CN117986246A - 4-氨基-嘧啶并[2,3-d]吡咯衍生物及其制备方法和用途 - Google Patents
4-氨基-嘧啶并[2,3-d]吡咯衍生物及其制备方法和用途 Download PDFInfo
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- CN117986246A CN117986246A CN202311255139.6A CN202311255139A CN117986246A CN 117986246 A CN117986246 A CN 117986246A CN 202311255139 A CN202311255139 A CN 202311255139A CN 117986246 A CN117986246 A CN 117986246A
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Abstract
本发明属于生物医药技术领域，具体涉及一种4‑氨基‑嘧啶并[2,3‑d]吡咯衍生物及其制备方法和用途。针对现有技术中存在的问题，本发明拟提供一种PIKfyve抑制剂4‑氨基‑嘧啶并[2,3‑d]吡咯衍生物及其制备方法和用途，本发明提供一种新的化合物4‑氨基‑嘧啶并[2,3‑d]吡咯衍生物，其具有式I所示的结构。本发明的化合物具有PIKfyve抑制剂的作用，还具有显著抑制肿瘤细胞增值的作用，可用于制备预防或治疗肿瘤、神经系统疾病、自体免疫疾病或过敏性疾病的药物，为疾病治疗药物的开发提供了新的选择。
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-嘧啶并[2,3-d]吡咯衍生物及其制备方法和用途。
背景技术
含FYVE结构的磷酸肌醇3-磷酸-5-激酶(FYVE domain-containingphosphatidylinositol 3-phosphate-5-kinase,PIKfyve)是哺乳动物体内的一种磷脂酰肌醇脂质激酶，也叫做PIPKIII。PIKfyve通过直接催化磷脂酰肌醇-3-磷酸(phosphatidylinositol 3-phosphate,PI3P)生成磷脂酰肌醇-3,5-二磷酸(phosphatidylinositol-3,5-bisphosphate,PI(3,5)P2)或磷脂酰肌醇-5-磷酸(phosphatidylinositol-5-phosphate,PI5P)。PIKfyve功能的缺失或抑制降低了PI(3,5)P2的细胞水平，而缺乏PI(3,5)P2的生物体通常充满增大的液泡。PIKfyve在调节膜运输以及维持溶酶体功能中发挥关键作用，还参与内体转运、转录调控和免疫调节等重要细胞生物学功能。细胞内蛋白质聚集物的积累是许多散发性的神经退行性疾病的共同特征，如阿尔茨海默症和额颞叶痴呆中的tau蛋白，以及帕金森病中的α-突触核蛋白，这些蛋白质聚集物导致神经元死亡的。错误折叠的蛋白质就像朊病毒的“种子”，它们会侵入神经元内吞通路，破坏溶酶体的完整性，诱导内源性细胞蛋白的错误折叠，最终导致细胞死亡。最近的研究表明，PIKfyve在这些神经退行性“种子”的内吞运输中的发挥的作用使其有可能成为一个有前途的治疗靶点。近年来的研究表明，PIKfyve也在炎症(如溃疡性结肠炎、克罗恩病等)、病原微生物感染、和肿瘤的发生发展中起重要作用，可作为潜在的疾病治疗靶点。
目前尚未有高选择性的PIKfyve抑制剂上市，但是已有若干分子被报道。其中，MOMIPP,Apilimod、ESK981、YM201636是具有代表性的几个化合物。然而，Apilimod在前期针对克罗恩肠病及类风湿性关节炎的临床实验中表现出极低的血浆浓度和不理想的生物利用度，终止了临床试验，该分子针对ALS、非霍奇金淋巴瘤的II期临床试验正在开展。ESK981针对前列腺癌和肾细胞癌等II临床试验也在进行中。而其他已报道的分子均处于临床前研究阶段或者仅作为分子工具进行基础研究。因此，发现高效、低毒、药物代谢性质优异的PIKfyve抑制剂具有重要的临床应用价值和科学意义。
发明内容
针对上述现有技术中存在的问题，本发明拟提供一种PIKfyve抑制剂4-氨基-嘧啶并[2,3-d]吡咯衍生物及其制备方法和用途。
本发明要解决的第一个技术问题为：提供了一种4-氨基-嘧啶并[2,3-d]吡咯衍生物。其结构如式I所示：
式I，
其中R1为 进一步地，R2为F，甲氧基或甲基。
其中，上述4-氨基-嘧啶并[2,3-d]吡咯衍生物中，其结构包括：
本发明还提供了一种上述4-氨基-嘧啶并[2,3-d]吡咯衍生物的制备方法，包括以下合成路线：
其中，Cy为/> 进一步地，R2为F，甲氧基或甲基。
本发明还提供了一种上述4-氨基-嘧啶并[2,3-d]吡咯衍生物药学上可接受的盐、溶剂化物、水合物、异构体、多晶型物，或其前药。
其中，所述4-氨基-嘧啶并[2,3-d]吡咯衍生物药学上可接受的盐中，包括与酸成盐，即通过母体化合物的游离碱与无机酸或有机酸的反应而得。
进一步的，所述的无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸或高氯酸中的至少一种。
进一步的，所述的有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸中的至少一种。
本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围，能适于用来与人类和其他哺乳动物的组织接触，而没有不当毒性、刺激、过敏反应等，其在对受者给药时能直接或间接地提供本发明的化合物或化合物的前药。
其中，本发明的溶剂化物是指一个或多个溶剂分子与本发明的4-氨基-嘧啶并[2,3-d]吡咯衍生物所形成的缔合物。形成溶剂化物的溶剂包括水、异丙醇、乙醇、甲醇、二甲基亚砜、乙酸乙酯或乙酸中的至少一种。
其中，本发明的水合物是指4-氨基-嘧啶并[2,3-d]吡咯衍生物药学上可接受的水合物。术语“水合物”表示进一步通过非共价分子间作用力结合化学计量或非化学计量的水的化合物。
本发明还提供了上述4-氨基-嘧啶并[2,3-d]吡咯衍生物药学上可接受的异构体。术语“异构体”是指化学组成相同但是原子或基团在空间排列上不同的化合物，包括非对映异构体、对映异构体、区域异构体、结构异构体、旋转异构体或互变异构体。
本发明还提供了上述4-氨基-嘧啶并[2,3-d]吡咯衍生物药学上可接受的多晶型物。术语“多晶型物”表示化合物或其复合物的固体结晶形式，其可以通过物理方法，例如X射线粉末衍射图或红外光谱进行表征。
本发明还提供了一种药物组合物，由式Ⅰ所示的4-氨基-嘧啶并[2,3-d]吡咯衍生物及其盐、溶剂化物、水合物、异构体、多晶型物或其前药，添加药学上可以接受的辅助性成分制备而成的。
进一步的，所述的辅助性成分包括环糊精、精氨酸或葡甲胺。所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、(C1-4烷基)-α-环糊精、(C1-4烷基)-β-环糊精、(C1-4烷基)-γ-环糊精、(羟基-C1-4烷基)-α-环糊精、(羟基-C1-4烷基)-β-环糊精、(羟基-C1-4烷基)-γ-环糊精、(羧基-C1-4烷基)-α-环糊精、(羧基-C1-4烷基)-β-环糊精、(羧基-C1-4烷基)-γ-环糊精、α-环糊精的糖类醚、β-环糊精的糖类醚、γ-环糊精的糖类醚、α-环糊精的磺丁基醚、β-环糊精的磺丁基醚和γ-环糊精的磺丁基醚。所述的辅助性成分还包含医学上可接受的载体、佐剂或媒剂。可用于药学上可接受的药物组合物还离子交换剂、氧化铝、硬脂酸铝、卵凝脂；缓冲物质包括磷酸盐、甘氨酸、精氨酸、山梨酸等。
上述药物组合物可以为液体形式或固体形式。其中，所述的液体形式可以为水溶液形式。所述的固体形式可以为粉末、颗粒、片剂或冻干粉形式。该药物组合物还含有注射用水、盐水溶液、葡萄糖水溶液、注射/输注用盐水、注射/输注用葡萄糖、格林氏溶液或含有乳酸盐的格林氏溶液。
本发明还提供了一种上述式Ⅰ所示的4-氨基-嘧啶并[2,3-d]吡咯衍生物及其盐、溶剂化物、水合物、异构体、多晶型物或其前药，以及药物组合物在制备预防或治疗肿瘤、神经系统疾病、自体免疫疾病或过敏性疾病的药物的用途。
其中，上述用途中，所述的肿瘤包括乳腺癌、宫颈癌、肝癌、肺癌、肾癌、前列腺癌或非霍奇金淋巴瘤等。
其中，上述用途中，所述的神经系统疾病包括肌萎缩侧索硬化症。
其中，上述用途中，所述的自体免疫疾病或过敏性病症包括溃疡性结肠炎、克罗恩病或类风湿性关节炎。
本发明的有益效果为：
本发明通过特有的方法合成了式Ⅰ所示的4-氨基-嘧啶并[2,3-d]吡咯衍生物，发现其具有显著抑制肿瘤细胞增值的作用，该衍生物及其盐、溶剂化物、水合物、异构体、多晶型物或其前药能够与药学上可以接受的辅助性成分制备成药物组合物或制剂，用于治疗肿瘤、神经系统疾病、自体免疫疾病或过敏性疾病等相关的疾病。
附图说明
图1所示为克隆实验结果图。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明，但不限制本发明。实施例中无特殊说明，反应的温度为室温，即20-30℃。
实施例1制备本发明的4-氨基-嘧啶并[2,3-d]吡咯衍生物L1
具体的操作步骤如下：
步骤a：中间体2的制备
称量原料1(20g,130mmol)和氨水(150mL,25％-28％工业氨水)加入到高压反应釜内，密封体系，插入温度计，将温度设置为130℃，反应4h后冷却至室温。将反应混悬液直接过滤，滤饼用乙醚淋洗后得到中间体2。1H NMR(400MHz,DMSO)δ:11.45(s,1H),8.03(s,1H),7.06(d,J＝3.2Hz,1H),6.88(s,2H),6.51(d,J＝3.3Hz,1H)。
步骤b：中间体3的制备
室温下，将上一步的中间体2(16g,112mmol)加入到200mL的四氢呋喃中，并分批加入NIS(37.8g,168mmol)，反应1h。将反应混悬液进行减压蒸发，得到固体混合物，加入水300mL，搅拌下计入硫代硫酸钠(8.8g,56mmol)，混合物从棕色变为黄色，持续搅拌0.5h后过滤，滤饼用乙醚淋洗后得到中间体3。1H NMR(400MHz,DMSO)δ:11.97(s,1H),8.07(s,1H),7.36(s,1H),6.56(s,2H)。
步骤c：中间体5的制备
将原料4(43g,200mmol,1equiv)加入到1000mL二氯甲烷中，并加入DMAP(12.2g,100mmol,0.5equiv)、三乙胺(52mL,400mmol,2equiv)进行搅拌。再将对甲苯磺酰氯(45.8g,240mmol,1.2equiv)溶于二氯甲烷中(200mL)，并分批加入上述反应体系内。室温下反应5小时后，进行减压浓缩得到粗品混合物。将粗品分散在2000mL乙醚中，搅拌1小时后过滤，并用乙醚淋洗2两次。减压蒸馏出去溶剂得到较纯的中间体5，无需进一步的纯化。1H NMR(400MHz,DMSO)δ:7.79(d,J＝8.3Hz,2H),7.47(d,J＝8.1Hz,2H),6.70(d,J＝7.0Hz,1H),4.40–4.30(m,1H),2.42(s,3H),1.77(dt,J＝24.2,14.3Hz,4H),1.54–1.41(m,2H),1.36(s,9H),1.21–1.14(m,2H)。
步骤d：中间体6的制备
将以上的中间体3(26g,100mmol,1equiv)溶解在200mL DMF中，并加入碳酸铯(65g,200mmol,2equiv)做缚酸剂，升温至80℃。分批加入以上的中间体5(44.4g,120mmol,1.2equiv)，于该温度下反应2小时。过滤除去无机盐等杂质，将母液浓缩得到粗品。将粗品分散在200mL乙腈中，搅拌1小时，并用乙醚洗涤滤饼后得到较纯的中间体6，无需进一步纯化。1H NMR(400MHz,DMSO)δ:8.08(s,1H),7.69(s,1H),7.05(d,J＝8.6Hz,1H),6.56(s,2H),4.57(dd,J＝15.7,7.9Hz,1H),4.08(dd,J＝10.3,5.1Hz,1H),2.12–1.95(m,2H),1.74–1.59(m,6H),1.42(s,9H)。
步骤e：中间体7的制备
将上一步的中间体6(36g,80mmol,1equiv)溶解在200mL二氧六环中，并分批加入4M/L的盐酸二氧六环溶液(66mL,264mmol,3.3equiv)。于室温下反应4小时后，大量固体析出，过滤，并用适量的二氧六环进行洗涤得到粗品。将粗品分散在水中，加入适量氢氧化钾调节pH直至pH>9，用乙酸乙酯进行萃取。减压浓缩得到粗品。再将粗品分散在100mL乙腈中，搅拌1小时，过滤，并用用乙醚淋洗滤饼得到较纯的中间体7，无需进一步纯化。1H NMR(400MHz,DMSO)δ:8.11(s,1H),7.36(s,1H),6.00(s,2H),4.66(dd,J＝13.1,9.5Hz,1H),3.34(s,1H),2.17–2.09(m,2H),1.86–1.70(m,6H)。
步骤f：L1的制备
将上一步中间体7(357mg,1mmol,1equiv)、benzofuran-2-ylboronic acid(178mg,1.1mmol,1.1equiv)、碳酸钾(276mg,2mmol,2equiv)和dppfPdCl2加入到25mL三颈瓶内，加入二氧六环/乙醇/水＝7:3:4(共计15mL)作为溶剂，置换氮气三次后转入80℃的油浴内反应2h。反应结束后将反应液浓缩至干后，拌样过柱子分离，即得到终产物L1。
其中，L1的表征参数为：1H NMR(400MHz,DMSO-d6)δ:8.17(s,1H),8.12(s,1H),7.64(s,2H),7.32–7.24(m,2H),7.12(s,1H),6.93(s,2H),4.61(t,J＝11.4Hz,1H),3.14(s,1H),2.33–2.16(m,2H),1.81–1.61(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.70,154.10,152.39,152.20,150.55,129.45,124.02,123.83,123.19,120.90,111.37,104.79,101.23,99.34,53.22,44.47,32.50,26.72.HRMS(ESI),m/z:348.1823[M+H]+。
采用相同的制备方法，得到L2-L19。
L2-L19的表征参数分别如下：
L2：1H NMR(400MHz,DMSO-d6)δ:11.20(s,1H),8.12(s,1H),7.62(s,1H),7.50(d,J＝8.3Hz,1H),7.45(s,1H),7.40(t,J＝2.8Hz,1H),7.21(dd,J＝8.2,1.7Hz,1H),6.47(t,J＝2.3Hz,1H),6.02(s,2H),4.59(t,J＝12.0Hz,1H),3.11(s,1H),2.29–2.13(m,2H),1.76–1.55(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.74,151.59,149.81,135.40,128.62,126.62,126.02,122.60,120.45,120.25,117.07,112.29,101.64,100.72,52.64,44.60,32.53,26.86.HRMS-ESI:calcd.for C20H22N6:346.1906,found:347.1980[M+H]+。
L3：1H NMR(400MHz,DMSO-d6)δ:8.16(s,1H),8.11–8.05(m,1H),7.77–7.72(m,1H),7.71(s,1H),7.66(s,1H),7.48–7.41(m,2H),5.96(s,2H),4.63(td,J＝10.4,8.7,6.1Hz,1H),3.10(m,1H),2.36–2.13(m,2H),1.77–1.60(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.68,151.97,149.87,140.28,139.02,130.51,125.15,125.06,125.01,123.60,123.50,122.27,107.76,101.37,52.95,44.58,32.64,26.82.HRMS-ESI:calcd.forC20H21N5S:363.1518,found:363.1595[M+H]+。
L4：1H NMR(400MHz,DMSO-d6)δ:8.18(s,1H),7.97(d,J＝7.8Hz,1H),7.86(d,J＝7.7Hz,1H),7.76(s,1H),7.45–7.32(m,3H),6.47(s,2H),4.67–4.55(m,1H),3.11(s,1H),2.32–2.11(m,2H),1.80–1.59(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.76,152.29,150.36,140.97,139.20,137.29,125.10,124.57,123.92,123.20,122.61,122.25,108.18,100.23,52.88,44.60,32.15,26.69.HRMS-ESI:calcd.for C20H21N6S:363.1518,found:363.1593[M+H]+。
L6：1H NMR(400MHz,DMSO-d6)δ:8.08(s,1H),7.47–7.36(m,6H),5.66(d,J＝1.7Hz,1H),5.32(d,J＝1.6Hz,1H),4.62–4.52(m,1H),3.12–3.05(m,1H),2.25–2.09(m,2H),1.74–1.58(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.34,151.87,150.09,142.50,141.17,129.18,128.89,127.58,122.45,115.49,115.06,101.08,52.81,44.54,32.55,26.74.HRMS-ESI:calcd.for C20H23N5:333.1953,found:333.2003[M+H]+。
L7：1H NMR(400MHz,DMSO-d6)δ:8.16(s,1H),8.04–7.94(m,4H),7.68(d,J＝7.8Hz,2H),7.53(pd,J＝6.9,1.5Hz,2H),6.14(s,2H),4.63(td,J＝11.5,10.1,6.1Hz,1H),3.11(t,J＝3.1Hz,1H),2.35–2.16(m,2H),1.81–1.60(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.81,151.85,150.40,133.79,132.95,132.11,128.85,128.18,128.09,127.54,126.95,126.79,126.16,121.90,115.70,100.35,52.76,44.58,32.41,26.83.HRMS-ESI:calcd.for C22H23N5:357.1953,found:357.2013[M+H]+。
L8：1H NMR(400 MHz,DMSO-d6)δ:8.11(s,1H),7.47(s,1H),6.98–6.88(m,3H),6.07(s,2H),4.56(tt,J＝11.7,3.7 Hz,1H),4.28(s,4H),3.12–3.07(m,1H),2.19(tt,J＝12.3,7.3 Hz,2H),1.74–1.53(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.65,151.68,149.95,144.04,142.85,128.58,121.73,120.98,117.95,117.32,115.18,100.26,64.60,52.58,32.23,26.76.HRMS-ESI:calcd.for C20H23N5O2:365.1852,found:365.1932[M+H]+。
L9：1H NMR(400 MHz,DMSO-d6)δ:11.34(s,1H),8.16(s,1H),7.70(s,1H),7.55(d,J＝7.8 Hz,1H),7.38(d,J＝8.0 Hz,1H),7.09(t,J＝7.5 Hz,1H),7.01(t,J＝7.4 Hz,1H),6.51(s,1H),6.43(s,2H),4.67–4.55(m,1H),3.14(t,J＝3.2 Hz,1H),2.34–2.14(m,2H),1.80–1.61(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.86,152.12,150.04,137.19,133.42,129.42,121.94,121.50,120.10,119.75,111.55,107.31,100.38,100.25,52.83,44.56,32.21,26.85.HRMS-ESI:calcd.for C20H22N6:346.1906,found:347.1980[M+H]+。
L10：1H NMR(400 MHz,DMSO-d6)δ:8.15(s,1H),8.06(s,1H),7.73–7.62(m,3H),7.44–7.29(m,2H),6.19(s,2H),4.62(t,J＝11.5 Hz,1H),3.11(s,1H),2.34–2.15(m,2H),1.79–1.59(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.86,155.26,152.01,150.12,142.98,127.88,125.26,123.52,121.93,121.01,115.08,112.02,103.13,101.04,52.78,44.63,32.29,26.77.HRMS-ESI:calcd.for C24H31N5O2:347.1746,found:348.1824[M+H]+。
L11：1H NMR(400 MHz,DMSO-d6)δ:8.16(s,1H),8.11(s,1H),7.52(d,J＝8.3 Hz,1H),7.41(s,1H),7.08(dd,J＝8.4,1.8 Hz,1H),7.04(s,1H),6.94(s,2H),4.66–4.55(m,1H),3.13(t,J＝3.2 Hz,1H),2.40(s,3H),2.30–2.15(m,2H),1.77–1.59(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.72,156.54,153.06,152.27,150.33,147.94,130.47,123.35,113.23,110.81,105.23,103.75,101.23,99.25,56.04,52.15,44.58,32.50,21.70.HRMS-ESI:calcd.forC21H23N5O:361.1903,found:362.1983[M+H]+。
L12：1H NMR(400 MHz,DMSO-d6)δ:8.15(s,1H),7.66(s,1H),7.65(s,1H),7.49–7.40(m,2H),6.37(s,2H),4.58(t,J＝12.1 Hz,1H),3.10(s,1H),2.28–2.10(m,2H),1.76–1.55(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.70,152.24,150.12,139.94,138.56,138.16,127.85,122.67,120.36,118.82,108.52,100.30,52.72,44.64,31.83,26.66.HRMS-ESI:calcd.forC18H19N5S2:369.082,found:370.1157[M+H]+。
L13：1H NMR(400 MHz,DMSO-d6)δ:8.18(s,1H),8.16(s,1H),7.69(dd,J＝9.2,4.0Hz,1H),7.44(d,J＝8.9 Hz,1H),7.12(s,1H),7.08(d,J＝9.4 Hz,1H),6.94(s,2H),4.61(t,J＝12.1Hz,1H),3.13(s,1H),2.33-2.15(m,2H),1.79–1.61(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.68,154.25,152.44,150.63,150.47,130.67,130.56,123.65,112.47,111.29,106.51,104.54,101.37,99.24,53.22,44.48,32.39,26.69.HRMS-ESI:calcd.forC20H20FN5O:365.1652,found:366.1721[M+H]+。
L14：1H NMR(400 MHz,DMSO-d6)δ:8.16(s,1H),8.11(s,1H),7.55(d,J＝8.9 Hz,1H),7.15(d,J＝2.6 Hz,1H),7.05(s,1H),6.94(s,2H),6.85(dd,J＝8.9,2.6 Hz,1H),4.60(t,J＝12.0Hz,1H),3.81(s,3H),3.14(s,1H),2.31–2.16(m,2H),1.80–1.60(m,6H).13CNMR(101 MHz,DMSO-d6)δ:157.68,156.47,152.96,152.39,150.53,148.94,130.17,123.05,112.21,111.81,104.93,103.55,101.43,99.28,56.06,56.00,53.20,44.48,32.42,26.70.HRMS-ESI:calcd.forC21H23N5O2:377.1852,found:378.1934[M+H]+。
L15：1H NMR(400 MHz,DMSO-d6)δ:8.14(s,1H),8.05(d,J＝2.2 Hz,1H),7.74(d,J＝1.8Hz,1H),7.69(d,J＝8.4 Hz,1H),7.55(s,1H),7.42(dd,J＝8.4,1.8 Hz,1H),7.01(d,J＝2.2 Hz,1H),6.06(s,2H),4.65–4.54(m,1H),3.12–3.09(m,1H),2.30–2.14(m,2H),1.76–1.57(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.67,152.52,152.38,152.28,150.51,132.78,129.54,125.10,123.03,120.67,110.88,104.91,100.95,99.29,53.15,44.49,32.43,26.71.HRMS-ESI:calcd.for C24H31N5O2:347.1746,found:348.1825[M+H]+。
L16：1H NMR(400 MHz,DMSO-d6)δ:8.17(s,1H),7.82(s,1H),7.66–7.59(m,2H),7.34–7.28(m,2H),6.76(s,2H),4.63(t,J＝12.0 Hz,1H),3.11(s,1H),2.39(s,3H),2.33–2.18(m,2H),1.76–1.63(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.68,153.31,152.48,150.30,147.10,130.79,124.44,123.42,123.25,119.77,111.21,110.88,103.85,100.24,53.18,44.56,32.44,26.66,9.53.HRMS-ESI:calcd.for C21H23N5O:361.1903,found:361.1983[M+H]+。
L17：1H NMR(400 MHz,DMSO-d6)δ:11.32(s,1H),8.15(s,1H),7.61(s,1H),7.46–7.39(m,2H),7.21(t,J＝7.6 Hz,1H),7.01(d,J＝7.1 Hz,1H),6.43(s,1H),4.76–4.64(m,1H),3.28(s,1H),2.31–2.15(m,2H),1.88–1.68(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.73,151.77,149.86,136.62,127.23,127.04,126.15,121.87,121.30,119.96,114.34,110.92,101.31,101.14,51.81,45.12,30.23,26.67.HRMS-ESI:calcd.for C20H22N6:346.1906,found:347.1983[M+H]+。
L18：1H NMR(400 MHz,DMSO-d6)δ:8.13(s,1H),8.08(s,1H),7.81(s,1H),7.74(d,J＝8.6 Hz,1H),7.56–7.50(m,2H),5.98(s,2H),4.59(t,J＝12.0 Hz,1H),4.09(s,3H),3.10(s,1H),2.30–2.15(m,2H),1.75–1.60(m,6H).13C NMR(101 MHz,DMSO-d6)δ:157.75,151.70,150.05,139.15,132.89,127.91,127.60,124.46,121.16,120.29,115.88,110.53,100.57,52.78,44.54,40.61,40.40,40.19,39.99,39.78,39.57,39.36,35.88,32.64,26.84.HRMS-ESI:calcd.for C20H23N7:361.2105,found:361.2045[M+H]+。
L19：1H NMR(400MHz,DMSO-d6)δ:8.11(s,1H),7.48(s,1H),7.04–6.99(m,2H),6.91(dd,J＝7.9,1.7Hz,1H),6.06(s,2H),4.60–4.51(m,1H),3.11–3.04(m,1H),2.26–2.06(m,2H),1.71–1.53(m,6H).13C NMR(101MHz,DMSO-d6)δ:157.64,151.69,149.95,148.16,146.61,129.26,122.10,121.12,115.40,109.37,109.10,101.53,100.30,52.76,44.52,32.63,26.80.HRMS-ESI:calcd.for C19H21N5O2:351.1695,found:351.1755[M+H]+。
实施例2体外化合物诱导巨泡实验
将对数生长期的HeLa或MDA-MB-231细胞在96孔培养板中培养，将实施例1得到的化合物L1-L19先配成10mmol/L的工作液备用。将化合物加入到细胞培养皿中，使化合物的浓度为100nM和1000nM。作用24h后，在倒置显微镜下观察细胞，并取5个不同视野的细胞进行拍照。对每张照片里产生巨泡的细胞和全部的细胞进行计数，同时计算产生巨泡的细胞在总细胞中的占比，取平均值得巨炮率(％)，结果如下表1所示。
表1本发明化合物诱导巨泡现象的能力
a将MDA-MB-231或Hela细胞用所测化合物在100或1000nM下处理24h，随机选取5个细胞视野拍照，定量空泡细胞的百分比。
结果表明，本发明化合物L1,L4，L7,L9，L11,L12，L13和L14均不同程度地诱导两种肿瘤细胞产生巨泡现象，且优于对照化合物MOMIPP(已报导的具有显著抑制PIKfyve激酶的化合物)。
实施例3化合物对PIKfyve酶的作用实验
抑制率和Kd值由Discover X(USA)根据公布的方案进行测定。Kd值采用11点3倍化合物稀释倍数和3个DMSO孔做对照进行测定。所有用于测量Kd的化合物在100％ DMSO中溶解。所有反应均在聚丙烯384孔板上进行，最终体积为0.02mL。室温振荡培养1h，用洗涤缓冲液洗涤亲和珠。然后将微珠重新悬浮在洗脱缓冲液中，在室温下振荡孵育30分钟，用qPCR法测定洗脱液中激酶的浓度，然后通过软件计算出Kd，结果如表2所示。
表2部分化合物的酶学活性
| 编号 | 抑制率％@1000nM | Kd,nM |
| L1 | 100 | 1.6 |
| L11 | 97.5 | 0.47 |
| L13 | 100 | 3.1 |
| L16 | 100 | 4.2 |
| MOMIPP | 99.5 | 3.8 |
结果表明，四个化合物(L1,L11，L13,L16)对PIKfyve激酶的结合常数混处于nM水平，部分优于对照化合物MOMIPP。
实施例4分子克隆实验
取对数期的HeLa或MDA-MB-231细胞在6孔培养板中培养(10000-15000个细胞/孔)。然后用所测化合物以设定的浓度梯度递增的方式处理细胞7×24h，然后用4％多聚甲醛在室温下固定细胞15min。随后用结晶紫染色，用光学显微镜观察，结果如图1所示。
结果表明，优选化合物L1和L11在Hela和MDA-MB-231细胞上能够显著抑制克隆形成，且显著优于对照化合物MOMIPP。
实施例5化合物L11的肿瘤抗增殖活性
所有培养基含青霉素100单位/mL，链霉素100μg/mL。取对数期的HeLa或MDA-MB-231细胞在96孔培养板中培养(10000-15000个细胞/孔)。然后用设定的梯度化合物处理细胞3×24h。按照标准方案用CCK-8法测定细胞活力，根据抑制率采用GraphPad Prism 8.0软件计算IC50值，所有实验重复进行3次。结果如表3所示。
表3优选分子对Hela和MDA-MB-231细胞的抗增殖活性
结果表明，化合物L1和L11均能强力地抑制肿瘤细胞Hela和MDA-MB-231细胞的增殖，且优于对照化合物MOMIPP，而类似物L10却不能抑制肿瘤细胞的增殖，这也说明了诱导巨泡现象的能力越强，对肿瘤细胞的杀伤力越强。
实施例6体内药代动力学分析
Balb/C小鼠随机分组(两组，每组6只)，实验前12h禁食不禁水。通过静脉(10mg/kg)和口服(50mg/kg)给与化合物L11，分别在不同时间点采集血样品。血样品采集过程中，放置于冰上保存，离心分离血浆，于-20℃冰箱内保存。同时配置系列浓度的标准品，并建立标准曲线。使用高效液相色谱与质谱分析处理数据。获取Cmax、Tmax、CL、T1/2、Vd、AUC及F％等药代参数，结果如下表4所示。
表4化合物L11的药代参数
| parameter | iv | po |
| Dose(mg/kg) | 10 | 50 |
| Cmax(μg/L) | 21658 | 10284 |
| T1/2(h) | 4.2 | 5.7 |
| CL(L/h/kg) | 0.276 | 0.076 |
| AUC0→t(μg/L*h) | 35840 | 127055 |
| Vz(L/kg) | 1.698 | 0.607 |
| F(％) | 70.9 |
结果表明，化合物L11具有良好的药物代谢动力学性质，尤其是具有较高的体内暴露量和半衰期，可以采用口服给药的方式进行治疗相应的疾病。
Claims (10)
1.一种4-氨基-嘧啶并[2,3-d]吡咯衍生物，其特征在于，结构如式I所示：
其中，R1为 进一步地，R2为F，甲氧基或甲基。
2.根据权利要求1所述的4-氨基-嘧啶并[2,3-d]吡咯衍生物，其特征在于：结构包括：
3.权利要求1或2所述的4-氨基-嘧啶并[2,3-d]吡咯衍生物的制备方法，其特征在于，包括以下合成路线：
其中，Cy为/>
进一步地，R2为F，甲氧基或甲基。
4.一种权利要求1或2所述的4-氨基-嘧啶并[2,3-d]吡咯衍生物的盐、溶剂化物、水合物、异构体、多晶型物或其前药。
5.一种药物组合物，其特征在于：由权利要求1或2所述的4-氨基-嘧啶并[2,3-d]吡咯衍生物及权利要求4所述的盐、溶剂化物、水合物、异构体、多晶型物或其前药，添加药学上可以接受的辅助性成分制备而成。
6.根据权利要求5所述的药物组合物，其特征在于：所述药学上可接受的盐包括与酸成盐，即通过母体化合物的游离碱与无机酸或有机酸的反应而得。
7.根据权利要求6所述的药物组合物，其特征在于：所述的无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸或高氯酸中的至少一种；所述的有机酸包括乙酸、丙酸、丙烯酸、草酸、D或L苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸中的至少一种。
8.根据权利要求5所述的药物组合物，其特征在于：所述的辅助性成分包括环糊精、精氨酸或葡甲胺。
9.权利要求1或2所述的4-氨基-嘧啶并[2,3-d]吡咯衍生物，权利要求4所述的盐、溶剂化物、水合物、异构体、多晶型物或其前药，权利要求5-8任一项所述的药物组合物在制备预防或治疗肿瘤、神经系统疾病、自体免疫疾病或过敏性疾病的药物的用途。
10.根据权利要求9所述的用途，其特征在于：所述的肿瘤包括乳腺癌、宫颈癌、肝癌、肺癌、肾癌、前列腺癌或非霍奇金淋巴瘤；所述的神经系统疾病包括肌萎缩侧索硬化症；所述的自体免疫疾病或过敏性病症包括溃疡性结肠炎、克罗恩病或类风湿性关节炎。
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