CN111978325A - 咪唑并哒嗪类mnk1/mnk2激酶抑制剂及其制备方法和应用 - Google Patents
咪唑并哒嗪类mnk1/mnk2激酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN111978325A CN111978325A CN201910431113.XA CN201910431113A CN111978325A CN 111978325 A CN111978325 A CN 111978325A CN 201910431113 A CN201910431113 A CN 201910431113A CN 111978325 A CN111978325 A CN 111978325A
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Abstract
本发明提供了一类咪唑并哒嗪类MNK1/MNK2激酶抑制剂及其制备方法和应用。具体地，本发明提供了一种式(I)所示的化合物：或其立体异构体、互变异构体或药学上可接受的盐。本发明的化合物可以用于制备治疗MNK(优选地包括MNK1和MNK2)活性或表达量相关的疾病或病症的药物组合物。
Description
技术领域
本发明属于医药技术领域，具体而言，本发明提供了一类新的咪唑并哒嗪类化合物或其立体异构体、几何异构体、互变异构体及其药学上可接受的盐、水合物、前药或溶剂合物，及其作为MNK1和MNK2激酶抑制剂的用途。
背景技术
蛋白激酶(protein kinases)在多种细胞功能中发挥着重要的作用，其异常活化与多种疾病相关。丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)能够接收多种细胞信号(包括生长因子、环境刺激和细胞因子)并被激活，从而调控细胞的增殖、分化、存活、细胞周期控制以及程序性细胞死亡。在接收这些刺激信号后，MAPKs能够激活下游的靶蛋白，即MAPK激活蛋白激酶家族(MAPK-activated protein kinases family，MAPKAPK)，该激酶家族其中包括丝裂原活化蛋白激酶作用激酶(MAPK-interactingkinases，MNKs)。MNK激酶属于丝氨酸/苏氨酸蛋白激酶，能够特异性的将真核起始因子eIF4E(eukaryotic initiation factor 4E)的Ser209磷酸化，从而间接的调控mRNA翻译。
真核起始因子eIF4E作为一种重要的转录因子，能够加强编码调控细胞周期蛋白与致癌蛋白mRNA的转录从而引起肿瘤相关蛋白表达的上调。eIF4E与骨架蛋白eIF4G和RNA解旋酶eIF4A组成了真核起始因子复合体eIF4F。由于eIF4E负责该复合体与mRNA的5’末端帽子结构结合，所以其在RNA翻译过程中发挥着不可替代的调控作用。在正常细胞中，eIF4E的活性被限制，这些肿瘤相关mRNA的转录得到抑制；而在肿瘤细胞或组织中，eIF4E的高表达或过度活化会引起这些mRNA转录水平的上调。在多种肿瘤和肿瘤细胞株中均检测到了eIF4E表达水平的上调，其中包括结肠癌、乳腺癌、膀胱癌、肺癌、前列腺癌、胃癌、霍奇经淋巴瘤和成神经细胞瘤。而在临床上，MNK激酶与eIF4E表达上调或过度激活往往伴随着耐药以及不良预后。更为重要的是，虽然MNKs是eIF4E调控的肿瘤形成的必不可少的条件，但抑制MNKs活性并不会影响正常细胞和动物的存活与生长。所以，通过小分子药物抑制MNKs是一种极具前景的肿瘤治疗手段。
eIF4E作为一个重要的翻译限速因子，MNK/eIF4E信号通路能够影响多种趋化因子、细胞因子以及免疫检查点蛋白的合成，进而调控免疫应答。MNK激酶抑制剂能够显著降低肿瘤细胞表面PD-L1的含量，而对PD-L1mRNA的表达无影响，同时MNK抑制剂能够降低激活性T细胞表面免疫检查点蛋白PD-1、TIM-3和LAG3的表达。肿瘤异种移植模型结果也证实，MNK激酶抑制剂能够降低小鼠体内50％的PD-L1含量，并且MNK抑制剂对PD-L1高表达的肿瘤模型更为敏感。同时，MNK激酶抑制剂能够显著增强细胞毒CD8+ T细胞的功能，抑制激活的调节性T细胞的分化，并促进中央记忆T细胞的形成。在小鼠结肠癌同种移植模型中，MNK抑制剂几乎完全抑制肿瘤的增殖。而在停药29天后再次接种相同的肿瘤，在不给药的情况下，小鼠的肿瘤增殖依旧得到了完全的控制。这也从侧面反映了MNK抑制剂能够激活模型鼠持久的抗肿瘤免疫应答。
随着近几年对MNKs结构及功能了解的深入，陆续有多个MNK抑制剂得到了报道，其中BAY1143269、Tomivosertib和ETC-206陆续进入了临床。在小鼠异种移植模型中，BAY1143269、Tomivosertib以及ETC-206均能够显著地抑制瘤块的生长，并延长小鼠的生存期。从已经公布的I期临床结果来看，Tomivosertib和ETC-206均能够显著降低病人体内eIF4E的磷酸化水平，并表现出初步的症状缓解。而目前临床结果也进一步证实，在体内条件下，MNK抑制剂能够通过调节肿瘤微环境发挥抗肿瘤效果。随着对MNK/eIF4E通路了解的不断深入，基于该通路的抑制剂开发将在靶向治疗和肿瘤免疫疗法中发挥更为重要作用。
综上所述，本领域迫切需要开发新的MNK激酶抑制剂。
发明内容
本发明的目的是开发一种新的MNK激酶抑制剂。
本发明的第一方面，提供了通式(I)所示的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物：
其中，
X为S或O；
R1和R2各自独立地选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
各个R各自独立选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
R3为H，或具有-NR4R5所示的结构，其中，R4和R5各自独立地选自下组：氢、取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
其中，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷胺基、-C(O)C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、C3-C8环烷基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、C1-C6烷氧基。
在另一优选例中，所述的X为O。
在另一优选例中，所述的R1和R2各自独立地为取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基。
在另一优选例中，所述的-NR1R2具有如下所示的结构：
其中，Y选自下组：无(即化学键)、O、S、NR6、或CHR6；
所述的R6选自下组：C1-C6烷基、C1-C6烷胺基、-C(O)C1-C6烷基、氨基、具有1-3个选自N、S和O的杂原子的5-10元杂环基。
在另一优选例中，所述的化合物具有如下式II所示的结构：
在另一优选例中，R3为含N的五元或六元杂环。
在另一优选例中，所述的化合物选自I-1至I-17。
本发明的第二方面，提供了一种药物组合物，所述药物组合物包括：(i)治疗有效量的本发明第一方面所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的一种或多种，以及(ii)药学上可接受的载体或赋形剂。
在另一优选例中，所述药物组合物具有选自下组的制剂形式：片剂、丸剂、颗粒剂、膜剂、滴丸、胶囊剂、注射剂、软胶囊、乳剂、脂质体、冻干粉、高分子微球，或者聚乙二醇衍生物。
在另一优选例中，所述的药物组合物用于治疗与MNK的活性或表达量相关的疾病或病症。
在另一优选例中，所述的MNK为MNK1或MNK2。
本发明的第三方面，提供了一种如本发明第一方面所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的用途，其特征在于，所述的化合物用于制备治疗或预防与MNK的活性或表达量相关的疾病或病症的药物组合物。
在另一优选例中，所述的疾病为癌症。
在另一优选例中，所述的癌症选自下组：白血病，淋巴瘤，霍奇金病，骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、极性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性嗜中性粒细胞白血病、极性未分化细胞白血病、退行发育性大细胞性淋巴瘤、成人T细胞ALL、伴有三谱系脊髓发育不良的AML、混合型谱系白血病、脊髓发育不良综合征、骨髓增生异常、多发性骨髓瘤和脊髓肉瘤、慢性淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病、套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤。
本发明的第四方面，提供了如本发明第一方面所述的式(I)化合物的制备方法，所述方法包括步骤：
在金属钯催化剂(优选为Pd(PPh3)4或Pd(dppf)Cl2)催化下，用式7化合物与
进行偶联反应，得到目标化合物(I)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，发现了一类对MNK激酶(优选为MNK1和MNK2)具有优异的抑制效果的新型化合物。该化合物可以作为活性成分，用于制备治疗与MNK激酶活性或表达量相关的疾病的药物组合物。在此基础上，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“10-20元芳基”是指具有10-20个碳原子的芳基，例如，萘基、蒽基、菲基或类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-12元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
如本文所用，术语“药学上可接受的盐”包括式(I)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、乳酸、草酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、苯甲酸、甲磺酸、对甲苯磺酸、水杨酸、苯基乙酸、杏仁酸，此外还包括无机碱的酸式盐。
活性成分
本发明合成了一系列结构通式(I)所述的化合物或其立体异构体、几何异构体、互变异构体及其药学上可接受的盐、水合物、前药或溶剂合物：
其中，
X为S或O；
R1和R2独立选自氢、卤素、任选地被取代的脂肪基、任选地被取代的芳香基、任选地被取代的杂芳香基、任选地被取代的环烷基、任选地被取代的杂环烷基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；
每个R独立选自氢、任选地被取代的脂肪基、任选地被取代的芳香基、任选地被取代的杂芳香基、任选地被取代的环烷基、任选地被取代的杂环烷基；
R1和R2可以一起形成任选地被取代的5-6元环烷烃、芳香基、杂环烷基或杂芳香基。
在另一方面，本发明提供一种药物组合物，其包含治疗有效量式(I)化合物或其立体异构体、几何异构体、互变异构体及其药学上可接受的盐、其前药及其水合物或溶剂合物的一种或多种，以及任选的药学上可接受的载体或赋形剂。
在又一方面，本发明“药学上可接受的盐”包括式(I)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、乳酸、草酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、苯甲酸、甲磺酸、对甲苯磺酸、水杨酸、苯基乙酸、杏仁酸，此外还包括无机碱的酸式盐。
本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明涉及的化合物或其药学上可接受的盐、水合物、前药可作为唯一的抗肿瘤药物单独使用，或者可以与现已上市的抗肿瘤药物联合使用，用于治疗和/预防肿瘤等。
在又一方面，本发明涉及式(I)化合物的制备方法，通过以下步骤实现：
从化合物1和2出发，经过关环、与甲氧羰基苯硼酸偶联、溴代、水解、与相应的胺缩合再偶联得到目标化合物。具体的说，所述制备方法包括如下步骤：
以3-氨基6-氯吡嗪1和溴代乙醛缩二乙醇2为原料，在氢溴酸中关环得到化合物3；
化合物3在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与甲氧基羰基苯硼酸偶联得到化合物4；
化合物4在N-溴代丁二酰亚胺作用下溴代得到化合物5；
化合物5在氢氧化锂作用下水解得到化合物6；
化合物6在缩合剂EDCI/HOBT或HATU作用下与相应的胺缩合得到化合物7。
化合物7在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与苯并呋喃-2-硼酸或苯并噻吩-2-硼酸偶联得到目标化合物(I)；
其中，以上X、R1和R2的定义如前所述。
优选的，本发明式(I)所示的化合物选自下表1中的化合物：
表1.化合物结构
式(I)化合物的制备
本发明所述的式(I)化合物可以通过以下步骤进行制备：
从化合物1和2出发，经过关环、与甲氧羰基苯硼酸偶联、溴代、水解、与相应的胺缩合再偶联得到目标化合物。具体的说，所述制备方法包括如下步骤：
1.以2-氨基5-溴吡啶1和溴代乙醛缩二乙醇2为原料，在氢溴酸中关环得到化合物3；
2.化合物3在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与甲氧基羰基苯硼酸偶联得到化合物4；
3.化合物4在N-溴代丁二酰亚胺作用下溴代得到化合物5；
4.化合物5在氢氧化锂作用下水解得到化合物6；
5.化合物6在缩合剂EDCI/HOBT或HATU作用下与相应的胺缩合得到化合物7。
6.化合物7在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与苯并呋喃-2-硼酸或苯并噻吩-2-硼酸偶联得到目标化合物(I)；
其中，以上X、R1和R2的定义如前所述。
药物组合物和施用方法
由于本发明化合物具有优异的MNK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)MNK激酶活性或表达量相关疾病(例如，结直肠癌，胃癌，甲状腺癌，肺癌，白血病，B细胞淋巴瘤，T细胞淋巴瘤，毛细胞淋巴瘤，霍奇金淋巴瘤，非霍奇金淋巴瘤，伯基特淋巴瘤，胰腺癌，黑素瘤，多发性骨髓瘤，脑癌，CNS癌，肾癌，前列腺癌，卵巢癌、乳腺癌、不受控制的细胞生长、增殖和/或存活、不适宜的细胞免疫应答、不适宜的细胞炎症应答、白血病和骨髓增生异常综合征、恶性淋巴瘤、头颈部肿瘤、肺肿瘤和肺转移瘤、胸部肿瘤、非小细胞肿瘤和小细胞肺肿瘤、胃肠肿瘤、内分泌肿瘤、乳房和其他妇科肿瘤、泌尿系肿瘤、肾、膀胱和前列腺肿瘤、皮肤肿瘤、肉瘤、肿瘤转移、神经变性病症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
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)。
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)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、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，季胺化合物；(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；和(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，如肠衣和其它本领域公知的材料。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，例知，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等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、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、甲醇铝和琼脂或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可接受的无菌含水或无水溶液、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。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如其他抗肿瘤或抗炎症药物)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如其他抗肿瘤或抗炎症药物)。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗MNK激酶活性或表达量相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，为达到所需结果，每千克每24小时给药的式(I)化合物的总量为约0.01-800mg，优选的总量为0.1-80mg/kg。如果必要，以几次单剂量的形式给药。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮(I-1)
步骤1：6-氯咪唑并[1,2-b]哒嗪的制备
将3-氨基-6-氯哒嗪(2.80g，21.61mmol)溶于30mL乙醇和18mL水的混合溶液中，加入溴代乙醛缩二乙醇(5.11g，25.94mmol)和48％氢溴酸水溶液(3mL)，升温至100℃反应8h。TLC板监测反应完全后，冷却反应液至室温后减压浓缩，加入100mL水，乙酸乙酯萃取，合并有机相后用饱和食盐水洗，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析分离，得到白色固体粉末2.05g，为中间体6-氯咪唑并[1,2-b]哒嗪，收率61.8％。
1H NMR(300MHz,DMSO-d6)δ(ppm):8.35(s,1H),8.23(d,J＝9.5Hz,1H),7.85(d,J＝1.1Hz,1H),7.36(d,J＝9.5Hz,1H).
步骤2：4-(咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯的制备
将6-氯咪唑并[1,2-b]哒嗪(2.0g，13.01mmol)溶于45mL 1,4-二氧六环和4.5mL水的混合溶液中，加入4-甲氧羰基苯硼酸(2.81g，15.63mmol)和三水磷酸钾(6.94g，26.05mmol)，以氮气充分置换反应装置内的空气，室温搅拌15min，加入四三苯基膦钯(0.72g，0.65mmol)，以氮气充分置换反应装置内的空气，室温继续搅拌15min后升温至95℃反应8h。TLC板监测反应完全后，冷却反应液至室温，硅藻土滤去不溶物，滤液减压浓缩，残留物经柱层析分离，得到白色固体1.9g，为中间体4-(咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯，收率为57.6％。
1H NMR(300MHz,CDCl3)δ(ppm):8.42(dd,J＝1.6,0.9Hz,1H),8.19–8.17(m,1H),8.16–8.14(m,1H),7.78(d,J＝9.4Hz,1H),7.72(d,J＝1.1Hz,1H),7.70(s,1H),7.69–7.67(m,1H),7.67–7.64(m,1H),3.98(s,3H).
步骤3：4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯的制备
将4-(咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯(1.5g，5.92mmol)溶于24mL乙腈和8mL二氯甲烷的混合溶液中，加入N-溴代丁二酰亚胺(1.26g，7.11mmol)，室温下搅拌反应8h。TLC板监测反应完全后，减压浓缩，加入100mL水，二氯甲烷萃取，合并有机相后用饱和食盐水洗，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析分离，得到黄色固体粉末1.62g，为中间体4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯，收率为82.3％。
步骤4：4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸的制备
将4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸甲酯(1.6g，4.82mmol)溶于20mL四氢呋喃和10mL甲醇的混合溶液中，缓慢滴加10mL LiOH(0.92g，38.54mmol)水溶液中，室温下搅拌4h。TLC板监测反应完全后，减压浓缩，加入20mL水稀释，缓慢滴加1M盐酸，将pH调至2～3，有大量白色固体析出，过滤收集滤饼，水洗，烘干得白色固体1.52g，为中间体4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸，收率为100％。
步骤5：(4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮
将4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯甲酸(360mg，1.14mmol)溶于3mL N,N-二甲基甲酰胺，依次加入吗啉(119mg，1.36mmol)、EDCI(261mg，1.36mmol)、HOBT(184mg，1.36mmol)、三乙胺(138mg，1.36mmol)和DMAP(14mg，0.11μmol)，升温至40℃反应8h。TLC板监测反应完全后，加入200mL二氯甲烷稀释，饱和食盐水洗(20mL×3)，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝100/1～100/3)分离，得到黄色固体粉末356mg，为中间体(4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮，收率为65.9％。
步骤6：(4-(3-(苯并噻吩-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮(I-1)的制备
将(4-(3-溴咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮(110mg，0.28mmol)溶于2mL1,4-二氧六环和0.2mL水的混合溶液中，加入苯并呋喃-2-硼酸(55mg，0.34mmol)和三水磷酸钾(138mg，0.52mmol)，以氮气充分置换反应装置内的空气，室温搅拌15min，加入四三苯基膦钯(30mg，26μmol)，以氮气充分置换反应装置内的空气，室温继续搅拌15min后升温至95℃反应8h。TLC板监测反应完全后，冷却反应液至室温，硅藻土滤去不溶物，滤液减压浓缩，残留物经柱层析分离，得到白色固体粉末67mg，(4-(3-(苯并噻吩-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(吗啉基)甲酮，收率为55.6％。
1H NMR(300MHz,CDCl3)δ(ppm):8.60(s,1H),7.86–7.76(m,2H),7.64(d,J＝7.9Hz,2H),7.52(dd,J＝12.7,6.7Hz,4H),7.35(d,J＝3.5Hz,1H),7.31–7.20(m,2H),3.67(d,J＝50.8Hz,8H)；MS:found m/z[M+H]+425.04,calcd.m/z[M]424.15.
实施例2
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-甲基哌嗪-1-基)甲酮(I-2)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-甲基哌嗪-1-基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.16(dd,J＝8.7,4.1Hz,3H),7.80–7.53(m,6H),7.35(dd,J＝17.6,7.8Hz,2H),3.74(d,J＝89.8Hz,4H),2.51(s,4H),2.39(s,3H)；MS:found m/z[M+H]+438.17,calcd.m/z[M]437.19.
实施例3
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌啶基)甲酮(I-3)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.39(s,1H),8.14(d,J＝5.3Hz,3H),7.76(s,1H),7.72(d,J＝7.2Hz,1H),7.69–7.53(m,4H),7.34(dd,J＝17.8,8.4Hz,2H),3.62(s,4H),1.71(d,J＝19.0Hz,4H),1.59(s,2H)；MS:found m/z[M-H]-421.02,calcd.m/z[M]422.17.
实施例4
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(N,N-二甲基胺基)甲酮(I-4)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(N,N-二甲基胺基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.41(s,1H),8.23(d,J＝9.4Hz,1H),8.16(d,J＝8.4Hz,2H),7.79(d,J＝0.8Hz,1H),7.76–7.63(m,4H),7.60(d,J＝8.2Hz,1H),7.41–7.30(m,2H),3.21(s,3H),3.11(s,3H)；MS:found m/z[M+H]+383.08,calcd.m/z[M]382.14.
实施例5
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(吡咯烷基)甲酮(I-5)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(吡咯烷基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.38(s,1H),8.15(t,J＝9.0Hz,3H),7.89–7.64(m,4H),7.64–7.46(m,2H),7.34(dd,J＝17.9,7.3Hz,2H),3.74(t,J＝6.5Hz,2H),3.55(t,J＝6.2Hz,2H),2.08–1.92(m,4H)；MS:found m/z[M+H]+408.54,calcd.m/z[M]408.16.
实施例6
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-乙酰基哌嗪-1-基)甲酮(I-6)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-乙酰基哌嗪-1-基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.18(dd,J＝8.8,3.5Hz,3H),7.71(dd,J＝15.7,8.3Hz,4H),7.60(t,J＝8.5Hz,2H),7.42–7.28(m,2H),3.65(d,J＝32.4Hz,8H),2.18(s,3H)；MS:found m/z[M+H]+465.97,calcd.m/z[M]465.18.
实施例7
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-二甲氨基哌啶基)甲酮(I-7)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-二甲氨基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.41(s,1H),8.17(dd,J＝8.8,7.1Hz,3H),7.67(ddd,J＝20.4,17.7,8.9Hz,6H),7.35(dd,J＝18.0,7.2Hz,2H),4.81(s,1H),3.93(s,1H),3.02(d,J＝63.5Hz,2H),2.52(dd,J＝15.5,9.5Hz,1H),2.38(s,6H),2.01(d,J＝45.9Hz,4H)；MS:found m/z[M+H]+466.30,calcd.m/z[M]465.22.
实施例8
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-甲基哌啶基)甲酮(I-8)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-甲基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.39(s,1H),8.16(dd,J＝13.3,5.7Hz,3H),7.80–7.53(m,6H),7.35(dd,J＝17.7,8.2Hz,2H),4.73(s,1H),3.82(s,1H),2.96(d,J＝68.5Hz,2H),1.79(d,J＝47.1Hz,5H),1.03(s,3H)；MS:found m/z[M+H]+437.13,calcd.m/z[M]436.19.
实施例9
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-异丙基哌嗪-1-基)甲酮(I-9)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-异丙基哌嗪-1-基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.23–8.10(m,3H),7.67(ddd,J＝30.9,15.6,7.3Hz,6H),7.35(dd,J＝17.5,8.2Hz,2H),3.88(s,2H),3.57(s,2H),2.82(dd,J＝13.3,6.4Hz,1H),2.62(d,J＝33.5Hz,4H),1.11(d,J＝6.3Hz,6H)；MS:found m/z[M+H]+466.30,calcd.m/z[M]465.22.
实施例10
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-哌啶基哌啶基)甲酮(I-10)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-哌啶基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.15(t,J＝8.0Hz,3H),7.66(ddd,J＝19.0,16.6,8.0Hz,6H),7.35(dd,J＝17.7,7.9Hz,2H),4.85(s,1H),3.93(s,1H),3.09(s,1H),2.84(s,1H),2.62(s,5H),1.69(s,4H),1.27(s,6H)；MS:found m/z[M+H]+506.26,calcd.m/z[M]505.25.
实施例11
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-吗啉基哌啶基)甲酮(I-11)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-吗啉基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.16(dd,J＝8.8,7.0Hz,3H),7.66(ddd,J＝19.4,16.2,7.9Hz,6H),7.42–7.29(m,2H),4.79(s,1H),3.92(s,1H),3.77(s,4H),3.04(d,J＝55.0Hz,2H),2.59(d,J＝15.4Hz,4H),2.51(d,J＝6.2Hz,1H),1.90(s,2H),1.58(s,2H)；MS:found m/z[M+H]+508.34,calcd.m/z[M]507.23.
实施例12
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐(I-12)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.40(s,1H),8.23–8.10(m,3H),7.67(ddd,J＝30.9,15.6,7.3Hz,6H),7.35(dd,J＝17.5,8.2Hz,2H),5.98(s,1H),3.49(d,J＝9.8Hz,8H)；MS:found m/z[M+H]+424.14,calcd.m/z[M]423.17.
实施例13
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-氨基哌啶基)甲酮三氟乙酸盐(I-13)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.48–8.38(m,2H),8.33(d,J＝8.3Hz,2H),8.04(d,J＝9.6Hz,1H),7.87–7.79(m,2H),7.70(d,J＝7.9Hz,1H),7.64(d,J＝8.3Hz,2H),7.36(dt,J＝15.6,7.2Hz,2H),4.40(s,1H),3.65(s,1H),3.16–2.92(m,3H),1.84(s,2H),1.35(s,2H)；MS:found m/z[M+H]+438.04,calcd.m/z[M]437.19.
实施例14
(R)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-氨基哌啶基)甲酮三氟乙酸盐(I-14)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.44(dd,J＝12.3,6.3Hz,2H),8.34(d,J＝7.1Hz,2H),8.05(d,J＝9.6Hz,1H),7.88–7.80(m,2H),7.70(t,J＝7.4Hz,3H),7.37(dt,J＝14.9,6.7Hz,2H),4.23(d,J＝98.7Hz,2H),3.08–2.91(m,3H),1.99(s,1H),1.74(s,1H),1.51(s,2H)；MS:found m/z[M+H]+438.04,calcd.m/z[M]437.19.
实施例15
(S)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(4-氨基哌啶基)甲酮三氟乙酸盐(I-15)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.41(dd,J＝35.2,9.5Hz,4H),8.07(d,J＝9.2Hz,1H),7.75(dd,J＝31.3,22.7Hz,5H),7.52–7.25(m,2H),4.31(d,J＝42.1Hz,2H),2.99(d,J＝62.7Hz,3H),1.87(d,J＝58.0Hz,2H),1.45(d,J＝40.8Hz,2H)；MS:found m/z[M+H]+438.17,calcd.m/z[M]437.19.
实施例16
(4-(3-(7-(吡咯烷-1-基)苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐(I-16)
可通过与实施例1中类似的方法制备(4-(3-(7-(吡咯烷-1-基)苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(400MHz,CDCl3)δ(ppm):9.07(s,1H),8.14(s,1H),7.99(d,J＝11.0Hz,1H),7.77(d,J＝7.4Hz,2H),7.61(d,J＝8.1Hz,2H),7.30(s,2H),7.10(s,1H),6.90(d,J＝7.0Hz,1H),4.01(s,4H),3.35(d,J＝31.2Hz,8H),1.66(s,4H)；MS:found m/z[M+H]+492.94,calcd.m/z[M]492.23.
实施例17
(4-(3-(7-(哌啶-1-基)苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐(I-17)
可通过与实施例1中类似的方法制备(4-(3-(7-(哌啶-1-基)苯并呋喃-2-基)咪唑并[1,2-b]哒嗪基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(400MHz,CDCl3)δ(ppm):9.05(s,1H),8.14(s,1H),7.98(d,J＝11.1Hz,1H),7.75(d,J＝7.3Hz,2H),7.59(d,J＝8.1Hz,2H),7.29(s,2H),7.07(s,1H),6.89(d,J＝7.0Hz,1H),3.99(s,4H),3.30(d,J＝31.2Hz,8H),1.79(s,4H),1.64(s,2H)；MS:found m/z[M+H]+507.04,calcd.m/z[M]506.24.
生物活性测试例1激酶水平测试
利用ADP-Glo激酶测试试剂盒(Promega,catalog No.V6930)，筛选化合物活性。所有激酶反应均在HEPES反应缓冲液(15mM HEPES pH7.4，20mM NaCl2，1mM EGTA，10mM MgCl2，0.1mg/mL BGG和0.02％Tween-20)中进行。最终MNK1反应液包含10nM MNK1(Carna，catalogNo.02-145)、100μM多肽底物(TATKSGSTTKNR，Genscript)、300μM ATP和不同浓度化合物；最终MNK2反应液包含3nM MNK1(Carna，catalog No.02-146)、50μM多肽底物(TATKSGSTTKNR，Genscript)、10μM ATP和不同浓度化合物。各反应中最终DMSO浓度为1％。具体实施方法为：
384孔板每孔加入4μL蛋白溶液，再加入2μL化合物溶液，1000rpm离心5min，摇床上室温孵育10min；
每孔加入4μL底物混合物(多肽底物和ATP)，1000rpm离心5min，摇床上室温孵育60min；
每孔加入10μL ADP-Glo试剂，1000rpm离心5min，摇床上室温孵育40min(避光)；
每孔加入20μL Detection试剂，1000rpm离心5min，摇床上室温孵育40min(避光)；
使用多功能酶标仪冷发光模块读取RLU(Relative luminescence unit)值。信号强度用以表征MNK酶的活性强度，并利用化合物稀释的8个浓度来计算实现50％酶活抑制所需的化合物浓度(IC50)。(实验结果见表2)
表2.化合物对MNK1和MNK2酶活的抑制活性
从上述结果中可见，本发明的化合物对于MNK1和MNK2均有优异的抑制活性。
生物活性测试例2肝微粒稳定性测试
选用Tolbutamide为参比化合物。具体方法如下：
配置0.1M K3PO4(pH 7.4)缓冲液及3×NADPH储存液(6mM，5mg/mL)，并在37℃水浴锅中预热；
受试化合物及参比化合物spiking solution的配置：将5μL化合物储备液(10nM)加入到95μL乙腈中；
1.5μM spiking solution in microsomes(0.75mg/mL)的配置：将1.5μL spikingsolution和18.75μL肝微粒溶液(20mg/mL)加入到479.75μL K3PO4缓冲液中；
取30μL spiking solution in microsomes加入到多孔板中，并在37℃条件下孵育5min；
每孔加入15μL NADPH储存液开始反应，并计时；
分别在0min、5min、15min、30min和45min加入150μL含IS的乙腈溶液，终止反应；
振荡10min后6000rpm离心15min；每孔取80μL上清LC/MS检测，计算T1/2。(实验结果见表3)
表3.化合物肝微粒体稳定性
从上述结果中可见，本发明的化合物在肝微粒体模型中具有良好的代谢稳定性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.通式(I)所示的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物：
其中，
X为S或O；
R1和R2各自独立地选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
各个R各自独立选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
R3为H，或具有-NR4R5所示的结构，其中，R4和R5各自独立地选自下组：氢、取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
其中，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷胺基、-C(O)C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、C3-C8环烷基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、C1-C6烷氧基。
2.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的X为O。
3.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的R1和R2各自独立地为取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基。
4.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的-NR1R2具有如下所示的结构：
其中，Y选自下组：无(即化学键)、O、S、NR6、或CHR6；
所述的R6选自下组：C1-C6烷基、C1-C6烷胺基、-C(O)C1-C6烷基、氨基、具有1-3个选自N、S和O的杂原子的5-10元杂环基。
5.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的化合物选自下组：
6.一种药物组合物，其特征在于，所述药物组合物包括：(i)治疗有效量的权利要求1-5中任一所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的一种或多种，以及(ii)药学上可接受的载体或赋形剂。
7.如权利要求6所述的药物组合物，其特征在于，所述的药物组合物用于治疗与MNK的活性或表达量相关的疾病或病症。
8.如权利要求1-5任一所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的用途，其特征在于，所述的化合物用于制备治疗或预防与MNK的活性或表达量相关的疾病或病症的药物组合物。
9.如权利要求8所述的用途，其特征在于，所述的疾病为癌症。
10.如权利要求1-5任一所述的式(I)化合物的制备方法，其特征在于，所述方法包括步骤：
在金属钯催化剂(优选为Pd(PPh3)4或Pd(dppf)Cl2)催化下，用式7化合物与
进行偶联反应，得到目标化合物(I)。
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| WO2014138692A1 (en) * | 2013-03-07 | 2014-09-12 | Califia Bio, Inc. | Mixed lineage kinase inhibitors and method of treatments |
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