CN108863919A - 用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法 - Google Patents

用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法 Download PDF

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CN108863919A
CN108863919A CN201810458169.XA CN201810458169A CN108863919A CN 108863919 A CN108863919 A CN 108863919A CN 201810458169 A CN201810458169 A CN 201810458169A CN 108863919 A CN108863919 A CN 108863919A
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yuan
heterocyclylalkyl
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CN108863919B (zh
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樊磊
胥珂馨
陈锞
张少华
杜武
李兴海
陈元伟
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Hinova Pharmaceuticals Inc
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Abstract

本发明涉及一种用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法。具体公开了式(Ⅰ)所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，用于治疗痛风或高尿酸血症。本发明实施例的化合物具有良好的URAT1抑制活性，可以用于痛风和高尿酸血症的治疗，还可用于复发性痛风发作、痛风性关节炎、高血压、心血管疾病、冠心病、莱‑萘二氏综合症、凯‑赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤‑鸟嘌呤磷酸核糖转移酶缺乏症等与URAT1活性异常疾病的治疗。

Description

用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法
技术领域
本发明属于药物合成领域，具体涉及磺酰胺类化合物及其制备方法，以及其用于治疗痛风或高尿酸血症的用途。
背景技术
痛风是尿酸单钠盐(monosodium urate，MSU)在关节和皮下等部位沉积而引起的以疼痛和肿胀为主要特征的炎症性疾病，是困扰人类最老的疾病之一。MSU沉积仪器痛风的前提是高尿酸血症，即血尿酸(serum uric acid，sUA)水平高于尿酸在血液中的溶解度的一种病理状态。高尿酸血症通常是由于尿酸产生过多和/或尿酸排泄降低引起，其中后者在高尿酸血症患者中约占90％。
目前高尿酸血症及痛风治疗药物主要包括：①用于痛风急性发作关节肿痛、疼痛等症状控制的消炎止痛药物，如秋水仙碱和非甾体抗炎药物(NSAID)等；②用于抑制尿酸生成的的药物。如别嘌醇、奥昔嘌醇和非布索坦等黄嘌呤氧化酶(XO)抑制剂；③用于尿酸排泄的药物，如丙磺舒和苯溴马隆等；④用于急性痛风发作时迅速降低血尿酸的尿酸分解药，如尿酸酶(uricase)以及聚乙二醇的尿酸酶(pegloticase)。但是，这些药物均具有比较严重的副作用，如秋水仙碱具有腹泻、呕吐、腹痛性痉挛等常见的不良反应，治疗有效剂量与其引起胃肠道症状的剂量相近；丙磺舒能引起肾绞痛和肾功能损害；苯溴马隆有引起爆发性肝炎的危险；别嘌醇具有肝脏及骨髓毒性和变态反应等不良反应；尿酸酶制剂为注射给药，病人的顺应性不如口服制剂，只适用于急性痛风发作时降低血尿酸，不宜作为长期治疗。
尿酸转运体1(urate transporter 1，URAT1)位于肾脏近曲小管的上皮细胞的刷状缘上，是近年来发现的位于肾脏的重要尿酸转运体，负责肾脏中尿酸的重吸收。经过证明，抑制URAT1就会抑制肾脏中尿酸的重吸收、增加尿液中尿酸的排泄，进而达到降低血尿酸和控制痛风发作的目的。例如，Lesinurad为阿斯利康研发的一种选择性尿酸在吸收抑制剂，通过抑制肾脏中URAT1转运体可以减少尿酸的分泌和降低血清中的尿酸含量，该药物于2015年12月份被FDA批准用于血中高水平尿酸(高尿酸血症)与痛风关联的治疗，2016年2月18日获得欧洲药品管理局(EMA)批准上市，将其与减少尿酸生成的药物(如别嘌呤醇和非布索坦)联用，可增加原本对上述药物应答不佳的痛风患者的应答率，但其单独用药仍然存在肾脏相关风险和疗效不佳，如何发挥URAT1抑制剂的最大效能并尽可能地克服其副作用，成为研究热点。
发明内容
本发明的目的在于提供一类可用于治疗痛风或高尿酸血症的磺酰胺类化合物及其制备方法。
本发明首先提供了如式(Ⅰ)所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或NXCOY的取代基所取代，
R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NRpRq，其中所述的环烷基、杂环烷基、杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代；
Rp、Rq分别独立地选自氢、C1-C6的烷基、3元-6元的环烷基、3元-6元的杂环烷基；
X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。
进一步地，所述R1、R2、R3、R4、R5、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。
进一步地，所述R1、R2、R3、R4、R5、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。
进一步地，所述R1、R2、R3、R4、R5、R7、R8、R9均为氢。
进一步地，所述R6选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。
进一步地，所述R6为氰基。
进一步地，所述R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元杂环芳基、-NRpRq，其中所述的环烷基、杂环烷基、杂环芳基分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。
进一步地，所述杂环烷基或者杂环芳基上有1～3个杂原子。
进一步地，所述杂原子为N、O或S。
进一步地，所述R选自
其中上述的基团分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物为如下化合物之一：
本发明还提供了制备前述化合物的方法，包括下述步骤：
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物在制备URAT1抑制剂类药物上的用途。
所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
本发明还提供了一种药物组合物，它是以前述的化合物或其立体异构体、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
实验结果表明，本发明的化合物是一种URAT1抑制剂，经过证明，可以用于治疗痛风和高尿酸血症，还可用于治疗复发性痛风发作、痛风性关节炎、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症。
对于本发明的化合物而言，其同位素取代物，如氘代、氚代、14C代以及15N代也具有相同的活性和用途。上述同位素取代物均属于本发明的范围。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(Ca～Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C1～C6)烷基是指包含1～6个碳原子的烷基。
所述C1～C6烷基是指C1、C2、C3、C4、C5、C6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。
所述3元-7元的环烷基是指3个-7个碳原子组成的环状烷基，例如环丙基、环丁基、环戊基、环己基、环庚基等等。
所述卤素是指氟原子、溴原子、氯原子、碘原子。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施部分使用的原料和仪器均可通过市场购买得到。
4-溴-1-萘腈：上海毕得医药科技有限公司；
联频哪醇硼酸酯：上海泽信化工科技有限公司；
氯化钠：天津市瑞金特化学品有限公司；
碳酸氢钠：天津博迪化工股份有限公司；
三乙胺：西亚试剂；
盐酸、二氯甲烷、乙酸乙酯、石油醚、N,N-二甲胺甲酰胺、1,4-二氧六环、二甲亚砜、乙酸钾、碳酸钠、均购买自成都市科龙化工试剂厂；
[1,1'-双(二苯基膦基)二茂铁]二氯化钯(简称：Pd(dppf)Cl2)、四三苯基膦钯、4-氨基-3-溴吡啶、环丙基磺酰氯、1-甲基-1H-咪唑-4-磺酰氯、1,2-二甲基-1H-咪唑-4-磺酰氯、噻吩-2-磺酰氯、吡啶-3-磺酰氯、3-氧代环丁烷磺酰氯、环戊烷磺酰氯、环己烷-1-磺酰氯、1-氧代环己烷-3-磺酰氯、1-氧代环己烷-4-磺酰氯、环庚烷-1-磺酰氯、1-噻唑-2-磺酰氯、吡啶-4-磺酰氯、1-嘧啶-5-磺酰氯、1-嘧啶-2-磺酰氯、1-吡嗪-2-磺酰氯、1-恶唑-2-磺酰氯、1-异恶唑-5-磺酰氯、1-呋喃-3-磺酰氯、1-呋喃-2-磺酰氯、1-氨基磺酰氯、1-乙氨基磺酰氯、1-环丙基氨基磺酰氯、2-氯噻吩-5-磺酰氯、3,5-二甲基异恶唑-4-磺酰氯，均购买自百灵威科技有限公司；
2-氟环丙基磺酰氯、3-N-甲基吡咯烷磺酰氯、3-氧代环戊烷磺酰氯、4-氟环己烷磺酰氯、2-氟环己烷磺酰氯、4-氟-1甲基吡咯烷-3-磺酰氯、2-氟-环戊烷-1-磺酰氯、4-氟-氧代环戊烷-3-磺酰氯、1-哌啶-3-磺酰氯、1-甲基哌啶-3-磺酰氯、1-哌啶-4-磺酰氯、1-甲基哌啶-4-磺酰氯、1-吡咯烷-3-磺酰氯、1-氮代环庚烷-4-磺酰氯、3-甲基哒嗪-6-磺酰氯、1-甲基吡唑-5-磺酰氯、1-咪唑-4-磺酰氯、1-甲基咪唑-5-磺酰氯、1,3,4-恶二唑-2-磺酰氯、1,3,4-噻二唑-2-磺酰氯、1-甲基-1,2,4-三氮唑-3-磺酰氯、1-甲基咪唑-4-磺酰氯，均购自成都普康生物科技有限公司；
上述原料试剂可不进行处理，直接使用。
实施例1、4-(4-氨基吡啶-3-基)-1-萘腈(Int 2)的合成
1)4-(频哪醇硼酸酯-3-基)-1-萘腈(Int1)的合成
向100mL的反应瓶中加入4-溴-1-萘腈(232mg，1mmol)，乙酸钾(196mg，2mmol)，联频哪醇硼酸酯(380mg，1.5mmol)，Pd(dppf)Cl2(73mg，0.1mmol),DMSO(5mL),氮气置换三次，加热到80℃搅拌反应6个小时。然后将反应液到入水中(30mL)，用乙酸乙酯萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体1(176mg)，收率63％。1H NMR(400MHz,Chloroform-d)δ8.88–8.72(m,1H),8.30–8.18(m,1H),8.08(d,J＝7.1Hz,1H),7.88(d,J＝7.2Hz,1H),7.72–7.56(m,2H),1.43(s,12H).
2)4-(4-氨基吡啶-3-基)-1-萘腈(Int 2)的合成
向100mL的反应瓶中加入Int 1(279mg，1mmol)，碳酸钠(212mg，2mmol)，4-氨基-3-溴吡啶(172mg，1mmol)，Pd(PPh3)4(58mg，0.05mmol),二氧六环(3mL),H2O(0.3ml),氮气置换三次，加热到110℃搅拌反应16个小时。然后将反应液到入水中(30mL)，用乙酸乙酯萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体2(140mg)，收率57％。MS:246.1(M+H+)。
1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝7.3Hz,1H),8.21(dt,J＝8.4,1.0Hz,1H),8.13(d,J＝5.7Hz,1H),7.94(s,1H),7.83(ddd,J＝8.3,6.4,1.7Hz,1H),7.72–7.62(m,2H),7.57(d,J＝7.4Hz,1H),6.72(d,J＝5.7Hz,1H),5.68(s,2H).
实施例2、N-(3-(4-氰基萘-1-基)吡啶-4-基)环丁基磺酰胺(4)的合成
向100mL的反应瓶中加入中间体2(245mg，1mmol)，二氯甲烷(8mL)，三乙胺(303mg，3mmol)，冰水浴条件下分批次加入环丁基磺酰氯(185mg,1.2mmol)，自然慢慢恢复至室温反应3个小时。反应完毕后，将反应液到入水中(30mL)，用二氯甲烷萃取三次(3×15ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物4(72mg)，收率20％。质谱:364.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,6H).
实施例3、N-(3-(4-氰基萘-1-基)吡啶-4-基)环丙基磺酰胺(1)
将制备化合物4的原料环丁基磺酰氯替换为环丙基磺酰氯，按照与化合物4相同的制备方法即可得到化合物1，质谱：350.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.39–1.13(m,4H).
实施例4、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟环丙基磺酰胺(2)
将制备化合物4的原料环丁基磺酰氯替换为2-氟环丙基磺酰氯，按照与化合物4相同的制备方法即可得到化合物2，质谱：368.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.74–1.81(m,1H)1.39–1.13(m,2H).
实施例5、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-N-甲基吡咯烷磺酰胺(3)
将制备化合物4的原料环丁基磺酰氯替换为3-N-甲基吡咯烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物3，质谱：393.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,2H).
实施例6、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-氧代环丁烷磺酰胺(5)
将制备化合物4的原料环丁基磺酰氯替换为3-氧代环丁烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物5，质谱：366.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.94–2.99(m,1H).
实施例7、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环戊烷磺酰胺(6)
将制备化合物4的原料环丁基磺酰氯替换为环戊烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物6，质谱：378.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,8H)
实施例8、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-氧代环戊烷磺酰胺(7)
将制备化合物4的原料环丁基磺酰氯替换为3-氧代环戊烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物7，质谱：380.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,2H).
实施例9、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟环己烷磺酰胺(8)
将制备化合物4的原料环丁基磺酰氯替换为4-氟环己烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物8，质谱：410.1(M+H+).
378.1(M+H+)，1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.99–1.78(m,4H)，1.74–1.66(m,1H)，1.45–1.01(m,4H).
实施例10、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟环己烷磺酰胺(9)
将制备化合物4的原料环丁基磺酰氯替换为2-氟环己烷磺酰氯，按照与化合物4相同的制备方法即可得到化合物9，质谱：410.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)，1.99–1.78(m,4H)，1.74–1.66(m,1H)，1.45–1.01(m,4H).
实施例11、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟-1甲基吡咯烷-3-磺酰胺(10)
将制备化合物4的原料环丁基磺酰氯替换为4-氟-1甲基吡咯烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物10，质谱：411.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,1H).
实施例12、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氟-环戊烷-1-磺酰胺(11)
将制备化合物4的原料环丁基磺酰氯替换为2-氟-环戊烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物11，质谱：396.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.45–1.01(m,7H).
实施例13、N-(3-(4-氰基萘-1-基)吡啶-4-基)-4-氟-氧代环戊烷-3-磺酰胺(12)
将制备化合物4的原料环丁基磺酰氯替换为4-氟-氧代环戊烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物12，质谱：398.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,1H).
实施例14、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-哌啶-3-磺酰胺(13)
将制备化合物4的原料环丁基磺酰氯替换为1-哌啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物13，质谱：393.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例15、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基哌啶-3-磺酰胺(14)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基哌啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物14，质谱：407.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.9(s,3H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例16、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环己烷-1-磺酰胺(15)
将制备化合物4的原料环丁基磺酰氯替换为环己烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物15，质谱：392.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.34–2.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,6H).
实施例17、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氧代环己烷-3-磺酰胺(16)
将制备化合物4的原料环丁基磺酰氯替换为1-氧代环己烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物16，质谱：394.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例18、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氧代环己烷-4-磺酰胺(17)
将制备化合物4的原料环丁基磺酰氯替换为1-氧代环己烷-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物17，质谱：394.1(M+H+)。
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),3.34–3.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例19、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-哌啶-4-磺酰胺(18)
将制备化合物4的原料环丁基磺酰氯替换为1-哌啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物18，质谱：393.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例20、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基哌啶-4-磺酰胺(19)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基哌啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物19，质谱：407.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14(s,3H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,4H).
实施例21、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡咯烷-3-磺酰胺(20)
将制备化合物4的原料环丁基磺酰氯替换为1-吡咯烷-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物20，质谱：379.1(M+H+).
393.1(M+H+)，1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,2H).
实施例22、N-(3-(4-氰基萘-1-基)吡啶-4-基)-环庚烷-1-磺酰胺(21)
将制备化合物4的原料环丁基磺酰氯替换为环庚烷-1-磺酰氯，按照与化合物4相同的制备方法即可得到化合物21，质谱：406.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.34–2.51(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,8H).
实施例23、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氮代环庚烷-4-磺酰胺(22)
将制备化合物4的原料环丁基磺酰氯替换为1-氮代环庚烷-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物22，质谱：407.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),4.14–4.31(m,1H)，3.14–3.31(m,4H)，2.74–2.81(m,1H)，1.74–1.81(m,6H)
实施例24、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-噻唑-2-磺酰胺(23)
将制备化合物4的原料环丁基磺酰氯替换为1-噻唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物23，质谱：393.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例25、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-噻唑-2-磺酰胺(24)
将制备化合物4的原料环丁基磺酰氯替换为噻吩-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物24，质谱：393.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例26、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡啶-3-磺酰胺(25)
将制备化合物4的原料环丁基磺酰氯替换为吡啶-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物25，质谱：387.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,2H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H).
实施例27、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡啶-4-磺酰胺(26)
将制备化合物4的原料环丁基磺酰氯替换为吡啶-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物26，质谱：387.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,2H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H).
实施例28、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-嘧啶-5-磺酰胺(27)
将制备化合物4的原料环丁基磺酰氯替换为1-嘧啶-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物27，质谱：388.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H).
实施例29、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-嘧啶-2-磺酰胺(28)
将制备化合物4的原料环丁基磺酰氯替换为1-嘧啶-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物28，质谱：388.1(M+H+).
388.1(M+H+)，1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H).
实施例30、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-吡嗪-2-磺酰胺(29)
将制备化合物4的原料环丁基磺酰氯替换为1-吡嗪-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物29，质谱：388.1(M+H+).
388.1(M+H+)，1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,3H).
实施例31、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3-甲基哒嗪-6-磺酰胺(30)
将制备化合物4的原料环丁基磺酰氯替换为3-甲基哒嗪-6-磺酰氯，按照与化合物4相同的制备方法即可得到化合物30，质谱：402.1(M+H+)。
1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.68–8.62(m,2H),8.24(d,J＝7.4Hz,1H),8.21–8.11(m,3H),7.89–7.78(m,2H),7.62–7.53(m,1H),7.47(ddd,J＝11.4,8.0,4.5Hz,2H),3.61(s,3H).
实施例32、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-恶唑-2-磺酰胺(31)
将制备化合物4的原料环丁基磺酰氯替换为1-恶唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物31，质谱：377.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例33、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-异恶唑-5-磺酰胺(32)
将制备化合物4的原料环丁基磺酰氯替换为1-异恶唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物32，质谱：377.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例34、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基吡唑-5-磺酰胺(33)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基吡唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物33，质谱：390.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H)
实施例35、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-咪唑-4-磺酰胺(34)
将制备化合物4的原料环丁基磺酰氯替换为1-咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物34，质谱：376.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)。
实施例36、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基咪唑-5-磺酰胺(35)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基咪唑-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物35，质谱：390.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H)
实施例37、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-呋喃-3-磺酰胺(36)
将制备化合物4的原料环丁基磺酰氯替换为1-呋喃-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物36，质谱：376.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例38、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-呋喃-2-磺酰胺(37)
将制备化合物4的原料环丁基磺酰氯替换为1-呋喃-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物37，质谱：376.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例39、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,3,4-恶二唑-2-磺酰胺(38)
将制备化合物4的原料环丁基磺酰氯替换为1,3,4-恶二唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物38，质谱：378.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例40、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,3,4-噻二唑-2-磺酰胺(39)
将制备化合物4的原料环丁基磺酰氯替换为1,3,4-噻二唑-2-磺酰氯，按照与化合物4相同的制备方法即可得到化合物39，质谱：394.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)
实施例41.N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基-1,2,4-三氮唑-3-磺酰胺(40)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基-1,2,4-三氮唑-3-磺酰氯，按照与化合物4相同的制备方法即可得到化合物40，质谱：391.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H),
实施例42、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,2-二甲基咪唑-4-磺酰胺(41)
将制备化合物4的原料环丁基磺酰氯替换为1,2-二甲基-1H-咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物41，质谱：404.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.33(s,3H),3.13(s,3H),
实施例43、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-甲基咪唑-4-磺酰胺(42)
将制备化合物4的原料环丁基磺酰氯替换为1-甲基咪唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物42，质谱：390.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.65–7.59(m,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,3H),
实施例44、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-氨基磺酰胺(43)
将制备化合物4的原料环丁基磺酰氯替换为1-氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物43，质谱：325.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(s,2H),
实施例45、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-乙氨基磺酰胺(44)
将制备化合物4的原料环丁基磺酰氯替换为1-乙氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物44，质谱：353.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,2H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H)，3.13(m,2H)，1.13(m,3H),
实施例46、N-(3-(4-氰基萘-1-基)吡啶-4-基)-1-环丙基氨基磺酰胺(45)
将制备化合物4的原料环丁基磺酰氯替换为1-环丙基氨基磺酰氯，按照与化合物4相同的制备方法即可得到化合物45，质谱：365.1(M+H+).
1H NMR(400MHz,Chloroform-d)δ8.74–8.66(m,1H),8.49(d,J＝5.1Hz,1H),8.41(dd,J＝8.4,5.2Hz,1H),8.23(dd,J＝6.9,5.4Hz,1H),8.11(dd,J＝7.4,5.4Hz,1H),7.90–7.80(m,1H),7.77–7.68(m,1H),7.65(dd,J＝7.4,5.3Hz,1H),7.58(dd,J＝8.5,5.2Hz,1H),7.37(s,1H),2.74–2.81(m,1H)1.39–1.13(m,4H).
实施例47、N-(3-(4-氰基萘-1-基)吡啶-4-基)-2-氯噻吩-5-磺酰胺(46)
将制备化合物4的原料环丁基磺酰氯替换为2-氯噻吩-5-磺酰氯，按照与化合物4相同的制备方法即可得到化合物46，质谱：426.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.25(d,J＝7.4Hz,1H),8.22–8.13(m,3H),7.82(ddd,J＝8.3,6.7,1.4Hz,1H),7.69(dd,J＝5.0,1.4Hz,1H),7.56(d,J＝7.6Hz,2H),7.50(d,J＝7.1Hz,1H),7.35(dd,J＝3.6,1.4Hz,1H),7.03(dd,J＝4.9,3.6Hz,1H).
实施例48、N-(3-(4-氰基萘-1-基)吡啶-4-基)-3,5-二甲基异恶唑-4-磺酰胺(47)
将制备化合物4的原料环丁基磺酰氯替换为3,5-二甲基异恶唑-4-磺酰氯，按照与化合物4相同的制备方法即可得到化合物47，质谱：405.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ8.25(d,J＝7.3Hz,1H),8.21(dt,J＝8.4,1.0Hz,1H),8.13(d,J＝5.7Hz,1H),7.94(s,1H),7.83(ddd,J＝8.3,6.4,1.7Hz,1H),7.72–7.62(m,2H),7.57(d,J＝7.4Hz,1H),6.72(d,J＝5.7Hz,1H),5.68(s,1H).
以下通过试验例的方式来说明本发明的有益效果。
试验例1、本发明化合物的生物学活性测定
测试例：本发明化合物对URAT1抑制活性的测定
1)实验材料：
胎牛血清(Invitrogen,Cat.No.10099141)
胰酶(Invitrogen,Cat.No.25200056)
磷酸盐缓冲液(Invitrogen,Cat.No.14190250)
杜尔伯科改良伊格尔培养基(Invitrogen,Cat.No.10564)
青霉素-链霉素(Invitrogen,Cat.No.15070-063)
转IT-293转染试剂(MIRUS BIO,Cat.No.MIR2706)
无血清优化改良伊格尔培养基(Invitrogen,Cat.No.31985-070)
尿酸盐阴离子转运体1质粒(Genecopoeia,Cat.No.EX-T4563-M03)
尿酸[8-14C](ARC,Cat.No.ARC0513-250UCI)
终极金TM XR闪烁液(PerkinElmer,Cat.No.6013111)
苯溴马隆(百灵威科技,Cat.No.3562-84-3)
D-葡萄糖酸钠盐(阿拉丁,Cat.No.527-07-1)
D-葡萄糖酸钾(阿拉丁,Cat.No.299-27-4)
葡萄糖酸钙(阿拉丁,Cat.No.299-28-5)
二甲基亚砜(Sigma,Cat.No.D2650)
离心管,15 ml(Greiner,Cat.No.07030115)
离心管,50 ml(BD Falcon,Cat.No.352098)
多聚D-赖氨酸96微孔板(BD,Cat.No.356461)
隔离96微孔板(PERKIN ELMER,Cat.No.6005040)
2)实验方法：
i)缓冲液配制
ii)细胞培养：
①将稳定表达hURAT1的HEK-293T细胞培养于10％FBS和1％P/S的DMEM培养基中，在5％二氧化碳的37度培养箱中培养过夜。
②将培养基去掉后用PBS清洗一次，然后加入胰酶消化2分钟，待细胞于培养皿分离后加入10毫升培养基终止消化。
③把细胞放入离心机1000转离心2分钟，加入新的10毫升培养基来重悬细胞，并计算细胞个数。将细胞个数调整为4x105个细胞每毫升。
④将上述计数好的细胞接种到96孔板中，每孔100微升。
⑤将接种好细胞的96孔板放置于37度细胞培养箱中培养过夜。
ⅲ)同位素碳14标记的尿酸吸收实验：
①在15毫升离心管中加入5毫升Cl-free HBSS缓冲液，然后加入碳14标记的尿酸，使尿酸的浓度达到2uCi/ml.
②将之前培养过夜的96孔板中的培养基吸干净，加入100毫升预热过的Cl-freeHBSS缓冲液清洗三次。
③将清洗好后的96孔板中的所以缓冲液吸干净。
④清洗好的96孔板上每孔中加入50微升含有碳14标记的尿酸的Cl-free HBSS缓冲液，然后加入需要测试的化合物的DMSO溶液。
⑤把上述96孔板在室温下静置5分钟后，将里面所有的液体吸干。
⑥加入100毫升预冷的无Cl离子Hanks平衡盐溶液缓冲液清洗三次。
⑦把板里残留的液体吸干净后，于每孔中加入50微升的细胞裂解液，在混匀器上以每分钟600转的速度振荡10分钟。
⑧加入50微升Ultima GoldTM XR scitillation cocktail闪烁液后，继续振荡10分钟。
将振荡好的板用封板膜贴好后，于MicroBeta Trilux上读数。
⑨将测试化合物溶解在DMSO中，然后将相同浓度的DMSO加入不包含测试化合物的HEK293/hURAT1细胞孔中。将各测试浓度下的细胞的尿酸摄取表示为相对DMSO对照的平均百分比抑制率。将对包含DMSO的孔得到的放射性值视为细胞的100％摄取。化合物的IC50值可通过不同浓度下的抑制率计算得出。
本发明上述化合物的活性数据如下表：
试验表明，本发明实施例的化合物具有良好的URAT1抑制活性，可以用于痛风和高尿酸血症的治疗，还可用于复发性痛风发作、痛风性关节炎、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症等与URAT1活性异常疾病的治疗。
综上所述，本发明公开的式(A)所示的新化合物，表现出了良好的URAT1抑制活性，为临床治疗与URAT1活性异常相关的疾病提供了一种新的药用可能。

Claims (15)

1.式(Ⅰ)所示化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代，
R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NRpRq，其中所述的环烷基、杂环烷基、杂环芳基分别独立地进一步被一个或多个任选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY的取代基所取代；
Rp、Rq分别独立地选自氢、C1-C6的烷基、3元-6元的环烷基、3元-6元的杂环烷基；
X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。
2.根据权利要求1所述的化合物，其特征在于：所述R1、R2、R3、R4、R5、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、-OX、-S(O)2X、-COX、-COOX、-CONXY、-NXY或-NXCOY，X、Y分别独立的选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基。
3.根据权利要求2所述的化合物，其特征在于：所述R1、R2、R3、R4、R5、R7、R8、R9分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。
4.根据权利要求3所述的化合物，其特征在于：所述R1、R2、R3、R4、R5、R7、R8、R9均为氢。
5.根据权利要求1所述的化合物，其特征在于：所述R6选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂环芳基、烷氧基。
6.根据权利要求5所述的化合物，其特征在于：所述R6为氰基。
7.根据权利要求1所述的化合物，其特征在于：所述R选自3元-7元的环烷基、3元-7元的杂环烷基、6元-12元的杂环芳基、-NRpRq，其中所述的环烷基、杂环烷基、杂环芳基分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。
8.根据权利要求7所述的化合物，其特征在于：所述杂环烷基或者杂环芳基上有1～3个杂原子。
9.根据权利要求8所述的化合物，其特征在于：所述杂原子为N、O或S。
10.根据权利要求9所述的化合物，其特征在于：所述R选自
其中上述的基团分别独立地被零个、一个或多个选自卤素、烷基、环烷基、杂环烷基、芳基、杂环芳基、氨基的取代基取代。
11.根据权利要求1-10任一项所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，所述化合物为如下化合物之一：
12.制备权利要求1-11任一项所述的化合物的方法，其特征在于：包括下述步骤：
13.权利要求1-12任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物在制备URAT1抑制剂类药物中的用途。
14.根据权利要求13所述的用途，其特征在于：所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
15.一种药物组合物，其特征在于：它是以权利要求1-11任一项所述的化合物或其立体异构体、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
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Publication number Priority date Publication date Assignee Title
CN111943957A (zh) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831556A (zh) * 2015-12-07 2017-06-13 成都海创药业有限公司 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831556A (zh) * 2015-12-07 2017-06-13 成都海创药业有限公司 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XINTUO YANG. ET AL: "Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
叶发青等: "《药物化学》", 30 June 2012, 浙江大学出版社 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111943957A (zh) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途

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