CN115232118B - 蛋白激酶抑制活性小分子及其衍生物、制备方法、药物组合物和应用 - Google Patents
蛋白激酶抑制活性小分子及其衍生物、制备方法、药物组合物和应用 Download PDFInfo
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- CN115232118B CN115232118B CN202110440537.XA CN202110440537A CN115232118B CN 115232118 B CN115232118 B CN 115232118B CN 202110440537 A CN202110440537 A CN 202110440537A CN 115232118 B CN115232118 B CN 115232118B
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- fluoro
- benzo
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- amino
- oxazin
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Abstract
本发明公开了一类蛋白激酶抑制活性小分子及其衍生物、制备方法、药物组合物和应用。该类小分子的化学结构如式(I)所示,其衍生物为所述小分子的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐、药学上可接受的盐或它们的混合物。该类小分子及其衍生物可高效抑制蛋白激酶和多种肿瘤细胞,可制备为治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病或心血管疾病的药物。
Description
技术领域
本发明涉及一类蛋白激酶抑制活性小分子及其衍生物、制备方法、药物组合物和应用,尤其涉及一类在分子和细胞水平均具有优异的生物活性的蛋白激酶抑制活性小分子及其衍生物、制备方法、药物组合物和应用。
背景技术
肿瘤最主要的特征就是逃避细胞凋亡和无限制增殖,这些均依赖如Mcl-1等抗凋亡蛋白的过表达。髓样细胞白血病1(Mcl-1)蛋白是Bcl-2家族抗凋亡蛋白成员,是多种肿瘤细胞存活的关键因子。Mcl-1通过结合并隔离线粒体外膜上的促凋亡蛋白Bak和Bax,从而阻止内细胞凋亡。在癌症患者中,Mcl-1的过表达与肿瘤耐药和复发高度相关。在多个血液瘤模型中,Mcl-1的快速消耗会导致肿瘤细胞凋亡和肿瘤体积减小甚至肿瘤消退。为了减少Mcl-1的表达,抑制其转录的蛋白激酶的活性则成为了一项重要的策略,以CDK9为代表的蛋白激酶均对Mcl-1的表达具有重要作用。
细胞周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)是一类重要的丝氨酸/苏氨酸蛋白激酶,共有21个成员。研究显示,CDK活性失调已成为癌症的重要标志。CDK与细胞周期(Cyclin)蛋白形成复合物,磷酸化下游相关信号通路蛋白,影响细胞周期进程。根据CDKs/Cyclin复合物功能的不同,可将CDKs分为周期型CDKs和转录型CDKs。其中,CDK9作为转录型CDK,对细胞内遗传信息的转录发挥着重要作用。CDK9及其细胞周期蛋白T1、T2a、T2b或K结合形成的复合物为正性转录延长因子(P-TEFb)。当NELF、DSIF等负性转录延长因子参与细胞转录的负性调节时,转录被抑制在起始复合物阶段,P-TEFb被招募至NELF、DSIF抑制转录延长的体系中,作用于磷酸化RNA聚合酶II(RNA polymerase II)大亚基C末端结构域Ser-2,使负性转录延长因子从转录复合物上脱离,从而促进继续进行转录。在许多恶性肿瘤细胞中,由于CDK蛋白激酶高度活化,导致细胞周期调控和转录异常。P-TEFb异二聚体中的CDK9活性被异常激活主要与过度增殖性疾病(例如癌症)、病毒诱导的感染性疾病或心血管疾病有关。从慢性淋巴细胞白血病或多发性骨髓瘤患者中分离出的活细胞检查结果发现,过度激活的CDK9通路可以增加Mcl-1等抗凋亡蛋白的表达,从而抑制细胞的正常凋亡。
发明内容
发明目的:本发明的第一目的是提供一类蛋白激酶抑制活性小分子及其衍生物,第二目的是提供所述蛋白激酶抑制活性小分子及其衍生物的制备方法,第三目的是提供一种包含所述蛋白激酶抑制活性小分子和/或其衍生物的药物组合物,第四目的是提供所述蛋白激酶抑制活性小分子及其衍生物、药物组合物在制备治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病或心血管疾病药物中的应用。
技术方案:本发明的蛋白激酶抑制活性小分子及其衍生物的化学结构如式(I)所示,所述衍生物为所述小分子的异构体、非对映异构体、对映异构体、互变异构体、溶剂化物、溶剂化物的盐、药学上可接受的盐或它们的混合物:
其中:
X为N或CH;
Y为N或CH;
W、Q各自独立地为O、S或NR4;
L为亚甲基或羰基;
n=0或1;
R1选自以下任一基团:
其中:G为N或CH;
R2为氢原子、卤素、C1-C6烷基、氰基、C1-C6烷氧基或C1-C6卤代烷基;
R3为氢原子、羟基、C1-C6烷基、C1-C6烷氨基、C1-C6烷氧基或Het1取代基,其中:C1-C6烷基、C1-C6烷氨基、C1-C6烷氧基或Het1取代基上还包含一个或多个卤素、羟基、氨基、杂原子、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氨基、C1-C6烷氧基或Het1取代基;所述Het1取代基为吗啉基、吗啉基烷基、吗啉基烷氧基、吗啉基烷氨基、哌嗪基、哌嗪基烷基、哌嗪基烷氧基、哌嗪基烷氨基、高哌嗪基、高哌嗪基烷基、高哌嗪基烷氧基、高哌嗪基烷氨基、哌啶基、哌啶基烷基、哌啶基烷氧基、哌啶基烷氨基,四氢吡咯基、四氢吡咯基烷基、四氢吡咯基烷氧基、四氢吡咯基烷氨基、四氢呋喃基、四氢呋喃烷基、四氢呋喃烷氧基、四氢呋喃烷氨基、四氢吡喃基、四氢吡喃烷基、四氢吡喃烷氧基或四氢吡喃烷氨基;
R4为氢原子、C1-C6烷基或-C(O)R12,其中C1-C6烷基上还包含一个或多个卤素、羟基、氨基、杂原子、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氨基、C1-C6烷氧基或Het1取代基;
R5为氢原子、羰基、卤素、C1-C6烷基、氰基或C1-C6卤代烷基;
R6为氢原子、卤素、C1-C6烷基、氰基或C1-C6卤代烷基;
R7为氢原子、羰基、卤素、C1-C6烷基、氰基或C1-C6卤代烷基;
R8为氢原子、卤素、C1-C6烷基、氰基或C1-C6卤代烷基;
其中:当R5为羰基时,R6不存在,R7不同时为羰基;当R7为羰基时,R8不存在,R5不同时为羰基;
R9、R10或R11为氢原子、卤素、C1-C6烷基、氰基、C1-C6烷氧基或C1-C6烷氨基;
R12为氢原子、C1-C6烷基,其中:C1-C6烷基上还包含一个或者多个卤素、羟基、氨基、杂原子或C1-C6烷基取代基;
R13为氢原子、C1-C6烷基或-C(O)R12。
优选,所述蛋白激酶抑制活性小分子及其衍生物结构中:
R1选自以下任一基团:
R2为氢原子、氟、氯、甲基、乙基、氰基或C1-C2卤代烷基;
R3为氢原子、羟基、C4-C6烷基、C4-C6烷氨基、C4-C6烷氧基或Het1取代基,其中:C4-C6烷基、C4-C6烷氨基、C4-C6烷氧基或Het1取代基上还包含一个或多个卤素、羟基、氨基、杂原子、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氨基、C1-C6烷氧基或Het1取代基;所述Het1取代基为吗啉基、吗啉基烷基、吗啉基烷氧基、吗啉基烷氨基、哌嗪基、哌嗪基烷基、哌嗪基烷氧基、哌嗪基烷氨基、高哌嗪基、高哌嗪基烷基、高哌嗪基烷氧基、高哌嗪基烷氨基、哌啶基、哌啶基烷基、哌啶基烷氧基、哌啶基烷氨基,四氢吡咯基、四氢吡咯基烷基、四氢吡咯基烷氧基、四氢吡咯基烷氨基、四氢呋喃基、四氢呋喃烷基、四氢呋喃烷氧基、四氢呋喃烷氨基、四氢吡喃基、四氢吡喃烷基、四氢吡喃烷氧基或四氢吡喃烷氨基;
R4为氢原子、C1-C6烷基或-C(O)R12;
R5为氢原子、羰基、氟原子、氯原子、C1-C3烷基、氰基或C1-C3卤代烷基;
R6为氢原子、氟原子、氯原子、C1-C3烷基、氰基或C1-C3卤代烷基;
R7为氢原子、羰基、氟原子、氯原子、C1-C3烷基、氰基或C1-C3卤代烷基;
R8为氢原子、氟原子、氯原子、C1-C3烷基、氰基或C1-C3卤代烷基;
其中:当R5为羰基时,R6不存在,R7不同时为羰基;当R7为羰基时,R8不存在,R5不同时为羰基;
R9为氢原子、氟原子、氯原子、C1-C3烷基、氰基、C1-C3烷氧基或C1-C3烷氨基;
R12为氢原子、C1-C3烷基,其中C1-C3烷基上还包含一个或者多个氟原子、氯原子、羟基、氨基、杂原子或C1-C3烷基取代基;
R13为氢原子、C1-C4烷基或-C(O)R12。
优选,所述蛋白激酶抑制剂及其衍生物结构中:
R1选自以下任一基团:
R2为氢原子、氟原子、氯原子、甲基、氰基或三氟甲基;
R3为氢原子、吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、4-异丙基基哌嗪基、高哌嗪基、N-甲基高哌嗪基、硫代吗啉-4-基、1,1-二氧代硫代吗啉-4-基、哌啶基、4-(N,N-二甲基)氨基哌啶基、4-(吗啉-4-基)哌啶基、3-二甲氨基吡咯烷基、2-甲氧基-N-甲基乙胺基、N1,N2-二甲基乙二胺基、4-乙酰基哌嗪基、4-丙酰基哌嗪基、4-正丁酰基哌嗪基、4-异丁酰基哌嗪基、4-环丙甲酰基哌嗪基、4-甲磺酰基哌嗪基、4-乙磺酰基哌嗪基、4-正丙磺酰基哌嗪基、4-异丙磺酰基哌嗪基、4-环丙磺酰基哌嗪基、N,N-二甲基氨基、N,N-二乙基氨基、N,N-二正丙基氨基、N,N-二异丙基氨基、(S)-3-甲基吗啉-4-基、N1,N1,N2-三甲基乙二胺基或1-(氧杂环丁-3-基)哌嗪-4-基;
R4为氢原子、甲基、乙基、正丙基、异丙基、环丙基或乙酰基;
R5为氢原子、羰基、氟原子、氯原子、甲基、乙基或氰基;
R6为氢原子、氟原子、氯原子、甲基、乙基或氰基;
R7为氢原子、羰基、氟原子、氯原子、甲基、乙基或氰基;
R8为氢原子、氟原子、氯原子、甲基、乙基或氰基;
其中:当R5为羰基时,R6不存在,R7不同时为羰基;当R7为羰基时,R8不存在,R5不同时为羰基;
R9为氢原子、氟原子、氯原子、甲基、乙基、氰基、甲氧基、乙氧基、甲氨基或乙氨基;
R12为氢原子、甲基、乙基、异丙基、环丙基,其中甲基、乙基、异丙基、环丙基上还包含一个或者多个氟原子、氯原子、羟基、氨基、杂原子或C1-C3烷基取代基;
R13为氢原子、甲基、乙基、异丙基或-C(O)R12。
优选,所述蛋白激酶抑制活性小分子为以下任一化合物:
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-1),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-甲基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-2),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-3),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-异丙基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-4),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(哌嗪-1-基甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-5),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(硫代吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-6),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((1,1-二氧硫代吗啉代)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-7),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-甲氧基乙基)(甲基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-8),
-4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-(二甲基氨基)乙基)(甲基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-9),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-10),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-11),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-12),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二乙基氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-13),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(((3-(二甲基氨基)吡咯烷-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-14),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(哌啶-1-基甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-15),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-吗啉代哌啶-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-16),
(S)-4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((3-甲基吗啉代)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-17),
4-乙基-6-(((4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-18),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-19),
4-乙基-6-((5-氯-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-20),
4-乙基-6-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-21),
4-乙基-6-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-22),
4-乙基-6-((4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-23),
4-乙基-6-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-24),
4-乙基-6-((4-(吡啶-4-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-25),
4-乙基-6-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-26),
4-乙基-6-((4-(1-乙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-27),
4-乙基-6-(((4-(吡啶-3-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-28),
4-乙基-6-(((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基]-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-29),
4-乙基-6-(((4-(吡啶-2-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-30),
N1-((4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-基)甲基)-N1,N2-二甲基乙烷-1,2-二胺(Ⅰ-31),
1-(6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)乙酮(Ⅰ-32),
4-乙基-6-((5-氟-4-(5-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-33),
4-乙基6-((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)--8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-34),
4-乙基-6-((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-35),
4-乙基-6-(((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-((二乙氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-36),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-N-甲基-N-(2-(甲基氨基)乙基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-8-羧酰胺(Ⅰ-37),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(4-乙酰基哌嗪-1-羰基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-38),
4-乙基-6-((4-(1-乙基-1H-苯并[d][1,2,3]三唑-6-基)-5-氟嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-39),
4-乙基-6-(((4-(1-乙基-1H-苯并[d][1,2,3]三唑-6-基)-5-氟嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-40),
4-乙基-6-((4-(1-乙基-1H-苯并[d][1,2,3]三唑-6-基)-5-氟嘧啶-2-基)氨基)-8-((二乙氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-41),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-丙酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-42),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-正丁酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-43),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-异丁酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-44),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-环丙甲酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-45),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(乙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-46),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(正丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-47),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(环丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-48),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(异丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-49),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二甲基氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-50),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二正丙基氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-51),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二异丙基氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-52),
4-环丙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-甲氧基乙基)(甲基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-53),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-54),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-55),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-56),
4-环丙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二乙基氨基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(Ⅰ-57)。
优选,所述药学上可接受的盐为所述蛋白激酶抑制活性小分子与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、苹果酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
本发明的蛋白激酶抑制活性小分子及其衍生物的制备方法为:
伯胺化合物1分别与带有三氟甲磺酸酯基或卤素的化合物2,经芳胺化反应得到所述化合物(I);
其中,X、Y、W、Q、L、n、R1、R2、R3、R5、R6、R7、R8的定义如前所述,Z为三氟甲磺酸酯基或者卤素;
将相应的酸或碱的溶液加入到以上方法制备的化合物(I)的溶液中,成盐完全后除去溶剂,即得所述化合物(I)药学上可接受的盐。
本发明的药物组合物包含所述蛋白激酶抑制活性小分子和/或其衍生物以及药学上可接受的载体。
所述蛋白激酶抑制活性小分子及其衍生物可以添加药学上可接受的载体制成常见的药用制剂,如注射剂、冻干制剂等无菌制剂,常用药用辅料包含增溶剂、稳定剂、渗透压调节剂、pH调节剂等,还可以附带相应的给药装置。
本发明的蛋白激酶抑制活性小分子及其衍生物、药物组合物在制备治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病或心血管疾病药物中的应用;所述过度增殖性疾病包括但不限于肺癌、前列腺癌、肝癌、胃癌、宫颈癌、结肠直肠癌、黑色素瘤、卵巢癌、乳腺癌、肾癌、神经系统肿瘤、急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞性白血病、慢性淋巴细胞白血病、多发性骨髓瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、滤泡性淋巴瘤。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类小分子及其衍生物具有高效的抑制活性,在分子水平上,CDK9激酶抑制IC50值最优小于10nM,达到纳摩尔浓度级别;在细胞水平上,MV4-11肿瘤细胞增殖抑制IC50值最优小于50nM,达到纳摩尔浓度级别;并且对多种肿瘤细胞均可以有效抑制增殖,达到纳摩尔浓度级别,最优小于50nM;
(2)该类小分子及其衍生物具有优异的水溶性,可提高其在生物体内的生物利用度,利于开发为相关靶点的各种剂型的治疗药物,尤其是注射剂;
(3)该类小分子及其衍生物和药物组合物应用广泛,可制备为治疗和/或预防与蛋白激酶相关的过度增殖性疾病、病毒诱导的感染性疾病、心血管疾病药物;在分子水平和细胞水平均可以发挥药效,并且治疗效果更优异,IC50值最优可达到纳摩尔浓度级别;
(4)化合物制备方法易操作,反应底物适用性广。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
试剂与材料:
化合物制备所使用的化学试剂来源于上海毕得医药科技有限公司、上海皓鸿生物医药科技有限公司、萨恩化学技术有限公司;
CDK9/Cyclin T1来源于美国Reaction Biology Corp.(Malvern PA)公司、MV4-11肿瘤细胞株来源于南京安纳康生物科技有限公司。
仪器:
1H-NMR采用BRUKER AVANCE-300型核磁共振仪(瑞士Brucker公司)测定,以TMS为内标,位移值(δ)单位为ppm;低分辨质谱采用expression紧凑型傅里叶变换质谱仪测定。
实施例1:4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(化合物I-1)的合成
(1)4-(4-氟-2-甲氧基苯基)-5-氟2-氯嘧啶(化合物1a)的合成
在25mL双颈瓶中加入4-氟-2-甲氧基苯硼酸(153mg,1.16mmol),2,4-二氯-5-氟嘧啶(100mg,0.6mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(146mg,0.2mmol),碳酸钠(424mg,4mmol),2mL的超纯水和12mL的1,4-二氧六环,氮气保护下,于100℃反应2h,反应结束后,加50mL水和100mL的乙酸乙酯,收集有机层,浓缩后柱层析分析纯化的白色固体118mg,收率73.7%。1H-NMR(300MHz,DMSO-d6)δ8.91(d,J=1.8Hz,1H),7.54(dd,J=8.5,6.8Hz,1H),7.16(dd,J=11.4,2.4Hz,1H),6.98(td,J=8.4,2.4Hz,1H),3.84(s,3H).ESI-MS m/z:257[M+H]+.
(2)5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-胺(化合物1b)的合成
在10mL厚壁耐压瓶中加入1a(285mg,1.16mmol)、氨水2mL,加入异丙醇1.5mL溶解,100℃反应6h,TLC检测原料点消失。将反应液降至室温,加入水15mL,乙酸乙酯萃取(25mL×3),合并有机层,减压蒸除溶剂,将残留物用硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得白色固体54mg,收率58.4%。1H-NMR(300MHz,DMSO-d6)δ8.27(d,J=2.1Hz,1H),7.40(dd,J=8.4,7.0Hz,1H),7.08(dd,J=11.5,2.3Hz,1H),6.90(td,J=8.4,2.3Hz,1H),6.68(s,2H),3.80(s,3H).ESI-MS m/z:238[M+H]+.
(3)2-(吗啉代甲基)-6-硝基-4-溴-苯酚(化合物2a)的合成
在100mL茄形瓶中加入4-溴-2-硝基水杨醛(2.0g,8.13mmol)和吗啉(849μL,9.76mmol),无水乙醇60mL溶解,三乙酰氧基硼氢化钠(5.17g,24.39mmol)分批加入到反应体系中,室温反应3h,TLC检测原料点消失。将反应液浓缩,残留物用硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得黄色固体1.83g,收率71.0%。1H NMR(400MHz,DMSO-d6)δ7.97(d,J=2.6Hz,1H),7.59(d,J=2.6Hz,1H),3.90(s,2H),3.67(t,J=4.7Hz,4H),2.66(t,J=4.7Hz,4H).ESI-MS m/z:316[M]+.
(4)6-(吗啉代甲基)-2-氨基-4-溴苯酚(化合物2b)的合成
在100mL茄形瓶中加入化合物2a(1.5g,4.73mmol),还原铁粉(1.32g,23.65mmol),氯化铵(1.27g,23.65mmol),超纯水15mL和95%乙醇45mL,85℃加热反应1h,TLC检测原料点消失。将反应液用硅藻土过滤,收集滤液,将滤液浓缩,残留物用硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得淡黄色固体1.32g,收率79.5%。1H NMR(400MHz,DMSO-d6)δ6.68(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),4.84(s,2H),3.61(t,J=4.6Hz,4H),3.59(s,2H),2.48-2.37(m,4H).ESI-MS m/z:286[M]+.
(5)8-(吗啉代甲基)-6-溴-2H-苯并[b][1,4]噁嗪-3(4H)-酮(化合物2c)的合成
在100mL茄形瓶中加入化合物2b(1.20g,4.18mmol),碳酸氢钠(1.05g,12.54mmol),乙二醇二甲醚30mL和超纯水30mL,冰浴下逐滴加入氯乙酰氯(6.27mmol,499μL)。加入完毕后室温搅拌30min,再加入碳酸铯(1.36g,4.18mmol),80℃加热回流6h。TLC检测原料点消失。将反应液冷却至室温,减压蒸除溶剂,将残留物用硅胶柱层析纯化(石油醚:乙酸乙酯=2:1)得白色固体0.87g,收率63.6%。1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.10(d,J=2.3z,1H),6.94(d,J=2.4Hz,1H),4.59(s,2H),3.56(t,J=4.6Hz,4H),3.44(s,2H),2.37(t,J=4.5Hz,4H).ESI-MS m/z:326[M]+.
(6)4-乙基-8-(吗啉代甲基)-6-溴-2H-苯并[b][1,4]噁嗪-3(4H)-酮(化合物2d)的合成
在50mL茄形瓶中加入化合物2c(0.30g,0.92mmol)和N,N-二甲基甲酰胺15mL,冰浴下加入NaH(60%,55mg,1.38mmol),冰浴30min后加入碘乙烷(110μL,1.38mmol),室温反应3h,TLC检测原料点消失,加入水50mL和乙酸乙酯100mL,收集有机层,饱和食盐水30mL洗涤2次,减压除去多余溶剂,柱层析纯化(石油醚:乙酸乙酯=3:1),得白色固体0.24g,收率73.4%。1H NMR(400MHz,DMSO-d6)δ7.30(d,J=2.2Hz,1H),7.21(d,J=2.2Hz,1H),4.64(s,2H),3.93(q,J=7.1Hz,2H),3.57(t,J=4.6Hz,4H),3.46(s,2H),2.38(t,J=4.5Hz,4H),1.12(t,J=7.1Hz,3H).ESI-MS m/z:354[M]+.
(7)4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(化合物I-1)的合成
在氮气保护的情况下,于25mL双颈瓶中加入化合物1b(67mg,0.280mmol),化合物2d(100mg,0.280mmol),三(二亚苄基丙酮)二钯(13mg,0.014mmol),2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯(15mg,0.028mmol)和叔丁醇钠(54mg,0.563mmol),加入无水甲苯15mL,100℃加热反应4h,将反应液过滤并浓缩,残留物用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),再次甲醇重结晶纯化后得到75mg黄色固体,收率52%。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.54(d,J=2.0Hz,1H),7.72(d,J=2.4Hz,1H),7.54(dd,J=8.5,6.8Hz,1H),7.34(d,J=2.4Hz,1H),7.13(dd,J=11.5,2.4Hz,1H),6.95(td,J=8.4,2.4Hz,1H),4.55(s,2H),3.89–3.75(m,5H),3.53(t,J=4.6Hz,4H),3.44(s,2H),2.43–2.29(m,4H),1.09(t,J=7.0Hz,3H).ESI-MS m/z:512[M+H]+.
采用与实施例1相似的操作,制得下列化合物:
实施例2:4-乙基-6-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(I-21)的合成
(1)5-溴-2-甲基-2H-吲唑(化合物3a)的合成
在250mL单颈烧瓶中加入5-溴吲唑(9.95g,50mmol),加入150mLDMF溶解,冰浴下缓慢加入氢化钠(60%,1.44g,60mmol),搅拌30min后加入碘甲烷(8.52g,60mmol),室温反应5h后,加入亚硫酸钠的饱和水溶液淬灭反应,乙酸乙酯萃取并浓缩,残留物经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1),得淡黄色固体4.1g,收率32.4%。1H-NMR(300MHz,DMSO-d6)δ8.34(s,1H),7.92-7.98(m,1H),7.57(dd,J=9.1,0.8Hz,1H),7.30(dd,J=9.1,1.9Hz,1H),4.17(s,3H).
(2)2-(5-溴-2-甲基-2H-吲唑-3-基)丙-2-醇(化合物3b)的合成
在氮气保护条件下,于50mL双颈瓶中加入化合物3a(2.1g,10mmol),加入10ml无水四氢呋喃溶解,于-78℃下缓慢加入LDA(15mmol),升温至0℃反应10min,降温至-78℃加入丙酮(1.1mL,15mmol),缓慢升至室温反应12h,将反应液过滤并浓缩,残留物用硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1),得黄色固体1.0g,收率37%。1H-NMR(300MHz,CDCl3)δ7.75(d,J=1.3Hz,1H),7.28(d,J=9.1Hz,1H),7.20-7.11(m,1H),4.17(s,3H),3.30-2.75(m,1H),1.72(s,6H).
(3)5-溴-3-异丙基-2-甲基-2H-吲唑(化合物3c)的合成
在50mL单颈烧瓶中加入化合物3b(538mg,2mmol),三乙基硅烷(3.20mL,20mmol),加入20mL二氯甲烷溶解,缓慢加入三氟乙酸(1.50mL,20mmol),于室温下反应24h,加入饱和碳酸氢钠溶液,二氯甲烷萃取,无水硫酸钠干燥,硅胶柱层析分离纯化(石油醚:乙酸乙酯=6:1),得黄色油状物260mg,收率51%。1H NMR(300MHz,CDCl3)δ7.84(d,J=1.3Hz,1H),7.47(d,J=9.0Hz,1H),7.26(dd,J=9.1,1.8Hz,1H),4.06(s,3H),3.27-3.36(m,1H),1.42(d,J=7.1Hz,6H).
(4)3-异丙基-2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2H-吲唑(化合物3d)的合成
在氮气保护条件下,于25mL双颈瓶中加入化合物3c(253mg,1mmol),联硼酸平那醇酯(381mg,1.5mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol),乙酸钾(114mg,3mmol)和无水二氧六环10mL,100℃反应12h,TLC监测原料反应完全。将反应液减压浓缩,残余物采用硅胶柱层析纯化得白色固体245mg,收率82%。ESI-MS m/z:301[M+H]+.
(5)4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-胺(化合物3f)的合成
以化合物3d(200mg,0.67mmol)为原料,参考化合物1b的合成方法,得白色固体165mg,收率92%。1H-NMR(300MHz,DMSO-d6)δ8.50-8.61(m,1H,),8.27(d,J=5.2Hz,1H),7.92(dd,J=9.1,1.3Hz,1H),7.52-7.66(m,1H),7.20(d,J=5.3Hz,1H),6.69-6.54(m,2H),4.12(s,3H),3.54-3.63(m,1),1.50(d,J=7.0Hz,6H).ESI-MS m/z:268[M+H]+.
(6)4-乙基-6-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(化合物I-21)的合成
以化合物3f(75mg,0.280mmol)和化合物2d(100mg,0.280mmol)为原料,参照化合物I-1的合成方法,得化合物I-29白色固体75mg,收率49.5%。1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.61(s,1H),8.48(d,J=5.3Hz,1H),8.05(dd,J=9.1,1.6Hz,1H),7.71(d,J=2.4Hz,1H),7.62(d,J=9.1Hz,1H),7.53(d,J=2.3Hz,1H),7.48(d,J=5.3Hz,1H),4.58(s,2H),4.14(s,3H),3.92(q,J=7.0Hz,2H),3.70–3.51(m,5H),3.49(s,2H),2.42(t,J=4.5Hz,4H),1.51(d,J=7.0Hz,6H),1.20(t,J=7.1Hz,3H).ESI-MS m/z:542
[M+H]+.
采用与实施例2相似的操作,制得下列化合物:
实施例3:小分子对CDK9激酶的抑制活性
由美国Reaction Biology Corp.(Malvern PA)公司通过HotSpotSM激酶法/荧光共振能量转移(FRET)法测试上述小分子对CDK9的抑制活性,以测试CDK9/Cyclin T1为例。
具体操作方法:CDK9/Cyclin T1用激酶稀释液稀释至合适浓度后待用。激酶反应混合物中含CDK9/Cyclin T1、Peptide substrate、HEPES(pH7.5)、BRIJ-35、MgCl2和EDTA。CDK9 phospho-peptide substrate用作100%磷酸化对照,不加ATP作为0%磷酸化对照。室温下反应1h后,向反应体系中加入适度稀释的Development Reagent A。室温下继续反应1h,加入Stop Reagent中止反应。激发光波长设为400nm,同时检测波长为445nm和520nm的荧光强度。按公式计算受试化合物抑制率(n=2),IC50由百分抑制率和对数浓度值作图求得,分析结果见表1。
表1CDK9激酶的抑制活性
注:“A”代表IC50值小于0.01μM,“B”代表IC50值在0.01μM到0.1μM之间,“C”代表IC50值大于0.1μM。
由表1可见,所有测试小分子对CDK9激酶均具有抑制活性,具体地,小分子I-1~I-18、I-23、I-25~I-28和I-30~I-56对CDK9激酶抑制活性的IC50值均小于0.01μM,为个位数纳摩尔浓度级别;其余小分子对CDK9激酶抑制活性的IC50值均达到十纳摩尔浓度级别。
实施例4:小分子对肿瘤细胞的抗增殖活性
具体操作方法:使用DMSO将化合物配制为10mM的储存浓度。用DMSO将化合物稀释为2mM的top dose(100%DMSO),将最高浓度点三倍稀释,共十个点。使用细胞相对应培养基将化合物稀释100倍,使化合物浓度为20μM的top dose(1%DMSO)。MV-4-11细胞铺板密度为4500cells/well,细胞铺板过夜,体积为20μL。加药体积为20μL,此时每个孔中为40μL,化合物最终浓度的top dose为10μM(0.5%DMSO),加药以后作用72h。每孔中加入20μL的CCL,20min后使用程序Luminescence进行检测,检测结果见表2。
表2MV4-11肿瘤细胞的抗增殖作用
注:“A”代表IC50值小于0.05μM,“B”代表IC50值在0.05μM到0.1μM之间,“C”代表IC50值大于0.1μM。
由表2可见,所有测试小分子对MV4-11细胞均有抑制作用,具体地,化合物I-11~I-13、I-23、I-25、I-32~I-43、I-46、I-47、I-50和I-55~I-57的MV4-11肿瘤细胞的抗增殖IC50值均小于0.05μM,达到十纳摩尔浓度级别;其他小分子均达到百纳摩尔浓度级别。
实施例5:小分子的抗肿瘤细胞谱检测
实验材料:实验中所用到材料均来源于南京安纳康生物科技有限公司。
实验方法:参考实施例4的测试方法进行测试,IC50值如表3所示。
表3抗肿瘤细胞谱
注:“A”代表IC50值小于0.05μM,“B”代表IC50值在0.05μM到0.1μM之间,“C”代表IC50值大于0.1μM。
由表3可见,上述测试小分子对各种实质性器官癌细胞均具有抑制活性,IC50值均达到纳摩尔浓度级别,个别小分子能达到十纳摩尔浓度级别。
因此,适用的疾病包括但不局限于各种恶性血液病,如急性髓细胞白血病、慢性髓细胞白血病、淋巴细胞性白血病、多发性骨髓瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、滤泡性淋巴瘤,以及实体瘤例如乳腺癌、非小细胞肺癌、肝癌、胃癌、黑色素瘤、肾癌、卵巢癌、前列腺癌、结肠癌和中枢神经系统肿瘤。
实施例6:小分子的水溶性测试
具体操作方法:取1mg化合物,精密称定。将化合物溶于加入色谱甲醇,配成1mg/mL的甲醇溶液,取100μL上述溶液,加入900μL的色谱甲醇,配成0.1mg/mL的甲醇溶液。重复上述操作,依次得到0.01mg/mL、0.001mg/mL和0.0001mg/mL的甲醇溶液。将上述五种浓度的甲醇溶液进行HPLC分析,进样量为10μL,检测波长为254nm,流动相为甲醇:水=90:10,得到相应的峰面积。以峰面积为纵坐标,化合物浓度为横坐标,建立标准曲线备用。用移液枪量取200μL PBS(pH=7.4),加入化合物至溶液呈浑浊状态,超声30min,若溶液澄清则继续加入化合物并超声,直至溶液至浑浊状态。之后将混悬液放入37℃摇床摇晃24h,10000rpm离心20min,取上清液进行HPLC分析,进样量为10μL,检测波长为254nm,流动相为甲醇:水=90:10,得到相应的峰面积。将峰面积带入标准曲线中,得到相应的溶解度(pH=7.4)。
表4化合物的水溶性数据
注:“A”代表溶解度大于50μg/mL,“B”代表溶解度在50μg/mL到10μg/mL之间,“C”代表溶解度小于10μg/mL。
由表4可见,上述测试小分子绝大部分具有良好的水溶性,其中I-10、I-31、I-37、I-40和I-46~I-49溶解度均大于50μg/mL,适于开发为相关靶点的各种剂型的治疗药物,尤其是注射剂。
Claims (10)
1.一种具有蛋白激酶抑制活性的小分子化合物,其特征在于,所述小分子化合物的化学结构如式(I)所示,
;
其中:
X为CH;
Y为N;
W为O,Q为NR4;
L为亚甲基或羰基;
n=1;
R1选自以下任一基团:
,其中:G为CH;
R2为氢原子、卤素;
R3为C1-C6烷氨基、吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、4-异丙基基哌嗪基、硫代吗啉-4-基、1,1-二氧代硫代吗啉-4-基、哌啶基、4-(N,N-二甲基)氨基哌啶基、4-(吗啉-4-基)哌啶基、3-二甲氨基吡咯烷基、2-甲氧基-N-甲基乙胺基、N 1,N 2-二甲基乙二胺基、4-乙酰基哌嗪基、4-丙酰基哌嗪基、4-正丁酰基哌嗪基、4-异丁酰基哌嗪基、4-环丙甲酰基哌嗪基、4-甲磺酰基哌嗪基、4-乙磺酰基哌嗪基、4-正丙磺酰基哌嗪基、4-异丙磺酰基哌嗪基、4-环丙磺酰基哌嗪基、N,N-二甲基氨基、N,N-二乙基氨基、N,N-二正丙基氨基、N,N-二异丙基氨基、(S)-3-甲基吗啉-4-基、N 1,N 1,N 2-三甲基乙二胺基或1-(氧杂环丁-3-基)哌嗪-4-基,其中:C1-C6烷氨基上还包含一个或多个C1-C6烷基、C1-C6烷氨基、C1-C6烷氧基;
R4为C1-C6烷基或-C(O)R12,其中C1-C6烷基上还包含一个或多个C1-C6烷基;
R5为氢原子;
R6为氢原子;
R7为氢原子、羰基;
R8为氢原子或不存在;
R9、R10为氢原子、卤素、C1-C6烷氧基;
R12为氢原子、C1-C6烷基,其中:C1-C6烷基上还包含一个或者多个C1-C6烷基取代基;
R13为氢原子、C1-C6烷基。
2.根据权利要求1所述的具有蛋白激酶抑制活性的小分子化合物,其特征在于,所述小分子化合物结构中:
R1选自以下任一基团:
;
G为CH;
R2为氢原子、氟、氯、甲基、乙基;
R3为C4-C6烷氨基、吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、4-异丙基基哌嗪基、硫代吗啉-4-基、1,1-二氧代硫代吗啉-4-基、哌啶基、4-(N,N-二甲基)氨基哌啶基、4-(吗啉-4-基)哌啶基、3-二甲氨基吡咯烷基、2-甲氧基-N-甲基乙胺基、N 1,N 2-二甲基乙二胺基、4-乙酰基哌嗪基、4-丙酰基哌嗪基、4-正丁酰基哌嗪基、4-异丁酰基哌嗪基、4-环丙甲酰基哌嗪基、4-甲磺酰基哌嗪基、4-乙磺酰基哌嗪基、4-正丙磺酰基哌嗪基、4-异丙磺酰基哌嗪基、4-环丙磺酰基哌嗪基、N,N-二甲基氨基、N,N-二乙基氨基、N,N-二正丙基氨基、N,N-二异丙基氨基、(S)-3-甲基吗啉-4-基、N 1,N 1,N 2-三甲基乙二胺基或1-(氧杂环丁-3-基)哌嗪-4-基,其中:C4-C6烷氨基上还包含一个或多个C1-C6烷基、C1-C6烷氨基;
R4为C1-C6烷基或-C(O)R12;
R5为氢原子;
R6为氢原子;
R7为氢原子、羰基;
R8为氢原子或不存在;
R9为氢原子、氟原子、氯原子、C1-C3烷氧基;
R12为氢原子、C1-C3烷基,其中:C1-C3烷基上还包含一个或者多个C1-C3烷基取代基;
R13为氢原子、C1-C4烷基。
3.根据权利要求1所述的具有蛋白激酶抑制活性的小分子化合物,其特征在于,所述小分子化合物结构中:
R1选自以下任一基团:
;
G为CH;
R2为氢原子、氟原子、氯原子、甲基;
R3为吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、4-异丙基基哌嗪基、硫代吗啉-4-基、1,1-二氧代硫代吗啉-4-基、哌啶基、4-(N,N-二甲基)氨基哌啶基、4-(吗啉-4-基)哌啶基、3-二甲氨基吡咯烷基、2-甲氧基-N-甲基乙胺基、N 1,N 2-二甲基乙二胺基、4-乙酰基哌嗪基、4-丙酰基哌嗪基、4-正丁酰基哌嗪基、4-异丁酰基哌嗪基、4-环丙甲酰基哌嗪基、4-甲磺酰基哌嗪基、4-乙磺酰基哌嗪基、4-正丙磺酰基哌嗪基、4-异丙磺酰基哌嗪基、4-环丙磺酰基哌嗪基、N,N-二甲基氨基、N,N-二乙基氨基、N,N-二正丙基氨基、N,N-二异丙基氨基、(S)-3-甲基吗啉-4-基、N 1,N 1,N 2-三甲基乙二胺基或1-(氧杂环丁-3-基)哌嗪-4-基;
R4为甲基、乙基、正丙基、异丙基、环丙基或乙酰基;
R5为氢原子;
R6为氢原子;
R7为氢原子、羰基;
R8为氢原子或不存在;
R9为氢原子、氟原子、氯原子、甲氧基、乙氧基;
R12为氢原子、甲基、乙基、异丙基或环丙基,其中:甲基、乙基、异丙基或环丙基上还包含一个或者多个C1-C3烷基取代基;
R13为氢原子、甲基、乙基、异丙基。
4.一种具有蛋白激酶抑制活性的小分子化合物,其特征在于,所述小分子化合物为以下任一化合物:
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-1),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-甲基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-2),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-3),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-异丙基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-4),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(哌嗪-1-基甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-5),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(硫代吗啉代甲基)-2H-苯并[b] [1,4]噁嗪 -3(4H)-酮(Ⅰ-6),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((1,1-二氧硫代吗啉代)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-7),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-甲氧基乙基)(甲基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-8),
-4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-(二甲基氨基)乙基)(甲基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-9),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-10),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-11),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-12),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二乙基氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-13),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(((3-(二甲基氨基)吡咯烷-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-14),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(哌啶-1-基甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-15),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-吗啉代哌啶-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-16),
(S)-4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((3-甲基吗啉代)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-17),
4-乙基-6-(((4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-18),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-19),
4-乙基-6-((5-氯-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-20),
4-乙基-6-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-21),
4-乙基-6-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-22),
4-乙基-6-((4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-23),
4-乙基-6-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3 (4H)-酮(Ⅰ-24),
4-乙基-6-((4-(吡啶-4-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-25),
4-乙基-6-((4-(1-异丙基-1H-苯并[d] [1,2,3]三唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H -苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-26),
4-乙基-6-((4-(1-乙基-1H-苯并[d] [1,2,3]三唑-6-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H -苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-27),
4-乙基-6-(((4-(吡啶-3-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-28),
4-乙基-6-(((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基] -8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-29),
4-乙基-6-(((4-(吡啶-2-基)嘧啶-2-基)氨基)-8-(吗啉代甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-30),
N 1-((4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-3,4-二氢-2H-苯并[b] [1,4]噁嗪-8-基)甲基)-N 1,N 2-二甲基乙烷-1,2-二胺(Ⅰ-31),
1-(6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2,3-二氢-4H-苯并[b] [1,4]噁嗪-4-基)乙酮(Ⅰ-32),
4-乙基-6-((5-氟-4-(5-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-33),
4-乙基6-((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)--8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-34),
4-乙基-6-((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-35),
4-乙基-6-(((5-氟-4-(1-异丙基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)-8-((二乙氨基)甲基)-2H -苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-36),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-N-甲基-N-(2-(甲基氨基)乙基)-3-氧代-3,4-二氢-2H-苯并[b] [1,4]噁嗪-8-羧酰胺(Ⅰ-37),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-(4-乙酰基哌嗪-1-羰基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-38),
4-乙基-6-((4-(1-乙基-1H-苯并[d] [1,2,3]三唑-6-基)- 5-氟嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-39),
4-乙基-6-(((4-(1-乙基-1H-苯并[d] [1,2,3]三唑-6-基)-5-氟嘧啶-2-基)氨基)-8-(( 4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-40),
4-乙基-6-((4-(1-乙基-1H-苯并[d] [1,2,3]三唑-6-基)-5-氟嘧啶-2-基)氨基)-8-((二乙氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-41),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-丙酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-42),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-正丁酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-43),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-异丁酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-44),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-环丙甲酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-45),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(乙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-46),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(正丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-47),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(环丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-48),
4-乙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(异丙基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-49),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二甲基氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-50),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二正丙基氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-51),
4-乙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二异丙基氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-52),
4-环丙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((((2-甲氧基乙基)(甲基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-53),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((甲基(2-(甲基氨基)乙基)氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-54),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-乙酰基哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-55),
4-环丙基-6-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((4-(甲基磺酰基)哌嗪-1-基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-56),
4-环丙基-6-(((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-8-((二乙基氨基)甲基)-2H-苯并[b] [1,4]噁嗪-3(4H)-酮(Ⅰ-57)。
5.一种权利要求1~4任一所述的具有蛋白激酶抑制活性的小分子化合物的药学上可接受的盐,其特征在于,所述药学上可接受的盐为所述小分子化合物与酸或碱形成的盐,其中所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、苹果酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子或铵阳离子盐的无机碱。
6.一种权利要求1~3任一所述的具有蛋白激酶抑制活性的小分子化合物或权利要求5所述的药学上可接受的盐的制备方法,其特征在于,所述制备方法为:
伯胺化合物1分别与带有三氟甲磺酸酯基或卤素的化合物2,经芳胺化反应得到所述化合物(I);
;
其中,X、Y、W、Q、L、n、R1、R2、R3、R5、R6、R7、R8的定义如权利要求1~3任一所述,Z为三氟甲磺酸酯基或者卤素;
将相应的酸或碱的溶液加入到以上方法制备的小分子(I)的溶液中,成盐完全后除去溶剂,即得所述化合物(I)的药学上可接受的盐。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~4任一所述的具有蛋白激酶抑制活性的小分子化合物或权利要求5所述的药学上可接受的盐以及药学上可接受的载体。
8.一种权利要求1~4任一所述的具有蛋白激酶抑制活性的小分子化合物在制备治疗和/或预防肺癌、急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞性白血病、慢性淋巴细胞白血病、结肠直肠癌、乳腺癌、弥漫性大B细胞淋巴瘤的药物中的应用。
9.一种权利要求5所述的药学上可接受的盐在制备治疗和/或预防肺癌、急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞性白血病、慢性淋巴细胞白血病、结肠直肠癌、乳腺癌、弥漫性大B细胞淋巴瘤的药物中的应用。
10.一种权利要求7所述的药物组合物在制备治疗和/或预肺癌、急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞性白血病、慢性淋巴细胞白血病、结肠直肠癌、乳腺癌、弥漫性大B细胞淋巴瘤的药物中的应用。
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