CN111303122A - 一种泊马度胺衍生物及其用途 - Google Patents
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
本发明涉及一种泊马度胺衍生物，该化合物的化学结构如下式(I)所示，式(I)中，R1是苯基或1,4‑苯并二恶烷基；R2是氯或溴；R3是氢或3‑甲基苯甲腈基；X为连接基团，该基团选自乙二胺、丙二胺、丁二胺、戊二胺、己二胺、哌嗪丁二酸、哌嗪戊二酸、哌嗪二甘醇酸、乙二胺丁二酸、乙二胺戊二酸、乙二胺二甘醇酸、丙二胺戊二酸、丁二胺戊二酸或戊二胺丙二酸。本发明所述的一种泊马度胺衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD‑1/PD‑L1)的相互结合，可用于制备PD‑1/PD‑L1抑制剂，该抑制剂的效果显著。
Description
技术领域
本发明涉及有机化合物，具体涉及一种泊马度胺衍生物，该衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)的相互结合，可用于治疗肿瘤。
背景技术
肿瘤免疫疗法被越来越多的运用在癌症治疗领域。目前，肿瘤免疫治疗主要运用的药物是大分子生物抗体。其中PD-1/PD-L1的抑制剂(也被称为免疫检查点抑制剂)对多种肿瘤有效。因此，近年来，PD-1/PD-L1成为抗肿瘤药物设计中最吸引人的一个靶标，同时也已被列为最具前景的肿瘤治疗靶点之一，因而备受关注。
PD-1/PD-L1抗体药物就其药效动力学而言具有靶点专属特异性和高效性等方面的优点。然而就其药代动力学而言，抗体药物的缺点也非常明显，首先，对相关组织和肿瘤细胞穿透性差，代谢半衰期长，口服生物利用度低等，其次，抗体药物具有免疫原性，因此会引起严重的不良反应，而且，抗体药物制造和分离纯化过程很复杂，导致其生产成本非常高昂。与大分子抗体药物相反，小分子化合物在药效动力学方面具有很多优势，例如，小分子化合物具有较好的口服生物利用度，对相关组织和肿瘤细胞渗透率高，半衰期合理等，而且小分子化合物具有毒性低，较高的选择性和有效性等优点，因此，小分子肿瘤免疫类药物有望克服大分子抗体药物存在的缺点。在肿瘤免疫治疗领域，小分子化合物既可以完善现有的抗体药物存在的不足，也可以与抗体药物共同使用发挥协同作用。随着科研人员在小分子肿瘤免疫药物研究中作出的巨大努力，一些高效的小分子化合物陆续被报道，其中有些小分子化合物已经进入临床研究。然而，迄今为止，没有一款小分子肿瘤免疫药物被FDA批准用于癌症相关治疗。因此，以小分子为基础的肿瘤免疫疗法仍然是肿瘤免疫治疗最值得的关注的科学领域之一。
公开号为WO2015/034820 A1的PCT专利申请公开了名称为1-({3-溴-4-[(2-甲基-3-苯基)甲氧基))苯基}-甲基)哌啶-2-羧酸结构式如下的间苯二酚二苯甲醚衍生物(见该专利申请的实施例8)：
上述PCT专利申请公开了所述衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)的相互结合，可用于治疗肿瘤。但是，上述PCT专利申请所公开的化合物对PD-1/PD-L1的抑制效果还不理想，其采用HTRF方法检测的IC50仅为146nM。因此，合成一种对PD-1/PD-L1抑制效果理想的化合物具有重要意义。
发明内容
本发明所要解决的技术问题是提供一种泊马度胺衍生物，该衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配1(PD-1/PD-L1)的相互结合，且效果显著。
本发明解决上述技术问题的方案如下：
一种泊马度胺衍生物，该衍生物的化学结构如下式(I)所示，
式(I)中，R1是苯基或1,4-苯并二恶烷基；R2是氯或溴；R3是氢或3-甲基苯甲腈基；X为连接基团，该基团选自乙二胺、丙二胺、丁二胺、戊二胺、己二胺、哌嗪丁二酸、哌嗪戊二酸、哌嗪二甘醇酸、乙二胺丁二酸、乙二胺戊二酸、乙二胺二甘醇酸、丙二胺戊二酸、丁二胺戊二酸或戊二胺丙二酸。本发明所述的一种泊马度胺衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)的相互结合，可用于制备PD-1/PD-L1抑制剂，该抑制剂的效果显著。
本发明所述的一种泊马度胺衍生物优选下述化合物之一：
所述一种泊马度胺衍生物P1的化学结构为：
所述一种泊马度胺衍生物P2的化学结构为：
所述一种泊马度胺衍生物P3的化学结构为：
所述一种泊马度胺衍生物P4的化学结构为：
所述一种泊马度胺衍生物P5的化学结构为：
所述一种泊马度胺衍生物P6的化学结构为：
所述一种泊马度胺衍生物P7的化学结构为：
所述一种泊马度胺衍生物P8的化学结构为：
所述一种泊马度胺衍生物P9的化学结构为：
所述一种泊马度胺衍生物P10的化学结构为：
所述一种泊马度胺衍生物P11的化学结构为：
所述一种泊马度胺衍生物P12的化学结构为：
所述一种泊马度胺衍生物P13的化学结构为：
所述一种泊马度胺衍生物P14的化学结构为：
所述一种泊马度胺衍生物P15的化学结构为：
所述一种泊马度胺衍生物P16的化学结构为：
所述一种泊马度胺衍生物P17的化学结构为：
上述一种泊马度胺衍生物的制备方法包括以下步骤：
本发明的一种泊马度胺衍生物的制备方法，该制备方法有两条合成路线
上述的反应式如下所示：
αReagents and conditions:(a)DCM,0℃,30min,90％；(b)NaHCO3,DMF,80℃,2hrs,40％；(c)AcOH,NaBH3CN,DMF,80℃,2hrs,15％～25％；(d)i.HATU,DIPEA,DMF,rt,1h,70％；ii.4M HCl/1,4-Dioxane,DCM,0℃,2hrs,90％；(e)HATU,DIPEA,DMF,rt,1h,15％～20％；(f)i.NMP,DIPEA,120℃,6hrs,25％～30％；ii.4M HCl/1,4-Dioxane,DCM,0℃,2hrs,90％；(g)AcOK,AcOH,100℃,6hrs,10％～20％.
路线二如下所示：
αReagents and conditions:(a)Pd(PPh3)4,DMSO,H2O,100℃,12hrs,25％～30％；(b)DCM,0℃,30min,90％；(c)NaHCO3,DMF,80℃,2hrs,40％；(d)Na2CO3,DMF,80℃,30min,60％；(e)AcOH,NaBH3CN,DMF,80℃,2hrs,15％～25％；(f)i.HATU,DIPEA,DMF,rt,1h,70％；ii.4M HCl/1,4-Dioxane,DCM,0℃,2hrs,90％；(g)HATU,DIPEA,DMF,rt,1h,15％～20％.
上述反应式中，R1是苯基或1,4-苯并二恶烷基；R2是氯或溴；R3是氢或3-甲基苯甲腈基；X为连接基团，该基团选自乙二胺、丙二胺、丁二胺、戊二胺、己二胺、哌嗪丁二酸、哌嗪戊二酸、哌嗪二甘醇酸、乙二胺丁二酸、乙二胺戊二酸、乙二胺二甘醇酸、丙二胺戊二酸、丁二胺戊二酸或戊二胺丙二酸。上述一种泊马度胺衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)的相互结合，可用于制备PD-1/PD-L1抑制剂，该抑制剂的抗肿瘤效果显著。所述的PD-1/PD-L1抑制剂由所述的一种泊马度胺衍生物和医学上可接受的辅料组成。
采用HTRF(均相时间分辨荧光)技术标准操作程序测定本发明所述的一种泊马度胺衍生物对PD-1/PD-L1的抑制效果，结果显示该化合物对PD-1/PD-L1抑制效果显著优于现有技术。
以下结合具体实施方式对本发明作进一步说明。
具体实施方式
实施例1(化合物制备及其鉴定)
本发明所述泊马度胺衍生物可采用下述方法之一制备：
制备方法一:将芳基苄溴化合物(1当量)，硼酸酯(1.2当量)，碳酸铯(1.2当量)和四三苯基膦钯(0.1当量)称量好后置入二甲基亚砜和水的混合溶剂中，氮气置换3次后，100度反应12小时。反应完毕后，将反应混合液倒入水中，乙酸乙酯萃取，有机相用盐水洗3次，并用无水硫酸钠干燥，硅胶过柱可得目标产物。
制备方法二:在冰浴中，逐滴加三溴化硼到芳基苄醇的二氯甲烷溶液里面。反应结束后，用甲醇淬灭反应，硅胶过柱可得目标产物。
制备方法三:将芳基苄醇化合物(1当量)，芳基苄溴化合物(1当量)，碳酸氢钠(1.2当量)，放到氮氮二甲基甲酰胺溶液中。将反应加热到60度，反应2小时。反应完毕后，将反应混合液倒入水中，乙酸乙酯萃取，有机相用盐水洗3次，并用无水硫酸钠干燥，硅胶过柱可得目标产物。
制备方法四:将6g芳基苄溴化合物和3.5g 3-溴甲基苯氰，3g碳酸钾加入30ml无水DMF中，搅拌，加热至80℃，反应4小时，TLC监测，反应结束后，将反应物倾入100mL水中，用乙酸乙酯(100mL×3)萃取，静置分液，有机相分别用5％的NaHCO3(20mL×3)、饱和食盐水(20mL×3)洗涤，然后用无水硫酸镁干燥，抽滤，减压除去乙酸乙酯，之后进行柱层析V(石油醚)：V(乙酸乙酯)＝2:1得目标产物。
制备方法五:将芳香醛化合物和60mg哌啶甲酸，2滴冰醋酸加入5ml无水甲醇中，搅拌，加热至60℃，反应4小时，然后加入42mg氰基硼氢化钠(NaBH3CN)，室温反应12小时，TLC监测，反应结束后，旋干溶剂，将反应物倾入100mL水中，用乙酸乙酯(20mL×3)萃取，静置分液，有机相分别用5％的NaHCO3(20mL×3)、饱和食盐水(20mL×3)洗涤，然后用无水硫酸镁干燥，抽滤，减压除去乙酸乙酯，之后进行柱层析V(二氯甲烷)：V(甲醇)＝20:1得白色固体化合物。
制备方法六:将有机酸(1当量)、有机胺(1当量)、HATU(1.2当量)、DIPEA(1.8当量)放到氮氮二甲基甲酰胺溶液中。室温反应，反应2小时。反应完毕后，将反应混合液倒入水中，乙酸乙酯萃取，有机相用盐水洗3次，并用无水硫酸钠干燥，硅胶过柱可得目标产物。
制备方法七:将反应物溶解到二氯甲烷溶液中，加入4M HCl/1,4-Dioxane(1mL)去除Boc保护基，反应结束后，旋干溶液可得产物。
制备方法八:将泊马度胺(1当量)，酸酐(1当量)，醋酸钾(1当量)溶解到醋酸溶液中，搅拌。将反应加热到100度，反应6小时。反应完毕后，将反应混合液倒入水中，乙酸乙酯萃取，有机相用盐水洗3次，并用无水硫酸钠干燥，硅胶过柱可得目标产物。
本发明所述泊马度胺衍生物P1的具体如下：
泊马度胺衍生物P1：将有机酸(1当量)、泊马度胺衍生物(1当量)、HATU(1.2当量)、DIPEA(1.8当量)放到氮氮二甲基甲酰胺溶液中。室温反应，反应2小时。反应完毕后，将反应混合液倒入水中，乙酸乙酯萃取，有机相用盐水洗3次，并用无水硫酸钠干燥，硅胶过柱可得目标产物P1。目标产物P1的鉴定结果如下：
N1-(2-(1-(3-bromo-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxamido)ethyl)-N5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glutaramide(P1).White solid(8mg,yield 17％).1H NMR(400MHz,DMSO)δ11.95(s,1H),11.14(s,1H),9.67(s,1H),8.46(d,J＝8.2Hz,1H),7.91(s,1H),7.81(t,J＝6.6Hz,2H),7.60(s,2H),7.52(d,J＝7.4Hz,1H),7.45(d,J＝5.9Hz,1H),7.39(d,J＝5.8Hz,1H),7.31(d,J＝6.3Hz,3H),7.22(dd,J＝21.0,10.4Hz,2H),5.20(s,2H),5.14(d,J＝12.6Hz,1H),4.34(dd,J＝7.3,5.1Hz,1H),3.65(d,J＝12.3Hz,1H),3.44(dd,J＝9.5,4.4Hz,1H),3.34(s,1H),3.16(d,J＝12.5Hz,3H),3.03(d,J＝12.5Hz,1H),2.88(d,J＝13.2Hz,1H),2.73(d,J＝9.8Hz,1H),2.67(d,J＝10.0Hz,1H),2.60(d,J＝18.3Hz,1H),2.48–2.40(m,2H),2.21(s,2H),2.11(s,1H),2.07(s,1H),1.91(d,J＝2.3Hz,1H),1.88–1.79(m,2H),1.72(d,J＝10.9Hz,1H),1.65(s,1H),1.52(s,2H),1.34(s,1H),1.26(s,1H),1.06(ddd,J＝9.3,6.5,3.0Hz,2H).HRMS m/z calcd for C47H50O8N6Br905.2868,found 905.2886[M+H+].HPLC:tR 19.130min,purity 96.901％.
本发明所述泊马度胺衍生物P2-17的制备方法与上述泊马度胺衍生物P1的制备方法相同。目标产物P1-17的鉴定结果分别如下所述：
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)piperidine-2-carboxamide(P2).Yellow oil(6mg,yield 18％).1H NMR(400MHz,DMSO)δ11.08(s,1H),7.92(s,1H),7.83–7.78(m,2H),7.73(s,1H),7.62(s,1H),7.51–7.42(m,5H),7.40(d,J＝7.2Hz,1H),7.29(dd,J＝15.9,7.3Hz,3H),7.21(d,J＝7.7Hz,1H),7.03(s,1H),7.00(d,J＝8.6Hz,1H),6.95(d,J＝7.0Hz,1H),6.48(d,J＝5.0Hz,1H),5.26(s,2H),5.20(s,2H),5.03(dd,J＝12.8,5.2Hz,1H),3.51(d,J＝5.3Hz,1H),3.24(d,J＝7.6Hz,2H),3.18(s,1H),3.10(dd,J＝13.0,5.6Hz,1H),3.06–2.98(m,1H),2.89–2.81(m,1H),2.73(dd,J＝15.7,8.2Hz,2H),2.56(d,J＝15.1Hz,1H),2.22(s,3H),2.00(dd,J＝15.0,6.7Hz,2H),1.91(t,J＝10.3Hz,1H),1.66(dd,J＝17.6,9.6Hz,2H),1.52(dd,J＝29.8,8.2Hz,4H),1.40(d,J＝12.4Hz,2H),0.86(t,J＝6.2Hz,1H).HRMS m/z calcd forC52H52O7N6Cl 907.3581,found 907.3586[M+H+].HPLC:tR 19.929 min,purity 96.443％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)piperidine-2-carboxamide(P3).Yellowoil(9mg,yield15％).1HNMR(400MHz,DMSO)δ11.08(s,1H),7.92(s,1H),7.80(d,J＝7.6Hz,2H),7.69(t,J＝5.6Hz,1H),7.62(t,J＝7.7Hz,1H),7.54–7.49(m,1H),7.49–7.40(m,4H),7.39(d,J＝7.1Hz,1H),7.31(d,J＝7.6Hz,2H),7.27(d,J＝7.5Hz,1H),7.21(d,J＝7.4Hz,1H),7.05(s,1H),6.98(dd,J＝7.7,3.5Hz,2H),6.43(t,J＝5.5Hz,1H),5.28(s,2H),5.20(s,2H),5.04(dd,J＝12.9,5.2Hz,1H),3.53(d,J＝13.0Hz,1H),3.20–3.14(m,4H),3.11–3.04(m,2H),2.99–2.90(m,2H),2.85(dd,J＝13.3,3.9Hz,1H),2.76(d,J＝11.2Hz,1H),2.72–2.68(m,1H),2.57(d,J＝15.4Hz,1H),2.21(s,3H),2.00(d,J＝6.4Hz,2H),1.92(d,J＝11.9Hz,1H),1.73–1.62(m,2H),1.56–1.43(m,4H),1.36(dd,J＝16.0,4.7Hz,3H).HRMS m/z calcd for C53H54O7N6Cl921.3737,found 921.3749[M+H+].HPLC:tR 20.142min,purity 95.642％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperidine-2-carboxamide(P4).Yellowoil(11mg,yield20％).1HNMR(400MHz,DMSO)δ11.08(s,1H),7.94(d,J＝16.1Hz,1H),7.81(t,J＝6.7Hz,2H),7.63(dd,J＝16.4,8.5Hz,2H),7.56–7.51(m,1H),7.47(dd,J＝14.9,10.9Hz,4H),7.40–7.35(m,1H),7.31(d,J＝7.4Hz,2H),7.27(d,J＝7.7Hz,1H),7.20(d,J＝7.6Hz,1H),7.06(s,1H),6.99(d,J＝6.5Hz,2H),6.45(s,1H),5.28(s,2H),5.21(s,2H),5.04(dd,J＝12.9,5.4Hz,1H),3.53(d,J＝13.7Hz,1H),3.47–3.36(m,1H),3.24(s,2H),3.18(t,J＝4.8Hz,3H),3.06(dd,J＝13.0,6.5Hz,1H),2.94(dd,J＝13.1,6.6Hz,1H),2.89–2.82(m,1H),2.76(d,J＝5.4Hz,1H),2.70(s,2H),2.57(d,J＝15.1Hz,1H),2.22(s,3H),2.03–1.96(m,2H),1.95–1.88(m,1H),1.69(dd,J＝25.3,10.4Hz,2H),1.59–1.49(m,2H),1.48–1.37(m,3H),1.32(dd,J＝10.0,9.5Hz,3H).HRMS m/z calcd for C54H56O7N6Cl 935.3894,found 935.3909[M+H+].HPLC:tR 20.846min,purity 95.446％.
N1-(2-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxamido)ethyl)-N4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)succinamide(P5).Colorlessoil(10mg,yield 19％).1HNMR(400MHz,DMSO)δ11.15(s,1H),9.69(s,1H),8.44(d,J＝8.4Hz,1H),7.93(s,1H),7.88(s,1H),7.83–7.78(m,2H),7.63(d,J＝7.7Hz,1H),7.60–7.56(m,1H),7.47(t,J＝7.8Hz,3H),7.39(d,J＝4.0Hz,1H),7.31(d,J＝8.4Hz,2H),7.30–7.25(m,1H),7.22(d,J＝7.4Hz,1H),7.19(s,1H),7.05(s,1H),6.65(s,1H),5.33(d,J＝4.7Hz,1H),5.30(d,J＝12.4Hz,2H),5.22(d,J＝17.1Hz,2H),5.14(d,J＝7.4Hz,1H),3.53(d,J＝10.8Hz,2H),3.23(s,1H),3.20–3.16(m,1H),3.10(dd,J＝12.4,8.0Hz,2H),2.83(s,2H),2.74(d,J＝5.5Hz,1H),2.68(s,1H),2.62(s,1H),2.38(d,J＝8.3Hz,1H),2.33(s,1H),2.23(d,J＝11.0Hz,3H),2.01(s,1H),1.96(s,1H),1.92–1.83(m,2H),1.72(d,J＝10.5Hz,1H),1.66(s,1H),1.53(d,J＝11.5Hz,1H),1.50–1.44(m,2H),1.34(s,1H).HRMS m/z calcd forC54H53O9N7Cl 978.3588,found 978.3579[M+H+].HPLC:tR 19.129min,purity 96.487％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)acetamido)ethyl)piperidine-2-carboxamide(P6).Colorless oil(3mg,yield 15.2％).1H NMR(400MHz,DMSO)δ11.15(s,1H),10.16(d,J＝6.5Hz,1H),8.63(dd,J＝8.4,3.5Hz,1H),7.95(d,J＝8.3Hz,1H),7.89(s,1H),7.85(d,J＝5.6Hz,1H),7.82–7.78(m,1H),7.77–7.73(m,1H),7.70(d,J＝5.8Hz,1H),7.62–7.58(m,1H),7.57–7.52(m,1H),7.50–7.44(m,3H),7.42–7.37(m,1H),7.33(d,J＝7.1Hz,2H),7.29(d,J＝7.4Hz,1H),7.23(d,J＝7.7Hz,1H),7.18(d,J＝7.4Hz,1H),6.93(s,1H),5.37–5.31(m,1H),5.16(dd,J＝17.6,5.7Hz,4H),5.03(d,J＝12.8Hz,1H),4.13(t,J＝9.6Hz,2H),3.54(d,J＝13.5Hz,1H),3.24(s,2H),3.17(d,J＝5.2Hz,1H),2.99–2.93(m,1H),2.86(d,J＝1.9Hz,1H),2.74(s,1H),2.66(d,J＝12.1Hz,2H),2.62(s,1H),2.33(s,1H),2.30(s,1H),2.25(d,J＝1.7Hz,3H),2.09(d,J＝6.4Hz,1H),1.80(d,J＝8.0Hz,1H),1.73(d,J＝10.8Hz,1H),1.64(d,J＝5.5Hz,1H),1.56–1.44(m,3H).HRMS m/z calcd for C54H53O10N7Cl994.3537,found 994.3533[M+H+].HPLC:tR 19.699min,purity 95.691％.
N1-(2-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxamido)ethyl)-N5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glutaramide(P7).Off-white solid(4.9mg,yield 16.3％).1H NMR(400MHz,DMSO)δ11.14(s,1H),9.66(s,1H),8.46(d,J＝8.4Hz,1H),7.93(s,1H),7.81(d,J＝7.6Hz,2H),7.76–7.70(m,2H),7.69–7.67(m,1H),7.66–7.62(m,1H),7.60(d,J＝7.2Hz,1H),7.48–7.39(m,2H),7.26–7.21(m,1H),7.18(d,J＝3.3Hz,1H),7.04(s,1H),6.92(d,J＝8.2Hz,1H),6.79–6.70(m,2H),5.36–5.31(m,1H),5.30(d,J＝13.4Hz,2H),5.18(d,J＝9.6Hz,2H),5.14(dd,J＝12.8,5.4Hz,1H),4.29(s,4H),4.24(d,J＝6.5Hz,2H),3.55–3.50(m,1H),3.23(s,1H),3.10(d,J＝6.5Hz,1H),2.89(s,1H),2.77–2.72(m,1H),2.69(d,J＝9.4Hz,1H),2.59(d,J＝11.3Hz,1H),2.42(s,1H),2.33(s,1H),2.23(s,3H),2.07(d,J＝6.1Hz,1H),2.03(s,1H),1.97(d,J＝6.7Hz,1H),1.88(s,1H),1.80(s,1H),1.64(d,J＝7.8Hz,2H),1.54(d,J＝6.5Hz,1H),1.49(s,1H),1.37(s,1H),1.35(s,1H),1.18(s,1H).HRMS m/z calcd for C57H57O11N7Cl 1050.3810,found 1050.3822[M+H+].HPLC:tR 19.179min,purity 95.153％.
N1-(2-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxamido)ethyl)-N5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glutaramide(P8).Off-white solid(3.9mg,yield 18.1％).1H NMR(400MHz,DMSO)δ11.11(s,1H),10.53(s,1H),8.24(s,1H),7.93(s,1H),7.89(d,J＝8.4Hz,1H),7.85(s,1H),7.81(d,J＝7.2Hz,3H),7.73(dd,J＝5.5,3.5Hz,1H),7.67(dd,J＝5.9,3.2Hz,1H),7.61(d,J＝7.7Hz,1H),7.46(s,1H),7.43(d,J＝6.9Hz,1H),7.23(d,J＝7.4Hz,1H),7.17(d,J＝7.4Hz,1H),7.04(s,1H),6.92(d,J＝8.2Hz,1H),6.79–6.73(m,2H),5.28(s,2H),5.19(s,2H),5.14–5.10(m,1H),4.29(s,4H),4.23(t,J＝6.6Hz,2H),3.51(d,J＝4.8Hz,1H),3.23(s,1H),3.12–3.08(m,2H),2.92–2.86(m,1H),2.78–2.73(m,1H),2.70(dd,J＝9.2,3.6Hz,1H),2.59(d,J＝15.5Hz,1H),2.38(d,J＝7.3Hz,2H),2.23(s,3H),2.10–2.06(m,2H),2.05–2.01(m,1H),1.89(s,1H),1.79(s,1H),1.73(d,J＝10.9Hz,1H),1.64(d,J＝7.8Hz,2H),1.53(s,1H),1.39(s,1H),1.37–1.33(m,2H).HRMS m/z calcd for C57H57O11N7Cl 1050.3810,found 1050.3834[M+H+].HPLC:tR18.836min,purity 96.912％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)acetamido)ethyl)piperidine-2-carboxamide(P9).White solid(2.3mg,yield 15.7％).1H NMR(400MHz,DMSO)δ11.15(s,1H),10.16(d,J＝6.4Hz,1H),8.63(dd,J＝8.5,3.4Hz,1H),7.91(d,J＝19.1Hz,1H),7.82(d,J＝11.0Hz,2H),7.78(d,J＝8.5Hz,1H),7.74–7.71(m,1H),7.67(dt,J＝8.2,4.3Hz,2H),7.63–7.59(m,1H),7.57–7.53(m,1H),7.45(dd,J＝9.4,5.3Hz,2H),7.25(d,J＝7.2Hz,1H),7.19(d,J＝4.0Hz,1H),7.05(s,1H),6.93(d,J＝8.1Hz,2H),6.77(dd,J＝9.3,4.6Hz,2H),5.29(s,1H),5.21(s,1H),5.16(s,2H),5.03(d,J＝12.9Hz,1H),4.29(s,4H),4.23(t,J＝6.5Hz,2H),3.57–3.51(m,1H),3.08(dd,J＝14.0,7.8Hz,2H),2.90(t,J＝10.3Hz,1H),2.66(d,J＝13.2Hz,2H),2.25(d,J＝6.1Hz,2H),2.08(d,J＝5.2Hz,1H),1.99(s,3H),1.92–1.86(m,1H),1.80(d,J＝10.8Hz,1H),1.64(d,J＝7.8Hz,2H),1.53(d,J＝4.6Hz,1H),1.49(d,J＝5.7Hz,1H),1.40(d,J＝7.5Hz,1H),1.35(s,1H).HRMS m/z calcd for C56H55O12N7Cl1052.3592,found 1052.3620[M+H+].HPLC:tR 19.557min,purity 96.638％.
N1-(2-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carboxamido)ethyl)-N4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)succinamide(P10).Colorless oil(4mg,yield 16.9％).1H NMR(400MHz,DMSO)δ11.14(s,1H),9.69(s,1H),8.45(d,J＝8.4Hz,1H),7.93(s,1H),7.88(s,1H),7.81(d,J＝9.2Hz,2H),7.63(d,J＝7.7Hz,1H),7.60–7.56(m,1H),7.46(s,1H),7.41(d,J＝8.1Hz,1H),7.22(d,J＝7.5Hz,1H),7.18(s,1H),7.03(s,1H),6.93(d,J＝8.2Hz,1H),6.81–6.72(m,2H),6.65(s,1H),6.55(d,J＝7.1Hz,1H),5.28(s,2H),5.17(d,J＝5.9Hz,2H),5.16–5.10(m,1H),4.29(s,4H),3.53(d,J＝9.4Hz,1H),3.26(s,1H),3.13–3.08(m,2H),2.94–2.83(m,2H),2.74(d,J＝6.5Hz,1H),2.69(dd,J＝10.2,2.2Hz,1H),2.62(d,J＝3.3Hz,1H),2.58(s,1H),2.38(d,J＝7.0Hz,1H),2.36–2.32(m,1H),2.22(s,3H),2.06(d,J＝5.8Hz,1H),2.02(d,J＝7.4Hz,1H),1.97(d,J＝6.3Hz,1H),1.88(s,1H),1.75–1.70(m,1H),1.65(s,1H),1.53(d,J＝4.9Hz,1H),1.49(s,1H),1.47–1.44(m,1H).HRMS m/z calcd for C56H55O11N7Cl 1036.3643,found 1036.3638[M+H+].HPLC:tR 19.048min,purity 96.228％.
5-(4-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carbonyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide(P11).Off-white solid(4.9mg,yield 15.1％).1H NMR(400MHz,DMSO)δ11.14(s,1H),9.70(s,1H),8.45(d,J＝8.4Hz,1H),7.94(s,1H),7.85–7.75(m,3H),7.62(t,J＝7.8Hz,2H),7.44(d,J＝7.4Hz,1H),7.32(s,1H),7.24(t,J＝7.5Hz,1H),7.17(d,J＝7.5Hz,1H),7.06(s,1H),6.92(d,J＝8.2Hz,1H),6.75(dd,J＝11.6,3.4Hz,2H),5.26(s,2H),5.21(s,2H),5.14(dd,J＝12.7,5.4Hz,1H),4.28(s,4H),3.66(d,J＝24.7Hz,2H),3.54(d,J＝13.9Hz,1H),3.49–3.43(m,2H),3.38(s,4H),3.18(d,J＝5.2Hz,1H),2.89(t,J＝12.4Hz,2H),2.60(d,J＝17.1Hz,1H),2.54(s,1H),2.40(s,3H),2.24(s,3H),2.04(d,J＝4.9Hz,2H),2.02–1.94(m,1H),1.85(dd,J＝14.3,7.1Hz,2H),1.64(s,3H),1.46(s,2H),1.31(d,J＝14.8Hz,2H).HRMS m/z calcd for C59H59O11N7Cl 1076.3956,found 1076.3936[M+H+].HPLC:tR 19.098min,purity 95.459％.
4-(4-(1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carbonyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-4-oxobutanamide(P12).White solid(10mg,yield 19％).1H NMR(400MHz,DMSO)δ11.15(s,1H),9.74(s,1H),8.49(d,J＝8.3Hz,1H),7.94(s,1H),7.82(d,J＝7.4Hz,3H),7.64(d,J＝7.6Hz,1H),7.60(d,J＝7.4Hz,1H),7.44(d,J＝7.2Hz,1H),7.32(s,1H),7.24(t,J＝7.6Hz,1H),7.18(d,J＝7.5Hz,1H),7.07(s,1H),6.92(d,J＝8.1Hz,1H),6.80–6.72(m,2H),5.30(d,J＝24.4Hz,2H),5.21(s,2H),5.15(dd,J＝12.7,5.4Hz,1H),4.28(s,4H),3.69(d,J＝42.4Hz,2H),3.54(d,J＝18.2Hz,2H),3.45(d,J＝7.4Hz,3H),3.37(d,J＝14.2Hz,2H),3.17(d,J＝5.1Hz,1H),2.89(dd,J＝20.5,8.9Hz,2H),2.69(s,3H),2.61(d,J＝18.3Hz,1H),2.24(s,3H),2.07(d,J＝10.3Hz,2H),1.97(d,J＝15.8Hz,1H),1.66(s,2H),1.46(s,2H),1.32(d,J＝10.5Hz,2H),0.86(t,J＝6.3Hz,1H).HRMS m/z calcd for C58H57O11N7Cl1062.3799,found 1062.3771[M+H+].HPLC:tR 19.062min,purity 95.683％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperidine-2-carboxamide(P13).Yellow solid(3.4mg,yield 16％).1H NMR(400MHz,DMSO)δ11.07(s,1H),7.96(s,1H),7.90(s,1H),7.79(s,2H),7.65–7.57(m,1H),7.51(s,1H),7.42(s,1H),7.38(s,1H),7.25(s,1H),7.19(s,1H),7.11(d,J＝8.5Hz,1H),7.01–6.94(m,2H),6.94–6.89(m,1H),6.81–6.73(m,2H),6.63(s,1H),5.23(s,2H),5.17(s,2H),5.00(d,J＝10.1Hz,1H),4.29(d,J＝3.2Hz,4H),3.50(d,J＝13.5Hz,1H),3.23(s,3H),2.83(d,J＝15.2Hz,1H),2.71(d,J＝7.0Hz,2H),2.57(s,1H),2.43(d,J＝15.1Hz,1H),2.23(s,3H),1.93(dt,J＝26.4,10.1Hz,3H),1.68(dd,J＝35.5,10.6Hz,2H),1.58–1.47(m,2H),1.36(d,J＝9.4Hz,2H),0.85(d,J＝11.7Hz,1H).HRMS m/zcalcd for C52H50O9N6Cl 937.3322,found 937.3329[M+H+].HPLC:tR 19.457min,purity96.637％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)piperidine-2-carboxamide(P14).Yellowsolid(6mg,yield 18.9％).1H NMR(400MHz,DMSO)δ11.09(s,1H),7.89(d,J＝16.4Hz,2H),7.79(s,2H),7.63–7.57(m,1H),7.53–7.36(m,3H),7.28–7.22(m,1H),7.18(d,J＝7.7Hz,2H),7.03(s,1H),6.95(dd,J＝18.7,7.6Hz,3H),6.79–6.73(m,2H),6.64(s,1H),5.26(s,2H),5.19(s,2H),5.04(dd,J＝13.2,5.5Hz,1H),3.51(s,1H),3.17(d,J＝5.1Hz,1H),3.08(d,J＝8.5Hz,1H),2.91(d,J＝11.3Hz,1H),2.86(dd,J＝12.5,2.5Hz,1H),2.79–2.67(m,2H),2.57(d,J＝19.2Hz,1H),2.23(s,3H),2.03–1.97(m,2H),1.90(s,1H),1.75(s,1H),1.69(d,J＝37.9Hz,3H),1.55(s,2H),1.43(dd,J＝14.3,9.9Hz,2H).HRMS m/z calcd forC53H52O9N6Cl 951.3479,found 951.3491[M+H+].HPLC:tR 19.750min,purity 95.520％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)piperidine-2-carboxamide(P15).Yellow solid(4.7mg,yield 15％).1H NMR(400MHz,DMSO)δ11.08(s,1H),7.92(s,1H),7.80(t,J＝6.9Hz,2H),7.73(s,1H),7.62(d,J＝7.7Hz,1H),7.53–7.46(m,1H),7.43(s,2H),7.24(t,J＝7.5Hz,1H),7.17(d,J＝7.6Hz,1H),7.08–6.97(m,2H),6.97–6.87(m,2H),6.79–6.71(m,2H),6.48(d,J＝4.6Hz,1H),5.26(s,2H),5.18(s,2H),5.03(dd,J＝12.8,5.4Hz,1H),4.29(s,4H),3.54–3.49(m,1H),3.22(d,J＝6.7Hz,2H),3.17(s,1H),3.10(d,J＝6.5Hz,1H),3.04–2.99(m,1H),2.90–2.82(m,1H),2.77–2.68(m,2H),2.56(d,J＝16.6Hz,1H),2.23(s,3H),2.00(dd,J＝15.3,7.2Hz,2H),1.92(d,J＝15.4Hz,1H),1.72(d,J＝15.1Hz,1H),1.65(d,J＝9.9Hz,1H),1.54–1.46(m,3H),1.41(d,J＝8.4Hz,2H),1.34(s,1H).HRMS m/z calcdfor C54H54O9N6Cl 965.3635,found 965.3635[M+H+].HPLC:tR 19.769min,purity 100％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)piperidine-2-carboxamide(P16).Yellow oil(2mg,yield 15.3％).1H NMR(400MHz,DMSO)δ11.08(s,1H),7.94(d,J＝15.3Hz,1H),7.80(s,2H),7.69(s,1H),7.62(t,J＝7.7Hz,1H),7.55–7.49(m,1H),7.47(s,1H),7.42(d,J＝7.3Hz,1H),7.26–7.21(m,1H),7.17(d,J＝7.8Hz,1H),7.04(s,1H),6.96(dd,J＝13.2,9.2Hz,2H),6.92(d,J＝8.2Hz,1H),6.83–6.71(m,2H),6.64(s,1H),6.43(s,1H),5.27(s,2H),5.18(s,2H),5.03(dd,J＝13.0,5.2Hz,1H),4.28(s,4H),3.51(s,1H),3.19–3.13(m,4H),3.11–3.02(m,2H),2.98–2.93(m,1H),2.88(d,J＝10.5Hz,1H),2.79(d,J＝14.5Hz,1H),2.70(d,J＝12.0Hz,2H),2.58(d,J＝17.6Hz,1H),2.33(s,1H),2.22(s,3H),2.02–1.97(m,2H),1.92(d,J＝16.9Hz,1H),1.75–1.62(m,2H),1.51–1.45(m,2H),1.37(dd,J＝13.9,7.5Hz,2H).HRMS m/z calcd for C55H56O9N6Cl 979.3792,found 979.3818[M+H+].HPLC:tR19.975min,purity 96.021％.
1-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperidine-2-carboxamide(P17).Yellow oil(3.8mg,yield 16.3％).1H NMR(400MHz,DMSO)δ11.08(s,1H),7.92(s,1H),7.80(d,J＝7.2Hz,1H),7.66(s,1H),7.61(d,J＝8.3Hz,1H),7.56–7.50(m,1H),7.47(s,1H),7.43(d,J＝7.1Hz,1H),7.26–7.20(m,1H),7.17(d,J＝6.9Hz,1H),7.04(s,1H),7.03–6.93(m,2H),6.92(d,J＝8.2Hz,1H),6.88–6.73(m,2H),6.65(s,1H),6.45(s,1H),5.27(s,2H),5.19(s,2H),5.03(dd,J＝8.2,6.7Hz,1H),4.28(s,4H),3.51(s,1H),3.23(s,2H),3.19(d,J＝6.9Hz,2H),3.12–3.00(m,2H),2.95(d,J＝7.9Hz,1H),2.88–2.83(m,1H),2.76(d,J＝5.5Hz,1H),2.71(d,J＝11.8Hz,2H),2.56(d,J＝11.2Hz,1H),2.34(s,1H),2.22(s,3H),2.00(dd,J＝13.8,5.0Hz,3H),1.94–1.87(m,1H),1.72(s,1H),1.65(d,J＝13.9Hz,1H),1.56(d,J＝5.7Hz,1H),1.45(t,J＝12.2Hz,3H),1.32(d,J＝5.1Hz,3H),0.86(t,J＝6.2Hz,1H).HRMS m/z calcd for C56H58O9N6Cl 993.3948,found 993.3960[M+H+].HPLC:tR20.246min,purity 100％.
实施例2、本发明所述的一种泊马度胺衍生物对PD-1/PD-L1的抑制效果研究
本发明化合物的对PD-1/PD-L1的抑制效果采用如下方法测试所证明。
这些效果表明本发明化合物对PD-1/PD-L1的抑制效果明显，其可用于治疗癌症，特别是治疗转移性非小细胞肺癌、尿路上皮癌和头颈部鳞状细胞癌。具体测试方法如下：
一、实验目的及原理
参考公开号为CN108593615A专利申请说明书第[0016]、[0017]和[0034]段所述方法，采用HTRF方法快速高效检测实施例1所制备的化合物(编号依次为P1～P17)对PD-1/PD-L1的抑制效果。HTRF(均相时间分辨荧光)检测技术是基于时间分辨荧光(TRF)和荧光共振能量转移(FRET)两大技术原理开通的高通量药物筛选技术。时间分辨荧光(TRF)利用稀土元素中镧系元素半衰期长，荧光比普通荧光持续时间长的特性，通过延迟50-100微秒排除背景，从而反映样品实际情况。荧光共振能量转移(FRET)是指在两个不同的荧光基团中，如果一个荧光基团(供体Donor)的发射光谱与另一个基团(受体Acceptor)的吸收光谱有一定的重叠，当这两个荧光基团间的距离合适时(一般小于
)，就可观察到荧光能量由供体向受体转移的现象，即以前一种基团的激发波长激发时，可观察到后一个基团发射的荧光。简单地说，就是在供体基团的激发状态下由一对偶极子介导的能量从供体向受体转移的过程。能量供给体－接受体(D–A)对之间发生有效能量转移的条件是苛刻的，主要包括：(1)能量供体的发射光谱与能量受体的吸收光谱必须重叠；(2)能量供体与能量受体的荧光生色团必须以适当的方式排列；(3)能量供体、能量受体之间必须足够接近，这样发生能量转移的几率才会高。HTRF是利用了具有穴状结构的铕(Eu)元素的螯和标记物作为一个能量供体(Donor)和XL665(改良过的别藻蓝蛋白)作为一个能量受体(Acceptor)，是基于Eu穴状化合物的供体与XL665受体(第二荧光标记物)之间的时间分辨荧光(TRF)和荧光共振能量转移(FRET)特性开通的高通量药物筛选技术。在荧光共振能量转移中，受体发射荧光的寿命等同与供体的发射荧光的寿命。因为Eu的荧光衰减周期较长，所以含Eu的供体会诱导XL665受体长时间地发射荧光，受体激发后产生的荧光便能持续较长时间，这样通过时间分辨就可以区分短寿命的自身散射荧光，这样从短寿命荧光背景中就很容易区分出FRET信号。当由于生物分子相互作用导致两个荧光基团接近时，在激发时被Eu穴状化合物捕获的部分能量释放，发射波长为620nm；另一部分能量转移到受体(Acceptor)上，发射波长为665nm。665nm的发射光仅由供体(Donor)引起的FRET产生。在HTRF检测试剂盒中，Eu穴状化合物的能量供体能够特异性的结合PD-L1蛋白，XL665能量受体能够特异性的结合PD-1蛋白，从而形成四个物质聚合的复合物。拉近Donor和Acceptor的距离，能量能够从Donor上转移到Acceptor上，使Acceptor产生荧光；若测试化合物能够阻断二者结合，则随着测试化合物浓度的增加，665nm/620nm的比值降低；待检测体系稳定后测定荧光值的变化便可量化阻断剂的效价IC50；检测的为HTRF两个荧光665nm和620nm，即时间分辨荧光(TRF)，当665nm/620nm的比值降低，阻断剂的效应越高。HTRF检测试剂盒，就是综合利用抗原抗体的特异性结合反应，受体供体间能量共振转移而开发的，高灵敏度，快速免洗，低背景的高通量检测技术。
二、试剂基本信息
三、实验试剂准备
四、实验过程
(1)向96孔板中每孔加入2μl的化合物稀释液，1000rpm离心1min.
(2)向每孔加入4μl(2.5X)PD-1混合液，1000rpm离心1min.
(3)向每孔加入4ul(2.5X)PD-L1混合液，1000rpm离心1min，室温孵育15min.
(4)每孔加入10μl(2X)测试混合液,1000rpm离心1min.
(5)室温孵育120min,使用Tecan酶标仪读取荧光值(Ex:320nM；Em:620and665nM).
(6)按下列公式计算抑制率，抑制率(Inibition)％＝(1-(各孔665nm/620nm信号值-低对照组平均值)/(高对照组平均值-低对照组平均值))*100。其中高对照组为没有加化合物处理，仅用等量浓度DMSO溶液加入反应体系组；低对照组为没有PD-1混合液，只加入等量detection检测混合液。该检测体系中，DMSO终浓度为0.5％。
下表列出了在PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定中测量的本发明的实施例1的IC50。化合物的IC50在100nM到10nM之间被标示为+；化合物的IC50在10nM到1nM之间被标示为++。具体见下表：
化合物P1～P17对PD-1/PD-L1的抑制效果
根据上述体外实验结果，我们可以得出本发明所述的一种泊马度胺衍生物能够抑制程序性细胞死亡受体1/程序性细胞死亡配体1(PD-1/PD-L1)的相互结合，且效果显著优于公开号为WO2015/034820A1的PCT专利申请所公开的化合物1-({3-溴-4-[(2-甲基-3-苯基)甲氧基))苯基}-甲基)哌啶-2-羧酸。
Claims (4)
1.一种泊马度胺衍生物，该衍生物的化学结构如下式(I)所示，
式(I)中，R1是苯基或1,4-苯并二恶烷基；R2是氯或溴；R3是氢或3-甲基苯甲腈基；X为连接基团，该基团选自乙二胺、丙二胺、丁二胺、戊二胺、己二胺、哌嗪丁二酸、哌嗪戊二酸、哌嗪二甘醇酸、乙二胺丁二酸、乙二胺戊二酸、乙二胺二甘醇酸、丙二胺戊二酸、丁二胺戊二酸或戊二胺丙二酸。
2.根据权利要求1所述的一种泊马度胺衍生物，其特征在于，所述的一种泊马度胺衍生物为下述化合物中的一种：
所述一种泊马度胺衍生物P1的化学结构为：
所述一种泊马度胺衍生物P2的化学结构为：
所述一种泊马度胺衍生物P3的化学结构为：
所述一种泊马度胺衍生物P4的化学结构为：
所述一种泊马度胺衍生物P5的化学结构为：
所述一种泊马度胺衍生物P6的化学结构为：
所述一种泊马度胺衍生物P7的化学结构为：
所述一种泊马度胺衍生物P8的化学结构为：
所述一种泊马度胺衍生物P9的化学结构为：
所述一种泊马度胺衍生物P10的化学结构为：
所述一种泊马度胺衍生物P11的化学结构为：
所述一种泊马度胺衍生物P12的化学结构为：
所述一种泊马度胺衍生物P13的化学结构为：
所述一种泊马度胺衍生物P14的化学结构为：
所述一种泊马度胺衍生物P15的化学结构为：
所述一种泊马度胺衍生物P16的化学结构为：
所述一种泊马度胺衍生物P17的化学结构为：
3.权利要求1或者2所述的一种泊马度胺衍生物在制备PD-1/PD-L1抑制剂中的应用。
4.根据权利要求3所述的应用，其特征在于，所述的PD-1/PD-L1抑制剂由权利要求1所述的一种泊马度胺衍生物和医学上可接受的辅料组成。
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| CN113307779A (zh) * | 2021-05-25 | 2021-08-27 | 中国药科大学 | 杂环取代联苯类化合物、制备方法及用途 |
| WO2024087332A1 (zh) * | 2022-10-26 | 2024-05-02 | 深圳先进技术研究院 | 一种用作靶蛋白降解剂的双功能化合物及其在靶蛋白溶酶体降解中的应用 |
| CN115925717A (zh) * | 2022-11-11 | 2023-04-07 | 武汉市武昌医院 | 一种d(+)-生物素衍生物、制备方法及应用 |
| CN115925717B (zh) * | 2022-11-11 | 2024-08-16 | 武汉市武昌医院 | 一种d(+)-生物素衍生物、制备方法及应用 |
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