CN115448921A - 一类咪唑烷并嘧啶酮化合物及在治疗HsClpP介导的疾病中的用途 - Google Patents
一类咪唑烷并嘧啶酮化合物及在治疗HsClpP介导的疾病中的用途 Download PDFInfo
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- CN115448921A CN115448921A CN202110640077.5A CN202110640077A CN115448921A CN 115448921 A CN115448921 A CN 115448921A CN 202110640077 A CN202110640077 A CN 202110640077A CN 115448921 A CN115448921 A CN 115448921A
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Abstract
本发明涉及一类咪唑烷并嘧啶酮化合物或其药学上可接受的盐、水合物或晶型在人酪蛋白裂解酶(HsClpP)介导的疾病治疗中的用途，属于化学医药领域。本发明所要解决的技术问题是提供一类咪唑烷并嘧啶酮化合物。特征在于具有咪唑烷并嘧啶酮的骨架结构，咪唑烷环上氮原子与其他取代基团连接。该类化合物具有显著的调控HsClpP的活性，可用于治疗HsClpP介导的相关疾病。
Description
技术领域
本发明涉及一类咪唑烷并嘧啶酮化合物或其药学上可接受的盐、水合物或晶型在HsClpP介导的疾病治疗中的用途，属于化学医药领域。
背景技术
HsClpP是一种存在于线粒体基质中的ATP依赖的去折叠酶肽酶蛋白复合物。HsClpP维持细胞器的动态平衡，控制蛋白质质量，调节线粒体代谢，在线粒体去折叠蛋白反应和氧化磷酸化完整性中发挥重要作用。当HsClpP异常表达或功能突变时，会导致线粒体功能障碍，诱发各类人体疾病。其中Perrault综合征(PRLTS)、帕金森病(PD)、阿尔茨海默病(AD)等神经系统疾病，肿瘤，以及肥胖、糖尿病等代谢综合征已被深入研究。HsClpP在人类疾病中的作用机制包括调节ROS和ATP的产生，影响线粒体呼吸链复合物酶的活性和Ca2+信号转导。目前各种临床前数据都支持将恢复HsClpP正常活性作为线粒体功能障碍的新治疗方案。该治疗方案为人类线粒体相关疾病的治疗和小分子的研究筛选优化提供了新的策略。
一些小分子已经被开发用于调控HsClpP蛋白水解活性。包括HsClpP抑制剂，如β-内酯类、苯酯类及硼酸拟肽类化合物。HsClpP激动剂，如ADEP类、D9以及依米立酮类(Imipridone)化合物。依米立酮类化合物结构特征在于具有咪唑啉并二氢嘧啶酮的核心骨架，咪唑啉环氮原子与其他取代基团连接。其中ONC201和ONC206分别被批准用于肿瘤治疗的临床试验。ONC201针对多个肿瘤的临床试验目前已进入II期临床阶段，针对H3 K27M突变胶质瘤已进入III期临床试验。ONC206于2020年被批准用于复发性中枢神经系统肿瘤的I期临床研究。
发明内容
本发明的目的在于提供一种咪唑烷并嘧啶酮类化合物。本发明的另一目的在于提供该类化合物的用途。具体地，本发明提供了如式Ⅰ所示的咪唑烷并嘧啶酮类化合物或其药学上可接受的盐、水合物或晶型：
其中Z1独立选自H、烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、杂芳基、芳烷基、杂芳基烷基、烷氧烷基、烷氧羰基、芳烷氧基、芳烷硫基和酰基自由基。Q独立选自以下基团:
其中R1～R6独立的选自氢、卤素、C1-C3取代的烷基；R7-R10独立的选自氢、卤素、C3-C6环烷基、C1-C6取代的烷基。Z2独立选自H、烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、杂芳基、芳烷基、杂芳基烷基、烷氧烷基、烷氧羰基、芳烷氧基，芳烷硫基和酰基自由基。
进一步地，所述化合物为式Ⅰ-1所示，Ar1和Ar2独立的选自芳基，杂环芳基，噻吩和苯基；Ar1和Ar2独立的选自0-5个R11取代的苯基，R11选自卤素、氰基、C1-C6的烷基、C3-C9取代的环烷基、C1-C6的卤烷基、-CF3、-NH2、-NO2、-SH、-SR11、-OH、C1-C6取代的烷氧基、-NR12R13、(C3-C9)环烷基(C2-C6)炔基、(C4-C8)环烯基、(C4-C8)环烯基烷基、取代的芳基、取代的杂环芳基、-COOH、-COOR16、-OCOOR16、C2-C6炔基、C2-C8烯基、-SO2OR16、-SO2NR16R17、-SO2R16、-NR15SO2R16、-CONR16R17、-COR16、-NR16COR17；R1～R6，R7-R10独立的选自氢、卤素、C3-C6环烷基、C1-C6取代的烷基；R11～R17独立的选自氢、卤素、C1-C3取代的烷基。
进一步优选的结构为式Ⅰ-2所示，Ar1和Ar2独立的选自0-5个R15取代的苯基；R15选自卤素、氰基、C1-C6的烷基、C3-C9取代的环烷基、C1-C6的卤烷基、-CF3、-NH2、-NO2、-SH、-SR11、-OH、C1-C6取代的烷氧基、-NR12R13、(C3-C9)环烷基(C2-C6)炔基、(C4-C8)环烯基、(C4-C8)环烯基烷基、取代的芳基、取代的杂环芳基、-COOH、-COOR16、-OCOOR16、(C2-C8)烯基、-SO2OR16、-SO2NR16R17、-SO2R16、-NR16SO2R17、-CONR16R17、-COR16、-NR16COR17；R1～R6，R7-R10独立的选自氢、卤素、C3-C6环烷基、C1-C6取代的烷基；R11～R17独立的选自氢、卤素、C1-C3取代的烷基。
进一步优选的，Ar1和Ar2独立的选自0-5个R15取代的苯基；R15独立的选自氢、卤素、氰基、-CH3、-CF3；R1-R14独立的选自氢、卤素、C1-C3取代的烷基。
其中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、氢氟酸盐、硫酸盐、磷酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、羟乙磺酸盐、对甲基苯磺酸盐、苯磺酸盐、萘磺酸盐、三氟乙酸盐、谷氨酸盐、天冬氨酸盐或生成的药学上可接受的盐。
本发明还提供了上述咪唑烷并嘧啶酮类化合物在治疗HsClpP介导的相关疾病中的用途。进一步的，所述神经系统疾病为亨廷顿氏病、帕金森症、Perrault综合症、阿尔兹海默症、遗传性痉挛性截瘫、Friedreich共济失调等。所述肿瘤为中枢神经系统肿瘤、脑肿瘤、外周神经系统肿瘤、嗜铬细胞瘤、副神经节瘤、神经内分泌肿瘤、肝癌、肺癌、胃癌、结肠癌、直肠癌、胰腺癌、乳腺癌、前列腺癌、子宫内膜癌、血液恶性肿瘤和淋巴系统肿瘤。
本发明通过大量的试验筛查，最终找到了与现有临床阶段的抗肿瘤化合物ONC201、ONC206活性更高且安全性相当的新化合物，为临床上HsClpP介导的相关疾病治疗提供了更好的选择。
所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然属于本发明保护的范围。本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括但并不限于口服、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂或载体混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如强甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如甘油；(d)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如季铵化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如高岭土；(i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其他本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂这些物质的混合物等。用于肠胃外注射的组合物可包含生理上课接受的无菌含水货无水溶液、分散液、悬浮液或乳液、和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药或者与其他药学上可接受的混合物联合给药。本发明所述同位素标记化合物是指与本文中所列化合物相同，但是其中的一个或多个原子被另一个原子取代，该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入化合物中的同位素包括氢、碳、氮、氧、硫，即2H、3H、13C、14C、15N、17O、18O、35S等。含有上述同位素和/或其它原子同位素的化合物及其立体异构体，以及该化合物、立体异构体的可药用的盐均应包含在本发明范围内。
根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。以下通过具体实施例的形式，对本发明的上述内容再做进一步的详细说明。但不应将此理解为本发明上述主体的方位仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明化合物18的HMBC图谱；
图2为本发明化合物对HsClpP蛋白热力学稳定性影响；
图3为本发明化合物对HsClpP酶水解活性的影响；
图4为本发明化合物ONC201、18和22的体外细胞毒性实验。
具体实施方式
所述的咪唑烷并嘧啶酮类化合物的制备方法，合成路线为：
路线一：
a.中间体1是在原料1和原料2碱性条件下关环得到的。所述反应温度为甲醇回流温度，所述的碱为甲醇钠，所述的原料1和原料2、甲醇钠的摩尔比为1:1:3，反应时间为3-24h。
b.中间体1经路易斯酸无水三氯化铝在室温条件下脱除对甲氧基苄基得到中间体2。所述的中间体1与无水三氯化铝摩尔比为1:3，干燥二氯甲烷做溶剂，反应时间为12-24h。反应液用1M氢氧化钠水溶液调至强碱性，分离有机相。水相用氯仿：甲醇(体积比10：1)萃取3遍，合并有机相，干燥后减压浓缩得到中间体2；
c.化合物4～17是在不同取代的芳基或烷基卤化物与中间体2反应得到的，所用的碱为碳酸铯、碳酸钾等中的任意一种，所用的溶剂为DMF、DMSO、乙腈中的一种。所述的反应温度为40-50度，所述的中间体2、卤化物、碱的摩尔比为1:2:3；所述反应时间为12-24h；
路线二：
d.中间体3是在不同取代的芳基或烷基卤化物与原料3反应得到的，所用的碱为碳酸铯、碳酸钾、三乙胺、二异丙基乙基胺等中的任意一种。所述的反应温度为室温，所述的原料3、卤化物、碱的摩尔比为1:1:1.5；所述反应时间为12-24h；
e.中间体4是中间体3脱除保护基后关环得到的。所述操作为室温条件下，向中间体3的二氯甲烷溶液中加入三氟乙酸，反应1-3h，减压浓缩除去三氟乙酸和二氯甲烷，残渣用1M氢氧化钠水溶液调至强碱性，二氯甲烷萃取后减压浓缩得到脱除保护基的产物，所述的二氯甲烷和三氟乙酸体积比为2:1；将脱除保护基的产物溶于乙醇中，分批次加入溴化氰。反应1-24h后，减压浓缩除去乙醇，得到白色的固体即为中间体4。
f.化合物18～22是中间体4和原料4在碱性条件下关环得到的。所述反应温度为甲醇回流温度，所述的碱为甲醇钠，所述的原料4和中间体4、甲醇钠的摩尔比为1:1:3，反应时间为3-24h。
实施例1：7-苄基-9,9-二氟-4-(4-甲氧基苄基)-2,4,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(中间体1a)的制备
将原料1：1-苄基-5,5-二氟-4-恶哌啶-3-羧酸甲酯盐酸盐(2g，6.27mmol)和原料2：N-(4-甲氧基苄基)-4,5-二氢-1H-咪唑-2-胺(1.29g，6.27mmol)溶于无水甲醇(100mL)中，加入甲醇钠(846mg，15.6mmol)后加热回流6h，TLC监测反应完全，减压浓缩除去溶剂，残渣混悬于水中，用二氯甲烷萃取3次，合并有机相，依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液经减压浓缩后混悬于乙酸乙酯打浆，过滤得到白色固体(2.06g，4.7mmol)，产率70％。1H NMR(400MHz,DMSO-d6)δ7.45–7.18(m,7H),6.84(d,J＝8.7Hz,2H),4.87(s,2H),4.03(t,J＝9.0Hz,2H),3.83–3.75(m,2H),3.73(s,2H),3.71(s,3H),3.20(d,J＝4.6Hz,2H),3.09(t,J＝12.3Hz,2H).HRMS(ESI):calcd.for[M+H]+439.1946，found439.1939。
实施例2：3-((9,9-二氟-4-(4-甲氧基苄基)-5-氧代-1,2,4,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(中间体1b)的制备
将原料1：1-(3-氰基苯)-5,5-二氟-4-氧哌啶-3-羧酸甲酯盐酸盐(3.44g，10mmol)和原料2：N-(4-甲氧基苄基)-4,5-二氢-1H-咪唑-2-胺(2.05g，10mmol)溶于无水甲醇(250mL)中，加入甲醇钠(1.35g，25mmol)后加热回流6h，TLC监测反应完全，减压浓缩除去溶剂，残渣混悬于水中，用二氯甲烷萃取3次，合并有机相，依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液经减压浓缩后混悬于乙酸乙酯打浆，过滤得到白色固体(2.78g，6.9mmol)，产率69％。1H NMR(400MHz,DMSO-d6)δ7.83–7.51(m,4H),7.31(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),4.88(s,2H),4.04(t,J＝9.0Hz,2H),3.86–3.76(m,4H),3.72(s,3H),3.30–3.20(m,2H),3.13(t,J＝12.2Hz,2H).HRMS(ESI):calcd.for[M+H]+464.1898，found464.1895。
实施例3：7-苄基-9,9-二氟-2,4,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(中间体2a)的制备
将中间体1a：7-苄基-9,9-二氟-4-(4-甲氧基苄基)-2,4,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮)(2g，4.5mmol)溶于干燥的二氯甲烷中(50mL),加入无水三氯化铝(1.82g，13.7mmol)，氮气保护下室温搅拌过夜，TLC监测原料反应完全，加水淬灭反应。加入氢氧化钠溶液调节pH至强碱性，分液，水层用甲醇：氯仿(1:9)萃取三次，合并至二氯甲烷相。合并的有机相依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液经减压浓缩后混悬于乙酸乙酯打浆，过滤得到白色固体(572mg，1.8mmol)，产率40％。1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.65–6.97(m,5H),4.17(s,2H),3.74(s,2H),3.61(s,2H),3.24–2.91(m,4H).HRMS(ESI):calcd.for[M+H]+319.1370，found 319.1367。
实施例4：3-((9,9-二氟-5-氧代-1,2,4,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(中间体2b)的制备
将中间体1b：3-((9,9-二氟-4-(4-甲氧基苄基)-5-氧代-1,2,4,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(2.5g，7.3mmol)溶于干燥的二氯甲烷(100mL)中，加入无水三氯化铝(2.9g，21.8mmol)，氮气保护下室温搅拌过夜，TLC监测原料反应完全，加水淬灭反应。加入氢氧化钠溶液调节pH至强碱性，分液，水层用甲醇：氯仿(1:9)萃取三次，合并至二氯甲烷相。合并的有机相依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液经减压浓缩后混悬于乙酸乙酯打浆，过滤得到白色固体(1.1g，3.2mmol)，产率44％。1H NMR(400MHz,DMSO-d6)δ7.84–7.55(m,4H),4.17(dd,J＝9.7,7.5Hz,2H),3.82(s,2H),3.62(dd,J＝9.7,7.5Hz,2H),3.21-3.12(m,4H).HRMS(ESI):calcd.for[M+H]+344.1323，found 344.1332。
实施例5：7-苄基-9,9-二氟-3-(2-甲基苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物4)的制备
将中间体2a：7-苄基-9,9-二氟-2,4,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(50mg，0.16mmol)溶于10mL干燥的乙腈中，依次加入无水碳酸钾(65mg，0.47mmol)和2-甲基苄基溴(59mg，0.32mmol)，氮气保护下加热50度反应过夜，TLC检测原料反应完全，加入过量甲醇反应1h猝灭反应。过滤，减压浓缩滤液，残渣经硅胶柱层析，甲醇：二氯甲烷(7:93)洗脱，减压浓缩得到白色固体(35mg，0.08mmol)，产率52％。1H NMR(400MHz,DMSO-d6)δ7.40–7.10(m,9H),4.51(s,2H),4.16(dd,J＝9.7,7.6Hz,2H),3.75(s,2H),3.53(dd,J＝9.8,7.5Hz,2H),3.25–3.08(m,4H),2.28(s,3H).HRMS(ESI):calcd.for[M+H]+423.1996，found 423.1993。
实施例6：7-苄基-9,9-二氟-3-(3-甲基苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物5)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-甲基苄基溴，得到白色固体，产率44％。1H NMR(400MHz,DMSO-d6)δ7.45–7.19(m,6H),7.18–7.06(m,3H),4.49(s,2H),4.15(dd,J＝9.7,7.5Hz,2H),3.75(s,2H),3.56(dd,J＝9.8,7.5Hz,2H),3.25–3.18(m,2H),3.17–3.08(m,2H),2.30(s,3H).HRMS(ESI):calcd.for[M+H]+423.1996，found 423.1993。
实施例7：7-苄基-9,9-二氟-3-(3-溴-4-氟苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物6)的制备
该目标产物的合成操作步骤同实施例5，得到白色泡状固体，其中原料为3-溴-4-氟苄基溴，产率60％。1H NMR(400MHz,DMSO-d6)δ7.70(dd,J＝6.8,2.0Hz,1H),7.44–7.26(m,7H),4.51(d,J＝2.5Hz,2H),4.16(dd,J＝9.7,7.5Hz,2H),3.76(s,2H),3.60(dd,J＝9.8,7.4Hz,2H),3.24–3.08(m,4H).HRMS(ESI):calcd.for[M+Na]+527.0670，found 527.0677。
实施例8：3-((3-(3,4-二氟苄基)-9,9-二氟-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物7)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3,4-二氟苄基溴，得到白色泡状固体，产率65％。1H NMR(400MHz,DMSO-d6)δ7.78(dq,J＝4.7,1.5Hz,2H),7.73–7.65(m,1H),7.59(t,J＝7.9Hz,1H),7.49–7.34(m,2H),7.20(ddd,J＝10.1,4.8,2.1Hz,1H),4.52(s,2H),4.25–4.11(m,2H),3.83(s,2H),3.66–3.56(m,2H),3.23(t,J＝4.4Hz,2H),3.17(t,J＝12.2Hz,2H).HRMS(ESI):calcd.for[M+H]+470.1604，found470.1601。
实施例9：3-((7-苄基-9,9-二氟-5-氧代-1,2,6,7,8,9-六氢咪唑并[1,2-a]吡啶基[3,4-e]嘧啶-3(5H)-基)甲基)苯甲酸甲酯(化合物8)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-溴甲基苯甲酸甲酯。反应得到白色泡状固体，产率60％。1H NMR(400MHz,DMSO-d6)δ7.98–7.86(m,2H),7.84–7.74(m,2H),7.69(dt,J＝7.8,1.5Hz,1H),7.66–7.50(m,3H),4.61(s,2H),4.17(dd,J＝9.7,7.5Hz,2H),3.86(s,3H),3.84(s,2H),3.60(dd,J＝9.7,7.4Hz,2H),3.25(t,J＝4.5Hz,2H),3.22–3.11(m,2H).HRMS(ESI):calcd.for[M+H]+492.1847，found492.1844。
实施例10：3-((3-苄基-9,9-二氟-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物9)的制备
该目标产物的合成操作步骤同实施例5，得到白色固体，其中原料为苄基溴，产率48％。1H NMR(400MHz,DMSO-d6)δ7.86–7.75(m,2H),7.69(dd,J＝7.9,1.6Hz,1H),7.59(t,J＝7.9Hz,1H),7.45–7.27(m,5H),4.54(s,2H),4.17(dd,J＝9.7,7.5Hz,2H),3.83(s,2H),3.58(dd,J＝9.7,7.5Hz,2H),3.24(t,J＝4.5Hz,2H),3.21–3.11(m,2H).HRMS(ESI):calcd.for[M+H]+434.1792，found 434.1786。
实施例11：3-((3-(3-氟苄基)-9,9-二氟-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物10)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-氟苄基溴，得到白色泡状固体，产率50％。1H NMR(400MHz,DMSO-d6)δ7.90–7.75(m,2H),7.72–7.65(m,1H),7.63–7.55(m,1H),7.47–7.36(m,1H),7.27–7.07(m,3H),4.56(s,2H),4.19(dd,J＝9.7,7.5Hz,2H),3.84(s,2H),3.62(dd,J＝9.8,7.4Hz,2H),3.24(t,J＝4.4Hz,2H),3.21–3.12(m,2H).HRMS(ESI):calcd.for[M+H]+452.1698，found452.1689。
实施例12：3-((3-(3-溴-4-氟苄基)-9,9-二氟-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物11)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-溴-4-氟苄基溴，得到白色泡状固体，产率58％。1H NMR(400MHz,DMSO-d6)δ7.83–7.76(m,2H),7.70(td,J＝6.4,1.7Hz,2H),7.59(t,J＝7.9Hz,1H),7.44–7.33(m,2H),4.52(s,2H),4.17(dd,J＝9.7,7.5Hz,2H),3.83(s,2H),3.60(t,J＝8.6Hz,2H),3.23(t,J＝4.5Hz,2H),3.21–3.14(m,3H).HRMS(ESI):calcd.for[M+H]+530.0803，found530.0801。
实施例13：3-((9,9-二氟-3-异戊基-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶基[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物12)的制备
该目标产物的合成操作步骤同实施例5，得到白色固体，其中原理为1-溴代异戊烷，产率35％。1H NMR(400MHz,DMSO-d6)δ7.81–7.74(m,2H),7.71–7.65(m,1H),7.62–7.55(m,1H),4.14(dd,J＝9.8,7.5Hz,2H),3.82(s,2H),3.67(dd,J＝9.9,7.5Hz,2H),3.39–3.27(m,2H),3.25–3.19(m,2H),3.19–3.10(m,2H),1.58(dp,J＝13.3,6.6Hz,1H),1.49–1.36(m,2H),0.91(s,3H),0.90(s,3H).HRMS(ESI):calcd.for[M+H]+414.2105，found 414.2104。
实施例14：3-((9,9-二氟-3-(4-甲基苄基)-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物13)的制备
该目标产物的合成操作步骤同实施例5，其中原料为4-甲基苄基溴，得到白色固体，产率41％。1H NMR(400MHz,DMSO-d6)δ7.78(dt,J＝5.5,1.7Hz,2H),7.69(dt,J＝7.9,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.28–7.11(m,4H),4.48(s,2H),4.15(dd,J＝9.7,7.5Hz,2H),3.83(s,2H),3.55(dd,J＝9.7,7.5Hz,2H),3.24(t,J＝4.5Hz,2H),3.20–3.07(m,2H),2.29(s,3H).HRMS(ESI):calcd.for[M+H]+448.1949，found 448.1947。
实施例15：3-((9,9-二氟-3-(3，4-二氯苄基)-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物14)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3,4-二氯苄基溴，得到白色固体，产率60％。1H NMR(400MHz,DMSO-d6)δ7.82–7.74(m,2H),7.73–7.54(m,4H),7.34(dd,J＝8.3,2.0Hz,1H),4.54(s,2H),4.18(dd,J＝9.7,7.5Hz,2H),3.84(s,2H),3.62(dd,J＝9.8,7.4Hz,2H),3.28–3.12(m,4H).HRMS(ESI):calcd.for[M+H]+502.1013，found 502.1007。
实施例16：3-((9,9-二氟-3-(3-甲基苄基)-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物15)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-甲基苄基溴，得到白色固体，产率44％。1H NMR(400MHz,DMSO-d6)δ7.42–7.20(m,6H),7.16–7.08(m,3H),4.49(s,2H),4.15(dd,J＝9.7,7.5Hz,2H),3.75(s,2H),3.56(dd,J＝9.8,7.5Hz,2H),3.28–3.08(m,4H),2.30(s,3H).HRMS(ESI):calcd.for[M+H]+448.1949，found 448.1943。
实施例17：3-((9,9-二氟-5-氧代-3-(吡啶-3-基甲基)-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶基[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物16)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-溴甲基吡啶，得到白色固体，产率31％。HRMS(ESI):calcd.for[M+H]+435.1745，found435.1740。
实施例18：3-((3-(环丙基甲基)-9,9-二氟-5-氧代-1,2,3,5,8,9-六氢咪唑并[1,2-a]吡啶基[3,4-e]嘧啶-7(6H)-基)甲基)苯甲腈(化合物17)的制备
该目标产物的合成操作步骤同实施例5，其中原料为3-溴甲基吡啶，得到白色固体，产率33％。HRMS(ESI):calcd.for[M+H]+398.1792，found 398.1795。
实施例19：叔丁基(2-((2-甲基苄基)氨基)乙基)氨基甲酸酯(中间体3a)的制备
在剧烈搅拌下，将2-甲基苄基溴(1.85g，10mmol)缓慢滴加到N-(叔丁氧羰基)-1,2-乙二胺(1.6g，10mmol)和三乙胺(1.2g，12mmol)的二氯甲烷(50mL)混合溶液中。室温反应5h，TLC检测原料反应完毕，加水淬灭反应并将有机相依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液减压浓缩后经硅胶柱层析，洗脱体系为甲醇：二氯甲烷＝20:1，洗脱组分经减压浓缩后得到无色透明油状液体1.71g，产率65％。1H NMR(400MHz,DMSO-d6)δ7.37–7.22(m,1H),7.12(d,J＝3.2Hz,3H),6.75(t,J＝5.8Hz,1H),3.64(s,2H),3.05(q,J＝6.3Hz,2H),2.58(t,J＝6.5Hz,2H),2.28(s,3H),1.37(s,9H).HRMS(ESI):calcd.for[M+H]+265.1916，found 265.1911。
实施例20：叔丁基(2-((4-三氟甲基苄基)氨基)乙基)氨基甲酸酯(中间体3b)的制备
该中间体的合成操作步骤同实施例19，得到无色透明的油状液体，产率78％。1HNMR(400MHz,DMSO-d6)δ7.66(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),6.74(t,J＝5.7Hz,1H),3.77(s,2H),3.03(q,J＝6.3Hz,2H),2.55–2.51(m,2H),2.29(s,1H),1.37(s,9H)。
实施例21：叔丁基(2-((3，4-二氟苄基)氨基)乙基)氨基甲酸酯(中间体3c)的制备
该中间体的合成操作步骤同实施例19，得到无色透明的油状液体，产率73％。1HNMR(400MHz,DMSO-d6)δ7.44–7.27(m,2H),7.21–7.09(m,1H),6.74(t,J＝5.8Hz,1H),3.66(s,2H),3.01(q,J＝6.3Hz,2H),2.54–2.50(m,2H),2.24(s,1H),1.37(s,9H)。
实施例22：叔丁基(2-((2，4-二氟苄基)氨基)乙基)氨基甲酸酯(中间体3d)的制备
该中间体的合成操作步骤同实施例19，得到无色透明的油状液体，产率68％。1HNMR(400MHz,DMSO-d6)δ7.48(td,J＝8.6,6.7Hz,1H),7.22–6.98(m,2H),6.73(t,J＝5.7Hz,1H),3.68(s,2H),3.02(q,J＝6.3Hz,2H),2.53(d,J＝6.5Hz,2H),2.29–2.02(m,1H),1.37(s,9H)。
实施例23：叔丁基(2-((3-溴-4-氟苄基)氨基)乙基)氨基甲酸酯(中间体3e)的制备
该中间体的合成操作步骤同实施例19，得到无色透明的油状液体，产率61％。1HNMR(400MHz,DMSO-d6)δ7.65(dd,J＝7.0,2.0Hz,1H),7.41–7.22(m,2H),6.73(t,J＝5.8Hz,1H),3.66(s,2H),3.01(q,J＝6.3Hz,2H),2.51(d,J＝2.4Hz,1H),2.23(s,1H),1.37(s,9H)。
实施例24：1-(2-甲基苄基)咪唑啉-2-亚胺氢溴酸盐(中间体4a)的制备
向叔丁基(2-((2-甲基苄基)氨基)乙基)氨基甲酸酯1.5g(5.7mmol)的二氯甲烷(16mL)溶液中缓慢滴加三氟乙酸(8mL)，滴加完毕后继续反应2小时，TLC监测原料反应完毕后，减压浓缩，得到的残渣溶于水中，加1M的NaOH溶液调pH至强碱性，二氯甲烷萃取三次，合并有机相，依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液减压浓缩后得到无色透明油状液体800mg。在通风橱内，将得到的800mg油状液体溶液溶于30mL无水乙醇中，剧烈搅拌条件下分批次加入溴化氰(725mg，6.84mmol)，5h后TLC监测原料反应完全。减压浓缩后得到白色固体(浓缩过程在通风橱内进行，回收的溶剂用强碱和双氧水处理)。将得到的白色固体混悬于乙酸乙酯打浆，过滤，得到白色固体(1.1g,4.1mmol)，两步产率72％。1HNMR(400MHz,DMSO-d6)δ8.24(s,2H),8.00(s,1H),7.30–7.10(m,4H),4.60(s,2H),3.64–3.51(m,2H),3.50–3.40(m,2H),2.27(s,3H).HRMS(ESI):calcd.for[M+H]+190.1344，found190.1345。
实施例25：1-(4-三氟甲基苄基)咪唑啉-2-亚胺氢溴酸盐(中间体4b)的制备
该中间体的合成操作步骤同实施例24，得到白色固体，两步产率68％。1HNMR(400MHz,DMSO-d6)δ8.24(s,2H),8.00(s,1H),7.79(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),4.71(s,2H),3.64–3.47(m,4H)。
实施例26：1-(3，4二氟苄基)咪唑啉-2-亚胺氢溴酸盐(中间体4c)的制备
该中间体的合成操作步骤同实施例24，得到白色固体，两步产率78％。1HNMR(400MHz,DMSO-d6)δ8.23(s,2H),7.97(s,1H),7.48(dtd,J＝11.0,9.4,8.1,5.3Hz,2H),7.21(ddt,J＝8.2,3.8,1.6Hz,1H),4.60(s,2H),3.53(d,J＝3.0Hz,4H)。
实施例27：1-(2，4-二氟苄基)咪唑啉-2-亚胺氢溴酸盐(中间体4d)的制备
该中间体的合成操作步骤同实施例24，得到白色固体，两步产率74％。1HNMR(400MHz,DMSO-d6)δ8.25(s,2H),7.97(s,1H),7.57–7.46(m,1H),7.38–7.29(m,1H),7.20–7.12(m,1H),4.66(s,2H),3.52(tt,J＝9.0,4.3Hz,4H)。
实施例28：1-(3-溴-4-氟苄基)咪唑啉-2-亚胺氢溴酸盐(中间体4e)的制备
该中间体的合成操作步骤同实施例24，得到白色固体，两步产率70％。1HNMR(400MHz,DMSO-d6)δ8.22(s,2H),7.96(s,1H),7.79–7.65(m,1H),7.48–7.35(m,2H),4.59(s,2H),3.65–3.39(m,4H)。
实施例29：7-苄基-3-(2-甲基苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物18的)制备
将1-(2-甲基苄基)咪唑啉-2-亚胺氢溴酸盐(1g，3.72mmol)和原料4(0.92g，3.72mmol)溶于无水甲醇(50mL)中，加入甲醇钠(500mg，9.3mmol)后加热回流3h，TLC监测反应完全，减压浓缩除去溶剂，残渣混悬于水中，用二氯甲烷萃取3次，合并有机相，依次用水洗涤三次，饱和食盐水洗涤一次，无水硫酸钠干燥。过滤，滤液减压浓缩后经硅胶柱层析纯化，洗脱体系甲醇：二氯甲烷(1:19)，合并洗脱组分，减压浓缩后得到白色固体(503mg1.3mmol)，产率35％。1H NMR(400MHz,DMSO-d6)δ7.48–7.10(m,9H),4.47(s,2H),4.01(dd,J＝9.7,7.4Hz,2H),3.63(s,2H),3.45(dd,J＝9.7,7.4Hz,2H),3.02(d,J＝2.0Hz,2H),2.66(t,J＝5.6Hz,2H),2.56(t,J＝5.6Hz,2H),2.28(s,3H).HRMS(ESI):calcd.for[M+Na]+409.2004,found 409.2001。
实施例30：7-苄基-3-(4-三氟甲基苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物19)的制备
该目标产物的合成操作步骤同实施例29，得到白色固体，产率31％。1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝7.7Hz,2H),7.54(d,J＝7.7Hz,2H),7.42–7.17(m,5H),4.58(s,2H),4.03(t,J＝8.5Hz,2H),3.63(s,2H),3.53(t,J＝8.5Hz,2H),3.02(s,2H),2.66(t,J＝5.6Hz,2H),2.56(t,J＝5.6Hz,2H)。
实施例31：7-苄基-3-(2，4-二氟苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物20)的制备
该目标产物的合成操作步骤同实施例29，得到白色固体，产率37％。1H NMR(400MHz,DMSO-d6)δ7.45(td,J＝8.6,6.6Hz,1H),7.37–7.23(m,6H),7.09(td,J＝8.6,2.6Hz,1H),4.51(s,2H),4.01(dd,J＝9.7,7.4Hz,2H),3.62(s,2H),3.52(dd,J＝9.7,7.3Hz,2H),3.01(s,2H),2.65(t,J＝5.7Hz,2H),2.55(t,J＝5.3Hz,2H)。
实施例32：7-苄基-3-(3，4-二氟苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物21)的制备
该目标产物的合成操作步骤同实施例29，得到白色固体，产率33％。1H NMR(400MHz,DMSO-d6)δ7.51–7.09(m,8H),4.47(s,2H),4.02(dd,J＝9.7,7.4Hz,2H),3.64(s,2H),3.52(dd,J＝9.7,7.4Hz,2H),3.04(s,2H),2.66(t,J＝5.7Hz,2H),2.56(t,J＝5.7Hz,2H)。
实施例33：7-苄基-3-(3-溴-4-氟苄基)-2,3,6,7,8,9-六氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(1H)-酮(化合物22)的制备
该目标产物的合成操作步骤同实施例29，得到白色固体，产率38％。1H NMR(400MHz,DMSO-d6)δ7.72–7.61(m,1H),7.42–7.20(m,7H),4.47(s,2H),4.01(dd,J＝9.7,7.4Hz,2H),3.63(s,2H),3.51(dd,J＝9.7,7.3Hz,2H),3.02(s,2H),2.65(t,J＝5.7Hz,2H),2.54(t,J＝5.6Hz,2H)。
以下通过实验例阐述本发明化合物的结构特征和有益效果。
实验例1：本实验通过化合物18的异核多键碳氢相关谱(HMBC)，对咪唑烷并嘧啶酮类化合物的结构特点进行表征。从图1中可以看出，2-甲基苄基的亚甲基氢与咪唑啉环的C-19，C-21有耦合信号，而与嘧啶酮的C-7无相关耦合信号，表明该类化合物的取代基连接在咪唑烷环的氮原子上。传统依米立酮类化合物骨架为咪唑啉并二氢嘧啶酮，取代基连接在二氢嘧啶酮的氮原子上。因此本发明的化合物是一类具有全新结构特征的咪唑烷并嘧啶酮化合物。
实验例2：差示扫描荧光(Differential Scanning Fluorimetry，DSF)实验
本实验通过检测相同浓度下ONC201、化合物18、22对HsClpP蛋白稳定性的影响，验证发明化合物与HsClpP的相互作用，并比较发明化合物和ONC201对HsClpP的相互作用强弱。反应体系：向RT-PCR八连管分别加入10μMHsClpP、5×SSYPRO Orange和100μM化合物溶液，每孔设置至少2个重复孔，室温孵育30min。反应体系为K2HPO4/KH2PO450 mM pH 7.6，KCl100mM，5％甘油。检测：使用RT-PCR仪器进行荧光检测。选择熔融曲线，设置温度40min内从25℃升至99℃，荧光检测通道选择SSYPRO Orange通道，记录数据。结果如图2所示，以DMSO为空白对照，上述化合物使HsClpP蛋白的Tm值右移，表明均对HsClpP的热稳定性产生了显著的影响。在相同浓度下，各自引起的Tm值变化大小顺序为化合物22>化合物18>ONC201，表明本发明化合物18和22对HsClpP蛋白热力学稳定性影响显著优于ONC201，是一类优异的HsClpP调控剂。
实验例3：化合物激动HsClpP酶水解短肽底物实验
本研究通过考察化合物对HsClpP蛋白水解AC-WLA-AMC底物作用的影响，评价化合物对HsClpP的调控活性。测试体系体积100uL，其中HsClpP蛋白终浓度0.5uM，底物AC-WLA-AMC终浓度200uM，待测化合物18，22，ONC201母液稀释成一系列梯度，终浓度设置为1uM、500nM、250nM、125nM、62.5nM、31.25nM。先将小分子与HsClpP蛋白溶液加入平底黑色96孔板中，每组设置三个复孔，室温孵育10min后再加入底物AC-WLA-AMC，立即使用荧光酶标仪检测孔中的荧光强度(激发光：360nm，发射光：440nm)，每间隔5min读数一次，每次读数前振荡5s，连续检测30min。阴性对照组使用DMSO替代小分子。记录不同浓度下对DMSO组的读数值倍数作为水解活性评价指数。使用Graphpadprism对得到的倍数值进行作图，计算EC50值。其他化合物母液稀释成10uM，测定方式如上所述。图3结果显示，随着浓度的升高，ONC201和发明化合物均能促进HsClpP蛋白水解AC-WLA-AMC底物的能力。计算得到发明化合物的EC50值低于ONC201，表明这类化合物促进HsClpP蛋白水解底物的能力明显强于ONC201，因此本发明化合物是一类活性优异的HsClpP调控剂。表1结果显示，在10uM单一浓度下，发明化合物和ONC201、ONC212针对HsClpP均显示出优异的调控性能。
| 化合物编号 | 调控效力* | 化合物编号 | 调控效力* | 化合物编号 | 调控效力* |
| 4 | ++ | 11 | ++ | 18 | ++ |
| 5 | ++ | 12 | ++ | 19 | ++ |
| 6 | ++ | 13 | ++ | 20 | ++ |
| 7 | ++ | 14 | ++ | 21 | ++ |
| 8 | ++ | 15 | ++ | 22 | ++ |
| 9 | ++ | 16 | ++ | ONC201 | ++ |
| 10 | ++ | 17 | ++ | ONC212 | ++ |
表1化合物5-17和ONC212在单一浓度下(10uM)促进HsClpP酶水解短肽底物的效力。*相对于空白对照组的效力：++表明效力增加值>空白对照组的50％(EC50)；+表明效力增加值<空白对照组的50％。
实验例4：体外抗肿瘤增殖实验
本实验目的是采用CCK-8检测发明化合物对体外肿瘤细胞增殖抑制活性。主要试剂：RPMI-1640，DMED高糖培养基，胎牛血清，胰酶等购自Gibco BRL公司。CCK8，DMSO为Sigma公司产品。体外实验时，待测化合物用DMSO配成10mM储存液于-20度冰箱避光保存备用，临用时用完全培养液稀释至所需浓度。本实验所用人肺癌细胞、结肠癌细胞、乳腺癌细胞、脑胶质瘤细胞、人髓性单核细胞白血病细胞、人Burkitt's淋巴瘤细胞均购于美国ATCC公司，由本实验室保存。以上所有细胞株均用含10％胎牛血清，100U/mL青霉素，100ug/mL链霉素的RPMI-1640完全培养基或DMED完全培养基在5％二氧化碳，37度条件下培养。试验方法：细胞培养过程中观察生长状态良好时，将细胞消化，离心进行收集。弃去之前的培养基，加入新鲜培养基重悬细胞，然后对细胞进行计数。根据不同细胞的生长速度确定细胞铺板浓度，一般为3000-5000个/孔，确定了铺板浓度后，用新鲜的培养基将细胞悬液稀释到所需浓度，然后加入96孔板中，每孔100uL，边孔中加入200uLPBS以防止培养基水分的蒸发。第二天，进行加药处理，首先用培养基将化合物稀释成一系列梯度，然后将药液加入96孔板中，每个梯度设置3个平行复孔。每板设置空白对照组，ONC201或ONC212为阳性对照组。药物处理72h后，先肉眼观察96孔板中细胞生长状况，然后向每孔中加入CCK-8溶液，置于在培养箱中孵育1-2h，最后于450nm下进行吸光度检测。计算得到每个药物浓度下的抑制率，细胞抑制率＝(空白对照组OD450-实验组OD450)/空白对照组OD450×100％，然后使用Graphpadprism软件进行IC50计算，结果见表2、表3、表4。
表2化合物发明化合物4-17和ONC212在单一浓度下(1uM)对黑色素瘤细胞(A-375)、HuH-7(人肝癌细胞)、MGC80-3(人胃癌细胞)、人卵巢癌细胞(SK-OV-3)的抑制率。
表3化合物18-22和ONC201、ONC212对结肠癌细胞(SW620 DLD-1)、人非小细胞肺癌细胞(A549)、人髓性单核细胞白血病细胞(MV-4-11)、人Burkitt's淋巴瘤细胞(Raji)、人胶质母细胞瘤细胞(A172)的抑制活性。
表4化合物18，22，ONC201体外对人结肠癌细胞(SW620，HCT 116，HT-29，SW480)、人结直肠腺癌上皮细胞(DLD-1)、人结直肠腺癌细胞(HCT-15，Caco2)和小鼠结肠癌细胞(CT26.WT)增殖的抑制活性。
化合物体外对肿瘤细胞增殖抑制实验结果显示，在单一浓度下(1uM)针对黑色素瘤细胞(A-375)、HuH-7(人肝癌细胞)、MGC80-3(人胃癌细胞)、人卵巢癌细胞(SK-OV-3)的抑制活性筛选中，表2中合成的化合物均对上述恶性肿瘤细胞有抑制作用，其中化合物5，7，10，11，13，14，15与已知的抑瘤活性最高的ONC212有相当甚至更优异的抑制增殖活性。表3中，化合物18与阳性对照ONC201相比，针对结肠癌细胞(SW620 DLD-1)、人非小细胞肺癌细胞(A549)、人髓性单核细胞白血病细胞(MV-4-11)、人Burkitt's淋巴瘤细胞(Raji)、人胶质母细胞瘤细胞(A172)的抑制活性均高出了一个数量级，在抗肿瘤药物的开发中显示出极大的潜力。化合物22较已知的抑瘤活性最高的ONC212在活性方面也提升了1-2个数量级。表4中，针对结肠癌相关肿瘤细胞的体外抑制活性显著优于阳性对照ONC201，凸显了该发明在肿瘤治疗相关领域的重要性。
实验例5：体外细胞毒性实验
本实验目的是采用CCK-8检测发明化合物在体外对人正常胚胎肾细胞HEK293和大鼠心肌细胞H9C2增殖的抑制活性。所采用的细胞培养方式、给药方式、检测方式同实验例3。结果如图4所示，针对HEK293细胞，化合物18和22的毒性跟ONC201对照无明显差异，浓度高达50uM时对细胞均无明显抑制活性。针对H9C2细胞，化合物18和ONC201均无明显抑制活性，但化合物22的细胞毒性略大于ONC201。
本领域技术人员应理解，对上面显示和描述的示例性实施方式，在不脱离其广泛的发明构思的前提下可以进行改变，本发明不限于所显示和描述的示例性实施方式，而是覆盖由权利要求限定的本发明的精神和范围。
Claims (10)
1.本发明提供了一类咪唑烷并嘧啶酮类化合物，其特征在于所述化合物如式Ⅰ所示：
Z1-Q
式Ⅰ
其中Z1独立选自H、烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、杂芳基、芳烷基、杂芳基烷基、烷氧烷基、烷氧羰基、芳烷氧基、芳烷硫基和酰基自由基；Q独立选自以下结构:
其中R1～R6独立的选自氢、卤素、C1-C3取代的烷基；R7-R10独立的选自氢、卤素、C3-C6环烷基、C1-C6取代的烷基；Z2独立选自H、烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、杂芳基、芳烷基、杂芳基烷基、烷氧烷基、烷氧羰基、芳烷氧基、芳烷硫基和酰基自由基。
2.根据权利要求1所述的咪唑烷并嘧啶酮类化合物，其特征在于所示化合物为式Ⅰ-1所示：
Ar1和Ar2独立的选自0-5个R15取代的芳基、杂环芳基、噻吩和苯基；R15选自卤素、氰基、C1-C6的烷基、C3-C9取代的环烷基、C1-C6的卤烷基、-CF3、-NH2、-NO2、-SH、-SR16、-OH、C1-C6取代的烷氧基、-NR16R17、(C3-C9)环烷基、(C2-C6)炔基、(C4-C8)环烯基、(C4-C8)环烯基烷基、取代的芳基、取代的杂环芳基、-COOH、-COOR16、-OCOOR16、C2-C8烯基、-SO2OR16、-SO2NR16R17、-SO2R16、-NR15SO2R16、-CONR16R17、-COR16、-NR16COR17；R1～R6、R7-R10独立的选自氢、卤素、C3-C6环烷基、C1-C6取代的烷基；R11～R17独立的选自氢、卤素、C1-C3取代的烷基。
3.根据权利要求2所述的咪唑烷并嘧啶酮类化合物，其特征在于所示化合物为式Ⅰ-2所示
Ar1和Ar2独立的选自0-5个R15取代的苯基，R15选自卤素、氰基、C1-C6的烷基、C3-C9取代的环烷基、C1-C6的卤烷基、-CF3、-NH2、-NO2、-SH、-SR16、-OH、C1-C6取代的烷氧基、-NR16R17、(C3-C9)环烷基(C2-C6)炔基、(C4-C8)环烯基、(C4-C8)环烯基烷基、取代的芳基、取代的杂环芳基、-COOH、-COOR16、-OCOOR16、C2-C6炔基、C2-C8烯基、-SO2OR16、-SO2NR16R17、-SO2R16、-NR15SO2R16、-CONR16R17、-COR16、-NR16COR17；R1～R6，R7-R10独立的选自氢，卤素，C3-C6环烷基、C1-C6取代的烷基；R11～R17独立的选自氢、卤素、C1-C3取代的烷基。
4.根据权利要求3所述的咪唑烷并嘧啶酮类化合物，其特征在于R1-R14独立的选自氢、卤素、C1-C3取代的烷基；R15选自氢、卤素、氰基、-CH3、-CF3。
5.所述咪唑烷并嘧啶酮类化合物，其结构式为：
6.权利要求1-5中所述的咪唑烷并嘧啶酮类化合物的任一原子的同位素取代。
7.权利要求1～6任一项所述的咪唑烷并嘧啶酮类化合物药学上可接受的盐、水合物或晶型，所述的盐优选的为本发明化合物可以与盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、羟乙磺酸、对甲基苯磺酸、苯磺酸、萘磺酸、三氟乙酸或天冬氨酸生成的药学上可接受的盐。
8.权利要求1～7任一项所述的咪唑烷并嘧啶酮类化合物及其盐、水合物或晶型在HsClpP介导的神经系统疾病、代谢综合征和肿瘤相关疾病的治疗中的用途。
9.权利要求1～7任一项所述的咪唑烷并嘧啶酮类化合物及其盐、水合物或晶型在治疗HsClpP调控的相关恶性肿瘤如：中枢神经系统肿瘤、脑肿瘤、外周神经系统肿瘤、嗜铬细胞瘤、副神经节瘤、神经内分泌肿瘤、肝癌、肺癌、胃癌、结肠癌、直肠癌、胰腺癌、乳腺癌、前列腺癌、子宫内膜癌、血液系统恶性肿瘤和淋巴系统肿瘤等的用途。
10.一种治疗HsClpP介导的疾病的药物组合物，其特征在于：以权利1-7任一一项所述依咪唑烷并嘧啶酮类化合物或其晶型、药学上可接受的盐、水合物或溶剂合物为活性成分，加上药学上可接受辅料或/和辅助性成分制备而成的制剂。
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