CN115215848A - 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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- CN115215848A CN115215848A CN202110423498.2A CN202110423498A CN115215848A CN 115215848 A CN115215848 A CN 115215848A CN 202110423498 A CN202110423498 A CN 202110423498A CN 115215848 A CN115215848 A CN 115215848A
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- amino
- pyrimidin
- oxide
- chroman
- protein kinase
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Description
技术领域
本发明涉及一类蛋白激酶抑制剂及其衍生物、制备方法、药物组合物和应用,尤其涉及一类具有优异的蛋白激酶及肿瘤细胞抑制活性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
恶性肿瘤极大地威胁着人类健康,研制抗肿瘤药物一直是生命科学中极具挑战性的领域。随着生物信息学、化学信息学和计算机科学介入的后基因组时代的到来,疾病治疗靶点逐渐明确,靶向性药物治疗成为主要趋势。蛋白激酶作为肿瘤治疗的一类重要靶点,开启了靶向性分子抗肿瘤治疗的历程。作为最大的蛋白质超家族之一,蛋白激酶(Proteinkinases)成员众多,功能多样。目前已知人类基因组共编码518种蛋白激酶,其中包括典型性激酶(478种)及非典型性激酶(40种),约占人类基因总数的1.7%。在所有的药理学靶点中,蛋白激酶数量超过25%。
蛋白激酶能够对特定的蛋白质进行磷酸化作用,而蛋白质的磷酸化是绝大多数信号通路组分可逆激活的共同机制。通过蛋白质的逐级磷酸化,可以使胞外信号逐级放大,引起细胞反应,对体内许多重要的生理过程起着关键性的调节作用。同时,激酶的功能异常也与肿瘤、免疫疾病、神经系统疾病、心血管疾病、传染病、糖尿病并发症等多种疾病密切相关。因此,基于激酶信号通路转导寻找潜在的疾病治疗新靶标受到了药物研究人员的广泛关注,利用蛋白激酶抑制剂调控细胞内异常激酶活性也成为相关疾病治疗的重要策略。但是,目前现有的蛋白激酶抑制剂易出现耐药性或者临床疗效差问题,尚未形成有效药物。
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,第三目的是提供一类包含所述蛋白激酶抑制剂和/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:
其中:
X或Y为CH、CR10或者N;
其中L为O或NR12;
R2、R3或R4为氢、卤素、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取代基上无取代或被至少1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取代基取代;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;
R5、R6、R7或R8为氢原子、卤素、C1-C6烷基或C1-C6烷氧基;
R9为氢、氰基、-C(O)R16、-C(O)OR16、-S(O)2R16、-C(O)NR17R18、-P(O)(OR18)2、-CH2OP(OR18)2、C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基;其中:所述C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
R10为氢、卤素、C1-C6烷基或氰基;
R11为氢、卤素、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或苄氧基取代的芳环;其中:所述C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基上无取代或被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、苯基、杂芳基或Het1取代,所述苯基或杂芳基上无取代或被至少1个卤素取代;
R12或R13为氢、C1-C6烷基或C3-C6环烷基;
R14或R15为氢、卤素或C1-C6烷基;
R16为C1-C6烷基、C3-C7环烷基、杂环基、苯基、苄基或者芳杂基;其中:C1-C6烷基、C3-C7环烷基、杂环基、苯基、苄基或者芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
R17或R18为C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基;其中:所述C1-C6烷基、C3-C7环烷基、杂烷基、苯基或芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
或者R17和R18与其所连接的氮原子一起形成环胺;
R19为氢、C1-C4烷基或苯基。
优选,所述蛋白激酶抑制剂及其衍生物结构中:
R5、R6、R7或R8为氢、卤素、C1-C3烷基或C1-C3烷氧基;
R10为氢、卤素、C1-C3烷基或氰基;
R11为氢、氟、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或苄氧基取代的芳环;其中:所述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、苯基、杂芳基、哌嗪基或吗琳基取代,所述苯基或杂芳基被1~2个氟原子取代。
优选,所述蛋白激酶抑制剂及其衍生物结构中:
R5、R6、R7或R8为氢、氟、甲基或甲氧基;
R10为氢、氟、氯或氰基;
R11为氢、氟、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-基氧基或1-(吡啶-4-基)甲氧基;
R14或R15为氢、卤素或C1-C3烷基。
优选,所述蛋白激酶抑制剂及其衍生物结构中:
R14或R15为氢、氟或甲基。
更具体地,所述蛋白激酶抑制剂为以下任一化合物:
7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-1),
2-亚氨基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-2),
7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-3),
4-吗啉基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-4),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-5),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-6),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-2-亚氨基-4-(4-甲基哌嗪-1-基)苯并二氢异噻喃2-氧化物(I-7),
7-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-8),
7-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-9),
7-((4-(4-氟-2-甲氧基苯基)-1,3,5-三嗪-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-10),
7-((4-(4-氟-2-甲氧基苯基)-1,3,5-三嗪-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-11),
7-((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-12),
7-((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-13),
2-亚氨基-7-((4-((2-甲氧基苯基)氨基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-14),
2-亚氨基-7-((4-(2-甲氧基苯氧基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-15),
7-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-16),
2-亚氨基-7-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-17),
7-((4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-18),
2-亚氨基-7-((4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-19),
7-((4-(苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-20),
7-((4-(4-氟苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-21),
7-((5-氟-4-(4-氟苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-22),
7-((4-(1H-吲哚-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-23),
7-((4-(1H-吲哚-4-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-24),
2-亚氨基-7-((4-(1-异丙基-1H-吲哚-4-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-25),
7-((4-(苯并[d][1,3]二恶酚-4-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-26),
7-((4-(2,2-二氟苯并[d][1,3]二恶唑-4-基]嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-27),
2-((2-亚氨基-2-氧化苯并二氢异噻喃-7-基)氨基)-4-(4-甲基-2-(甲氨基)噻唑-5-基)嘧啶-5-腈(I-28),
7-((4-(1-异丙基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-29),
2-亚氨基-7-((4-(1-异丙基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-30),
7-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-31),
2-亚氨基-7-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-32),
7-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-33),
7-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-34),
2-亚氨基-7-(((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-35),
7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-36),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-37),
7-((5-氟-4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-38),
7-((5-氟-4-(3-异丙基-2-甲基-2H-吲唑-5-基)吡啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-39),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-4-吗啉代苯并二氢异噻喃2-氧化物(I-40),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-4-(4-甲基哌嗪-1-基)苯并二氢异噻喃2-氧化物(I-41),
7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-42),
3,3-二氟-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-43),
1-((7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-2-氧化苯并二氢异噻喃-2-亚烷基)氨基)丙基-2-酮(I-44),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)-2λ4-苯并二氢异噻喃2氧化物(I-45)。
本发明设计化合物通过多种信号通路的蛋白激酶的协同抑制作用,在多种肿瘤细胞系中表现出强效的抗增殖效果,可克服潜在的耐药性以及达到更有效的治疗诸如肿瘤等疾病的作用;并且本发明的抑制剂结构母核新颖,未见相关资料报道,具有保护开发的价值。
在上述蛋白激酶抑制剂衍生物中,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;其中:所述酸为无机酸或有机酸,所述碱为无机碱或有机碱;所述酸更具体为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、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,所述碱更具体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。
上述蛋白激酶抑制剂及其衍生物的制备方法为:
伯胺化合物B与卤代化合物A,经偶联反应得到化合物I;
其中:
化合物A的制备方法:R1取代的硼酸D1或者R1取代的硼酸频哪醇酯D2与卤代化合物C经偶联反应得到化合物A;
化合物B的制备方法:间硝基卤代化合物E与巯基化合物F经烷基化反应得到化合物G,化合物G经还原、氨基保护、环合、脱氨基保护、还原、氧化,或者进一步缩合得到化合物B;
R1、R2、R3、R4、R5、R6、R7、R8、Q、X、Y的定义如前所述,Z为溴或氯,M为卤素;
将相应的酸或碱加入到上述的蛋白激酶抑制剂的溶液中,成盐完全后除去溶剂,即得所述蛋白激酶抑制剂的药学上可接受的盐。
上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构成药物组合物;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、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/固体填料、稀释剂、pH调节剂、渗透压调节剂、稳定剂等常用药用辅料。
上述蛋白激酶抑制剂及其衍生物可应用于制备治疗和/或预防过度增殖性疾病、病毒诱导的感染性疾病或心血管疾病的药物;所述过度增殖性疾病具体为肺癌、前列腺癌、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、淋巴瘤或白血病,更具体为急性髓细胞白血病、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'slymphoma)、滤泡性淋巴瘤、乳腺癌、非小细胞肺癌、黑色素瘤、肾癌、卵巢癌、前列腺癌、结肠癌或中枢神经系统肿瘤药物。
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均可有效抑制CDK9激酶活性,CDK9激酶抑制IC50值最优小于50nM;还可以抑制MV4-11肿瘤细胞增殖,MV4-11肿瘤细胞增殖抑制IC50值最优小于50nM;并且具有广泛的蛋白激酶和肿瘤细胞抑制谱系,对多种蛋白激酶抑制率均大于80%,抑制率最优达到95%以上,在分子水平达到了优异的生物活性;还对多种肿瘤细胞抑制IC50值均小于1μM,达到纳摩尔浓度级别,最优小于50nM,在细胞水平也达到了优异的生物活性;
(2)该类蛋白激酶抑制剂及其衍生物应用广泛,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或心血管疾病药物;所述药物在分子水平和细胞水平均可以发挥优异药效,IC50值最优可达到纳摩尔浓度级别,具有广阔的应用前景;
(3)该类蛋白激酶抑制剂及其衍生物制备方法简便易行,反应底物适应性强。
附图说明
图1为化合物I-29的1H-NMR谱图;
图2为化合物I-29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:
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,阳性药BAY1251152来源于MCE。
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1:7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2,2-二氧化物(化合物I-1)的合成
1、2-氯-4-苯基嘧啶(化合物A-1)的合成
在25mL双颈瓶中加入苯硼酸(化合物D2-1)(268mg,2.2mmol),2,4-二氯嘧啶(化合物C-1)(258mg,2mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(146mg,0.2mmol),碳酸钠(424mg,4mmol),2mL的水和12mL的1,4-二氧六环,氮气保护下,于100℃反应12h,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335mg,收率88%。ESI-MS m/z:191[M+H]+。
2、7-氨基苯并二氢异噻喃-2,2-二氧化物(化合物B-1)的合成
(1)2-((3-硝基苄基)硫代)乙酸(化合物G-1)的合成
在250mL单颈瓶中加入3-硝基溴苄(化合物E-1)(21.6g,0.1mol),巯基乙酸乙酯(化合物F-1)(13.2g,0.11mol),150mL甲醇,于冰浴条件下,缓慢加入氢氧化钠(8g,0.2mol),室温下搅拌2h,反应完成后旋干溶剂,加浓盐酸调pH至2,用3×200mL的乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,抽滤后滤液浓缩后得黑褐色油状物18.5g,收率81%。ESI-MS m/z:228[M+H]+。
(2)2-((3-氨基苄基)硫代)乙酸(化合物H-1)的合成
在250mL单颈瓶中加入化合物G-1(11.4g,0.05mol),铁粉(27.9g,0.5mol)和氯化铵(26.7g,0.5mol),120mL无水乙醇,40mL水,于90℃下回流反应4h,趁热抽滤,无水乙醇洗涤3次,滤液浓缩后得淡黄色固体7.9g,收率80%。ESI-MS m/z:198[M+H]+。1H-NMR(300MHz,DMSO-d6)δ9.69(s,1H),6.95(t,J=7.7Hz,1H),6.51(t,J=2.0Hz,1H),6.37-6.47(m,2H),3.64(s,2H),3.12(s,2H),1.84(s,2H)。
(3)2-((3-((((9H-芴-9-基)甲氧基)羰基)氨基)苄基)硫基)乙酸(化合物I-1)的合成
在250mL单颈瓶中加入化合物H-1(5.9g,30mmol),氯甲基-9-芴基甲酯(8.3g,33mmol),碳酸氢钠(12.6g,150mmol),100mL 1,4-二氧六环和50mL水,室温反应48h后,浓缩反应液,浓盐酸调pH至2,3×200mL乙酸乙酯萃取,无水硫酸钠干燥,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=5∶1)得白色固体4.5g,收率36%。ESI-MS m/z:420[M+H]+。1H-NMR(300MHz,DMSO-d6)δ12.61(s,1H),9.76(s,1H),7.84(dd,J=46.0,7.4Hz,4H),7.13-7.62(m,7H),6.94(d,J=7.5Hz,1H),4.47(d,J=6.7Hz,2H),4.32(d,J=6.7Hz,1H),3.76(s,2H),3.13(s,2H)。
(4)(9H-芴-9-基)甲基(4-氧代苯并二氢异噻喃-7-基)氨基甲酸酯(化合物J-1)的合成
在100mL茄形瓶中加入化合物H-1(4.19g,10mmol)和五氧化二磷(4.26g,30mmol),加入60mL甲苯,氮气保护下于100℃反应12h,TLC检测原料点消失。冷却至室温后,抽滤,滤液浓缩后得粗品,直接进行下一步反应。
(5)7-氨基苯并二氢异噻喃-4-酮(化合物K-1)的合成
在50mL茄形瓶中加入粗品化合物J-1,无水乙醇30mL溶解,3mL哌啶,加热回流4h,将反应液冷却至室温,减压除去多余溶剂,柱层析纯化(石油醚∶乙酸乙酯=2∶1),得淡黄色固体0.98g,收率55%。ESI-MS m/z:180[M+H]+。1H-NMR(300MHz,DMSO-d6)δ7.60-7.72(m,1H),6.47(dd,J=8.6,2.1Hz,1H),6.33(s,1H),6.20(s,2H),3.81(s,2H),3.44(s,2H)。
(6)苯并二氢异噻喃-7-胺(化合物L-1)的合成
在25mL单颈瓶中加入化合物K-1(896mg,5.00mmol),三乙基硅烷(3.48g,30mmol)和三氟乙酸(12.54g,110mmol),室温下反应5h,加饱和碳酸氢钠淬灭,3×10mL乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析纯化(石油醚∶乙酸乙酯=4∶1),得淡黄色固体653mg,收率79%。ESI-MS m/z:166[M+H]+。1H-NMR(400MHz,DMSO-d6)δ6.79(d,J=8.0Hz,1H),6.40(dd,J=8.0,2.4Hz,1H),6.36(d,J=2.4Hz,1H),4.91(s,2H),3.56(s,2H),2.76(s,4H)。
(7)7-氨基苯并二氢异噻喃2,2-二氧化物(化合物B-1)的合成
在25mL单颈瓶中加入化合物L-1(495mg,3mmol),加入8mL二氯甲烷溶解,缓慢加入间氯过氧苯甲酸(1038mg,6mmol),室温反应8h后,加入饱和亚硫酸钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥并浓缩,得白色固体503mg固体,收率86%。ESI-MS m/z:198[M+H]+。1H-NMR(400MHz,DMSO-d6)δ7.66(d,J=8.6Hz,1H),6.47(dd,J=8.6,2.3Hz,1H),6.32(d,J=2.2Hz,1H),6.20(s,2H),4.16(s,2H),3.23-3.34(m,4H)。
3、7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2,2-二氧化物(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A-1(114mg,0.60mmol),化合物B-1(130mg,0.66mmol),醋酸钯(14mg,0.06mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(36mg,0.06mmol)和碳酸铯(391mg,1.20mmol),加入无水甲苯10mL,100℃加热反应3~5h,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),再次重结晶纯化后得到白色固体128mg,收率61%。ESI-MS m/z:352[M+H]+。1H-NMR(300MHz,Chloroform-d)δ8.35(d,J=1.9Hz,1H),7.65(s,1H),7.59(d,J=2.3Hz,1H),7.42-7.54(m,2H),7.33(s,1H),7.26(s,1H),7.17(d,J=8.3Hz,1H),6.94(s,1H),6.75-6.86(m,2H),4.25(s,2H),3.25-3.43(m,4H)。
采用与实施例1相似的操作,制得下列化合物:
实施例2:2-亚氨基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2-氧化物(化合物I-2)的合成
1、7-氨基-2-亚氨基苯并二氢异噻喃-2-氧化物(化合物M-1)的合成
在5mL的单颈瓶中加入化合物L-1(330mg,2mmol),碘苯二乙酸(1288mg,4mmol),氨基甲酸铵(156mg,2mmol),2mL甲醇,室温反应2h后,经TLC检测原料消失,浓缩反应液,残留物用硅胶柱层析分离纯化(二氯甲烷∶甲醇=120∶1),得淡黄色固体146mg,收率37%。ESI-MS m/z:197[M+H]+。1H-NMR(300MHz,Chloroform-d)δ6.77(d,J=8.4Hz,1H),6.52-6.49(m,1H),6.46(dd,J=8.4,2.2Hz,1H),6.20(s,2H),4.16(s,2H),3.26-3.36(m,4H),2.02(s,1H).
2、2-亚氨基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2-氧化物(化合物I-2)的合成
在氮气保护的情况下,于25mL双颈瓶中加入化合物A-1(114mg,0.60mmol),化合物M-1(129mg,0.66mmol),醋酸钯(14mg,0.06mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(36mg,0.06mmol)和碳酸铯(391mg,1.20mmol),加入无水甲苯10mL,100℃加热反应3~5h,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=90∶1),得到淡黄色固体86mg,收率41%。ESI-MS m/z:351[M+H]+。1H-NMR(300MHz,Chloroform-d)δ8.40(d,J=5.6Hz,1H),7.85(s,1H),7.45-7.52(m,2H),7.28-7.40(m,3H),7.08(td,J=1.5,0.8Hz,1H),6.95-7.05(m,3H),4.26(s,2H),3.28-3.49(m,4H),2.32(s,1H)。
采用与实施例2相似的操作,制得下列化合物:
实施例3:7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2-氧化物(化合物I-3)的合成
1、7-氨基苯并二氢异噻喃-2-氧化物(化合物N-1)的合成
在25mL单颈瓶中加入化合物L-1(495mg,3mmol),加入8mL二氯甲烷溶解,冰浴条件下缓慢加入间氯过氧苯甲酸(519mg,3mmol),室温反应4h后,加入饱和亚硫酸钠溶液淬灭,二氯甲烷萃取,无水硫酸钠干燥并浓缩,得白色固体475mg固体,收率87%。ESI-MS m/z:182[M+H]+。
2、7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2-氧化物(化合物I-3)的合成
在氮气保护的情况下,于25mL双颈瓶中加入化合物A-1(114mg,0.60mmol),化合物N-1(109mg,0.60mmol),醋酸钯(14mg,0.06mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(36mg,0.06mmol)和碳酸铯(391mg,1.20mmol),加入无水甲苯10mL,100℃加热反应3~5h,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=60∶1),得到白色固体76mg,收率38%。ESI-MSm/z:336[M+H]+。1H-NMR(300MHz,Chloroform-d)δ8.40(d,J=5.2Hz,1H),7.53-7.44(m,2H),7.42-7.30(m,3H),7.10(dt,J=1.9,1.0Hz,1H),7.05-6.92(m,3H),6.83(s,1H),3.83(d,J=1.0Hz,2H),2.96-2.86(m,2H),2.81-2.72(m,2H)。
采用与实施例3相似的操作,制得下列化合物:
实施例4:4-吗啉基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2,2-二氧化物(化合物I-4)的合成
1、7-氨基-4-吗啉基苯并二氢异噻喃-2,2-二氧化物(化合物M-2)的合成
(1)4-吗啉基苯并二氢异噻喃-7-胺(化合物L-2)的合成
在25mL单颈瓶中加入化合物J-1粗品约1g,氰基硼氢化钠(378mg,6mmol),吗啡啉(261mg,3mmol),10mL的甲醇,反应2h后,加入2滴冰醋酸,40℃下过夜反应,TLC检测原料反应完全,加1N NaOH调节pH至7,3×20mL二氯甲烷萃取,有机相浓缩后,加入10mL二氯甲烷和2mL的哌啶,室温搅拌10min后,浓缩反应液,残留物用硅胶柱层析分离纯化(石油醚∶乙酸乙酯=1∶1),得淡黄色固体276mg。ESI-MS m/z:251[M+H]+。
(2)7-氨基-4-吗啉基苯并二氢异噻喃-2,2-二氧化物(化合物M-2)的合成在10mL的单颈瓶中加入化合物L-2(250mg,1mmol),加入6mL的二氯甲烷溶解,缓慢加入间氯过氧苯甲酸(346mg,2mmol),室温反应约6h后,加入饱和亚硫酸钠淬灭,二氯甲烷萃取,饱和碳酸氢钠溶液洗涤三次,无水硫酸钠干燥,浓缩后得淡黄色固体233mg,收率83%。ESI-MSm/z:283[M+H]+。1H-NMR(300MHz,Chloroform-d)δ7.24(dd,J=8.4,1.0Hz,1H),6.50-6.62(m,2H),6.18(s,2H),4.59(dd,J=14.9,1.0Hz,1H),4.34(dd,J=6.8,1.0Hz,1H),4.09(td,J=5.2,1.0Hz,1H),3.99-3.81(m,5H),3.47(dd,J=14.6,5.3Hz,1H),2.94(ddd,J=12.8,6.4,5.6Hz,2H),2.33(ddd,J=12.8,6.3,5.7Hz,2H)。
2、4-吗啉基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃-2,2-二氧化物(化合物I-4)的合成
在氮气保护的情况下,于25mL双颈瓶中加入化合物A-1(114mg,0.60mmol),化合物M-2(169mg,0.60mmol),醋酸钯(14mg,0.06mmol),2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(36mg,0.06mmol)和碳酸铯(391mg,1.20mmol),加入无水甲苯10mL,100℃加热反应2h,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=30∶1),得到淡黄色固体89mg,收率34%。ESI-MSm/z:437[M+H]+。1H-NMR(300MHz,Chloroform-d)δ8.41(d,J=5.6Hz,1H),7.85(s,1H),7.45-7.53(m,2H),7.43(dd,J=8.4,1.0Hz,1H),7.30-7.40(m,3H),7.13(dt,J=1.9,1.0Hz,1H),7.04(dd,J=8.4,1.9Hz,1H),6.99(d,J=5.6Hz,1H),4.62(dd,J=14.9,1.0Hz,1H),4.37(dd,J=14.9,1.0Hz,1H),4.09-4.27(m,5H),3.87(dd,J=14.5,5.3Hz,1H),3.49(dd,J=14.5,5.2Hz,1H),2.96(ddd,J=12.8,6.8,5.3Hz,2H),2.34(ddd,J=12.7,6.6,5.3Hz,2H)。
采用与实施例2和实施例4相似的操作,制得下列化合物:
实施例5:化合物对蛋白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)法测试对蛋白激酶的抑制活性,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(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
注:“A”代表IC50值小于50nM,“B”代表IC50值在50nM到0.1μM之间,“C”代表IC50值在0.1μM到1μM,“D”代表IC50值大于1μM。
如表1所示,所有测试化合物对CDK9激酶活性均有抑制作用,其中化合物I-5~I-13、I-16~I-19、I-21~I-22、I-25和I-29~I-45抑制CDK9激酶的IC50值均小于50nM。
实施例6:化合物I-30、I-37的蛋白激酶谱筛选
化合物I-30、I-37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)法测试对蛋白激酶家族的抑制活性。
具体操作方法:各蛋白激酶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蛋白激酶、Peptide substrate、HEPES(pH7.5)、BRIJ-35、MgCl2和EDTA。蛋白激酶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(荧光素)的荧光强度。按公式计算受试化合物1μM浓度下的蛋白激酶抑制率(n=2),其中抑制率大于等于80%的分析结果见表2。
表2化合物的蛋白激酶谱
注:“A”代表Inhibition≥95%,“B”代表90%≤Inhibition<95%,“C”代表85%≤Inhibition<90%,“D”代表80%≤Inhibition<85%。
如表2所示,测试化合物对多种蛋白激酶均有良好的抑制活性,蛋白激酶抑制谱系广泛。其中化合物I-30、I-37对ACK1、ALK1、ALK2、ALK4、ARK5、Aurora-c、AXL、BMX、c-kit、c-Src、CAMK2a/2b/2d/2g/K1/K2、CDC7、CDK1/2/3/4/5/6/7/8/12/13/14/16/17、CK2a、CK2a2、CLK1/2/4、DDR1、DYRK1A/1B/2/3、ERK7、FAK、FER、FGR、FLT3、GCK、GLK、GSK3a/3b、HGK、HIPK1/2/3/4、HPK1、IRAK1、JAK2/3、JNK1/2/3、LATS2、LCK、LOK、LRRK2、MAK、MAST3、MINK、MLK1/2/3、MUSK、NEK3/4、P38d/38g、PIM3、PKCa/g、PKD2、ROCK1/2、ROS、STK16/33、TAOK1/2/3、TBK1、TGFBR2、TNIK、TRKC、TYK2、YES、YSK4的抑制率大于等于95%,抑制效果尤为突出。
实施例7: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3。
表3化合物对MV4-11肿瘤细胞的抗增殖作用
注:“A”代表IC50值小于50nM,“B”代表IC50值在50nM到0.1μM之间,“C”代表IC50值在0.1μM到1μM,“D”代表IC50值大于1μM。
如表3所示,所有测试化合物对MV4-11肿瘤细胞均有抑制作用,其中化合物I-18~I-19、I-23~I-25、I-30~I-45抑制MV4-11肿瘤细胞的IC50值均小于50nM。
实施例8:化合物的抗肿瘤细胞谱检测
实验原理:用CTG法测定对肿瘤细胞株786-O、A498、MDA-MB-231等的抑制作用,体外测试抗肿瘤增殖活性的CTG法是一种检测细胞存活和生长的方法,其检测原理为:活细胞中的ATP腺嘌呤核苷酸参与生物体内多种酶促反应,是活细胞新陈代谢的一个重要指标,其含量直接反应了细胞的数量及状态。细胞裂解后可释放ATP,与细胞活力检测试剂CTG产生化学发光,发光的强度与ATP的量,即活细胞的数量在一定范围成正比,从而定量检测活细胞数量。
具体操作方法如下:
1、化合物配制
(1)使用DMSO将化合物配制为10mM的储存浓度;
(2)使用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10个点;
(3)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)。
2、细胞铺板与检测
(1)所测细胞铺板密度为5000cells/well,细胞铺板过夜,体积为20μL;
(2)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;
(3)每个孔中加入20μL的CTG,20分钟后使用Luminescence进行检测,3、结果分析
分析结果见表4。
表4化合物的肿瘤细胞谱抗增殖活性测试
注:“A”代表IC50值小于50nM,“B”代表IC50值在50nM到0.1μM之间,“C”代表IC50值在0.1μM到1μM。
如表4所示,代表性化合物I-30~I-31、I-34、I-36和I-37对各种实质性器官癌均有抑制作用,抑制浓度均达到纳摩尔浓度级别,且活性均显著优于阳性药BAY1251152(CDK9抑制剂,目前处于临床I期);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'slymphoma)、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、胃癌、肾癌、肝癌、卵巢癌、前列腺癌、结肠癌和中枢神经系统肿瘤。
Claims (10)
1.一种蛋白激酶抑制剂及其衍生物,其特征在于,所述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:
其中:
X或Y为CH、CR10或者N;
其中L为O或NR12;
R2、R3或R4为氢、卤素、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取代基上无取代或被至少1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取代基取代;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;
R5、R6、R7或R8为氢、卤素、C1-C6烷基或C1-C6烷氧基;
R9为氢、氰基、-C(O)R16、-C(O)OR16、-S(O)2R16、-C(O)NR17R18、-P(O)(OR19)2、-CH2OP(OR19)2、C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基;其中:所述C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
R10为氢、卤素、C1-C6烷基或氰基;
R11为氢、卤素、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或苄氧基取代的芳环;其中:所述C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基上无取代或被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、苯基、杂芳基或Het1取代,所述苯基或杂芳基上无取代或被至少1个卤素取代;
R12或R13为氢、C1-C6烷基或C3-C6环烷基;
R14或R15为氢、卤素或C1-C6烷基;
R16为C1-C6烷基、C3-C7环烷基、杂环基、苯基、苄基或者芳杂基;其中:C1-C6烷基、C3-C7环烷基、杂环基、苯基、苄基或者芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
R17或R18为C1-C6烷基、C3-C7环烷基、杂环基、苯基或芳杂基;其中:所述C1-C6烷基、C3-C7环烷基、杂烷基、苯基或芳杂基上无取代或被1~3个卤素、羟基、氰基、C1-C3烷基、C1-C3烷氧基、氨基、烷基氨基、二烷基氨基、N-甲基-N-乙酰氨基、环胺、卤代C1-C3烷基或C1-C3氟烷氧基取代;
或者R17和R18与其所连接的氮原子一起形成环胺;
R19为氢、C1-C4烷基或苯基。
2.根据权利要求1所述的蛋白激酶抑制剂及其衍生物,其特征在于,所述蛋白激酶抑制剂及其衍生物结构中:
R5、R6、R7或R8为氢、卤素、C1-C3烷基或C1-C3烷氧基;
R10为氢、卤素、C1-C3烷基或氰基;
R11为氢、氟、硝基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或苄氧基取代的芳环;其中:所述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、苯基、杂芳基、哌嗪基或吗琳基取代,所述苯基或杂芳基被1~2个氟原子取代。
3.根据权利要求1所述的蛋白激酶抑制剂及其衍生物,其特征在于,所述蛋白激酶抑制剂及其衍生物结构中:
R5、R6、R7或R8为氢、氟、甲基或甲氧基;
R10为氢、氟、氯或氰基;
R11为氢、氟、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-基氧基或1-(吡啶-4-基)甲氧基;
R14或R15为氢、卤素或C1-C3烷基。
4.根据权利要求1所述的蛋白激酶抑制剂及其衍生物,其特征在于,所述蛋白激酶抑制剂及其衍生物结构中:
R14或R15为氢、氟或甲基。
5.根据权利要求1所述的蛋白激酶抑制剂及其衍生物,其特征在于,所述蛋白激酶抑制剂为以下任一化合物:
7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-1),
2-亚氨基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-2),
7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-3),
4-吗啉基-7-((4-苯基嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-4),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-5),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-6),
7-((5-氟-4-(4-氟-2-甲氧基苯基)嘧啶-2-基)氨基)-2-亚氨基-4-(4-甲基哌嗪-1-基)苯并二氢异噻喃2-氧化物(I-7),
7-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-8),
7-((4-(2-(苄氧基)-4-氟苯基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-9),
7-((4-(4-氟-2-甲氧基苯基)-1,3,5-三嗪-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-10),
7-((4-(4-氟-2-甲氧基苯基)-1,3,5-三嗪-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-11),
7-((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-12),
7-((5-氟-4-(4-氟-2-甲氧基苯基)吡啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-13),
2-亚氨基-7-((4-((2-甲氧基苯基)氨基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-14),
2-亚氨基-7-((4-(2-甲氧基苯氧基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-15),
7-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-16),
2-亚氨基-7-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-17),
7-((4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-18),
2-亚氨基-7-((4-(1-异丙基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-19),
7-((4-(苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-20),
7-((4-(4-氟苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-21),
7-((5-氟-4-(4-氟苯并呋喃-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-22),
7-((4-(1H-吲哚-7-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-23),
7-((4-(1H-吲哚-4-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-24),
2-亚氨基-7-((4-(1-异丙基-1H-吲哚-4-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-25),
7-((4-(苯并[d][1,3]二恶酚-4-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-26),
7-((4-(2,2-二氟苯并[d][1,3]二恶唑-4-基]嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-27),
2-((2-亚氨基-2-氧化苯并二氢异噻喃-7-基)氨基)-4-(4-甲基-2-(甲氨基)噻唑-5-基)嘧啶-5-腈(I-28),
7-((4-(1-异丙基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-29),
2-亚氨基-7-((4-(1-异丙基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-30),
7-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-31),
2-亚氨基-7-((4-(1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-32),
7-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基]嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-33),
7-((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-34),
2-亚氨基-7-(((4-(1-异丙基-1H-苯并[d][1,2,3]三唑-6-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-35),
7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-36),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-37),
7-((5-氟-4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-38),
7-((5-氟-4-(3-异丙基-2-甲基-2H-吲唑-5-基)吡啶-2-基)氨基)-2-亚氨基苯并二氢异噻喃2-氧化物(I-39),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-4-吗啉代苯并二氢异噻喃2-氧化物(I-40),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-4-(4-甲基哌嗪-1-基)苯并二氢异噻喃2-氧化物(I-41),
7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2-氧化物(I-42),
3,3-二氟-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)苯并二氢异噻喃2,2-二氧化物(I-43),
1-((7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-2-氧化苯并二氢异噻喃-2-亚烷基)氨基)丙基-2-酮(I-44),
2-亚氨基-7-((4-(3-异丙基-2-甲基-2H-吲唑-5-基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)-2λ4-苯并二氢异噻喃2-氧化物(I-45)。
6.根据权利要求1~5任一所述的蛋白激酶抑制剂及其衍生物,其特征在于,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;其中:所述酸为无机酸或有机酸,所述碱为无机碱或有机碱。
8.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~7任一所述的蛋白激酶抑制剂和/或其衍生物以及药学上可接受的载体。
9.一种权利要求1~7任一所述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或心血管疾病药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述过度增殖性疾病为肺癌、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、伯基特氏淋巴瘤或滤泡性淋巴瘤。
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