CN116056706A - 可用作二酰基甘油酰基转移酶2抑制剂的新的联芳基衍生物及其用途 - Google Patents
可用作二酰基甘油酰基转移酶2抑制剂的新的联芳基衍生物及其用途 Download PDFInfo
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- CN116056706A CN116056706A CN202180054182.9A CN202180054182A CN116056706A CN 116056706 A CN116056706 A CN 116056706A CN 202180054182 A CN202180054182 A CN 202180054182A CN 116056706 A CN116056706 A CN 116056706A
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- Prior art keywords
- phenyl
- amino
- pyrazin
- ethoxyphenoxy
- acid
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Abstract
本发明涉及一种表现出二酰基甘油酰基转移酶2(DGAT2)抑制剂活性并由化学式(1)表示的联芳基衍生物化合物、包含所述化合物作为活性成分的药物组合物及其用途。
Description
技术领域
本发明涉及一种由式(1)表示的对二酰基甘油酰基转移酶2(DGAT2)显示出抑制活性的联芳基衍生物化合物、包含所述化合物作为活性成分的药物组合物及其用途。
背景技术
随着经济发展,生活标准的提高,方便食品的频繁食用以及以肉为主的饮食习惯的改变,导致体内热量的过度积累。现代人饮食生活的这些变化,也导致因缺乏运动而造成的热量消耗减少,导致代谢疾病例如肥胖症、高脂血症、糖尿病、心血管疾病、冠状动脉疾病的严重流行。具体而言,肥胖症是迅速增加的疾病之一,并且据报道是代谢疾病例如糖尿病的原因。通过控制参与作为肥胖症的主要原因的甘油三酯的生物合成途径的酶的功能来开发用于代谢疾病的治疗剂,正在引起人们的关注。
中性脂肪例如甘油三酯(TG),作为体内的能量来源在储存功能中发挥非常重要的作用。然而,当中性脂肪在器官或组织中过度积累时,它们引起肥胖症、高甘油三酯血症、脂肪肝等,从而引起严重疾病例如糖尿病、动脉硬化、代谢异常和器官功能减退。二酰基甘油酰基转移酶是甘油三酯生物合成中的关键酶,存在于哺乳动物的各种不同组织中,是在作为甘油三酯合成的主要途径的磷酸甘油途径的最后一步中通过将脂肪酰基辅酶A与二酰基甘油的羟基结合来合成TG的一种酶。目前已知有两种亚型——DGAT1和DGAT2。尽管它们的生化功能相似,但区别在于DGAT1主要在小肠和脂肪组织中表达,而DGAT2主要在肝脏和脂肪组织中表达。另外,在基因家族方面,DGAT1属于ACAT家族,而DGAT2属于MGAT家族。因此,预计它们在TG生物合成中的作用也不同。
包括动物研究在内的几项研究显示,DGAT2主要对体内TG的生物合成有贡献。与几乎不合成TG并由于皮肤层异常而在出生后不久死亡的DGAT2敲除小鼠不同,DGAT1敲除小鼠显示出TG水平的略微下降,并且小鼠的生存没有问题(Stone SJ等,2000.Nat.Genet.25:87-90)。此外,作为通过在脂肪肝动物模型中使用反义寡核苷酸(ASO)降低DGAT1或DGAT2表达水平的结果,只有当DGAT2的量减少时脂肪肝症状才会得到缓解,并且肝脏中葡萄糖的产生速率才会显著降低(Choi CS等,2007.Hepatology.45:1366-74)。
潜在的分子机制尚未被完全阐明,但据认为DGAT2的抑制导致多个参与脂质生产的蛋白质的编码基因的表达下调,所述蛋白质例如甾醇调节元件结合蛋白1c(SREBP1c)和硬脂酰辅酶A-去饱和酶1(SCD1)。同时,据认为氧化途径由诸如肉毒碱棕榈酰基转移酶1(CPT1)的基因的增加所诱导。这种变化反过来导致肝脏DAG和TAG脂质水平的降低,从而改善肝脏中的胰岛素响应性。此外,DGAT2的抑制抑制肝脏VLDL TAG分泌并降低循环胆固醇水平。最后,血浆载脂蛋白B(APOB)水平受到抑制,这据认为是由在新合成的APOB蛋白的脂化中TAG的供应减少所造成的。也就是说,当DGAT2被抑制时,显示出对血糖控制和血浆胆固醇谱两者的有益效应,这意味着DGAT2的抑制可应用于代谢障碍的治疗。
发明内容
技术问题
本发明的一个目的是提供一种对二酰基甘油酰基转移酶2(DGAT2)显示出抑制活性的由式(1)表示的新的联芳基衍生物化合物。
本发明的另一个目的是提供一种制备所述联芳基衍生物化合物的方法。
本发明的另一个目的是提供一种包含所述联芳基衍生物化合物作为活性成分,用于治疗与DGAT2相关的代谢疾病的药物组合物及其制备方法。
本发明的又一个目的是提供一种在受试者中治疗与DGAT2相关的代谢疾病的方法,其中通过使用与常规化合物相比具有改进的物理和化学性质的联芳基衍生物化合物作为活性成分,提高了在疾病动物模型中的功效并提高了在所述受试者中的功效和服用方便性。
技术解决方案
为了实现上述目的,本发明提供了一种下式(1)的化合物或其可药用盐或异构体:
[式(1)]
其中
A、D和E各自独立地是CH或N;
R1是烷基、环烷基或卤代烷基;
R2是-G-J-L;
其中G是-C(=O)-或直接连键;
J是亚烷基、亚烯基、亚烷基-亚芳基、亚烯基-亚芳基、亚烷氧基-亚芳基、亚芳基、亚杂芳基-亚杂环烷基、亚杂芳基-亚芳基或亚杂芳基-氧基-亚环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、羧基烷基、羧基烷氧基、环烷基或芳基;
其中所述烷基、亚烷基、羧基烷基、羧基烷氧基或芳基任选地被选自羟基、卤素、烷基和烷氧基的一个或多个取代基取代;并且
所述亚杂环烷基或亚杂芳基包括一个或多个选自N、O和S的杂原子。
根据本发明的式(1)的化合物可以形成可药用盐。可药用盐可以包括从下述酸形成的酸加成盐:无机酸例如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸,有机酸例如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、延胡索酸、马来酸和水杨酸,或磺酸例如甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸,所述酸形成包括可药用阴离子的无毒酸加成盐。此外,可药用羧酸盐包括与碱金属或碱土金属例如锂、钠、钾、钙和镁的盐,与氨基酸例如赖氨酸、精氨酸和胍的盐,有机盐例如二环己胺、N-甲基-D-葡萄糖胺、三(羟甲基)甲基胺、二乙醇胺、胆碱和三乙胺。根据本发明的式(1)的化合物可以通过常规方法转变成它们的盐。
同时,由于根据本发明的式(1)的化合物可以具有不对称碳中心和不对称轴或平面,因此它们可以作为E-或Z-异构体、R-或S-异构体、外消旋混合物或非对映异构体混合物和每种非对映异构体存在,这些都在本发明的范围之内。
在本文中,除非另有指明,否则术语“式(1)的化合物”用于指称所有式(1)的化合物,包括其可药用盐和异构体。
在本文中,使用下述为取代基定义的概念来定义式(1)的化合物。
术语“卤素”或“卤”意味着氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“烷基”或“亚烷基”意味着直链或支链烃类,可以包含单键、双键或叁键,并且优选为C1-C10烷基或C1-C10亚烷基或C1-C7烷基或C1-C7亚烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、乙炔基、乙烯基、三氟甲基等。
术语“烯基”或“亚烯基”意味着具有至少一个碳-碳双键的直链或支链烃类,并且优选为C2-C10烯基或C2-C10亚烯基或C2-C7烯基或C2-C7亚烯基。烯基的实例包括但不限于乙烯基、烯丙基、丁烯基、异丙烯基、异丁烯基等。
术语“环烷基”意味着部分或完全饱和的单环或稠合环烃类,并且优选为C3-C10-环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。
除非另有定义,否则术语“烷氧基”意味着具有1至10个碳原子的烷氧基。
术语“芳基”或“亚芳基”意味着芳香族烃类,优选为C5-C12芳基或C5-C12亚芳基,更优选为C6-C10芳基或C6-C10亚芳基,并且包括但不限于苯基、萘基等。
术语“杂芳基”或“亚杂芳基”意味着3至12元、更优选地5至12元的芳香族烃类,其形成包括一个或多个选自N、O和S的杂原子作为环成员的单环或稠合环(其可以与苯环或C3-C8环烷基稠合)。杂芳基的实例包括但不限于吡啶基、嘧啶基、哒嗪基、吡嗪基、二唑基、异二唑基、四唑基、三唑基、吲哚基、吲唑基、异唑基、唑基、噻唑基、异噻唑基、呋喃基、苯并呋喃基、咪唑基、硫苯基、苯并噻唑、苯并咪唑、喹啉基、吲哚啉基、1,2,3,4-四氢异喹啉基、3,4-二氢异喹啉基、噻唑并吡啶基、2,3-二氢苯并呋喃、2,3-二氢噻吩、2,3-二氢吲哚、苯并[1,3]二英、色满、硫色满、1,2,3,4-四氢喹啉、4H-苯并[1,3]二英、2,3-二氢苯并[1,4]-二英、6,7-二氢-5H-环戊并[d]嘧啶等。
术语“杂环烷基”或“亚杂环烷基”意味着部分或完全饱和的烃类,其形成包括一个或多个选自N、O和S的杂原子的单环或稠合环,并且优选为3至12元杂环烷基或亚杂环烷基或5至12元杂环烷基或亚杂环烷基。杂环烷基或亚杂环烷基的实例包括但不限于吡咯烷基、哌啶基、吗啉基、咪唑啉基、哌嗪基、四氢呋喃、四氢硫呋喃等。
根据本发明的一个实施方式,在上式(1)中
A、D和E各自独立地是CH或N;
R1是C1-C7烷基、C3-C10环烷基或卤代-C1-C7烷基;
R2是-G-J-L;
其中G是-C(=O)-或直接连键;
J是C1-C7亚烷基、C2-C7亚烯基、C1-C7亚烷基-C6-C10亚芳基、C2-C7亚烯基-C6-C10亚芳基、C1-C7亚烷氧基-C6-C10亚芳基、C6-C10亚芳基、5至12元亚杂芳基-5至12元亚杂环烷基、5至12元亚杂芳基-C6-C10亚芳基或5至12元亚杂芳基-氧基-C3-C10亚环烷基;
L是氢、卤素、氨基、硝基、羧基、羧基-C1-C7烷基、羧基-C1-C7烷氧基、C3-C10环烷基或C6-C10芳基;
其中所述烷基、亚烷基、羧基烷基、羧基烷氧基或芳基任选地被选自羟基、卤素、C1-C7烷基和C1-C7烷氧基的1至4个取代基取代;并且
所述亚杂环烷基或亚杂芳基包括选自N、O和S的1至4个杂原子。
根据本发明的代表性的式(1)的化合物包括但不限于下述化合物:
N-(6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)-3-苯基丙酰胺;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸甲酯;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸;
2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸;
2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸甲酯;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二氟乙酸乙酯;
3-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
(R)-1-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;
N-(6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)-3-苯基丙酰胺;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基-2,2-二氟乙酸;
3-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸;
(E)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙-1-苯-1-基)苯基)-2-甲基丙酸;
3-(4-(1-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基-2-甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)苯基)乙酸;
(1r,4r)-4-((2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸;
N-(6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)-3-苯基丙酰胺;
3-(4-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
(R)-1-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸;
3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸;
3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基)-2-甲基丙酸;
(R)-1-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;和
(1r,4r)-4-((2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸。
除非另有指明,否则本文中使用的术语和缩略语均保留它们的原始含义。
本发明还提供了一种制备式(1)的化合物的方法。在后文中,将在示例性反应的基础上解释所述制备式(1)的化合物的方法,以便说明本发明。然而,本领域技术人员可以在式(1)的结构的基础上通过各种不同方法制备式(1)的化合物,并且此类方法应该被解释为在本发明的范围之内。也就是说,式(1)的化合物可以通过本文描述的方法或通过组合现有技术中公开的各种不同方法来制备,这些方法应该被解释为在本发明的范围之内。因此,用于制备式(1)的化合物的方法不限于下述方法。
本发明的式(1)的化合物可以按照下述反应路线1的方法通过将取代的胺基团直接引入到化合物(2)中,或通过将受保护的胺引入到化合物(2)中,除去保护基团以获得化合物(3),并在化合物(3)上进行酰胺化反应来制备。
[反应路线1]
化合物(2)可以按照下述反应路线2的方法使用2-乙氧基苯酚作为起始原料来制备。
[反应路线2]
此外,化合物(3)可以按照下述反应路线3的方法来制备。
[反应路线3]
在式(4)的化合物中,酰胺衍生物可以通过用亚硫酰氯或草酰氯处理适合的酸,然后用氨水处理来获得。例如,可以按照下述反应路线4的方法制备4-(3-氨基-3-酮基丙基)苯甲酸甲酯。在式(4)的化合物中,胺衍生物可以通过将氨基引入到通过二氧杂硼杂环戊烷核心中间体与各种不同种类的氯代芳基化合物之间的交叉偶联反应获得的化合物中,以合成氨基芳基中间体来获得。例如,可以按照下述反应路线5的方法制备2-(4-(2-氨基嘧啶-4-基)苯基)乙酸乙酯。
[反应路线4]
[反应路线5]
在本说明书的制备方法中未具体描述的化合物是已知化合物或可以通过已知合成方法或类似方法从已知化合物容易地合成的化合物。
通过上述方法获得的式(1)的化合物,可以通过常规方法例如重结晶、离子电渗、硅胶柱层析或离子交换层析从反应产物分离或纯化。
正如上文解释的,根据本发明所述的化合物、用于制备它们的起始原料或中间体可以通过各种不同的方法制备,所述方法应该被解释为就式(1)的化合物的制备而言在本发明的范围之内。
根据本发明的式(1)的化合物对二酰基甘油酰基转移酶2(DGAT2)表现出抑制活性。因此,本发明提供了一种用于治疗与DGAT2相关的疾病的药物组合物,其包含式(1)的化合物或其可药用盐或异构体以及可药用载体。在体内转变成式(1)的化合物的各种不同类型的前体药物,也在本发明的范围之内。
可以通过本发明的药物组合物治疗的与DGAT2相关的示例性疾病包括但不限于选自脂肪肝、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、糖尿病、肥胖症、高脂血症、动脉粥样硬化和高胆固醇血症的疾病。
在本发明中,除了本发明的活性成分之外,“药物组合物”还可以包含其他组分例如载体、稀释剂、赋形剂等。因此,如果需要,所述药物组合物可以包含可药用载体、稀释剂、赋形剂或其组合。所述药物组合物便于化合物在身体中的给药。给药所述化合物的各种不同方法包括但不限于口服、注射、气溶胶、肠胃外和局部给药。
在本文中,“载体”意味着便于将化合物添加到细胞或组织中的化合物。例如,二甲基亚砜(DMSO)是一种常规载体,便于许多有机化合物在活细胞或组织中的给药。
在本文中,“稀释剂”意味着不仅使生物活性形式稳定,而且在溶解化合物的溶剂中稀释的化合物。在本领域中,使用在缓冲液中溶解的盐作为稀释剂。一种常用缓冲液是模拟体液中的盐形式的磷酸盐缓冲盐水。由于缓冲溶液可以在低浓度下控制所述溶液的pH,因此缓冲稀释剂几乎不改变化合物的生物活性。
在本文中,“可药用”意味着不损害化合物的生物活性和物理性质的性质。
根据本发明的化合物可以被配制成各种不同的药物给药剂型。在本发明的药物组合物的制备中,将活性组分、具体来说是式(1)的化合物或其可药用盐或异构体,与考虑到待制备的剂型而选择的可药用载体混合。例如,如果需要,本发明的药物组合物可以被配制成注射剂、口服制剂等。
本发明的化合物可以使用已知的制药载体和赋形剂通过常规方法来配制,并插入到单元或多单元容器中。所述制剂可以是在油或水性溶剂中的溶液、悬液或乳液,并包含常规分散剂、悬浮剂或稳定剂。此外,所述化合物可以是例如干粉形式,其在使用前溶解在灭菌的无热原水中。本发明的化合物可以通过使用常规的栓剂基料例如可可脂或其他甘油酯配制成栓剂。用于口服给药的固体形式包括胶囊、片剂、丸剂、粉剂和颗粒剂。优选的是胶囊和片剂。片剂和丸剂优选被肠溶包衣。固体形式通过将本发明的化合物与选自惰性稀释剂例如蔗糖、乳糖或淀粉、润滑剂例如硬脂酸镁、崩解剂、粘合剂等的至少一种载体混合来制备。
如果需要,根据本发明的化合物或包含它们的药物组合物可以与其他药物例如其他代谢障碍治疗剂联合给药。
根据本发明的式(1)的化合物的剂量由医生根据患者的体重、年龄和疾病状况开出的处方确定。根据给药的频率和强度,成人的典型剂量在每天约0.3至500mg的范围内。成人肌肉内或静脉内给药的典型日剂量在每天约1至300mg的范围内,其可以在分单位剂量中给药。一些患者需要更高的每日剂量。
在本文中,术语“治疗”用于表示在表现出疾病症状的受试者中阻止、延迟疾病或改善疾病的进展。
有利效果
根据本发明的式(1)的新的联芳基衍生物化合物对二酰基甘油酰基转移酶2(DGAT2)表现出出色的抑制活性,并因此可以有用地用于与DGAT2相关的代谢障碍的预防、缓解或治疗。此外,根据本发明的式(1)的新的联芳基衍生物化合物表现出提高的亲脂性和肝脏选择性,从而通过增加向肝脏的暴露来提高功效,并且由于在疾病动物模型和临床实践中半衰期相对长,因此预计具有服用方便的优点。
具体实施方式
在下文中,利用下述实施例更详细地解释本发明。然而必须理解,本发明的保护范围不限于所述实施例。
在下面的实施例中,M表示摩尔浓度,N表示当量浓度。此外,在反应路线、制备例和实施例中使用的缩略语和术语的描述如下:
DCM:二氯甲烷
DIPEA:N,N-二异丙基乙胺
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
NMP:N-甲基吡咯烷酮
Pd(dppf)Cl2.CH2Cl2:[1,1'-联(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(1:1)
TEA:三乙胺
THF:四氢呋喃
PyBroP:三吡咯烷基溴化鏻六氟磷酸盐
制备例1:2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪的合成
步骤1:3-溴-5-(2-乙氧基苯氧基)吡啶的合成
在0℃下向NMP(100ml)添加60%氢化钠(1.82g,46mmol),并在氮气存在下向其缓慢逐滴添加2-乙氧基苯酚(6.1g,44mmol)。在将反应溶液在室温搅拌1小时后,向其逐滴添加3,5-二溴吡啶(7.2g,30.4mmol),并在150℃搅拌72小时。在反应完成后,将反应混合物冷却至室温,用水(120ml)稀释,添加5N氢氧化钠水溶液(15ml),并用乙醚萃取。在硫酸镁上脱水后,在减压下除去溶剂,并通过柱层析进行纯化,得到所需产物(得率:19.5%)。
1H NMR(500MHz,氯仿-D):δ8.32(d,J=1.2Hz,1H),8.26(d,J=2.4Hz,1H),7.28(s,1H),7.20(s,1H),7.09(d,J=7.9Hz,1H),7.04-6.87(m,2H),4.01(t,J=7.0Hz,2H),1.24(t,J=7.0Hz,3H)
步骤2:(5-(2-乙氧基苯氧基)吡啶-3-基)硼酸的合成
向甲苯(30ml)添加在步骤1中得到的3-溴-5-(2-乙氧基苯氧基)吡啶(1.74g,5.92mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二氧杂硼杂环戊烷)(2.25g,8.87mmol,1.5eq)、乙酸钾(2.32g,23.66mmol)和Pd(dppf)Cl2.CH2Cl2(48mg,0.06mmol),并在120℃回流下搅拌12小时。在反应完成后,将反应混合物通过硅藻土垫过滤,用甲苯洗涤,在减压下除去溶剂,并且不需独立的纯化过程即可进行下一个反应。
m/z(M+H)+:C13H14BNO4的计算值为259.0,实测值为260.1
步骤3:2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪的合成
向1,4-二烷(20ml)/水(1ml)添加在步骤2中得到的(5-(2-乙氧基苯氧基)吡啶-3-基)硼酸(1.53g,5.92mmol)、2,6-二氯吡嗪(0.97g,6.5mmol,1.1eq)、碳酸钠(1.25g,11.81mmol)和Pd(dppf)Cl2.CH2Cl2(48mg,0.06mmol),并在120℃回流下搅拌12小时。在反应完成后,将得到的物质通过硅藻土垫过滤,用甲苯洗涤,在减压下除去溶剂,通过柱层析进行纯化,得到所需产物(两步得率:39%)。
1H-NMR(400MHz,氯仿-D)δ8.90(s,2H),8.57(s,1H),8.41(d,j=4Hz,1H),7.81(d,J=4Hz,1H),7.20(m,1H),7.13(m,1H),7.02(m,2H),4.06(q,2H),1.24(t,3H)
制备例2:2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪的合成
步骤1:1-(3-溴苯氧基)-2-乙氧基苯的合成
将2-乙氧基苯酚(4.33g,31.4mmol)、1-溴-3-碘苯(6ml,47.1mmol)、氯化亚铜(I)(1.553g,15.69mmol)、2,2,6,6-四甲基-3,5-庚二酮(1.310ml,6.27mmol)和碳酸铯(10.22g,31.4mmol)溶解在70ml NMP中并加热至120℃。在搅拌16小时后,将反应混合物冷却至室温。将反应用1N盐酸水溶液终止,然后用二乙醚萃取。将有机层用盐水洗涤,在硫酸镁上脱水,并在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:5),得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D)δ:7.14-7.12(m,3H),7.04-7.03(m,2H),7.00-6.98(m,1H),6.97-6.93(m,1H),6.88-6.86(m,1H),4.03(q,2H,J=7.35Hz),1.26(t,3H,J=7.03Hz)
步骤2:2-(3-(2-乙氧基苯氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
的合成
向甲苯(30ml)添加在步骤1中得到的1-(3-溴苯氧基)-2-乙氧基苯(1.74g,5.94mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二氧杂硼杂环戊烷)(2.26g,8.90mmol,1.5eq)、乙酸钾(2.33g,23.74mmol)和Pd(dppf)Cl2.CH2Cl2(48mg,0.06mmol),并在120℃回流下搅拌12小时。在反应完成后,将得到的产物通过硅藻土垫过滤,用甲苯洗涤,在减压下除去溶剂,通过柱层析进行纯化,得到所需产物(得率:45%)。
1H-NMR(500MHz,氯仿-D):δ7.48(d,1H),7.43(s,1H),7.28(t,1H),7.09(t,1H),6.94~7.03(m,4H),4.06(q,2H),1.32(s,12H),1.28(t,3H)
步骤3:2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪的合成
向1,4-二烷(20ml)/水(1ml)添加在步骤2中得到的2-(3-(2-乙氧基苯氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(0.9g,2.65mmol)、2,6-二氯吡嗪(0.43g,2.91mmol,1.1eq)、碳酸钠(0.56g,5.29mmol)和Pd(dppf)Cl2.CH2Cl2(22mg,0.03mmol),并在120℃回流下搅拌12小时。在反应完成后,将得到的产物通过硅藻土垫过滤,用甲苯洗涤,在减压下除去溶剂,通过柱层析进行纯化,得到所需产物(得率:75%)。
1H-NMR(500MHz,氯仿-D)δ8.85(s,1H),8.49(s,1H),7.68(d,1H),7.61(s,1H),7.40(t,1H),7.14(t,1H),7.05(d,J=6Hz,1H),7.02(d,J=6Hz,2H),6.95(t,1H),4.05(q,2H),1.26(t,3H)
制备例3:2-氯-6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪的合成
使用2-乙氧基苯酚(1.5g,10.86mmol)和2,6-二溴吡啶(3.86g,16.28mmol),以与制备例2相似的方式得到所需产物(得率:44.9%)。
m/z(M+H)+:C17H14ClN3O2的计算值为327.77,实测值为328.0制备例4:2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪的合成
步骤1:3-乙氧基吡啶-1-氧化物的合成
将3-乙氧基吡啶(1.683g,13.67mmol)溶解在DCM(32.5ml)中,然后在10℃下向其添加间氯过氧苯甲酸(3.07g,17.77mmol),并在室温搅拌22小时。添加硫代硫酸钠并在15℃搅拌3小时。在反应完成后,将得到的产物用DCM萃取。在减压下除去溶剂,通过柱层析进行纯化,得到所需产物(得率:87%)。
1H-NMR(500MHz,氯仿-D)δ7.96(t,J=2.0Hz,1H),7.92-7.83(m,1H),7.15(dd,J=8.7,6.3Hz,1H),6.86(dd,J=8.5,2.1Hz,1H),4.05(q,J=7.0Hz,2H),1.44(t,J=6.9Hz,3H)
步骤2:2-(3-溴苯氧基)-3-乙氧基吡啶的合成
将在步骤1中得到的3-乙氧基吡啶-1-氧化物(825mg,5.93mmol)和3-溴苯酚(1.02g,5.93mmol)溶解在THF(19ml)中,向其添加DIPEA(3.83ml,21.94mmol)和PyBroP(3.59g,7.71mmol),并在室温搅拌17小时。在反应完成后,将得到的产物在减压下浓缩,用DCM稀释,并将有机层用1N氢氧化钠水溶液洗涤。将得到的产物在硫酸镁上脱水,在减压下除去有机溶剂,并通过硅胶柱进行纯化,得到所需产物(得率:88%)。
1H-NMR(400MHz,氯仿-D):δ7.73(dd,J=5.0,1.4Hz,1H),7.28(td,J=3.4,1.8Hz,2H),7.24-7.19(m,2H),7.12-7.02(m,2H),7.02-6.91(m,1H),6.82-6.66(m,1H),4.13(q,J=7.0Hz,2H),1.46(td,J=7.1,4.6Hz,3H)
步骤3:2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪的合成
使用在步骤2中得到的2-(3-溴苯氧基)-3-乙氧基吡啶(1.54g,5.24mmol),以与制备例2的步骤2和3相似的方式得到所需产物(得率:24.4%)。
1H-NMR(400MHz,氯仿-D):δ8.90(s,1H),8.49(s,1H),7.84(dd,J=8.7,1.4Hz,2H),7.71(dd,J=4.8,1.6Hz,1H),7.52(t,J=7.8Hz,1H),7.33-7.26(m,1H),7.24-7.15(m,1H),6.98(dd,J=7.8,5.0Hz,1H),4.17(q,J=7.0Hz,2H),1.48(t,J=7.1Hz,3H)
制备例5:3-苯基丙酰胺的合成
在0℃下向氨水(189ml)逐滴添加溶解在THF(46ml)中的3-苯基丙酰氯(4.5ml,30.3mmol),然后搅拌1小时。在减压下除去有机溶剂,用水稀释并用乙酸乙酯萃取。将有机溶剂在硫酸镁上脱水并在减压下移除。通过硅胶柱进行纯化,得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D):δ7.29-7.25(m,2H),7.22-7.20(m,3H),5.44(s,1H),5.35(s,1H),2.97(t,J=7.6Hz,2H),2.53(t,J=7.6Hz,2H)
制备例6:2-(4-(2-氨基-2-酮基乙基)苯基)乙酸甲酯的合成
步骤1:2,2'-(1,4-亚苯基)二乙酸二甲酯的合成
在0℃下向甲醇(20ml)缓慢逐滴添加乙酰氯(2.9ml,40.8mmol)。然后溶解1,4-亚苯基二乙酸(4.0g,20.6mmol),并将反应混合物在回流下搅拌5小时。在通过TLC确认反应完成后,将得到的产物冷却至室温,并在减压下除去有机溶剂。将反应产物用100mL乙酸乙酯稀释,用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上脱水,并在减压下除去有机溶剂,得到所需产物。
1H-NMR(500MHz,氯仿-D):δ7.24(s,2H),3.68(s,3H),3.61(s,2H)
步骤2:2-(4-(2-甲氧基-2-酮基乙基)苯基)乙酸的合成
将在步骤1中得到的2,2'-(1,4-亚苯基)二乙酸二甲酯(4.58g,20.6mmol)溶解在THF(30ml)和甲醇(10ml)中,向其缓慢逐滴添加10ml 2N氢氧化钠,并在室温搅拌3小时。在减压下除去有机溶剂,用水稀释,并用2N盐酸溶液酸化。在用乙酸乙酯萃取后,将有机溶剂在硫酸镁上脱水并在减压下移除。进行重结晶,得到所需产物(得率:30%)。
1H-NMR(500MHz,氯仿-D):δ7.25(d,J=4.9Hz,4H),3.68(s,3H),3.66-3.62(2H),3.61(s,2H)
步骤3:2-(4-氨甲酰基苯氧基)-2-甲基丙酸甲酯的合成
将在步骤2中得到的2-(4-(2-甲氧基-2-酮基乙基)苯基)乙酸(1.0g,4.8mmol)溶解在30ml二氯甲烷中,并在室温下缓慢逐滴添加亚硫酰氯(0.7ml,9.6mmol)。在室温搅拌4小时后,在减压下除去有机溶剂。将得到的产物溶解在5ml THF中,然后在0℃下缓慢逐滴添加到25%氨水溶液。在搅拌1小时后,过滤得到的固体,得到所需产物(得率:74%)。
1H-NMR(500MHz,DMSO-D6):δ7.42(s,1H),7.15(dd,J=12.2,7.9Hz,4H),6.83(s,1H),3.60(s,2H),3.57(d,J=4.3Hz,3H),3.30(s,2H)
制备例7:2-(4-(3-氨基-3-酮基丙基)苯基)乙酸甲酯的合成
步骤1:(E)-3-(4-(2-甲氧基-2-酮基乙基)苯基)丙烯酸叔丁酯的合成
将2-(4-溴苯基)乙酸甲酯(16.4g,71.56mmol)、丙烯酸叔丁酯(18.0g,143.0mmol)和三乙胺(50ml,0.35mol)溶解在200ml二甲基甲酰胺中。在通过氮气鼓泡除去溶解的氧气后,逐滴添加联(三苯基膦)二氯化钯(2.5g,3.58mmol),并在75℃搅拌12小时。在减压下除去有机溶剂,用乙酸乙酯稀释,用盐水洗涤,在硫酸镁上脱水,然后在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:3),得到所需产物(得率:79%)。
1H-NMR(500MHz,氯仿-D):δ7.56(d,J=15.9Hz,1H),7.46(d,J=8.7Hz,2H),7.28(d,J=7.9Hz,2H),6.34(d,J=15.9Hz,1H),3.70(s,3H),3.64(s,2H),1.53(s,9H)
步骤2:3-(4-(2-甲氧基-2-酮基乙基)苯基)丙酸叔丁酯的合成
将在步骤1中得到的(E)-3-(4-(2-甲氧基-2-酮基乙基)苯基)丙烯酸叔丁酯(5.0g,18.0mmol)溶解在50ml甲醇中,并向其逐滴添加钯炭(0.5g,0.452mmol)。通过使用氢气球进行还原反应。在确认反应完成后,将得到的产物用硅藻土垫过滤,并在减压下除去有机溶剂,得到所需产物(得率:93%)。
1H-NMR(500MHz,氯仿-D):δ7.17(dd,J=18.3,7.9Hz,4H),3.68(s,3H),3.59(s,2H),2.88(t,J=7.9Hz,2H),2.52(t,J=7.6Hz,2H),1.41(s,9H)
步骤3:3-(4-(2-甲氧基-2-酮基乙基)苯基)丙酸的合成
将在步骤2中得到的3-(4-(2-甲氧基-2-酮基乙基)苯基)丙酸叔丁酯(4.67g,16.8mmol)溶解在100ml 20%三氟乙酸/二氯甲烷溶液中,并在室温搅拌2小时。在确认反应完成后,在减压下除去有机溶剂,并进行重结晶,得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D):δ9.58(s,2H),7.18(dd,J=19.0,7.9Hz,4H),3.70(s,3H),3.61(s,2H),2.95(t,J=7.6Hz,2H),2.69(t,J=7.9Hz,2H)
步骤4:2-(4-(3-氨基-3-酮基丙基)苯基)乙酸甲酯的合成
使用在步骤3中得到的3-(4-(2-甲氧基-2-酮基乙基)苯基)丙酸(3.73g,16.8mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:65%)。
1H-NMR(500MHz,氯仿-D):δ7.18(q,J=7.7Hz,4H),5.41(s,2H),3.66(d,J=15.9Hz,3H),3.59(s,2H),3.02-2.87(2H),2.51(t,J=7.6Hz,2H)
制备例8:2-(4-(3-氨基-3-酮基丙基)苯基-2-甲基丙酸甲酯的合成
步骤1:(E)-3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)丙烯酸叔丁酯的合成
使用2-(4-溴苯基)-2-甲基丙酸甲酯(1.0g,3.89mmol)和丙烯酸叔丁酯(0.98g,7.8mmol),以与制备例7的步骤1相似的方式得到所需产物(得率:79%)。
1H-NMR(500MHz,氯仿-D):δ7.56(dd,J=15.9,4.3Hz,1H),7.51-7.42(2H),7.41-7.31(m,2H),6.34(dd,J=15.9,4.9Hz,1H),3.66(d,J=4.9Hz,3H),1.58(d,J=4.9Hz,6H),1.53(d,J=4.9Hz,9H)
步骤2:2-(4-(3-(叔丁氧基)-3-酮基丙基)苯基)-2-甲基丙酸甲酯的合成
使用在步骤1中得到的(E)-3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)丙烯酸叔丁酯(0.93g,3.06mmol),以与制备例7的步骤2相似的方式通过还原反应得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.23(s,2H),7.15(d,J=7.9Hz,2H),3.63(s,3H),2.87(t,J=7.9Hz,2H),2.52(t,J=7.9Hz,2H),1.55(s,6H),1.40(s,9H)
步骤3:3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)丙酸的合成
使用在步骤2中得到的2-(4-(3-(叔丁氧基)-3-酮基丙基)苯基)-2-甲基丙酸甲酯(0.90g,2.92mmol),以与制备例7的步骤3相似的方式得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.26(d,J=7.3Hz,2H),7.16(d,J=7.9Hz,2H),3.66(s,3H),3.03-2.84(2H),2.82-2.55(2H),1.56(s,6H)
步骤4:2-(4-(3-氨基-3-酮基丙基)苯基)-2-甲基丙酸甲酯的合成
使用在步骤3中得到的3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)丙酸(0.7g,2.8mmol),以与制备例6的步骤3相似的方式通过酰胺化反应得到所需产物(得率:99%)。
1H-NMR(500MHz,氯仿-D):δ7.25(dd,J=6.4,2.1Hz,2H),7.17(d,J=7.9Hz,2H),5.36(s,2H),3.64(s,3H),3.00-2.90(2H),2.52(t,J=7.6Hz,2H),1.56(d,J=4.3Hz,6H)
制备例9:2-(4-(2-乙氧基-1,1-二氟-2-酮基乙基)苯基)乙酸的合成
步骤1:2-(4-碘苯基)乙酸叔丁酯的合成
向2-(4-碘苯基)乙酸(13.0g,49.6mmol)添加叔丁醇(130ml),并在氮气鼓泡下搅拌直至它变得透明。添加二碳酸二叔丁酯(10.83g,49.6mmol)并搅拌至溶解,然后向其添加4-二甲基氨基吡啶(6.06g,49.6mmol)并在室温搅拌1小时。将有机溶剂在减压下浓缩,并通过硅胶柱进行纯化(乙酸乙酯:正己烷=1:9),得到所需产物(得率:68.9%)。
1H-NMR(500MHz,氯仿-D):δ7.63(d,J=7.95Hz,2H),7.01(d,J=8.55Hz,2H),3.45(s,2H),1.42(s,9H)
步骤2:2-(4-(2-(叔丁氧基)-2-酮基乙基)苯基)-2,2-二氟乙酸乙酯的合成向溶解在DMSO(80ml)中的活化的铜粉(4.37g,68.6mmol)添加在步骤1中得到的2-(4-碘苯基)乙酸叔丁酯(8.4g,26.4mmol)和2-溴-2,2-二氟乙酸酯(5.36g,26.4mmol)。在60℃搅拌12小时后,将得到的产物倾倒在冰和氯化铵水溶液中,然后用二乙醚萃取。将有机层用氯化铵水溶液和盐水洗涤,然后在硫酸镁上脱水。将有机层在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:正己烷=1:9),得到所需产物(得率:60%)。
1H-NMR(400MHz,氯仿-D):δ7.56(d,J=8Hz,2H),7.36(d,J=8Hz,2H),4.31(q,J=8Hz,2H),1.44(s,9H),1.30(t,J=8Hz,3H)
步骤3:2-(4-(2-乙氧基-1,1-二氟-2-酮基乙基)苯基)乙酸的合成
将在步骤2中得到的2-(4-(2-(叔丁氧基)-2-酮基乙基)苯基)-2,2-二氟乙酸乙酯(5g,15.91mmol)溶解在DCM(10ml)中,然后向其添加溶解在DCM(50ml)中的三氟乙酸(15ml),并在室温搅拌1小时。在添加甲苯并在减压下除去溶剂后,不需进一步纯化即得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D):δ7.58(d,J=7.95Hz,2H),7.37(d,J=7.95Hz,2H),4.28(q,J=6.7Hz,2H),3.69(s,2H),1.30(t,J=7.03Hz,3H)
制备例10:3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯的合成
步骤1:2-(4-(3-叔丁氧基-2,2-二甲基-3-酮基丙基)苯基)乙酸的合成
向无水四氢呋喃(164ml)添加二异丙胺(14.0ml,98mmol),并在-78℃下向其缓慢逐滴添加2.5M正丁基锂(39.3ml,98mmol)。将反应溶液在相同温度下搅拌20分钟。在将温度升高至室温并搅拌10分钟后,将反应溶液再次降低到-78℃并搅拌10分钟。向反应溶液逐滴添加溶解在无水四氢呋喃(163ml)中的异丁酸叔丁酯(14.16g,98mmol)将反应溶液在-78℃搅拌1小时,并缓慢逐滴添加到溶解在无水四氢呋喃(163ml)中的2-(4-(溴甲基)苯基)乙酸(7.5g,32.7mmol)。将反应溶液加热至室温并搅拌20分钟。通过向反应溶液添加1N盐酸水溶液(100ml)终止反应,然后用二乙醚萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(甲醇:二氯甲烷=1:9),得到所需产物(得率:92%)。
1H-NMR(500MHz,氯仿-D):δ7.20(d,J=7.9Hz,2H),7.14(d,J=7.9Hz,2H),3.64(s,2H),2.83(s,2H),1.63-1.40(m,9H),1.18-1.06(6H)
步骤2:3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯的合成
使用在步骤1中得到的2-(4-(3-叔丁氧基-2,2-二甲基-3-酮基丙基)苯基)乙酸(6.82g,23.33mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:52.7%)。
1H-NMR(400MHz,氯仿-D):δ7.20-7.09(m,4H),5.33(d,J=36.1Hz,2H),3.54(s,2H),2.80(s,2H),1.42(s,9H),1.11(s,6H)
制备例11:(R)-1-(2-氨基嘧啶-4-基)哌啶-3-甲酸乙酯的合成
步骤1:(R)-1-(2-氯嘧啶-4-基)哌啶-3-甲酸乙酯的合成
将2,4-二氯嘧啶(0.5g,3.36mmol)溶解在乙醇(6.71ml)中,并向其添加(R)-哌啶-3-甲酸乙酯(0.621ml,4.03mmol)和TEA(0.187ml,1.343mmol)。将反应混合物在85℃搅拌3小时。在减压下除去溶剂后,将得到的产物溶解在乙酸乙酯中并用水洗涤。通过硅胶柱进行纯化,得到所需产物(得率:86%)。
1H-NMR(500MHz,氯仿-D):δ8.05(d,J=6.1Hz,1H),6.47(d,J=6.4Hz,1H),4.51-4.11(m,3H),4.06(s,1H),3.43(dd,J=13.4,9.5Hz,1H),3.36-3.21(m,1H),2.67-2.46(m,1H),2.22-2.03(m,1H),1.96-1.79(m,2H),1.69-1.59(m,1H),1.33-1.23(m,3H)
步骤2:(R)-1-(2-((叔丁氧基羰基)氨基)嘧啶-4-基)哌啶-3-甲酸乙酯的合成
在将步骤1中得到的(R)-1-(2-氯嘧啶-4-基)哌啶-3-甲酸乙酯(0.78g,2.89mmol)、氨基甲酸叔丁酯(0.407g,3.47mmol)、碳酸铯(2.36g,7.23mmol)、4,5-联(二苯基膦)-9,9-二甲基黄嘌呤(0.201g,0.347mmol)和三(二亚苯甲基丙酮)二钯(0)(0.265g,0.289mmol)溶解在50ml 1,4-二烷中之后,在搅拌下通过氮气鼓泡除去溶解的氧气,然后在气密容器中阻断外部空气的流入。将反应混合物在145℃搅拌6小时,然后冷却至室温。在通过硅藻土垫过滤并在减压下除去有机溶剂后,将得到的产物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下移除。通过硅胶柱进行纯化,得到所需产物(得率:11.8%)。
m/z(M+H)+:C17H26N4O4的计算值为350.42,实测值为351.2
步骤3:(R)-1-(2-氨基嘧啶-4-基)哌啶-3-甲酸乙酯的合成
在将步骤2中得到的(R)-1-(2-((叔丁氧基羰基)氨基)嘧啶-4-基)哌啶-3-甲酸乙酯(0.120g,0.342mmol)溶解在DCM(3ml)中之后,向其添加溶解在DCM中的三氟乙酸(0.3ml),并在室温搅拌2小时。在减压下除去溶剂后,将得到的产物溶解在DCM中并用水洗涤。通过硅胶柱进行纯化,得到所需产物(得率:58.3%)。
1H-NMR(500MHz,氯仿-D):δ7.68(d,J=6.7Hz,1H),6.49-6.21(1H),6.07(d,J=6.7Hz,1H),4.31(d,J=13.1Hz,1H),4.16(q,J=7.1Hz,2H),4.01(d,J=13.1Hz,1H),3.43-3.30(1H),3.30-3.16(1H),2.63-2.47(m,1H),2.19-2.03(m,1H),1.91-1.76(m,2H),1.65-1.46(m,1H),1.26(t,J=7.0Hz,3H)
制备例12:3-(3-(6-氨基吡啶-2-基)苯基)-2,2-二甲基丙酸叔丁酯的合成
步骤1:3-(3-溴苯基)-2,2-二甲基丙酸叔丁酯的合成
使用1-溴-3-(溴甲基)苯(20.0g,80mmol),以与制备例10的步骤1相似的方式得到所需产物(得率77%)。
1H-NMR(400MHz,氯仿-D):δ7.37-7.30(m,2H),7.16-7.04(m,2H),2.78(s,2H),1.44(s,9H),1.13(s,6H)
步骤2:2,2-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯
基-丙酸叔丁酯的合成
在将步骤1中得到的3-(3-溴苯基)-2,2-二甲基丙酸叔丁酯(19.3g,61.6mmol)、4,4,4,4,5,5,5,5-八甲基-2,2-联(1,3,2-二氧杂硼杂环戊烷)(18.78g,73.9mmol)、乙酸钾(18.14g,185mmol)和Pd(dppf)Cl2.CH2Cl2(2.52g,3.08mmol)溶解在616ml 1,4-二烷中之后,在搅拌下通过氮气鼓泡除去溶解的氧气,然后在气密容器中阻断外部空气的流入。将反应混合物在110℃搅拌16小时,然后冷却至室温。在通过硅藻土垫过滤并除在减压下去有机溶剂后,通过硅胶柱进行纯化(乙酸乙酯:己烷),得到所需产物(得率:69.8%)。
1H-NMR(400MHz,氯仿-D):δ7.72-7.55(m,2H),7.26-7.17(m,2H),2.83(s,2H),1.45(s,9H),1.33(s,12H),1.13(s,6H)
步骤3:3-(3-(6-氨基吡啶-2-基)-苯基)-2,2-二甲基丙酸叔丁酯的合成
在将6-氯吡啶-2-胺(5.53g,43mmol)、在步骤2中得到的2,2-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基-丙酸叔丁酯(15.5g,43mmol)、2M碳酸钠水溶液(64.5ml,129mmol)和联(三苯基膦)二氯化钯(3.02g,4.30mmol)溶解在358ml二甲氧基乙烷中之后,在搅拌下通过氮气鼓泡除去溶解的氧气,然后在气密容器中阻断外部空气的流入。将反应混合物在100℃搅拌16小时并冷却至室温。在通过硅藻土垫过滤并在减压下除去有机溶剂后,将得到的产物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下移除。通过硅胶柱进行纯化(乙酸乙酯:己烷),得到所需产物(得率:41.6%)。
m/z(M+H)+:C20H26N2O2的计算值为326.44,实测值为327.2制备例13:2-(4-(3-氨基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯的合成
步骤1:2-(4-(3-甲氧基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯的合成
将3-(4-羟基苯基)丙酸甲酯(2.17g,12.04mmol)、硫酸镁(0.29g,2.41mmol)和碳酸钾(6.66g,48.2mmol)溶解在DMF(30.1ml)中,并向其进一步添加2-溴-2-甲基丙酸叔丁酯(9.40g,42.1mmol)。将反应混合物在75℃搅拌16小时,然后冷却至室温。在通过硅藻土垫过滤并在减压下除去有机溶剂后,将得到的产物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下移除。通过硅胶柱进行纯化(乙酸乙酯:己烷),得到所需产物(得率:62%)。
步骤2:3-(4-((1-(叔丁氧基)-2-甲基-1-酮基丙-2-基)氧基)苯基)丙酸的合成
在将2-(4-(3-甲氧基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯(2.4g,7.44mmol)溶解在THF(15ml)和甲醇(15ml)中之后,向其进一步添加1N氢氧化钠(15ml)并在室温搅拌6小时。将反应混合物用盐酸水溶液酸化,用乙酸乙酯萃取并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去(得率:100%)。
步骤3:2-(4-(3-氨基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯的合成
将3-(4-((1-(叔丁氧基)-2-甲基-1-酮基丙-2-基)氧基)苯基)丙酸(2.30g,7.46mmol)溶解在DCM(37ml)中,在室温下向其进一步添加草酰氯(1.31ml,14.92mmol)和DMF(0.058ml,0.75mmol)。将反应混合物在室温下搅拌30分钟,在减压下除去溶剂,然后添加THF(19ml)。将温度降低至0℃,向其缓慢滴加25%氢氧化铵(8.71ml,224mmol)。在减压下除去有机溶剂,通过添加乙酸乙酯来萃取反应混合物,并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下移除,得到所需产物(得率:87%)。
1H-NMR(400MHz,氯仿-D):δ7.11-7.01(m,2H),6.77(dt,J=9.3,2.5Hz,2H),5.33(s,2H),2.89(t,J=7.5Hz,2H),2.53-2.44(m,2H),1.53(s,6H),1.43(s,9H)
制备例14:2-(4-(3-氨基-3-酮基丙基)苯基)-2-甲基丙酸苯甲酯的合成
使用2-(4-溴苯基)-2-甲基丙酸(5.00g,20.57mmol)和苯甲基溴(4.22g,24.68mmol),顺序进行与制备例13的步骤1、制备例7的步骤1、3和4相似的方法,得到所需产物(得率:60%)。
1H-NMR(400MHz,氯仿-D):δ7.66-7.59(m,1H),7.54-7.40(m,2H),7.40-7.25(m,5H),7.19-7.10(m,2H),6.47-6.40(m,1H),5.61(s,2H),5.09(s,2H),1.59(s,6H)
制备例15:3-(4-(1-氨基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯的合成
步骤1:3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯
的合成
使用2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(5.40g,19.91mmol)和异丁酸叔丁酯(3.45g,23.90mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:78%)。
1H-NMR(400MHz,氯仿-D):δ7.20(d,J=8.2Hz,2H),7.09(d,J=8.2Hz,2H),3.63(s,3H),2.78(s,2H),1.54(s,6H),1.41(s,9H),1.11(s,6H)
步骤2:3-(4-(1-氨基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯的
合成
使用在步骤1中得到的3-(4-(1-甲氧基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.50g,1.50mmol),顺序进行与制备例13的步骤2和3相似的方法,得到所需产物(得率:76%)。
1H-NMR(400MHz,氯仿-D):δ7.25(d,J=8.2Hz,2H),7.11(d,J=8.2Hz,2H),5.85(s,1H),5.31(s,1H),2.78(s,2H),1.53(s,6H),1.41(s,9H),1.10(s,6H)
制备例16:2-(4-(2-氨基-2-酮基乙基)苯氧基)-2-甲基丙酸叔丁酯的合成
使用2-(4-羟基苯基)乙酸甲酯(2.00g,12.04mmol)和2-溴-2-甲基丙酸叔丁酯(9.40g,42.1mmol),以与制备例13相似的方式得到所需产物(得率:54%)。
1H-NMR(400MHz,氯仿-D):δ7.12(dd,J=11.4,2.7Hz,2H),6.83(td,J=5.7,3.7Hz,2H),5.43(d,J=26.5Hz,2H),3.50(s,2H),1.57-1.50(m,6H),1.45-1.37(m,9H)
制备例17:2-(4-(2-氨基嘧啶-4-基)苯基)乙酸乙酯的合成
使用2-(4-溴苯基)乙酸乙酯(27.6g,114mmol),以与制备例12的步骤2和3和制备例11的步骤2和3相似的方式得到所需产物(得率:17.2%)。
m/z(M+H)+:C14H15N3O2的计算值为257.29,实测值为258.1
制备例18:(1r,4r)-4-((2-氨基嘧啶-4-基)氧基)环己烷-1-甲酸甲酯的合成
步骤1:(1r,4r)-4-羟基环己烷-1-甲酸甲酯的合成
在将(1r,4r)-4-羟基环己烷-1-甲酸(0.300g,2.081mmol)溶解在甲醇(10ml)中之后,向其添加硫酸(0.017ml,0.312mmol)。在60℃搅拌16小时,在减压下除去有机溶剂,并通过硅胶柱进行纯化,得到所需产物(得率:100%)。
1H-NMR(400MHz,氯仿-D):δ8.25(d,J=5.9Hz,1H),6.64-6.50(m,1H),5.16-5.05(1H),3.73-3.62(m,3H),2.35(tt,J=11.4,3.7Hz,1H),2.18(dt,J=12.8,3.5Hz,2H),2.07(dd,J=14.2,3.7Hz,2H),1.74-1.56(m,2H),1.49(ddd,J=23.0,12.7,3.5Hz,2H)
步骤2:(1r,4r)-4-((2-氯嘧啶-4-基)氧基)环己烷-1-甲酸甲酯的合成
在将2,4-二氯嘧啶(0.28g,1.91mmol)溶解在DMF(10ml)中之后,向其添加在步骤1中获得的(1r,4r)-4-羟基环己烷-1-甲酸甲酯(0.33g,2.10mmol)和碳酸铯(2.56g,4.78mmol)。在80℃搅拌3小时后,将反应混合物用二乙醚稀释并用水洗涤。将有机溶剂在硫酸镁上脱水,并通过硅胶柱进行纯化,得到所需产物(得率:39.8%)。
1H-NMR(400MHz,氯仿-D):δ8.25(d,J=5.9Hz,1H),6.64-6.50(m,1H),5.16-5.05(1H),3.73-3.62(m,3H),2.35(tt,J=11.4,3.7Hz,1H),2.18(dt,J=12.8,3.5Hz,2H),2.07(dd,J=14.2,3.7Hz,2H),1.74-1.56(m,2H),1.49(ddd,J=23.0,12.7,3.5Hz,2H)
步骤3:(1r,4r)-4-((2-氨基嘧啶-4-基)氧基)环己烷-1-甲酸甲酯的合成
使用在步骤2中得到的(1r,4r)-4-((2-氯嘧啶-4-基)氧基)环己烷-1-甲酸甲酯(0.21g,0.76mmol),以与制备例11的步骤2相似的方式得到所需产物(得率:69%)。
1H-NMR(400MHz,氯仿-D)δ7.98(d,J=5.9Hz,1H),6.01(d,J=5.5Hz,1H),5.02-4.89(m,1H),4.82(s,2H),3.68(dd,J=7.3,2.7Hz,5H),2.44-2.26(m,1H),2.20-1.99(m,4H),1.71-1.57(m,2H),1.52(s,1H),1.41(dd,J=12.6,3.4Hz,1H)
实施例1:N-(6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)-3-苯基丙酰胺的合成
在将制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.1g,0.305mmol)、制备例5中得到的3-苯基丙酰胺(0.055g,0.366mmol)、碳酸铯(0.249g,0.763mmol)、4,5-联(二苯基膦)-9,9-二甲基黄嘌呤(21mg,0.037mmol)和三(二亚苯甲基丙酮)二钯(0)(28mg,0.031mmol)溶解在15ml 1,4-二烷中之后,在搅拌下通过氮气鼓泡除去溶解的氧气,然后在气密容器中阻断外部空气的流入。将反应混合物在110℃搅拌16小时,然后冷却至室温。在通过硅藻土垫过滤并在减压下除去有机溶剂后,将得到的产物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下移除。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:2),得到所需产物(得率:67%)。
m/z(M+H)+:C26H24N4O3的计算值为440.50,实测值为441.1
实施例2:2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸甲酯的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.32g,0.976mmol)和在制备例6中得到的2-(4-(2-氨基-2-酮基乙基)苯基)乙酸甲酯(0.243g,1.172mmol),以与实施例1相似的方式得到所需产物(得率:22.6%)。
1H NMR(500MHz,氯仿-D):δ9.50(s,1H),8.86(s,1H),8.67(s,1H),8.61(s,1H),8.33(s,1H),7.67(d,J=1.8Hz,1H),7.27(4H),7.17(1H),7.08(d,J=7.3Hz,1H),7.00-6.94(m,2H),3.99(q,J=6.7Hz,2H),3.76(s,2H),3.67(s,3H),3.62(s,2H),1.19(t,J=6.7Hz,3H)
实施例3:2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸的合成
将在实施例2中得到的2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸甲酯(110mg,0.221mmol)溶解在THF(6ml)和甲醇(2ml)中。向其添加溶解在水(2ml)中的氢氧化钠(44mg,1.103mmol),然后在室温搅拌4小时。在将反应冷却至室温后,使用1N盐酸水溶液将反应混合物滴定至pH 4.5,用乙酸乙酯稀释并除去水层。将得到的产物在硫酸镁上脱水,并在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:1),得到所需产物(得率:33.6%)。
m/z(M+H)+:C27H24N4O5的计算值为484.51,实测值为485.1
实施例4:2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸的合成
步骤1:2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)氨基)-3-酮基丙基)苯基)
乙酸甲酯的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.20g,0.61mmol)和制备例7中得到的2-(4-(3-氨基-3-酮基丙基)苯基)乙酸甲酯(0.14g,0.61mmol),以与实施例1相似的方式得到所需产物(得率:35%)。
1H-NMR(400MHz,氯仿-D):δ9.51(s,1H),8.87(s,1H),8.70(s,1H),8.36(d,J=10Hz,2H),7.68(s,1H),7.25(m,5H),7.10(d,1H),6.94~7.02(m,2H),4.02(q,2H),3.66(s,3H),3.58(s,2H),3.06(t,2H),2.77(t,2H),1.21(t,3H)
步骤2:2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基
丙基)苯基)乙酸的合成
将在步骤1中得到的酯化合物(0.11g,2.39mmol)以与实施例3相似的方式水解,得到所需产物(得率:28%)。
1H-NMR(400MHz,DMSO-D6):δ10.87(s,1H),9.34(s,1H),9.00(s,2H),8.33(s,1H),7.89(s,1H),7.17(m,7H),7.02(t,1H),4.03(t,2H),3.51(s,2H),2.92(t,2H),2.78(t,2H),1.10(t,3H)
实施例5:2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸甲酯的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.25g,0.76mmol)和在制备例8中得到的2-(4-(3-氨基-3-酮基丙基)苯基-2-甲基丙酸甲酯(0.19g,0.76mmol),以与实施例1相似的方式得到所需产物(得率:51%)。
1H NMR(400MHz,氯仿-D):δ9.51(s,1H),8.86(s,1H),8.72(s,1H),8.37(d,J=4Hz,1H),7.99(s,1H),7.70(s,1H),7.25(m,3H),7.20(m,2H),7.12(m,1H),7.03(m,2H),4.03(q,2H),3.06(t,2H),2.78(t,2H),1.55(s,6H),1.22(t,3H)
实施例6:2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二氟乙酸乙酯的合成
步骤1:6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-胺的合成
标题化合物作为实施例3中2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸的制备过程中的副产物获得。
m/z(M+H)+:C17H16N4O2的计算值为308.3,实测值为309.1
步骤2:2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基
乙基)苯基)-2,2-二氟乙酸乙酯的合成
在将制备例9中得到的2-(4-(2-乙氧基-1,1-二氟-2-酮基乙基)苯基)乙酸(0.02g,0.077mmol)溶解在DCM(0.4ml)中之后,添加草酰氯(0.02g,0.155mmol)和1滴DMF。将反应混合物在室温搅拌1小时,并在减压下除去溶剂。在将浓缩物溶解在THF(0.2ml)中之后,将温度降低到0℃,将步骤1中得到的6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-胺(0.02g,0.065mmol)溶解到THF(0.2ml)中,并向其添加TEA(0.022g,0.216mmol)。在室温搅拌16小时后,添加水,并将反应混合物用乙酸乙酯萃取。在用水和盐水洗涤后,将有机层在硫酸镁上脱水并在减压下浓缩。通过柱层析进行纯化,得到所需产物(得率:13%)。
1H-NMR(500MHz,氯仿-D):δ9.49(s,1H),8.84(s,1H),8.74(s,1H),8.38(s,1H),7.91(s,1H),7.67(s,1H),7.66(d,J=7.9Hz,2H),7.46(d,J=7.9Hz,2H),7.21(1H),7.11(1H),7.03-6.99(2H),4.30(q,J=7.95Hz,2H),4.03(q,J=6.15Hz,2H),3.86(s,2H),1.31(t,J=6.15Hz,3H),1.22(t,J=7.95Hz,3H)
实施例7:3-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.1g,0.305mmol)和制备例10中得到的3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.081g,0.277mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:12%)。
1H-NMR(400MHz,甲醇-D4):δ9.34(s,1H),8.89(s,1H),8.85-8.74(m,1H),8.23(d,J=2.7Hz,1H),7.91(q,J=1.4Hz,1H),7.33-7.19(m,3H),7.19-7.06(m,4H),7.01(t,J=7.5Hz,1H),3.99(q,J=7.0Hz,2H),3.72(s,2H),2.82(s,2H),1.18-1.01(m,9H)
实施例8:(R)-1-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.1g,0.305mmol)和制备例11中得到的(R)-1-(2-氨基嘧啶-4-基)哌啶-3-甲酸乙酯(0.069g,0.277mmol),以与实施例1和实施例3相似的方式得到所需产物(得率:49%)。
1H-NMR(400MHz,甲醇-D4):δ9.45(s,1H),8.88(d,J=1.8Hz,1H),8.64(s,1H),8.21(d,J=2.7Hz,1H),7.96(d,J=6.4Hz,1H),7.92(t,J=2.3Hz,1H),7.31-7.21(m,1H),7.21-7.16(1H),7.16-7.09(m,1H),7.06-6.95(m,1H),6.42(d,J=6.4Hz,1H),4.50-4.06(1H),4.01(q,J=7.0Hz,2H),3.53-3.33(m,1H),3.23(s,1H),2.62-2.40(1H),2.19-2.01(1H),1.81(d,J=12.3Hz,2H),1.68-1.44(1H),1.14(t,J=6.9Hz,3H)
实施例9:3-(3-(6-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸的合成
使用在制备例1中得到的2-氯-6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪(0.1g,0.305mmol)和制备例10中得到的3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.091g,0.277mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:26.9%)。
1H-NMR(400MHz,甲醇-D4):δ9.36(s,1H),8.89(d,J=1.8Hz,1H),8.65-8.50(1H),8.25(d,J=2.7Hz,1H),7.99-7.88(m,2H),7.84(d,J=7.8Hz,1H),7.65(t,J=7.8Hz,1H),7.40(d,J=7.3Hz,1H),7.34(dd,J=8.0,5.7Hz,2H),7.30-7.24(m,1H),7.20(dd,J=8.0,1.6Hz,2H),7.15(d,J=8.2Hz,1H),7.11-6.95(m,1H),4.04-3.91(2H),2.95(s,2H),1.19(s,6H),1.13(t,J=7.1Hz,3H)
实施例10:N-(6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)-3-苯基丙酰胺的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.1g,0.306mmol)和在制备例5中得到的3-苯基丙酰胺(0.055g,0.367mmol),以与实施例1相似的方式得到所需产物(得率:60%)。
1H NMR(500MHz,氯仿-D):δ9.44(s,1H),8.70(s,1H),8.00(s,1H),7.57(1H),7.50(s,1H),7.36(1H),7.28-7.25(2H),7.21-7.19(3H),7.10(1H),7.05-6.98(3H),6.90(1H),4.30(q,J=7.3Hz,2H),3.04(t,J=7.65Hz,2H),2.69(t,J=7.95Hz,2H),1.23(3H)
实施例11:2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.250g,0.765mmol)和在制备例6中得到的2-(4-(2-氨基-2-酮基乙基)苯基)乙酸甲酯(0.190g,0.918mmol),顺序地以与实施例1和实施例3相似的方式得到所需产物(得率:34.1%)。
1H NMR(300MHz,甲醇-D):δ9.35(s,1H),8.61(s,1H),8.52(s,1H),7.45(1H),7.40(d,J=1.25Hz,1H),7.26(1H),7.13(m,4H),7.02(1H),6.94-6.89(3H),6.81(1H),3.95(2H),3.59(s,2H),3.39(s,2H),1.18(3H)
实施例12:2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸的合成
步骤1:2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)
苯基)乙酸甲酯的合成
使用在制备例4中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.10g,0.31mmol)和制备例11中得到的2-(4-(3-氨基-3-酮基丙基)苯基)乙酸甲酯(0.07g,0.31mmol),以与实施例1相似的方式得到所需产物(得率:75%)。
1H-NMR(400MHz,氯仿-D):δ9.45(s,1H),8.71(s,1H),8.11(s,1H),7.51(d,J=12Hz,1H),7.51(s,1H),7.36(t,1H),7.16(d,J=8Hz,2H),7.14(d,J=8Hz,2H),7.09(t,1H),6.90~6.98(m,3H),6.89(t,1H),4.06(t,2H),3.67(s,3H),3.59 9s,2H),3.01(t,2H),2.65(t,2H),1.24(t,3H)
步骤2:2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)
苯基)乙酸的合成
将在步骤1中得到的酯化合物(0.11g,2.39mmol)以与实施例3相似的方式水解,得到所需产物(得率:69%)。
1H-NMR(400MHz,氯仿-D):δ9.49(s,1H),8.91(s,1H),8.67(s,1H),7.47(d,1H),7.43(s,1H),7.35 9t,1H),7.11~7.26(m,5H),6.97~7.05(m,3H),6.91(t,1H),4.06(t,2H),3.61(s,2H),3.00(t,2H),2.68(t,2H),1.26(t,3H)
实施例13:2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.080g,0.245mmol)和在制备例13中得到的2-(4-(3-氨基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯(0.075g,0.245mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:64%)。
1H-NMR(400MHz,氯仿-D):δ9.43(s,1H),8.65-8.52(m,2H),7.51-7.41(m,2H),7.36-7.27(m,1H),7.10-6.91(m,6H),6.91-6.76(m,3H),4.01(q,J=6.9Hz,2H),2.93(t,J=6.9Hz,2H),2.63(d,J=5.0Hz,2H),1.56(s,6H),1.23(t,J=7.1Hz,3H)
实施例14:2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基-2,2-二氟乙酸的合成
步骤1:6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-胺的合成
标题化合物作为实施例11中2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸的制备过程中的副产物获得。
m/z(M+H)+:C18H17N3O2的计算值为307.3,实测值为308.1
步骤2:2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)
苯基-2,2-二氟乙酸的合成
使用在制备例9中得到的2-(4-(2-乙氧基-1,1-二氟-2-酮基乙基)苯基)乙酸(0.046g,0.178mmol)和步骤1中得到的6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-胺(0.061g,0.199mmol),顺序地以与实施例6和实施例3相似的方式得到所需产物(得率:5.7%)。
1H-NMR(500MHz,甲醇-D4):δ9.19(s,1H),8.66(s,1H),7.65(1H),7.54-7.52(3H),7.35-7.33(3H),7.10(1H),7.04-6.98(2H),6.90-6.88(2H),3.94(q,J=7.3Hz,2H),3.74(s,1H),1.10(t,J–6.7Hz,3H)
实施例15:3-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.10g,0.306mmol)和在制备例10中得到的3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.089g,0.306mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:74%)。
1H NMR(400MHz,氯仿-D):δ9.43(s,1H),8.68(s,1H),8.19(s,1H),7.56-7.47(m,2H),7.34(t,J=8.0Hz,1H),7.18(td,J=7.8,5.6Hz,4H),7.13-7.05(m,1H),7.05-6.93(m,3H),6.90(t,J=7.8Hz,1H),4.03(q,J=7.0Hz,2H),3.76-3.69(m,2H),2.88(s,2H),1.29-1.16(m,9H)
实施例16:2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.10g,0.306mmol)和在制备例14中得到的2-(4-(3-氨基-3-酮基丙基)苯基)-2-甲基丙酸苯甲酯(0.099g,0.306mmol),以与实施例1和制备例7的步骤2相似的方式得到所需产物(得率:31%)。
1H NMR(400MHz,氯仿-D):δ9.44(s,1H),8.68(s,1H),8.34(s,1H),7.58-7.45(m,2H),7.39-7.27(m,3H),7.17(d,J=8.2Hz,2H),7.10(td,J=7.8,1.5Hz,1H),7.06-6.94(m,3H),6.94-6.85(m,1H),4.03(q,J=7.0Hz,2H),3.10-2.95(m,2H),2.70(t,J=7.5Hz,2H),1.57(s,6H),1.24(t,J=6.6Hz,3H)
实施例17:(E)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙-1-苯-1-基)苯基)-2-甲基丙酸的合成
标题化合物作为获得实施例16的过程中的副产物获得(得率:41%)。
1H NMR(400MHz,氯仿-D):δ9.60(s,1H),8.92(d,J=31.1Hz,1H),8.70(d,J=0.9Hz,1H),7.84-7.72(m,1H),7.61-7.42(m,6H),7.38(td,J=7.9,2.4Hz,1H),7.19-7.10(m,1H),7.10-6.97(m,3H),6.97-6.87(m,1H),6.59(d,J=15.6Hz,1H),4.08-3.99(m,2H),1.63(s,6H),1.33-1.19(m,3H)
实施例18:3-(4-(1-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.10g,0.306mmol)以及在制备例15中得到的3-(4-(1-氨基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.098g,0.306mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:77%)。
1H NMR(400MHz,氯仿-D):δ9.46(s,1H),8.69-8.60(m,1H),7.57(s,1H),7.53-7.44(m,2H),7.36-7.26(m,3H),7.19(d,J=8.7Hz,2H),7.15-7.06(m,1H),6.98(ddd,J=8.0,5.0,1.6Hz,2H),6.94-6.85(m,2H),4.01(q,J=7.0Hz,2H),2.88(s,2H),1.66(s,6H),1.28-1.13(m,9H)
实施例19:2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基-2-甲基丙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.08g,0.245mmol)和制备例16中得到的2-(4-(2-氨基-2-酮基乙基)苯氧基)-2-甲基丙酸叔丁酯(0.072g,0.245mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:62%)。
1H-NMR(400MHz,氯仿-D):δ9.42(s,1H),8.67(s,1H),8.40(d,J=12.3Hz,1H),7.54-7.42(m,2H),7.32(td,J=7.9,2.0Hz,1H),7.20(q,J=4.0Hz,2H),7.16-7.05(m,1H),7.04-6.84(m,6H),4.02(qd,J=7.0,1.5Hz,2H),3.69(d,J=2.7Hz,2H),1.59(d,J=15.1Hz,6H),1.30-1.16(m,3H)
实施例20:2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)苯基)乙酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.140g,0.428mmol)和在制备例17中得到的2-(4-(2-氨基嘧啶-4-基)苯基)乙酸乙酯(0.1g,0.389mmol),以与实施例1和实施例3相似的方式得到所需产物(得率:0.69%)。
m/z(M+H)+:C30H25N5O4的计算值为519.56,实测值为520.1
实施例21:(1r,4r)-4-((2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸的合成
使用在制备例2中得到的2-氯-6-(3-(2-乙氧基苯氧基)苯基)吡嗪(0.100g,0.306mmol)和制备例18中得到的(1r,4r)-4-((2-氨基嘧啶-4-基)氧基)环己烷-1-甲酸甲酯(0.085g,0.337mmol),顺序地以与实施例1和实施例3相似的方式得到所需产物(得率:22.8%)。
1H-NMR(400MHz,DMSO-D6):δ10.09(s,1H),9.38(s,1H),8.75(s,1H),8.25(d,J=5.9Hz,1H),7.78(d,J=8.2Hz,1H),7.70(t,J=2.1Hz,1H),7.41(t,J=8.0Hz,1H),7.21-7.10(m,2H),7.08-7.01(m,1H),7.00-6.91(m,1H),6.85(dd,J=7.8,2.3Hz,1H),6.43-6.33(m,1H),4.95(dd,J=10.3,4.3Hz,1H),4.00(q,J=6.9Hz,2H),2.18(s,1H),2.11(d,J=7.8Hz,2H),1.93(d,J=9.6Hz,2H),1.55-1.34(m,4H),1.12(t,J=7.1Hz,3H)
实施例22:N-(6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)-3-苯基丙酰胺的合成
使用在制备例3中得到的2-氯-6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪(0.1g,0.305mmol)和制备例5中得到的3-苯基丙酰胺(0.059g,0.397mmol),以与实施例1相似的方式得到所需产物(得率:52.1%)。
m/z(M+H)+:C26H24N4O3的计算值为440.50,实测值为441.1
实施例23:3-(4-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸的合成
使用在制备例3中得到的2-氯-6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪(0.070g,0.214mmol)和制备例10中得到的3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.056g,0.194mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:74.4%)。
1H-NMR(500MHz,甲醇-D4):δ9.32(s,1H),8.75(s,1H),8.05(d,J=7.6Hz,1H),7.99-7.85(1H),7.30(d,J=8.2Hz,2H),7.28-7.23(m,1H),7.23-7.16(3H),7.13(d,J=6.7Hz,1H),7.10-6.96(m,2H),3.99(q,J=6.9Hz,2H),3.79(s,2H),2.87(s,2H),1.17(s,7H),1.09(t,J=6.9Hz,4H)
实施例24:(R)-1-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸的合成
使用在制备例3中得到的2-氯-6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪(0.070g,0.214mmol)和(R)-1-(2-氨基嘧啶-4-基)哌啶-3-甲酸乙酯(0.048g,0.194mmol),以与实施例1和实施例3相似的方式得到所需产物(得率:20%)。
1H-NMR(400MHz,甲醇-D4):δ9.40(s,1H),8.54(s,1H),8.00(d,J=7.8Hz,1H),7.93(d,J=6.4Hz,1H),7.85(t,J=7.8Hz,1H),7.19(t,J=8.0Hz,1H),7.15(dd,J=7.8,1.4Hz,1H),7.07(d,J=6.9Hz,1H),6.98(t,J=7.1Hz,1H),6.93(d,J=8.2Hz,1H),6.36(d,J=6.4Hz,1H),4.61-4.32(1H),4.29-4.04(1H),3.94(q,J=7.0Hz,2H),3.26-3.01(m,2H),2.41(t,J=3.9Hz,1H),2.08(t,J=4.8Hz,1H),1.87-1.68(m,2H),1.52(d,J=12.8Hz,1H),1.04(t,J=6.9Hz,3H)
实施例25:3-(3-(6-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸的合成
使用在制备例3中得到的2-氯-6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪(0.140g,0.427mmol)和制备例12中得到的3-(3-(6-氨基吡啶-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.127g,0.388mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:16%)。
1H-NMR(400MHz,甲醇-D4)δ9.40(s,1H),8.57-8.44(1H),8.06(d,J=6.9Hz,1H),7.98-7.89(m,2H),7.89-7.82(m,1H),7.76(t,J=8.0Hz,1H),7.43(dd,J=10.5,7.8Hz,2H),7.35(t,J=7.5Hz,1H),7.30-7.20(m,2H),7.20-7.14(m,1H),7.11(d,J=8.2Hz,1H),7.01(t,J=7.5Hz,1H),6.96(d,J=8.2Hz,1H),4.54(s,1H),3.97(q,J=7.0Hz,2H),3.46(s,0H),2.95(s,2H),1.19(s,7H),1.06(t,J=6.9Hz,3H)
实施例26:2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例14中得到的2-(4-(3-氨基-3-酮基丙基)苯基)-2-甲基丙酸苯甲酯(0.079g,0.244mmol),以与实施例1和制备例7的步骤2相似的方式得到所需产物(得率:16%)。
1H-NMR(400MHz,氯仿-D):δ9.41(s,1H),8.68(s,1H),8.25(d,J=8.2Hz,1H),7.73(d,J=5.0Hz,1H),7.64(q,J=2.1Hz,2H),7.48-7.38(m,1H),7.30-7.09(m,6H),6.97(dd,J=7.8,5.0Hz,1H),4.19-4.11(m,2H),3.01(t,J=7.5Hz,2H),2.71(t,J=7.5Hz,2H),1.52(s,6H),1.46(t,J=7.1Hz,3H)
实施例27:3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例10中得到的3-(4-(2-氨基-2-酮基乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.071g,0.244mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:62%)。
1H-NMR(400MHz,氯仿-D):δ9.42(s,1H),8.70(s,1H),8.37(s,1H),7.76-7.69(m,1H),7.68-7.61(m,2H),7.43(t,J=8.2Hz,1H),7.23-7.10(m,6H),6.97(dd,J=7.8,5.0Hz,1H),4.18-4.07(m,2H),3.72(s,2H),2.85(s,2H),1.49-1.41(m,3H),1.19(s,6H)
实施例28:2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例13中得到的2-(4-(3-氨基-3-酮基丙基)苯氧基)-2-甲基丙酸叔丁酯(0.075g,0.244mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:56%)。
1H-NMR(400MHz,DMSO-D6):δ10.74(s,1H),9.26(s,1H),8.93(s,1H),7.92(d,J=7.8Hz,1H),7.81(t,J=1.8Hz,1H),7.60(dd,J=5.0,1.4Hz,1H),7.56-7.41(m,2H),7.18(dd,J=7.5,2.1Hz,1H),7.13-7.00(m,3H),6.78-6.65(m,2H),4.11(q,J=7.0Hz,2H),2.87-2.76(m,2H),2.69(t,J=7.5Hz,2H),1.42(s,6H),1.33(t,J=7.1Hz,3H)
实施例29:3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例15中得到的3-(4-(1-氨基-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.078g,0.244mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:59%)。
1H NMR(400MHz,氯仿-D):δ9.43(s,1H),8.68(s,1H),7.72-7.59(m,3H),7.56(s,1H),7.41(t,J=8.2Hz,1H),7.29(d,J=8.2Hz,2H),7.23-7.07(m,4H),7.00-6.88(m,1H),4.18-4.05(m,2H),2.84(s,2H),1.65(s,6H),1.44(t,J=6.9Hz,3H),1.16(s,6H)
实施例30:2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基)-2-甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例16中得到的2-(4-(2-氨基-2-酮基乙基)苯氧基)-2-甲基丙酸叔丁酯(0.072g,0.244mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:35%)。
1H-NMR(400MHz,DMSO-D6):δ10.94(s,1H),9.23(s,1H),8.94(s,1H),7.93(d,J=8.2Hz,1H),7.83(t,J=1.8Hz,1H),7.61(dd,J=5.0,1.4Hz,1H),7.58-7.43(m,2H),7.19(d,J=8.7Hz,3H),7.07(dd,J=8.0,4.8Hz,1H),6.74(d,J=8.7Hz,2H),4.20-4.07(m,2H),3.66(s,2H),1.45(s,6H),1.33(t,J=7.1Hz,3H)
实施例31:(R)-1-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例11中得到的(R)-1-(2-氨基嘧啶-4-基)哌啶-3-甲酸乙酯(0.055g,0.222mmol),以与实施例1和实施例3相似的方式得到所需产物(得率:20%)。
1H-NMR(400MHz,甲醇-D4):δ9.36(s,1H),8.61(s,1H),7.96(d,J=6.4Hz,1H),7.86(d,J=7.8Hz,1H),7.77(t,J=2.1Hz,1H),7.66(dd,J=4.8,1.6Hz,1H),7.51(d,J=7.8Hz,1H),7.46(dd,J=8.5,2.1Hz,1H),7.11(dd,J=8.0,4.8Hz,2H),6.41(d,J=6.4Hz,1H),4.48-4.29(1H),4.29-4.17(1H),4.13(q,J=7.0Hz,2H),3.35(d,J=9.1Hz,1H),3.23-2.96(1H),2.52-2.39(1H),2.07(s,1H),1.80(d,J=10.5Hz,2H),1.57(d,J=3.7Hz,1H),1.37(t,J=7.1Hz,3H)
实施例32:3-(3-(6-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.08g,0.244mmol)和制备例12中得到的3-(3-(6-氨基吡啶-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.072g,0.222mmol),以与实施例1和制备例11的步骤3相似的方式得到所需产物(得率:26%)。
1H-NMR(400MHz,甲醇-D4):δ9.40(s,1H),8.62-8.47(1H),7.91(s,1H),7.86(t,J=8.5Hz,2H),7.80(d,J=2.3Hz,1H),7.76-7.59(m,2H),7.58-7.43(m,2H),7.43-7.27(m,3H),7.21(d,J=8.2Hz,1H),7.13(td,J=5.1,2.7Hz,2H),4.22-4.10(m,2H),2.96(s,2H),1.36(t,J=6.9Hz,3H),1.20(s,7H)
实施例33:(1r,4r)-4-((2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸的合成
使用在制备例4中得到的2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪(0.10g,0.305mmol)和制备例18中得到的(1r,4r)-4-((2-氨基嘧啶-4-基)氧基)环己烷-1-甲酸甲酯(0.084g,0.336mmol),顺序地以与实施例1和实施例3相似的方式得到所需产物(得率:42.2%)。
1H-NMR(400MHz,DMSO-D6):δ10.09(s,1H),9.40(s,1H),8.82(s,1H),8.26(d,J=5.5Hz,1H),7.94(d,J=7.8Hz,1H),7.86(t,J=2.1Hz,1H),7.61(dd,J=5.0,1.4Hz,1H),7.55-7.43(m,2H),7.16(dd,J=7.5,2.1Hz,1H),7.07(dd,J=8.0,4.8Hz,1H),6.36(d,J=5.9Hz,1H),4.96(t,J=4.8Hz,1H),4.12(q,J=7.0Hz,2H),2.24-2.05(m,3H),1.93(d,J=9.6Hz,2H),1.56-1.37(4H),1.33(t,J=7.1Hz,3H)
实验例:对DGAT2酶活性的抑制作用的测量
通过对根据本发明的式(1)的化合物进行下述实验,研究了对DGAT2酶活性的抑制作用。
1.DGAT2表达载体的制备
为了制备作为DGAT2表达载体的pBacPAK9-DGAT2,将通过聚合酶链反应(PCR)扩增的人类DGAT2基因克隆到pBacPAK9(clonctech)载体的EcoR1和Xho1位点中。在PCR中使用的引物的核苷酸序列是正向引物5'CTATAAATACGGATCCCGGGAATTCATGGACTACAAGGACGACGATGACAAGCTTAAGACCCTCATAGCCGCC和反向引物5'TAAGCGGCCGCCCTGCAGGCCTCGAGTCAGTTCACCTCCAGGAC。反应溶液的组成是含有50ng cDNA克隆(OriGene),200μM dATP、dCTP、dTTP、dGTP,200nM每种引物,1单位的Tag DNA聚合酶(Toyobo),1 x PCR缓冲液,并将终体积调整到20μl。反应条件是在95℃变性5分钟,然后是30次的94℃20秒、60℃20秒和72℃90秒,然后在72℃继续反应7分钟。
2.DGAT2表达和膜蛋白的制备
使用BacPack杆状病毒表达系统(Clontech),在作为昆虫细胞的Sf-21细胞中表达重组人类DGAT2蛋白。简要的制造过程如下。首先,使用Bacfectin将pBacPAK9-DGAT2表达载体与BacPAK6病毒DNA(Bsu36I消化物)转染到sf21细胞中,以制备表达重组DGAT2的杆状病毒。将由此制备的杆状病毒以10MOI(感染复数)感染Sf-21细胞,并在72小时后收集感染的昆虫细胞并分离膜蛋白。为了分离膜蛋白,将细胞沉积物溶解在含有250mM蔗糖、10mM Tris(pH 7.4)和1mM乙二胺四乙酸(EDTA)的蔗糖溶液中,然后使用杜恩斯匀浆器匀浆,通过以600×g离心15分钟获取上清液,将其以100,000×g离心1小时以舍弃上清液,并将剩余的沉积物重悬浮在20mM HEPES缓冲液(pH7.4)中。将所制备的过表达DGAT2的膜蛋白分成100μl并储存在-80℃下直至使用。使用BCA蛋白质测定试剂盒(Thermo Scientific)对蛋白质浓度定量。
3.对DGAT2酶活性的抑制作用的测量
体外DGAT2分析使用基于SPA(闪烁接近测定法)原理的磷脂快闪板(PerkinElmer)进行。首先,将从3nM至10μM(终浓度,1%DMSO)的连续5倍稀释的DGAT2抑制化合物混合在含有2μg DGAT2膜蛋白和20mM HEPES、20mM MgCl2、1mg/mL BSA、50μM 1,2sn-油酰基甘油(Sigma)的缓冲溶液中,置于96孔快闪板(FlashPlate)中并在37℃反应20分钟,然后添加1μM[14C]油酰基辅酶A(PerkinElmer,NEC651050UC)以使终体积为100μL,然后在37℃反应15分钟。在酶反应完成后,添加100μL异丙醇,将板用薄膜密封,并将板在摇板器中缓慢摇动。第二天,在Topcounter(Packard)中测量放大的闪烁信号(cpm),以测量作为反应产物的[14C]标记的三酰基甘油(TG)的产生程度。将未用化合物处理时的测量值用作阳性对照,并将化合物处理组的测量值计算为相对%,以度量化合物对TG产生的抑制作用。IC50值是将TG产生抑制50%的化合物浓度,通过使用PRISM(Graphpad Inc.)用非线性回归曲线处理根据化合物浓度的响应值来确定。
作为测量式(1)的化合物对DGAT2酶作用的抑制作用的结果,各个实施例化合物的具体IC50值如下面的表1中所示。
[表1]
实施例 | <![CDATA[IC<sub>50</sub>(μM)]]> | 实施例 | <![CDATA[IC<sub>50</sub>(μM)]]> | 实施例 | <![CDATA[IC<sub>50</sub>(μM)]]> |
1 | 0.035 | 12 | 0.17 | 23 | 0.061 |
2 | 0.027 | 13 | 0.33 | 24 | 7.4 |
3 | 3.4 | 14 | 3.1 | 25 | 0.45 |
4 | 0.29 | 15 | 0.013 | 26 | 0.021 |
5 | 0.011 | 16 | 0.021 | 27 | 0.0074 |
6 | 0.12 | 17 | 0.24 | 28 | 0.21 |
7 | 0.036 | 18 | 0.022 | 29 | 0.0067 |
8 | 1.8 | 19 | 0.43 | 30 | 0.25 |
9 | 0.16 | 20 | 3.9 | 31 | 9.2 |
10 | 0.019 | 21 | 1.2 | 32 | 0.07 |
11 | 0.37 | 22 | 2.1 | 33 | 3.4 |
Claims (5)
1.一种下式(1)的化合物或其可药用盐或异构体:
[式(1)]
其中
A、D和E各自独立地是CH或N;
R1是烷基、环烷基或卤代烷基;
R2是-G-J-L;
其中G是-C(=O)-或直接连键;
J是亚烷基、亚烯基、亚烷基-亚芳基、亚烯基-亚芳基、亚烷氧基-亚芳基、亚芳基、亚杂芳基-亚杂环烷基、亚杂芳基-亚芳基或亚杂芳基-氧基-亚环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、羧基烷基、羧基烷氧基、环烷基或芳基;
其中所述烷基、亚烷基、羧基烷基、羧基烷氧基或芳基任选地被选自羟基、卤素、烷基和烷氧基的一个或多个取代基取代;并且
所述亚杂环烷基或亚杂芳基包括一个或多个选自N、O和S的杂原子。
2.根据权利要求1所述的化合物或其可药用盐或异构体,其中
A、D和E各自独立地是CH或N;
R1是C1-C7烷基、C3-C10环烷基或卤代-C1-C7烷基;
R2是-G-J-L;
其中G是-C(=O)-或直接连键;
J是C1-C7亚烷基、C2-C7亚烯基、C1-C7亚烷基-C6-C10亚芳基、C2-C7亚烯基-C6-C10亚芳基、C1-C7亚烷氧基-C6-C10亚芳基、C6-C10亚芳基、5至12元亚杂芳基-5至12元亚杂环烷基、5至12元亚杂芳基-C6-C10亚芳基或5至12元亚杂芳基-氧基-C3-C10亚环烷基;
L是氢、卤素、氨基、硝基、羧基、羧基-C1-C7烷基、羧基-C1-C7烷氧基、C3-C10环烷基或C6-C10芳基;
其中所述烷基、亚烷基、羧基烷基、羧基烷氧基或芳基任选地被选自羟基、卤素、C1-C7烷基和C1-C7烷氧基的1至4个取代基取代;并且
所述亚杂环烷基或亚杂芳基包括选自N、O和S的1至4个杂原子。
3.根据权利要求1所述的化合物或其可药用盐或异构体,其中所述化合物选自:
N-(6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)-3-苯基丙酰胺;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸甲酯;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸;
2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸;
2-(4-(3-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸甲酯;
2-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二氟乙酸乙酯;
3-(4-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
(R)-1-(2-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(5-(2-乙氧基苯氧基)吡啶-3-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;
N-(6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)-3-苯基丙酰胺;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)乙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)乙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基-2,2-二氟乙酸;
3-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸;
(E)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙-1-苯-1-基)苯基)-2-甲基丙酸;
3-(4-(1-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基-2-甲基丙酸;
2-(4-(2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)苯基)乙酸;
(1r,4r)-4-((2-((6-(3-(2-乙氧基苯氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸;
N-(6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)-3-苯基丙酰胺;
3-(4-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
(R)-1-(2-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(6-(2-乙氧基苯氧基)吡啶-2-基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯基)-2-甲基丙酸;
3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯基)-2,2-二甲基丙酸;
2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-3-酮基丙基)苯氧基)-2-甲基丙酸;
3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-甲基-1-酮基丙-2-基)苯基)-2,2-二甲基丙酸;
2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)-2-酮基乙基)苯氧基)-2-甲基丙酸;
(R)-1-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)哌啶-3-甲酸;
3-(3-(6-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)吡啶-2-基)苯基)-2,2-二甲基丙酸;和
(1r,4r)-4-((2-((6-(3-((3-乙氧基吡啶-2-基)氧基)苯基)吡嗪-2-基)氨基)嘧啶-4-基)氧基)环己烷-1-甲酸。
4.一种用于治疗与二酰基甘油酰基转移酶2(DGAT2)相关的疾病的药物组合物,其包含权利要求1至3中的任一项中所定义的式(1)的化合物或其可药用盐或异构体作为活性成分,以及可药用载体。
5.根据权利要求4所述的药物组合物,其中所述与DGAT2相关的疾病选自脂肪肝、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、糖尿病、肥胖症、高脂血症、动脉粥样硬化和高胆固醇血症。
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TWI817191B (zh) | 2023-10-01 |
MX2023002429A (es) | 2023-03-22 |
US20230322706A1 (en) | 2023-10-12 |
AU2021337476A1 (en) | 2023-05-18 |
EP4206193A1 (en) | 2023-07-05 |
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