CN114292259A - 4-氨基酸侧链取代的喹唑啉衍生物及其应用 - Google Patents
4-氨基酸侧链取代的喹唑啉衍生物及其应用 Download PDFInfo
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- CN114292259A CN114292259A CN202111446817.8A CN202111446817A CN114292259A CN 114292259 A CN114292259 A CN 114292259A CN 202111446817 A CN202111446817 A CN 202111446817A CN 114292259 A CN114292259 A CN 114292259A
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Abstract
本发明公开了一类具有PI3K抑制活性的6‑(吡啶‑4‑基)‑4‑取代氨基的喹唑啉和喹啉类化合物，其为具式(I)结构的化合物或其药学上可接受的盐的溶剂合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物，包括外消旋混合物。该类化合物对PI3K具有良好的抑制作用，展现出良好的抗肿瘤效果，具有制备用于治疗对PI3Kδ和/或PI3Kα有响应的疾病的药物的前景。本发明还涉及这些化合物可以作为PI3K抑制剂的医药用途。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种4-氨基酸侧链取代的喹唑啉衍生物及其应用。
背景技术
随着人们对PI3K功能和作用的认识，发现PI3K在自身免疫性疾病，实体瘤和血液瘤的 发生发展中起着关键作用，以PI3K为靶点的抑制剂有望成为新的抗肿瘤药物，在临床中发挥 重要作用。
PI3K(磷脂酰肌醇-3-激酶)是一种脂激酶家族成员，是PI3K/AKT/mTOR信号通路的重 要组成部分。PI3K研究最广泛的为I类PI3K，可分为PI3Kα，PI3Kβ，PI3Kδ和PI3Kγ。PI3Kα的突变与恶性肿瘤有关；PI3Kβ能够激活血小板，与血栓性疾病的发展有关，并且在PTEN缺失的肿瘤中，PI3Kβ会促进肿瘤的恶变；PI3Kγ和PI3Kδ主要存在于B细胞中，与血液瘤，自身免疫性疾病密切有关；PI3K信号异常包括PIK3CA、PIK3CB、AKT基因的突变和扩增以及PTEN负调控功能的丧失等，与多种肿瘤包括前列腺癌、乳腺癌、子宫内膜癌、肺癌、肝癌、 结肠癌、血液瘤、淋巴瘤等的发生发展密切相关。特别是对PI3Kδ的抑制作用在众多血液瘤如CLL,ALL,MCL,FL,NHL,MM,BCL,DLBCL中有效。因此开发PI3K抑制剂前景看好。
idelalisib(CAL-101)是第一个被批准的PI3K抑制剂，对PI3Kδ具有选择性抑制作用， 2014年被FDA批准用于CLL,NHL和SLL的治疗。另一个PI3K抑制剂copanlisib(BAY 80-6946) 也在近日被FDA批准上市，用于治疗滤泡性淋巴瘤，copanlisib是一个泛PI3K抑制剂，对PI3Kα， PI3Kβ，PI3Kδ和PI3Kγ都具有非常强的抑制作用。另外的PI3K抑制剂包括dactolisib(BEZ-235)， GDC-0941,duvelisib等仍在研发中。目前PI3K抑制剂的价值并未被完全开发，适应症仅仅在 个别血液瘤的治疗上。因此，仍需大力开发新的PI3K抑制剂，扩展其适应症，满足临床需求。
其中，idelalisib(CAL-101)、copanlisib(BAY 80-6946)和dactolisib(BEZ-235)的结构式如 下：
发明内容
为了克服上述现有技术的缺点，本发明的目的在于提供一种4-氨基酸侧链取代的喹唑啉衍 生物及其应用，该类化合物对PI3Kδ和/或PI3Kα具有良好的抑制作用，展现出良好的抗肿瘤 效果。
为了达到上述目的，本发明采用以下技术方案予以实现：
本发明公开了一种4-氨基酸侧链取代的喹唑啉衍生物，为式(I)所示化合物及其溶剂合 物、对映异构体、非对映异构体、互变异构体和对映异构体的任意比例的混合物中的一种，或 者式(I)所示化合物药学上可接受的盐及其溶剂合物、对映异构体、非对映异构体、互变异 构体或对映异构体的任意比例的混合物中的一种；
所述式(I)化合物的结构式为：
其中，X为CH或者N；
R1为氢、氰基、硝基或三氟甲基；
R2为烷基；
R3与R4各自独立的为氢、烷基、环烷基、杂环烷基，其任选地被0个或1个以下基团所取代：异丙基、苯基、吗啉基或二乙氨基；
或者R3、R4与他们相连的N一起形成3至8元饱和或不饱和单杂环，其任选地被0个或1个以下基团所取代：烷基、环烷基。
优选地，R2为甲基、乙基、异丙基、叔丁基或苄基；R1为氢、氰基、硝基或三氟甲基。
优选地，当R3为氢时，R4为甲基、乙基、丙基、丁基、异丙基、环戊基或哌啶基，R4可进一步被异丙基、苯基、吗啉基或二乙氨基所取代。
优选地，当R3与R4成环时，R3与R4连接成吡咯烷环或哌啶环，哌啶环可进一步被甲基 取代。
优选地，式(I)化合物的结构式选自下列化合物中的一个：
本发明还公开了基于上述4-氨基酸侧链取代的喹唑啉衍生物在制备药物中的应用，所述药 物为用于治疗对PI3Kδ和/或PI3Kα有响应的疾病的药物。
优选地，所述对PI3Kδ和/或PI3Kα有响应的疾病为自身免疫性疾病。
优选地，所述自身免疫性疾病为癌症、内风湿性关节炎、红斑狼疮或多样性硬化症。
进一步优选地，所述癌症为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、 慢性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤、B细胞淋 巴瘤、T细胞淋巴瘤和弥散性大B细胞淋巴瘤中的一种。
优选地，所述癌症为前列腺癌、乳腺癌、子宫内膜癌、肺癌、肝癌、结肠癌、胰腺癌和肾 癌中的一种。
与现有技术相比，本发明具有以下有益效果：
本发明提供的4-氨基酸侧链取代的喹唑啉衍生物，通过对其进行PI3Kδ激酶活性测定实 验，证明本发明提供的优选化合物相比阳性药Idelalisib，对PI3Kδ激酶活性的抑制作用更强； 通过对PI3K激酶选择性活性实验，证明本发明化合物对PI3K的四种激酶(PI3Kα，PI3Kβ， PI3Kδ和PI3Kγ)均有明显的抑制作用；通过肿瘤细胞体外细胞增殖测定实验，证明本发明优 选化合物对SU-DHL-6细胞具有很强的抑制活性，具有良好的抗人淋巴瘤作用。
本发明提供的4-氨基酸侧链取代的喹唑啉衍生物在制备药物中的应用，其能够利用该类化 合物对PI3K的抑制作用，尤其是对不同亚型的PI3K的抑制作用，制备治疗对PI3Kδ和/或PI3Kα 有响应的疾病的药物，特别是制备抗肿瘤药物，为病人和医生提供更多的临床选择。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案，下面将对本发明实施例中的技术方案进 行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分的实施例，而不是全部的实 施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所 有其他实施例，都应当属于本发明保护的范围。
需要说明的是，本发明的说明书和权利要求书是用于区别类似的对象，而不必用于描述特 定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换，以便这里描述的本发 明的实施例能够以除了在这里描述的那些以外的顺序实施。此外，术语“包括”和“具有”以及他 们的任何变形，意图在于覆盖不排他的包含，例如，包含了一系列步骤或单元的过程、方法、 系统、产品或设备不必限于清楚地列出的那些步骤或单元，而是可包括没有清楚地列出的或对 于这些过程、方法、产品或设备固有的其它步骤或单元。
下面对本发明做进一步详细描述，所述是对本发明的解释而不是限定：
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
“烷基”指饱和的脂族烃基团。包括1至12个碳原子的直链或支链基团。优选含有1至10 个碳原子的中等大小烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基 等。更优选的是含有1至6个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。
“环烷基”指3至8元全碳单环、全碳5元/6元或6元/6元稠和环或多环稠和环(“稠和”环 意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个环具 有完全连接的π电子系统，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、 环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。
“烷氧基”表示-O-(未取代的烷基)和-O(未取代的环烷基)。代表性的实例包括但不限于 甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“单杂环”表示含有一个杂原子的单环基团，在环中具有3到6个环原子，其中一个杂原子 选自N、O，其余环原子是C。杂环烷基包括并不限于四氢吡喃基、吗啉基、吡咯烷基、四氢 呋喃基、哌啶基、哌嗪基等。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：(1) 与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、 硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、 己酸、对甲苯磺酸、水杨酸等。(2)存在于母体化合物中的酸性质子被金属离子代替或者与有 机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙 醇胺、二乙醇胺、三乙醇胺等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、 水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给 药给动物的过程。
“药用载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性 质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露 醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝 胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、 玉米油、花生油等。
前述的药物组合物中，除了包括药学上可接受的载体外，还可以包括在药(剂)学上常用 的辅剂，例如：抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面 活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、 香精或它们的结合等。
1、合成化合物1-24的具体实施例 代表性化合物的结构式、编号如下：
下面给出上述化合物合成的实施例： 实施例1
(S)-2-((6-溴-4-喹唑啉基)氨基)-N-丁基丙酰胺(中间体1-d)
向10mL的圆底烧瓶中加入4-氯-6-溴喹唑啉(200mg,0.83mmol)，中间体1-c(151mg,1.0 mmol),N,N-二异丙基乙胺(160mg,1.24mmol)和异丙醇10mL，体系加热搅拌回流2h，TLC 显示反应完全，冷却至室温，将异丙醇蒸干，加入饱和NaCl溶液，乙酸乙酯萃取三次，使用 无水Na2SO4干燥，柱色谱分离得到白色固体粉末122mg，收率54.2％。1H NMR(400MHz, CDCl3)δ8.60(s,1H Ar-H),7.90(d,J＝2.0Hz,1H Ar-H),7.65(dd,J＝8.9,2.0Hz,1H Ar-H),7.48 (d,J＝8.9Hz,1H Ar-H),6.34(s,1H NH),4.80(t,J＝7.0Hz,1HCH),3.46–3.34(m,2H CH2), 1.63(d,J＝7.1Hz,3H CH3),1.58(dd,J＝15.0,7.4Hz,2HCH2),1.46–1.34(m,2H CH2),0.96(t, J＝7.3Hz,3H CH3).
(S)-N-丁基-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰胺(化合物1)
取中间体(S)-2-((6-溴-4-喹唑啉基)氨基)-N-丁基丙酰胺(280mL，0.80mmol)、2-甲氧基-5-吡啶硼酸(184mg，1.20mmol)、Na2CO3(170mg，1.60mmol)、PdCl2(dppf)(71 mg，0.097mmol)，乙二醇二甲醚(8mL)和H2O(2mL)N2保护，加热回流约2.5h，TLC 显示反应完全。待冷却后减压蒸干柱色谱分离得到白色固体65mg，收率63.4％。1H NMR(400 MHz,CDCl3)δ8.38(d,J＝2.3Hz,1H Ar-H),8.18(s,1H NH),8.11(d,J＝6.2Hz,1H Ar-H),7.86 –7.77(m,2H Ar-H),7.70(dd,J＝8.7,1.8Hz,1H Ar-H),7.54(d,J＝8.6Hz,1H Ar-H),6.78(d,J＝8.6Hz,1H Ar-H),6.40(t,J＝5.5Hz,Ar-H),4.73(t,J＝7.0Hz,1H CH),3.97(s,3H OCH3),3.55 (ddd,J＝13.6,6.8Hz,1H),3.29(ddd,J＝13.8,6.9,2.0Hz,1H),1.62(d,J＝7.2Hz,3HCH3),1.59 –1.51(m,2H CH2),1.38(dd,J＝15.0,7.4Hz,2H CH2),0.94(t,J＝7.3Hz,3HCH3).ESI-MS m/z: 380.2[M+H]+.
实施例2
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-异丙基丙酰胺(中间体2-d)
制备方法同中间体1-d，收率63.7％。1H NMR(400M Hz,CDCl3)δ8.59(s,1H Ar-H),7.92 (d,J＝1.9Hz,1H Ar-H),7.67(dd,J＝8.9,2.0Hz,1H Ar-H),7.51(d,J＝8.9Hz,1HAr-H),6.09(s, 1H NH),4.75(t,J＝6.9Hz,1H CH),4.17(dd,J＝14.1,6.6Hz,1H CH),1.59(d,J＝7.0Hz,3H CH3),1.23(dt,J＝9.8,4.9Hz,6H CH3×2).
(S)-N-异丙基-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰胺(化合物2)
制备方法同化合物1，收率45％。1H NMR(400MHz,DMSO-d6)δ8.68(dd,J＝6.0,1.8Hz, 2H Ar-H),8.39(d,J＝6.8Hz,2H NH),8.19(dd,J＝8.7,2.5Hz,1H Ar-H),8.09(dd,J＝8.7,1.6Hz, 1H Ar-H),7.94(d,J＝7.8Hz,1H Ar-H),7.71(d,J＝8.6Hz,1H Ar-H),6.98(d,J＝8.6Hz,1H Ar-H),4.78(t,J＝7.2Hz,1H CH),3.92(s,3H OCH3),3.86(dd,J＝13.8,6.8Hz,1H CH),1.45(d, J＝7.1Hz,3H CH3),1.06(dd,J＝13.6,6.6Hz,6H CH3×2).ESI-MSm/z:366.1[M+H]+.
实施例3
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-丙基丙酰胺(中间体3-d)
制备方法同中间体1-d，收率53.2％。1H NMR(400MHz,CDCl3)δ8.68(s,1H Ar-H),8.11– 8.05(m,1H Ar-H),7.95(d,J＝1.9Hz,1H NH),7.81(dd,J＝8.9,2.0Hz,1H Ar-H),7.70(d,J＝8.8Hz,1H Ar-H),5.03(t,J＝7.1Hz,1H CH),3.90(s,3H CH3),1.66(d,J＝7.2Hz,3H CH3),1.28 (s,2H CH2),0.15–0.05(m,2H CH2).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-N-丙基丙酰胺(化合物3)
制备方法同化合物1，收率52.2％。1H NMR(400MHz,DMSO-d6)δ8.70(s,2H Ar-H),8.41 (s,2H Ar-H),8.20(d,J＝5.2Hz,1H Ar-H),8.14–8.01(m,2H Ar-H),7.73(d,J＝7.8Hz,1H Ar-H),6.99(d,J＝8.2Hz,1H Ar-H),4.79(s,1H CH),3.92(s,3H OCH3),3.04(s,2H CH2),1.53– 1.44(m,3H CH3),1.40(d,J＝6.7Hz,2H CH2),0.82(d,J＝2.5Hz,3H CH3).ESI-MS m/z:366.1 [M+H]+.
实施例4
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-(2-(二乙基氨基)乙基)丙酰胺(中间体4-d)
制备方法同中间体1-d，收率54.0％。1H NMR(400MHz,CDCl3)δ8.58(d,J＝7.3Hz,1HAr-H),8.17(dd,J＝13.4,1.8Hz,1H Ar-H),7.73(dd,J＝8.9,2.0Hz,1H Ar-H),7.61(dd,J＝17.8, 8.9Hz,1H Ar-H),7.33(S,1H NH),3.74(s,1H CH),3.55–3.41(m,4H CH2×2),3.04(dd,J＝25.2, 18.2Hz,6H CH3×2),1.60(d,J＝7.2Hz,4H CH2×2),1.25(dd,J＝13.2,6.3Hz,3H CH3).
(S)-N-(2-(二乙基氨基)乙基)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰胺(化合物4)
制备方法同化合物1，收率43.7％。1H NMR(400MHz,DMSO-d6)δ8.78(s,1H Ar-H),8.71 (d,J＝2.3Hz,1H Ar-H),8.51(d,J＝6.6Hz,1H NH),8.46(s,1H NH),8.37(s,1H Ar-H),8.24(dd, J＝8.7,2.5Hz,1H Ar-H),8.15(dd,J＝8.7,1.5Hz,1H Ar-H),7.77(d,J＝8.6Hz,1H Ar-H),7.00(d, J＝8.6Hz,1H Ar-H),4.81–4.75(m,1H CH),3.92(s,3H OCH3),3.14(d,J＝7.1Hz,4H CH2×2), 1.51(d,J＝7.2Hz,4H CH2×2),1.16(t,J＝7.0Hz,9H CH3×3).ESI-MS m/z:423.2[M+H]+.
实施例5
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-(2-吗啉代乙基)丙酰胺(中间体5-d)
制备方法同中间体1-d，收率44.0％。1H NMR(400MHz,CDCl3)δ8.55(s,1H Ar-H),7.92(d, J＝1.9Hz,1H NH),7.66(dd,J＝8.9,2.0Hz,1H Ar-H),7.47(dd,J＝17.4,7.8Hz,2H Ar-H),4.88– 4.77(m,1H CH),3.73(t,J＝4.5Hz,3H CH3),3.56(d,J＝5.8Hz,2H CH2),3.47(d,J＝5.5Hz,2H CH2),2.64(t,J＝5.8Hz,4H CH2×2),2.57(d,J＝3.6Hz,4H CH2×2).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-N-(2-吗啉代乙基)(化合物5)
制备方法同化合物1，收率33.2％。1H NMR(400MHz,DMSO-d6)δ8.73–8.68(m,2H Ar-H), 8.43(s,1H NH),8.39(d,J＝7.1Hz,1H NH),8.20(dd,J＝8.7,2.5Hz,1H Ar-H),8.12(dd,J＝8.7, 1.6Hz,1H Ar-H),7.94(t,J＝5.5Hz,1H Ar-H),7.74(d,J＝8.7Hz,1H Ar-H),6.99(d,J＝8.6Hz, 1H Ar-H),4.79(t,J＝7.1Hz,1H CH),3.92(s,3H OCH3),3.43(s,4H CH2×2),3.17(dq,J＝13.4, 6.8Hz,2H CH2),2.33–2.25(m,6H CH2×3),1.47(d,J＝7.2Hz,3HCH3).ESI-MS m/z:437.2[M +H]+.
实施例6
(S)-N-苄基-2-((6-溴喹唑啉-4-基)氨基)丙酰胺(中间体6-d)
制备方法同中间体1-d，收率65.3％。1H NMR(400MHz,CDCl3)δ8.59(s,1H Ar-H),7.92(d, J＝2.0Hz,1H Ar-H Ar-H),7.62(dd,J＝8.9,2.0Hz,1H Ar-H),7.43(d,J＝8.9Hz,1H Ar-H),7.37 (d,J＝4.1Hz,4H Ar-H),7.33(dd,J＝4.9,3.6Hz,1H Ar-H),7.28(s,1HNH),4.84(t,J＝7.0Hz, 1H CH),4.63(dt,J＝14.9,7.6Hz,2H CH2),1.68(d,J＝7.1Hz,3HCH3).
(S)-N-苄基-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰胺(化合物6)
制备方法同化合物1，收率63.4％。1H NMR(400MHz,DMSO-d6)δ8.72(dd,J＝19.8,2.0Hz, 2H Ar-H),8.62(t,J＝6.1Hz,1H Ar-H),8.49(s,1H NH),8.42(d,J＝6.8Hz,1HNH),8.21(dd,J＝ 8.7,2.6Hz,1H Ar-H),8.13(dd,J＝8.7,1.8Hz,1H Ar-H),7.77(d,J＝8.7Hz,1H Ar-H),7.32– 7.24(m,4H Ar-H),7.23–7.17(m,1H Ar-H),7.00(d,J＝8.6Hz,1HAr-H),4.90–4.77(m,1H CH), 4.31(dd,J＝5.8,3.0Hz,2H CH2),3.93(s,3H OCH3),1.54(d,J＝7.2Hz,3H CH3).ESI-MS m/z: 414.1[M+H]+.
实施例7
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-(1-异丙基哌啶-4-基)丙酰胺(中间体7-d)
制备方法同中间体1-d，收率72.4％。1H NMR(400MHz,CDCl3)δ8.57(s,1H Ar-H),7.96(d, J＝1.9Hz,1H Ar-H),7.67(q,J＝7.0Hz,1H NH),7.53–7.47(m,2H Ar-H),6.48(d,J＝7.7Hz,1H NH),4.78(t,J＝7.0Hz,1H CH),3.90(dd,J＝7.2,3.5Hz,1H CH),2.85(d,J＝6.5Hz,3H CH3), 2.33(dd,J＝23.2,14.3Hz,4H CH2×2),2.03(t,＝11.0Hz,4H CH2×2),1.07(t,J＝5.4Hz,6H CH3×2).
(S)-N-(1-异丙基哌啶-4-基)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰 胺(化合物7)
制备方法同化合物1，收率63.4％。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H Ar-H),8.71(s, 1H Ar-H),8.25–8.20(m,1H NH),8.15(d,J＝8.6Hz,1H Ar-H),7.76(d,J＝8.7Hz,1H Ar-H),7.70 (d,J＝8.2Hz,1H Ar-H),7.56(t,J＝7.6Hz,1H Ar-H),7.00(d,J＝8.6Hz,1H Ar-H),4.78(td,J＝ 13.8,6.8Hz,2H CH×2),3.92(s,3H CH3),3.84(s,1H CH),1.77–1.99(m,8H CH2×4),1.47(s,3H CH3),1.24(s,6H CH3×2).ESI-MS m/z:449.2[M+H]+.
实施例8
(S)-2-((6-溴喹唑啉-4-基)氨基)-1-(吡咯烷-1-基)丙-1-酮(中间体8-d)
制备方法同中间体1-d，收率67.7％。1H NMR(400MHz,CDCl3)δ8.51(s,1H Ar-H),8.37(s, 1H NH),7.88(d,J＝2.0Hz,1H Ar-H),7.54(dd,J＝8.9,2.1Hz,1H Ar-H),7.34(d,J＝8.9Hz,1H Ar-H),5.04(p,J＝6.9Hz,1H Ar-H),4.11(dt,J＝9.9,6.9Hz,1H CH),3.88–3.78(m,2H CH2), 3.63–3.48(m,2H CH2),2.17–2.04(m,2H CH2),2.02–1.91(m,2H CH2),1.61(d,J＝7.0Hz,3H CH3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-1-(吡咯烷-1-基)丙-1-酮(化 合物8)
制备方法同化合物1，收率77.2％。1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝7.1Hz,1HAr-H),8.63–8.56(m,2H Ar-H),8.30(s,1H NH),8.14(dd,J＝8.7,2.5Hz,1H Ar-H),8.02(dd,J＝ 8.7,1.6Hz,1H Ar-H),7.63(d,J＝8.7Hz,1H Ar-H),6.95(d,J＝8.6Hz,1H Ar-H),5.02(t,J＝7.1 Hz,1H CH),3.91(s,3H OCH3),3.78–3.51(m,2H CH2),3.39–3.27(m,2HCH2),1.93(dd,J＝ 13.3,6.7Hz,2H CH2),1.81(dd,J＝13.4,6.7Hz,2H CH2),1.44(d,J＝7.0Hz,3H CH3).ESI-MS m/z:378.1[M+H]+.
实施例9
(S)-2-((6-溴喹唑啉-4-基)氨基)-N-环戊基丙酰胺(中间体9-d)
制备方法同中间体1-d，收率47.8％。1H NMR(400MHz,CDCl3)δ8.54(s,1H Ar-H),7.90(d, J＝1.9Hz,1H NH),7.80(d,J＝6.6Hz,1H Ar-H),7.61(dd,J＝8.9,2.0Hz,1H Ar-H),7.42(d,J＝ 8.9Hz,1H Ar-H),4.73(t,J＝7.0Hz,1H CH),4.29(dd,J＝13.5,6.6Hz,1HCH),2.07–1.95(m, 2H CH2),1.72–1.60(m,4H CH2×2),1.58(d,J＝7.1Hz,2H CH2),1.52–1.44(m,3H CH3).
(S)-N-环戊基-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)丙酰胺(化合物9)
制备方法同化合物1，收率55.3％。1H NMR(400MHz,DMSO-d6)δ8.69(dd,J＝6.7,1.7Hz, 2H Ar-H),8.40(s,1H NH),8.36(t,J＝8.1Hz,1H Ar-H),8.20(dd,J＝8.7,2.6Hz,1H Ar-H),8.10 (dd,J＝8.7,1.7Hz,1H),8.02(d,J＝7.3Hz,1H NH),7.72(d,J＝8.7Hz,1HAr-H),6.98(dd,J＝ 8.6,2.9Hz,1H Ar-H),4.80(t,J＝7.2Hz,1H CH),4.00(dd,J＝13.4,6.6Hz,1H CH),3.92(s,3H OCH3),1.77(dt,J＝10.7,6.2Hz,2H CH2),1.62(dt,J＝8.2,5.5Hz,2H CH2),1.52–1.46(m,2H CH2),1.44(d,J＝7.2Hz,3H CH3),1.41–1.32(m,2H CH2).ESI-MS m/z:392.2[M+H]+.
实施例10
(S)-2-((6-溴喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)丙-1-酮(中间体10-d)
制备方法同中间体1-d，收率56.8％。1H NMR(400MHz,CDCl3)δ8.55(s,1H Ar-H),7.89(d, J＝1.9Hz,1H NH),7.77(d,J＝5.9Hz,1H Ar-H),7.65(dd,J＝8.9,2.0Hz,1H Ar-H),7.48(d,J＝ 8.9Hz,1H Ar-H),5.25(t,J＝6.8Hz,1H CH),3.96–3.73(m,2H CH2),3.68(dd,J＝9.5,3.6Hz, 2H CH2),2.61–2.47(m,4H CH2×2),2.37(s,3H CH3),1.53(d,J＝6.9Hz,3H CH3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)丙-1-酮 (化合物10)
制备方法同化合物1，收率52.2％。1H NMR(400MHz,DMSO-d6)δ8.70(dd,J＝15.7,1.9 Hz,2H Ar-H),8.52(d,J＝7.3Hz,1H Ar-H),8.43(s,1H NH),8.19(dd,J＝8.7,2.6Hz,1H Ar-H), 8.11(dd,J＝8.7,1.7Hz,1H Ar-H),7.73(d,J＝8.7Hz,1H Ar-H),6.98(d,J＝8.7Hz,1H Ar-H), 5.30(t,J＝7.1Hz,1H CH),3.91(s,3H OCH3),3.66–3.42(m,4H CH2×2),2.40–2.21(m,4H CH2×2),2.16(s,3H CH3),1.40(d,J＝6.9Hz,3H CH3).ESI-MS m/z:407.2[M+H]+.
实施例11
(S)-2-((6-(5-氰基-6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-N-(2-吗啉代乙基)丙 酰胺(化合物11)
制备方法同化合物5，收率33.4％。1H NMR(400MHz,DMSO-d6)δ8.97(d,J＝2.5Hz,1HAr-H),8.72(dd,J＝7.3,2.0Hz,2H Ar-H),8.43(s,1H NH),8.34(d,J＝7.2Hz,1H Ar-H),8.18(dd, J＝8.7,1.7Hz,1H Ar-H),8.00(t,J＝5.5Hz,1H Ar-H),7.77–7.72(m,J＝8.7Hz,1H Ar-H),4.81 (t,J＝7.2Hz,1H CH),4.07(s,3H OCH3),3.45(s,4H CH2×2),3.20(dt,J＝12.6,6.8Hz,2H CH2), 2.32(d,J＝6.5Hz,6H CH2×3),1.49(d,J＝7.2Hz,3H CH3).ESI-MSm/z:262.2[M+H]+.
实施例12
(S)-2-((6-(5-氰基-6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-N-(2-(二乙氨基)乙 基)丙酰胺(化合物12)
制备方法同化合物4，收率43.3％。1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝2.4Hz,1HAr-H),8.75(d,J＝2.3Hz,2H Ar-H),8.46(s,1H NH),8.37(d,J＝6.6Hz,1H Ar-H),8.23–8.17 (m,2H Ar-H),7.77(d,J＝8.7Hz,1H NH),4.85–4.76(m,1H CH),4.07(s,3H OCH3),2.83(s, 6H CH2×3),1.91(s,2H CH2),1.50(d,J＝7.2Hz,3H CH3),1.04(t,J＝7.0Hz,6HCH3×2). ESI-MS m/z:448.2[M+H]+.
实施例13
(S)-2-甲氧基-5-(4-((1-(4-甲基哌嗪-1-基)-1-氧代丙烷-2-基)氨基)喹唑啉-6-基) 烟腈(化合物13)
制备方法同化合物10，收率37.3％。1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝2.5Hz,1H Ar-H),8.70(d,J＝2.5Hz,2H Ar-H),8.48–8.40(m,2H Ar-H),8.15(dd,J＝8.7,1.6Hz,1H Ar-H),7.73(d,J＝8.7Hz,1H NH),5.31(t,J＝7.1Hz,1H CH),4.07(s,3H OCH3),3.68–3.43(m, 4H CH2×2),3.36(s,3H CH3),2.31(d,J＝36.1Hz,4H CH2×2),2.18(s,3H CH3).ESI-MS m/z: 432.2[M+H]+.
实施例14
(S)-2-((6-(6-甲氧基-5-(三氟甲基)吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌 嗪-1-基)丙-1-酮(化合物14)
制备方法同化合物10，收率47.7％。1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝2.0Hz,1H Ar-H),8.73(d,J＝1.5Hz,1H Ar-H),8.49(d,J＝7.4Hz,1H Ar-H),8.46(d,J＝2.1Hz,1HAr-H), 8.43(s,1H Ar-H),8.18(dd,J＝8.7,1.8Hz,1H Ar-H),7.74(d,J＝8.7Hz,1H NH),5.30(t,J＝7.1 Hz,1H CH),4.06(s,3H OCH3),3.69–3.48(m,4H CH2×2),2.28–2.36(m,Hz,4H CH2×2),2.18(s, 3H CH3),1.42(d,J＝6.9Hz,3H).ESI-MS m/z:475.2[M+H]+.
实施例15
(S)-2-((6-(6-甲氧基-5-硝基吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基) 丙-1-酮(化合物15)
制备方法同化合物10，收率52.6％。1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝2.2Hz,1H Ar-H),8.83(d,J＝2.2Hz,1H Ar-H),8.74(d,J＝1.2Hz,1H Ar-H),8.50(d,J＝7.3Hz,1HAr-H), 8.43(s,1H Ar-H),8.18(dd,J＝8.7,1.6Hz,1H Ar-H),7.75(d,J＝8.7Hz,1H NH),5.31(t,J＝7.1 Hz,1H CH),4.10(s,3H OCH3),3.67–3.53(m,4H CH2×2),2.40(d,J＝37.3Hz,4H CH2×2),2.24 (s,3H CH3),1.43(d,J＝6.9Hz,3H CH3).ESI-MS m/z:452.2[M+H]+.
实施例16
(S)-2-((6-溴喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)丁-1-酮(中间体16-d)
制备方法同中间体1-d，收率48.4％。1H NMR(400MHz,CDCl3)δ8.53(s,1H Ar-H),7.86(d, J＝2.0Hz,1H NH),7.77(d,J＝5.6Hz,1H Ar-H),7.62(dd,J＝8.9,2.1Hz,1H Ar-H),7.45(d,J＝ 8.9Hz,1H Ar-H),5.24(d,J＝5.7Hz,1H CH),3.95–3.80(m,3H CH3),3.78–3.66(m,4H CH2×2), 2.58–2.46(m,4H CH2×2),2.08–1.96(m,2H CH2),1.92–1.77(m,3HCH3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)丁-1-酮 (化合物16)
制备方法同化合物10，收率40.3％。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H Ar-H),8.67 (d,J＝2.2Hz,1H Ar-H),8.46(d,J＝8.2Hz,1H Ar-H),8.42(s,1H Ar-H),8.18(dd,J＝8.6,2.4Hz, 1H Ar-H),8.09(dd,J＝8.7,1.3Hz,1H Ar-H),7.73(d,J＝8.7Hz,1H Ar-H),6.99–6.94(m,J＝8.6 Hz,1H NH),5.20(dd,J＝14.0,7.6Hz,1H CH),3.91(s,3H OCH3),3.75–3.46(m,4H CH2×2), 2.35(s,2H CH2),2.25(s,2HCH2),2.16(s,3H CH3),1.80–1.90(m,2H CH2),0.98(t,J＝7.3Hz, 3H CH3).ESI-MS m/z:421.2[M+H]+.
实施例17
(S)-2-((6-溴喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)己-1-酮(中间体17-d)
制备方法同中间体1-d，收率32.9％。1H NMR(400MHz,CDCl3)δ8.51(s,1H Ar-H),7.83(d, J＝2.0Hz,1H NH),7.56(dd,J＝8.9,2.0Hz,2H Ar-H),7.37(d,J＝8.9Hz,1H Ar-H),5.32–5.19 (m,1H CH),3.96–3.62(m,3H CH3),2.63(d,J＝4.2Hz,2H CH2),2.54(d,J＝7.3Hz,4H CH2×2), 1.96-2.38(m,4H CH2×2),1.73–1.90(m,4H CH2×2),1.49–1.26(m,3HCH3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)己-1-酮 (化合物17)
制备方法同化合物10，收率33.6％。1H NMR(400MHz,DMSO-d6)δ8.75(s,1H Ar-H),8.68 (d,J＝2.2Hz,1H Ar-H),8.49–8.40(m,2H Ar-H),8.20(dd,J＝8.6,2.4Hz,1H)Ar-H,8.11(d,J＝ 7.6Hz,1H Ar-H),7.73(d,J＝8.6Hz,1H Ar-H),6.98(d,J＝8.6Hz,1H NH),5.28(q,J＝7.2Hz, 1H CH),3.92(s,3H OCH3),3.58–3.72(s,2H CH2),3.45–3.54(m,2HCH2),2.36(s,2H CH2), 2.25(s,2H CH2),2.17(s,3H CH3),1.86–1.78(m,J＝7.2Hz,2HCH2),1.36(ddd,J＝12.4,11.0, 5.8Hz,4H CH2×2),0.86(t,J＝6.9Hz,3H CH3).ESI-MS m/z:449.2[M+H]+.
实施例18
(S)-2-((6-溴喹唑啉-4-基)氨基)-3-甲基-1-(4-甲基哌嗪-1-基)丁-1-酮(中间体18-d)
制备方法同中间体1-d，收率43.8％。1H NMR(400MHz,CDCl3)δ8.49(s,1H Ar-H),7.86(d, J＝7.3Hz,1H NH),7.72(d,J＝2.0Hz,1H Ar-H),7.53(dd,J＝8.9,2.0Hz,1H Ar-H),7.34(d,J＝ 8.9Hz,1H Ar-H),5.07(t,J＝8.0Hz,1H CH),3.89(dd,J＝17.6,13.1Hz,3HCH3),2.70–2.56(m, 2H CH2),2.55–2.40(m,2H CH2),2.37(s,4H CH2×2),1.10(d,J＝6.6Hz,3H CH3),1.05(d,J＝ 6.8Hz,3H CH3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-3-甲基-1-(4-甲基哌嗪-1-基) 丁-1-酮(化合物18)
制备方法同化合物10，收率32.7％。1H NMR(400MHz,DMSO-d6)δ8.81(s,1H Ar-H),8.70 (s,1H Ar-H),8.46(s,2H Ar-H),8.22(d,J＝6.9Hz,1H Ar-H),8.13(d,J＝7.4Hz,1HAr-H),7.75 (d,J＝7.5Hz,1H Ar-H),6.98(d,J＝7.8Hz,1H NH),5.11(s,1H CH),3.92(s,3H OCH3),3.75(s, 2H CH2),3.58(s,2H CH2),2.37(d,J＝34.6Hz,4H CH2×2),2.20(s,3HCH3),0.98(d,J＝19.8Hz, 6H CH3×2).ESI-MS m/z:435.2[M+H]+.
实施例19
(S)-2-((6-溴喹唑啉-4-基)氨基)-3,3-二甲基-1-(4-甲基哌嗪-1-基)丁-1-酮(中间体 19-d)
制备方法同中间体1-d，收率38.6％。1H NMR(400MHz,CDCl3)δ8.58(s,1H Ar-H),7.95(d, J＝2.0Hz,1H NH),7.79(dd,J＝8.9,2.0Hz,1H Ar-H),7.68(d,J＝8.9Hz,1H Ar-H),6.50(d,J＝ 9.0Hz,1H Ar-H),5.57(d,J＝9.0Hz,1H CH),3.90–3.70(m,3H CH3),2.60–2.33(m,4H CH2×2), 2.32(d,J＝6.7Hz,4H CH2×2),1.10(s,9H CH3×3).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-3，3-二甲基-1-(4-甲基哌嗪-1- 基)丁-1-酮(化合物19)
制备方法同化合物10，收率30.5％。1H NMR(400MHz,DMSO-d6)δ8.86(s,1H Ar-H),8.73 (s,1H Ar-H),8.48(s,1H Ar-H),8.25(d,J＝7.0Hz,1H Ar-H),8.12(d,J＝8.4Hz,1HAr-H),7.97 (d,J＝8.6Hz,1H Ar-H),7.77(d,J＝8.5Hz,1H Ar-H),6.97(d,J＝8.6Hz,1HNH),5.56(d,J＝8.6 Hz,1H CH),3.92(s,3H OCH3),3.84–3.53(m,4H CH2×2),2.41–2.24(m,J＝31.7Hz,4H CH2×2),2.15(t,3H CH3),1.09(t,9H CH3×3).ESI-MS m/z:449.2[M+H]+.
实施例20
(S)-2-((6-溴喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)-3-苯基丙-1-酮(中间体20-d)
制备方法同中间体1-d，收率63.4％。1H NMR(400MHz,CDCl3)δ8.51(d,J＝6.6Hz,1HAr-H),7.72(dd,J＝11.2,2.0Hz,2H Ar-H),7.53(ddd,J＝13.5,8.9,2.0Hz,1H Ar-H),7.33(t,J＝ 3.6Hz,5H Ar-H),7.28(s,1H Ar-H),5.52–5.42(m,1H CH),3.75(d,J＝5.0Hz,2HCH2),3.64– 3.54(m,3H CH3),3.40(dd,J＝13.3,6.2Hz,4H CH2×2),2.45(dd,J＝48.4,9.4Hz,2H CH2),2.27 –2.17(m,4H CH2×2).
(S)-2-((6-(6-甲氧基吡啶-3-基)喹唑啉-4-基)氨基)-1-(4-甲基哌嗪-1-基)-3-苯基 丙-1-酮(化合物20)
制备方法同化合物10，收率30.5％。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝1.7Hz,1H Ar-H),8.72–8.67(m,2H Ar-H),8.40(d,J＝2.5Hz,1H Ar-H),8.24–8.19(m,1H Ar-H),8.12(dd, J＝8.7,1.8Hz,1H Ar-H),7.74(dd,J＝8.6,1.8Hz,1H Ar-H),7.35(d,J＝7.3Hz,2H Ar-H),7.26(t, J＝7.5Hz,2H Ar-H),7.18(t,J＝7.3Hz,1H Ar-H),7.00(d,J＝8.6Hz,1H NH),5.53(q,J＝7.6Hz, 1H CH),3.94(s,3H OCH3),3.42(d,J＝16.4Hz,4H CH2×2),3.23–3.11(m,2H CH2),2.27–2.10 (m,4H CH2×2),2.09(s,3H CH3).ESI-MS m/z:483.2[M+H]+.测定值：483.3
实施例21
(S)-2-甲氧基-5-(4-((1-(4-甲基哌嗪-1-基)-1-氧代丙烷-2-基)氨基)吡啶并[3,2-d] 嘧啶-6-基)烟腈(化合物21)
制备方法同化合物13，收率22.5％。1H NMR(600MHz,DMSO-d6)δ9.46(s,1H,Ar-H),9.26 (s,1H,Ar-H),8.69(d,J＝7.4Hz,1H,Ar-H),8.50(d,J＝11.6Hz,2H,Ar-H),8.18(d,J＝8.7Hz, 1H,NH),5.26(s,1H,CH),4.10(s,3H,OCH3),3.59(s,3H,CH,CH2),3.51(s,1H,CH),2.37(d,J＝ 17.7Hz,2H,CH2),2.30(s,2H,CH2),2.19(s,3H,CH3),1.48(d,J＝6.7Hz,3H,CH3).ESI-MS m/z: 432.5[M+H]+.
实施例22
(S)-2-((6-(6-甲氧基-5-(三氟甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氨基)-1-(4-甲基哌嗪- 1-基)丙-1-酮(化合物22)
制备方法同化合物14，收率50.5％。1H NMR(600MHz,DMSO-d6)δ9.49(s,1H,Ar-H),8.93 (s,1H,Ar-H),8.65(d,J＝7.1Hz,1H,Ar-H),8.58(d,J＝8.8Hz,1H,Ar-H),8.51(s,1H,Ar-H),8.21 (d,J＝8.7Hz,1H,NH),5.31–5.16(m,1H,CH),4.10(s,3H,OCH3),3.59(d,J＝14.0Hz,4H, CH2×2),2.33(d,J＝39.5Hz,4H,CH2×2),2.19(s,3H,CH3),1.47(d,J＝6.7Hz,3H,CH3).ESI-MS m/z:475.3[M+H]+.
实施例23
(S)-2-甲氧基-5-(4-((1-(4-甲基哌嗪-1-基)-1-氧代丁烷-2-基)氨基)吡啶[3,2-d]嘧 啶-6-基)烟腈(化合物23)
制备方法同化合物10，收率31.4％。1H NMR(600MHz,DMSO-d6)δ9.43(s,1H,Ar-H),9.20 (s,1H,Ar-H),8.62(d,J＝7.7Hz,1H,Ar-H),8.47(d,J＝7.1Hz,2H,Ar-H),8.16(d,J＝8.7Hz,1H, NH),5.23(dd,J＝13.4,6.6Hz,1H,CH),4.10(s,3H,OCH3),3.64(s,2H,CH2),3.55(s,2H,CH2), 2.46–2.32(m,2H,CH2),2.29(d,J＝13.4Hz,2H,CH2),2.19(s,3H,CH3),2.01–1.86(m,2H, CH2),0.97(t,J＝7.1Hz,3H,CH3).ESI-MS m/z:432.5[M+H]+.
实施例24
(S)-2-((6-(6-甲氧基-5-(三氟甲基)吡啶-3-基)吡啶[3,2-d]嘧啶-4-基)氨基)-1-(4- 甲基哌嗪-1-基)丁酮(化合物24)
制备方法同化合物10，收率33.4％。1H NMR(600MHz,DMSO-d6)δ9.48(s,1H,Ar-H),8.89 (s,1H,Ar-H),8.55(s,2H,Ar-H),8.50(s,1H,Ar-H),8.19(d,J＝8.8Hz,1H,NH),5.22(d,J＝5.9 Hz,1H,CH),4.10(s,3H,OCH3),3.69–3.59(m,2H,CH2),3.59–3.49(m,2H,CH2),3.35(s,3H, CH3),2.51(s,2H,CH2),2.37(dd,J＝22.9,5.0Hz,2H,CH2),2.29(s,2H,CH2),0.94(t,J＝7.3Hz, 3H,CH3).ESI-MS m/z:489.5[M+H]+.
2、本发明化合物对PI3Kδ激酶活性的测定
测试方法：以阳性药Idelalisib作为对照组，将测试的化合物样品用DMSO溶解，配制10mM 母液，然后把化合物加到筛选体系中，化合物检测浓度范围是0.1nM–10μM，按照3倍梯度 进行稀释，每个浓度做两个复孔。所有的酶反应体系组成如下：40mM Tris,pH值7.4,10mM MgCl2,0.1mg/mL BSA,1mmol/L DTT,10μM ATP,0.2ug/mL PI3Kδ，100μmol/L PI(L-α-磷脂 酰肌醇)；同时加入不同浓度的待筛化合物，组成50μl的反应体系，在30℃下反应40分钟后， 用荧光素酶的方法检测体系内的ADP含量，再反应5分钟后，在MD-SpectraMax M5多功能 酶标仪上检测化学发光信号，化学发光信号值强度与酶活性抑制成正比。检测到的化学发光信 号值，代入如下公式：
％activity＝{(Lu药物–Lu本底)/(Lu酶–Lu本底)}×100％,
然后用Graphpad Prism5软件处理，计算出化合物的IC50值。本发明化合物的生化学活 性通过以上的试验进行测试，本发明化合物对PI3Kδ的IC50值见表1。
表1本发明化合物对PI3Kδ激酶的IC50值
| 化合物编号 | IC<sub>50</sub>值(nM) | 化合物编号 | IC<sub>50</sub>值(nM) |
| 1 | B | 2 | B |
| 3 | B | 4 | B |
| 5 | C | 6 | C |
| 7 | C | 8 | B |
| 9 | B | 10 | A |
| 11 | B | 12 | B |
| 13 | A | 14 | B |
| 15 | A | 16 | B |
| 17 | B | 18 | B |
| 19 | C | 20 | B |
| 21 | B | 22 | B |
| 23 | A | 24 | B |
| Idelalisib | B |
A表示IC50<1nM；B表示IC50范围1-10nM；C表示IC50范围10-50nM。
结论：本发明优选化合物对PI3Kδ激酶活性具有显著的抑制作用，强于Idelalisib。
3、本发明化合物对PI3K激酶的选择性活性的测定
采用上述相似的方法，测试本发明化合物对PI3K激酶的各个亚型(包括PI3Kα，PI3Kβ， PI3Kδ和PI3Kγ)的活性。本发明部分化合物以及对照组阳性药Idelalisib对PI3K激酶的各个 亚型(包括PI3Kα，PI3Kβ，PI3Kδ和PI3Kγ)的活性见表2。
表2本发明化合物对PI3K激酶各个亚型的IC50值
结论：本发明优选化合物对PI3Kα，PI3Kβ，PI3Kδ和PI3Kγ的IC50值的表明，本发明化 合物对PI3K的四种激酶均有明显的抑制作用。
4、本发明化合物对肿瘤细胞的体外细胞增殖测定
测试方法：测定本发明化合物对多种肿瘤细胞(包括HCT-116(人结肠癌细胞，PI3CA突 变：H1047R)；MCF-7(人乳腺癌细胞，PI3CA突变：E545K)；SU-DHL-6(人淋巴瘤细胞)； Ramos(B细胞淋巴瘤细胞)；Raji(淋巴瘤细胞))的细胞增殖抑制活性。将测试的化合物样 品和阳性药(Idelalisib和BEZ235)分别用DMSO溶解，配制成一系列浓度梯度的母液(1000 μM，100μM，10μM，1μM)。使用RPMI1640培养基，胎牛血清，胰蛋白酶，MTT,青霉素， 链霉素等实验材料。于96孔板每孔加入浓度为8000-10000个/mL的细胞悬液200μL，置于37℃，5％CO2培养箱中，24h后，加入样品溶液，2μL/孔，设三孔，置于37℃，5％CO2培养箱中孵 育72h，于2000转/min的离心机，离心10min，弃去上清液，加入2μL/孔的MTT，孵育4h 弃去上清液，每孔加入150mL DMSO,溶解后用全自动酶标仪测490nm和570nm下的光密度值 (OD)，以溶液对照处理的肿瘤细胞为对照组，按照下式求得化合物对白血病细胞的抑制率：
细胞抑制率＝(1-给药组平均OD值/对照组平均OD值)×100％
在抑制率的基础上通过改良寇氏法计算出IC50值。以Idelalisib和BEZ235作为阳性对照 药进行测试。本发明化合物的细胞活性通过此试验进行测试，其中代表性化合物的抗肿瘤细胞 活性见表3。
表3本发明化合物对五种肿瘤细胞的IC50(`x±SD，n＝3)
-表示未测试。
结论：化合物对SU-DHL-6细胞具有很强的抑制活性，对其他肿瘤细胞活性较弱，说明本 发明优选化合物具有较强的抗人淋巴肿瘤作用，且具有良好的选择性。
已经通过举例说明和实施例的方式比较详细地描述了上述发明，以用于阐述和理解的目的。 对于本领域技术人员显而易见的是，可以在后附权利要求的范围内进行改变和改进。因此，应 该理解上述说明意在是举例说明性的而不是限制性的。因此，本发明的范围不应该参考上述说 明书而确定，而应该参考下列后附的权利要求以及由权利要求授权的等价物的全部范围而确定。
以上内容仅为说明本发明的技术思想，不能以此限定本发明的保护范围，凡是按照本发明 提出的技术思想，在技术方案基础上所做的任何改动，均落入本发明权利要求书的保护范围之 内。
Claims (10)
1.一种4-氨基酸侧链取代的喹唑啉衍生物，其特征在于，为式(I)所示化合物及其溶剂合物、对映异构体、非对映异构体、互变异构体和对映异构体的任意比例的混合物中的一种，或者式(I)所示化合物药学上可接受的盐及其溶剂合物、对映异构体、非对映异构体、互变异构体或对映异构体的任意比例的混合物中的一种；
所述式(I)化合物的结构式为：
其中，X为CH或者N；
R1为氢、氰基、硝基或三氟甲基；
R2为烷基；
R3与R4各自独立的为氢、烷基、环烷基、杂环烷基，其任选地被0个或1个以下基团所取代：异丙基、苯基、吗啉基或二乙氨基；
或者R3、R4与他们相连的N一起形成3至8元饱和或不饱和单杂环，其任选地被0个或1个以下基团所取代：烷基、环烷基。
2.根据权利要求1所述的化合物，其特征在于，R2为甲基、乙基、异丙基、叔丁基或苄基；R1为氢、氰基、硝基或三氟甲基。
3.根据权利要求1所述的化合物，其特征在于，当R3为氢时，R4为甲基、乙基、丙基、丁基、异丙基、环戊基或哌啶基，R4可进一步被异丙基、苯基、吗啉基或二乙氨基所取代。
4.根据权利要求1所述的化合物，其特征在于，当R3与R4成环时，R3与R4连接成吡咯烷环或哌啶环，哌啶环可进一步被甲基取代。
5.根据权利要求1-4任一项所述的化合物，其特征在于，式(I)化合物的结构式选自下列化合物中的一个：
6.权利要求1～5中任何一项所述的化合物在制备药物中的应用，其特征在于，所述药物为用于治疗对PI3Kδ和/或PI3Kα有响应的疾病的药物。
7.根据权利要求6所述的应用，其特征在于，所述对PI3Kδ和/或PI3Kα有响应的疾病为自身免疫性疾病。
8.根据权利要求7所述的应用，其特征在于，所述自身免疫性疾病为癌症、内风湿性关节炎、红斑狼疮或多样性硬化症。
9.根据权利要求8所述的应用，其特征在于，所述癌症为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤和弥散性大B细胞淋巴瘤中的一种。
10.根据权利要求8所述的应用，其特征在于，所述癌症为前列腺癌、乳腺癌、子宫内膜癌、肺癌、肝癌、结肠癌、胰腺癌和肾癌中的一种。
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| CN115894451A (zh) * | 2022-12-20 | 2023-04-04 | 西安爱思益生物科技有限公司 | 一种含硒的PI3Kδ抑制剂及其在PI3Kδ过度表达所引起的疾病中的应用和药物 |
| CN116239594A (zh) * | 2023-03-05 | 2023-06-09 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6-(咪唑并[1,2-a]吡啶-6-基)喹唑啉衍生物及用途 |
| CN116239594B (zh) * | 2023-03-05 | 2023-09-22 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 6-(咪唑并[1,2-a]吡啶-6-基)喹唑啉衍生物及用途 |
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