CN115286617B - 一种靶向降解nampt的protac化合物及其应用 - Google Patents
一种靶向降解nampt的protac化合物及其应用 Download PDFInfo
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- CN115286617B CN115286617B CN202210722273.1A CN202210722273A CN115286617B CN 115286617 B CN115286617 B CN 115286617B CN 202210722273 A CN202210722273 A CN 202210722273A CN 115286617 B CN115286617 B CN 115286617B
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Abstract
本发明公开了一种靶向降解NAMPT的PROTAC化合物或其药用盐，结构如下所示：本发明制备的化合物能够下调细胞外NAMPT蛋白水平，激活免疫系统，具有化疗和免疫治疗双重功效。作为首次报道的NAMPT蛋白降解靶向嵌合体，具有进一步的开发和研究价值。
Description
技术领域
本发明属于医药技术领域，具体地说，涉及一种靶向降解NAMPT的PROTAC化合物及其应用。
背景技术
烟酰胺腺嘌啉二核苷酸(NAD)是细胞氧化还原过程中最重要的辅酶之一，在细胞的生理过程中起着至关重要的作用。NAD的合成可通过从头合成途径和三条补救合成途径等实现。哺乳动物中NAD主要是依赖以烟酰胺为起始原料的补救途径获得，烟酰胺磷酸核糖转移酶(NAMPT)是该途径的限速酶。相比于正常细胞，肿瘤细胞具有更高的增殖速率和能量需求，因此NAMPT处于高表达状态，是抗肿瘤研究中的一个重要靶点。近期有文献报道，NAMPT能分泌到细胞外，具有类细胞因子作用，能够通过激活NF-KB途径、PI3K-MAPK途径以及下游的AKT、ERK和GSK3β的磷酸化，上调VEGF和金属蛋白酶MMPs的基因表达和蛋白生成，同时上调基质细胞衍生因子SDF-1的表达，对趋化因子受体CXCR4和CXCR7的亲和力增加，促进肿瘤细胞增殖、侵袭和转移。细胞外NAMPT同时其也具有免疫抑制的作用，能够影响NF-KB、JAK-STAT3通路，促使细胞向M2型分化，抑制T细胞活性，促进IL-10的分泌，具有免疫抑制的作用。同时其也能提高IDO蛋白水平，导致免疫逃逸。
目前已进入临床的NAMPT抑制剂有FK866和CHS828，其能通过特异性、非竞争性抑制NAMPT蛋白，从而抑制肿瘤生长。但是NAMPT抑制剂单独使用时会带来一些问题。其一是NAMPT靶点被抑制后，细胞受负反馈调节可能会使NAMPT蛋白水平上调，因此需要更高浓度的抑制剂来达到原先抑制水平，而高浓度抑制剂可能会引起毒副作用和耐药性。其二是NAMPT蛋白水平上调可能导致细胞外NAMPT的上调，促使肿瘤免疫逃逸的发生。临床研究表明，FK866和CHS828在低剂量下抑瘤效果较差，而在高剂量下会引起剂量限制性毒性血小板减少症和胃肠道毒副作用。这也是FK866在临床二期试验后一直处于停滞状态的原因。
因此，利用蛋白降解靶向嵌合体的优势，急需设计合成靶向NAMPT的蛋白降解靶向嵌合体，直接调控细胞内NAMPT水平，降低细胞内NAD水平，使细胞能量耗竭而死。同时通过细胞内NAMPT水平的降低减少NAMPT的分泌，下调细胞外NAMPT蛋白水平，从而抑制肿瘤生长、侵袭和转移。
发明内容
本发明的第一个目的是提供一种靶向降解NAMPT的PROTAC化合物。
本发明的另一个目的是提供一种所述靶向降解NAMPT的PROTAC化合物在制备抗肿瘤的药物中的应用。
为了实现上述目的，本发明采用的技术方案如下：
本发明的第一方面提供了一种靶向降解NAMPT的PROTAC化合物或其药用盐，结构如下所示：
X选自O、S；
Y选自
n选自1至13的正整数，优选2至12的正整数(如2、3、4、5、6、7、8、9、10、11)；
m选自1至13的正整数，优选1至5的正整数(如1、2、3、4、5)；
R选自：
较优选的，所述靶向降解NAMPT的PROTAC化合物中，Y选自以下结构的一种：
最优选的，所述NAMPT蛋白降解靶向嵌合体选自以下结构的一种：
所述药用盐是与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、乳酸、柠檬酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、酒石酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。
本发明的第二方面提供了一种所述靶向降解NAMPT的PROTAC化合物在制备抗肿瘤的药物中的应用。
所述肿瘤选自卵巢癌、乳腺癌、结肠癌、肺癌、肝癌、肾癌、非小细胞肺癌、前列腺癌、甲状腺癌、皮肤癌、胰腺癌、乳腺癌、膀胱癌、骨髓增生异常综合症、淋巴瘤、食管癌、胃肠道癌、骨肉瘤、白血病、中枢或外周神经系统的肿瘤。
所述肿瘤细胞选自A2780细胞株(人卵巢癌细胞)、HeLa细胞株(宫颈细胞)。
本发明的第三方面提供了一种所述靶向降解NAMPT的PROTAC化合物或其药用盐在制备NAMPT蛋白抑制剂或降解剂中的应用。
由于采用上述技术方案，本发明具有以下优点和有益效果：
本发明制备的化合物表现出良好的NAMPT酶抑制活性，能通过泛素蛋白酶体途径下调细胞内的NAMPT蛋白水平，对多种肿瘤细胞(如A2780和HeLa)有很好的抑制作用。本发明的化合物抗肿瘤谱较广，能够明显抑制肿瘤组织生长，可以应用于NAMPT介导的肿瘤疾病的治疗。
本发明制备的化合物能够下调细胞外NAMPT蛋白水平，激活免疫系统，具有化疗和免疫治疗双重功效。作为首次报道的NAMPT蛋白降解靶向嵌合体，具有进一步的开发和研究价值。
附图说明
图1是蛋白降解靶向嵌合分子对A2780细胞内NAMPT蛋白表达的影响示意图。
图2是蛋白降解靶向嵌合分子对HeLa细胞内NAMPT蛋白表达的影响示意图。
图3是在裸鼠A2780移植瘤模型中，蛋白降解靶向嵌合分子化合物I-3、对照分子FK866和735组小鼠肿瘤的生长曲线、体重变化和肿瘤大小、H&E组织染色和免疫组化评价示意图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1化合物1的合成
步骤a.4-((4-硝基苯基)磺酰基)哌嗪-1-羧酸叔丁酯：
将对硝基磺酰氯(5.0g，22.60mmol)、单Boc哌嗪(4.2g，22.60mmol)溶于DCM(70mL)中，室温下加TEA(5mL)，反应0.5h，TLC监测。反应结束，加1M稀盐酸(40mL)调至弱酸性，DCM萃取，浓缩，得白色固体8.0g，收率95％。1H NMR(600MHz,DMSO-d6)δ8.39(d,J＝8.9Hz,2H),7.94(d,J＝8.9Hz,2H),3.53(t,J＝5.1Hz,4H),3.04(t,J＝5.0Hz,4H),1.41(s,9H).
步骤b.4-((4-氨基苯基)磺酰基)哌嗪-1-羧酸叔丁酯的合成：
将底物4-((4-硝基苯基)磺酰基)哌嗪-1-羧酸叔丁酯(4.0g，10.78mmol)溶于DCM/MeOH(4:1，50mL)中，加10％Pd/C(1.15g，1.08mmol)，H2保护，室温反应过夜，TLC监测。反应结束，过滤，DCM、MeOH洗，收集滤液，蒸干溶剂，得白色固体3.5g，收率94％。1H NMR(600MHz,DMSO-d6)δ7.33(d,J＝8.7Hz,2H),6.65(d,J＝8.8Hz,2H),6.10(s,2H),3.37(t,J＝4.8Hz,4H),2.73(t,J＝5.0Hz,4H),1.34(s,9H).
步骤c.4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-羧酸叔丁酯的合成：
将三光气(289mg，0.97mmol)溶于DCM(5mL)中，0℃搅拌；将化合物4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-羧酸叔丁酯(827mg，2.43mmol)溶于DCM(7mL)中，加入TEA(0.44mL，3.15mmol)，将其加入三光气的DCM溶液中，5min后室温反应1h。将3-氨甲基吡啶(262mg，2.43mmol)溶于DCM(5mL)中，加入TEA(0.44mL，3.15mmol)，将其加入上述反应液中，室温反应2h，TLC监测。反应结束，减压旋干溶剂，柱层析(DCM/MeOH＝100:3)，得白色固体1.13g，收率98％。1H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.53(d,J＝1.7Hz,1H),8.45(dd,J＝4.8,1.6Hz,1H),7.72-7.69(m,1H),7.66-7.62(m,2H),7.60-7.55(m,2H),7.38-7.33(m,1H),6.91(t,J＝6.0Hz,1H),4.34(d,J＝5.9Hz,2H),3.41-3.35(m,4H),2.81-2.77(m,4H),1.34(s,9H).
步骤d.1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲的合成：
将底物4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-羧酸叔丁酯(510mg，1.07mmol)溶于DCM(10mL)中，室温滴加TFA(5mL)，室温反应1h，TLC监测。反应完全，蒸干溶剂，得白色固体403mg，收率100％。1H NMR(600MHz,DMSO-d6)δ9.53(s,1H),8.73-8.48(m,3H),7.78(d,J＝7.9Hz,1H),7.69(d,J＝8.9Hz,2H),7.63(d,J＝8.9Hz,2H),7.48-7.40(m,1H),7.26(t,J＝6.0Hz,1H),4.36(d,J＝5.9Hz,2H),3.20-3.16(m,4H),3.11-2.99(m,4H).
步骤e.7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酸甲酯的合成：
将底物7-溴庚酸(282mg，1.35mmol)溶于MeOH(6mL)中，滴加氯化亚砜(0.3mL)，室温反应1h，TLC监测。反应完全，蒸干溶剂，溶于DMF(4mL)中，加入1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲(506mg，1.35mmol)、K2CO3(932mg，6.75mmol)、KI(224mg，1.35mmol)，室温反应过夜。反应完全，EA萃取，浓缩，柱层析，得白色固体177mg，收率26％。1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.53(d,J＝1.8Hz,1H),8.46(dd,J＝4.8,1.6Hz,1H),7.73-7.69(m,1H),7.64(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.38-7.34(m,1H),6.91(t,J＝6.0Hz,1H),4.34(d,J＝5.7Hz,2H),3.55(s,3H),2.82(s,4H),2.38(s,4H),2.24(t,J＝7.4Hz,2H),2.21(t,J＝7.2Hz,2H),1.51-1.43(m,2H),1.36-1.28(m,2H),1.26-1.13(m,4H).
步骤f.(2S,4R)-1-((S)-3,3-二甲基-2-(7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酰胺基)丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺的合成：
将底物7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酸甲酯(177mg，0.34mmol)溶于THF/MeOH/H2O(V/V/V＝4/2/1)的混合溶液(7mL)中，室温下加LiOH(51mg，2.13mmol)，室温反应4h，TLC监测。反应完全，减压旋干溶剂，加水(1mL)，1M的HCl水溶液调至酸性。减压旋干溶剂，复溶于干燥DMF(2mL)中，室温下加VHL配体(63mg，0.14mmol)、HATU(161mg，0.42mmol)、DIPEA(55mg，0.42mmol)中，室温反应5h，TLC监测。反应完全，EA萃取，浓缩，柱层析，得化合物I-1白色固体48mg，收率15％。1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.99(s,1H),8.54(d,J＝1.6Hz,1H),8.46(dd,J＝4.6,1.2Hz,1H),8.36(d,J＝7.8Hz,1H),7.75(d,J＝9.3Hz,1H),7.72(d,J＝7.8Hz,1H),7.66(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.44(d,J＝8.2Hz,2H),7.41-7.32(m,3H),6.92(t,J＝6.0Hz,1H),5.09(d,J＝3.6Hz,1H),4.97-4.89(m,1H),4.51(d,J＝9.3Hz,1H),4.43(t,J＝8.0Hz,1H),4.35(d,J＝5.9Hz,2H),4.28(s,1H),3.65-3.56(m,2H),2.83(s,4H),2.46(s,3H),2.38(s,4H),2.26-2.18(m,3H),2.12-2.05(m,1H),2.05-1.98(m,1H),1.84-1.77(m,1H),1.52-1.40(m,2H),1.38(d,J＝7.0Hz,3H),1.36-1.28(m,2H),1.20(s,4H),0.93(s,9H).13C NMR(150MHz,DMSO-d6)δ171.98,170.58,169.59,154.77,151.40,148.69,148.05,147.73,144.84,144.61,135.50,134.94,131.08,129.67,128.84,128.78,126.34,126.09,123.42,117.16,68.72,58.50,57.19,56.31,56.19,51.64,47.66,45.87,40.49,37.68,35.13,34.80,28.49,26.44,26.40,26.04,25.29,22.36,15.94.HR-ESI-MS calcd forC47H63N9O7S2[M+H]+930.4365,found 930.4376.
实施例2
将实施例1步骤e中的7-溴庚酸替换为8-溴辛酸，其他同实施例1，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.98(s,1H),8.53(d,J＝1.8Hz,1H),8.45(dd,J＝4.8,1.5Hz,1H),8.36(d,J＝7.8Hz,1H),7.75(d,J＝9.3Hz,1H),7.73-7.69(m,1H),7.65(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.40-7.34(m,3H),6.96(t,J＝6.0Hz,1H),5.08(d,J＝3.6Hz,1H),4.97-4.88(m,1H),4.50(d,J＝9.4Hz,1H),4.42(t,J＝8.0Hz,1H),4.34(d,J＝5.9Hz,2H),4.30-4.25(m,1H),3.64-3.55(m,2H),2.82(s,4H),2.45(s,3H),2.37(s,4H),2.26-2.17(m,3H),2.11-2.04(m,1H),2.04-1.97(m,1H),1.82-1.76(m,1H),1.50-1.39(m,2H),1.37(d,J＝7.0Hz,3H),1.35-1.29(m,2H),1.23-1.15(m,6H),0.92(s,9H).13C NMR(150MHz,DMSO-d6)δ172.01,170.57,169.60,154.81,151.41,148.69,148.04,147.73,144.88,144.61,135.51,134.95,131.07,129.67,128.82,126.35,126.05,123.42,117.16,68.73,58.50,57.19,56.30,56.20,51.63,47.67,45.89,40.49,37.69,35.13,34.84,28.55,26.64,26.41,26.06,25.33,22.37,15.94.HR-ESI-MS calcdfor C48H65N9O7S2[M+H]+944.4521,found 944.4553.
实施例3
将实施例1步骤e中的7-溴庚酸替换为9-溴壬酸，其他同实施例1，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),8.98(s,1H),8.53(d,J＝1.2Hz,1H),8.45(d,J＝4.6Hz,1H),8.35(d,J＝7.8Hz,1H),7.75(d,J＝9.3Hz,1H),7.71(d,J＝7.9Hz,1H),7.65(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.43(d,J＝8.2Hz,2H),7.40-7.31(m,3H),6.91(t,J＝6.0Hz,1H),5.08(d,J＝3.6Hz,1H),4.96-4.88(m,1H),4.51(d,J＝9.4Hz,1H),4.42(t,J＝8.0Hz,1H),4.34(d,J＝5.9Hz,2H),4.27(s,1H),3.66-3.55(m,2H),2.82(s,4H),2.45(s,3H),2.38(s,4H),2.27-2.17(m,3H),2.12-2.05(m,1H),2.04-1.97(m,1H),1.83-1.76(m,1H),1.51-1.39(m,2H),1.37(d,J＝7.0Hz,3H),1.35-1.28(m,2H),1.19(s,8H),0.92(s,9H).13C NMR(150MHz,DMSO-d6)δ172.00,170.58,169.60,154.77,151.40,148.69,148.04,147.72,144.83,144.60,135.49,134.94,131.07,129.67,128.83,128.78,126.34,126.07,123.41,117.15,68.71,58.51,57.23,56.31,56.18,51.63,47.66,45.88,40.49,37.68,35.13,34.83,28.80,28.63,28.58,26.72,26.40,26.10,25.33,22.36,15.94.HR-ESI-MS calcd for C49H67N9O7S2[M+H]+958.4678,found958.4690.
实施例4
将实施例1步骤e中的7-溴庚酸替换为10-溴癸酸，其他同实施例1，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.98(s,1H),8.53(d,J＝1.8Hz,1H),8.45(dd,J＝4.7,1.6Hz,1H),8.36(d,J＝7.8Hz,1H),7.76(d,J＝9.3Hz,1H),7.73-7.69(m,1H),7.64(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.39-7.31(m,3H),6.91(t,J＝6.0Hz,1H),5.08(d,J＝3.6Hz,1H),4.96-4.88(m,1H),4.51(d,J＝9.4Hz,1H),4.42(t,J＝8.0Hz,1H),4.34(d,J＝5.9Hz,2H),4.30-4.25(m,1H),3.64-3.55(m,2H),2.82(s,4H),2.45(s,3H),2.37(s,4H),2.26-2.16(m,3H),2.11-2.05(m,1H),2.03-1.97(m,1H),1.82-1.76(m,1H),1.52-1.40(m,2H),1.37(d,J＝7.0Hz,3H),1.35-1.28(m,2H),1.19(s,10H),0.93(s,9H).13C NMR(150MHz,DMSO-d6)δ172.01,170.57,169.60,154.77,151.41,148.69,148.04,147.72,144.84,144.60,135.50,134.94,131.07,129.67,128.83,128.78,126.34,126.06,123.41,117.15,68.71,58.51,57.22,56.30,56.19,51.63,47.66,45.88,40.49,37.68,35.14,34.85,28.83,28.66,28.58,26.72,26.40,26.11,25.36,22.36,15.94.HR-ESI-MS calcd for C50H69N9O7S2[M+H]+972.4834,found972.4828.
实施例5
将实施例1步骤e中的7-溴庚酸替换为11-溴十一酸，其他同实施例1，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.98(s,1H),8.53(s,1H),8.45(d,J＝3.9Hz,1H),8.35(d,J＝7.7Hz,1H),7.75(d,J＝9.3Hz,1H),7.71(d,J＝7.8Hz,1H),7.64(d,J＝8.7Hz,2H),7.57(d,J＝8.8Hz,2H),7.43(d,J＝8.1Hz,2H),7.38(d,J＝8.2Hz,2H),7.37-7.32(m,1H),6.92(t,J＝5.8Hz,1H),5.08(d,J＝3.5Hz,1H),4.96-4.89(m,1H),4.51(d,J＝9.3Hz,1H),4.42(t,J＝8.0Hz,1H),4.34(d,J＝5.8Hz,2H),4.28(s,1H),3.64-3.56(m,2H),2.82(s,4H),2.45(s,3H),2.37(s,4H),2.26-2.18(m,3H),2.12-2.05(m,1H),2.04-1.97(m,1H),1.84-1.76(m,1H),1.51-1.41(m,2H),1.37(d,J＝7.0Hz,3H),1.34-1.29(m,2H),1.19(s,12H),0.93(s,9H).13CNMR(150MHz,DMSO-d6)δ172.00,170.57,169.60,154.77,151.39,148.68,148.03,147.72,144.83,144.59,135.49,134.93,131.06,129.66,128.82,128.77,126.34,126.07,123.40,117.14,68.71,58.50,57.21,56.30,56.17,51.62,47.65,45.87,40.48,37.67,35.12,34.85,28.86,28.65,28.58,26.74,26.40,26.09,25.36,22.34,15.93.HR-ESI-MS calcd for C51H71N9O7S2[M-H]-984.4845,found 984.4847.
实施例6
将实施例1步骤e中的7-溴庚酸替换为12-溴十二酸，其他同实施例1，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.98(s,1H),8.53(d,J＝1.7Hz,1H),8.45(dd,J＝4.7,1.5Hz,1H),8.36(d,J＝7.8Hz,1H),7.76(d,J＝9.3Hz,1H),7.73-7.69(m,1H),7.65(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.39-7.34(m,3H),6.91(t,J＝6.0Hz,1H),5.09(d,J＝3.6Hz,1H),4.96-4.87(m,1H),4.51(d,J＝9.4Hz,1H),4.42(t,J＝8.0Hz,1H),4.34(d,J＝5.9Hz,2H),4.30-4.25(m,1H),3.65-3.56(m,2H),2.81(s,4H),2.45(s,3H),2.37(s,4H),2.27-2.18(m,3H),2.11-2.05(m,1H),2.03-1.98(m,1H),1.83-1.77(m,1H),1.53-1.40(m,2H),1.37(d,J＝7.0Hz,3H),1.35-1.28(m,2H),1.19(s,14H),0.93(s,9H).13C NMR(150MHz,DMSO-d6)δ172.03,170.59,169.61,154.78,151.41,148.70,148.05,147.73,144.85,144.61,135.51,134.96,131.08,129.67,128.84,128.79,126.35,126.05,123.42,117.16,68.73,58.52,57.22,56.32,56.20,51.63,47.67,45.88,40.49,37.69,35.15,34.87,28.92,28.88,28.69,28.61,26.74,26.41,26.10,25.38,22.37,15.95.HR-ESI-MS calcd for C52H73N9O7S2[M+H]+1000.5147,found 1000.5146.
实施例7
步骤a-d同实施例1；
步骤e 2-(2-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)乙氧基)乙酸叔丁酯的合成：
将1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲(581mg，1.55mmol)、2-(2-碘乙氧基)乙酸叔丁酯(488mg，1.71mmol)、K2CO3(1.07g，7.55mmol)溶于5mL的DMF中，室温反应过夜。反应完全，EA萃取，浓缩，柱层析，得白色固体198mg，收率24％。1HNMR(600MHz,DMSO-d6)δ9.23(s,1H),8.53(d,J＝2.2Hz,1H),8.46(dd,J＝4.7,1.6Hz,1H),7.73-7.70(m,1H),7.65(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.37-7.34(m,1H),6.93(t,J＝6.0Hz,1H),4.34(d,J＝5.9Hz,2H),3.91(s,2H),3.49(t,J＝5.5Hz,2H),2.82(s,4H),2.50-2.46(m,6H),1.38(s,9H).
步骤f(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)乙氧基)乙酰胺基)丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺的合成：
将底物2-(2-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)乙氧基)乙酸叔丁酯(125mg，0.24mmol)溶于DCM(5mL)中，加TFA(4mL)，室温反应1h，TLC监测。反应完全，蒸干溶剂，复溶于干燥DMF(3mL)中，加VHL配体(104mg，0.24mmol)、HATU(267mg，0.70mmol)、DIPEA(151mg，1.17mmol)，室温反应4h，TLC监测。反应完全，浓缩，反相柱层析，冻干机干燥，得白色固体65mg，收率31％。1HNMR(600MHz,DMSO-d6)δ9.19(s,1H),8.98(s,1H),8.53(d,J＝1.4Hz,1H),8.45(d,J＝6.6Hz,2H),7.70(d,J＝7.8Hz,1H),7.66(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.44(d,J＝8.2Hz,2H),7.40-7.32(m,3H),7.26(d,J＝9.7Hz,1H),6.91(t,J＝5.9Hz,1H),5.12(d,J＝3.5Hz,1H),4.97-4.86(m,1H),4.49(d,J＝9.6Hz,1H),4.43(t,J＝8.2Hz,1H),4.34(d,J＝6.0Hz,2H),4.28(s,1H),3.89(dd,J＝26.6,15.2Hz,2H),3.62-3.48(m,4H),2.95-2.76(m,4H),2.53-2.50(m,6H),2.45(s,3H),2.09-2.00(m,1H),1.81-1.73(m,1H),1.39(d,J＝7.0Hz,3H),0.84(s,9H).13CNMR(150MHz,DMSO-d6)δ170.45,168.98,168.36,154.78,151.42,148.69,148.05,147.74,144.86,144.72,135.52,134.94,131.09,129.69,128.87,126.29,125.97,123.42,117.21,69.44,68.74,68.55,58.53,56.48,55.56,51.93,47.75,45.87,40.48,37.73,35.58,26.09,22.42,15.96.HR-ESI-MS calcd for C44H57N9O8S2[M+H]+904.3844,found 904.3853.
实施例8
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-碘乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.98(s,1H),8.53(d,J＝1.6Hz,1H),8.45(dd,J＝4.7,1.2Hz,1H),8.42(d,J＝7.7Hz,1H),7.70(d,J＝7.8Hz,1H),7.65(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),7.43(d,J＝8.2Hz,2H),7.40-7.31(m,4H),6.91(t,J＝5.9Hz,1H),5.13(d,J＝3.5Hz,1H),4.95-4.87(m,1H),4.53(d,J＝9.6Hz,1H),4.47-4.41(m,1H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.93(s,2H),3.64-3.54(m,4H),3.53-3.44(m,4H),2.82(s,4H),2.49-2.42(m,9H),2.09-2.01(m,1H),1.83-1.72(m,1H),1.37(d,J＝7.0Hz,3H),0.91(s,9H).13C NMR(150MHz,DMSO-d6)δ170.42,168.98,168.44,154.78,151.42,148.70,148.05,147.73,144.85,144.70,135.51,134.95,131.09,129.67,128.86,128.81,126.30,126.04,123.42,117.15,70.43,69.58,69.38,68.75,68.34,58.53,56.50,55.64,51.93,47.74,45.89,40.49,37.70,35.71,26.27,26.20,22.44,15.96.HR-ESI-MS calcdfor C46H61N9O9S2[M+H]+948.4106,found 948.4139.
实施例9
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.98(s,1H),8.53(d,J＝1.6Hz,1H),8.45(dd,J＝4.7,1.6Hz,1H),8.42(d,J＝7.7Hz,1H),7.73-7.68(m,1H),7.65(d,J＝9.0Hz,2H),7.57(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.39-7.33(m,4H),6.91(t,J＝6.0Hz,1H),5.13(d,J＝3.6Hz,1H),4.94-4.86(m,1H),4.54(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.95(s,2H),3.63-3.49(m,8H),3.49-3.46(m,2H),3.44(t,J＝5.8Hz,2H),2.81(s,4H),2.49-2.40(m,9H),2.09-2.00(m,1H),1.82-1.74(m,1H),1.37(d,J＝7.0Hz,3H),0.93(s,9H).13C NMR(150MHz,DMSO-d6)δ170.43,169.00,168.49,154.78,151.42,148.70,148.06,147.74,144.86,144.67,135.51,134.96,131.09,129.68,128.86,128.81,126.31,126.26,126.00,123.43,117.15,70.44,69.76,69.58,68.75,68.22,58.54,56.55,56.49,55.67,51.90,47.73,45.88,40.50,37.70,35.69,26.21,22.42,15.96.HR-ESI-MS calcd for C48H65N9O10S2[M+H]+992.4369,found992.4391.
实施例10
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.98(s,1H),8.53(d,J＝1.5Hz,1H),8.45(dd,J＝4.7,1.4Hz,1H),8.42(d,J＝7.7Hz,1H),7.71(d,J＝7.8Hz,1H),7.64(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.43(d,J＝8.2Hz,2H),7.40-7.32(m,4H),6.92(t,J＝6.0Hz,1H),5.13(d,J＝3.5Hz,1H),4.94-4.86(m,1H),4.54(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.96(s,2H),3.62-3.49(m,10H),3.48-3.41(m,6H),2.81(s,4H),2.49-2.41(m,9H),2.09-1.99(m,1H),1.82-1.73(m,1H),1.37(d,J＝7.0Hz,3H),0.94(s,9H).13CNMR(150MHz,DMSO-d6)δ170.43,169.00,168.48,154.78,151.42,148.70,148.05,147.73,144.85,144.66,135.51,134.95,131.08,129.68,128.85,128.80,126.31,126.25,126.01,123.42,117.14,70.43,69.84,69.72,69.67,69.58,68.75,68.23,58.54,56.54,56.48,55.68,51.89,47.73,45.88,40.49,37.69,35.69,26.29,26.21,22.40,15.95.HR-ESI-MS calcd for C50H69N9O11S2[M+Na]+1058.4450,found1058.4468.
实施例11
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-2-2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.98(s,1H),8.53(d,J＝1.6Hz,1H),8.45(dd,J＝4.7,1.6Hz,1H),8.43(d,J＝7.7Hz,1H),7.73-7.69(m,1H),7.65(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.40-7.32(m,4H),6.91(t,J＝6.0Hz,1H),5.13(d,J＝3.5Hz,1H),4.94-4.87(m,1H),4.55(d,J＝9.6Hz,1H),4.45(t,J＝8.3Hz,1H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.96(s,2H),3.62-3.50(m,10H),3.49-3.45(m,6H),3.45-3.41(m,4H),2.81(s,4H),2.49-2.41(m,9H),2.08-2.01(m,1H),1.82-1.74(m,1H),1.37(d,J＝7.0Hz,3H),0.94(s,9H).13C NMR(150MHz,DMSO-d6)δ170.43,169.01,168.49,154.77,151.42,148.70,148.05,147.73,144.85,144.66,135.51,134.96,131.08,129.68,128.85,128.80,126.31,126.01,123.42,117.14,70.42,69.84,69.77,69.73,69.67,69.58,68.75,68.22,58.54,56.54,56.48,55.68,51.90,47.73,45.88,40.49,37.70,35.70,26.29,26.21,22.41,15.95.HR-ESI-MS calcd for C52H73N9O12S2[M+Na]+1102.4712,found 1102.4754.
实施例12
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(4-(2-溴乙基)-1H-1,2,3-三唑-1-基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.22(s,1H),8.98(s,1H),8.53(d,J＝1.7Hz,1H),8.45(dd,J＝4.8,1.6Hz,1H),8.42(d,J＝7.7Hz,1H),7.83(s,1H),7.73-7.69(m,1H),7.65(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.44(d,J＝8.3Hz,2H),7.39-7.31(m,3H),7.28(d,J＝9.5Hz,1H),6.93(t,J＝6.0Hz,1H),5.13(d,J＝3.5Hz,1H),4.95-4.84(m,1H),4.58-4.47(m,3H),4.43(t,J＝8.2Hz,1H),4.34(d,J＝5.9Hz,2H),4.27(s,1H),3.99-3.89(m,2H),3.88-3.79(m,2H),3.63-3.53(m,2H),2.84(s,4H),2.75-2.69(m,2H),2.55(t,J＝7.6Hz,2H),2.50-2.42(m,7H),2.09-2.01(m,1H),1.81-1.73(m,1H),1.37(d,J＝7.0Hz,3H),0.90(s,9H).13C NMR(150MHz,DMSO-d6)δ170.41,169.00,168.00,154.80,151.46,148.71,148.08,147.76,144.88,144.82,144.70,135.53,134.98,131.11,129.70,128.87,128.84,126.30,126.10,123.45,122.53,117.20,69.24,69.07,68.75,58.53,56.83,56.50,55.74,51.48,49.02,47.76,45.88,40.51,37.74,35.66,26.27,26.21,22.85,22.48,15.98.HR-ESI-MS calcd for C48H62N12O8S2[M-H]-997.4182,found 997.4181.
实施例13
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-(4-(2-溴乙基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.21(s,1H),8.97(s,1H),8.53(d,J＝0.9Hz,1H),8.45(dd,J＝4.4,0.7Hz,1H),8.42(d,J＝7.7Hz,1H),7.80(s,1H),7.73-7.69(m,1H),7.64(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.39(d,J＝9.5Hz,1H),7.37-7.34(m,3H),6.92(t,J＝5.9Hz,1H),5.15(d,J＝3.4Hz,1H),4.93-4.85(m,1H),4.54(d,J＝9.5Hz,1H),4.48-4.42(m,3H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.97-3.85(m,2H),3.82-3.74(m,2H),3.63-3.47(m,6H),2.83(s,4H),2.71(t,J＝7.6Hz,2H),2.54(t,J＝7.6Hz,2H),2.49-2.42(m,7H),2.09-2.01(m,1H),1.81-1.74(m,1H),1.33(d,J＝7.0Hz,3H),0.92(s,9H).13C NMR(150MHz,DMSO-d6)δ170.48,169.10,168.55,154.85,151.51,148.73,148.11,147.79,144.91,144.77,144.68,135.58,135.04,131.14,129.74,128.92,128.87,126.36,126.10,123.51,122.62,117.24,70.35,69.64,69.42,68.99,68.81,58.63,56.87,56.58,55.76,51.48,49.18,47.78,45.91,40.54,37.74,35.85,26.27,22.86,22.41,16.01.HR-ESI-MS calcd for C50H66N12O9S2[M+H]+1043.4590,found1043.4636.
实施例14
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-(2-(4-(2-溴乙基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.98(s,1H),8.53(d,J＝1.7Hz,1H),8.45(dd,J＝4.7,1.4Hz,1H),8.43(d,J＝7.7Hz,1H),7.78(s,1H),7.71(d,J＝7.9Hz,1H),7.65(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.43(d,J＝8.3Hz,2H),7.40-7.32(m,4H),6.94(t,J＝5.9Hz,1H),5.14(d,J＝3.5Hz,1H),4.93-4.84(m,1H),4.55(d,J＝9.6Hz,1H),4.49-4.40(m,3H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.95(s,2H),3.76(t,J＝5.3Hz,2H),3.62-3.54(m,4H),3.52-3.46(m,6H),2.83(s,4H),2.74-2.68(m,2H),2.55-2.52(m,2H),2.49-2.42(m,7H),2.09-2.01(m,1H),1.81-1.73(m,1H),1.34(d,J＝7.0Hz,3H),0.93(s,9H).13C NMR(150MHz,DMSO-d6)δ170.45,169.02,168.51,154.81,151.46,148.72,148.08,147.75,144.89,144.70,135.55,134.99,131.11,129.70,128.87,128.83,126.32,126.26,126.07,123.46,122.51,117.19,70.45,69.75,69.53,68.80,58.57,56.85,56.54,55.70,51.46,49.24,47.76,45.88,40.51,37.74,35.76,26.30,26.22,22.86,22.41,15.98.HR-ESI-MS calcd for C52H70N12O10S2[M-H]-1085.4707,found 1085.4667.
实施例15
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-(2-(2-(4-(2-溴乙基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.98(s,1H),8.53(d,J＝1.7Hz,1H),8.49-8.41(m,2H),7.78(s,1H),7.71(d,J＝7.8Hz,1H),7.65(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),7.46-7.41(m,2H),7.40-7.33(m,4H),6.94(t,J＝5.8Hz,1H),5.15(d,J＝3.5Hz,1H),4.94-4.86(m,1H),4.55(d,J＝9.6Hz,1H),4.47-4.40(m,3H),4.34(d,J＝5.9Hz,2H),4.29(s,1H),3.95(s,2H),3.75(t,J＝5.2Hz,2H),3.63-3.53(m,6H),3.53-3.50(m,2H),3.49-3.44(m,6H),2.83(s,4H),2.70(t,J＝7.6Hz,2H),2.56-2.51(m,2H),2.49-2.42(m,7H),2.10-2.02(m,1H),1.82-1.73(m,1H),1.36(d,J＝7.0Hz,3H),0.93(s,9H).13CNMR(150MHz,DMSO-d6)δ170.46,169.03,168.51,154.81,151.45,148.72,148.08,147.75,144.89,144.70,135.54,134.99,131.11,129.70,128.87,128.83,126.33,126.27,126.08,123.45,122.48,117.19,70.43,69.84,69.72,69.66,69.60,69.54,68.78,58.57,56.85,56.52,55.71,51.46,49.22,47.76,45.87,40.51,37.73,35.73,26.30,26.22,22.86,22.43,15.98.HR-ESI-MS calcd for C54H74N12O11S2[M-H]-1129.4969,found1129.4939.
实施例16
将实施例7步骤e中的2-(2-碘乙氧基)乙酸叔丁酯替换为2-(2-(2-(2-(2-(2-(4-(2-溴乙基)-1H-1,2,3-三唑-1-基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯，其他同实施例7，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.97(s,1H),8.53(d,J＝1.8Hz,1H),8.45(dd,J＝4.7,1.6Hz,1H),8.43(d,J＝7.7Hz,1H),7.78(s,1H),7.73-7.69(m,1H),7.65(d,J＝8.9Hz,2H),7.58(d,J＝8.9Hz,2H),7.44-7.41(m,2H),7.40-7.33(m,4H),6.95(t,J＝5.9Hz,1H),5.14(d,J＝3.6Hz,1H),4.94-4.86(m,1H),4.54(d,J＝9.6Hz,1H),4.47-4.41(m,3H),4.34(d,J＝5.9Hz,2H),4.28(s,1H),3.95(s,2H),3.75(t,J＝5.3Hz,2H),3.63-3.57(m,4H),3.57-3.51(m,6H),3.48-3.43(m,8H),2.83(s,4H),2.70(t,J＝7.6Hz,2H),2.55-2.51(m,2H),2.49-2.42(m,7H),2.08-2.02(m,1H),1.81-1.75(m,1H),1.37(d,J＝7.0Hz,3H),0.94(s,9H).13C NMR(150MHz,DMSO-d6)δ170.49,169.05,168.56,154.84,151.49,148.73,148.10,147.78,144.92,144.73,135.58,135.02,131.14,129.71,128.90,128.85,126.35,126.30,126.08,123.49,122.52,117.22,70.46,69.87,69.78,69.74,69.66,69.62,69.56,68.80,58.59,56.86,56.54,55.73,51.48,49.24,47.79,45.90,40.53,37.75,35.75,26.32,26.25,22.87,22.46,16.00.HR-ESI-MS calcd forC56H78N12O12S2[M+H]+1175.5376,found 1175.5422.
实施例17化合物17的合成
步骤a.5-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)戊酰胺的合成
将底物5-溴戊酸(500mg，2.76mmol)溶于草酰氯(5mL)中，60℃回流反应1h，减压旋干溶剂，复溶于干燥THF(5mL)中，0℃加至化合物4-氨基-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮的THF溶液(628mg，2.30mmol，10mL)中，65℃回流5h，TLC监测。反应完全，加水析出固体，过滤，滤饼水洗，干燥得乳白色固体600mg，收率60％。1H NMR(300MHz,CDCl3)δ9.42(s,1H),8.82(d,J＝8.5Hz,1H),8.21(s,1H),7.78-7.66(m,1H),7.55(d,J＝6.8Hz,1H),4.96(dd,J＝12.3,5.4Hz,1H),3.45(t,J＝6.3Hz,2H),3.01-2.86(m,1H),2.86-2.69(m,2H),2.51(t,J＝7.0Hz,2H),2.26-2.12(m,1H),2.05-1.83(m,4H).
步骤b.N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)-5-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)戊酰胺的合成：
将底物1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲(221mg，0.59mmol)溶于DMF(4mL)中，室温加5-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)戊酰胺(254mg，0.59mmol)、K2CO3(407mg，2.95mmol)、KI(196mg，1.18mmol)，室温反应过夜。反应完全，加水析出固体，过滤，滤饼水洗、干燥，柱层析，得白色固体50mg，收率12％。1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.66(s,1H),9.26(s,1H),8.53(s,1H),8.48-8.40(m,2H),7.81(t,J＝7.9Hz,1H),7.71(d,J＝7.7Hz,1H),7.64(d,J＝8.7Hz,2H),7.60(d,J＝7.3Hz,1H),7.57(d,J＝8.7Hz,2H),7.35(dd,J＝7.7,4.8Hz,1H),6.96(t,J＝5.6Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),4.34(d,J＝5.8Hz,2H),3.00-2.67(m,5H),2.61(d,J＝17.1Hz,1H),2.57-2.51(m,1H),2.49-2.14(m,8H),2.09-2.02(m,1H),1.61-1.51(m,2H),1.48-1.38(m,2H).13C NMR(150MHz,DMSO-d6)δ172.69,171.85,169.71,167.64,166.62,154.79,148.67,148.03,144.88,136.48,136.03,135.50,134.95,131.41,128.84,126.27,126.01,123.41,118.25,117.17,116.97,56.61,51.49,48.89,45.75,40.48,36.12,30.90,22.39,21.96.HR-ESI-MS calcd for C35H38N8O8S[M-H]-729.2461,found 729.2445.
实施例18
将实施例17步骤a中的5-溴戊酸替换为7-溴庚酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.66(s,1H),9.24(s,1H),8.53(s,1H),8.45(d,J＝8.1Hz,2H),7.82(t,J＝7.8Hz,1H),7.71(d,J＝7.8Hz,1H),7.64(d,J＝8.8Hz,2H),7.61(d,J＝7.3Hz,1H),7.57(d,J＝8.8Hz,2H),7.35(dd,J＝7.9,4.9Hz,1H),6.94(t,J＝5.6Hz,1H),5.14(dd,J＝12.9,5.5Hz,1H),4.34(d,J＝5.9Hz,2H),3.00-2.69(m,5H),2.64-2.58(m,1H),2.57-2.51(m,1H),2.46-2.33(m,5H),2.24(s,2H),2.10-2.02(m,1H),1.63-1.53(m,2H),1.42-1.18(m,7H).13C NMR(150MHz,DMSO-d6)δ172.74,171.99,169.76,167.68,166.66,154.81,148.70,148.06,144.91,136.54,136.09,135.54,134.98,131.44,128.89,126.26,125.98,123.46,118.28,117.19,116.96,57.10,51.57,48.90,45.78,40.50,36.45,30.92,28.32,26.40,24.66,21.98.HR-ESI-MS calcd for C37H42N8O8S[M-H]-757.2774,found 757.2766.
实施例19
将实施例17步骤a中的5-溴戊酸替换为9-溴壬酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.17(s,1H),9.68(s,1H),9.25(s,1H),8.55(d,J＝1.7Hz,1H),8.51-8.45(m,2H),7.84(t,J＝7.8Hz,1H),7.75-7.71(m,1H),7.67(d,J＝8.9Hz,2H),7.63(d,J＝7.3Hz,1H),7.59(d,J＝8.9Hz,2H),7.37(dd,J＝7.7,4.8Hz,1H),6.97(t,J＝6.0Hz,1H),5.16(dd,J＝12.9,5.5Hz,1H),4.36(d,J＝5.9Hz,2H),2.97-2.78(m,5H),2.67-2.61(m,1H),2.60-2.53(m,1H),2.45(t,J＝7.4Hz,2H),2.39(s,4H),2.23(t,J＝7.8Hz,2H),2.12-2.05(m,1H),1.66-1.57(m,2H),1.39-1.21(m,10H).13C NMR(150MHz,DMSO-d6)δ172.69,171.99,169.71,167.68,166.63,154.79,148.69,148.04,144.86,136.55,136.06,135.51,134.94,131.41,128.83,126.18,126.04,123.41,118.23,117.14,116.89,57.21,51.62,48.89,45.87,40.48,36.49,30.90,28.70,28.59,28.41,26.68,26.07,24.69,21.96.HR-ESI-MS calcd for C39H46N8O8S[M-H]-785.3087,found 785.3084.
实施例20
将实施例17步骤a中的5-溴戊酸替换为11-溴十一酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.15(s,1H),9.68(s,1H),9.21(s,1H),8.53(d,J＝1.8Hz,1H),8.48-8.43(m,2H),7.82(t,J＝7.8,1H),7.72-7.69(m,1H),7.64(d,J＝8.9Hz,2H),7.60(d,J＝7.3Hz,1H),7.57(d,J＝8.9Hz,2H),7.35(dd,J＝7.8,4.8Hz,1H),6.92(t,J＝6.0Hz,1H),5.14(dd,J＝12.9,5.5Hz,1H),4.34(d,J＝5.9Hz,2H),2.94-2.72(m,5H),2.64-2.58(m,1H),2.57-2.51(m,1H),2.44(t,J＝7.4Hz,2H),2.37(s,3H),2.24-2.16(m,2H),2.09-2.03(m,1H),1.63-1.56(m,2H),1.35-1.15(m,15H).13C NMR(150MHz,DMSO-d6)δ172.71,172.01,169.74,167.69,166.65,154.79,148.70,148.06,144.87,136.56,136.08,135.52,134.96,131.43,128.87,126.21,126.01,123.43,118.25,117.16,116.91,57.20,51.61,48.90,45.88,40.49,36.50,30.92,28.87,28.84,28.80,28.64,28.44,26.74,26.08,24.73,21.97.HR-ESI-MS calcd for C41H50N8O8S[M+H]+815.3545,found 815.3550.
实施例21
将实施例17步骤a中的5-溴戊酸替换为2-(2-碘乙氧基)乙酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.17(s,1H),10.30(s,1H),9.21(s,1H),8.61(d,J＝8.5Hz,1H),8.54(d,J＝1.8Hz,1H),8.45(dd,J＝4.7,1.5Hz,1H),7.79(t,J＝7.8Hz,1H),7.75-7.70(m,1H),7.63-7.57(m,3H),7.51(d,J＝8.9Hz,2H),7.36(dd,J＝7.7,4.7Hz,1H),6.95(t,J＝5.9Hz,1H),5.15(dd,J＝13.1,5.4Hz,1H),4.35(d,J＝5.9Hz,2H),4.11(s,2H),3.68(t,J＝5.4Hz,2H),2.95-2.86(m,1H),2.75(s,4H),2.66-2.58(m,3H),2.57-2.50(m,5H),2.11-2.03(m,1H).13C NMR(150MHz,DMSO-d6)δ172.66,169.67,169.36,168.12,166.61,154.78,148.70,148.04,144.78,136.31,135.83,135.51,134.96,131.24,128.71,125.93,124.37,123.41,118.27,117.11,116.00,70.24,68.94,56.63,51.76,48.93,45.84,40.50,30.91,21.93.HR-ESI-MS calcd for C34H36N8O9S[M+H]+733.2399,found733.2407.
实施例22
将实施例17步骤a中的5-溴戊酸替换为2-(2-(2-碘乙氧基)乙氧基)乙酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.17(s,1H),10.33(s,1H),9.34(s,1H),8.71(d,J＝8.4Hz,1H),8.53(d,J＝0.8Hz,1H),8.45(dd,J＝4.5,1.0Hz,1H),7.86(t,J＝7.8Hz,1H),7.73-7.69(m,1H),7.67-7.61(m,3H),7.53(d,J＝8.8Hz,2H),7.35(dd,J＝7.6,4.8Hz,1H),7.06(t,J＝6.0Hz,1H),5.15(dd,J＝12.9,5.5Hz,1H),4.34(d,J＝6.0Hz,2H),4.17(s,2H),3.75-3.69(m,2H),3.61-3.57(m,2H),3.45(t,J＝5.7Hz,2H),2.93-2.85(m,1H),2.76(s,4H),2.64-2.57(m,1H),2.56-2.51(m,1H),2.47-2.35(m,6H),2.09-2.03(m,1H).13C NMR(150MHz,DMSO-d6)δ172.69,169.69,169.39,168.21,166.65,154.84,148.70,148.05,144.90,136.52,135.96,135.56,134.97,131.30,128.82,125.95,124.36,123.45,118.32,117.14,116.00,70.73,70.25,69.77,69.55,68.37,56.51,51.89,48.96,45.82,40.49,30.91,21.95.HR-ESI-MS calcd for C36H40N8O10S[M+H]+777.2661,found 777.2656.
实施例23
将实施例17步骤a中的5-溴戊酸替换为2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙酸，其他同实施例17，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.16(s,1H),10.35(s,1H),9.24(s,1H),8.72(d,J＝8.4Hz,1H),8.53(d,J＝1.4Hz,1H),8.45(dd,J＝4.7,1.2Hz,1H),7.86(t,J＝7.8Hz,1H),7.74-7.69(m,1H),7.67-7.61(m,3H),7.56(d,J＝8.9Hz,2H),7.35(dd,J＝7.7,4.7Hz,1H),6.98-6.90(m,1H),5.15(dd,J＝13.0,5.4Hz,1H),4.34(d,J＝5.9Hz,2H),4.19(s,2H),3.73(dd,J＝5.6,3.6Hz,2H),3.63(dd,J＝5.5,3.7Hz,2H),3.49(dd,J＝5.8,3.7Hz,2H),3.42(dd,J＝5.7,3.8Hz,2H),3.38(t,J＝5.8Hz,2H),2.93-2.85(m,1H),2.78(s,4H),2.64-2.57(m,1H),2.57-2.51(m,1H),2.48-2.35(m,6H),2.09-2.03(m,1H).13C NMR(150MHz,DMSO-d6)δ172.68,169.68,169.37,168.20,166.66,154.80,148.70,148.06,144.87,136.51,135.96,135.53,134.97,131.30,129.64,128.86,125.96,124.39,123.44,118.32,117.14,116.05,70.78,70.23,69.76,69.69,69.54,68.18,56.50,51.86,48.95,45.85,40.49,30.91,21.93.HR-ESI-MS calcd for C38H44N8O11S[M+H]+821.2923,found 821.2921.
实施例24
步骤a.7-(2-(2,6-二氧代哌啶-3-基)-1-氧化异吲哚啉-4-基)庚-6-炔酸的合成
将底物3-(4-溴-1-氧化异吲哚啉-2-基)哌啶-2,6-二酮(187mg，,0.56mmol)、6-庚炔酸(77mg，0.61mmol)、Pd(PPh3)Cl2(78mg，0.11mmol)、CuI(21mg，0.11mmol)溶于DMF(5mL)中，加入TEA(0.5mL)，N2保护，80℃反应5h，TLC监测。反应结束，加水析出固体，2M稀盐酸调至弱酸性，过滤，滤饼水洗、干燥，柱层析，得黄棕色固体162mg，收率80％。1H NMR(600MHz,DMSO-d6)δ12.04(s,1H),10.98(s,1H),7.71(d,J＝7.4Hz,1H),7.63(d,J＝7.5Hz,1H),7.52(t,J＝7.6Hz,1H),5.14(dd,J＝13.4,4.6Hz,1H),4.45(d,J＝17.6Hz,1H),4.31(d,J＝17.7Hz,1H),2.96-2.86(m,1H),2.64-2.56(m,1H),2.50-2.39(m,3H),2.37-2.17(m,2H),2.05-1.97(m,1H),1.73-1.63(m,2H),1.62-1.53(m,2H).
步骤b.1-(4-((4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧化异吲哚啉-4-基)庚-6-炔酰基)哌嗪-1-基)磺酰基)苯基)-3-(吡啶-3-基甲基)脲的合成
将底物1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲(49mg，0.13mmol)溶于DCM(4mL)中，室温加入7-(2-(2,6-二氧代哌啶-3-基)-1-氧化异吲哚啉-4-基)庚-6-炔酸(43mg，0.12mmol)、HOBt(21mg，0.16mmol)、EDCI(30mg，0.16mmol)、DIPEA(0.1mL)，MeOH(0.1mL)，室温反应5h，TLC监测。反应完全，浓缩，柱层析，得白色固体47mg，收率50％。1HNMR(600MHz,DMSO-d6)δ10.98(s,1H),9.19(s,1H),8.52(d,J＝1.6Hz,1H),8.45(dd,J＝4.7,1.4Hz,1H),7.72-7.68(m,2H),7.64(d,J＝8.9Hz,2H),7.60(dd,J＝7.6,0.8Hz,1H),7.57(d,J＝8.9Hz,2H),7.51(t,J＝7.6Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.91(t,J＝6.0Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.8Hz,1H),4.33(d,J＝5.9Hz,2H),4.30(d,J＝17.7Hz,1H),3.50(s,4H),2.96-2.88(m,1H),2.88-2.76(m,4H),2.58(d,J＝17.7Hz,1H),2.49-2.43(m,3H),2.30(t,J＝7.3Hz,2H),2.03-1.96(m,1H),1.65-1.56(m,2H),1.56-1.48(m,2H).13C NMR(150MHz,DMSO-d6)δ172.84,170.92,170.49,167.64,154.75,148.68,148.05,144.98,143.84,135.50,134.94,133.84,131.93,128.81,128.53,126.03,123.41,122.56,118.79,117.24,96.17,76.56,51.55,46.93,45.98,45.74,44.01,40.49,31.35,31.19,27.50,23.63,22.28,18.50.HR-ESI-MS calcd for C37H39N7O7S[M+H]+726.2704,found 726.2737.
实施例25
将实施例24步骤a中的6-庚炔酸替换为8-壬炔酸，其他同实施例24，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ10.97(s,1H),9.21(s,1H),8.52(d,J＝1.8Hz,1H),8.45(dd,J＝4.7,1.3Hz,1H),7.70(d,J＝7.7Hz,2H),7.64(d,J＝8.9Hz,2H),7.62(d,J＝7.6Hz,1H),7.57(d,J＝8.8Hz,2H),7.51(t,J＝7.6Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.92(t,J＝6.0Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.6Hz,1H),4.33(d,J＝5.9Hz,2H),4.30(d,J＝17.6Hz,1H),3.49(s,4H),2.93-2.88(m,1H),2.81(d,J＝19.2Hz,4H),2.63-2.55(m,1H),2.48-2.39(m,3H),2.23(t,J＝7.4Hz,2H),2.04-1.97(m,1H),1.56-1.48(m,2H),1.47-1.41(m,2H),1.41-1.35(m,2H),1.28-1.23(m,2H).13C NMR(150MHz,DMSO-d6)δ172.76,170.91,170.62,167.61,154.74,148.67,148.03,144.98,143.70,135.48,134.91,133.96,131.93,128.80,128.52,125.99,123.39,122.52,118.82,117.21,96.29,76.37,51.60,46.91,46.01,45.74,44.05,40.47,31.89,31.15,28.06,27.99,27.81,24.42,22.33,18.61.HR-ESI-MS calcd for C39H43N7O7S[M-H]-752.2872,found 752.2857.
实施例26
将实施例24步骤a中的6-庚炔酸替换为10-十一炔酸，其他同实施例24，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.01(s,1H),9.24(s,1H),8.54(d,J＝1.7Hz,1H),8.47(dd,J＝4.6,1.0Hz,1H),7.72(d,J＝7.4Hz,2H),7.66(d,J＝8.8Hz,2H),7.64(d,J＝7.6Hz,1H),7.60(d,J＝8.8Hz,2H),7.53(t,J＝7.6Hz,1H),7.37(dd,J＝7.8,4.8Hz,1H),6.94(t,J＝6.0Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.6Hz,1H),4.36(d,J＝5.9Hz,2H),4.32(d,J＝17.6Hz,1H),3.51(s,4H),2.98-2.89(m,1H),2.83(d,J＝24.3Hz,4H),2.65-2.58(m,1H),2.50-2.41(m,3H),2.23(t,J＝7.4Hz,2H),2.07-2.01(m,1H),1.60-1.53(m,2H),1.45-1.37(m,4H),1.31-1.23(m,6H).13C NMR(150MHz,DMSO-d6)δ172.78,170.93,170.67,167.62,154.75,148.68,148.04,144.99,143.68,135.49,134.93,133.99,131.93,128.82,128.55,125.95,123.40,122.53,118.83,117.21,96.35,76.34,51.60,46.90,46.04,45.76,44.07,40.48,31.97,31.16,28.69,28.58,28.31,28.18,27.96,24.49,22.36,18.70.HR-ESI-MS calcd for C41H47N7O7S[M+H]+782.3330,found 782.3373.
实施例27
将实施例24步骤b中的1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲替换为1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)硫脲，其他同实施例24，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.16(s,1H),8.63(s,1H),8.56(d,J＝1.7Hz,1H),8.47(dd,J＝4.8,1.6Hz,1H),7.80(d,J＝8.8Hz,2H),7.77-7.73(m,1H),7.70(dd,J＝7.6,0.8Hz,1H),7.65(d,J＝8.9Hz,2H),7.60(dd,J＝7.6,0.9Hz,1H),7.51(t,J＝7.6Hz,1H),7.39-7.35(m,1H),5.15(dd,J＝13.4,5.1Hz,1H),4.78(d,J＝5.4Hz,2H),4.44(d,J＝17.7Hz,1H),4.29(d,J＝17.7Hz,1H),3.58-3.45(m,4H),2.97-2.77(m,5H),2.63-2.55(m,1H),2.49-2.42(m,3H),2.31(t,J＝7.3Hz,2H),2.04-1.95(m,1H),1.67-1.56(m,2H),1.56-1.48(m,2H).13C NMR(150MHz,DMSO-d6)δ180.69,172.89,170.95,170.54,167.66,148.93,148.21,144.14,143.86,135.26,134.12,133.86,131.94,128.56,128.37,123.42,122.58,121.43,118.80,96.19,76.58,51.55,46.94,46.01,45.78,44.69,44.04,31.37,31.21,27.51,23.63,22.30,18.52.HR-ESI-MS calcd for C37H39N7O6S2[M+H]+742.2476,found 742.2485.
实施例28
制备方法与实施例25相同，只是将脲替换为硫脲。
1H NMR(600MHz,DMSO-d6)δ10.99(s,1H),10.17(s,1H),8.64(s,1H),8.56(d,J＝1.4Hz,1H),8.47(dd,J＝4.7,1.2Hz,1H),7.81(d,J＝8.8Hz,2H),7.77-7.73(m,1H),7.70(dd,J＝7.5,0.5Hz,1H),7.65(d,J＝8.8Hz,2H),7.62(dd,J＝7.6,0.7Hz,1H),7.51(t,J＝7.6Hz,1H),7.37(dd,J＝7.7,4.7Hz,1H),5.14(dd,J＝13.3,5.2Hz,1H),4.78(d,J＝5.3Hz,2H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),3.51(s,4H),2.95-2.78(m,5H),2.62-2.55(m,1H),2.49-2.40(m,3H),2.24(t,J＝7.4Hz,2H),2.04-1.97(m,1H),1.57-1.49(m,2H),1.47-1.35(m,4H),1.28-1.23(m,2H).13C NMR(150MHz,DMSO-d6)δ180.69,172.81,170.95,170.68,167.63,148.92,148.20,144.14,143.72,135.24,134.11,133.99,131.94,128.56,128.36,123.40,122.55,121.39,118.83,96.32,76.40,51.61,46.93,46.04,45.78,44.67,44.08,31.93,31.18,28.08,28.02,27.83,24.44,22.35,18.64.HR-ESI-MScalcd for C39H43N7O6S2[M+H]+770.2789,found 770.2805.
实施例29
制备方法与实施例26相同，只是将脲替换为硫脲。
1H NMR(600MHz,DMSO-d6)δ10.98(s,1H),10.11(s,1H),8.60(s,1H),8.56(d,J＝1.5Hz,1H),8.47(dd,J＝4.7,1.4Hz,1H),7.81(d,J＝8.8Hz,2H),7.77-7.73(m,1H),7.70(d,J＝7.5Hz,1H),7.65(d,J＝8.8Hz,2H),7.62(dd,J＝7.6,0.7Hz,1H),7.51(t,J＝7.6Hz,1H),7.37(dd,J＝7.7,4.9Hz,1H),5.14(dd,J＝13.3,5.2Hz,1H),4.78(d,J＝5.5Hz,2H),4.43(d,J＝17.6Hz,1H),4.30(d,J＝17.5Hz,1H),3.50(d,J＝2.7Hz,4H),2.95-2.80(m,5H),2.62-2.56(m,1H),2.48-2.39(m,3H),2.21(t,J＝7.5Hz,2H),2.05-1.98(m,1H),1.58-1.51(m,2H),1.43-1.35(m,4H),1.28-1.21(m,6H).13C NMR(150MHz,DMSO-d6)δ180.67,172.79,170.94,170.71,167.63,148.92,148.19,144.11,143.69,135.24,134.10,134.00,131.93,128.56,128.36,123.39,122.54,121.39,118.83,96.36,76.35,51.60,46.91,46.06,45.78,44.69,44.08,31.99,31.16,28.71,28.60,28.32,28.20,27.97,24.49,22.36,18.71.HR-ESI-MS calcd for C41H47N7O6S2[M+H]+798.3102,found798.3138.
实施例30
步骤a.4-(羟甲基)哌啶-1-羧酸叔丁酯的合成
将底物4-哌啶甲醇(5.0g，43.48mmol)溶于DCM(20mL)中，室温下加(Boc)2O(9.5g，43.48mmol)，室温反应3h，TLC检测。反应完全，浓缩，柱层析，得白色固体8.8g，收率95％。1HNMR(600MHz,CDCl3)δ4.11(s,2H),3.48(d,J＝6.4Hz,2H),2.68(t,J＝11.5Hz,2H),1.77(d,J＝10.3Hz,1H),1.70(d,J＝13.5Hz,2H),1.67-1.59(m,1H),1.44(s,9H),1.19-1.05(m,2H).
步骤b.4-(碘甲基)哌啶-1-羧酸叔丁酯的合成
将三苯基膦(1.58g，6.05mmol)、咪唑(822mg，12.09mmol)溶于干燥DCM(20mL)中，0℃下加I2(1.54g，6.05mmol)，搅拌至完全溶解，随后滴加4-(羟甲基)哌啶-1-羧酸叔丁酯的合成的DCM溶液(1.0g，4.65mmol，6mL)，逐渐升至室温反应过夜。反应完全，DCM萃取，浓缩，柱层析，得无色油状物1.27g，收率84％。1H NMR(600MHz,CDCl3)δ4.10(d,J＝12.3Hz,2H),3.09(d,J＝6.6Hz,2H),2.67(t,J＝12.0Hz,2H),1.82(d,J＝13.2Hz,2H),1.64-1.59(m,1H),1.44(s,9H),1.19-1.07(m,2H).
步骤c.4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-甲酸叔丁酯的合成
将底物2-(2,6-二氧代哌啶-3-基)-5,6-二氟异二氢吲哚-1,3-二酮(2.30g，7.82mmol)、单Boc哌嗪(1.42g，22.60mmol)溶于NMP(15mL)中，室温下加DIPEA(5.04g，39.10mmol)，90℃反应3h，TLC检测。反应完全，冷却后加水析出固体，过滤，滤饼水洗、干燥，柱层析，得黄色固体2.35g，收率65％。1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),7.75(d,J＝11.2Hz,1H),7.48(d,J＝7.3Hz,1H),5.11(dd,J＝13.0,5.4Hz,1H),3.49(s,4H),3.26-3.16(m,4H),2.93-2.83(m,1H),2.62-2.47(m,2H),2.07-2.00(m,1H),1.42(s,9H).
步骤d.4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯的合成
将底物4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-甲酸叔丁酯(318mg，0.69mmol)溶于DCM(4mL)中，0℃下缓慢滴加TFA(4mL)，0℃反应2h，TLC监测。反应完全，低温旋干溶剂，复溶于DMF(4mL)中，室温下加4-(碘甲基)哌啶-1-羧酸叔丁酯(270mg，0.83mmol)、K2CO3(382mg，2.77mmol)，室温反应过夜。反应完全，减压旋干溶剂，柱层析，得黄色固体95mg，收率25％。1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),7.72(d,J＝11.4Hz,1H),7.44(d,J＝7.4Hz,1H),5.10(dd,J＝13.0,5.4Hz,1H),3.92(s,2H),3.24(s,4H),2.93-2.84(m,1H),2.82-2.56(m,3H),2.56-2.47(m,5H),2.18(d,J＝6.8Hz,2H),2.06-1.99(m,1H),1.76-1.63(m,3H),1.39(s,9H),1.00-0.91(m,2H).
步骤e.1-(4-((4-(2-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-2-氧代乙氧基)乙基)哌嗪-1-基)磺酰基)苯基)-3-(吡啶-3-基甲基)脲的合成
将底物2-(2-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)乙氧基)乙酸叔丁酯(43mg，0.08mmol)溶于DCM(4mL)中，室温滴加TFA(3mL)，室温反应1h，TLC监测。反应完全，减压旋干溶剂。将底物4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯(45mg，0.08mmol)溶于DCM(4mL)中，0℃缓慢滴加TFA(3mL)，0℃反应2h，TLC监测；反应完全，减压旋干溶剂。两项混合，复溶于干燥DCM/MeOH(V/V＝8/1)的混合溶液(4.5mL)中，加HOBt(16mg，0.12mmol)、EDCI(23mg，0.12mmol)、DIPEA(31mg，0.24mmol)，室温反应过夜。反应完全，减压旋干溶剂，柱层析，得黄色固体19mg，收率26％。1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),9.23(s,1H),8.52(s,1H),8.45(d,J＝4.6Hz,1H),7.75-7.68(m,2H),7.65(d,J＝8.8Hz,2H),7.58(d,J＝8.7Hz,2H),7.44(d,J＝7.3Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.93(t,J＝5.8Hz,1H),5.10(dd,J＝13.0,5.4Hz,1H),4.33(d,J＝5.8Hz,2H),4.26(d,J＝12.5Hz,1H),4.11-3.98(m,2H),3.72(d,J＝11.4Hz,1H),3.50-3.43(m,2H),3.24(s,4H),2.93-2.75(m,6H),2.63-2.43(m,13H),2.15(d,J＝7.0Hz,2H),2.08-1.99(m,1H),1.79-1.67(m,2H),1.63(d,J＝12.7Hz,1H),1.05-0.94(m,1H),0.94-0.82(m,1H).13C NMR(150MHz,DMSO-d6)δ172.73,169.88,166.85,166.65,166.17,158.16,156.46,154.78,148.69,148.06,145.37,144.89,135.51,134.95,128.89,128.76,125.93,123.42,117.15,111.84,69.36,68.03,63.50,56.49,52.80,51.75,49.57,49.05,45.93,44.21,41.07,40.49,32.56,30.94,30.81,30.05,22.06.HR-ESI-MS calcd for C44H53FN10O9S[M+H]+917.3774,found 917.3786.
实施例31
步骤a-d同实施例30；
步骤e 1-(4-((4-(7-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-7-氧代庚基)哌嗪-1-基)磺酰基)苯基)-3-(吡啶-3-基甲基)脲的合成
将底物7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酸甲酯(49mg，0.095mmol)溶于THF/MeOH/H2O(V/V/V＝4/2/1)的混合溶液(7mL)中，室温下加LiOH(20mg，0.83mmol)，室温反应4h，TLC监测。反应完全，浓缩，1M稀盐酸调至弱酸性，旋干溶剂。底物4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯(53mg，0.095mmol)溶于DCM(4mL)中，0℃缓慢滴加TFA(3mL)，0℃反应2h，TLC监测；反应完全，旋干溶剂。两项混合，复溶于干燥DCM/MeOH(V/V＝8/1)的混合溶液(4.5mL)，加HOBt(19mg，0.14mmol)、EDCI(27mg，0.14mmol)、DIPEA(25mg，0.19mmol)，室温反应过夜，TLC监测。反应完全，浓缩，柱层析，得黄色固体25mg，收率28％。1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),9.21(s,1H),8.53(d,J＝1.7Hz,1H),8.45(dd,J＝4.7,1.5Hz,1H),7.75-7.68(m,2H),7.64(d,J＝8.9Hz,2H),7.57(d,J＝8.9Hz,2H),7.44(d,J＝7.4Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.92(t,J＝6.0Hz,1H),5.10(dd,J＝13.0,5.4Hz,1H),4.39-4.30(m,3H),3.80(d,J＝13.2Hz,1H),3.23(s,4H),3.00-2.69(m,6H),2.63-2.57(m,1H),2.56-2.45(m,6H),2.38(s,4H),2.29-2.13(m,6H),2.08-1.97(m,1H),1.83-1.64(m,3H),1.47-1.38(m,2H),1.37-1.28(m,2H),1.26-1.16(m,4H),1.03-0.93(m,1H),0.92-0.82(,1H).13C NMR(150MHz,DMSO-d6)δ172.74,170.20,169.87,166.64,166.17,158.16,156.47,154.78,148.71,148.06,145.36,144.87,135.53,134.96,128.87,128.76,126.00,123.44,117.17,113.62,112.01,111.84,63.60,57.18,52.83,51.65,49.55,49.05,45.89,44.95,40.95,40.50,32.71,32.33,31.03,30.94,30.18,28.64,26.57,26.01,24.82,22.06.HR-ESI-MS calcd for C47H59FN10O8S[M+H]+943.4295,found 943.4291.
实施例32
将实施例31步骤e中的7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酸甲酯替换为9-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)壬酸甲酯，其他同实施例31，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),9.22(s,1H),8.52(d,J＝1.2Hz,1H),8.45(dd,J＝4.7,1.4Hz,1H),7.77-7.68(m,2H),7.64(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.44(d,J＝7.4Hz,1H),7.35(dd,J＝7.8,4.8Hz,1H),6.93(t,J＝5.9Hz,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.38-4.30(m,3H),3.81(d,J＝12.8Hz,1H),3.23(s,4H),3.02-2.71(m,6H),2.59(d,J＝17.3Hz,1H),2.56-2.45(m,6H),2.37(s,4H),2.26-2.15(m,6H),2.08-1.97(m,1H),1.82-1.64(m,3H),1.49-1.38(m,2H),1.37-1.28(m,2H),1.23-1.17(m,8H),1.03-0.93(m,1H),0.93-0.82(m,1H).13CNMR(150MHz,DMSO-d6)δ172.83,170.39,169.95,166.71,166.24,158.21,156.53,154.87,148.73,148.11,145.44,145.38,144.91,135.60,135.07,128.93,128.81,126.10,123.53,123.41,123.34,117.24,113.65,112.06,111.89,63.67,57.29,52.89,51.70,49.60,49.11,45.95,45.05,41.03,40.55,32.76,32.45,31.11,30.99,30.25,28.86,28.82,28.78,26.77,26.15,24.95,22.12.HR-ESI-MS calcd forC49H63FN10O8S[M+H]+971.4608,found 971.4624.
实施例33
将实施例31步骤e中的7-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)庚酸甲酯替换为5-(4-((4-(3-(吡啶-3-基甲基)脲基)苯基)磺酰基)哌嗪-1-基)戊酸甲酯，其他同实施例31，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.10(s,1H),9.24(s,1H),8.65-8.36(m,2H),7.71(dd,J＝10.4,7.9Hz,2H),7.68-7.63(m,2H),7.61-7.54(m,2H),7.44(d,J＝7.3Hz,1H),7.35(dd,J＝7.8,4.7Hz,1H),6.94(t,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.34(d,J＝5.9Hz,3H),3.86-3.70(m,1H),3.24(m,5H),2.98-2.72(m,7H),2.66-2.57(m,1H),2.43(d,J＝18.4Hz,4H),2.34-2.13(m,7H),2.06-2.02(m,1H),1.75(s,1H),1.66(d,J＝14.1Hz,2H),1.45-1.33(m,4H),0.96(s,1H),0.91-0.84(m,1H).13C NMR(150MHz,DMSO-d6)δ173.17,170.64,170.31,167.08,166.61,158.58,156.90,155.23,149.12,148.49,145.72,145.33,135.96,135.41,129.32,129.20,126.40,123.88,117.64,114.07,112.44,112.28,63.94,57.11,53.22,51.95,49.94,49.51,46.28,45.33,41.37,40.95,33.08,32.58,31.41,30.57,25.93,23.05,22.51.HR-ESI-MS calcd for C45H55FN10O8S[M+H]+915.3982,found915.3920.
实施例34
将底物1-(4-(哌嗪-1-基磺酰基)苯基)-3-(吡啶-3-基甲基)脲(375mg，1.00mmol)溶于DMF(4mL)中，室温加5-((3-溴丙基)氨基)-2-(2,6-二氧代哌啶-3-基)-6-氟异二氢吲哚-1,3-二酮(452mg，1.10mmol)、K2CO3(690mg，5.00mmol)、KI(166mg，1.00mmol)，室温反应过夜。反应完全，EA萃取、浓缩、干燥，柱层析，得白色固体75mg，收率11％。1H NMR(600MHz,DMSO-d6)δ11.08(s,1H),9.26(s,1H),8.53(d,J＝2.2Hz,1H),8.45(dd,J＝4.8,1.7Hz,1H),7.77-7.68(m,1H),7.70-7.61(m,2H),7.63-7.56(m,2H),7.47(d,J＝10.2Hz,1H),7.34(ddd,J＝7.8,4.8,0.9Hz,1H),7.07(d,J＝7.1Hz,1H),7.00(d,J＝3.1Hz,1H),6.96(t,J＝6.0Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),4.98(d,J＝2.5Hz,1H),4.35(d,J＝5.9Hz,2H),3.25(d,J＝6.2Hz,2H),2.87(dq,J＝13.9,5.4,4.4Hz,3H),2.62-2.55(m,1H),2.48-2.27(m,6H),2.25-2.05(m,2H),2.04--1.95(m,1H),1.79-1.55(m,2H).13C NMR(150MHz,DMSO-d6)δ173.82,173.25,170.52,167.56,167.09,155.29,149.10,148.47,145.33,143.34,143.25,135.97,135.48,130.42,129.33,126.38,123.91,117.69,110.13,109.98,105.37,83.83,55.36,51.99,49.29,46.20,40.96,31.41,29.43,28.94,27.91,26.67,22.65.HR-ESI-MS calcd for C33H35FN8O7S[M+H]+707.2406,found 707.2360.
实施例35
将实施例34中的5-((3-溴丙基)氨基)-2-(2,6-二氧代哌啶-3-基)-6-氟异二氢吲哚-1,3-二酮替换为5-((9-溴壬基)氨基)-2-(2,6-二氧代哌啶-3-基)-6-氟异二氢吲哚-1,3-二酮，其他同实施例34，制备的化合物结构如下：
1H NMR(600MHz,DMSO-d6)δ11.07(s,1H),9.25(s,1H),8.71-8.32(m,2H),7.71(dt,J＝7.8,2.0Hz,1H),7.68-7.62(m,2H),7.61-7.56(m,2H),7.54(d,J＝10.3Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.34(d,J＝5.9Hz,2H),3.23(q,J＝6.7Hz,2H),2.96-2.68(m,5H),2.63-2.50(m,2H),2.37(s,4H),2.20(t,J＝7.3Hz,2H),2.00(dtd,J＝13.0,5.4,2.4Hz,1H),1.54(p,J＝7.2Hz,2H),1.40-1.08(m,13H).13C NMR(151MHz,DMSO-d6)δ172.70,170.00,167.12,166.61,154.78,153.78,152.14,148.67,148.02,144.85,142.86,142.77,135.50,134.93,129.99,128.82,126.02,123.39,117.13,116.01,109.83,109.69,104.84,57.19,51.62,48.82,45.87,42.22,40.48,30.95,28.87,28.79,28.66,28.02,26.72,26.30,26.09,22.18.HR-ESI-MS calcd for C39H47FN8O7S[M-H]-789.3200,found789.3137.
实施例36
1H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.98(s,1H),8.37(d,J＝7.8Hz,1H),7.77(d,J＝9.3Hz,1H),7.65(d,J＝8.9Hz,2H),7.57(d,J＝8.8Hz,2H),7.43(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.35-7.28(m,4H),7.26-7.22(m,1H),6.84(t,J＝5.9Hz,1H),5.09(d,J＝3.5Hz,1H),4.98-4.88(m,1H),4.51(d,J＝9.4Hz,1H),4.42(t,J＝8.0Hz,1H),4.32(d,J＝5.9Hz,2H),4.30-4.25(m,1H),3.66-3.54(m,2H),2.81(s,4H),2.45(s,3H),2.38(s,4H),2.26-2.17(m,3H),2.12-2.04(m,1H),2.03-1.96(m,1H),1.84-1.75(m,1H),1.53-1.40(m,2H),1.37(d,J＝7.0Hz,3H),1.35-1.28(m,2H),1.23-1.15(m,8H),0.92(s,9H).13C NMR(150MHz,DMSO-d6)δ172.02,170.60,169.60,154.73,151.43,147.74,144.95,144.63,139.96,131.09,129.68,128.87,128.80,128.30,127.10,126.77,126.36,125.92,117.07,68.73,58.52,57.25,56.31,56.21,51.65,47.68,45.90,42.75,37.70,35.15,34.84,28.83,28.65,28.60,26.74,26.42,26.13,25.36,22.40,15.96.HR-ESI-MS calcd forC50H68N8O7S2[M+H]+957.4725,found 957.4712.
实施例37本发明化合物对NAMPT抑制活性测试
步骤a：样品测试液配置：50mM Tris HCl(pH 7.5)、12.5mM MgCl2、0.4mM PRPP(磷酸核糖焦磷酸)，2mM ATP，30μg/mL乙醇脱氢酶，10μg/mL NMNAT(烟酰胺单核苷酸腺苷转移酶)、1.5％乙醇、2mM DTT(二硫苏糖醇)、0.02％BSA、2μg/mLNAMPT。
步骤b：待测化合物用DMSO配制成起始浓度为100μM，并用DMSO进行3倍稀释7次，随后在96孔板中加入上述配制的不同浓度的化合物0.5μL和样品测试液20μL；
步骤c：室温孵育5min后，加入0.2μM的NAM溶液4.5μL；
步骤d：37℃下孵育15min后，在95℃下加热1min终止反应；
步骤e：反应液放置冰上冷却，加入20％苯乙酮10μL、2M的KOH溶液10μL，涡旋在冰上放置2min，加入88％甲酸45μL，在37℃下孵育10min；
步骤f：使用酶标仪测试激发波长为382nm、发射波长为445nm处的荧光值。
步骤g：根据公式：A＝R/(1+(C/IC50)S)+B(其中A为酶活性，C为化合物浓度，R、IC50、S、B为待拟合参数)，在origin软件中将酶活性对化合物浓度的曲线进行拟合，得到化合物的IC50。
实验结果：本发明化合物对NAMPT蛋白的IC50值如表1所示，测试化合物表现出优秀的抑制活性，但与NAMPT抑制剂FK866和735相比均有所降低。
表1目标化合物对NAMPT的抑制活性(单位nM)
实施例38本发明化合物对A2780细胞株的体外抗肿瘤活性测试(IC50)
步骤a：接种7×103个/孔细胞(100μL)于96孔板中，周围加入100μL的PBS；
步骤b：放置于细胞孵育箱中37℃、5％CO2条件下培养24h后，弃培养基，加入不含FBS的培养基100μL；
步骤c：继续放置于细胞孵育箱中培养24h，加入不同浓度的待测化合物100μL(DMSO配制为起始浓度20μM，1640培养基3倍稀释)，并设置三复孔；放置于细胞孵育箱中培养72h，弃培养基，加入含有10％CCK8的培养基100μL；
步骤d：在37℃下孵育40min后，用酶标仪测试样品在452nm处的OD值。
步骤e：利用GraphPad模拟计算其IC50。
实验结果：本发明化合物对肿瘤细胞半数抑制浓度IC50值如表2所示，大部分化合物对A2780细胞表现出优秀的抗增值作用(IC50<1μM)。其中化合物I-1～I-6、I-9、I-25、I-26对A2780体外抑制活性均小于100nM，尤其是化合物I-2～I-6、I-9、I-25、I-26对A2780体外抑制活性均优于CN111454327A中的化合物16。
表2目标化合物细胞对A2780细胞株的半数抑制浓度(IC50μM)
实施例39本发明化合物对HeLa细胞株的体外抗肿瘤活性测试(IC50μM)
操作方法步骤同实施例34。实验结果：本发明化合物对HeLa细胞株的半数抑制浓度IC50值如表3所示。大部分化合物对HeLa细胞表现出优秀的抗肿瘤活性(IC50<1μM)，尤其是化合物I-1～I-6、I-25、I-26、I-28、I-29、I-31对HeLa的体外抑制活性均优于CN111454327A中的化合物16。
表3目标化合物细胞对HeLa细胞株的半数抑制浓度IC50(单位μM)
实施例40本发明化合物在A2780细胞株中对NAMPT降解活性测试
步骤a：将处于对数生长期的A2780细胞按6×105个/孔的密度接种于6孔板中，每孔加2mL的1640培养基，37℃、5％CO2培养24h；
步骤b：吸走1640培养基，每孔加RPMI基础培养基，37℃、5％CO2培养24h；
步骤c：吸走培养基，加入1640培养基配制的药物(每孔2mL)，37℃、5％CO2培养24h；
步骤d：吸走培养基，PBS润洗一遍，加入新配制的细胞裂解液，冰浴孵育0.5h；
步骤e：研磨后收集细胞裂解物于离心管中，每隔5min涡旋1次，重复3次；
步骤f：将装有细胞裂解物的离心管置于离心机中离心(4℃，1.2×104rpm，15min)；
步骤g：96孔板每孔加入PBS(18μL)、细胞上清液(2μL)、新配制的BCA测试液(200μL)，酶标仪测试蛋白浓度；
步骤h：取上清液(60μL)于离心管中，加入蛋白上样缓冲液(15μL)，置于金属浴加热使蛋白变性(100℃，15min)；
步骤i：按蛋白浓度测试结果取按总蛋白含量(30μg)进行电泳(90V，2h)；
步骤j：快速转膜仪进行转膜(25V，7min)；
步骤k：快速封闭液室温封闭0.5h，TBST洗3次；
步骤l：孵一抗(1:1000)，置于2-8℃过夜；
步骤m：回收一抗，TBST洗3次，每次10min；
步骤n：室温下孵二抗1.5h；
步骤o：回收二抗，TBST洗3次，每次10min；
步骤p：Odyssey双色红外激光成像系统扫描显影，内参为GAPDH。
实验结果：本发明化合物在A2780细胞株中对NAMPT蛋白的降解活性如图1所示，图1是蛋白降解靶向嵌合分子对A2780细胞内NAMPT蛋白表达的影响示意图。其中，A、B是不同浓度的化合物I-3(图中显示为化合物3)与A2780细胞孵育24h，细胞内NAMPT含量的变化，并利用Jmage J对蛋白条带进行分析；C-K是不同浓度的化合物与A2780细胞孵育24h，细胞内NAMPT含量的变化。测试结果显示，本发明化合物在A2780细胞株中具有优秀的降解NAMPT蛋白活性，其中化合物I-3-I-6、I-9-I-11、I-31、I-32降解活性最佳。
实施例41本发明化合物在HeLa细胞株中对NAMPT降解活性测试
操作方法步骤同实施例36。实验结果：本发明化合物在HeLa细胞中对NAMPT蛋白的降解活性如图2所示，图2是蛋白降解靶向嵌合分子对HeLa细胞内NAMPT蛋白表达的影响示意图。其中，A是部分化合物在500nM单浓度下与HeLa细胞孵育24h，细胞内NAMPT含量的变化；B-D是不同浓度的化合物I-14、I-31、I-32与A2780细胞孵育24h，细胞内NAMPT含量的变化。测试结果显示，本发明化合物在HeLa细胞株中具有优秀的降解NAMPT蛋白活性，其中化合物I-3、I-9、I-15、I-31、I-32降解活性最佳。
实施例42本发明化合物I-3体内抗肿瘤活性测试
步骤a：购买A2780移植瘤裸鼠，继续饲养5天，当皮下肿瘤长至120mm3后，开始体内实验；
步骤b：将裸鼠随机分为4组，分别为Control组(生理盐水)、化合物I-3组、FK866组和735组；
步骤c：按以2μM/kg剂量进行尾静脉注射给药，单次注射体积为0.2mL/只，每3天给药一次，持续给药7次；
步骤d：每3天测量裸鼠体重和肿瘤大小，肿瘤大小测量方法：测量小鼠肿瘤的长径(a)和短径(b)，根据计算公式V＝1/2×a×b2计算每只小鼠的肿瘤体积大小；
步骤e：第21天处死裸鼠，解剖取出A2780肿瘤，称量肿瘤重量，计算抑瘤率，并进行T检验。
实验结果：本发明化合物I-3显示出优秀的抗肿瘤药效(TGI＝88.1％)，显著优于阳性对照药FK866组(TGI＝62.9％)和735组(TGI＝49.8％)，且毒性低于对照组。图3是在裸鼠A2780移植瘤模型中，蛋白降解靶向嵌合分子化合物I-3、对照分子FK866和735组小鼠肿瘤的生长曲线、体重变化和肿瘤大小、H&E组织染色和免疫组化评价示意图。A是裸鼠A2780移植瘤模型中，iv 2μM/kg时，化合物I-3、735和FK866组小鼠肿瘤的生长曲线；B是裸鼠A2780移植瘤模型中，iv 2μM/kg时，化合物I-3、735和FK866组小鼠的体重变化；C是裸鼠A2780移植瘤模型中，iv 2μM/kg时，给药7次后化合物I-3、735和FK866组小鼠的肿瘤大小，圈表示小鼠死亡；D是H&E组织染色评价化合物I-3、735和FK866组的器官和组织毒性(箭头表示出现坏死和出血)；E是免疫组化评价化合物I-3、735和FK866组的瘤内Ki67表达水平(肿瘤增殖标记分子)和NAMPT蛋白水平。表明靶向降解NAMPT的PROTAC分子化合物I-3比NAMPT抑制剂FK866和735体内抗肿瘤活性更优秀，且毒副作用更低。
与CN111454327A发明的化合物相比，本发明化合物(如化合物I-2～I-6，)对A2780和HeLa细胞的体外抑制活性更强，尤其是化合物I-3具有最优的体外降解活性和抗增殖活性，对A2780的IC50<0.5nM，在A2780细胞株对NAMPT的DC50<0.17nM，抑制活性和降解活性比CN111454327A中的化合物16提升了50倍以上。此外，体内药效学实验发现，本发明化合物I-3在A2780裸鼠移植瘤模型中，抑瘤率达到88.1％，显著优于NAMPT抑制剂FK866(62.9％)和735(49.8％)，且安全性更高。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。
Claims (4)
1.一种靶向降解NAMPT的PROTAC化合物或其药用盐，其特征在于，所述NAMPT蛋白降解靶向嵌合体选自以下结构的一种：
2.一种靶向降解NAMPT的PROTAC化合物在制备抗肿瘤的药物中的应用，其特征在于，所述肿瘤选自卵巢癌；
所述NAMPT蛋白降解靶向嵌合体选自以下结构的一种：
3.一种靶向降解NAMPT的PROTAC化合物在制备抗肿瘤的药物中的应用，其特征在于，所述肿瘤选自宫颈癌；
所述NAMPT蛋白降解靶向嵌合体选自以下结构的一种：
4.一种靶向降解NAMPT的PROTAC化合物或其药用盐在制备NAMPT蛋白抑制剂或降解剂中的应用，其特征在于，所述NAMPT蛋白降解靶向嵌合体选自以下结构的一种：
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| WO2018132372A1 (en) * | 2017-01-10 | 2018-07-19 | Sanford Burnham Prebys Medical Discovery Institute | Small molecule activators of nicotinamide phosphoribosyltransferase (nampt) and uses thereof |
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| CN111454327A (zh) * | 2020-04-02 | 2020-07-28 | 中国人民解放军第二军医大学 | 一种nampt蛋白降解靶向嵌合体及其制备方法和应用 |
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