CN115703758B - 一类用作激酶抑制剂的化合物及其制备方法和用途 - Google Patents
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Abstract
Description
技术领域
本发明属于医药技术领域。具体地，本发明涉及一类吲哚酮化合物、其制备方法和用途以及包含所述化合物的药物组合物。所述化合物可用于治疗和/或预防由IKKε和/或TBK1机制介导的疾病的药物中的用途。
背景技术
IKB激酶ε(IKKε)，也称为IKB激酶-3(IKK3)或诱导型IKB激酶(IKKi)。TANK结合激酶-1(TBK1)也称为T2K或NF-κB活化激酶，是丝氨酸-苏氨酸激酶。研究表明蛋白激酶在很多细胞功能-包括信号转导、转录调节、细胞运动和细胞分裂中起着关键作用。异常可导致某些疾病状况的发展和维持。几种癌基因还被证实可编码蛋白激酶，提示激酶在肿瘤发生中发挥着作用。
已知1KKε的同系物1KKα和IKKβ在IKK途径中起着关键作用。研究已经证实IKKε参与调节转录因子(例如所述NF-κB家族)和干扰素调节因子3(IRF3)的替代机制，已知所述转录因子和干扰素调节因子3均参与控制许多调节蛋白(包括促炎性细胞因子)的表达。IKKε直接使NF-κB家族成员cRel的C-末端磷酸化，导致cRel复合物的解离，从而增加cRel的核积累。
异常的1KKε活性与许多的疾病(包括癌症和肥胖)有关。研究已经证实，编码IKKε的基因(IKBE)在某些乳癌细胞系和源自患者的肿瘤中被扩增和过度表达。此外，抑制这些细胞系中的IKBE基因表达，促进了细胞死亡(Boehm et al.,Cell,2007,129,1065-1079)。IKKε还被证实可使雌激素受体磷酸化，并且其活性与乳癌肿瘤中的它莫西芬(tamoxifen)抗性有联系(Guo et al.,The Journal of Biological Chemistry,2010,285,3676-3684)。在人卵巢癌细胞系和原发肿瘤中1KKε频繁地过度表达，IKKε过度表达使细胞对顺铂产生抗性，如果抑制IKKε的表达，可以恢复细胞对于顺铂的敏感性(Guo et al.,TheAmerican Journal of Pathology,2009,175,324-333)。这些现象提示IKKε抑制剂具有治疗某些癌症的功效。
在先天免疫系统中，TBK1在LPS结合Toll-样受体4(TLR4)或双链RNA(来自双链RNA病毒)结合TLR3时活化。它也因促炎细胞因子TNF和IL-I而活化。活化后，TBK1磷酸化并激活干扰素调节因子3(IRF3)，该转录因子会诱发产生干扰素β和趋化因子，如白介素-8(IL-8)和RANTES。这些物质在介导宿主对细菌和病毒感染的防御中起到作用。不表达干扰素β或IRF3的小鼠不发生LPS诱导的感染性休克。这些观察结果表明，抑制TBK1化合物可能具有治疗/预防感染性休克和/或治疗炎性疾病的功效。
TBK1还可以被缺氧活化并刺激促血管生成因子例如血管内皮生长因子(VEGF)和1L-1的产生。缺氧24小时后TBK1的表达上升2.5-3倍,与VEGF的表达增加相似。缺氧诱导的VEGF表达可以通过TBK1的siRNA敲除而消除。在恶性结肠癌和乳癌细胞中TBKI mRNA和蛋白质的水平升高。TBK1还通过RalB/Sec5效应子复合物被募集并被活化：在癌细胞中，该途径经由慢性RalB活化的组成型接合，限制了细胞凋亡程序的起始。原癌基因KRAS在广泛的人肿瘤中产生变异，所述肿瘤大多数是侵略性的并且对标准治疗响应很差。研究已经证实，在KRAS依赖性肿瘤细胞系中敲除TBK1导致细胞死亡。这些现象提示：TBK1抑制剂可具有治疗某些癌症的功效(Barbie et al.,Nature,2009,462,5,108-114)。
研究已经证实，IKKε和TBK1都可在许多癌细胞系中将Akt磷酸化而激活(Ouetal.,MolecularCel1,2011,41,458-70:Xie et al.,PNAS,2011,108,16,6474-6479)。Akt是一种主要的信号激酶，在许多信号途径中作为枢纽在细胞增殖和存活中起着中枢作用。此外，已经证实在许多NSCLC细胞系中，TBK-1的siRNA敲除抑制了细胞存活。这些结果进一步地通过使用TBK1和1KKε激酶的小分子双重抑制剂而得到验证，所述抑制剂能够抑制Akt磷酸化以及对TBK1敲除敏感的NSCLC癌细胞系的增殖。这进一步提示了TBK1/IKKε抑制剂在治疗癌症中的作用(Ou et al.,Molecular Cel1,2011,41,458-70)。
IKKε敲除的小鼠可以免受高脂肪饮食诱导的肥胖、肝和脂肪的慢性炎症、肝性脂肪变性以及全身胰岛素抗性。这种鼠还显示出经由解偶联蛋白UCPl表达增强的能量消耗的增加(Chiang et al.，Cell，2009,138,961-975)。这些现象提示IKKε抑制剂可具有治疗肥胖和相关病症例如肥胖、糖尿病、非酒精性脂肪肝的功效。
原发性开角型青光眼(POAG)是不可逆失明的主要原因,其在世界范围内的患者数目高达三千五百万人。该疾病具有遗传异质性，视神经病变诱导反应蛋白(OPTN)中的突变与一种与正常眼内压相关的POAG，称为正常眼压青光眼(NTG)或低压青光眼(LTG)有关。,有报道称肿瘤坏死因子α(TNFα)能加重POAG和LTG患者的视神经头的损伤程度。而且,接触TNFα10能诱导从头表达视神经病变诱导反应蛋白。这些观察结果表明，某些形式的POAG可能由对此细胞因子的异常应答造成。因此，本文所述化合物可用于治疗POAG和/或与视神经病变诱导反应蛋白活性有关的疾病。
综上，IKKε和/或TBK1活性异常可以导致多种疾病发生，包括炎症性疾病、自身免疫性疾病、癌症、代谢性疾病和神经退行性疾病等。具体来说，包括炎症和组织修复障碍，尤其是类风湿性关节炎、炎症性肠病、哮喘和慢性阻塞性肺疾病(COPD)；骨关节炎、骨质疏松和纤维化疾病；皮肤病，包括银屑病、特应性皮炎和紫外辐射(UV)诱导的皮肤损伤；自身免疫性疾病，包括系统性红斑狼疮、多发性硬化、银屑病关节炎和强直性(ankylosing)脊椎炎；组织和器官排异、阿尔茨海默症、中风、动脉粥样硬化、再狭窄、肥胖、糖尿病、非酒精性脂肪肝，肾小球肾炎、癌症，包括霍奇金病(Hodgkin'sdisease)、恶病质、感染有关的炎症，包括某些病毒感染，包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、共济失调毛细血管扩张症、原发性开角型青光眼和脓毒性休克。
发明内容
发明人惊奇地发现了某些具有特定取代形式的吲哚酮是IKKε和/或TBK1的抑制剂，这是出人意料的。因此预期其可以用于治疗由IKKε和/或TBK1活性异常导致的疾病。
本发明的目的是提供一种通式(I)的化合物、制备所述通式(I)的化合物的方法、所述通式(I)的化合物的用途以及包含所述通式(I)的化合物的药物组合物。
其中：
R1选自：氢、氘、卤素、CN、NHR、OR4、SR4、CH2R4，其中，R4选自H、C1-6的直链或直链的烷烃，取代的C1-6直链或直链的烷烃、芳烃、取代的芳烃；
R2选自：NO2、*-NHR5、R6，
其中，R5选自H,氘、C1-12的直链或直链的烷烃，取代的C1-12直链或直链的烷烃、芳烃、取代的芳烃、酰基、磺酰基、亚磺酰基、胺酰基、硫酰基、胺硫酰基，R6选自-COOCH3、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、三氮唑基，吡啶基，嘧啶基，吡咯烷基，吡咯酮基，哌啶基，哌嗪基或吗啉基；
R3选自:
本发明的化合物还包括基于通式(I)结构的化合物，以及它们的同分异构体、对映异构体、非对映异构体或外消旋体。
一种通式(I)的化合物，优选地，R1选自：氢、氘、卤素、CN、NHR、OR4、SR4、CH2R4，其中，R4选自：H、C1-6的直链或直链的烷烃，取代的C1-6直链或直链的烷烃、芳烃、取代的芳烃，R2选自NO2；R3选自：
更优选地，R1选自：氢、卤素、CN；R2选自NO2；R3选自：
进一步优选地，R1选自：氢、F；R2选自NO2；R3选自：
一种通式(I)的化合物，优选地，
R1选自：氢、氘、卤素、CN、NHR、OR4、SR4、CH2R4，其中，R4选自：H、C1-6的直链或直链的烷烃，取代的C1-6直链或直链的烷烃、芳烃、取代的芳烃；R2选自*-NHR5，其中，R5选自：H,氘、C1-12的直链或直链的烷烃，取代的C1-12直链或直链的烷烃、芳烃、取代的芳烃、酰基、磺酰基、亚磺酰基、胺酰基、硫酰基、胺硫酰基；R3选自：
更优选地，R1选自：氢、卤素、CN；R2选自*-NHR5，其中，R5选自:H,氘、C1-12的直链或直链的烷烃，取代的C1-12直链或直链的烷烃、芳烃、取代的芳烃、酰基、磺酰基、亚磺酰基、胺酰基、硫酰基、胺硫酰基；R3选自：
进一步优选地，R1选自：氢、F；R2选自：*-NHR5，其中，R5选自：H,氘、C1-12的直链或直链的烷烃，取代的C1-12直链或直链的烷烃、芳烃、取代的芳烃、酰基、磺酰基、亚磺酰基、胺酰基、硫酰基、胺硫酰基；R3选自：
一种通式(I)的化合物，优选地，R1选自：氢、氘、卤素、CN、NHR、OR4、SR4、CH2R4，其中，R4选自H、C1-6的直链或直链的烷烃，取代的C1-6直链或直链的烷烃、芳烃、取代的芳烃；R2选自R6，其中，R6选自-COOCH3、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、三氮唑基，吡啶基，嘧啶基，吡咯烷基，吡咯酮基，哌啶基，哌嗪基或吗啉基；
R3选自：
更优选地，R1选自：氢、卤素、CN；R2选自R6，其中，R6选自：-COOCH3、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、三氮唑基，吡啶基，嘧啶基，吡咯烷基，吡咯酮基，哌啶基，哌嗪基或吗啉基；R3选自：
进一步优选地，R1选自氢、F；R2选自R6，其中，R6选自：-COOCH3、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、咪唑基、噻唑基、三氮唑基，吡啶基，嘧啶基，吡咯烷基，吡咯酮基，哌啶基，哌嗪基或吗啉基；R3选自：
进一步优选地，R1选自：氢、F；R2选自-COOCH3；R3选自：
另一方面，本发明提供一种制备通式(I)结构化合物的方法，其中一种通式(I)的制备方法：
将式7结构的化合物与叔丁醇，4-二甲氨基吡啶(和二环己基碳二亚胺常温搅拌，制得式6结构的化合物；在碱性，冰浴及无水无氧条件下条件，式6结构的化合物制成式5结构的化合物；然后在无水及碱性条件下，和DPPA发生柯提斯重排反应并关环制得4。然后在酸性条件下脱羧制成3结构的化合物。式3结构的化合物和原苯甲酸三甲(乙)酯反应制得式2结构的化合物；式2结构的化合物与芳香胺反应制得式I结构的化合物。
另一种制备通式(I)结构化合物的方法，包括以下步骤：
冰浴及无水无氧条件下，将式12结构的化合物与丙二酸二乙酯在碱性条件下反应制得式11结构的化合物；在还原剂存在下，式11结构的化合物还原为式10结构的化合物；然后将吲哚酮的6位氨基衍生得到式9结构的化合物；在酸性条件下，式9结构的化合物和原苯甲酸三甲(乙)酯反应制得式8结构的化合物；式8结构的化合物与芳香胺反应制得式(I)结构的化合物。
优选地，在步骤(a)中，所述碱为氢化钠，醇钠(钾)、氢氧化钠(钾)等；在步骤b中，还原剂为氢、钯碳/氢供体，金属、金属氢化物；在步骤d中，所述的催化剂为酸或酸酐。
另一种通式(I)结构化合物的制备方法，包括以下步骤：
式15结构的化合物在酸性条件下，和原苯甲酸三甲(乙)酯反应制得式14结构的化合物；式14结构的化合物与芳香胺反应制得式13结构的化合物，然后式13结构的化合物的6位溴在钯催化下发生SUZUKI反应，得到式(I)结构的化合物。
另一种制备通式(I)结构化合物的方法，包括以下步骤：
式17结构的化合物在酸性条件下，和原苯甲酸三甲(乙)酯反应制得式16结构的化合物；式16结构的化合物与芳香胺反应制得式(I)结构的化合物。
再一方面，本发明的化合物是IKKε和/或TBK1的抑制剂，因此可用于治疗与异常的1KKε和/或TBK1活性有关的或由其导致的疾病。本发明提供式(I)结构的化合物在制备用于治疗或预防由IKKε和/或TBKI活性异常导致的疾病的药物中的用途。所述疾病包括炎症性疾病、自身免疫性疾病、癌症、代谢性疾病和神经退行性疾病等。具体的，所述疾病涉及炎症和组织修复障碍，尤其是类风湿性关节炎、炎症性肠病、哮喘和慢性阻塞性肺疾病(COPD)；骨关节炎、骨质疏松和纤维化疾病；皮肤病，包括银屑病、特应性皮炎和紫外辐射(UV)诱导的皮肤损伤；自身免疫性疾病，包括系统性红斑狼疮、多发性硬化、银屑病关节炎和强直性(ankylosing)脊椎炎；组织和器官排异、阿尔茨海默症、中风、动脉粥样硬化、再狭窄、肥胖、糖尿病、非酒精性脂肪肝，肾小球肾炎、癌症，包括霍奇金病(Hodgkin's disease)、恶病质、感染有关的炎症，包括某些病毒感染，包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、共济失调毛细血管扩张症、原发性开角型青光眼和脓毒性休克。
由于本发明的化合物对IKKε和TBK1的选择性，而对其他激酶例如JNK没有选择性，所以预期它们可以用于治疗疾病，伴随比更低选择性的化合物更少的副作用。还预期它们可以特别用于治疗特异性地由异常的IKKε和/或TBK1活性导致的患者的靶向疾病。
特别地，本发明的化合物被预期可用于治疗癌症，具体地治疗其中与异常的IKKε和/或TBK1活性有关的疾病的患者人群。IKKε已经牵涉于乳癌，包括它莫西芬抗性乳癌、卵巢癌，包括顺铂抵抗性卵巢癌，其中肿瘤生长和/或存活依赖于IKKε激酶活性的癌症、隐匿Ras突变的癌症和Ras依赖性肿瘤以及涉及1q32基因位点扩增的癌症.TBK-1己经牵涉于隐匿K-ras突变的癌症和K-ras依赖性肿瘤、隐匿Ras突变的癌症和Ras依赖性的癌症、乳癌、肺癌，尤其是非小细胞肺癌(NSCLC)、卵巢癌、前列腺癌、骨髓瘤和白血病。
除了特异性地与IKKε和/或TBK1有关的癌症之外，本发明的化合物被预期特别地用于治疗和预防肥胖、糖尿病和非酒精性脂肪肝(其中牵涉有IKKε)；治疗和预防脓毒性休克以及原发性开角型青光眼(所有这些中均涉有TBK1)。
又一方面，本发明提供了一种药物组合物，其包含本发明所述的通式(I)结构的化合物和药学上可接受的载体或赋形剂。这样的组合物可以含有本发明的化合物作为唯一的活性成分，也可以还含有其他几种额外的活性成分。这种其他活性药剂可以是本发明的其他化合物，或者其可以是不同的治疗药剂，例如靶向上述疾病之一，尤其是与本发明的化合物靶向的相同疾病的药剂。本发明的化合物可以与所述额外药剂共同配方，或者其可以单独配方，并与所述额外药剂连续、同时或序贯地给予。
在本发明的某些实施方案中，所述药物组合物为固体口服制剂、液体口服制剂或注射剂。优选地，所述固体口服制剂为片剂、胶囊或颗粒剂；所述液体口服制剂为糖浆剂或口服溶液剂；和/或所述注射剂为注射用水针、注射用粉针或小输液。
在本发明范围内，除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明涉及到被多个取代基取代时，各取代基可以相同或不相同。
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C、14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
术语“烷基”是指“直链或支链烷基基团”,优选含有1至12个碳原子的烷基，非限制性实施例包括，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正壬基，及其各种支链异构体等；更优选的是含有1至4个碳原子的低级烷基，非限制性实施例包括甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的，当被取代时，取代基优选为1至5个，独立地选自F、Cl、Br、I、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧基、羧酸酯基、杂环烷巯基。
在本文中,“环烷基”的定义是单环烷基环,如环丙基、环丁基、环戊基、环己基或环庚基。
在本文中,“卤素”定义为氯、氟、溴、碘。
本文所用术语“芳基”指0-12芳香基团,它可以是苯并稠合基团,例如苯基或萘基。
“烷氧基”是指-O-烷基，其中烷基如本文上面所定义。烷氧基可以是取代的或未取代的，其非限制性实施例包括，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基或己氧基，优选具有1至12元烷氧基。当被取代时，取代基优选为1至5个，独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧基、羧酸酯基或杂环烷基巯基。
“任选”、“任选的”或“任选地”意味着随后所描述地事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。例如，“芳基任选被烷基取代”意味着烷基可以但不必须存在，该说明包括芳基被烷基取代的情形和芳基不被烷基取代的情形。
“取代或未取代的”是指基团可以被取代或不被取代的情形，若在本发明中没有指出基团可以被取代，则表示该基团为未取代的情形。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形，如果所述的基团被氢原子取代，形成的基团与被氢原子取代的基团相同。基团被取代的情形，例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代，形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。
本发明包括通式(I)的化合物的盐。通常，所述化合物与酸形成加成盐，所述酸是例如无机酸、强有机羧酸例如烷基羧酸，例如具有1至4个碳原子的未取代的或例如被卤素取代的烷基羧酸,例如饱和或不饱和的二羧酸，例如羟基羧酸，例如氨基酸,或者所述酸是有机磺酸，例如未取代的或例如被卤素取代的(C,-C)-烷基-或芳基-磺酸。可药用的酸加成盐通常包括从以下酸形成的那些：盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、琥珀酸、高氯酸、富马酸、马来酸、乙醇酸、乳酸、水杨酸、草酰乙酸、甲磺酸、乙磺酸、对甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羟乙磺酸、抗坏血酸、苹果酸、邻苯二甲酸、天冬氨酸和谷氨酸、赖氨酸和精氨酸。本身不是可药用的盐,例如衍生自例如草酸的酸的那些盐可以作为中间体用于获得本发明的化合物及其可药用的酸加成盐。
附图说明
图1：阳性对照药Staurosporine及实施例I-1,I-2,I-3的抑制曲线。
具体实施方式
下面结合实施例对本发明做进一步的说明，实施例仅为解释和说明性的，绝不意味着以任何方式限制本发明的范围。
化合物的结构是通过核磁共振氢谱(1H NMR)和/或质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AV400型核磁共振波谱仪。
MS的测定是用Thermo scientific(ESI)质谱仪进行的。
酶活性测试使用Biotek酶标仪(Synergy 4)进行的。
薄层层析硅胶板使用烟台黄海GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm,薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于百灵威科技，3A科技、前衍科技、Sigma、Carna、Promega等公司。
实施例中如无特殊说明，反应温度是室温。
室温为最适宜的反应温度，为20～30℃。
实施例1(制备实施例)
甲基-(E)-3-(((1-甲基-3-(4-甲基哌嗪-1-yl)-2-氧-1,2,3,4-四氢喹啉-6-基)氨基)(苯基)亚甲基)-2-氧化吲哚-6-羧酸酯(I-1)
a)Trimethyl orthobenzoate,Ac2O,Toluene,120℃,10h；b)Sodium tert-butoxide,BINAP,Pd2(dba)3,dioxane,100℃,10h；c)CH3OH/DMF,65℃,5h.
步骤a)将89.3mL甲苯加至250mL三颈瓶中，再加入27mL乙酸酐,搅拌下，加入18.9g氧化吲哚-6-羧酸甲酯，升温至110℃，开始滴加34ml原苯甲酸三甲酯，滴加完毕，搅拌反应8h。降温至0℃，继续搅拌2h，抽滤，固体用40mL甲苯洗涤，再用20mL甲苯和20mL乙酸乙酯的混合溶剂洗涤。收集固体于60℃鼓风干燥干燥，得产品19.33g，收率80％，HPLC检测，纯度86％(产物及其异构体)。
步骤b)将6-溴-1-甲基-3-(4-甲基哌嗪-1-基)-3,4-二氢喹啉-2(1H)-酮(300mg,0.89mmol)溶于二氧六环(10毫升)溶液中，添加苯甲酮亚胺(241mg,1.33mmol)、叔丁醇钠(256mg,2.66mmol)、三(二亚苄-BASE丙酮)二钯(Pd2(dba)3)(81mg,0.09mmol)和1,1'-联萘-2,2'-双二苯膦(BINAP)(55mg,0.09mmol)，在100℃、N2条件下搅拌16h,LCMS和TLC检测反应完成后，冷却至室温，缓慢加入HCl(10mL,1M)。2h后，用乙酸乙酯(30mL×3)萃取，水相加入饱和碳酸钠水溶液调节pH＝10，然后再用乙酸乙酯(3mL×30mL)萃取。合并有机相并用无水硫酸钠干燥，抽滤并减压下浓缩。残余物用硅胶柱层析(硅胶，CH2Cl2:CH3OH＝10:1)纯化得到6-氨基-1-甲基-3-(4-甲基哌嗪-1-基)-3,4-二氢喹啉-2(1H)-酮(150mg,yield:58％).MS obsd.(ESI+):[(M+H)+]275.2.1H NMR(400MHz,DMSO-d6)δ6.76-6.71(m,1H),6.44-6.41(m,2H),4.96-4.83(m,2H),4.09(s,1H),3.15(s,3H),2.92-2.86(m,1H),2.76-2.71(m,1H),2.59(t,J＝4.8Hz,4H),2.23-2.19(m,4H),2.10(s,3H).
步骤c)将130ml甲醇和30ml DMF分别加至250ml三颈瓶中，室温搅拌下，加入19.16g(E)-3-(甲氧基(苯基)亚甲基)-2-氧代二氢吲哚-6-羧酸甲酯和15.74g 6-氨基-1-甲基-3-(4-甲基哌嗪-1-基)-3,4-二氢喹啉-2(1H)-酮，升温至70℃，继续搅拌4h，反应完毕，停止加热，加入KOH的甲醇溶液(2.13g KOH，21.3mL甲醇溶解)，滴加完毕，降至室温，搅拌2h析晶，抽滤，固体用50mL冷甲醇洗涤1次，收集固体于50℃鼓风干燥箱至恒重，约3h。得产品23.62g，收率93％。HPLC检测，纯度为100％。MS obsd.(ESI+):[(M+H)+]552.3.1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),10.95(s,1H),7.62-7.57(m,2H),7.57-7.52(m,2H),7.44-7.41(m,2H),7.19(dd,J＝8.0,1.6Hz,1H),6.86(d,J＝8.8Hz,1H),6.81(d,J＝2.4Hz,1H),6.74(dd,J＝8.8,2.4Hz,1H),5.80(d,J＝8.4Hz,1H),3.77(s,3H),3.15(s,3H),3.13-3.10(m,1H),2.90-2.76(m,2H),2.56-2.54(m,2H),2.46-2.44(m,2H),2.22-2.16(m,4H),2.11(s,3H).
HPLC:99.12％(214nm),98.44％(254nm).
实施例2(制备实施例)
(Z)-3-((4-(2-(二甲氨基)甲基)-1h-咪唑-1-基)苯基)氨基)(苯基)亚甲基)-2-氧吲哚-6-羧酸甲酯(I-2)
a)K2CO3,DMF,80℃,16h；b)Dimethylamine,THF,NaBH3CN,MeOH,25℃,2h；c)Fe,NH4Cl,EtOH,H2O,80℃,1h；d)1.DMF,AcOH,90℃,8h.
步骤a)将1-氟-4-硝基苯(2.00g,14.20mmol)和1h-咪唑-2-甲醛(1.50g,15.60mmol)的DMF(30mL)溶液中加入K2CO3(2.36g,17.00mmol)，80℃，N2条件下搅拌16h,LCMS和TLC检测反应完成后，将反应混合物倒入水中，过滤后，收集沉淀并干燥，得到所需产品1-(4-硝基苯)咪唑-2-甲醛(2.90g，得率:94％)，无需进一步纯化，直接用于下一步。MSobsd.(ESI+):[(M+H)+]218.1.1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.37(d,J＝8.9Hz,2H),7.91(s,1H),7.82(d,J＝8.9Hz,2H),7.51(s,1H).
步骤b)将1-(4-硝基苯基)咪唑-2-甲醛(2.90g,13.40mmol)和二甲胺溶于THF(6ml)和甲醇(30ml)中，室温氮气下搅拌0.5h，然后按比例加入NaBH3CN(1.26g,20.10mmol)。搅拌反应2h,LCMS和TLC监测反应完成后，用盐水(30mL)稀释反应溶液，用EA(3×30mL)萃取反应溶液。水层用NH3.H2O调pH值>7，用EA(3×30mL)萃取。合并有机层并用Na2SO4干燥，减压下过滤、浓缩，得到所需产品，二甲基({[1-(4-硝基苯基)咪唑-2-基]甲基})胺(1.30g，得率:40％)，无需进一步纯化，直接用于下一步。MS obsd.(ESI+):[(M+H)+]247.2.1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝8.9Hz,2H),7.96(d,J＝8.9Hz,2H),7.58(s,1H),7.06(s,1H),3.43(s,2H),2.14(s,6H).
步骤c)在将二甲基({[1-(4-硝基苯基)咪唑-2-基]甲基})胺(1.30g,5.30mmol)溶于20mL乙酸乙酯/水＝1/1中，加入铁粉(0.89g,15.90mmol)和氯化铵(0.85g,15.90mmol)。80℃搅拌反应混合物1h,LCMS和TLC监测反应完成后，加硅藻土过滤反。滤液用乙酸乙酯(3×30mL)萃取，然后用Na2SO4干燥有机层，减压过滤和浓缩。残渣经制备液相纯化得到所需产品4-{2-[(二甲氨基)甲基]咪唑-1-基}苯胺(213mg，产率:19％)。MS obsd.(ESI+):[(M+H)+]217.3.1H NMR(400MHz,DMSO-d6)δ7.18(d,J＝1.2Hz,1H),7.16–7.13(m,2H),6.90(d,J＝1.2Hz,1H),6.63–6.61(m,2H),5.33(s,2H),3.25(s,2H),2.11(s,6H).
HPLC:100％(214nm),98.88％(254nm).
步骤d)将3-(甲氧基(苯基)亚甲基)-2-氧代二氢吲哚-6-羧酸甲酯(172mg,0.55mmol)在DMF(10mL)添加乙酸(10mL),反应混合物在90℃搅拌15min,然后将入4-{2-[(二甲氨基)甲基]咪唑-1-基}苯胺(120mg,0.55mmol)。90℃搅拌反应8h,LCMS和TLC监测反应完成后，加入H2O(20mL)，用乙酸乙酯(3×20mL)萃取反应溶液。合并有机层并用Na2SO4干燥，在减压下过滤和浓缩。残余物采用制备液相进行纯化，得到产品甲基(Z)-3-((4-(2-(二甲氨基)甲基)-1h-咪唑-1-基)苯基)氨基)(苯基)亚甲基)-2-氧吲哚-6-羧酸(53.47mg,yield:20％)。MS obsd.(ESI+):[(M+H)+]494.1.1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.01(s,1H),7.63–7.58(m,3H),7.55-7.53(m,2H),7.43(d,J＝1.4Hz,1H),7.41-7.39(m,2H),7.33(d,J＝1.2Hz,1H),7.21(dd,J＝8.2,1.6Hz,1H),6.99-6.97(m,2H),6.94(d,J＝1.2Hz,1H),5.87(d,J＝8.2Hz,1H),3.78(s,3H),3.25(s,2H),2.06(s,6H).
HPLC:99.59％(214nm),99.67％(254nm).
实施例3(制备实施例)
(E)3-(((4-(1-(2-(4-methylpiperazin-1-yl)乙酰基)环丙基)苯基)氨基)苯亚甲基)-2-氧化吲哚-6-羧酸甲酯(I-3)
a)PyHBr3,AcOH，60℃,16h；b)K2CO3,KI,MeCN,75℃,4h；c)H2,EA,rt,16h；d)AcOH,DMF,90℃,5h
步骤a)在1-[1-(4-硝基苯基)环丙基]乙酮(2.5g,12.18mmol)的醋酸(20mL)溶液入三溴化吡啶(4.68g,14.62mmol)，60℃下搅拌16h，反应完成后，减压浓缩得到粗产物，无需提纯即可用于下一步。MS obsd.(ESI+):[(M+H)+]282.0.
步骤b)将1-甲基哌嗪(1.82g,0.018mol)、KI(2.01g,0.012mol)和K2CO3(5.02g,0.036mol)加入到2-溴-1-[1-(4-硝基苯基)环丙基]乙酮(3.45g,0.012mol)MeCN(50mL)溶液中。将反应混合物在75℃下搅拌4h，反应完成后用硅藻土过滤。滤液在减压下浓缩。用硅胶柱层析纯化(DCM/MeOH＝10/1)，得到2-(4-甲基哌嗪-1-基)-1-(1-(4-硝基苯基)环丙基)乙酮1.2g，产率为33％。MS obsd.(ESI+):[(M+H)+]304.2.1H NMR(400MHz,CDCl3)δ8.23(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),3.10(s,2H),2.73-2.35(m,8H),2.33(s,3H),1.72(q,J＝3.8Hz,2H),1.22(q,J＝3.8Hz,2H).
步骤c)将2-(4-甲基哌嗪-1-基)-1-[1-(4-硝基苯基)环丙基]乙酮(1.2g,3.96mmol)溶于乙酸乙酯(60mL)溶液中，加入10％ Pd/C(100mg)。反应混合物在25℃、H2下搅拌16h。反应完成后，用硅藻土过滤，滤液减压浓缩，残余物用制备液相进行纯化，得到所需产品(320mg，收率:30％)。MS obsd.(ESI+):[(M+H)+]274.3.1H NMR(400MHz,DMSO-d6)δ7.00(d,J＝8.3Hz,2H),6.51(d,J＝8.3Hz,2H),5.07(s,2H),3.05(s,2H),2.32-2.24(m,8H),2.10(s,3H),1.32(dd,J＝6.6,3.3Hz,2H),0.97(dd,J＝6.6,3.3Hz,2H).
HPLC:99.53％(214nm),98.39％(254nm).
步骤d)将1-[1-(4-氨基苯基)环丙基]-2-(4-甲基哌嗪-1-基)乙酮(150mg,0.55mmol)溶于DMF(4mL)和AcOH(2mL)溶液中，加入3-(甲氧基(苯基)亚甲基)-2-氧代二氢吲哚-6-羧酸甲酯(170mg,0.55mmol)。将反应混合物在90℃下搅拌5h，反应完成后，将混合物减压浓缩。采用制备高效液相色谱法对残渣进行纯化，得到产物(100mg，产率33％)。MSobsd.(ESI+):[(M+H)+]551.2.1H NMR(400MHz,CDCl3)δ12.16(s,1H),8.43(s,1H),7.62-7.50(m,4H),7.43(dd,J＝8.1,1.4Hz,2H),7.38(dd,J＝8.3,1.5Hz,1H),7.11(d,J＝8.5Hz,2H),6.76(d,J＝8.5Hz,2H),5.98(d,J＝8.3Hz,1H),3.86(s,3H),3.13-3.05(m,4H),3.04(s,2H),2.82-2.74(m,2H),2.56-2.48(m,2H),2.47(s,3H),1.56(d,J＝3.2Hz,2H),1.08(d,J＝3.2Hz,2H).
HPLC:98.52％(214nm),98.47％(254nm).
实施例4(测试例/效果例)
按如下方法测试了本发明的化合物针对所述1KKε和TBK1酶的活性：使用基于发光法的均相激酶检测试剂盒来进行抑制研究。激酶反应后剩余的ATP被ADP-Glo试剂消耗，新生成ADP则被激酶检测试剂还原成ATP，随后ATP在荧光素酶的作用下与荧光素反应发光，发光信号与激酶活性呈正相关。
激酶抑制测定在25℃以384孔板形式进行。在ATP(40μM)的表观Km处基于ADP-Glo激酶检测试验(Promega)使用10个点的曲线重复测定了化合物1C50值。最终反应条件含有0.1mg/mL MBP底物、40μL ATP、1nM TBK1激酶,以及激酶反应缓冲液中0.5％DMSO,所述激酶反应缓冲液由40mM Tris、20mM MgCl2、0.10％BSA和0.5mM DTT组成。
化合物稀释剂是由2mM DMSO原液通过稀释到DMSO中而制备的。化合物稀释系列被进一步在激酶反应缓冲液中稀释以得到2％的DMSO原液,试验中的最终浓度为0.5％DMS0。
所述激酶磷酸化试验通过加入所述底物/ATP混合液起始,TBK1激酶的反应进行1小时。加入ADP-Glo试剂终止反应，并消耗掉剩余的ATP。在与激酶检测试剂孵育40min后新生成的ADP转化为ATP，通过检测ATP与荧光素反应发出稳定的“辉光”型荧光，可计算化合物在该浓度下对TBK1的抑制作用。测试了实施例对TBK1的IC50值。
实验仪器、试剂及耗材
实验步骤
1、激酶反应条件:
2.1制备1x激酶反应缓冲液:
| 名称 | 储液浓度 | 体积 | 终浓度 |
| Tris | 1M(25X) | 240μL | 40mM |
| MgCl2 | 1M(50X) | 120μL | 20mM |
| BSA | 7.5％(75X) | 80μL | 0.10％ |
| DTT | 1M(500X) | 3μL | 0.5mM |
| ddH2O | 5557μL |
2.2化合物筛选:
2.2.1在稀释板中用DMSO对化合物进行4倍稀释，化合物起始浓度为10mM。
2.2.2将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。
2.2.3用1X的酶反应缓冲液配制准备2X激酶。
2.2.4向反应板中每孔加入2μl激酶(步骤3中配制)。
2.2.5向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟。
2.2.6用1X的酶反应缓冲液配制4x MBP Protein和ATP(ATP终浓度10μM)混合液，向反应板中加入1μl 4x MBP Protein/ATP混合液。
2.2.7用封板膜封住板子1000g离心30秒，室温反应60分钟。
2.2.8转移4μL ADP-Glo到384反应板中1000rpm/min,离心1min，25℃孵育40min。
2.2.9转移8μL Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。
2.2.10使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
3.数据分析
3.1计算每孔的比率
3.2抑制率计算如下:
所有阳性对照孔1μM Staurosporine孔的读值的平均值
所有阴性对照孔DMSO孔的读值的平均值
3.3计算IC50并绘制化合物的抑制曲线(附图1)：
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：用Graphpad7.0软件进行数据分析。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X:化合物浓度log值Y:抑制率(％inhibition)
3.4 QC
Z factor>0.5；S/B>2
综述：发明人惊奇地发现了某些具有特定取代形式的吲哚酮是IKKε和/或TBK1的抑制剂，这是出人意料的。因此预期其可以用于治疗由IKKε和/或TBK1活性异常导致的疾病，所述疾病包括炎症性疾病、自身免疫性疾病、癌症、代谢性疾病和神经退行性疾病等。本发明的化合物在治疗特异性地与IKKε和/或TBK1有关的癌症之外，预期在治疗和预防特异性地与IKKε和/或TBK1有关的肥胖、糖尿病和非酒精性脂肪肝方面，有更好的治疗效果，具有明显的优势。
Claims (12)
1.一种通式(Ⅰ)结构的化合物或其药学上可接受的盐：
R1选自：氢、氘、卤素、CN；
R2选自：COOCH3；
R3选自:
2.如权利要求1所述的化合物或其药学上可接受的盐，
R1选自：氢、F；
R2选自：-COOCH3；
R3选自：
3.一种药物组合物，其包括权利要求1-2中任一项所述化合物和药学上可接受的载体、稀释剂或赋形剂。
4.根据权利要求3所述的药物组合物，其中，所述药物组合物为片剂、胶囊或颗粒剂。
5.权利要求1-2任一项的化合物在制备由IKKε和/或TBK1活性异常引起或由其导致的疾病的药物中的用途。
6.根据权利要求5的用途，所述疾病包括炎症性疾病、自身免疫性疾病、癌症、代谢性疾病和神经退行性疾病。
7.根据权利要求6的用途，所述疾病包括炎症性肠病、哮喘或慢性阻塞性肺疾病、骨关节炎、骨质疏松、组织修复障碍、纤维化疾病、皮肤病、组织或器官排异、动脉粥样硬化、肥胖症、糖尿病、非酒精性脂肪肝、肾小球肾炎、癌症、恶病质、成人呼吸窘迫综合征、共济失调毛细血管扩张症、原发性开角型青光眼或脓毒性休克。
8.根据权利要求6的用途，所述疾病包括乳癌、卵巢癌、肺癌、前列腺癌、骨髓瘤、白血病、肥胖症、脓毒性休克以及原发性开角型青光眼。
9.根据权利要求7的用途，所述疾病包括炎症性肠病、哮喘或慢性阻塞性肺疾病、成人呼吸窘迫综合征、骨关节炎、骨质疏松、组织修复障碍、纤维化疾病。
10.根据权利要求7的用途，所述疾病包括皮肤病、自身免疫性疾病、组织或器官排异、肾小球肾炎、癌症、恶病质、共济失调毛细血管扩张症、原发性开角型青光眼或脓毒性休克。
11.根据权利要求7的用途，所述疾病包括动脉粥样硬化、肥胖症、糖尿病、非酒精性脂肪肝。
12.根据权利要求11的用途，所述疾病包括肥胖症、II型糖尿病、非酒精性脂肪肝。
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