CN106279041A - 苯基嘧啶衍生物及其制备方法和用途 - Google Patents
苯基嘧啶衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN106279041A CN106279041A CN201610671943.6A CN201610671943A CN106279041A CN 106279041 A CN106279041 A CN 106279041A CN 201610671943 A CN201610671943 A CN 201610671943A CN 106279041 A CN106279041 A CN 106279041A
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- Prior art keywords
- piperazine
- methylpyrimidine
- phenyl
- formula
- methyl
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- -1 substituted-phenyl Chemical group 0.000 claims description 22
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 18
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Abstract
本发明属于化学医药领域，具体涉及苯基嘧啶衍生物及其制备方法和用途。本发明提供的苯基嘧啶衍生物，作为特异性GPR119抑制剂，其结构如式I所示，为预防和治疗、Ⅱ型糖尿病、肥胖症以及脂代谢紊乱等相关的代谢紊乱疾病提供了一种新的选择。
Description
技术领域
本发明涉及一种苯基嘧啶衍生物及其制备方法和用途。
背景技术
糖尿病是由多重因素引起的，并且其特征在于，在禁食状态下或者在口服葡萄糖耐量试验期间在给药葡萄糖之后，血浆葡萄糖水平升高(高血糖)，通常有两种公认形式的糖尿病，在Ⅰ型糖尿病或者胰岛素-依赖型糖尿病(IDDM)中，患者产生很少或者不产生胰岛素，而胰岛素是用于调节葡萄糖的激素。在Ⅱ型糖尿病或者非胰岛素-依赖型糖尿病(NIDDM)，体内仍然产生胰岛素。Ⅱ型糖尿病患者对于胰岛素在主要的胰岛素敏感性组织(肌肉，肝脏和脂肪组织)中刺激胰岛素和脂质代谢的作用具有抗性。这些患者通常具有正常水平的胰岛素，并且当他们通过分泌增大量的胰岛素而补偿胰岛素的降低作用时，它们可能具有高胰岛素血症(升高的血浆胰岛素水平)。这样血清葡萄糖水平没有高到足以满足Ⅱ型糖尿病标准的程度，在Ⅱ型糖尿病患者中，即使增高的血浆胰岛素水平也不足以克服显著的胰岛素抗性。患有胰岛素抗性或者Ⅱ型糖尿病的很多患者常具有几种症状，这几种症状一起称为综合征X或代谢综合征。具有这种综合征的患者的特征是具有三种或更多种选自下列五种症状的症状：(1)腹部肥胖；(2)高甘油三酯血症；(3)低的高密度脂蛋白胆固醇(HDL)；(4)高血压；和(5)增高的空腹血糖，如果患者也患糖尿病，则这也在Ⅱ型糖尿病的特征范围内。每一这些症状都是在发表的Third Report of the National CholesterolEducation Program Expert Panel on Detection,Evaluation and Treatment of HighBlood Cholesterol in Adults(Adult Treatment Panelm,or ATPIn),NationalInstitutes of Health,2001,NIH Publication No.3601-3670中定义的，具有代谢综合征的患者，不论他们是否具有或者发展成明显的糖尿病，其发展成上述与Ⅱ型糖尿病一起发生的大血管和微血管并发症例如动脉粥样硬化和冠心病的危险都增加。治疗Ⅱ型糖尿病的可用方法有几种，每一种方法都有其自身的局限性和潜在危险。体育运动和减少饮食中卡路里的摄入量通常可以显著改善糖尿病的状况，是通常用于Ⅱ型糖尿病和与胰岛素抵抗相关的前糖尿病状况的建议一线疗法。由于不容易改变的习惯的生活方式和食用过量食物，特别是脂肪含量高的食物和碳水化合物，因此该疗法的顺应性非常差，药理学治疗集中于三个病理生理学区域：(1)肝脏葡糖糖生产(双胍)，(2)胰岛素抵抗(PPAR激动剂)，和(3)胰岛素分泌。双胍是一类广泛用于治疗Ⅱ型糖尿病的药物。最熟知的两种双胍—苯乙双胍和二甲双胍能够使得高血糖在某种程度上得到矫正。双胍主要通过抑制肝脏葡萄糖生产而发挥作用，并且还认为他们可以温和的改良胰岛素的敏感性。双胍可以用于单独或者与其他抗糖尿病药物(比如胰岛素或者胰岛素促泌剂)组合使用，不具有增加低血糖的风险。然而，苯乙双胍和二甲双胍可以诱发乳酸中毒和恶心/腹泻。相对于苯乙双胍，二甲双胍具有较低的副作用风险，因此被广泛开在处方中用于治疗Ⅱ型糖尿病。格列酮类药物(即5-苄基噻唑烷-2,4-二酮)是一类能够改善高血糖症和其它Ⅱ型糖尿病症状的较新化合物。当前市售的格列酮(罗格列酮和吡格列酮)是过氧化物酶体增殖剂活化的受体PPARγ亚型的激动剂。PPAR-γ激动剂显著地增强数种Ⅱ型糖尿病动物模型中肌肉、肝脏和脂肪组织中的胰岛素敏感性，从而部分或者完全使得升高的血浆葡萄糖水平恢复正常，不会发生低血糖。另一种广泛应用的药物治疗涉及给药胰岛素促泌剂，比如磺酰脲(例如甲苯磺丁脲和格列甲嗪)。这些药物通过刺激胰腺β-细胞分泌更多胰岛素而升高血浆胰岛素水平。胰腺β细胞中胰岛素分泌受葡萄糖和一系列新陈代谢、神经和激素信号的严格调节。葡萄糖通过代谢以形成AP和其它信号分子而刺激胰岛素形成和分泌，同时其它胞外信号通过胞质膜上GPCR的存在作为胰岛素分泌增效剂或者抑制剂。磺酰脲和相关的胰岛素促泌剂通过阻断β-细胞中ATP依赖性K+通道发挥作用，这使得细胞去极化和开放依赖于电压的Ca2+通道，同时刺激胰岛素释放。该机制是非胰岛素依赖性机制，由此，不论周围葡萄糖水平如何，胰岛素分泌都可以存在。这可以使得胰岛素即使在葡萄糖水平低时都得到分泌，从而导致低血糖，在严重的情形中这可能会是致命的。因此，必须对胰岛素促泌剂的给药进行谨慎控制。通常将胰岛素促泌剂用作治疗Ⅱ型糖尿病的一线药物。G蛋白耦联受体(G Protein-Coupled Receptors，GPCRs),是一大类膜蛋白受体的统称。这类受体的共同点是其立体结构中都有七个跨膜α螺旋，且其肽链的C端和连接第5和第6个跨膜螺旋的胞内环上都有G蛋白(鸟苷酸结合蛋白)的结合位点。G受体偶联蛋白在β细胞上过表达并调节胰岛素的分泌从而改变血浆内葡萄糖水平，这些G蛋白偶联受体能够通过G蛋白的亚型Gs来相对升高体内腺苷-3，5-环化-磷酸(cAMP,一种环状核苷酸),cAMP能够刺激G蛋白耦联受体包括GLP-1，GIP,β2-肾上腺素受体以及GPR119受体。与G蛋白耦联受体相关的疾病为数众多，并且大约40％的现代药物都以G蛋白耦联受体作为靶点。GPR119是存在于Xp26.1染色体的A型视紫红质孤立G蛋白耦联受体，这个受体是同Gs(G蛋白偶联受体的一个亚型)结合，一旦此受体收到刺激，多种细胞中的cAMP水平将会显著地升高包括胰岛瘤中的β细胞。GPR119受体被普遍认为大量存在于胰岛β细胞中，但是特异性胃肠道细胞中也同样存在。GPR119的生物学功能为调节胰岛素分泌的促进肠降血糖和GLP-1的释放。当GPR119b被激动后，与其偶联的G蛋白α亚基与β，γ亚基解离，并分别介导胞内部同信号通路。GPR119的促胰岛素分泌作用呈明显的葡萄糖依赖性。此外，GPR119还可以促进GLP-1的释放，因为DPPV抑制剂减缓GLP-1的失活，两者的协同作用可以使GLP-1在长时间内处于活性状态，从而有效的调节血糖平衡。激动GPR119需要类似于溶血卵凝脂之类的配体，通过刺激体内胰岛胰岛素分泌以及大量胰岛瘤细胞株例如NIT-1和HIT-T15来发挥疗效。一些特异性激动GPR119的化合物被广泛用于治疗炎症，过敏，自身免疫性疾病，代谢紊乱疾病，癌症以及心血管疾病。所以，发现一种具有良好药效学性质的新的GPR119激动剂以及成为目前在糖尿病领域的一个热点，尤其是发现一种特异性的GPR119激动剂，但可惜的是，迄今为止，尚未有发现。
发明内容
本发明的目的之一就在于提供一种苯基嘧啶衍生物。
技术方案是：一种通式(I)化合物、其药物可接受的盐、水合物或前药：
其中：
R1选自H、叔丁氧羰基、C1～C6烷基、C1～C6烷基氧基、C1～C6烷基酯、C2～C6烯基、C2～C6炔基、取代的芳香基、取代的芳香杂环基或取代苯基取代的C1～C6烷基；所述的取代基选自H、C1～C6烷基、卤素取代的C1～C6烷基、C1～C6烷氧基、羟基、-CN、NHCOOR’、COOR’或取代的芳香基，取代的C1～C6烷基；
R2选自H、羟基、卤素、C1～C6烷基、C1～C6烷基氧基或C1～C6烷基酯；
R3选自H、羟基、卤素、C1～C6烷基、C1～C6烷基氧基或C1～C6烷基酯；
R4选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R5选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R6选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R7选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
X选自O、S,N。
作为优选，所述R1选自H、叔丁氧羰基，C1～C6烷基、C1～C6烷基酯、C2～C6烯基、C2～C6炔基或取代的苯基；R2选自H、卤素或甲基；R3选自H、卤素或甲基；R4选自H,或卤素；R5选自H或卤素；R6选自H或卤素；R7选自H或卤素。
作为优选，所述R1选自H、叔丁氧羰基、C1～C6烷基或C1～C6烷基酯；R2选自H或甲基；R3选自H或甲基；R4为H；R5为H；R6为H；R7为H。
作为优选，所述X选自O或N。
作为优选，所述X为O。
本发明的目的之二就在于提供一种苯基嘧啶衍生物的制备方法。
该方法涉及的主要反应式为：
反应条件:(a)碳酸铯,碘化钾,乙腈，600C.(b)四三苯基膦钯，1N碳酸钠饱和溶液，甲苯：乙醇＝1:1，氮气保护，800C。
反应条件:(c)碳酸钾,碘化钾,N,N-二甲基甲酰胺，600C。(d)三氟乙酸，二氯甲烷，室温。(e)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温.。(f)氢化钠，N,N-二甲基甲酰胺，冰浴至室温。
本发明目的之三在于提供了一种药物组合物，是由上述的苯基嘧啶衍生物添加一种或几种药学上可接受的辅料制备而成的。本发明所述的组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。本发明所述的组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。口服组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。以肠胃外给予本发明组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。
技术方案是：一种药物组合物，该药物组合物包括药物可接受的载体以及治疗有效量的上述的通式(I)化合物、其药物可接受的盐、水合物或前药。
本发明的目的之四在于提供一种苯基嘧啶衍生物及其盐、水合物或前药的用途。
技术方案是：一种通式(I)化合物、其药物可接受的盐、水合物或前药，或者上述的药物组合物在制备治疗肥胖、预防肥胖或Ⅱ型糖尿病的药物中的用途。
本发明的有益效果在于：在合成方面合成(1)路线简单易行，原料便宜易得。(2)反应条件温和，后处理方便。在药效方面(1)可以有效地调节甘油三脂,在控制体重方面效果明显，能明显增加体内葡萄糖消耗，提高糖耐量，进而达到预防治疗与肥胖，Ⅱ型糖尿病，以及糖脂紊乱相关疾病的作用。(3)无明显毒副作用。
附图说明
图1为本发明苯基嘧啶衍生物通式；
图2为本发明口服葡萄糖耐量实验(OGTT)；
图3为及静脉葡萄糖耐量实验(IGTT)
其中，Normal表示正常组；HFD(Model)表示高脂饲料诱导组；Met表示二甲双胍；64表示N-叔丁氧羰基-(4-甲基-1-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪；71表示N-丁酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪；Blood Glucose表示血糖；AUC表示峰面积。
具体实施方式
下面将结合附图对本发明作进一步说明。
图1所示的苯基嘧啶衍生物通式是通过以下实施例1-71制取的。
实施例1 Boc-4-(2-氯-5-甲基嘧啶)-哌嗪合成
将100mg(0.61mmol)2,4-二氯五甲基嘧啶与171.39mg(0.92mmol)N-Boc-哌嗪于100mL圆底烧瓶中，加入碳酸钾168.36mg(1.2mol)在50℃下搅拌过夜，将反应溶液倾倒入冰水中，立刻有大量白色固体析出，过滤，用乙醚洗涤2～3次，抽干，得白色固体180.5mg,产率94％。
产物参数如下：1H NMR(400MHz,CDCl3)δ7.94(s,1H),3.82(s,4H),3.50(s,4H),2.25(s,3H),1.43(s,9H).MS(ES),m/z:313.3[M+H]+；HPLC purity:98.0％。
实施例2 N-叔丁氧羰基-4-(2-(4-甲氧基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与106.4mg(0.7mol)对甲氧基基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体110mg,产率44.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.93(d,2H,J＝6.4Hz),7.39(s,1H),7.04(s,1H),3.82(s,3H),3.50(s,8H),2.25(s,3H),1.43(s,9H).MS(ES),m/z:385.3[M+H]+；HPLC purity:98.0％。
实施例3 Boc-4-(2-(4-乙氧基基苯基)-5-甲基嘧啶-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与116.2mg(0.7mol)对乙氧基氧基基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体100.6mg,产率39.4％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.23(d,1H,J＝8.8Hz),7.19(s,1H),6.89(d,1H,J＝8.8Hz),7.04(s,1H),3.91(m,2H),3.52(d,8H,J＝2.8Hz),2.17(s,3H),1.42(s,9H).0.98(m,3H)MS(ES),m/z:395.23[M+H]+；HPLC purity:98.1％。
实施例4 N-叔丁氧羰基-4-(2-(4-氯-3-三氟甲基)苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与156.8mg(0.7mol)4-氯-3-三氟甲基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体72.3mg,产率50.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.22(s,1H),8.96(d,2H,J＝8.8Hz),3.59-3.54(m,4H),3.52-3.49(m,4H),2.24(s,3H),1.50(s,9H).MS(ES),m/z:457.12[M+H]+；HPLC purity:98.4％。
实施例5 N-叔丁氧羰基-4-(2-(5-氟-4-甲基-2-三氟甲基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与154.8mg(0.7mol)4-氟-3-三氟甲基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体120.3mg,产率41.4％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.37(d,2H,J＝8.8Hz),8.31(s,1H),7.67(d,2H,J＝8.8Hz),3.57-3.55(m,4H),3.54-3.50(m,4H),2.30(s,3H),1.49(s,9H).MS(ES),m/z:455.12[M+H]+；HPLC purity:98.2％。
实施例6 N-叔丁氧羰基-4-(2-(4-氰基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与102.83mg(0.7mol)4-氰基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体114.2mg,产率47.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.49(d,2H,J＝8.8Hz),8.29(s,1H),7.75(d,2H,J＝8.8Hz),3.60-3.56(m,4H),3.55-3.50(m,4H),2.29(s,3H),1.50(s,9H).MS(ES),m/z:380.1[M+H]+；HPLC purity:98.7％。
实施例7 N-叔丁氧羰基-4-(2-(2-氟-4-甲氧基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与119mg(0.7mol)2-氟-4-甲氧基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体120.2mg,产率47.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.57(t,1H,J＝8.8Hz),7.13(t,1H,J＝8.8Hz),7.05(d,1H,J＝8.8Hz),3.34(s,3H),3.55-3.52(m,4H),3.51-3.48(m,3H),2.27(s,3H),1.43(s,9H).MS(ES),m/z:403.12[M+H]+；HPLC purity:98.1％。
实施例8 N-叔丁氧羰基-4-(2-吡啶基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与86.03mg(0.7mol)2-吡啶硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体100.9mg,产率44.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ9.57(s,1H),8.66(d,2H,J＝8.0Hz),8.27(s,1H),3.59-3.55(m,4H),3.43-3.40(m,4H),2.32(s,3H),1.50(s,9H).MS(ES),m/z:356.1[M+H]+；HPLC purity:98.9％。
实施例9 N-叔丁氧羰基-4-(2-(3-羟基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与95.9mg(0.7mol)3-羟基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体117.5mg,产率51.7％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.92(d,2H,J＝8.8Hz),7.31(t,1H,J＝8.8Hz),6.94(d,1H,J＝8.8Hz),3.59-3.55(s,4H),3.51-3.48(m,4H),2.24(s,3H),1.50(s,9H).MS(ES),m/z:371.4[M+H]+；HPLC purity:98.1％。
实施例10 N-叔丁氧羰基-4-(2-(4-噻吩基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与89.3mg(0.7mol)3-羟基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体115.2mg,产率50.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.52(t,1H,J＝8.8Hz),8.29(m,2H),7.29(m,2H),3.56-3.54(m,4H),3.51-3.48(m,4H),2.29(s,3H),1.49(s,9H).MS(ES),m/z:361.4[M+H]+；HPLC purity:98.3％。
实施例11 N-叔丁氧羰基-4-(2-(2-氟)-吡啶基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与98.6mg(0.7mol)3-羟基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体121.3mg,产率50.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.90(s,1H),7.40(d,1H,J＝8.8Hz),7.11(m,1H),3.58-3.55(m,4H),3.51-3.48(m,4H),2.29(s,3H),1.49(s,9H).MS(ES),m/z:374.4[M+H]+；HPLC purity:98.7％。
实施例12 N-叔丁氧羰基-4-(2-喹啉基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与121.1mg(0.7mol)3-喹啉硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体124.5mg,产率47.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.13(s,1H),8.32(S,1H),8.18(d,1H,J＝8.8Hz)7.96(d,1H,J＝8.8Hz),7.76(m,1H),3.62-3.59(m,4H),3.58-3.55(m,4H),2.31(s,3H),1.51(s,9H).MS(ES),m/z:406.5[M+H]+；HPLC purity:98.2％。
实施例13 N-叔丁氧羰基-4-(2-(4-羟基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与97.3mg(0.7mol)4-羟基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体130.5mg,产率56.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.16(d,2H,J＝8.8Hz),7.90(s,1H),7.40(d,1H,J＝8.8Hz),3.57-3.52(m,4H),3.50-3.45(m,4H),2.29(s,3H),1.49(s,9H).MS(ES),m/z:374.4[M+H]+；HPLC purity:98.1％。
实施例14 N-叔丁氧羰基-4-(2-(4-醛基苯基)-5-甲基嘧啶)-4-哌嗪合成
将200mg(0.64mol)Boc-4-(2-氯-5-甲基嘧啶)-哌嗪与106.4mg(0.7mol)4-醛基苯硼酸于100mL三颈瓶内，加入四三苯基膦钯60mg,用胶塞封住瓶口，抽真空，并通入氮气，来回换气3～4次，用针孔打入甲苯：乙醇＝1:1溶液4mL,1N碳酸钠溶液1mL,于80摄氏度下搅拌6h,将反应后的溶液悬干拌样，用柱层析纯化，洗脱剂条件：石油醚：乙酸乙酯＝3:1，干燥悬干得白色固体100.5mg,产率41.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.87(s,1H),8.67(d,1H,J＝8.8Hz),8.29(s,1H),7.98(s,1H,J＝8.8Hz),7.62(t,1H,J＝8.8Hz),3.61-3.59(m,4H),3.58-3.55(m,4H),2.29(s,3H),1.50(s,9H).MS(ES),m/z:383.4[M+H]+；HPLC purity:98.2％。
实施例15 N-叔丁氧羰基-4-(2-(4-对甲基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同60.9mg(0.32mmol)对甲基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物100.2mg,产率70.7％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.30(d,2H,J＝8.8Hz),8.23(s,1H),7.06(d,1H,J＝8.8Hz),3.58-3.53(m,4H),3.50-3.45(m,4H),2.44(s,3H),2.26(s,3H),1.49(s,9H).MS(ES),m/z:525.6[M+H]+；HPLC purity:98.4％。
实施例16 N-叔丁氧羰基-4-(2-(2,4-二甲基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同65.4mg(0.32mmol)2,4-二甲基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物110.2mg,产率76.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.29(d,2H,J＝8.8Hz),8.22(s,1H),7.55(d,2H,J＝8.8Hz),7.20(s,1H),7.08(s,2H,J＝8.8Hz),3.57-3.54(m,4H),3.49-3.44(m,4H),2.75(s,3H),2.38(s,3H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:539.6[M+H]+；HPLCpurity:98.5％。
实施例17 N-叔丁氧羰基-4-(2-(4-甲氧基-2-硝基苯基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同80.5mg(0.32mmol)4-甲氧基-2-硝基苯基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物110.2mg,产率76.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.36(d,2H,J＝8.8Hz),8.24(s,1H),7.79(d,1H,J＝8.8Hz),7.25(s,1H),7.02(s,1H,J＝8.8Hz),3.96(s,3H),3.57-3.53(m,4H),3.49-3.45(m,4H),2.26(s,3H),1.49(s,9H).MS(ES),m/z:586.1[M+H]+；HPLC purity:98.7％。
实施例18 N-叔丁氧羰基-4-(2-(4-甲磺酰基-2-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同80.5mg(0.32mmol)4-甲磺酰基-2-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol)乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物112.2mg,产率70.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.36(d,2H,J＝8.8Hz),8.24(s,1H),8.13(d,1H,J＝8.8Hz),8.07(d,1H,J＝8.8Hz),7.07(d,2H,J＝8.8Hz),3.58-3.54(m,4H),3.53-3.49(m,4H),3.11(s,3H),2.27(s,3H),1.49(s,9H).MS(ES),m/z:611.5[M+Na]+；HPLCpurity:98.3％。
实施例19 N-叔丁氧羰基-4-(2-(4-甲磺酰基-4-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同80.5mg(0.32mmol)4-甲磺酰基-4-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物102.2mg,产率68.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.23(s,1H),7.55(d,2H,J＝8.8Hz),7.07(d,2H,J＝8.8Hz),7.01(m,1H),3.96(s,3H),3.59-3.54(m,4H),3.50-3.45(m,4H),2.26(s,3H),1.50(s,9H).MS(ES),m/z:581.4[M+Na]+；HPLC purity:98.3％。
实施例20 N-叔丁氧羰基-4-(2-(4-溴-2-三氟甲基-苯磺酰基苯基-5-甲基嘧
啶)-4哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同103.5mg(0.32mmol)4-溴-2-三氟甲基-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物122.2mg,产率68.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(d,2H,J＝8.8Hz),8.20(s,1H),8.10(s,1H),7.89(d,1H,J＝8.8Hz),7.79(d,1H,J＝8.8Hz),7.13(d,2H,J＝8.8Hz),3.59-3.54(m,4H),3.50-3.45(m,4H),2.28(s,3H),1.49(s,9H).MS(ES),m/z:651.1[M+H]+；HPLCpurity:98.1％。
实施例21 N-叔丁氧羰基-4-(2-(4-噻吩-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同58.4mg(0.32mmol)4-噻吩-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物110.2mg,产率79.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.38(d,2H,J＝8.8Hz),8.29(s,1H),7.74(d,1H,J＝4.0Hz),7.55(d,1H,J＝4.0Hz),7.17(d,2H,J＝8.8Hz),7.11(t,1H,J＝4.0Hz),3.74-3.70(m,4H),3.62-3.57(m,4H),2.33(s,3H),1.50(s,9H).MS(ES),m/z:517.3[M+H]+；HPLC purity:98.3％。
实施例22 N-叔丁氧羰基-4-(2-(3,5-二甲基-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同65.4mg(0.32mmol)3,5-二甲基-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物120.2mg,产率82.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.23(s,1H),7.47(s,2H),7.08(d,1H,J＝8.8Hz),3.58-3.55(m,4H),3.50-3.45(m,4H),2.36(s,6H),2.26(s,3H),1.53(s,9H).MS(ES),m/z:539.6[M+H]+；HPLC purity:98.1％。
实施例23 N-叔丁氧羰基-4-(2-(1,4-二恶英-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同75.1mg(0.32mmol)1,4-二恶英-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物121.2mg,产率78.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.23(s,1H),7.09(d,2H,J＝8.8Hz),6.93(d,1H,J＝8.8Hz),4.33-4.31(m,2H),4.29-4.27(m,2H),3.58-3.56(m,4H),3.51-3.48(m,4H),2.36(s,6H),2.26(s,3H),1.53(s,9H).MS(ES),m/z:569.3[M+H]+；HPLC purity:98.2％。
实施例24 N-叔丁氧羰基-4-(2-(3,5-二甲基-2,3-二氢异恶唑苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同78.2mg(0.32mmol)3,5-二甲基-2,3-二氢异恶唑苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物114.2mg,产率73.4％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.23(s,1H),7.70(d,1H,J＝8.8Hz),7.45(d,1H,J＝8.8Hz),7.06(d,2H,J＝8.8Hz),6.55(d,1H,J＝8.8Hz),3.54-3.52(m,4H),3.51-3.48(m,4H),2.26(s,3H),1.53(s,9H).MS(ES),m/z:579.3[M+H]+；HPLC purity:98.1％。
实施例25 N-叔丁氧羰基-4-(2-(4-N,N二甲基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同45.9mg(0.32mmol)4-N,N二甲基苯磺酰酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物98.2mg,产率76.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.35(d,2H,J＝8.8Hz),8.33(d,2H,J＝8.8Hz),8.24(s,1H),8.06(d,2H,J＝8.8Hz),7.06(d,2H,J＝8.8Hz),3.58-3.55(m,4H),3.50(s,4H),2.26(s,3H),1.48(s,9H).MS(ES),m/z:556.3[M+H]+；HPLC purity:98.7％。
实施例26 N-叔丁氧羰基-4-(2-(4(2,5-二氯噻吩苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同80.32mg(0.32mmol)2,5-二氯噻吩苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物112.2mg,产率72.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.23(s,1H),7.06(d,2H,J＝8.8Hz),7.00(s,1H),3.59-3.56(m,4H),3.50-3.45(s,4H),2.98(s,6H),2.26(s,3H),1.50(s,9H).MS(ES),m/z:586.4[M+H]+；HPLC purity:98.6％。
实施例27 N-叔丁氧羰基-4-(2-(4-硝基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪
合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同70.91mg(0.32mmol)24-硝基苯磺酰酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物114.1mg,产率75.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.35(d,2H,J＝8.8Hz),8.33(d,2H,J＝8.8Hz),8.24(s,1H),8.06(d,2H,J＝8.8Hz),7.06(d,2H,J＝8.8Hz),3.58-3.55(m,4H),3.50(s,4H),2.26(s,3H),1.48(s,9H).MS(ES),m/z:556.3[M+H]+；HPLC purity:98.7％。
实施例28 N-叔丁氧羰基-4-(2-(4-丙基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同45.6mg(0.32mmol)4-丙基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物93.1mg,产率72.7％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.43(d,2H,J＝8.8Hz),8.26(d,2H,J＝8.8Hz),7.36(d,2H,J＝8.8Hz),3.57-3.52(m,8H),3.24(m,2H),2.28(s,3H),1.51(s,9H),1.13(m,2H),0.86(m,3H).MS(ES),m/z:477.3[M+H]+；HPLC purity:98.8％。
实施例29 N-叔丁氧羰基-4-(2-(4-氟苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同62.2mg(0.32mmol)4-氟苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物115.3mg,产率80.7％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.23(s,1H),7.86(t,2H,J＝8.8Hz),7.19(d,2H,J＝8.8Hz),7.05(d,2H,J＝8.8Hz),3.58-3.55(m,4H),3.51-3.47(m,4H),2.26(s,3H),1.49(s,9H).MS(ES),m/z:529.1[M+H]+；HPLC purity:98.5％。
实施例30 N-叔丁氧羰基-4-(2-(4-乙基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同41.1mg(0.32mmol)4-乙基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物98.7mg,产率79.5％。
产物参数如下：。1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.13(s,1H),7.76(t,2H,J＝8.8Hz),7.09(d,2H,J＝8.8Hz),7.25(d,2H,J＝8.8Hz),3.51-3.55(m,4H),3.43-3.49(m,4H),2.21(s,3H),1.59(s,9H)；MS(ES),m/z:515.1[M+H]+；HPLC purity:98.5％.
实施例31 N-叔丁氧羰基-4-(2-(4(2-氟苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同19.3mg(0.32mmol)2-氟苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物68.7mg,产率79.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.23(s,1H),7.86(t,2H,J＝8.8Hz),7.19(d,2H,J＝8.8Hz),7.05(d,2H,J＝8.8Hz),3.58-3.55(m,4H),3.51-3.47(m,4H),2.26(s,3H),1.49(s,9H).MS(ES),m/z:479.5[M+H]+；HPLC purity:98.5％。
实施例32 N-叔丁氧羰基-4-(2-(4(2-氰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同62.7mg(0.32mmol)2-氰基苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物110.2mg,产率84.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.22(s,1H),7.35(t,1H,J＝8.8Hz),7.23(d,1H,J＝8.8Hz),7.02(d,2H,J＝8.8Hz),5.13(s,2H),3.60-3.58(m,4H),3.51-3.49(m,4H),2.24(s,3H),1.49(s,9H).MS(ES),m/z:486.2[M+H]+；HPLCpurity:98.6％。
实施例33 N-叔丁氧羰基-4-(2-(4(3-氟苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同19.3mg(0.32mmol)3-氟苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物70.3mg,产率80.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.36(d,2H,J＝8.8Hz),8.25(s,1H),7.66(t,1H,J＝8.8Hz),7.45(t,1H,J＝8.8Hz),7.08(d,2H,J＝8.8Hz),5.36(s,2H),3.62-3.60(m,4H),3.54-3.52(m,4H),2.27(s,3H),1.52(s,9H).MS(ES),m/z:479.2[M+H]+；HPLCpurity:98.7％。
实施例34 N-叔丁氧羰基-4-(2-(4(4-甲氧基苄基)苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同64.3mg(0.32mmol)4-甲氧基苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物99.3mg,产率75.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.22(s,1H),7.38(d,2H,J＝8.8Hz),7.02(d,2H,J＝8.8Hz),6.92(d,2H,J＝8.8Hz),5.05(s,2H),3.82(s,3H),3.60-3.57(m,4H),3.51-3.48(m,4H),2.24(s,3H),1.49(s,9H).MS(ES),m/z:491.2[M+H]+；HPLC purity:98.7％。
实施例35 N-叔丁氧羰基-4-(2-(4(4-氯苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同65.7mg(0.32mmol)4-氯苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物100.2mg,产率75.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.22(s,1H),8.01(s,1H),7.77(d,1H,J＝8.8Hz),7.38(d,1H,J＝8.8Hz),7.02(d,2H,J＝8.8Hz),5.34(s,2H),3.59-3.57(m,4H),3.51-3.50(m,4H),2.24(s,3H),1.49(s,9H).MS(ES),m/z:495.2[M+H]+；HPLC purity:98.7％。
实施例36 N-叔丁氧羰基-4-(2-(4(3-氯苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同65.7mg(0.32mmol)3-氯苄3-氯苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物101.3mg,产率75.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.22(s,1H),7.40(d,1H,J＝8.8Hz),7.37(d,1H,J＝8.8Hz),7.33(s,1H),7.01(d,2H,J＝8.8Hz),5.09(s,2H),3.60-3.58(m,4H),3.51-3.48(m,4H),2.24(s,3H),1.49(s,9H).MS(ES),m/z:495.4[M+H]+；HPLC purity:98.1％。
实施例37 N-叔丁氧羰基-4-(2-(4(2-三氟甲基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同76.5mg(0.32mmol)2-三氟甲基苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物112.2mg,产率79.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.22(s,1H),7.46(s,1H),7.39(s,1H),7.02(d,2H,J＝8.8Hz),5.10(s,2H),3.60-3.58(m,4H),3.52-3.50(m,4H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:529.2[M+H]+；HPLC purity:98.5％。
实施例38 N-叔丁氧羰基-4-(2-(4(4-溴苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同79.9mg(0.32mmol)4-溴苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物100.3mg,产率69.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(d,2H,J＝8.8Hz),8.22(s,1H),7.52(d,2H,J＝8.8Hz)),7.34(d,2H,J＝8.8Hz),7.02(d,2H,J＝8.8Hz),5.08(s,2H),3.60-3.58(m,4H),3.54-3.52(m,4H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:539.1[M+H]+；HPLCpurity:98.5％。
实施例39 N-叔丁氧羰基-4-(2-(4(2-溴苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同79.5mg(0.32mmol)2-溴苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物98.2mg,产率63.4％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(d,2H,J＝8.8Hz),8.22(s,1H),8.01(s,1H),7.58(t,2H,J＝8.8Hz)),7.34(t,1H,J＝8.8Hz),7.19(t,1H,J＝8.8Hz),7.05(d,2H,J＝8.8Hz),5.20(s,2H),3.59-3.58(m,4H),3.54-3.52(m,4H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:539.1[M+H]+；HPLC purity:98.7％。
实施例40 N-叔丁氧羰基-4-(2-(4-苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同54.7mg(0.32mmol)4-苄基溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物98.3mg,产率79.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.22(s,1H),8.01(s,1H),7.46(t,2H,J＝8.8Hz),7.39(t,1H,J＝8.8Hz),7.04(d,2H,J＝8.8Hz),5.13(s,2H),3.59-3.58(m,4H),3.51-3.50(m,4H),2.24(s,3H),1.49(s,9H).MS(ES),m/z:461.2[M+H]+；HPLC purity:98.04％。
实施例41 N N-叔丁氧羰基-4-(2-(4(4-氟苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同60.4mg(0.32mmol)4-氟苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物98.1mg,产率76.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(d,2H,J＝8.8Hz),8.22(s,1H),7.46(t,2H,J＝8.8Hz),7.57(d,2H,J＝8.8Hz),7.34(t,1H,J＝8.8Hz),7.19(t,2H,J＝8.8Hz),7.05(d,2H,J＝8.8Hz),5.20(s,2H),3.59-3.58(m,4H),3.54-3.52(m,4H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:479.2[M+H]+；HPLC purity:98.6％。
实施例42 N-叔丁氧羰基-4-(2-(4-苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同56.3mg(0.32mmol)4-苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物104.3mg,产率76.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.38(d,2H,J＝8.8Hz),8.25(s,1H),7.46(t,2H,J＝8.8Hz),7.46(d,2H,J＝8.8Hz),7.43(t,1H,J＝8.8Hz),,7.20(d,2H,J＝8.8Hz),5.20(s,2H),3.58-3.55(m,4H),3.54-3.51(m,4H),2.25(s,3H),1.50(s,9H).MS(ES),m/z:511.2[M+H]+；HPLC purity:98.6％。
实施例43 N-叔丁氧羰基-4-(2-(4-环丙磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同44.9mg(0.32mmol)4-环丙磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物101.3mg,产率76.7％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.35(d,2H,J＝8.8Hz),8.19(s,1H),7.31(d,2H,J＝8.8Hz),5.20(s,2H),3.58-3.55(m,4H),3.54-3.51(m,4H),2.20(s,3H),1.41(s,9H).MS(ES),m/z:575.2[M+H]+；HPLC purity:98.4％。
实施例44 N-叔丁氧羰基-4-(2-(4-三氟甲基苯磺酰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同78.3mg(0.32mmol)4-三氟甲基苯磺酰氯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物112.3mg,产率71.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.25(d,2H,J＝8.8Hz),8.16(s,1H),7.90(d,2H,J＝8.8Hz),7.72(d,2H,J＝8.8Hz),6.68(d,2H,J＝8.8Hz),5.20(s,2H),3.52-3.50(m,4H),3.44-3.52(m,4H),2.18(s,3H),1.41(s,9H).MS(ES),m/z:579.2[M+H]+；HPLCpurity:98.6％。
实施例45 N-叔丁氧羰基-4-(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同79.7mg(0.32mmol)4-甲磺酰基苄溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物122.3mg,产率84.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(d,2H,J＝8.8Hz),8.25(s,1H),7.97(d,2H,J＝8.8Hz),7.67(d,2H,J＝8.8Hz),7.02(d,2H,J＝8.8Hz),5.25(s,2H),3.59-3.58(m,4H),3.52-3.50(m,4H),2.25(s,3H),1.49(s,9H).MS(ES),m/z:539.2[M+H]+；HPLCpurity:98.6％。
实施例46 N-叔丁氧羰基-4-(2-(4-乙氧基-4-丁氧羰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同62.4mg(0.32mmol)溴丁酸乙酯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物112.3mg,产率86.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.22(s,1H),6.94(d,2H,J＝8.8Hz),4.18-4.14(m,2H),4.09-4.07(m,2H),3.59-3.58(m,4H),3.52-3.50(m,4H),2.55-2.47(m,2H),2.24(s,3H),2.19-2.10(m,2H),1.50(s,9H).MS(ES),m/z:485.8[M+H]+；HPLC purity:98.4％。
实施例47 N-叔丁氧羰基-4-(2-(1-乙氧基-2-丁氧羰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同62.4mg(0.32mmol)溴异丁酸乙酯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物102.3mg,产率78.6％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.22(s,1H),6.94(d,2H,J＝8.8Hz),4.63(t,1H,J＝4.0Hz),4.26-4.14(m,2H),3.59-3.58(m,4H),3.52-3.50(m,4H),2.24(s,3H),1.50(s,9H),1.12-1.08(m,3H),1.05-1.01(m,2H),0.89-0.84(m,3H).MS(ES),m/z:485.2[M+H]+；HPLC purity:98.5％。
实施例48 N-叔丁氧羰基-4-(2-(4-乙氧基-4-已氧羰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同71.3mg(0.32mmol)溴己酸乙酯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物105.3mg,产率76.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.22(s,1H),6.96(d,2H,J＝8.8Hz),4.67(t,1H,J＝4.0Hz),4.26-4.18(m,2H),3.60-3.58(m,4H),3.53-3.51(m,4H),2.24(s,3H),2.02-1.98(m,2H),1.50(s,9H),1.31-1.22(m,6H),0.95-0.86(m,3H).MS(ES),m/z:535.2[M+Na]+；HPLC purity:98.3％。
实施例49 N-叔丁氧羰基-4-(2-(4-乙氧基-4-丙氧羰基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同58.1mg(0.32mmol)溴丙酸乙酯于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物99.3mg,产率78.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.22(s,1H),6.94(d,2H,J＝8.8Hz),4.82(t,1H,J＝4.0Hz),4.26-4.18(m,2H),3.60-3.58(m,4H),3.53-3.51(m,4H),2.24(s,3H),2.02-1.98(m,2H),1.50(s,9H),1.32-1.28(m,3H),1.25-1.21(m,3H).MS(ES),m/z:471.2[M+H]+；HPLC purity:98.4％。
实施例50 N-叔丁氧羰基-4-(2-(4-丙基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同39.3mg(0.32mmol)溴丙烷于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物88.2mg,产率79.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.24(d,2H,J＝8.8Hz),8.15(s,1H),6.88(d,2H,J＝8.8Hz),3.93-3.89(m,2H),3.52-3.50(m,4H),3.47-3.45(m,4H),2.17(s,3H),1.42(s,9H),0.98-0.95(m,3H).MS(ES),m/z:413.2[M+H]+；HPLC purity:98.5％。
实施例51 N-叔丁氧羰基-4-(2-(4-戊基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同48.3mg(0.32mmol)溴戊烷于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物87.2mg,产率73.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.30(d,2H,J＝8.8Hz),8.22(s,1H),6.95(d,2H,J＝8.8Hz),4.01(t,2H,J＝4.0Hz),3.59-3.58(m,4H),3.51-3.50(m,4H),2.24(s,3H),1.83-1.78(m,2H),1.42(s,9H),1.44-1.37(m,4H),0.96-0.88(m,3H).MS(ES),m/z:441.2[M+H]+；HPLC purity:98.5％。
实施例52 N-叔丁氧羰基-4-(2-(4-异丁基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同43.9mg(0.32mmol)溴异丁烷于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物86.4mg,产率75.1％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.23(d,2H,J＝8.8Hz),8.14(s,1H),6.87(d,2H,J＝8.8Hz),3.71-3.69(m,2H),3.52-3.51(m,4H),3.45-3.43(m,4H),2.16(s,3H),1.42(s,9H),2.06-1.97(m,4H),0.97-0.89(m,3H).MS(ES),m/z:427.2[M+H]+；HPLCpurity:98.1％。
实施例53 N-叔丁氧羰基-4-(2-(4-异丙基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同39.3mg(0.32mmol)溴异丙烷于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物89.4mg,产率79.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.22(s,1H),6.95(d,2H,J＝8.8Hz),4.65-4.62(m,2H),3.60-3.58(m,4H),3.55-3.54(m,4H),2.25(s,3H),1.50(s,9H),1.37(s,3H),1.36(s,3H).MS(ES),m/z:413.2[M+H]+；HPLC purity:98.0％。
实施例54 N-叔丁氧羰基-4-(2-(4-丁基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同43.8mg(0.32mmol)溴丁烷于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物90.3mg,产率78.5％。
产物参数如下：。1H NMR(400MHz,CDCl3)δ8.30(d,2H,J＝8.8Hz),8.22(s,1H),6.95(d,2H,J＝8.8Hz),4.01(t,2H,J＝4.0Hz),3.59-3.58(m,4H),3.51-3.50(m,4H),2.24(s,3H),1.83-1.78(m,2H),1.42(s,9H),1.44-1.37(m,4H),0.96-0.88(m,3H)；MS(ES),m/z:441.2[M+H]+；HPLC purity:98.5％.
实施例55 N-叔丁氧羰基-4-(2-(4-烯丙基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同38.7mg(0.32mmol)烯丙基溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物94.3mg,产率85.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.31(d,2H,J＝8.8Hz),8.22(s,1H),6.97(d,2H,J＝8.8Hz),6.13-6.03(m,1H),5.45(d,1H,J＝12Hz),5.32(d,1H,J＝12Hz),4.60(d,2H,J＝8.0Hz),3.60-3.58(m,4H),3.60-3.58(m,4H),3.51-3.49(m,4H),2.24(s,3H),1.48(s,9H).MS(ES),m/z:411.3[M+H]+；HPLC purity:98.1％。
实施例56 N-叔丁氧羰基-4-(2-(4-炔丙基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同38.0mg(0.32mmol)炔丙基溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物91.3mg,产率83.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.35(d,2H,J＝8.8Hz),8.23(s,1H),7.04(d,2H,J＝8.8Hz),4.75(s,2H),3.60-3.58(m,4H),3.52-3.50(m,4H),2.54-2.52(m,1H),2.25(s,3H),1.48(s,9H).MS(ES),m/z:409.2[M+H]+；HPLC purity:98.5％。
实施例57 N-叔丁氧羰基-4-(2-(4-环戊烷基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.27mmol)Boc-4-(2-(4-羟基苯基)-5-甲基嘧啶-4-哌嗪同47.6mg(0.32mmol)环戊烷溴于25ml圆底烧瓶中，加入碘化钾22.2mg(0.13moL),碳酸铯175.5mg(0.54mmol),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物90.3mg,产率76.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.29(d,2H,J＝8.8Hz),8.21(s,1H),6.92(d,2H,J＝8.8Hz),3.59-3.58(m,4H),3.51-3.48(m,4H),2.24(s,3H),1.92-1.79(m,8H),1.48(s,9H).MS(ES),m/z:439.2[M+H]+；HPLC purity:98.6％。
实施例58 4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶)-4-哌嗪
将100mg(0.18mmol)N-叔丁氧羰基-4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-基)哌嗪于25ml圆底烧瓶中,冰浴下缓缓滴加二氯甲烷：三氟乙酸醋酸混合溶液共4mL,反应过夜后将二氯甲烷与三氟乙酸溶液悬干，加入4mL10％NaOH溶液调至碱性，乙酸乙酯萃取，悬干后得到产物60.6mg,产率76.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(t,2H,J＝8.8Hz),8.18(s,1H),7.97(d,2H,J＝8.0Hz),7.66(d,2H,J＝8.0Hz),7.02(d,2H,J＝8.0Hz),5.23(s,2H),3.54(m,48H),3.05(s,3H),3.03(s,4H).MS(ES),m/z:439.1[M+H]+；HPLC purity:98.5％。
实施例59 ((S)-叔丁氧羰基-(2,3-二甲基-1-(-4-(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,61.1mg(0.26mmol)Boc-L-缬氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体80.4mg,产率56.2％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.25(d,2H,J＝8.8Hz),8.20(s,1H),7.91(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),6.96(d,2H,J＝8.8Hz),5.17(s,2H),4.44(t,1H,J＝4.0Hz),3.76-3.66(m,4H),3.53-3.45(m,4H),3.00(s,3H),2.76-2.73(m,1H),2.19(s,3H),1.37(s,9H),0.93-0.91(m,3H),0.86-0.85(m,3H).MS(ES),m/z:638.4[M+H]+；HPLCpurity:98.3％。
实施例60 N-叔丁氧羰基-吡咯烷-4-(5-甲基-2(4-((4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,48.9mg(0.26mmol)Boc-L-脯氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体86.6mg,产率63.6％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.28(s,2H),8.18(s,1H),7.91(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),6.97(d,2H,J＝8.8Hz),5.17(s,2H),3.73-3.57(m,4H),3.40(t,2H,J＝8.0Hz),3.00(s,3H),2.19(s,3H),1.83(s,2H),1.42-1.35(m,9H),1.14(t,2H,J＝8.0Hz).MS(ES),m/z:636.3[M+H]+；HPLC purity:98.5％。
实施例61 (S)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,48.9mg(0.26mmol)Boc-D-丙氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体78.5mg,产率58.5％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.28(s,2H),8.19(s,1H),7.91(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),6.97(d,2H,J＝8.8Hz),5.17(s,2H),4.61(s,1H),3.77-3.48(m,8H),3.00(s,3H),2.20(s,3H),1.38(m,9H),1.28(d,3H,J＝8.0Hz).MS(ES),m/z:610.4[M+H]+；HPLC purity:98.6％。
实施例62 (R)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶)-4-哌嗪
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,48.9mg(0.26mmol)Boc-L-丙氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体79.5mg,产率59.3％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.32(d,2H,J＝8.8Hz),8.27(s,1H),7.98(d,2H,J＝8.0Hz),7.67(d,2H,J＝8.0Hz),7.03(d,2H,J＝8.8Hz),5.24(s,2H),4.69(t,1H,J＝4.0Hz),3.82-3.74(m,4H),3.69-3.52(m,4H),3.06(s,3H),2.26(s,3H),1.46(s,9H),1.35(d,3H,J＝8.0Hz).MS(ES),m/z:610.3[M+H]+；HPLC purity:98.6％。
实施例63 N-叔丁氧羰基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,30.0mg(0.26mmol)Boc-甘氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体84.2mg,产率61.4％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.26(d,2H,J＝8.8Hz),8.19(s,1H),7.90(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),6.96(d,2H,J＝8.8Hz),5.16(s,2H),3.96(s,2H),3.72(s,2H),3.51(s,4H),3.45(s,2H),2.99(s,3H),2.19(s,3H),1.39(s,9H).MS(ES),m/z:596.1[M+H]+；HPLC purity:98.1％。
实施例64 N-叔丁氧羰基-(4-甲基-1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,50.2mg(0.26mmol)Boc-D-丝氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体79.8mg,产率55.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.26(d,2H,J＝8.8Hz),7.90(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),6.96(d,2H,J＝8.8Hz),5.17(s,2H),3.76-3.46(m,8H),2.99(s,3H),2.18(s,3H),1.77(s,2H),1.37(s,9H),0.95-0.92(m,3H),0.91-0.87(m,3H).MS(ES),m/z:652.4[M+H]+；HPLC purity:98.2％c。
实施例65 ((S)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,55.6mg(0.26mmol)Boc-D-苯丙氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体84.2mg,产率55.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.28(d,2H,J＝8.8Hz),8.21(s,1H),7.98(d,2H,J＝8.0Hz),7.67(d,2H,J＝8.0Hz),7.29-7.21(m,5H),7.03(d,2H,J＝8.8Hz),5.24(s,2H),6.96(d,2H,J＝8.8Hz),5.17(s,2H),3.70-3.31(m,8H),3.17(s,3H),2.18(s,3H),1.43(s,9H).MS(ES),m/z:686.4[M+H]+；HPLC purity:98.9％。
实施例66 (R)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,55.7mg(0.26mmol)Boc-L-苯丙氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体90.2mg,产率59.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.23(t,2H,J＝8.8Hz),8.15(s,1H),7.90(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),7.22-7.12(m,3H),6.96(d,2H,J＝8.8Hz),6.44(d,2H,J＝8.8Hz),5.16(s,2H),2.99(s,8H),2.96(s,3H),2.11(s,3H),1.35(s,9H).MS(ES),m/z:686.5[M+H]+；HPLC purity:98.8％。
实施例67 ((R)-叔丁氧羰基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,54.5mg(0.26mmol)Boc-L-苯甘氨酸,69.4mg(0.44mmol)1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),11.1mg(0.11mmol)4-二氨基吡啶于25ml圆底烧瓶中,加入二氯甲烷10mL,反应12小时后，加水10mL洗涤，合并二氯甲烷层，无水硫酸钠干燥后悬干得棕色固体88.3mg,产率60.0％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.21(t,2H,J＝8.8Hz),8.14(s,1H),7.91(d,2H,J＝8.0Hz),7.60(d,2H,J＝8.0Hz),7.32-7.31(m,3H),6.94(d,2H,J＝8.8Hz),5.16(s,2H),3.84-3.33(m,8H),3.00(s,8H),2.11(s,3H),1.35(s,9H).MS(ES),m/z:672.4[M+H]+；HPLC purity:98.5％。
实施例68 N-异丁基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,31.97mg(0.26mmol)异丁基溴，加入碘化钾22.2mg(0.13moL),碳酸铯169.5mg(0.44moL),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物91.3mg,产率86.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.34(t,2H,J＝8.8Hz),8.18(s,1H),7.97(d,2H,J＝8.0Hz),7.66(d,2H,J＝8.0Hz),7.02(d,2H,J＝8.0Hz),5.23(s,2H),3.54(m,48H),3.05(s,3H),3.03(s,4H),2.24(s,3H),0.93(m,3H).MS(ES),m/z:495.2[M+H]+；HPLCpurity:98.5％。
实施例69 N-乙酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,39.75mg(0.26mmol)溴乙酸乙酯，加入碘化钾22.2mg(0.13moL),碳酸铯169.5mg(0.44moL),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物88.5mg,产率76.9％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(t,2H,J＝8.8Hz),8.18(s,1H),7.97(d,2H,J＝8.0Hz),7.66(d,2H,J＝8.0Hz),7.02((d,2H,J＝8.0Hz),5.23(s,2H),4.20(s,2H),3.63(m,4H),3.28(s,2H),3.06(s,3H),2.75(s,4H),2.23(s,3H),1.29(m,3H).MS(ES),m/z:525.6[M+H]+；HPLC purity:98.1％。
实施例70 N-异丙酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,47.06mg(0.26mmol)溴丙酸乙酯，加入碘化钾22.2mg(0.13moL),碳酸铯169.5mg(0.44moL),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物90.5mg,产率78.6％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.27(t,2H,J＝8.8Hz),8.11(s,1H),7.90(d,2H,J＝8.0Hz),7.59(d,2H,J＝8.0Hz),6.96(d,2H,J＝8.0Hz),5.16(s,2H),4.12(t,2H,J＝8.0Hz),3.55(m,4H),3.29(m,1H),2.99(s,3H),2.73(s,4H),2.17(s,3H),1.29(m,3H),1.21(m,3H).MS(ES),m/z:539.6[M+H]+；HPLC purity:98.2％。
实施例71 N-丁酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪合成
将100mg(0.22mmol)4-(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-)哌嗪,50.7mg(0.26mmol)溴丁酸乙酯，加入碘化钾22.2mg(0.13moL),碳酸铯169.5mg(0.44moL),乙腈10mL，反应12h后，向反应液中加入大量的水,有固体析出，过滤得到产物93.5mg,产率76.8％。
产物参数如下：1H NMR(400MHz,CDCl3)δ8.33(t,2H,J＝8.8Hz),8.20(s,1H),7.97(d,2H,J＝8.0Hz),7.66(d,2H,J＝8.0Hz),7.02(d,2H,J＝8.0Hz),5.23(s,2H),4.14(t,2H,J＝8.0Hz),3.65(m,4H),3.06(s,3H),2.71(s,4H),2.52(s,2H),2.39(m,2H),2.23(s,3H),1.27(m,3H).MS(ES),m/z:553.7[M+H]+；HPLC purity:98.5％。
环式AMP实验：
①验准备-稳定细胞系的产生
将HEK293细胞保持在添加了10％FBS(胎牛血清)，1％抗生素和2mM的L-谷氨酰胺的DMEM培养基中。将细胞用Fugene6(Roche)以含有人GPR119的pcDNA5/FRT载体和pOG44载体的DNA混和物(1:9)转染。在48小时后，将培养基更换为添加了400ug/mL的潮霉素的DMEM培养基以便对稳定转染细胞选择。
②式AMP实验
GPR119激动剂在过表达的人源GPR119的HEK293细胞上进行测定。细胞内环式AMP的改变通过环式AMP荧光测定仪(cAMP dynamic 2 HTRF kit)进行测定.将接种的细胞在含有20mM的HEPES,PH＝7.4，Hank盐平衡溶液，0.01％BSA(牛血清蛋白)，1mM的IBMX(3-异丁基-1-甲基-黄嘌呤)稀释为浓度1mM，以2×103/每孔在384孔板下培养，随后加入500nL待测化合物(待测化合物为上述实施例1-71的产物)。细胞在37℃下孵育45分钟，再向细胞中加入等体积的(20μL)的HTRF试剂，抗-cAMP-Cryptate和cAMP-XL665.室温下孵育1小时后，在HTRF读数仪上读数，并建立标准曲线。测定结果如下表一：
表一
从表一可以看出，上述实施例记载的化合物显示优异的GPR119激动剂作用，其EC50范围在350～10nM之间，并具有明显的构效关系。
小鼠口服/静脉葡萄糖耐量试验(OGTT/IGTT)：
将C57BL/6J小鼠五只一组放入单独的笼子，置于温度，湿度和光线可控的房间(21℃～23℃，12小时-12小时白天-黑夜循环)。他们喂食标准饮食或高脂肪饮食，并可自由饮用水。24天后给予口服和静脉N-叔丁氧羰基-(4-甲基-1-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪(实施例64产物)或N-丁酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪(实施例71产物)，测定体内血糖含量。体内葡萄糖通过在0、30、60和120分钟的血液采集测定。试验结果见图2和图3。
从图2和图3可以看出，N-叔丁氧羰基-(4-甲基-1-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪和N-丁酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶-4-哌嗪在口服葡萄糖耐量实验(OGTT)以及静脉葡萄糖耐量实验(IGTT)中表现出明显的降低小鼠体内葡萄糖效果，其降低低葡萄糖效果明显优于二甲双胍组，试验表明所测试的化合物能明显降低血浆内葡糖糖水平，表明本发明化合物具有治疗糖尿病的潜力。
本发明中所用的仪器来自下表二：
表二
本发明中所用的原料来自：所用试剂纯度为分析纯或者是工业级，高效液相所用试剂为色谱纯，纯化水由Milipore纯化水系统制备，TLC所用硅胶板为青岛海洋化工厂生产的GF254荧光板，硅胶色谱分离所用硅胶是由青岛海洋化工厂生产，目数为300～400目及60～100目。实验中所用到的原料如N-Boc哌嗪，2,4-二氯五甲基嘧啶，EDCI，DMAP，取代磺酰氯，碳酸铯、碘化钾，四三苯基膦吧，取代的苯硼酸均通过成都代理公司购得(原料厂家如成都红胜科技，陕西瑞科，河南伟嘉油脂化学有限公司等)其他溶剂，试剂如二氯甲烷，乙腈。N,N二甲基甲酰胺，无水硫酸钠，乙酸乙酯，石油醚，氢氧化钠，浓盐酸，无水乙醇均在成都金牛恒力有限公司购买。实验中所用到的细胞是从本实验室细胞库获得、牛血清蛋白、培养基从GIBICO BRL公司购得，C57BL/6J小鼠和其所需要的高脂饲料从中国西部动物实验中心购得。
本发明中，如无特别说明，FBS为胎牛血清，DMEM是含氨基酸和葡萄糖的培养基，BSA为牛血清蛋白，HEPES为4-羟乙基哌嗪乙磺酸，IBMX是3-异丁基-1-甲基-黄嘌呤，mM为mmol/L，％为质量百分比。
Claims (10)
1.通式(I)化合物、其药物可接受的盐、水合物或前药：
其中：
R1选自H、叔丁氧羰基、C1～C6烷基、C1～C6烷基氧基、C1～C6烷基酯、C2～C6烯基、C2～C6炔基、取代的芳香基、取代的芳香杂环基或取代苯基取代的C1～C6烷基；所述的取代基选自H、C1～C6烷基、卤素取代的C1～C6烷基、C1～C6烷氧基、羟基、-CN、NHCOOR’、COOR’或取代的芳香基,取代的C1～C6烷基；
R2选自H、羟基、卤素、C1～C6烷基、C1～C6烷基氧基或C1～C6烷基酯；
R3选自H、羟基、卤素、C1～C6烷基、C1～C6烷基氧基或C1～C6烷基酯；
R4选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R5选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R6选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
R7选自H、羟基、卤素、C1～C6烷基氧基或C1～C6烷基酯；
X选自O、S,N。
2.根据权利要求1所述的化合物，其特征在于：所述R1选自H、叔丁氧羰基，C1～C6烷基、C1～C6烷基酯、C2～C6烯基、C2～C6炔基或取代的苯基；R2选自H、卤素或甲基；R3选自H、卤素或甲基；R4选自H,或卤素；R5选自H或卤素；R6选自H或卤素；R7选自H或卤素。
3.根据权利要求2所述的化合物，其特征在于：所述R1选自H、叔丁氧羰基、C1～C6烷基或C1～C6烷基酯；R2选自H或甲基；R3选自H或甲基；R4为H；R5为H；R6为H；R7为H。
4.根据权利要求1-3任一权利要求所述的化合物，其特征在于：所述X选自O或N。
5.根据权利要求4所述的化合物，其特征在于：所述X为O。
6.根据权利要求1所述的化合物，其特征在于：所述化合物选自(S)-叔丁氧羰基-(2,3-二甲基-1-(-4-(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、N-叔丁氧羰基-吡咯烷-4-(5-甲基-2(4-((4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、(S)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、(R)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶)-4-哌嗪、N-叔丁氧羰基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基)苯基-5-甲基嘧啶)-4-哌嗪、N-叔丁氧羰基-(4-甲基-1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、(S)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、(R)-叔丁氧羰基-(1-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、(R)-叔丁氧羰基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、N-异丁基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、N-乙酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、N-异丙酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪、N-丁酸乙酯基-(2-(-4-(5-甲基(2-(4-甲磺酰基苄基苯基-5-甲基嘧啶)-4-哌嗪。
7.一种制备权利要求1-6任一权利要求所述的化合物的方法，该方法包括以下步骤：
①通式II和通式III的化合物反应生成通式IV和通式V的化合物；
②通式IV和通式V的化合物反应生成通式VI的化合物；
③通式VI的化合物反应生成通式VII的化合物；
④通式VVII的化合物反应生成通式VIII的化合物；
⑤通式VIII的化合物反应生成通式I的化合物；
其中a、b、c、d、e分别为各步骤的反应条件，e反应条件为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,4-二甲氨基吡啶,二氯甲烷,室温。
8.一种制备权利要求1-6任一权利要求所述的化合物的方法，该方法包括以下步骤：
①通式II和通式III的化合物反应生成通式IV和通式V的化合物；
②通式IV和通式V的化合物反应生成通式VI的化合物；
③通式VI的化合物反应生成通式VII的化合物；
④通式VVII的化合物反应生成通式VIII的化合物；
⑤通式VIII的化合物反应生成通式I的化合物；
其中a、b、c、d、f分别为各步骤的反应条件，f反应条件为氢化钠，N,N-二甲基甲酰胺，冰浴至室温。
9.一种药物组合物，该药物组合物包括药物可接受的载体以及治疗有效量的权利要求1-6任一权利要求所述的通式(I)化合物、其药物可接受的盐、水合物或前药。
10.权利要求1-6任一权利要求所述的通式(I)化合物、其药物可接受的盐、水合物或前药，或者权利要求9所述的药物组合物在制备治疗肥胖、预防肥胖或Ⅱ型糖尿病的药物中的用途。
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