CN113549018B - 蛋白激酶抑制剂及其衍生物,制备方法、药物组合物和应用 - Google Patents
蛋白激酶抑制剂及其衍生物,制备方法、药物组合物和应用 Download PDFInfo
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- CN113549018B CN113549018B CN202010329894.4A CN202010329894A CN113549018B CN 113549018 B CN113549018 B CN 113549018B CN 202010329894 A CN202010329894 A CN 202010329894A CN 113549018 B CN113549018 B CN 113549018B
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- pyrimidin
- methyl
- isopropyl
- quinazolin
- indazol
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
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Abstract
本发明公开了一种蛋白激酶抑制剂及其衍生物,制备方法、药物组合物和应用。该蛋白激酶抑制剂的化合物结构如式(I),该蛋白激酶抑制剂衍生物涉及所述蛋白激酶抑制剂的异构体、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,该蛋白激酶抑制剂及其衍生物对蛋白激酶具有高效的抑制作用,可以降低或抑制细胞中蛋白激酶的活性,可用于制备治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病和/或心血管疾病药物,并且该类化合物合成方法简便,易操作。
Description
技术领域
本发明涉及一种蛋白激酶抑制剂及其衍生物,制备方法、药物组合物和应用,尤其涉及一种可制备为治疗和/或预防过度增殖性疾病如癌症、病毒诱导的感染性疾病和/或心血管疾病药物的蛋白激酶抑制剂及其衍生物,制备方法、药物组合物和应用。
背景技术
蛋白激酶在人体中广泛存在并发挥着重要的生理功能,当蛋白激酶出现异常调节或突变后,往往易引发过度增殖性疾病、心脑血管疾病、糖尿病、炎症和免疫***疾病等。
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,它与细胞周期蛋白(cyclins)结合形成二聚体复合物,进而发挥调节作用,包括催化磷酸化相应下游底物,驱动细胞周期各项进程,依序完成DNA合成和有丝***,引起细胞的生长和增殖。其中,CDK9作为细胞周期蛋白依赖性激酶,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。此外,在其它恶性肿瘤如淋巴瘤、神经母细胞瘤、原发性神经外胚层肿瘤、横纹肌肉瘤和***癌中,存在CDK9介导的相关通路基因异常或蛋白水平表达异常增高,而这些异常调控均与CDK9过度参与抗凋亡因子的表达和肿瘤细胞的增殖过程有关。
发明内容
发明目的:本发明的第一目的是提供一种蛋白激酶抑制剂及其衍生物,第二目的是提供所述蛋白激酶抑制剂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剂及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剂及其衍生物在制备治疗和/或预防过度增殖性疾病如癌症、病毒诱导的感染性疾病和/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剂及其衍生物具有式(I)的结构,所述衍生物为所述化合物的异构体、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:
V、W、X、Y或Z为CR4或氮原子;
R1为或/>
R2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、Het1取代基被一个或多个卤素、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;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;
R3为氢原子、卤素、C1-C6烷基或氰基;
R4为氢原子、卤素、C1-C6烷基、C1-C6烷氧基或氰基;
R5为芳环上任一位置取代的氢原子、卤素、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或苯氧基,其中C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基被1-3个卤素、C1-C6烷基、C3-C7环烷基、杂环基、C1-C6烯基、C1-C6炔基、至少1个卤素取代的苯基、至少1个卤素取代的杂芳基或Het1取代;
R6或R7为一个或多个氢原子、卤素、C1-C3烷基、C1-C3烷氧基或C1-C3烷氨基;
Q为氧原子或亚氨基。
优选,所述蛋白激酶抑制剂及其衍生物结构中:
V为氮原子;
R2为氢原子、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、Het1取代基被一个或多个氟原子、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;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;
R3为氢原子、氟原子、氯原子、氰基或C1-C6烷基;
R4为氢原子、氟原子、C1-C3烷基或C1-C3烷氧基;
R5为芳环上任一位置取代的氢原子、氟原子、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基、苯氧基,其中C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基被1-3个氟原子、C1-C6烷基、C3-C7环烷基、C1-C6烯基、C1-C6炔基、1-2个氟原子取代的苯基、1-2个氟原子取代的杂芳基、哌嗪基或吗琳基;
R6或R7为一个或多个氢原子、氟原子、C1-C3烷基、C1-C3烷氧基或C1-C3烷氨基。
优选,所述蛋白激酶抑制剂及其衍生物具有式(II)的结构:
其中:
R1为或/>
R2为氢原子、甲基、吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、4-(2-甲氧基乙基)哌嗪基、高哌嗪基、N-甲基高哌嗪基、硫代吗啉-4-基、哌啶基、4-(N,N-二甲基)氨基哌啶基、(N-甲基哌嗪-4-基)哌啶基、3-甲氨基吡咯烷基、(吗啉-4-基)甲基、(哌嗪-1-基)甲基、(4-甲基哌嗪-1-基)甲基、(N-甲基高哌嗪-1-基)甲基、(四氢吡喃-4-基)氨基、(四氢呋喃-3-基)氨基、(N-甲基哌啶-4-基)氨基、2-(二甲氨基)乙氨基、2-甲氧基乙氨基、3-甲氧基丙氨基、2,5-二氮杂双环[2.2.1]庚基-2-基、4-甲基哌嗪-3-酮基、(S)-3-甲基哌嗪基、(R)-3-甲基哌嗪基、(8-氮杂双环[3.2.1]辛烷-3-基)氨基、(R)-2-甲基哌嗪基、(S)-2-甲基哌嗪基、吡咯烷基、(2-甲氧基乙基)氨基、(3-甲氧基丙基)氨基、(四氢吡喃-4-基)氨基、(四氢呋喃-3-基)氨基、N,N-二甲基氨基、叠氮基或4,4-二氟哌啶基;
R3为氢原子、氟原子、氯原子、甲基或氰基;
R4为氢原子、氟原子、甲基或甲氧基;
R5为氢原子、氟原子、硝基、甲基、三氟甲基、乙基、甲氧基、二氟甲氧基、三氟甲氧基、甲氨基、二甲氨基、乙氧基、丁氧基、异丙氧基、异丁氧基、1-环丙基甲氧基、1-环戊基甲氧基、1-环已基甲氧基、苯氧基、苄氧基、1-苯基乙氧基、4-氟苄氧基、2,4-二氟苄氧基、苄氨基、3-(4-甲基哌嗪-1-基)丙氧基、3-吗啉基-1-基丙氧基、丁-2-烯-1-基氧基、丁-2-炔-1-基氧基、1-(吡啶-4-基)甲氧基;
R6、R7为一个或多个氢原子、氟原子、C1-C3烷基、甲氧基或甲氨基;
Q为氧原子或亚氨基。
进一步优选,所述蛋白激酶抑制剂及其衍生物结构中:
R1为苯基、2-甲氧基苯基、4-氟-2-甲氧基苯基、2-乙氧基苯基、4-氟-2-乙氧基苯基、2-苄氧基苯基、4-氟-2-苄氧基苯基、3-异丙基-2-甲基-2H-吲唑-5-基、7-氟-3-异丙基-2-甲基-2H-吲唑-5-基、1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基、4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基、1-甲基-1H-吲哚-3-基、1-甲基-1H-苯并[d][1,2,3]***-6-基或1-异丙基-1H-苯并[d][1,2,3]***-6-基;
R2为氢原子、吗啉-4-基、哌嗪基、哌啶基、4-甲基哌嗪基、高哌嗪基、N-甲基高哌嗪基、4-乙基哌嗪基、(哌啶-4-基)氨基、(1-甲基哌啶-4-基)氨基、2,5-二氮杂双环[2.2.1]庚基-2-基、(2-氨基乙基)氨基、(2-(甲基氨基)乙基)氨基、(2-(二甲基氨基)乙基)氨基、(2-(二甲基氨基)乙基)(甲基)氨基、(3-甲氧基乙基)氨基、(3-甲氧基丙基)氨基、4-甲基哌嗪-2-酮基、4-甲基哌嗪-3-酮基、(S)-3-甲基哌嗪基、(R)-3-甲基哌嗪基、(R)-2-甲基哌嗪基、(S)-2-甲基哌嗪基、(8-氮杂双环[3.2.1]辛烷-3-基)氨基、吡咯烷基、(2-甲氧基乙基)氨基、(3-甲氧基丙基)氨基、(四氢吡喃-4-基)氨基、(四氢呋喃-3-基)氨基、N,N-二甲基氨基、叠氮基或4,4-二氟哌啶基。
优选,所述蛋白激酶抑制剂为以下任一化合物:
4-(4-甲基哌嗪-1-基)-N-(4-苯基嘧啶-2-基)喹唑啉-7-胺(I-1),
N-(4-(2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-2),
N-(4-(4-氟-2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-3),
N-(5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-4),
N-(4-(2-乙氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-5),
N-(4-(2-乙氧基-4-氟苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-6),
N-(4-(2-(苄氧基)苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-7),
N-(4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-8),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-9),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-吗啉基喹唑啉-7-胺(I-10),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(哌嗪-1-基)喹唑啉-7-胺(I-11),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-12),
4-(4-乙基哌嗪-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-13),
4-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-1-甲基哌嗪-2-酮(I-14),
1-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-4-甲基哌嗪-2-酮(I-15),
(S)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(3-甲基哌嗪-1-基)喹唑啉-7-胺(I-16),
(R)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(3-甲基哌嗪-1-基)喹唑啉-7-胺(I-17),
(R)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(2-甲基哌嗪-1-基)喹唑啉-7-胺(I-18),
(S)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(2-甲基哌嗪-1-基)喹唑啉-7-胺(I-19),
4-(1,4-高哌嗪-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-20),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(4-甲基-1,4-高哌嗪-1-基)喹唑啉-7-胺(I-21),
4-(2,5-二氮杂双环[2.2.1]庚基-2-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-22),
N4-(8-氮杂双环[3.2.1]辛烷-3-基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-23),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(哌啶-4-基)喹唑啉-4,7-二胺(I-24),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(1-甲基哌啶-4-基)喹唑啉-4,7-二胺(I-25),
N4-(2-(二甲基氨基)乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-26),
N4-(2-氨基乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-27),
N4-(2-(二甲基氨基)乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-甲基喹唑啉-4,7-二胺(I-28),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(2-(甲基氨基)乙基)喹唑啉-4,7-二胺(I-29),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(2-甲氧基乙基)喹唑啉-4,7-二胺(I-30),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(3-甲氧基丙基)喹唑啉-4,7-二胺(I-31),
5-(7-(((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-2,5-二氮杂双环叔丁基[2.2.1]庚烷-2-羧酸酯(I-32),
N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-33),
N-(4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-34),
N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-35),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(四氢呋喃-3-基)喹唑啉-4,7-二胺(I-36),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(四氢-2H-吡喃-4-基)喹唑啉-4,7-二胺(I-37),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4,N4-二甲基喹唑啉-4,7-二胺(I-38),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-2-甲基-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-39),
4-(叠氮基-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-40),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(哌啶-1-基)喹唑啉-7-胺(I-41),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(吡咯烷-1-基)喹唑啉-7-胺(I-42),
1-(4-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)哌嗪-1-基)乙酮(I-43),
4-(4,4-二氟哌啶-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-44),
N-(4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-45),
N-(4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-46),
N4-(2-甲氧基苯基)-N2-(4-(4-甲基哌嗪-1-基)喹唑啉-7-基)嘧啶-2,4-二胺(I-47),
N-(4-(2-甲氧基苯氧基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-48),
N-(4-(1-异丙基-1H-苯并[d][1,2,3]***-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-49),
N-(4-(1-甲基-1H-苯并[d][1,2,3]***-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-50)。
优选,所述药学上可接受的盐为所述蛋白激酶抑制剂与酸或碱形成的盐,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、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剂及其衍生物的制备方法,其特征在于,所述制备方法为:
溴代化合物A0先转化为硼酸频那醇酯A1再经偶联反应得到化合物A,或者溴代化合物A0直接经偶联得到化合物A;化合物B1经烷基化反应引入R2,得到化合物B;化合物A与化合物B经烷基化反应得到得到化合物(I);
其中,W、V、X、Y、Z、R1、R2、R3的定义如权利要求1~4任一所述;
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,成盐完全后减压除去溶剂,即得所述蛋白激酶抑制剂的药学上可接受的盐。
本发明的药物组合物包含所述蛋白激酶抑制剂和/或其衍生物以及药学上可接受的载体。
所述蛋白激酶抑制剂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,如片剂、胶囊、糖浆、悬浮剂、注射剂,可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明的蛋白激酶抑制剂及其衍生物在制备治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病和/或心血管疾病药物中的应用。
优选,所述过度增殖性疾病为肺癌、***癌、***、结肠直肠癌、黑色素瘤、卵巢癌、乳腺癌、肾癌、神经***肿瘤、淋巴瘤或白血病。
所述蛋白激酶抑制剂及其衍生物可制备为治疗和/或预防急性髓细胞白血病、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、乳腺癌、非小细胞肺癌、黑色素瘤、肾癌、卵巢癌、***癌、结肠癌或中枢神经***肿瘤药物。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类蛋白激酶抑制剂及其衍生物和药物组合物可有效抑制CDK9激酶活性,CDK9激酶抑制IC50值均不超过1μM,最优不超过0.1μM,可达到纳摩尔浓度级别;还可以抑制MV4-11肿瘤细胞增殖,MV4-11肿瘤细胞增殖抑制IC50值大多不超过1μM,最优不超过0.1μM;并且对多种肿瘤细胞均有抑制作用,多种肿瘤细胞抑制IC50值均不超过1μM,最优可达到纳摩尔浓度级别;应用广泛,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和/或心血管疾病药物;
(2)该类药物应用广泛,可用于治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病和/或心血管疾病;所述药物可从酶水平和细胞水平发挥药效,效果更优异,IC50值最优可达到纳摩尔浓度级别;
(3)化合物制备方法简便、易操作。
附图说明
图1为化合物I-22的1H NMR谱图;
图2为化合物I-22的质谱图。
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:
4,7-二氯喹唑啉、N-甲基哌嗪、4-苯基嘧啶-2-胺、4,5-双二苯基膦-9,9-二甲基氧杂蒽、(2-甲氧基苯基)硼酸、[1,1’-双(二苯基膦基)二茂铁]二氯化钯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紧凑型型傅里叶变换质谱仪测定。
实施例1:4-(4-甲基哌嗪-1-基)-N-(4-苯基嘧啶-2-基)喹唑啉-7-胺(化合物I-1)的合成
(1)7-氯-4-(4-甲基哌嗪-1-基)喹唑啉(化合物B-1)的合成
在50mL单颈瓶中加入4,7-二氯喹唑啉(199mg,1.00mmol),加入10mL二氯甲烷溶解,缓慢加入N-甲基哌嗪(110mg,1.10mmol)和三乙胺(111mg,1.10mmol)的二氯甲烷溶液,滴加完毕后室温搅拌反应大约12h,TLC监测反应结束后,将反应液浓缩,残留物用硅胶柱层析分离纯化(二氯甲烷:甲醇=100:1),得到234mg淡黄色固体,收率89%;ESI-MS m/z:263[M+H]+。
(2)4-(4-甲基哌嗪-1-基)-N-(4-苯基嘧啶-2-基)喹唑啉-7-胺(化合物I-1)的合成
向25mL二颈瓶中加入4-苯基嘧啶-2-胺(34mg,0.20mmol),化合物B-1(53mg,0.20mmol),碳酸铯(130mg,0.40mmol),醋酸钯(4.5mg,0.02mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(11.5mg,0.02mmol),无水甲苯5~10mL溶解,用氮气进行脱气,在氮气保护条件下,100℃加热反应2~6h,将反应液过滤并浓缩,残留物用硅胶柱层析分离纯化(二氯甲烷:甲醇=100:1),得到28mg淡黄色固体,收率35%;1H NMR(300MHz,DMSO-d6)δ10.32(s,1H),8.51(d,J=5.7Hz,1H),8.35(s,1H),8.23(dd,J=8.5,0.4Hz,1H),7.95–8.06(m,2H),7.78(dd,J=2.2,0.6Hz,1H),7.56–7.62(m,1H),7.55–7.38(m,2H),7.35(dd,J=8.4,2.3Hz,1H),7.16(d,J=5.6Hz,1H),3.66–3.73(m,4H),2.50–2.59(m,4H),2.26(s,3H).ESI-MS m/z:398[M+H]+。
实施例2:N-(4-(2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(化合物I-2)的合成
(1)4-(2-甲氧基苯基)嘧啶-2-胺(化合物A-1)的合成
向25mL茄形瓶中加入(2-甲氧基苯基)硼酸(502mg,3.3mmol),4-氯嘧啶-2-胺(390mg,3.0mmol),[1,1’-双(二苯基膦基)二茂铁]二氯化钯(110mg,0.15mmol),碳酸钠(636mg,6.0mmol),1,4-二氧六环12mL和纯净水2mL,用氮气进行脱气,在氮气保护条件下,100℃加热反应6h,反应液用乙酸乙酯萃取,浓缩后柱层析纯化(乙酸乙酯:石油醚=1:1),再重结晶纯化得淡黄粉末450mg,收率75%;ESI-MS m/z:202[M+H]+。
(2)N-(4-(2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(化合物I-2)的合成
以化合物A-1(40mg,0.20mmol),化合物B-1(53mg,0.20mmol)为原料,按照实施例1的合成方法,得白色固体39mg,收率45%;1H NMR(300MHz,DMSO-d6)δ10.25(s,1H),8.47(d,J=5.6Hz,1H),8.35(s,1H),8.24(dd,J=8.5,0.5Hz,1H),7.74(dd,J=2.3,0.5Hz,1H),7.55(dd,J=7.8,1.3Hz,1H),7.44(d,J=5.7Hz,1H),7.40–7.29(m,2H),7.14(td,J=7.6,1.3Hz,1H),7.00(dd,J=7.6,1.4Hz,1H),3.87(s,3H),3.63–3.70(m,4H),2.47–2.57(m,4H),2.37(s,3H).ESI-MS m/z:428[M+H]+。
采用与实施例1~2相似的操作,制得下列化合物:
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实施例3:化合物对CDK9激酶活性的抑制作用
所合成的化合物由美国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(香豆素)和520nm(荧光素)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1化合物对CDK9激酶活性的抑制作用
表中,“A”代表IC50值小于0.1μM,“B”代表IC50值在0.1μM到1μM之间,“C”代表IC50值大于1μM。
如表1所示,所有化合物对CDK9激酶活性均有抑制作用,其中化合物I-1、I-2、I-5、I-7~I-10、I-18~I-19、I-27、I-32和I-38~I-40抑制CDK9激酶的IC50值不超过1μM,其余化合物抑制CDK9激酶的IC50值不超过0.1μM,可达到纳摩尔浓度级别。
实施例4:化合物对肿瘤细胞的抗增殖作用
实验原理:用MTT法测定对白血病细胞株MV4-11肿瘤细胞株的抑制作用,体外测试抗肿瘤增殖活性的MTT法是一种检测细胞存活和生长的方法,其检测原理为活细胞线粒体中的NADP相关的脱氢酶(琥珀酸脱氢酶)能使外源性MTT还原为难溶性的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中,而死细胞无此功能。利用二甲基亚砜(DMSO)或三联液(10%SDS-5%异丁醇-0.01mol/L HCl)溶解细胞中的紫色结晶物甲瓒,以酶联免疫检测仪检测570nm波长处的光吸收值(OD值),可间接反映活细胞量。
具体操作方法:将处于对数生长期的肿瘤细胞按一定的细胞量接种于96孔培养板内,培养24h后加入受试化合物(悬浮细胞接板后可直接加),细胞在37℃、5%CO2条件下继续培养48h或72h后,加入MTT继续培养4h,用DMSO溶解结晶,利用酶联免疫检测仪在570nm波长处测定其OD值,计算化合物的抑制率和IC50值,分析结果见表2和表3。
表2化合物对MV4-11肿瘤细胞的抗增殖作用
表中,“A”代表IC50值小于0.1μM,“B”代表IC50值在0.1μM到1μM之间,“C”代表IC50值大于1μM。
表3化合物I-12对各类肿瘤细胞株的抑制作用
如表2所示,所有化合物对MV4-11肿瘤细胞均有抑制作用,其中化合物I-3~I-4、I-6、I-9、I-13、I-21、I-32和I-38抑制MV4-11肿瘤细胞的IC50值不超过1μM,化合物I-10~I-12、I-14~I-20、I-22~I-31、I-33~I-37和I-39~I-46抑制MV4-11肿瘤细胞的IC50值不超过0.1μM,可达到纳摩尔浓度级别。
如表3所示,化合物I-12对各种实质性器官癌均有抑制作用,其中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、黑色素瘤、肾癌、卵巢癌、***癌、结肠癌和中枢神经***肿瘤。
综上所述,本发明的蛋白激酶抑制剂及其衍生物、药物组合物可制备成抗癌药物,还可以制备成治疗其他疾病的药物,包括心脏、病毒学、炎症和疼痛中相关疾病的药物。
Claims (7)
1.一种CDK9激酶抑制剂类化合物及其衍生物,其特征在于,所述CDK9激酶抑制剂类化合物及其衍生物具有式(II)的结构,所述衍生物为所述化合物的药学上可接受的盐:
其中:
R1为
R2为氢原子、吗啉-4-基、哌嗪基、4-甲基哌嗪基、4-乙基哌嗪基、高哌嗪基、N-甲基高哌嗪基、哌啶基、(N-甲基哌嗪-4-基)哌啶基、(四氢吡喃-4-基)氨基、(四氢呋喃-3-基)氨基、(N-甲基哌啶-4-基)氨基、2-(二甲氨基)乙氨基、2-甲氧基乙氨基、3-甲氧基丙氨基、2,5-二氮杂双环[2.2.1]庚基-2-基、4-甲基哌嗪-3-酮基、(S)-3-甲基哌嗪基、(R)-3-甲基哌嗪基、(8-氮杂双环[3.2.1]辛烷-3-基)氨基、(R)-2-甲基哌嗪基、(S)-2-甲基哌嗪基、吡咯烷基、(2-甲氧基乙基)氨基、(3-甲氧基丙基)氨基、(四氢吡喃-4-基)氨基、(四氢呋喃-3-基)氨基、N,N-二甲基氨基、4,4-二氟哌啶基、(哌啶-4-基)氨基、(2-氨基乙基)氨基、(2-(甲基氨基)乙基)氨基、(2-(二甲基氨基)乙基)(甲基)氨基、(3-甲氧基乙基)氨基、4-甲基哌嗪-2-酮基;
R3为氢原子、氟原子;
R4为氢原子;
R5为氢原子、氟原子、甲氧基、乙氧基、苄氧基;
R6、R7为一个或多个氢原子、氟原子、C1-C3烷基、甲氧基;
Q为氧原子或亚氨基。
2.根据权利要求1所述的CDK9激酶抑制剂类化合物及其衍生物,其特征在于,所述CDK9激酶抑制剂类化合物及其衍生物结构中:
R1为苯基、2-甲氧基苯基、4-氟-2-甲氧基苯基、2-乙氧基苯基、4-氟-2-乙氧基苯基、2-苄氧基苯基、4-氟-2-苄氧基苯基、3-异丙基-2-甲基-2H-吲唑-5-基、7-氟-3-异丙基-2-甲基-2H-吲唑-5-基、1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基、4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基、1-甲基-1H-吲哚-3-基。
3.一种CDK9激酶抑制剂类化合物及其衍生物,其特征在于,所述CDK9激酶抑制剂类化合物为以下任一化合物:
4-(4-甲基哌嗪-1-基)-N-(4-苯基嘧啶-2-基)喹唑啉-7-胺(I-1),
N-(4-(2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-2),
N-(4-(4-氟-2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-3),
N-(5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-4),
N-(4-(2-乙氧基苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-5),
N-(4-(2-乙氧基-4-氟苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-6),
N-(4-(2-(苄氧基)苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-7),
N-(4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-8),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-9),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-吗啉基喹唑啉-7-胺(I-10),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(哌嗪-1-基)喹唑啉-7-胺(I-11),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-12),
4-(4-乙基哌嗪-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-13),
4-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-1-甲基哌嗪-2-酮(I-14),
1-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-4-甲基哌嗪-2-酮(I-15),
(S)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(3-甲基哌嗪-1-基)喹唑啉-7-胺(I-16),
(R)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(3-甲基哌嗪-1-基)喹唑啉-7-胺(I-17),
(R)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(2-甲基哌嗪-1-基)喹唑啉-7-胺(I-18),
(S)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(2-甲基哌嗪-1-基)喹唑啉-7-胺(I-19),
4-(1,4-高哌嗪-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-20),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(4-甲基-1,4-高哌嗪-1-基)喹唑啉-7-胺(I-21),
4-(2,5-二氮杂双环[2.2.1]庚基-2-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-22),
N4-(8-氮杂双环[3.2.1]辛烷-3-基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-23),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(哌啶-4-基)喹唑啉-4,7-二胺(I-24),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(1-甲基哌啶-4-基)喹唑啉-4,7-二胺(I-25),
N4-(2-(二甲基氨基)乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-26),
N4-(2-氨基乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-4,7-二胺(I-27),
N4-(2-(二甲基氨基)乙基)-N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-甲基喹唑啉-4,7-二胺(I-28),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(2-(甲基氨基)乙基)喹唑啉-4,7-二胺(I-29),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(2-甲氧基乙基)喹唑啉-4,7-二胺(I-30),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(3-甲氧基丙基)喹唑啉-4,7-二胺(I-31),
5-(7-(((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)-2,5-二氮杂双环叔丁基[2.2.1]庚烷-2-羧酸酯(I-32),
N-(4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-33),
N-(4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-34),
N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-35),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(四氢呋喃-3-基)喹唑啉-4,7-二胺(I-36),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4-(四氢-2H-吡喃-4-基)喹唑啉-4,7-二胺(I-37),
N7-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-N4,N4-二甲基喹唑啉-4,7-二胺(I-38),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-2-甲基-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-39),
4-(叠氮基-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-40),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(哌啶-1-基)喹唑啉-7-胺(I-41),
N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)-4-(吡咯烷-1-基)喹唑啉-7-胺(I-42),
1-(4-(7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)喹唑啉-4-基)哌嗪-1-基)乙酮(I-43),
4-(4,4-二氟哌啶-1-基)-N-(4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)喹唑啉-7-胺(I-44),
N-(4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-45),
N-(4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-46),
N4-(2-甲氧基苯基)-N2-(4-(4-甲基哌嗪-1-基)喹唑啉-7-基)嘧啶-2,4-二胺(I-47),
N-(4-(2-甲氧基苯氧基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-48),
N-(4-(1-异丙基-1H-苯并[d][1,2,3]***-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-49),
N-(4-(1-甲基-1H-苯并[d][1,2,3]***-6-基)嘧啶-2-基)-4-(4-甲基哌嗪-1-基)喹唑啉-7-胺(I-50)。
4.根据权利要求1~3任一所述的CDK9激酶抑制剂类化合物及其衍生物,其特征在于,所述药学上可接受的盐为所述CDK9激酶抑制剂与酸形成的盐,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、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。
5.一种权利要求1~4任一所述的CDK9激酶抑制剂类化合物及其衍生物的制备方法,其特征在于,所述制备方法为:
溴代化合物A0先转化为硼酸频那醇酯A1再经偶联反应得到化合物A,或者溴代化合物A0直接经偶联反应得到化合物A;化合物B1经烷基化反应引入R2,得到化合物B;化合物A与化合物B经烷基化反应得到得到化合物(I);
其中,W、V、X、Y、Z、R1、R2、R3的定义如权利要求1~3任一所述;
将相应的酸的溶液加入到以上方法制备的化合物(I)的溶液中,成盐完全后减压除去溶剂,即得所述CDK9激酶抑制剂类化合物的药学上可接受的盐。
6.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~4任一所述CDK9激酶抑制剂类化合物和/或其衍生物以及药学上可接受的载体。
7.一种权利要求1~4任一所述的CDK9激酶抑制剂类化合物及其衍生物在制备治疗和/或预防肺癌、***癌、***、结肠直肠癌、黑色素瘤、卵巢癌、乳腺癌、肾癌、神经***肿瘤、淋巴瘤或白血病的药物中的应用。
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