CN112479988B - 取代联苯类化合物及其制备方法、用途和药物组合物 - Google Patents

取代联苯类化合物及其制备方法、用途和药物组合物 Download PDF

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CN112479988B
CN112479988B CN202011429556.4A CN202011429556A CN112479988B CN 112479988 B CN112479988 B CN 112479988B CN 202011429556 A CN202011429556 A CN 202011429556A CN 112479988 B CN112479988 B CN 112479988B
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蒋晟
王天雨
郝海平
王敏敏
蔡适
张婉衡
张阔军
邱亚涛
肖易倍
郑帅
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Yaokang Zhongtuo Jiangsu Pharmaceutical Technology Co ltd
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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取代联苯类化合物及其制备方法、用途和药物组合物，该类化合物如下式Ⅰ所示，或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物。该类化合物结构新颖，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。

Description

取代联苯类化合物及其制备方法、用途和药物组合物
技术领域
本发明涉及药物化学技术，尤其涉及取代联苯类化合物及其制备方法、用途和药物组合物。
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 membrane3)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：本发明的第一目的是提供一系列通过调控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的取代联苯类化合物；
本发明的第二目的是提供所述取代联苯类化合物的制备方法；
本发明的第三目的是提供所述的含有取代联苯类化合物的药物组合物。
技术方案：为了实现上述目的，如本发明所述一种如下式I所示的取代联苯类化合物：
X1,X2,X3,X4独立地为氮或碳；
R1独立地为氢,氘,卤素,-(CH2)1-6NR5R6,-O-(CH2)1-6NR5R6,-NR5R6,-(CH2)1-6-O-(CH2)1-6R5R6,-(CH2)1-6-O-(CH2)1-6NR5R6,-C(O)NR5R6,-COO-(CH2)0-6NR5R6,-S-(CH2)1-6NR5R6,-S(O)2-(CH2)0-6NR5R6,-(CH2)1-6R5R6；
R1中，所述的R5或R6独立地选自下列基团：氢,卤素,C1-4烷基,取代或未取代羟基,取代或未取代氨基,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；其中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羟基被以下一个或多个任意取代基取代：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；或者R5、R6和它们相连的氮原子一起形成一个5-7元的取代或未取代的碳杂环，所述碳杂环中，杂原子为氮，或氮和氧，杂原子数为1-4个；
R2独立地为氢,氘,卤素,-OR7,-N3,硝基,氰基,三氟甲基,-NR7,-S(O)2R7,-C(O)R7,-COOR7,OC(O)R7,C1-4羧基,C1-4酯基或C1-4酰胺基,C1-4烷基,C1-4烷氧基,芳环，芳杂环；其中所述的R7独立地选自下列基团：氢,卤素,C1-4烷基,取代或未取代羟基,取代或未取代氨基,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；其中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羟基被以下一个或多个任意取代基取代：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；
R3为氢、氘、氰基、卤素、乙烯基、三氟甲基、甲氧基或C1-4烷基；
每个R4独立地为氢、氘或未取代的羟基、取代或未取代的氨基、卤素、取代或未取代的烷基、取代或未取代的烷氧基、或相邻两个R4与苯环的两个原子形成4-7元取代或未取代的碳环或杂环；其中所述的取代的烷基或取代的烷氧基的取代基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任意一个或多个：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羟基被以下任意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；当相邻的两个R4和与它们相连的苯环上的两个原子共同形成4-7元的取代的碳环或取代的杂环时，所述的取代的碳环或取代的杂环的取代基为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；当取代基为多个时，所述的取代基相同或不同；
m为1、2或3；
n为1或2。
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。
进一步地，所述化合物包括以下任意一种结构：
上述的取代联苯类化合物的制备方法，当X1是氮时，所述化合物的合成路线如下式II所示：
其中，式II中R1,R2,R3,R4,X2,m,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-1与H-2经Suzuki偶联反应得到化合物H-3；
(2)化合物H-3与H-4经Suzuki偶联反应得到化合物H-5。
其中，步骤(1)中偶联反应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、[1,1"-双(二苯基膦基)二茂铁]二氯化钯等钯催化剂。
优选地，步骤(2)中偶联反应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、[1,1"-双(二苯基膦基)二茂铁]二氯化钯等钯催化剂。
本发明所述的取代联苯类化合物的应用，所述应用为所述取代联苯类化合物以及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。
本发明所述的取代联苯类化合物的应用，所述应用为所述取代联苯类化合物以及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。
本发明所述的取代联苯类化合物的应用，所述应用为所述取代联苯类化合物以及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。
本发明所述的含有取代联苯类化合物的药物组合物，所述药物组合物为由所述五元杂环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。
本发明所述的含有取代联苯类化合物的药物组合物，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：与现有技术相比，本发明具有如下优点：
本发明提供一类免疫检查点小分子抑制剂，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。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1
合成路线：
化合物1-B的合成
将10g化合物2,6-二溴甲苯，30g双联频哪醇硼酸酯和24g醋酸钾用200mL的1，4-二氧六环溶解，再加入1g[1,1"-双(二苯基膦基)二茂铁]二氯化钯，氮气保护，移至130℃搅拌过夜。TLC监测，原料反应完全，停止反应，旋干溶剂，加入400mL乙酸乙酯，水洗一次，饱和食盐水洗一次，每次100mL。有机相浓缩柱层析(石油醚：乙酸乙酯(体积比，以下同)＝25：1)纯化，得9.8g化合物1-B。
化合物1-D的合成
将化合物对1g的2-氯-5-羟甲基吡啶和3.4g的化合物1-B用25mL的1，4-二氧六环/水(10：1)溶解，加入200mg的四三苯基膦钯和2.6g的碳酸钾。置于85℃条件下反应一小时。TLC监测原料反应完毕，过滤掉不溶物，滤液浓缩柱层析(二氯甲烷：甲醇＝50：1)纯化，得1.02g白色固体化合物1-D。
化合物1-E的合成
将500mg化合物1-D，480mg溴苯，640mg磷酸钾和120mg的2nd X-Phos Pd催化剂用20mL四氢呋喃/水(3：1)溶解，氮气保护，置于80℃条件下过夜反应。TLC监测原料反应完毕，浓缩柱层析(二氯甲烷：甲醇＝60：1)纯化，得460mg化合物1-E。
化合物1-F的合成
将240mg化合物1-D溶于10mL二氯甲烷中，室温搅拌，加入408mg戴斯-马丁试剂，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171mg 1-E。
化合物1的合成
将25mg化合物1-E和9mg乙醇胺用3mL1：1的甲醇和二氯甲烷溶解，加入0.02mL冰醋酸，室温搅拌一小时，随后加入26mg氰基硼氢化钠，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20mg白色固体化合物1。1HNMR(400MHz,Chloroform-d)δ8.63(d,J＝2.2Hz,1H),7.76(dd,J＝8.0,2.3Hz,1H),7.46–7.26(m,9H),3.87(s,2H),3.69(t,J＝5.1Hz,2H),2.84(t,J＝5.1Hz,2H),2.15(s,3H).
实施例2
参照实施例1合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物2。1H NMR(300MHz,Chloroform-d)δ8.71–8.56(m,1H),7.73(dd,J＝8.0,2.3Hz,1H),7.51–7.26(m,9H),3.85(s,2H),3.38(q,J＝5.7Hz,2H),2.82(t,J＝5.8Hz,2H),2.15(s,3H),1.97(s,3H).
实施例3
参照实施例1合成方法，将2-氯-5-羟甲基吡啶替换为2-氯-6-羟甲基吡啶，可制得化合物3。1H NMR(300MHz,Chloroform-d)δ8.58(d,J＝5.0Hz,1H),7.94(dd,J＝7.5,2.0Hz,1H),7.68–7.26(m,9H),3.90(s,2H),3.61(t,J＝4.9Hz,2H),2.94(t,J＝5.3Hz,2H),2.27(s,3H).
实施例4
参照实施例1合成方法，将2-氯-5-羟甲基吡啶替换为2-氯-4-羟甲基吡啶，可制得化合物4。1H NMR(300MHz,Chloroform-d)δ7.94(dd,J＝7.5,2.0Hz,1H),7.65–7.07(m,10H),3.64(s,2H),3.63(t,J＝4.7Hz,2H),2.80(t,J＝4.8Hz,2H),2.27(s,3H).
实施例5
合成路线
化合物2-B的合成
将2.49g甲醇溶于40mL四氢呋喃中，氮气保护，0℃条件下分批加入1.86g钠氢，搅拌一小时后，将3g的2，6-二氯烟酸用10mL四氢呋喃溶解，滴入上述反应液中，移至60℃搅拌3小时，TLC监测反应完全。加入甲醇淬灭，过滤得2.1g白色固体化合物2-B。
化合物2-C的合成
将2.0g化合物2-B溶于甲醇中，0℃条件下搅拌，缓慢滴入2.4mL氯化亚砜，移至70℃反应3小时，TLC监测反应完毕，旋干溶剂，加入300mL乙酸乙酯，水洗两次，饱和食盐水洗一次，旋干柱层析(石油醚：乙酸乙酯＝5：1)得1.8g化合物2-C。
化合物2-D的合成
参考化合物1-D的合成，可制得化合物2-D。
化合物2-E的合成
将180mg四氢铝锂分批加入10mL四氢呋喃中，再将600mg的化合物2-D用10mL四氢呋喃溶解，滴入上述溶液中，移至室温反应2小时，TLC监测反应完毕。加入水淬灭，旋干溶剂，柱层析(二氯甲烷：甲醇＝80：1)得160mg化合物2-E。
化合物2-F的合成
参考化合物1-E的合成方法，可制得化合物2-F。
化合物2-G的合成
参考化合物1-F的合成方法，可制得化合物2-G。
化合物5的合成
参考化合物1的合成方法，可制得化合物5。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例6
参照实施例5合成方法，将乙醇胺替换成丙氨酸，可制得化合物6。1H NMR(300MHz,Chloroform-d)δ7.60(d,J＝7.3Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.12(s,3H),3.85(s,2H),3.66(s,2H),2.25(s,3H).
实施例7
参照实施例5合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物7。1H NMR(300MHz,Chloroform-d)δ7.62(d,J＝7.2Hz,1H),7.48–7.31(m,8H),7.11(d,J＝7.0Hz,1H),4.01(s,3H),3.82(s,2H),3.40(q,J＝5.6Hz,2H),2.81(t,J＝4.5Hz,2H),2.25(s,3H),2.00(s,3H).
实施例8
参照实施例5合成方法，将乙醇胺替换成(R)-3-吡咯烷醇，可制得化合物8。1H NMR(300MHz,Chloroform-d)δ7.57(d,J＝7.4Hz,1H),7.45–7.28(m,8H),7.02(d,J＝7.2Hz,1H),4.00(s,3H),3.87–3.78(m,3H),3.39–3.05(m,2H),2.81–2.64(m,2H),2.25(s,3H),1.94–1.79(m,2H).
实施例9
参照实施例5合成方法，将乙醇胺替换成乙二胺，可制得化合物9。1H NMR(300MHz,Chloroform-d)δ7.53(d,J＝7.2Hz,1H),7.44–7.23(m,8H),7.00(d,J＝7.1Hz,1H),3.99(s,3H),3.80(s,2H),3.64(t,J＝5.0Hz,2H),3.21(t,J＝5.1Hz,2H),2.24(s,3H).
实施例10
参照实施例5合成方法，将乙醇胺替换成(s)-(+)-4氨基-3羟基丁酸，可制得化合物10。1H NMR(300MHz,Chloroform-d)δ7.62(d,J＝7.3Hz,1H),7.47–7.29(m,8H),7.04(d,J＝7.2Hz,1H),4.02(s,3H),3.82(s,2H),3.74(d,J＝6.3Hz,2H),3.68-3.55(m,1H),2.54(d,J＝5.2Hz,2H),2.25(s,3H).
实施例11
参照实施例5合成方法，将乙醇胺替换成L-哌啶甲酸，可制得化合物11。1H NMR(300MHz,Chloroform-d)δ7.62(d,J＝7.2Hz,1H),7.52–7.31(m,8H),7.04(d,J＝7.3Hz,1H),4.19–4.13(m,1H),4.04(s,3H),3.80(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),4.62–2.57(m,2H),2.25(s,3H),1.87–1.73(m,4H),1.63–1.59(m,2H).
实施例12
参照实施例5合成方法，将乙醇胺替换成L-丝氨酸，可制得化合物12。1H NMR(300MHz,Chloroform-d)δ7.60(d,J＝7.3Hz,1H),7.50–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.04(s,3H),3.80(s,2H),3.75(d,J＝7.3Hz,2H),3.51(t,J＝5.5Hz,2H),2.25(s,3H).
实施例13
参照实施例5合成方法，将乙醇胺替换成丙醇胺，可制得化合物13。1H NMR(300MHz,Chloroform-d)δ7.54(d,J＝7.4Hz,1H),7.45–7.23(m,8H),6.98(d,J＝7.4Hz,1H),3.99(s,3H),3.78(s,2H),3.64(t,J＝5.3Hz,2H),2.58(t,J＝5.5Hz,2H),2.25(s,3H),1.61(q,J＝5.9Hz,2H).
实施例14
参照实施例5合成方法，将乙醇胺替换成(-)-2-甲基丙醇胺，可制得化合物14。1HNMR(300MHz,Chloroform-d)δ7.54(d,J＝7.4Hz,1H),7.45–7.23(m,8H),6.98(d,J＝7.4Hz,1H),3.99(s,3H),3.78(s,2H),3.64(t,J＝5.3Hz,2H),2.58(t,J＝5.5Hz,2H),2.25(s,3H),1.61(q,J＝5.9Hz,2H).
实施例15
参照实施例5合成方法，将乙醇胺替换成2-(甲基胺)丙醇，可制得化合物15。1HNMR(300MHz,Chloroform-d)δ7.61(d,J＝7.3Hz,1H),7.48–7.30(m,8H),7.01(d,J＝7.4Hz,1H),4.02(s,3H),3.78(s,2H),3.51(t,J＝5.1Hz,2H),2.82(s,3H),2.62(t,J＝5.2Hz,2H),2.25(s,3H).
实施例16
参照实施例5合成方法，将乙醇胺替换成(S)-5-氨基甲基吡咯烷-2-酮，可制得化合物16。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.02(d,J＝7.3Hz,1H),4.00(s,3H),3.83(d,J＝1.5Hz,3H),2.82(dd,J＝12.1,4.0Hz,1H),2.61(dd,J＝12.0,8.6Hz,1H),2.40–2.32(m,2H),2.25(s,3H),1.88–1.60(m,2H).
实施例17
参照实施例5合成方法，将乙醇胺替换成3-羟基氮杂环丁烷，可制得化合物17。1HNMR(300MHz,Chloroform-d)δ7.59(d,J＝7.3Hz,1H),7.47–7.28(m,8H),7.02(d,J＝7.3Hz,1H),4.33–4.27(m,1H),4.00(s,3H),3.88(s,2H),3.64–3.55(m,2H),3.30–3.22(m,2H),2.25(s,3H).
实施例18
参照实施例5合成方法，将乙醇胺替换成3-甲基-3-吖啶醇，可制得化合物18。1HNMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.48–7.28(m,8H),7.02(d,J＝7.3Hz,1H),4.34–4.26(m,1H),4.00(s,3H),3.88(s,2H),3.63–3.54(m,2H),3.30–3.22(m,2H),2.25(s,3H),1.34(s,3H).
实施例19
参考实施例5合成方法，将乙醇胺替换成3-甲基-3-羟基吡咯烷，可制得化合物19。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.3Hz,1H),7.47–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.33–4.27(m,1H),4.00(s,3H),3.88(s,2H),2.69–2.58(m,2H),2.42–2.32(m,2H),2.25(s,3H),1.39(s,3H).
实施例20
参考实施例5合成方法，将2,6-二氯烟酸替换成3,5-二氯吡嗪-2-甲酸，可制得化合物20。1H NMR(300MHz,Chloroform-d)δ8.10(s,1H),7.48–7.26(m,8H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.23(s,3H).
实施例21
参考实施例5合成方法，将2，6-二溴甲苯替换成2，6-二溴氯苯，可制得化合物21。1H NMR(300MHz,Chloroform-d)δ7.66(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H).
实施例22
参考实施例5合成方法，将2,6-二溴甲苯替换成2，6-二溴氟苯，可制得化合物22。1H NMR(300MHz,Chloroform-d)δ7.64(d,J＝7.4Hz,1H),7.48–7.27(m,8H),7.01(d,J＝7.3Hz,1H),4.00(s,3H),3.82(s,2H),3.74(t,J＝5.3Hz,2H),2.82(t,J＝5.2Hz,2H).
实施例23
参考实施例5合成方法，将2,6-二溴甲苯替换成2，6-二溴-1-三氟甲基苯，可制得化合物23。1H NMR(300MHz,Chloroform-d)δ7.58(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例24
参考实施例5合成方法，将溴苯替换成6-溴-1,4-苯并噁烷，可制得化合物24。1HNMR(400MHz,Methanol-d4)δ7.71(d,J＝7.5Hz,1H),7.34–7.20(m,3H),7.05(d,J＝7.4Hz,1H),6.88(d,J＝8.2Hz,1H),6.83–6.74(m,2H),4.27(s,4H),4.00(s,3H),3.86(s,2H),3.72(t,J＝5.5Hz,2H),2.79(t,J＝5.5Hz,2H),2.19(s,3H).
实施例25
参考实施例24的合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物25。1HNMR(500MHz,Methanol-d4)δ7.71(d,J＝7.4Hz,1H),7.34–7.20(m,3H),7.06(d,J＝7.4Hz,1H),6.89(d,J＝8.2Hz,1H),6.84–6.74(m,2H),4.29(s,4H),4.01(s,3H),3.83(s,2H),3.37(t,J＝6.3Hz,2H),2.77(t,J＝6.3Hz,2H),2.20(s,3H),1.96(s,3H).
实施例26
参考实施例5的合成方法，将化合物2-B合成中甲醇替换成乙醇，可制得化合物26。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.32(q,J＝4.9Hz,2H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H),1.36(t,J＝5.3Hz,3H).
实施例27
参考实施例26的合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物27。1HNMR(300MHz,Chloroform-d)δ7.62(d,J＝7.2Hz,1H),7.48–7.31(m,8H),7.11(d,J＝7.0Hz,1H),4.32(q,J＝4.9Hz,2H),3.82(s,2H),3.40(q,J＝5.6Hz,2H),2.81(t,J＝4.5Hz,2H),2.25(s,3H),2.00(s,3H),1.36(t,J＝5.3Hz,3H).
实施例28
参考实施例26的合成方法，将乙醇替换成异丙醇，可制得化合物28。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.72–4.67(m,2H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H),1.36(d,J＝5.3Hz,6H).
实施例29
参考实施例28的合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物29。1HNMR(300MHz,Chloroform-d)δ7.62(d,J＝7.2Hz,1H),7.48–7.31(m,8H),7.11(d,J＝7.0Hz,1H),4.72–4.67(m,2H),3.82(s,2H),3.40(q,J＝5.6Hz,2H),2.81(t,J＝4.5Hz,2H),2.25(s,3H),2.00(s,3H),1.36(d,J＝5.3Hz,6H).
实施例30
参考实施例26的合成方法，将乙醇替换成苯甲醇，可制得化合物30。1H NMR(300MHz,Chloroform-d)δ7.66–7.28(m,14H),7.01(d,J＝7.3Hz,1H),5.56(s,2H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例31
参考实施例30的合成方法，将乙醇胺替换成N-乙酰基乙二胺，可制得化合物31。1HNMR(300MHz,Chloroform-d)δ7.66–7.28(m,14H),7.11(d,J＝7.0Hz,1H),5.56(s,2H),3.82(s,2H),3.40(q,J＝5.6Hz,2H),2.81(t,J＝4.5Hz,2H),2.25(s,3H),2.00(s,3H),1.36(d,J＝5.3Hz,6H).
实施例32
参考实施例26的合成方法，将乙醇替换成3-羟甲基苯甲腈，可制得化合物32。1HNMR(300MHz,Chloroform-d)δ7.69–7.28(m,13H),7.01(d,J＝7.3Hz,1H),5.56(s,2H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例33
参考实施例5的合成方法，将2，6-二氯烟酸替换成2，3，6-三氯盐酸，可制得化合物33。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,7H),7.01(d,J＝7.3Hz,1H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例34
参照实施例5合成方法，将2，6-二氯烟酸替换成2，6-二氯-4-羟甲基吡啶，可制得化合物34。1H NMR(300MHz,Chloroform-d)δ7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),6.59(d,J＝7.4Hz,1H),4.00(s,3H),3.82(s,2H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例35
参照实施例5合成方法，可制得化合物35。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),4.82(s,2H),4.00(s,3H),3.70(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.25(s,3H).
实施例36
参考实施例5的合成方法，可制得化合物36。1H NMR(300MHz,Chloroform-d)δ7.59(d,J＝7.4Hz,1H),7.46–7.28(m,8H),7.01(d,J＝7.3Hz,1H),3.90(s,3H),2.25(s,3H).
实施例37
参考实施例5的合成方法，可制得化合物37。1H NMR(400MHz,Chloroform-d)δ8.55(d,J＝7.7Hz,1H),7.41(ddd,J＝6.5,3.5,1.6Hz,3H),7.38–7.29(m,5H),7.20(d,J＝7.8Hz,1H),4.12(s,3H),3.83(t,J＝5.1Hz,2H),3.70–3.62(m,2H),2.24(s,3H).
实施例38
合成路线
化合物3-B的合成
将2-甲基-3-溴苯酚用DMF溶解，加入1-溴-3-氯丙烷和无水碳酸钾，50摄氏度搅拌反应。过夜,TLC监测反应完毕。乙酸乙酯萃取，饱和碳酸氢钠洗，饱和食盐水洗，浓缩得化合物3-B。
化合物3-C的合成
将化合物3-B用乙腈溶解，加入哌啶-4-醇和三乙胺，85摄氏度条件下加热反应，过夜反应完全。柱层析得化合物3-C。
化合物38的合成
参考实施例5的合成方法，可由化合物3-C和2-E经三步反应制得化合物38。1H NMR(300MHz,Chloroform-d)δ7.70(d,J＝7.4Hz,1H),7.58–7.28(m,6H),7.01(d,J＝7.3Hz,1H),4.05(t,J＝5.3Hz,2H),4.00(s,3H),3.88(t,J＝5.3Hz,1H),3.70(s,2H),3.40(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.51–2.34(m,6H),2.25(s,3H),1.80–1.67(m,6H).
实施例39
参考实施例38的合成方法，可制得化合物39。1H NMR(300MHz,Chloroform-d)δ7.70(d,J＝7.4Hz,1H),7.58–7.28(m,6H),7.01(d,J＝7.3Hz,1H),4.05(t,J＝5.3Hz,2H),4.00(s,3H),3.88(t,J＝5.3Hz,1H),3.70(s,2H),3.40(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,2H),2.51–2.34(m,6H),2.25(s,3H),1.80–1.67(m,8H).
实施例40
参考实施例39的合成方法，可制得化合物40。1H NMR(300MHz,Chloroform-d)δ7.70(d,J＝7.4Hz,1H),7.58–7.28(m,6H),7.01(d,J＝7.3Hz,1H),4.05(t,J＝5.3Hz,2H),4.00(s,3H),3.88(t,J＝5.3Hz,1H),3.70(s,2H),3.40(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,6H),2.51–2.34(m,6H),2.25(s,3H),1.80–1.67(m,2H).
实施例41
参考实施例40的合成方法，可制得化合物41。1H NMR(300MHz,Chloroform-d)δ7.70(d,J＝7.4Hz,1H),7.58–7.28(m,6H),7.01(d,J＝7.3Hz,1H),4.05(t,J＝5.3Hz,2H),4.00(s,3H),3.88(t,J＝5.3Hz,1H),3.70(s,2H),3.40(t,J＝5.3Hz,2H),2.84(t,J＝5.2Hz,6H),2.51–2.34(m,6H),2.25(s,3H),1.80–1.67(m,2H).
实施例42
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1-66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。
试验例1
药理试验证明，本发明的PD-1/PD-L1抑制活性，可用于制备抗肿瘤药物。下面是本发明部分化合物的药理实验结果：
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：A＝1nM-100nM；B＝100.01nM-1000nM；C＝1001-10000nM.
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Claims (6)

1.一种取代联苯类化合物，其特征在于，所述化合物为以下任意一种结构：
2.权利要求1所述取代联苯类化合物在制备免疫检查点抑制剂中的应用。
3.权利要求1所述取代联苯类化合物在制备具有PD-1/PD-L1抑制活性的抑制剂中的应用。
4.权利要求1所述取代联苯类化合物在制备抗肿瘤药物中的应用。
5.一种药物组合物，其特征在于：所述药物组合物包含权利要求1所述取代联苯类化合物作为活性成分和药学上可接受的载体。
6.根据权利要求5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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