CN115322077A - 一类烷基酚类化合物及其制备方法 - Google Patents

一类烷基酚类化合物及其制备方法 Download PDF

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CN115322077A
CN115322077A CN202110513466.1A CN202110513466A CN115322077A CN 115322077 A CN115322077 A CN 115322077A CN 202110513466 A CN202110513466 A CN 202110513466A CN 115322077 A CN115322077 A CN 115322077A
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CN115322077B (zh
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南发俊
李静雅
张正
段亚南
张仰明
陈丹丹
戴成球
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Shanghai Institute of Materia Medica of CAS
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Priority to EP22806814.4A priority patent/EP4353706A1/en
Priority to JP2023570222A priority patent/JP2024518569A/ja
Priority to PCT/CN2022/092317 priority patent/WO2022237852A1/zh
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Abstract

本发明提供了一类烷基酚类化合物及其制备方法，具体地，本发明提供了一种如化学式I表示的新型烷基多酚类化合物，其制备方法以及所述化合物在治疗代谢综合症上的用途。

Description

一类烷基酚类化合物及其制备方法
技术领域
本发明属于药学领域，具体而言，涉及一类结构新颖的烷基酚类化合物，其制备方法以及该类化合物作为DRAK2激酶抑制剂在代谢综合症治疗药物上的用途。
背景技术
死亡相关凋亡诱导蛋白激酶2(Death Associated Related Apoptotic ProteinKinase2,DRAK2)为苏氨酸/丝氨酸激酶，是死亡相关蛋白激酶(Death-associated ProteinKinase,DAPK)家族中的一员(J.Biol.Chem.1998,273,29066)。DAPK家族成员在多种细胞死亡信号通路中发挥着关键作用。除DRAK2外，迄今为止还确定了其他四个DAP激酶家族成员，包括DAPK1、DAPK2、DAPK3和DRAK1。五个DAPK成员的氨基酸序列同源性严格限制在N-端激酶区，而C-端区域是独特的，其独特性为每个激酶调节功能所必需(Med.Res.Rev.2019,39,349)。
糖尿病(Diabetes)是一种代谢性疾病，主要包括1型糖尿病和2型糖尿病两类。1型糖尿病(T1D)是一种慢性自身免疫性疾病，它可造成胰岛β细胞损伤，导致胰岛素缺乏进而引发高血糖。而2型(T2D)糖尿病的发病机制较为复杂，主要是患者胰岛β细胞无法产生足够的胰岛素来满足机体的需求，同时伴随着胰岛素抵抗和胰岛β细胞功能紊乱。Christopher证实了随着病程的发展，T2D患者的β细胞持续损伤和衰减是病情恶化的根本因素。因此，不论是T1D还是T2D都存在着胰岛β细胞凋亡。此外，高糖、高脂和某些细胞因子通过胰岛素受体底物-2(insulin receptor substrate-2,IRS-2)信号通路诱导胰岛β细胞凋亡(Science.2005,307,380)。
研究表明，高糖、高脂(J.Cell.Biochem.2008,105,1073)和某些细胞因子(J.Immunol.2009,182,4762)可促进DRAK2细胞水平的高表达，导致胰岛β细胞的凋亡增加。经反义RNA验证，β细胞凋亡的增加与DRAK2基因密切相关，提示DRAK2可能在外来刺激诱导糖尿病的发生发展过程中起介导作用。因此靶向DRAK2的小分子抑制剂具有治疗糖尿病的潜力。然而现阶段关于DRAK2的小分子抑制剂鲜有报道。首个DRAK2抑制剂为2014年被报道的SC82510(Neurochem.Res.2014,39,403)，但其化学结构未知。该化合物可以较低的IC50值抑制DRAK2,在1nM浓度下能够诱导轴突再生和分支，但其中具体机制未知。
目前已经报道的DRAK2抑制剂主要有三类。第一类是5-芳基噻吩并[2,3-b]吡啶类化合物，代表性化合物22b对DRAK2有中等的抑制率，IC50为0.86μM(J.Med.Chem.2014,57,7624)；第二类是靛玉红-3′-单肟类化合物，此类抑制剂对DRAK2的活性抑制较好，代表性化合物compound 16的IC50为3nM(Bioorg.Med.Chem.Lett.2016,26,2719)；第三类是2-亚苄基苯并呋喃-3-酮类，代表性化合物41的IC50为0.25μM(Eur.J.Med.Chem.2017,130,195)。然而，以上三类化合物均未进行进一步的深入研究开发。鉴于DRAK2抑制剂在糖尿病等代谢综合症治疗中的潜力，开发具有新型DRAK2小分子抑制剂非常具有价值。
Figure BDA0003061202670000021
发明内容
本发明的目的是提供一种新型烷基多酚类化合物
该类化合物可作为具有新型结构骨架的DRAK2小分子抑制剂。
该类化合物可以用于开发成为代谢综合症治疗药物，包括但不限于：糖尿病、高血脂、肥胖、非酒精性脂肪肝、胆汁性肝硬化。
本发明的第一方面，提供了一种如下式I所示的化合物，或其药学上可接受的盐：
Figure BDA0003061202670000022
其中，
R1选自下组：氢、羟基、卤素、取代或未取代的胺基，取代或未取代的C1-C6烷氧基；
R2选自下组：氢、CN、C1-C8烷基、5-7元杂芳基、3-7元环烷烃、C2-C10烯基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc，优选为氢、氰基、甲基、5-7元杂芳基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc，更优选为氰基、吡啶环、取代苯环、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc；
Ra各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为C1-C8烷基；
Rb各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为C1-C8烷基、C3-C10环烷基和5-7元杂芳基，更优选为乙烯基、C1-C3烷基、C3-C6环烷基和5元杂芳基；
Rc各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为甲基和乙烯基；
R3选自下组：H，卤素原子，C1-C10烷基，C3-C6环烷基；
R4选自下组：H、OH、取代或未取代的C1-C8烷氧基，优选为OH或甲氧基；
Ar选自下组：取代或未取代的苯环、取代或未取代的5-9元杂芳基、
Figure BDA0003061202670000031
Figure BDA0003061202670000032
X1为化学键、O、NH、NHC(O)、NHS(O)2、NHC(O)NH、NHS(O)2NH或S；
X2选自下组：化学键，C1-C6烷基氨基羰基，C1-C4烷基羰基；
n为0-10，优选为0-6；
Linker选自下组：取代或未取代的C1-C6烷烃，取代或未取代的C1-C6烯烃，取代或未取代的苯环、取代或未取代的5-7元杂芳环，取代或未取代的3-6元环烷烃，优选为C1-C6烯烃、取代苯环、噻吩环和呋喃环，更优选为烯烃和苯环；
除非特别说明，所述的取代是指基团上的氢原子被选自下组的一个或多个取代基替代：卤素、羟基、羧基、C1-C6烷基、C2-C10酯基。
在另一优选例中，Ar选自下组：取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代的吲哚环、取代或未取代的嘧啶环、取代或未取代的苯并咪唑、取代或未取代的吲唑、取代或未取代的苯并三唑，优选为苯环或吲哚环。
在另一优选例中，所述的R1选自下组：氢、氟和氯。
在另一优选例中，R2选自下组：氢、氰基、甲基、5-7元杂芳基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc；
Ra各自独立地选自下组：C1-C8烷基；
Rb各自独立地选自下组：乙烯基、C1-C3烷基、C3-C6环烷基、5元杂芳基；
Rc各自独立地选自下组：甲基、乙烯基。
在另一优选例中，R2选自下组：氰基、吡啶环、取代苯环、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc。
在另一优选例中，R3选自下组：氢、卤素、异丙基和环己烷。
在另一优选例中，X2选自下组：化学键、NHS(O)2、或-C(＝O)-NH-。
在另一优选例中，所述的式I化合物具有如下式II所示的结构：
Figure BDA0003061202670000033
在另一优选例中，所述化合物选自下组：
Figure BDA0003061202670000041
Figure BDA0003061202670000051
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的用途，用于制备治疗或预防死亡相关凋亡诱导蛋白激酶2(DRAK2)活性或表达量相关的适应症的药物组合物。
在另一优选例中，所述的适应症为代谢综合症。
在另一优选例中，所述代谢综合症包括但不限于：糖尿病、高血脂、肥胖、非酒精性脂肪肝、胆汁性肝硬化。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包含(1)作为活性成分的如本发明第一方面所述的化合物，或其药学上可接受的盐；和(2)药学上可接受的载体。
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
本申请的发明人经过广泛而深入地研究，首次研发出一类基于烷基酚类母核设计的化合物，其对于DRAK2蛋白有良好的抑制作用。鉴于目前所报道的小分子DRAK2抑制剂数量有限，烷基多酚类化合物骨架的新颖性具有进一步深入研究的价值，可以为接下来研究新型的DRAK2小分子抑制剂提供了值得借鉴的方向。基于上述发现，发明人完成了本发明。
术语
在本文中，所述的烷基优选为脂肪族烷基，可以是直链烷基或支链烷基，非限制性地包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等；形如“C1-C8”的表述意在包括具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的相应基团，例如，“C1-C8烷基”指具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的烷基，“C2-C10烯基”指具有2个、3个、4个、5个、6个、7个、8个、9个或10个碳原子的烯基。
在本文中，所述烯基优选为乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基，或类似基团。
所述芳基指6至10元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，且所述的基团具有共轭的π电子体系，例如苯基和萘基。所述芳基环可以与杂环基、杂芳基或环烷基环稠合，非限制性实施例含苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃。
所述杂芳基指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述的杂芳基可以稠合于芳基、杂环基或者环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
在本发明中除非另外指出，
Figure BDA0003061202670000061
表示连接位点。
除非特别说明，本发明所描述的结构式意在包括所有的互变异构、光学异构和立体异构形式(如对映异构体、非对映异构体，几何异构体或构象异构体)：例如含双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体、互变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或互变异构体的混合物都属于本发明的范围。
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、1H-苯并[d]咪唑与3H-苯并[d]咪唑，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。
制备方法
本发明的化合物能够采用以下路线进行制备：
本发明的第二方面，提供一种第一方面所述的化合物或其药学上可接受的盐的制备方法，连接基团为顺式双键时目标化合物的合成路线以烷基炔H1为起始原料，-78℃下以四氢呋喃为溶剂缓慢加入正丁基锂，之后滴加到溶于四氢呋喃的二溴烷烃H2中，反应过夜得到化合物H3。接下来将H3在醋酸镍和硼氢化钠的条件下以乙醇为溶剂氢化还原得到化合物H4。H4再在碘化亚铜、三苯基膦及甲醇锂的条件下，与联硼酸频那醇酯在室温下偶联得到中间体H5。H5和中间体H6在NaOtBu、Ruphos及Pd2(dba)3的条件下，在甲苯和水的混合溶剂中于80℃下反应过夜得到化合物H7。最后将H7在N,N-二甲基苯胺和三氯化铝的条件下脱除苄基即可得到目标化合物H8。其中n和m为1-10，X为氧，硫，氮。在实施方式中，所述化合物或其药学上可接受的盐通过以下路线制备：
Figure BDA0003061202670000071
连接基团为苯环时目标化合物的合成路线卤代醇H9在对甲苯磺酸的催化条件下与3,4-二氢-2H-吡喃反应得到中间体H10。H10再在碘化亚铜、三苯基膦及甲醇锂的条件下与联硼酸频那醇酯在室温下偶联得到中间体H11。H11与取代的溴苯H12经Suzuki偶联反应得到中间体H13，随后脱保护得到中间体H14，H14再经Appel反应得到溴代中间体H15，之后H15与联硼酸频那醇酯偶联生成中间体H16，H16经Suzuki偶联反应得到中间体H17，最后在钯碳催化氢化还原脱除苄基即可得到目标产物H18。其中n为1-10；X为氧，硫，氮；R为C1-C8烷基。
在实施方式中，所述化合物或其药学上可接受的盐通过以下路线制备：
Figure BDA0003061202670000072
具有其他不同取代基的本发明的化合物可以通过以下具体方法制备：
路线一：
Figure BDA0003061202670000081
路线二：
Figure BDA0003061202670000082
路线三：
Figure BDA0003061202670000091
路线四：
Figure BDA0003061202670000092
药物组合物和施用方法
由于本发明化合物具有优异的激酶抑制的活性，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治疗、预防以及缓解由于激酶(例如DRAK2)的活性或表达量异常引起的相关疾病。
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或其药理上可接受的盐及药理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5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”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的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
Figure BDA0003061202670000101
)、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、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
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。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
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联合给药。在一些优选的实施方式中，本发明的化合物可以与其他小分子化合物一同形成PROTAC，或者与其他大分子化合物例如单抗共同形成ADC施用。
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，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。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。
与现有技术相比，本发明的主要优点包括：
本发明的化合物能有效抑制DRAK2激酶，可在微摩尔浓度下抑制DRAK2活性，结构简单新颖，易于合成制备，且具有更好的口服吸收。
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(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring HarborLaboratoryPress,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
下述制备实施例中，NMR用Varian生产的Mercury-Vx 400M仪器测定，NMR定标：δH7.26 ppm(CDCl3),2.50ppm(DMSO-d6)；质谱用Agilent 1200Quadrupole LC/MS液质联用仪或SHIMADZU GCMS-QP5050A测定；试剂主要由上海化学试剂公司提供；TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产，型号HSGF 254；化合物纯化使用的正相柱层析硅胶为山东青岛海洋化工厂分厂生产，型号zcx-11，200-300目。
本文缩写所对应的的中文如下：
DMAP:4-二甲氨基吡啶；DCM:二氯甲烷；DMF：N,N-二甲基甲酰胺；HOBT：1-羟基苯并三唑；MeOH：甲醇；THF：四氢呋喃；TBSCl：叔丁基二甲基氯硅烷
实施例1
Figure BDA0003061202670000111
-78℃下，向溶于四氢呋喃的烷基炔化合物(4.54mmol)中逐滴加入正丁基锂(1.89mL，2.4M in hexane，4.54mmol)，将反应液逐渐温暖到室温反应30分钟。冷却到-78℃，依次加入六甲基磷酰三胺(0.79mL,4.54mmol)和溶于四氢呋喃(5mL)中的二溴烷烷(3.78mmol)溶液，加毕反应液逐渐升高至室温，搅拌2小时。反应结束后，加NH4Cl饱和溶液(10mL)淬灭反应，用乙酸乙酯(3×10mL)萃取，合并有机相，加入饱和食盐水(10mL)洗涤，有机相用无水硫酸钠干燥，旋转蒸发仪浓缩除去溶剂，柱层析分离纯化(石油醚)得到中间体化合物A。1H NMR(400MHz,Chloroform-d)δ3.40(t,J＝8.0Hz,2H),2.23-2.05(m,4H),1.88-1.84(m,2H),1.53-1.21(m,16H),0.89(t,J＝6.8Hz,3H).
将醋酸镍(93.74mg，0.378mmol)溶于2mL的无水乙醇中，加入硼氢化钠(14.36mg，0.378mmol)，加毕氮气换气三次，氢气换气三次，室温搅拌15分钟之后，加入乙二胺(0.1mL，1.51mmol)，反应15分钟后，滴加溶于无水乙醇(1mL)的中间体A(0.775mmol)溶液，室温搅拌2小时，TLC跟踪检测。反应完毕后，用硅藻土过滤固体，石油醚洗涤滤渣，浓缩滤液，最后柱层析纯化(石油醚)分离得到中间体B。1H NMR(400MHz,Chloroform-d)δ5.42-5.27(m,2H),3.40(t,J＝7.0Hz,2H),2.10-1.93(m,4H),1.85(t,J＝7.3Hz,2H),1.46-1.39(m,2H),1.37-1.24(m,14H),0.89(t,J＝6.0Hz,3H).
往三颈瓶中依次加入碘化亚铜(4.8mg，0.025mmol)，三苯基磷(8.6mg，0.033mmol)，甲醇锂(20mg，0.5mmol)，联硼酸频那醇酯(96.5mg，0.38mmol)，加毕氮气换气三次，加入溶于N,N-二甲基甲酰胺中间体B(73mg，0.25mmol)溶液。反应液在室温下搅拌18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，经硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]分离得到中间体化合物C。1H NMR(400MHz,Chloroform-d)δ5.31-5.25(m,2H),2.02-1.86(m,4H),1.29-1.17(m,30H),0.81(t,J＝6.2Hz,3H),0.70(t,J＝8.0Hz,2H).
溴苯二酚或溴苯三酚(2.64mmol)溶于20mL丙酮中，依次加入碳酸钾(547mg，4mmol)，苄溴(0.72mL，6.07mmol)，加毕50℃搅拌过夜，TLC跟踪检测。反应完毕后，冷却至室温，硅藻土过滤固体，二氯甲烷洗涤滤渣后浓缩滤液，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]分离得到中间体化合物D。1H NMR(400MHz,Chloroform-d)δ7.47-7.30(m,10H),6.78-6.75(m,2H),6.54(s,1H),5.03-4.98(m,4H).
向三颈频中依次加入中间体化合物C(0.271mmol)，叔丁醇钠(78.1mg,0.813mmol)，Ruphos(31mg,0.0664mmol)，Pd2(dba)3(30mg,0.0328mmol)，中间体化合物D(0.325mmol)，加毕氮气置换多次，依次加入甲苯(3mL)和去离子水0.3mL之后，加热80℃搅拌18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，用硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析分离纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物E。1H NMR(400MHz,Chloroform-d)δ7.37-7.23(m,10H),6.41-6.34(m,3H),5.32-5.22(m,2H),4.98-4.91(m,4H),2.46(t,J＝7.8Hz,2H),1.99-1.89(m,4H),1.56-1.47(m,2H),1.29-1.18(m,16H),0.83-0.78(m,3H).
中间体E(0.144mmol)溶于4mL二氯甲烷中，加入N,N-二甲基苯胺(0.12mL，0.938mmol)，三氯化铝(115.2mg，0.864mmol)，室温反应2小时，TLC跟踪检测。反应完毕之后，加入5mL二氯甲烷稀释，然后倒入5mL的1N HCL溶液之中搅拌5分钟，分离油相，水相二氯甲烷(2×5mL)萃取，合并有机相，加入10mL饱和食盐水洗涤，油相无水硫酸钠干燥，浓缩干溶剂，柱层析得到终产物1。1H NMR(400MHz,Chloroform-d)δ6.26-6.22(m,2H),6.17(s,1H),5.37-5.32(m,2H),4.80-4.65(m,2H),2.48(t,J＝7.8Hz,2H),2.05-1.97(m,4H),1.66(t,J＝7.2Hz,2H),1.33-1.26(m,16H),0.87(t,J＝7.2Hz,3H).
用实施例一中同样的方法合成以下化合物
Figure BDA0003061202670000131
Figure BDA0003061202670000141
实施例2
Figure BDA0003061202670000142
卤代醇(11.36mmol)溶于12mL二氯甲烷溶液中，0℃下往上述溶液中依次加入3,4-2H-二氢吡喃(1.1mL，12.17mmol)，对甲苯磺酸水合物(10mg，0.0526mmol)，加毕室温反应2小时，TLC跟踪检测。反应完毕之后，直接浓缩干溶剂，最后柱层析分离纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物F。1H NMR(400MHz,Chloroform-d)δ4.60(dd,J＝4.4,2.8Hz,1H),3.92-3.81(m,2H),3.58-3.49(m,4H),2.18-2.09(m,2H),1.88-1.76(m,1H),1.76-1.65(m,1H),1.61-1.51(m,4H).
往三颈瓶中依次加入碘化亚铜(26mg，0.134mmol)，三苯基磷(45mg，0.174mmol)，甲醇锂(102mg，2.68mmol)，联硼酸频那醇酯(510mg，2.01mmol)，氮气换气三次，加入溶于N,N-二甲基甲酰胺(3.0mL)的中间体化合物F(1.34mmol)溶液之后，在室温下搅拌18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，用硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析分离[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物G。1H NMR(400MHz,Chloroform-d)δ4.59(q,J＝3.9Hz,1H),3.86(td,J＝8.3,4.2Hz,1H),3.68(ddd,J＝9.5,6.7,2.6Hz,1H),3.55-3.42(m,1H),3.42-3.29(m,1H),1.92-1.77(m,1H),1.70(q,J＝7.7Hz,3H),1.63-1.45(m,4H),1.32-1.15(m,12H),0.90-0.74(m,2H).
往三颈频中依次加入中间体化合物H(0.271mmol)，叔丁醇钠(78.1mg，0.813mmol)，Ruphos(31mg，0.0664mmol)，Pd2(dba)3(30mg，0.0328mmol)，中间体化合物G(0.325mmol)，加毕氮气换气多次，依次加入甲苯(3mL)和去离子水(0.3mL)后，加热80℃反应18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，用硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析分离纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物I。1H NMR(400MHz,Chloroform-d)δ7.17(t,J＝7.6Hz,1H),7.00(d,J＝6.4Hz,3H),4.57(t,J＝3.8Hz,1H),3.87(t,J＝9.6Hz,1H),3.77(q,J＝7.5Hz,1H),3.54-3.44(m,1H),3.40(q,J＝7.5Hz,1H),2.68(q,J＝6.6Hz,2H),2.56(t,J＝7.9Hz,2H),1.97-1.78(m,3H),1.77-1.66(m,1H),1.65-1.46(m,6H),1.39-1.22(m,6H),0.87(t,J＝6.8Hz,3H).
中间体化合物I(2.25mmol)溶于甲醇(10mL)中，加入对甲苯磺酸水合物(20mg，0.05mmol)，室温搅拌3h，TLC跟踪检测。反应完毕之后，浓缩溶剂，柱层析分离纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝5:1]得到中间体化合物J。1H NMR(400MHz,Chloroform-d)δ7.18(t,J＝7.6Hz,1H),7.03-6.97(m,3H),3.66(t,J＝7.6Hz,2H),2.67(t,J＝7.9Hz,2H),2.57(t,J＝7.9Hz,2H),1.89(q,J＝7.2Hz,2H),1.59(q,J＝7.5Hz,2H),1.50(s,1H),1.39-1.24(m,6H),0.87(t,J＝6.9Hz,3H).
中间体化合物J(1.41mmol)，四溴化碳(701mg，2.1mmol)溶于3mL二氯甲烷中，冷却至0℃。三苯基磷(550mg，2.1mmol)溶于二氯甲烷(1mL)中，逐滴加入到上述溶液中，温暖到室温，反应3小时，TLC跟踪检测。反应完毕之后，浓缩溶剂。柱层析分离纯化(石油醚)得到中间体化合物K。1H NMR(400MHz,Chloroform-d)δ7.25-7.15(m,1H),7.05-6.96(m,3H),3.39(t,J＝6.6Hz,2H),2.74(t,J＝7.4Hz,2H),2.57(t,J＝7.9Hz,2H),2.16(p,J＝7.0Hz,2H),1.59(q,J＝7.5Hz,2H),1.39-1.22(m,6H),0.88(t,J＝6.6Hz,3H).
往三颈瓶中依次加入碘化亚铜(26mg，0.134mmol)，三苯基磷(45mg，0.174mmol)，甲醇锂(102mg，2.68mmol)，联硼酸频那醇酯(510mg，2.01mmol)，加毕氮气换气三次，加入溶于N,N-二甲基甲酰胺(3.0mL)的中间体化合物K(1.34mmol)溶液后，室温搅拌18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，用硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析分离[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物L。1HNMR(400MHz,Chloroform-d)δ7.16(t,J＝7.7Hz,1H),7.01-6.94(m,3H),2.63-2.50(m,4H),1.72(t,J＝7.9Hz,2H),1.62-1.51(m,2H),1.41-1.15(m,18H),0.93-0.77(m,5H).
往三颈频中依次加入中间体化合物D(0.271mmol)，叔丁醇钠(78.1mg，0.813mmol)，Ruphos(31mg，0.0664mmol)，Pd2(dba)3(30mg，0.0328mmol)，中间体化合物L(0.325mmol)，氮气换气多次，依次加入甲苯(3mL)和去离子水(0.3mL)后，加热80℃反应18小时，TLC跟踪检测。反应完毕之后，反应液用乙酸乙酯稀释，用硅藻土过滤固体，乙酸乙酯洗涤滤渣后浓缩滤液，最后柱层析分离纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]得到中间体化合物M。1H NMR(400MHz,Chloroform-d)δ7.48-7.29(m,10H),7.20(s,1H),7.05-6.96(m,3H),6.52-6.44(m,3H),5.07-5.00(m,4H),2.73-2.49(m,6H),2.02-1.89(m,2H),1.67-1.58(m,2H),1.35-1.29(m,6H),0.89(t,J＝7.2Hz,3H).
苄基保护的中间体(0.2mmol)溶于2mL EA和2mL MeOH的混合溶剂中，加入钯碳，氮气换气多次，氢气换气多起，室温反应过夜。反应完毕之后，通过硅藻土过滤，浓缩滤液，柱层析分离[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]得到终产物17。1HNMR(400MHz,Chloroform-d)δ7.20-7.16(m,1H),7.03-6.96(m,3H),6.28-6.22(m,2H),6.18(s,1H),2.62-2.50(m,6H),1.95-1.87(m,2H),1.64-1.56(m,2H),1.34-1.28(m,6H),0.88(t,J＝6.8Hz,3H).
用实施例二中同样的方法合成以下化合物
Figure BDA0003061202670000161
Figure BDA0003061202670000171
Figure BDA0003061202670000181
实施例3
Figure BDA0003061202670000182
氢化铝锂(1.1g，28.54mmol)溶于20mL重蒸THF中，0℃下缓慢加入溶于10mL THF的3,5-二甲氧基苯基丙酸(2.0g，9.51mmol)，逐渐温暖到室温，反应3小时，TLC跟踪检测。反应完毕后，加入20mL乙醚稀释，缓慢滴加2mL水淬灭反应，有灰白色固体生成，加入50mL 15％的氢氧化钠溶液碱化，分液，水相乙醚(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝5:1]分离得到中间体化合物18-a,淡粉色油状物，收率：95％。1H NMR(400MHz,Chloroform-d)δ6.37(m,2H),6.31(s,1H),3.78(m,6H),3.68(t,J＝7.8Hz,2H),2.66(m,2H),1.89(t,J＝7.3Hz,2H),1.27(s,1H).
18-a(1.1g，5.61mmol)溶于30mL二氯甲烷中，冷却至-78℃，逐滴加入三溴化硼(33.6mL，1M in DCM，33.6mmol)，30分钟内加完，逐渐温暖至室温，反应3小时，TLC跟踪检测。反应完毕后，冷却至0℃，逐滴加入水(10mL)，乙酸乙酯(3×10mL)萃取，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到中间体化合物18-b，收率41％.1HNMR(400MHz,Chloroform-d)δ6.30-6.24(m,2H),6.21(s,1H),5.12-5.06(m,2H),3.41-3.34(m,2H),2.70-2.61(m,2H),2.16-2.05(m,2H).
18-b(2.64mmol)溶于20mL丙酮中，加入碳酸钾(547mg，4mmol)，苄溴(0.72mL，6.07mmol)，50℃反应回流过夜，TLC跟踪检测。反应完毕后，冷却至室温，用硅藻土过滤固体，二氯甲烷洗涤滤渣，浓缩干滤液，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]分离得到中间体化合物18-c，收率57％。1H NMR(400MHz,Chloroform-d)δ7.46-7.29(m,10H),6.52-6.43(m,3H),5.05-5.00(m,4H),3.42-3.33(m,2H),2.76-2.66(m,2H),2.19-2.08(m,2H).
2-正戊基呋喃(0.38mL，2.44mmol)溶于5mL THF中，冷却至0℃，逐滴加入正丁基锂(0.78mL，2.4M in hexane，1.86mmol)，反应30分钟。加入溶于3mL THF中的18-c(337mg，2.44mmol)，反应5小时，TLC跟踪检测。反应完毕后，加入10mL饱和氯化铵溶液淬灭反应，水相乙醚(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]分离得到中间体化合物18-d。1H NMR(400MHz,Chloroform-d)δ7.36-7.25(m,10H),6.41-6.36(m,3H),5.82-5.71(m,2H),4.96-4.94(m,4H),2.61-2.37(m,6H),1.92-1.75(m,2H),1.56-1.51(m,2H),1.28-1.23(m,4H),0.82(t,J＝6.8Hz,3H).
中间体18-d(0.144mmol)溶于4mL二氯甲烷中，加入N,N-二甲基苯胺(0.12mL，0.938mmol)，三氯化铝(115.2mg，0.864mmol)，室温反应2小时，TLC跟踪检测。反应完毕之后，加入5mL二氯甲烷稀释，然后倒入5mL的1N HCL溶液之中搅拌5分钟，分离油相，水相二氯甲烷(2×5mL)萃取，合并有机相，加入10mL饱和食盐水洗涤，油相无水硫酸钠干燥，浓缩干溶剂，柱层析得到终产物18。1H NMR(400MHz,Chloroform-d)δ6.28-6.22(m,2H),6.18(s,1H),5.89-5.82(m,2H),4.86-4.73(m,2H),2.62-2.48(m,6H),1.97-1.84(m,2H),1.71-1.54(m,2H),1.38-1.27(m,4H),0.88(t,J＝6.8Hz,3H).
用实施例3同样的方法合成化合物19。
Figure BDA0003061202670000191
1H NMR(400MHz,Chloroform-d)δ6.58-6.54(m,2H),6.27-6.21(m,2H),6.17(s,1H),4.92-4.86(m,2H),2.80-2.71(m,4H),2.55(t,J＝7.6Hz,2H),1.95-1.91(m,2H),1.65-1.61(m,2H),1.36-1.32(m,4H),0.89(t,J＝6.8Hz,3H).
实施例4
Figure BDA0003061202670000201
依次往烧瓶中加入3-碘苯乙酸(200mg，0.761mmol)，Pd(PPh3)2Cl2(16mg,0.023mmol),碘化亚铜(4.4mg，0.023mmol)，三乙胺(0.3mL)，氮气换气多次，加入1-己炔(0.1mL，0.913mmol)，乙腈(3mL)，室温反应过夜，TLC跟踪检测。反应完毕后，通过硅藻土过滤固体，乙酸乙酯洗涤表面，滤液浓缩，最后柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到中间体化合物55-a，65mg，黑色油状物，收率40％。1H NMR(400MHz,Chloroform-d)δ10.27(s,1H),7.33-7.15(m,4H),3.59(s,2H),2.39(t,J＝7.0Hz,2H),1.63-1.41(m,4H),0.94(t,J＝7.4Hz,3H).
5-氨基间苯二酚盐酸盐(300mg，1.86mmol)，咪唑(1.01g，14.85mmol)溶于7mL THF中，加入溶于7mLTHF中的TBSCl(1.12g)，室温反应3小时，，TLC跟踪检测。反应完毕后，浓缩干溶剂，加15mL水，二氯甲烷(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝5:1]分离得到中间体化合物55-b，555mg，无色油状物，收率85％。1H NMR(400MHz,Chloroform-d)δ5.85-5.83(m,2H),5.78(t,J＝2.1Hz,1H),3.55(s,2H),0.97-0.95(m,18H),0.19-0.16(m,12H).
HOBT(41mg，0.30mmol)，EDCI(58mg，0.30mmol)溶于1mLDCM中，0℃下，加入溶于2mLDCM中的中间体55-a(106mg，0.30mmol)，55-b(65mg，0.30mmol)的混合溶液，加入三乙胺(0.038mL，0.3mmol)，室温反应过夜，TLC跟踪检测。反应完毕后，加15mL水，EA(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝7:1]分离得到中间体化合物55-c，88mg，无色固体，收率：53％。1H NMR(400MHz,Chloroform-d)δ7.20-7.15(m,2H),7.12(t,J＝7.8Hz,1H),7.04(dt,J＝7.6,1.7Hz,1H),6.81(s,1H),6.47-6.42(m,2H),5.90(s,1H),3.46(s,2H),2.23(t,J＝7.0Hz,2H),1.45-1.36(m,2H),1.35-1.25(m,2H),0.79-0.75(m,21H),0.00--0.20(m,12H).
55-c(88mg，0.159mmol)溶于2mL THF中，0℃下加入nBu4N+F-(0.38mL，1M in THF，0.38mmol)，室温反应1小时，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝15:1]分离得到中间体化合物55-d 40mg，无色固体，收率77％。1HNMR(400MHz,Methanol-d4)δ7.33(s,1H),7.27-7.21(m,3H),6.58(d,J＝2.2Hz,2H),6.02(t,J＝2.1Hz,1H),3.59(s,2H),2.40(t,J＝6.9Hz,2H),1.61-1.43(m,4H),0.96(t,J＝7.2Hz,3H).
55-d(0.2mmol)溶于2mL EA和2mL MeOH的混合溶剂中，加入钯碳，氮气换气多次，氢气换气多起，室温反应过夜。反应完毕之后，通过硅藻土过滤，浓缩滤液，柱层析分离[洗脱剂:V(二氯甲烷你):V(甲醇)＝20:1]得到终产物55。1H NMR(400MHz,Methanol-d4)δ7.23-7.17(m,1H),7.16-7.09(m,2H),7.08-7.02(m,1H),6.61-6.55(m,2H),6.02(t,J＝2.2Hz,1H),3.58(s,2H),2.58(t,J＝7.6Hz,2H),1.6-1.55(m,2H),1.33-1.27(m,6H),0.87(t,J＝6.8Hz,3H).
实施例5
Figure BDA0003061202670000211
化合物11(38mg，0.125mmol)溶于2mL丙酮中，加入碳酸钾(86mg，0.624mmol)，碘甲烷(17.8mg，0.125mmol)，室温反应过夜，TLC跟踪检测。反应完毕后，通过硅藻土过滤，丙酮洗涤多次，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝10:1]分离得到产物7,15mg，无色油状物，收率：38％。1H NMR(400MHz,Chloroform-d)δ6.32(s,1H),6.28-6.21(m,2H),5.38-5.31(m,2H),4.92(s,1H),3.76(s,3H),2.55-2.47(m,2H),2.04-1.97(m,4H),1.60-1.56(m,2H),1.35-1.24(m,14H),0.88(t,J＝5.8Hz,3H).
实施例6
Figure BDA0003061202670000212
化合物11(38mg，0.125mmol)溶于2mL丙酮中，加入碳酸钾(86mg，0.624mmol)，碘甲烷(89mg，0.624mmol)，室温反应过夜，TLC跟踪检测。反应完毕后，通过硅藻土过滤，丙酮洗涤多次，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝30:1]分离得到产物8,33mg，无色油状物，收率：80％。1H NMR(400MHz,Chloroform-d)δ6.37-6.32(m,2H),6.29(s,1H),5.40-5.28(m,2H),3.80-3.76(m,6H),2.58-2.51(m,2H),2.07-1.96(m,4H),1.65-1.57(m,2H),1.35-1.26(m,14H),0.86(t,5.6Hz,3H).
实施例7
Figure BDA0003061202670000213
酚类化合物(0.164mmol)，NCS(26mg，0.197mmol)溶于0.6mL二氯甲烷中，加入DMSO(0.0023mL，0.0328mmol)，室温反应3小时，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝4:1]分离得到相应产物25。1H NMR(400MHz,Chloroform-d)δ6.39(s,1H),6.30(s,1H),5.62(s,1H),5.42-5.28(m,2H),4.75(s,1H),2.68-2.58(m,2H),2.05-1.99(m,4H),1.62-1.55(m,2H),1.41-1.28(m,14H),0.88(d,J＝5.6Hz,3H).
利用实施例7同样的方法合成28.
Figure BDA0003061202670000221
1H NMR(400MHz,Chloroform-d)δ7.18(t,J＝7.7Hz,1H),7.02-6.99(m,3H),6.40(d,J＝2.9Hz,1H),6.30(d,J＝2.9Hz,1H),5.61(s,1H),4.74(s,1H),2.71-2.64(m,4H),2.59-2.55(m,2H),1.94-1.90(m,2H),1.34-1.27(m,8H),0.89(t,J＝6.4Hz,3H).
实施例8
Figure BDA0003061202670000222
乙酰乙酸乙酯(46mg，0.355mmol)溶于2mL THF中，冷却至0℃，加入NaH(10mg，0.391mmol)，搅拌5分钟，加入正丁基锂(0.17mL，2.4M in hexane，0.391mmol)反应5分钟，在加入溶于1mL THF的K1(100mg，0.355mmol)，0℃下搅拌12小时，TLC跟踪检测。反应完毕后，加5mL水淬灭反应，EA(3×5mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯[洗脱剂:V(石油醚):V(乙酸乙酯)＝20:1]分离得到中间体化合物22-a 70mg，无色油状物，60％。1H NMR(400MHz,Chloroform-d)δ7.18(dd,J＝8.9,6.7Hz,1H),7.02-6.95(m,3H),4.19(q,J＝7.2Hz,2H),3.41(s,2H),2.62-2.53(m,6H),1.66-1.61(m,4H),1.36-1.24(m,6H),0.88(t,J＝6.8Hz,3H)。
硫脲(23mg，0.30mmol)溶于0.5mL水中，70℃加热溶解，加入碳酸钾(42mg，0.30mmol)，取出加入到22-a(62mg，0.193mmol)中，105℃反应，待溶剂蒸干，冷却至室温，加入0.5mL水将固体溶解，溶液呈乳白色，加1N HCl盐酸调节pH至酸性，有白色粘稠固体析出，倒去上层液体，固体用水(2×3mL)洗涤，加2mLEA溶解，加入无水硫酸钠干燥，柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝2:1]分离得到产物24，14mg，白色固体，收率24％。1HNMR(400MHz,Chloroform-d)δ10.61-10.50(m,2H),7.19(t,J＝7.8Hz,1H),7.05-6.94(m,3H),5.75(s,1H),2.66-2.53(m,4H),2.43(t,J＝7.0Hz,2H),1.62-1.55(m,2H),1.37-1.28(m,8H),0.88(t,J＝6.8Hz,3H).
实施例9
Figure BDA0003061202670000231
氯乙酸(53mg，0.558mmol)溶于1mL水中，缓慢滴加溶于0.5mL THF中的25(92mg，0.279mmol)中，100℃反应过夜，冷却至室温，逐滴加入0.2mL浓盐酸，重新加热回流，TLC跟踪检测。反应完毕后，EA(3×2mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到产物22，3.2mg，白色固体，收率3％。1H NMR(400MHz,Methanol-d4)δ7.17(t,J＝7.5Hz,1H),7.04-6.97(m,3H),5.44(s,1H),2.65(t,J＝7.6Hz,2H),2.57(t,J＝7.6Hz,2H),2.40(t,J＝7.6Hz,2H),1.96-1.85(m,2H),1.63-1.59(m,2H),1.35-1.29(m,6H),0.89(t,J＝7.0Hz,3H).
实施例10
Figure BDA0003061202670000232
化合物38(18mg，0.0578mmol)悬浮于0.5mL水中，逐滴加入溶于1mL甲醇中的乙酸酐(13mg，0.133mmol)中，室温反应2小时，TLC跟踪检测。反应完毕后，冷却室温，浓缩干溶剂，倾倒上层水，柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到产物40，16mg，无色油状物，收率90％。1H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.78(s,1H),7.31(s,1H),7.17(t,J＝7.7Hz,1H),7.04-6.94(m,3H),6.50(s,1H),6.34(s,1H),2.61-2.53(m,6H),2.18(s,3H),1.95-1.89(m,2H),1.62-1.55(m,2H),1.38-1.27(m,6H),0.88(t,J＝5.6Hz,3H).
实施例11
Figure BDA0003061202670000241
化合物38(26mg，0.0836mmol)溶于0.5mLHFIP中，加入MeOTf(0.014mL，0.125mmol)，室温反应1h，TLC跟踪检测。反应完毕后，加入2mL1 N HCl淬灭反应，EA(3×2mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝4:1]分离得到产物41,6.3mg，棕红色油状物，收率，24％。1H NMR(400MHz,Chloroform-d)δ7.18(t,8.0Hz,1H),7.03-6.97(m,3H),6.08-6.01(m,2H),5.97-5.93(m,1H),2.80(s,3H),2.63-2.50(m,6H),1.97-1.85(m,2H),1.63-1.57(m,2H),1.37-1.29(m,6H),0.90-0.86(m,3H).
实施例12
Figure BDA0003061202670000242
化合物38(33mg，0.106mmol)投入烧瓶中，加入1mL THF，0.5mL无水乙醚中，0℃下缓慢加入到溶于0.5mL THF的BrCN中，室温反应过夜。TLC跟踪检测。反应完毕后，浓缩反应液，柱层析分离[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]得到终产物42,15mg，油状物，收率：42％。1H NMR(400MHz,Chloroform-d)δ7.19(t,J＝7.8Hz,1H),7.03-6.96(m,3H),6.42-6.39(m,2H),6.34(t,J＝1.7Hz,1H),6.12-5.48(m,2H),2.64-2.51(m,6H),1.97-1.85(m,2H),1.63-1.56(m,2H),1.36-1.29(m,6H),0.88(t,J＝6.6Hz,3H).
实施例13
Figure BDA0003061202670000243
化合物38(33mg，0.106mmol)，叔丁醇钾(36mg，0.318mmol)，Pd2(dba)3(10mg，0.011mmol)，iPrCl(10mg，0.080mmol)投入三颈瓶中，氮气换气三次，加入1-溴吡啶(0.012mL，0.127mmol)，加入dioxane(2mL)，100℃反应过夜，TLC跟踪检测。反应完毕后，加5mL水淬灭反应，EA(3×5mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到产物43，20mg棕色固体，收率45％。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J＝5.2,1.8Hz,1H),7.46(ddd,J＝8.7,7.1,1.8Hz,1H),7.17(t,J＝8.6Hz,1H),7.01-6.96(m,3H),6.89(dd,J＝8.7,2.2Hz,1H),6.75-6.67(m,2H),6.62-6.55(m,2H),6.40(t,J＝1.8Hz,1H),2.63-2.51(m,6H),1.95-1.85(m,2H),1.63-1.54(m,2H),1.34-1.24(m,8H),0.88(t,J＝6.6Hz,3H).
实施例14
Figure BDA0003061202670000251
化合物38(35mg，0.113mmol)，碳酸钾(30.4mg，0.225mmol)溶于0.8mL丙酮，0.2mL水中，0℃下加入丙烯酰氯(10.1mg，0.113mmol)，室温搅拌1h，TLC跟踪检测。反应完毕后，加3mL水淬灭反应，EA(3×3mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩干溶剂，最后柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到产物44,20mg，无色油状物，收率：48％。1H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.83(s,1H),7.37(s,1H),7.17(t,J＝7.7Hz,1H),7.02-6.95(m,3H),6.53(t,J＝1.8Hz,1H),6.47-6.40(m,2H),6.22(dd,J＝16.9,10.4Hz,1H),5.79(d,J＝10.4Hz,1H),2.62-2.53(m,6H),1.96-1.86(m,2H),1.63-1.53(m,2H),1.34-1.27(m,6H),0.87(t,J＝5.6Hz,3H).
实施例15
Figure BDA0003061202670000252
化合物38(25.8,0.083mmol)和碘(1mg，0.0013mmol)加入烧瓶中，敞口室温，滴加亚磷酸二乙酯(23mg，0.166mmol)，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝3:1]分离得到产物45,4.0mg，收率13％。1H NMR(400MHz,Chloroform-d)δ7.17(t,J＝7.7Hz,1H),7.02-6.95(m,3H),6.47(t,J＝2.2Hz,1H),6.34-6.30(m,2H),5.44-5.35(m,2H),4.20-4.04(m,4H),2.63-2.48(m,6H),1.94-1.84(m,2H),1.61-1.56(m,2H),1.33-1.27(m,12H),0.90-0.85(m,3H).
实施例16
Figure BDA0003061202670000261
化合物38(33mg，0.106mmol)，乙基乙氧甲叉乙腈(19mg，0.110mmol)溶于0.4mLEtOH中，微波反应10分钟，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝3:1]分离得到顺反异构体混合产物46，20mg，白色固体，收率：45％。1H NMR(400MHz,Chloroform-d)δ10.66(d,J＝13.5Hz,1H),7.81(d,J＝13.5Hz,1H),7.19(t,J＝7.8Hz,1H),7.04-6.95(m,3H),6.53-6.41(m,3H),5.72(s,1H),4.29(q,J＝7.1Hz,2H),2.64-2.54(m,6H),1.98-1.87(m,2H),1.64-1.54(m,2H),1.40-1.24(m,9H),0.88(t,J＝6.6Hz,3H).
实施例17
Figure BDA0003061202670000262
对三氟甲基苯甲酸(1.0g，5.26mmol)溶于2mL二氯亚砜中，加热回流2小时，浓缩干溶剂，得到酰氯化合物。化合物38(32.5mg，0.104mmol)溶于1mL THF中，氮气换气多次，加入三乙胺(0.030mL，0.209mmol)，0℃下加入酰氯(22mg，0.104mmol)，室温反应过夜，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(石油醚):V(乙酸乙酯)＝5:1]分离得到产物47，25mg，棕红色固体，收率50％。1H NMR(400MHz,Chloroform-d)δ7.96-7.85(m,3H),7.78-7.71(m,3H),7.45(s,1H),7.17(t,J＝7.8Hz,1H),7.03-6.94(m,3H),6.59(t,J＝1.7Hz,1H),6.55(t,J＝1.7Hz,1H),2.63-2.53(m,6H),1.97-1.87(m,2H),1.63-1.54(m,2H),1.33-1.25(m,6H),0.87(t,J＝5.6Hz,3H).
实施例18
Figure BDA0003061202670000271
化合物38(18mg,0.0554mmol),溶于2mL DCM中，0℃下加入吡啶(11.8mg，0.150mmol)，取代磺酰氯(0.0665mmol)，室温反应过夜，TLC跟踪检测。反应完毕后，浓缩反应液，柱层析纯化[洗脱剂:V(二氯甲烷):V(甲醇)＝20:1]分离得到39。1H NMR(400MHz,Chloroform-d)δ7.61(t,J＝7.4Hz,1H),7.52(s,1H),7.45-7.38(m,3H),7.12(t,J＝1.8Hz,1H),7.00(t,J＝1.8Hz,1H),6.94(t,J＝1.8Hz,1H),6.75(s,1H),3.57(q,J＝7.4Hz,2H),3.08-2.93(m,6H),2.39-2.27(m,2H),2.09-1.98(m,2H),1.75(q,J＝6.5,5.7Hz,9H),1.31(t,J＝5.6Hz,3H).
采用实施例18同样的方法合成以下化合物
Figure BDA0003061202670000272
Figure BDA0003061202670000281
实施例19 DRAK2抑制活性评价
1.实验目的
采用激酶检测试剂盒ADP-GLO测定化合物对激酶的抑制活性
2.实验原理
DRAK2是丝氨酸/苏氨酸蛋白激酶。ADP-Glo&#8482；Kinase Assay(ADP-Glo&#8482；激酶检测试剂盒)是一种发光法的激酶检测试剂盒，它可以检测激酶反应中所形成的ADP；该试剂盒可先将ADP转化成ATP，然后ATP再被Ultra-Glo&#8482；萤光素酶捕获最终转化成光。发出的光信号和相应的ATP是成正相关的，通过此方法，可以测定小分子化合物对DRAK2的抑制活性。
3.实验样品
试验前将化合物溶于DMSO，配制母液，使用时用培养液稀释至所需浓度。
4.实验方法
一、激酶测定
1.每次测定向孔中添加1μl化合物
2.除了不含酶的对照孔外，向测定板的每个孔中添加2μl激酶溶液(改为添加2μl1x激酶缓冲液)。
3.在测定板的每个孔中加入2μlATP
4.摇动板并离心
二、停止测定
加入2.5μl ADP-GloTM试剂以终止激酶反应并消耗掉未消耗的ATP，仅留下ADP和非常低的ATP背景在室温下孵育60分钟
三、检测分析
加入5μl激酶检测试剂以将ADP转化为ATP，并引入荧光素酶和荧光素来检测ATP。
四、数据处理
使用Envision测量发光
五、曲线拟合
1.从Envision程序复制值
2.抑制百分比＝(最大采样率)/(最大-最小)X 100。
“最小是指无酶控制的比例，而最大是指DMSO控制的比例”
3.数据用GraphPad Prism 5.0处理
通过此方法，我们就可以得到小分子化合物对DRAK2的抑制活性数据
5.实验结果：(以化合物1等四个化合物为例，但不局限于这些化合物)
表1部分化合物DRAK2抑制活性测试结果
化合物编号 DRAK2(IC<sub>50</sub>,μM)
1 7.73±0.70
17 4.94±1.18
28 4.06±0.35
39 4.93±1.09
注：IC50为样品药物对DRAK2抑制活性的评价，半数50％有效浓度。
6、结果与讨论：
测试结果显示该类化合物在微摩尔水平上可以有效抑制DRAK2活性，该类化合物作为一类新颖的DRAK2抑制剂，可用于开发成为新型的包括但不限于糖尿病等代谢综合症的治疗药物。
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)

1.一种如下式I所示的化合物，或其药学上可接受的盐：
Figure FDA0003061202660000011
其中，
R1选自下组：氢、羟基、卤素、取代或未取代的胺基，取代或未取代的C1-C6烷氧基；
R2选自下组：氢、CN、C1-C8烷基、5-7元杂芳基、3-7元环烷烃、C2-C10烯基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc，优选为氢、氰基、甲基、5-7元杂芳基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc，更优选为氰基、吡啶环、取代苯环、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc；
Ra各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为C1-C8烷基；
Rb各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为C1-C8烷基、C3-C10环烷基和5-7元杂芳基，更优选为乙烯基、C1-C3烷基、C3-C6环烷基和5元杂芳基；
Rc各自独立地选自下组：C1-C8烷基、C3-C10环烷基、5-7元杂芳基，C2-C10烯基，优选为甲基和乙烯基；
R3选自下组：H，卤素原子，C1-C10烷基，C3-C6环烷基；
R4选自下组：H、OH、取代或未取代的C1-C8烷氧基，优选为OH或甲氧基；
Ar选自下组：取代或未取代的苯环、取代或未取代的5-9元杂芳基、
Figure FDA0003061202660000012
Figure FDA0003061202660000013
X1为化学键、O、NH、NHC(O)、NHS(O)2、NHC(O)NH、NHS(O)2NH或S；
X2选自下组：化学键，C1-C6烷基氨基羰基，C1-C4烷基羰基；
n为0-10，优选为0-6；
Linker选自下组：取代或未取代的C1-C6烷烃，取代或未取代的C1-C6烯烃，取代或未取代的苯环、取代或未取代的5-7元杂芳环，取代或未取代的3-6元环烷烃，优选为C1-C6烯烃、取代苯环、噻吩环和呋喃环，更优选为烯烃和苯环；
除非特别说明，所述的取代是指基团上的氢原子被选自下组的一个或多个取代基替代：卤素、羟基、羧基、C1-C6烷基、C2-C10酯基。
2.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，Ar选自下组：取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代的吲哚环、取代或未取代的嘧啶环、取代或未取代的苯并咪唑、取代或未取代的吲唑、取代或未取代的苯并三唑，优选为苯环或吲哚环。
3.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R2选自下组：氢、氰基、甲基、5-7元杂芳基、-P(O)(ORa)2、-SO2Rb、-(C＝O)Rc；
Ra各自独立地选自下组：C1-C8烷基；
Rb各自独立地选自下组：乙烯基、C1-C3烷基、C3-C6环烷基、5元杂芳基；
Rc各自独立地选自下组：甲基、乙烯基。
4.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R3选自下组：氢、卤素、异丙基和环己烷。
5.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，X2选自下组：化学键、NHS(O)2、或-C(＝O)-NH-。
6.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述的式I化合物具有如下式II所示的结构：
Figure FDA0003061202660000021
7.如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述化合物选自下组：
Figure FDA0003061202660000022
Figure FDA0003061202660000031
8.如权利要求1-7任一所述的化合物的用途，其特征在于，用于制备治疗或预防死亡相关凋亡诱导蛋白激酶2(DRAK2)活性或表达量相关的适应症的药物组合物。
9.如权利要求8所述的用途，其特征在于，所述的适应症为代谢综合症。
10.一种药物组合物，其特征在于，所述的药物组合物包含(1)作为活性成分的如权利要求1-7任一所述的化合物，或其药学上可接受的盐；和(2)药学上可接受的载体。
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