CN116693536A - 吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 - Google Patents
吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 Download PDFInfo
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- CN116693536A CN116693536A CN202310020896.9A CN202310020896A CN116693536A CN 116693536 A CN116693536 A CN 116693536A CN 202310020896 A CN202310020896 A CN 202310020896A CN 116693536 A CN116693536 A CN 116693536A
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- alkyl
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- compound
- pyrrolotriazinone
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- -1 Pyrrolotriazinone compound Chemical class 0.000 title claims abstract description 51
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- 125000000217 alkyl group Chemical group 0.000 claims description 131
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 30
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
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Abstract
本发明公开了一种吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用。本发明提供了一种如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐;本发明的吡咯并三嗪酮类化合物结构新颖,对GPR139受体有较强的激动活性。
Description
技术领域
本发明涉及一种吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用。
背景技术
精神***症在全世界影响着超过2000万人。其症状根据其临床特征可大致划分为三类:阳性症状、阴性症状和认知功能障碍。阳性症状是指正常功能行为的夸大或歪曲,包括幻觉、妄想、思维混乱等。阴性症状是指正常情绪反应或其他思维过程中所存有的一些缺陷,包括情感淡然、贫语症、动机与快感丧失、消极厌世等抑郁样特征。认知功能障碍主要表现为注意力、记忆力、学习能力等下降。
以药物研发的历史脉络和药理学特性划分,当前的抗精神***症药物可以分为三代。第一代抗精神病药物也被称为典型抗精神病药物,是多巴胺D2受体的强效拮抗剂。目前常用的包括氟哌啶醇、氯丙嗪、奋乃静等,可以有效抑制精神***症阳性症状,但长期服用这类药物会诱发类似帕金森病的锥体外系反应。第二代抗精神病药物包括氯氮平、利培酮、帕利哌酮等,通过双重阻断多巴胺D2受体和血清素2A(5-HT2A)受体而产生作用。由于抑制5-HT2A受体可以间接促进多巴胺神经元释放多巴胺,因此第二代药物诱发的锥体外系副作用明显降低。但是,二代药物的代谢综合征(过度肥胖、胰岛素抵抗、血脂异常和高血压)的风险高于传统抗精神病药物。第三代抗精神***症药物包括阿立哌唑(aripiprazole)、依匹哌唑(brexpiprazole)和卡利拉嗪(cariprazine)三种,是多巴胺D2受体的部分激动剂。作为多巴胺的“稳定剂”,第三代药物稳定大脑多巴胺环路活性在适中范围,大大降低了锥体外系副作用,安全性也得到明显提升。第二代与第三代也合称为非典型抗精神***症药物。目前,所有针对精神***症治疗的药物都能有效缓解阳性症状,然而绝大部分药物在改善阴性症状和认知功能方面药效有限或无效。因此,亟需研发针对精神***症阴性症状和认知障碍的全新作用机制药物。
孤儿受体GPR139是从人类基因组的生物信息学分析中鉴定到的,属于A类G蛋白偶联受体(GPCR)。在哺乳动物中,GPR139主要在中枢神经***中表达,最高表达部位为纹状体、垂体、缰核、丘脑和下丘脑(Matsuo等,Biochem Biophys Res Commun 2005,331:363-369),在啮齿动物和人类缰核的内侧GPR139高度表达。多项研究表明缰核与精神***症具有一定联系。啮齿类动物缰核的整体结构损伤会导致其社交活动减少、认知功能损伤、对压力刺激的过度反应等精神***症相关的症状(Wang等,Neuroreport 2013,24:276-280)。慢性精神***症患者与正常人对比其缰核发生钙化的频率更高,而且缰核的体积也发生改变(Sandyk等,Int J Neurosci 1992,67:19-30)。功能核磁共振(fMRI)研究显示,正常人在做匹配任务时,当发生错误时其缰核会被激活,而在慢性精神***症患者中,发生匹配错误后,其缰核并没有明显激活(Shepard等,Schizophr Bull 2006,32:417-421)。在GPR139敲除的小鼠模型上表现出自发运动下降、感觉运动门控缺陷、认知障碍等与精神***症相关的行为特征,通过给予多巴胺D2受体拮抗剂氟哌啶醇可以改善其症状(Dao等,Neuropsychopharmacology 2021)。基于这些结果,靶向GPR139有潜力能够开发新型抗精神***症药物,尤其是针对阴性症状的药物。
2018年被报道的选择性GPR139激动剂JNJ-63533054(EC50=16 nM)可以减少酒精依赖性大鼠的自我饮酒和痛觉过敏(Kononoff等,eNeuro 2018,5),但在体内研究中并没有表现出明显的行为调节。2021年日本Takeda公司公布了一种具有苯并三嗪酮结构的选择性GPR139激动剂TAK-041(EC50=22nM),已被证实在小鼠模型上可用于治疗与精神***症相关的阴性症状(Reichard等,J Med Chem 2021,64:11527-11542),目前已成功进入临床Ⅱ期试验。
发明内容
本发明要解决的技术问题是现有的GPR139受体激动剂的结构单一的缺陷,本发明提供了一种吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用。本发明的吡咯并三嗪酮类化合物结构新颖,对GPR139受体有较强的激动活性。
本发明通过下述技术方案解决上述技术问题。
本发明提供了一种如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐;
其中,
R1、R2、R3和R4独立地为H、卤素、C1-6烷基、C3-6环烷基、-O-C1-6烷基、被1个、2个或3个R1-1取代的C1-6烷基、被1个、2个或3个R1-2取代的C3-6环烷基或被1个、2个或3个R1-3取代的-O-C1-6烷基;
R1-1、R1-2和R1-3独立地为卤素;
R5为H或C1-6烷基;
R6和R7独立地为H、C1-6烷基、C3-6环烷基、被1个、2个或3个R6-1取代的C1-6烷基或被1个、2个或3个R6-2取代的C3-6环烷基;
R6-1独立地为卤素、-O-C1-6烷基或-NRaRb;
R6-2独立地为卤素、-O-C1-6烷基或-NRaRb;
Ra和Rb独立地为C1-6烷基;
或,Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基;所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-6元杂环烷基;
Ra-1独立地为C1-6烷基;
Q为C6-10芳环、5-10元杂芳环、C3-6环烷基或5-6元杂环烷基;所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-10元杂芳环;
n为0、1、2、3、4或5;
R8独立地为卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-1和R8-2独立地为卤素;
或,R8与R7一起形成-(CH2)m-,m为2或3;
带“*”、“#”的碳原子为非手性碳原子或手性碳原子,当为手性碳原子时,独立地为S构型和/或R构型。
在某一方案中,如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐中,某些基团的定义可如下所述,其他基团的定义可如本发明任一方案所述(以下简称“在某一方案中”):
其中,
R1、R2、R3和R4独立地为H、卤素、C1-6烷基、C3-6环烷基、-O-C1-6烷基、被1个、2个或3个R1-1取代的C1-6烷基、被1个、2个或3个R1-2取代的C3-6环烷基或被1个、2个或3个R1-3取代的-O-C1-6烷基;
R1-1、R1-2和R1-3独立地为卤素;
R5为H或C1-6烷基;
R6和R7独立地为H、C1-6烷基、C3-6环烷基、被1个、2个或3个R6-1取代的C1-6烷基或被1个、2个或3个R6-2取代的C3-6环烷基;
R6-1独立地为卤素、-O-C1-6烷基或-NRaRb;
R6-2独立地为卤素、-O-C1-6烷基或-NRaRb;
Ra和Rb独立地为C1-6烷基;
或,Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基;所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-6元杂环烷基;
Ra-1独立地为C1-6烷基;
Q为C6-10芳环或5-10元杂芳环;所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-10元杂芳环;
n为0、1、2、3、4或5;
R8独立地为卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-1和R8-2独立地为卤素;
或,R8与R7一起形成-(CH2)m-,m为2或3;
带“*”、“#”的碳原子为非手性碳原子或手性碳原子,当为手性碳原子时,独立地为S构型和/或R构型。
在某一方案中,
为/> 例如/>为
其中,*、#、R1、R2、R3、R4、R5、R6、R7、R8、Q和n的定义如前所述。
在某一方案中,R1、R2和R3独立地为H或C1-6烷基。
在某一方案中,R4独立地为H。
在某一方案中,R5为H。
在某一方案中,R6为H。
在某一方案中,R7为C1-6烷基或被1个、2个或3个R6-1取代的C1-6烷基。
在某一方案中,R6-1独立地为-NRaRb。
在某一方案中,Ra和Rb独立地为C1-6烷基。在某一方案中,n为0或1。
在某一方案中,R8为卤素、-OH、-CN、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
或,R8与R7一起形成-(CH2)m-,m为2或3;例如,R8为卤素、-OH、C1-6烷基、-O-C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;或,R8与R7一起形成-(CH2)m-,m为2或3。
在某一方案中,R1、R2、R3和R4中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,例如为甲基。
在某一方案中,R1-1、R1-2和R1-3中,所述卤素为F、Cl、Br或I。
在某一方案中,R6和R7中,所述C1-6烷基和被1个、2个或3个R6-1取代的C1-6烷基中的C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,例如为甲基或乙基。
在某一方案中,Ra和Rb中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,例如为甲基。
在某一方案中,当Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基,所述的5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基中的5-6元杂环烷基独立地为杂原子独立地选自N和O,杂原子的个数为1个或2个的5-6元杂环烷基;例如为
在某一方案中,Ra-1中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,例如为甲基。
在某一方案中,Q中,所述C6-10芳环为苯环或萘环,例如为苯环。
在某一方案中,Q中,所述5-10元杂芳环为5-6元杂芳环,例如为吡啶环,再例如为
在某一方案中,Q中,所述C3-6环烷基为环丙基、环丁基、环戊基或环已基,例如为环己基。
在某一方案中,R8中,所述卤素独立地为F、Cl、Br或I,例如为F、Cl或Br。
在某一方案中,R8中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,例如为甲基。
在某一方案中,R8中,所述-O-C1-6烷基和被1个、2个或3个R8-2取代的-O-C1-6烷基中的-O-C1-6烷基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基,例如为甲氧基。
在某一方案中,R8-1和R8-2中,所述卤素独立地为F、Cl、Br或I,例如为F。
在某一方案中,当R8与R7一起形成-(CH2)m-,m为3。
在某一方案中,当Q为苯环时,为/>R8-a、R8-b、R8-c和R8-d独立地为H、卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-e为H、卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
或者,R8-e与R7一起形成-(CH2)m-,m为2或3。
在某一方案中,为/>
在某一方案中,R6为H。
在某一方案中,R7为-CH3、-CH2CH3、例如为-CH3、-CH2CH3或/>
在某一方案中,R8独立地为F、Cl、Br、-OH、-CH3、-OCH3、-OCF3、-CF3或CN,例如为F、Cl、Br、-OH、-CH3、-OCH3或-OCF3。
在某一方案中,为/>
例如为/>
在某一方案中,为/>
例如为/>
在某一方案中,所述如式I所示的吡咯并三嗪酮类化合物选自以下任一化合物:
本发明还提供了一种药物组合物,所述药物组合物包含如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,以及药用辅料。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐的制备方法:其包括以下步骤:化合物II和化合物III发生缩合反应;
其中,*、#、R1、R2、R3、R4、R5、R6、R7、R8、Q和n的定义如前任一方案所述。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或所述药物组合物在制备药物中的应用,所述药物用于治疗和/或预防GPR139受体相关的疾病;所述GPR139受体相关的疾病可为精神***症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或所述药物组合物在制备药物中的应用,所述药物用于治疗和/或预防精神***症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
如无特别说明,本发明所用术语具有如下含义:
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数(例如C1~6)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基和正己基等。
术语“环烷基”是指具有指定的碳原子数(例如C3~6)的、仅由碳原子组成的环状基团。环烷基包括但不限于环丙基、环丁基、环戊基和环己基等。
术语“杂环烷基”是指具有指定环原子数(例如5-6元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基和哌啶基等。
术语“芳环”是指具有指定的碳原子数(例如C6-10)的、仅由碳原子组成的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。芳环包括但不限于苯环和萘环等。
术语“杂芳环”是指具有指定环原子数(例如5-10元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。杂芳环通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳环包括但不限于呋喃环、吡咯环、噻吩环、吡唑环、咪唑环、噁唑环、噻唑环、吡啶环、嘧啶环、吲哚环等。
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。例如,-OCH3是指甲氧基。
当任意变量(例如基团Ra-1)在化合物的定义中多次出现时,它们的定义互相独立、互不影响。例如,被3个Ra-1取代的5-6元杂环烷基是指5-6元杂环烷基会被3个Ra-1取代,3个Ra-1的定义互相独立的、互不影响。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化,但可由本领域技术人员视情况调整。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“治疗”是指下述任一情形:(1)缓解疾病的一种或多种生物学表现;(2)干扰引发疾病的生物级联中的一个或多个点;(3)减缓疾病的一种或多种生物学表现发展。
术语“预防”是指降低发生疾病的风险。
术语“患者”是指已经或即将接受治疗的任何动物,优选哺乳动物,最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的吡咯并三嗪酮类化合物结构新颖,对GPR139受体有较强的激动活性。
附图说明
图1为生物测试实施例3中的结果图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1:(S)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-1)的制备
步骤1:吡咯并[1,2-d][1,2,4]三嗪-4(3H)-酮的制备
将2-吡咯甲醛(1.00g,10.52mmol)和肼基甲酸乙酯(1.20g,11.57mmol)溶于DMF(10mL)中,90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60%在矿物油中,0.235g,5.26mmol),90℃搅拌12小时。反应液加水稀释,乙酸乙酯萃取三次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至20% EA/PE),得黄色固状的标题化合物(0.90g,收率63%)。1H NMR(800MHz,DMSO-d6)δ12.24(s,1H),8.24(s,1H),7.77–7.75(m,1H),6.84–6.82(m,2H).13C NMR(201MHz,DMSO-d6)δ144.72,132.44,125.60,116.23,115.43,109.10.HRMS(ESI)C6H6N3O3 +[M+H]+计算值:136.0505;实测值:136.0508。
步骤2:2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(1.17g,8.44mmol)溶解在丙酮(8mL)溶液中,然后将吡咯并[1,2-d][1,2,4]三嗪-4(3H)-酮(0.38g,2.81mmol)加入其中。在搅拌状态下加入溴乙酸乙酯(0.939g,5.62mmol),55℃搅拌3小时。反应液加水稀释,乙酸乙酯萃取,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5% EA/PE),得淡黄色油状的标题化合物(0.49g,收率78%)。1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.81(d,J=2.5Hz,1H),6.90(dd,J=3.7,1.4Hz,1H),6.88–6.85(m,1H),4.85(s,2H),4.17(q,J=7.0Hz,2H),1.21(t,J=7.2Hz,3H).HRMS(ESI)C10H12N3O3 +[M+H]+计算值:222.0873;实测值:222.0875。
步骤3:2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(0.40g,1.81mmol)溶解在THF:H2O(1:1,8mL)溶液中,在0℃条件下加入氢氧化锂(0.227g,5.42mmol),室温搅拌2小时。然后使用1M盐酸调节PH至2左右,减压蒸干溶剂,得相应固体标题化合物(0.35g,粗品),其不经进一步纯化使用。HRMS(ESI)C8H8N3O3 +[M+H]+计算值:194.0560;实测值:194.0561。
步骤4:(S)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-1)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.100g,0.51mmol)溶解于DMF(6mL)溶液中,然后加入HATU(0.393g,1.03mmol)室温搅拌30分钟。依次加入DIPEA(0.201g,1.55mmol)和(S)-1-(4-氟苯基)乙胺(0.108g,0.77mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取两次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50%EA/PE),得白色固体化合物(I-1)(0.100g,收率61%)。1H NMR(800MHz,DMSO-d6)δ8.62(d,J=7.9Hz,1H),8.27(s,1H),7.78(d,J=2.2Hz,1H),7.37–7.34(m,2H),7.17–7.13(m,2H),6.86(dd,J=3.6,1.4Hz,1H),6.85–6.83(m,1H),4.96-4.92(m,1H),4.68and 4.66(ABq,J=16.7Hz,2H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.81,161.02(d,J=242.5Hz),144.59,140.46(d,J=3.3Hz),132.32,127.88(2C,d,J=8.1Hz),125.61,117.02,115.88,114.91(2C,d,J=20.9Hz),109.60,52.91,47.49,22.36.HRMS(ESI)C16H16FN4O2 +[M+H]+计算值:315.1252;实测值:315.1251。
实施例2:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-2)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.15g,0.77mmol)溶解于DMF(6mL)溶液中,然后加入HATU(0.59g,1.55mmol)室温搅拌30分钟。依次加入DIPEA(0.301g,2.33mmol)和(S)-1-(4-甲基苯基)乙胺(0.126g,0.93mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取两次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50%EA/PE),得白色固体化合物(I-2)(0.092g,收率38%)。1H NMR(800MHz,DMSO-d6)δ8.56(d,J=8.0Hz,1H),8.27(s,1H),7.78(d,J=2.9Hz,1H),7.20(d,J=8.0Hz,2H),7.13(d,J=7.9Hz,2H),6.86(dd,J=3.7,1.4Hz,1H),6.84(dd,J=3.7,2.8Hz,1H),4.91-4.88(m,1H),4.67and 4.65(ABq,J=16.4Hz,2H),2.27(s,3H),1.35(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.66,144.59,141.23,135.70,132.28,128.76(2C),125.88(2C),125.61,117.00,115.86,109.56,52.88,47.78,22.36,20.60.HRMS(ESI)C17H19N4O2 +[M+H]+计算值:311.1503;实测值:311.1504。
实施例3:(S)-N-(1-(4-甲氧基苯基)乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-3)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-3)(0.060g,收率23%)。1HNMR(800MHz,DMSO-d6)δ8.53(d,J=8.0Hz,1H),8.27(s,1H),7.78(d,J=2.2Hz,1H),7.26–7.21(m,2H),6.91–6.87(m,2H),6.86(dd,J=3.7,1.4Hz,1H),6.85–6.83(m,1H),4.91-4.87(m,1H),4.67and 4.64(ABq,J=16.3Hz,2H),3.73(s,3H),1.35(d,J=6.9Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.61,158.07,144.59,136.17,132.28,127.12(2C),125.61,117.01(2C),115.87,113.61,109.57,55.05,52.88,47.44,22.35.HRMS(ESI)C17H19N4O3 +[M+H]+计算值:327.1452;实测值:327.1452。
实施例4:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-4)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-苯乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-4)(0.070g,收率30%)。1H NMR(800MHz,DMSO-d6)δ8.62(d,J=8.0Hz,1H),8.27(s,1H),7.78(d,J=3.5Hz,1H),7.34–7.30(m,4H),7.25–7.21(m,1H),6.86(dd,J=3.6,1.4Hz,1H),6.84(dd,J=3.7,2.8Hz,1H),4.96-4.92(m,1H),4.69and 4.67(ABq,J=16.3Hz,2H),1.37(d,J=6.9Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.76,144.59,144.25,132.30,128.24(2C),126.67,125.94(2C),125.61,117.02,115.87,109.58,52.90,48.06,22.38.HRMS(ESI)C16H17N4O2 +[M+H]+计算值:297.1346;实测值:297.1347。
实施例5:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-5)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-5)(0.120g,收率40%)。1H NMR(800MHz,DMSO-d6)δ8.67(d,J=7.8Hz,1H),8.28(s,1H),7.78(d,J=2.3Hz,1H),7.45(d,J=8.7Hz,2H),7.32(d,J=8.3Hz,2H),6.86(dd,J=3.7,1.4Hz,1H),6.84(t,J=3.3Hz,1H),5.00–4.94(m,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.96,147.04,144.60,143.81,132.34,127.82(2C),125.61,120.89(2C),120.09(q,J=256.3Hz),117.03,115.88,109.62,52.92,47.60,22.23.HRMS(ESI)C17H16F3N4O3 +[M+H]+计算值:381.1169;实测值:381.1170。
实施例6:(S)-N-1-(4-氯苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-6)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-6)(0.112g,收率51%)。1H NMR(800MHz,DMSO-d6)δ8.65(d,J=7.8Hz,1H),8.27(s,1H),7.78(d,J=1.8Hz,1H),7.38(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),6.86(d,J=2.2Hz,1H),6.84(t,J=3.3Hz,1H),4.95–4.90(m,1H),4.69and 4.67(ABq,J=16.6Hz,2H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.90,144.58,143.36,132.32,131.20,128.17(2C),127.86(2C),125.60,117.02,115.88,109.60,52.91,47.60,22.19.HRMS(ESI)C16H16ClN4O2 +[M+H]+计算值:331.0956,实测值:331.0955。
实施例7:(S)-N-(1-(4-羟基苯基)乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-7)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-4-(1-氨基乙基)苯酚,其余所需原料,试剂及制备方法同实施例2。
得白色固体化合物(I-7)(0.074 g,收率45%)。1H NMR(800 MHz,DMSO-d6)δ9.26(s,1H),8.48(d,J=8.0 Hz,1H),8.27(s,1H),7.78(d,J=1.5 Hz,1H),7.13–7.10(m,2H),6.86(dd,J=3.7,1.4 Hz,1H),6.84(dd,J=3.7,2.9 Hz,1H),6.72–6.69(m,2H),4.88–4.83(m,1H),4.65 and 4.63(ABq,J=16.4 Hz,2H),1.33(d,J=7.0 Hz,3H).13C NMR(201 MHz,DMSO-d6)δ165.55,156.14,144.61,134.33,132.29,127.14(2C),125.63,117.03,115.89,114.92(2C),109.58,52.89,47.46,22.33.HRMS(ESI)C16H17N4O3 +[M+H]+计算值:313.1295,实测值:313.1298。
实施例8:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯丙基)乙酰胺(化合物I-8)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-苯基丙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-8)(0.095 g,收率59%)。1H NMR(800MHz,DMSO-d6)δ8.55(d,J=8.5Hz,1H),8.27(s,1H),7.78(d,J=2.2 Hz,1H),7.34–7.29(m,4H),7.25–7.22(m,1H),6.86(dd,J=3.6,1.4Hz,1H),6.84(dd,J=3.7,2.9 Hz,1H),4.74–4.69(m,2H),4.67(d,J=16.3 Hz,1H),1.74–1.66(m,2H),0.86(t,J=7.4 Hz,3H).13C NMR(201 MHz,DMSO-d6)δ166.11,144.59,143.32,132.28,128.21(2C),126.71,126.42(2C),125.62,117.02,115.88,109.58,54.29,52.91,29.22,10.98.HRMS(ESI)C17H19N4O2 +[M+H]+计算值:311.1503,实测值:311.1501。
实施例9:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1,2,3,4-四氢萘-1-基)乙酰胺(化合物I-9)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1,2,3,4-四氢-1-萘胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-9)(0.100 g,收率59%)。1HNMR(800 MHz,DMSO-d6)δ8.55(d,J=8.6 Hz,1H),8.30(s,1H),7.81(d,J=2.9 Hz,1H),7.22–7.18(m,1H),7.20–7.13(m,2H),7.11–7.07(m,1H),6.87(dd,J=3.6,1.4 Hz,1H),6.85(t,J=3.2 Hz,1H),5.02–4.97(m,1H),4.70 and 4.62(ABq,J=16.4 Hz,2H),2.78–2.68(m,2H),1.93–1.84(m,2H),1.77–1.65(m,2H).13C NMR(201 MHz,DMSO-d6)δ166.15,144.63,137.18,137.05,132.37,128.74,128.12,126.79,125.86,125.69,117.04,115.87,109.57,53.12,46.74,29.81,28.73,20.06.HRMS(ESI)C18H19N4O2 +[M+H]+计算值:322.1503,实测值:322.1502。
实施例10:N-(2-(二甲基氨基)-1-苯基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-10)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成N1,N1-二甲基-2-苯基乙烷-1,2-二胺,其余所需原料,试剂及制备方法同实施例7,得棕色泡沫状固体化合物(I-10)(0.050g,收率28%)。1H NMR(800MHz,DMSO-d6)δ8.80(d,J=9.0Hz,1H),8.30(s,1H),7.79(d,J=2.3Hz,1H),7.46–7.39(m,4H),7.34(t,J=6.9Hz,1H),6.88(dd,J=3.7,1.4Hz,1H),6.86(t,J=3.6Hz,1H),5.41–5.27(m,1H),4.82and 4.76(ABq,J=16.6Hz,2H),3.48–3.32(m,2H),2.82(brs,6H).13C NMR(201MHz,DMSO-d6)δ166.03,144.58,142.08,132.28,128.20(2C),126.87,126.66(2C),125.58,117.04,115.91,109.62,64.44,52.84,50.95,45.14(2C).HRMS(ESI)C18H22N5O2 +[M+H]+计算值:340.1768,实测值:340.1767。
实施例11:(S)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-11)的制备
步骤1:5-甲基吡咯-2-甲醛的制备
将二氯甲烷(12mL)加入三颈圆底烧瓶,然后向其中加入DMF(0.854g,11.7mmol),置换氮气。在0℃下向其滴加POCl3(1.79g,11.7mmol),室温搅拌15分钟,然后在0℃条件下加入2-甲基吡咯(1.0g,12.3mmol),室温搅拌30分钟。将无水醋酸钠(4.6g,56.0mmol)溶解于13mL水中,在室温条件下缓慢加入圆底烧瓶中,80℃搅拌20分钟。反应液加水稀释,二氯甲烷萃取两次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至20%EA/PE),得淡黄色固体标题化合物(0.600g,收率44%)。1HNMR(800MHz,DMSO-d6)δ11.86(s,1H),9.30(s,1H),6.89–6.86(m,1H),6.03–5.99(m,1H),2.24(s,3H).HRMS(ESI)C6H8NO+[M+H]+计算值:110.0600,实测值:110.0599。
步骤2:6-甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮的制备
将5-甲基吡咯-2-甲醛(2.00g,18.33mmol)和肼基甲酸乙酯(2.29g,21.99mmol)溶于DMF(20mL)中,90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60%在矿物油中,0.733g,9.16mmol),90℃搅拌12小时。反应液加水稀释,以乙酸乙酯萃取三次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至10%EA/PE),得黄色固体标题化合物(1.70g,收率62%)。1H NMR(800MHz,DMSO-d6)δ11.82(s,1H),8.04(s,1H),6.64(d,J=3.6Hz,1H),6.47(d,J=3.6Hz,1H),2.69(s,3H).HRMS(ESI)C7H8N3O+[M+H]+计算值:150.0662,实测值:150.0662。
步骤3:2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(4.73g,34.19mmol)溶解在丙酮溶液(35mL),然后将6-甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮(1.70g,11.40mmol)加入上述溶液中。在搅拌状态下加入溴乙酸乙酯(3.81g,5.62mmol),55℃搅拌过夜。反应液加水稀释,乙酸乙酯萃取,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5% EA/PE),得淡黄色固体标题化合物(2.25g,收率81%)。1H NMR(800MHz,DMSO-d6)δ8.13(s,1H),6.71(d,J=3.7Hz,1H),6.53(dd,J=3.7,1.0Hz,1H),4.74(s,2H),4.17and 4.15(ABq,J=7.2Hz,2H),2.68(s,3H),1.21(t,J=7.1Hz,3H).HRMS(ESI)C11H14N3O3 +[M+H]+计算值:236.1030,实测值:236.1029。
步骤4:2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(2.25g,9.56mmol)溶解在THF:H2O(1:1,20mL)溶液中,在0℃条件下加入氢氧化锂(1.20g,28.69mmol),室温搅拌2小时。使用1M盐酸调节PH至2左右,减压蒸干溶剂,得相应固体标题化合物(1.7g,粗品),其不经进一步纯化使用。HRMS(ESI)C9H10N3O3 +[M+H]+计算值:208.0717,实测值:208.0717。
步骤5:(S)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-11)的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.120g,0.57mmol)溶解于DMF(7mL)溶液中,然后加入HATU(0.440g,1.14mmol)室温搅拌30分钟。依次加入DIPEA(0.187g,1.71mmol)和(S)-1-(4-氟苯基)乙胺(0.089g,0.62mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取两次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50% EA/PE),得白色固体化合物(I-11)(0.110g,收率57%)。1H NMR(800MHz,DMSO-d6)δ8.58(d,J=7.9Hz,1H),8.08(s,1H),7.38–7.34(m,2H),7.17–7.12(m,2H),6.67(d,J=3.7Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),4.96–4.91(m,1H),4.58and 4.56(ABq,J=16.5Hz,2H),2.69(s,3H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.02,161.03(d,J=242.1Hz),146.22,140.54(d,J=2.9Hz),132.65,130.75,127.90(2C,d,J=8.1Hz),125.73,115.42,114.91(2C,d,J=21.3Hz),108.28,52.70,47.48,22.43,14.67.HRMS(ESI)C17H18FN4O2 +[M+H]+计算值:329.1408,实测值:329.1409。
实施例12:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-12)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲基苯基)乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-12)(0.080g,收率42%)。1H NMR(800MHz,DMSO-d6)δ8.52(d,J=7.9Hz,1H),8.07(s,1H),7.20(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),4.92–4.87(m,1H),4.57and 4.55(ABq,J=16.4Hz,2H),2.69(s,3H),2.27(s,3H),1.35(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.88,146.23,141.32,135.70,132.62,130.74,128.77(2C),125.90(2C),125.74,115.41,108.26,52.67,47.77,22.43,20.61,14.68.HRMS(ESI)C18H21N4O2 +[M+H]+计算值:325.1659,实测值:325.1659。
实施例13:(S)-N-(1-(4-甲氧基苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-13)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-13)(0.118g,收率59%)。1H NMR(800MHz,DMSO-d6)δ8.49(d,J=8.0Hz,1H),8.07(s,1H),7.25–7.22(m,2H),6.90–6.87(m,2H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),4.92–4.87(m,1H),4.57and 4.54(ABq,J=16.3Hz,2H),3.73(s,3H),2.69(s,3H),1.35(d,J=6.9Hz,3H).13CNMR(201MHz,DMSO-d6)δ165.81,158.07,146.23,136.26,132.62,130.74,127.14(2C),125.73,115.41,113.61(2C),108.25,55.06,52.65,47.44,22.43,14.68.HRMS(ESI)C18H20NaN4O3 +[M+Na]+计算值:363.1428,实测值:363.1428。
实施例14:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-14)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-苯乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-14)(0.085g,收率47%)。1H NMR(800MHz,DMSO-d6)δ8.57(d,J=7.9Hz,1H),8.08(s,1H),7.35–7.30(m,4H),7.25–7.21(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.6,1.0Hz,1H),4.97–4.91(m,1H),4.59and 4.57(ABq,J=16.3Hz,2H),2.69(s,3H),1.37(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.97,146.23,144.34,132.63,130.74,128.25(2C),126.67,125.96(2C),125.73,115.42,108.26,52.68,48.05,22.45,14.67.HRMS(ESI)C17H19N4O2 +[M+H]+计算值:311.1503,实测值:311.1503。
实施例15:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-15)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-15)(0.125g,收率54%)。1H NMR(800MHz,DMSO-d6)δ8.64(d,J=7.7Hz,1H),8.08(s,1H),7.46–7.43(m,2H),7.32(d,J=7.9Hz,2H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.6,1.0Hz,1H),4.99–4.94(m,1H),4.59(s,2H),2.69(s,3H),1.38(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.17,147.04,146.23,143.90,132.68,130.76,127.84(2C),125.73,120.90(2C),120.11(q,J=255.7Hz),115.43,108.31,52.72,47.60,22.28,14.66.HRMS(ESI)C18H17NaF3N4O3 +[M+Na]+计算值:417.1145,实测值:417.1145。
实施例16:(S)-N-1-(4-氯苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-16)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-16)(0.088g,收率44%)。1H NMR(800MHz,DMSO-d6)δ8.61(d,J=7.8Hz,1H),8.08(s,1H),7.40–7.37(m,2H),7.36–7.33(m,2H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.6,1.0Hz,1H),4.95–4.90(m,1H),4.59and 4.57(ABq,J=16.3Hz,2H),2.69(s,3H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.11,146.22,143.44,132.66,131.20,130.75,128.17(2C),127.88(2C),125.72,115.42,108.29,52.70,47.59,22.26,14.67.HRMS(ESI)C17H18Cl4N4O2 +[M+H]+计算值:345.1113,实测值:345.1118。
实施例17:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-氟苯基)乙基)乙酰胺(化合物I-17)的制备
步骤1:6,8-二甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮的制备
将3,5-二甲基-2-吡咯甲醛(1.00g,8.12mmol)和肼基甲酸乙酯(1.01g,9.74mmol)溶于DMF(10mL)中,90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60%在矿物油中,0.325g,8.12mmol),90℃搅拌12小时。反应液加水稀释,以乙酸乙酯萃取三次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至10%EA/PE),得淡黄色固体标题化合物(0.85g,收率64%)。1H NMR(800MHz,DMSO-d6)δ11.64(s,1H),8.07(s,1H),6.32(s,1H),2.65(s,3H),2.20(s,3H).13C NMR(201MHz,DMSO-d6)δ146.49,131.66,129.34,122.65,117.86,116.86,14.33,10.01.HRMS(ESI)C8H10N3O+[M+H]+计算值:164.0818;实测值:164.0817。
步骤2:2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(4.32g,31.25mmol)溶解在丙酮溶液(35mL),然后将6,8-二甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮(1.70g,10.42mmol)加入上述溶液中。在搅拌状态下加入溴乙酸乙酯(3.48g,20.84mmol),55℃搅拌过夜。反应液加水稀释,乙酸乙酯萃取,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5%EA/PE),得黄色固体标题化合物(2.20g,收率84%)。1H NMR(800MHz,DMSO-d6)δ8.17(s,1H),6.39(s,1H),4.71(s,2H),4.17and 4.15(ABq,J=7.2Hz,2H),2.64(s,3H),2.22(s,3H),1.21(t,J=7.1Hz,3H).HRMS(ESI)C12H16N3O3 +[M+H]+计算值:250.1186;实测值:250.1186。
步骤3:2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(2.10g,8.42mmol)溶解在THF:H2O(1:1,10mL)溶液中,在0℃条件下加入氢氧化锂(1.06g,25.27mmol),室温搅拌2小时。使用1M盐酸调节PH至2左右,减压蒸干溶剂,得相应固体标题化合物(1.8g,粗品),其不经进一步纯化使用。HRMS(ESI)C10H12N3O3 +[M+H]+计算值:222.0873;实测值:222.0874。
步骤4:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-氟苯基)乙基)乙酰胺(I-17)的制备
将2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.200g,0.90mmol)溶解于DMF(7mL)溶液中,然后加入HATU(0.688g,1.80mmol)室温搅拌30分钟。依次加入DIPEA(0.292g,2.25mmol)和(S)-1-(4-氟苯基)乙胺(0.138g,0.99mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取两次,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50% EA/PE),得白色固体化合物I-17(0.160g,收率51%)。1H NMR(800MHz,DMSO-d6)δ8.55(d,J=7.9Hz,1H),8.11(s,1H),7.39–7.32(m,2H),7.14(t,J=8.9Hz,2H),6.36(s,1H),4.97–4.91(m,1H),4.55and 4.53(ABq,J=16.4Hz,2H),2.64(s,3H),2.21(s,3H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.13,161.02(2C,d,J=242.5Hz),146.22,140.56,131.60,130.04,127.90(2C,d,J=8.1Hz),122.83,118.39,117.29,114.91(d,J=21.3Hz),52.55,47.44,22.43,14.49,9.97.HRMS(ESI)C18H20FN4O2 +[M+H]+计算值:343.1565;实测值:343.1567。
实施例18:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-18)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲基苯基)乙胺,其余所需原料,试剂及制备方法同实施例17步骤4,得白色固体化合物(I-18)(0.180g,收率58%)。1H NMR(800MHz,DMSO-d6)δ8.49(d,J=8.0Hz,1H),8.10(s,1H),7.20(d,J=8.0Hz,2H),7.12(d,J=7.9Hz,2H),6.36(s,1H),4.93–4.86(m,1H),4.54and 4.52(ABq,J=16.2Hz,2H),2.64(s,3H),2.27(s,3H),2.21(s,3H),1.35(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.97,146.21,141.34,135.68,131.56,130.02,128.76(2C),125.90(2C),122.83,118.35,117.28,52.52,47.73,22.43,20.61,14.49,9.96.HRMS(ESI)C19H23N4O2 +[M+H]+计算值:339.1816;实测值:339.1818。
实施例19:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-甲氧基苯基)乙基)乙酰胺(化合物I-19)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺,其余所需原料,试剂及制备方法同实施例17步骤4,得淡黄色固体化合物(I-19)(0.150g,收率46%)。1H NMR(800MHz,DMSO-d6)δ8.47(d,J=8.0Hz,1H),8.10(s,1H),7.27–7.19(m,2H),6.90–6.86(m,2H),6.35(s,1H),4.92–4.87(m,1H),4.54and 4.51(ABq,J=14.3Hz,2H),3.73(s,3H),2.64(d,J=0.9Hz,3H),2.21(s,3H),1.35(d,J=6.9Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.90,158.05,146.20,136.27,131.53,130.01,127.13(2C),122.82,118.33,117.25,113.59(2C),55.05,52.50,47.39,22.40,14.46,9.94.HRMS(ESI)C19H23N4O3 +[M+H]+计算值:355.1765;实测值:355.1764。
实施例20:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-20)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-苯乙胺,其余所需原料,试剂及制备方法同实施例17步骤4,得白色固体化合物(I-20)(0.130g,收率44%)。1H NMR(800MHz,DMSO-d6)δ8.55(d,J=8.0Hz,1H),8.11(s,1H),7.32(d,J=4.4Hz,4H),7.26–7.20(m,1H),6.35(s,1H),4.97–4.92(m,1H),4.56and 4.54(ABq,J=16.2Hz,2H),2.64(s,3H),2.21(s,3H),1.37(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.06,146.20,144.34,131.55,130.01,128.22(2C),126.64,125.95(2C),122.82,118.34,117.25,52.52,48.00,22.42,14.46,9.94.HRMS(ESI)C18H21N4O2 +[M+H]+计算值:325.1659;实测值:325.1659。
实施例21:(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-21)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺,其余所需原料,试剂及制备方法同实施例17步骤4,得白色固体化合物(I-21)(0.240g,收率65%)。1H NMR(800MHz,DMSO-d6)δ8.61(d,J=7.7Hz,1H),8.11(s,1H),7.47–7.43(m,2H),7.32(d,J=8.1Hz,2H),6.36(s,1H),5.00–4.94(m,1H),4.56(s,2H),2.64(s,3H),2.21(s,3H),1.38(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.26,147.02,146.20,143.89,131.59,130.04,127.83(2C),122.82,120.87(2C),120.10(q,J=256.7Hz),118.38,117.27,52.55,47.54,22.25,14.44,9.93.HRMS(ESI)C19H20F3N4O3 +[M+H]+计算值:409.1482;实测值:409.1483。
实施例22:(S)-N-1-(4-氯苯基)乙基-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-22)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐,其余所需原料,试剂及制备方法同实施例17步骤4,得白色固体化合物(I-22)(0.140g,收率43%)。1H NMR(800MHz,DMSO-d6)δ8.58(d,J=7.8Hz,1H),8.11(s,1H),7.40–7.36(m,2H),7.36–7.33(m,2H),6.36(s,1H),4.95–4.89(m,1H),4.55and 4.53(ABq,J=16.3Hz,2H),2.64(s,3H),2.21(s,3H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.22,146.21,143.47,131.61,131.18,130.05,128.17(2C),127.89(2C),122.83,118.40,117.29,52.55,47.56,22.26,14.48,9.97.HRMS(ESI)C18H20ClN4O2 +[M+H]+计算值:359.1269;实测值:359.1268。
实施例23:(S)-N-(1-(萘-1-乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-23)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(1-萘基)乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-23)(0.130g,收率72%)。1H NMR(800MHz,DMSO-d6)δ8.74(d,J=7.9Hz,1H),8.28(s,1H),7.90–7.87(m,3H),7.83–7.78(m,2H),7.53–7.49(m,2H),7.49–7.47(m,1H),6.86(dd,J=3.6,1.4Hz,1H),6.84(t,J=3.3Hz,1H),5.14–5.09(m,1H),4.73and 4.71(ABq,J=16.3Hz,2H),1.47(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.94,144.62,141.74,132.85,132.33,132.06,127.89,127.65,127.45,126.15,125.65,125.63,124.89,124.00,117.03,115.89,109.60,53.01,48.24,22.18.HRMS(ESI)C20H19N4O2 +[M+H]+计算值:347.1503,实测值:347.1507。
实施例24:(S)-N-(1-(4-溴苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-24)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-溴苯)乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-24)(0.130g,收率66%)。1H NMR(800MHz,DMSO-d6)δ8.65(d,J=7.7Hz,1H),8.27(s,1H),7.78(d,J=2.1Hz,1H),7.53–7.50(m,2H),7.30–7.26(m,2H),6.86(dd,J=3.6,1.4Hz,1H),6.84(t,J=3.3Hz,1H),4.93–4.88(m,1H),4.68and 4.65(ABq,J=16.8Hz,2H),1.35(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.93,144.60,143.83,132.35,131.12(2C),128.27(2C),125.61,119.69,117.05,115.91,109.64,52.92,47.70,22.18.HRMS(ESI)C16H16BrN4O2 +[M+H]+计算值:375.0451,实测值:375.0450。
实施例25:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-吡啶-2-基)乙基)乙酰胺(化合物I-25)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(吡啶-2-基)乙胺,其余所需原料,试剂及制备方法同实施例2,得白色固体化合物(I-25)(0.110g,收率71%)。1H NMR(800MHz,DMSO-d6)δ8.69(d,J=7.9Hz,1H),8.52(dd,J=4.7,0.9Hz,1H),8.28(s,1H),7.79(dd,J=1.5,0.8Hz,1H),7.78–7.75(m,1H),7.37(d,J=7.9Hz,1H),7.28–7.25(m,1H),6.86(dd,J=3.7,1.4Hz,1H),6.85–6.83(m,1H),5.01–4.96(m,1H),4.73and 4.70(ABq,J=16.4Hz,2H),1.40(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.11,162.20,148.79,144.61,136.81,132.34,125.62,122.14,120.30,117.03,115.90,109.62,52.95,49.91,21.08.HRMS(ESI)C15H16N5O2 +[M+H]+计算值:298.1299,实测值:298.1299。
实施例26:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-萘-1-基)乙基)乙酰胺(化合物I-26)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(1-萘基)乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-26)(0.130g,收率74%)。1HNMR(800MHz,DMSO-d6)δ8.71(d,J=7.8Hz,1H),8.09(s,1H),7.90–7.86(m,3H),7.82(d,J=2.0Hz,1H),7.52–7.49(m,2H),7.49–7.46(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),5.13–5.08(m,1H),4.64and 4.61(ABq,J=16.4Hz,2H),2.70(s,3H),1.47(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.17,146.25,141.82,132.86,132.65,132.05,130.73,127.87,127.63,127.46,126.13,125.75,125.64,124.92,123.98,115.42,108.27,52.85,48.22,22.22,14.68.HRMS(ESI)C21H21N4O2 +[M+H]+计算值:361.1659,实测值:361.1656。
实施例27:(S)-N-1-(4-溴苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-27)的制备
将实施例11步骤3中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-溴苯)乙胺,其余所需原料,试剂及制备方法同实施例11步骤5,得白色固体化合物(I-27)(0.140g,收率74%)。1H NMR(800MHz,DMSO-d6)δ8.62(d,J=7.8Hz,1H),8.08(s,1H),7.54–7.49(m,2H),7.30–7.27(m,2H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),4.93–4.88(m,1H),4.59and 4.56(ABq,J=16.3Hz,2H),2.69(s,3H),1.35(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.12,146.21,143.89,132.66,131.09(2C),130.75,128.27(2C),125.72,119.67,115.42,108.29,52.69,47.66,22.21,14.67.HRMS(ESI)C17H18BrN4O2 +[M+H]+计算值:388.0608,实测值:388.0609。
实施例28:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-2-基)乙基)乙酰胺(化合物I-28)的制备
将实施例11步骤3中11步骤3替换成(S)-1-(吡啶-2-基)乙胺,其余所需原料,试剂及制备方法同实施例11步骤3,得白色固体化合物(I-28)(0.080g,收率53%)。1H NMR(800MHz,DMSO-d6)δ8.65(d,J=7.8Hz,1H),8.52(d,J=5.7Hz,1H),8.08(s,1H),7.77(td,J=7.6,1.8Hz,1H),7.38(d,J=7.8Hz,1H),7.28–7.24(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),5.01–4.96(m,1H),4.63and 4.60(ABq,J=16.3Hz,2H),2.69(s,3H),1.40(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.31,162.26,148.77,146.23,136.79,132.65,130.74,125.72,122.13,120.31,115.43,108.29,52.73,49.87,21.11,14.67.HRMS(ESI)C16H18N5O2 +[M+H]+计算值:312.1455,实测值:312.1454。
实施例29:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-3-基)乙基)乙酰胺(化合物I-29)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-(吡啶-3-基)乙胺,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物(I-29)(0.064g,收率41%)。1H NMR(800MHz,DMSO-d6)δ8.71(d,J=7.7Hz,1H),8.54(d,J=2.4Hz,1H),8.45(dd,J=4.8,1.7Hz,1H),8.28(s,1H),7.79(d,J=2.2Hz,1H),7.73–7.71(m,1H),7.37–7.35(m,1H),6.86(dd,J=3.6,1.4Hz,1H),6.84(t,J=3.3Hz,1H),5.00–4.96(m,1H),4.70and 4.68(ABq,J=16.6Hz,2H),1.41(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.08,148.00,147.74,144.61,139.51,133.58,132.37,125.62,123.41,117.05,115.92,109.65,52.97,46.26,21.98.HRMS(ESI)C15H16N5O2 +[M+H]+计算值:298.1299,实测值:298.1295。
实施例30:N-(2-吗啉-1-苯乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-30)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.08g,0.41mmol)溶解于DMF(6mL)溶液中,然后加入HATU(0.315g,0.83mmol)室温搅拌30分钟。依次加入DIPEA(0.134g,1.03mmol)和2-吗啉-4-基-1-苯基乙胺(CAS#38060-08-1,0.094g,0.45mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5% MeOH/DCM),得棕色泡沫状化合物I-30(0.035g,收率22%)。1H NMR(800MHz,DMSO-d6)δ8.27(s,1H),7.92(t,J=5.7Hz,1H),7.79(d,J=1.9Hz,1H),7.36–7.31(m,2H),7.30–7.26(m,1H),7.25–7.21(m,2H),6.88–6.86(m,1H),6.85–6.83(m,1H),4.59and 4.57(ABq,J=16.3Hz,2H),3.73–3.67(m,1H),3.56–3.51(m,4H),3.49(d,J=6.8Hz,1H),3.32(d,J=6.1Hz,1H),2.38–2.24(m,4H).13CNMR(201MHz,DMSO-d6)δ166.62,144.52,137.71,132.35,128.54(2C),128.02(2C),127.33,125.59,117.07,115.94,109.66,67.92,66.37(2C)52.86,50.10(2C),40.27.HRMS(ESI)C20H24N5O3 +[M+H]+计算值:382.1874,实测值:382.1875。
实施例31:(R)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-31)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(R)-1-(4-氟苯基)乙胺,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-31(0.130g,收率79%)。1H NMR(800MHz,DMSO-d6)δ8.62(d,J=7.9Hz,1H),8.27(s,1H),7.78(d,J=2.2Hz,1H),7.37–7.34(m,2H),7.17–7.13(m,2H),6.86(dd,J=3.7,1.4Hz,1H),6.84(t,J=3.3Hz,1H),4.96–4.92(m,1H),4.68and 4.65(ABq,J=16.4Hz,2H),1.36(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ165.83,161.04(d,J=242.1Hz),144.61,140.48,132.33,127.89(2C,d,J=8.1Hz),125.62,117.04,115.90,114.93(2C,d,J=21.3Hz),109.61,52.92,47.51,22.38.HRMS(ESI)C16H16FN4O2 +[M+H]+计算值:315.1252,实测值:315.1252。
实施例32:(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲基)苯基)乙基)乙酰胺(化合物I-32)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-[4-(三氟甲基)苯基]乙胺盐酸盐,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-32(0.105g,收率79%)。1H NMR(800MHz,DMSO-d6)δ8.75(d,J=7.7Hz,1H),8.28(s,1H),7.79(d,J=2.9Hz,1H),7.70(d,J=8.3Hz,2H),7.55(d,J=8.4Hz,2H),6.86(dd,J=3.7,1.4Hz,1H),6.85–6.83(m,1H),5.03–4.98(m,1H),4.70(s,2H),1.39(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.10,149.25,144.61,132.37,127.41(q,J=31.5Hz),126.74(2C),125.62,125.20(2C,q,J=3.7Hz),124.33(q,J=271.8Hz),117.05,115.91,109.64,52.93,48.07,22.16.HRMS(ESI)C17H16F3N4O2 +[M+H]+计算值:365.1220,实测值:365.1219。
实施例33:(S)-N-(1-(4-氰基苯乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-33)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-4-(1-氨基乙基)苯甲氰盐酸盐,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-33(0.060g,收率72%)。1H NMR(800MHz,DMSO-d6)δ8.75(d,J=7.7Hz,1H),8.28(s,1H),7.82–7.80(m,2H),7.78(d,J=2.3Hz,1H),7.53–7.51(m,2H),6.86(dd,J=3.7,1.4Hz,1H),6.85–6.83(m,1H),5.01–4.96(m,1H),4.70(s,2H),1.38(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.17,150.20,144.61,132.38,132.33(2C),126.95(2C),125.61,118.88,117.06,115.92,109.66,109.52,52.95,48.19,22.03.HRMS(ESI)C17H16N5O2 +[M+H]+计算值:322.1299,实测值:322.1297。
实施例34:(S)-N-(2-甲基-1-苯丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-34)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-2-甲基-1-苯基丙-1-胺盐酸盐,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-34(0.035g,收率41%)。1H NMR(800MHz,DMSO-d6)δ8.53(d,J=9.0Hz,1H),8.26(s,1H),7.78(d,J=4.7Hz,1H),7.34–7.31(m,2H),7.29–7.27(m,2H),7.25–7.22(m,1H),6.85(dd,J=3.7,1.4Hz,1H),6.84(t,J=3.4Hz,1H),4.74and 4.65(ABq,J=15.9Hz,2H),4.56(t,J=8.6Hz,1H),1.98–1.93(m,1H),0.91(d,J=6.7Hz,3H),0.73(d,J=6.7Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.02,144.55,142.33,132.21,128.08(2C),127.09(2C),126.71,125.59,117.00,115.90,109.57,58.83,52.85,32.99,19.77,18.91.HRMS(ESI)C18H21N4O2 +[M+H]+计算值:325.1659,实测值:325.1659。
实施例35:(S)-N-(2-(4-甲基哌嗪)-1-苯基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-35)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.05g,0.25mmol)溶解于DMF(6mL)溶液中,然后加入HATU(0.197g,0.51mmol)室温搅拌30分钟。依次加入DIPEA(0.084g,0.64mmol)和2-(4-甲基哌嗪-1-基)-1-苯基乙烷-1-胺(CAS#775349-54-7,0.063g,0.28mmol),室温搅拌过夜。反应液加水稀释,乙酸乙酯萃取,合并的有机相用盐水洗涤,经无水Na2SO4干燥,过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5%MeOH/DCM),得棕色泡沫状化合物I-35(0.025g,收率24%)。1H NMR(800MHz,DMSO-d6)δ8.19(s,1H),7.86(t,J=5.7Hz,1H),7.79(d,J=1.8Hz,1H),7.33(t,J=7.4Hz,2H),7.28–7.26(m,1H),7.24–7.22(m,2H),6.88–6.86(m,1H),6.86–6.84(m,1H),4.59and 4.57(ABq,J=15.6Hz,2H),3.69–3.65(m,1H),3.53(t,J=7.0Hz,1H),3.35–3.31(m,1H),2.50–2.18(m,8H),2.16(s,3H).HRMS(ESI)C21H27N6O2 +[M+H]+计算值:395.2190,实测值:395.2192。
实施例36:(S)-N-(1-环己基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-36)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-环己基乙胺,其余所需原料,试剂及制备方法同实施例7,得淡黄色固体化合物I-36(0.090g,收率57%)。1H NMR(800MHz,DMSO-d6)δ8.27(s,1H),7.91(d,J=8.7Hz,1H),7.80–7.77(m,1H),6.87–6.83(m,2H),4.66and 4.58(ABq,J=16.2Hz,2H),3.65–3.59(m,1H),1.76 -1.64(m,4H),1.62–1.54(m,1H),1.33–1.22(m,1H),1.20–1.05(m,3H),1.00(d,J=6.7Hz,3H),0.97–0.82(m,2H).13CNMR(201MHz,DMSO-d6)δ166.13,145.04,132.70,126.10,117.47,116.33,109.99,53.35,49.35,42.90,29.26,29.22,26.48,26.23,26.21,18.16.HRMS(ESI)C16H23N4O2 +[M+H]+计算值:303.1816,实测值:303.1815。
实施例37:(S)-N-(1-(4-氟苯基)-2-甲基丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-37)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-37(0.100g,收率80%)。1H NMR(800MHz,DMSO-d6)δ8.55(d,J=8.9Hz,1H),8.26(s,1H),7.78(d,J=2.3Hz,1H),7.34–7.30(m,2H),7.17–7.13(m,2H),6.85(dd,J=3.6,1.4Hz,1H),6.84–6.82(m,1H),4.74and 4.65(ABq,J=16.4Hz,2H),4.56(t,J=8.6Hz,1H),1.97–1.91(m,1H),0.91(d,J=6.7Hz,3H),0.72(d,J=6.7Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.08,161.03(d,J=242.5Hz),144.56,138.58,132.25,128.94(2C,d,J=8.1Hz),125.60,117.03,115.92,114.80(2C,d,J=20.9Hz),109.61,58.19,52.87,32.99,19.68,18.92.HRMS(ESI)C18H20FN4O2 +[M+H]+计算值:343.1565,实测值:343.1564。
实施例38:(S)-N-(2-甲基-1-(4-三氟甲基)苯丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-38)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-2-甲基-1-(4-(三氟甲基)苯基)丙-1-胺,其余所需原料,试剂及制备方法同实施例7,得白色固体化合物I-38(0.110g,收率77%)。1H NMR(800MHz,DMSO-d6)δ8.66(d,J=8.7Hz,1H),8.26(s,1H),7.79–7.76(m,1H),7.70(d,J=8.4Hz,2H),7.52(d,J=8.3Hz,2H),6.86–6.84(m,1H),6.84–6.82(m,1H),4.76and 4.68(ABq,J=16.1Hz,2H),4.65(t,J=8.4Hz,1H),2.04–1.95(m,1H),0.93(d,J=6.7Hz,3H),0.74(d,J=6.7Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.83,147.69,145.02,132.73,128.36(2C),127.89(q,J=31.5Hz),126.05,125.48(2C,q,J=3.7Hz),124.13(q,J=264.9Hz),117.50,116.39,110.09,59.06,53.32,33.20,20.08,19.22.HRMS(ESI)C19H20F3N4O2 +[M+H]+计算值:393.1533,实测值:393.1535。
实施例39:(S)-N-(1-(4-氟苯基)-2-甲基丙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-39)的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.080g,0.39mmol)溶解于DMF(5mL)溶液中,然后加入HATU(0.295g,0.78mmol)室温搅拌20分钟。依次加入DIPEA(0.125g,0.98mmol)和(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐(0.089g,0.62mmol),室温搅拌过夜。制备方法同实施例26,得白色固体化合物I-39(0.110g,收率79%)。1H NMR(800MHz,DMSO-d6)δ8.50(d,J=8.9Hz,1H),8.06(s,1H),7.35–7.29(m,2H),7.17–7.12(m,2H),6.66(d,J=3.6Hz,1H),6.50(d,J=2.6Hz,1H),4.64(d,J=16.3Hz,1H),4.58–4.54(m,2H),2.67(s,3H),1.96–1.88(m,1H),0.91(d,J=6.6Hz,3H),0.72(d,J=6.8Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.25,161.02(d,J=242.5Hz),146.18,138.63(d,J=2.9Hz),132.57,130.73,128.93(2C,d,J=8.1Hz),125.70,115.43,114.78(2C,d,J=21.3Hz),108.28,58.16,52.57,33.00,19.67,18.91,14.67.HRMS(ESI)C19H22FN4O2 +[M+H]+计算值:357.1721,实测值:357.1722。
实施例40:(S)-N-(2-甲基-1-(4-三氟甲基)苯丙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-40)的制备
将实施例I-39中的(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐替换成(S)-2-甲基-1-(4-(三氟甲基)苯基)丙-1-胺,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-40(0.120g,收率76%)。1H NMR(800MHz,DMSO-d6)δ8.61(d,J=8.7Hz,1H),8.06(s,1H),7.70(d,J=8.4Hz,2H),7.52(d,J=8.3Hz,2H),6.66(d,J=3.6Hz,1H),6.50(dd,J=3.7,1.0Hz,1H),4.68–4.63(m,2H),4.59(d,J=16.3Hz,1H),2.67(s,3H),2.02–1.97(m,1H),0.92(d,J=6.6Hz,3H),0.74(d,J=6.7Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.54,147.29,146.18,132.60,130.74,129.02(q,J=35.1Hz)127.91(2C),125.70,124.99(2C,q,J=8.2Hz),124.33(q,J=271.7Hz),115.44,108.30,58.58,52.58,32.74,19.61,18.75,14.66.HRMS(ESI)C20H22F3N4O2 +[M+H]+计算值:407.1689,实测值:407.1690。
实施例41:(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯丙基)乙酰胺(化合物I-41)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-苯基丙胺,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-41(0.05g,收率31%)。1H NMR(800MHz,DMSO-d6)δ8.51(d,J=8.4Hz,1H),8.07(s,1H),7.34–7.28(m,4H),7.25–7.21(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.1Hz,1H),4.73–4.69(m,1H),4.62and 4.57(ABq,J=16.2Hz,2H),2.68(d,J=1.0Hz,3H),1.73–1.66(m,2H),0.85(t,J=7.3Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.29,146.21,143.38,132.61,130.73,128.20(2C),126.70,126.44(2C),125.73,115.41,108.25,54.28,52.65,29.25,14.67,10.97.HRMS(ESI)C18H21N4O2 +[M+H]+计算值:325.1659,实测值:325.1659。
实施例42:(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1,2,3,4-四氢萘-1-基)乙酰胺(化合物I-42)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1,2,3,4-四氢-1-萘胺,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-42(0.085g,收率63%)。1H NMR(800MHz,DMSO-d6)δ8.51(d,J=8.7Hz,1H),8.10(s,1H),7.22–7.19(m,1H),7.17–7.14(m,2H),7.10–7.08(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),5.02–4.97(m,1H),4.60and 4.57(ABq,J=16.4Hz,2H),2.78–2.68(m,5H),1.92–1.84(m,2H),1.77–1.66(m,2H).13C NMR(201MHz,DMSO-d6)δ166.33,146.25,137.24,137.04,132.70,130.74,128.71,128.12,126.76,125.83,125.80,115.39,108.23,52.87,46.72,29.82,28.74,20.09,14.70.HRMS(ESI)C19H21N4O2 +[M+H]+计算值:337.1659,实测值:337.1657。
实施例43:(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-3-基)乙基)乙酰胺(化合物I-43)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-(吡啶-3-基)乙胺,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-43(0.065g,收率52%)。1H NMR(800MHz,DMSO-d6)δ8.67(d,J=7.7Hz,1H),8.54(d,J=2.3Hz,1H),8.45(dd,J=4.7,1.6Hz,1H),8.08(s,1H),7.73–7.71(m,1H),7.37–7.35(m,1H),6.67(d,J=3.6Hz,1H),6.51(dd,J=3.7,1.1Hz,1H),5.00–4.96(m,1H),4.60(s,2H),2.69(d,J=0.9Hz,3H),1.41(d,J=7.0Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.26,147.98,147.75,146.23,139.57,133.59,132.69,130.76,125.73,123.40,115.43,108.32,52.75,46.23,22.01,14.67.HRMS(ESI)C16H18N5O2 +[M+H]+计算值:312.1455,实测值:312.1454。
实施例44:N-(2-(二甲基氨基)-1-苯基乙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-44)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成N1,N1-二甲基-2-苯基乙烷-1,2-二胺,其余所需原料,试剂及制备方法同实施例26,得棕色泡沫状固体化合物I-44(0.055g,收率40%)。1H NMR(800MHz,DMSO-d6)δ8.56(d,J=5.3Hz,1H),8.07(s,1H),7.33(d,J=4.4Hz,4H),7.26–7.23(m,1H),6.67(d,J=3.7Hz,1H),6.51(dd,J=3.7,1.0Hz,1H),4.96(s,1H),4.61and 4.58(ABq,J=16.2Hz,2H),2.68(s,4H),2.21(brs,6H),1.26–1.22(m,1H).13C NMR(201MHz,DMSO-d6)δ166.76,149.59,146.68,133.09,131.22,128.68(2C),127.40,127.15(2C),126.16,115.92,108.78,64.66,53.08,51.23,45.48(2C),15.14.HRMS(ESI)C19H24N5O2 +[M+H]+计算值:354.1925,实测值:354.1927。
实施例45:(R)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-45)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(R)-1-(4-氟苯基)乙胺,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-45(0.040g,收率18%)。1H NMR(800MHz,DMSO-d6)δ8.59(d,J=7.9Hz,1H),8.08(s,1H),7.38–7.34(m,2H),7.17–7.13(m,2H),6.67(d,J=3.6Hz,1H),6.50(d,J=2.6Hz,1H),4.96–4.92(m,1H),4.58and 4.55(ABq,J=16.0Hz,2H),2.69(s,3H),1.36(d,J=6.9Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.02,161.03(d,J=242.1Hz),146.23,140.54(d,J=3.3Hz),132.65,130.75,127.90(d,J=8.1Hz,2C),125.73,115.43,114.91(2C,d,J=20.9Hz),108.29,52.69,47.48,22.43,14.67.HRMS(ESI)C17H18FN4O2 +[M+H]+计算值:329.1408,实测值:329.1407。
实施例46:(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲基)苯基)乙基)乙酰胺(化合物I-46)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-[4-(三氟甲基)苯基]乙胺盐酸盐,其余所需原料,试剂及制备方法同实施例26,得白色固体化合物I-46(0.092g,收率71%)。1H NMR(800MHz,DMSO-d6)δ8.71(d,J=7.6Hz,1H),8.08(s,1H),7.69(d,J=8.5Hz,2H),7.55(d,J=8.3Hz,2H),6.67(d,J=3.6Hz,1H),6.50(dd,J=3.7,1.0Hz,1H),5.03–4.98(m,1H),4.61(s,2H),2.69(s,3H),1.39(d,J=7.2Hz,3H).13C NMR(201MHz,DMSO-d6)δ166.30,149.32,146.23,132.69,130.77,127.32(q,J=31.5Hz),126.75(2C),125.73,125.19(2C,q,J=3.7Hz),124.34(q,J=271.8Hz),115.44,108.32,52.71,48.04,22.20,14.66.HRMS(ESI)C18H18F3N4O2 +[M+H]+计算值:379.1376,实测值:379.1377。
生物测试实施例1:本发明化合物对GPR139的激动活性测定
本发明化合物对GPR139的激动活性采用钙流检测实验(Molecular Devices)来测定。具体操作方法如下:
(1)细胞培养(CHO-K1细胞系,细胞培养基:Ham’s F12+10% FBS+1% PS(青链霉素Penicillin-
Streptomycin)。
(2)在10cm培养皿中,用2mL PBS缓冲液(HyClone,Cat#SH30028.02)洗涤细胞,去除缓冲液,再加入1mL胰酶(Thermo,Cat#25300054)消化细胞2分钟;加入2mL细胞培养基终止消化,吹打混匀,1000rmp离心3分钟。
(3)将细胞重悬并调整细胞密度为3×106/mL,取1mL的细胞液于10cm培养皿(10mL细胞培养基),过夜培养。
(4)待细胞密度至60%进行转染,转染前1小时细胞换液;将GPR139质粒和TransIT-2020分别加入Opti-MEM(转染比例:1μg GPR139质粒+16μL TransIT-2020+1000μLOpti-MEM),吹打混匀室温孵育20分钟;逐滴加入含细胞的培养皿中轻轻混匀,转染16至20小时。
(5)细胞经胰酶消化之后用17mL细胞培养基重悬,铺入黑色底透384孔板(Greiner,Cat#781091)
中,每孔加入40μL细胞液,细胞数为15000~20000个/孔;37℃,5% CO2孵育16小时。
(6)配制试剂:将待测化合物用DMSO配制成10mM浓度的储存液,然后用0.1%BSA(牛
血清白蛋白)溶液稀释至30μM,再3倍梯度稀释,16个浓度点;激动剂阳性对照TAK-041和空白对照DMSO均为30μM起始,16个浓度点。
(7)用排枪将不同浓度的待测化合物转移到384孔板(Greiner,Cat#784201)上,每孔20μL,1000rmp离心1分钟。
(8)去除384孔黑板中的细胞培养液,向每孔中加入20μL 1×染料(FLIPRCalcium6 Assay
Explorer Kit,Cat#R8190,含2.5mM丙磺舒)溶液后,37℃孵育60分钟;室温平衡15分钟。
(9)使用FLIPR(Molecular Devices)将不同浓度的待测化合物转移到384孔黑板上,每孔10μL,用FLIPR读取钙流信号(最大激发光:470~495nm,最大发射光515~575nm)。
(10)使用GraphPad Prism(版本8.0)分析数据,数据显示为平均值±标准差,浓度响应曲线的拟合采用非线性回归,计算出EC50值。
结果:本发明化合物对GPR139的激动活性如表1所示。
表1.
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注:上表中,Emax=本申请化合物的最大效应/TAK-041的最大效应;NT,未测试。
生物测试实施例2:化合物腹腔注射给药后在小鼠体内药代动力学研究
化合物在雄性小鼠体内单剂量腹腔注射给药后,于不同时间点采集血样和脑组织,LC-MS/MS测定小鼠血浆和脑组织中化合物的浓度并计算相关药代参数,考察化合物在小鼠体内药代特征及脑分布。
2.1实验设计
36只雄性C57小鼠按体重随机分为4组,每组9只。给药前1天禁食不禁水12~14h,给药后4h给食。化合物溶媒:10% DMSO+10%solutol(聚乙二醇-12羟基硬脂酸酯)+80%生理盐水。
2.2样品采集
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL,置于EDTAK2离心管中并放置冰浴上。5000rpm,4℃离心10min,收集血浆。IP血浆和脑组织采集时间点:0.5h、2h和4h,分析检测前,所有血浆样品存于-80℃。脑组织采集时间点0.5h、2h和4h,小鼠放血安乐死后取脑组织清洗干净,准确称量后用50%甲醇水按照1:4匀浆,匀浆液样品存于-80℃待分析。
2.3数据处理
数据采集及控制***软件为Analyst1.5.1软件(Applied Biosystem)。图谱样品峰积分方式为自动积分;采用样品峰面积和内标峰面积的比值作为指标,和样品的浓度进行回归。回归方式:线性回归,权重系数为1/X2。药代动力学参数用WinNonlinProfessional v6.3(Pharsight,USA)用非房室模型分析处理。Cmax为实测的最大血药浓度,血药浓度-时间曲线下面积AUC(0→t)由梯形法计算得到,tmax为给药后血药浓度达峰时间。实验数据“均数”(Mean,n=3)表示。
2.4实验结果
注:NA表示无法计算。
生物测试实施例3:化合物给药后对BALB/c小鼠的行为学研究
对BALB/c小鼠腹腔注射不同剂量的I-5,通过社会交互实验来验证所开发化合物对于精神***症阴性症状的治疗效果
3.1实验对象
实验对象为6周龄、体重约22克的雄性BALB/c野生型小鼠,采购自上海灵畅生物科技有限公司。饲养在SPF级饲养设施,每笼2只,12小时明暗循环,随意获取食物和水。本项目中所有行为实验均在光循环期间完成。本实验全程遵守实验动物福利伦理相关法规和各项规定,并接受伦理委员会和实验室动物管理者的监督与检查。
3.2行为***
本实验所使用的行为箱长、宽、高均为40厘米。实验过程中,4只小鼠同时在4个行为箱中进行试验。本实验使用EthoVision XT进行实验设置和视频录制。
3.3实验流程
将小鼠随机分为6组,分别是阴性对照组;阳性对照组:TAK-041(3mg/kg),TAK-041(1mg/kg);实验组:I-5(3mg/kg),I-5(1mg/kg),I-5(0.3mg/kg),每组≥12只。
小鼠购入时为5周龄,观察一周后,待其6周龄,并且体重长至22克左右时开始实验。每次实验前,提前18小时对实验鼠进行限食。实验当天,提前1小时,将小鼠转移至行为学实验室中熟悉环境。接下来通过腹腔注射给药,每只小鼠给药后放回原鼠笼。20分钟后,将实验鼠放入行为箱中适应10分钟,然后将刺激鼠(同批次BALB/c)放入行为箱中远离实验鼠的角落,任两只小鼠自由探索10分钟,通过摄像机监测记录小鼠活动,并存档。
对实验数据进行分析。计算每只实验鼠在10分钟内的社交交互时间(包括接近、嗅、理毛、追逐、攻击等),通过单因素方差分析对不同组之间每只小鼠总社交时间进行分析。在分析过程中,未进行社交和社交时间低于10秒的小鼠被排除在外。
3.4实验结果
实验结果如图1和下表:
该实验结果表明,化合物I-5在3mg/kg剂量下,对小鼠社交障碍具有显著的改善作用。
Claims (13)
1.一种如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐;
其中,
R1、R2、R3和R4独立地为H、卤素、C1-6烷基、C3-6环烷基、-O-C1-6烷基、被1个、2个或3个R1-1取代的C1-6烷基、被1个、2个或3个R1-2取代的C3-6环烷基或被1个、2个或3个R1-3取代的-O-C1-6烷基;
R1-1、R1-2和R1-3独立地为卤素;
R5为H或C1-6烷基;
R6和R7独立地为H、C1-6烷基、C3-6环烷基、被1个、2个或3个R6-1取代的C1-6烷基或被1个、2个或3个R6-2取代的C3-6环烷基;
R6-1独立地为卤素、-O-C1-6烷基或-NRaRb;
R6-2独立地为卤素、-O-C1-6烷基或-NRaRb;
Ra和Rb独立地为C1-6烷基;
或,Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基;所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-6元杂环烷基;
Ra-1独立地为C1-6烷基;
Q为C6-10芳环、5-10元杂芳环、C3-6环烷基或5-6元杂环烷基;所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-10元杂芳环;
n为0、1、2、3、4或5;
R8独立地为卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-1和R8-2独立地为卤素;
或,R8与R7一起形成-(CH2)m-,m为2或3;
带“*”、“#”的碳原子为非手性碳原子或手性碳原子,当为手性碳原子时,独立地为S构型和/或R构型。
2.如权利要求1所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐;其特征在于,
其中,
R1、R2、R3和R4独立地为H、卤素、C1-6烷基、C3-6环烷基、-O-C1-6烷基、被1个、2个或3个R1-1取代的C1-6烷基、被1个、2个或3个R1-2取代的C3-6环烷基或被1个、2个或3个R1-3取代的-O-C1-6烷基;
R1-1、R1-2和R1-3独立地为卤素;
R5为H或C1-6烷基;
R6和R7独立地为H、C1-6烷基、C3-6环烷基、被1个、2个或3个R6-1取代的C1-6烷基或被1个、2个或3个R6-2取代的C3-6环烷基;
R6-1独立地为卤素、-O-C1-6烷基或-NRaRb;
R6-2独立地为卤素、-O-C1-6烷基或-NRaRb;
Ra和Rb独立地为C1-6烷基;
或,Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基;所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-6元杂环烷基;
Ra-1独立地为C1-6烷基;
Q为C6-10芳环或5-10元杂芳环;所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种,杂原子的个数为1个、2个或3个的5-10元杂芳环;
n为0、1、2、3、4或5;
R8独立地为卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-1和R8-2独立地为卤素;
或,R8与R7一起形成-(CH2)m-,m为2或3;
带“*”、“#”的碳原子为非手性碳原子或手性碳原子,当为手性碳原子时,独立地为S构型和/或R构型。
3.如权利要求1或2所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,为/> 例如/>为其中,*、#、R1、R2、R3、R4、R5、R6、R7、R8、Q和n的定义如权利要求1或2所述。
4.如权利要求1-3中任一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,其满足以下条件中的一种或多种:
(1)R1、R2和R3独立地为H或C1-6烷基;
(2)R4独立地为H;
(3)R5为H;
(4)R6为H;
(5)R7为C1-6烷基或被1个、2个或3个R6-1取代的C1-6烷基;
(6)R6-1独立地为-NRaRb;
(7)Ra和Rb独立地为C1-6烷基;
(8)n为0或1;和
(9)R8为卤素、-OH、-CN、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
或,R8与R7一起形成-(CH2)m-,m为2或3;例如,R8为卤素、-OH、C1-6烷基、-O-C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;或,R8与R7一起形成-(CH2)m-,m为2或3。
5.如权利要求1-3中任一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,其满足以下条件中的一种或多种:
(1)R1、R2、R3和R4中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
(2)R1-1、R1-2和R1-3中,所述卤素为F、Cl、Br或I;
(3)R6和R7中,所述C1-6烷基和被1个、2个或3个R6-1取代的C1-6烷基中的C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
(4)Ra和Rb中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
(5)Q中,所述C6-10芳环为苯环或萘环;
(6)Q中,所述5-10元杂芳环为5-6元杂芳环;
(7)R8中,所述卤素独立地为F、Cl、Br或I;
(8)R8中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
(9)R8中,所述-O-C1-6烷基和被1个、2个或3个R8-2取代的-O-C1-6烷基中的-O-C1-6烷基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基;
(10)R8-1和R8-2中,所述卤素独立地为F、Cl、Br或I;
(11)当R8与R7一起形成-(CH2)m-,m为3;
(12)当Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基,所述的5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基中的5-6元杂环烷基独立地为杂原子独立地选自N和O,杂原子的个数为1个或2个的5-6元杂环烷基;
(13)Ra-1中,所述C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,和
(14)Q中,所述C3-6环烷基为环丙基、环丁基、环戊基或环已基。
6.如权利要求5所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,其满足以下条件中的一种或多种:
(1)R1、R2、R3和R4中,所述C1-6烷基为甲基;
(2)R6和R7中,所述C1-6烷基和被1个、2个或3个R6-1取代的C1-6烷基中的C1-6烷基独立地为甲基或乙基;
(3)Ra和Rb中,所述C1-6烷基为甲基;
(4)Q中,所述C6-10芳环为苯环;
(5)Q中,所述5-10元杂芳环为吡啶环,例如为
(6)R8中,所述卤素为F、Cl或Br;
(7)R8中,所述C1-6烷基为甲基;
(8)R8中,所述-O-C1-6烷基和被1个、2个或3个R8-2取代的-O-C1-6烷基中的-O-C1-6烷基为甲氧基;
(9)R8-1和R8-2中,所述卤素为F;
(10)当Ra和Rb与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个Ra-1取代的5-6元杂环烷基,所述的5-6元杂环烷基为
(11)Ra-1中,所述C1-6烷基为甲基;和
(12)Q中,所述C3-6环烷基为环己基。
7.如权利要求1-3中任一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,其满足以下条件中的一种或多种:
(1)当Q为苯环时,为/>R8-a、R8-b、R8-c和R8-d独立地为H、卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
R8-e为H、卤素、-OH、-CN、-NH2、C1-6烷基、-O-C1-6烷基、被1个、2个或3个R8-1取代的C1-6烷基或被1个、2个或3个R8-2取代的-O-C1-6烷基;
或者,R8-e与R7一起形成-(CH2)m-,m为2或3;
(2)为/>
(3)R6为H;
(4)R7为-CH3、-CH2CH3、例如为-CH3、-CH2CH3或
8.如权利要求1-3中任一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,R8独立地为F、Cl、Br、-OH、-CH3、-OCH3、-OCF3、-CF3或CN,例如为F、Cl、Br、-OH、-CH3、-OCH3或-OCF3;
较佳地,为/> 例如为/>
更佳地,为/>
例如为
9.如权利要求1或2所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,其特征在于,所述如式I所示的吡咯并三嗪酮类化合物选自以下任一化合物:
10.一种药物组合物,其特征在于,所述药物组合物包含如权利要求1-9任一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐,以及药用辅料。
11.如权利要求1-9任一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐的制备方法,其特征在于,其包括以下步骤:化合物II和化合物III发生缩合反应;
其中,*、#、R1、R2、R3、R4、R5、R6、R7、R8、Q和n的定义如权利要求1-9任一项所述。
12.如权利要求1-9任一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或如权利要求10所述的药物组合物在制备药物中的应用,所述药物用于治疗和/或预防GPR139受体相关的疾病;所述GPR139受体相关的疾病可为精神***症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
13.如权利要求1-9任一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或如权利要求10所述的药物组合物在制备药物中的应用,所述药物用于治疗和/或预防精神***症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
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