一种咪唑并吡啶巯乙酸类衍生物及其制备方法与应用转让专利
申请号 : CN201610629605.6
文献号 : CN106083847B
文献日 : 2018-10-30
发明人 : 刘新泳 , 孟青 , 展鹏 , 方增军 , 赵彤 , 孙卓森 , 孙秀琨
申请人 : 山东大学
摘要 :
本发明涉及一种咪唑并吡啶巯乙酸类衍生物及其制备方法和应用。所述化合物具有式I、II、III所示的结构。本发明还涉及含有式I、II、III结构化合物的制备方法以及药物组合物。本发明还提供上述化合物在制备抗痛风的药物中的应用。
权利要求 :
1.一种咪唑并吡啶巯乙酸类衍生物，其特征在于，具有如下通式I或III所示的结构：其中，
R1为-CH2-,-*CH(CH3)-或-CH2CH2CH2-；*代表手性碳原子；
R2为-OH或-OCH2CH3；
Ar为1-萘基、2,4,6-三甲基苯基、4-环丙基-1-萘基或2-萘基。
2.一种咪唑并吡啶巯乙酸类衍生物，其特征在于，是下述结构的化合物之一：
3.如权利要求1所述的咪唑并吡啶巯乙酸类衍生物的制备方法，其特征在于通式I的制备方法如下：以2-氯-3-硝基吡啶a1为初始原料，首先与芳胺a2发生熔融反应生成中间体a3；然后中间体a3在氢气和钯炭的催化下还原生成中间体a4；接着中间体a4在乙醇和水的混合溶液中与乙基黄原酸钾反应生成关键中间体a5，最后此关键中间体a5在二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种酯反应生成目标产物I；部分酯类目标化合物反应后氢氧化锂水解得到羧酸类目标化合物；
合成路线一如下：
试剂及条件进一步限定如下:(i)氟化钾，120℃；(ii)钯炭，氢气，乙醇，室温；(iii)乙基黄原酸钾，碳酸氢钠，乙醇，水，60℃；(iv)酯，碳酸钾，DMF，室温；(v)氢氧化锂，四氢呋喃，乙醇，冰浴；
其中，R1、R2、Ar同上述通式I所示；
所述的酯为溴乙酸乙酯，4-溴丁酸乙酯或2-氯丙酸乙酯。
4.如权利要求1所述的咪唑并吡啶巯乙酸类衍生物的制备方法，其特征在于通式III的制备方法如下：以3-氯-2-硝基吡啶c1为初始原料，首先与芳胺c2在氮气保护下生成中间体c3；然后中间体c3在氢气和钯炭的催化下还原生成中间体c4；接着中间体c4与1,1’-硫代羰基二咪唑在四氢呋喃溶剂中反应生成关键中间体c5，最后此关键中间体c5在二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种酯反应生成目标产物III；部分酯类目标化合物反应后氢氧化锂水解得到羧酸类目标化合物；
合成路线三如下：
试剂及条件进一步限定如下:(viii)醋酸钯，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，碳酸铯，90℃，二氧六环；(ii)钯炭，氢气，乙醇，室温；(ix)1,1'-硫代羰基二咪唑，三乙胺，四氢呋喃，60℃；(iv)酯，碳酸钾，DMF，室温；(v)氢氧化锂，四氢呋喃，乙醇，冰浴；
其中，R1、R2、Ar同上述通式III所示；
所述的酯为溴乙酸乙酯，4-溴丁酸乙酯，2-氯丙酸乙酯。
5.权利要求1或2所述的咪唑并吡啶巯乙酸类衍生物在制备抗痛风的药物中的应用。
6.一种抗痛风药物组合物，包含权利要求1或2所述咪唑并吡啶巯乙酸类衍生物和一种或多种药学上可接受载体或赋形剂。
说明书 :
一种咪唑并吡啶巯乙酸类衍生物及其制备方法与应用
技术领域
[0001] 本发明属于有机化合物合成与医药应用技术领域，具体涉及一种咪唑并吡啶巯乙酸类衍生物及其制备方法及应用。
背景技术
[0002] 痛风是指是长期嘌呤代谢障碍及(或)尿酸排泄减少，血尿酸增高引起组织损伤的一组临床综合征。高尿酸血症是痛风最重要的生化基础。痛风与高尿酸血症都与人体内的尿酸水平有关。正常成人每日约产生尿酸750mg，其中80％为内源性，20％为外源性尿酸，这些尿酸进入尿酸代谢池，其中1/3经肠道分解代谢，2/3经肾脏排泄，从而可维持体内尿酸水平的稳定。目前能够降低血尿酸的药物主要有两类：一类是抑制尿酸产生的黄嘌呤氧化酶抑制剂，另外一类是促进尿酸排泄的尿酸盐转运蛋白抑制剂。尿酸盐转运蛋白1(URAT1)是目前促进尿酸排泄药物的一个新型靶标，其基因突变所导致的URATI活性增加或基因表达增加是高尿酸血症的重要发病机制之一。Lesinurad(RDEA594)是一种新近上市的用于治疗痛风的增加尿酸排泄口服药，可抑制肾脏近端小管尿酸转运子URAT1。但该化合物肝脏毒性较为严重，因此将该类化学结构进行进一步修饰，对发现高效、毒性低、疗效好且具有自主知识产权的新型抗痛风药物具有重大意义。
[0003]
发明内容
[0004] 针对现有技术的不足，本发明提供了一种咪唑并吡啶巯乙酸类衍生物及其制备方法，本发明还提供了上述化合物作为抗痛风药物的活性筛选结果及其应用。
[0005] 本发明的技术方案如下：
[0006] 一、咪唑并吡啶巯乙酸类衍生物
[0007] 本发明的咪唑并吡啶巯乙酸类衍生物，具有如下通式I、II或III所示的结构：
[0008]
[0009] 其中，
[0010] R1为-CH2-,-*CH2(CH3)-,-CH(CH3)2-或-CH2CH2CH2-；*代表手性碳原子；
[0011] R2为-OH或-OCH2CH3；
[0012] Ar为1-萘基、2,4,6-三甲基苯基、4-环丙基-1-萘基或2-萘基。
[0013] 根据本发明优选的，咪唑并吡啶巯乙酸类衍生物是下列之一：
[0014] 表1.化合物M1～T8的结构式
[0015]
[0016]
[0017]
[0018]
[0019] 二、咪唑并吡啶巯乙酸类衍生物的制备方法
[0020] 本发明咪唑并吡啶巯乙酸类衍生物的制备方法如下列之一：
[0021] (1)3-芳基-咪唑[4,5-b]并吡啶巯乙酸类衍生物(通式I)的制备方法
[0022] 3-芳基-咪唑[4,5-b]并吡啶巯乙酸类衍生物的制备方法，步骤如下：
[0023] 以2-氯-3-硝基吡啶a1为初始原料，首先与芳胺a2发生熔融反应生成中间体a3；然后中间体a3在氢气和钯炭的催化下还原生成中间体a4；接着中间体a4在乙醇和水的混合溶液中与乙基黄原酸钾反应生成关键中间体a5，最后此关键中间体a5在二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种酯反应生成目标产物I；部分酯类目标化合物反应后氢氧化锂水解得到羧酸类目标化合物；
[0024] 合成路线一如下：
[0025]
[0026] 试剂及条件:(i)氟化钾，120℃；(ii)钯炭，氢气，乙醇，室温；(iii)乙基黄原酸钾，碳酸氢钠，乙醇，水，60℃；(iv)酯，碳酸钾，DMF，室温；(v)氢氧化锂，四氢呋喃，乙醇，冰浴；
[0027] 其中，R1、R2、Ar同上述通式I所示。
[0028] 所述的酯为溴乙酸乙酯，4-溴丁酸乙酯，2-氯丙酸乙酯或2-溴-2-甲基丙酸乙酯；
[0029] 本发明所述的室温是指20-30℃。
[0030] (2)1-芳基-咪唑[4,5-c]并吡啶巯乙酸类衍生物(通式II)的制备方法
[0031] 1-芳基-咪唑[4,5-c]并吡啶巯乙酸类衍生物的制备方法，步骤如下：
[0032] 以4-氯-3-硝基吡啶b1为初始原料，首先与芳胺b2在碳酸氢钠的作用下生成中间体b3；然后中间体b3在氢气和钯炭的催化下还原生成中间体b4；接着中间体b4在乙醇和水的混合溶液中与乙基黄原酸钾反应生成关键中间体b5，最后此关键中间体b5在二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种酯反应生成目标产物II；部分酯类目标化合物反应后氢氧化锂水解得到羧酸类目标化合物；
[0033] 合成路线二如下：
[0034]
[0035] 试剂及条件:(vii)碳酸氢钠，乙醇，60℃；(ii)钯炭，氢气，乙醇，室温；(iii)乙基黄原酸钾，碳酸氢钠，乙醇，水，60℃；(iv)酯，碳酸钾，DMF，室温；(v)氢氧化锂，四氢呋喃，乙醇，冰浴；
[0036] R1、R2、Ar同上述通式II所示。
[0037] 所述的酯为溴乙酸乙酯，4-溴丁酸乙酯，2-氯丙酸乙酯，2-溴-2-甲基丙酸乙酯；
[0038] 本发明所述的室温是指20-30℃。
[0039] (3)1-芳基-咪唑[4,5-b]并吡啶巯乙酸类衍生物(通式III)的制备方法
[0040] 1-芳基-咪唑[4,5-b]并吡啶巯乙酸类衍生物的制备方法，步骤如下：
[0041] 以3-氯-2-硝基吡啶c1为初始原料，首先与芳胺c2在氮气保护下生成中间体c3；然后中间体c3在氢气和钯炭的催化下还原生成中间体c4；接着中间体c4与1,1’-硫代羰基二咪唑在四氢呋喃溶剂中反应生成关键中间体c5，最后此关键中间体c5在二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种酯反应生成目标产物III；部分酯类目标化合物反应后氢氧化锂水解得到羧酸类目标化合物；
[0042] 合成路线三如下：
[0043]
[0044] 试剂及条件:(viii)醋酸钯，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，碳酸铯，90℃，二氧六环；(ii)钯炭，氢气，乙醇，室温；(ix)1,1'-硫代羰基二咪唑，三乙胺，四氢呋喃，60℃；(iv)酯，碳酸钾，DMF，室温；(v)氢氧化锂，，四氢呋喃，乙醇，冰浴；
[0045] R1、R2、Ar同上述通式III所示；
[0046] 所述的酯为溴乙酸乙酯，4-溴丁酸乙酯，2-氯丙酸乙酯，2-溴-2-甲基丙酸乙酯；
[0047] 本发明所述的室温是指20-30℃。
[0048] 三、咪唑并吡啶巯乙酸类衍生物的应用
[0049] 本发明公开了咪唑并吡啶巯乙酸类衍生物降血尿酸活性筛选结果及其作为抗痛风药物的首次应用。通过实验证明本发明的咪唑并吡啶巯乙酸类衍生物可作为降血尿酸药物应用。具体地说，作为降血尿酸化合物用于制备抗痛风药物。本发明还提供上述化合物在制备抗痛风的药物中的应用。
[0050] 目标化合物的抗痛风活性
[0051] 对按照上述方法合成的40个化合物(化合物的结构式见表1)，并对其进行了抗痛风活性筛选，它们的抗痛风活性数据列于表2中，以苯溴马隆和RDEA594为阳性对照。
[0052] 由表2可以看出化合物M2、X4、X6、X7、Q3均呈现出较好的抗痛风活性，抗痛风活性均强于阳性对照药物。
[0053] 因此，本发明的咪唑并吡啶巯乙酸类衍生物是一系列结构新颖的URAT1抑制剂，可作为抗痛风的先导化合物加以利用。
[0054] 本发明的咪唑并吡啶巯乙酸类衍生物可作为URAT1抑制剂应用。具体地说，作为URAT1抑制剂用于制备抗痛风药物。
[0055] 一种抗痛风药物组合物，包括本发明的咪唑并吡啶巯乙酸类衍生物和一种或多种药学上可接受载体或赋形剂。
具体实施方式
[0056] 通过下述实例有助于理解本发明，但是不能限制本发明的内容，在下列实例中，所有目标化合物的编号与表1相同。
[0057] 合成路线：
[0058]
[0059] 实施例1.中间体3-(1-萘基)-2-巯基-3H-咪唑[4,5-b]吡啶(5)的合成
[0060] 将2-氯-3-硝基吡啶(1)(1g,6.33mmol)、1-萘胺(2)(1.81g,12.66mmol)与氟化钾(0.55g,9.495mmol)混合于圆底烧瓶中，120℃熔融反应12h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入50mL水，二氯甲烷萃取三次，饱和食盐水水洗三次，无水硫酸钠干燥后蒸干，乙醇－石油醚重结晶得到黄色的中间体N-(1-萘基)-3-硝基-2-胺(3)。收率70.0％。熔点:154-156℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ10.26(s,1H,NH),8.57(dd,J＝8.3,1.6Hz,1H,Pyr-H),8.34(dd,J＝4.4,1.6Hz,1H,Pyr-H),7.99(d,J＝8.9Hz,1H,Naph-H),7.94(d,J＝8.8Hz,1H,Naph-H),7.87(d,J＝8.2Hz,1H,Naph-H),7.75(d,J＝
7.3Hz,1H,Naph-H),7.58-7.51(m,3H,Naph-H),6.92(dd,J＝8.3,4.5Hz,1H,Pyr-H).13C NMR(100MHz,d6-DMSO)δ155.82,151.75,135.89,134.83,134.37,129.82,129.04,128.75,
126.82,126.63,126.57,126.22,124.03,123.10,114.40.C15H11N3O2(Exact Mass:265.09).[0061] 将中间体3(1g,3.77mmol)溶于30mL乙醇中，钯炭(0.1g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得白色的中间体N2-(1-萘基)吡啶-2,3-双胺(4)。收率85.3％。熔点:171-172.5℃。
7.3Hz,1H,Naph-H),7.58-7.51(m,3H,Naph-H),6.92(dd,J＝8.3,4.5Hz,1H,Pyr-H).13C NMR(100MHz,d6-DMSO)δ155.82,151.75,135.89,134.83,134.37,129.82,129.04,128.75,
126.82,126.63,126.57,126.22,124.03,123.10,114.40.C15H11N3O2(Exact Mass:265.09).[0061] 将中间体3(1g,3.77mmol)溶于30mL乙醇中，钯炭(0.1g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得白色的中间体N2-(1-萘基)吡啶-2,3-双胺(4)。收率85.3％。熔点:171-172.5℃。
[0062] 波谱数据：1H NMR(400MHz,d6-DMSO)δ8.05(d,J＝7.8Hz,1H,Naph-H),7.88(d,J＝8.9Hz,1H,Naph-H),7.76(s,1H,NH),7.57(d,J＝4.3Hz,1H,Pyr-H),7.55(d,J＝3.3Hz,1H,Naph-H),7.50-7.38(m,4H,Naph-H),6.97(dd,J＝7.6,1.3Hz,1H,Pyr-H),6.64(dd,J＝7.6,
4.8Hz,1H,Pyr-H),5.11(s,2H,NH2).13C NMR(100MHz,d6-DMSO)δ145.51,138.31,135.32,
134.53,132.98,128.52,128.04,126.36,126.09,125.39,123.55,122.51,120.56,118.17,
116.66.C15H13N3(235.11)。
4.8Hz,1H,Pyr-H),5.11(s,2H,NH2).13C NMR(100MHz,d6-DMSO)δ145.51,138.31,135.32,
134.53,132.98,128.52,128.04,126.36,126.09,125.39,123.55,122.51,120.56,118.17,
116.66.C15H13N3(235.11)。
[0063] 将中间体4(0.61g,2.6mmol)、乙基黄原酸钾(0.5g,3.1mmol)以及碳酸氢钠(0.05g,0.6mmol)溶解到水(8mL)和乙醇(40mL)的混合溶液中，回流5h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入10mL水和4mL的2M氢氧化钠溶液后生成沉淀，过滤，用2M盐酸溶液将滤液pH调至7，产生沉淀，过滤得白色的中间体3-(1-萘基)-2-巯基-3H-咪唑[4,5-b]吡啶(5)。收率92.8％。熔点:241-244℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ
13.37(s,1H,SH),8.16(d,J＝8.3Hz,1H,Pyr-H),8.10(d,J＝8.2Hz,1H,Naph-H),8.01(dd,J＝5.0,1.3Hz,1H,Pyr-H),7.74-7.68(m,2H,Naph-H),7.63-7.57(m,2H,Naph-H),7.49–7.45(m,1H,Pyr-H),7.28-7.24(m,2H,Naph-H).13C NMR(100MHz,d6-DMSO)δ171.63,147.62,
142.92,134.49,131.60,130.45,130.12,128.84,128.55,127.58,126.99,126.26,125.46,
123.22,119.70,117.45.
13.37(s,1H,SH),8.16(d,J＝8.3Hz,1H,Pyr-H),8.10(d,J＝8.2Hz,1H,Naph-H),8.01(dd,J＝5.0,1.3Hz,1H,Pyr-H),7.74-7.68(m,2H,Naph-H),7.63-7.57(m,2H,Naph-H),7.49–7.45(m,1H,Pyr-H),7.28-7.24(m,2H,Naph-H).13C NMR(100MHz,d6-DMSO)δ171.63,147.62,
142.92,134.49,131.60,130.45,130.12,128.84,128.55,127.58,126.99,126.26,125.46,
123.22,119.70,117.45.
[0064] 实施例2.化合物M1的制备
[0065] 将中间体5(0.5g,1.86mmol)与碳酸钾(0.31g,2.232mmol)混合于10mLDMF中，搅拌15分钟后滴加溴乙酸乙酯(0.46g,2.787mmol)，室温下搅拌4h(TLC检测反应完毕)。反应完毕，减压旋蒸除去溶剂，向残留物中加入30mL乙酸乙酯，饱和氯化钠水溶液洗涤(3×10mL)，分取有机层，无水硫酸钠干燥，过滤，产物快速柱层析得到目标化合物M1。白色固体，产率
67.1％，熔点:116.5-117℃。
67.1％，熔点:116.5-117℃。
[0066]
[0067] 化合物M1波谱数据：1H NMR(400MHz,d6-DMSO)δ8.25(d,J＝8.8Hz,1H,Pyr-H),8.16(d,J＝8.2Hz,1H,Naph-H),8.12-8.09(m,2H,Naph-H),7.78-7.72(m,2H,Naph-H),7.64(t,J＝8.0Hz,1H,Naph-H),7.51(t,J＝8.0Hz,1H,Pyr-H),7.31(dd,J＝7.9,4.9Hz,1H,Naph-H),7.09(d,J＝8.4Hz,1H,Pyr-H),4.25(d,J＝2.6Hz,2H,CH2),4.13(q,J＝7.1Hz,2H,CH2),1.18(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ168.52,154.74,150.94,
143.38,135.40,134.51,131.01,130.16,130.13,129.02,128.19,127.93,127.47,126.33,
125.86,122.59,119.17,61.75,33.49,14.46.C20H17N3O2S(Exact Mass:363.10).[0068] 实施例3.化合物M2的制备
143.38,135.40,134.51,131.01,130.16,130.13,129.02,128.19,127.93,127.47,126.33,
125.86,122.59,119.17,61.75,33.49,14.46.C20H17N3O2S(Exact Mass:363.10).[0068] 实施例3.化合物M2的制备
[0069] 操作同实施例2，所不同的是，所用酯为4-溴丁酸乙酯。白色固体,产率:72.3％，熔点:100-103℃。
[0070]
[0071] 化合物M2波谱数据：1H NMR(400MHz,d6-DMSO)δ8.22(dd,J＝6.7,2.6Hz,1H,Pyr-H),8.15-8.09(m,3H,Naph-H),7.76-7.71(m,2H,Naph-H),7.62(t,J＝7.9Hz,1H,Naph-H),7.49(t,J＝7.7Hz,1H,Pyr-H),7.30(dd,J＝7.9,4.9Hz,1H,Naph-H),7.05(d,J＝8.4Hz,1H,Pyr-H),4.02(q,J＝7.1Hz,2H,CH2),3.37-3.33(m,2H,CH2),2.39(t,J＝7.3Hz,2H,CH2),
1.99(p,J＝7.2Hz,2H,CH2),1.14(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ
172.67,155.52,150.97,143.16,135.58,134.49,130.82,130.41,130.25,129.00,128.14,
127.99,127.39,126.30,125.63,122.55,119.03,60.34,32.63,30.63,24.77,
14.52.C22H21N3O2S(391.14)。
1.99(p,J＝7.2Hz,2H,CH2),1.14(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ
172.67,155.52,150.97,143.16,135.58,134.49,130.82,130.41,130.25,129.00,128.14,
127.99,127.39,126.30,125.63,122.55,119.03,60.34,32.63,30.63,24.77,
14.52.C22H21N3O2S(391.14)。
[0072] 实施例4.化合物M3的制备
[0073] 操作同实施例2，所不同的是，所用酯为2-氯丙酸乙酯。白色固体,产率:69.5％，熔点:144-145℃。
[0074]
[0075] 化合物M3波谱数据：1H NMR(400MHz,d6-DMSO)δ8.24(dd,J＝6.6,2.6Hz,1H,Pyr-H),8.16-8.11(t,3H,Naph-H),7.77-7.70(m,2H,Naph-H),7.64(t,J＝8.0Hz,1H,Naph-H),7.50(t,J＝8.2Hz,1H,Pyr-H),7.34–7.31(m,1H,Naph-H),7.05(t,J＝7.7Hz,1H,Pyr-H),
4.77-4.70(m,1H,CH),4.09(q,J＝7.1Hz,2H,CH2),1.57(t,J＝7.6Hz,3H,CH3),1.19-1.08(m,3H,CH3).13C NMR(100MHz,d6-DMSO)δ171.31,153.85,150.70,143.56,135.42,134.48,
131.00,130.17,130.14,129.01,128.19,127.99,127.47,126.29,125.98,122.49,119.24,
61.78,43.60,18.21,14.33.C21H19N3O2S(377.12)。
4.77-4.70(m,1H,CH),4.09(q,J＝7.1Hz,2H,CH2),1.57(t,J＝7.6Hz,3H,CH3),1.19-1.08(m,3H,CH3).13C NMR(100MHz,d6-DMSO)δ171.31,153.85,150.70,143.56,135.42,134.48,
131.00,130.17,130.14,129.01,128.19,127.99,127.47,126.29,125.98,122.49,119.24,
61.78,43.60,18.21,14.33.C21H19N3O2S(377.12)。
[0076] 实施例5.化合物M4的制备
[0077] 操作同实施例2，所不同的是，所用酯为2-溴-2-甲基丙酸乙酯。白色固体,产率:72.6％，熔点:135-136℃。
[0078]
[0079] 化合物M4波谱数据：1H NMR(400MHz,d6-DMSO)δ8.22(d,J＝8.1Hz,1H,Pyr-H),8.15-8.09(m,3H,Naph-H),7.74(t,J＝7.7Hz,1H,Naph-H),7.68(d,J＝6.9Hz,1H,Naph-H),
7.63(t,J＝7.4Hz,1H,Naph-H),7.50(t,J＝7.5Hz,1H,Pyr-H),7.31(dd,J＝8.0,4.8Hz,1H,Naph-H),7.00(d,J＝8.4Hz,1H,Pyr-H),4.12-4.10(m,2H,CH2),1.70(s,3H,CH3),1.63(s,
3H,CH3),1.10(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.83,153.12,150.14,
143.77,135.45,134.44,130.85,130.37,130.27,129.01,128.16,127.96,127.42,126.27,
126.15,122.41,119.26,61.72,53.13,26.79(2×C),14.30.C22H21N3O2S(391.14)。
7.63(t,J＝7.4Hz,1H,Naph-H),7.50(t,J＝7.5Hz,1H,Pyr-H),7.31(dd,J＝8.0,4.8Hz,1H,Naph-H),7.00(d,J＝8.4Hz,1H,Pyr-H),4.12-4.10(m,2H,CH2),1.70(s,3H,CH3),1.63(s,
3H,CH3),1.10(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.83,153.12,150.14,
143.77,135.45,134.44,130.85,130.37,130.27,129.01,128.16,127.96,127.42,126.27,
126.15,122.41,119.26,61.72,53.13,26.79(2×C),14.30.C22H21N3O2S(391.14)。
[0080] 实施例6.化合物M5的制备
[0081] 将M1(0.3g,0.826mmol)溶于5mL四氢呋喃和5mL乙醇的混合溶液中，将氢氧化锂(0.2g,8.26mmol)溶于少量水中，慢慢滴加到上述溶液中，冰浴下搅拌1h(TLC检测反应完毕)。反应完毕，减压旋蒸除去溶剂，向残留物中加入10mL水，滴加2M HCl溶液至PH3-4，过滤，得到目标化合物M5。白色固体，产率87.1％，熔点:129-130℃。
[0082]
[0083] 化合物M5波谱数据：1H NMR(400MHz,d6-DMSO)δ8.24(d,J＝7.6Hz,1H),8.10-8.16(m,3H),7.80–7.69(m,2H),7.64(t,J＝7.4Hz,1H),7.50(t,J＝7.6Hz,1H),7.31(dd,J＝7.8,5.0Hz,1H),7.09(d,J＝8.4Hz,1H),4.19(s,2H,CH2).13C NMR(101MHz,d6-DMSO)δ
169.78,155.10,150.95,143.27,135.44,134.50,130.96,130.20,130.17,129.00,128.18,
127.93,127.50,126.32,125.77,122.67,119.11,34.09.C18H13N3O2S(335.07)。
169.78,155.10,150.95,143.27,135.44,134.50,130.96,130.20,130.17,129.00,128.18,
127.93,127.50,126.32,125.77,122.67,119.11,34.09.C18H13N3O2S(335.07)。
[0084] 实施例7.化合物M6的制备
[0085] 操作同实施例6。白色固体，产率:92.3％，熔点:129-130℃。
[0086]
[0087] 化合物M6波谱数据：1H NMR(400MHz,d6-DMSO)δ12.13(s,1H,OH),8.22(dd,J＝6.6,2.7Hz,1H,Pyr-H),8.15-8.08(m,3H,Naph-H),7.76-7.71(m,2H,Naph-H),7.62(t,J＝
7.9Hz,1H,Naph-H),7.49(t,J＝8.1Hz,1H,Pyr-H),7.30(dd,J＝8.0,4.9Hz,1H,Naph-H),
7.05(d,J＝8.4Hz,1H,Pyr-H),3.36-3.33(m,2H,CH2),2.33(t,J＝7.3Hz,2H,CH2),2.00-
1.95(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.25,155.56,150.97,143.14,135.59,
134.48,130.82,130.41,130.26,129.00,128.16,128.00,127.39,126.31,125.64,122.55,
119.02,32.82,30.76,24.77.C20H17N3O2S(363.10)。
7.9Hz,1H,Naph-H),7.49(t,J＝8.1Hz,1H,Pyr-H),7.30(dd,J＝8.0,4.9Hz,1H,Naph-H),
7.05(d,J＝8.4Hz,1H,Pyr-H),3.36-3.33(m,2H,CH2),2.33(t,J＝7.3Hz,2H,CH2),2.00-
1.95(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.25,155.56,150.97,143.14,135.59,
134.48,130.82,130.41,130.26,129.00,128.16,128.00,127.39,126.31,125.64,122.55,
119.02,32.82,30.76,24.77.C20H17N3O2S(363.10)。
[0088] 实施例8.化合物M7的制备
[0089] 操作同实施例6。白色固体,产率:91.5％，熔点:110-112℃。
[0090]
[0091] 化合物M7波谱数据：1H NMR(400MHz,d6-DMSO)δ8.23(d,J＝7.5Hz,1H,Pyr-H),8.15-8.11(m,3H,Naph-H),7.76-7.70(m,2H,Naph-H),7.63(t,J＝7.5Hz,1H,Naph-H),
7.52-7.47(m,1H,Pyr-H),7.31(dd,J＝7.9,4.9Hz,1H,Naph-H),7.06(d,J＝8.5Hz,1H,Pyr-H),4.68(qd,J＝7.2,2.5Hz,1H,CH),1.59(dd,J＝18.5,7.2Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.83,154.44,150.71,143.43,135.50,134.48,130.92,130.23,129.01,
128.23,127.99,127.96,127.43,126.30,125.89,122.53,119.17,44.71,18.99.C19H15N3O2S(349.09)。
7.52-7.47(m,1H,Pyr-H),7.31(dd,J＝7.9,4.9Hz,1H,Naph-H),7.06(d,J＝8.5Hz,1H,Pyr-H),4.68(qd,J＝7.2,2.5Hz,1H,CH),1.59(dd,J＝18.5,7.2Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.83,154.44,150.71,143.43,135.50,134.48,130.92,130.23,129.01,
128.23,127.99,127.96,127.43,126.30,125.89,122.53,119.17,44.71,18.99.C19H15N3O2S(349.09)。
[0092] 实施例9.化合物M8的制备
[0093] 操作同实施例6。白色固体,产率:93.7％，熔点:165-166℃。
[0094]
[0095] 化合物M8波谱数据：1H NMR(400MHz,d6-DMSO)δ8.22(d,J＝8.2Hz,1H,Pyr-H),8.15-8.11(m,3H,Naph-H),7.73(t,J＝7.7Hz,1H,Naph-H),7.67(dd,J＝7.2,1.1Hz,1H,Naph-H),7.62(t,J＝8.0Hz,1H,Naph-H),7.49(t,J＝8.1Hz,1H,Pyr-H),7.33-7.30(m,1H,Naph-H),7.00(d,J＝8.4Hz,1H,Pyr-H),1.68(s,6H,CH3×2).13C NMR(100MHz,d6-DMSO)δ
174.49,153.48,150.13,143.75,135.50,134.41,130.76,130.55,130.36,128.98,128.15,
128.00,127.37,126.27,126.17,122.47,119.21,53.97,26.85,26.82.C20H17N3O2S(363.10)。
174.49,153.48,150.13,143.75,135.50,134.41,130.76,130.55,130.36,128.98,128.15,
128.00,127.37,126.27,126.17,122.47,119.21,53.97,26.85,26.82.C20H17N3O2S(363.10)。
[0096] 实施例10.中间体3-均三甲苯基-2-巯基-3H-咪唑并[4,5-b]-2-吡啶(9)的合成[0097] 将2-氯-3-硝基吡啶(1)(1g,6.33mmol)、均三甲基苯胺(6)(1.71g,12.66mmol)与氟化钾(0.55g,9.495mmol)混合于圆底烧瓶中，120℃熔融反应12h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入50mL水，二氯甲烷萃取三次，饱和食盐水水洗三次，无水硫酸钠干燥后蒸干，乙醇－石油醚重结晶得到黄色的中间体N-均三甲苯基-3-硝基-2-胺(7)。收率67.1％。熔点:158-160℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ9.53(s,1H,NH),8.50(dd,J＝8.3,1.7Hz,1H,Pyr-H),8.32(dd,J＝4.4,1.7Hz,1H,Pyr-H),6.94(s,2H,Ph-H),6.83(dd,J＝8.3,4.4Hz,1H,Pyr-H),2.27(s,3H,CH3),2.06(s,6H,2×CH3).13C NMR(100MHz,d6-DMSO)δ156.36,151.68,136.15,135.98,135.80,133.99,128.86,128.20,
113.35,21.02,18.52.C14H15N3O2(Exact Mass:257.12).
113.35,21.02,18.52.C14H15N3O2(Exact Mass:257.12).
[0098] 将中间体7(1g,3.89mmol)溶于30mL乙醇中，钯炭(0.1g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得白色的中间体N2-均三甲苯基-2,3-二胺(8)。收率70.8％。熔点:172.5-174℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ7.19(dd,J＝4.9,1.4Hz,1H,Pyr-H),6.85(s,2H,Ph-H),6.81(s,H,NH),6.78-6.76(m,2H,Pyr-H),6.40(dd,J＝7.4,4.9Hz,1H),4.90(s,2H,NH2),2.23(s,3H CH3),2.04(s,6H,2×CH3).13C NMR(100MHz,d6-DMSO)δ146.61,136.58,135.53,135.13,133.98,130.92,128.72,118.62,113.93,20.99,18.76.C14H17N3(Exact Mass:227.14).[0099] 将中间体8(0.2g,0.88mmol)、乙基黄原酸钾(0.21g,1.32mmol)以及碳酸氢钠(0.017g,0.2mmol)溶解到水(3mL)和乙醇(15mL)的混合溶液中，回流5h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入5mL水和2mL的2M氢氧化钠溶液后生成沉淀，过滤，用2M盐酸溶液将滤液pH调至7，产生沉淀，过滤得白色的中间体3-均三甲苯基-2-巯基-
3H-咪唑并[4,5-b]-2-吡啶(9)。收率75.1％。熔点:274-280℃。
3H-咪唑并[4,5-b]-2-吡啶(9)。收率75.1％。熔点:274-280℃。
[0100] 波谱数据:1H NMR(400MHz,d6-DMSO)δ13.23(s,1H,SH),8.07(dd,J＝5.0,1.3Hz,1H,Pyr-H),7.63(dd,J＝7.9,1.3Hz,1H,Pyr-H),7.24(dd,J＝7.9,5.0Hz,1H,Pyr-H),7.06
13
(s,2H,Ph-H),2.33(s,3H,CH3),1.85(s,6H,2×CH3). C NMR(100MHz,d6-DMSO)δ170.09,
146.04,143.13,139.03,136.61,130.48,129.29,125.30,119.55,117.43,21.15,17.95.[0101] 实施例11.化合物X1的制备
13
(s,2H,Ph-H),2.33(s,3H,CH3),1.85(s,6H,2×CH3). C NMR(100MHz,d6-DMSO)δ170.09,
146.04,143.13,139.03,136.61,130.48,129.29,125.30,119.55,117.43,21.15,17.95.[0101] 实施例11.化合物X1的制备
[0102] 操作同实施例2，所不同的是使用中间体9。白色固体,产率:67.1％，熔点:115-116.5℃。
[0103]
[0104] 化合物X1波谱数据：1H NMR(400MHz,d6-DMSO)δ8.15(dd,J＝4.8,1.4Hz,1H,Pyr-H),8.02(dd,J＝8.0,1.4Hz,1H,Pyr-H),7.27(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.14(s,2H,PhH),4.26(s,2H,CH2),4.13(q,J＝7.1Hz,2H,CH2),2.36(s,3H,CH3),1.85(s,6H,2×CH3),13
1.17(t,J＝7.1Hz,3H,CH3). C NMR(100MHz,d6-DMSO)δ168.54,153.91,149.37,143.33,
140.13,136.89,135.44,129.72,129.23,125.65,118.83,61.73,32.95,21.20,17.55,
14.45.ESI-MS:m/z 356.4[M+H]+.C19H21N3O2S(355.14)。
1.17(t,J＝7.1Hz,3H,CH3). C NMR(100MHz,d6-DMSO)δ168.54,153.91,149.37,143.33,
140.13,136.89,135.44,129.72,129.23,125.65,118.83,61.73,32.95,21.20,17.55,
14.45.ESI-MS:m/z 356.4[M+H]+.C19H21N3O2S(355.14)。
[0105] 实施例12.化合物X2的制备
[0106] 操作同实施例11，所不同的是，所用卤代烷为4-溴丁酸乙酯。油状物,产率:71.9％。
[0107]
[0108] 化合物X2波谱数据：1H NMR(400MHz,d6-DMSO)δ8.13(dd,J＝4.8,1.4Hz,1H,Pyr-H),8.03(dd,J＝8.0,1.4Hz,1H,Pyr-H),7.27(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.12(s,2H,Ph-H),4.04(q,J＝7.1Hz,2H,CH2),3.38-3.34(2H,CH2),2.43(t,J＝7.3Hz,2H,CH2),2.35(s,3H,CH3),2.00(p,J＝7.2Hz,2H,CH2),1.81(s,6H,2×CH3),1.15(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.67,154.57,149.34,143.17,139.94,136.73,135.58,129.67,129.45,125.46,118.74,60.37,32.63,30.13,24.90,21.17,17.59,
14.52.C21H25N3O2S(383.17)。
14.52.C21H25N3O2S(383.17)。
[0109] 实施例13.化合物X3的制备
[0110] 操作同实施例11，所不同的是，所用卤代烷为2-氯丙酸乙酯。白色固体,产率:68.5％，熔点:70-70.5℃。
[0111]
[0112] 化合物X3波谱数据:1H NMR(400MHz,d6-DMSO)δ8.16(dd,J＝4.8,1.4Hz,1H,Pyr-H),8.03(dd,J＝8.0,1.4Hz,1H,Pyr-H),7.28(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.13(s,2H,Ph-H),4.73(q,J＝7.3Hz,1H,CH),4.12(q,J＝7.1Hz,2H,CH2),2.35(s,3H,CH3),1.83(s,6H,13
2×CH3),1.60(d,J＝7.3Hz,3H,CH3),1.14(t,J＝7.1Hz,3H,CH3). C NMR(100MHz,d6-DMSO)δ171.38,153.12,149.09,143.50,140.15,136.79,136.75,135.47,129.73,139.70,
129.20,125.75,118.92,61.80,43.09,21.19,18.17,17.56,17.52,14.35.ESI-MS:m/z
370.4[M+H]+.C20H23N3O2S(369.15)。
2×CH3),1.60(d,J＝7.3Hz,3H,CH3),1.14(t,J＝7.1Hz,3H,CH3). C NMR(100MHz,d6-DMSO)δ171.38,153.12,149.09,143.50,140.15,136.79,136.75,135.47,129.73,139.70,
129.20,125.75,118.92,61.80,43.09,21.19,18.17,17.56,17.52,14.35.ESI-MS:m/z
370.4[M+H]+.C20H23N3O2S(369.15)。
[0113] 实施例14.化合物X4的制备
[0114] 操作同实施例11，所不同的是，所用酯为2-溴-2-甲基丙酸乙酯。白色固体,产率:73.6％，熔点:93-95℃。
[0115]
[0116] 化合物X4波谱数据：1H NMR(400MHz,d6-DMSO)δ8.14(dd,J＝4.8,1.3Hz,1H,Pyr-H),7.99(dd,J＝8.0,1.3Hz,1H,Pyr-H),7.26(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.12(s,2H,Ph-H),4.10(q,J＝7.1Hz,2H,CH2),2.35(s,3H,CH3),1.82(s,6H,2×CH3),1.73(s,6H,2×CH3),1.05(t,J＝7.1Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.90,152.84,148.58,143.44,140.02,136.70,135.54,129.67,129.39,125.68,118.82,61.70,52.53,26.88,
21.19,17.55,14.26.ESI-MS:m/z 384.4[M+H]+.C21H25N3O2S(383.17)。
21.19,17.55,14.26.ESI-MS:m/z 384.4[M+H]+.C21H25N3O2S(383.17)。
[0117] 实施例15.化合物X5的制备
[0118] 操作同实施例6，所不同的是被水解的化合物为X1。白色固体,产率:94.2％，熔点:190-200.5℃。
[0119]
[0120] 化合物X5波谱数据：1H NMR(400MHz,d6-DMSO)δ8.14(dd,J＝4.8,1.4Hz,1H,Pyr-H),8.03(dd,J＝8.0,1.4Hz,1H,Pyr-H),7.27(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.14(s,2H,Ph-H),4.19(s,2H,CH2),2.36(s,3H,CH3),1.85(s,6H,2×CH3).13C NMR(100MHz,d6-DMSO)δ169.79,154.25,149.38,143.26,140.07,136.90,135.48,129.69,129.32,125.59,118.78,
33.40,21.20,17.57.ESI-MS:m/z 326.4[M-H]+.C17H21N3O2S(327.10)。
33.40,21.20,17.57.ESI-MS:m/z 326.4[M-H]+.C17H21N3O2S(327.10)。
[0121] 实施例16.化合物X6的制备
[0122] 操作同实施例6，所不同的是被水解的化合物为X2。白色固体,产率:90.9％，熔点:138-140℃。
[0123]
[0124] 化合物X6波谱数据：1H NMR(400MHz,d6-DMSO)δ8.13(dd,J＝4.8,1.3Hz,1H,Pyr-H),8.03(dd,J＝8.0,1.3Hz,1H,Pyr-H),7.27(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.12(s,2H,Ph-H),3.47-3.42(m,2H,CH2),2.38-2.35(m,5H,CH2+CH3),2.01-1.94(m,2H,CH2),1.82(s,6H,2×CH3).13C NMR(100MHz,d6-DMSO)δ174.23,154.61,149.34,143.15,139.93,136.73,
135.60,129.67,129.47,125.47,118.73,32.82,30.29,24.90,21.18,17.59.C19H21N3O2S(355.14)。
135.60,129.67,129.47,125.47,118.73,32.82,30.29,24.90,21.18,17.59.C19H21N3O2S(355.14)。
[0125] 实施例17.化合物X7的制备
[0126] 操作同实施例6，所不同的是被水解的化合物为X3。白色固体,产率:93.3％，熔点:148-149.5℃。
[0127]
[0128] 化合物X7波谱数据：1H NMR(400MHz,d6-DMSO)δ13.14(s,1H,OH),8.16(dd,J＝4.8,1.3Hz,1H,Pyr-H),8.05(dd,J＝8.0,1.3Hz,1H,Pyr-H),7.28(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.13(s,2H,Ph-H),4.69(q,J＝7.2Hz,1H,CH),2.36(s,3H,CH3),1.83(s,6H,2×CH3),1.61(d,J＝7.3Hz,3H,CH3).13C NMR(100MHz,d6-DMSO)δ172.84,153.52,149.10,
143.42,140.08,136.84,136.71(s),135.52(s),129.71,129.66,129.31,125.71,118.86,
43.75,21.19,18.64,17.59,17.56.ESI-MS:m/z 340.4[M-H]+.C18H19N3O2S(341.12)。
143.42,140.08,136.84,136.71(s),135.52(s),129.71,129.66,129.31,125.71,118.86,
43.75,21.19,18.64,17.59,17.56.ESI-MS:m/z 340.4[M-H]+.C18H19N3O2S(341.12)。
[0129] 实施例18.化合物X8的制备
[0130] 操作同实施例6，所不同的是被水解的化合物为X4。白色固体,产率:93.9％，熔点:180-183℃。
[0131]
[0132] 化合物X8波谱数据：1H NMR(400MHz,d6-DMSO)δ8.15(dd,J＝4.8,1.4Hz,1H,Pyr-H),8.02(dd,J＝8.0,1.4Hz,1H,Pyr-H),7.26(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.11(s,2H,Ph-H),2.35(s,3H,CH3),1.81(s,6H,2×CH3),1.74(s,6H,2×CH3).13C NMR(100MHz,d6-DMSO)δ174.48,153.11,148.54,143.45,139.91,136.70,135.58,129.63,125.74,118.78,53.16,26.88,21.19,17.58.ESI-MS:m/z 354.4[M-H]+.C19H21N3O2S(355.14)。
[0133] 实施例19.中间体3-(4-环丙基-1-萘基)-2-巯基-3H-咪唑[4,5-b]吡啶(20)的合成
[0134] 将4-溴-1-萘胺(10)(20.0g，90mmol)、环丙基硼酸(10.0g，116mmol)、磷酸钾(64.0g，300mmol)与四三苯基膦钯(7.0g，6mmol)加入到100mL甲苯与4mL水的混合溶剂中，在氮气保护下于100℃反应12h(TLC检测反应完毕)。反应完毕，冷却，向反应液中加入100mL的水溶液，用乙酸乙酯萃取三次后加入硫酸钠干燥。过滤，经减压蒸馏得到13.8g中间体4-环丙基-1-萘胺(11)，收率83.6％。波谱数据：1H NMR(400MHz,d6-DMSO)δ8.25(d,J＝7.9Hz,1H,Naph-H),8.07(d,J＝8.2Hz,1H,Naph-H),7.49(ddd,J＝8.2,6.8,1.1Hz,1H,Naph-H),
7.39(ddd,J＝8.1,6.8,1.2Hz,1H,Naph-H),7.00(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝
7.7Hz,1H,Naph-H),5.54(s,2H,NH2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH2),0.57-
0.53(m,2H,CH2).ESI-MS:m/z 184.2[M+H]+.C13H13N(Exact Mass:183.10).
7.39(ddd,J＝8.1,6.8,1.2Hz,1H,Naph-H),7.00(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝
7.7Hz,1H,Naph-H),5.54(s,2H,NH2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH2),0.57-
0.53(m,2H,CH2).ESI-MS:m/z 184.2[M+H]+.C13H13N(Exact Mass:183.10).
[0135] 将2-氯-3-硝基吡啶(1)(1g,6.33mmol)、4-环丙基-1-萘胺(11)(1.73g,9.495mmol)与氟化钾(0.55g,9.495mmol)混合于圆底烧瓶中，120℃熔融反应12h(TLC检测反应完毕)。反应完毕，冷却，向残留物中加入30mL二氯甲烷，饱和氯化钠水溶液洗涤(3×
10mL)，分取有机层，无水硫酸钠干燥，过滤后蒸干，乙醇－石油醚重结晶得到黄色的中间体N-(4-环丙基-1-萘基)-3-硝基-2-胺(14)。收率68.8％。熔点:159-160.5℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ10.16(s,1H,NH),8.55(dd,J＝8.3,1.7Hz,1H,Pyr-H),8.46(d,J＝
8.3Hz,1H,Naph-H),8.30(dd,J＝4.4,1.7Hz,1H,Pyr-H),7.95(d,J＝8.2Hz,1H,Naph-H),
7.64-7.52(m,3H,Naph-H),7.30(d,J＝7.6Hz,1H,Naph-H),6.89(dd,J＝8.3,4.5Hz,1H,Pyr-H),2.46-2.39(m,1H,CH),1.10-1.06(m,2H,CH2),0.77-0.74(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ155.87,151.98,137.77,135.85,134.04,133.21,130.04,128.90,
126.54,126.50,125.09,124.04,123.73,123.53,114.21,13.30,7.14.C18H15N3O2(Exact Mass:305.12).
10mL)，分取有机层，无水硫酸钠干燥，过滤后蒸干，乙醇－石油醚重结晶得到黄色的中间体N-(4-环丙基-1-萘基)-3-硝基-2-胺(14)。收率68.8％。熔点:159-160.5℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ10.16(s,1H,NH),8.55(dd,J＝8.3,1.7Hz,1H,Pyr-H),8.46(d,J＝
8.3Hz,1H,Naph-H),8.30(dd,J＝4.4,1.7Hz,1H,Pyr-H),7.95(d,J＝8.2Hz,1H,Naph-H),
7.64-7.52(m,3H,Naph-H),7.30(d,J＝7.6Hz,1H,Naph-H),6.89(dd,J＝8.3,4.5Hz,1H,Pyr-H),2.46-2.39(m,1H,CH),1.10-1.06(m,2H,CH2),0.77-0.74(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ155.87,151.98,137.77,135.85,134.04,133.21,130.04,128.90,
126.54,126.50,125.09,124.04,123.73,123.53,114.21,13.30,7.14.C18H15N3O2(Exact Mass:305.12).
[0136] 将中间体14(1g,3.28mmol)溶于30mL乙醇中，钯炭(0.1g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得白色的中间体N2-(4-环丙基-1-萘基)吡啶-2,3-二胺(17)。收率56.4％。熔点:171-172℃。1
波谱数据：H NMR(400MHz,d6-DMSO)δ8.39(d,J＝8.3Hz,1H,Naph-H),8.03(d,J＝8.3Hz,
1H,Naph-H),7.71(s,1H,NH),7.56(t,J＝8.0Hz,1H,Naph-H),7.47(t,J＝7.6Hz,1H,Naph-H),7.41(d,J＝7.7Hz,1H,Naph-H),7.31(dd,J＝4.8,1.4Hz,1H,Pyr-H),7.20(d,J＝7.7Hz,
1H,Naph-H),6.94(dd,J＝7.6,1.5Hz,1H,Pyr-H),6.59(dd,J＝7.5,4.8Hz,1H,Pyr-H),5.12
13
(s,2H,NH2),2.37-2.30(m,1H,CH),1.05-1.00(m,2H,CH2),0.71-0.67(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ146.00,136.61,135.04,134.16,133.71,132.57,128.74,126.05,
125.26,124.85,124.20,123.95,120.24,119.08,116.12,13.24,6.86.C18H17N3(Exact Mass:275.14).
波谱数据：H NMR(400MHz,d6-DMSO)δ8.39(d,J＝8.3Hz,1H,Naph-H),8.03(d,J＝8.3Hz,
1H,Naph-H),7.71(s,1H,NH),7.56(t,J＝8.0Hz,1H,Naph-H),7.47(t,J＝7.6Hz,1H,Naph-H),7.41(d,J＝7.7Hz,1H,Naph-H),7.31(dd,J＝4.8,1.4Hz,1H,Pyr-H),7.20(d,J＝7.7Hz,
1H,Naph-H),6.94(dd,J＝7.6,1.5Hz,1H,Pyr-H),6.59(dd,J＝7.5,4.8Hz,1H,Pyr-H),5.12
13
(s,2H,NH2),2.37-2.30(m,1H,CH),1.05-1.00(m,2H,CH2),0.71-0.67(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ146.00,136.61,135.04,134.16,133.71,132.57,128.74,126.05,
125.26,124.85,124.20,123.95,120.24,119.08,116.12,13.24,6.86.C18H17N3(Exact Mass:275.14).
[0137] 将中间体17(2g,7.27mmol)、乙基黄原酸钾(1.4g,8.72mmol)以及碳酸氢钠(0.14g,1.67mmol)溶解到水(10mL)和乙醇(50mL)的混合溶液中，回流5h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入25mL水和10mL的2M氢氧化钠溶液后生成沉淀，过滤，用2M盐酸溶液将滤液PH调至7，产生沉淀，过滤得白色的中间体3-(4-环丙基-1-萘基)-2-巯基-3H-咪唑[4,5-b]吡啶(20)。收率86.2％。熔点:294-296℃。波谱数据:1H NMR(400MHz,d6-DMSO)δ13.36(s,1H,SH),8.54(d,J＝8.5Hz,1H,Pyr-H),7.99(dd,J＝5.0,1.3Hz,1H,Pyr-H),7.66(ddd,J＝16.7,8.1,1.2Hz,2H,Naph-H,),7.50-7.42(m,3H,Naph-H+Pyr-H),7.26-7.23(m,2H,Naph-H),2.57-2.52(m,1H,CH),1.19-1.11(m,2H,CH2),0.90-
0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ171.71,147.68,142.89,141.44,134.17,
130.33,129.92,128.11,127.26,126.91,125.43,125.26,123.74,123.39,119.66,117.41,
13.42,7.55,7.34.
0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ171.71,147.68,142.89,141.44,134.17,
130.33,129.92,128.11,127.26,126.91,125.43,125.26,123.74,123.39,119.66,117.41,
13.42,7.55,7.34.
[0138] 实施例20.化合物Q1的制备
[0139] 操作同实施例2，所不同的是，此实施例使用中间体20。白色固体,产率:67.1％，熔点:141-143.5℃。
[0140]
[0141] 化合物Q1波谱数据：1H NMR(400MHz,d6-DMSO)δ8.59(d,J＝8.5Hz,1H,Pyr-H),8.10(s,1H,Naph-H),8.08(d,J＝1.8Hz,1H,Naph-H),7.70(t,J＝8.2Hz,1H,Naph-H),7.61(d,J＝7.6Hz,1H,Pyr-H),7.51(t,J＝7.6Hz,1H,Pyr-H),7.47(d,J＝7.5Hz,1H,Naph-H),
7.31-7.28(m,1H,Naph-H),7.07(d,J＝8.3Hz,1H,Naph-H),4.24(d,J＝2.3Hz,2H,CH2),
4.13(q,J＝7.0Hz,2H,CH2),2.61-2.54(m,1H,CH),1.20-1.15(m,5H,CH2+CH3),0.93-0.82(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ168.53,154.91,151.00,143.32,142.59,135.39,
134.20,130.08,128.37,127.86,127.56,127.39,125.81,125.45,123.30,123.12,119.11,
61.75,33.46,14.47,13.45,7.77,7.45.C23H21N3O2S(403.14)。
7.31-7.28(m,1H,Naph-H),7.07(d,J＝8.3Hz,1H,Naph-H),4.24(d,J＝2.3Hz,2H,CH2),
4.13(q,J＝7.0Hz,2H,CH2),2.61-2.54(m,1H,CH),1.20-1.15(m,5H,CH2+CH3),0.93-0.82(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ168.53,154.91,151.00,143.32,142.59,135.39,
134.20,130.08,128.37,127.86,127.56,127.39,125.81,125.45,123.30,123.12,119.11,
61.75,33.46,14.47,13.45,7.77,7.45.C23H21N3O2S(403.14)。
[0142] 实施例21.化合物Q2的制备
[0143] 操作同实施例20，所不同的是，所用酯为4-溴丁酸乙酯。白色固体,产率:71.9％，熔点:79-80.5℃。
[0144]
[0145] 化合物Q2波谱数据：1H NMR(400MHz,d6-DMSO)δ8.57(d,J＝8.5Hz,1H,Pyr-H),8.11–8.06(m,2H,Naph-H),7.68(ddd,J＝8.3,6.9,1.1Hz,1H,Naph-H),7.60(d,J＝7.6Hz,
1H,Naph-H),7.51–7.47(m,1H,Pyr-H),7.44(d,J＝7.5Hz,1H,Naph-H),7.29(dd,J＝8.0,
4.9Hz,1H,Pyr-H),7.03(d,J＝8.3Hz,1H,Naph-H),4.02(q,J＝7.1Hz,2H,CH2),3.36-3.32(m,2H,CH2),2.59-2.54(d,J＝22.2Hz,1H,CH),2.39(t,J＝7.3Hz,2H,CH2),2.02-1.95(m,
2H,CH2),1.17-1.11(m,5H,CH2+CH3),0.91-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
172.67,155.69,151.03,143.11,142.36,135.56,134.17,130.17,128.65,127.80,127.62,
127.30,125.59,125.43,123.29,123.08,118.97,60.35,40.61,40.40,40.19,39.98,
39.78,39.57,39.36,32.62,30.58,24.76,14.51,13.43,7.72,7.42.C25H25N3O2S(431.17)。
1H,Naph-H),7.51–7.47(m,1H,Pyr-H),7.44(d,J＝7.5Hz,1H,Naph-H),7.29(dd,J＝8.0,
4.9Hz,1H,Pyr-H),7.03(d,J＝8.3Hz,1H,Naph-H),4.02(q,J＝7.1Hz,2H,CH2),3.36-3.32(m,2H,CH2),2.59-2.54(d,J＝22.2Hz,1H,CH),2.39(t,J＝7.3Hz,2H,CH2),2.02-1.95(m,
2H,CH2),1.17-1.11(m,5H,CH2+CH3),0.91-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
172.67,155.69,151.03,143.11,142.36,135.56,134.17,130.17,128.65,127.80,127.62,
127.30,125.59,125.43,123.29,123.08,118.97,60.35,40.61,40.40,40.19,39.98,
39.78,39.57,39.36,32.62,30.58,24.76,14.51,13.43,7.72,7.42.C25H25N3O2S(431.17)。
[0146] 实施例22.化合物Q3的制备
[0147] 操作同实施例20，所不同的是，所用酯为2-氯丙酸乙酯。白色固体,产率:68.5％，熔点:111.5-112℃。
[0148]
[0149] 化合物Q3波谱数据：1H NMR(400MHz,d6-DMSO)δ8.58(d,J＝8.5Hz,1H,Pyr-H),8.10(d,J＝7.1Hz,2H,Naph-H),7.69(t,J＝8.2Hz,1H,Naph-H),7.59(t,J＝8.2Hz,1H,Naph-H),7.50(t,J＝8.3Hz,1H,Naph-H),7.45(dd,J＝7.5,3.1Hz,1H,Pyr-H),7.32-7.29(m,1H,Pyr-H),7.03(t,J＝7.4Hz,1H,Naph-H),4.75-4.66(m,1H,CH),4.18-4.06(m,2H,CH2),2.59-2.53(m,1H,CH),1.55(t,J＝7.2Hz,3H,CH3),1.18-1.10(m,5H,CH2+CH3),0.91-
0.82(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ171.36,153.97,150.73,143.52,142.60,
135.40,134.15,130.07,128.34,127.93,127.61,127.40,125.96,125.46,123.26,122.98,
119.21,61.80,43.54,18.18,14.32,13.42,7.75,7.47.C24H23N3O2S(417.15)。
0.82(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ171.36,153.97,150.73,143.52,142.60,
135.40,134.15,130.07,128.34,127.93,127.61,127.40,125.96,125.46,123.26,122.98,
119.21,61.80,43.54,18.18,14.32,13.42,7.75,7.47.C24H23N3O2S(417.15)。
[0150] 实施例23.化合物Q4的制备
[0151] 操作同实施例20，所不同的是，所用酯为2-溴-2-甲基丙酸乙酯。白色固体,产率:73.6％，熔点:117.5-118℃。
[0152]
[0153] 化合物Q4波谱数据：1H NMR(400MHz,d6-DMSO)δ8.58(d,J＝8.5Hz,1H,Pyr-H),8.11-8.07(m,2H,Naph-H),7.71–7.67(m,1H,Naph-H),7.56(d,J＝7.6Hz,1H,Naph-H),7.51(t,J＝8.1Hz,1H,Pyr-H),7.45(d,J＝7.6Hz,1H,Naph-H),7.30(dd,J＝8.0,4.8Hz,1H,Pyr-H),6.98(d,J＝8.3Hz,1H,Naph-H),4.14-4.06(m,2H,CH2),2.60-2.53(m,1H,CH),1.70(s,
3H,CH3),1.63(s,3H,CH3),1.19-1.14(m,2H,CH2),1.10(t,J＝7.1Hz,3H,CH3),0.93-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.85,153.34,150.20,143.69,142.40,135.45,
134.12,130.18,128.61,127.83,127.58,127.34,126.09,125.44,123.27,122.94,119.20,
61.71,53.07,26.80,26.79,14.30,13.42,7.78,7.41.C25H25N3O2S(431.17)。
3H,CH3),1.63(s,3H,CH3),1.19-1.14(m,2H,CH2),1.10(t,J＝7.1Hz,3H,CH3),0.93-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.85,153.34,150.20,143.69,142.40,135.45,
134.12,130.18,128.61,127.83,127.58,127.34,126.09,125.44,123.27,122.94,119.20,
61.71,53.07,26.80,26.79,14.30,13.42,7.78,7.41.C25H25N3O2S(431.17)。
[0154] 实施例24.化合物Q5的制备
[0155] 操作同实施例6，所不同的是此实施例被水解的是Q1。白色固体,产率:94.2％，熔点:202-204℃。
[0156]
[0157] 化合物Q5波谱数据：1H NMR(400MHz,d6-DMSO)δ12.99(s,1H,OH),8.59(d,J＝8.5Hz,1H,Pyr-H),8.11-8.08(d,J＝13.0Hz,2H,Naph-H),7.70(ddd,J＝8.3,6.9,1.0Hz,
1H,Naph-H),7.61(d,J＝7.6Hz,1H,Naph-H),7.53–7.49(m,1H,Pyr-H),7.46(d,J＝7.6Hz,
1H,Naph-H),7.30(dd,J＝7.9,4.9Hz,1H,Pyr-H),7.07(d,J＝8.3Hz,1H,Naph-H),4.18(s,
2H,CH2),2.61-2.54(m,1H,CH),1.19-1.14(m,2H,CH2),0.93-0.83(d,J＝42.1Hz,2H,CH2).13C NMR(100MHz,d6-DMSO)δ169.79,155.24,151.01,143.24,142.54,135.42,134.19,
130.09,128.43,127.84,127.56,127.37,125.75,125.44,123.30,123.19,119.07,33.90,
13.45,7.75,7.46.C21H17N3O2S(375.10)。
1H,Naph-H),7.61(d,J＝7.6Hz,1H,Naph-H),7.53–7.49(m,1H,Pyr-H),7.46(d,J＝7.6Hz,
1H,Naph-H),7.30(dd,J＝7.9,4.9Hz,1H,Pyr-H),7.07(d,J＝8.3Hz,1H,Naph-H),4.18(s,
2H,CH2),2.61-2.54(m,1H,CH),1.19-1.14(m,2H,CH2),0.93-0.83(d,J＝42.1Hz,2H,CH2).13C NMR(100MHz,d6-DMSO)δ169.79,155.24,151.01,143.24,142.54,135.42,134.19,
130.09,128.43,127.84,127.56,127.37,125.75,125.44,123.30,123.19,119.07,33.90,
13.45,7.75,7.46.C21H17N3O2S(375.10)。
[0158] 实施例25.化合物Q6的制备
[0159] 操作同实施例6，所不同的是此实施例被水解的是Q2。白色固体,产率:90.9％，熔点:103-105℃。
[0160]
[0161] 化合物Q6波谱数据：1H NMR(400MHz,d6-DMSO)δ8.57(d,J＝8.5Hz,1H,Pyr-H),8.12–8.07(m,2H,Naph-H),7.68(t,J＝8.1Hz,1H,Naph-H),7.60(d,J＝7.6Hz,1H,Naph-H),
7.50(t,J＝7.9Hz,1H,Pyr-H),7.44(d,J＝7.6Hz,1H,Naph-H),7.30(dd,J＝8.0,4.9Hz,1H,Pyr-H),7.04(d,J＝8.4Hz,1H,Naph-H),4.05-4.00(m,2H,CH2),2.59-2.54(m,1H,CH),2.32(t,J＝7.3Hz,2H,CH2),1.99–1.92(m,2H,CH2),1.18-1.14(m,2H,CH2),0.91-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.24,155.77,150.90,143.11,142.40,135.43,134.16,
130.14,128.59,127.84,127.64,127.32,125.59,125.44,123.31,123.07,119.03,32.80,
30.72,24.74,13.43,7.74,7.43.C23H21N3O2S(403.14)。
7.50(t,J＝7.9Hz,1H,Pyr-H),7.44(d,J＝7.6Hz,1H,Naph-H),7.30(dd,J＝8.0,4.9Hz,1H,Pyr-H),7.04(d,J＝8.4Hz,1H,Naph-H),4.05-4.00(m,2H,CH2),2.59-2.54(m,1H,CH),2.32(t,J＝7.3Hz,2H,CH2),1.99–1.92(m,2H,CH2),1.18-1.14(m,2H,CH2),0.91-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.24,155.77,150.90,143.11,142.40,135.43,134.16,
130.14,128.59,127.84,127.64,127.32,125.59,125.44,123.31,123.07,119.03,32.80,
30.72,24.74,13.43,7.74,7.43.C23H21N3O2S(403.14)。
[0162] 实施例26.化合物Q7的制备
[0163] 操作同实施例6，所不同的是此实施例被水解的是Q3。白色固体,产率:93.3％，熔点:122-128℃。
[0164]
[0165] 化合物Q7波谱数据：1H NMR(400MHz,d6-DMSO)δ13.18(s,1H,OH),8.58(d,J＝8.5Hz,1H,Naph-H),8.14-8.09(m,2H,Naph-H),7.69(t,J＝7.7Hz,1H,Naph-H),7.61(dd,J＝7.6,4.3Hz,1H,Pyr-H),7.53-7.49(m,1H,Naph-H),7.46(dd,J＝7.6,2.4Hz,1H,Pyr-H),
7.31(ddd,J＝8.0,4.9,0.6Hz,1H,Naph-H),7.05(d,J＝8.4Hz,1H,Pyr-H),4.69(qd,J＝
7.2,3.1Hz,1H,CH),2.60-2.55(m,1H,CH),1.59(dd,J＝17.5,7.2Hz,3H,CH3),1.18-1.14(m,2H,CH2),0.92-0.83(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.82,154.44,150.78,
143.41,142.52,135.45,134.15,130.09,128.42,127.92,127.59,127.37,125.89,125.46,
123.32,123.04,119.14,44.33,18.84,13.46,7.70,7.47.C22H19N3O2S(389.12)。
7.31(ddd,J＝8.0,4.9,0.6Hz,1H,Naph-H),7.05(d,J＝8.4Hz,1H,Pyr-H),4.69(qd,J＝
7.2,3.1Hz,1H,CH),2.60-2.55(m,1H,CH),1.59(dd,J＝17.5,7.2Hz,3H,CH3),1.18-1.14(m,2H,CH2),0.92-0.83(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.82,154.44,150.78,
143.41,142.52,135.45,134.15,130.09,128.42,127.92,127.59,127.37,125.89,125.46,
123.32,123.04,119.14,44.33,18.84,13.46,7.70,7.47.C22H19N3O2S(389.12)。
[0166] 实施例27.化合物Q8的制备
[0167] 操作同实施例6，所不同的是此实施例被水解的是Q4。白色固体,产率:93.9％，熔点:171-175℃。
[0168]
[0169] 化合物Q8波谱数据：1H NMR(400MHz,d6-DMSO)δ8.57(d,J＝8.5Hz,1H,Pyr-H),8.11(d,J＝1.0Hz,1H,Naph-H),8.10(s,1H,Naph-H),7.68(t,J＝8.2Hz,1H,Pyr-H),7.55(d,J＝7.6Hz,1H,Naph-H),7.50(t,J＝7.6Hz,1H,Naph-H),7.44(d,J＝7.6Hz,1H,Naph-H),
7.32-7.29(m,1H,Pyr-H),6.99(d,J＝8.3Hz,1H,Naph-H),2.59-2.53(m,1H,CH),1.68(s,
6H,2×CH3),1.18-1.14(m,2H,CH2),0.93-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
174.47,153.56,150.20,143.68,142.29,135.48,134.10,130.26,128.76,127.82,127.61,
127.29,126.12,125.41,123.28,123.00,119.16,53.64,26.80,13.43,7.77,
7.38.C23H21N3O2S(403.14)。
7.32-7.29(m,1H,Pyr-H),6.99(d,J＝8.3Hz,1H,Naph-H),2.59-2.53(m,1H,CH),1.68(s,
6H,2×CH3),1.18-1.14(m,2H,CH2),0.93-0.81(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
174.47,153.56,150.20,143.68,142.29,135.48,134.10,130.26,128.76,127.82,127.61,
127.29,126.12,125.41,123.28,123.00,119.16,53.64,26.80,13.43,7.77,
7.38.C23H21N3O2S(403.14)。
[0170] 实施例28.中间体1-(4-环丙基-1-萘基)-2-巯基-1H-咪唑[4,5-c]吡啶(21)的合成
[0171] 将4-溴-1-萘胺(10)(20.0g，90mmol)、环丙基硼酸(10.0g，116mmol)、磷酸钾(64.0g，300mmol)与四三苯基膦钯(7.0g，6mmol)加入到100mL甲苯与4mL水的混合溶剂中，在氮气保护下于100℃反应12h(TLC检测反应完毕)。反应完毕，冷却，向反应液中加入100mL的水溶液，用乙酸乙酯萃取三次后加入硫酸钠干燥。过滤，经减压蒸馏得到13.8g中间体4-环丙基-1-萘胺(11)，收率83.6％。波谱数据：1H NMR(400MHz,d6-DMSO)δ8.25(d,J＝7.9Hz,1H,Naph-H),8.07(d,J＝8.2Hz,1H,Naph-H),7.49(ddd,J＝8.2,6.8,1.1Hz,1H,Naph-H),
7.39(ddd,J＝8.1,6.8,1.2Hz,1H,Naph-H),7.00(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝
7.7Hz,1H,Naph-H),5.54(s,2H,NH2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH2),0.57-
0.53(m,2H,CH2).ESI-MS:m/z 184.2[M+H]+.C13H13N(Exact Mass:183.10).
7.39(ddd,J＝8.1,6.8,1.2Hz,1H,Naph-H),7.00(d,J＝7.6Hz,1H,Naph-H),6.59(d,J＝
7.7Hz,1H,Naph-H),5.54(s,2H,NH2),2.17-2.10(m,1H,CH),0.94-0.90(m,2H,CH2),0.57-
0.53(m,2H,CH2).ESI-MS:m/z 184.2[M+H]+.C13H13N(Exact Mass:183.10).
[0172] 将4-氯-3-硝基吡啶(12)(1g,6.33mmol)、4-环丙基-1-萘胺(11)(1.4g,7.6mmol)与碳酸氢钠(1.6g,18.9mmol)溶于50mL乙醇溶液中，60℃回流10h(TLC检测反应完毕)。反应完毕，冷却，向残留物中加入30mL二氯甲烷，饱和氯化钠水溶液洗涤(3×10mL)，分取有机层，无水硫酸钠干燥，过滤，产物快速柱层析得到黄色的中间体N-(4-环丙基-1-萘基)-3-硝基-4-胺(15)。收率69.8％。熔点:116-118℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ10.06(s,1H,NH),9.14(s,1H,Pyr-H),8.51(d,J＝8.3Hz,1H,Pyr-H),8.08(d,J＝6.1Hz,1H,Naph-H),7.91(d,J＝8.1Hz,1H,Pyr-H),7.69-7.65(m,1H,Naph-H),7.59-7.55(m,1H,Naph-H),7.45(d,J＝7.6Hz,1H,Naph-H),7.36(d,J＝7.6Hz,1H,Naph-H),6.29(s,1H,Naph-H),2.50-
13
2.45(m,1H,CH),1.14-1.09(m,2H,CH2),0.81-0.77(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ
153.31,148.80,148.56,139.84,134.39,132.24,130.39,130.16,127.21,127.14,125.51,
125.35,123.71,123.65,110.49,13.31,7.35(2×C).ESI-MS:m/z 306.4[M+H]+.C18H15N3O2(Exact Mass:305.12).
13
2.45(m,1H,CH),1.14-1.09(m,2H,CH2),0.81-0.77(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ
153.31,148.80,148.56,139.84,134.39,132.24,130.39,130.16,127.21,127.14,125.51,
125.35,123.71,123.65,110.49,13.31,7.35(2×C).ESI-MS:m/z 306.4[M+H]+.C18H15N3O2(Exact Mass:305.12).
[0173] 将中间体15(1g,3.28mmol)溶于30mL乙醇中，钯炭(0.1g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得白色的中间体N4-(4-环丙基-1-萘基)吡啶-3,4-二胺(18)。收率76.2％。熔点:192-193℃。
[0174] 波谱数据：ESI-MS:m/z 276.4[M+H]+.C18H17N3(Exact Mass:275.14).
[0175] 将中间体18(0.1g,0.36mmol)、乙基黄原酸钾(0.07g,0.43mmol)以及碳酸氢钠(0.007g,0.0828mmol)溶解到水(2mL)和乙醇(10mL)的混合溶液中，回流5h(TLC检测反应完毕)。反应完毕，冷却，向反应后的溶液中加入5mL水和2mL的2M氢氧化钠溶液后生成沉淀，过滤，用2M盐酸溶液将滤液PH调至7，产生沉淀，过滤得白色的中间体1-(4-环丙基-1-萘基)-2-巯基-1H-咪唑[4,5-c]吡啶(21)。收率79.8％。熔点:199.5-201℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ8.89(s,1H,Pyr-H),8.59(d,J＝8.5Hz,1H,Pyr-H),8.42(d,J＝6.3Hz,
1H,Naph-H),7.71(t,J＝8.0Hz,1H,Naph-H),7.63(d,J＝7.6Hz,1H,Naph-H),7.54(t,J＝
7.4Hz,1H,Naph-H),7.48(d,J＝7.6Hz,1H,Naph-H),7.42(d,J＝8.4Hz,1H,Pyr-H),7.05(d,J＝6.3Hz,1H,Naph-H),2.60-2.54(m,1H,CH),1.18-1.15(m,2H,CH2),0.89-0.86(m,2H,
13
CH2). C NMR(100MHz,d6-DMSO)δ175.26,145.09,142.71,137.55,134.27,130.90,129.35,
128.53,127.83,127.78,127.40,125.55,123.97,123.42,123.33,106.44,13.43,7.77,
7.62.ESI-MS:m/z 318.2[M+H]+.C18H17N3(Exact Mass:317.10).
1H,Naph-H),7.71(t,J＝8.0Hz,1H,Naph-H),7.63(d,J＝7.6Hz,1H,Naph-H),7.54(t,J＝
7.4Hz,1H,Naph-H),7.48(d,J＝7.6Hz,1H,Naph-H),7.42(d,J＝8.4Hz,1H,Pyr-H),7.05(d,J＝6.3Hz,1H,Naph-H),2.60-2.54(m,1H,CH),1.18-1.15(m,2H,CH2),0.89-0.86(m,2H,
13
CH2). C NMR(100MHz,d6-DMSO)δ175.26,145.09,142.71,137.55,134.27,130.90,129.35,
128.53,127.83,127.78,127.40,125.55,123.97,123.42,123.33,106.44,13.43,7.77,
7.62.ESI-MS:m/z 318.2[M+H]+.C18H17N3(Exact Mass:317.10).
[0176] 实施例29.化合物P1的制备
[0177] 操作同实施例2，所不同的是此实施例中的中间体为21。白色固体,产率:76.1％，熔点:117-120℃。
[0178]
[0179] 化合物P1波谱数据：1H NMR(400MHz,d6-DMSO)δ8.97(s,1H,Pyr-H),8.61(d,J＝8.5Hz,1H,Pyr-H),8.22(d,J＝5.5Hz,1H,Naph-H),7.72(t,J＝7.7Hz,1H,Naph-H),7.66(d,J＝7.6Hz,1H,Naph-H),7.55(t,J＝7.6Hz,1H,Naph-H),7.48(d,J＝7.6Hz,1H,Naph-H),
7.05(d,J＝8.2Hz,1H,Pyr-H),6.90(dd,J＝5.5,0.9Hz,1H,Naph-H),4.24(d,J＝1.9Hz,2H,CH2),4.13(q,J＝7.0Hz,2H,CH2),2.62-2.55(m,1H,CH),1.20-1.15(m,5H,CH2+CH3),0.90-
0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ168.47,155.42,143.09,143.06,142.61,
140.54,140.33,134.30,129.40,128.23,128.05,127.65,127.17,125.70,123.39,122.60,
105.61,61.79,34.06,14.46,13.43,7.77,7.71.ESI-MS:m/z 404.3[M+H]+.C23H21N3O2S(403.14)。
7.05(d,J＝8.2Hz,1H,Pyr-H),6.90(dd,J＝5.5,0.9Hz,1H,Naph-H),4.24(d,J＝1.9Hz,2H,CH2),4.13(q,J＝7.0Hz,2H,CH2),2.62-2.55(m,1H,CH),1.20-1.15(m,5H,CH2+CH3),0.90-
0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ168.47,155.42,143.09,143.06,142.61,
140.54,140.33,134.30,129.40,128.23,128.05,127.65,127.17,125.70,123.39,122.60,
105.61,61.79,34.06,14.46,13.43,7.77,7.71.ESI-MS:m/z 404.3[M+H]+.C23H21N3O2S(403.14)。
[0180] 实施例30.化合物P2的制备
[0181] 操作同实施例29，所不同的是，所用酯为4-溴丁酸乙酯。油状物，产率:69.6％。
[0182]
[0183] 化合物P2波谱数据：1H NMR(400MHz,d6-DMSO)δ8.98(s,1H,Pyr-H),8.59(d,J＝8.5Hz,1H,Pyr-H),8.21(d,J＝5.5Hz,1H,Naph-H),7.70(t,J＝7.7Hz,1H,Naph-H),7.65(d,J＝7.6Hz,1H,Naph-H),7.52(t,J＝7.7Hz,1H,Naph-H),7.45(d,J＝7.6Hz,1H,Naph-H),
7.01(d,J＝8.3Hz,1H,Pyr-H),6.86(d,J＝6.3Hz,1H,Naph-H),4.02(q,J＝7.1Hz,2H,CH2),
3.34(t,J＝7.1Hz,2H,CH2),2.60-2.53(m,1H,CH),2.38(t,J＝7.3Hz,2H,CH2),1.98(p,J＝
7.2Hz,2H,CH2),1.18-1.11(m,5H,CH2+CH3),0.89-0.86(m,2H,CH2).13C NMR(101MHz,d6-DMSO)δ172.67,156.16,143.04,142.84,142.45,140.75,140.18,134.27,129.49,128.32,
128.17,127.56,127.23,125.67,123.38,122.57,105.50,60.35,32.59,31.21,24.68,
14.50,13.40,7.75,7.66.ESI-MS:m/z 433.0[M+H]+.C25H25N3O2S(431.17)。
7.01(d,J＝8.3Hz,1H,Pyr-H),6.86(d,J＝6.3Hz,1H,Naph-H),4.02(q,J＝7.1Hz,2H,CH2),
3.34(t,J＝7.1Hz,2H,CH2),2.60-2.53(m,1H,CH),2.38(t,J＝7.3Hz,2H,CH2),1.98(p,J＝
7.2Hz,2H,CH2),1.18-1.11(m,5H,CH2+CH3),0.89-0.86(m,2H,CH2).13C NMR(101MHz,d6-DMSO)δ172.67,156.16,143.04,142.84,142.45,140.75,140.18,134.27,129.49,128.32,
128.17,127.56,127.23,125.67,123.38,122.57,105.50,60.35,32.59,31.21,24.68,
14.50,13.40,7.75,7.66.ESI-MS:m/z 433.0[M+H]+.C25H25N3O2S(431.17)。
[0184] 实施例31.化合物P3的制备
[0185] 操作同实施例29，所不同的是，所用酯为2-氯丙酸乙酯。油状物，产率:68.5％。
[0186]
[0187] 化合物P3波谱数据：1H NMR(400MHz,d6-DMSO)δ8.99(s,1H,Pyr-H),8.61(d,J＝8.5Hz,1H,Pyr-H),8.23(d,J＝6.4Hz,1H,Naph-H),7.72(t,J＝8.0Hz,1H,Pyr-H),7.66(t,J＝7.9Hz,1H,Naph-H),7.58–7.52(m,1H,Naph-H),7.47(dd,J＝7.5,2.6Hz,1H,Naph-H),
7.02(t,J＝7.7Hz,1H,Naph-H),6.91(ddd,J＝5.5,2.6,0.9Hz,1H,Naph-H),4.74-4.66(m,
1H,CH),4.17-4.07(m,2H,CH2),2.61-2.55(m,1H,CH),1.56(t,J＝7.2Hz,3H,CH3),1.18-
13
1.10(m,5H,CH2+CH3),0.90-0.87(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ171.26,154.47,
143.05,142.81,142.68,140.60,140.45,134.26,129.42,128.30,128.05,127.64,127.18,
125.70,123.37,122.50,105.70,61.87,44.31,18.37,18.19,14.37,13.42,7.79.ESI-MS:
m/z 418.0[M+H]+.C24H23N3O2S(417.15)。
7.02(t,J＝7.7Hz,1H,Naph-H),6.91(ddd,J＝5.5,2.6,0.9Hz,1H,Naph-H),4.74-4.66(m,
1H,CH),4.17-4.07(m,2H,CH2),2.61-2.55(m,1H,CH),1.56(t,J＝7.2Hz,3H,CH3),1.18-
13
1.10(m,5H,CH2+CH3),0.90-0.87(m,2H,CH2). C NMR(100MHz,d6-DMSO)δ171.26,154.47,
143.05,142.81,142.68,140.60,140.45,134.26,129.42,128.30,128.05,127.64,127.18,
125.70,123.37,122.50,105.70,61.87,44.31,18.37,18.19,14.37,13.42,7.79.ESI-MS:
m/z 418.0[M+H]+.C24H23N3O2S(417.15)。
[0188] 实施例32.化合物P4的制备
[0189] 操作同实施例29，所不同的是，所用酯为2-溴-2-甲基丙酸乙酯。白色固体,产率:71.4％，熔点:140-142℃。
[0190]
[0191] 化合物P4波谱数据：1H NMR(400MHz,d6-DMSO)δ8.97(s,1H,Pyr-H),8.60(d,J＝8.5Hz,1H,Pyr-H),8.22(d,J＝5.5Hz,1H,Naph-H),7.71(t,J＝8.2Hz,1H,Naph-H),7.62(d,J＝7.6Hz,1H,Naph-H),7.54(t,J＝8.0Hz,1H,Naph-H),7.46(d,J＝7.6Hz,1H,Naph-H),
6.97(d,J＝8.3Hz,1H,Pyr-H),6.87(d,J＝6.3Hz,1H,Naph-H),4.15-4.07(m,2H,CH2),
2.61-2.54(m,1H,CH),1.70(s,3H,CH3),1.63(s,3H,CH3),1.20-1.15(m,2H,CH2),1.11(t,J＝7.1Hz,3H,CH3),0.90-0.86(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.77,153.59,
142.87,142.72,142.18,140.72,140.67,134.23,129.52,128.32,128.20,127.59,127.19,
125.68,123.35,122.44,105.73,61.76,53.39,26.73,14.29,13.40,7.73.ESI-MS:m/z
432.2[M+H]+.C25H25N3O2S(431.17)。
6.97(d,J＝8.3Hz,1H,Pyr-H),6.87(d,J＝6.3Hz,1H,Naph-H),4.15-4.07(m,2H,CH2),
2.61-2.54(m,1H,CH),1.70(s,3H,CH3),1.63(s,3H,CH3),1.20-1.15(m,2H,CH2),1.11(t,J＝7.1Hz,3H,CH3),0.90-0.86(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.77,153.59,
142.87,142.72,142.18,140.72,140.67,134.23,129.52,128.32,128.20,127.59,127.19,
125.68,123.35,122.44,105.73,61.76,53.39,26.73,14.29,13.40,7.73.ESI-MS:m/z
432.2[M+H]+.C25H25N3O2S(431.17)。
[0192] 实施例33.化合物P5的制备
[0193] 操作同实施例6，所不同的是此实施例中被水解的是P1。白色固体,产率:95.1％，熔点:164.8-167.5℃。
[0194]
[0195] 化合物P5波谱数据：1H NMR(400MHz,d6-DMSO)δ8.98(s,1H,Pyr-H),8.61(d,J＝8.5Hz,1H,Pyr-H),8.22(d,J＝5.4Hz,1H,Naph-H),7.72(t,J＝7.7Hz,1H,Naph-H),7.66(d,J＝7.6Hz,1H,Naph-H),7.54(t,J＝7.5Hz,1H,Naph-H),7.48(d,J＝7.6Hz,1H,Naph-H),
7.06(d,J＝8.4Hz,1H,Pyr-H),6.89(d,J＝5.4Hz,1H,Naph-H),4.18(s,2H,CH2),2.62-2.55(m,1H,CH),1.20-1.15(m,2H,CH2),0.91-0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
169.64,155.94,143.09,142.97,142.48,140.63,140.21,134.30,129.43,128.20,128.17,
127.61,127.16,125.67,123.40,122.68,105.57,34.99,13.44,7.78,7.66.C21H17N3O2S(375.10)。
7.06(d,J＝8.4Hz,1H,Pyr-H),6.89(d,J＝5.4Hz,1H,Naph-H),4.18(s,2H,CH2),2.62-2.55(m,1H,CH),1.20-1.15(m,2H,CH2),0.91-0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ
169.64,155.94,143.09,142.97,142.48,140.63,140.21,134.30,129.43,128.20,128.17,
127.61,127.16,125.67,123.40,122.68,105.57,34.99,13.44,7.78,7.66.C21H17N3O2S(375.10)。
[0196] 实施例34.化合物P6的制备
[0197] 操作同实施例6，所不同的是此实施例中被水解的是P2。白色固体,产率:94.2％，熔点:213-214℃。
[0198]
[0199] 化合物P6波谱数据：1H NMR(400MHz,d6-DMSO)δ9.50(s,1H,Pyr-H),8.63(d,J＝8.5Hz,1H,Pyr-H),8.50(d,J＝6.5Hz,1H,Naph-H),7.79(d,J＝7.6Hz,1H,Naph-H),7.78–
7.73(m,1H,Naph-H),7.59–7.55(m,1H,Naph-H),7.49(dd,J＝14.4,7.0Hz,2H,Naph-H),
7.19(d,J＝8.4Hz,1H,Pyr-H),3.41(td,J＝7.0,1.8Hz,2H,CH2),2.64-2.57(m,1H,CH),
2.34(t,J＝7.3Hz,2H,CH2),2.00(p,J＝7.1Hz,2H,CH2),1.21-1.17(m,2H,CH2),0.92-0.88(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.11,163.01,147.68,143.84,140.84,134.97,
134.28,132.54,129.01,128.54,127.83,127.48,126.90,125.78,123.36,122.46,107.90,
32.78,31.68,24.45,13.45,7.90,7.84.ESI-MS:m/z 276.4[M+H]+.C23H21N3O2S(403.14)。
7.73(m,1H,Naph-H),7.59–7.55(m,1H,Naph-H),7.49(dd,J＝14.4,7.0Hz,2H,Naph-H),
7.19(d,J＝8.4Hz,1H,Pyr-H),3.41(td,J＝7.0,1.8Hz,2H,CH2),2.64-2.57(m,1H,CH),
2.34(t,J＝7.3Hz,2H,CH2),2.00(p,J＝7.1Hz,2H,CH2),1.21-1.17(m,2H,CH2),0.92-0.88(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ174.11,163.01,147.68,143.84,140.84,134.97,
134.28,132.54,129.01,128.54,127.83,127.48,126.90,125.78,123.36,122.46,107.90,
32.78,31.68,24.45,13.45,7.90,7.84.ESI-MS:m/z 276.4[M+H]+.C23H21N3O2S(403.14)。
[0200] 实施例35.化合物P7的制备
[0201] 操作同实施例6，所不同的是此实施例中被水解的是P3。白色固体,产率:92.3％，熔点:160.5-163.5℃。
[0202]
[0203] 化合物P7波谱数据：1H NMR(400MHz,d6-DMSO)δ9.14(s,1H,Pyr-H),8.62(d,J＝8.5Hz,1H,Pyr-H),8.30(d,J＝5.7Hz,1H,Naph-H),7.75-7.67(m,2H,Naph-H),7.57-7.53(m,1H,Naph-H),7.48(d,J＝7.6Hz,1H,Pyr-H),7.06(t,J＝6.4Hz,2H,Naph-H),4.68(d,J＝
25.1Hz,1H,CH),2.59(d,J＝27.6Hz,1H,CH),1.60(dd,J＝16.0,7.2Hz,3H,CH3),1.18(d,J
13
＝17.7Hz,2H,CH2),0.89(d,J＝14.1Hz,2H,CH2). C NMR(100MHz,d6-DMSO)δ172.60,
156.50,143.95,143.24,140.81,140.68,138.61,134.27,129.33,128.35,127.78,127.68,
127.27,125.72,123.38,122.51,106.27,45.10,18.78,13.44,7.83,7.69.ESI-MS:m/z
389.8[M+H]+.C22H19N3O2S(389.12)。
25.1Hz,1H,CH),2.59(d,J＝27.6Hz,1H,CH),1.60(dd,J＝16.0,7.2Hz,3H,CH3),1.18(d,J
13
＝17.7Hz,2H,CH2),0.89(d,J＝14.1Hz,2H,CH2). C NMR(100MHz,d6-DMSO)δ172.60,
156.50,143.95,143.24,140.81,140.68,138.61,134.27,129.33,128.35,127.78,127.68,
127.27,125.72,123.38,122.51,106.27,45.10,18.78,13.44,7.83,7.69.ESI-MS:m/z
389.8[M+H]+.C22H19N3O2S(389.12)。
[0204] 实施例36.化合物P8的制备
[0205] 操作同实施例6，所不同的是此实施例中被水解的是P4。白色固体,产率:94.0％，熔点:227-229℃。
[0206]
[0207] 化合物P8波谱数据：C23H21N3O2S(403.14)。
[0208] 实施例37.中间体1-(4-环丙基-1-萘基)-2-巯基-1H-咪唑[4,5-c]吡啶(22)的合成
[0209] 中间体4-环丙基-1-萘胺(11)的制备见实施例28。
[0210] 将醋酸钯(0.007g,0.0315mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.036g,0.063mmol)溶于2mL二氧六环中，室温下搅拌15分钟，同时将3-氯-2-硝基吡啶(13)(0.1g,0.63mmol)、4-环丙基-1-萘胺(11)(0.13g,0.76mmol)与碳酸铯(0.41g,1.26mmol)溶于10mL二氧六环中，将上述两溶液混合，氮气保护下90℃回流12h(TLC检测反应完毕)。反应完毕，冷却，向残留物中加入30mL二氯甲烷，饱和氯化钠水溶液洗涤(3×
10mL)，分取有机层，无水硫酸钠干燥，过滤，产物快速柱层析得到黄色的中间体N-(4-环丙基-1-萘基)-2-硝基-3-胺(16)。收率60.6％。熔点:76-79℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ9.45(s,1H,NH),8.50(d,J＝8.4Hz,1H,Pyr-H),7.95(d,J＝8.4Hz,1H,Pyr-H),7.90(d,J＝5.2Hz,1H,Naph-H),7.66(t,J＝7.6Hz,1H,Naph-H),7.56(t,J＝8.0Hz,1H,Pyr-H),
7.45-7.40(m,2H,Naph-H),7.34(d,J＝7.6Hz,1H,Naph-H),7.00(d,J＝8.6Hz,1H,Naph-H),
2.48-2.43(m,1H,CH),1.12-1.08(m,2H,CH2),0.80-0.76(m,2H,CH2).13C NMR(100MHz,CDCl3)δ141.23,140.65,139.67,136.96,134.75,131.81,130.18,129.98,126.94,126.76,
126.05,125.37,123.87,123.83,122.74,13.35,6.67.ESI-MS:m/z 306.4[M+H]+.C18H15N3O2(Exact Mass:305.12).
10mL)，分取有机层，无水硫酸钠干燥，过滤，产物快速柱层析得到黄色的中间体N-(4-环丙基-1-萘基)-2-硝基-3-胺(16)。收率60.6％。熔点:76-79℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ9.45(s,1H,NH),8.50(d,J＝8.4Hz,1H,Pyr-H),7.95(d,J＝8.4Hz,1H,Pyr-H),7.90(d,J＝5.2Hz,1H,Naph-H),7.66(t,J＝7.6Hz,1H,Naph-H),7.56(t,J＝8.0Hz,1H,Pyr-H),
7.45-7.40(m,2H,Naph-H),7.34(d,J＝7.6Hz,1H,Naph-H),7.00(d,J＝8.6Hz,1H,Naph-H),
2.48-2.43(m,1H,CH),1.12-1.08(m,2H,CH2),0.80-0.76(m,2H,CH2).13C NMR(100MHz,CDCl3)δ141.23,140.65,139.67,136.96,134.75,131.81,130.18,129.98,126.94,126.76,
126.05,125.37,123.87,123.83,122.74,13.35,6.67.ESI-MS:m/z 306.4[M+H]+.C18H15N3O2(Exact Mass:305.12).
[0211] 将中间体16(0.2g,0.66mmol)溶于20mL乙醇中，钯炭(0.02g)加入溶液中，氢气置换三次后，室温下搅拌过夜(TLC检测反应完毕)。停止反应，过滤，减压蒸馏后乙酸乙酯重结晶得黄色的中间体N3-(4-环丙基-1-萘基)吡啶-2,3-二胺(19)。收率73.2％。熔点:143.5-144℃。波谱数据：ESI-MS:m/z 276.1[M+H]+.C18H17N3(Exact Mass:275.14).
[0212] 将中间体19(0.1g,0.36mmol)、1,1’-硫代羰基二咪唑(0.1g,0.58mmol)以及三乙胺(0.08mL)溶于30mL四氢呋喃中，60℃回流5h(TLC检测反应完毕)。反应完毕，冷却，减压蒸馏除去溶剂，向残留物中加入30mL二氯甲烷，饱和氯化钠水溶液洗涤(3×10mL)，分取有机层，无水硫酸钠干燥，过滤，产物快速柱层析得到黄色的中间体1-(4-环丙基-1-萘基)-2-巯基-1H-咪唑[4,5-b]吡啶(22)。收率70.9％。熔点:246-247℃。波谱数据：1H NMR(400MHz,d6-DMSO)δ13.71(s,1H,SH),8.56(d,J＝8.5Hz,1H,Naph-H),8.21(dd,J＝5.0,1.3Hz,1H,Pyr-H),7.69-7.65(m,1H,Naph-H),7.56(d,J＝7.6Hz,1H,Naph-H),7.52-7.48(m,1H,Naph-H),7.44(d,J＝7.6Hz,1H,Naph-H),7.27(d,J＝8.3Hz,1H,Naph-H),7.07(dd,J＝7.9,5.0Hz,1H,Pyr-H),6.91(dd,J＝7.9,1.3Hz,1H,Pyr-H),2.57-2.53(m,1H,CH),1.19-1.11(m,2H,CH2),0.89-0.82(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.02,146.05,143.67,
141.79,134.32,129.86,129.73,128.57,127.74,127.55,127.14,125.46,123.49,123.47,
118.87,116.71,13.40,7.67,7.45.ESI-MS:m/z 318.4[M+H]+.C18H17N3(Exact Mass:
317.10).
141.79,134.32,129.86,129.73,128.57,127.74,127.55,127.14,125.46,123.49,123.47,
118.87,116.71,13.40,7.67,7.45.ESI-MS:m/z 318.4[M+H]+.C18H17N3(Exact Mass:
317.10).
[0213] 实施例38.化合物T1的制备
[0214] 操作同实施例2，所不同的是，此实施例中的中间体为22。油状物,产率:77.6％。
[0215]
[0216]
[0217] 化合物T1波谱数据：ESI-MS:m/z 404.1[M+H]+.C23H21N3O2S(403.14)。
[0218] 实施例39.化合物T2的制备
[0219] 操作同实施例38，所不同的是，所用卤代烷为4-溴丁酸乙酯。油状物,产率:71.1％。
[0220]
[0221] 化合物T2波谱数据：ESI-MS:m/z 432.4[M+H]+.C25H25N3O2S(431.17)。
[0222] 实施例40.化合物T3的制备
[0223] 操作同实施例38，所不同的是，所用卤代烷为2-氯丙酸乙酯。油状物,产率:69.4％。
[0224]
[0225] 化合物T3波谱数据：ESI-MS:m/z 418.4[M+H]+.C24H23N3O2S(417.15)。
[0226] 实施例41.化合物T4的制备
[0227] 操作同实施例38，所不同的是，所用卤代烷为2-溴-2-甲基丙酸乙酯。油状物,产率:74.8％。
[0228]
[0229] 化合物T4波谱数据：ESI-MS:m/z 431.9[M+H]+.C25H25N3O2S(431.17)。
[0230] 实施例42.化合物T5的制备
[0231] 操作同实施例6，所不同的是，此实例中被水解的化合物为T1。白色固体,产率:93.3％，熔点:151.5-153℃。
[0232]
[0233] 化合物T5波谱数据：1H NMR(400MHz,d6-DMSO)δ8.60(d,J＝8.5Hz,1H,Pyr-H),8.38(dd,J＝4.8,1.4Hz,1H,Pyr-H),7.73-7.69(m,1H,Naph-H),7.65(d,J＝7.6Hz,1H,Naph-H),7.53(t,J＝7.6Hz,1H,Naph-H),7.47(d,J＝7.6Hz,1H,Naph-H),7.23(dd,J＝8.0,
1.4Hz,1H,Pyr-H),7.12-7.07(m,2H,Naph-H),4.13(s,2H,CH2),2.61-2.54(m,1H,CH),
1.19-1.14(m,2H,CH2),0.90-0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ169.65,157.69,
155.98,144.08,142.73,134.30,130.97,129.60,128.60,128.12,127.54,127.24,125.64,
123.44,122.83,118.17,117.52,36.32,13.44,7.76,7.59.ESI-MS:m/z 376.1[M+H]+.C21H17N3O2S(375.10)。
1.4Hz,1H,Pyr-H),7.12-7.07(m,2H,Naph-H),4.13(s,2H,CH2),2.61-2.54(m,1H,CH),
1.19-1.14(m,2H,CH2),0.90-0.87(m,2H,CH2).13C NMR(100MHz,d6-DMSO)δ169.65,157.69,
155.98,144.08,142.73,134.30,130.97,129.60,128.60,128.12,127.54,127.24,125.64,
123.44,122.83,118.17,117.52,36.32,13.44,7.76,7.59.ESI-MS:m/z 376.1[M+H]+.C21H17N3O2S(375.10)。
[0234] 实施例43.化合物T6的制备
[0235] 操作同实施例6，所不同的是，此实例中被水解的化合物为T2。白色固体,产率:94.5％，熔点:94-97℃。
[0236]
[0237] 化合物T6波谱数据：1H NMR(400MHz,d6-DMSO)δ8.58(d,J＝8.5Hz,1H,Naph-H),8.38(dd,J＝4.7,1.3Hz,1H,Pyr-H),7.69(t,J＝7.5Hz,1H,Naph-H),7.64(d,J＝7.6Hz,1H,Naph-H),7.51(t,J＝7.5Hz,1H,Naph-H),7.44(d,J＝7.6Hz,1H,Naph-H),7.20(dd,J＝7.9,
1.3Hz,1H,Pyr-H),7.10(dd,J＝7.9,4.8Hz,1H,Pyr-H),7.04(d,J＝8.3Hz,1H,Naph-H),
4.08(s,2H,CH2),2.59-2.54(m,1H,CH),2.20(t,J＝7.2Hz,2H,CH2),1.95-1.88(m,2H,CH2),
1.18-1.13(m,2H,CH2),0.88-0.85(m,2H,CH2).13C NMR(101MHz,d6-DMSO)δ157.63,156.06,
144.09,142.64,134.26,130.97,129.62,128.64,128.13,127.50,127.29,125.63,123.40,
122.69,118.16,117.48,34.41,31.68,25.38,13.40,7.72,7.63.C23H21N3O2S(403.14)。
1.3Hz,1H,Pyr-H),7.10(dd,J＝7.9,4.8Hz,1H,Pyr-H),7.04(d,J＝8.3Hz,1H,Naph-H),
4.08(s,2H,CH2),2.59-2.54(m,1H,CH),2.20(t,J＝7.2Hz,2H,CH2),1.95-1.88(m,2H,CH2),
1.18-1.13(m,2H,CH2),0.88-0.85(m,2H,CH2).13C NMR(101MHz,d6-DMSO)δ157.63,156.06,
144.09,142.64,134.26,130.97,129.62,128.64,128.13,127.50,127.29,125.63,123.40,
122.69,118.16,117.48,34.41,31.68,25.38,13.40,7.72,7.63.C23H21N3O2S(403.14)。
[0238] 实施例44.化合物T7的制备
[0239] 操作同实施例6，所不同的是，此实例中被水解的化合物为T3。白色固体,产率:93.9％，熔点:156-158℃。
[0240]
[0241] 化合物T7波谱数据：1H NMR(400MHz,d6-DMSO)δ8.60(d,J＝8.5Hz,1H,Naph-H),8.39(d,J＝4.5Hz,1H,Pyr-H),7.70(t,J＝7.7Hz,1H,Naph-H),7.64(d,J＝7.6Hz,1H,Naph-H),7.55-7.50(m,1H,Naph-H),7.46(d,J＝7.6Hz,1H,Naph-H),7.22(dd,J＝7.9,1.4Hz,1H,Pyr-H),7.11(dd,J＝7.9,4.8Hz,1H,Pyr-H),7.04(dd,J＝8.2,4.4Hz,1H,Naph-H),4.59-
4.54(m,1H,CH),2.60-2.54(m,1H,CH),1.64-1.57(m,3H,CH3),1.16(d,J＝8.8Hz,2H,CH2),
0.88(s,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.95,157.42,156.09,144.12,142.66,
134.28,130.68,129.61,128.68,128.12,127.51,127.30,125.64,123.45,122.69,118.19,+
117.53,47.44,19.88,13.44,7.78,7.52.ESI-MS:m/z 390.1[M+H] .C22H19N3O2S(389.12)。
4.54(m,1H,CH),2.60-2.54(m,1H,CH),1.64-1.57(m,3H,CH3),1.16(d,J＝8.8Hz,2H,CH2),
0.88(s,2H,CH2).13C NMR(100MHz,d6-DMSO)δ172.95,157.42,156.09,144.12,142.66,
134.28,130.68,129.61,128.68,128.12,127.51,127.30,125.64,123.45,122.69,118.19,+
117.53,47.44,19.88,13.44,7.78,7.52.ESI-MS:m/z 390.1[M+H] .C22H19N3O2S(389.12)。
[0242] 实施例45.化合物T8的制备
[0243] 操作同实施例6，所不同的是，此实例中被水解的化合物为T4。白色固体,产率:90.9％，熔点:160-165℃。
[0244]
[0245] 化合物T8波谱数据：1H NMR(400MHz,d6-DMSO)δ8.59(d,J＝8.5Hz,1H,Naph-H),8.42(dd,J＝4.7,1.4Hz,1H,Pyr-H),7.71(t,J＝7.6Hz,1H,Naph-H),7.62(d,J＝7.6Hz,1H,Naph-H),7.53(t,J＝7.6Hz,1H,Naph-H),7.45(d,J＝7.6Hz,1H,Naph-H),7.23(dd,J＝8.0,
1.4Hz,1H,Pyr-H),7.13(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.00(d,J＝8.4Hz,1H,Naph-H),
2.60-2.54(m,1H,CH),1.70(s,6H,2×CH3),1.17(dd,J＝8.4,1.8Hz,2H,CH2),0.88(q,J＝
13
5.6Hz,2H,CH2). C NMR(100MHz,d6-DMSO)δ174.39,155.87,155.11,144.48,142.65,
134.21,130.18,129.70,128.69,128.15,127.53,127.30,125.63,123.37,122.58,118.58,
117.96,53.95,26.75,13.40,7.72,7.68.ESI-MS:m/z 404.3[M+H]+.C23H21N3O2S(403.14)。
1.4Hz,1H,Pyr-H),7.13(dd,J＝8.0,4.8Hz,1H,Pyr-H),7.00(d,J＝8.4Hz,1H,Naph-H),
2.60-2.54(m,1H,CH),1.70(s,6H,2×CH3),1.17(dd,J＝8.4,1.8Hz,2H,CH2),0.88(q,J＝
13
5.6Hz,2H,CH2). C NMR(100MHz,d6-DMSO)δ174.39,155.87,155.11,144.48,142.65,
134.21,130.18,129.70,128.69,128.15,127.53,127.30,125.63,123.37,122.58,118.58,
117.96,53.95,26.75,13.40,7.72,7.68.ESI-MS:m/z 404.3[M+H]+.C23H21N3O2S(403.14)。
[0246] 实施例46.目标化合物的体内抗痛风活性试验(分两个批次)
[0247] 测试材料和方法
[0248] (1)实验动物：雄性昆明小鼠，由山东大学实验动物中心提供。
[0249] (2)样品处理：待测化合物临用前用乙醇和CMC-Na配成适当的浓度。
[0250] (3)造模药物：黄嘌呤、氧嗪酸钾。
[0251] (4)阳性对照药：苯溴马隆、RDEA594。其中，RDEA594是一种新近上市的用于治疗痛风的增加尿酸排泄口服药。
[0252] (5)测试方法：每组灌胃口服药物0.2mL并开始计时，3小时灌胃黄嘌呤0.2mL，随即腹腔注射氧嗪酸钾0.2mL，在给药后6小时摘眼球取血，30度凝血后离心得血清。免疫法分析血清中的尿酸浓度。
[0253] 表2.化合物M1～Q8(批次1)、T1～T8(批次2)的结构及抗痛风的活性
[0254]化合物 尿酸值μmol/L 化合物 尿酸值μmol/L
M1 1507.6±229.2 T1 353.5±35.6
M2 634.7±97.7 T2 334±65.7
M3 1321.5±183.5 T3 339±29.8
M4 1363±184.7 T4 306±46.8
M5 1307.5±195.3 T5 342±44.1
M6 1342±144.3 T6 330±29.1
M7 1307.2±133.1 T7 189.7±67.8
M8 1229±150.2 T8 295.2±54
X1 1255.2±184 造模 576.5±120.5
X2 1107.7±195.1 空白 262±43.6
X3 983.2±122.6 空白(灌喂CMC-Na) 286±90.9
X4 689.2±53.4 RDEA594 409.5±124.3
X5 1310.2±155.8
X6 655.2±210.8
X7 727.2±150.7
X8 1288±211.5
Q1 1344.75±287.5
Q2 1422.6±194.4
Q3 672±76.2
Q4 1328.2±163.8
Q5 824±109.9
Q6 1490.7±269.9
Q7 763.2±248.7
Q8 1448±216.7
造模 1462.6±194.3
空白 377.2±27.6
苯溴马隆 762.5±30.3
M1 1507.6±229.2 T1 353.5±35.6
M2 634.7±97.7 T2 334±65.7
M3 1321.5±183.5 T3 339±29.8
M4 1363±184.7 T4 306±46.8
M5 1307.5±195.3 T5 342±44.1
M6 1342±144.3 T6 330±29.1
M7 1307.2±133.1 T7 189.7±67.8
M8 1229±150.2 T8 295.2±54
X1 1255.2±184 造模 576.5±120.5
X2 1107.7±195.1 空白 262±43.6
X3 983.2±122.6 空白(灌喂CMC-Na) 286±90.9
X4 689.2±53.4 RDEA594 409.5±124.3
X5 1310.2±155.8
X6 655.2±210.8
X7 727.2±150.7
X8 1288±211.5
Q1 1344.75±287.5
Q2 1422.6±194.4
Q3 672±76.2
Q4 1328.2±163.8
Q5 824±109.9
Q6 1490.7±269.9
Q7 763.2±248.7
Q8 1448±216.7
造模 1462.6±194.3
空白 377.2±27.6
苯溴马隆 762.5±30.3
[0255] 结论：由表2可以看出批次1中，化合物M2、X4、X6、X7、Q3均呈现出显著的抗痛风活性，抗痛风活性均优于或相当于于阳性对照药物苯溴马隆；批次2中，T1-T8的活性远优于药物RDEA594，取得了意想不到的效果。可作为全新结构的药物先导物进一步开发。