CN113121464A - 五元杂环取代的联苯类化合物及其制备方法和用途 - Google Patents
五元杂环取代的联苯类化合物及其制备方法和用途 Download PDFInfo
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- CN113121464A CN113121464A CN202110433588.XA CN202110433588A CN113121464A CN 113121464 A CN113121464 A CN 113121464A CN 202110433588 A CN202110433588 A CN 202110433588A CN 113121464 A CN113121464 A CN 113121464A
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- substituted biphenyl
- methanol
- membered heterocycle
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Abstract
本发明公开了能够阻断PD‑1/PD‑L1信号通路的免疫检查点抑制剂五元杂环取代的联苯类化合物及其制备方法和用途，该类化合物如下式Ⅰ所示，结构新颖，可口服给药，解决了单抗类免疫检查点抑制剂的治疗和耐药的缺陷，且作为小分子抑制剂制备简单，方便工业生产；可通过调控PD‑1/PD‑L1信号通路，以肿瘤免疫疗法来治疗多种相关肿瘤疾病，具有潜在的成药前景。
Description
技术领域
本申请属于生物医药技术，具体涉及一种五元杂环取代的联苯类化合物及其制备方法和用途。
背景技术
恶性肿瘤是一类严重威胁人类健康和生命的疾病。目前来讲，肿瘤治疗的方式包括手术、放疗、化疗以及靶向治疗等。肿瘤免疫治疗，是指通过刺激机体免疫系统来提高抗肿瘤免疫效应，从而抑制和杀伤肿瘤细胞的一种治疗方法。免疫治疗的研究已有近百年历史，随着肿瘤学，免疫学以及分子生物学的综合发展和交叉渗透，免疫治疗取得了多方面的成果，为肿瘤治疗带来了新希望。
免疫检查点抑制剂是目前比较火热的免疫治疗药物。肿瘤细胞通过上调免疫检查点受体的表达，抑制免疫细胞T细胞活性，完成肿瘤细胞的免疫逃逸。免疫检查点抑制剂则是通过抑制免疫检查点通路，解除免疫细胞T细胞的抑制，激活机体对肿瘤细胞的免疫杀伤，实现肿瘤治疗的作用。目前，已发现的免疫检查点有CTLA-4(cytotoxic T lymphocyte-associated antigen-4)，PD-1(Programmed cell death 1)和TIM3(T cell membrane 3)等(见Drew M.Pardoll,Nature Review Cancer,2012,12,252)。
程序性死亡受体1(PD-1)是一类免疫球蛋白，属于CD28超家族。PD-1由288个氨基酸组成，拥有一个免疫球蛋白可变区域和细胞质区域。与CTLA-4及其他家族蛋白不同的是，PD-1是单分子结构，且人与鼠的PD-1蛋白存在大约60％的相同氨基酸序列，而CTLA-4仅为16％。PD-1作为一类免疫检查点抑制剂，在胸腺细胞有表达，并且激活的T细胞、B细胞、自然杀伤细胞和树突细胞均可以上调PD-1的表达。多项关于PD-1缺陷小鼠的研究中显示，这些PD-1缺陷小鼠易患自身免疫疾病。PD-1有两类天然配体，PD-L1和PD-L2。当激活的T细胞上调PD-1的表达时，机体会通过产生PD-1的配体与PD-1结合从而抑制T细胞活性。然而肿瘤细胞也能通过表达PD-L1，从而抑制机体的抗肿瘤免疫活性(见Yasumasa Ishida,YasutoshiAgata,et al.The EMBO Journal,1992,11,3887)。因此，抑制PD-1/PD-L1信号通路，可修复机体抗肿瘤免疫活性，以PD-1/PD-L1信号通路为靶点的抑制剂研究也成为一项研究热点。
2014年，百时美施贵宝和默沙东分别上市了靶向PD-1/PD-L1的单克隆抗体nivolumab和pembrolizumab用于黑色素瘤的治疗。随后罗氏和阿斯利康也上市各自的抗PD-1/PD-L1的单克隆抗体药物atezolizumab和durvalumab。国内的恒瑞和百济神州的单克隆药物也进入了三期临床，预计于年内上市。目前已经上市的PD-1/PD-L1信号通路抑制剂均是单克隆抗体药物，然而单克隆抗体药物口服生物利用度较差，且生产较为昂贵困难。临床研究也显示，单克隆抗体药物由于自身较长的半衰期和难控制免疫应答，导致了多种机体免疫相关的不良反应。目前为止，市场上仍没有非抗体类的PD-1/PD-L1信号通路的小分子抑制剂。因此，研制具有良好抗肿瘤活性的新型PD-1/PD-L1小分子抑制剂具有重大意义。
发明内容
发明目的：针对现有PD-1/PD-L1单抗药物生产昂贵、需注射给药及肿瘤治疗范围有限等缺陷，本申请提供了一种PD-1/PD-L1小分子抑制剂化合物及其制备方法与应用。
技术方案：本申请公开了一种如下式Ⅰ所示的五元杂环取代的联苯类化合物：
其中，环A和环B独立地为芳环或芳杂环；
X1，X2，X3，X4，X5，X6独立地为N或C；
Y1，Y2独立地为O、S、C或N；
Z1，Z2，Z3，Z4独立地为N、C或O；
每个R1和R2独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基或取代或未取代的烷氧基、氨基酸；
R3和R4独立地为氢、氘、氰基、卤素、乙烯基、三氟甲基、甲氧基或C1-4烷基；
m和n独立地为1、2或3。
优选地，所述化合物包括其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。
进一步的，每个R1和R2中，所述的取代的烷基或取代的烷氧基的取代基可以是下列基团中的一个或多个：卤素、C1-4烷基、羟基、C1-4烷氧基、氰基、三氟甲基、C1-4羧基、C1-4酯基或C1-4酰胺基；所述的取代的羟基或取代的氨基中的取代基为下列基团中的一个或多个：C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基；其中所述C1-8烷基、C1-8酰胺基、C1-8酯基、C1-8羧基、C1-8羟基任选地可被以下一个或多个取代基取代：羟基、羧基、氰基、氨基、环烷基、芳基、杂环基、烯基、炔基；当取代基为多个时，所述的取代基相同或不同。
进一步的，所述
中，
是指其为单键或双键，当其为单键时，Z1和Z3为-O-或-NH-或-S-，当其为双键时，Z1和Z3为＝N-；
所述
中，
是指其为单键或双键，当其为单键时，Z2和Z4为-O-或-NH-或-S-，当其为双键时，Z2和Z4为＝N-或＝C-；
所述
中，
是指其为单键或双键，当Y1和Y2为N时，此处为
当Y1和Y2为S或O时，此处为-O-或-S-；
作为优选，环A和环B为苯环。
作为优选，X1，X2，X3，X4，X5，X6为C。
作为优选，
中，
是双键，Z1、Z2、Z3和Z4是N，Y1和Y2是C。
作为优选，R3和R4为C或Br或Cl。
作为优选，当R1或R2为取代的氨基，取代基为C1-8羟基时，所述的C1-8羟基为CH2CH2OH和CH2CH2CH2OH；或当R1或R2为取代的氨基，取代基为C1-8酰胺基时，所述C1-8酰胺基选自乙酰胺、丙酰胺、丁酰胺；或当R1或R2为取代的氨基，取代基为C1-8羧基时，所述C1-8羧基选自乙酸、丙酸、(R)-3-羟基-2-甲基丙酸、(S)-3-羟基-2-甲基丙酸。
进一步，所述化合物包括以下任意一种结构：
优选地，当Y1和Y2是O，Z1,Z2,Z3和Z4是N时，所述化合物的合成路线如下所示：
其中，除Y1,Y2,Z1,Z2,Z3和Z4外，A,B,R1,R2,R3,R4,X1,X2,X3,X4,X5,X6,m和n与所述式Ⅰ中的定义一致，具体合成步骤如下：
(1)化合物H-2与二硫化碳反应得到化合物H-3；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；所采用试剂为三光气或氯甲酸甲酯；所采用催化剂为三乙烯二胺；反应温度为0℃至40℃；
(2)化合物H-3与水合肼反应得到化合物H-4；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；反应温度为60℃至100℃；
(3)化合物H-1与H-4缩合得到化合物H-5；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；所采用缩合剂包括但不限于：(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐、对甲苯磺酸；反应温度为60℃至100℃；
(4)化合物H-5经suziki偶联反应得到化合物H-6；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；所采用的碱包括但不限于：碳酸钠、碳酸钾、碳酸氢钾、碳酸氢钠，反应温度为60℃至120℃；所采用的催化剂包括四三苯基膦钯等钯催化剂；
(5)参照步骤(1)和(2)得到化合物H-7；
(6)化合物H-6与H-7缩合得到化合物H-8；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；所采用缩合剂包括但不限于：(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐、对甲苯磺酸；反应温度为60℃至100℃；
(7)化合物H-5与H-8经suziki偶联反应得到化合物H-9；所采用的溶剂包括但不限于：苯、甲苯、乙醇、甲醇、1，4-二氧六环、四氢呋喃、丙酮、乙腈、乙酸乙酯、正己烷、二氯甲烷、氯仿、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂；所采用的碱包括但不限于：碳酸钠、碳酸钾、碳酸氢钾、碳酸氢钠，反应温度为60℃至120℃；所采用的催化剂包括四三苯基膦钯等钯催化剂。本申请还公开了所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备作为免疫检查点抑制剂中的应用。
本申请还公开了所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备具有PD-1/PD-L1抑制活性的抑制剂中的应用。
本申请还公开了所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备抗肿瘤药物中的应用。
本申请还公开了一种药物组合物，其中含有所述的五元杂环取代的联苯类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物作为活性成分，以及药学上可接受的载体。
所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
有益效果：本申请提供了一类PD-1/PD-L1小分子免疫检查点抑制剂，结构新颖，可口服给药，解决了单抗类免疫检查点抑制剂的治疗和耐药的缺陷，且作为小分子抑制剂制备简单，方便工业生产；可通过调控PD-1/PD-L1信号通路，以肿瘤免疫疗法来治疗多种相关肿瘤疾病，具有潜在的成药前景。
具体实施方式
以下结合实施例对本申请作进一步说明。
实施例1
合成路线：
化合物1-A的合成
将化合物3-氨基苯甲醇(2g)及三乙烯二胺(5.38g)用50mL丙酮溶解，室温搅拌10min后，滴加二硫化碳10mL，继续室温搅拌一小时，TLC监测原料反应完全。过滤，滤饼用石油醚洗，收集滤饼，干燥后溶于50mL氯仿中，室温搅拌，氮气保护条件下，将三光气(1.43g)溶于10mL氯仿中滴入，过夜反应。TLC监测原料反应完毕，过滤掉不溶物，滤液浓缩柱层析(石油醚：乙酸乙酯＝3：1)纯化，得白色固体化合物1-A(1.02g)。
化合物1-B的合成
将化合物1-A(1.02g)用6mL甲醇溶解，滴入一水合肼(594mg)，65℃回流搅拌，两小时后反应完毕。旋干溶剂，加入二氯甲烷打浆，过滤得白色固体1-B(934mg)。
化合物1-C的合成
将化合物1-B(600mg)及2-甲基-3-溴苯甲酸(980mg)用20mL四氢呋喃/甲醇(5：1)溶解，加入EDCI(1.72g)，65℃条件下反应一小时，TLC监测，原料反应完。旋干溶剂，经柱层析(二氯甲烷：甲醇＝70：1)纯化，得化合物1-D(560mg)。
化合物1-D的合成
将化合物1-C(560mg)溶于10mL二氯甲烷中，室温搅拌，加入戴斯-马丁试剂(796mg)，半小时后，TLC监测反应完毕，加入50mL二氯甲烷，饱和硫代硫酸钠洗三次，每次15mL，有机相浓缩柱层析(二氯甲烷：甲醇＝90：1)纯化，得化合物1-D(371mg)。
化合物1-E的合成
将化合物1-D(60mg)和乙醇胺(15mg)用甲醇及二氯甲烷(1：1，3mL)溶解，加入0.02mL冰醋酸，室温搅拌一小时，随后加入氰基硼氢化钠(50mg)，继续搅拌12h，TLC监测反应完毕，旋干溶剂经柱层析(二氯甲烷：甲醇＝15：1)及饱和碳酸氢钠洗涤，得白色固体化合物1-E(30mg)。
化合物1-F的合成
将2-甲基-3-溴苯甲酸(5.38g)，双联频哪醇硼酸酯(7.62g)和醋酸钾(4.9g)用100mL1，4-二氧六环溶解，氮气保护。搅拌条件下，加入Pd(dppf)Cl2(2.78g)，置于110℃条件下过夜反应。TLC监测反应完毕，旋干溶剂，加入乙酸乙酯溶解后，硅藻土过滤掉不溶物，滤液旋干经柱层析(石油醚：乙酸乙酯＝6：1)得化合物1-F(6.4g)。
化合物1-G的合成
参考化合物1-C的合成，可制得化合物1-G。
化合物1-H的合成
参考化合物1-D的合成，可制得化合物1-H。
化合物1-I的合成
参考化合物1-E的合成，可制得化合物1-I。
化合物1的合成
将化合物1-E(22mg)和化合物1-I(25mg)用2mL四氢呋喃和0.67mL水溶解，加入磷酸钾(23.5mg)和第二代X-Phos预钯催化剂(2.178mg)。氮气保护，65℃条件下过夜反应。TLC监测反应完全，旋干溶液经柱层析(二氯甲烷：甲醇＝3：1)，得白色固体化合物1。1H NMR(300MHz,Methanol-d4)δ7.96(dd,J＝7.9,1.4Hz,2H),7.91(d,J＝2.2Hz,2H),7.57–7.45(m,6H),7.38(dd,J＝7.7,1.4Hz,2H),7.24(dt,J＝6.5,1.8Hz,2H),4.29(s,4H),3.90–3.81(m,4H),3.27–3.14(m,4H),2.41(s,6H).
实施例2
参考实施例1的合成方法，将乙醇胺替换为甘氨酸，可制得化合物2。1H NMR(300MHz,Methanol-d4)δ7.97–7.91(m,2H),7.60(s,2H),7.54–7.46(m,4H),7.38(t,J＝7.8Hz,4H),7.09(d,J＝7.6Hz,2H),3.84(s,4H),3.45(s,4H),2.40(s,6H).
实施例3
参考实施例1的合成方法，将乙醇胺替换为N-(2-氨基乙基)乙酰胺，可制得化合物3。1H NMR(300MHz,Methanol-d4)δ7.93(dd,J＝7.6Hz,1.2Hz,2H),7.64–7.47(m,6H),7.35(t,J＝7.1Hz,4H),7.14(d,J＝6.5Hz,2H),3.91(s,4H),3.67(t,J＝5.1Hz,4H),3.17–3.06(m,4H),2.38(s,6H),1.87(s,2H).
实施例4
参考实施例1的合成方法，将乙醇胺替换为(R)-3-吡咯烷醇，可制得化合物4。1HNMR(300MHz,Methanol-d4)δ7.93(dd,J＝7.9,1.4Hz,2H),7.59(t,J＝1.9Hz,2H),7.56–7.44(m,4H),7.40–7.29(m,4H),7.09(d,J＝7.6Hz,2H),4.38(dp,J＝9.2,3.2Hz,2H),3.82–3.57(m,4H),2.93–2.73(m,4H),2.68–2.48(m,4H),2.39(s,6H),2.18(dd,J＝13.7,7.2Hz,2H),1.76(ddd,J＝14.0,7.1,4.4Hz,2H).
实施例5
参考实施例1的合成方法，将乙醇胺替换为(2R,5R)-5-hydroxypyrrolidine-2-carboxylic acid，可制得化合物5。1H NMR(500MHz,Chloroform-d)δ7.70(dd,J＝6.8,2.7Hz,2H),7.53(tt,J＝2.1,1.0Hz,2H),7.49–7.40(m,4H),7.24–7.11(m,4H),7.07(dt,J＝7.3,2.1Hz,2H),4.25–4.21(m,4H),4.10(dt,J＝12.5,1.0Hz,2H),3.98(dt,J＝12.3,0.9Hz,2H),2.40(s,6H),1.95–1.72(m,8H).
实施例6
参考实施例1的合成方法，将乙醇胺替换为L-丝氨酸，可制得化合物6。1H NMR(300MHz,Methanol-d4)δ7.84–7.71(m,2H),7.51(s,2H),7.41–7.35(m,4H),7.21(t,J＝7.1Hz,4H),6.97(d,J＝6.5Hz,2H),4.03(d,J＝4.9Hz,4H),3.84(s,4H),3.12(m,2H),2.29(s,6H).
实施例7
参考实施例1的合成方法，将乙醇胺替换为N-甲基乙醇胺，可制得化合物7。1H NMR(300MHz,Methanol-d4)δ7.99(dd,J＝7.0,1.2Hz,2H),7.87(d,J＝3.1Hz,2H),7.59–7.42(m,6H),7.37(dt,J＝7.0,1.8Hz,2H),7.15(dd,J＝7.1,1.0Hz,2H),4.01(s,4H),3.82–3.75(m,4H),3.21(t,J＝6.5Hz,4H),2.35(s,6H),1.98(s,6H).
实施例8
参考实施例1的合成方法，将乙醇胺替换为丙醇胺，可制得化合物8。1H NMR(300MHz,Methanol-d4)δ7.87(dd,J＝7.5,1.3Hz,2H),7.64–7.52(m,4H),7.41(dd,J＝7.1,1.2Hz,2H),7.21–6.99(m,6H),4.04(s,4H),3.67(d,J＝5.0Hz,4H),2.76(t,J＝4.7Hz,4H),2.31(s,6H),1.73(t,J＝5.0Hz,4H).
实施例9
参考实施例1的合成方法，将乙醇胺替换为(R)-(-)-2-氨基-1-丙醇，可制得化合物9。1H NMR(300MHz,Methanol-d4)δ7.91(dd,J＝7.1,1.5Hz,2H),7.79(d,J＝4.5Hz,2H),7.51–7.38(m,6H),7.21(dt,J＝7.4,1.5Hz,2H),7.03(dd,J＝7.4,1.5Hz,2H),4.12(s,4H),3.80–3.71(m,4H),3.21–3.09(m,2H),2.35(s,6H),1.67(s,6H).
实施例10
参考实施例1的合成方法，将乙醇胺替换为L-脯氨醇，可制得化合物10。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.8,2.7Hz,2H),7.49–7.40(m,4H),7.36(tt,J＝2.0,0.9Hz,2H),7.27–7.10(m,6H),3.79–3.53(m,8H),2.68(d,J＝9.5Hz,2H),2.56(d,J＝9.5Hz,2H),2.40(s,6H),1.67(t,J＝7.9Hz,4H),1.61(t,J＝7.5Hz,4H).
实施例11
参考实施例1的合成方法，3-氨基苯甲醇替换为3-氨基-5-氟苯甲醇，可制得化合物11。1H NMR(300MHz,Methanol-d4)δ7.91(dd,J＝6.8,1.8Hz,2H),7.80(d,J＝3.9Hz,2H),7.51–7.42(m,4H),7.31(dd,J＝7.4,1.2Hz,2H),7.12(dt,J＝7.1,1.2Hz,2H),4.12(s,4H),3.87–3.75(m,4H),3.17(d,J＝6.5Hz,4H),2.39(s,6H).
实施例12
参考实施例1的合成方法，将乙醇胺替换为(-)-2-甲基-D-丝氨酸，可制得化合物12。1H NMR(300MHz,Methanol-d4)δ7.95–7.78(m,2H),7.62(s,2H),7.49–7.38(m,4H),7.25(t,J＝6.2Hz,4H),6.98(d,J＝5.9Hz,2H),4.10(d,J＝5.2Hz,4H),3.88(s,4H),2.42(s,6H),1.64(s,6H).
实施例13
参考实施例1的合成方法，将乙醇胺替换为2-甲基丝氨酸，可制得化合物13。1HNMR(300MHz,Methanol-d4)δ7.92–7.75(m,2H),7.59(s,2H),7.44–7.33(m,4H),7.20(t,J＝6.7Hz,4H),6.94(d,J＝6.1Hz,2H),4.09(d,J＝5.6Hz,4H),3.85(s,4H),2.43(s,6H),1.66(s,6H).
实施例14
参考实施例1的合成方法，将乙醇胺替换为(S)-(+)-4-氨基-3-羟基丁酸，可制得化合物14。1H NMR(300MHz,Methanol-d4)δ7.79(d,J＝6.8Hz,2H),7.50–7.40(m,4H),7.36(dt,J＝2.0,1.0Hz,2H),7.23(t,J＝7.5Hz,2H),7.13–7.02(m,4H),3.98(d,J＝4.9Hz,2H),3.84–3.72(m,4H),3.01–2.79(m,4H),2.49–2.42(m,4H),2.40(s,6H).
实施例15
参考实施例1的合成方法，将3-氨基苯甲醇替换为对氨基苯甲醇，可制得化合物15。1H NMR(300MHz,Methanol-d4)δ7.93(dd,J＝7.9,1.4Hz,2H),7.63–7.55(m,4H),7.49(t,J＝7.8Hz,2H),7.42–7.29(m,6H),3.78(s,4H),3.73–3.66(m,4H),2.75–2.70(m,4H),2.38(s,6H).
实施例16
参考实施例3的合成方法，将3-氨基苯甲醇替换为对氨基苯甲醇，可制得化合物16。1H NMR(300MHz,Methanol-d4)δ7.95(d,J＝7.9Hz,2H),7.70(d,J＝8.2Hz,4H),7.52(dd,J＝16.2,8.0Hz,6H),7.36(d,J＝7.5Hz,2H),4.18(s,4H),3.53(t,J＝5.9Hz,4H),3.14(t,J＝6.0Hz,4H),2.39(s,6H),2.01(s,6H).
实施例17
参考实施例4的合成方法，将3-氨基苯甲醇替换为对氨基苯甲醇，可制得化合物17。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.8,2.7Hz,2H),7.49–7.41(m,4H),7.18–7.14(m,4H),7.10(dt,J＝7.6,1.1Hz,4H),3.82(d,J＝5.1Hz,2H),3.45(s,4H),3.23(d,J＝9.5Hz,2H),2.88–2.77(m,6H),2.41(s,6H),1.79(d,J＝22.0Hz,4H).
实施例18
参考实施例2的合成方法，将3-氨基苯甲醇替换为对氨基苯甲醇，可制得化合物18。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.48(t,J＝7.5Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.19–7.13(m,4H),7.07(dt,J＝7.5,1.0Hz,4H),3.92(s,4H),3.62(s,4H),2.41(s,6H).
实施例19
参考化合物1的合成，将1-I合成中的乙醇胺替换为(R)-3-吡咯烷醇，可制得化合物19。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.52–7.44(m,3H),7.44–7.36(m,3H),7.28–7.05(m,6H),3.84(s,4H),3.66–3.45(m,4H),2.94(t,J＝6.3Hz,2H),2.73–2.62(m,4H),2.41(s,6H),1.82(d,J＝3.8Hz,2H).
实施例20
参考化合物1的合成，将1-I合成中的乙醇胺替换为N-(2-氨基乙基)乙酰胺，可制得化合物20。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.7,2.8Hz,2H),7.49–7.41(m,6H),7.25–7.13(m,4H),7.08(s,2H),3.79(s,4H),3.53(t,J＝5.0Hz,2H),3.37(t,J＝3.8Hz,2H),2.97–2.73(m,4H),2.41(s,6H),2.04(s,3H).
实施例21
参考化合物1的合成，可制得化合物21。1H NMR(300MHz,Methanol-d4)δ8.45(d,J＝0.8Hz,1H),7.70(dd,J＝7.5,2.0Hz,2H),7.51–7.44(m,3H),7.39(dd,J＝7.5,2.0Hz,2H),7.23(t,J＝7.5Hz,1H),7.20–7.13(m,3H),7.11–7.01(m,3H),3.79(s,2H),3.73(s,2H),3.58(t,J＝5.5Hz,2H),3.53(t,J＝5.5Hz,2H),2.94(t,J＝5.1Hz,2H),2.79(t,J＝5.4Hz,2H),2.41(s,6H).
实施例22
参考化合物1的合成，可制得化合物22。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.48(t,J＝7.5Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.19–7.14(m,4H),7.10(dt,J＝7.5,1.1Hz,2H),7.04(dt,J＝7.5,1.0Hz,2H),4.04(d,J＝4.9Hz,1H),3.82(d,J＝5.1Hz,1H),3.73(t,J＝1.0Hz,2H),3.58(t,J＝5.5Hz,2H),3.43(d,J＝1.0Hz,2H),3.23(d,J＝9.5Hz,1H),2.85–2.76(m,5H),2.41(s,6H),1.79(d,J＝22.0Hz,2H).
实施例23
参考化合物1的合成，可制得化合物23。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.7,2.8Hz,2H),7.49–7.41(m,5H),7.23(t,J＝7.5Hz,1H),7.20–7.14(m,3H),7.09–7.00(m,3H),3.87(s,2H),3.79(s,2H),3.53(t,J＝5.5Hz,2H),3.37(t,J＝5.5Hz,2H),2.94(t,J＝5.5Hz,2H),2.76(t,J＝5.5Hz,2H),2.41(s,6H),2.04(s,3H).
实施例24
参考化合物1的合成，可制得化合物24。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.51–7.45(m,3H),7.39(dd,J＝7.5,2.0Hz,2H),7.23(t,J＝7.4Hz,1H),7.19–7.14(m,3H),7.13–7.06(m,3H),3.84–3.79(m,3H),3.53(t,J＝5.5Hz,2H),3.43(d,J＝1.0Hz,2H),3.23(d,J＝9.5Hz,1H),2.94(t,J＝5.5Hz,2H),2.88–2.74(m,3H),2.41(s,6H),1.79(d,J＝22.0Hz,2H).
实施例25
参考化合物1的合成，可制得化合物25。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.7,2.8Hz,2H),7.59–7.36(m,5H),7.28–7.20(m,2H),7.20–7.13(m,2H),7.13–6.97(m,3H),3.85–3.66(m,4H),3.58(t,J＝5.0Hz,2H),3.37(t,J＝5.5Hz,2H),2.96–2.74(m,4H),2.41(s,6H),2.04(s,3H).
实施例26
参考化合物1的合成，可制得化合物26。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.48(t,J＝7.5Hz,2H),7.42–7.36(m,3H),7.33–7.28(m,1H),7.22–7.10(m,4H),7.04(dt,J＝7.5,1.0Hz,2H),3.74(dt,J＝4.5,1.0Hz,4H),3.72(t,J＝5.0Hz,2H),3.58(t,J＝5.0Hz,2H),2.79(s,2H),2.41(s,6H).
实施例27
参考化合物1的合成，可制得化合物27。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.7,2.8Hz,2H),7.50–7.38(m,4H),7.22–7.09(m,4H),7.04(dt,J＝7.5,1.1Hz,4H),3.87(t,J＝1.0Hz,2H),3.73(t,J＝1.0Hz,2H),3.58(d,J＝5.0Hz,2H),3.37(s,2H),2.78(d,J＝18.5Hz,4H),2.41(s,6H),2.04(s,3H).
实施例28
参考化合物1的合成，可制得化合物28。1H NMR(300MHz,Methanol-d4)δ7.90(dd,J＝7.2,2.3Hz,2H),7.57–7.47(m,4H),7.36(tt,J＝2.0,0.9Hz,2H),7.23(t,J＝7.5Hz,2H),7.17(ddt,J＝7.5,2.0,0.9Hz,2H),7.07(dt,J＝7.3,2.1Hz,2H),3.81(s,4H),3.53(t,J＝5.5Hz,4H),2.94(t,J＝5.5Hz,4H).
实施例29
参考化合物1的合成，可制得化合物29。1H NMR(300MHz,Methanol-d4)δ7.99(dd,J＝7.3,2.2Hz,2H),7.58–7.48(m,4H),7.46(tt,J＝1.9,1.0Hz,2H),7.23(t,J＝7.5Hz,2H),7.17(ddt,J＝7.5,2.0,0.9Hz,2H),7.07(dt,J＝7.3,2.1Hz,2H),3.79(s,4H),3.53(t,J＝5.0Hz,4H),2.94(s,J＝5.4Hz,4H).
实施例30
参考化合物1的合成，可制得化合物30。1H NMR(300MHz,Methanol-d4)δ7.93–7.77(m,2H),7.64–7.51(m,4H),7.46(tt,J＝1.9,1.0Hz,2H),7.23(t,J＝7.5Hz,2H),7.18–7.00(m,4H),3.79(s,4H),3.53(t,J＝5.5Hz,4H),2.94(t,J＝5.5Hz,4H).
实施例31
参考化合物1的合成，可制得化合物31。1H NMR(300MHz,Methanol-d4)δ7.54(dd,J＝7.5,2.0Hz,2H),7.52–7.44(m,4H),7.32(dd,J＝7.4,2.1Hz,2H),7.24–7.14(m,4H),7.10–7.04(m,2H),3.81(s,4H),3.53(t,J＝5.0Hz,4H),2.94(s,J＝5.5Hz,4H).
实施例32
参考化合物1的合成，可制得化合物32。1H NMR(300MHz,Methanol-d4)δ8.09(t,J＝2.0Hz,2H),7.84(dt,J＝7.5,2.0Hz,2H),7.70(dd,J＝7.5,2.0Hz,2H),7.56(t,J＝7.5Hz,2H),7.48(t,J＝7.5Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.08(dt,J＝7.5,2.0Hz,2H),3.50(t,J＝5.0Hz,4H),3.39(t,J＝5.5Hz,4H),2.41(s,6H).
实施例33
参考化合物1的合成，可制得化合物33。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.3,2.2Hz,2H),7.58–7.42(m,4H),7.42–7.31(m,2H),7.26–7.14(m,2H),7.05(t,J＝2.1Hz,1H),7.02–6.85(m,3H),5.10–4.93(m,2H),4.67(t,J＝5.0Hz,2H),3.57(dd,J＝11.9,4.9Hz,4H),3.26–3.14(m,4H),2.41(s,6H).
实施例34
参考化合物1的合成，可制得化合物34。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.48(t,J＝7.5Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.29(tt,J＝1.9,1.0Hz,2H),7.23–7.10(m,6H),4.53(s,4H),3.71(t,J＝5.5Hz,4H),2.76(t,J＝5.4Hz,4H),2.41(s,6H).
实施例35
参考化合物1的合成，可制得化合物35。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.8,2.7Hz,2H),7.49–7.40(m,4H),7.36(t,J＝7.4Hz,2H),7.19(dt,J＝7.5,2.0Hz,2H),7.12(t,J＝2.0Hz,2H),6.96(dt,J＝7.5,2.0Hz,2H),4.11(t,J＝5.2Hz,4H),3.57(t,J＝4.9Hz,4H),2.92(t,J＝5.5Hz,4H),2.78(t,J＝5.5Hz,4H),2.40(s,6H).
实施例36
参考化合物1的合成，可制得化合物36。1H NMR(300MHz,Methanol-d4)δ8.02(t,J＝2.0Hz,2H),7.84(dt,J＝7.5,2.0Hz,2H),7.70(dd,J＝7.5,2.0Hz,2H),7.56(t,J＝7.5Hz,2H),7.48(t,J＝7.5Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.08(dt,J＝7.5,2.0Hz,2H),3.50(t,J＝5.5Hz,4H),3.21(t,J＝5.5J＝7.5,2.0Hz,4H),2.41(s,6H).
实施例37
参考化合物1的合成，可制得化合物37。1H NMR(300MHz,Methanol-d4)δ7.77–7.67(m,4H),7.48(t,J＝7.5Hz,2H),7.45–7.35(m,4H),7.32–7.16(m,4H),3.53(t,J＝5.0Hz,4H),2.61(t,J＝5.5Hz,4H),2.41(s,6H).
实施例38
参考化合物1的合成，可制得化合物38。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.49(dt,J＝13.2,7.5Hz,4H),7.45–7.34(m,4H),7.21(t,J＝1.9Hz,2H),7.01(dt,J＝7.3,2.0Hz,2H),2.93(t,J＝5.2Hz,4H),2.55(t,J＝5.5Hz,4H),2.41(s,6H).
实施例39
参考化合物1的合成，将EDCI替换成劳森试剂，可制得化合物39。1H NMR(300MHz,Methanol-d4)δ7.60(dd,J＝7.4,2.1Hz,2H),7.53–7.39(m,6H),7.26(dtt,J＝7.5,2.0,1.1Hz,2H),7.19(t,J＝7.5Hz,2H),7.12(dt,J＝7.5,2.1Hz,2H),3.80(s,4H),3.53(t,J＝5.0Hz,4H),2.94(t,J＝5.5Hz,4H),2.57(s,6H).
实施例40
合成路线
化合物2-A的合成
将化合物2-甲基-3-溴苯甲腈(8.62mmol)和盐酸羟胺(12.9mmol)用30mL乙醇溶解，搅拌的情况下滴加三乙胺(12.9mmol)。将反应移至90℃条件加热搅拌反应过夜。TLC检测反应原料消失，浓缩，石油醚：乙酸乙酯＝2：1柱层析，得白色固体化合物2-A。
化合物2-B的合成
将化合物2-A用30mL三氯乙酸酐溶解，110℃条件下搅拌，TLC检测反应原料消失，石油醚：乙酸乙酯＝2：1柱层析，得白色固体化合物2-B。
化合物2-C的合成
将化合物2-B用DMF溶解，加入DBU，室温条件下反应，TLC检测反应原料消失，石油醚：乙酸乙酯＝1：1柱层析，得白色固体化合物2-C。
化合物2-D，2-E的合成
参考化合物1-E和1-I的合成方法，可制得化合物2-D和2-E。
化合物40的合成
参考化合物1的合成方法，可制得化合物40。1H NMR(300MHz,Methanol-d4)δ7.89(dd,J＝7.5,2.0Hz,2H),7.54(t,J＝7.5Hz,2H),7.46(tt,J＝2.0,1.1Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.23(t,J＝7.5Hz,2H),7.20–7.14(m,2H),7.07(dt,J＝7.3,2.1Hz,2H),3.79(s,4H),3.53(t,J＝5.0Hz,4H),2.94(t,J＝5.5Hz,4H),2.53(s,6H).
实施例41
合成路线
化合物3-A的合成
将化合物2-甲基-3-溴苯甲酸用甲醇溶解，加入水合肼，65摄氏度反应，两小时后监测，原料反应完全，旋干，用石油醚打浆的白色固体化合物3-A。
化合物3-B的合成
将乙酰氨基苯甲醇用吡啶溶解，冰浴条件下滴入三氟甲磺酸酐，加料完毕移至80摄氏度反应，四小时后TLC监测反应完全，油泵抽去吡啶，柱层析得化合物3-B。
化合物3-C的合成
将化合物3-B溶于无水乙醇中，加入20％的乙醇钠，室温反应，过夜。反应完毕后，旋掉乙醇，冰浴下加入水中，有白色固体析出，过滤得化合物3-C。
化合物3-D的合成
将化合物3-A和3-C溶于乙醇中，95摄氏度条件下回流，过夜反应。反应完毕，浓缩，柱层析得化合物3-D。
化合物3-E，3-F的合成
参考化合物1-E和1-I的合成方法，可制得化合物3-E和3-F。
化合物41的合成
参考化合物1的合成方法，可制得化合物41。1H NMR(300MHz,Methanol-d4)δ7.48–7.43(m,4H),7.43–7.39(m,2H),7.38(tt,J＝1.9,1.0Hz,2H),7.25–7.16(m,4H),7.12(dt,J＝7.3,2.1Hz,2H),3.80(dd,J＝2.6,1.6Hz,6H),3.53(d,J＝5.0Hz,4H),2.94(s,4H),2.41(s,6H).
实施例42
参考化合物1的合成，可制得化合物42。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝7.5,2.0Hz,2H),7.51–7.44(m,4H),7.39(dd,J＝7.5,2.0Hz,2H),7.25–7.16(m,4H),7.07(dt,J＝7.0,2.2Hz,2H),3.86(s,4H),2.72–2.65(m,4H),2.61(t,J＝5.6Hz,4H),2.41(s,6H).
实施例43
参考化合物1的合成，可制得化合物43。1H NMR(300MHz,Methanol-d4)δ7.70(dd,J＝6.8,2.7Hz,2H),7.49–7.40(m,4H),7.36(tt,J＝2.0,0.9Hz,2H),7.23(t,J＝7.4Hz,2H),7.17(ddt,J＝7.5,2.1,1.0Hz,2H),7.07(dt,J＝7.5,2.1Hz,2H),4.06(s,2H),3.84–3.70(m,4H),3.07(d,J＝12.5Hz,2H),2.57(d,J＝12.5Hz,2H),2.43(s,4H),2.40(s,6H),1.91(d,J＝12.4Hz,4H).
实施例44
合成路线
化合物4-A的合成
将化合物2-甲基-3-溴苯甲酸用丙酮溶解，加入硫氰化钾，室温条件下搅拌反应。TLC监测反应至原料反应完，旋干溶剂经柱层析纯化，得化合物4-A。
化合物4-B的合成
将化合物4-A与3-氨基苯甲醇用丙酮溶解，回流条件下搅拌反应，TLC监测至原料反应完毕，旋干溶剂，用THF溶解，加入碳酸钾，0℃搅拌情况下，滴入碘甲烷，反应完毕后，旋干溶剂经柱层析纯化，得化合物4-B。
化合物4-C的合成
将化合物4-B用乙醇溶解，加入盐酸羟胺和DBU，TLC监测至原料反应完毕，旋干溶剂经柱层析纯化，得化合物4-C。
化合物4-D，4-E的合成
参考化合物1-E和1-I的合成方法，可制得化合物4-D和4-E。
化合物44的合成
参考化合物1的合成，可制得化合物44。1H NMR(300MHz,Methanol-d4)δ7.89(dd,J＝7.5,2.0Hz,2H),7.54(t,J＝7.5Hz,2H),7.46(tt,J＝2.0,1.1Hz,2H),7.39(dd,J＝7.5,2.0Hz,2H),7.30–7.15(m,4H),7.07(dt,J＝7.3,2.1Hz,2H),3.81(s,4H),3.53(t,J＝5.0Hz,4H),2.94(t,J＝5.5Hz,4H),2.53(s,6H).
实施例45
片剂
将实施例1中制得的化合物1(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合，制粒，压片。
此外，可以根据药典2015版常规制剂法，将实施例1-44制得的化合物赋予不同的药物辅料制成胶囊剂、散剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等。
比较例
根据WO2021031788中实施例7公开的方法制备以下代表化合物A，并通过氢谱、碳谱和质谱鉴定结构无误：
药理实验化合物对PD-1/PD-L1相互作用抑制效果的测定：
(一)试剂及耗材
(二)仪器
离心机(生产厂家：Eppendorf，型号：5430)
酶标仪(生产厂家：Perkin Elmer，型号：EnVision)
(三)实验方法
(1)配制1×modified TR-FRET assay buffer。
(2)化合物浓度梯度的配制：受试化合物测试浓度为30000nM起始，3倍稀释，10个浓度点，单孔检测。在384孔板中稀释成100倍终浓度的溶液，然后用Echo550转移200nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加200nL的100％DMSO。
(3)用1×modified TR-FRET assay buffer配制4倍终浓度的PD-L1-Biotin溶液。
(4)在化合物孔和阳性对照孔分别加5μL的4倍终浓度的PD-L1-Biotin溶液；在阴性对照孔中加5μL的1×modified TR-FRET assay buffer。
(5)1000rpm离心30秒，振荡混匀后室温孵育15分钟。
(6)用1×modified TR-FRET assay buffer配制4倍终浓度的PD-1-Eu和2倍终浓度的Dye labeled acceptor混合溶液。
(7)加入15μL PD-1-Eu和Dye labeled acceptor混合溶液(其中含5μL的4倍终浓度的PD-1-Eu和10μL 2倍终浓度的Dye labeled acceptor)。
(8)1000rpm离心30秒，振荡混匀后室温孵育90分钟。
(9)将384孔板1000rpm离心30秒，振荡混匀后用EnVision读取665nm和620nm的荧光强度，并计算TR-FRET ratio(665nm emission/620nm emission)。
(四)数据分析
计算公式
％Inhibition＝(Ratio_max-Ratio_sample)/(Ratio_max-Ratio_min)*100
其中：Ratio_sample是样品孔的比值；Ratio_min：阴性对照孔比值均值，代表没有PD-1/PD-L1相互作用孔的读数；Ratio_max：阳性对照孔比值均值，代表没有化合物抑制孔的读数。
拟合量效曲线
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
(五)实验结果
下表为化合物对PD-1/PD-L1相互作用抑制活性的活性范围或IC50。范围如下：
根据上述结果可见，本申请实施例化合物均表现出优异的PD-1/PD-L1抑制活性，其中活性最好的实施例4，抑制活性达到了30.9nM，明显优于化合物A。显示本发明的五元杂环取代的联苯类化合物可用作免疫检查点PD-1/PD-L1抑制剂。
Claims (10)
1.一种如式Ⅰ所示的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物：
环A和环B独立地为芳环或芳杂环；
X1，X2，X3，X4，X5，X6独立地为N或C；
Y1，Y2独立地为O、S、C或N；
Z1，Z2，Z3，Z4独立地为N、C或O；
每个R1和R2独立地为氢、氘、取代或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基或取代或未取代的烷氧基、氨基酸；
R3和R4独立地为氢、氘、氰基、卤素、乙烯基、三氟甲基、甲氧基或C1-4烷基；
m和n独立地为1、2或3。
2.根据权利要求1所述的五元杂环取代的联苯类类化合物，其特征在于，所述
中，
是指其为单键或双键，当其为单键时，Z1和Z3为-O-或-NH-或-S-，当其为双键时，Z1和Z3为＝N-；
所述
中，
是指其为单键或双键，当其为单键时，Z2和Z4为-O-或-NH-或-S-，当其为双键时，Z2和Z4为＝N-或＝C-；
所述
中，
是指其为单键或双键，当Y1和Y2为N时，此处为
当Y1和Y2为S或O时，此处为-O-或-S-。
3.根据权利要求1所述的五元杂环取代的联苯类类化合物，其特征在于，环A和环B为苯环，X1，X2，X3，X4，X5，X6为C，
中，
是双键，Z1、Z2、Z3和Z4是N，Y1和Y2是C，R3和R4为C或Br或Cl。
4.根据权利要求1所述的五元杂环取代的联苯类化合物，其特征在于，所述化合物包括以下任意一种结构：
5.权利要求1-4中任一所述的五元杂环取代的联苯类化合物的制备方法，其特征在于，当Y1和Y2是O，Z1,Z2,Z3和Z4是N时，所述化合物的合成路线如下所示：
包括以下步骤：
(1)化合物H-2与二硫化碳反应得到化合物H-3；
(2)化合物H-3与水合肼反应得到化合物H-4；
(3)化合物H-1与H-4缩合得到化合物H-5；
(4)化合物H-5经suziki偶联反应得到化合物H-6；
(5)参照步骤(1)和(2)得到化合物H-7；
(6)化合物H-6与H-7缩合得到化合物H-8；
(7)化合物H-5与H-8经suziki偶联反应得到化合物H-9。
6.权利要求1～4任一项所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备免疫检查点抑制剂中的应用。
7.权利要求1～4中任一项所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备具有PD-1/PD-L1抑制活性的抑制剂中的应用。
8.权利要求1～4任一项所述的五元杂环取代的联苯类化合物，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物在制备抗肿瘤药物中的应用。
9.一种药物组合物，其中含有权利要求1～4中任一项所述的五元杂环取代的联苯类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物作为活性成分和药学上可接受的载体。
10.根据权利要求9所述的药物组合物，其特征在于，所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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