CN116589395A - 咔唑甲基苯基醚类衍生物、其制备方法和应用 - Google Patents
咔唑甲基苯基醚类衍生物、其制备方法和应用 Download PDFInfo
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- CN116589395A CN116589395A CN202310551837.4A CN202310551837A CN116589395A CN 116589395 A CN116589395 A CN 116589395A CN 202310551837 A CN202310551837 A CN 202310551837A CN 116589395 A CN116589395 A CN 116589395A
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- acid
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- carbazole
- methylphenyl ether
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- -1 Carbazole methylphenyl ether derivative Chemical class 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
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- 125000001424 substituent group Chemical group 0.000 claims description 21
- CLFRCXCBWIQVRN-UHFFFAOYSA-N 2,5-dihydroxybenzaldehyde Chemical compound OC1=CC=C(O)C(C=O)=C1 CLFRCXCBWIQVRN-UHFFFAOYSA-N 0.000 claims description 18
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 11
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
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Abstract
本发明公开了咔唑甲基苯基醚类衍生物、其制备方法和应用,咔唑甲基苯基醚类衍生物的结构如通式I或II所示:
Description
技术领域
本发明公开了一类咔唑甲基苯基醚类衍生物、及其制备方法和用途。具体而言,涉及通式I和通式II所示的咔唑甲基苯基醚类衍生物,其制备方法以及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。
背景技术
当今,癌症是世界上对人类危害最大的疾病之一,也是导致人类死亡的主要原因。每年都有大量的人罹患各种癌症,大量的资源被用于癌症的治疗。近年来,肿瘤免疫治疗(Immunology Oncology Therapy)已成为恶性肿瘤治疗领域的重要手段之一,它正在给各种类型肿瘤的治疗带来革命性的变化。
免疫系统不仅能够通过影响破坏肿瘤侵袭和转移能力的肿瘤抑制基因来发挥调节癌症命运的作用;而且,它还能促进肿瘤细胞转化,促进肿瘤生长,从而塑造肿瘤细胞的免疫原性。免疫系统由共刺激信号(T细胞受体)和共抑制信号(免疫检查点)来调节。共刺激信号通路刺激免疫系统释放级联免疫调节蛋白,通过阻止病原体生长来消除病原体。免疫系统检查点不仅维持自我耐受,而且在对病原感染作出免疫反应时保护正常组织免受不必要的损伤。不幸的是,肿瘤细胞已经学会利用刺激免疫检查点和逃避细胞毒性免疫系统的机制,尤其是针对肿瘤抗原特异性T细胞的机制。这在一定程度上解释了包括实体和血液类型在内的恶性肿瘤的转移性质,并阐明了肿瘤免疫逃逸的本质。免疫检查点抑制剂通过配体-受体相互作用来阻断免疫检查点,继而恢复共刺激性T细胞的抗肿瘤免疫反应达到肿瘤治疗的目的。抑制性的免疫检查点分子作为癌症免疫治疗的靶点已引起广泛关注,它们已经在多种癌症治疗方面得到广泛的应用。由于分别发现免疫检查点分子CTLA-4和PD-1,美国免疫学家詹姆斯·埃利森(James P Alison)和日本免疫学家本庶佑(Tasuku Honjo)共同获得2018年诺贝尔生理学或医学奖。众所周知,肿瘤免疫治疗领域最重要的进展之一是PD-1/PD-L1通路抑制剂的发现、开发和临床应用,PD-1/PD-L1通路因此成为肿瘤免疫学领域最有希望的靶点之一。
程序性细胞死亡蛋白-1(PD-1)(也称为CD279)是一种免疫共抑制分子。它是一种由288个氨基酸组成的I型跨膜糖蛋白。它是由日本学者本庶佑从凋亡的小鼠T细胞杂交瘤2B4.11中发现的。PD-1蛋白由活化的T细胞、B细胞、自然杀伤细胞、巨噬细胞和树突状细胞表达。PD-1蛋白有两种配体:程序性死亡配体-1(PD-L1)和程序性死亡配体-2(PD-L2),属于B7家族,具有37%的序列同源性。PD-L1蛋白(也称为B7H1或CD274)存在于许多不同免疫细胞(抗原呈递细胞、B细胞、T细胞)、组织细胞(包括心、肺、肝、胰岛、血管内皮、上皮细胞、肌肉细胞等)和肿瘤细胞的表面。PD-L2蛋白(CD273)的表达受限,仅见于树突状细胞(DCs)和少数肿瘤细胞系。PD-1/PD-L1通路抑制剂可以通过干扰PD-1蛋白和PD-L1蛋白的相互作用来阻断该通路,从而增强T细胞的活性,促进细胞毒性T淋巴细胞的增殖,增强机体抗肿瘤免疫反应。研究表明,PD-1/PD-L1通路抑制剂对多种类型的肿瘤均显示出良好的治疗效果,如:黑色素瘤、非小细胞肺癌、尿路上皮细胞癌、肾细胞癌、头颈鳞状细胞癌、经典霍奇金淋巴瘤等。近年来,靶向PD-1/PD-L1信号通路的单克隆抗体药物(MAbs)在临床研究中展现出了显著的抗肿瘤效果,且毒性较低,因而发展十分迅速,应用越来越广泛。迄今为止,美国食品和药物管理局(FDA)已批准了七种针对PD-1/PD-L1通路的单克隆抗体药物用于临床治疗,包括四种PD-1单抗(Pembrolizumab、Nivolumab、Cemiplimab和Dostarlimab)和三种PD-L1单抗(Atezolizumab、Durvalumab、Avelumab)。
发明内容
本发明解决的技术问题是提供一种具有抑制PD-1/PD-L1相互作用的咔唑甲基苯基醚类衍生物及其制备方法、和其在制备预防或治疗与PD-1/PD-L1信号通路有关疾病药物中的用途。
如通式I或II所示的咔唑甲基苯基醚类衍生物及其立体异构体以及其可药用盐,
R1可以是下列之一:氢、C1-8饱和烷基、C1-5烷氧基;
R2可以是下列之一:R3可以是下列之一: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,取代基可以是氢、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、噁唑基或四氮唑基;
R4可以是下列之一:R5可以是下列之一: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,取代基可以是氢、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、噁唑基或四氮唑基。
另外,上述反应中的起始原料及中间体较容易得到。通式I或通式II所述药学上可接受的盐包括不同酸所成的盐,如与下列无机酸或有机酸形成的盐:盐酸,氢溴酸,磷酸,硫酸,甲烷磺酸,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。通式I或通式II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。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、通式II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的化合物将分为八步(路线一)。
路线一:
(a)以式1所示的对硝基苯甲醇为原料,三异丙基氯硅烷作为保护基,进行保护硝基苯甲醇上的羟基的反应,得到中间体2;
(b)通过铁粉和氯化铵作为还原剂,将中间体2上的硝基还原成氨基得到中间体3;
(c)以中间体3和式4所示的4-溴-3-碘苯衍生物为原料,通过Buchward反应得到中间体5;
(d)中间体5在醋酸钯催化,高温下发生分子内N-芳香化反应直接关环生成中间体6;
(e)中间体6在四丁基氟化铵TBAF的作用下,将中间体6上的羟基保护基团进行脱保护,得到中间体7;
(f)中间体7为原料,通过与式8所示的2,5-二羟基苯甲醛发生Mitsunobu反应,得到中间体9;
(g)以中间体9为原料,在碱性条件下与各种取代芳基卤化物R2-Cl反应,得到中间体10;
(h)以含醛基的中间体10为原料,与取代的N-乙酰基乙二胺进行还原胺化反应得到目标化合物Z1-Z4;
化合物4中的取代基R1、取代芳基卤化物R2-Cl中的取代基R2以及取代的N-乙酰基乙二胺中的取代基R3的定义同目标化合物中。
为了制备本发明通式II所述的化合物,依据通式II的结构,本发明制备通式II化合物将分为六步,中间体3与路线一中的中间体3相同(路线二)。
路线二:
(a)中间体3和中间体10进行Buckward偶联反应得到中间体11;
(b)中间体11在醋酸钯催化,高温下发生分子内N-芳香化反应直接关环生成中间体12;
(c)中间体12在四丁基氟化铵存在的条件下脱硅醚保护得到关键中间体13;
(d)中间体13为原料,通过与2,4-二羟基苯甲醛发生Mitsunobu反应,得到中间体15;(e)中间体15在碱性条件下与各种取代芳基卤化物R4-Cl反应,得到中间体16;
(f)以含醛基的中间体16为原料,与取代N-乙酰基乙二胺或取代氨基乙醇,进行还原胺化反应得到目标化合物Z5-Z9;中间体10中的取代基R1、取代芳基卤化物R4-Cl中的取代基R4以及取代的N-乙酰基乙二胺或取代氨基乙醇中的取代基R5的定义同目标化合物中。
本发明取得的有益效果是:目前靶向PD-L1蛋白的小分子化合物,多数是以联苯结构为母核,本发明专利中的咔唑甲基苯基醚类衍生物在化合物结构骨架上进行了突破,结构更为新颖,创新性更强,同时化合物Z8、Z9也显示出较好的生物活性。因此这一系列的咔唑甲基苯基醚类衍生物具备更高的开发潜力和研究价值。
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BrukerAV-400BrukerAV-600型核磁共振仪。质谱用ZAD-2F和VG300质谱仪。HPLC纯度测定方法:通过HPLC(高效液相色谱)分析确定化合物的纯度,并确认其纯度在96%以上。使用C18柱(InertSustainC18,4.6×250mm,5μm),Shimadzu LC-20A进行HPLC分析,在254nm进行UV检测。
实施例1:
N-{2-[2-(4-氟苯基氧基)-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z1)
(1)三异丙基-(4-硝基苄氧基)硅烷
在一个250mL的单口圆底烧瓶中,加入4-硝基苄醇(9.2g,60.1mmol,1.0eq),二氯甲烷(130mL),搅拌溶解后,加入咪唑(8.5g,126.2mmol,2.1eq),再缓慢滴加三异丙基氯硅烷(13.8g,72.2mmol,1.2eq),加料完毕后,体系出现白色沉淀,反应液由澄清变浑浊。反应室温搅拌过夜,TLC检测原料反应完全后,反应体系用水洗两遍,无水硫酸钠干燥,减压浓缩至干得粗品即中间体2:20.3克,不需要纯化,直接投下一步。
(2)4-三异丙基硅氧甲基苯胺
室温下,向250mL单颈圆底烧瓶中添加三异丙基-(4-硝基苄氧基)硅烷(中间体2)(17.2g,55.3mmol,1.0eq)、甲醇(100mL)和水(33mL),搅拌。向反应混合物中添加铁粉(9.2g,165.4mmol,3.0eq)和氯化铵(8.8mg,165.1mmol,3.0eq)。然后,将反应混合物加热至50℃持续反应8小时。TLC检测反应结束后,将反应混合物冷却至室温,并通过压制的硅藻土垫过滤。滤液减压浓缩至干,将残渣倒入水中并用DCM萃取(两次)。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥并浓缩得残余物,过柱纯化(洗脱剂:PE/EA=10:1,v/v)得产品即中间体3:14.5克,类白色固体,收率:93.5%。1H NMR(600MHz,Chloroform-d):δ7.19–7.15(m,2H),6.71–6.67(m,2H),4.75(s,2H),3.62(s,2H),1.24–1.15(m,3H),1.11(d,J=7.1Hz,18H).
(3)(2-溴-5-甲基苯基)-(4-三异丙基硅氧甲基苯基)胺
在一个50mL的单口圆底烧瓶中,加入醋酸钯(22.4mg,0.1mmol,0.05eq)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(86.8mg,0.15mmol,0.075eq),DMF(15mL),氮气置换两次后,室温搅拌20分钟。然后,加入4-三异丙基硅氧甲基苯胺(中间体3)(614.9mg,2.2mmol,1.1eq),1-溴-2-碘-4-甲基苯(化合物4)(593.8mg,2.0mmol,1.0eq),碳酸铯(912.2mg,2.8mmol,1.4eq),加料完毕后,氮气置换三次,升温至120℃反应4小时。TLC检测反应完成后,停止加热,反应体系降至室温,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,减压浓缩至干后,过柱纯化得产品即中间体5:731.9毫克,收率:81.6%。
(4)2-甲基-6-三异丙基硅氧甲基-9H-咔唑
在一个50mL的单口圆底烧瓶中,加入(2-溴-5-甲基苯基)-(4-三异丙基硅氧甲基苯基)胺(中间体5)(448.5mg,1.0mmol,1.0eq)和N,N-二甲基乙酰胺(12mL),搅拌溶解后,再加入碳酸钾(276.4mg,2.0mmol,2.0eq),醋酸钯(11.2mg,0.05mmol,0.05eq)和2-(二环己基膦基)联苯(CyJohnPhos)(35.0mg,0.1mmol,0.1eq),加料完毕后,反应体系用氮气置换三次,室温下搅拌15分钟后,再升温至130℃反应4小时。TLC检测反应完成后,停止加热,反应体系降至室温,加入水和乙酸乙酯,搅拌后静置分层,水相再用乙酸乙酯萃取两次。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,减压浓缩至干后得残渣,过柱纯化得产品即中间体6:205.1毫克,收率:55.8%。1H NMR(600MHz,Chloroform-d):δ8.04(d,J=1.6Hz,1H),7.96(d,J=7.9Hz,1H),7.89(d,J=22.7Hz,1H),7.44–7.35(m,2H),7.22(s,1H),7.08(dd,J=8.0,1.4Hz,1H),5.02(s,2H),2.55(s,3H),1.31–1.21(m,3H),1.16(d,J=7.3Hz,18H).
(5)(7-甲基-9H-咔唑-3-基)甲醇
室温下,向2-甲基-6-三异丙基硅氧甲基-9H-咔唑(即中间体6)(183.8mg,0.5mmol,1.0eq)的四氢呋喃(8mL)溶液中加入1M的TBAF水溶液(1.0ml,1.0mmol,2.0eq),加料完毕后,室温搅拌过夜。TLC检测显示原料反应完全后,减压蒸除溶剂,加入乙酸乙酯和水,搅拌5分钟后,静置分层,有机相再用水洗涤一次,无水硫酸钠干燥,浓缩至剩余少量溶剂时,加入10mL石油醚,搅拌20分钟后过滤,滤饼烘干后得白色固体即中间体7:97.4毫克,收率:92.2%。1H NMR(400MHz,DMSO-d6):δ11.05(s,1H),7.99–7.91(m,2H),7.38(d,J=8.2Hz,1H),7.30(dd,J=8.3,1.6Hz,1H),7.25(s,1H),6.96(dd,J=8.0,1.5Hz,1H),5.11(t,J=5.7Hz,1H),4.61(d,J=5.7Hz,2H),2.46(s,3H).
(6)2-羟基-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲醛
在一个带温度计和滴加装置的25mL三颈圆底烧瓶中,加入(7-甲基-9H-咔唑-3-基)甲醇(即中间体7)(422.6mg,2.0mmol,1.0eq),2,5-二羟基苯甲醛(303.8mg,2.2mmol,1.1eq)和三苯基膦(577.0mg,2.2mmol,1.1eq),再加入四氢呋喃(30mL),搅拌溶解后,冰浴降温至0℃,再缓慢滴加DIAD(444.8mg,2.2mmol,1.1eq),加料完毕后,缓慢升至室温反应过夜。TLC检测反应达到平衡后,反应液不用处理,直接过柱纯化得类白色固体即中间体9:64.9毫克,收率:9.8%。
(7)室温下,向中间体2-羟基-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲醛(即中间体9)(214mg,0.65mmol1.0eq),碳酸铯(274mg,0.84mmol,1.3eq),碘化钠(50mg,0.33mmol0.5eq)和不同的取代芳甲基氯衍生物(4-氟氯苄)(103mg,0.71mmol,1.1eq)的混合物中加入DMF(5.0mL)。加料完毕后,开搅拌,并将反应混合物加热至60℃保温反应两小时。TLC检测原料反应完全后,向反应混合物中加入饱和食盐水,体系中析出大量固体,过滤,滤饼烘干后得到中间体10,不用纯化,直接投下一步反应。
(8)N-{2-[2-(4-氟苯基氧基)-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z1)
室温下,向一个25mL的单口圆底烧瓶中加入中间体2-(4-氟苄氧基)-5-(7-甲基-9H-咔唑-3-基甲氧基)-苯甲醛(中间体10)(43.9mg,0.1mmol,1.0eq),N-(2-氨基乙基)-乙酰胺(20.4mg,0.2mmol,2.0eq)和DMF(2mL),搅拌溶解后,滴加1滴冰醋酸,搅拌20分钟后,加入氰基硼氢化钠(12.6mg,0.2mmol,2.0eq),室温搅拌过夜。薄层色谱(TLC)显示反应完成后,减压蒸除溶剂后得到残渣,制备HPLC纯化后得到目标化合物Z1:15.2mg,收率:28.1%,类白色固体。HPLC纯度:96.56%。1H NMR(400MHz,Chloroform-d):δ8.12(s,1H),8.07(d,J=1.3Hz,1H),7.95(d,J=8.0Hz,1H),7.45–7.36(m,4H),7.25(s,1H),7.13–7.04(m,3H),7.02–6.91(m,2H),6.87(d,J=8.9Hz,1H),6.50(s,1H),5.18(s,2H),5.03(s,2H),3.87(s,2H),3.30(q,J=5.5Hz,2H),2.74(t,J=5.4Hz,2H),2.54(s,3H),1.91(s,3H).
实施例2:
N-{2-[2-(3,5-二氟苯甲基氧基)-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z2).
用3,5-二氟苄氯代替同等摩尔量的4-氟氯苄,其他操作同实施例1,得类白色固体:10.2mg,收率:21.2%。HPLC纯度:96.32%。1H NMR(600MHz,Chloroform-d):δ8.09(s,2H),7.95(d,J=7.9Hz,1H),7.47–7.40(m,2H),7.26(s,1H),7.09(d,J=8.1Hz,1H),6.96(ddd,J=12.7,9.5,3.9Hz,3H),6.90(dd,J=8.8,3.1Hz,1H),6.83–6.75(m,2H),6.04(s,1H),5.19(s,2H),5.05(s,2H),3.83(s,2H),3.30(q,J=5.6Hz,2H),2.71(t,J=5.8Hz,2H),2.55(s,3H),1.94(s,3H).
实施例3:
N-{2-[2-(3-氟-苯甲基氧基)-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z3).
用间氟氯苄代替同等摩尔量的4-氟氯苄,其他操作同实施例1,得到类白色固体:14.4mg,收率:24.3%。HPLC纯度:95.78%。1H NMR(600MHz,Chloroform-d):δ8.24(s,1H),8.08–8.05(m,1H),7.94(d,J=7.9Hz,1H),7.50–7.29(m,3H),7.23(s,1H),7.18(dt,J=7.9,1.2Hz,1H),7.13(dt,J=9.5,2.1Hz,1H),7.07(dd,J=7.9,1.2Hz,1H),7.03(td,J=7.9,2.2Hz,1H),6.99(d,J=3.0Hz,1H),6.92(dd,J=8.8,3.0Hz,1H),6.83(d,J=8.9Hz,1H),6.50(s,1H),5.17(s,2H),5.06(s,2H),3.86(s,2H),3.30(q,J=5.5Hz,2H),2.72(dd,J=7.2,3.9Hz,2H),2.53(s,3H),1.91(s,3H).
实施例4:
N-{2-[2-苯甲基氧基-5-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z4).
用氯苄代替同等摩尔量的4-氟氯苄,其他操作同实施例1,得到类白色固体:9.3mg,收率:18.2%。HPLC纯度:96.22%。1H NMR(400MHz,Chloroform-d):δ8.19(s,1H),8.08(d,J=1.5Hz,1H),7.95(d,J=7.9Hz,1H),7.49–7.31(m,7H),7.24(s,1H),7.08(dd,J=8.1,1.4Hz,1H),6.98–6.86(m,3H),6.18(s,1H),5.18(s,2H),5.07(s,2H),3.81(s,2H),3.26(q,J=5.5Hz,2H),2.67(t,J=5.6Hz,2H),2.54(s,3H),1.90(s,3H).
目标化合物Z5-Z9的制备方法与Z1类似,区别在于用2,4-二羟基苯甲醛(化合物14)代替2,5-二羟基苯甲醛(化合物8)与中间体13进行Mitsunobu反应得到中间体15,再和不同的取代芳甲基氯衍生物进行亲核取代反应得到中间体16,最后再和适当的胺进行还原胺化反应即可得到目标化合物Z5-Z9。
实施例5:
N-{2-[2-(4-氟苯甲基氧基)-4-(7-甲基9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z5).
取代基R1为甲基,化合物15的制备方法重复实施例1中中间体9的制备过程,不同之处仅在于“将2,5-二羟基苯甲醛(化合物8)替换为同等摩尔量的2,4-二羟基苯甲醛(化合物14)”。
其次,将实施例1中间体10制备过程中的“中间体9原料替换成同等摩尔量的化合物15”,即得化合物16。
将实施例1目标化合物制备过程中的“中间体10原料替换成同等摩尔量的化合物16”,即得本实施例的目标化合物。得到灰白色固体:9.2mg,收率:16.1%。HPLC纯度:97.24%。1H NMR(500MHz,Chloroform-d):δ8.10(s,1H),8.03(s,1H),7.94(d,J=7.9Hz,1H),7.39–7.37(m,1H),7.37–7.32(m,2H),7.22–7.12(m,4H),7.12–7.06(m,1H),7.02(dd,J=11.3,6.7Hz,2H),6.66–6.54(m,2H),5.11(d,J=2.9Hz,4H),4.05(s,2H),3.43(s,2H),3.00(s,2H),2.54(s,3H),1.91(s,3H).
实施例6:
N-{2-[2-(3,5-二氟苯甲基氧基)-4-(7-甲基-9H-咔唑l-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z6).
取代基R1为甲基,化合物15的制备方法重复实施例2中中间体9的制备过程,不同之处仅在于“将2,5-二羟基苯甲醛(化合物8)替换为同等摩尔量的2,4-二羟基苯甲醛(化合物14)”。
其次,将实施例2中间体10制备过程中的“中间体9原料替换成同等摩尔量的化合物15”,即得化合物16。
将实施例2目标化合物制备过程中的“中间体10原料替换成同等摩尔量的化合物16”,即得本实施例的目标化合物。得到类白色固体:8.1mg,收率:12.8%。HPLC纯度:98.22%。1H NMR(500MHz,Chloroform-d):δ8.03(d,J=1.5Hz,1H),7.89(d,J=7.9Hz,1H),7.43–7.34(m,2H),7.30–7.23(m,2H),7.07(dt,J=8.1,2.1Hz,2H),6.99(dd,J=8.0,1.5Hz,1H),6.88(ddd,J=9.2,6.8,2.4Hz,1H),6.71(d,J=7.3Hz,2H),5.22(s,2H),5.15(s,2H),4.00(s,2H),3.35(dd,J=6.9,5.2Hz,2H),2.92(t,J=6.0Hz,2H),2.49(s,3H),1.89(s,3H).
实施例7:
N-{2-[2-(3-氟苯甲基氧基)-4-(7-甲基-9H-咔唑-3-基甲氧基)苯甲基氨基]乙基}乙酰胺(Z7).
取代基R1为甲基,化合物15的制备方法重复实施例3中中间体9的制备过程,不同之处仅在于“将2,5-二羟基苯甲醛(化合物8)替换为同等摩尔量的2,4-二羟基苯甲醛(化合物14)”。
其次,将实施例3中间体10制备过程中的“中间体9原料替换成同等摩尔量的化合物15”,即得化合物16。
将实施例3目标化合物制备过程中的“中间体10原料替换成同等摩尔量的化合物16”,即得本实施例的目标化合物。得到淡黄色固体:11.3mg,收率:21.2%。HPLC纯度:97.65%。1H NMR(500MHz,Chloroform-d):δ8.12(d,J=6.0Hz,1H),8.07(s,1H),7.95(d,J=7.9Hz,1H),7.47–7.34(m,4H),7.25(dt,J=1.5,0.8Hz,1H),7.21(d,J=8.0Hz,1H),7.11–7.04(m,3H),6.66–6.56(m,2H),5.16(s,2H),5.04(d,J=4.7Hz,2H),3.86(d,J=5.0Hz,2H),3.35(d,J=5.4Hz,2H),2.80(t,J=5.5Hz,2H),2.54(s,3H),1.93(d,J=2.8Hz,3H).
实施例8:
3-{5-(9H-咔唑-3-基甲氧基)-2-[(2-羟基-乙基氨基)甲基]苯氧基甲基}苯甲腈(Z8).
3-[5-(9H-咔唑-3-基甲氧基)-2-甲酰基苯氧基甲基]苯甲腈与2-氨基乙醇反应,制备条件参照实施例7(将相应的不同取代基中间体进行同等摩尔量替换),得到类白色固体:8.2mg,收率:16.1%。HPLC纯度:98.12%。1H NMR(500MHz,Methanol-d4):δ8.11(s,1H),8.05(d,J=7.8Hz,1H),7.86(d,J=1.7Hz,1H),7.77(d,J=7.8Hz,1H),7.67(dt,J=7.8,1.4Hz,1H),7.53(t,J=7.8Hz,1H),7.49–7.43(m,3H),7.42–7.33(m,2H),7.21–7.14(m,1H),6.84–6.76(m,2H),5.29(s,2H),5.24(s,2H),4.22(d,J=5.8Hz,2H),3.77(dd,J=6.1,4.4Hz,2H),3.12–3.05(m,2H).
实施例9:
2-{5-(9H-咔唑-3-基甲氧基)-2-[2-羟基乙基氨基)甲基]苯氧基甲基}异烟腈(Z9).
2-[5-(9H-咔唑-3-基甲氧基)-2-甲酰基苯氧基甲基]异烟腈与2-氨基乙醇反应,制备条件参照实施例7(将相应的不同取代基中间体进行同等摩尔量替换),得到类白色固体:5.3mg,收率:10.6%。HPLC纯度:98.36%。1H NMR(500MHz,Chloroform-d):δ8.79(d,J=2.1Hz,1H),8.73(d,J=1.9Hz,1H),8.15(d,J=2.3Hz,1H),8.01(s,1H),7.95(d,J=7.8Hz,1H),7.34(dt,J=32.0,7.9Hz,4H),7.24(d,J=8.4Hz,1H),7.20–7.05(m,2H),6.64(d,J=2.3Hz,2H),5.16(d,J=8.4Hz,4H),4.05(s,2H),3.67(t,J=5.2Hz,2H),2.98–2.89(m,2H).HRMS(ESI):exactmasscalculatedforC29H27N4O3[M+H]+479.2078,found479.2081.
化合物的药理活性:
1、体外活性评价化合物对PD-1与PD-L1相互作用的抑制活性:体外蛋白水平的检测方法采用Cisbio公司PD-1/PD-L1bindingassaykit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64ICP01PEG)简单描述如下,384孔白色酶标板,每孔加入4μlPD-1蛋白和4μlPD-L1蛋白,然后每孔再加入2μl稀释液或者用稀释液稀释的目标化合物,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后用多功能酶标仪检测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
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Claims (10)
1.如通式I所示的咔唑甲基苯基醚类衍生物及其立体异构体以及其可药用盐,
R1是下列一种:氢、C1-8饱和烷基、C1-5烷氧基;
R2是下列一种:R3是下列一种: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,取代基是氢、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、噁唑基或四氮唑基。
2.如通式II所示的咔唑甲基苯基醚类衍生物及其立体异构体以及其可药用盐,
R1是下列一种:氢、C1-8饱和烷基、C1-5烷氧基;
R4是下列一种:R5是下列一种: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,取代基是氢、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、噁唑基或四氮唑基。
3.根据权利要求2所述的咔唑甲基苯基醚类衍生物及其立体异构体以及其可药用盐,所述咔唑甲基苯基醚类衍生物为下列之一:
3-{5-(9H-咔唑-3-基甲氧基)-2-[(2-羟基-乙基氨基)甲基]苯氧基甲基}苯甲腈,
2-{5-(9H-咔唑-3-基甲氧基)-2-[2-羟基乙基氨基)甲基]苯氧基甲基}异烟腈,
4.根据权利要求1或2所述的咔唑甲基苯基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,为所述咔唑甲基苯基醚类衍生物与无机酸、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。
5.根据权利要求4所述的咔唑甲基苯基醚类衍生物及其立体异构体以及其可药用盐,其特征在于,所述的无机酸是盐酸、氢溴酸、磷酸或硫酸;所述的有机酸是甲磺酸、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;所述的碱金属离子是锂离子,钠离子或钾离子;所述的碱土金属离子是钙离子或镁离子;所述的能提供生理上可接受的阳离子的有机碱是甲胺、二甲胺、三甲胺、哌啶或吗啉。
6.制备权利要求1所述的咔唑甲基苯基醚类衍生物的方法,其特征在于,其制备路线如下:
(a)以式1所示的对硝基苯甲醇为原料,三异丙基氯硅烷作为保护基,进行保护硝基苯甲醇上的羟基的反应,得到中间体2;
(b)通过铁粉和氯化铵作为还原剂,将中间体2上的硝基还原成氨基得到中间体3;
(c)以中间体3和式4所示的4-溴-3-碘苯衍生物为原料,通过Buchward反应得到中间体5;
(d)中间体5在醋酸钯催化,高温下发生分子内N-芳香化反应直接关环生成中间体6;
(e)中间体6在四丁基氟化铵TBAF的作用下,将中间体6上的羟基保护基团进行脱保护,得到中间体7;
(f)中间体7为原料,通过与式8所示的2,5-二羟基苯甲醛发生Mitsunobu反应,得到中间体9;
(g)以中间体9为原料,在碱性条件下与各种取代芳基卤化物R2-Cl反应,得到中间体10;
(h)以含醛基的中间体10为原料,与取代的N-乙酰基乙二胺进行还原胺化反应得到目标化合物Z1-Z4;
化合物4中的取代基R1、取代芳基卤化物R2-Cl中的取代基R2以及取代的N-乙酰基乙二胺中的取代基R3的定义同目标化合物中。
7.制备权利要求2所述的咔唑甲基苯基醚类衍生物的方法,其特征在于,其制备路线如下:
(a)中间体3和中间体10进行Buckward偶联反应得到中间体11;
(b)中间体11在醋酸钯催化,高温下发生分子内N-芳香化反应直接关环生成中间体12;
(c)中间体12在四丁基氟化铵存在的条件下脱硅醚保护得到关键中间体13;
(d)中间体13为原料,通过与2,4-二羟基苯甲醛发生Mitsunobu反应,得到中间体15;
(e)中间体15在碱性条件下与各种取代芳基卤化物R4-Cl反应,得到中间体16;
(f)以含醛基的中间体16为原料,与取代N-乙酰基乙二胺或取代氨基乙醇,进行还原胺化反应得到目标化合物Z5-Z9;中间体10中的取代基R1、取代芳基卤化物R4-Cl中的取代基R4以及取代的N-乙酰基乙二胺或取代氨基乙醇中的取代基R5的定义同目标化合物中。
8.根据权利要求1-6任一项所述的咔唑甲基苯基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。
9.根据权利要求8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、感染性疾病或自身免疫性疾病。
10.根据权利要求9的应用,其特征在于,所述的癌症是皮肤癌、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、脑瘤或头颈癌;所述的感染性疾病是细菌感染或病毒感染;所述的自身免疫性疾病是器官特异性身免疫病或系统性身免疫病,其中,所述的器官特异性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、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或急性特发性多神经炎,所述的系统性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、硬皮病或自身免疫性溶血性贫血。
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