CN114853634A - 烟醇醚类衍生物、及其制法和药物组合物与用途 - Google Patents

烟醇醚类衍生物、及其制法和药物组合物与用途 Download PDF

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CN114853634A
CN114853634A CN202210287082.7A CN202210287082A CN114853634A CN 114853634 A CN114853634 A CN 114853634A CN 202210287082 A CN202210287082 A CN 202210287082A CN 114853634 A CN114853634 A CN 114853634A
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bromo
pyridine
methyleneoxy
chlorobenzyl
phenylbenzyloxy
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冯志强
陈晓光
杨阳
郑义
来芳芳
季鸣
周川
张莉婧
王克
薛妮娜
李凌
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Institute of Materia Medica of CAMS
Tianjin Chase Sun Pharmaceutical Co Ltd
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Institute of Materia Medica of CAMS
Tianjin Chase Sun Pharmaceutical Co Ltd
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Abstract

公开了一类烟醇醚类衍生物、及其制法和药物组合物与用途。具体而言，涉及通式I所示的烟醇醚类衍生物，其可药用盐，其立体异构体及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与PD‑1/PD‑L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
Figure DDA0003560318310000011

Description

烟醇醚类衍生物、及其制法和药物组合物与用途
发明领域
本发明公开了一类烟醇醚类衍生物、及其制法和药物组合物与用途。具体而言，涉及通式I所示的烟醇醚类衍生物，其可药用盐，其立体异构体及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病方面的用途。
发明背景
随着对肿瘤免疫研究的深入，人们发现肿瘤微环境可以保护肿瘤细胞不被机体免疫系统识别和杀伤，肿瘤细胞的免疫逃逸在肿瘤发生、发展中扮演了非常重要的角色。2013年Science杂志将肿瘤免疫治疗列为十大突破之首，再次让免疫治疗成为肿瘤治疗领域的“焦点”。机体免疫细胞的激活或抑制是通过正性信号和负性信号来调节，其中程序性死亡分子1(programmed death 1，PD-1)/PD-1配体 (PD-1ligand，PD-L1)便是负性免疫调节信号，抑制了肿瘤特异性CD8+T细胞的免疫活性，介导了免疫逃逸。
肿瘤细胞所具有的逃避免疫系统的能力，是通过在其表面产生的程序性死亡配体(PD-L1)结合到T细胞的PD-1蛋白上实现的。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子，肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2，导致肿瘤微环境中PD-1通路持续激活，T细胞功能被抑制而不能发现肿瘤以至于不能向免疫系统发出需要攻击肿瘤和杀伤肿瘤细胞的治疗。PD-1抗体是针对PD-1 或者PD-L1的一种抗体蛋白，使得前两种蛋白不能发生结合，阻断这一通路，部分恢复T细胞的功能，使这些细胞能够继续杀伤肿瘤细胞。
基于PD1/PDL1的免疫疗法是当前备受瞩目的新一代免疫疗法，旨在利用人体自身的免疫系统抵御肿瘤，通过阻断PD-1/PD-L1信号通路诱导凋亡，具有治疗多种类型肿瘤潜力。最近，一系列令人惊喜的研究结果证实PDl/PD-Ll抑制性抗体对多种肿瘤具有强大的抗瘤活性，格外引人注目。2014年9月4日美国默克的
Figure RE-GDA0003636330710000011
(pembrolizumab)成为FDA批准的首例PD-1单抗用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者。目前，默沙东正在30多种不同类型的癌症中调查Keytruda的潜力，包括各类血液癌症、肺癌、乳腺癌、膀胱癌、胃癌、头颈部癌症。2014年12月22日，制药巨头百时美施贵宝公司不负重望，率先发力，获得美国食品药品监督管理局(FDA)加速批准，其研发的抗癌免疫疗法药物nivolumab以Opdivo的商品名上市，用于治疗对其它药物没有应答的不可切除的或转移性黑色素瘤患者，是继默沙东Keytruda之后第二个在美国上市的 PD-1抑制剂。FDA于2015年3月4日批准了nivolumab用于治疗在经铂为基础化疗期间或化疗后发生疾病进展的转移性鳞性非小细胞肺癌。根据默沙东公布的 Keytruda(pembrolizumab)治疗实体瘤的一项Ib期KEYNOTE-028研究数据， Keytruda治疗在25例胸膜间皮瘤(pleuralmesothelioma，PM)患者中取得了28％的总缓解率(ORR)，并有48％的患者病情稳定，疾病控制率达到了76％。对当前任何已获批药物均无治疗反应的晚期霍奇金淋巴瘤(HL)患者，接受默沙东 Keytruda和百时美Opdvio治疗后，能够达到完全缓解。在2015AACR年会上，约翰霍普金斯基梅尔癌症中心(Kimmel Cancer Center)的肿瘤内科学副教授Leisha A.Emens,MD,PhD做出的报道指出，罗氏的MPDL3280A这一具有抗PD-L1作用的单克隆抗体，在晚期三阴性乳腺癌中表现出了持久的疗效。
虽然肿瘤免疫治疗被认为是靶向治疗后癌症治疗的革命。但是，单抗治疗药物有其本身的缺陷：易被蛋白酶分解，因而在体内不稳定，不能口服；易产生免疫交叉反应；产品质量不易控制，制作技术要求高；大量制备和纯化比较困难，生产成本高；使用不方便，只能注射或点滴。所以，PDl/PD-Ll相互作用小分子抑制剂是肿瘤免疫治疗的更佳选择。
发明内容
本发明解决的技术问题是提供一种具有抑制PDl/PD-Ll相互作用的结构通式I 的烟醇醚类衍生物，以及其立体异构体及其可药用盐，其制备方法、药物组合物和其在制备预防或治疗与PDl/PD-Ll信号通路有关疾病药物中的用途。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供一类如通式I所示的烟醇醚类衍生物及其立体异构体以及其可药用盐，
Figure RE-GDA0003636330710000031
式中
R1选自:
Figure RE-GDA0003636330710000032
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure RE-GDA0003636330710000033
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA)所示：
Figure RE-GDA0003636330710000034
式中
R1选自:
Figure RE-GDA0003636330710000041
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure RE-GDA0003636330710000042
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-1)所示：
Figure RE-GDA0003636330710000043
式中
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure RE-GDA0003636330710000044
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
优选的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-2)所示：
Figure RE-GDA0003636330710000051
式中
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure RE-GDA0003636330710000052
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
以上通式中，优选的的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述R3选自
Figure RE-GDA0003636330710000061
R＝甲基、乙基、丙基、异丙基、丁基、戊基、己基、庚基、辛基；
X选自：氢、氟、氯、溴、甲基、乙烯基、三氟甲基。
最优选的化合物选自：
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure RE-GDA0003636330710000062
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000071
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure RE-GDA0003636330710000072
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000073
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure RE-GDA0003636330710000074
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐
Figure RE-GDA0003636330710000075
(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure RE-GDA0003636330710000081
(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000082
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]甘氨酸
Figure RE-GDA0003636330710000083
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]缬氨酸
Figure RE-GDA0003636330710000084
N-巴豆氰基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000085
N，N-二(羟乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000091
N-(2-甲磺酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000092
N-(2-乙酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000093
3-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺基]丁烯-2-酸
Figure RE-GDA0003636330710000094
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]牛磺酸
Figure RE-GDA0003636330710000095
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]亮氨酸
Figure RE-GDA0003636330710000101
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]酪氨酸
Figure RE-GDA0003636330710000102
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]异亮氨酸
Figure RE-GDA0003636330710000103
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]天冬酰胺
Figure RE-GDA0003636330710000104
N-羟乙基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000105
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸
Figure RE-GDA0003636330710000111
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
Figure RE-GDA0003636330710000112
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸钠盐
Figure RE-GDA0003636330710000113
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸钙盐
Figure RE-GDA0003636330710000114
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000115
以上所述通式中的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于，所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子，钠离子，钾离子；所述的碱土金属离子选自钙离子，镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2－羟乙基)胺。
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法：
为了制备本发明通式I所述的化合物，依据通式I的结构，本发明制备通式I 化合物将分为五步。
Figure RE-GDA0003636330710000121
(a)以2-溴-3-碘甲苯1和苯或取代苯的硼酸或硼酸酯为基本原料，通过suzuki偶联反应得到中间体化合物2；
(b)以中间体2为原料，通过溴代试剂使甲基溴化得到溴代物中间体3；
(c)以中间体3为原料，在碱性条件下与2，4-二羟基-X取代苯甲醛反应，得到苄芳醚中间体4；
(d)以中间体4为原料，在碱性条件下与吡啶-3-亚甲基卤反应，得到中间体化合物5；
(e)以含醛基的中间体化合物5为原料，与含氨基或亚氨基的HR3缩合及还原得到目标化合物I；
所述的R1、R3、X的定义同第一方面所述相同。
另外，上述反应中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸加成盐，如下列无机酸或有机酸的酸加成盐：盐酸，氢溴酸，磷酸，硫酸，甲磺酸，对甲苯磺酸，三氟乙酸，枸杞酸，马来酸，酒石酸，富马酸，柠檬酸，乳酸。通式I 所述药学上可接受的盐还包括不同碱金属盐(锂，钠，钾盐)，碱土金属盐(钙，镁盐)及铵盐，和能提供生理上可接受的阳离子的有机碱的盐，如甲胺，二甲胺，三甲胺，哌啶，吗啉及三(2－羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。在所述的通式I化合物及其溶剂化物和其盐的制备过程中，不同结晶条件可能出现多晶或共晶。
本发明技术方案的第三方面是提供了一种药物组合物，所述的药物组合物包含作为有效成分的本发明第一方面所述的烟醇醚类衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
本发明还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂 (包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂 (包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为 0.01-100mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供了烟醇醚类衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌。所述的感染性疾病选自细菌感染、病毒感染。所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
有益技术效果：
本发明化合物对PD-1/PD-L1相互作用具有很高的抑制活性，远高于已报道的化合物；与PD-L1蛋白具有很强的结合能力，亲和力kD值为2.025E-11，甚至强于PD-L1 的抗体；并具有解除PD-L1抑制IFNγ的能力，其IC50在1.8×10-10mol/L水平；体内药效研究表明，本发明化合物无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长，并可明显增加小鼠血液中、脾脏中各淋巴细胞数量。
附图说明
图1显示了实施例4(YPD29B)在10nM时就能部分解除PD-L1对IFNγ的抑制作用，并且经过不同浓度作用后，测定其IC50在1.8×10-10mol/L水平。
图2、图3显示了对于黑色素瘤高转移株B16F10，实施例5的45mg/kg、实施例4盐酸盐的15mg/kg和实施例4钠盐的15mg/kg剂量无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长。
图4显示了实施例5、实施例4钠盐和实施例4盐酸盐可增加肿瘤浸润的各淋巴细胞比例。
图5显示了实施例4钠盐增加脾中各淋巴细胞比例。
图6显示了对于黑色素瘤高转移株B16F10肺转移模型，实施例4钠盐在 15mg/kg剂量下时能显著抑制肺部转移灶数量。
图7显示了实施例化合物4和5可增加小鼠血液中各淋巴细胞数量。
图8显示了对于小鼠乳腺癌EMT6皮下移植瘤模型，实施例4钠盐具有一定的抗肿瘤作用；其中，实施例4钠盐10mg、15mg能产生20％和22％的抑瘤率；另外联合环磷酰胺给药后，实施例4钠盐能使环磷酰胺的抑瘤率从85％提高到95％。
图9显示了对于小鼠Lewis肺癌胸水模型，在发生胸水的小鼠中，空白组的平均胸水量为0.3ml，给药组能降低到0.2ml。
图10显示了对于小鼠Lewis肺癌胸水模型，给药组能显著提高小鼠的胸腺指数。
图11显示了对于小鼠结肠癌MC38皮下移植瘤模型，实施例4钠盐具有显著的抗肿瘤作用；联合环磷酰胺CTX给药后，具有良好的协同作用。
图12显示了初步确定实施例4的结合蛋白为PD-L1。
图13、图14显示了进一步采用Biacore实验证实，实施例4与PD-L1具有很强的结合能力，亲和力kD值为2.025E-11，甚至强于PD-L1的抗体。
具体实施方式
以下将结合实施例对发明作进一步说明，但并不限制本发明的范围。
测定仪器：核磁共振光谱用Vaariaan Mercury 300型核磁共振仪。质谱用 ZAD-2F和VG300质谱仪。
实施例1：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure RE-GDA0003636330710000171
2-溴-3-苯基甲苯：
置2-溴-3-碘甲苯(700mg)于100ml单口瓶中，加入二氧六环/水(体积比5/1) 搅拌，鼓吹氩气10min排除溶液中溶解的氧气，然后依次加入苯硼酸(350mg)、碳酸铯(1800mg)、三苯基膦合钯(80mg)。氩气保护，80-100℃下搅拌12h。停止反应，降至室温，用硅藻土过滤。滤液减压浓缩后，加入水和乙酸乙酯萃取3 次。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到2-溴-3-苯基甲苯无色油状物480mg。1H NMR(400MHz,DMSO-d6)，δ7.49 –7.29(m,7H,Ar-H),7.14(d,1H,Ar-H),2.42(s,3H,Ar-CH3)。MS(FAB):248(M+1)。 2-溴-3-苯基苄溴；
称取原料2-溴-3-苯基甲苯(450mg)于100ml单口瓶中，加入40ml CCl4,使之溶解完全，搅拌下加入NBS(360mg)，升温至80℃，回流，然后加入过氧化苯甲酰(8mg)，2h后再次加入过氧化苯甲酰(8mg)，继续反应2h，停止反应，冷至室温，加水淬灭反应，然后加入二氯甲烷和水进行萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到2-溴-3-苯基苄溴黄色油状物 380mg。直接用于下一步的反应。
2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛：
称取2,4-二羟基-5-氯苯甲醛(160mg)置于50ml单口瓶中，以12ml无水乙腈溶解，然后加入碳酸氢钠(200mg)。室温搅拌40min后，将2-溴-3-苯基苄溴 (380mg)溶于16ml DMF中，用恒压滴液漏斗缓慢加入至反应体系，加热回流至反应完全。降至室温，加入水和乙酸乙酯进行萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛白色固体300mg。1H NMR(400MHz,DMSO-d6)δ10.99(s,1H, -OH),10.03(s,1H,-CHO),7.64(d,1H,Ar-H),7.57(d,1H,Ar-H),7.45(m,4H,Ar-H), 7.37(d,2H,Ar-H),6.67(d,1H,Ar-H),6.59(s,1H,Ar-H),5.25(s,2H,-CH2-)。MS (FAB):418(M+1)。
2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛：
将2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(100mg)置于50ml单口瓶中，用6ml DMF溶解。加入碳酸铯(127.53mg)，室温搅拌15min后，滴加3-溴代亚甲基吡啶(76.65mg)的DMF(4ml)溶液。在80℃下搅拌2h后停止反应。降至室温，加入水和乙酸乙酯萃取分离，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体70mg。1H NMR(400MHz, DMSO-d6)δ10.26(s,1H,-CHO),8.00(s,1H,Ar-H),7.83(dd,2H,Ar-H),7.72(d,1H, Ar-H),7.61(t,2H,Ar-H),7.55–7.23(m,6H,Ar-H),6.95(s,1H,Ar-H),6.81(d,1H, Ar-H),5.35(s,2H,-CH2-),5.30(s,2H,-CH2-)。MS(FAB):510(M+1)
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯：
将2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(80mg)溶于5mlDMF中，加入消旋丝氨酸乙酯(59mg)，冰醋酸(57mg)至反应体系中。室温搅拌20min后，加入氰基硼氢化钠(25mg)，25℃下搅拌14h。停止反应，加入水和乙酸乙酯萃取分离。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，再加乙醇回流至反应完全，蒸干，通过硅胶柱层析得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯淡黄色油状物60mg，然后与氯化氢乙醇溶液反应得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯的盐酸盐白色固体。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H, -HCl),9.41(s,1H,-HCl),9.06(s,1H,-ArH),8.88–8.76(m,1H,-ArH),8.56(d,J＝ 7.9Hz,1H,-ArH),8.01–7.86(m,1H,-ArH),7.64(d,J＝13.4Hz,2H,-ArH),7.56– 7.30(m,7H,-ArH),7.12(s,1H,-ArH),5.42(s,2H,-CH2-),5.32(s,2H,-CH2-),4.18(s, 2H,-CH2-),4.13–4.07(m,1H,-CH-),4.04(m,2H,-CH2-),3.94(dd,1H,-CH2-),3.82(dd,1H,-CH2-),1.15(t,J＝7.1Hz,3H,-CH3).MS(FAB):626(M).
实施例2、N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000191
将N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯淡黄色油状物60mg溶于甲醇/水(4ml/1ml)中，加入氢氧化锂一水合物(20mg)，室温搅拌2h后，冰浴下加入醋酸数滴调节PH值至酸性，减压过滤得到N-[2-(吡啶-3- 亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸白色固体45mg。1H NMR (400MHz,DMSO-d6)δ8.73(s,1H,-ArH),8.55(d,1H,-ArH),7.97(d,1H,-ArH), 7.65(d,1H,-ArH),7.54–7.51(m,2H,-ArH),7.47(d,2H,-ArH),7.44(d1H,-ArH), 7.42-7.40(m,2H,-ArH),7.39–7.36(m,2H,-ArH),7.11(s,1H,-ArH),5.32(s,2H, -CH2-),5.28(m,2H,-CH2-),3.94(s,2H,-CH2-),3.69(dd,1H,-CH2-),3.62(dd,1H, -CH2-),3.16(t,1H,-CH-).MS(FAB):599(M+1)。
实施例3：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure RE-GDA0003636330710000192
用L-丝氨酸乙酯代替消旋丝氨酸乙酯，操作同实施例1，得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯白色固体。1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝2.1Hz,1H,-ArH),8.55(dd,J＝4.8,1.7Hz,1H, -ArH),7.88(d,J＝7.9Hz,1H,-ArH),7.65(dd,J＝7.6,1.7Hz,1H,-ArH),7.54–7.45 (m,3H,-ArH),7.45–7.35(m,6H,-ArH),7.06(s,1H,-ArH),5.30(s,2H,-CH2-),5.24 (s,2H,-CH2-),4.81(t,J＝5.8Hz,1H,-CH-),3.99(q,J＝7.1Hz,2H,-CH2-),3.74– 3.57(m,2H,-CH2-),3.54(t,J＝5.6Hz,2H,-CH2-),1.12(t,J＝7.1Hz,3H,-CH3).MS (FAB):626(M).
实施例4：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000201
用(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯代替消旋N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯，操作同实施例2，得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H,-ArH),8.55(d, J＝4.7Hz,1H,-ArH),7.97(d,J＝7.9Hz,1H,-ArH),7.65(d,J＝8.7Hz,1H,-ArH), 7.54–7.51(m,2H,-ArH),7.47(d,J＝7.7Hz,2H,-ArH),7.44(d,J＝1.7Hz,1H, -ArH),7.42-7.40(m,2H,-ArH),7.39–7.36(m,2H,-ArH),7.11(s,1H,-ArH),5.32(s, 2H,-CH2-),5.28(m,2H,-CH2-),3.94(s,2H,-CH2-),3.69(dd,J＝11.1,4.7Hz,1H, -CH2-),3.62(dd,J＝11.1,6.2Hz,1H,-CH2-),3.16(t,J＝5.4Hz,1H,-CH-).MS (FAB):599(M+1)。[α]27 D＝-1.84(C＝0.434，DMSO)。
实施例5：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure RE-GDA0003636330710000202
将598毫克(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸和60毫升无水乙醇置于100毫升圆底烧瓶中，冰水浴搅拌下加入6毫升二氯亚砜，2滴DMF，室温搅拌2小时后加热回流至反应完全，减压除去溶剂得到(S) -N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐白色固体。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H,-HCl),9.41(s,1H,-HCl),9.06 (s,1H,-ArH),8.88–8.76(m,1H,-ArH),8.56(d,J＝7.9Hz,1H,-ArH),8.01–7.86 (m,1H,-ArH),7.64(d,J＝13.4Hz,2H,-ArH),7.56–7.30(m,7H,-ArH),7.12(s,1H, -ArH),5.42(s,2H,-CH2-),5.32(s,2H,-CH2-),4.18(s,2H,-CH2-),4.13–4.07(m,1H, -CH-),4.04(m,2H,-CH2-),3.94(dd,J＝12.1,2.9Hz,1H,-CH2-),3.82(dd,J＝12.1, 3.8Hz,1H,-CH2-),1.15(t,J＝7.1Hz,3H,-CH3).MS(FAB):626(M)。[α]27 D＝-1.90 (C＝0.422，乙醇)。
实施例6：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐
Figure RE-GDA0003636330710000211
将598毫克(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸和60毫升无水异丙醇置于100毫升圆底烧瓶中，冰水浴搅拌下加入6毫升二氯亚砜，2滴DMF，室温搅拌2小时后加热回流至反应完全，减压除去溶剂得到(S) -N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸异丙酯盐酸盐白色固体。1HNMR(400MHz,DMSO-d6)δ9.62(s,1H,-HCl),9.40(s,1H,-HCl), 9.10(s,1H,-ArH),8.86(d,1H,-ArH),8.59(d,J＝7.6Hz,1H,-ArH),8.01–7.91(m, 1H,-ArH),7.73–7.64(m,2H,-ArH),7.57–7.46(m,3H,-ArH),7.46–7.37(m,4H, -ArH),7.16(s,1H,-ArH),5.47(s,2H,-CH2-),5.36(s,2H,-CH2-),4.92(m1H,-CH-), 4.30–4.15(m,2H,-CH2-),4.05(s,1H,-CH-),3.97(dd,J＝12.0,3.0Hz,1H,-CH2-), 3.84(dd,J＝12.0,3.8Hz,1H,-CH2-),1.20(d,J＝6.4Hz,3H,-CH3),1.18(d,J＝6.4 Hz,3H,-CH3).MS(FAB):640(M)。[α]27 D＝-5.33(C＝0.075，甲醇)。
实施例7：(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure RE-GDA0003636330710000212
用D-丝氨酸乙酯代替消旋丝氨酸乙酯，操作同实施例1，得到(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯白色固体。1H NMR(400MHz,DMSO-d6)δ8.68(d,1H,-ArH),8.55(dd,1H,-ArH),7.88(d,1H,-ArH), 7.65(dd,J＝7.6,1.7Hz,1H,-ArH),7.54–7.45(m,3H,-ArH),7.45–7.35(m,6H, -ArH),7.06(s,1H,-ArH),5.30(s,2H,-CH2-),5.24(s,2H,-CH2-),4.81(t,J＝5.8Hz, 1H,-CH-),3.99(q,J＝7.1Hz,2H,-CH2-),3.74–3.57(m,2H,-CH2-),3.54(t,2H, -CH2-),1.12(t,J＝7.1Hz,3H,-CH3).MS(FAB):626(M).
实施例8：(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000221
用(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯代替消旋N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯，操作同实施例2，得到(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H,-ArH),8.55(d, J＝4.7Hz,1H,-ArH),7.97(d,J＝7.9Hz,1H,-ArH),7.65(d,J＝8.7Hz,1H,-ArH), 7.54–7.51(m,2H,-ArH),7.47(d,J＝7.7Hz,2H,-ArH),7.44(d,J＝1.7Hz,1H, -ArH),7.42-7.40(m,2H,-ArH),7.39–7.36(m,2H,-ArH),7.11(s,1H,-ArH),5.32(s, 2H,-CH2-),5.28(m,2H,-CH2-),3.94(s,2H,-CH2-),3.69(dd,J＝11.1,4.7Hz,1H, -CH2-),3.62(dd,J＝11.1,6.2Hz,1H,-CH2-),3.16(t,J＝5.4Hz,1H,-CH-).MS (FAB):599(M+1)。[α]
实施例9：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氯-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure RE-GDA0003636330710000222
用2-(吡啶-3-亚甲氧基)-4-(2-氯-3-苯基苄氧基)苯甲醛代替2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)苯甲醛，用L-丝氨酸乙酯代替消旋丝氨酸乙酯，操作同实施例1，得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氯-3-苯基苄氧基)-5-氯苄基] 丝氨酸乙酯；用(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氯-3-苯基苄氧基)-5-氯苄基] 丝氨酸乙酯代替N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯，操作同实施例2，得到白色固体(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氯 -3-苯基苄氧基)-5-氯苄基]丝氨酸。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H, -ArH),8.51(d,J＝4.6Hz,1H,-ArH),7.93(d,J＝7.6Hz,1H,-ArH),7.63(d,J＝7.4 Hz,1H,-ArH),7.54–7.33(m,9H,-ArH),7.12(s,1H,-ArH),5.31(s,2H,-CH2-),5.25 (m,2H,-CH2-),3.91(s,2H,-CH2-),3.66(dd,J＝11.0,4.0Hz,1H,-CH2-),3.59(dd,J ＝11.0,6.0Hz,1H,-CH2-),3.14(t,J＝4.8Hz,1H,-CH-).MS(FAB):554(M+1)。
实施例10：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氟-3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure RE-GDA0003636330710000231
用2-(吡啶-3-亚甲氧基)-4-(2-氟-3-苯基苄氧基)苯甲醛代替2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)苯甲醛，用L-丝氨酸乙酯代替消旋丝氨酸乙酯，操作同实施例1，得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氟-3-苯基苄氧基)-5-氯苄基] 丝氨酸乙酯；用(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氟-3-苯基苄氧基)-5-氯苄基] 丝氨酸乙酯代替N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯，操作同实施例2，得到白色固体(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-氟 -3-苯基苄氧基)-5-氯苄基]丝氨酸。1H NMR(400MHz,DMSO-d6)δ8.72(dd,J＝8.0, 1.9Hz,1H,-ArH),8.56(dd,J＝4.8,1.5Hz,1H,-ArH),7.97(d,J＝7.9Hz,1H,-ArH), 7.72–7.30(m,10H,-ArH),7.16(d,J＝15.1Hz,1H,-ArH),5.35(d,J＝6.7Hz,2H, -CH2-),5.27(dd,J＝15.2,3.2Hz,2H,-CH2-),3.95(s,2H,-CH2-),3.70(dd,J＝11.2, 4.5Hz,1H,-CH2-),3.63(dd,J＝11.2,6.2Hz,1H,-CH2-),3.18(t,J＝5.3Hz,1H, -CH-).MS(FAB):538(M+1)。
实施例11：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(3-苯基苄氧基)-5-氯苄基]丝氨酸
Figure RE-GDA0003636330710000241
用2-(吡啶-3-亚甲氧基)-4-(3-苯基苄氧基)苯甲醛代替2-(吡啶-3-亚甲氧基)-4-(2-溴 -3-苯基苄氧基)苯甲醛，用L-丝氨酸乙酯代替消旋丝氨酸乙酯，操作同实施例1，得到(S)-N-[2-(吡啶-3-亚甲氧基)-4-(3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯；用 (S)-N-[2-(吡啶-3-亚甲氧基)-4-(3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯代替N-[2- (吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丝氨酸乙酯，操作同实施例 2，得到白色固体(S)-N-[2-(吡啶-3-亚甲氧基)-4-(苯基苄氧基)-5-氯苄基]丝氨酸。1H NMR(400MHz,DMSO-d6)δ8.67(s,1H,Ar-H),8.50(s,1H,Ar-H),7.91(d,J ＝5.6Hz,1H,Ar-H),7.75(s,1H,Ar-H),7.61(d,J＝13.2Hz,3H,Ar-H),7.44(d,J＝ 15.2Hz,5H,Ar-H),7.36(d,J＝8.4Hz,2H,Ar-H),7.09(s,1H,Ar-H),5.29(s,2H, -CH2-),5.19(m,2H,-CH2-),3.90(s,2H,-CH2-),3.69-3.55(m,2H,-CH2-),3.12(m,1H, -CH-).MS(FAB):520(M+1)。
实施例12：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]甘氨酸
Figure RE-GDA0003636330710000242
(1)2-溴-3-苯基-甲苯
置2-溴-3-碘甲苯(350mg)于50ml单口瓶中，加入二氧六环/水搅拌，鼓吹氩气10min，排除溶液中溶解的氧气，然后分别加入苯硼酸(172.65mg),碳酸铯 (961.2mg)，三苯基膦合钯(40.91mg)。氩气保护，80-100℃下搅拌12h。停止反应，降至室温，用硅藻土过滤。滤液减压浓缩后，加入水和乙酸乙酯萃取3次。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干。通过硅胶柱层析(石油醚)，得到无色油状物221mg。1H NMR(400MHz,DMSO-d6)，δ7.49–7.29(m,7H,Ar-H),7.14(d,1H,Ar-H),2.42(s,3H,Ar-CH3)。
(2)2-溴-3-溴甲基-1,1'-联苯
称取2-溴-3-苯基-甲苯(234mg)于100ml单口瓶中，加入20ml CCl4,使之溶解完全，搅拌下加入NBS(178mg)，升温至80℃，回流，然后加入过氧化苯甲酰(4mg)，2h后再次加入过氧化苯甲酰(4mg)，继续反应2h，停止反应，冷至室温，加入适量水，用二氯甲烷进行萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，得到黄色油状物192mg。直接用于下一步的反应。
(3)2-羟基-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
称取2,4-二羟基-5-氯苯甲醛(73.94mg)置于50ml单口瓶中，以6ml无水乙腈溶解，然后加入碳酸氢钠(98.88mg)。室温搅拌40min后，将2-溴-3-溴甲基-1,1'-联苯(192mg)溶于8ml DMF中，用恒压滴液漏斗缓慢加入至反应体系，加热回流至反应完全。降至室温，加入水和乙酸乙酯进行萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体2-羟基-4-(2-溴 -3-苯基苄氧基)-5-氯苯甲醛152mg。1H NMR(500MHz,DMSO-d6)δ11.18(s,1H, -OH),10.09(s,1H,-CHO),7.74(s,1H,-ArH),7.66(d,1H,-ArH),7.57(t,1H,-ArH), 7.51(m,2H,-ArH),7.46(d,1H,-ArH),7.42(d,3H,-ArH),6.85(s,1H,-ArH),5.37(s, 2H,-CH2-).
(4)2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛
将2-羟基-4-(2-溴-3-苯基苄氧基)-5氯苯甲醛(100mg)置于50ml单口瓶中，用6mlDMF溶解，加入碳酸铯(127.53mg)。室温搅拌15min后，滴加吡啶-3-亚甲氧基溴(76.65mg)的DMF(4ml)溶液。在80℃下搅拌2h后停止反应。降至室温，加入水和乙酸乙酯萃取分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，通过硅胶柱层析得到白色固体60mg。1H NMR(400MHz,DMSO-d6) δ10.14(s,1H,-CHO),8.71(d,J＝1.6Hz,1H,-ArH),8.54(d,J＝4.8Hz,1H,-ArH), 7.94(d,J＝7.8Hz,1H,-ArH),7.83(s,1H,-ArH),7.66(d,J＝7.6Hz,1H,-ArH),7.50 (t,J＝7.6Hz,1H,-ArH),7.48–7.32(m,7H,-ArH),7.20(s,1H,-ArH),5.42(s,2H, -CH2-),5.41(s,2H,-CH2-).
(5)N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]甘氨酸
将2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苯甲醛(80mg)溶于5mlDMF 中，加入甘氨酸乙酯(49mg，0.472mmol)，冰醋酸(57mg)至反应体系中。室温搅拌20min后，加入氰基硼氢化钠(25mg)，25℃下搅拌14h。停止反应，加入水和乙酸乙酯萃取分离。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸干，再加乙醇回流至反应完全，蒸干，通过硅胶柱层析得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]甘氨酸乙酯淡黄色油状物70mg，然后将其溶于甲醇/水(4ml/1ml)中，加入氢氧化锂一水合物(20mg)，室温搅拌2h 后，冰浴下加入醋酸数滴调节PH值至酸性，减压过滤得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]甘氨酸白色固体45mg。1HNMR(400MHz, DMSO)δ8.73(d,J＝1.7Hz,1H,-ArH),8.55(dd,J＝4.8,1.6Hz,1H,DMSO),7.96(dt,J＝7.9,1.9Hz,1H,DMSO),7.65(dd,J＝7.6,1.6Hz,1H,-ArH),7.55–7.35(m, 9H,-ArH),7.12(s,1H,-ArH),5.33(s,2H,-CH2-),5.29(s,2H,-CH2-),3.91(s,2H, -CH2-),3.11(s,2H,-CH2-).MS(FAB):569(M+1)。
实施例13：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]缬氨酸
Figure RE-GDA0003636330710000261
用缬氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]缬氨酸白色固体。1H NMR(400MHz,DMSO) δ8.69(s,1H,-ArH),8.56(d,J＝3.9Hz,1H,-ArH),7.88(d,J＝7.8Hz,1H,-ArH), 7.66(d,J＝7.4Hz,1H,-ArH),7.55–7.33(m,9H,-ArH),7.06(s,1H,-ArH),5.31(s, 2H,-CH2-),5.22(d,J＝11.2Hz,2H,-CH2-),3.52(s,2H,-CH2-),2.91(d,J＝6.4Hz, 1H,-CH-),1.80(dq,J＝13.2,6.5Hz,1H,-CH-),0.86(dd,J＝18.9,6.7Hz,6H,-CH3). MS(FAB):611(M+1)。
实施例14：N-巴豆氰基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000271
用3-氨基巴豆腈代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N-巴豆氰基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺白色固体。1H NMR(400MHz,)δ8.70(s,1H,-ArH),8.55(d,J＝4.2Hz,1H,-ArH),7.99–7.81(m,1H, -ArH),7.65(d,J＝7.0Hz,1H,-ArH),7.58–7.31(m,9H,-ArH),7.11(d,J＝33.8Hz, 1H),6.30(s,1H,＝CH),5.28(d,J＝14.1Hz,4H,-CH2-),3.27(s,2H,-CH2-),2.21– 1.96(m,3H).MS(FAB):576(M+1)。
实施例15：N，N-二(羟乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000272
用二(羟乙基)胺代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N，N- 二(羟乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺白色固体。1H NMR(400MHz,DMSO-d6)δ8.68(s,1H,ArH),8.58-8.51(m,1H,ArH),7.88(d,J＝ 7.2Hz,1H,ArH),7.65(d,J＝7.6Hz,1H,ArH),7.56-7.32(m,9H,ArH),7.05(d,J＝ 2.4Hz,1H,ArH),5.29(s,2H,-OCH2-),5.24(s,2H,-OCH2-),4.35(s,2H,-OH),3.58 (s,2H,-CH2-),3.41(br s,4H,-CH2-),2.51(m,4H,-CH2-,overlapped in solvent peak).. MS(FAB):598(M+1)。
实施例16：N-(2-甲磺酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5- 氯苄胺
Figure RE-GDA0003636330710000273
用甲磺酰基乙胺代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N-(2-甲磺酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺白色固体。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H,ArH),8.55(d,J＝4.4Hz,1H,ArH),7.89(d, J＝7.6Hz,1H,ArH),7.65(d,J＝8.0Hz,1H,ArH),7.56-7.33(m,9H,ArH),7.07(s, 1H,ArH),6.95(s,1H,-NH-),5.30(s,2H,-OCH2-),5.25(s,2H,-OCH2-),3.64(s,2H, -CH2-),3.01(m,2H,-CH2-),2.88(s,3H,-CH3),2.59(t,J＝6.4Hz,2H,-CH2-).MS (FAB):631(M)。
实施例17：N-(2-乙酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5- 氯苄胺
Figure RE-GDA0003636330710000281
用乙酰氨基乙二胺代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N-(2-乙酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺白色固体。1HNMR(400MHz,DMSO-d6)δ8.69(s,1H,ArH),8.55(d,J＝4.0Hz,1H,ArH),7.88(d, J＝8.0Hz,1H,ArH),7.80(t,J＝6.0Hz,1H,-NH-),7.65(d,J＝6.0Hz,1H,ArH), 7.57-7.35(m,9H,ArH),7.07(s,1H,ArH),5.30(s,2H,-OCH2-),5.25(s,2H,-OCH2-), 3.65(s,2H,-CH2-),3.12(q,J＝6.0Hz,2H,-CH2-),2.54(t,J＝6.4Hz,2H,-CH2-), 1.78(s,3H).MS(FAB):595(M)。
实施例18：3-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺基]丁烯-2-酸
Figure RE-GDA0003636330710000282
用3-氨基巴豆酸代替甘氨酸乙酯，操作同实施例12，不用水解直接得到3-[2-(吡啶 -3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺基]丁烯-2-酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.74(s,1H,ArH),8.55(d,J＝4.4Hz,1H,ArH),7.98(d,J＝8.0Hz, 1H,ArH),7.65(dd,J1＝7.6Hz,J2＝1.2Hz,1H,ArH),7.55-7.34(m,9H,ArH),7.13(s, 1H,ArH),5.33(s,2H,-OCH2-),5.29(s,2H,-OCH2-),3.85(dd,J1＝52.4Hz,J2＝13.2 Hz,,2H),3.05(s,1H,＝CH),1.12(d,J＝6.4Hz,3H)MS(FAB):594(M+1)。
实施例19：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]牛磺酸
Figure RE-GDA0003636330710000291
用牛黄酸代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]牛磺酸白色固体。1H NMR(400MHz, DMSO)δ8.79(s,1H),8.62(d,J＝4.8Hz,1H),8.42(d,J＝7.2Hz,1H),7.85(t,J＝ 4.8Hz,1H),7.43(m,9H),7.04(s,1H),5.37(s,2H),5.24(s,2H),4.33(s,2H),3.39(m, 2H),2.97(m,2H),2.65(br,1H).MS(FAB):618(M+1)。
实施例20：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]亮氨酸
Figure RE-GDA0003636330710000292
用亮氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2- 溴-3-苯基苄氧基)-5-氯苄基]亮氨酸白色固体。1H NMR(400MHz,DMSO)δ8.69(s,1H),8.52(d,J＝4.8Hz,1H),8.42(d,J＝7.2Hz,1H),7.85(t,J＝4.8Hz,1H),7.43(m, 9H),7.04(s,1H),5.37(s,2H),5.24(s,2H),3.79(m,2H),3.18(m,1H),1.86(m,1H), 1.41(m,2H),0.74(m,6H).MS(FAB):624(M)。
实施例21：N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]酪氨酸
Figure RE-GDA0003636330710000293
用酪氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2- 溴-3-苯基苄氧基)-5-氯苄基]酪氨酸白色固体。1H NMR(400MHz,DMSO)δ8.62(s,1H),8.50(d,J＝3.2Hz,1H),7.81(t,J＝7.6Hz,1H),7.60(t,J＝9.2Hz,1H),7.38(m, 8H),7.21(s,1H),7.00(s,1H),6.93(d,J＝8.0Hz,2H),6.59(d,J＝8.0Hz,2H),5.25(s, 2H),5.17(s,2H),3.64(m,2H),3.21(t,J＝6.8Hz,1H),2.78(m,2H)..MS(FAB):674 (M)。
实施例22 N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]异亮氨酸
Figure RE-GDA0003636330710000301
用异亮氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]异亮氨酸白色固体。1H NMR(400MHz, DMSO)δ8.64(s,1H),8.50(d,J＝4.8Hz,1H),8.38(d,J＝7.2Hz,1H),7.82(t,J＝4.8 Hz,1H),7.43(m,9H),7.00(s,1H),5.25(s,2H),5.18(s,2H),3.63(m,2H),3.48(m, 1H),2.28(m,1H),1.50(m,2H),1.06(m,3H),0.73(m,3H).MS(FAB):624(M)。
实施例23 N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]天冬酰胺
Figure RE-GDA0003636330710000302
用天冬酰胺乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]天冬酰胺白色固体。1H NMR(400MHz, DMSO)δ11.96(s,1H),8.72(s,1H),8.52(d,J＝8.0Hz,1H),8.16(s,1H),7.68(t,J＝8.0 Hz,1H),7.44(m,10H),7.01(m,2H),5.26(s,2H),5.21(s,2H),3.65(m,2H),3.35(m, 1H),2.65(m,2H).MS(FAB):625(M+1)。
实施例24 N-羟乙基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure RE-GDA0003636330710000311
用2-羟基乙胺代替甘氨酸乙酯，操作同实施例12，不用水解直接得到N-羟乙基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺白色固体。1H NMR(400MHz, DMSO-d6)δ8.70(s,1H,Ar-H),8.54(d,J＝15.4Hz,1H,Ar-H),7.92(s,1H,Ar-H), 7.72–7.25(m,10H),7.11(s,1H,Ar-H),5.30(s,2H,-CH2-),5.28(s,2H,-CH2-),3.89 (m,2H,-CH2-),3.54(s,2H,-CH2-),2.76(s,2H,-CH2-).MS(FAB):554(M+1)。
实施例25 N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]丙氨酸
Figure RE-GDA0003636330710000312
用丙氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2- 溴-3-苯基苄氧基)-5-氯苄基]丙氨酸白色固体。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H,Ar-H),8.53(m,1H,Ar-H),7.93(d,J＝8.0Hz,1H,Ar-H),7.61(d,J＝8.1Hz, 1H,Ar-H),7.53–7.31(m,9H,Ar-H),7.08(s,1H,Ar-H),5.29(s,2H,-CH2-),5.27– 5.23(m,2H,-CH2-),3.96–3.77(m,2H,-CH2-),3.12(m,1H,-CH-),1.19(d,J＝7.0 Hz,3H,-CH3).MS(FAB):582(M+1)。
实施例26 N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸
Figure RE-GDA0003636330710000313
用脯氨酸乙酯代替甘氨酸乙酯，操作同实施例12，得到N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]脯氨酸白色固体。1H NMR(400MHz, DMSO-d6)δ8.72(s,1H,ArH),8.56(d,J＝6.0Hz,1H,ArH),7.95(d,J＝8.0Hz,1H, ArH),7.66(d,J＝7.6Hz,1H,ArH),7.5-7.34(m,9H,ArH),7.12(s,1H,ArH), 5.35-5.27(m,4H,-OCH2-),3.95(dd,J1＝51.6Hz,J2＝13.2Hz,2H,-CH2-),3.12(m, 1H,-CH-),2.67(m,1H,-CH2-),2.07(m,1H,-CH2-),1.89(m,1H,-CH2-),1.78(m,1H, -CH2-),1.68(m,1H,-CH2-),0.84(m,1H,-CH2-).MS(FAB):608(M)。
实施例27：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸钠盐
Figure RE-GDA0003636330710000321
将299mg(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸溶于1ml 0.5N氢氧化钠水溶液中，室温搅拌30分钟后，滴加无水乙醇至出现固体，加热溶解之后自然降至室温，并置于冰箱冷冻，过滤得到白色固体300mg。1H NMR(400MHz,Methanol-d4)δ8.65(s,1H,-ArH),8.49(d,1H,-ArH),8.04(d,1H, -ArH),7.63(d,J＝8.0Hz,1H,-ArH),7.50–7.34(m,8H,-ArH),7.31(d,J＝7.5Hz, 1H,-ArH),6.84(s,1H,-ArH),5.28(s,2H,-CH2-),5.23(s,2H,-CH2-),3.85–3.74(m, 2H,-CH2-),3.72(d,J＝4.6Hz,1H,-CH2-),3.67(m,1H,-CH2-),3.15(t,J＝5.6Hz, 1H,-CH-)。MS(FAB):599(M+1)。
实施例28：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸钙盐
Figure RE-GDA0003636330710000322
将243毫克(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基] 丝氨酸钠盐溶于5ml水中，室温搅拌下滴加2.22毫升1％二氯化钙水溶液，搅拌过夜，过滤，水洗，干燥得到白色固体240毫克。MS(FAB):599(M+1)。
实施例29：(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure RE-GDA0003636330710000331
将299毫克(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸和74毫克的4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮溶于10毫升DMF中，加入催化量的碘化钾，在30℃下搅拌至不再反应，倾入到搅拌的冰冷饱和碳酸氢钠水溶液中，过滤，水洗固体，干燥得到产物98毫克。MS(FAB):711(M+1)。
药理活性
1、体外活性评价：体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1 bindingassay kit检测试剂盒。
PD-1/PD-L1小分子抑制剂的筛选原理和方法
1)原理：PD-1蛋白带HIS标签，PD-1的配体PD-L1带hFc标签，分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合，激光激发后，能量能够从供体Eu上转移到受体XL665，使得XL665发光，而加入抑制剂 (化合物或抗体)后，阻断PD-1与PD-L1的结合，使得Eu和XL665距离较远，能量不能转移，XL665不会发光。
2)实验方法：具体方法可参考Cisbio公司的PD-1/PD-L1试剂盒(货号 64CUS000C-2)。简单叙述如下，384孔白色酶标板，每孔加入2μl稀释液或者用稀释液稀释的目标化合物，然后每孔再加入4μl PD-1蛋白和4μl PD-L1蛋白，常温孵育15min，再每孔加入10μlanti-Tag1-Eu3+和anti-Tag2-XL665的混合液，室温孵育1h-4h后用Envison仪器检测665nm和620nm处的荧光信号。HTRF率＝(665nm/620nm)*104。每个化合物检测8-10个浓度，采用Graphpad软件计算IC50。 3)筛选结果见表1：
表1.实施例化合物在分子水平对PD-1与PD-L1相互作用的抑制活性评价筛选结果：
实施例 IC<sub>50</sub>(M) 实施例 IC<sub>50</sub>(M)
1 1.48×10<sup>-7</sup> 16 1.99×10<sup>-7</sup>
4 &lt;10<sup>-13</sup> 17 5.51×10<sup>-7</sup>
6 8.23×10<sup>-8</sup> 18 2.33×10<sup>-9</sup>
8 4.29×10<sup>-8</sup> 19 1.62×10<sup>-5</sup>
9 4.01×10<sup>-8</sup> 20 6.10×10<sup>-8</sup>
10 1.34×10<sup>-7</sup> 21 4.06×10<sup>-7</sup>
11 3.18×10<sup>-7</sup> 22 4.99×10<sup>-6</sup>
12 4.11×10<sup>-8</sup> 23 8.35×10<sup>-7</sup>
13 2.00×10<sup>--7</sup> 24 5.38×10<sup>-8</sup>
14 2.69×10<sup>-5</sup> 25 5.29×10<sup>-9</sup>
15 5.10×10<sup>-8</sup> 26 10<sup>-12</sup>～10<sup>-13</sup>
Cisbio HTRF检测结果表明，实施例4化合物在分子水平可显著抑制PD-1与PD-L1的相互作用，IC50<10-13mol/L。
2、实施例4化合物解除配体PD-L1抑制IFNγ的能力
IFNγ的表达水平能够反映T淋巴细胞的增殖活性。利用提取的人PBMC(人单个核细胞)，在anti-CD3/anti-CD28抗体激活T淋巴细胞的基础上，加入配体PD-L1抑制T淋巴细胞，考察待测化合物解除配体抑制作用的能力。
具体操作如下，采用达科为公司的人淋巴细胞分离液(货号DKW-KLSH-0100) 提取人全血中的PBMC，将PBMC接种到96孔板中，每孔接种数为3×105个。分别加入人的PD-L1蛋白(终浓度5μg/ml)，anti-CD3/anti-CD28抗体(终浓度 1μg/ml)和等比例稀释的实施例4化合物。72h后采用Cisbio公司的IFNγ检测试剂盒检测上清中IFNγ的表达量。实验结果显示，实施例4(YPD29B)在10nM时就能部分解除PD-L1对IFNγ的抑制作用，并且经过不同浓度作用后，测定其IC50在1.8×10-10mol/L水平(图1)。
3、实施例4化合物体内药效
药效学研究方法如下：
皮下移植瘤方法如下：将培养的特定肿瘤细胞消化后离心收集细胞，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为5×106/ml，将0.2ml细胞混悬液接种到C57BL/6或Bablc小鼠右侧腋下。接种后次日动物随机分组，每组6-7 只，称重后给药，待测化合物每天给药1次，监测小鼠肿瘤体积大小，待肿瘤体积达到一定大小后，称量小鼠体重，眼眶取血后脱颈处死小鼠，剥取肿瘤组织、胸腺组织和脾组织并分别称重。最后计算肿瘤抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
B16F10肺转移模型方法如下：将培养的B16F10肿瘤细胞消化离心，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为2.5×106/ml，将0.2ml细胞通过尾静脉注射入到C57BL/6小鼠体内，肿瘤细胞将在小鼠肺部聚集。接种后次日动物随机分组，每组6-7只，称重后给药，待测化合物每天给药1次，3周后称量小鼠体重，处死动物，剥取小鼠肺组织并称重，包式液固定后计数肺部肿瘤数目。最后计算化合物对肿瘤的抑制率，以肿瘤抑制率评价抗肿瘤作用强度。
Lewis肺癌胸水模型方法如下：将小鼠皮下Lewis移植瘤肿匀浆后，用无菌生理盐水清洗两遍后计数，用生理盐水调整细胞浓度为2.5×105/ml，将0.2ml细胞注射入到C57BL/6小鼠胸腔内。接种后次日动物随机分组，每组6-7只，称重后给药，待测化合物每天给药1次，待对照组小鼠体重突然下降时处死动物，用注射器抽取胸腔内的积液，记录积液体积。
在以上各模型作用机制研究中，各类型T细胞占总细胞比例的试验方法采用流式细胞术方法，具体步骤如下：先处理样品，对于血液组织，在处理小鼠时，取小鼠的眼眶血，先用红细胞裂解液去除红细胞后，然后用PBS溶液进行漂洗后收集细胞；对于小鼠的肿瘤和脾脏器官，先用匀浆器研磨组织，再加入PBS缓冲液稀释，然后用300目的筛网过滤。计数各样本的细胞数后，取1×106的细胞加入EP管中后进行流式抗体的染色，在冰上孵育1h后，用PBS溶液漂洗2遍。用 BD公司的VERSE流式仪器进行细胞群的分析。其中，肿瘤组织总上样细胞数为1 ×105个，血液和脾脏组织总上样细胞数为1×104个。在流式仪器上圈门后分析各类型T细胞占总进样细胞数的比例。
(1)黑色素瘤高转移株B16F10皮下移植瘤模型
对于黑色素瘤高转移株B16F10，实施例5的45mg/kg、实施例4盐酸盐的 15mg/kg和实施例4钠盐的15mg/kg剂量无论从肿瘤体积还是重量上，都可显著的抑制皮下肿瘤的生长(图2、图3和表2)，其对肿瘤重量的抑制率分别可达到45.27％、 38.37％和64.11％。
表2实施例对B16F10皮下移植肿瘤的抑制作用
Figure RE-GDA0003636330710000361
T/C：相对肿瘤增殖率
TGI：肿瘤增殖抑制率
NA：不适用
*P<0.05vs空白对照
从其作用机制分析，实施例5、实施例4钠盐和实施例4盐酸盐可增加肿瘤浸润的各淋巴细胞比例(图4，表3)，实施例4钠盐增加脾中各淋巴细胞比例(图5，表4)。
表3实施例4和5对肿瘤浸润的各T细胞占总细胞比例的影响
Figure RE-GDA0003636330710000362
表4实施例4钠盐对脾脏中各T细胞占总细胞比例的影响
Figure RE-GDA0003636330710000363
Figure RE-GDA0003636330710000371
(2)黑色素瘤高转移株B16F10肺转移模型
对于黑色素瘤高转移株B16F10肺转移模型，实施例4钠盐在15mg/kg剂量下时能显著抑制肺部转移灶数量(图6，表5)。
表5实施例化合物对B16F10肺转移肿瘤的抑制作用
Figure RE-GDA0003636330710000372
T/C：相对肿瘤增殖率
TGI：肿瘤增殖抑制率
NA：不适用
*P<0.05vs空白对照
从其作用机制分析，实施例化合物4和5可增加小鼠血液中各淋巴细胞数量 (图7，表6)。
表6实施例对血液中各T细胞占总细胞比例的影响
Figure RE-GDA0003636330710000373
Figure RE-GDA0003636330710000381
(3)小鼠乳腺癌EMT6皮下移植瘤模型
对于小鼠乳腺癌EMT6皮下移植瘤模型，实施例4钠盐具有一定的抗肿瘤作用。其中，实施例4钠盐10mg、15mg能产生20％和22％的抑瘤率(图8，表6)。另外联合环磷酰胺给药后，实施例4钠盐能使环磷酰胺的抑瘤率从85％提高到95％ (图8，表7)。
表7实施例4对EMT6皮下移植瘤的抑制作用
Figure RE-GDA0003636330710000382
T/C：相对肿瘤增殖率
TGI：肿瘤增殖抑制率
NA：不适用
*P<0.05vs空白对照
(4)小鼠Lewis肺癌胸水模型
对于小鼠Lewis肺癌胸水模型，实施例4钠盐具有一定的抗肿瘤作用。其中，空白组的胸水发生率为75％，实施例4钠盐10mg能使胸水发生率降低到33％(表8)。在发生胸水的小鼠中，空白组的平均胸水量为0.3ml，给药组能降低到0.2ml (图9，表9)。并且给药组能显著提高小鼠的胸腺指数(图10)。
表8实施例4对Lewis肺癌胸水发生率的作用
Figure RE-GDA0003636330710000391
表9实施例4对Lewis肺癌胸水量的作用
Figure RE-GDA0003636330710000392
(5)小鼠结肠癌MC38皮下移植瘤模型
对于小鼠结肠癌MC38皮下移植瘤模型，实施例4钠盐具有显著的抗肿瘤作用。联合环磷酰胺CTX给药后，具有良好的协同作用(图11，表10)。
表10.IMMH-010对小鼠结肠癌MC38皮下移植瘤的影响
Figure RE-GDA0003636330710000393
T/C：相对肿瘤增殖率
TGI：肿瘤增殖抑制率
NA：不适用
*P<0.05vs空白对照，***P<0.001vs空白对照，##p<0.01vs环磷酰胺
4、利用Biacore设备测试实施例4以及PD-L1抗体与PD-L1蛋白的相互作用
(1)实验原理
表面等离子体是一种金属表面的电磁波，由自由振动的光子和电子相互作用产生。表面等离子体共振(surface-plasmon resonance，SPR)是一种发生在两种介质表面的光学现象，这种现象可以由光子或电子诱导。光从光密介质射入光疏介质发生全反射现象，会形成消逝波进入光疏介质。当全反射的消逝波与金属表面的等离子波相遇时，可能会发生共振，反射光能量下降，在反射光能量谱上出现共振峰，这种共振称为表面等离子体共振，引起表面等离子体共振的入射角称为SPR角。SPR生物传感器提供了一个灵敏的、实时监测分子将相互作用的非标记检测技术。该传感器检测的是SPR角的变化，SPR又与金属表面的折射率相关。当有分析物结合到芯片表面后，导致了芯片表面折射率的改变，从而引起SPR角度变化，这就是SPR生物传感器实时检测分子间相互作用的基本原理。在相互作用分析时，SPR角度的改变被实时记录在传感图上。
(2)实验方法：
采用捕获法将PD-L1蛋白捕获于NTA芯片Fc4通道上；结合缓冲液体系为 PBS-P+，pH7.4，0.01％DMSO。将配制好的一系列浓度的化合物及PD-L1抗体流经芯片表面，进行相互作用测定。
(3)实验结果：
表11实施例4化合物和PD-L1抗体与PD-L1的亲和力
Figure RE-GDA0003636330710000401
初步确定实施例4的结合蛋白为PD-L1(图12)。进一步采用Biacore实验证实，实施例4与PD-L1具有很强的结合能力，亲和力kD值为2.025E-11，甚至强于PD-L1的抗体(表11，图12-14)。

Claims (13)

1.如通式I所示的烟醇醚类衍生物及其立体异构体以及其可药用盐，
Figure FDA0003560318280000011
式中
R1选自:
Figure FDA0003560318280000012
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure FDA0003560318280000013
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
2.根据权利要求1的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA)所示：
Figure FDA0003560318280000014
式中
R1选自:
Figure FDA0003560318280000021
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure FDA0003560318280000022
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
3.根据权利要求2的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-1)所示：
Figure FDA0003560318280000023
式中
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure FDA0003560318280000024
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
4.根据权利要求2的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述的化合物如式(IA-2)所示：
Figure FDA0003560318280000031
式中
R3选自：取代的C1-8饱和烷氨基、取代的C2-6不饱和烷氨基、取代的C2-6氮杂环-1-基，取代基选自氢、氟、氯、溴、碘、羟基、C1-5烷基、C1-5烷氧基、氨基、C1-6烷氨基、乙酰氨基、氰基、脲基、胍基、脲氨基、胍氨基、磺酰氨基、氨磺酰基、甲磺酰氨基、羟基甲酰基、C1-8烷氧甲酰基、巯基、咪唑基、噻唑基、噁唑基、四氮唑基、
Figure FDA0003560318280000032
所述的取代基包括单取代、双取代、三取代、四取代；
X选自：氢、氟、氯、溴、碘、C1-4烷基、乙烯基、三氟甲基、甲氧基。
5.根据权利要求1-4任一项的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于,所述R3选自
Figure FDA0003560318280000041
R＝甲基、乙基、丙基、异丙基、丁基、戊基、己基、庚基、辛基；
X选自：氢、氟、氯、溴、甲基、乙烯基、三氟甲基。
6.根据权利要求1的烟醇醚类衍生物及其立体异构体以及其可药用盐，所述的化合物选自：
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure FDA0003560318280000042
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure FDA0003560318280000051
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure FDA0003560318280000052
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯盐酸盐
Figure FDA0003560318280000053
(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸乙酯
Figure FDA0003560318280000054
(R)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure FDA0003560318280000055
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]甘氨酸
Figure FDA0003560318280000061
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]缬氨酸
Figure FDA0003560318280000062
N-巴豆氰基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure FDA0003560318280000063
N，N-二(羟乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure FDA0003560318280000064
N-(2-甲磺酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure FDA0003560318280000065
N-(2-乙酰胺基乙基)-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure FDA0003560318280000071
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]牛磺酸
Figure FDA0003560318280000072
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]亮氨酸
Figure FDA0003560318280000073
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]酪氨酸
Figure FDA0003560318280000074
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]异亮氨酸
Figure FDA0003560318280000075
N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄基]天冬酰胺
Figure FDA0003560318280000081
N-羟乙基-2-(吡啶-3-亚甲氧基)-4-(2-溴-3-苯基苄氧基)-5-氯苄胺
Figure FDA0003560318280000082
(S)-N-[2-(吡啶-3-亚甲氧基)-4-(2-溴-3-(苯基)苄氧基)-5-氯代苄基]丝氨酸
Figure FDA0003560318280000083
7.根据权利要求1的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于，所述的药用盐包括与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。
8.根据权利要求7的烟醇醚类衍生物及其立体异构体以及其可药用盐，其特征在于，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子，钠离子，钾离子；所述的碱土金属离子选自钙离子，镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2－羟乙基)胺。
9.制备权利要求1-8任一项所述的烟醇醚类衍生物及其立体异构体以及其可药用盐的方法：
Figure FDA0003560318280000091
为了制备本发明通式I所述的化合物，依据通式I的结构，本发明制备通式I化合物分为两步：
(a)以2-羟基-4-(2-溴-3-R1苄氧基)-X取代的苯甲醛1为原料，在碱性条件下与吡啶-3-亚甲基卤反应得到含醛基的中间体化合物2；
(b)以含醛基的中间体化合物2为原料，与含氨基或亚氨基的HR3缩合及还原得到目标化合物I；
所述的R1、R3、X的定义同权利要求1-8任一项所述。
10.一种药物组合物，其特征在于，所述的药物组合物包含作为有效成分的权利要求1-8任一项所述的烟醇醚类衍生物及其立体异构体以及其可药用盐和药学上可接受的载体或赋形剂。
11.权利要求1-8任一项所述的烟醇醚类衍生物及其立体异构体以及其可药用盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。
12.根据权利要求11的应用，其特征在于，所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
13.根据权利要求12的应用，其特征在于，所述的癌症选自皮肤癌、肺癌、泌尿系肿瘤、血液肿瘤、乳腺癌、胶质瘤、消化系统肿瘤、生殖系统肿瘤、淋巴瘤、神经系统肿瘤、脑瘤、头颈癌；所述的感染性疾病选自细菌感染、病毒感染；所述的自身免疫性疾病选自器官特异性自身免疫病、系统性自身免疫病，其中，所述的器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血。
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