CN113563260A - 苯甲酰胺类化合物、制备方法及用途 - Google Patents
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Abstract
本发明公开了如式I所示结构的苯甲酰胺类化合物、制备方法及用途,该化合物作为PD‑L1抑制剂,对于阻断PD‑1/PD‑L1信号通路具有明显作用,能够有效缓解和治疗癌症等相关疾病。
Description
技术领域
本发明涉及化学医药技术领域,特别涉及作为PD-L1抑制剂的苯甲酰胺类化合物、制备方法及用途。
背景技术
恶性肿瘤是一类严重威胁人类健康和生命的疾病。目前来讲,肿瘤治疗的方式包括手术、放疗、化疗及靶向治疗等。肿瘤免疫治疗,是指通过刺激机体免疫***来提高抗肿瘤免疫效应,从而抑制和杀伤肿瘤细胞的一种治疗方法。免疫治疗的研究已有近百年的历史,随着肿瘤学、免疫学以及分子生物学的综合发张和交叉渗透,免疫治疗取得了多方面的成果,为肿瘤治疗带来了新希望。
程序性死亡受体-1(Programmed Cell Death-1,PD-1)及其配体PD-L1(B7·H1)属于CD28/B7超家族。PD-1主要表达在T细胞、B细胞、自然杀伤细胞(Natua1 Killer Cell,NK细胞)的膜表面,PD-L1主要表达于成熟的CD4T细胞、CD8T细胞、B细胞、单核细胞、树突状细胞(Dendritic Cells,DCs)、巨噬细胞等造血细胞及一些非造血细胞,如内皮细胞、胰岛细胞、肥大细胞等的膜表面。其中PD-L1在多种肿瘤中高表达,如肺癌、胃癌、多发性骨髓、黑色素瘤和乳腺癌等。肿瘤细胞表面上的PD-L1的表达与T细胞表面的配体相互作用,可诱导T细胞的凋亡或降低T细胞的反应活性,从而抑制肿瘤免疫应答,使肿瘤细胞逃避免疫攻击。因此阻断PD1/PD-L1信号通路的拮抗剂,可促进T细胞的激活、逆转肿瘤免疫微环境、增强内源性抗肿瘤免疫效应。靶向PD-1/PD-L1抑制剂在肿瘤免疫治疗领域有着广阔的应用前景。目前抗PD-1/PD-L1抗体治疗在临床上己显示具有优势作用,然而生物大分子也具有一些缺点,例如免疫原性以及给药途径的限制。因此,仍需要开发具有更好药效的靶向PD-1/PD-L1抑制剂。本发明的发明人发现一类小分子药物能特异性地调控和/或调解PD-L1及其相关蛋白激酶的转导,从而用于治疗与PD-1/PD-L1相关的疾病。
发明内容
发明目的:本发明目的是提供苯甲酰胺类化合物。
本发明另一目的是提供所述苯甲酰胺类化合物的制备方法。
本发明另一目的是提供所述苯甲酰胺类化合物的用途。
技术方案:本发明提供如式I所示结构的苯甲酰胺类化合物:
其中,环A和环B独立地为芳环或芳杂环;
L为键、-CH2O-、-OCH2-、-CH2CH2-、-NH(C=O)-、-(C=O)NH-、-(S=O)2NH-、-NH(S=O)2-、-O(C=O)-、-(C=O)O-或者相邻的两个R4和与它们相连的苯环上的两个原子共同形成一个5-7元的取代或者未取代的碳环氧基、取代或者未取代的碳杂环氧基;
R1独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基、取代或未取代的烷氧基;
R2独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基、取代或未取代的烷氧基;
R3独立地为氢、氘、卤素、氰基、取代或未取代的烷基;
R4独立地为氢、氘、卤素、氰基、取代或未取代的烷基;
m为1或2;
n为1或2;
D为1、2或3。
进一步地,R1为所述取代的烷基或者所述的取代的烷氧基时,取代基为下列取代基中的一个或多个:卤素、C1-C4烷基、羟基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;所述的取代的羟基或所述的取代的氨基中的取代基为下列取代基的一个或多个:C1-C4烷基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;当取代基为多个时,所述的取代基相同或者不同;
R2为所述的取代的烷基或者所述的取代的烷氧基时,取代基为下列取代基中的一个或多个:卤素、C1-C4烷基、羟基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;所述的取代的羟基或所述的取代的氨基中的取代基为下列取代基的一个或多个:C1-C4烷基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;当取代基为多个时,所述的取代基相同或者不同;
中,R5和R6独立地为氢、取代或未取代的烷基、烷氧基、羟烷基或者氨基烷基;或者R5、R6和它们相连的氮原子一起形成一个5-7元的取代或未取代的碳杂环;所述碳杂环中,杂原子为氮,或氮和氧,杂原子数为1-4个;
R5或R6中,所述的取代的烷基中的取代基为下列基团的一个或多个:卤素、C1-C4烷基、羟基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;R5、R6和与它们相连的氮原子一起形成一个5-7元的取代的碳杂环时。所述的取代的碳杂环中的取代基为下列基团的一个或多个:卤素、C1-C4烷基、羟基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;当取代基为多个时,所述的取代基相同或者不同;中,R7和R8独立地为氢或C1-C4的烷基。
进一步地,所述的芳环优选C6-C14芳环。所述的C6-C14芳环优选C6-C10芳环,更优选苯环;所述的杂芳环优选为杂原子选自氮、氧和硫,杂原子数为1-4个的C2-C10杂芳环。所述的C2-C10杂芳环优选杂原子为氮或氧,杂原子数为1-3个的C2-C6杂芳环,所述的C2-C6杂芳环优选为吡啶环。
进一步地,
进一步地,所述的如式I所示结构的苯甲酰胺类化合物,为如下任一种:
进一步地,该化合物还包括其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。
一种药物组合物,其含有治疗有效量的一种或多种如式I所示结构的苯甲酰胺类化合物,及药学上可接受的载体或辅料。
所述的如式I所示结构的苯甲酰胺类化合物的制备方法,包括如下步骤:
(1)式II化合物与式III化合物经缩合反应得到式IV化合物;
(2)式IV化合物与式V化合物经铃木反应得到式VI化合物;
(3)经过四丁基氟化铵催化的脱保护反应将式VI化合物的-OPg1转化为-OH;
(4)式VII化合物经羟基选择性氧化反应得到式VIII化合物;
(5)式VIII化合物经还原胺化反应得到式IX化合物;
(6)式X化合物与式XI化合物经铃木反应得到式XII化合物;
(7)式XII化合物经还原胺化反应得到式XIII化合物;
(8)式XIV化合物与式XV化合物经还原胺化反应得到式XVI化合物。
如式I所示结构的苯甲酰胺类化合物在制备作为免疫检查点抑制剂、具PD-l/PD-L1信号通路的抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
药物组合物在制备作为免疫检查点抑制剂、具PD-l/PD-L1信号通路的抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
有益效果:本发明的苯甲酰胺类化合物对于阻断PD1/PD-L1信号通路具有明显作用,能够有效缓解和治疗癌症等相关疾病。
具体实施方式
实施例1:合成化合物JL-1:(R)-4-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤一:合成化合物3
称取原料2(2.34g,10mmol)溶于无水DMF中,0℃加入HATU(4.18g,11mmol),加入DIPEA(8.71mL 50mmol),室温下反应10min。室温下加入另一原料1(4.77mL,20mmol),升温至60℃,反应12h。待反应完全,加入EA萃取(50mL×3),水洗(30mL)一次,饱和食盐水(30mL)洗涤一次,无水硫酸钠干燥,过滤,蒸干溶剂,得到黄色油状物,制砂,柱层析纯化(PE∶EA=50∶1)得到无色油状物3(3.92g,86%)。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.13(d,J=1.5Hz,1H),7.86(dd,J=7.5,1.7Hz,1H),7.77(dd,J=7.6,1.6Hz,1H),7.66-7.53(m,2H),7.37(t,J=7.5Hz,1H),4.89(s,2H),0.88(s,9H),0.09(s,6H).MS(ESI,m/z):455.1[M+1]+.
步骤二:合成化合物5
称取化合物3(4.56g,10mmol),苯硼酸(1.34g,11mmol),Pd(dppf)Cl2(0.73g,1.0mmol),K2CO3(2.76g,20mmol)溶于二氧六环(60mL)和水(6mL)中,氩气保护,85℃条件下回流6h。待反应完全,旋干反应液,加入EA溶解,抽滤,滤液浓缩制砂,柱层析纯化(PE∶EA=80∶1)得到化合物5(4.21g,93%)。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.14(d,J=1.5Hz,1H),7.87(dd,J=6.7,2.2Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.6Hz,1H),7.54-7.41(m,6H),7.39-7.30(m,1H),4.90(s,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):453.2[M+1]+.
步骤三:合成化合物6
称取化合物5(4.53g,10mmol)溶于四氢呋喃中,加入四丁基氟化铵(3.92g,15mmol),室温条件下反应2h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(DCM∶MeOH=60∶1)得到化合物6(3.35g,99%)。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.18(d,J=1.6Hz,1H),7.96(dd,J=7.5,1.7Hz,1H),7.76(dd,J=7.5,1.7Hz,1H),7.61(d,J=7.5Hz,1H),7.53(dd,J=7.6,1.6Hz,1H),7.50-7.41(m,5H),7.36(ddt,J=6.6,5.6,2.9Hz,1H),5.25-4.38(m,3H).MS(ESI,m/z):339.1[M+1]+.
步骤四:合成化合物7
称取化合物6(3.39g,10mmol)溶于二氯甲烷中,加入活性二氧化锰(8.69g,100mmol),氩气保护,升温至50℃,反应15h。待反应完全,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=100∶1)得到化合物7(3.00g,89%)。1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),10.06(s,1H),9.12(d,J=1.4Hz,1H),8.29(dd,J=7.7,1.6Hz,1H),7.96(dd,J=7.5,1.7Hz,1H),7.65(d,J=7.4Hz,1H),7.53(dd,J=7.6,1.6Hz,1H),7.50-7.41(m,5H),7.41-7.31(m,1H).MS(ESI,m/z):337.1[M+1]+.
步骤五:合成化合物JL-1
称取化合物7(337mg,1.0mmol),(R)-(+)-4-氨基-3-羟基丁酸(420mg,5.0mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(2mL,2mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(1.06g,5.0mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=10∶1)得到化合物JL-1(286mg,65%)。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.14(s,1H),8.21(tt,J=9.2,7.9Hz,1H),8.16(d,J=1.5Hz,1H),7.86(dd,J=6.8,2.1Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.41(m,6H),7.39-7.32(m,1H),4.75(d,J=7.5Hz,1H),4.51-3.77(m,3H),3.31-2.78(m,2H),2.57-2.16(m,2H).MS(ESI,m/z):440.1[M+1]+.
实施例2:合成化合物JL-38:2-氯-N-(5-(4,5-二氢-1H-咪唑-2-基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
步骤一:合成化合物JL-38
称取化合物7(3.39g,10mmol)溶于二氯甲烷中,加入乙二胺(3.34mL,50mmol),氩气保护,缓慢加入NBS(4.24mL,50mmol)。待反应完全,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=100∶1)得到化合物JL-38(3.39g,90%)。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.66(d,J=1.5Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.93(dd,J=7.1,2.1Hz,1H),7.60(d,J=7.5Hz,1H),7.54-7.42(m,6H),7.37(ddd,J=8.9,4.8,3.9Hz,1H),5.81-5.33(m,1H),3.52(td,J=7.1,4.9Hz,2H),3.32(t,J=7.1Hz,2H).MS(ESI,m/z):377.1[M+1]+.
实施例3:合成化合物JL-56:(S)-4-(((6-(2-氯-3-环己基苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤一:合成化合物10
称取化合物3(4.56g,10mmol),环己烯-1-基硼酸9(1.39g,11mmol),Pd(dppf)Cl2(0.73g,1.0mmol),K2CO3(2.76g,20mmol)溶于二氧六环(60mL)和水(6mL)中,氩气保护,85℃条件下回流6h。待反应完全,旋干反应液,加入EA溶解,抽滤,滤液浓缩制砂,柱层析纯化(PE∶EA=90∶1)得到化合物10(3.89g,85%)。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.14(d,J=1.5Hz,1H),7.76(ddd,J=13.9,7.5,1.5Hz,2H),7.58(d,J=7.6Hz,1H),7.54(dd,J=7.5,1.4Hz,1H),7.34(t,J=7.5Hz,1H),6.09(tt,J=6.2,1.0Hz,1H),4.90(s,2H),2.80(ddt,J=8.0,7.1,1.0Hz,2H),2.16-1.94(m,2H),1.71(pd,J=6.7,1.3Hz,2H),1.67-1.57(m,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):457.2[M+1]+.
步骤二:合成化合物11
称取化合物10(4.57g,10mmol)溶于甲醇中,加入10%Pd-C(500mg),通入氢气,升温至65℃,反应8h。待反应完全,抽滤反应液,滤液浓缩,制砂,柱层析纯化(PE∶EA=100∶1)得到化合物11(3.90g,85%)。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.14(d,J=1.5Hz,1H),7.78(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.58(d,J=7.5Hz,1H),7.51(t,J=7.5Hz,1H),7.35(dd,J=7.6,1.9Hz,1H),4.90(s,2H),3.18(pd,J=7.0,0.6Hz,1H),2.06-1.84(m,2H),1.69-1.48(m,6H),1.46-1.35(m,2H),0.89(s,9H),0.10(s,6H).MS(ESI,m/z):459.2[M+1]+.
步骤三:合成化合物12
称取化合物11(4.59g,10mmol)溶于四氢呋喃中,加入四丁基氟化铵(3.92g,15mmol),室温条件下反应2h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(DCM∶MeOH=100∶1)得到化合物12(3.41g,99%)。1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.18(d,J=1.6Hz,1H),7.87(dd,J=7.4,1.6Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.61(d,J=7.5Hz,1H),7.48(t,J=7.5Hz,1H),7.35(ddd,J=7.5,1.6,0.6Hz,1H),5.01-4.69(m,3H),3.18(pd,J=7.0,0.6Hz,1H),2.14-1.75(m,4H),1.70-1.50(m,4H),1.49-1.37(m,2H).MS(ESI,m/z):345.1[M+1]+.
步骤四:合成化合物13
称取化合物12(3.45g,10mmol)溶于二氯甲烷中,加入活性二氧化锰(8.69g,100mmol),氩气保护,升温至50℃,反应15h。待反应完全,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=120∶1)得到化合物13(3.05g,89%)。1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.06(s,1H),9.12(d,J=1.6Hz,1H),8.44-8.20(m,1H),7.87(dd,J=7.4,1.6Hz,1H),7.65(d,J=7.5Hz,1H),7.48(t,J=7.4Hz,1H),7.36(ddd,J=7.5,1.5,0.6Hz,1H),3.18(pd,J=7.0,0.6Hz,1H),2.16-1.74(m,4H),1.70-1.50(m,4H),1.50-1.36(m,2H).MS(ESI,m/z):343.1[M+1]+.
步骤五:合成化合物JL-56
称取化合物13(343mg,1.0mmol),(S)-(+)-4-氨基-3-羟基丁酸(420mg,5.0mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(2mL,2mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(1.06g,5.0mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=10∶1)得到化合物JL-62(290mg,65%)。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.39(s,1H),8.32-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.79(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.50(t,J=7.5Hz,1H),7.34(ddd,J=7.5,1.5,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.38-3.92(m,3H),3.41-3.11(m,1H),3.11-2.88(m,2H),2.55-2.24(m,2H),2.19-1.82(m,2H),1.72-1.50(m,6H),1.48-1.31(m,2H).MS(ESI,m/z):446.2[M+1]+.
实施例4:合成化合物JL-73:(R)-4-(((6-(3-((S)-1-((5-((((R)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤一:合成化合物15
称取化合物3(4.56g,10mmol)溶于四氢呋喃中,加入四丁基氟化铵(3.92g,15mmol),室温条件下反应2h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(DCM∶MeOH=50∶1)得到化合物15(3.38g,99%)。1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.18(d,J=1.6Hz,1H),7.77(td,J=7.3,1.5Hz,2H),7.66-7.59(m,1H),7.59-7.50(m,1H),7.41(t,J=7.5Hz,1H),4.91(dd,J=8.4,6.3Hz,1H),4.82(dd,J=7.3,1.0Hz,2H).MS(ESI,m/z):341.0[M+1]+.
步骤二:合成化合物16
称取化合物15(3.42g,10mmol)溶于二氯甲烷中,加入活性二氧化锰(8.69g,100mmol),氩气保护,升温至50℃,反应15h。待反应完全,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=100∶1)得到化合物16(3.06g,90%)。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.07(d,J=1.0Hz,1H),9.12(d,J=1.4Hz,1H),8.48-8.11(m,1H),7.76(dd,J=7.5,1.5Hz,1H),7.65(d,J=7.5Hz,1H),7.59(dd,J=7.6,1.5Hz,1H),7.41(t,J=7.5Hz,1H).MS(ESI,m/z):339.0[M+1]+.
步骤三:合成化合物19
称取化合物17(2.64g,10mmol)和化合物18(4.29g,25mmol)溶于无水甲苯中,加入Pd(dppf)Cl2(731mg,1.0mmol),碳酸铯(8.15g,25mmol),氩气保护,升温至40℃,反应15h。待反应完全,抽滤反应液,滤液浓缩,制砂,柱层析纯化(PE∶EA=150∶1)得到化合物26(3.24g,81%)。1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.90(dd,J=7.5,0.3Hz,1H),7.15(t,J=7.5Hz,1H),7.06(ddd,J=7.6,1.6,0.6Hz,1H),6.68(dd,J=7.4,1.6Hz,1H),6.61(d,J=7.5Hz,1H),5.17(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.49-2.83(m,2H),2.51(q,J=7.1Hz,2H),1.01(s,9H),0.20(s,6H).MS(ESI,m/z):400.2[M+1]+.
步骤四:合成化合物20
称取化合物19(4.00g,10mmol)溶于四氢呋喃中,加入四丁基氟化铵(3.92g,15mmol),室温条件下反应2h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(DCM∶MeOH=100∶1)得到化合物20(2.82g,99%)。1H NMR(400MHz,DMSO-d6)δ9.93(d,J=0.5Hz,1H),8.95(s,1H),7.94(dd,J=7.5,0.5Hz,1H),7.44-6.92(m,2H),6.80-6.32(m,2H),5.17(td,J=7.0,0.5Hz,1H),3.96(s,3H),3.10-2.95(m,1H),2.89(dt,J=12.4,7.1Hz,1H),2.62-2.25(m,2H).MS(ESI,m/z):283.1[M+1]+.
步骤五:合成化合物21
称取化合物20(2.85g,10mmol)溶于二氯甲烷中,加入吡啶(2.01mL,25mmol),三乙胺(2.78mL,20mmol),DMAP(122mg,1.0mmol),氩气保护,在-20℃条件下缓慢加入三氟甲磺酸酐(2.02mL,12mmol),反应30min。升温至室温,反应6h。加入二氯甲烷(100mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=60∶1)得到化合物21(3.76g,90%)。1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.90(dd,J=7.5,0.4Hz,1H),7.23(t,J=7.4Hz,1H),7.15(ddd,J=7.5,1.7,0.6Hz,1H),7.01(dd,J=7.3,1.7Hz,1H),6.61(d,J=7.5Hz,1H),5.11(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.43-2.75(m,2H),2.73-2.27(m,2H).MS(ESI,m/z):418.0[M+1]+.
步骤六:合成化合物22
称取化合物21(4.17g,10mmol)溶于二氧六环中,加入联硼酸频那醇酯(3.05g,12mmol),醋酸钾(2.94g,30mmol),Pd(dppf)Cl2(731mg,1.0mmol),氩气保护,85℃条件下反应16h。旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=50∶1)得到化合物22(3.36g,85%)。1H NMR(400MHz,DMSO-d6)δ9.90(d,J=0.5Hz,1H),7.89(dd,J=7.5,0.4Hz,1H),7.44-7.19(m,2H),7.13(t,J=7.4Hz,1H),6.62(d,J=7.5Hz,1H),5.08(td,J=7.0,0.7Hz,1H),4.00(s,3H),3.59-2.85(m,2H),2.49(q,J=7.0Hz,2H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):396.2[M+1]+.
步骤七:合成化合物23
称取化合物22(3.95g,10mmol)溶于DMF(15mL)和DCM(15mL)的混合溶液中,加入Palou’Chlor2-氯-1,3-双(甲氧羰基)胍(2.52g,12mmol),三氟乙酸(74uL,1.0mmol),氩气保护,室温条件下反应12h。加入Na2CO3饱和溶液(20mL)Na252O3饱和溶液(10mL),加入DCM(100mL)萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=50∶1)得到化合物23(3.48g,81%)。1H NMR(400MHz,DMSO-d6)δ9.93(d,J=0.5Hz,1H),7.95(d,J=0.3Hz,1H),7.27(d,J=0.9Hz,1H),7.25(s,1H),7.15(s,1H),5.11(t,J=7.0Hz,1H),4.01(s,3H),3.35-2.83(m,2H),2.48(qd,J=7.0,1.5Hz,2H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):430.2[M+1]+.
步骤八:合成化合物24
称取化合物23(4.30g,10mmol)和化合物16(3.40g,10mmol)溶于二氧六环(60mL)和水(10mL)的混合溶液中,加入Pd(dppf)Cl2(731mg,1.0mmol),碳酸钾(6.52g,20mmol),氩气保护,升温至85℃,反应15h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=5∶1)得到化合物24(4.84g,86%)。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.07(d,J=0.9Hz,1H),9.93(d,J=0.5Hz,1H),9.09(d,J=1.5Hz,1H),8.35-8.21(m,1H),8.08(d,J=0.5Hz,1H),7.85(dd,J=6.1,2.9Hz,1H),7.66(d,J=7.5Hz,1H),7.54-7.44(m,2H),7.43-7.32(m,2H),7.26(ddd,J=5.7,3.3,0.7Hz,1H),5.15(td,J=7.0,0.6Hz,1H),3.96(s,3H),3.02(dt,J=12.3,7.1Hz,1H),2.77(ddd,J=12.3,7.3,6.7Hz,1H),2.66-2.17(m,2H).MS(ESI,m/z):562.1[M+1]+.
步骤九:合成化合物JL-73
称取化合物24(562mg,1.0mmol),(R)-(+)-4-氨基-3-羟基丁酸(840mg,10mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(4mL,4mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(2.12g,10mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=8∶1)得到化合物JL-73(546mg,71%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.02-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.79-7.72(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.28-4.00(m,6H),3.92(s,3H),3.13-2.88(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.32(m,6H).MS(ESI,m/z):768.2[M+1]+.
实施例5:合成化合物JL-170:(R)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤一:合成化合物25
称取化合物16(340mg,1.0mmol),(S)-(+)-4-氨基-3-羟基丁酸(420mg,5.0mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(2mL,2mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(1.06g,5.0mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=15∶1)得到化合物25(288mg,65%)。1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.48(s,1H),8.16(d,J=1.6Hz,1H),7.92-7.74(m,2H),7.70(dd,J=7.5,1.4Hz,1H),7.64-7.60(m,1H),7.60-7.53(m,1H),7.37(t,J=7.5Hz,1H),4.75(d,J=7.6Hz,1H),4.33-3.95(m,3H),3.20-2.80(m,2H),2.56-2.16(m,2H).MS(ESI,m/z):442.0[M+1]+.
步骤二:合成化合物26
称取化合物23(430mg,1.0mmol),(R)-(+)-4-氨基-3-羟基丁酸(420mg,5.0mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(2mL,2mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(1.06g,5.0mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=15∶1)得到化合物26(368mg,69%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),7.98-7.80(m,1H),7.78(s,1H),7.34-7.22(m,2H),7.18-7.06(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.21-4.00(m,3H),3.92(s,3H),3.55-2.37(m,4H),2.75-1.98(m,4H),1.27(s,6H),1.22(s,6H).MS(ESI,m/z):533.2[M+1]+.
步骤三:合成化合物JL-170
称取化合物25(441mg,1.0mmol)和化合物26(533mg,1.0mmol)溶于二氧六环(10mL)和水(1mL)的混合溶液中,加入Pd(dppf)Cl2(731mg,1.0mmol),碳酸钾(6.52g,20mmol),氩气保护,升温至85℃,反应15h。待反应完全,旋干反应液,加入MeOH(50mL)溶解,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=15∶1)得到化合物JL-170(546mg,71%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.03-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.62(d,J=2.8Hz,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.40-3.97(m,6H),3.92(s,3H),3.20-2.84(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.24(m,6H).MS(ESI,m/z):768.2[M+1]+.
实施例6:合成化合物JL-207:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-(4,5-二氢-1H-咪唑-2-基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤一:合成化合物27
称取化合物16(3.38g,10mmol)溶于二氯甲烷中,加入乙二胺(3.34mL,50mmol),氩气保护,缓慢加入NBS(4.24mL,50mmol)。待反应完全,二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=100∶1)得到化合物27(3.40g,90%)。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.65(d,J=1.4Hz,1H),8.07(dd,J=7.5,1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.63(d,J=7.6Hz,1H),7.58(dd,J=7.5,1.5Hz,1H),7.38(t,J=7.5Hz,1H),5.87(t,J=5.0Hz,1H),3.52(tdd,J=7.1,5.0,0.9Hz,2H),3.33(td,J=7.0,0.9Hz,2H).MS(ESI,m/z):379.0[M+1]+.
步骤二:合成化合物JL-207
称取化合物27(378mg,1.0mmol)和化合物26(533mg,1.0mmol)溶于二氧六环(10mL)和水(1mL)的混合溶液中,加入Pd(dppf)Cl2(731mg,1.0mmol),碳酸钾(6.52g,20mmol),氩气保护,升温至85℃,反应15h。待反应完全,旋干反应液,加入MeOH(50mL)溶解,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=15∶1)得到化合物JL-207(501mg,71%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.96-7.78(m,2H),7.77(s,1H),7.66-7.53(m,2H),7.47(t,J=7.4Hz,1H),7.42-7.33(m,2H),7.32-7.17(m,1H),5.60(t,J=5.0Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.30-3.99(m,3H),3.92(s,3H),3.59-3.44(m,2H),3.41-3.29(m,2H),3.17-2.94(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.28(m,4H).MS(ESI,m/z):705.2[M+1]+.
实施例7:合成化合物JL-276:(S)-4-(((6-(3-((S)-1-((3-溴-5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
步骤七:合成化合物28
称取化合物22(3.95g,10mmol)溶于DMF(15mL)和DCM(15mL)的混合溶液中,加入NBS(2.14g,12mmol),氩气保护,室温条件下反应12h。加入Na2CO3饱和溶液(20mL)Na2S2O3饱和溶液(10mL),加入DCM(100mL)萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=50∶1)得到化合物28(3.83g,81%)。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.14(s,1H),7.36-7.21(m,2H),7.13(t,J=7.5Hz,1H),5.30-4.95(m,1H),4.00(s,3H),3.39-2.85(m,2H),2.46(qd,J=7.0,2.0Hz,2H),1.24(d,J=20.1Hz,12H).MS(ESI,m/z):474.1[M+1]+.
步骤八:合成化合物29
称取化合物28(4.74g,10mmol)和化合物16(3.40g,10mmol)溶于二氧六环(60mL)和水(10mL)的混合溶液中,加入Pd(dppf)Cl2(731mg,1.0mmol),碳酸钾(6.52g,20mmol),氩气保护,升温至85℃,反应15h。待反应完全,旋干反应液,加入EA(150mL)溶解,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,蒸干溶剂,制砂,柱层析纯化(PE∶EA=5∶1)得到化合物29(5.20g,86%)。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.07(d,J=0.9Hz,1H),9.93(s,1H),9.09(d,J=1.5Hz,1H),8.26(dd,J=7.4,1.8Hz,1H),8.21(s,1H),7.83(dd,J=7.2,1.8Hz,1H),7.66(d,J=7.5Hz,1H),7.57-7.45(m,2H),7.42-7.34(m,2H),7.31-7.22(m,1H),5.26-4.97(m,1H),3.96(s,3H),3.01(dt,J=12.5,7.2Hz,1H),2.77(dt,J=12.2,7.1Hz,1H),2.49(q,J=7.0Hz,2H).MS(ESI,m/z):606.0[M+1]+.
步骤九:合成化合物JL-276
称取化合物29(606mg,1.0mmol),(S)-(+)-4-氨基-3-羟基丁酸(840mg,10mmol)溶于DMF中,加入浓度为1N的氢氧化钠水溶液(4mL,4mmol),氩气保护,室温条件下反应。反应进行3h后,加入NaBH(OAc)3(2.12g,10mmol),室温条件下反应1h。待反应完全,加入过量三氟乙酸淬灭反应,抽滤反应液,滤液浓缩,制砂,柱层析纯化(DCM∶MeOH=8∶1)得到化合物JL-276(576mg,71%)。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,7.9Hz,1H),7.82(d,J=7.3Hz,2H),7.75(dd,J=7.5,1.5Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.29(dd,J=7.2,2.2Hz,1H),5.51-4.95(m,1H),4.75(d,J=7.5Hz,2H),4.21-3.98(m,6H),3.91(s,3H),3.21-2.89(m,5H),2.78(dt,J=12.5,7.1Hz,1H),2.55-2.31(m,6H).MS(ESI,m/z):812.2[M+1]+.
实施例8:合成化合物JL-2:(S)-4-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.14(s,1H),8.29-8.18(m,1H),8.16(d,J=1.6Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.54-7.40(m,6H),7.40-7.31(m,1H),4.75(d,J=7.6Hz,1H),4.34-3.89(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.55-2.25(m,2H).MS(ESI,m/z):440.1[M+1]+.
实施例9:合成化合物JL-3:(S)-2-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.6Hz,1H),7.54-7.40(m,6H),7.40-7.30(m,1H),6.03(t,J=9.7Hz,1H),4.76(t,J=7.0Hz,1H),4.31-3.97(m,2H),3.97-3.51(m,2H),1.51(s,3H).MS(ESI,m/z):440.1[M+1]+.
实施例10:合成化合物JL-4:(R)-2-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.86(dd,J=6.6,2.3Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.6Hz,1H),7.53-7.40(m,6H),7.40-7.31(m,1H),6.03(t,J=9.7Hz,1H),4.76(t,J=7.0Hz,1H),4.42-3.97(m,2H),3.97-3.68(m,2H),1.51(s,3H).MS(ESI,m/z):440.1[M+1]+.
实施例11:合成化合物JL-5:2-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-2-甲基丙酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.14(s,1H),8.19(d,J=1.5Hz,1H),7.88(dd,J=6.9,2.1Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.4Hz,1H),7.54-7.40(m,6H),7.41-7.32(m,1H),5.33(t,J=10.1Hz,1H),4.25(d,J=10.1Hz,2H),1.50(s,6H).MS(ESI,m/z):424.1[M+1]+.
实施例12:合成化合物JL-6:((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)
甘氨酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),10.72(s,1H),8.19(d,J=1.5Hz,1H),7.91(dd,J=6.5,2.5Hz,1H),7.65(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.54-7.42(m,6H),7.42-7.32(m,1H),4.90-4.09(m,2H),3.90-3.28(m,3H).MS(ESI,m/z):396.1[M+1]+.
实施例13:合成化合物JL-7:((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)
甘氨酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),10.14(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=5.7,3.2Hz,1H),7.68(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.40(m,6H),7.39-7.27(m,1H),5.02-4.23(m,1H),4.17(dd,J=9.6,0.5Hz,2H),2.53(s,2H),1.40(s,6H).MS(ESI,m/z):438.1[M+1]+.
实施例14:合成化合物JL-8:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.14(s,1H),8.23(d,J=1.4Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.67(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.29(m,1H),4.01(td,J=7.0,0.9Hz,1H),3.85(d,J=1.6Hz,2H),3.35-2.85(m,2H),2.12(q,J=7.0Hz,2H).MS(ESI,m/z):422.1[M+1]+.
实施例15:合成化合物JL-9:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.14(s,1H),8.23(d,J=1.4Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.67(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),4.01(td,J=7.0,1.0Hz,1H),3.85(d,J=1.6Hz,2H),3.35-2.82(m,2H),2.37-1.91(m,2H).MS(ESI,m/z):422.1[M+1]+.
实施例16:合成化合物JL-10:1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.14(s,1H),8.18(d,J=1.6Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),3.85(s,2H),3.58-3.17(m,4H),3.07-2.82(m,1H).MS(ESI,m/z):422.1[M+1]+.
实施例17:合成化合物JL-11:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.08(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.32(m,1H),3.78(s,2H),3.20-3.04(m,1H),3.03-2.86(m,3H),2.75(p,J=7.0Hz,1H),2.17-1.55(m,2H).MS(ESI,m/z):436.1[M+1]+.
实施例18:合成化合物JL-12:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.08(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.40-7.30(m,1H),3.78(s,2H),3.08-2.83(m,4H),2.75(p,J=7.0Hz,1H),2.23-1.45(m,2H).MS(ESI,m/z):436.1[M+1]+.
实施例19:合成化合物JL-13:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.31(m,1H),3.79(s,2H),3.27-2.90(m,2H),2.88-2.67(m,1H),2.57-2.36(m,1H),2.14-1.88(m,2H),1.28(s,3H).MS(ESI,m/z):450.2[M+1]+.
实施例20:合成化合物JL-14:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.57-7.40(m,6H),7.39-7.30(m,1H),3.79(s,2H),3.13(dd,J=12.4,0.8Hz,1H),3.05-2.92(m,1H),2.76(ddd,J=12.2,7.4,6.7Hz,1H),2.51(dt,J=12.3,7.0Hz,1H),2.15-1.79(m,2H),1.28(s,3H).MS(ESI,m/z):450.2[M+1]+.
实施例21:合成化合物JL-15:(2S,4S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-4-羟基吡咯烷-2-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.89(dd,J=7.0,2.0Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.58(d,J=7.4Hz,1H),7.55-7.40(m,6H),7.40-7.31(m,1H),4.38-4.14(m,2H),4.04-3.74(m,2H),3.69(td,J=7.0,0.6Hz,1H),3.40-3.08(m,1H),3.07-2.84(m,1H),2.54-2.24(m,1H),2.18-1.95(m,1H).MS(ESI,m/z):452.1[M+1]+.
实施例22:合成化合物JL-16:(3R,4R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-4-异丙基吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.40(s,1H),8.17(d,J=1.4Hz,1H),7.91-7.79(m,1H),7.72(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.4Hz,1H),7.55-7.47(m,2H),7.47-7.40(m,4H),7.40-7.29(m,1H),3.95-3.62(m,2H),3.52-3.09(m,1H),3.05-2.85(m,1H),2.82-2.39(m,3H),2.01(dddd,J=8.5,5.4,3.0,1.5Hz,1H),1.81(dpd,J=13.7,6.8,0.8Hz,1H),0.95(ddd,J=15.0,6.8,1.5Hz,6H).MS(ESI,m/z):478.2[M+1]+.
实施例23:合成化合物JL-17:(3R,4R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.41(m,6H),7.40-7.30(m,1H),3.89-3.62(m,2H),3.30-3.08(m,1H),3.02-2.84(m,1H),2.74-2.42(m,3H),2.24(p,J=6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):450.2[M+1]+.
实施例24:合成化合物JL-18:(3S,4S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.39-7.31(m,1H),3.99-3.50(m,2H),3.20-2.95(m,1H),2.95-2.78(m,1H),2.70-2.46(m,3H),2.24(p,J=6.8Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):450.2[M+1]+.
实施例25:合成化合物JL-19:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.67(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.56-7.40(m,6H),7.40-7.31(m,1H),3.84(s,2H),3.12(t,J=6.9Hz,1H),2.99-2.71(m,2H),1.98-1.23(m,6H).MS(ESI,m/z):450.2[M+1]+.
实施例26:合成化合物JL-20:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.28(s,1H),8.18(d,J=1.4Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.67(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.57-7.41(m,6H),7.40-7.32(m,1H),3.84(s,2H),3.12(t,J=6.9Hz,1H),2.94-2.72(m,2H),2.05-1.44(m,6H).MS(ESI,m/z):450.2[M+1]+.
实施例27:合成化合物JL-21:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.31(m,1H),3.79(d,J=1.5Hz,2H),3.14-2.27(m,5H),2.18-1.38(m,4H).MS(ESI,m/z):450.2[M+1]+.
实施例28:合成化合物JL-22:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.71(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.31(m,1H),3.79(d,J=1.5Hz,2H),3.18-2.82(m,2H),2.80-2.66(m,2H),2.61-2.44(m,1H),1.96-1.48(m,4H).MS(ESI,m/z):450.2[M+1]+.
实施例29:合成化合物JL-23:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.42(m,6H),7.41-7.29(m,1H),3.77(s,2H),3.25-2.83(m,2H),2.80-2.56(m,2H),1.95-1.68(m,4H),1.16(s,3H).MS(ESI,m/z):464.2[M+1]+.
实施例30:合成化合物JL-24:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.40(m,6H),7.41-7.30(m,1H),3.77(s,2H),3.14-2.82(m,2H),2.83-2.52(m,2H),1.93-1.60(m,4H),1.16(s,3H).MS(ESI,m/z):464.2[M+1]+.
实施例31:合成化合物JL-25:(R)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.41-7.30(m,1H),5.06(s,1H),3.81(s,2H),3.11(d,J=2.2Hz,2H),2.86-2.64(m,2H),2.15-1.63(m,4H).MS(ESI,m/z):466.2[M+1]+.
实施例32:合成化合物JL-26:(S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.28(s,1H),8.17(d,J=1.6Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.41-7.30(m,1H),5.06(s,1H),3.81(s,2H),3.11(s,2H),2.95-2.46(m,2H),2.23-1.57(m,4H).MS(ESI,m/z):466.2[M+1]+.
实施例33:合成化合物JL-27:(2S,3S)-1-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-2-甲基哌啶-3-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.28(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=6.9,2.1Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.56-7.42(m,6H),7.41-7.31(m,1H),4.01-3.42(m,2H),3.07-2.64(m,3H),2.52(q,J=6.9Hz,1H),2.17-1.49(m,4H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):464.2[M+1]+.
实施例34:合成化合物JL-28:2-((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)-2-氮杂双环[2.2.2]辛烷-4-羧酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.43(s,1H),8.17(d,J=1.5Hz,1H),7.93-7.78(m,1H),7.72(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.5Hz,1H),7.54-7.40(m,6H),7.40-7.28(m,1H),3.79(s,2H),3.36(d,J=12.4Hz,1H),3.17(d,J=12.3Hz,1H),3.04-2.73(m,1H),2.15-1.70(m,8H).MS(ESI,m/z):476.2[M+1]+.
实施例35:合成化合物JL-29:2-氯-N-(5-((二甲氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.18(d,J=1.6Hz,1H),7.94(dd,J=6.5,2.4Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.42(m,6H),7.42-7.32(m,1H),3.76(s,2H),2.29(s,6H).MS(ESI,m/z):366.1[M+1]+.
实施例36:合成化合物JL-30:2-氯-N-(5-(((2-羟乙基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.16(d,J=1.5Hz,1H),7.90(dd,J=6.6,2.4Hz,1H),7.81(tt,J=9.1,7.1Hz,1H),7.68(dd,J=7.5,1.4Hz,1H),7.59(d,J=7.5Hz,1H),7.54-7.42(m,6H),7.38(tq,J=5.0,3.5Hz,1H),4.56(t,J=6.4Hz,1H),4.21(d,J=9.0Hz,2H),3.66(td,J=7.1,6.3Hz,2H),2.87(q,J=7.0Hz,2H).MS(ESI,m/z):382.1[M+1]+.
实施例37:合成化合物JL-31:2-氯-N-(5-((3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=6.7,2.3Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.42(m,6H),7.42-7.34(m,1H),3.83(s,2H),3.00(d,J=7.0Hz,4H),2.35-1.73(m,J=6.9Hz,1H),1.00(d,J=6.8Hz,3H).MS(ESI,m/z):392.2[M+1]+.
实施例38:合成化合物JL-32:2-氯-N-(5-((3-羟基氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.18(d,J=1.4Hz,1H),7.91(dd,J=6.5,2.5Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.43(m,6H),7.42-7.34(m,1H),4.09-3.91(m,2H),3.83(s,2H),3.29-2.99(m,4H).MS(ESI,m/z):394.1[M+1]+.
实施例39:合成化合物JL-33:2-氯-N-(5-((3-羟基-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.4Hz,1H),7.56-7.41(m,6H),7.40-7.33(m,1H),4.65(s,1H),3.86(s,2H),3.52-2.90(m,4H),1.32(s,3H).MS(ESI,m/z):408.1[M+1]+.
实施例40:合成化合物JL-34:2-氯-N-(5-((3-甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.40(m,6H),7.40-7.32(m,1H),3.96(pq,J=7.0,1.4Hz,1H),3.80(s,2H),3.26-3.13(m,5H),3.07(dd,J=12.4,7.0Hz,2H).MS(ESI,m/z):408.1[M+1]+.
实施例41:合成化合物JL-35:2-氯-N-(5-((3-(羟甲基)-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.6Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.39-7.29(m,1H),4.32(t,J=6.4Hz,1H),3.83(s,2H),3.49(d,J=6.4Hz,2H),3.27-2.83(m,4H),1.07(s,3H).MS(ESI,m/z):422.2[M+1]+.
实施例42:合成化合物JL-36:2-氯-N-(5-((3-(羟甲基)氮杂环丁烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.5Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.61(d,J=7.6Hz,1H),7.55-7.41(m,6H),7.40-7.32(m,1H),3.82(s,2H),3.54(dd,J=7.0,6.0Hz,2H),3.17(t,J=6.1Hz,1H),3.07(d,J=7.0Hz,4H),2.18(p,J=7.0Hz,1H).MS(ESI,m/z):408.1[M+1]+.
实施例43:合成化合物JL-37:2-氯-N-(5-(((((1r,3r)-3-羟基环丁基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.60(d,J=7.4Hz,1H),7.55-7.41(m,6H),7.41-7.31(m,1H),5.94(tt,J=9.4,7.1Hz,1H),4.30-4.02(m,3H),3.81(hd,J=7.0,2.4Hz,1H),2.70(t,J=7.0Hz,2H),2.20-2.02(m,1H),2.03-1.69(m,4H).MS(ESI,m/z):422.2[M+1]+.
实施例44:合成化合物JL-39:2-氯-N-(5-(((5-氧代吡咯烷基-3-基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.59(s,1H),7.54-7.42(m,6H),7.41-7.32(m,1H),7.31-7.24(m,1H),4.21-3.81(m,2H),3.61-3.21(m,3H),2.69-2.40(m,2H),2.25-2.02(m,1H).MS(ESI,m/z):421.1[M+1]+.
实施例45:合成化合物JL-40:(R)-2-氯-N-(5-((3-羟基吡咯烷-1-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.18(d,J=1.4Hz,1H),7.91(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.40-7.32(m,1H),4.19(h,J=7.0Hz,1H),3.97(d,J=7.1Hz,1H),3.77(s,2H),3.47-3.17(m,1H),2.98-2.53(m,3H),1.93-1.50(m,2H).MS(ESI,m/z):408.1[M+1]+.
实施例46:合成化合物JL-41:2-氯-N-(5-((((1R,2S)-2-羟基环戊基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J=1.5Hz,1H),7.88(dd,J=6.5,2.5Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.58(d,J=7.4Hz,1H),7.54-7.41(m,6H),7.41-7.30(m,1H),4.50(d,J=5.7Hz,1H),4.08-3.92(m,2H),3.87(qd,J=7.0,5.8Hz,1H),3.12(dq,J=8.4,7.0Hz,1H),2.91(td,J=9.0,8.4Hz,1H),1.88-1.50(m,6H).MS(ESI,m/z):422.2[M+1]+.
实施例47:合成化合物JL-42:(S)-2-氯-N-(5-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.0,1.9Hz,1H),7.76-7.65(m,2H),7.57(d,J=7.5Hz,1H),7.55-7.41(m,6H),7.40-7.30(m,1H),6.79(tt,J=9.2,7.6Hz,1H),4.42-3.92(m,2H),3.72(dp,J=8.2,7.0Hz,1H),3.22-2.64(m,2H),2.48-2.15(m,2H),2.13-1.86(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):435.2[M+1]+.
实施例48:合成化合物JL-43:2-氯-N-(5-((6-氧代-2,5-重氮杂螺[3.4]辛-2-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.17(d,J=1.5Hz,1H),7.85(dd,J=7.1,1.9Hz,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.57(m,2H),7.55-7.41(m,6H),7.39-7.29(m,1H),3.84(s,2H),3.36(d,J=3.3Hz,4H),2.37(t,J=7.1Hz,2H),2.09-1.73(m,2H).MS(ESI,m/z):447.2[M+1]+.
实施例49:合成化合物JL-44:2-氯-N-(5-((7-氧代-2,6-二氮杂螺[3.4]辛-2-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.17(d,J=1.5Hz,1H),7.85(dd,J=7.1,1.9Hz,1H),7.73(dd,J=7.5,1.5Hz,1H),7.65-7.41(m,8H),7.39-7.30(m,1H),3.82(s,2H),3.46(dt,J=5.1,0.6Hz,2H),3.28-2.90(m,4H),2.40(d,J=0.7Hz,2H).MS(ESI,m/z):447.2[M+1]+.
实施例50:合成化合物JL-45:2-氯-N-(5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.63-7.56(m,2H),7.56-7.42(m,6H),7.41-7.30(m,1H),3.75(d,J=2.4Hz,2H),3.50-3.22(m,2H),2.92-2.66(m,3H),2.66-2.33(m,3H),1.92-1.67(m,2H).MS(ESI,m/z):461.2[M+1]+.
实施例51:合成化合物JL-46:(R)-N-(5-((3-(1H-四唑-5-基)吡咯烷-1-基)甲基)吡啶-2-基)-2-氯-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.54(dd,J=7.5,1.8Hz,1H),7.51-7.42(m,5H),7.42-7.31(m,1H),4.05(p,J=7.0Hz,1H),3.77(s,2H),3.63-3.31(m,2H),3.01(ddd,J=12.3,7.4,6.7Hz,1H),2.61-2.37(m,1H),2.28-2.09(m,2H).MS(ESI,m/z):460.2[M+1]+.
实施例52:合成化合物JL-47:2-氯-N-(5-((1-氧代-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.84(dd,J=7.2,1.8Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.56-7.41(m,7H),7.40-7.32(m,1H),3.77(s,2H),3.45(d,J=5.9Hz,2H),3.02-2.52(m,4H),1.96(td,J=7.1,4.3Hz,4H).MS(ESI,m/z):461.2[M+1]+.
实施例53:合成化合物JL-48:2-氯-N-(5-((3-氧代-2,8-二氮杂螺[4.5]十烷-8-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.17(d,J=1.5Hz,1H),7.93-7.80(m,1H),7.76(dd,J=7.5,1.4Hz,1H),7.64-7.55(m,2H),7.54-7.48(m,2H),7.48-7.41(m,4H),7.39-7.29(m,1H),3.78(s,2H),3.52-3.21(m,2H),2.76(dt,J=12.4,7.1Hz,2H),2.63(dt,J=12.4,7.1Hz,2H),2.39(d,J=0.7Hz,2H),2.08-1.62(m,4H).MS(ESI,m/z):475.2[M+1]+.
实施例54:合成化合物JL-49:2-氯-N-(5-((1-氧代-2,9-二氮杂螺[5.5]十一烷-9-基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.17(d,J=1.5Hz,1H),7.94-7.80(m,1H),7.76(dd,J=7.5,1.5Hz,1H),7.59(d,J=7.6Hz,1H),7.56-7.47(m,3H),7.44(d,J=4.0Hz,4H),7.41-7.32(m,1H),3.78(s,2H),3.24(td,J=7.0,6.0Hz,2H),2.76(dt,J=12.4,7.1Hz,2H),2.64(dt,J=12.4,7.1Hz,2H),2.16(dt,J=12.4,7.1Hz,2H),1.96(dt,J=12.4,7.1Hz,2H),1.76(ddd,J=18.1,7.6,6.4Hz,2H),1.67-1.54(m,2H).MS(ESI,m/z):489.2[M+1]+.
实施例55:合成化合物JL-50:(S)-4-(((6-(2-氰基-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.40(s,1H),8.32-8.12(m,2H),8.04-7.95(m,1H),7.87-7.79(m,2H),7.73-7.64(m,3H),7.62-7.48(m,3H),7.46-7.36(m,1H),4.75(d,J=7.6Hz,1H),4.31-3.93(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.55-2.26(m,2H).MS(ESI,m/z):431.2[M+1]+.
实施例56:合成化合物JL-51:(S)-4-(((6-(2-甲基-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.40(s,1H),8.28-8.14(m,2H),7.80(dd,J=7.5,1.5Hz,1H),7.69(dd,J=7.5,1.4Hz,1H),7.60(d,J=1.7Hz,1H),7.58(d,J=1.7Hz,1H),7.54-7.47(m,2H),7.46-7.34(m,4H),4.75(d,J=7.6Hz,1H),4.35-3.96(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.53-2.31(m,5H).MS(ESI,m/z):420.2[M+1]+.
实施例57:合成化合物JL-52:(S)-4-(((6-([1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.38(s,1H),8.29-8.14(m,2H),8.11(t,J=1.4Hz,1H),7.97(ddd,J=6.6,2.4,1.5Hz,1H),7.69(dd,J=7.5,1.5Hz,1H),7.67-7.50(m,5H),7.49-7.39(m,2H),7.38-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.30-3.97(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.57-2.31(m,2H).MS(ESI,m/z):406.2[M+1]+.
实施例58:合成化合物JL-53:((S)-4-(((6-(2-氯-3-(2,3-二氢苯并[b][1,4]二恶英-6-基)苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.43(s,1H),8.32-8.12(m,2H),7.79(dd,J=7.0,2.0Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.53-7.36(m,2H),7.32(dd,J=7.5,1.5Hz,1H),7.09(d,J=1.6Hz,1H),6.96(d,J=7.5Hz,1H),4.75(d,J=7.6Hz,1H),4.28(d,J=1.4Hz,4H),4.21-3.98(m,3H),3.33-2.83(m,2H),2.53-2.26(m,2H).MS(ESI,m/z):498.1[M+1]+.
实施例59:合成化合物JL-54:(S)-4-(((6-(2-氯-3-(2,3-二氢苯并呋喃-6-基)苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.43(s,1H),8.31-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.4,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.52-7.40(m,2H),7.37-7.27(m,2H),7.07(d,J=1.5Hz,1H),4.75(d,J=7.6Hz,1H),4.56(td,J=7.0,1.5Hz,2H),4.28-3.98(m,3H),3.23(td,J=7.1,1.0Hz,2H),3.13-2.88(m,2H),2.52-2.31(m,2H).MS(ESI,m/z):482.1[M+1]+.
实施例60:合成化合物JL-55:(S)-4-((((6-(2-氯-2′,3′,4′,5′-四氢-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.28(s,1H),8.31-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.80(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.61-7.51(m,2H),7.34(t,J=7.5Hz,1H),6.09(tt,J=6.2,1.0Hz,1H),4.75(d,J=7.6Hz,1H),4.38-3.93(m,3H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.80(tq,J=7.0,1.0Hz,2H),2.53-2.29(m,2H),2.19-1.99(m,2H),1.87-1.51(m,4H).MS(ESI,m/z):444.2[M+1]+.
实施例61:合成化合物JL57:(S)-4-(((6-(2-氯-3′-甲氧基-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),10.28(s,1H),8.29-8.17(m,1H),8.16(d,J=1.6Hz,1H),7.78(dd,J=7.5,1.5Hz,1H),7.70(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.50-7.34(m,3H),7.31(dd,J=7.5,1.5Hz,1H),7.17-7.07(m,1H),7.00-6.87(m,1H),4.75(d,J=7.6Hz,1H),4.37-4.00(m,3H),3.83(s,3H),3.38-2.87(m,2H),2.58-2.29(m,2H).MS(ESI,m/z):470.1[M+1]+.
实施例62:合成化合物JL-58:(S)-4-(((6-(2-氯-3′-氟-5′-甲氧基-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),10.40(s,1H),8.29-8.18(m,1H),8.16(d,J=1.6Hz,1H),7.84(dd,J=7.5,1.5Hz,1H),7.71(dd,J=7.5,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.43(t,J=7.5Hz,1H),7.30(dd,J=7.5,1.6Hz,1H),7.07(dt,J=8.0,1.5Hz,1H),6.98(t,J=1.5Hz,1H),6.79(dt,J=7.9,1.5Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.98(m,3H),3.81(s,3H),3.25-2.90(m,2H),2.57-2.29(m,2H).MS(ESI,m/z):488.1[M+1]+.
实施例63:合成化合物JL-59:(S)-2-氯-3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-N-(5-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.16(d,J=1.6Hz,1H),7.79(dd,J=6.3,2.7Hz,1H),7.75-7.72(m,1H),7.70(d,J=1.6Hz,1H),7.57(d,J=7.5Hz,1H),7.48-7.39(m,2H),7.32(dd,J=7.5,1.5Hz,1H),7.09(d,J=1.6Hz,1H),6.96(d,J=7.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.28(d,J=1.4Hz,4H),4.19-4.01(m,2H),3.75(dp,J=8.2,7.0Hz,1H),3.05-2.72(m,2H),2.42-2.22(m,2H),2.07-1.87(m,1H),1.74(dq,J=12.4,7.0Hz,1H).MS(ESI,m/z):493.2[M+1]+.
实施例64:合成化合物JL-60:(S)-2-氯-3-(1-甲基-1H-吲唑-4-基)-N-(5-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.22-8.13(m,2H),7.87-7.66(m,5H),7.57(d,J=7.5Hz,1H),7.51(q,J=7.5Hz,2H),7.36(dd,J=7.5,1.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.31-3.98(m,2H),3.81(s,3H),3.73(dq,J=8.2,7.0Hz,1H),3.19-2.68(m,2H),2.43-2.22(m,2H),1.98(dq,J=13.0,7.1Hz,1H),1.74(dq,J=12.5,7.0Hz,1H).MS(ESI,m/z):489.2[M+1]+.
实施例65:合成化合物JL-61:(S)-2-氯-3-(2,3-二氢苯并呋喃-6-基)-N-(5-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.4,1.5Hz,1H),7.75-7.68(m,2H),7.57(d,J=7.5Hz,1H),7.51-7.40(m,2H),7.37-7.27(m,2H),7.07(d,J=1.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),4.56(td,J=7.0,1.5Hz,2H),4.31-3.99(m,2H),3.75(dp,J=8.2,7.0Hz,1H),3.23(td,J=7.1,1.0Hz,2H),3.05-2.68(m,2H),2.41-2.18(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.74(dq,J=12.4,7.1Hz,1H).MS(ESI,m/z):477.2[M+1]+.
实施例66:合成化合物JL-62:(S)-2-氯-3′-甲氧基-N-(5-((((5-氧代吡咯烷基-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.16(d,J=1.6Hz,1H),7.77(dd,J=7.5,1.5Hz,1H),7.75-7.67(m,2H),7.57(d,J=7.5Hz,1H),7.49-7.36(m,3H),7.31(dd,J=7.5,1.5Hz,1H),7.20-7.07(m,1H),7.01-6.88(m,1H),6.79(tt,J=9.2,7.6Hz,1H),4.27-3.97(m,2H),3.87-3.63(m,4H),2.99-2.75(m,2H),2.46-2.19(m,2H),2.08-1.88(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):465.2[M+1]+.
实施例67:合成化合物JL-63:(S)-4-(((6-(2-氯-[1,1′-联苯]-3-甲酰胺基)-2-((5-氰基吡啶-3-基)甲氧基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.74(s,1H),8.76(d,J=1.6Hz,1H),8.73-8.61(m,1H),8.14(t,J=1.5Hz,1H),7.94-7.74(m,2H),7.71(d,J=7.6Hz,1H),7.60-7.48(m,2H),7.48-7.42(m,2H),7.42-7.31(m,3H),7.25(d,J=7.5Hz,1H),5.38-5.08(m,2H),4.75(d,J=7.6Hz,1H),4.28-4.04(m,1H),3.99(dd,J=12.4,9.2Hz,1H),3.73(dd,J=12.4,9.1Hz,1H),3.04(qdd,J=12.4,8.0,7.0Hz,2H),2.58-2.28(m,2H).MS(ESI,m/z):572.2[M+1]+.
实施例68:合成化合物JL-64:(S)-4-(((2-(苄氧基)-6-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.74(s,1H),7.91-7.75(m,2H),7.70(d,J=7.5Hz,1H),7.56(dd,J=7.5,1.6Hz,1H),7.51-7.46(m,1H),7.46-7.25(m,11H),5.23(qt,J=12.4,0.9Hz,2H),4.75(d,J=7.6Hz,1H),4.25-3.88(m,3H),3.04(qdd,J=12.4,8.0,7.0Hz,2H),2.60-2.27(m,2H).MS(ESI,m/z):546.2[M+1]+.
实施例69:合成化合物JL-65:(S)-4-(((5-(2-氯-[1,1′-联苯]-3-羧酰胺基)吡嗪-2-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),10.86(s,1H),8.34(s,1H),8.13-7.94(m,2H),7.86(dd,J=5.7,3.4Hz,1H),7.60-7.40(m,6H),7.40-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.42-4.03(m,3H),3.08(qdd,J=12.4,9.0,7.0Hz,2H),2.54-2.29(m,2H).MS(ESI,m/z):441.1[M+1]+.
实施例70:合成化合物JL-66:(S)-4-(((2-(2-氯-[1,1′-联苯]-3-羧酰胺基)嘧啶-5-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),11.21(s,1H),8.43(s,2H),8.18-7.84(m,2H),7.65-7.40(m,6H),7.40-7.26(m,1H),4.75(d,J=7.6Hz,1H),4.56-4.17(m,2H),4.16-4.03(m,1H),3.03(qdd,J=12.4,7.9,7.0Hz,2H),2.58-2.30(m,2H).MS(ESI,m/z):441.1[M+1]+.
实施例71:合成化合物JL-67:(S)-4-(((6-(2-氯-[1,1′-联苯]-3-羧酰胺基)哒嗪-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),10.82(s,1H),8.02(p,J=9.1Hz,1H),7.85(dd,J=5.7,3.4Hz,1H),7.73(d,J=7.5Hz,1H),7.66(d,J=7.4Hz,1H),7.56-7.40(m,6H),7.39-7.30(m,1H),4.75(d,J=7.6Hz,1H),4.39-3.99(m,3H),3.08(qdd,J=12.4,9.0,7.0Hz,2H),2.52-2.32(m,2H).MS(ESI,m/z):441.1[M+1]+.
实施例72:合成化合物JL-68:(S)-4-((4-(2-氯-[1,1′-联苯]-3-羧酰胺基)苄基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),9.25(s,1H),8.19(tt,J=8.6,7.9Hz,1H),7.88(dd,J=5.4,3.5Hz,1H),7.81-7.69(m,2H),7.54-7.40(m,7H),7.40-7.32(m,2H),4.75(d,J=7.6Hz,1H),4.21-4.00(m,1H),3.95-3.71(m,2H),3.17-2.90(m,2H),2.49-2.32(m,2H).MS(ESI,m/z):439.1[M+1]+.
实施例73:合成化合物JL-69:(S)-4-((4-(2-氯-[1,1′-联苯]-3-羧酰胺基)-2-甲基苄基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.33(s,1H),8.02-7.81(m,1H),7.67-7.52(m,1H),7.52-7.41(m,6H),7.40-7.30(m,3H),7.15(dt,J=7.5,1.0Hz,1H),4.75(d,J=7.6Hz,1H),4.26-4.03(m,1H),3.97-3.65(m,2H),3.04(qdd,J=12.3,7.9,7.0Hz,2H),2.58-2.27(m,2H),2.26-2.17(m,3H).MS(ESI,m/z):453.2[M+1]+.
实施例74:合成化合物JL-70:(S)-4-((4-(2-氯-[1,1′-联苯]-3-羧酰胺基)-2-甲氧基苄基)氨基)-3-羟基丁酸
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),9.48(s,1H),7.83(dd,J=6.1,2.9Hz,1H),7.66-7.55(m,1H),7.54-7.41(m,6H),7.40-7.29(m,3H),7.22(t,J=0.8Hz,1H),4.75(d,J=7.6Hz,1H),4.09(dq,J=7.8,7.0Hz,1H),3.96-3.69(m,5H),3.03(qdd,J=12.4,8.0,7.0Hz,2H),2.52-2.21(m,2H).MS(ESI,m/z):469.1[M+1]+.
实施例75:合成化合物JL-71:(S)-2-氯-N-(4-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)苯基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.88(dd,J=5.4,3.5Hz,1H),7.76(d,J=1.3Hz,1H),7.75-7.67(m,2H),7.56-7.47(m,3H),7.47-7.31(m,6H),6.77(tt,J=8.4,7.6Hz,1H),4.00-3.82(m,2H),3.72(dp,J=8.2,7.0Hz,1H),3.05-2.73(m,2H),2.31(td,J=7.1,1.5Hz,2H),2.05-1.89(m,1H),1.82-1.66(m,1H).MS(ESI,m/z):434.2[M+1]+.
实施例76:合成化合物JL-72:(S)-2-氯-N-(3-甲氧基-4-((((5-氧杂吡咯烷-2-基)甲基)氨基)甲基)苯基)-[1,1′-联苯]-3-羧酰胺
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.88(dd,J=5.7,3.3Hz,1H),7.73(d,J=8.2Hz,1H),7.56-7.41(m,6H),7.42-7.30(m,3H),7.22(t,J=0.8Hz,1H),6.94(tt,J=8.3,7.7Hz,1H),3.91-3.78(m,5H),3.76-3.66(m,1H),3.10-2.76(m,2H),2.47-2.18(m,2H),2.08-1.89(m,1H),1.74(dq,J=12.5,7.1Hz,1H).MS(ESI,m/z):464.2[M+1]+.
实施例77:合成化合物JL-74:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)
-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.01-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-4.00(m,6H),3.92(s,3H),3.25-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.27(m,6H).MS(ESI,m/z):768.2[M+1]+.
实施例78:合成化合物JL-75:(S)-2-(((6-(3-((S)-1-((5-((((S)-2-羧基-1-羟基丙烷-2-基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.99(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.10-6.01(m,1H),6.00-5.91(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.90-4.77(m,1H),4.77-4.68(m,1H),4.26-3.99(m,4H),3.97-3.79(m,7H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.42(m,2H),1.51(d,J=5.0Hz,6H).MS(ESI,m/z):768.2[M+1]+.
实施例79:合成化合物JL-76:(R)-2-(((6-(3-((S)-1-((5-((((R)-2-羧基-1-羟基丙烷-2-基)氨基)甲基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.99(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.62(d,J=2.8Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.12-6.01(m,1H),6.01-5.92(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.90-4.77(m,1H),4.77-4.70(m,1H),4.30-3.98(m,4H),3.98-3.71(m,7H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.62-2.43(m,2H),1.51(d,J=5.0Hz,6H).MS(ESI,m/z):768.2[M+1]+.
实施例80:合成化合物JL-77:(S)-2-(((6-(3-(1-((5-(((2-羧基丙烷-2-基)氨基)甲基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶基-3-基)甲基)氨基)-2-甲基丙酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),11.86(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.4Hz,1H),7.62(d,J=2.7Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.52(t,J=10.2Hz,1H),5.36(t,J=10.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.50-4.17(m,4H),3.92(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H),1.54(d,J=1.5Hz,6H),1.49(d,J=1.5Hz,6H).MS(ESI,m/z):736.2[M+1]+.
实施例81:合成化合物JL-78:(S)-((6-(3-(1-((5-(((羧甲基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰氨基)吡啶-3-基)甲基)甘氨酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.22(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.87-7.75(m,2H),7.72(dd,J=7.5,1.5Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.49-4.15(m,4H),3.92(s,3H),3.60-3.40(m,4H),3.39-3.21(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H).MS(ESI,m/z):680.2[M+1]+.
实施例82:合成化合物JL-79:(S)-3-(((6-(3-(1-((5-(((1-羧基-2-甲基丙烷-2-基)氨基)甲基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氨基)-3-甲基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.85(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,1H),7.28(ddd,J=6.8,2.1,0.5Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.54(td,J=9.6,5.7Hz,2H),4.32-4.05(m,4H),3.92(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.66-2.40(m,6H),1.42(d,J=0.8Hz,6H),1.37(d,J=0.8Hz,6H).MS(ESI,m/z):764.2[M+1]+.
实施例83:合成化合物JL-80:(S)-1-((6-(3-((S)-1-((5-(((S)-2-羧基氮杂环丁烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.68(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.09-3.95(m,2H),3.94-3.76(m,7H),3.22-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.41(m,2H),2.13(qd,J=7.1,4.5Hz,4H).MS(ESI,m/z):732.2[M+1]+.
实施例84:合成化合物JL-81:(R)-1-((6-(3-((S)-1-((5-(((R)-2-羧氮杂环丁烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.69(m,2H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.99(tdd,J=7.0,2.1,0.9Hz,2H),3.95-3.69(m,7H),3.22-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.38(m,2H),2.29-1.97(m,4H).MS(ESI,m/z):732.2[M+1]+.
实施例85:合成化合物JL-82:(S)-1-((6-(3-(1-((5-((3-羧基氮杂环丁烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)
吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.01-3.86(m,5H),3.86(s,2H),3.46-3.25(m,8H),3.04(dt,J=12.4,7.1Hz,1H),2.93(p,J=7.0Hz,2H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.51(d,J=7.2Hz,1H),2.46(d,J=7.4Hz,1H).MS(ESI,m/z):732.2[M+1]+.
实施例86:合成化合物JL-83:(R)-1-((6-(3-((S)-1-((5-(((R)-3-羧基吡咯烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯
甲酰胺基吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.58(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.02-3.67(m,7H),3.22-2.89(m,9H),2.85-2.71(m,3H),2.49(q,J=7.3Hz,2H),1.96-1.71(m,4H).MS(ESI,m/z):760.2[M+1]+.
实施例87:合成化合物JL-84:(S)-1-((6-(3-((S)-1-((5-(((S)-3-羧基吡咯烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲
酰胺基吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.81(m,2H),3.81-3.71(m,2H),3.10-2.93(m,7H),2.93-2.72(m,5H),2.49(q,J=7.3Hz,2H),2.05-1.70(m,4H).MS(ESI,m/z):760.2[M+1]+.
实施例88:合成化合物JL-85:(R)-1-((6-(3-((S)-1-((5-(((R)-3-羧基-3-甲基吡咯烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.79(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.99-3.84(m,5H),3.84-3.71(m,2H),3.20-2.93(m,5H),2.90-2.70(m,3H),2.57-2.40(m,4H),2.11-1.84(m,4H),1.28(d,J=0.8Hz,6H).MS(ESI,m/z):788.3[M+1]+.
实施例89:合成化合物JL-86:(S)-1-((6-(3-((S)-1-((5-(((S)-3-羧基-3-甲基吡咯烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.79(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.00-3.82(m,5H),3.82-3.71(m,2H),3.22-3.09(m,2H),3.08-2.94(m,3H),2.87-2.69(m,3H),2.57-2.44(m,4H),2.10-1.89(m,4H),1.28(d,J=0.8Hz,6H)..MS(ESI,m/z):788.3[M+1]+.
实施例90:合成化合物JL-87:(2S,4S)-1-((6-(3-((S)-1-((5-((((2S,4S)-2-羧基-4-羟基吡咯烷-1-基)甲基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-羟基吡咯烷-2-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.05(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77-7.72(m,2H),7.66-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.34-4.14(m,4H),3.96-3.87(m,5H),3.82(dd,J=12.4,2.5Hz,2H),3.62(tdd,J=7.0,1.7,0.6Hz,2H),3.33-3.16(m,2H),3.12-2.89(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.44(m,2H),2.41-2.28(m,1H),2.12-1.89(m,3H).MS(ESI,m/z):792.2[M+1]+.
实施例91:合成化合物JL-88:(3R,4R)-1-((6-(3-((S)-1-((5-(((3R,4R)-3-羧基-4-异丙基吡咯烷-1-基)甲基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-异丙基吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.81(s,2H),10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.62(d,J=1.3Hz,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.34(dd,J=7.5,1.9Hz,1H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.96-3.82(m,5H),3.81-3.71(m,2H),3.32-3.19(m,2H),3.09-2.89(m,3H),2.84-2.67(m,5H),2.66-2.56(m,2H),2.49(q,J=7.3Hz,2H),2.19-1.95(m,2H),1.74(dqdd,J=13.6,6.8,3.0,0.7Hz,2H),0.94(dd,J=6.8,1.5Hz,6H),0.89(dd,J=6.8,1.5Hz,6H).MS(ESI,m/z):844.3[M+1]+.
实施例92:合成化合物JL-89:(3R,4R)-1-((6-(3-((S)-1-((5-(((3R,4R)-3-羧基-4-甲基吡咯烷-1-基)甲基)-3)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.87(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.72(m,2H),3.30-3.15(m,2H),3.11-2.89(m,3H),2.78(ddd,J=12.4,7.4,6.7Hz,1H),2.70-2.40(m,8H),2.21(dt,J=13.7,6.9Hz,2H),0.99(d,J=1.7Hz,3H),0.97(d,J=1.6Hz,3H).MS(ESI,m/z):788.3[M+1]+.
实施例93:合成化合物JL-90:(3S,4S)-1-((6-(3-((S)-1-((5-(((3S,4S)-3-羧基-4-甲基吡咯烷-1-基)甲基)-3)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.87(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.73(m,2H),3.09-2.98(m,3H),2.97-2.85(m,2H),2.78(ddd,J=12.4,7.4,6.7Hz,1H),2.70-2.44(m,8H),2.21(dt,J=13.7,6.9Hz,2H),0.99(d,J=1.7Hz,3H),0.97(d,J=1.6Hz,3H).MS(ESI,m/z):788.3[M+1]+.
实施例94:合成化合物JL-91:(S)-1-((6-(3-((S)-1-((5-(((S)-2-羧基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77-7.69(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(s,3H),3.90-3.79(m,4H),3.12(td,J=6.9,3.2Hz,2H),3.06-2.98(m,1H),2.97-2.71(m,5H),2.55-2.42(m,2H),1.92-1.43(m,12H).MS(ESI,m/z):788.3[M+1]+.
实施例95:合成化合物JL-92:(R)-1-((6-(3-((S)-1-((5-(((R)-2-羧基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),10.61(s,1H),8.18(d,J=1.4Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78-7.69(m,2H),7.65-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(s,3H),3.90-3.78(m,4H),3.12(td,J=6.9,3.2Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.93-2.69(m,5H),2.58-2.40(m,2H),1.88-1.48(m,12H).MS(ESI,m/z):788.3[M+1]+.
实施例96:合成化合物JL-93:(R)-1-((6-(3-((S)-1-((5-(((R)-3-羧基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),10.68(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.81-3.72(m,2H),3.14(dd,J=12.4,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.86(m,3H),2.84-2.62(m,5H),2.60-2.43(m,4H),1.85-1.53(m,8H).MS(ESI,m/z):788.3[M+1]+.
实施例97:合成化合物JL-94:(S)-1-((6-(3-((S)-1-((5-(((S)-3-羧基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),10.68(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.62(d,J=3.0Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.91-3.82(m,2H),3.80-3.72(m,2H),3.10-2.94(m,3H),2.88(ddd,J=12.4,6.9,3.7Hz,2H),2.83-2.66(m,5H),2.61-2.42(m,4H),1.85-1.55(m,8H).MS(ESI,m/z):788.3[M+1]+.
实施例98:合成化合物JL-95:(S)-1-((6-(3-((S)-1-((5-(((S)-3-羧基-3-甲基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.76(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.08-3.82(m,5H),3.82-3.72(m,2H),3.16-2.97(m,3H),2.93(dd,J=12.4,4.4Hz,2H),2.85-2.64(m,5H),2.54-2.43(m,2H),1.98-1.63(m,8H),1.16(s,6H).MS(ESI,m/z):816.3[M+1]+.
实施例99:合成化合物JL-96:(R)-1-((6-(3-((S)-1-((5-(((R)-3-羧基-3-甲基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.76(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.66-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.00-3.82(m,5H),3.77(d,J=3.0Hz,2H),3.09-2.95(m,3H),2.87(dd,J=12.4,3.4Hz,2H),2.84-2.60(m,5H),2.54-2.44(m,2H),1.93-1.68(m,8H),1.16(s,6H).MS(ESI,m/z):816.3[M+1]+.
实施例100:合成化合物JL-97:(R)-1-((6-(3-((S)-1-((5-(((R)-3-羧基-3-羟基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.66(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.0,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.86(d,J=12.9Hz,2H),3.92(s,3H),3.89-3.75(m,4H),3.20-2.95(m,5H),2.87-2.69(m,5H),2.56-2.43(m,2H),2.07-1.76(m,8H).MS(ESI,m/z):820.2[M+1]+.
实施例101:合成化合物JL-98:(S)-1-((6-(3-((S)-1-((5-(((S)-3-羧基-3-羟基哌啶-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.66(s,2H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.66-7.60(m,1H),7.60-7.52(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.88(s,1H),4.84(s,1H),3.92(s,3H),3.89-3.74(m,4H),3.20-2.95(m,5H),2.90-2.65(m,5H),2.55-2.43(m,2H),2.03-1.70(m,8H).MS(ESI,m/z):820.2[M+1]+.
实施例102:合成化合物JL-99:(2S,3S)-1-((6-(3-((S)-1-((5-((((2S,3S)-3-羧基-2-甲基哌啶-1-基)甲基)-3)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-2-甲基哌啶-3-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.80(s,2H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.90-3.79(m,2H),3.79-3.65(m,2H),3.15-2.98(m,3H),2.83-2.68(m,5H),2.63-2.42(m,4H),1.99-1.58(m,8H),1.19(d,J=3.7Hz,3H),1.17(d,J=3.7Hz,3H).MS(ESI,m/z):816.3[M+1]+.
实施例103:合成化合物JL-100:(S)-2-((6-(3-(1-((5-((4-羧基-2-氮杂双环[2.2.2])辛烷-2-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)-2-氮杂双环[2.2.2]辛烷-4-羧酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),11.85(s,1H),10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.47(t,J=7.4Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.94-3.82(m,5H),3.80(s,2H),3.34(dd,J=21.0,12.4Hz,2H),3.17(dd,J=12.4,5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.88-2.70(m,3H),2.57-2.44(m,2H),2.09-1.72(m,16H).MS(ESI,m/z):840.3[M+1]+.
实施例104:合成化合物JL-101:(S)-2-氯-3-(1-(((3-氯-5-((二甲基氨基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((二甲氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.1,1.9Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.64-7.56(m,2H),7.56-7.49(m,1H),7.42-7.33(m,2H),7.31-7.22(m,1H),5.13(td,J=7.0,0.7Hz,1H),3.93(s,3H),3.91-3.63(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.49(q,J=7.1Hz,2H),2.37(s,6H),2.33(s,6H).MS(ESI,m/z):620.2[M+1]+.
实施例105:合成化合物JL-102:(S)-2-氯-3-(1-((3-氯-5-((((2-羟乙基)氨基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((((2-羟乙基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.91(tt,J=9.1,7.1Hz,1H),8.15(d,J=1.6Hz,1H),7.87-7.76(m,3H),7.73(dd,J=7.5,1.5Hz,1H),7.59(d,J=2.6Hz,1H),7.58-7.53(m,1H),7.49(t,J=7.4Hz,1H),7.37(dd,J=4.6,0.6Hz,2H),7.31-7.23(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.54(dt,J=8.5,6.3Hz,2H),4.38-4.09(m,4H),3.93(s,3H),3.80-3.57(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.94-2.71(m,5H),2.49(q,J=6.8Hz,2H).MS(ESI,m/z):652.2[M+1]+.
实施例106:合成化合物JL-103:(S)-2-氯-3-(1-(((3-氯-6-甲氧基-5-((3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.77(ddd,J=10.9,7.4,1.5Hz,2H),7.70(s,1H),7.60(d,J=4.3Hz,1H),7.58-7.54(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.08-3.77(m,7H),3.14-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.43(m,2H),2.06(dpd,J=13.8,6.9,4.8Hz,2H),1.01(d,J=1.7Hz,3H),0.99(d,J=1.8Hz,3H).MS(ESI,m/z):672.2[M+1]+.
实施例107:合成化合物JL-104:(S)-2-氯-3-(1-((3-氯-5-((3-羟基氮杂环丁烷-1-基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-羟基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.79(dd,J=7.4,1.5Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.72(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.27(ddd,J=6.1,2.8,0.6Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.09-3.76(m,11H),3.24-2.89(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.38(m,2H).MS(ESI,m/z):676.2[M+1]+.
实施例108:合成化合物JL-105:(S)-2-氯-3-(1-((3-氯-5-((3-羟基-3-甲基氮杂环丁烷-1-基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-羟基-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76-7.69(m,2H),7.61(d,J=4.0Hz,1H),7.60-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.32-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.65(s,1H),4.54(s,1H),3.92(d,J=6.0Hz,4H),3.89-3.81(m,3H),3.30(qd,J=12.4,8.3Hz,8H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.41(m,2H),1.35(s,3H),1.34(s,3H).MS(ESI,m/z):704.2[M+1]+.
实施例109:合成化合物JL-106:(S)-2-氯-3-(1-(((3-氯-6-甲氧基-5-((3-甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-
甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77-7.69(m,2H),7.66-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.34(m,2H),7.31-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.06-3.90(m,6H),3.89-3.75(m,3H),3.24-3.19(m,7H),3.19-3.12(m,3H),3.11-2.98(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.49(q,J=7.3Hz,2H).MS(ESI,m/z):704.2[M+1]+.
实施例110:合成化合物JL-107:(S)-2-氯-3-(1-((3-氯-5-((3-(羟甲基)-3-甲基氮杂环丁烷-1-基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-(羟甲基)-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.74(dd,J=7.5,1.4Hz,1H),7.70(s,1H),7.64-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25(t,J=6.4Hz,2H),4.00-3.74(m,7H),3.52(s,2H),3.49(s,2H),3.24-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.38(m,2H),1.11(s,3H),1.07(s,3H).MS(ESI,m/z):732.3[M+1]+.
实施例111:合成化合物JL-108:(S)-2-氯-3-(1-((3-氯-5-((3-(羟甲基)氮杂
环丁烷-1-基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-(羟甲基)氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.66-7.60(m,1H),7.60-7.55(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.34(m,2H),7.32-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),3.91(d,J=8.3Hz,5H),3.82(s,2H),3.54(ddd,J=6.9,6.0,0.8Hz,4H),3.23-2.91(m,11H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.41(m,2H),2.19(p,J=7.0Hz,2H).MS(ESI,m/z):704.2[M+1]+.
实施例112:合成化合物JL-109:2-氯-3-((S)-1-((3-氯-5-(((((1R,3S)-3-羟基环丁基)甲基)氨基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-
(5-(((((1R,3R)-3-羟基环丁基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.70(m,2H),7.62(d,J=3.4Hz,1H),7.59(d,J=1.7Hz,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.89(tt,J=9.4,7.1Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.33-4.12(m,6H),3.92(s,3H),3.79(hd,J=7.0,2.7Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.87-2.58(m,5H),2.54-2.40(m,2H),2.28-1.69(m,10H).MS(ESI,m/z):732.3[M+1]+.
实施例113:合成化合物JL-110:(S)-2-氯-3-(1-((3-氯-5-(4,5-二氢-1H-咪唑-2-基)-6-甲氧基吡啶-2-基)氧基)-2,3二氢-1H-茚-4-基)-N-(5-(4,5-二氢-1H-咪唑-2-
基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),8.05(s,1H),7.82(dd,J=7.4,1.6Hz,1H),7.63(d,J=7.6Hz,1H),7.58(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.37(dd,J=4.6,0.6Hz,2H),7.32-7.21(m,1H),5.60(t,J=5.0Hz,1H),5.41(t,J=5.1Hz,1H),5.15(td,J=7.0,0.6Hz,1H),4.00(s,3H),3.68-3.44(m,4H),3.43-3.27(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.42(m,2H).MS(ESI,m/z):642.2[M+1]+.
实施例114:合成化合物JL-111∶2-氯-3-((1S)-1((3-氯-6-甲氧基-5-(((5-氧代吡咯烷-3-基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((5-氧代吡咯烷-3-基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78-7.69(m,2H),7.65-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),7.23-7.09(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.20(dd,J=12.4,8.8Hz,1H),4.12-3.87(m,6H),3.54-3.28(m,6H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.67-2.34(m,7H),2.22-2.05(m,1H).MS(ESI,m/z):730.2[M+1]+.
实施例115:合成化合物JL-112:2-氯-3-((S)-1-((3-氯-5-(((R)-3-羟基吡咯烷-1-基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.72(dd,J=7.5,1.4Hz,1H),7.69(s,1H),7.64-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.31-7.23(m,1H),5.12(td,J=7.0,0.7Hz,1H),4.19(hd,J=7.0,1.0Hz,2H),4.00-3.84(m,5H),3.84-3.69(m,3H),3.56(d,J=7.0Hz,1H),3.39-3.21(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.65(m,7H),2.56-2.37(m,2H),1.99-1.71(m,2H),1.71-1.54(m,2H).MS(ESI,m/z):704.2[M+1]+.
实施例116:合成化合物JL-113:2-氯-3-((S)-1-((3-氯-5-((((1R,2S)-2-羟基环戊基)氨基)甲基)-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((((1R,2S)-2-羟基环戊基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(d,J=7.6Hz,2H),7.69-7.61(m,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.51(d,J=5.7Hz,1H),4.45(d,J=5.7Hz,1H),4.22(dd,J=12.4,9.1Hz,1H),4.12-3.95(m,3H),3.95-3.78(m,5H),3.36-3.23(m,1H),3.22-3.08(m,2H),3.08-2.92(m,2H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.43(m,2H),1.92-1.38(m,12H).MS(ESI,m/z):732.3[M+1]+.
实施例117:合成化合物JL-114:2-氯-3-(S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.62(d,J=2.8Hz,1H),7.60-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-3.95(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.91(dddd,J=12.6,7.6,6.9,0.6Hz,2H),2.85-2.69(m,3H),2.56-2.41(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):758.3[M+1]+.
实施例118:合成化合物JL-115:(S)-2-氯-3-(1-((3-氯-6-甲氧基-5-((6-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((6-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.69(s,1H),7.65-7.56(m,2H),7.55-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.06-3.77(m,7H),3.48-3.28(m,8H),3.04(dt,J=12.4,7.1Hz,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.44(m,2H),2.36(t,J=7.1Hz,4H),1.95(td,J=7.2,1.8Hz,2H),1.92-1.78(m,2H).MS(ESI,m/z):782.3[M+1]+.
实施例119:合成化合物JL-116:(S)-2-氯-3-(1-((3-氯-6-甲氧基-5-((7-氧代-2,6-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((7-氧代-2,6-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.75(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.57-7.44(m,3H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.91(d,J=6.5Hz,4H),3.87-3.76(m,3H),3.52-3.42(m,4H),3.16-2.95(m,9H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.44(m,4H),2.43(d,J=0.6Hz,2H).MS(ESI,m/z):782.3[M+1]+.
实施例120:合成化合物JL-117:2-氯-3-((1S)-1-((3-氯-6-甲氧基-5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.63-7.60(m,1H),7.60-7.57(m,1H),7.55-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(s,3H),3.84(d,J=6.6Hz,2H),3.80-3.65(m,2H),3.46-3.24(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.88-2.37(m,15H),1.93-1.63(m,4H).MS(ESI,m/z):810.3[M+1]+.
实施例121:合成化合物JL-118:3-((S)-1-((5-(((R)-3-(1H-四唑-5-基)吡咯烷-1-基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((R)-3-(1H-四唑-5-基)吡咯烷-1-基)甲基)吡啶-2-基)-2-氯苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),12.62(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.10-3.83(m,7H),3.77(d,J=3.4Hz,2H),3.55-3.40(m,2H),3.18(ddd,J=11.9,6.7,0.7Hz,2H),3.09-2.87(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.32(m,4H),2.30-2.09(m,4H).MS(ESI,m/z):808.3[M+1]+.
实施例122:合成化合物JL-119:(S)-2-氯-3-(1-((3-氯-6-甲氧基-5-((1-氧代-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((1-氧代-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.70(s,1H),7.64-7.60(m,1H),7.60-7.57(m,1H),7.51-7.42(m,3H),7.40-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.93(d,J=8.8Hz,5H),3.78(s,2H),3.42(dd,J=5.9,0.5Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.93-2.57(m,9H),2.49(q,J=7.0Hz,2H),2.04-1.85(m,8H).MS(ESI,m/z):810.3[M+1]+.
实施例123:合成化合物JL-120:(S)-2-氯-3-(1-((3-氯-6-甲氧基-5-((3-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)甲基]吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-氧代-2,8-二氮杂螺[4.5]十烷-8-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.76(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.63-7.56(m,4H),7.47(t,J=7.4Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.92(d,J=3.3Hz,5H),3.78(s,2H),3.44(d,J=5.3Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.89-2.72(m,5H),2.66(dtd,J=12.4,7.1,4.4Hz,4H),2.55-2.43(m,2H),2.40(d,J=0.7Hz,4H),1.90-1.70(m,8H).MS(ESI,m/z):838.3[M+1]+.
实施例124:合成化合物JL-121:(S)-2-氯-3-(1-((3-氯-6-甲氧基-5-((1-氧代-2,9-二氮杂螺[5.5]十一烷-9-基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((1-氧代-2,9-二氮杂螺[5.5]十一烷-9-基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.77(dd,J=7.5,1.5Hz,1H),7.68(s,1H),7.64-7.60(m,1H),7.60-7.58(m,1H),7.51-7.43(m,3H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),3.95(s,2H),3.92(s,3H),3.78(s,2H),3.23(td,J=6.9,5.9Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.91-2.60(m,9H),2.53-2.44(m,2H),2.12(dq,J=12.4,7.1Hz,4H),1.95(dtd,J=12.4,7.1,1.0Hz,4H),1.81-1.70(m,3H),1.70-1.54(m,5H).MS(ESI,m/z):866.3[M+1]+.
实施例125:合成化合物JL-122:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(6-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-3-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.54(d,J=1.6Hz,1H),7.92(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.76-7.70(m,2H),7.68(d,J=8.2Hz,1H),7.62(dd,J=7.5,1.6Hz,1H),7.58-7.46(m,2H),7.45-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.70(p,J=8.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.21-3.97(m,4H),3.91(s,3H),3.83-3.65(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.99-2.86(m,2H),2.85-2.69(m,3H),2.58-2.42(m,2H),2.37-2.20(m,4H),2.07-1.86(m,2H),1.85-1.69(m,2H).MS(ESI,m/z):758.3[M+1]+.
实施例126:合成化合物JL-123:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)苯甲酰胺
合成方法如实施例4。1HNMR(400MHz,DMSO-d6)δ9.14(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.79-7.74(m,3H),7.69(dd,J=8.2,4.6Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.77(tt,J=8.3,7.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99-3.82(m,5H),3.74(tp,J=8.2,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,2H),2.84-2.67(m,3H),2.59-2.40(m,2H),2.29(t,J=6.9Hz,4H),2.07-1.88(m,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):757.3[M+1]+.
实施例127:合成化合物JL-124:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)嘧啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.46(s,2H),7.87(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(dd,J=8.2,7.3Hz,2H),7.60(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.99-6.84(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.27(d,J=9.9Hz,2H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.72(dpd,J=8.2,7.0,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.69(m,3H),2.53-2.43(m,2H),2.36-2.21(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):759.2[M+1]+.
实施例128:合成化合物JL-125:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡嗪吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.39(s,1H),7.98(s,1H),7.87-7.74(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.78-6.63(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.13(qdd,J=12.4,11.4,9.2Hz,4H),3.91(s,3H),3.85-3.64(m,2H),3.11-2.86(m,3H),2.86-2.69(m,3H),2.56-2.41(m,2H),2.36-2.17(m,4H),2.10-1.86(m,2H),1.86-1.68(m,2H).MS(ESI,m/z):759.2[M+1]+.
实施例129:合成化合物JL-126:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(6-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)哒嗪吡啶-3-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.82-7.74(m,3H),7.72-7.65(m,3H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.80-6.64(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.13(qdd,J=12.4,11.4,9.2Hz,4H),3.91(s,3H),3.83-3.65(m,2H),3.14-2.86(m,3H),2.86-2.67(m,3H),2.58-2.41(m,2H),2.36-2.18(m,4H),2.08-1.87(m,2H),1.85-1.69(m,2H).MS(ESI,m/z):759.2[M+1]+.
实施例130:合成化合物JL-127:2-氯-N-(6-氯-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.93-7.80(m,3H),7.78(s,1H),7.69(dd,J=8.2,4.6Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.05(tt,J=9.0,7.6Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.38-4.02(m,4H),3.91(s,3H),3.72(dpd,J=8.2,7.0,3.0Hz,2H),3.12-2.59(m,6H),2.54-2.41(m,2H),2.34-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):792.2[M+1]+.
实施例131:合成化合物JL-128:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.72(d,J=7.5Hz,1H),7.69(s,1H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.29-4.01(m,4H),3.92(d,J=1.5Hz,6H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,2H),2.83-2.68(m,3H),2.57-2.43(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.05-1.86(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):788.3[M+1]+.
实施例132:合成化合物JL-129:N-(6-溴-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.83-7.76(m,3H),7.76-7.71(m,2H),7.69(d,J=8.2Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.34(dd,J=7.5,1.9Hz,1H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.03(tt,J=8.8,7.6Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.27-4.02(m,4H),3.91(s,3H),3.72(dpd,J=8.2,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.69(m,5H),2.56-2.42(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):836.2[M+1]+.
实施例133:合成化合物JL-130:N-(6-(苄氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.78(d,J=6.5Hz,2H),7.74-7.69(m,2H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.48(d,J=7.4Hz,1H),7.45-7.42(m,1H),7.42-7.31(m,6H),7.31-7.23(m,2H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.24(qt,J=12.4,1.0Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.83(m,2H),2.83-2.69(m,3H),2.59-2.43(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.07-1.88(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):864.3[M+1]+.
实施例134:合成化合物JL-131:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.85-8.75(m,1H),8.73-8.65(m,1H),8.13(t,J=1.5Hz,1H),7.80-7.72(m,3H),7.69(d,J=8.2Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.02(tt,J=9.1,7.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.37-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.86(m,2H),2.83-2.70(m,3H),2.57-2.42(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.05-1.89(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):890.3[M+1]+.
实施例135:合成化合物JL-132:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(3-甲基-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.69(dd,J=8.2,4.6Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.30(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.12(dt,J=7.4,1.0Hz,1H),6.88(dtt,J=12.3,8.6,7.7Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.90-3.78(m,2H),3.77-3.66(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.55-2.45(m,2H),2.39-2.12(m,7H),2.06-1.87(m,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):771.3[M+1]+.
实施例136:合成化合物JL-133:2-氯-N-(3-氯-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚吡啶-4-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74-7.65(m,3H),7.62(dd,J=7.5,1.5Hz,1H),7.51-7.32(m,5H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.00-6.83(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.04-3.88(m,5H),3.72(dpd,J=8.1,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.55-2.43(m,2H),2.39-2.18(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):791.2[M+1]+.
实施例137:合成化合物JL-134:N-(3-溴-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)-2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.80(dd,J=7.3,1.6Hz,2H),7.77(s,1H),7.70(dd,J=8.2,5.0Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.44(m,2H),7.44-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.19(q,J=7.8Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.05(m,2H),4.05-3.88(m,5H),3.73(dpd,J=7.8,7.0,0.8Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.68(m,5H),2.59-2.42(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.06-1.88(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):835.2[M+1]+.
实施例138:合成化合物JL-135:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(3-氰基-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.99(d,J=1.5Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75-7.65(m,3H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.06-6.82(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.03-3.84(m,5H),3.72(dpd,J=8.1,6.9,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.58-2.42(m,2H),2.40-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):782.3[M+1]+.
实施例139:合成化合物JL-136:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(3-甲氧基-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),7.82(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.69(dd,J=8.2,7.3Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.25(m,5H),7.20(d,J=1.4Hz,1H),6.88(dtt,J=10.6,8.3,7.7Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.96-3.80(m,8H),3.72(dpd,J=8.1,7.0,3.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.69(m,5H),2.56-2.42(m,2H),2.39-2.17(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):787.3[M+1]+.
实施例140:合成化合物JL-137:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(3,5-二甲氧基-4-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)苯基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(s,1H),7.67(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.32(m,4H),7.28(ddd,J=7.0,2.1,0.6Hz,1H),6.96(s,2H),6.96-6.82(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.28-3.94(m,4H),3.91(s,3H),3.90(s,6H),3.73(dp,J=8.3,7.0Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,2H),2.83-2.68(m,3H),2.56-2.40(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.09-1.86(m,2H),1.77(dq,J=12.3,7.0Hz,2H).MS(ESI,m/z):817.3[M+1]+.
实施例141:合成化合物JL-138:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(2-氧代-6-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)-1,2-二氢吡啶-3-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),9.58(s,1H),7.81-7.75(m,2H),7.74(d,J=8.1Hz,1H),7.68(d,J=8.2Hz,1H),7.61(dd,J=7.5,1.5Hz,1H),7.49(dd,J=7.7,1.6Hz,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.38(dt,J=8.0,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.64(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.67(m,5H),2.57-2.38(m,3H),2.29(td,J=7.1,1.7Hz,4H),2.08-1.90(m,2H),1.77(dddd,J=14.3,12.5,7.0,4.7Hz,2H).MS(ESI,m/z):774.2[M+1]+.
实施例142:合成化合物JL-139:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(6-氧代-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)-1,6-二氢吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.43(s,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.69(s,1H),7.67(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.19(dt,J=6.8,1.0Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.23(d,J=6.8Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.64(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.83(m,2H),2.82-2.65(m,4H),2.57-2.41(m,2H),2.29(td,J=7.1,1.7Hz,4H),2.08-1.87(m,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):774.2[M+1]+.
实施例143:合成化合物JL-140:2-溴-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.3,1.6Hz,1H),7.82-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.57(m,2H),7.52(t,J=7.4Hz,1H),7.43(t,J=7.4Hz,1H),7.35(dd,J=7.5,1.8Hz,1H),7.28(ddd,J=7.2,1.7,0.5Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.23-3.98(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.70(m,3H),2.49(q,J=7.1Hz,2H),2.36-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):802.2[M+1]+.
实施例144:合成化合物JL-141:3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基基)-2,3-二氢-1H-茚-4-基)-2-氰基-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.15(d,J=1.6Hz,1H),7.95(dd,J=6.9,2.1Hz,1H),7.80-7.73(m,2H),7.73-7.64(m,4H),7.61(d,J=7.6Hz,1H),7.51(dd,J=7.4,1.6Hz,1H),7.41(t,J=7.4Hz,1H),7.31(ddd,J=7.5,1.6,0.6Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.04(dt,J=12.3,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.68(m,3H),2.49(q,J=6.8Hz,2H),2.40-2.20(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):749.3[M+1]+.
实施例145:合成化合物JL-142:3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基基)-2,3-二氢-1H-茚-4-基)-2-甲基-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.15(d,J=1.6Hz,1H),7.85-7.73(m,4H),7.69(dd,J=8.2,7.3Hz,2H),7.61(d,J=7.5Hz,1H),7.54-7.43(m,2H),7.33(t,J=7.4Hz,1H),7.26(ddd,J=7.5,1.6,0.6Hz,1H),7.00-6.71(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.31-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.03(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,2H),2.85-2.68(m,3H),2.59-2.41(m,5H),2.39-2.14(m,4H),1.97(dq,J=12.4,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):738.3[M+1]+.
实施例146:合成化合物JL-143:3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基基)-2,3-二氢-1H-茚-4-基)-2-甲基-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.15(d,J=1.5Hz,1H),8.09(t,J=1.5Hz,1H),7.93(dt,J=7.4,1.5Hz,1H),7.81-7.74(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.62(t,J=7.4Hz,2H),7.56-7.45(m,2H),7.34(t,J=7.4Hz,1H),7.28(ddd,J=7.6,1.7,0.6Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-4.00(m,4H),3.92(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.02(dt,J=12.3,7.1Hz,1H),2.96-2.86(m,2H),2.85-2.70(m,3H),2.56-2.38(m,2H),2.37-2.20(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.85-1.66(m,2H).MS(ESI,m/z):724.3[M+1]+.
实施例147:合成化合物JL-144:3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基基)-2,3-二氢-1H-茚-4-基)-2-甲氧基-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.15(d,J=1.6Hz,1H),7.98(dd,J=7.5,1.5Hz,1H),7.83-7.64(m,5H),7.60(d,J=7.5Hz,1H),7.52-7.38(m,2H),7.32(t,J=7.4Hz,1H),7.22(ddd,J=7.5,1.6,0.6Hz,1H),6.99-6.69(m,2H),5.14(td,J=7.0,0.7Hz,1H),4.23-4.00(m,4H),3.91(s,3H),3.84-3.63(m,5H),3.11-2.66(m,6H),2.53-2.42(m,2H),2.40-2.21(m,4H),1.97(dq,J=12.5,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):754.3[M+1]+.
实施例148:合成化合物JL-145:3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基基)-2,3-二氢-1H-茚-4-基)-2-羟基-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶吡啶-2-基)苯
甲酰胺
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.41(s,1H),8.15(d,J=1.5Hz,1H),7.91(dd,J=7.5,1.5Hz,1H),7.77(d,J=7.5Hz,2H),7.73-7.57(m,4H),7.48(dd,J=7.4,1.6Hz,1H),7.35(t,J=7.5Hz,2H),7.24(ddd,J=7.5,1.6,0.7Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.14(td,J=7.0,0.7Hz,1H),4.31-4.01(m,4H),3.91(s,3H),3.73(dpd,J=7.8,7.0,0.9Hz,2H),3.07(dt,J=12.4,7.1Hz,1H),2.97-2.67(m,5H),2.55-2.43(m,2H),2.38-2.21(m,4H),1.97(dq,J=12.4,7.0Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):740.3[M+1]+.
实施例149:合成化合物JL-146:(S)-4-(((5-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-2-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.42(s,1H),8.54(d,J=1.6Hz,
1H),8.26(p,J=8.7Hz,1H),8.06-7.84(m,2H),7.77(s,1H),7.73(dd,J=7.4,1.6Hz,1H),7.62(dd,J=7.5,1.6Hz,1H),7.56-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.32-3.98(m,6H),3.92(s,3H),3.20-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.54-2.32(m,6H).MS(ESI,m/z):768.2[M+1]+.
实施例150:合成化合物JL-147:(S)-4-((4-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)苄基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.14(s,1H),8.22(tt,J=8.6,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.76(d,J=7.6Hz,3H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.28-3.99(m,4H),3.92(s,3H),3.89-3.66(m,2H),3.13-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.27(m,6H).MS(ESI,m/z):767.2[M+1]+.
实施例151:合成化合物JL-148:(S)-4-(((2-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)-2-氯苯甲酰胺基)嘧啶基-5-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.20(s,1H),8.44(s,2H),8.07-7.83(m,3H),7.77(s,1H),7.60(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.43-4.18(m,2H),4.18-4.11(m,1H),4.11-4.00(m,3H),3.92(s,3H),3.19-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.28(m,6H).MS(ESI,m/z):769.2[M+1]+.
实施例152:合成化合物JL-149:(S)-4-(((5-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡嗪-2-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.84(s,1H),8.39(s,1H),8.18(p,J=9.1Hz,1H),8.01(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84-7.74(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.38-3.99(m,6H),3.92(s,3H),3.20-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.30(m,6H).MS(ESI,m/z):769.2[M+1]+.
实施例153:合成化合物JL-150:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)-2-氯苯甲酰胺基)哒嗪-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.81(s,1H),8.18(p,J=9.1Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.83-7.72(m,3H),7.68(d,J=7.5Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(dd,J=7.6,1.4Hz,2H),4.35-3.94(m,6H),3.92(s,3H),3.20-2.90(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):769.2[M+1]+.
实施例154:合成化合物JL-151:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)-2-氯吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.73(s,1H),8.25(tt,J=9.2,8.0Hz,1H),8.01-7.85(m,2H),7.82(dt,J=7.5,0.8Hz,2H),7.77(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.29-3.96(m,6H),3.91(s,3H),3.17-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.29(m,6H).MS(ESI,m/z):802.2[M+1]+.
实施例155:合成化合物JL-152:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)-2-氯苯甲酰胺基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.72(d,J=7.5Hz,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,3H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.25-3.95(m,6H),3.92(d,J=1.3Hz,6H),3.18-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.25(m,6H).MS(ESI,m/z):798.2[M+1]+.
实施例156:合成化合物JL-153:(S)-4-(((6-(((S)-4-(3-((6-溴-5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)吡啶吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),8.23(tt,J=8.9,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.85-7.77(m,2H),7.73(d,J=7.4Hz,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.5Hz,2H),4.31-3.99(m,6H),3.91(s,3H),3.15-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.33(m,6H).MS(ESI,m/z):846.1[M+1]+.
实施例157:合成化合物JL-154:(S)-4-(((6-(((S)-4-(3-((6-(苄氧基)-5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.79(dd,J=7.5,1.5Hz,1H),7.78-7.68(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.52-7.21(m,10H),5.24(qt,J=12.4,1.0Hz,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.20-3.94(m,6H),3.91(s,3H),3.19-2.87(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.26(m,6H).MS(ESI,m/z):874.3[M+1]+.
实施例158:合成化合物JL-155:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰氨基)-2-((5-氰基吡啶-3-基)甲氧基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.74(s,1H),8.80-8.76(m,1H),8.75-8.69(m,1H),8.13(t,J=1.5Hz,1H),7.92(ttd,J=9.1,8.0,5.2Hz,2H),7.79(dd,J=7.5,1.5Hz,1H),7.76-7.71(m,2H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.37(m,1H),7.37-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.40-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.21-4.11(m,1H),4.11-4.02(m,3H),4.02-3.95(m,1H),3.91(s,3H),3.73(dd,J=12.4,9.2Hz,1H),3.17-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.65-2.32(m,6H).MS(ESI,m/z):900.2[M+1]+.
实施例159:合成化合物JL-156:(S)-4-((4-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)-2-甲基苄基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.23(s,1H),8.07(tt,J=8.7,7.9Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.12(dt,J=7.4,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(d,J=1.4Hz,1H),4.74(d,J=1.4Hz,1H),4.21-3.98(m,4H),3.92(s,3H),3.82(qdd,J=12.4,8.7,1.1Hz,2H),3.15-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.54-2.31(m,6H),2.22(d,J=0.5Hz,3H).MS(ESI,m/z):781.2[M+1]+.
实施例160:合成化合物JL-157:(S)-4-((4-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)-2-氯苄基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.10(s,1H),8.32-8.13(m,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.67(d,J=1.4Hz,1H),7.62(dd,J=7.5,1.5Hz,1H),7.53-7.31(m,5H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.19-4.11(m,2H),4.11-4.01(m,3H),3.97(ddd,J=12.4,8.5,1.0Hz,1H),3.91(s,3H),3.16-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):801.2[M+1]+.
实施例161:合成化合物JL-158:(S)-4-(((6-(((S)-4-(3-((3-溴-4-((((S)-3-羧基-2-羟基丙基)氨基)甲基)苯基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.52(s,1H),8.21(p,J=8.0Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.3,1.5Hz,2H),7.75(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.52-7.44(m,2H),7.43-7.32(m,3H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.30-3.94(m,6H),3.91(s,3H),3.15-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H).MS(ESI,m/z):845.1[M+1]+.
实施例162:合成化合物JL-159:(S)-4-((4-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)-2-氰基苄基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),8.31(s,1H),8.16(p,J=8.0Hz,1H),7.98(d,J=1.4Hz,1H),7.97-7.86(m,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.72(dd,J=7.5,1.5Hz,1H),7.62(dd,J=7.5,1.5Hz,1H),7.53-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.22-4.00(m,5H),4.00-3.84(m,4H),3.16-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,6H).MS(ESI,m/z):792.2[M+1]+.
实施例163:合成化合物JL-160:(S)-4-((4-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)-2-甲氧基苄基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.39(s,1H),8.01-7.91(m,1H),7.91-7.85(m,1H),7.82(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.24(m,5H),7.20(d,J=1.4Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(s,1H),4.74(s,1H),4.20-4.11(m,1H),4.11-4.01(m,3H),3.95-3.76(m,8H),3.16-2.88(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.32(m,6H).MS(ESI,m/z):797.2[M+1]+.
实施例164:合成化合物JL-161:(S)-4-(((6-(((S)-4-(3-((4-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3,5-二甲氧基苯基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚基-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),9.71(s,1H),8.08-7.97(m,1H),7.97-7.89(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(s,1H),7.62(dd,J=7.5,1.5Hz,1H),7.49(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.8,0.5Hz,1H),6.96(s,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.24-3.94(m,6H),3.91(d,J=4.2Hz,9H),3.21-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.33(m,6H).MS(ESI,m/z):827.2[M+1]+.
实施例165:合成化合物JL-162:(S)-4-(((6-(((S)-4-(3-((6-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-2-氧代-1,2-二氢吡啶-3-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.05(s,1H),9.58(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82-7.74(m,2H),7.61(dd,J=7.5,1.5Hz,1H),7.54-7.44(m,2H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.38(dt,J=8.2,1.0Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.74(d,J=1.4Hz,2H),4.27-4.01(m,4H),3.92(s,3H),3.89-3.78(m,1H),3.78-3.63(m,2H),3.18-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.30(m,6H).MS(ESI,m/z):784.2[M+1]+.
实施例166:合成化合物JL-163:(S)-4-(((6-(3-((S)-1-((5-((((S)
-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰)-2-氧代-1,2-二氢吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.80(s,1H),9.43(s,1H),7.93(tt,J=9.3,8.0Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.61(dd,J=7.5,1.6Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.19(dt,J=6.9,0.9Hz,1H),6.23(d,J=6.8Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.19-3.99(m,4H),3.92(s,3H),3.90-3.80(m,2H),3.79-3.68(m,1H),3.19-2.85(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.29(m,6H).MS(ESI,m/z):784.2[M+1]+.
实施例167:合成化合物JL-164:(S)-4-(((6-(((S)-4-(2-溴-3-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.64(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.4Hz,1H),8.04-7.87(m,1H),7.85(dd,J=7.3,1.6Hz,1H),7.81-7.72(m,2H),7.67-7.57(m,2H),7.52(t,J=7.4Hz,1H),7.43(t,J=7.4Hz,1H),7.35(dd,J=7.5,1.8Hz,1H),7.28(ddd,J=7.3,1.8,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-3.98(m,6H),3.91(s,3H),3.18-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.28(m,6H).MS(ESI,m/z):812.2[M+1]+.
实施例168:合成化合物JL-165:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氰基苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.57(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.03-7.85(m,2H),7.80-7.74(m,2H),7.74-7.64(m,2H),7.61(d,J=7.6Hz,1H),7.51(dd,J=7.4,1.6Hz,1H),7.41(t,J=7.4Hz,1H),7.31(ddd,J=7.5,1.6,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.26-3.99(m,6H),3.92(s,3H),3.14-2.92(m,5H),2.77(ddd,J=12.4,7.3,6.7Hz,1H),2.60-2.32(m,6H).MS(ESI,m/z):759.2[M+1]+.
实施例169:合成化合物JL-166:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6--甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)-2-甲基苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.59(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.81-7.71(m,4H),7.61(d,J=7.5Hz,1H),7.53-7.42(m,2H),7.33(t,J=7.4Hz,1H),7.26(ddd,J=7.5,1.6,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.33-3.99(m,6H),3.92(s,3H),3.22-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.20(m,9H).MS(ESI,m/z):748.3[M+1]+.
实施例170:合成化合物JL-167:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)苯甲酰胺)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.44(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.4Hz,1H),8.09(t,J=1.5Hz,1H),8.01-7.85(m,2H),7.81-7.72(m,2H),7.62(t,J=7.4Hz,2H),7.57-7.47(m,2H),7.34(t,J=7.4Hz,1H),7.28(ddd,J=7.6,1.7,0.6Hz,1H),5.13(td,J=6.9,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.34-3.97(m,6H),3.92(s,3H),3.17-2.88(m,5H),2.79(ddd,J=12.3,7.4,6.8Hz,1H),2.63-2.25(m,6H).MS(ESI,m/z):734.3[M+1]+.
实施例171:合成化合物JL-168:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-甲氧基苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.48(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.6Hz,1H),8.03-7.85(m,2H),7.79-7.71(m,2H),7.69(dd,J=7.5,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.52-7.38(m,2H),7.32(t,J=7.4Hz,1H),7.22(ddd,J=7.5,1.6,0.6Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,2H),4.23-3.98(m,6H),3.92(s,3H),3.80(s,3H),3.15-2.92(m,5H),2.79(ddd,J=12.3,7.4,6.8Hz,1H),2.55-2.32(m,6H).MS(ESI,m/z):764.3[M+1]+.
实施例172:合成化合物JL-169:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)-2-羟基苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例4。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.68(s,1H),10.41(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.02-7.84(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64(dd,J=7.6,1.5Hz,1H),7.60(d,J=7.5Hz,1H),7.48(dd,J=7.5,1.6Hz,1H),7.35(td,J=7.5,1.5Hz,2H),7.24(ddd,J=7.5,1.6,0.6Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,2H),4.28-3.98(m,6H),3.92(s,3H),3.16-2.92(m,5H),2.80(ddd,J=12.3,7.3,6.7Hz,1H),2.56-2.27(m,6H).MS(ESI,m/z):750.2[M+1]+.
实施例173:合成化合物JL-171:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.88(m,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.70(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.79(tt,J=9.2,7.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.98(m,5H),3.92(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.14-2.95(m,3H),2.95-2.71(m,3H),2.56-2.24(m,6H),1.97(dq,J=12.6,7.0Hz,1H),1.78(ddd,J=12.4,7.4,6.2Hz,1H).MS(ESI,m/z):763.2[M+1]+.
实施例174:合成化合物JL-172:(S)-4-(((6-(((S)-4-(3-((5-((((S)-2-羧基-1-羟基丙-2-基)氨基)甲基)吡啶吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氧-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.03(t,J=9.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.21-3.99(m,5H),3.96-3.71(m,5H),3.20-2.91(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.62-2.04(m,4H),1.52(s,3H).MS(ESI,m/z):768.2[M+1]+.
实施例175:合成化合物JL-173:(S)-4-(((6-(((S)-4-(3-((5-((((R)-2-羧基-1-羟基丙-2-基)氨基)甲基)吡啶吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.00-7.83(m,2H),7.80-7.72(m,2H),7.69-7.53(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.03(t,J=9.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.24-3.98(m,5H),3.95-3.76(m,5H),3.19-2.91(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,4H),1.52(s,3H).MS(ESI,m/z):768.2[M+1]+.
实施例176:合成化合物JL-174:(S)-4-(((6-(((S)-4-(3-((5-(((2-羧基丙-2-基)氨基)甲基)吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.92(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),8.01-7.88(m,1H),7.86(dd,J=7.4,1.6Hz,1H),7.80-7.73(m,2H),7.62(d,J=2.7Hz,1H),7.61-7.57(m,1H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.36(t,J=10.2Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.42-4.18(m,2H),4.18-3.98(m,3H),3.92(s,3H),3.18-2.92(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.30(m,4H),1.54(s,3H),1.49(s,3H).MS(ESI,m/z):752.2[M+1]+.
实施例177:合成化合物JL-175:(S)-4-(((6-(((S)-4-(3-((5-(((羧甲基)氨基)甲基)吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.24(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,1H),4.39-4.20(m,2H),4.19-4.00(m,3H),3.96-3.78(m,4H),3.64-3.35(m,2H),3.23-2.86(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.63-2.31(m,4H).MS(ESI,m/z):724.2[M+1]+.
实施例178:合成化合物JL-176:3-(((6-(3-((S)-1-((5-(((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氨基)-3-甲基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.85(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.79-7.73(m,2H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.53(t,J=9.6Hz,1H),4.31-3.98(m,5H),3.92(s,3H),3.14-2.88(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.64-2.30(m,6H),1.42(s,3H),1.37(s,3H).MS(ESI,m/z):766.2[M+1]+.
实施例179:合成化合物JL-177:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.95(m,4H),3.95-3.76(m,5H),3.20-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.27(m,4H),2.12(q,J=7.0Hz,2H).MS(ESI,m/z):750.2[M+1]+.
实施例180:合成化合物JL-178:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.96(m,4H),3.94-3.78(m,5H),3.21-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.31(m,4H),2.26-1.98(m,2H).MS(ESI,m/z):750.2[M+1]+.
实施例181:合成化合物JL-179:1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.89(m,1H),7.86(dd,J=7.4,1.6Hz,1H),7.79-7.70(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.99(m,3H),3.92(s,3H),3.86(s,2H),3.38(dd,J=7.0,0.9Hz,4H),3.18-2.86(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.59-2.32(m,4H).MS(ESI,m/z):750.2[M+1]+.
实施例182:合成化合物JL-180:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.81(m,2H),7.80-7.70(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.98(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.19-2.89(m,7H),2.84-2.72(m,2H),2.54-2.31(m,4H),2.01-1.72(m,2H).MS(ESI,m/z):764.2[M+1]+.
实施例183:合成化合物JL-181:(S)-1-((6-(3-((S)-1-((5-((((S)-3-
羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.80-7.70(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.99(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.17-2.66(m,9H),2.55-2.31(m,4H),1.97-1.74(m,2H).MS(ESI,m/z):764.2[M+1]+.
实施例184:合成化合物JL-182:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.79(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.22-3.99(m,3H),3.92(s,3H),3.78(d,J=3.0Hz,2H),3.14-2.91(m,5H),2.78(dddd,J=12.4,7.4,6.7,2.8Hz,2H),2.59-2.29(m,5H),2.08-1.84(m,2H),1.28(s,3H).MS(ESI,m/z):778.2[M+1]+.
实施例185:合成化合物JL-183:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.98(m,3H),3.92(s,3H),3.78(d,J=3.0Hz,2H),3.16-2.90(m,5H),2.84-2.67(m,2H),2.58-2.29(m,5H),2.00-1.82(m,2H),1.28(s,3H).MS(ESI,m/z):778.2[M+1]+.
实施例186:合成化合物JL-184:(2S,4S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-羟基吡咯烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.05(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.82(m,2H),7.78-7.72(m,2H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.29-4.18(m,2H),4.18-4.01(m,3H),3.96-3.78(m,5H),3.65(td,J=7.0,0.6Hz,1H),3.34-3.21(m,1H),3.16-2.89(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.26(m,5H),2.07-1.88(m,1H).MS(ESI,m/z):780.2[M+1]+.
实施例187:合成化合物JL-185:(3R,4R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-异丙基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-3.98(m,3H),3.91(s,3H),3.86-3.70(m,2H),3.28-3.14(m,1H),3.13-2.89(m,4H),2.84-2.55(m,4H),2.54-2.33(m,4H),2.07(dtdt,J=8.6,7.0,5.5,1.5Hz,1H),1.74(dpd,J=13.7,6.8,0.7Hz,1H),0.94(dd,J=6.8,1.5Hz,3H),0.89(dd,J=6.8,1.4Hz,3H).MS(ESI,m/z):806.3[M+1]+.
实施例188:合成化合物JL-186:(3R,4R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.81(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.99(m,3H),3.92(s,3H),3.86-3.70(m,2H),3.26-3.14(m,1H),3.14-2.91(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.69-2.33(m,7H),2.21(dt,J=13.8,6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):778.3[M+1]+.
实施例189:合成化合物JL-187:(3S,4S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.83(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-3.97(m,3H),3.92(s,3H),3.86-3.70(m,2H),3.13-2.94(m,4H),2.94-2.85(m,1H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.68-2.32(m,7H),2.21(dt,J=13.8,6.9Hz,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):778.3[M+1]+.
实施例190:合成化合物JL-188:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.02-7.81(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.98(m,3H),3.92(s,3H),3.90-3.76(m,2H),3.19-2.96(m,4H),2.96-2.70(m,3H),2.58-2.29(m,4H),1.91-1.43(m,6H).MS(ESI,m/z):778.3[M+1]+.
实施例191:合成化合物JL-189:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),8.00-7.82(m,2H),7.77(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.27-3.99(m,3H),3.92(s,3H),3.90-3.77(m,2H),3.21-2.91(m,4H),2.90-2.69(m,3H),2.56-2.28(m,4H),1.82-1.40(m,6H).MS(ESI,m/z):778.3[M+1]+.
实施例192:合成化合物JL-190:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-4.00(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.15-2.86(m,5H),2.83-2.61(m,3H),2.60-2.33(m,5H),1.92-1.26(m,4H).MS(ESI,m/z):778.3[M+1]+.
实施例193:合成化合物JL-191:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.03-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.28-3.99(m,3H),3.92(s,3H),3.78(d,J=2.5Hz,2H),3.14-2.94(m,4H),2.93-2.62(m,4H),2.61-2.30(m,5H),1.87-1.53(m,4H).MS(ESI,m/z):778.3[M+1]+.
实施例194:合成化合物JL-192:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.76(d,J=7.3Hz,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-4.00(m,3H),3.92(s,3H),3.77(d,J=3.1Hz,2H),3.16-2.92(m,4H),2.91-2.72(m,3H),2.71-2.58(m,1H),2.54-2.28(m,4H),1.95-1.63(m,4H),1.16(s,3H).MS(ESI,m/z):792.2[M+1]+.
实施例195:合成化合物JL-193:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.76(d,J=7.3Hz,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.99(m,3H),3.92(s,3H),3.77(d,J=3.1Hz,2H),3.15-2.88(m,5H),2.85-2.62(m,3H),2.56-2.31(m,4H),1.97-1.62(m,4H),1.16(s,3H).MS(ESI,m/z):792.2[M+1]+.
实施例196:合成化合物JL-194:(S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.81(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.75(d,J=7.6Hz,1H),4.19-3.98(m,3H),3.92(s,3H),3.88-3.73(m,2H),3.16-2.92(m,5H),2.90-2.63(m,3H),2.56-2.29(m,4H),2.06-1.71(m,4H).MS(ESI,m/z):794.2[M+1]+.
实施例197:合成化合物JL-195:(R)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.75(d,J=7.6Hz,1H),4.25-3.97(m,3H),3.92(s,3H),3.87-3.67(m,2H),3.17-2.91(m,5H),2.90-2.66(m,3H),2.51-2.27(m,4H),2.02-1.74(m,4H).MS(ESI,m/z):794.2[M+1]+.
实施例198:合成化合物JL-196:(2S,3S)-1-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)-2-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.86(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.00-7.82(m,2H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.20-3.97(m,3H),3.92(s,3H),3.84-3.64(m,2H),3.14-2.88(m,4H),2.85-2.66(m,3H),2.64-2.31(m,5H),1.98-1.60(m,4H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):792.2[M+1]+.
实施例199:合成化合物JL-197:2-((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-甲氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰氨基)吡啶-3-基)甲基)-2-氮杂双环[2.2.2]辛烷-4-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.90(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.26-3.98(m,3H),3.91(s,3H),3.80(s,2H),3.36-3.12(m,2H),3.12-2.92(m,3H),2.84-2.71(m,2H),2.60-2.27(m,4H),2.09-1.34(m,8H).MS(ESI,m/z):804.2[M+1]+.
实施例200:合成化合物JL-198:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((二甲基氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.96-7.71(m,4H),7.62(d,J=1.8Hz,1H),7.59(d,J=1.8Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.33(m,2H),7.32-7.21(m,1H),5.13(td,J=7.0,0.7Hz,1H),4.76(d,J=7.6Hz,1H),4.24-3.99(m,3H),3.92(s,3H),3.85-3.66(m,2H),3.15-2.93(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.56-2.31(m,10H).MS(ESI,m/z):694.2[M+1]+.
实施例201:合成化合物JL-199:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-(((2-羟乙基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,7.9Hz,1H),7.86-7.75(m,3H),7.73(dd,J=7.5,1.5Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.14(td,J=7.0,0.7Hz,1H),4.75(d,J=7.6Hz,1H),4.53(t,J=6.3Hz,1H),4.34-4.16(m,2H),4.16-3.99(m,3H),3.92(s,3H),3.81-3.56(m,2H),3.15-2.94(m,3H),2.94-2.70(m,3H),2.56-2.30(m,4H).MS(ESI,m/z):710.2[M+1]+.
实施例202:合成化合物JL-200:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-甲基氮杂-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.99(m,3H),3.92(s,3H),3.82(s,2H),3.13-2.93(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.55-2.29(m,4H),2.15-1.93(m,J=6.9Hz,1H),0.99(d,J=6.8Hz,3H).MS(ESI,m/z):720.2[M+1]+.
实施例203:合成化合物JL-201:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-羟基氮杂环丁烷-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.80(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.94(m,4H),3.92(s,3H),3.89-3.77(m,2H),3.75(d,J=7.1Hz,1H),3.15(dd,J=12.4,6.9Hz,2H),3.10-2.94(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.63-2.30(m,4H).MS(ESI,m/z):722.2[M+1]+.
实施例204:合成化合物JL-202:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.54(s,1H),4.25-3.99(m,3H),3.92(s,3H),3.86(s,2H),3.38-3.21(m,4H),3.13-2.93(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.32(m,4H),1.34(s,3H).MS(ESI,m/z):736.2[M+1]+.
实施例205:合成化合物JL-203:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-甲氧基吡啶-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.19-3.94(m,4H),3.92(s,3H),3.89-3.74(m,2H),3.25-3.15(m,5H),3.13-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.33(m,4H).MS(ESI,m/z):736.2[M+1]+.
实施例206:合成化合物JL-204:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-(羟甲基)-3-甲基氮杂-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.82(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25(t,J=6.4Hz,1H),4.19-3.99(m,3H),3.92(s,3H),3.83(s,2H),3.50(d,J=6.4Hz,2H),3.19(d,J=12.4Hz,2H),3.13-2.93(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.61-2.33(m,4H),1.07(s,3H).MS(ESI,m/z):750.2[M+1]+.
实施例207:合成化合物JL-205:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-(羟甲基)氮杂环丁烷-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.66-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.97(m,3H),3.92(s,3H),3.82(s,2H),3.69-3.46(m,2H),3.17(t,J=6.0Hz,1H),3.14-2.92(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.32(m,4H),2.19(p,J=7.0Hz,1H).MS(ESI,m/z):736.2[M+1]+.
实施例208:合成化合物JL-206:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-(((((1R,3R)-3-羟基环丁基)甲基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.82(m,2H),7.80-7.70(m,2H),7.67-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.99(m,6H),3.92(s,3H),3.79(hd,J=7.0,2.9Hz,1H),3.20-2.92(m,3H),2.87-2.57(m,3H),2.55-2.32(m,4H),2.16-1.78(m,5H).MS(ESI,m/z):750.2[M+1]+.
实施例209:合成化合物JL-208:(3S)-4-(((5-氯-6-(((1S)-4-(2-氯-3-((5-(((5-氧代吡咯烷-3-基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.00-7.82(m,2H),7.78-7.70(m,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.22-7.12(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.93(m,5H),3.92(s,3H),3.54-3.26(m,3H),3.13-2.91(m,3H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.67-2.33(m,6H),2.20-2.06(m,1H).MS(ESI,m/z):749.2[M+1]+.
实施例210:合成化合物JL-209:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚基-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.77(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.32-3.98(m,4H),3.92(s,3H),3.77(d,J=3.6Hz,2H),3.57(d,J=7.1Hz,1H),3.38-3.22(m,1H),3.15-2.93(m,3H),2.89-2.65(m,4H),2.56-2.28(m,4H),2.01-1.71(m,1H),1.69-1.55(m,1H).MS(ESI,m/z):736.2[M+1]+.
实施例211:合成化合物JL-210:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((((1R,2S)-2-羟基环戊基)氨基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.02-7.83(m,2H),7.80-7.71(m,2H),7.67-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.45(d,J=5.7Hz,1H),4.24-3.93(m,5H),3.92(s,3H),3.90-3.82(m,1H),3.20-2.92(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.28(m,4H),1.88-1.54(m,6H).MS(ESI,m/z):750.2[M+1]+.
实施例212:合成化合物JL-211:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((6-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.83(m,2H),7.80-7.68(m,2H),7.65-7.56(m,2H),7.53-7.43(m,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.21-3.99(m,3H),3.92(s,3H),3.84(s,2H),3.45-3.24(m,4H),3.15-2.92(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.29(m,6H),1.92(dt,J=19.6,7.1Hz,2H).MS(ESI,m/z):775.2[M+1]+.
实施例213:合成化合物JL-212:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((7-氧代-2,6-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),8.03-7.83(m,2H),7.77(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.66-7.58(m,2H),7.55(t,J=5.0Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.34-3.99(m,3H),3.92(s,3H),3.83(s,2H),3.60-3.39(m,2H),3.20-2.87(m,7H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.25(m,6H).MS(ESI,m/z):775.2[M+1]+.
实施例214:合成化合物JL-213:(3S)-4-(((5-氯-6-(((1S)-4-(2-氯-3-((5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.14(d,J=1.5Hz,1H),8.01-7.81(m,2H),7.79-7.72(m,2H),7.68-7.57(m,2H),7.54-7.44(m,2H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.99(m,3H),3.92(s,3H),3.75(d,J=2.6Hz,2H),3.52-3.21(m,2H),3.14-2.93(m,3H),2.85-2.57(m,6H),2.55-2.33(m,5H),1.89-1.69(m,2H).MS(ESI,m/z):789.2[M+1]+.
实施例215:合成化合物JL-214:(S)-4-(((6-(((S)-4-(3-((5-(((R)-3-(1H-四唑-5-基)吡咯烷-1-基)甲基)吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.02-7.81(m,2H),7.77(s,2H),7.67-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.45-7.29(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.23-3.92(m,4H),3.92(s,3H),3.77(d,J=3.4Hz,2H),3.53-3.33(m,1H),3.18(ddd,J=12.4,7.2,0.7Hz,1H),3.13-2.86(m,4H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.60-2.33(m,5H),2.31-2.09(m,2H).MS(ESI,m/z):788.2[M+1]+.
实施例216:合成化合物JL-215:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((1-氧代-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),8.01-7.81(m,2H),7.76(d,J=7.3Hz,2H),7.68-7.57(m,2H),7.53-7.42(m,2H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.27-3.99(m,3H),3.92(s,3H),3.78(s,2H),3.42(d,J=5.9Hz,2H),3.21-2.89(m,3H),2.85-2.59(m,5H),2.56-2.34(m,4H),1.95(td,J=7.1,5.3Hz,4H).MS(ESI,m/z):789.2[M+1]+.
实施例217:合成化合物JL-216:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((3-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.66-7.54(m,3H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-3.98(m,3H),3.91(s,3H),3.78(s,2H),3.43(dt,J=5.5,0.6Hz,2H),3.15-2.92(m,3H),2.85-2.72(m,3H),2.65(dt,J=12.4,7.1Hz,2H),2.55-2.28(m,6H),1.79(t,J=7.1Hz,4H).MS(ESI,m/z):803.3[M+1]+.
实施例218:合成化合物JL-217:(S)-4-(((5-氯-6-(((S)-4-(2-氯-3-((5-((1-氧代-2,9-二氮杂螺[5.5]十一烷-9-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.15(d,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.62-7.56(m,2H),7.53-7.43(m,2H),7.44-7.32(m,2H),7.28(ddd,J=7.1,2.1,0.6Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.29-3.99(m,3H),3.91(s,3H),3.78(s,2H),3.23(td,J=6.9,5.9Hz,2H),3.14-2.93(m,3H),2.86-2.73(m,3H),2.67(dt,J=12.4,7.1Hz,2H),2.57-2.31(m,4H),2.10(dt,J=12.4,7.1Hz,2H),1.95(dt,J=12.4,7.1Hz,2H),1.80-1.69(m,2H),1.67-1.50(m,2H).MS(ESI,m/z):817.3[M+1]+.
实施例219:合成化合物JL-218:(R)-4-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.31-4.00(m,5H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.12-2.84(m,4H),2.83-2.68(m,2H),2.57-2.19(m,6H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.68(m,1H).MS(ESI,m/z):763.2[M+1]+.
实施例220:合成化合物JL-219:(S)-4-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.25-4.00(m,5H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.15-2.85(m,4H),2.83-2.66(m,2H),2.56-2.18(m,6H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.62(m,1H).MS(ESI,m/z):763.2[M+1]+.
实施例221:合成化合物JL-220:(S)-2-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(d,J=6.1Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.28-5.84(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.4,7.7Hz,4H),3.95-3.79(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.39(m,2H),2.35-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.52(s,3H).MS(ESI,m/z):763.2[M+1]+.
实施例222:合成化合物JL-221:(R)-2-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.77(d,J=6.1Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.12-5.82(m,1H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.4,7.7Hz,4H),3.95-3.79(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.41(m,2H),2.40-2.13(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.52(s,3H).MS(ESI,m/z):763.2[M+1]+.
实施例223:合成化合物JL-222:2-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-2-甲基丙酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.61(s,1H),8.17(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.81-7.71(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.45-7.29(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.36(t,J=10.2Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.42-4.00(m,4H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.83(m,1H),2.85-2.67(m,2H),2.56-2.42(m,2H),2.39-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.66(m,1H),1.54(s,3H),1.49(s,3H).MS(ESI,m/z):747.2[M+1]+.
实施例224:合成化合物JL-223:((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)甘氨酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.61(s,1H),8.18(d,J=1.6Hz,1H),7.83-7.76(m,2H),7.75-7.65(m,2H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.41-4.21(m,2H),4.12(qd,J=12.4,9.2Hz,2H),3.98-3.80(m,4H),3.73(dp,J=8.2,7.0Hz,1H),3.61-3.38(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.66(m,2H),2.62-2.43(m,2H),2.37-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.69(m,1H).MS(ESI,m/z):719.2[M+1]+.
实施例225:合成化合物JL-224:3-(((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-甲基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.53(t,J=9.6Hz,1H),4.32-3.99(m,4H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.62-2.42(m,4H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.69(m,1H),1.42(s,3H),1.37(s,3H).MS(ESI,m/z):761.3[M+1]+.
实施例226:合成化合物JL-225:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99(td,J=7.0,0.7Hz,1H),3.94-3.80(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.18-2.98(m,3H),2.96-2.85(m,1H),2.84-2.68(m,2H),2.55-2.42(m,2H),2.38-2.21(m,2H),2.12(q,J=7.1Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H).MS(ESI,m/z):745.2[M+1]+.
实施例227:合成化合物JL-226:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氮杂环丁烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.99(td,J=7.0,0.9Hz,1H),3.94-3.81(m,5H),3.73(dp,J=8.2,7.0Hz,1H),3.20-2.97(m,3H),2.96-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.58-2.42(m,2H),2.39-2.23(m,2H),2.23-2.04(m,2H),2.04-1.89(m,1H),1.86-1.68(m,1H).MS(ESI,m/z):745.2[M+1]+.
实施例228:合成化合物JL-227:1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基氮杂环丁烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.38(dd,J=7.0,0.9Hz,4H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,2H),2.83-2.68(m,2H),2.57-2.39(m,2H),2.37-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.87-1.67(m,1H).MS(ESI,m/z):745.2[M+1]+.
实施例229:合成化合物JL-228:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.87-7.82(m,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.63(m,3H),3.20-2.85(m,6H),2.84-2.69(m,3H),2.57-2.41(m,2H),2.37-2.21(m,2H),2.10-1.67(m,4H).MS(ESI,m/z):759.2[M+1]+.
实施例230:合成化合物JL-229:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.63(m,3H),3.14-2.84(m,6H),2.84-2.68(m,3H),2.55-2.43(m,2H),2.38-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.91-1.68(m,3H).MS(ESI,m/z):759.2[M+1]+.
实施例231:合成化合物JL-230:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)苯甲酰胺)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.57(m,3H),3.13-2.96(m,3H),2.96-2.85(m,1H),2.84-2.66(m,3H),2.55-2.39(m,3H),2.29(td,J=7.1,1.7Hz,2H),2.07-1.86(m,3H),1.84-1.68(m,1H),1.28(s,3H).MS(ESI,m/z):773.3[M+1]+.
实施例232:合成化合物JL-231:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)苯甲酰胺)吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.85-3.64(m,3H),3.18-2.85(m,4H),2.83-2.68(m,3H),2.58-2.41(m,3H),2.29(td,J=7.1,1.7Hz,2H),2.05-1.88(m,3H),1.85-1.59(m,1H),1.28(s,3H).MS(ESI,m/z):773.3[M+1]+.
实施例233:合成化合物JL-232:(2S,4S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-4-羟基吡咯烷-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.34-4.02(m,4H),3.97-3.80(m,5H),3.79-3.58(m,2H),3.31-3.21(m,1H),3.11-2.84(m,3H),2.84-2.68(m,2H),2.55-2.43(m,2H),2.41-2.20(m,3H),2.06-1.89(m,2H),1.84-1.70(m,1H).MS(ESI,m/z):775.2[M+1]+.
实施例234:合成化合物JL-233:(3R,4R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-4-异丙基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.63-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.61(m,3H),3.26-3.15(m,1H),3.10-2.84(m,3H),2.83-2.55(m,5H),2.54-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.17-1.88(m,2H),1.86-1.63(m,2H),0.91(ddd,J=14.9,6.8,1.5Hz,6H).MS(ESI,m/z):801.3[M+1]+.
实施例235:合成化合物JL-234:(3R,4R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.64(m,3H),3.33-3.14(m,1H),3.10-2.85(m,3H),2.76(dddd,J=12.4,9.7,7.5,6.9Hz,2H),2.67-2.40(m,5H),2.36-2.12(m,3H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):773.3[M+1]+.
实施例236:合成化合物JL-235:(3S,4S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-4-甲基吡咯烷-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.63(m,3H),3.11-2.98(m,2H),2.97-2.84(m,2H),2.76(dddd,J=12.4,9.7,7.5,6.9Hz,2H),2.67-2.41(m,5H),2.38-2.12(m,3H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.69(m,1H),0.98(d,J=6.8Hz,3H).MS(ESI,m/z):773.3[M+1]+.
实施例237:合成化合物JL-236:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺)吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.90-3.79(m,2H),3.73(dp,J=8.2,7.0Hz,1H),3.12(t,J=6.9Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.95-2.64(m,5H),2.54-2.41(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.43(m,7H).MS(ESI,m/z):773.3[M+1]+.
实施例238:合成化合物JL-237:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚基-4-基)苯甲酰胺)吡啶-3-基)甲基)哌啶-2-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.61(s,1H),8.18(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.59(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.98-3.61(m,6H),3.12(t,J=6.9Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.62(m,5H),2.56-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.45(m,7H).MS(ESI,m/z):773.3[M+1]+.
实施例239:合成化合物JL-238:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.62(m,3H),3.15-2.84(m,4H),2.84-2.62(m,4H),2.60-2.42(m,3H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.54(m,5H).MS(ESI,m/z):773.3[M+1]+.
实施例240:合成化合物JL-239:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.88-3.63(m,3H),3.12-2.84(m,4H),2.83-2.64(m,4H),2.62-2.42(m,3H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.50(m,5H).MS(ESI,m/z):773.3[M+1]+.
实施例241:合成化合物JL-240:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.63(m,3H),3.15-2.57(m,8H),2.54-2.42(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.90-1.64(m,5H),1.16(s,3H).MS(ESI,m/z):787.3[M+1]+.
实施例242:合成化合物JL-241:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-3-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.74(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.87-3.62(m,3H),3.14-2.97(m,2H),2.97-2.84(m,2H),2.84-2.64(m,4H),2.56-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.90-1.66(m,5H),1.16(s,3H).MS(ESI,m/z):787.3[M+1]+.
实施例243:合成化合物JL-242:(S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.88-3.62(m,3H),3.16-2.98(m,3H),2.97-2.65(m,5H),2.55-2.43(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.08-1.66(m,6H).MS(ESI,m/z):788.3[M+1]+.
实施例244:合成化合物JL-243:(R)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-3-羟基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.84(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.89-3.60(m,3H),3.15-2.98(m,3H),2.96-2.85(m,1H),2.85-2.67(m,4H),2.49(q,J=7.3Hz,2H),2.29(td,J=7.1,1.7Hz,2H),2.08-1.59(m,6H).MS(ESI,m/z):788.3[M+1]+.
实施例245:合成化合物JL-244:(2S,3S)-1-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-2-甲基哌啶-3-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.73(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84-3.65(m,3H),3.11-2.97(m,2H),2.95-2.85(m,1H),2.82-2.67(m,4H),2.58(q,J=6.9Hz,1H),2.49(q,J=7.2Hz,2H),2.29(td,J=7.1,1.7Hz,2H),2.07-1.60(m,6H),1.17(d,J=6.8Hz,3H).MS(ESI,m/z):787.3[M+1]+.
实施例246:合成化合物JL-245:2-((6-(2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)-2-氮杂双环[2.2.2]辛烷-4-羧酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.62(m,3H),3.36-3.12(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.68(m,3H),2.55-2.41(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.09-1.66(m,10H).MS(ESI,m/z):799.3[M+1]+.
实施例247:合成化合物JL-246:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((二甲基氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84-7.71(m,3H),7.65(d,J=8.2Hz,1H),7.60(dd,J=7.5,1.8Hz,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.31-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.87-3.62(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.43(m,2H),2.38(s,6H),2.34-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.67(m,1H).MS(ESI,m/z):689.2[M+1]+.
实施例248:合成化合物JL-247:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-((((S)-5-氧代吡咯烷-2-基))甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((((2-羟基苯基)氨基)氨基)甲基)-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.88-7.75(m,3H),7.72(dd,J=7.5,1.5Hz,1H),7.68-7.56(m,3H),7.47(t,J=7.5Hz,1H),7.42-7.34(m,2H),7.32-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.7Hz,1H),4.53(t,J=6.3Hz,1H),4.39-4.00(m,4H),3.92(s,3H),3.83-3.57(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.66(m,5H),2.49(q,J=7.3Hz,2H),2.37-2.16(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.62(m,1H).MS(ESI,m/z):705.2[M+1]+.
实施例249:合成化合物JL-248:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-((((S)-5-氧代吡咯烷-2-基))甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-甲基氮杂-1-基)甲基基)-2-吡啶基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.82(s,2H),3.71(dq,J=8.2,7.0Hz,1H),3.13-2.96(m,5H),2.96-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.55-2.39(m,2H),2.38-2.19(m,2H),2.14-1.87(m,2H),1.85-1.69(m,1H),0.99(d,J=6.8Hz,3H).MS(ESI,m/z):715.2[M+1]+.
实施例250:合成化合物JL-249:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-羟基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.73(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.2,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.21-3.89(m,6H),3.89-3.65(m,4H),3.15(dd,J=12.4,6.9Hz,2H),3.05(dd,J=12.4,7.0Hz,3H),2.97-2.85(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.49(q,J=7.3Hz,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.69(m,1H).MS(ESI,m/z):717.2[M+1]+.
实施例251:合成化合物JL-250:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.54(s,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.86(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.41-3.19(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,1H),2.83-2.69(m,2H),2.53-2.44(m,2H),2.37-2.20(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.3,6.2Hz,1H),1.34(s,3H).MS(ESI,m/z):731.2[M+1]+.
实施例252:合成化合物JL-251:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-甲氧基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),4.03-3.89(m,4H),3.88-3.77(m,2H),3.77-3.66(m,1H),3.25-3.15(m,5H),3.13-2.97(m,3H),2.96-2.84(m,1H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.59-2.38(m,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.68(m,1H).MS(ESI,m/z):731.2[M+1]+.
实施例253:合成化合物JL-252:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-(羟甲基)-3-甲基氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25(t,J=6.4Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.50(d,J=6.4Hz,2H),3.19(d,J=12.4Hz,2H),3.09-2.96(m,3H),2.96-2.85(m,1H),2.84-2.67(m,2H),2.54-2.42(m,2H),2.35-2.17(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.78(ddd,J=12.4,7.4,6.2Hz,1H),1.07(s,3H).MS(ESI,m/z):745.3[M+1]+.
实施例254:合成化合物JL-253:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-(羟甲基)氮杂环丁烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.81-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.82(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.65-3.42(m,2H),3.17(t,J=6.0Hz,1H),3.14-2.97(m,5H),2.97-2.85(m,1H),2.84-2.68(m,2H),2.55-2.43(m,2H),2.38-2.24(m,2H),2.17(dq,J=14.0,7.0Hz,1H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.65(m,1H).MS(ESI,m/z):731.2[M+1]+.
实施例255:合成化合物JL-254:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((1R,3R)-3-羟基环丁基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.81-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.50(tt,J=9.4,7.1Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.26-4.00(m,5H),3.91(s,3H),3.87-3.64(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.84-2.57(m,4H),2.54-2.42(m,2H),2.38-2.21(m,2H),2.15-1.69(m,7H).MS(ESI,m/z):745.3[M+1]+.
实施例256:合成化合物JL-255:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(4,5-二氢-1H-咪唑-2-基)吡啶-2-基)苯甲酰胺
合成方法如实施例6。1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.69(d,J=1.6Hz,1H),8.11(dd,J=7.5,1.5Hz,1H),7.81(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.70-7.57(m,3H),7.47(t,J=7.4Hz,1H),7.43-7.33(m,2H),7.31-7.22(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.60(t,J=5.0Hz,1H),5.12(td,J=7.0,0.7Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.92(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.57-3.44(m,2H),3.41-3.26(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.67(m,2H),2.59-2.41(m,2H),2.37-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.86-1.65(m,1H).MS(ESI,m/z):700.2[M+1]+.
实施例257:合成化合物JL-256:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((5-氧代吡咯烷-3-基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),7.22-7.10(m,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.25-4.06(m,2H),4.06-3.93(m,2H),3.91(s,3H),3.73(dp,J=8.2,7.0Hz,1H),3.54-3.28(m,3H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.69(m,2H),2.67-2.41(m,4H),2.38-2.21(m,2H),2.21-2.06(m,1H),1.97(dq,J=12.4,7.0Hz,1H),1.87-1.69(m,1H).MS(ESI,m/z):744.2[M+1]+.
实施例258:合成化合物JL-257:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.65-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.7,2.4,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.37-4.01(m,3H),3.92(s,3H),3.86-3.64(m,3H),3.57(d,J=7.2Hz,1H),3.38-3.25(m,1H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.66(m,6H),2.55-2.43(m,2H),2.38-2.21(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.70(m,2H),1.70-1.57(m,1H).MS(ESI,m/z):731.2[M+1]+.
实施例259:合成化合物JL-258:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((((1R,2S)-2-羟基环戊基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.76(d,J=9.0Hz,2H),7.68(d,J=8.2Hz,1H),7.64-7.56(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.45(d,J=5.7Hz,1H),4.25-4.05(m,2H),4.05-3.96(m,2H),3.95-3.82(m,4H),3.73(dp,J=8.2,7.0Hz,1H),3.20-2.85(m,4H),2.83-2.68(m,2H),2.54-2.42(m,2H),2.38-2.17(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.56(m,7H).MS(ESI,m/z):745.3[M+1]+.
实施例260:合成化合物JL-259:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((6-氧代-2,5-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.75(dd,J=7.5,1.5Hz,1H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.53-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.47-3.26(m,4H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.68(m,2H),2.53-2.43(m,2H),2.41-2.22(m,4H),2.07-1.85(m,3H),1.84-1.69(m,1H).MS(ESI,m/z):770.3[M+1]+.
实施例261:合成化合物JL-260:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((7-氧代-2,6-二氮杂螺[3.4]辛烷-2-基)甲基)吡啶吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.78(s,1H),7.74(dd,J=7.5,1.4Hz,1H),7.68(d,J=8.2Hz,1H),7.63-7.58(m,2H),7.55(t,J=5.0Hz,1H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83(s,2H),3.73(dp,J=8.2,7.0Hz,1H),3.52-3.42(m,2H),3.14-2.97(m,5H),2.96-2.84(m,1H),2.84-2.65(m,2H),2.55-2.45(m,2H),2.43(d,J=0.6Hz,2H),2.36-2.19(m,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.68(m,1H).MS(ESI,m/z):770.3[M+1]+.
实施例262:合成化合物JL-261:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.14(d,J=1.5Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.73(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.57(m,2H),7.55-7.44(m,2H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.62(m,3H),3.47-3.24(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.85(m,1H),2.84-2.64(m,5H),2.64-2.41(m,5H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.69(m,3H).MS(ESI,m/z):784.3[M+1]+.
实施例263:合成化合物JL-262:N-(5-(((R)-3-(1H-四唑-5-基)吡咯烷-1-基)甲基)吡啶-2-基)-2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.22-4.04(m,2H),4.04-3.93(m,1H),3.91(s,3H),3.84-3.75(m,2H),3.75-3.64(m,1H),3.55-3.43(m,1H),3.18(ddd,J=12.4,7.2,0.7Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.85(m,2H),2.76(dddd,J=12.4,9.7,7.4,6.8Hz,2H),2.56-2.36(m,3H),2.36-2.09(m,4H),1.97(dq,J=12.4,7.0Hz,1H),1.84-1.68(m,1H).MS(ESI,m/z):783.3[M+1]+.
实施例264:合成化合物JL-263:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((1-氧代-2,7-二氮杂螺[3.5]壬烷-7-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.72(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,2H),7.52-7.31(m,4H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.83-3.62(m,3H),3.42(d,J=5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.83-2.59(m,6H),2.54-2.44(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.95(td,J=7.1,5.3Hz,5H),1.85-1.64(m,1H).MS(ESI,m/z):784.3[M+1]+.
实施例265:合成化合物JL-264:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((3-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.84(dd,J=7.4,1.6Hz,1H),7.80-7.71(m,2H),7.68(d,J=8.2Hz,1H),7.64-7.55(m,3H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.86-3.64(m,3H),3.43(dt,J=5.5,0.6Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.84(m,1H),2.84-2.60(m,6H),2.53-2.43(m,2H),2.40(d,J=0.6Hz,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.67(m,5H).MS(ESI,m/z):798.3[M+1]+.
实施例266:合成化合物JL-265:2-氯-3-((S)-1-((3-氯-6-甲氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((1-氧代-2,9-二氮杂螺[5.5]十一烷-9-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.77(d,J=7.5Hz,2H),7.68(d,J=8.2Hz,1H),7.63-7.56(m,2H),7.52-7.43(m,2H),7.43-7.32(m,2H),7.28(ddd,J=6.9,2.1,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.12(qd,J=12.4,9.2Hz,2H),3.91(s,3H),3.84-3.62(m,3H),3.23(td,J=6.9,5.9Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.85-2.61(m,6H),2.53-2.44(m,2H),2.29(td,J=7.1,1.7Hz,2H),2.10(dt,J=12.4,7.1Hz,2H),1.96(ddt,J=12.4,10.4,7.0Hz,3H),1.85-1.67(m,3H),1.67-1.54(m,2H).MS(ESI,m/z):812.3[M+1]+.
实施例267:合成化合物JL-266:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-3-氯-6-乙氧基吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.04(m,2H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.71(m,2H),7.66-7.55(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.26(qd,J=8.0,1.6Hz,2H),4.19-3.99(m,6H),3.14-2.91(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.53-2.33(m,6H),1.45(t,J=8.0Hz,3H).MS(ESI,m/z):782.2[M+1]+.
实施例268:合成化合物JL-267:(S)-4-(((6-(3-((S)-1-((6-(烯丙氧基)-5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.01(m,2H),7.85(dd,J=7.5,1.5Hz,1H),7.80-7.68(m,2H),7.66-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.00(ddt,J=16.1,10.4,6.1Hz,1H),5.43-5.26(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.82-4.66(m,4H),4.30-3.97(m,6H),3.15-2.91(m,5H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.56-2.30(m,6H).MS(ESI,m/z):794.2[M+1]+.
实施例269:合成化合物JL-268:(S)-4-(((6-(3-((S)-1-((6-(苄氧基)-5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.24(tt,J=9.3,7.9Hz,1H),8.18-8.03(m,2H),7.86-7.69(m,3H),7.66-7.56(m,2H),7.53-7.31(m,7H),7.31-7.22(m,2H),5.32-5.17(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.32-3.97(m,6H),3.14-2.89(m,5H),2.78(ddd,J=12.4,7.3,6.8Hz,1H),2.55-2.33(m,6H).MS(ESI,m/z):844.2[M+1]+.
实施例270:合成化合物JL-269:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-(((5-氰基吡啶-3-基)甲氧基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.80-8.75(m,1H),8.71(d,J=1.5Hz,1H),8.24(tt,J=9.3,7.9Hz,1H),8.16-8.10(m,2H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.72(m,2H),7.61(dd,J=7.5,1.5Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.30(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.36-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.31-3.96(m,6H),3.17-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.57-2.31(m,6H).MS(ESI,m/z):870.2[M+1]+.
实施例271:合成化合物JL-270:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟丙基)氨基)甲基)-3-氯-6-(((5-(甲基磺酰基)吡啶-3-基)甲氧基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰胺基吡啶-3-基)甲基)氨基)-3-
羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.72(d,J=1.5Hz,1H),8.65-8.57(m,1H),8.36-8.21(m,1H),8.19(t,J=1.5Hz,1H),8.15(d,J=1.4Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.72(m,2H),7.61(dd,J=7.5,1.5Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.41-5.24(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.25-3.95(m,6H),3.26(s,3H),3.15-2.89(m,5H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.32(m,6H).MS(ESI,m/z):923.2[M+1]+.
实施例272:合成化合物JL-271:2-氯-3-((S)-1-((3-氯-6-乙氧基-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.5Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.97-6.72(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.26(qd,J=8.0,1.6Hz,2H),4.20-4.03(m,4H),3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.91(dtt,J=12.4,7.5,0.6Hz,2H),2.86-2.69(m,3H),2.58-2.43(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H),1.45(t,J=8.0Hz,3H).MS(ESI,m/z):772.3[M+1]+.
实施例273:合成化合物JL-272:3-((S)-1-((6-(烯丙氧基)-3-氯-5-(((((S)
-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=7.5,1.5Hz,1H),7.81-7.75(m,2H),7.69(dd,J=8.2,7.3Hz,2H),7.65-7.58(m,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=6.8,2.1,0.5Hz,1H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),6.00(ddt,J=16.1,10.4,6.1Hz,1H),5.47-5.23(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.77(dt,J=6.1,1.0Hz,2H),4.44-3.94(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.65(m,5H),2.56-2.40(m,2H),2.39-2.17(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):784.3[M+1]+.
实施例274:合成化合物JL-273:3-((S)-1-((6-(苄氧基)-3-氯-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲
酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.15(d,J=1.4Hz,1H),7.84-7.75(m,3H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.51-7.31(m,7H),7.31-7.23(m,2H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),5.33-5.16(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.25-3.98(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.67(m,5H),2.49(q,J=7.0Hz,2H),2.37-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):834.3[M+1]+.
实施例275:合成化合物JL-274:2-氯-3-((S)-1-((3-氯-6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.80-8.76(m,1H),8.74-8.60(m,1H),8.19-8.06(m,2H),7.82(dd,J=7.4,1.6Hz,1H),7.80-7.75(m,2H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),7.02-6.69(m,2H),5.39-5.20(m,2H),5.13(td,6Hz,1H),4.24-4.00(m,4H),J=7.0,0.3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.70(m,5H),2.60-2.44(m,2H),2.37-2.15(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):860.3[M+1]+.
实施例276:合成化合物JL-275:2-氯-3-((S)-1-((3-氯-6-((5-(甲基磺酰基)吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷吡啶-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.72(d,J=1.7Hz,1H),8.66-8.58(m,1H),8.19(t,J=1.5Hz,1H),8.15(d,J=1.4Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.80-7.75(m,2H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.44-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.84(dtt,J=33.3,9.2,7.6Hz,2H),5.42-5.22(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.32-3.96(m,4H),3.73(dpd,J=8.0,7.0,1.1Hz,2H),3.26(s,3H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.69(m,5H),2.55-2.42(m,2H),2.38-2.20(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.5,7.1Hz,2H).MS(ESI,m/z):913.3[M+1]+.
实施例277:合成化合物JL-277:3-((S)-1-((3-溴-6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例7。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.85-8.74(m,1H),8.73-8.65(m,1H),8.22-8.06(m,2H),7.85-7.76(m,3H),7.71(dd,J=14.3,8.2Hz,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.0,2.0,0.7Hz,1H),6.84(dtt,J=33.2,9.2,7.6Hz,2H),5.37-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.23-3.99(m,4H),3.73(dpd,J=8.1,7.0,1.1Hz,2H),3.04(dt,J=12.4,7.1Hz,1H),2.98-2.70(m,5H),2.59-2.41(m,2H),2.39-2.19(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):904.2[M+1]+.
实施例278:合成化合物JL-278:(S)-4-(((6-(3-((S)-1-((5-((((S)-3-羧基-2-羟基丙基)氨基)甲基)-6-((5-氰基吡啶-3-基)甲氧基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-2-氯苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),10.61(s,1H),8.80-8.75(m,1H),8.74-8.67(m,1H),8.24(tt,J=9.3,7.9Hz,1H),8.15(d,J=1.5Hz,1H),8.11(t,J=1.5Hz,1H),7.91(tt,J=9.2,7.9Hz,1H),7.79(ddd,J=9.8,7.5,1.6Hz,2H),7.71(d,J=7.5Hz,1H),7.65-7.57(m,2H),7.47(t,J=7.5Hz,1H),7.42-7.31(m,2H),7.28(ddd,J=6.9,2.2,0.7Hz,1H),6.56(d,J=7.5Hz,1H),5.35-5.18(m,2H),5.11(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,2H),4.28-3.91(m,6H),3.17-2.92(m,5H),2.79(dt,J=12.3,6.9Hz,1H),2.53-2.33(m,6H).MS(ESI,m/z):836.3[M+1]+.
实施例279:合成化合物JL-279:2-氯-3-((S)-1-((6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.86-8.75(m,1H),8.74-8.63(m,1H),8.15(d,J=1.5Hz,1H),8.11(t,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78(dd,J=7.5,1.4Hz,1H),7.74-7.65(m,3H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.42-7.32(m,2H),7.29(ddd,J=6.9,2.2,0.7Hz,1H),6.83(dtt,J=27.7,9.2,7.6Hz,2H),6.56(d,J=7.5Hz,1H),5.36-5.19(m,2H),5.11(td,J=7.0,0.6Hz,1H),4.08(dd,J=21.0,9.1Hz,3H),3.83-3.55(m,3H),3.06(dt,J=12.4,7.1Hz,1H),2.98-2.72(m,5H),2.46(q,J=6.9Hz,2H),2.36-2.16(m,4H),1.97(dq,J=12.4,6.9Hz,2H),1.77(dq,J=12.4,7.1Hz,2H).MS(ESI,m/z):826.3[M+1]+.
实施例280:合成化合物JL-280:(3S)-4-(((5-氯-6-(((1S)-4-(2-氯-3-((5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)氨基甲酰基)苯基)-2,3-二氢-1H-茚-1-基)氧基)-2-((5-氰基吡啶-3-基)甲氧基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.61(s,1H),8.79-8.76(m,1H),8.71(d,J=1.4Hz,1H),8.13(q,J=1.4Hz,2H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.71(m,2H),7.63-7.57(m,2H),7.54-7.43(m,2H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),5.44-5.19(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.75(d,J=7.6Hz,1H),4.24-3.97(m,3H),3.75(d,J=2.6Hz,2H),3.43-3.24(m,2H),3.15-2.90(m,3H),2.85-2.63(m,5H),2.61-2.32(m,6H),1.79(td,J=7.1,0.7Hz,2H).MS(ESI,m/z):891.3[M+1]+.
实施例281:合成化合物JL-281:2-氯-3-((S)-1-((3-氯-6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)-N-(5-((8-氧代-2,7-二氮杂螺[4.4]壬烷-2-基)甲基)吡啶-2-基)苯甲酰胺
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.82-8.75(m,1H),8.71(d,J=1.4Hz,1H),8.13(q,J=1.4Hz,2H),7.82(dd,J=7.4,1.6Hz,1H),7.78-7.73(m,2H),7.69(d,J=8.1Hz,1H),7.64-7.57(m,2H),7.54-7.44(m,2H),7.44-7.32(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),5.36-5.18(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.11(qd,J=12.4,9.2Hz,2H),3.84-3.61(m,3H),3.49-3.25(m,2H),3.04(dt,J=12.4,7.1Hz,1H),2.96-2.85(m,1H),2.84-2.63(m,6H),2.61-2.42(m,4H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.88-1.67(m,3H).MS(ESI,m/z):886.3[M+1]+.
实施例282:合成化合物JL-282:(S)-4-(((6-(((S)-4-(3-((5-((((S)-2-羧基-1-羟基丙烷-2-基)氨基)甲基)吡啶-2-基)氨基甲酰基)-2-氯苯基)-2,3-二氢-1H-茚-1-基)氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)吡啶-3-基)甲基)氨基)-3-羟基丁酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),11.97(s,1H),10.61(s,1H),8.82-8.74(m,1H),8.74-8.64(m,1H),8.18(d,J=1.5Hz,1H),8.13(t,J=1.5Hz,1H),7.93(tt,J=9.3,8.0Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.72(m,2H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.03(t,J=9.7Hz,1H),5.42-5.20(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(dd,J=7.2,6.8Hz,2H),4.20-3.98(m,5H),3.97-3.74(m,2H),3.23-2.87(m,3H),2.78(ddd,J=12.4,7.4,6.8Hz,1H),2.58-2.29(m,4H),1.52(s,3H).MS(ESI,m/z):870.2[M+1]+.
实施例283:合成化合物JL-283:(S)-2-(((6-(2-氯-3-((S)-1-((3-氯-6-((5-氰基吡啶-3-基)甲氧基)-5-(((((S)-5-氧代吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)氧基)-2,3-二氢-1H-茚-4-基)苯甲酰氨基)吡啶-3-基)甲基)氨基)-3-羟基-2-甲基丙酸
合成方法如实施例5。1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.61(s,1H),8.85-8.76(m,1H),8.73-8.62(m,1H),8.18(d,J=1.5Hz,1H),8.13(t,J=1.5Hz,1H),7.82(dd,J=7.4,1.6Hz,1H),7.79-7.73(m,2H),7.69(d,J=8.1Hz,1H),7.61(dd,J=7.5,1.4Hz,2H),7.47(t,J=7.5Hz,1H),7.43-7.31(m,2H),7.28(ddd,J=7.1,1.9,0.7Hz,1H),6.90(tt,J=9.2,7.7Hz,1H),6.03(t,J=9.7Hz,1H),5.42-5.17(m,2H),5.13(td,J=7.0,0.6Hz,1H),4.76(t,J=6.9Hz,1H),4.10(qdd,J=12.4,9.5,6.9Hz,4H),3.96-3.79(m,2H),3.73(dp,J=8.2,7.0Hz,1H),3.04(dt,J=12.4,7.1Hz,1H),2.97-2.84(m,1H),2.77(ddt,J=12.2,7.5,6.8Hz,2H),2.56-2.42(m,2H),2.29(td,J=7.1,1.7Hz,2H),1.97(dq,J=12.4,7.0Hz,1H),1.85-1.69(m,1H),1.52(s,3H).MS(ESI,m/z):865.3[M+1]+.
实验例1PD1/PD-L1抑制活性测定实验
(一)实验设备与试剂
(二)实验过程
1.配制1×modified TR-FRET assay buffer。
2.化合物浓度梯度的配制:受试化合物测试浓度为10000nM起始,3倍稀释,10个浓度点,单孔检测。在384孔板中稀释成100倍终浓度的溶液,然后用Ech0550转移200nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加200nL的100%DMSO。
3.用1×modified TR-FRET assay buffer配制4倍终浓度的PD-L1-Biotin溶液。
4.化合物孔和阳性对照孔分别加5μL的4倍终浓度的PD-L1-Biotin溶液;在阴性对照孔中加5μL的1×modified TR-FRET assay buffer。
5.1000rpm离心30秒,振荡混匀后室温孵育15分钟。
6.用1×modified TR-FRET assay buffer配制4倍终浓度的PD-1-Eu和2倍终浓度的Dye labeled acceptor混合溶液。
7.加入15μL PD-1-Eu和Dye labeled acceptor混合溶液(其中含5μL的4倍终浓度的PD-1-Eu和10μL2倍终浓度的Dye labeled acceptor)。
8.1000rpm离心30秒,振荡混匀后室温孵育90分钟。
9.将384孔板1000rpm离心30秒,振荡混匀后用EnVision读取665nm和620nm的荧光强度,并计算TR-FRET ratio(665nm emission/620nm emission)。
(三)数据分析
计算公式:
其中:Ratiosample是样品孔的比值;RatiOmin:阴性对照孔比值均值,代表没有PD-1/PD-L1相互作用孔的读数;Ratiomax:阳性对照孔比值均值,代表没有化合物抑制孔的读数。拟合量效曲线:
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
(四)实验结果
PD1/PD-L1抑制活性测定实验结果如下表所示,C:IC50>100nM;B:IC50=100nM-10nM;A:IC50<10nM;
化合物编号 | IC<sub>50</sub>(nM) | 化合物编号 | IC<sub>50</sub>(nM) |
JL-1 | B | JL-143 | B |
JL-2 | A | JL-144 | B |
JL-3 | A | JL-145 | A |
JL-4 | B | JL-146 | A |
JL-5 | B | JL-147 | A |
JL-6 | A | JL-148 | A |
JL-7 | B | JL-149 | A |
JL-8 | A | JL-150 | B |
JL-9 | A | JL-151 | C |
JL-10 | B | JL-152 | B |
JL-11 | A | JL-153 | C |
JL-12 | A | JL-154 | B |
JL-13 | A | JL-155 | B |
JL-14 | A | JL-156 | B |
JL-15 | B | JL-157 | B |
JL-16 | A | JL-158 | C |
JL-17 | A | JL-159 | B |
JL-18 | A | JL-160 | B |
JL-19 | A | JL-161 | B |
Claims (11)
1.一种如式I所示结构的苯甲酰胺类化合物:
其中,环A和环B独立地为芳环或芳杂环;
L为键、-CH2O-、-OCH2-、-CH2CH2-、-NH(C=O)-、-(C=O)NH-、-(S=O)2NH-、-NH(S=O)2-、-O(C=O)-、-(C=O)O-或者相邻的两个R4和与它们相连的苯环上的两个原子共同形成一个5-7元的取代或者未取代的碳环氧基、取代或者未取代的碳杂环氧基;
R1独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基、取代或未取代的烷氧基;
R2独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基、取代或未取代的烷氧基;
R3独立地为氢、氘、卤素、氰基、取代或未取代的烷基;
R4独立地为氢、氘、卤素、氰基、取代或未取代的烷基;
m为1或2;
n为1或2;
p为1、2或3。
2.根据权利要求1所述的如式I所示结构的苯甲酰胺类化合物,其特征在于:
R1为所述取代的烷基或者所述的取代的烷氧基时,取代基为下列取代基中的一个或多个:卤素、C1-C4烷基、羟基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;所述的取代的羟基或所述的取代的氨基中的取代基为下列取代基的一个或多个:C1-C4烷基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;当取代基为多个时,所述的取代基相同或者不同;
R2为所述的取代的烷基或者所述的取代的烷氧基时,取代基为下列取代基中的一个或多个:卤素、C1-C4烷基、羟基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;所述的取代的羟基或所述的取代的氨基中的取代基为下列取代基的一个或多个:C1-C4烷基、苄基、氰基取代基的苄基、C1-C4烷氧基、C1-C4羧基、C1-C4酯基或C1-C4酰胺基;当取代基为多个时,所述的取代基相同或者不同;
中,R5和R6独立地为氢、取代或未取代的烷基、烷氧基、羟烷基或者氨基烷基;或者R5、R6和它们相连的氮原子一起形成一个5-7元的取代或未取代的碳杂环;所述碳杂环中,杂原子为氮,或氮和氧,杂原子数为1-4个;
3.根据权利要求1所述的如式I所示结构的苯甲酰胺类化合物,其特征在于:所述芳环为C6-C14芳环;所述杂芳环的杂原子为氮、氧或硫,杂原子数为1-4个。
7.根据权利要求1-6任一项所述的如式I所示结构的苯甲酰胺类化合物,其特征在于:该化合物还包括其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。
8.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1-7中任一项所述的如式I所示结构的苯甲酰胺类化合物,及药学上可接受的载体或辅料。
9.根据权利要求1-7任一项所述的如式I所示结构的苯甲酰胺类化合物的制备方法,其特征在于:包括如下步骤:
(1)式II化合物与式III化合物经缩合反应得到式IV化合物;
(2)式IV化合物与式V化合物经铃木反应得到式VI化合物;
(3)经过四丁基氟化铵催化的脱保护反应将式VI化合物的-OPg1转化为-OH;
(4)式VII化合物经羟基选择性氧化反应得到式VIII化合物;
(5)式VIII化合物经还原胺化反应得到式IX化合物;
(6)式X化合物与式XI化合物经铃木反应得到式XII化合物;
(7)式XII化合物经还原胺化反应得到式XIII化合物;
(8)式XIV化合物与式XV化合物经还原胺化反应得到式XVI化合物。
10.权利要求1-7任一项所述的如式I所示结构的苯甲酰胺类化合物在制备作为免疫检查点抑制剂、具PD-1/PD-L1信号通路的抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
11.权利要求8的药物组合物在制备作为免疫检查点抑制剂、具PD-1/PD-L1信号通路的抑制活性的抑制剂、抗肿瘤药物、抗感染药物中的用途。
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