd,J＝8.4,6.1,3.4Hz,4H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ194.5,165.0,158.0,150.8,143.1,137.4,134.8,133.3,132.4,130.5,129.4,128.6,127.5,125.6,125.0,123.7,120.5,117.8,114.9,113.8,66.7,53.7,51.4,48.2,10.0.
实施例77
5-(N-(2-(4-(4-乙酰基苯甲酰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D9)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝2.3Hz,1H),7.96–7.90(m,2H),7.83(dd,J＝9.2,2.3Hz,1H),7.80–7.73(m,2H),7.68(d,J＝9.2Hz,1H),7.31–7.20(m,5H),7.17–7.09(m,2H),6.99(td,J＝8.0,1.4Hz,1H),6.75(dd,J＝7.3,1.4Hz,1H),4.40(d,J＝0.9Hz,2H),3.73(dd,J＝6.0,3.3Hz,2H),3.62(dd,J＝6.2,3.3Hz,2H),3.35–3.20(m,2H),3.10(td,J＝6.0,3.3Hz,4H),2.86(tt,J＝6.4,0.9Hz,2H),2.58(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ197.4,170.2,165.0,158.0,149.1,143.1,141.0,138.9,138.0,132.8,130.7,129.7,128.9,128.8,128.1,127.5,127.5,127.1,126.6,125.6,125.0,121.4,120.5,117.3,113.8,50.7,49.9,47.2,47.0,35.0,26.4,10.0.
实施例78
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-6-氟苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R1)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.89(d,J＝8.8Hz,1H),7.63(d,J＝8.7Hz,1H),7.32–7.26(m,1H),7.17(dt,J＝14.9,7.2Hz,3H),6.99–6.77(m,4H),4.60(s,2H),4.47(q,J＝7.1Hz,2H),3.60(t,J＝4.8Hz,4H),3.25(t,J＝8.4Hz,2H),2.85(t,J＝4.9Hz,4H),2.59(d,J＝7.7Hz,5H),1.48(s,9H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ162.5(d,J＝245Hz),159.9,155.8,154.8(d,J＝5.7Hz),142.9,138.4,134.7,130.4(d,J＝10.6Hz),129.3,128.6,128.5,126.4(d,J＝6.3Hz),125.6,121.6,118.3(d,J＝13.1Hz),116.9,112.9,111.7(d,J＝22.9Hz),79.8,61.5,53.3,49.6,41.8,36.0,28.5,14.4,9.4.19F NMR(376MHz,CDCl3)δ-111.5.HRMS(ESI)[M+H]+calcd forC36H42FN3O7S:680.2806；found:680.2805.
实施例79
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-环己基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R2)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.9Hz,1H),7.92(dd,J＝8.8,1.9Hz,1H),7.67(d,J＝8.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.13–7.03(m,2H),4.58–4.41(m,4H),3.51(s,4H),3.10(t,J＝7.9Hz,2H),2.78(t,J＝4.9Hz,4H),2.62(s,3H),1.69–1.52(m,4H),1.47(s,9H),1.47–1.42(m,3H),1.41–1.37(m,1H),1.14(q,J＝7.3Hz,2H),1.03(q,J＝11.2,9.9Hz,4H),0.7(t,J＝11.9Hz,2H).13C NMR(101MHz,CDCl3)δ160.1,155.9,154.9,151.4,143.1,135.9,131.3,130.0,129.5,128.6,126.4,125.7,124.7,121.6,120.2,113.1,80.0,61.7,53.1,46.0,45.8,35.2,35.0,33.2,28.6,26.5,26.2,14.5,9.5.HRMS(ESI)[M+H]+calcd for C36H49N3O7S:668.3369；found:668.3366.
实施例80
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-(三氟甲基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R3)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.13(d,J＝1.8Hz,1H),7.92(dd,J＝8.8,1.9Hz,1H),7.68(d,J＝8.8Hz,1H),7.37(d,J＝8.0Hz,2H),7.26–7.14(m,2H),7.07(d,J＝7.9Hz,2H),6.99(td,J＝7.5,1.2Hz,1H),6.92(dd,J＝8.0,1.2Hz,1H),4.52(s,2H),4.48(q,J＝7.1Hz,2H),4.37(s,2H),3.41–3.22(m,4H),2.59(s,3H),2.58–2.51(m,4H),1.47(t,J＝7.1Hz,3H),1.45(s,9H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,154.8,151.5,143.3,140.0,135.8,129.9,129.9,129.6,128.9,128.7,126.2,125.6,125.2(q,J＝3.7Hz),123.2(q,J＝295.8Hz),120.1,113.3,80.0,61.8,52.8,50.8,46.0,28.5,14.5,9.5.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)[M+H]+calcd for C36H40F3N3O7S:716.2617；found:716.2617.
实施例81
5-(N-(2-(4-(叔丁氧基羰基)-3,5-二甲基哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R4)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.8Hz,1H),7.92(dd,J＝8.8,1.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.51(dd,J＝7.7,1.6Hz,1H),7.29(dd,J＝7.7,1.6Hz,1H),7.19–7.07(m,5H),6.89–6.82(m,2H),4.69(s,2H),4.48(q,J＝7.1Hz,2H),4.17(p,J＝6.6Hz,2H),3.38–3.29(m,2H),2.86(dd,J＝11.7,4.3Hz,2H),2.74(d,J＝11.6Hz,2H),2.60(s,3H),2.56(dd,J＝9.9,6.5Hz,2H),1.54–1.40(m,12H),1.20(d,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.7,151.6,143.1,138.3,135.3,131.1,129.6,129.6,128.7,128.6,128.6,126.6,126.3,125.6,125.0,121.5,120.2,113.2,79.8,61.7,58.2,50.3,47.3,46.8,35.2,28.6,20.9,14.5,9.5.HRMS(ESI)[M+H]+calcd for C38H47N3O7S:690.3213；found:690.3221.
实施例82
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-4-(三氟甲基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R5)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝1.8Hz,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.65(d,J＝8.8Hz,1H),7.55(d,J＝8.0Hz,1H),7.36–7.27(m,2H),7.21–7.09(m,3H),6.93–6.87(m,2H),4.55(s,2H),4.48(q,J＝7.1Hz,2H),3.59–3.46(m,4H),3.35(dd,J＝9.1,6.5Hz,2H),2.81(t,J＝4.9Hz,4H),2.66–2.59(m,5H),1.48(s,9H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,154.8,151.5,143.3,138.1,135.3,135.2,131.1,130.2,129.7,128.7,128.6,126.7,126.3,125.6,125.3,121.7,117.0,113.3,80.3,61.8,52.8,49.9,46.5,34.9,28.5,14.5,9.5.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)[M+H]+calcd for C37H42F3N3O7S:730.2774；found:730.2766.
实施例83
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氟苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R6)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.86(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.8Hz,1H),7.21–7.02(m,5H),6.93(d,J＝7.5Hz,3H),4.53(s,2H),4.48(q,J＝7.3Hz,2H),3.66–3.40(m,4H),3.36(t,J＝7.9Hz,2H),2.74(t,J＝5.0Hz,4H),2.65(d,J＝8.1Hz,2H),2.61–2.58(m,3H),1.47(s,9H),1.45(t,J＝7.3Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0(d,J＝244.4Hz),160.0,156.0,154.9,147.3(d,J＝3.9Hz),143.2,138.3,135.4,133.9(d,J＝7.1Hz),129.6,128.7,128.6,126.7,126.3,125.6,122.0(d,J＝8.4Hz),121.6,116.4(d,J＝23.1Hz),115.3(d,J＝22.3Hz),113.3,80.1,61.7,53.2,49.9,46.4,34.9,28.5,14.5,9.5.19F NMR(376MHz,CDCl3)δ-117.0.HRMS(ESI)[M+H]+calcd forC36H42FN3O7S:680.2806；found:680.2802.
实施例84
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-(三氟甲氧基苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R7)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝1.9Hz,1H),7.91(dd,J＝8.8,1.9Hz,1H),7.67(d,J＝8.7Hz,1H),7.24(dd,J＝7.8,1.5Hz,1H),7.18(td,J＝7.7,1.6Hz,1H),7.05–6.87(m,6H),4.57–4.44(m,4H),4.31(s,2H),3.47–3.24(m,4H),2.68–2.48(m,7H),1.51–1.37(m,12H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,154.8,151.4,148.6,143.2,135.9,134.6,130.1,130.0,129.8,129.6,128.7,126.3,125.6,123.1(q,J＝291.6Hz),120.8,120.0,113.3,80.0,61.7,52.8,50.6,45.9,28.5,14.5,9.5.19F NMR(376MHz,CDCl3)δ-57.9.HRMS(ESI)[M+H]+calcd for C36H40F3N3O8S:732.2566；found:732.2559.
实施例85
5-(N-(4-(4-(叔丁氧基羰基)哌嗪-1-羰基)苯基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R8)
按照3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.63–7.53(m,2H),7.37(dd,J＝8.4,2.4Hz,2H),7.25–7.15(m,3H),7.15–7.06(m,4H),4.46(q,J＝7.2Hz,2H),3.89–3.60(m,4H),3.58–3.24(m,6H),2.79(t,J＝7.5Hz,2H),2.54(s,2H),1.55–1.36(m,12H).13C NMR(101MHz,CDCl3)δ169.7,159.9,156.0,154.6,143.1,140.8,137.8,135.1,133.6,129.4,129.1,128.9,128.6,128.2,126.8,126.7,125.6,122.1,113.0,80.6,61.7,52.2,35.3,28.5,14.5,9.5.HRMS(ESI)[M+Na]+calcd for C36H41N3O8S:698.2512；found:698.2521.
实施例86
5-(N-(2-(4-(叔丁氧基羰基)哌啶-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R9)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝2.8Hz,1H),7.88(d,J＝9.4Hz,1H),7.64(dd,J＝8.9,2.4Hz,1H),7.45(d,J＝7.7Hz,1H),7.23(d,J＝8.0Hz,1H),7.19–7.02(m,5H),6.91(d,J＝7.1Hz,2H),4.56(s,2H),4.48(qd,J＝7.1,2.2Hz,2H),3.31(t,J＝8.0Hz,2H),2.96(d,J＝11.7Hz,2H),2.69(t,J＝11.4Hz,2H),2.62–2.53(m,5H),2.37–2.22(m,1H),1.94(d,J＝13.0Hz,2H),1.79(t,J＝11.8Hz,2H),1.49–1.43(m,12H).13C NMR(101MHz,CDCl3)δ174.4,160.1,155.9,152.2,143.0,138.6,135.8,131.0,129.8,129.6,128.7,128.5,128.5,126.5,126.4,125.8,124.4,121.6,119.9,113.2,80.5,61.7,53.2,49.6,46.1,41.8,34.8,29.0,28.2,14.5,9.6.HRMS(ESI)[M+H]+calcd for C37H44N2O7S:661.2947；found:661.2957.
实施例87
2-(4-(N-(2-(4-叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-2-甲基苯氧基)乙酸乙酯(M-R10)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.68–7.60(m,2H),7.44(d,J＝7.7Hz,1H),7.27(s,1H),7.23–7.06(m,5H),6.91(d,J＝7.2Hz,2H),6.75(dd,J＝8.7,2.4Hz,1H),4.71(d,J＝2.5Hz,2H),4.49(d,J＝2.5Hz,2H),4.28(t,J＝7.2Hz,2H),3.63–3.43(m,4H),3.24(dt,J＝8.1,4.5Hz,2H),2.90–2.72(m,4H),2.62–2.53(m,2H),2.33(s,3H),1.49(s,9H),1.34–1.26(m,3H).13C NMR(101MHz,CDCl3)δ168.3,159.3,154.9,151.5,138.7,132.3,131.3,130.2,129.9,128.7,128.6,128.6,126.9,126.5,124.7,120.2,110.7,80.0,65.6,61.7,53.0,49.7,46.6,35.0,28.6,16.5,14.3.HRMS(ESI)[M+H]+calcd for C35H45N3O7S:652.3056；found:652.3069.
实施例88
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R11)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.63(d,J＝8.8Hz,1H),7.41(dd,J＝7.9,1.7Hz,1H),7.28(d,J＝8.2Hz,1H),7.09(ddd,J＝7.1,3.8,2.4Hz,2H),6.96(d,J＝7.7Hz,2H),6.78(d,J＝7.8Hz,2H),4.57(s,2H),4.48(q,J＝7.1Hz,2H),3.52(t,J＝4.8Hz,4H),3.33–3.25(m,2H),2.79(t,J＝4.9Hz,4H),2.61(s,3H),2.56(dd,J＝9.3,6.5Hz,2H),2.24(s,3H),1.50–1.43(m,12H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.9,151.5,143.1,136.1,135.7,135.4,131.0,130.0,129.5,129.3,128.8,128.5,126.4,125.6,124.8,121.6,120.3,113.1,80.0,61.7,53.1,49.6,46.4,34.4,28.5,21.0,14.5,9.5.HRMS(ESI)[M+H]+calcd for C37H45N3O7S:676.3056；found:676.3061.
实施例89
5-(N-苄基-N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R12)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.11(d,J＝1.9Hz,1H),7.91(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.7Hz,1H),7.30(dd,J＝7.8,1.6Hz,1H),7.23–7.08(m,4H),7.02(td,J＝7.5,1.2Hz,1H),6.94(td,J＝8.5,8.1,1.5Hz,3H),4.53(s,2H),4.48(q,J＝7.1Hz,2H),4.33(s,2H),3.45–3.19(m,4H),2.64–2.51(m,7H),1.51–1.43(m,12H).13C NMR(101MHz,CDCl3)δ160.0,155.8,154.8,151.5,143.1,136.4,135.5,130.4,129.6,129.4,128.7,128.5,128.4,127.8,126.4,125.7,124.6,121.6,120.1,113.1,79.9,61.7,52.7,50.8,45.3,28.5,14.5,9.5.HRMS(ESI)[M+H]+calcd for C35H41N3O7S:648.2743；found:648.2730.
实施例90
5-(N-(丁-3-炔-1-基)-N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R13)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝1.9Hz,1H),7.92(dd,J＝8.8,1.9Hz,1H),7.67(d,J＝8.8Hz,1H),7.38(dd,J＝7.9,1.6Hz,1H),7.27(d,J＝8.7Hz,1H),7.13–7.05(m,2H),4.56(s,2H),4.48(q,J＝7.1Hz,2H),3.58–3.43(m,4H),3.33–3.24(m,2H),2.79(t,J＝4.9Hz,4H),2.62(s,3H),2.30–2.21(m,2H),1.83(t,J＝2.6Hz,1H),1.47(s,9H),1.45(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,154.9,151.7,143.2,135.6,131.0,130.2,129.6,129.1,126.4,125.7,125.1,121.7,120.6,113.2,80.8,80.0,70.2,61.7,53.2,46.6,46.4,28.6,18.7,14.5,9.5.HRMS(ESI)[M+H]+calcd forC32H39N3O7S:610.2587；found:610.2595.
实施例91
(E)-3-(4-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨基磺酰基)苯基)丙烯酸乙酯(M-R14)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.86–7.79(m,2H),7.69(d,J＝16.1Hz,1H),7.65–7.59(m,2H),7.41(dd,J＝8.0,1.6Hz,1H),7.29(dd,J＝7.8,1.7Hz,1H),7.23–7.07(m,5H),6.94–6.87(m,2H),6.53(d,J＝16.1Hz,1H),4.54(s,2H),4.29(q,J＝7.1Hz,2H),3.53(t,J＝4.7Hz,4H),3.33–3.24(m,2H),2.80(t,J＝4.7Hz,4H),2.63–2.54(m,2H),1.48(s,9H),1.35(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ166.4,154.9,151.6,142.4,141.3,138.5,138.4,130.9,130.1,128.9,128.7,128.6,128.6,127.8,126.6,124.8,121.6,120.3,80.0,61.0,53.1,49.6,46.5,35.0,28.6,14.4.HRMS(ESI)[M+H]+calcd forC35H43N3O6S:634.2951；found:634.2957.
实施例92
3-(3-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)苯基)丙酸乙酯(M-R15)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.70(d,J＝3.5Hz,2H),7.44(t,J＝3.0Hz,2H),7.38(d,J＝7.5Hz,1H),7.28(d,J＝9.5Hz,1H),7.22–7.06(m,5H),6.90(d,J＝7.1Hz,2H),4.52(s,2H),4.09(q,J＝7.0Hz,2H),3.64–3.44(m,4H),3.26(t,J＝8.4Hz,2H),3.06–2.98(m,2H),2.82–2.78(m,4H),2.67–2.56(m,4H),1.48(s,9H),1.24–1.17(m,3H).13C NMR(101MHz,CDCl3)δ172.4,154.9,151.6,142.2,140.4,138.6,132.8,131.1,130.1,129.4,128.8,128.7,128.6,127.1,126.6,125.2,124.8,120.3,80.0,60.7,53.1,49.6,46.6,35.6,35.1,30.8,28.6,14.3.HRMS(ESI)[M+H]+calcd for C35H45N3O6S:636.3107；found:636.3100.
实施例93
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-2,3-二氢苯并呋喃-2-羧酸乙酯(M-R16)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.68(d,J＝8.7Hz,1H),7.60(s,1H),7.44(d,J＝7.6Hz,1H),7.28(d,J＝9.2Hz,1H),7.23–7.06(m,5H),7.01–6.87(m,3H),5.30(dd,J＝10.8,6.8Hz,1H),4.49(s,2H),4.28(q,J＝7.2Hz,2H),3.65–3.35(m,6H),3.25(t,J＝8.4Hz,2H),2.87–2.73(m,4H),2.59(t,J＝7.2Hz,2H),1.48(s,9H),1.33(t,J＝7.2Hz,4H).13C NMR(101MHz,CDCl3)δ170.4,162.6,154.9,151.5,138.7,132.9,131.3,130.2,129.1,128.7,128.6,126.5,126.4,124.8,124.4,120.2,110.2,80.1,80.0,62.1,53.1,49.7,46.6,35.1,33.4,28.6,14.3.HRMS(ESI)[M+H]+calcd for C35H43N3O7S:650.2900；found:650.2896.
实施例94
6-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨基磺酰基)色氨-2-羧酸乙酯(M-R17)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ7.59(d,J＝8.8Hz,1H),7.53(s,1H),7.43(d,J＝7.6Hz,1H),7.32–7.27(m,1H),7.23–7.06(m,5H),7.02(dt,J＝8.6,2.3Hz,1H),6.91(d,J＝7.1Hz,2H),4.81(t,J＝3.8Hz,1H),4.49(s,1H),4.26(q,J＝6.8Hz,2H),3.64–3.44(m,4H),3.27–3.23(m,2H),2.94–2.69(m,6H),2.59(t,J＝8.7Hz,2H),2.38–2.17(m,2H),1.48(s,9H),1.29(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ170.3,157.1,155.0,151.5,138.7,131.9,131.3,130.2,129.2,128.7,128.6,127.2,126.5,124.7,122.1,120.2,117.8,80.0,74.1,61.8,53.1,49.7,46.7,35.1,28.6,24.0,23.1,14.3.HRMS(ESI)[M+H]+calcd forC36H45N3O7S:664.3056；found:664.3060.
实施例95
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R18)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.16(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.7Hz,1H),7.41(dd,J＝8.0,1.7Hz,1H),7.31–7.26(m,1H),7.14–7.06(m,2H),7.02(dd,J＝5.1,1.2Hz,1H),6.80(dd,J＝5.2,3.4Hz,1H),6.58(dd,J＝3.4,1.1Hz,1H),4.57(s,2H),4.48(q,J＝7.1Hz,2H),3.54–3.49(m,4H),3.39–3.30(m,2H),2.86–2.75(m,6H),2.61(s,3H),1.49–1.42(m,12H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.9,151.6,143.1,140.6,135.6,130.9,130.2,129.6,128.9,127.1,126.3,125.7,125.3,124.9,123.9,121.6,120.4,113.2,80.0,61.7,53.1,49.5,46.3,29.0,28.6,14.5,9.5.HRMS(ESI)[M+H]+calcd for C34H41N3O7S2:668.2464；found:668.2460.
实施例96
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(吡啶-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R19)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.33(ddd,J＝4.9,1.9,0.9Hz,1H),8.12(d,J＝1.8Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.61(d,J＝8.7Hz,1H),7.51–7.37(m,2H),7.23(td,J＝7.7,1.6Hz,1H),7.09–6.97(m,3H),6.92(dt,J＝7.7,1.1Hz,1H),4.57(s,2H),4.47(q,J＝7.1Hz,2H),3.60–3.52(m,2H),3.53–3.44(m,4H),2.91–2.81(m,2H),2.77(t,J＝5.0Hz,4H),2.59(s,3H),1.49–1.42(m,12H).13C NMR(101MHz,CDCl3)δ160.0,158.6,155.9,154.9,151.5,149.3,143.0,136.4,135.6,131.3,130.0,129.5,128.7,126.4,125.7,124.8,123.4,121.7,121.5,120.4,113.1,80.0,61.7,53.0,48.1,46.7,37.0,28.5,14.5,9.5.HRMS(ESI)[M+H]+calcd for C35H42N4O7S:663.2852；found:663.2865.
实施例97
5-(N-(2-(4-(2,2-二甲基丁酰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R20)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18–8.13(m,1H),7.88(dd,J＝8.8,1.9Hz,1H),7.67–7.60(m,1H),7.37(dd,J＝7.6,1.6Hz,1H),7.32–7.27(m,1H),7.21–7.05(m,5H),6.94–6.87(m,2H),4.57(s,2H),4.48(q,J＝7.1Hz,2H),3.75(t,J＝4.9Hz,4H),3.36–3.28(m,2H),2.83(t,J＝4.9Hz,4H),2.65–2.56(m,5H),1.65(q,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H),1.26(s,6H),0.91(t,J＝7.5Hz,3H).13C NMR(101MHz,CDCl3)δ175.7,160.0,155.9,151.3,143.1,138.5,135.6,131.0,130.2,129.6,128.9,128.6,128.6,126.6,126.4,125.6,124.9,121.6,120.5,113.2,61.7,53.4,49.5,46.8,45.5,43.1,35.1,33.4,26.7,14.5,9.6,9.5.HRMS(ESI)[M+H]+calcd for C37H45N3O6S:660.3107；found:660.3120.
实施例98
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(呋喃-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R21)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18–8.13(m,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.64(d,J＝8.8Hz,1H),7.40(dd,J＝8.0,1.6Hz,1H),7.26–7.22(m,1H),7.15(dd,J＝1.8,0.8Hz,1H),7.12–7.04(m,2H),6.17(dd,J＝3.2,1.9Hz,1H),5.84(dd,J＝3.2,0.9Hz,1H),4.54(s,2H),4.48(q,J＝7.1Hz,2H),3.51(t,J＝4.9Hz,4H),3.43–3.34(m,2H),2.78(t,J＝4.9Hz,4H),2.70–2.64(m,2H),2.61(s,3H),1.48–1.43(m,12H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.9,152.3,151.6,143.1,141.4,135.7,131.1,130.1,129.5,128.9,126.3,125.7,124.9,121.6,120.4,113.2,110.3,106.3,80.0,61.7,53.1,46.6,46.2,28.6,27.3,14.5,9.5.HRMS(ESI)[M+H]+calcd for C34H41N3O8S:652.2693；found:652.2703.
实施例99
6-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-4-氧代-4H-铬烯-2-羧酸乙酯(M-R22)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.61(d,J＝2.3Hz,1H),8.06(dd,J＝8.9,2.4Hz,1H),7.68(d,J＝8.8Hz,1H),7.42–7.36(m,1H),7.30–7.26(m,1H),7.20–7.05(m,6H),6.95–6.89(m,2H),4.59(s,2H),4.49(q,J＝7.1Hz,2H),3.53(t,J＝4.9Hz,4H),3.38–3.30(m,2H),2.80(t,J＝4.9Hz,4H),2.65–2.57(m,2H),1.48(s,9H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ177.2,160.1,157.6,154.9,152.7,151.6,138.4,138.3,132.7,130.6,130.0,128.9,128.7,126.6,125.8,124.9,124.4,120.4,120.3,115.3,80.0,63.5,53.1,49.6,46.4,35.0,28.6,14.2.HRMS(ESI)[M+H]+calcd for C36H41N3O8S:676.2693；found:676.2700.
实施例100
5-(N-(2-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R23)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝1.9Hz,1H),7.87(dd,J＝8.8,1.9Hz,1H),7.63(d,J＝8.8Hz,1H),7.37(dd,J＝7.7,1.6Hz,1H),7.23(dd,J＝7.7,1.6Hz,1H),7.20–7.01(m,5H),6.93–6.87(m,2H),4.56(s,2H),4.48(q,J＝7.1Hz,2H),3.66(t,J＝5.3Hz,4H),3.34–3.26(m,2H),2.74(t,J＝5.3Hz,4H),2.64–2.56(m,5H),1.83(t,J＝5.3Hz,4H),1.48–1.43(m,12H).13C NMR(101MHz,CDCl3)δ160.0,156.6,155.9,152.1,143.1,138.6,135.8,130.9,130.0,129.5,128.7,128.6,128.6,126.5,126.4,125.7,124.5,121.6,120.1,113.1,79.5,61.7,50.7,49.5,46.2,36.1,34.9,33.3,28.5,14.5,9.5.HRMS(ESI)[M+H]+calcd for C39H47N3O7S:702.3213；found:702.3217.
实施例101
5-(N-(2-(2-(叔丁氧基羰基)-2,8-二氮杂螺[4.5]癸-8-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R24)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝1.8Hz,1H),7.87(dd,J＝8.8,1.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.38(d,J＝7.7Hz,1H),7.27–7.21(m,1H),7.21–7.01(m,5H),6.94–6.88(m,2H),4.57(s,2H),4.48(q,J＝7.1Hz,2H),3.56–3.09(m,6H),2.80(dd,J＝12.4,6.6Hz,4H),2.66–2.57(m,5H),1.74(t,J＝7.1Hz,2H),1.66(d,J＝5.6Hz,4H),1.50–1.42(m,12H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.9,143.1,138.6,135.9,130.8,130.0,129.5,128.7,128.6,126.5,126.4,125.7,124.3,121.6,120.1,113.1,79.3,61.7,51.1,49.5,46.1,44.3,40.4,39.5,35.5,34.9,28.7,14.5,9.5.HRMS(ESI)[M+H]+calcdfor C40H49N3O7S:716.3369；found:716.3384.
实施例102
5-(N-((2-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)甲基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R25)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.24(dd,J＝5.0,1.8Hz,1H),8.14(t,J＝1.2Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.75(dd,J＝7.6,1.9Hz,1H),7.65(d,J＝8.7Hz,1H),7.15(q,J＝7.3,6.8Hz,3H),6.97(dd,J＝7.6,4.8Hz,1H),6.92–6.86(m,2H),4.48(q,J＝7.1Hz,2H),4.44(s,2H),3.52(t,J＝5.0Hz,4H),3.30(dd,J＝9.2,6.5Hz,2H),3.00(t,J＝5.0Hz,4H),2.69–2.51(m,5H),1.54–1.40(m,12H).13C NMR(101MHz,CDCl3)δ161.2,160.0,156.0,154.9,147.4,143.2,138.4,138.1,135.3,129.6,128.7,128.6,126.7,126.2,125.6,123.9,121.6,119.4,113.3,80.0,61.7,50.9,49.8,46.7,34.8,28.5,14.5.HRMS(ESI)[M+H]+calcd for C35H42N4O7S:663.2852；found:663.2839.
实施例103
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸乙酯(M-R26)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.30(dd,J＝1.8,0.6Hz,1H),7.93(dd,J＝8.6,0.6Hz,1H),7.83(dd,J＝8.6,1.7Hz,1H),7.47–7.40(m,1H),7.28(dd,J＝7.8,1.7Hz,1H),7.20–7.06(m,5H),6.92–6.86(m,2H),4.59(s,2H),4.43(q,J＝7.1Hz,2H),3.52(t,J＝5.0Hz,4H),3.37–3.28(m,2H),2.80(d,J＝2.7Hz,7H),2.64–2.56(m,2H),1.48(s,9H),1.44(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ163.0,154.9,151.6,144.0,141.0,140.1,138.5,136.8,130.9,130.1,129.8,128.8,128.6,128.6,126.5,124.8,124.5,123.7,123.3,120.3,80.0,61.7,53.1,49.5,46.4,34.9,28.6,14.5,13.4.HRMS(ESI)[M+H]+calcdfor C36H43N3O6S2:678.2672；found:678.2684.
实施例104
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-吗啉基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-R27)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(M4-14)所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18(dd,J＝2.0,0.6Hz,1H),7.96(dd,J＝8.8,1.9Hz,1H),7.67(dd,J＝8.8,0.6Hz,1H),7.39(dd,J＝8.0,1.6Hz,1H),7.29–7.19(m,1H),7.11–7.03(m,2H),4.54(s,2H),4.48(q,J＝7.1Hz,2H),3.58–3.48(m,8H),3.22(t,J＝7.2Hz,2H),2.79(t,J＝5.0Hz,4H),2.62(s,3H),2.26(t,J＝7.1Hz,2H),2.21(t,J＝4.7Hz,4H),1.47(s,9H),1.45(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,155.9,154.9,151.4,143.2,135.5,131.0,129.9,129.5,128.8,126.4,125.6,124.7,121.7,120.2,113.2,80.1,66.9,61.7,56.9,53.7,53.0,47.1,45.0,28.6,14.5,9.6.HRMS(ESI)[M+H]+calcd for C34H46N4O8S:671.3115；found:671.3116.
实施例105
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-6-氟苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R1)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R1，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝1.9Hz,1H),7.88(dd,J＝8.7,1.9Hz,1H),7.80(d,J＝8.8Hz,1H),7.36(q,J＝7.7Hz,1H),7.22–7.08(m,3H),7.06–6.92(m,2H),6.88–6.82(m,2H),4.53(s,2H),3.33(t,J＝4.7Hz,4H),3.15(t,J＝8.3Hz,2H),2.75(t,J＝4.8Hz,4H),2.55(s,3H),2.43(t,J＝8.3Hz,2H),1.39(s,9H).13C NMR(101MHz,DMSO-d6)δ162.5(d,J＝247.1Hz),161.8,154.7(d,J＝83.8Hz),154.6,138.7,133.9,130.5(d,J＝78.0Hz),128.8(d,J＝17.9Hz),126.7,125.7,121.3,118.3(d,J＝13.3Hz),117.2,113.1,112.0,79.5,53.1,49.6,42.2,35.4,28.5,9.5.19F NMR(376MHz,DMSO)δ-111.8.HRMS(ESI)[M-H]-calcd for C34H38FN3O7S:650.2336；found:650.2332.
实施例106
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-环己基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R2)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R2，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝1.9Hz,1H),7.91(dd,J＝8.7,1.9Hz,1H),7.83(d,J＝8.7Hz,1H),7.45–7.39(m,1H),7.29–7.21(m,1H),7.12(d,J＝7.6Hz,2H),4.43(s,2H),3.38(s,4H),3.02(t,J＝7.3Hz,2H),2.74(t,J＝4.9Hz,4H),2.57(s,3H),1.48(d,J＝7.5Hz,3H),1.40(s,9H),1.33(d,J＝12.6Hz,2H),1.07–0.95(m,6H),0.59(d,J＝11.5Hz,2H).13C NMR(101MHz,DMSO)δ161.8,155.2,154.4,151.5,134.6,131.9,130.2,129.8,128.7,125.7,124.3,121.4,120.4,113.1,79.4,52.8,46.5,46.4,34.9,34.6,32.9,28.5,26.4,26.0,9.5.HRMS(ESI)[M-H]-calcd for C34H45N3O7S:638.2900；found:638.2897.
实施例107
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-(三氟甲基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R3)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R3，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(d,J＝8.8Hz,1H),7.89(d,J＝8.7Hz,1H),7.48(d,J＝8.0Hz,2H),7.17(dt,J＝30.9,8.5Hz,4H),6.99–6.90(m,2H),4.49(s,2H),4.37(s,2H),3.23(s,4H),2.56(d,J＝10.6Hz,7H),1.39(s,9H).13C NMR(101MHz,DMSO-d6)δ160.7,155.1,153.9,151.1,143.7,141.0,134.5,130.4,129.3(q,J＝39.3Hz),128.7,128.3,127.9,127.5,126.2,124.7(q,J＝4.0Hz),124.4,124.1(q,J＝271.8Hz),123.8,121.7,119.8,113.1,78.9,52.1,51.0,46.5,28.0,9.0.19F NMR(376MHz,DMSO)δ-61.1.HRMS(ESI)[M-H]-calcd for C34H36F3N3O7S:686.2148；found:686.2146.
实施例108
5-(N-(2-(4-(叔丁氧基羰基)-3,5-二甲基哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R4)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R4，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝1.9Hz,1H),7.93(dd,J＝8.7,1.9Hz,1H),7.80(d,J＝8.7Hz,1H),7.46–7.40(m,1H),7.33–7.25(m,1H),7.13(dd,J＝14.9,7.3Hz,5H),6.88–6.82(m,2H),4.57(s,2H),4.03–3.96(m,2H),3.25(dd,J＝9.9,6.3Hz,2H),2.84–2.70(m,4H),2.56(s,3H),2.42(dd,J＝9.6,6.4Hz,2H),1.38(s,9H),1.03(d,J＝6.7Hz,6H).13C NMR(101MHz,DMSO)δ161.5,154.7,153.6,151.3,138.0,133.5,131.1,129.9,128.8,128.4,128.3,126.3,125.1,124.2,120.9,120.0,112.6,78.7,57.2,50.1,46.8,46.5,34.3,28.0,20.0,9.1.HRMS(ESI)[M-H]-calcd for C36H43N3O7S:660.2743；found:660.2731.
实施例109
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-4-(三氟甲基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R5)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R5，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝2.0Hz,1H),7.93(dd,J＝8.7,1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.57(d,J＝7.9Hz,1H),7.42–7.35(m,2H),7.21–7.07(m,3H),7.00–6.94(m,2H),4.53(s,2H),3.41(s,4H),3.33(t,J＝7.8Hz,2H),2.81(t,J＝4.8Hz,4H),2.57(d,J＝3.9Hz,5H),1.41(s,9H).13C NMR(101MHz,DMSO-d6)δ161.1,154.9,153.9,151.3,138.2,136.4,133.8,129.7(q,J＝25.3Hz),128.4,128.3,126.2,125.6,124.1(q,J＝270Hz),121.2,116.5,112.8,79.0,51.8,50.2,46.4,34.0,28.0,9.0.19F NMR(376MHz,DMSO)δ-60.8.HRMS(ESI)[M-H]-calcd for C35H38F3N3O7S:700.2304；found:700.2298.
实施例110
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)-5-氟苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R6)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R6，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.9Hz,1H),7.89(dd,J＝8.7,1.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.22–7.03(m,6H),7.01–6.95(m,2H),4.48(s,2H),3.35(dd,J＝18.3,10.5Hz,6H),2.72(t,J＝4.8Hz,4H),2.56(s,5H),1.40(s,9H).13C NMR(101MHz,DMSO-d6)δ161.4,157.6,154.7,153.9,147.2,138.2,134.6(d,J＝7.4Hz),133.8,129.8,128.4,128.3,126.2,125.1,122.2,120.9,115.3,114.6(d,J＝22.0Hz),112.6,78.9,52.4,49.9,46.3,34.0,28.0,9.0.19F NMR(376MHz,DMSO)δ-118.4.HRMS(ESI)[M-H]-calcd forC34H38FN3O7S:650.2336；found:650.2336.
实施例111
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-(三氟甲氧基苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R7)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R7，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝1.9Hz,1H),8.02(dd,J＝8.8,1.9Hz,1H),7.88(d,J＝8.7Hz,1H),7.21(dd,J＝7.7,1.6Hz,1H),7.16–7.02(m,5H),6.99–6.90(m,2H),4.47(s,2H),4.30(s,2H),3.35–3.12(m,4H),2.57(d,J＝6.4Hz,7H),1.39(s,9H).13C NMR(101MHz,DMSO-d6)δ160.7,155.0,153.9,151.0,147.3,135.5,134.6,130.5,129.9,129.4,129.2,128.1,124.9(q,J＝248.9Hz),124.2,121.6,120.5,119.7,113.0,78.8,52.0,50.7,46.3,28.0,9.0.19F NMR(376MHz,DMSO)δ-57.0.HRMS(ESI)[M+H]+calcd for C34H36F3N3O8S:704.2253；found:704.2248.
实施例112
5-(N-(4-(4-(叔丁氧基羰基)哌嗪-1-羰基)苯基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R8)
按照3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸(TZ-S76)所用方法，将3-甲基-5-(N-(4-((4-(叔丁氧羰基)哌嗪-1-基)甲基)苯基)-N-苯乙基氨磺酰)苯并呋喃-2-羧酸乙酯(M8-76)替换为M-R8，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝1.9Hz,1H),7.81(d,J＝8.8Hz,1H),7.60(dd,J＝8.8,1.9Hz,1H),7.39(d,J＝8.3Hz,2H),7.25(t,J＝7.2Hz,2H),7.21–7.10(m,5H),3.88(t,J＝7.3Hz,2H),3.66–3.24(m,8H),2.69(t,J＝7.2Hz,2H),2.51(s,3H),1.42(s,9H).13C NMR(101MHz,DMSO)δ168.5,160.8,155.2,153.8,143.8,139.6,138.1,135.0,132.5,129.1,128.8,128.4,128.2,127.7,126.3,126.3,124.1,121.8,112.8,79.2,50.8,34.2,28.0,8.9.HRMS(ESI)[M-H]-calcd for C34H37N3O8S:646.2223；found:646.2224.
实施例113
5-(N-(2-(4-(叔丁氧基羰基)哌啶-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R9)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R9，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.0Hz,1H),7.92(dt,J＝8.8,1.8Hz,1H),7.81(dd,J＝8.8,1.7Hz,1H),7.37(d,J＝7.6Hz,1H),7.26(t,J＝7.7Hz,1H),7.21–7.03(m,5H),6.94(d,J＝7.2Hz,2H),4.48(s,2H),3.26(t,J＝7.9Hz,2H),2.93(d,J＝11.4Hz,2H),2.66(t,J＝11.3Hz,2H),2.58(d,J＝1.7Hz,3H),2.49(s,2H),2.37–2.24(m,1H),1.84(d,J＝12.9Hz,2H),1.60(q,J＝15.0,13.5Hz,2H),1.39(s,9H).13C NMR(101MHz,DMSO)δ174.1,161.8,155.2,152.4,138.8,134.7,131.4,130.1,129.6,128.8,128.8,128.7,126.7,125.9,124.0,121.4,120.2,113.1,80.0,52.8,49.7,46.3,41.3,34.2,29.0,28.2,9.5.HRMS(ESI)[M-H]-calcd for C35H40N2O7S:631.2478；found:631.2481.
实施例114
2-(4-(N-(2-(4-叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-2-甲基苯氧基)乙酸(TZ-R10)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R10，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝8.6Hz,2H),7.40(d,J＝7.6Hz,1H),7.28(t,J＝7.7Hz,1H),7.23–7.06(m,5H),6.96(dd,J＝23.6,8.2Hz,3H),4.74(s,2H),4.43(s,2H),3.42(s,4H),3.22–3.13(m,2H),2.76(t,J＝4.8Hz,4H),2.51(s,2H),2.26(s,3H),1.42(d,J＝1.8Hz,9H).13C NMR(101MHz,DMSO)δ169.9,159.5,153.9,151.2,138.4,131.5,130.4,129.5,129.1,128.4,128.3,127.1,126.7,126.2,124.0,120.1,111.5,78.9,65.6,52.3,49.5,46.4,34.1,28.1,16.0.HRMS(ESI)[M-H]-calcd for C33H41N3O7S:622.2587；found:622.2587.
实施例115
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(4-甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R11)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R11，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝2.3Hz,1H),7.93–7.86(m,1H),7.80(dd,J＝8.7,1.7Hz,1H),7.37(d,J＝7.6Hz,1H),7.26(t,J＝7.6Hz,1H),7.16–7.05(m,2H),6.93(d,J＝7.5Hz,2H),6.81–6.75(m,2H),4.49(s,2H),3.38(s,4H),3.22(t,J＝7.7Hz,2H),2.74(t,J＝4.9Hz,4H),2.56(d,J＝1.7Hz,3H),2.44(t,J＝7.8Hz,2H),2.16(s,3H),1.40(s,9H).13C NMR(101MHz,DMSO)δ161.4,154.7,153.9,151.2,135.2,135.2,134.3,131.1,129.7,129.2,128.9,128.3,128.3,125.3,123.9,120.9,120.1,112.7,78.9,52.3,49.3,46.2,33.4,28.0,20.5,9.1.HRMS(ESI)[M-H]-calcd for C35H41N3O7S:646.2587；found:646.2593.
实施例116
5-(N-苄基-N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R12)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R12，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.1Hz,1H),7.96(dt,J＝8.8,1.9Hz,1H),7.84(dd,J＝8.8,1.7Hz,1H),7.27–7.08(m,5H),7.01–6.97(m,4H),4.46(s,2H),4.28(s,2H),3.24(s,4H),2.58–2.54(m,7H),1.39(s,9H).13C NMR(101MHz,DMSO)δ161.7,155.3,154.3,151.5,136.3,135.1,131.2,129.9,129.6,128.8,128.6,128.4,127.7,126.1,124.2,121.7,120.3,113.2,79.4,52.5,51.7,46.3,28.5,9.5.HRMS(ESI)[M-H]-calcd forC33H37N3O7S:618.2274；found:618.2274.
实施例117
5-(N-(丁-3-炔-1-基)-N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R13)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R13，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.1Hz,1H),7.91(dd,J＝8.7,1.9Hz,1H),7.82(d,J＝8.7Hz,1H),7.36(d,J＝7.7Hz,1H),7.26(t,J＝7.6Hz,1H),7.17–7.04(m,2H),4.49(s,2H),3.52–3.30(m,4H),3.21(t,J＝7.5Hz,2H),2.79(q,J＝2.3Hz,1H),2.77–2.68(m,4H),2.57(s,3H),2.17(t,J＝7.3Hz,2H),1.40(s,9H).13C NMR(101MHz,DMSO)δ161.4,154.8,153.9,151.3,134.0,131.2,129.8,129.5,128.5,125.2,124.1,121.0,120.3,112.7,81.0,78.9,72.9,52.3,46.8,46.5,28.1,18.1,9.1.HRMS(ESI)[M-H]-calcd forC30H35N3O7S:580.2117；found:580.2119.
实施例118
(E)-3-(4-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨基磺酰基)苯基)丙烯酸(TZ-R14)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R14，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝1.9Hz,4H),7.54(dd,J＝16.0,1.9Hz,1H),7.41(d,J＝7.7Hz,1H),7.31(t,J＝7.7Hz,1H),7.26–7.10(m,5H),6.99–6.92(m,2H),6.74(dd,J＝16.0,1.9Hz,1H),4.51(s,2H),3.44(s,4H),3.29–3.21(m,2H),2.78(t,J＝4.6Hz,4H),2.53(dt,J＝4.0,2.1Hz,2H),1.43(s,9H).13C NMR(101MHz,DMSO)δ168.4,153.9,151.3,139.5,139.3,138.8,138.2,131.2,129.4,128.5,128.4,128.4,127.4,126.7,126.3,124.1,120.2,78.9,52.4,49.4,46.3,34.1,28.1.HRMS(ESI)[M-H]-calcd forC33H39N3O6S:604.2481；found:604.2489.
实施例119
3-(3-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)苯基)丙酸(TZ-R15)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R15，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.75–7.65(m,2H),7.57–7.49(m,2H),7.39–7.24(m,2H),7.22–7.04(m,5H),6.91(d,J＝7.3Hz,2H),4.45(s,2H),3.40(s,4H),3.19(d,J＝8.5Hz,2H),2.93–2.88(m,2H),2.77–2.72(m,4H),2.50–2.40(m,4H),1.42(s,9H).13C NMR(101MHz,DMSO)δ174.4,153.9,151.2,143.6,139.2,138.3,132.8,131.2,129.4,129.3,128.4,128.3,126.5,126.2,124.4,124.0,120.2,78.9,52.3,49.3,46.3,36.7,34.0,30.8,28.0,18.5.HRMS(ESI)[M-H]-calcd for C33H41N3O6S:606.2638；found:606.2634.
实施例120
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-2,3-二氢苯并呋喃-2-羧酸(TZ-R16)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R16，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.64(d,J＝9.4Hz,2H),7.39(d,J＝7.6Hz,1H),7.28(t,J＝7.7Hz,1H),7.23–7.07(m,5H),6.96(dd,J＝13.6,7.9Hz,3H),5.3–5.2(m,1H),4.42(s,2H),3.63–3.35(m,5H),3.33–3.12(m,3H),2.75(s,4H),2.51(d,J＝6.0Hz,2H),1.42(s,9H).13C NMR(101MHz,DMSO)δ172.2,162.9,153.9,151.2,138.4,131.5,130.9,129.5,128.4,128.4,127.9,126.2,124.2,124.0,120.1,109.2,81.1,78.9,52.4,49.4,46.3,34.1,33.0,28.1.HRMS(ESI)[M-H]-calcd for C33H39N3O7S:620.2430；found:620.2432.
实施例121
6-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨基磺酰基)色氨-2-羧酸(TZ-R17)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R17，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ7.58–7.50(m,2H),7.38(d,J＝7.6Hz,1H),7.26(d,J＝8.0Hz,1H),7.23–7.06(m,5H),6.97–6.91(m,3H),4.68(d,J＝4.6Hz,1H),4.41(s,2H),3.41(s,4H),3.17(d,J＝8.3Hz,2H),2.83–2.62(m,6H),2.50(s,2H),2.08(s,2H),1.41(s,9H).13C NMR(101MHz,DMSO)δ157.8,153.9,151.2,138.4,131.5,129.6,129.5,128.7,128.4,128.3,126.5,126.2,124.0,123.0,120.1,116.9,78.9,74.9,52.3,49.5,46.4,34.2,28.0,23.5,22.6.HRMS(ESI)[M-H]-calcd for C34H41N3O7S:634.2587；found:634.2590.
实施例122
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R18)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R18，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝1.9Hz,1H),7.93(dd,J＝8.7,1.9Hz,1H),7.84(d,J＝8.7Hz,1H),7.37(dd,J＝7.7,1.7Hz,1H),7.30–7.22(m,2H),7.17–7.05(m,2H),6.83(dd,J＝5.1,3.4Hz,1H),6.68–6.63(m,1H),4.50(s,2H),3.38(s,4H),3.33–3.25(m,2H),2.73(q,J＝8.8,6.3Hz,6H),2.58(s,3H),1.40(s,9H).13C NMR(101MHz,DMSO)δ161.1,154.9,153.9,151.3,140.1,134.3,131.0,129.5,128.5,127.0,125.6,125.3,124.2,124.1,121.2,120.2,112.9,78.9,52.4,49.4,46.2,28.1,28.0,9.1.HRMS(ESI)[M-H]-calcd for C32H37N3O7S2:640.2151；found:640.2157.
实施例123
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(吡啶-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R19)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R19，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.32(dt,J＝4.7,1.6Hz,1H),8.20(d,J＝1.9Hz,1H),7.90(dd,J＝8.7,1.9Hz,1H),7.81(d,J＝8.7Hz,1H),7.56(td,J＝7.6,1.9Hz,1H),7.38(dd,J＝7.7,1.6Hz,1H),7.26(td,J＝7.6,1.6Hz,1H),7.17–7.05(m,3H),6.97(d,J＝7.8Hz,1H),4.53(s,2H),3.54–3.28(m,6H),2.83–2.66(m,6H),2.57(s,3H),1.40(s,9H).13CNMR(101MHz,DMSO)δ161.2,158.0,154.8,153.9,151.2,148.9,136.4,134.4,131.3,129.5,129.2,128.3,125.5,124.0,123.0,121.5,121.1,120.2,112.8,78.9,52.3,47.5,46.1,35.8,28.0,9.1.HRMS(ESI)[M-H]-calcd for C33H38N4O7S:633.2383；found:633.2380.
实施例124
5-(N-(2-(4-(2,2-二甲基丁酰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R20)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R20，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝1.8Hz,1H),7.95(dd,J＝8.7,1.9Hz,1H),7.84(d,J＝8.8Hz,1H),7.41(dd,J＝7.7,1.6Hz,1H),7.29(td,J＝7.6,1.7Hz,1H),7.22–7.07(m,5H),6.98–6.91(m,2H),4.54(s,2H),3.63(s,4H),3.39–3.22(m,2H),2.78(t,J＝4.8Hz,4H),2.59(s,3H),2.56–2.51(m,2H),1.60(q,J＝7.4Hz,2H),1.17(s,6H),0.81(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO)δ174.2,161.2,154.9,151.0,138.3,134.3,131.2,129.5,129.4,128.4,128.3,126.2,125.7,124.0,121.2,120.1,112.8,52.7,49.4,46.3,44.8,42.2,34.0,32.6,26.3,9.4,9.1.HRMS(ESI)[M-H]-calcd for C35H41N3O6S:630.2638；found:630.2641.
实施例125
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-(呋喃-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R21)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R21，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝1.9Hz,1H),7.91(dd,J＝8.8,1.9Hz,1H),7.83(d,J＝8.7Hz,1H),7.42–7.32(m,2H),7.26(td,J＝7.6,1.7Hz,1H),7.17–7.04(m,2H),6.25(dd,J＝3.2,1.9Hz,1H),5.95(d,J＝3.2Hz,1H),4.47(s,2H),3.50–3.24(m,6H),2.73(t,J＝4.9Hz,4H),2.63–2.55(m,5H),1.40(s,9H).13C NMR(101MHz,DMSO)δ161.3,154.8,153.9,151.8,151.2,141.7,134.2,131.2,129.6,129.3,128.4,125.4,124.1,121.1,120.2,112.8,110.3,106.1,78.9,52.3,46.5,46.3,28.0,26.7,9.1.HRMS(ESI)[M-H]-calcd for C32H37N3O8S:622.2223；found:622.2230.
实施例126
6-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-4-氧代-4H-铬烯-2-羧酸(TZ-R22)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R22，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.17(d,J＝8.7Hz,1H),7.87(d,J＝9.0Hz,1H),7.35(d,J＝7.7Hz,1H),7.26(t,J＝7.6Hz,1H),7.14(dt,J＝20.4,8.4Hz,5H),6.99–6.84(m,3H),4.53(s,2H),3.56–3.37(m,4H),3.30(t,J＝7.9Hz,2H),2.86–2.65(m,4H),2.55(t,J＝7.9Hz,2H),1.41(s,9H).13C NMR(101MHz,DMSO)δ201.5,163.1,154.4,151.7,138.8,133.8,131.6,130.5,130.1,129.8,128.9,128.8,128.8,126.7,124.5,122.8,120.6,119.2,79.4,52.8,49.9,46.6,34.5,29.9,28.5.HRMS(ESI)[M-H]-calcd forC34H37N3O8S:646.2223；found:646.2234.
实施例127
5-(N-(2-(2-(叔丁氧基羰基)-2,7-二氮杂螺[3.5]壬-7-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R23)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R23，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝1.9Hz,1H),7.88(dd,J＝8.7,2.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.35(dd,J＝7.7,1.6Hz,1H),7.25(td,J＝7.6,1.7Hz,1H),7.20–7.02(m,5H),6.91(dt,J＝6.1,1.5Hz,2H),4.47(s,2H),3.69–3.44(m,4H),3.24(t,J＝8Hz,2H),2.78–2.63(m,4H),2.56(s,3H),2.51–2.45(m,2H),1.72(t,J＝5.3Hz,4H),1.38(s,9H).13C NMR(101MHz,DMSO)δ162.0,156.1,155.1,152.4,138.8,134.5,131.6,130.4,129.8,128.8,128.7,126.7,125.4,124.1,121.2,120.8,120.4,113.0,78.8,50.4,49.8,46.3,35.9,34.4,33.2,28.6,9.6.HRMS(ESI)[M-H]-calcd for C37H43N3O7S:672.2743；found:672.2732.
实施例128
5-(N-(2-(2-(叔丁氧基羰基)-2,8-二氮杂螺[4.5]癸-8-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R24)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R24，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝1.9Hz,1H),7.82(dd,J＝8.7,1.9Hz,1H),7.73(d,J＝8.7Hz,1H),7.38–7.32(m,1H),7.25(td,J＝7.6,1.7Hz,1H),7.20–7.01(m,5H),6.94–6.88(m,2H),4.47(s,2H),3.33–3.17(m,4H),3.10(t,J＝7.2Hz,2H),2.85–2.62(m,4H),2.54(s,3H),2.49–2.44(m,2H),1.67(t,J＝7.2Hz,2H),1.60–1.44(m,4H),1.39(s,9H).13C NMR(101MHz,DMSO)δ161.9,154.3,153.7,152.0,138.4,133.6,131.0,130.3,129.3,128.3,128.2,126.2,124.2,123.5,120.2,120.0,112.3,78.1,50.4,49.3,45.9,43.9,43.8,34.7,33.9,28.2,9.1.HRMS(ESI)[M-H]-calcd for C38H45N3O7S:686.2900；found:686.2916.
实施例129
5-(N-((2-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)甲基)-N-苯乙基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R25)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R25，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.25–8.17(m,2H),7.92(dd,J＝8.8,1.9Hz,1H),7.81(d,J＝8.7Hz,1H),7.71(dd,J＝7.6,1.8Hz,1H),7.23–7.09(m,3H),7.04(dd,J＝7.6,4.8Hz,1H),6.98–6.92(m,2H),4.42(s,2H),3.40(t,J＝5.0Hz,4H),3.28(t,J＝8Hz,2H),2.95(t,J＝5.0Hz,4H),2.57(s,3H),2.53(t,J＝8Hz,2H),1.41(s,9H).13C NMR(101MHz,DMSO)δ161.3,160.5,154.8,154.0,146.6,138.1,137.8,133.7,129.7,128.4,128.3,126.2,125.4,124.3,121.1,118.8,112.7,78.9,50.3,49.9,46.8,34.0,28.0,9.1.HRMS(ESI)[M-H]-calcd for C33H38N4O7S:633.2383；found:633.2374.
实施例130
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-苯乙基氨磺酰基)-3-甲基苯并[b]噻吩-2-羧酸(TZ-R26)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R26，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝1.8Hz,1H),8.19(d,J＝8.5Hz,1H),7.88(dd,J＝8.5,1.8Hz,1H),7.41(dd,J＝7.7,1.7Hz,1H),7.27(td,J＝7.6,1.6Hz,1H),7.21–7.05(m,5H),6.96–6.88(m,2H),4.53(s,2H),3.39(t,J＝4.8Hz,4H),3.31–3.22(m,2H),2.76(d,J＝6.1Hz,7H),2.50–2.45(m,2H),1.41(s,9H).13C NMR(101MHz,DMSO)δ164.3,153.9,151.2,142.9,140.3,138.3,135.6,131.2,129.4,128.3,128.3,126.2,124.0,123.6,122.2,120.1,78.9,52.3,49.4,46.2,33.9,28.1,12.5.HRMS(ESI)[M-H]-calcd forC34H39N3O6S2:648.2202；found:648.2211.
实施例131
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-(2-吗啉基乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-R27)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法，将3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯替换为M-R27，其余条件均一致。
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝1.9Hz,1H),7.94(dd,J＝8.8,1.9Hz,1H),7.83(d,J＝8.7Hz,1H),7.44(dd,J＝7.7,1.6Hz,1H),7.30–7.21(m,1H),7.10(ddd,J＝15.9,7.7,1.2Hz,2H),4.48(s,2H),3.50–3.28(m,8H),3.16(t,J＝6.9Hz,2H),2.76(t,J＝5.0Hz,4H),2.57(s,3H),2.17–2.10(m,6H),1.41(s,9H).13C NMR(101MHz,DMSO)δ161.4,154.7,153.9,151.0,134.2,131.4,129.7,129.3,128.2,125.3,123.9,120.9,120.0,112.6,78.9,66.0,56.0,53.1,52.3,46.9,45.0,28.0,9.1.HRMS(ESI)[M-H]-calcd forC32H42N4O8S:641.2645；found:641.2653.
实施例132
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)-N-甲基氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D10)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝2.3Hz,1H),7.85(dd,J＝9.2,2.2Hz,1H),7.68(d,J＝9.2Hz,1H),7.16–7.08(m,2H),6.99(ddd,J＝8.7,7.4,1.4Hz,1H),6.75(dd,J＝7.1,1.3Hz,1H),4.43–4.30(m,2H),3.62(ddd,J＝20.9,6.1,3.4Hz,4H),3.08(dt,J＝6.0,3.6Hz,4H),2.66(s,3H),2.58(s,3H),1.45(s,9H).13C NMR(101MHz,DMSO)δ165.0,158.1,154.8,148.9,143.1,134.3,129.7,127.4,127.2,126.9,125.8,125.0,121.5,120.1,117.4,113.8,79.4,55.2,49.8,45.6,36.2,28.4,10.0.HRMS(ESI)[M-H]-calcd forC27H33N3O7S:543.2039；found:543.2039.
实施例133
5-(N-(2-(4-(叔丁氧基羰基)哌嗪-1-基)苄基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(TZ-D11)
按照3-甲基-5-(N-(2-氟苄基)-N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(TZ-S14)所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.2Hz,1H),7.64(d,J＝9.0Hz,1H),7.51(t,J＝7.7Hz,1H),7.18–7.08(m,2H),6.96(td,J＝7.8,1.3Hz,1H),6.77(dd,J＝7.3,1.3Hz,1H),4.21(dd,J＝7.8,1.0Hz,2H),3.62(ddd,J＝20.9,6.1,3.4Hz,4H),3.08(dt,J＝6.0,3.6Hz,4H),2.58(s,3H),1.45(s,9H).13C NMR(101MHz,DMSO)δ165.0,157.9,154.8,148.4,143.1,135.4,129.3,127.9,127.6,127.6,125.5,125.0,121.3,120.2,117.1,113.3,79.4,49.8,45.6,45.6,28.4,10.0.HRMS(ESI)[M-H]-calcdfor C26H31N3O7S:529.1883；found:529.1883.
生物活性实验
1.1细胞培养与传代
人胚胎肾细胞系HEK293传代培养，培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10％ FBS的MEM培养基，置于95％空气和5％二氧化碳的湿润气氛下37℃恒温培养。当细胞融合至90％时，弃去旧培养基，用2mL PBS洗涤细胞2次，弃去PBS后加入2mL 0.25％胰蛋白酶-0.25％ EDTA混合消化液，置显微镜下观察，当细胞变圆后迅速加入2mL完全培养基终止消化，轻轻吹打，收集细胞。800rpm，4℃，离心5min，弃去上清，用完全培养基重悬细胞，分瓶培养，隔天换液。
1.2TGR5活性评价
TGR5活性用Glosensor cAMP(遗传改造的发光萤火虫荧光素酶)实验评价。HEK293细胞以30000细胞/孔的密度铺在96孔板上，在含5％FBS的DMEM培养基中，置于95％空气和5％二氧化碳的湿润气氛下37℃恒温培养12小时。用Lipofectamine 2000试剂给HEK293细胞转染pcDNA3.1 Glosensor质粒和FLAG标记的TGR5质粒。于95％空气和5％二氧化碳的湿润气氛下37℃恒温培养48小时后，用含2％ Glosensor cAMP底物的细胞培养基处理细胞2小时。在室温下，用含相应浓度待测化合物溶液(PBS缓冲液中稀释)与细胞共孵育至少5分钟，每个化合物三个复孔，以INT777作为阳性化合物，DMSO作为溶剂对照。在多模板阅读器(PerkinElmer EnVision)上读取每秒每孔发光(LCPS)，并使用GraphPad Prism 7.0分析数据。
上述实验中EC50数值较低的化合物，具有良好的TGR5激动活性。
1.3细胞增殖抑制实验
通过CCK8法检测化合物的细胞增殖抑制能力。HEK293细胞以30％的密度接种于96孔板，孵育18h使细胞贴壁后，移除原有培养基，每孔加入给定浓度的待测化合物，对照组加入等量的DMSO。每个化合物设置三个复孔。给药24h后，CCK8法检测细胞活力，空白组为不加入细胞的孔，随后用酶标仪在490nm处读取其OD值。细胞活力的计算公式为：细胞活力(％)＝(OD待测-OD空白)/(OD对照-OD空白)×100。
上述实验中对HEK293细胞活力较高、CC50数值较高的化合物，具有良好的安全性。
1.4心肌细胞缺氧/复氧损伤模型及药效评价
将H9C2细胞接种于96孔板中使用DMEM培养液培养，培养24h后给予对应浓度的待测化合物处理。将孔板移入三气培养箱中，先通入N2和CO2进行细胞缺氧(1％ O2)，处理24h。再将细胞置于37℃，5％CO2培养箱中复氧4小时。用CCK8法检测细胞活力。
上述实验中对H9C2细胞活力较高、EC50数值较低的化合物，对心肌细胞缺氧/复氧损伤有良好的保护作用。
1.5小鼠心肌缺血再灌注损伤模型制备及心肌梗死面积评价
1.5.1小鼠心肌缺血再灌注损伤模型制备
使用SPF级C57BL/6小鼠(雄性，8-10周，20-25g)，提前药物灌胃3天，术前禁食水8h。异氟烷麻醉、固定、脱毛，经口腔气管插管后，连接小动物呼吸机维持呼吸。将小鼠仰卧，四肢固定于循环加热手术台上，连接小动物心电图检测仪肢导电极，记录术中心电变化。手术区域备皮消毒，于胸骨左侧第3、4肋间剪开皮肤，逐层钝性分离皮下组织、肌肉，打开胸腔，用开胸器撑开肋间、充分暴露心脏，剪开心包，采用带线6-0线缝合针于心耳下缘2mm处穿过心肌表层，待加压结扎LAD。缺血30min后，松解结扎线，即发生再灌注，构建心肌缺血再灌注损伤模型。
1.5.2心肌梗死面积评价
伊文思蓝-TTC染色。再灌注24h后，在缺血时结扎冠状动脉的位置再次结扎，从心尖灌注1％伊文思蓝染液0.3ml，摘取心脏，预冷的PBS缓冲液冲洗，-20℃冰冻30min，取出后迅速沿垂直左心室长轴的方向横切5～6片厚约1mm的心肌组织片，置于2％TTC溶液中37℃避光孵育30min。蓝色为正常心肌组织，红色为缺血心肌组织，灰白色为梗死心肌组织。
心肌梗死面积的计算。采用Image-Pro Plus 6.0进行面积统计分析，分别计算左心室面积(全部心肌，LV)、缺血危险区面积(红色+白色，AAR)和梗死区面积(白色，IF)。用AAR/LV评价结扎的位置是否一致，即经历缺血的缺血危险区是否相同，用IF/AAR评估心肌梗死的面积。
TGR5激动活性结果表示
A:0.1μM<EC50<10μM
B:10μM<EC50<50μM
C:50μM<EC50<100μM
表1.1化合物TZ-S8-TZ-S105、TZ-W7、TZ-D1-TZ-D11、TZ-R1-TZ-R27的TGR5激动活性
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实验结果表明：本发明化合物具有以下一个或多个方面的效果：
(1)具有良好的TGR5激动活性；
(2)对心肌细胞缺氧/复氧损伤有保护作用；
(3)可以减少心肌缺血再灌注损伤的心梗面积；
(4)具有良好的安全性。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解：根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (15)

1.化合物用于制备药物中的用途，所述药物用于预防或治疗与TGR5相关的疾病，所述化合物选自式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，
其中，
X1为砜、羰基、亚甲基，所述亚甲基基任选地被1或2个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基；
X2为CH＝CH、O或CH2-CH2；
R1为H、苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基，所述苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基或C2-C6炔基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基、卤代C1-C6烷基、卤代C1-C6烷氧基；
R2为H或C1-C6烷基，任选地，R2与X2形成呋喃环；任选地，所述呋喃环被C1-C6烷基所取代；
R3选自氢、苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯氧基、苯甲酰基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基、8-10元含氮螺杂环基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基或8-10元含氮螺杂环基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基、C1-C6烷酰基-苯基-C1-C6烷酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
R5选自：羟基、-O-R6、-NH-R7；R6、R7独立地选自C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、苯基；
n1、n2、n3各自独立地选自0、1、2、3、4、5、6；
任选地，与R1之间的任意一个或多个亚甲基上的碳被氧代。
2.权利要求1的用途，所述化合物具有如式(II)所示的结构，
其中，X1、R1、R3、R4、R5、R6、R7、n1、n3如权利要求1所述；
R8为C1-C6烷基。
3.权利要求2的用途，其中，
X1为砜或亚甲基；
R1为苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3选自苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯氧基、苯甲酰基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基、C1-C6烷酰基-苯基-C1-C6烷酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为1或2。
4.权利要求2或3的用途，其中，
X1为砜或亚甲基；
R1为苯基，所述苯基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3选自苯基、萘基、喹啉基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、-S-卤代C1-C6烷基、单或双C1-C6烷基取代的胺甲酰基、二(C1-C6烷基)氨基、苯基、吡啶基、苯氧基、苯甲酰基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为1；
R8为甲基。
5.权利要求2-4任一项的用途，其中，
X1为砜或亚甲基；
R1为苯基或吡啶基，所述苯基或吡啶基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
n1为1或2；
R3为氢或苯基；
任选地，R3被一个或多个R4取代；
R4选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷酰基、吗啉基、哌嗪基、哌嗪甲基、哌啶基；所述吗啉基、哌嗪基、哌嗪甲基、哌啶基任选地被一个或多个选自以下的基团所取代：未取代的C1-C6烷基、苯基取代的C1-C6烷基、未取代的C1-C6烷氧羰基、未取代的C1-C6烷酰基、苯基取代的C1-C6烷酰基、C1-C6烷基磺酰基、单或双C1-C6烷基取代的胺甲酰基；
任选地，所述吗啉基、哌嗪基、哌嗪甲基和哌啶基中的N与C1-C6烷基形成季铵；
n3为0或1；
R8为甲基；
R5为羟基或-NH-R7；R7选自C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、苯基；
任选地，与R1之间的任意一个亚甲基上的碳被氧代。
6.权利要求1的用途，所述化合物中，
X1为羰基或亚甲基，所述亚甲基基任选地被1或2个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基；
X2为CH＝CH或CH2-CH2；
R1为H、苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基；
R2为H；
R3为苯基，任选地，R3被一个或多个R4取代；
R4选自：二(C1-C6烷基)氨基、单或双C1-C6烷基取代的胺甲酰基；
n1选自0、1、2、3、4、5、6；
n2为0；
n3为0或1。
7.权利要求1的用途，所述化合物具有式(III)所示的结构，
其中，X1’为砜；
R1’选自H、苯基、5-6元杂芳基、5-6元环烷基、5-6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基，所述苯基、5-6元杂芳基、5-6元环烷基或5-6元杂环基任选地被一个或多个选自以下的基团所取代：卤素、硝基、氰基、羟基、C1-C6烷基、C1-C6酰基、卤代C1-C6烷基、卤代C1-C6烷氧基；
R3’选自任选被一个或多个R4取代的苯基；
R4’选自：卤素、硝基、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、哌嗪基、哌啶基、8-10元含氮螺杂环基；所述哌嗪基、哌啶基、8-10元含氮螺杂环基上的N任选被C1-C6烷氧羰基取代；
R5’为羟基；
R8’为C1-C6烷基；
n1’、n3’各自独立地选自0、1、2。
8.权利要求1的用途，所述化合物具有式(IV)所示的结构，
其中，X2为CH＝CH、O或CH2-CH2；
R2为H或C1-C6烷基，n2为0或1。
9.权利要求1-8任一项的用途，所述化合物选自：
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10.权利要求1-9任一项的用途，所述与TGR5相关的疾病选自：与TGR5相关的肝脏疾病、心血管疾病、消化系统疾病、神经系统疾病、内分泌系统疾病或皮肤或结缔组织疾病。
11.权利要求1-9任一项的用途，所述与TGR5相关的疾病选自：代谢性疾病、肿瘤、炎性肠病相关疾病。
12.权利要求1-9任一项的用途，所述与TGR5相关的疾病选自：与DNA/RNA病毒感染相关的疾病。
13.权利要求1-9任一项的用途，所述与TGR5相关的疾病选自：动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、胆汁淤积性肝病、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、葡萄糖代谢障碍、高血糖、高脂血症(例如，高胆固醇血症)、胆石、肝硬化、胆汁淤积(例如肝内胆汁淤积)；
心肌梗塞/心肌梗死、心肌缺血、心肌缺血再灌注损伤相关疾病；
炎性肠病相关疾病，选自：溃疡性结肠炎、克罗恩病、未定型结肠炎、结肠炎相关结直肠癌；
肿瘤，选自：乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤；
肌萎缩性侧索硬化症、多发性硬化、囊性纤维化、哮喘。
14.化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式，所述化合物如权利要求5-8任一项所定义；
优选地，所述化合物的酯为乙酯；
优选地，所述化合物选自：
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15.一种药物组合物，其包含根据权利要求14所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式；任选地，所述药物组合物还包含药学上可接受的载体或赋形剂。
CN202310421546.3A 2022-04-18 2023-04-18 Tgr5调节剂及其应用 Pending CN117137901A (zh)

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