CN115894373A - N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用 - Google Patents

N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用 Download PDF

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CN115894373A
CN115894373A CN202211323580.9A CN202211323580A CN115894373A CN 115894373 A CN115894373 A CN 115894373A CN 202211323580 A CN202211323580 A CN 202211323580A CN 115894373 A CN115894373 A CN 115894373A
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dmso
nmr
bromophenyl
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陈新
黑晓源
雒智杰
戚颖
钱明成
赵帅
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Changzhou University
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Abstract

本发明属于药物化学领域，涉及N‑取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用。本发明以苯乙酮或不同取代基的苯乙酮为原料，经克莱森缩合反应，成环，再经取代，水解反应，酰胺偶联反应，最终得到一系列新的吡唑类衍生物，结构如式(1)所示，其中R1为氢原子，卤素原子，硝基或甲氧基；R2为氢原子，卤素原子，氰基，硝基或甲氧基；R3为卤素原子。对合成的所有化合物均进行了G蛋白依赖性信号通路的功能活性筛选，发现这些新的衍生物可以作为β2肾上腺素受体的激动剂、别构激动剂(PAM)、拮抗剂、别构拮抗剂(NAM)调节剂。

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N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用
技术领域
本发明属于药物化学领域，特别涉及一种N-取代苄基吡唑类衍生物的制备方法以及其作为β2肾上腺素受体别构调节剂的应用。
背景技术
G蛋白偶联受体(G-protein coupled receptor，GPCR)是一类具有七次跨膜结构的膜受体蛋白,也是关键的药物靶标，目前FDA批准的药物中有超过30％是靶向GPCR的。GPCR可分为六类，但只有四类(A,B,C和F)存在于人类中。其中，A 类(视紫红质)含有最多数量的GPCR(人类中有719个)。大约一半的A类GPCR是涉及气味(信息素受体)或视觉(视紫红质)的感觉受体。肾上腺素受体(AR)是一类A型亚家族的GPCR，在交感神经系统中发挥着重要功能。例如，β1-肾上腺素受体(β1AR)拮抗剂用于心血管疾病，而β2-肾上腺素受体(β2AR)拮抗剂用于治疗哮喘。
现有GPCR类药物中，绝大多数是靶向GPCRs的正构结合位点，在该位点上，内源性配体结合诱导信号转导,这种方法产生的化合物要么直接激活目标GPCR(激动剂)，要么阻断内源性配体的作用(拮抗剂或反向激动剂),因此在不同亚型之间的高度保守给研发选择性药物带来了很大挑战。
别构配体(也称变构配体)是通过与正构配体结合位点在构象上不同而影响受体活性。别构配体通过诱导GPCR蛋白的构象变化来调节其作用，这些变化从变构结合囊转移到正构位点或直接到效应蛋白偶联位点,由于其结合位置保守性相对较低，可能具有更好的亚型选择性。靶向GPCR中的别构类的药物相比传统的药物除了有更好的选择性,还能降低因脱靶效应引起的潜在药物副作用。此外，别构调节剂也可以与正构配体协同作用，能够将受体锁定在特定的构象，从而使得受体表现出特异性的信号转导，进而使得别构调节剂具有不同于正构配体的药效特点。β2AR拮抗剂是非常经典的GPCRs药物，在心力衰竭、高血压、冠心病、心律失常、心绞痛等疾病的治疗中扮演着重要的角色，是治疗心血管类疾病的基石。因此，β2AR别构拮抗剂的开发和设计对各类心血管类疾病的治疗具有重要的意义。
2017年,本实验室同美国杜克大学科学家合作，报道了一个小分子负向别构调节剂化合物15(Cmpd-15，如式2所示),它是第一个2-肾上腺素受体胞内别构拮抗剂(Proc.Natl.Acad.Sci.USA,2017,114:1708-1713；Nature,2017,548:480-484)。不过，由于Cmpd-15是一个肽类化合物，水溶性较差，且生物活性不太高，其结构的相对不稳定性可能会影响其成药性。
Figure BDA0003911528130000021
吡唑(C3H3N2H)是含氮杂环化合物，具有良好的稳定性和广谱药理性质，已成为药物设计中很有吸引力的核心骨架。
本发明为了拓展先导物的结构类型，提高其活性、稳定性和成药性，利用骨架跃迁(Scaffold hopping)策略，将Cmpd-15的肽类核心结构替换为吡唑骨架。基于骨架跃迁策略，保留Cmpd-15三个部位的关键官能团，形成以吡唑为核心结构的杂环衍生物，并评价新杂环衍生物对β2AR的活性和特异性。新杂环衍生物的设计思路如式3所示，将Cmpd-15左侧、中间和右侧的药效团分别连接于吡唑环上，则形成吡唑类(pyrazole type)化合物。预计所设计杂环衍生物的稳定性好于Cmpd-15，有可能提高与β2AR相结合能力，成药性也比较好。
Figure BDA0003911528130000022
考虑到由α-取代苯乙酸制备的酰胺键极易水解，无法稳定存在。于是决定去除酰胺键，连接不同取代基的苄基(式4)，从而使最终目标化合物稳定存在。
Figure BDA0003911528130000031
发明内容
本发明以不同取代基的苯乙酮为原料，经克莱森缩合，成环，再经取代，酯水解和酰胺偶联反应最终得到一系列新的吡唑类衍生物。本发明的目的在于制备N-取代吡唑类衍生物，以开发出化学结构稳定、生物活性高、受体亚型选择性好和水溶性改善的全新杂环衍生物，作为β2-AR的别构调节剂，为研发心脑血管、糖尿病和癌症疾病的新药提供新的方向。
N-取代苄基吡唑环类似物结构：
Figure BDA0003911528130000032
表1 N-取代苄基吡唑类衍生物的结构
Figure BDA0003911528130000033
Figure BDA0003911528130000041
Figure BDA0003911528130000051
N-取代苄基吡唑环衍生物的合成路线：
Figure BDA0003911528130000052
N-取代苄基吡唑类衍生物的具体合成方法步骤如下：
具体合成步骤为：
(1)冰浴下，将取代苯乙酮1和草酸二乙酯溶解在乙醇中，加入乙醇钠后室温反应过夜，生成β-酮酸酯化合物2。苯乙酮1：草酸二乙酯：乙醇钠的摩尔比为1：1.2：3。
(2)冰浴下，将化合物2在肼一水合物的作用下，于乙酸中反应过夜，生成吡唑环结构化合物3。化合物2：肼一水合物的摩尔比为1：1.2。
(3)加热回流条件下，将化合物3，碳酸钾和取代氯化苄溶解于乙腈中，生成化合物4。化合物3：碳酸钾：取代氯化苄的摩尔比为1：1.2：1.3；其中所述取代基氯化苄的取代基R2为卤原子，甲氧基，硝基，氰基等。
(4)在室温下，将化合物4溶解于甲醇中，加入4N氢氧化钠溶液，反应过夜，生成化合物5。
(5)冰浴下，将化合物5和化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(Bioorganic&Medicinal Chemistry,2018,26:2320-2330)在偶联试剂(HOAT，NMM，EDCI)的作用下，于DMF中发生酰胺偶联反应，得到化合物6。化合物5：HOAT：化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺：NMM：EDCI的摩尔比例为1：1.2：1：0.7：1.2。
N-取代苄基吡唑的新衍生物可作为β2-AR的激动剂、拮抗剂、别构激动剂、别构拮抗剂；
进一步，表1中化合物H30、H31、H32有激动活性，可作为β2-AR的激动剂；
进一步，表1中化合物H31同时具有激动活性和别构活性，可作为β2-AR的别构激动剂；
进一步，表1中化合物H2、H3、H5、H6、H8、H9、H10、H11、H12、H17、H22、H23、H34、H35、H54、H55、I2、I4、I6，具有β2AR拮抗作用，可作为β2-AR的拮抗剂；
进一步，表1中化合物H2、H22、H23、H34、H54、H55、I2、I4、I6同时具有拮抗活性和别构活性，可作为β2-AR的别构拮抗剂；
进一步，表1中化合物H2、H4、H7、H13、H16、H22、H23、H24、H25、H26、H27、H28、H29、H31、H33、H34、H37、H38、H43、H44、H45、H46、H47、H48、H49、H50、H51、H52、H53、H54、H55、I2、I3、I4、I6、I7、I8、I9，有别构活性，可以作为β2-AR别构调节剂。
本发明的有益效果为：
N-取代苄基吡唑新衍生物可作为β2-AR的激动剂、拮抗剂、别构激动剂、别构拮抗剂，为研发心脑血管、糖尿病和癌症疾病的新药提供新的方向。
附图说明
图1为H31的结构图和ISO浓度依赖曲线；
图2为化合物H30、H31、H32的EC50曲线。
具体实施方式
N-取代苄基吡唑类衍生物的制备：
实施例1：
Figure BDA0003911528130000071
(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺H1的制备
步骤一：2,4-二氧代-4-苯基丁酸乙酯的制备
冰浴下，将苯乙酮(500mg，3.4mmo1)，草酸二乙酯(0.61Ml，5.2mmol)和乙醇钠(5mL，20％质量含量，0.0lmmol)依次加入反应器中，于乙醇中剧烈搅拌至全部溶解，室温反应过夜。冰浴下，用4N盐酸调pH至2-3，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩得粗产物2,4-二氧代-4-苯基丁酸乙酯。
步骤二：4-苯基吡唑-1-甲酸酯的制备
将步骤一的粗产物溶解在10mL乙酸中，冰浴下缓慢滴加肼一水合物(0.3mL，6.2mmol)，室温反应10h后，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩柱层析纯化(石油醚：乙酸乙酯＝5:1)，得到740.6mg乳白色固体化合物4-苯基吡唑-1-甲酸酯，两步产率共82％。1H NMR(400MHz,CDCl3):δ7.73-7.67(m,2H),7.40-7.29(m,3H),6.97(s,1H),4.17(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H).
步骤三:N-2苄基-苯基吡唑-1-甲酸酯的制备
将苯基吡唑-1-甲酸酯(500mg，2.3mmol)溶解在10mL乙腈中，加入碳酸钾(415.4mg，3mmol)和氯化苄(0.27ml，2.3mmol)，90℃加热至回流，反应12h。乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝50:1)，得到538.4mg白色固体化合物N-2苄基-苯基吡唑-1-甲酸酯，产率为76％。1H NMR(300MHz,DMSO-d6):δ7.90 -7.86(m,2H),7.45-7.40(m,3H),7.37-7.24(m,4H),7.21-7.18(m,2H),5.77(s,2H),4.30(q,J＝7.1Hz,2H),1.28(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO-d6):δ159.0,149.5,137.4,133.5,132.0,128.8,128.6,128.2,127.6,127.0,125.3,108.4,61.1,54.4,14.0.
步骤四：N-2苄基-苯基吡唑-1-羧酸的制备
将N-2苄基-苯基吡唑-1-甲酸酯(538.4mg，1.8mmol)溶解在12mL甲醇中，加入4mL4N氢氧化钠溶液，室温搅拌10h。冰浴条件下加入4N盐酸调pH至4，乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩，得到425.5mg白色固体化合物N-2苄基-苯基吡唑-1-羧酸，产率为87％。
步骤五：(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺的制备
将N-2苄基-苯基吡唑-1-羧酸(30mg，0.1mmol)和HOAT(24.5mg，0.2mmo1)溶解于5mLDMF中，氮气保护下室温搅拌10min后，0℃下加入化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(38.5mg，0.1mmo1)，继续搅拌10min后，0℃下加入N-甲基吗啡啉(0.009mL，008mmol)，搅拌10min，加入EDCI(24.8mg，0.1mmo1)，保持0℃搅拌1h，至室温反应12h。乙酸乙酯(30mL)萃取，用饱和食盐水洗涤有机相，浓缩柱层析(二氯甲烷：甲醇＝40:1)，得到19mg白色固体化合物(S)-1-苄基-N-[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-苯基-1H-吡唑-5-甲酰胺，产率为34％。1HNMR(300MHz,DMSO-d6):δ8.78(d,J＝8.6Hz,1H),8.09(q,J＝4.5Hz,1H),7.76(d,J＝7.2Hz,2H),7.57(s,1H),7.47-7.20(m,10H),7.13-7.11(m,2H),5.73-5.56(m,2H),4.63(ddd,J＝10.4,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H).13C NMR(75MHz,DMSO-d6):δ170.8,159.0,148.9,141.0,137.7,136.4,132.4,132.0,130.2,129.2,128.9,128.4,128.2,128.0,127.3,125.0,121.4,104.9,54.2,53.7,36.9,25.7.HRMS(ESI,m/z):Calcd.forC27H25BrN4O2[M+Na]+539.1059,found:539.1056.
实施例2：
Figure BDA0003911528130000091
(S)-1-苄基-1[3-(3-溴苯基)-1-酰化甲氨基-2-基]-3-邻甲基苯基-1H-吡唑-5-甲酰胺H2的制备
其他条件同实施例1，将苯乙酮改为2-甲基苯乙酮，产物为白色固体，产率为29％。1HNMR(400MHz,DMSO-d6)：δ8.91(dd,J＝34.6,8.7Hz,1H),8.19-8.16(m,1H),7.57-7.45(m,2H),7.37-7.17(m,10H),7.12(d,J＝6.8Hz,2H),5.77-5.60(m,2H),4.63(td,J＝10.8,10.1,6.5Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.94(t,J＝12.2Hz,1H),2.62(d,J＝4.5Hz,3H),2.47(s,3H).13C NMR(75MHz,DMSO-d6)δ170.9,159.1,149.2,141.1,137.8,135.4,135.2,132.0,132.0,131.0,130.2,129.2,128.5,128.3,128.3,127.8,127.4,127.3,126.0,121.4,107.8,54.20,53.6,36.9，25.7,21.2.HRMS(ESI,m/z):Calcd.forC28H27BrN4O2[M+Na]+553.1215,found:553.1210.
实施例3：
Figure BDA0003911528130000092
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H3的制备
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，产物为白色固体，产率为32％。1HNMR(300MHz,DMSO-d6)：δ8.84(d,J＝8.7Hz,1H),8.17(d,J＝4.6Hz,1H),7.59-7.54(m,3H),7.45(s,1H),7.39-7.09(m,10H),5.73-5.55(m,2H),4.63(ddd,J＝10.6,8.6,4.3Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H),2.95(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.5Hz,3H),2.35(s,3H).13C NMR(75MHz,DMSO-d6)：δ170.9,159.0,149.0,141.1,138.0,137.7,136.3,132.3,132.0,130.2,129.2,128.8,128.6,128.4,128.3,127.3,125.5,122.2,121.4,105.1,54.2,53.6,36.9,25.7,21.1.HRMS(ESI,m/z):Calcd.for C28H27BrN4O2[M+Na]+553.1215,found:553.1210.
实施例4：
Figure BDA0003911528130000101
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(对甲苯基)-1H-吡唑-5-甲酰胺H4的制备
其他条件同实施例1，将苯乙酮改为4-甲基苯乙酮，产物为白色固体，产率为34％。1HNMR(400MHz,DMSO-d6)：δ8.78(d,J＝8.6Hz,1H),8.10(d,J＝4.6Hz,1H),7.65(d,J＝8.0Hz,2H),7.57(s,1H),7.37(d,J＝10.3Hz,2H),7.31-7.18(m,7H),7.11(d,J＝6.7Hz,2H),5.71-5.55(m,2H),4.63(ddd,J＝10.7,8.6,4.3Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.7Hz,1H),2.63(d,J＝4.5Hz,3H),2.32(s,3H).13C NMR(75MHz,DMSO-d6)δ170.9,159.1,149.0,141.1,137.8,137.3,136.4,132.0,130.3,129.7,129.5,129.2,128.4,128.3,127.4,125.0,121.4,104.7,54.2,53.6,36.9,25.7,20.8.HRMS(ESI,m/z):Calcd.for C28H27BrN4O2[M+Na]+553.1215,found:553.1210.
实施例5：
Figure BDA0003911528130000102
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-甲氧基苯基)-1H-吡唑-5-甲酰胺H5的制备
其他条件同实施例1，将苯乙酮改为对甲氧基苯乙酮，产物为白色固体，产率为32％。1H NMR(400MHz,DMSO-d6)：δ8.75(d,J＝8.6Hz,1H),8.09(d,J＝4.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.57(s,1H),7.38(d,J＝7.9Hz,1H),7.29-7.19(m,6H),7.11-7.10(m,2H),7.01(d,J＝8.9Hz,2H),5.70-5.54(m,2H),4.62(ddd,J＝10.6,8.5,4.4Hz,1H),3.78(s,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.62(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.9,159.1,159.1,148.8,141.0,137.8,136.3,132.0,130.3,129.2,128.4,128.2,127.3,127.3,126.3,125.1,121.4,114.3,104.4,55.2,54.1,53.5,36.9,25.7.HRMS(ESI,m/z):Calcd.for C28H27BrN4O2[M+Na]+569.1154,found:569.1160.
实施例6：
Figure BDA0003911528130000111
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-氟苯基)-1H-吡唑-5-甲酰胺H6的制备
其他条件同实施例1，将苯乙酮改为2-氟苯乙酮，产物为白色固体，产率为33％。1HNMR(400MHz,DMSO-d6)δ8.93(d,J＝8.6Hz,1H),8.11(d,J＝4.8Hz,1H),7.94(t,J＝6.9Hz,1H),7.56(s,1H),7.45-7.17(m,10H),7.12(d,J＝6.4Hz,2H),5.77-5.61(m,2H),4.64(td,J＝9.4,8.6,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.95(t,J＝12.2Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.9,160.9,158.9,157.6,143.4,141.1,137.6,136.1,,131.9,130.2,129.9,129.8,129.8,129.2,128.4,128.2,127.9,127.4,124.8,121.4,120.1,120.0,116.4,116.2,108.2,108.0,54.2,53.8,36.7,25.7.HRMS(ESI,m/z):Calcd.for C27H24BrFN4O2[M+Na]+557.0964,found:557.0964.
实施例7：
Figure BDA0003911528130000112
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氟苯基)-1H-吡唑-5-甲酰胺H7的制备
其他条件同实施例1，将苯乙酮改为3-氟苯乙酮，产物为白色固体，产率为34％。1HNMR(400MHz,DMSO-d6)δ8.78(d,J＝8.6Hz,1H),8.10(d,J＝4.8Hz,1H),7.65(d,J＝7.9Hz,2H),7.57(s,1H),7.38-7.18(m,9H),7.11(d,J＝6.2Hz,2H),5.71-5.54(m,2H),4.63(ddd,J＝10.7,8.6,4.3Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.7Hz,1H),2.63(d,J＝4.5Hz,3H),2.32(s,3H).13C NMR(75MHz,DMSO-d6)δ170.8,164.2,161.0,158.9,147.9,147.7,141.0,137.5,136.7,134.9,134.8,132.0,131.1,131.0,130.3,129.2,128.4,128.3,127.4,127.4,121.4,121.10,114.9,114.6,111.6,111.3,105.4,54.2,53.8,37.0,25.7.HRMS(ESI,m/z):Calcd.for C27H24BrFN4O2[M+Na]+557.0964,found:557.0964.
实施例8：
Figure BDA0003911528130000121
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氟苯基)-1H-吡唑-5-甲酰胺H8的制备
其他条件同实施例1，将苯乙酮改为4-氟苯乙酮，产物为白色固体，产率为33％。1HNMR(400MHz,DMSO-d6)δ8.78(d,J＝8.6Hz,1H),8.10(d,J＝4.6Hz,1H),7.78(dd,J＝8.7,5.6Hz,2H),7.56(s,1H),7.37(d,J＝8.0Hz,2H),7.30-7.19(m,7H),7.12-7.01(m,2H),5.71-5.55(m,2H),4.63(ddd,J＝10.6,8.6,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ171.3,159.4,148.5,141.5,138.1,137.0,132.4,130.7,129.7,129.5,129.4,128.8,128.7,127.8,127.5,127.4,121.8,116.4,116.1,105.3,54.6,54.1,37.4,26.1.HRMS(ESI,m/z):Calcd.for C27H24BrFN4O2[M+Na]+557.0964,found:557.0964.
实施例9：
Figure BDA0003911528130000122
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氯苯基)-1H-吡唑-5-甲酰胺H9的制备
其他条件同实施例1，将苯乙酮改为3-氯苯乙酮，产物为白色固体，产率为29％。1HNMR(300MHz,DMSO-d6)δ8.78(d,J＝8.7Hz,1H),8.12(d,J＝4.7Hz,1H),7.77(t,J＝1.8Hz,1H),7.71(d,J＝7.6Hz,1H),7.57(s,1H),7.51-7.46(m,2H),7.42-7.36(m,2H),7.31-7.18(m,5H),7.12(dd,J＝7.6,1.9Hz,2H),5.73-5.56(m,2H),4.64(ddd,J＝10.4,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.8,147.5,141.0,137.5,136.7,134.5,133.7,132.0,131.0,130.2,129.2,128.4,128.3,127.8,127.4,124.5,123.5,121.4,105.4,54.2,53.8,37.0,25.7.HRMS(ESI,m/z):Calcd.for C27H24BrClN4O2[M+Na]+573.0669,found:573.0667.
实施例10：
Figure BDA0003911528130000131
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氯苯基)-1H-吡唑-5-甲酰胺H10的制备
其他条件同实施例1，将苯乙酮改为4-氯苯乙酮，产物为白色固体，产率为30％。1HNMR(300MHz,DMSO-d6)δ8.80(d,J＝8.6Hz,1H),8.10(q,J＝4.1Hz,1H),7.78-7.76(m,2H),7.57(s,1H),7.52-7.49(m,2H),7.41-7.36(m,2H),7.31-7.18(m,5H),7.12(dd,J＝7.9,2.1Hz,2H),5.73-5.55(m,2H),4.64(ddd,J＝10.5,8.5,4.4Hz,1H),3.11(dd,J＝13.7,4.4Hz,1H),2.92(dd,J＝13.5,10.7Hz,1H),2.63(d,J＝4.6Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.9,147.8,141.0,137.5,136.6,132.5,132.0,131.3,130.3,129.2,129.0,128.4,128.2,127.4,126.7,121.4,105.1,54.9,54.2,53.7,36.9,25.7.HRMS(ESI,m/z):Calcd.for C27H24BrClN4O2[M+Na]+573.0669,found:573.0667.
实施例11：
Figure BDA0003911528130000132
(S)-1-苄基-3-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H11的制备
其他条件同实施例1，将苯乙酮改为2-溴苯乙酮，产物为白色固体，产率为33％。1HNMR(300MHz,DMSO-d6)δ8.91(d,J＝8.6Hz,1H),8.14(q,J＝4.5Hz,1H),7.74(dd,J＝8.0,1.2Hz,1H),7.66(dd,J＝7.7,1.8Hz,1H),7.56(s,1H),7.48-7.42(m,2H),7.38-7.19(m,7H),7.17-7.12(m,2H),5.75-5.57(m,2H),4.62(ddd,J＝10.6,8.4,4.4Hz,1H),3.09(dd,J＝13.5,4.4Hz,1H),2.94(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.6Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.9,158.9,148.0,141.1,137.6,135.4,133.5,133.4,132.0,131.0,130.2,129.9,129.2,128.4,128.3,127.9,127.4,127.4,121.4,121.0,108.5,54.3,53.8,36.8,25.6.HRMS(ESI,m/z):Calcd.for C27H24Br2N4O2[M+Na]+619.0164,found:619.0147.
实施例12：
Figure BDA0003911528130000141
(S)-1-苄基-3-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H12的制备
其他条件同实施例1，将苯乙酮改为3-溴苯乙酮，产物为白色固体，产率为30％。1HNMR(300MHz,DMSO-d6)δ8.84(d,J＝8.7Hz,1H),8.18(d,J＝4.6Hz,1H),7.91(t,J＝1.6Hz,1H),7.75(d,J＝7.8Hz,1H),7.58-7.52(m,3H),7.44-7.36(m,2H),7.32-7.2(m,5H),7.11(dd,J＝7.5,1.8Hz,2H),5.73-5.56(m,2H),4.64(ddd,J＝10.6,8.6,4.4Hz,1H),3.12(dd,J＝13.6,4.4Hz,1H),2.94(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.8,147.4,141.0,137.5,136.6,134.7,132.0,131.2,130.7,130.3,129.2,128.4,128.3,127.4,123.9,122.3,1214,105.5,54.2,53.8,37.0,25.7.
实施例13：
Figure BDA0003911528130000142
(S)-1-苄基-3-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H13的制备
其他条件同实施例1，将苯乙酮改为4-溴苯乙酮，产物为白色固体，产率为34％。1HNMR(300MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.14(d,J＝4.5Hz,1H),7.72-7.63(m,4H),7.57(s,1H),7.44(s,1H),7.37(d,J＝7.9Hz,1H),7.32-7.17(m,5H),7.13-7.10(m,2H),5.72-5.54(m,2H),4.63(td,J＝9.5,8.6,4.3Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.97-2.88(m,1H),2.62(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.9,147.8,141.0,137.5,136.6,132.0,131.9,131.6,130.2,129.2,128.4,128.2,127.4,127.0,121.4,121.0,105.1,54.2,53.7,36.9,25.7.
实施例14：
Figure BDA0003911528130000151
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-硝基苯基)-1H-吡唑-5-甲酰胺H14的制备
其他条件同实施例1，将苯乙酮改为2-硝基苯乙酮，产物为白色固体，产率为36％。1HNMR(300MHz,DMSO-d6)：δ8.89(d,J＝8.6Hz,1H),8.12(d,J＝4.7Hz,1H),7.88(d,J＝7.9Hz,1H),7.78-7.72(m,2H),7.64-7.54(m,2H),7.37(d,J＝7.9Hz,1H),7.30-7.17(m,6H),7.10-7.07(m,2H),5.61(q,J＝14.7Hz,2H),4.62(dt,J＝13.2,4.6Hz,1H),3.09(dd,J＝13.6,4.5Hz,1H),2.95-2.87(m,1H),2.62(d,J＝4.6Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.6,148.6,144.7,141.0,137.3,136.3,132.5,131.9,130.2,130.1,129.4,129.2,128.3,128.2,127.4,127.4,125.5,123.8,121.4,107.0,54.2,53.9,36.8,25.6.HRMS(ESI,m/z):Calcd.for C27H24BrN5O4[M+Na]+584.0909,found:584.0900.
实施例15：
Figure BDA0003911528130000161
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-硝基苯基)-1H-吡唑-5-甲酰胺H15的制备
其他条件同实施例1，将苯乙酮改为3-硝基苯乙酮，产物为白色固体，产率为34％。1HNMR(300MHz,DMSO-d6)：δ8.87(d,J＝8.7Hz,1H),8.52(t,J＝2.0Hz,1H),8.2-8.13(m,3H),7.75(t,J＝8.0Hz,1H),7.64(s,1H),7.57(d,J＝1.8Hz,1H),7.39-7.36(m,1H),7.32-7.18(m,5H),7.12(dd,J＝7.7,1.9Hz,2H),5.78-5.59(m,2H),4.65(ddd,J＝10.5,8.7,4.4Hz,1H),3.12(dd,J＝13.6,4.5Hz,1H),2.93(dd,J＝13.6,10.5Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.7,148.3,146.9,140.9,137.4,136.9,134.0,132.0,131.1,130.7,130.3,129.2,128.4,128.3,127.5,127.4,122.6,121.4,119.2,105.7,54.2,53.9,37.0,25.7.
实施例16：
Figure BDA0003911528130000162
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-硝基苯基)-1H-吡唑-5-甲酰胺H16的制备
其他条件同实施例1，将苯乙酮改为4-硝基苯乙酮，产物为白色固体，产率为35％。H NMR(300MHz,DMSO-d6)δ8.78(d,J＝8.6Hz,1H),8.12(d,J＝4.7Hz,1H),7.69(d,J＝8.8Hz,2H),7.57(s,1H),7.39-7.18(m,7H),7.11(dd,J＝7.6,1.9Hz,2H),7.01(d,J＝8.8Hz,2H),5.71-5.53(m,2H),4.63(ddd,J＝10.5,8.5,4.3Hz,1H),3.78(s,3H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H)..13C NMR(75MHz,DMSO-d6)δ171.0,159.2,148.9,141.1,137.8,136.4,136.3,132.0,130.3,129.3,128.4,128.3,127.4,126.4,125.1,121.4,114.3,104.4,55.2,53.6,36.9,25.7.
实施例17：
Figure BDA0003911528130000171
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(3-氰基苯基)-1H-吡唑-5-甲酰胺H17的制备
其他条件同实施例1，将苯乙酮改为3-氰基苯乙酮，产物为白色固体，产率为29％。1HNMR(300MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.13-8.06(m,3H),7.81(d,J＝7.7Hz,1H),7.66(t,J＝7.8Hz,1H),7.53(d,J＝17.1Hz,2H),7.39-7.11(m,8H),5.73-5.56(m,2H),4.65(dq,J＝8.7,4.6Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.95-2.87(m,1H),2.63(d,J＝4.2Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.8,147.0,140.9,137.4,136.9,133.6,132.0,131.5,130.3,130.3,129.5,129.3,128.4,128.3,127.4,121.4,118.6,112.1,105.5,54.2,53.9,37.0,25.7.HRMS(ESI,m/z):Calcd.for C28H24BrN5O2[M+Na]+564.1011,found:564.1008.
实施例18：
Figure BDA0003911528130000172
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(4-氰基苯基)-1H-吡唑-5-甲酰胺H18的制备
其他条件同实施例1，将苯乙酮改为4-氰基苯乙酮，产物为白色固体，产率为30％。1HNMR(300MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.11(d,J＝4.7Hz,1H),7.95-7.89(m,4H),7.56(s,1H),7.52(s,1H),7.37(d,J＝7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J＝7.6,2.0Hz,2H),5.74-5.57(m,2H),4.65(dq,J＝10.5,4.5Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.8,147.2,140.9,137.3,136.9,136.7,133.0,132.0,130.3,129.2,128.4,128.3,127.5,127.4,125.6,121.4,118.8,110.2,105.9,54.2,53.9,37.0,25.7.
实施例19：
Figure BDA0003911528130000181
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(2-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H19的制备
其他条件同实施例1，将氯化苄改为2-甲基氯化苄，产物为白色固体，产率为39％。1HNMR(300MHz,DMSO-d6)δ8.78(d,J＝8.6Hz,1H),8.08(d,J＝4.7Hz,1H),7.76(d,J＝7.1Hz,2H),7.56(s,1H),7.44(t,J＝7.1Hz,3H),7.38-7.27(m,3H),7.22-7.09(m,3H),7.02(t,J＝7.2Hz,1H),6.56(d,J＝7.6Hz,1H),5.65(q,J＝15.4Hz,2H),4.60(td,J＝9.4,8.6,4.4Hz,1H),3.09(dd,J＝13.6,4.5Hz,1H),2.91(dd,J＝13.6,10.5Hz,1H),2.62(d,J＝4.2Hz,3H),2.31(s,3H).13C NMR(75MHz,DMSO-d6)δ170.9,159.0,148.8,141.0,136.8,136.3,135.1,132.4,132.0,130.2,129.9,129.2,128.9,128.2,128.0,127.1,126.5,125.9,124.9,121.4,104.9,54.2,51.5,36.9,25.6,18.8.HRMS(ESI,m/z):Calcd.for C28H27BrN4O2[M+Na]+553.1215,found:553.1210.
实施例20：
Figure BDA0003911528130000182
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H20的制备
其他条件同实施例1，将氯化苄改为3-甲基氯化苄，产物为白色固体，产率为39％。1HNMR(300MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.10(d,J＝4.7Hz,1H),7.78-7.75(m,2H),7.58(s,1H),7.47-7.30(m,6H),7.23-7.11(m,2H),7.04(d,J＝7.5Hz,1H),6.96(s,1H),6.89(d,J＝7.6Hz,1H),5.66-5.54(m,2H),4.62(ddd,J＝10.5,8.5,4.4Hz,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H),2.22(s,3H).13CNMR(75MHz,DMSO-d6)δ170.9,159.1,148.8,141.1,137.6,137.5,136.5,132.4,132.0,130.2,129.2,128.9,128.3,128.2,128.0,127.9,125.0,124.5,121.4,104.9,54.2,53.6,36.9,25.6,21.0.
实施例21：
Figure BDA0003911528130000191
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(4-甲基苄基)-3-苯基-1H-吡唑-5-甲酰胺H21的制备
其他条件同实施例1，将氯化苄改为4-甲基氯化苄，产物为白色固体，产率为45％。1HNMR(300MHz,DMSO-d6)δ8.77(d,J＝8.6Hz,1H),8.10(d,J＝4.7Hz,1H),7.76(d,J＝7.1Hz,2H),7.57(s,1H),7.46-7.29(m,6H),7.21(t,J＝7.7Hz,1H),7.05(dd,J＝9.6,4.6Hz,4H),5.67-5.50(m,2H),4.67-4.59(m,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.4Hz,3H),2.23(s,3H).13C NMR(75MHz,DMSO-d6)δ170.9,159.1,148.8,141.0,136.5,136.3,134.7,132.4,132.0,130.3,129.2,128.9,128.2,128.0,127.4,125.0,121.4,104.9,54.2,53.4,36.91,25.7,20.7.
实施例22：
Figure BDA0003911528130000192
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-甲氧基苄基)-3-苯基-1H-吡唑-5-甲酰胺H22的制备
其他条件同实施例1，将氯化苄改为3-甲氧基氯化苄，产物为白色固体，产率为55％。1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.14(d,J＝4.7Hz,1H),7.77(d,J＝7.6Hz,2H),7.57(d,J＝1.9Hz,1H),7.47-7.39(m,3H),7.33(dt,J＝14.4,8.0Hz,3H),7.18(dt,J1＝10.6,J2＝7.8Hz,2H),6.79(dd,J1＝8.1,J2＝2.6Hz,1H),6.71(t,J＝2.0Hz,1H),6.65(d,J＝7.6Hz,1H),5.68-5.55(m,2H),4.63(m,1H),3.67(s,3H),3.11(dd,J1＝13.6,J2＝4.4Hz,1H),2.94(dd,J1＝13.6,J2＝10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.76,158.99,158.83,148.73,140.81,139.03,136.28,132.19,131.80,130.05,129.30,129.04,128.73,128.02,127.83,124.79,121.20,119.19,112.91,112.38,104.78,54.71,54.06,53.39,36.71,25.47.
实施例23：
Figure BDA0003911528130000201
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-甲氧基苄基)-3-苯基-1H-吡唑-5-甲酰胺H23的制备
其他条件同实施例1，将氯化苄改为4-甲氧基氯化苄，产物为白色固体，产率为53％。1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝8.6Hz,1H),8.14(q,J＝4.6Hz,1H),7.85-7.80(m,2H),7.78-7.71(m,2H),7.58(t,J＝1.8Hz,1H),7.37-7.32(m,3H),7.30(s,1H),7.19(s,1H),7.12-7.08(m,2H),6.83-6.79(m,2H),5.62(d,J＝14.4Hz,1H),5.49(d,J＝14.4Hz,1H),4.65(m,1H),3.69(s,5H),3.12(dd,J1＝13.7,J2＝4.4Hz,1H),2.95-2.90(m,1H),2.64(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.99,158.64,132.04,130.31,129.67,129.05,128.93,128.84,128.76,125.17,125.01,121.44,113.84,113.76,55.08,54.26,53.15,25.73.
实施例24：
Figure BDA0003911528130000202
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H24的制备
其他条件同实施例1，将氯化苄改为2-氟氯化苄，产物为白色固体，产率为64％。1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.12(d,J＝4.9Hz,1H),7.76(d,J＝7.6Hz,2H),7.56(s,1H),7.44(m,3H),7.39-7.26(m,4H),7.24-7.12(m,2H),7.06(t,J＝7.5Hz,1H),6.81(t,J＝7.6Hz,1H),5.82-5.61(m,2H),4.62(m,1H),3.11(dd,J1＝13.7,J2＝4.4Hz,1H),2.98-2.86(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.93,158.93,149.18,141.03,136.79,132.34,132.04,130.29,129.27,128.97,128.28,128.13,125.06,124.90,124.54,121.43,115.34,115.13,105.05,54.23,36.98,25.71.
实施例25：
Figure BDA0003911528130000211
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H25的制备
其他条件同实施例1，将氯化苄改为3-氟氯化苄，产物为白色固体，产率为65％。1HNMR(400MHz,DMSO-d6)δ8.83(d,J＝8.7Hz,1H),8.12(d,J＝4.7Hz,1H),7.85-7.73(m,2H),7.57(s,1H),7.51-7.41(m,3H),7.40-7.27(m,4H),7.20(t,J＝7.8Hz,1H),7.07(m,1H),6.97-6.89(m,2H),5.76-5.56(m,2H),4.64(ddd,J1＝10.7,J2＝8.5,J3＝4.4Hz,1H),3.12(dd,J1＝13.6,J2＝4.4Hz,1H),2.94(m,1H),2.64(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.60,163.00,160.58,158.69,148.87,140.74,140.25,140.18,136.26,132.06,131.75,130.17,130.09,129.95,128.96,128.67,127.95,127.82,124.77,123.02,121.13,114.04,113.90,113.68,104.77,53.93,52.93,36.66,25.40.
实施例26：
Figure BDA0003911528130000221
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氟苄基)-3-苯基-1H-吡唑-5-甲酰胺H26的制备
其他条件同实施例1，将氯化苄改为4-氟氯化苄，产物为白色固体，产率为65％。1HNMR(400MHz,DMSO-d6)δ8.81(d,J＝8.6Hz,1H),8.12(q,J＝4.6Hz,1H),7.80-7.73(m,2H),7.57(s,1H),7.44(t,J＝7.6Hz,2H),7.41-7.29(m,4H),7.24-7.16(m,3H),7.12-7.06(m,2H),5.68(d,J＝14.7Hz,1H),5.55(d,J＝14.7Hz,1H),4.64(ddd,J1＝10.7,J2＝8.6,J3＝4.4Hz,1H),3.12(dd,J1＝13.6,J2＝4.4Hz,1H),2.93(m,1H),2.64(d,J＝4.5Hz,3H).13CNMR(101MHz,DMSO-d6)δ170.91,159.04,149.02,141.06,136.36,133.88,132.39,132.03,130.27,129.63,129.55,129.24,128.93,128.28,128.06,125.03,121.41,115.27,115.06,105.02,54.22,25.70.
实施例27：
Figure BDA0003911528130000222
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H27的制备
其他条件同实施例1，将氯化苄改为2-氯代氯化苄，产物为白色固体，产率为68％。1HNMR(400MHz,DMSO-d6)δ8.85(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.79-7.73(m,2H),7.55(s,1H),7.51(s,1H),7.45(dd,J1＝8.4,J2＝7.1Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,2H),7.22-7.13(m,2H),6.53(dd,J1＝7.7,J2＝1.7Hz,1H),5.82-5.64(m,2H),4.59(ddd,J1＝10.6,J2＝8.6,J3＝4.4Hz,1H),3.10(dd,J1＝13.6,J2＝4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.62(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.90,158.79,149.34,140.98,137.05,135.55,132.29,132.03,131.25,130.25,129.25,129.15,128.96,128.91,128.26,128.16,127.82,127.37,125.06,121.41,104.99,54.19,51.72,36.97,25.68.
实施例28：
Figure BDA0003911528130000231
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H28的制备
其他条件同实施例1，将氯化苄改为3-氯代氯化苄，产物为白色固体，产率为67％。1HNMR(400MHz,DMSO-d6)δ8.83(d,J＝8.6Hz,1H),8.10(q,J＝4.5Hz,1H),7.82-7.73(m,2H),7.56(s,1H),7.47-7.41(m,3H),7.38-7.34(m,2H),7.32-7.28(m,3H),7.22-7.17(m,2H),7.06(m,1H),5.69(d,J＝15.0Hz,1H),5.59(d,J＝15.0Hz,1H),4.63(ddd,J1＝10.6,J2＝8.6,J3＝4.4Hz,1H),3.11(dd,J1＝13.6,J2＝4.4Hz,1H),2.94(dd,J1＝14.5,J2＝3.9Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.89,158.98,149.20,141.02,140.16,136.57,133.03,132.03,130.37,129.00,128.25,127.43,127.18,126.00,125.07,121.43,105.08,54.23,36.94,25.72.
实施例29：
Figure BDA0003911528130000232
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氯苄基)-3-苯基-1H-吡唑-5-甲酰胺H29的制备
其他条件同实施例1，将氯化苄改为4-氯代氯化苄，产物为白色固体，产率为70％。1HNMR(400MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.09(q,J＝4.6Hz,1H),7.76(dd,J1＝8.3,J2＝1.3Hz,2H),7.55(d,J＝1.9Hz,1H),7.44(m,3H),7.38-7.27(m,5H),7.20(t,J＝7.8Hz,1H),7.15-7.11(m,2H),5.68(d,J＝14.9Hz,1H),5.56(d,J＝14.9Hz,1H),4.61(ddd,J1＝10.8,J2＝8.7,J3＝4.3Hz,1H),3.10(dd,J1＝13.7,J2＝4.4Hz,1H),2.91(m,1H),2.62(d,J＝4.5Hz,3H).
实施例30：
Figure BDA0003911528130000241
(S)-1-(2-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H30的制备
其他条件同实施例1，将氯化苄改为2-溴氯化苄，产物为白色固体，产率为70％。1HNMR(300MHz,DMSO-d6)δ8.87(d,J＝8.7Hz,1H),8.13(d,J＝4.7Hz,1H),7.78-7.76(m,2H),7.61(dd,J＝7.3,1.9Hz,1H),7.55(s,2H),7.45(t,J＝7.4Hz,2H),7.37-7.16(m,6H),6.45(dd,J＝7.1,2.2Hz,1H),5.69(q,J＝16.0Hz,2H),4.58(ddd,J＝10.5,8.6,4.4Hz,1H),3.10(dd,J＝13.5,4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H).13C NMR(75MHz,DMSO-d6)δ170.8,158.7,149.3,141.0,137.1,137.1,132.4,132.3,132.0,130.2,129.2,129.1,128.9,128.2,128.1,127.9,127.8,125.0,121.4,121.3,105.0,54.9,54.2,36.9,25.6.HRMS(ESI,m/z):Calcd.for C27H24Br2N4O2[M+Na]+619.0164,found:619.0147.
实施例31：
Figure BDA0003911528130000242
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H31的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，产物为白色固体，产率为68％。1HNMR(300MHz,DMSO-d6)δ8.85(d,J＝8.6Hz,1H),8.13(d,J＝4.7Hz,1H),7.77(d,J＝7.0Hz,2H),7.56(s,1H),7.48-7.17(m,10H),7.09(d,J＝7.7Hz,1H),5.74-5.53(m,2H),4.62(ddd,J＝10.6,8.6,4.4Hz,1H),3.12(dd,J＝13.6,4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.9,149.1,141.0,140.4,136.5,132.3,132.0,130.6,130.3,130.2,130.0,129.2,129.0,128.2,128.1,126.4,125.0,121.6,121.4,105.1,54.2,53.1,36.9,25.7.
实施例32：
Figure BDA0003911528130000251
(S)-1-(4-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H32的制备
其他条件同实施例1，将氯化苄改为4-溴氯化苄，产物为白色固体，产率为70％。1HNMR(300MHz,DMSO-d6):δ8.85(d,J＝8.6Hz,1H),8.13(d,J＝4.7Hz,1H),7.77(d,J＝7.0Hz,2H),7.56(s,1H),7.48-7.17(m,10H),7.09(d,J＝7.7Hz,1H),5.74-5.53(m,2H),4.62(ddd,J＝10.6,8.6,4.4Hz,1H),3.12(dd,J＝13.6,4.5Hz,1H),2.93(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6):δ170.8,158.9,149.1,141.0,140.4,136.5,132.3,132.0,130.6,130.3,130.2,130.0,129.2,129.0,128.2,128.1,126.4,125.0,121.6,121.4,105.1,54.2,53.1,36.9,25.7.
实施例33：
Figure BDA0003911528130000252
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-碘苄基)-3-苯基-1H-吡唑-5-甲酰胺H33的制备
其他条件同实施例1，将氯化苄改为3-碘氯化苄，产物为白色固体，产率为71％。1HNMR(400MHz,DMSO-d6)δ8.82(d,J＝8.6Hz,1H),8.11(d,J＝4.6Hz,1H),7.81-7.72(m,2H),7.63-7.52(m,3H),7.45(t,J＝7.6Hz,2H),7.40(s,1H),7.38-7.32(m,2H),7.29(d,J＝7.9Hz,1H),7.20(t,J＝7.8Hz,1H),7.08(m,2H),5.64(d,J＝15.0Hz,1H),5.54(d,J＝14.9Hz,1H),4.62(m,1H),3.11(dd,J1＝13.7,J2＝4.4Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.96,159.04,149.24,141.04,140.30,136.58,136.23,136.00,132.35,132.08,130.72,130.35,129.35,129.04,128.29,128.22,126.81,125.12,121.49,105.11,94.82,54.28,53.03,48.72,36.99,25.80.
实施例34：
Figure BDA0003911528130000261
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H34的制备
其他条件同实施例1，将氯化苄改为2-硝基氯化苄，产物为白色固体，产率为71％。1HNMR(400MHz,DMSO-d6)δ8.83(d,J＝8.7Hz,1H),8.08(dd,J1＝8.0,J2＝1.5Hz,2H),7.82-7.74(m,2H),7.58(m,1H),7.55-7.49(m,3H),7.46(t,J＝7.6Hz,2H),7.38-7.32(m,2H),7.26(d,J＝7.6Hz,1H),7.17(t,J＝7.8Hz,1H),6.64(dd,J1＝7.8,J2＝1.5Hz,1H),6.05(d,J＝16.6Hz,1H),5.93(d,J＝16.6Hz,1H),4.55(ddd,J1＝10.5,J2＝8.6,J3＝4.5Hz,1H),3.09(dd,J1＝13.6,J2＝4.5Hz,1H),2.90(m,1H),2.61(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.79,158.63,149.47,147.34,140.93,136.89,134.13,133.28,132.20,132.00,130.22,129.24,128.99,128.64,128.24,125.09,124.73,121.37,105.23,54.11,51.42,36.95,25.67.
实施例35：
Figure BDA0003911528130000271
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H35的制备
其他条件同实施例1，将氯化苄改为3-硝基氯化苄，产物为白色固体，产率为70％。1HNMR(300MHz,DMSO-d6)δ8.85(d,J＝8.7Hz,1H),8.14-8.10(m,2H),8.02(d,J＝1.6Hz,1H),7.80-7.77(m,2H),7.61–7.52(m,3H),7.48-7.43(m,3H),7.38-7.27(m,3H),7.18(t,J＝7.7Hz,1H),5.85-5.69(m,2H),4.65-4.57(m,1H),3.10(dd,J＝13.6,4.4Hz,1H),2.91(dd,J＝13.6,10.7Hz,1H),2.62(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.9,149.3,147.7,141.0,139.9,136.6,134.0,132.2,132.0,130.2,130.0,129.2,129.0,128.2,125.1,122.4,122.0,121.4,105.2,54.2,53.1,36.9,25.6.HRMS(ESI,m/z):Calcd.for C27H24BrN5O4[M+Na]+584.0909,found:584.0900.
实施例36：
Figure BDA0003911528130000272
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-硝基苄基)-3-苯基-1H-吡唑-5-甲酰胺H36的制备
其他条件同实施例1，将氯化苄改为4-硝基氯化苄，产物为白色固体，产率为72％。1HNMR(300MHz,DMSO-d6):δ8.83(d,J＝8.7Hz,1H),8.09-8.06(m,2H),7.78-7.76(m,2H),7.62-7.43(m,6H),7.36(t,J＝7.3Hz,2H),7.26(d,J＝7.7Hz,1H),7.17(t,J＝7.7Hz,1H),6.65-6.62(m,1H),6.07-5.89(m,2H),4.55(ddd,J＝10.4,8.6,4.5Hz,1H),3.09(dd,J＝13.6,4.5Hz,1H),2.90(dd,J＝13.6,10.5Hz,1H),2.60(d,J＝4.5Hz,3H).13C NMR(75MHz,DMSO-d6):δ170.7,158.6,149.4,147.3,140.9,136.9,134.1,133.3,132.3,132.0 130.2,129.2,129.0,128.6,128.2,125.1,124.7,121.3,105.2,54.1,51.4,36.9,25.6.
实施例37：
Figure BDA0003911528130000281
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(2-氰基苄基)-3-苯基-1H-吡唑-5-甲酰胺H37的制备
其他条件同实施例1，将氯化苄改为2-氰基氯化苄，产物为白色固体，产率为74％。1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝8.7Hz,1H),8.09(q,J＝4.6Hz,1H),7.86-7.72(m,3H),7.58-7.41(m,6H),7.35(m,2H),7.28(d,J＝7.8Hz,1H),7.18(t,J＝7.8Hz,1H),6.85(d,J＝7.9Hz,1H),5.91(d,J＝15.7Hz,1H),5.79(d,J＝15.7Hz,1H),4.61(ddd,J1＝10.5,J2＝8.6,J3＝4.4Hz,1H),3.11(dd,J1＝13.6,J2＝4.5Hz,1H),2.91(m,1H),2.62(d,J＝4.5Hz,3H).13CNMR(101MHz,DMSO-d6)δ170.94,158.87,149.52,141.21,141.01,136.77,133.63,133.06,132.23,132.08,130.34,129.33,129.07,128.34,127.43,125.16,121.46,117.32,110.44,105.24,54.22,52.23,37.01,25.78.
实施例38：
Figure BDA0003911528130000282
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(4-氰基苄基)-3-苯基-1H-吡唑-5-甲酰胺H38的制备
其他条件同实施例1，将氯化苄改为4-氰基氯化苄，产物为白色固体，产率为73％。1HNMR(300MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.11(d,J＝4.7Hz,1H),7.95-7.89(m,4H),7.56(s,1H),7.52(s,1H),7.37(d,J＝7.8,2.1Hz,1H),7.31-7.18(m,5H),7.12(dd,J＝7.6,2.0Hz,2H),5.74-5.57(m,2H),4.65(dq,J＝10.5,4.5Hz,1H),3.11(dd,J＝13.6,4.5Hz,1H),2.91(dd,J＝13.6,10.6Hz,1H),2.63(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.83,158.82,149.32,143.36,140.99,136.60,132.39,132.24,131.99,130.24,129.21,128.95,128.26,128.16,127.93,127.62,127.00,125.06,121.38,118.74,110.15,105.10,54.18,53.53,36.93,25.68.
实施例39：
Figure BDA0003911528130000291
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H39的制备
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为3-甲基氯化苄，得到30mg白色固体化合物，产率为34％。1H NMR(300MHz,DMSO-d6)：δ8.78(d,J＝8.5Hz,1H),8.11(d,J＝4.4Hz,1H),7.56(d,J＝14.6Hz,3H),7.39-7.30(m,4H),7.23-7.12(m,3H),7.03(d,J＝7.3Hz,1H),6.95(s,1H),6.88(d,J＝7.5Hz,1H),5.66-5.54(m,2H),4.63(dq,J＝9.0,4.5Hz,1H),3.10(dd,J＝13.6,4.1Hz,1H),2.93(t,J＝12.0Hz,1H),2.63(d,J＝4.4Hz,3H),2.35(s,3H),2.22(s,3H).13C NMR(75MHz,DMSO-d6)：δ170.9,159.1,148.9,141.1,138.0,137.7,137.5136.4,132.4,132.0,130.3,129.2,128.8,128.6,128.3,128.2,128.0,127.9,125.5,124.4,122.2,121.4,105.0,54.2,53.6,36.9,25.7,21.1,21.0.HRMS(ESI,m/z):Calcd.for C29H29BrN4O2[M+Na]+631.0320,found:631.0313.
实施例40：
Figure BDA0003911528130000301
(S)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(4-甲基苄基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H40的制备
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为4-甲基氯化苄，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)：δ8.80(d,J＝8.6Hz,1H),8.14(d,J＝4.6Hz,1H),7.58-7.53(m,3H),7.40-7.30(m,4H),7.23-7.13(m,2H),7.03(q,J＝8.1Hz,4H),5.66-5.50(m,2H),4.63(ddd,J＝10.7,8.5,4.4Hz,1H),3.11(dd,J＝13.6,4.3Hz,1H),2.97-2.89(m,1H),2.63(d,J＝4.4Hz,3H),2.35(s,3H),2.23(s,3H).13C NMR(75MHz,DMSO-d6)：δ170.9,159.0,148.9,141.1,138.0,136.5,136.3,134.7,132.4,132.0,130.2,129.2,128.9,128.8,128.6,128.2,127.4,125.5,122.2,121.4,105.0,54.2,53.4,36.9,25.7,21.1,20.7.
实施例41：
Figure BDA0003911528130000302
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H41的制备
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝8.6Hz,1H),8.13(q,J＝4.5Hz,1H),7.66(t,J＝8.2Hz,3H),7.45-7.42(m,2H),7.38-7.15(m,7H),7.08(d,J＝7.9Hz,1H),5.71-5.55(m,2H),4.62(ddd,J＝10.4,8.5,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.93(dd,J＝13.5,10.7Hz,1H),2.63(d,J＝4.6Hz,3H),2.35(s,3H).13C NMR(75MHz,DMSO-d6)δ170.8,158.9,149.2,141.0,140.4,138.0,136.4,132.2,132.0,130.6,130.2,130.0,129.2,128.9,128.8,128.2,126.3,125.6,122.2,121.6,121.4,105.1,54.2,53.0,36.9,25.7,21.1.
实施例42：
Figure BDA0003911528130000311
(S)-1-(4-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(间甲苯基)-1H-吡唑-5-甲酰胺H42的制备
其他条件同实施例1，将苯乙酮改为3-甲基苯乙酮，氯化苄改为4-溴氯化苄，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)δ8.79(d,J＝8.6Hz,1H),8.11(d,J＝4.6Hz,1H),7.56(t,J＝8.7Hz,3H),7.47-7.42(m,3H),7.38-7.28(m,3H),7.22-7.14(m,2H),7.06(d,J＝8.4Hz,2H),5.69-5.51(m,2H),4.62(ddd,J＝10.6,8.6,4.4Hz,1H),3.11(dd,J＝13.6,4.4Hz,1H),2.92(dd,J＝13.0,10.1Hz,1H),2.62(d,J＝4.5Hz,3H),2.35(s,3H).13C NMR(75MHz,DMSO-d6)δ171.3,159.4,149.6,141.5,138.5,137.6,136.8,132.7,132.4,131.7,130.7,130.0,129.7,129.3,129.2,128.7,126.0,122.6,121.8,121.0,105.5,54.6,53.6,37.4,26.1,21.5.
实施例43：
Figure BDA0003911528130000312
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(4-氟苯基)-1H-吡唑-5-甲酰胺H43的制备
其他条件同实施例1，将苯乙酮改为4-氟苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.83(d,J＝8.6Hz,1H),8.12(q,J＝4.6Hz,1H),7.79(dd,J1＝8.6,J2＝5.7Hz,2H),7.56(s,1H),7.45 -7.33(m,4H),7.32-7.17(m,5H),7.09(d,J＝7.7Hz,1H),5.67(d,J＝15.1Hz,1H),5.57(d,J＝15.0Hz,1H),4.63(ddd,J1＝10.6,J2＝8.5,J3＝4.4Hz,1H),3.11(dd,J1＝13.6,J2＝4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.87,158.93,148.34,140.99,140.33,136.66,132.03,130.66,130.35,130.28,130.11,129.29,128.25,127.14,127.06,126.41,121.63,121.44,116.02,115.81,104.98,54.23,53.10,36.96,25.72.
实施例44：
Figure BDA0003911528130000321
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(2-氯苯基)-1H-吡唑-5-甲酰胺H44的制备
其他条件同实施例1，将苯乙酮改为2-氯苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.95(d,J＝8.6Hz,1H),8.12(q,J＝4.5Hz,1H),7.80-7.75(m,1H),7.58-7.53(m,3H),7.46-7.43(m,1H),7.42-7.33(m,4H),7.30(dt,J1＝7.7,J2＝1.3Hz,1H),7.24(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.11(dt,J1＝7.9,J2＝1.3Hz,1H),5.67(q,J＝14.9Hz,2H),4.63(ddd,J1＝10.7,J2＝8.6,J3＝4.4Hz,1H),3.10(dd,J1＝13.6,J2＝4.4Hz,1H),2.94(m,1H),2.63(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.90,158.85,146.71,141.07,140.20,135.63,131.99,131.05,131.00,130.62,130.38,130.33,130.18,129.70,129.24,128.22,127.47,126.46,121.60,121.39,108.68,54.26,53.16,36.77,25.68.
实施例45：
Figure BDA0003911528130000331
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-(3-氯苯基)-1H-吡唑-5-甲酰胺H45的制备
其他条件同实施例1，将苯乙酮改为3-氯苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.81(d,J＝8.6Hz,1H),8.12(q,J＝4.5Hz,1H),7.78(t,J＝1.9Hz,1H),7.72(dt,J1＝7.9,J2＝1.4Hz,1H),7.56(t,J＝1.8Hz,1H),7.52-7.46(m,2H),7.46-7.39(m,2H),7.36(m,2H),7.31-7.27(m,1H),7.22(dt,J1＝15.6,J2＝7.8Hz,2H),7.11-7.07(m,1H),5.73-5.54(m,2H),4.64(ddd,J1＝10.5,J2＝8.6,J3＝4.5Hz,1H),3.11(dd,J1＝13.6,J2＝4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H).13CNMR(101MHz,DMSO-d6)δ170.76,158.77,147.75,140.92,140.15,136.74,134.36,133.75,132.01,130.99,130.65,130.36,130.26,130.10,129.26,128.22,127.89,126.40,124.61,123.58,121.61,121.40,105.49,54.19,53.19,25.68.
实施例46：
Figure BDA0003911528130000332
(S)-1-(3-溴苄基)-3-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H46的制备
其他条件同实施例1，将苯乙酮改为2-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)：δ8.92(d,J＝8.6Hz,1H),8.12(q,J＝4.5Hz,1H),7.74(dd,J1＝8.0,J2＝1.2Hz,1H),7.65(dd,J1＝7.8,J2＝1.8Hz,1H),7.55(t,J＝1.8Hz,1H),7.48-7.42(m,3H),7.39-7.28(m,4H),7.25(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.12(dt,J1＝7.9,J2＝1.3Hz,1H),5.66(q,J＝15.0Hz,2H),4.62(ddd,J1＝10.7,J2＝8.5,J3＝4.4Hz,1H),3.09(dd,J1＝13.6,J2＝4.4Hz,1H),2.93(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.91,158.86,148.33,141.07,140.23,135.46,133.56,133.32,131.99,131.01,130.62,130.33,130.18,130.03,129.26,128.24,127.97,126.46,121.61,121.40,121.09,108.56,54.30,25.69.
实施例47：
Figure BDA0003911528130000341
(S)-1-(3-溴苄基)-3-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H47的制备
其他条件同实施例1，将苯乙酮改为3-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝8.7Hz,1H),8.11(q,J＝4.5Hz,1H),7.92(t,J＝1.8Hz,1H),7.76(dt,J＝7.8,1.3Hz,1H),7.55(m,2H),7.49(s,1H),7.46-7.40(m,2H),7.36(m,2H),7.29(dt,J1＝7.7,J2＝1.4Hz,1H),7.22(dt,J1＝15.8,J2＝7.8Hz,2H),7.11-7.07(m,1H),5.68(d,J＝15.0Hz,1H),5.58(d,J＝15.0Hz,1H),4.63(ddd,J1＝10.4,J2＝8.5,J3＝4.5Hz,1H),3.11(dd,J1＝13.6,J2＝4.5Hz,1H),2.91(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.74,158.74,147.63,140.91,140.15,136.72,134.57,132.01,131.26,130.78,130.65,130.36,130.26,130.09,129.25,128.21,127.48,126.39,123.93,122.31,121.60,121.39,105.48,54.17,53.17,36.98,25.67.
实施例48：
Figure BDA0003911528130000351
(S)-1-(3-溴苄基)-3-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1H-吡唑-5-甲酰胺H48的制备
其他条件同实施例1，将苯乙酮改为4-溴苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝8.6Hz,1H),8.11(q,J＝4.5Hz,1H),7.71(d,J＝8.5Hz,2H),7.65(d,J＝8.6Hz,2H),7.56(t,J＝1.8Hz,1H),7.44(m,2H),7.38-7.33(m,2H),7.29(d,J＝7.6Hz,1H),7.22(dt,J1＝15.5,J2＝7.8Hz,2H),7.09(d,J＝7.7Hz,1H),5.68(d,J＝14.9Hz,1H),5.57(d,J＝15.0Hz,1H),4.63(ddd,J1＝10.6,J2＝8.6,J3＝4.5Hz,1H),3.11(dd,J1＝13.7,J2＝4.5Hz,1H),2.92(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.79,158.82,148.09,140.96,140.20,136.71,132.00,131.94,131.51,130.64,130.35,130.24,130.11,129.25,128.21,127.02,126.41,121.60,121.40,121.18,105.19,54.20,53.13,36.94,25.68.
实施例49：
Figure BDA0003911528130000352
(S)-1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-(2-硝基苯基)-1H-吡唑-5-甲酰胺H49的制备
其他条件同实施例1，将苯乙酮改为2-硝基苯乙酮，氯化苄改为3-溴氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝8.6Hz,1H),8.11(q,J＝4.5Hz,1H),7.89(dd,J1＝8.0,J2＝1.1Hz,1H),7.79-7.71(m,2H),7.62(ddd,J1＝8.5,J2＝6.9,J3＝2.0Hz,1H),7.53(t,J＝1.8Hz,1H),7.44(dt,J1＝8.0,J2＝1.5Hz,1H),7.36(dt,J1＝8.0,J2＝1.5Hz,1H),7.31-7.16(m,5H),7.05(d,J＝7.7Hz,1H),5.60(q,J＝15.0Hz,2H),4.60(ddd,J1＝10.5,J2＝8.5,J3＝4.5Hz,1H),3.09(dd,J1＝13.7,J2＝4.6Hz,1H),2.90(m,1H),2.62(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.78,158.53,148.62,144.94,140.95,139.93,136.32,132.51,131.94,130.53,130.37,130.22,130.15,130.06,129.49,129.26,128.21,126.33,125.42,123.89,121.63,121.39,107.08,54.23,53.31,36.83,25.66.
实施例50：
Figure BDA0003911528130000361
(S)-1-(3-溴苄基)-N-(3-(3,5-二溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H50的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为76％。1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.78-7.75(m,2H),7.63(t,J＝1.8Hz,1H),7.57(d,J＝1.8Hz,2H),7.48-7.40(m,4H),7.37-7.31(m,2H),7.23(t,J＝7.8Hz,1H),7.08(d,J＝7.9Hz,1H),5.69(d,J＝15.0Hz,1H),5.57(d,J＝15.0Hz,1H),4.62(ddd,J1＝10.7,J2＝8.6,J3＝4.4Hz,1H),3.11(dd,J1＝13.5,J2＝4.4Hz,1H),2.91(m,1H),2.63(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.59,158.95,149.18,143.00,140.33,136.47,132.27,131.33,130.60,130.30,130.06,128.98,128.12,126.31,125.00,122.05,121.60,105.01,53.94,53.08,36.59,25.68.
实施例51：
Figure BDA0003911528130000371
(S)-1-(3-溴苄基)-N-(3-(3,5-二氯苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H51的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二氯苯基)-N-甲基丙酰胺，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)：δ8.85(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.79-7.73(m,2H),7.48-7.44(m,2H),7.43(d,J＝4.3Hz,2H),7.39(q,J＝1.7Hz,3H),7.37-7.32(m,2H),7.23(t,J＝7.8Hz,1H),7.08(d,J＝7.7Hz,1H),5.69(d,J＝15.0Hz,1H),5.57(d,J＝15.0Hz,1H),4.64(ddd,J1＝10.7,J2＝8.7,J3＝4.4Hz,1H),3.13(dd,J1＝13.6,J2＝4.5Hz,1H),2.93(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.60,158.94,149.18,142.48,140.35,136.45,133.57,132.27,130.60,130.30,130.04,128.98,128.10,126.29,126.12,125.00,121.60,105.02,53.87,53.09,36.66,25.68.
实施例52：
Figure BDA0003911528130000372
(S)-1-(3-溴苄基)-N-(3-(3,5-二氟苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H52的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3,5-二氟苯基)-N-甲基丙酰胺，产物为白色固体，产率为72％。1H NMR(400MHz,DMSO-d6)δ8.83(d,J＝8.7Hz,1H),8.10(q,J＝4.6Hz,1H),7.79-7.74(m,2H),7.49-7.42(m,4H),7.38-7.31(m,2H),7.23(t,J＝7.8Hz,1H),7.09(dt,J1＝7.8,J2＝1.3Hz,1H),7.06-6.97(m,3H),5.76-5.69(m,1H),5.60(d,J＝15.0Hz,1H),4.67(ddd,J1＝10.6,J2＝8.6,J3＝4.5Hz,1H),3.15(dd,J1＝13.6,J2＝4.5Hz,1H),2.96(m,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.64,158.91,149.18,140.37,136.39,132.26,130.59,130.30,130.04,128.98,128.14,126.29,125.01,121.60,112.42,112.17,105.03,53.89,53.11,25.69.
实施例53：
Figure BDA0003911528130000381
(S)-N-(3-(3-溴-5-氟苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1-(3-溴苄基)-3-苯基-1H-吡唑-5-甲酰胺H53的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(3-溴-5-氟苯基)-N-甲基丙酰胺，产物为白色固体，产率为74％。1H NMR(400MHz,DMSO-d6)：δ8.84(d,J＝8.7Hz,1H),8.11(q,J＝4.6Hz,1H),7.79-7.74(m,2H),7.48–7.40(m,5H),7.38-7.31(m,3H),7.28-7.16(m,2H),7.09(d,J＝8.0Hz,1H),5.70(d,J＝15.0Hz,1H),5.59(d,J＝15.0Hz,1H),4.65(ddd,J1＝10.6,J2＝8.6,J3＝4.5Hz,1H),3.14(dd,J1＝13.6,J2＝4.5Hz,1H),2.94(m,1H),2.63(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.62,158.94,149.18,140.35,136.44,132.27,130.60,130.30,130.05,128.97,126.30,125.01,121.60,105.03,53.92,53.10,36.71,25.69.
实施例54：
Figure BDA0003911528130000391
(S)-1-(3-溴苄基)-N-(3-(2-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H54的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(2-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为66％。1H NMR(400MHz,DMSO-d6)：δ8.85(d,J＝8.7Hz,1H),8.01(q,J＝4.5Hz,1H),7.80-7.74(m,2H),7.55(dd,J1＝8.0,J2＝1.3Hz,1H),7.45(m,4H),7.39-7.31(m,3H),7.29-7.17(m,2H),7.11(m,2H),5.71(d,J＝15.0Hz,1H),5.58(d,J＝14.9Hz,1H),4.77(m,1H),3.05(dd,J1＝14.1,J2＝10.2Hz 1H),2.62(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.55,158.90,149.16,140.42,137.09,136.45,132.48,132.29,131.34,130.65,130.30,130.04,128.97,128.62,128.13,127.43,126.42,125.06,124.27,121.62,105.13,53.10,52.17,37.48,25.88.
实施例55：
Figure BDA0003911528130000392
(S)-1-(3-溴苄基)-N-(3-(4-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H55的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物(S)-2-氨基-3-(4-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为70％。1H NMR(400MHz,DMSO-d6)：δ8.82(d,J＝8.6Hz,1H),8.10(q,J＝4.6Hz,1H),7.80-7.74(m,2H),7.44(m,6H),7.38-7.31(m,2H),7.28-7.20(m,3H),7.11-7.05(m,1H),5.70(d,J＝15.1Hz,1H),5.60(d,J＝15.0Hz,1H),4.63(ddd,J1＝10.4,J2＝8.5,J3＝4.5Hz,1H),3.09(dd,J1＝13.7,J2＝4.5Hz,1H),2.92(m,1H),2.62(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)：δ170.87,158.93,149.17,140.41,137.61,136.51,132.29,131.36,131.01,130.63,130.27,130.02,128.94,128.11,126.32,125.07,121.61,119.58,105.09,54.20,25.69.
实施例56：
Figure BDA0003911528130000401
1-(3-溴苄基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-3-苯基-1H-吡唑-5-甲酰胺H56的制备
其他条件同实施例1，将氯化苄改为3-溴氯化苄，将化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺改为化合物2-氨基-3-(3-溴苯基)-N-甲基丙酰胺，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.83(d,J＝8.6Hz,1H),8.10(d,J＝5.1Hz,1H),7.77(d,J＝7.6Hz,2H),7.56(s,1H),7.48-7.40(m,4H),7.39-7.17(m,6H),7.09(d,J＝7.8Hz,1H),5.73-5.54(m,2H),4.62(td,J1＝9.7,J2＝4.3Hz,1H),3.11(dd,J1＝14.0,J2＝4.4Hz,1H),2.92(t,J＝12.1Hz,1H),2.63(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.82,141.00,132.00,130.64,130.28,130.06,128.96,126.36,125.03,54.20,25.68.
实施例57：
Figure BDA0003911528130000411
(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I1的制备
步骤一：4-(2-溴苯基)-2,4-二氧代丁酸乙酯的制备
冰浴下，将2-溴苯乙酮(500mg，2.5mmo1)，草酸二乙酯(0.6mL，5.5mmol)和乙醇钠(5mL，20％质量含量，0.0lmmol)依次加入反应器中，于乙醇中剧烈搅拌至溶解后，室温搅拌10h。冰浴下，用4N盐酸调pH至2-3，乙酸乙酯(30mL)萃取，再用饱和食盐水洗涤有机相，浓缩得粗产物4-(2-溴苯基)-2,4-二氧代丁酸乙酯。
步骤二：5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯的制备
将步骤一的粗产物溶解在10mL的乙酸中，冰浴下缓慢滴加肼一水合物(0.3mL，6.0mmol)，室温下搅拌8h。乙酸乙酯(30mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝5:1)，得到740mg乳白色固体化合物5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯，两步产率共80％。
步骤三:1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯的制备
将5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯500mg，1.7mmol)溶解在10mL乙腈中，加入碳酸钾(415.4mg，3mmol)和氯化苄(0.27ml，2.3mmol)，90℃加热至回流，反应12h。乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝5:1)，得到130mg白色固体化合物1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯，产率为20％。
步骤四：1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸的制备
将1-苄基-5-(2-溴苯基)-1H-吡唑-3-甲酸乙酯(130mg，0.3mmol)溶解在12mL甲醇中，加入4mL4N氢氧化钠溶液，室温搅拌10h。冰浴条件下加入4N盐酸调pH至4，乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩，得到108mg白色固体1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸，产率为90％。
步骤五：(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺的制备
将1-苄基-5-(2-溴苯基)-1H-吡唑-3-羧酸(30mg，0.1mmol)和HOAT(24.5mg，0.2mmo1)溶解在5mLDMF中，氮气保护下室温搅拌10min后，0℃下加入化合物(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺(38.5mg，0.1mmo1)，继续搅拌10min后，0℃加入N-甲基吗啡啉(0.009mL，008mmol)，搅拌10min，加入EDCI(24.8mg，0.1mmo1)，保持0℃搅拌1h，至室温反应12h。乙酸乙酯(20mL)萃取，再用饱和食盐水洗涤有机相，浓缩柱层析(石油醚：乙酸乙酯＝1:1)，得到22mg白色固体化合物(S)-1-苄基-5-(2-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺，产率为44％。1H NMR(300MHz,DMSO-d6)：δ8.13(t,J＝6.4Hz,2H),7.78-7.75(m,1H),7.50(s,1H),7.45-7.17(m,9H),6.92(t,J＝3.7Hz,2H),6.76(s,1H),5.22(t,J＝16.5Hz,2H),4.70(q,J＝8.4Hz,1H),3.07–2.98(m,2H),2.62(d,J＝4.4Hz,3H).13C NMR(101MHz,DMSO-d6)：δ171.0,160.8,145.3,143.0,140.9,136.3,132.9,132.3,132.0,131.6,130.4,130.2,129.2,128.4,128.3,127.9,127.6,127.0,123.6,121.4,107.9,53.7,53.4,37.2,25.6.
实施例58：
Figure BDA0003911528130000421
(S)-1-苄基-5-(3-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I2的制备
其他条件同实施例57,将2-溴苯乙酮改为3-溴苯乙酮，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.12(t,J＝7.0Hz,2H),7.63-7.59(m,2H),7.48(s,1H),7.43-7.36(m,3H),7.32-7.18(m,5H),6.99(d,J＝7.4Hz,2H),6.89(s,1H),5.46(s,2H),4.69(td,J＝8.7,5.2Hz,1H),3.10–3.00(m,2H),2.61(d,J＝4.7Hz,3H).13C NMR(101MHz,DMSO-d6)δ171.0,160.6,145.5,143.4,140.9,136.9,132.0,131.9,131.5,131.1,131.0,130.2,129.2,128.7,128.4,127.7,127.6,126.6,122.0,121.4,107.4,53.6,53.5,37.2,25.6.
实施例59：
Figure BDA0003911528130000431
(S)-1-苄基-5-(4-溴苯基)-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-1H-吡唑-3-甲酰胺I3的制备
其他条件同实施例57，将2-溴苯乙酮改为4-溴苯乙酮，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.12-8.06(m,2H),7.67-7.62(m,2H),7.47(t,J＝1.8Hz,1H),7.39-7.35(m,3H),7.33-7.23(m,4H),7.19(t,J＝7.7Hz,1H),7.00-6.96(m,2H),6.85(s,1H),5.45(s,2H),4.68(td,J1＝8.8,J2＝5.2Hz,1H),3.03(m,2H),2.61(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.94,160.63,145.55,143.83,140.85,136.88,131.99,131.89,130.61,130.18,129.21,128.65,128.48,128.33,127.60,126.52,122.58,121.37,107.15,53.59,25.59.
实施例60：
Figure BDA0003911528130000432
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(间甲苯基)-1H-吡唑-3-甲酰胺I4的制备
其他条件同实施例57,将2-溴苯乙酮改为3-甲基苯乙酮，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)δ8.11-8.08(m,2H),7.48(s,1H),7.38-7.17(m,10H),7.02-7.00(m,2H),6.80(s,1H),5.44(s,2H),4.69(td,J＝8.6,5.4Hz,1H),3.11-2.98(m,2H),2.62(d,J＝4.5Hz,3H),2.29(s,3H).13C NMR(101MHz,DMSO-d6)δ171.0,160.8,145.5,145.2,140.9,138.25,137.2,132.0,130.2,129.7,129.2,128.8,128.6,128.4,127.6,126.6,125.6,121.4,106.7,53.6,53.2,37.3,25.6,20.9.
实施例61：
Figure BDA0003911528130000441
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(对甲苯基)-1H-吡唑-3-甲酰胺I5的制备
其他条件同实施例57，将2-溴苯乙酮改为4-甲基苯乙酮，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)δ8.11-8.08(m,2H),7.48(s,1H),7.38-7.16(m,10H),6.99(d,J＝6.7Hz,2H),6.79(s,1H),5.43(s,2H),4.70(td,J＝8.6,5.4Hz,1H),3.07-3.03(m,2H),2.62(d,J＝4.5Hz,3H),2.31(s,3H).13C NMR(101MHz,DMSO-d6)δ171.0,160.8,145.5,145.1,140.9,138.6,137.2,132.0,130.2,129.5,129.2,128.6,128.4,128.3,127.5,126.5,121.4,106.6,53.6,53.1,37.3,25.6,20.8.
实施例62：
Figure BDA0003911528130000442
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(3-甲氧基苯基)-1H-吡唑-3-甲酰胺I6的制备
其他条件同实施例57，将2-溴苯乙酮改为3-甲氧基苯乙酮，产物为白色固体，产率为73％。11H NMR(400MHz,DMSO-d6)δ8.19(q,J＝4.6Hz,1H),8.10(d,J＝8.6Hz,1H),7.48(t,J＝1.8Hz,1H),7.36(t,J＝7.9Hz,2H),7.31(dd,J1＝8.1,J2＝6.3Hz,2H),7.26(m,2H),7.19(t,J＝7.7Hz,1H),6.99(m,4H),6.91(t,J＝2.1Hz,1H),6.85(s,1H),5.45(s,2H),4.69(td,J1＝8.8,J2＝5.1Hz,1H),3.69(s,3H),3.17–2.97(m,2H),2.61(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.99,160.75,159.35,145.49,144.87,140.89,137.19,132.02,130.12,129.22,128.67,128.37,127.55,126.46,121.38,120.73,113.80,106.89,55.13,53.63,25.60.
实施例63：
Figure BDA0003911528130000451
(S)-1-苄基-N-(3-(3-溴苯基)-1-(甲基氨基)-1-氧代丙烷-2-基)-5-(4-甲氧基苯基)-1H-吡唑-3-甲酰胺I7的制备
其他条件同实施例57，将2-溴苯乙酮改为4-甲氧基苯乙酮，产物为白色固体，产率为73％。1H NMR(300MHz,DMSO-d6)δ8.08(m,1H),7.47(t,J＝1.7Hz,1H),7.37(dt,J1＝7.5,J2＝1.8Hz,1H),7.34-7.21(m,9H),7.02-6.95(m,2H),6.78(s,1H),5.43(s,2H),4.67(td,J1＝8.6,J2＝5.2Hz,1H),3.12-2.94(m,2H),2.61(d,J＝4.5Hz,3H),2.32(s,3H).13C NMR(75MHz,DMSO-d6)δ171.02,160.84,145.50,145.16,140.88,138.70,137.18,132.03,130.24,129.54,129.27,128.68,128.48,128.38,127.57,126.50,126.45,121.42,106.61,53.63,53.13,37.28,25.64,20.85.
实施例64：
Figure BDA0003911528130000452
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-甲基苄基)-5-苯基-1H-吡唑-3-甲酰胺I8的制备
其他条件同实施例57，将2-溴苯乙酮改为苯乙酮，氯化苄改为3-甲基氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)：δ8.14-8.03(m,1H),7.44(m,3H),7.37(dt,J1＝7.8,J2＝1.6Hz,1H),7.25(dt,J1＝7.7,J2＝1.4Hz,1H),7.18(q,J＝7.5Hz,1H),7.05(d,J＝7.6Hz,1H),6.81(d,J＝3.5Hz,2H),6.75(d,J＝7.6Hz,1H),5.40(s,2H),4.69(td,J1＝8.7,J2＝5.2Hz,1H),3.13–2.97(m,1H),2.62(d,J＝4.6Hz,2H),2.22(s,1H).13CNMR(101MHz,DMSO-d6)δ170.99,160.79,145.46,145.02,140.87,137.77,136.96,132.00,130.17,129.36,129.22,129.04,128.92,128.59,128.55,128.33,128.19,127.15,123.60,121.39,106.78,53.60,53.19,37.27,25.60,21.01.
实施例65：
Figure BDA0003911528130000461
(S)-N-(3-(3-溴苯基)-1-(甲氨基)-1-氧代丙烷-2-基)-1-(3-氟苄基)-5-苯基-1H-吡唑-3-甲酰胺I9的制备
其他条件同实施例57，将将2-溴苯乙酮改为苯乙酮，氯化苄改为3-氟氯化苄，产物为白色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ8.10(m,2H),7.48-7.44(m,2H),7.41(dd,J1＝7.3,J2＝2.5Hz,1H),7.39-7.31(m,4H),7.25(d,J＝7.7,1H),7.19(t,J＝7.7Hz,1H),7.09(m,1H),5.75(s,1H),5.47(s,1H),4.69(m,1H),3.05(m,2H),2.62(d,J＝4.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ170.97,160.73,145.71,145.16,140.87,139.90,139.83,132.02,130.76,130.68,130.17,129.23,129.15,128.99,128.57,128.35,122.55,121.39,114.55,114.35,113.55,113.33,106.92,54.94,53.63,52.67,37.23,25.62.
生物活性测试
cAMP的累积水平主要利用GloSensor方法，一种基于生物发光的cAMP生物传感器(Promega)来测试。将状态良好的HEK293T细胞种于6孔板或者35MM细胞培养皿中，放置在37℃，5％CO2培养箱培养24h，使细胞贴壁生长。后用转染试剂将β2肾上腺素受体质粒和pGloSensorTM-22FcAMP质粒转入细胞内，放于37℃5％ CO2培养箱培养24h，使目的基因转录和表达。接着将转染了质粒的细胞均匀种于96孔板，在37℃，5％CO2培养箱培养24h。最后，吸弃96孔板旧的培养液，用新的培养液洗一遍细胞，然后加入含GloSensorTMcAMP Reagent、血清和CO2-independent medium的平衡培养液在37℃，5％CO2培养箱培养1-2h或直到获得一个稳定的背景信号。将异丙肾上腺素(ISO)用DMSO溶解，除菌过滤后作为化合物母液用培养液稀释到不同浓度梯度(所配制的化合物中DMSO浓度小于或等于0.1％)。将配制好的化合物迅速加入到含HEK293T细胞的96孔板中开始给药刺激。通过多功能酶标仪可以观测到加入化合物后的生物发光信号快速上升，当信号值上升到顶点不再升高时立即加入不同浓度梯度(8μM,20μM,50μM,100μM)的化合物。同时立即用多功能酶标仪收集生物发光信号，生物发光信号值随化合物浓度增加而升高。最后将数据整理后用GraphPad Prism8软件处理以浓度为横坐标，信号值、倍数值响应值为纵坐标获得激动剂、拮抗剂和别构调节剂的量效关系曲线和合物的EC50或IC50值。
表2 N-取代苄基吡唑类衍生物的功能活性统计表
Figure BDA0003911528130000471
Figure BDA0003911528130000481
注：其中“+”表示具有相应活性“-”表示无相应活性
表3具有别构调节剂活性新衍生物与Cmpd-15的活性比较结果
Figure BDA0003911528130000491
注：a数值表示为相对于Cmpd-15的阻断活性
在Glosensor cAMP累积试验测试结果中，新化合物H2,H3,H5,H6,H8,H9,H10,H11,H12,H17,H22,H23,H34,H35,H54,H55I2,I4,I6具有β2AR拮抗作用；H4,H7,H13,H16,H24,H25等38个化合物有β2AR别构调节效应(见表2)。其中H16,H24,H25,H33,H43,H44,H45,H49,H50的别构效应强于Cmpd-15(见表3)；当N-2位苄基上取代基为Br时(H30,H31,H32)，新化合物活性发生翻转，均具有激动作用(见图2)；尤其是含有间Br的衍生物H31，不仅具有激动β2AR的作用，还能发挥正向别构调节β2AR激动剂ISO的功能活性。随着该化合物浓度的不断升高，ISO的量效曲线呈现有限的上移趋势(见图1)，表明化合物H31能够正向别构调节β2AR激动剂ISO的功能活性，即H31为β2AR的激动剂，也是β2AR别构激动剂。H30，H32为β2AR的部分激动剂。
同时，这些结果表明，Cmpd-15结构中右边(S)-2-氨基-3-(3-溴苯基)-N-甲基丙酰胺为重要活性部分，若将该部分换为其他不同取代的胺,所得化合物的拮抗活性较弱或没有。此外，吡唑苄基苯环上有吸电子取代基(例如，NO2，F和Br等)的新化合物具有更好的别构活性,其中N-2位取代化合物别构拮抗活性均好N-1位取代化合物。

Claims (5)

1.一种N-取代苄基吡唑类衍生物在作为β2肾上腺素受体别构调节剂中的应用，其特征在于：所述吡唑类衍生物的结构如式1中化合物H或化合物I所示：
Figure FDA0003911528120000011
所述R1＝H,F,Cl,Br,I,NO2,OCH3中的任意一种；
所述R2＝H,F,Cl,Br,NO2,OCH3,CN中的任意一种；
所述R3＝F,Cl,Br中的任意一种；
所述R4＝H,F,Cl,Br中的任意一种。
2.根据权利要求1所述一种N-取代苄基吡唑类衍生物在作为β2肾上腺素受体别构调节剂中的应用，其特征在于：所述β2肾上腺素受体别构调节剂包括β2肾上腺素受体别构激动剂和β2肾上腺素受体别构拮抗剂；其中作为β2肾上腺素受体别构激动剂的N-取代苄基吡唑类衍生物的结构式为：
Figure FDA0003911528120000012
3.根据权利要求2所述一种N-取代苄基吡唑类衍生物在作为β2肾上腺素受体别构调节剂中的应用，其特征在于：所述作为β2肾上腺素受体别构拮抗剂的N-取代苄基吡唑类衍生物为以下结构式中的一种：
Figure FDA0003911528120000021
4.一种N-取代苄基吡唑类衍生物在作为β2肾上腺素受体激动剂中的应用，其特征在于：所述N-取代苄基吡唑类衍生物为以下结构式中的一种：
Figure FDA0003911528120000022
5.一种N-取代苄基吡唑类衍生物在作为β2肾上腺素受体拮抗剂的应用，其特征在于：吡唑类衍生物的结构式为：
Figure FDA0003911528120000031
所述R1＝H,F,Cl,Br,I,NO2,OCH3中的任意一种；
所述R2＝H,F,Cl,Br,NO2,OCH3,CN中的任意一种；
所述R3＝F,Cl,Br中的任意一种；
所述R4＝H,F,Cl,Br中的任意一种；
或
Figure FDA0003911528120000032
CN202211323580.9A 2022-10-27 2022-10-27 N-取代苄基吡唑衍生物在作为β2肾上腺素受体别构调节剂、拮抗剂和激动剂的应用 Pending CN115894373A (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024109642A1 (zh) * 2023-07-28 2024-05-30 常州大学 一种苯并氮杂环类化合物作为β2-肾上腺素受体别构调节剂的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024109642A1 (zh) * 2023-07-28 2024-05-30 常州大学 一种苯并氮杂环类化合物作为β2-肾上腺素受体别构调节剂的应用

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