CN105164113B - 吡咯酰胺抑制剂 - Google Patents
吡咯酰胺抑制剂 Download PDFInfo
- Publication number
- CN105164113B CN105164113B CN201480021667.8A CN201480021667A CN105164113B CN 105164113 B CN105164113 B CN 105164113B CN 201480021667 A CN201480021667 A CN 201480021667A CN 105164113 B CN105164113 B CN 105164113B
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- CN
- China
- Prior art keywords
- pyrrole
- phenyl
- carboxamides
- methyl
- isophthalic acid
- Prior art date
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
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Abstract
本发明提供式(I)化合物(I)其中R1、R2、R3和R10具有任何在本说明书中定义的值,及其药学可接受的盐,其可用作疾病和病症包括炎性疾病、癌症和AIDS的治疗中的药剂。本发明还提供了包含一种或多种式(I)化合物的药物组合物。
Description
背景技术
布罗莫结构域(bromodomains)是指保守的蛋白结构折叠,其与存在于一些蛋白中的N-乙酰化赖氨酸残基结合。含有布罗莫结构域的蛋白的BET家族包括四个成员(BRD2、BRD3、BRD4和BRDt)。BET家族的每个成员用两个布罗莫结构域以识别主要但非完全在组蛋白的氨基末端尾部上存在的N-乙酰化的赖氨酸残基。这些相互作用通过募集转录因子到染色质内特定基因组位置以调节基因表达。例如,结合组蛋白的BRD4募集转录因子P-TEFb到启动子,导致细胞周期进程中涉及的基因子集的表达(Yang 等,Mol. Cell. Biol. 28:967-976 (2008))。BRD2和BRD3也作为生长促进基因的转录调节因子发挥作用(LeRoy等,Mol. Cell 30:51-60 (2008))。最近已确认BET家族成员对于几种癌症类型的维持是重要的(Zuber 等,Nature 478:524-528 (2011);Mertz 等;Proc. Nat’l. Acad. Sci. 108:16669-16674 (2011);Delmore 等,Cell 146:1-14,(2011);Dawson 等,Nature 478:529-533 (2011))。BET家族成员也通过经典的NF-KB通路参与介导急性炎性应答(Huang等,Mol.Cell. Biol. 29:1375-1387 (2009)),导致与细胞因子产生有关的基因上调(Nicodeme等,Nature 468:1119-1123,(2010))。已经表明,在动物模型中,通过BET布罗莫结构域抑制剂的细胞因子诱导的抑制是治疗炎症介导的肾疾病的有效方法(Zhang等,J. Biol. Chem.287:28840-28851 (2012))。BRD2功能已与对血脂异常或脂肪形成的不当调节、升高的炎症概况和对自身免疫性疾病增加的易感性的倾向相联系(Denis,Discovery Medicine 10:489-499 (2010))。人免疫缺陷病毒利用BRD4启动从稳定整合的病毒DNA转录病毒RNA(Jang 等,Mol. Cell,19:523-534 (2005))。在潜在T细胞感染和潜伏性单核细胞感染的模型中也已证实BET布罗莫结构域抑制剂重新激活HIV转录(Banerjee等,J. LeukocyteBiol. doi:10.1189/jlb.0312165)。BRDt在精子生成中起着重要作用,其被BET布罗莫结构域抑制剂所阻断(Matzuk等,Cell 150:673-684 (2012))。因此,正在寻求抑制BET家族布罗莫结构域与其同源乙酰化赖氨酸蛋白结合的化合物,用于治疗癌症、炎性疾病、肾脏疾病、涉及代谢或脂肪积累的疾病和一些病毒感染,以及提供用于男性避孕的方法。因此,对开发治疗这些适应症的新的药物存在持续的医疗需求。
发明概述
一方面,本发明涉及式(I)化合物或其可药用盐:
(I)
其中
R1是C1-C3烷基;
R2是氢或C1-C3烷基;
R3是-C(O)-C1-C3烷基、COOH、或-C(O)NR8R9;
R8和R9是选自下述之一:
(i) R8和R9都是H;
(ii) R8是H和R9是C1-C3亚烷基-C(O)O-C1-C3烷基或OH;和
(iii) R8是C1-C3亚烷基-芳基和R9是C1-C3亚烷基-C(O)-C1-C3烷基;
R10是芳基或杂芳基,其中 R10可被1至3个指定为R40、R41、和R42的取代基取代并且独立地选自:
NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;
R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被一、二或三个指定为R15、R16和R17的取代基取代,
R15、R16和R17独立地选自:
OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,
其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基;
R26是C1-C3亚烷基-C3-C6环烷基;
R20和R22独立地选自 H和C1-C6烷基;和
R30和R32独立地选自 H和C1-C4烷基。
在一些实施方案中,R1是甲基。在一些实施方案中,R2是氢。在一些实施方案中,R3是-C(O)NR8R9。在一些实施方案中,R8和R9都是H。在一些实施方案中,R10是杂芳基,其可被1至3个指定为R40、R41和R42的取代基取代并且独立地选自:
NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被一、二或三个指定为R15、R16和R17的取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是未被取代的杂芳基。在一些这样的实施方案中所述未被取代的杂芳基是苯并咪唑基或吲哚基。
在一些实施方案中,R10是苯基,其可被1至3个指定为R40、R41和R42的取代基取代并且独立地选自:NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被一、二或三个指定为R15、R16和R17的取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是苯基,其被一个取代基R41取代并任选进一步被1或2个指定为R40和R42的取代基取代;其中
R41是-L-R12;
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2;和
R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中 L不存在并且R12是任选被取代的环丙基。
在一些实施方案中,R10是苯基,其被一个取代基R41取代并且任选进一步被1或2个指定为R40和R42的取代基取代;其中
R41是-L-R12;
L不存在或为-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基或O;
R12是C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C6烷基:C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其中所述C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的;
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2;和
R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中 L不存在和R12是任选被取代的环丙基。
在一些实施方案中,R10是
;
其中
L是-NH-或O;
R12是苯基、C3-C6环烷基、5-元杂环烷基或6-元杂环烷基;其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C3烷基:苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基;其中所述苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基的每一个是任选被取代的;
m是0或1;
R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中 L不存在和R12是任选被取代的环丙基,和
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
、或,其中 R41选自:NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被指定为R15、R16和R17的一、二或三个取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
、或,其中 R41是-L-R12。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
、或,其中
R41是-L-R12;
L不存在或是-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基或O;和
R12是C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C6烷基:C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其中所述C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中 R41选自:NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被指定为R15、R16和R17的一、二或三个取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中 R41是-L-R12。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中
R41是-L-R12;
L不存在或为-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基或O;和
R12是C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者 R12是被选自下述取代基取代的C1-C6烷基:C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其中所述C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中
R41是-L-R12;
L是-NH-或O;和
R12是苯基、C3-C6环烷基、5-元杂环烷基或6-元杂环烷基;其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C3烷基:苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基;其中所述苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基的每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中 R41选自:NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被指定为R15、R16和R17的一、二或三个取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中 R41是-L-R12。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中
R41是-L-R12;
L不存在或者为-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基、或O;和
R12是C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C6烷基:C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其中所述C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中
R41是-L-R12;
L不存在或者 -C2-C3亚烯基;和
R12是5至12元杂芳基或苯基,其中每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
,其中 R41选自:NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中 L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其可被指定为R15、R16和R17的一、二或三个取代基取代;R15、R16和R17独立地选自:OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,其中基团R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中 R41是-L-R12。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中
R41是-L-R12;
L不存在或者是-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基、或O;和
R12是C3-C10环烷基、3至 8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C6烷基:C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基,其中 所述C3-C6环烷基、3至 8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的。
在一些实施方案中,R10是苯基,其被指定为R41的一个取代基取代并且具体为:
其中
R41是-L-R12;
L不存在;和
R12是5至12元杂芳基或苯基,其中每一个是任选被取代的。
在一些实施方案中,式I化合物选自:
5-(2-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酰胺;
5-(3-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[3-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{3-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酰胺;
5-(4-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{4-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-[4-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(苄基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(四氢呋喃-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-溴噻吩-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(3,4,5-三甲氧基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(四氢呋喃-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3R)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-(2-{[(4,5-二甲基呋喃-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[3,5-二(三氟甲基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(2,6-二氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(2-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(3-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(环丙基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[4-(三氟甲基)苄基]氨基}苯基)-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(4-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氰基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-溴苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3,4-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(2-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环己基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[4-(二甲基氨基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(噻吩-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(3,5-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)吡咯烷-1-甲酸叔丁基酯;
4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)哌啶-1-甲酸叔丁基酯;
2-甲基-5-{2-[(吡咯烷-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(哌啶-4-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
4-(2-{[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}乙基)哌啶-1-甲酸叔丁基酯;
[顺式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯;
[反式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯;
2-甲基-5-(2-{[2-(哌啶-4-基)乙基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-(2-{[(顺式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(反式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
[4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯;
[3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯;
5-{2-[(4-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-羟基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-({[5-(羟基甲基)呋喃-2-基]甲基}氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(1H-吲哚-5-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)(噻吩-2-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(环己基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢呋喃-3-基氨基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡咯烷-3-基氨基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(哌啶-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(环丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-1-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢-2H-噻喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-2-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢-2H-吡喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(1-氮杂双环[2.2.2]辛烷-3-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[三环[3.3.1.13,7]癸烷-2-基氨基]苯基}-1H-吡咯-3-甲酰胺;
5-[2-(环庚基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(1,2,3,4-四氢萘-2-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-{2-[(2-氟环己基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(苯基乙酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(苯基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-(2-{[(4-氯苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环己基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(苯基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(吡啶-3-基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3,3,3-三氟丙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-{2-[(苄基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-氯苄基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(2,2,2-三氟乙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-羟基苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酰胺;
5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-氨基-6-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)-β-丙氨酸甲基酯;
N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)甘氨酸甲基酯;
5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-N-羟基-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(4-甲基哌嗪-1-基)甲基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-(3'-羟基联苯-4-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3',4',5'-三甲氧基联苯-4-基)-1H-吡咯-3-甲酰胺;
5-[4-(呋喃-3-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(吡啶-4-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(1-甲基-1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺;
5-[3'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3'-(吗啉-4-基)联苯-4-基]-1H-吡咯-3-甲酰胺;
5-{3'-[(呋喃-2-基甲基)氨基甲酰基]联苯-4-基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{4-[(1E)-3-甲氧基丙-1-烯-1-基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[4'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(嘧啶-5-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(甲基磺酰基)氨基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-[4-(1-苄基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[4-(3,5-二甲基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(喹啉-6-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(4-甲基哌嗪-1-基)羰基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(1H-吲哚-6-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-氨基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-4-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(4-苯氧基苯氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-环戊基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(异喹啉-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-3-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(3-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(喹啉-5-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氯-2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(1H-吲哚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-2-基氧基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[4-(甲基磺酰基)苯氧基]苯基}-1H-吡咯-3-甲酰胺;
3-{2-[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯氧基]苯基}丙酸甲基酯;
2-甲基-5-[2-(3-甲基苯氧基)苯基]-1H-吡咯-3-甲酰胺;
5-{2-[4-(1H-咪唑-1-基)苯氧基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(5,6,7,8-四氢萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-甲氧基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(萘-2-基氧基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(3-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-乙基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(6-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(5-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-苄基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3,4,5-三甲氧基苯基)-1H-吡咯-3-甲酰胺;
5-(联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(3'-甲氧基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺;
5-(2'-乙酰基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(吡啶-3-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(1-甲基-1H-吲哚-5-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{3-[(E)-2-苯基乙烯基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{3'-[(4-甲基哌嗪-1-基)甲基]联苯-3-基}-1H-吡咯-3-甲酰胺;
5-(4'-{[2-(二甲基氨基)乙基]氨基甲酰基}联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(5-氨基-2-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{5-[(甲基磺酰基)氨基]-2-苯氧基苯基}-1H-吡咯-3-甲酰胺;
5-(1H-苯并咪唑-4-基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(1H-吲哚-7-基)-2-甲基-1H-吡咯-3-甲酰胺;
[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸乙基酯;
[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸;
5-[2-(苄基氧基)-5-(2-羟基乙基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2,4-二氟苯氧基)-5-氨磺酰基苯基]-2-甲基-1H-吡咯-3-甲酰胺;
和其可药用盐。
另一方面,本发明提供了用于治疗或预防病症的方法,所述病症通过抑制BET得到改善。所述方法包括给患者单独或与药学上可接受的载体结合施用治疗有效量的式(I)化合物。
一些方法是针对治疗或预防炎性疾病或癌症或艾滋病。
另一方面,本发明涉及治疗患者癌症的方法,包括向有此需要的患者施用治疗有效量的式(I)化合物或其药学上可接受的盐。在某些实施方案中,所述癌症选自:听觉神经瘤、急性白血病、急性淋巴细胞白血病、急性髓细胞白血病(单核细胞白血病、成髓细胞白血病、腺癌白血病、血管肉瘤白血病、星形细胞瘤白血病、髓细胞单核细胞白血病和原髓细胞白血病)、急性t细胞白血病、基底细胞癌、胆小管癌、膀胱癌、脑癌、乳腺癌、支气管源性癌、宫颈癌、软骨肉瘤、脊索瘤、绒膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞(粒细胞)白血病、慢性粒性白血病、结肠癌、结直肠癌、颅咽管癌、囊腺癌、弥散性大B细胞淋巴癌、异常增生(dysproliferative)变化(发育异常和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多、尤因肉瘤、纤维肉瘤、滤泡性淋巴瘤、胚细胞睾丸癌、神经胶质瘤、恶性胶质瘤、神经胶质肉瘤、重链病、成血管细胞瘤、肝脏肿瘤、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤(lympagiendotheliosarcoma)、淋巴管肉瘤、成淋巴细胞白血病、淋巴瘤(Hodgkin型和非Hodgkin型),膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增生病变,T细胞或B细胞源的淋巴癌、白血病、淋巴癌、髓样癌、成髓细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓源性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NUT midline carcinoma,NMC)、非小细胞肺癌、少突胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体肿瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。在某些实施方案中,所述方法进一步包括施用治疗有效量的至少一种另外治疗剂。在某些实施方案中,另外的治疗剂选自阿糖胞苷、硼替佐米和5-氮杂胞苷。
另一方面,本发明涉及治疗患者疾病或病症的方法,包括给有此需要的患者施用治 疗有效量的式(I)化合物或其药学上可接受的盐,其中所述疾病或病症选自:阿狄森氏病、急 性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特氏病、大疱性皮肤病、心肌病、心脏 肥大、慢性阻塞性肺病(COPD)、克罗恩病、皮炎、湿疹、巨细胞动脉炎、肾小球肾炎、心 脏衰竭、肝炎、垂体炎、炎性肠道疾病、川崎症、狼疮性肾炎、多发性硬化、心肌炎、肌 炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆 汁性肝硬化、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血 症、系统性红斑狼疮、高安氏动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠 炎、葡萄膜炎、白癜风、脉管炎和韦格纳氏肉芽肿。在某些实施方案中,所述方法进一步包 括施用治疗有效量的至少一种另外的治疗剂。
另一方面,本发明涉及治疗患者慢性肾脏疾病或病症的方法,包括给有此需要的患 者施用治疗有效量的式(I)化合物或其药学上可接受的盐,其中所述疾病或病症选自:糖尿病 肾病、高血压肾病、HIV相关性肾病、肾小球肾炎、狼疮性肾炎、IgA肾病、局灶性节段性 肾小球硬化、膜性肾小球肾炎、微小病变肾病、多囊性肾病和肾小管间质性肾炎。在某些实 施方案中,所述方法进一步包括施用治疗有效量的至少一种另外的治疗剂。
另一方面,本发明涉及治疗患者急性肾脏损伤或疾病或病症的方法,包括给有此需 要的患者施用治疗有效量的式(I)化合物或其药学上可接受的盐,其中所述急性肾脏损伤或疾 病或病症选自:缺血-再灌注诱发的肾脏疾病、心脏和大型手术诱发的肾脏疾病、经皮冠状 动脉介入治疗诱发的肾脏疾病、放射造影剂诱发的肾病、脓毒症诱发的肾脏疾病、肺炎诱发 的肾病以及药物毒性诱发的肾病。在某些实施方案中,所述方法进一步包括施用治疗有效量 的至少一种另外的治疗剂。
另一方面,本发明涉及治疗患者艾滋病的方法,包括给有此需要的患者施用治疗有 效量的式(I)化合物或其药学上可接受的盐。在某些实施方案中,所述方法进一步包括施用治 疗有效量的至少一种另外的治疗剂。
另一方面,本发明涉及治疗患者肥胖、血脂异常、高胆固醇血症、阿尔茨海默氏病、代谢综合征、脂肪肝、II型糖尿病、胰岛素抗性、糖尿病性视网膜病变或糖尿病性神经病变的方法,包括向有此需要的患者施用治疗有效量的式(I)化合物或其药学上可接受的盐。 在某些实施方案中,所述方法进一步包括施用治疗有效量的至少一种另外的治疗剂。
另一方面,本发明提供男性患者避孕的方法,包括给有此需要的患者施用治疗有效量的式(I)化合物或其药学上可接受的盐。在某些实施方案中,所述方法进一步包括施用治疗有效量的至少一种另外的治疗剂。
另一方面,本发明进一步提供式(I)化合物单独或与第二种活性药剂组合在制备用于治疗或预防本文公开的疾病和病症的药物(含或不含药学可接受的载体)中的用途。
本发明还提供了含有式(I)化合物或药学上可接受的盐单独或与第二种活性药剂组合的药物组合物。在某些实施方案中,所述药物组合物包含治疗有效量的式(I)化合物或其药学可接受的盐,以及药学可接受的载体。
发明详述
本文公开了式(I)化合物
(I)
其中R1、R2和R10在上文的发明概述和下文的发明详述中进行定义。此外,还公开了包含此类化合物的组合物和用这些化合物和组合物治疗疾病和病症的方法。
本文所公开的化合物可含有一个或多个变量,其在本文任何取代基中或式中出现多于一次。在每次出现时变量的定义独立于其另一次出现的定义。此外,取代基的组合的先决条件是这种组合能够形成稳定的化合物。稳定的化合物是可从反应混合物中被分离的化合物。
a) 定义
值得注意的是,如在本说明书和意欲保护的权利要求中使用的,单数形式“一”、“一个”和“该”包括复数指代,除非上下文另有明确规定。因此,例如,提及“一种化合物”包括单个化合物以及一种或多种相同或不同的化合物,提及“任选地药学可接受的载体”是指单一的任选的药学可接受的载体以及一种或多种药学可接受的载体等。
当在说明书和所附的权利要求中使用时,除非作不同的指定,以下术语具有所指出的含义:
本文所用术语“烷基”是指饱和的直链或支链烃链基团。在一些情况下,烷基基团中的碳原子数目通过前缀“Cx-Cy”表示,其中x是取代基中最小的碳原子数目,并且y是取代基中最大的碳原子数目。因此,例如“C1-C6烷基”是指包含1至6个碳原子的烷基取代基,并且“C1-C3烷基”是指包含1至3个碳原子的烷基取代基。烷基的代表性实例包括,但不限于,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、1-甲基丁基、2-甲基丁基、3-甲基丁基、3,3-二甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-甲基丙基、2-甲基丙基、1-乙基丙基、1,2,2-三甲基丙基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
本文所用术语“卤代烷基”是指如本文所定义的烷基基团,其中一个、两个、三个、四个、五个或六个氢原子被卤素替代。术语“C1-C6卤代烷基”是指如本文所定义的C1-C6烷基,其中一个、两个、三个、四个、五个、六个或七个氢原子被卤素替代。术语“C1-C3卤代烷基”是指如本文所定义的C1-C3烷基,其中一个、两个、三个、四个、五个或六个氢原子被卤素替代。卤代烷基的代表性实例包括,但不限于,氯甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、三氟甲基、二氟甲基、五氟乙基、2-氯-3-氟戊基、三氟丁基、三氟丙基、2,2,3,3,3-五氟丙基和2,2,3,3,4,4,4-七氟丁基。
术语“烷撑”或“亚烷基”是指衍生自,例如1至10个碳原子或1至6个碳原子的(C1-C6亚烷基)或1至4个碳原子或2至3个碳原子(C2-C3亚烷基)的直链或支链的饱和烃链的二价基团。烷撑和亚烷基的实例包括但不限于-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-和-CH2CH(CH3)CH2-。
本文使用的术语“烯基”是指含有2至10个碳原子并含有至少一个碳-碳双键的直链或支链的烃链,任选地被1、2或3个卤素原子取代。术语“C2-C6烯基”是指包含2-6个碳原子的烯基。烯基的非限制性实例包括丁-1,3-二烯基、乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基和3-癸烯基。
术语“亚烯基”是指由2至4个碳原子的直链或支链烃衍生的二价基团并且包含至少一个碳-碳双键。亚烯基的代表性实例包括,但不限于,-CH=CH-和-CH2CH=CH-。
本文所用术语“芳基”是指苯基或双环芳基。所述双环芳基是萘基或稠合至单环C5-C7环烷基的苯基。芳基的非限制性实例包括二氢茚基(茚满基)、茚基、萘基、二氢萘基和四氢萘基。芳基通过包含在双环的环系统中的任何碳原子连接到母体分子部分,并且可以是未被取代的或被取代的。
本文所用术语“C3-C10环烷基”是指C3至C8单环的环烷基或C6至C10双环的环烷基。C3至C8单环的环烷基是含有三至八个碳原子的单环碳环体系。单环环体系的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。双环的C6至C10环烷基是稠合至单环的C4至C6环烷基环的单环C4至C6环烷基。单环的和双环的环烷基基团可以含有一个或两个烷撑桥,每个由一个、两个、三个或四个碳原子的长度组成,并且每一个桥连接环系统的两个非相邻的碳原子。含有这类烷撑桥的C3-C10环烷基的非限制性实例包括双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷、三环[3.3.1.03,7]壬烷(八氢-2,5-甲桥并环戊二烯(methanopentalene)或降金刚烷)和三环[3.3.1.13,7]癸烷(金刚烷)。单环和双环环烷基基团可以通过包含在环系统中的任何可取代的原子连接到母体分子部分。
本文所用术语“卤代”或“卤素”是指Cl、Br、I和F。
术语“3-至 8-元杂环烷基”是指具有碳原子和1至3个独立选自S、N和O的杂原子的非芳族环状基团,其中当存在两个O原子或一个O原子和一个S原子时,所述两个O原子或一个O原子和一个S原子分别地不互相连接。杂环烷基环中的氮和硫杂原子可任选被氧化(例如1,1-二氧代四氢噻吩基、1,2-二氧代-1,2-噻唑烷基、1,1-二氧代硫代吗啉基))并且氮原子可任选被季铵化。除非另有指明,前述杂环烷基可以是C-连接的或N-连接的,只要这种连接是可能的并导致形成稳定的结构。例如,哌啶基可以是哌啶-1-基 (N-连接的) 或哌啶-4-基 (C-连接的)。
“4-元杂环烷基”是具有3个碳原子和选自1个O;1个S;和1个N的1个杂原子的4-元单环环烷基环。4-元杂环烷基的举例性实例包括氧杂环丁基、氮杂环丁基和硫杂环丁基。
“5-元杂环烷基”是具有1至4个碳原子和选自1个O;1个S;1个N;2个N;3个N;1个S和1个N;1个S和2个N;1个O和1个N;和1个O和2个N 的1至3个杂原子的5-元单环环烷基环。5-元单环杂环烷基的举例性实例包括四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、咪唑烷基、噁唑烷基、咪唑啉基、异噁唑烷基、吡咯烷基、2-吡咯啉基和3-吡咯啉基。
“6-元杂环烷基”是具有3至5个碳原子和选自1个O;2个O;3个O;1个S;2个S;3个S;1个N;2个N;3个N;1个S、1个O和1个N;1个S和1个N;1个S和2个N;1个S和1个O;1个S和2个O;1个O和1个N;和1个O和2个N的1至3个杂原子的6-元单环环烷基环。6-元单环杂环烷基的举例性实例包括四氢吡喃基、二氢吡喃基、二噁烷基、1,3-二氧杂环戊烷基、1,4-二噻烷基、六氢嘧啶基、吗啉基、哌嗪基、哌啶基、2H-吡喃基、4H-吡喃基、吡唑烷基、吡唑啉基、1,2,3,6-四氢吡啶基、四氢噻喃基、硫代吗啉基、噻噁烷基和三噻烷基。
“7-元杂环烷基”是具有5或6个碳原子和选自1个O;2个O;1个S;2个S;1个N;2个N;1个S、1个O和1个N;1个S和1个N;1个S和2个N;1个S和1个O;1个S和2个O;1个O和1个N;和1个O和2个N的1至3个杂原子的7-元单环环烷基环。7-元单环杂环烷基举例性实例包括氮杂环庚烷基、2,3,4,5-四氢-1H-氮杂䓬基、氧杂环庚烷基、2,3,4,5-四氢-1H-氧杂䓬基、硫杂环庚烷基和2,3,4,5-四氢-1H-硫杂䓬基。
“8-元杂环烷基”是具有5至7个碳原子和选自1个O;2个O;3个O;1个S;2个S;3个S;1个N;2个N;3个N;1个S、1个O和1个N;1个S和1个N;1个S和2个N;1个S和1个O;1个S和2个O;1个O和1个N;和1个O和2个N的1至3个杂原子的8-元的单环环烷基环。8-元单环杂环烷基的举例性实例包括氮杂环辛基、硫杂环辛基、氧杂环辛基、3,4,5,6-四氢-2H-氧杂辛因基等。
单环杂环烷基可含有一个或两个亚烷基桥,每一个亚烷基桥由不超过四个碳原子组成并且每一个亚烷基桥连接环体系中的两个不相邻的原子。这类桥接的杂环烷基的实例包括,但不限于氮杂双环[2.2.1]庚基(包括2-氮杂双环[2.2.1]庚-2-基)、8-氮杂双环[3.2.1]辛烷-8-基和1-氮杂双环[2.2.2]辛烷-3-基。
本文所用术语 “杂芳基”,除非另有指明,是指单环5或6元杂芳基和双环 8至12元杂芳基。
“5-元杂芳基”是含有1至4个碳原子和选自1个O;1个S;1个N;2个N;3个N;4个N;1个S和1个N;1个S和2个N;1个O和1个N;和1个O和2个N的1至4个杂原子的5-元单环芳族环基团。5-元杂芳基的举例性实例包括,但不限于,呋喃基、2-呋喃基、3-呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡唑基、吡咯基、2-或3-吡咯基、噻吩基、2-噻吩基、3-噻吩基、四唑基、噻唑基、噻二唑和三唑基。
“6-元杂芳基”是含有 3至5碳原子和选自1个N;2个N;和3个N 的1至3个杂原子的6-元单环芳族环基团。6-元杂芳基的举例性实例包括,但不限于,吡啶基、2-、3-或4-吡啶基、嘧啶基、2-、4-或5-嘧啶基、吡嗪基、哒嗪基、3-或4-哒嗪基、2-吡嗪基和三嗪基。
“8-至12-元双环杂芳基”是通过5-或6-元杂芳基稠合至:(1) 独立选择的5-元杂芳基;(2) 独立选择的6-元杂芳基 (例如萘啶基、蝶啶基、酞嗪基、嘌呤基等);(3) C5-C8单环环烷基;(4) 5-至7-元杂环烷基;或(5)苯环(例如苯并咪唑基、苯并呋喃基、苯并呋咱基(benzofurazanyl)、2H-1-苯并吡喃基、苯并噻二嗪基、苯并噻嗪基、苯并噻唑基、苯并噻吩基、苯并噁唑基、噌啉基、呋喃并吡啶基、吲哚啉基、吲嗪基、吲哚基或2-、3-、4-、5-、6-或7-吲哚基、3H-吲哚基、喹唑啉基、喹啉基、喹喔啉基、异吲哚基和异喹啉基)上形成的环结构,其中所述稠合连接在相邻的环原子上。所述稠合可以在5-或6-元杂芳基的氮原子上(例如吲嗪)或碳原子上。
本文所用术语 “杂原子”是指氮、氧和硫。
本文所用术语“氧代”是指 =O基团。
如果基团被描述成是“被取代的”,则非氢基团代替了该基团的任何可取代的原子的氢。因此,例如,被取代的杂环基是其中至少有一个非氢基团替代了该杂环基团上的氢的杂环基团。应当知道,如果基团上发生一个以上的取代,则各个非氢基团可以相同或不同(除非另外说明)。
如果基团被描述成“被任选取代的”,则该基团可以是(1)未被取代的或(2)被取代的。如果基团被说成是被最高达某个特定数目的非氢基团任选取代,则该基团可以是:(1)未被取代;或(2)被最高达到该特定数目的非氢基团取代,或者被最高达到该基团上可取代位置的最高数目的非氢取代基取代,该值较小。因此,例如,如果基团被描述成任选被最多3个非氢基团取代的杂芳基,则可取代位置小于3的任何杂芳基可任选地被最多只能像该杂芳基具有的可取代位置一样多的非氢基团取代。举例来说,四唑基(它只有一个可取代位置)可任选地被最多一个非氢基团取代。再例如,如果氨基氮被描述成可任选地被最多2个非氢基团取代,则伯氨基氮可任选地被最多2个非氢基团取代,而仲氨基氮可任选地被最多只1个非氢基团取代。
术语“治疗(treat、treating、treatment)”是指缓解或消除疾病和/或其伴随症状的方法。
术语“预防(prevent、preventing、prevention)”是指预防疾病和/或其伴随症状发作或阻止个体患病的方法。在本文中使用时,“预防”还包括延缓疾病和/或其伴随症状的发作和降低个体患病的危险。
短语“治疗有效量”是指化合物或其药学可接受的盐的量,当单独或与另一种药物制剂联合施用治疗特定个体或个体群体中时,其足以防止发展或一定程度上缓解被治疗的疾病或病症的一种或多种症状。例如,在人或其它哺乳动物中,对于特定的疾病和被治疗的个体,治疗有效量可以在实验室或临床环境中通过实验确定,或可以是由美国食品和药物管理局或等效的外国机构的指南所要求的量。
术语“个体”或“患者”在本文中定义为指动物,例如哺乳动物,包括但不限于:灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选的实施方案中,所述个体是人。
式(I)化合物可以包含一个或多个不对称取代的原子。式(I)化合物还可以作为单个立体异构体(包括对映体和非对映体)及其混合物存在。式(I)化合物的单个立体异构体可由含有不对称或手性中心的市售可得的原料合成,或通过制备外消旋混合物,随后使用那些本领域技术人员已知的方法将各个立体异构体拆分制备。拆分的实例是,例如,(ⅰ)将对映体混合物与手性助剂连接,通过重结晶或色谱法将所得到的非对映体混合物分离,随后释放光学纯产物;或(ii)将对映异构体或非对映体的混合物在手性色谱柱上分离。
式(I)化合物也可包括碳-碳双键、碳-氮双键、环烷基或杂环基周围取代基的排布产生的各种几何异构体及其混合物。碳-碳双键或碳-氮双键周围取代基被指定为Z或E构型并且环烷基或杂环基周围取代基被指定为顺式或反式构型。
在本发明中应当理解的是,本文所公开的化合物可以显示出互变异构现象并且所有互变异构体都包含在本发明的范围内。
因此,本说明书中的结构式图可以仅表示可能的互变异构体、几何或立体异构体形式中的一种。但是应当理解,本发明包括任何互变异构、几何或立体异构形式,和它们的混合物,并且不仅仅局限于结构式中使用的任何一种互变异构体、几何或立体异构形式。
式I化合物可以以药学可接受的盐的形式使用。术语“药学可接受的盐”指那些盐,它们在合理的医学判断范围内,适用于与人类和较低等的动物的组织接触而没有过多的毒性、刺激性、变态反应等,并且与合理的利益/风险比相称。
药学可接受的盐已描述于S. M. Berge 等 J. Pharmaceutical Sciences,1977,66: 1-19。
式(I)的化合物可以包含碱性或酸性官能团或两者,并且可以在需要时,通过使用合适的酸或碱转换成药学可接受的盐。该盐可以在本发明化合物的最终分离和纯化过程中原位制备。
酸加成盐的实例包括,但不限于:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐)、乳酸盐、苹果酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。含有碱性氮的基团也可以用下列试剂如低级烷基卤化物季铵化,例如,但不限于:甲基、乙基、丙基和丁基的氯、溴和碘化物;硫酸二烷基酯例如,硫酸二甲基酯、二乙基酯、二丁基酯和二戊基酯;长链卤化物,例如,但不限于,癸基、月桂基、十四烷基和硬脂基的氯、溴和碘化物;芳烷基卤化物,例如,苄基和苯乙基的溴化物等。由此获得水或油溶性或可分散的产品。可用于形成药学可接受的酸加成盐的酸的实例,包括无机酸如盐酸、氢溴酸、硫酸和磷酸,以及有机酸如乙酸、富马酸、马来酸、4-甲基苯磺酸、琥珀酸和柠檬酸。
碱加成盐可以在本发明化合物的最终分离和纯化过程中,通过使含羧酸的基团与合适的碱,例如,但不限于,药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐,或与氨或有机伯、仲或叔胺反应来原位制备。药学上可接受的盐包括,但不限于,基于碱金属或碱土金属阳离子盐,例如但不限于锂、钠、钾、钙、镁和铝盐等,和无毒季氨和胺阳离子,包括铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺等。可用于形成碱加成盐的有机胺的其它的实例包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
术语“药学可接受的前药”或“前药”指本发明化合物的那些前药,它们在合理的医学判断范围内,适用于与人类和较低等的动物的组织接触而没有过多的毒性、刺激性、变态反应等,并且与合理的利益/风险比相称,并且对于它们预期的用途是有效的。
本发明包括通过合成方式形成的式(I)化合物或通过前药在体内生物转化形成的式(I)化合物。
本文所述的化合物可以以未溶剂化以及溶剂化形式,包括水合形式,例如半水合物的形式存在。通常,就本发明目的而言,与药学可接受的溶剂,例如水和乙醇等的溶剂化形式等同于未溶剂化形式。
通用合成
本文所述的化合物,包括通式(I)和具体实施例的化合物,可以通过本领域已知的方法,例如,通过方案1-5所示的反应路线制备。除非另有说明,用于以下方案的变量R1、R2、R8、R9、R10、R12、R20、R22和R10的取代基具有在发明概述和发明详述部分中描述的含义。
方案的描述和具体实施例中使用的缩略语具有下列含义:DMAP代表4-二甲基氨基吡啶,DME代表1,2-二甲氧基乙烷,DMF代表二甲基甲酰胺,DMSO代表二甲基亚砜,EDAC或EDCI或EDC代表1-乙基-3-[3-(二甲基氨基)丙基]-碳化二亚胺盐酸盐,HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐,HOBT代表1-羟基苯并三唑水合物,HPLC代表高效液相色谱,Pd2(dba)3代表三(二苄叉基丙酮)二钯(0),PdCl2(dppf)代表[1,1'-二(二苯基膦基)二茂铁]二氯化钯(II);SFC代表超临界流体色谱和TFA代表三氟乙酸,THF代表四氢呋喃和triflate代表三氟甲磺酸盐。
可用方案1所示的通用步骤制备通式(I)化合物。其中 R101是甲基、乙基或叔丁基的(1)与式(2)化合物在碱,例如,但不限于,氢化钠的存在下,在溶剂例如四氢呋喃或乙醚中,在约0℃至约30℃的温度下反应,得到式(3)化合物。通过(3)与乙酸铵/乙酸在溶剂例如,但不限于,乙醇和水中并且在升高温度 (例如约60 oC至约100 oC)下反应,可将(3)转化成吡咯 (4)。通过与酸,例如盐酸或三氟乙酸水溶液反应,或者通过 (4) 与碱,例如氢氧化锂或氢氧化钠,在溶剂例如,但不限于,四氢呋喃和水中反应,可将(4)的酯基水解,得到酸(5)。通过(5) 与氯化铵或取代的胺,在偶合剂例如HOBT、HATU或EDAC存在下,并且在碱例如二异丙基乙胺或三乙胺存在下,在溶剂例如四氢呋喃、二噁烷或二甲基甲酰胺中,在约0℃至约40℃温度下反应,可制备式I的酰胺。
方案 1
另一种选择为,可用方案2所示的通用步骤制备通式(I)化合物。通过使 (6)分别与 N-碘代琥珀酰亚胺(N-iodosuccinamide)或N-溴代碘琥珀酰亚胺,在溶剂例如,但不限于,四氢呋喃中,在约-78℃至约0℃温度下反应,可将(6)转化成其中 X是I或Br的(7)。通过(7) 与式(8)的硼酸或其衍生物(例如频哪醇酯)在Suzuki偶合条件下(N. Miyama and A.Suzuki,Chem. Rev. 1995,95:2457-2483,J. Organomet. Chem. 1999,576:147-148)反应,可将其中 X是Br或I的 (7)转化成通式(I)化合物。例如,偶合条件可在钯催化剂和碱存在下并任选在配体存在下,在溶剂中,在升高的温度 (例如约80 oC至约150 oC)下实施。该反应可通过微波辐射促进。钯催化剂的实例包括,但不限于,四(三苯基膦)钯(0)、三(二苄叉基丙酮)二钯(0)、二氯化双(三苯基膦)钯(II)和乙酸钯(II)。可用的合适的碱的实例包括,但不限于,钠、钾和铯的碳酸盐或磷酸盐和氟化铯。合适配体的实例包括,但不限于,1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷杂金刚烷、2-二环己基膦基-2′,4′,6′-三异丙基联苯 (X-phos)和1,1'-双(二苯基膦)二茂铁(1,1'-bis(diphenylphosphanyl)ferrocene)。合适溶剂的非限制性实例包括甲醇、乙醇、二甲氧基乙烷、N,N-二甲基甲酰胺、二甲亚砜、二噁烷、四氢呋喃和水或其混合物。
方案 2
其中 R10是被取代的苯基并且其中一个取代基是NR20R22或L-R12和L是-NH-、NHCO-或-NHSO2-的通式(I)化合物可应用例如,但不限于,方案 3中示出的合成路线制备。用铁粉在氯化铵存在下,在溶剂例如,但不限于,四氢呋喃、乙醇或水,或其混合物中,并在约80℃至约120℃的温度下可将式(9)的硝基化合物还原成式(10)的苯胺类化合物。另一种选择为,用氯化锡在盐酸中,在约80℃至约120℃的温度下进行该还原。将(9)转化为(10)也可以在催化剂例如氧化铂或钯/炭存在下,在溶剂例如乙醇或甲醇中,在氢气压下进行。在偶合剂例如HATU或EDAC存在下并在碱例如二异丙基乙基胺(aminde)或三乙胺存在下,在溶剂例如四氢呋喃、二噁烷或二甲基甲酰胺中,在约0℃至约40℃的温度下,用式R12COOH的羧酸处理苯胺 (10) ,得到式(11)的酰胺。在碱例如三乙胺或二异丙基乙胺存在下,在溶剂例如二氯甲烷或四氢呋喃中和在约0℃至约40℃的温度下,用式R12SO2Cl的磺酰基氯处理苯胺(10)得到磺酰胺(12)。在还原剂例如,但不限于,三乙氧基硼氢化钠、MP-氰基硼氢化物 (大孔三乙基铵甲基聚苯乙烯氰基硼氢化物)树脂、氰基硼氢化钠或硼氢化钠存在下,和在酸,例如,但不限于,乙酸存在下,在例如,但不限于,二氯甲烷、甲醇或乙醇的溶剂或者溶剂混合物中,用合适的醛或酮处理苯胺(10)得到式(13)的苯胺。在催化剂,例如,但不限于,乙酸Cu(II)和酸,例如,但不限于,肉豆蔻酸和碱,例如,但不限于,2,6-二甲基吡啶存在下,在溶剂,例如,但不限于,甲苯中,使式(10)化合物与式R12B(OH)2的硼酸或其衍生物(例如频哪醇酯)反应,得到式(14)化合物,从而可制备式(14)化合物。
方案 3
其中 R104是芳基或杂芳基的通式(I)化合物可应用例如,但不限于,方案 4示出的合成路线制备。在上述Suzuki偶合条件下通过化合物(15)与式(16)的硼酸或其衍生物(例如频哪醇酯)反应,可将其中如在发明简述中所定义 R103是与R10的取代基相同 (卤素除外),m是0、1或2和R102是Br、I或三氟甲磺酰氧基的化合物(15),转化成式(17)化合物。
方案 4
目标化合物,例如其中R105是与R10的取代基相同(卤素除外)和n是0、1或2的(19)、(20)和(21)化合物可应用例如,但不限于,方案 5示出的反应路线制备。用式R12-OH的醇取代其中 R106是氟的(18)化合物中的氟原子的反应可在溶剂例如,但不限于,二甲亚砜、二甲基甲酰胺、二噁烷或四氢呋喃中和在碱例如,但不限于,铯、钾或钠的碳酸盐或氢化钠存在下,和在约40℃至约120℃的温度下完成,从而可得到式(19)的化合物。另一种选择为,其中R106是Br、I、Cl或三氟甲磺酰氧基的式(18)化合物与如在发明简述中所定义的其中 R12是芳基、杂芳基、环烷基或杂芳基的R12OH的醇的反应可得到式(19)化合物。这一转化可在催化剂例如,但不限于乙酸Cu(II)和酸,例如,但不限于,吡啶甲酸和碱,例如但不限于,磷酸钾存在下,在溶剂例如,但不限于,二甲亚砜或二甲基甲酰胺中,在约70℃至约140℃的温度下进行。用铁粉在氯化铵存在下,在溶剂例如,但不限于,四氢呋喃、乙醇或水或其混合物中,和在约80℃至约120℃的温度下,可将其中 n是1和R105是NO2的式(19)化合物还原成式(20)的苯胺。另一种选择为,用氯化锡在盐酸中,在约80℃至约120℃的温度下进行该还原。该还原也可以在催化剂例如氧化铂或钯/炭存在下,在溶剂例如乙醇或甲醇中,在氢气压下进行。在碱例如三乙胺或二异丙基乙胺存在下,在溶剂例如二氯甲烷或四氢呋喃中,和在约0℃至约40℃的温度下,用式R12SO2Cl的磺酰基氯处理苯胺(20)得到磺酰胺(21)。
方案 5
应认识到,所述合成反应路线和在合成实施例部分中举例说明的具体实施例是说明性的,并且不视为限制在所附权利要求中限定的本发明的范围。所述合成方法和具体实施例的所有替换、修饰和等同物均包括在权利要求的范围之内。
对于每个单个步骤最佳的反应条件和反应时间可以根据所采用的具体反应物和所用的反应物中存在的取代基而变化。除非另有说明,溶剂、温度和其它反应条件可以由本领域技术人员容易地选择。具体方法提供在合成实施例部分。反应可以以常规的方式进行后处理,例如通过从残余物中除去溶剂并根据本领域已知的方法学进一步纯化,所述方法学例如,但不限于,结晶、蒸馏、萃取、研制和色谱。除非另有说明,所述原料和试剂可商购获得或可以由本领域技术人员使用化学文献中描述的方法由可商购获得的材料制备。
常规实验,包括反应条件、试剂和合成路线顺序的适当操作,与反应条件不能相容的任何化学官能团的保护,和在该方法的反应顺序中在适当的点的脱保护都包括在本发明的范围内。合适的保护基团和使用这些合适的保护基团用于保护和脱保护不同取代基的方法,是本领域技术人员熟知的,其实例可见于T. Greene和P. Wuts,Protecting Groups inOrganic Synthesis (3rd ed.),John Wiley & Sons,NY (1999),其通过引用方式以其整体并入本文。本发明化合物的合成可以通过类似于在上文中描述的合成反应路线和具体实施例中所述方法来完成。
原料,如果不能商购,可通过选自标准有机化学技术,类似于合成已知的、结构类似的化合物的技术,或类似于上述反应路线或在合成实施例部分中所述的方法来制备。
当需要化合物的旋光形式时,它可以通过进行本文所述的方法之一使用光学活性的原料(例如通过不对称诱导合适的反应步骤来制备)来获得,或通过使用标准方法(如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物来获得。
类似地,当需要化合物的纯几何异构体时,它可以通过进行上述方法之一,使用纯几何异构体作为原料,或通过使用标准方法,如色谱分离来拆分化合物或中间体的几何异构体的混合物来制备。
应认识到,所述合成反应路线和在合成实施例部分中举例说明的具体实施例是说明性的,并且不视为限制在所附权利要求中限定的本发明的范围。所述合成方法和具体实施例的所有替换、修饰和等同物均包括在权利要求的范围之内。
对于每个单个步骤最佳的反应条件和反应时间可以根据所采用的具体反应物和所用的反应物中存在的取代基而变化。除非另有说明,溶剂、温度和其它反应条件可以由本领域技术人员容易地选择。具体方法提供在合成实施例部分。反应可以以常规的方式进行后处理,例如通过从残余物中除去溶剂并根据本领域已知的方法学进一步纯化,所述方法学例如,但不限于,结晶、蒸馏、萃取、研制和色谱。除非另有说明,所述原料和试剂可商购获得或可以由本领域技术人员使用化学文献中描述的方法由可商购获得的材料制备。
常规实验,包括反应条件、试剂和合成路线顺序的适当操作,与反应条件不能相容的任何化学官能团的保护,和在该方法的反应顺序中在适当的点的脱保护都包括在本发明的范围内。合适的保护基团和使用这些合适的保护基团用于保护和脱保护不同取代基的方法,是本领域技术人员熟知的,其实例可见于T. Greene和P. Wuts,Protecting Groups inOrganic Synthesis (3rd ed.),John Wiley & Sons,NY (1999),其通过引用方式以其整体并入本文。本发明化合物的合成可以通过类似于在上文中描述的合成反应路线和具体实施例中所述方法来完成。
原料,如果不能商购,可通过选自标准有机化学技术,类似于合成已知的、结构类似的化合物的技术,或类似于上述反应路线或在合成实施例部分中所述的方法来制备。
当需要化合物的旋光形式时,它可以通过进行本文所述的方法之一使用光学活性的原料(例如通过不对称诱导合适的反应步骤来制备)来获得,或通过使用标准方法(如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物来获得。
类似地,当需要化合物的纯几何异构体时,它可以通过进行上述方法之一,使用纯几何异构体作为原料,或通过使用标准方法,如色谱分离来拆分化合物或中间体的几何异构体的混合物来制备。
药物组合物
本发明还提供药物组合物,其包含治疗有效量的式(I)化合物或其药学可接受的盐以及药学可接受的载体、稀释剂或赋形剂。短语“药物组合物”指适用于以医学或兽医用途施用的组合物。
单独包含式(I)化合物或包含式(I)化合物与第二活性药剂组合的药物组合物,可以口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如通过粉剂,软膏或滴剂)、经颊或作为经口或鼻喷雾施用于个体。如本文所用术语“肠胃外”是指给药方式,其包括静脉内、肌内、腹膜内、胸骨内、皮下和关节内注射和输注。
在本文所用术语“药学可接受的载体”是指无毒的惰性固体、半固体或液体填充剂、稀释剂、包封材料或任何类型的制剂助剂。可以作为药学可接受的载体的材料的一些实例是:糖类例如,但不限于,乳糖,葡萄糖和蔗糖;淀粉类例如,但不限于,玉米淀粉和马铃薯淀粉;纤维素及其衍生物类例如,但不限于,羧甲基纤维素钠、乙基纤维素和醋酸纤维素;西黄蓍胶粉;麦芽;明胶;滑石;赋形剂例如,但不限于,可可脂和栓剂蜡;油类例如,但不限于,花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,例如丙二醇;酯类例如,但不限于,油酸乙酯和月桂酸乙酯;琼脂;缓冲剂类例如,但不限于,氢氧化镁和氢氧化铝;藻酸;无热原水;等渗盐水;林格氏溶液;乙醇和磷酸盐缓冲溶液,以及其它无毒的相容性润滑剂类,例如但不限于,月桂基硫酸钠和硬脂酸镁,以及着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂,根据配制者的判断,防腐剂和抗氧化剂也可存在于组合物中。
用于肠胃外注射的药物组合物包含药学可接受的无菌水性或非水性溶液、分散液、悬浮液或乳液,以及在使用之前重构成无菌注射溶液或分散体的无菌粉末。合适的水性和非水性载体,稀释剂,溶剂或赋形剂的实例包括水、乙醇、多元醇类(如甘油、丙二醇、聚乙二醇等)、植物油类(如橄榄油)、可注射有机酯类(如油酸乙酯)及其合适的混合物。例如,通过使用包衣材料如卵磷脂,通过在分散液的情况下维持所要求的粒径和通过使用表面活性剂,可以保持适当的流动性。
这些组合物还可以包含佐剂,如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗菌剂和抗真菌剂来保证防止微生物的作用,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等。也可包括等渗剂,例如糖类、氯化钠等。可注射的药物形式的延长吸收可以通过在组合物中包含延迟吸收的试剂,例如单硬脂酸铝和明胶来实现。
在某些情况下,为了延长药物的作用,期望延缓药物从皮下或肌内注射的吸收。这可以通过使用水溶性差的晶体或无定形物质的液体悬浮液来实现。该药物的吸收速率取决于其溶解速率,这反过来又可能取决于晶体大小和晶型。或者,胃肠外施用的药物形式的延迟吸收可通过在油性介质中溶解或悬浮药物而实现。
可注射的储库形式是通过在可生物降解的聚合物如聚丙交酯 -聚乙交酯中形成药物的微囊基质来制备。根据药物与聚合物的比例和所用的具体聚合物的性质,可以控制药物释放的速率。其它生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。储库注射制剂也可以通过将药物包埋在与身体组织相容的脂质体或微乳中制备。
可注射的组合物可以进行灭菌,例如通过细菌截留过滤器过滤或通过加入无菌固体组合物形式的灭菌剂,其可以在使用前溶解或分散在无菌水或其它无菌可注射介质中。
用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在某些实施方案中,固体剂型可以含有1%到95%(w/w)的式I化合物。在某些实施方案中,式I化合物可以5%到70%(w/w)的比例存在于固体剂型中。在这些固体剂型中,活性化合物可以与下列混合:至少一种惰性的、药学上可接受的赋形剂或载体(如柠檬酸钠或磷酸二钙)和/或a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶解阻滞剂如石蜡;f)吸收促进剂如季铵化合物;g)湿润剂如鲸蜡醇和单硬脂酸甘油酯;h)吸收剂如高岭土和膨润土和i)润滑剂,例如如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠和它们的混合物。在胶囊、片剂和丸剂的情况下,该剂型还可以包含缓冲剂。
该药物组合物可以是单位剂型。在这种形式中,组合物被细分为含有适量活性成分的单位剂量。该单位剂量形式可以是包装的组合物、含有组合物的离散量的包装如包装的片剂、胶囊和在小瓶或安瓿中的粉末。另外,单位剂量形式可以是胶囊、片剂、扁囊剂或锭剂本身,或者其可以是适当数量的任何这些单位剂量形式的包装。根据特定的应用和活性组分的效力,在单位剂量制剂中活性成分的量可以变化或调整,从0.1mg至1000mg,从1mg至100mg,或从1%至95%(w/w)的单位剂量。该组合物可以,如果需要,还含有其它相容的治疗剂。
要施用给患者的剂量可以通过所使用的特定化合物的效力和患者的状况、体重或表面积来确定。剂量的大小还决定于在特定的患者中施用的具体化合物不利的副作用的存在、性质和程度。在确定要治疗的疾病的治疗或预防中待施用的化合物的有效量时,医生评估的因素,例如该化合物的循环血浆水平、化合物的毒性和/或疾病的进展等。在一般情况下,对于代表性的患者,化合物的剂量从大约1微克/公斤至100毫克/公斤。
如同对患者的体重和整体健康情况的考量,施用时式I化合物的施用频次由包括但不限于以下的因素决定:所述化合物的LD50、药代动力学特征、禁忌药和在各浓度下所述化合物的副作用。可以单剂服用或分剂量服用。
在本发明的制药方法中使用的化合物可以以每天约0.001mg/kg至约100mg/kg的初始剂量施用。在某些实施方案中,日剂量范围从约0.1 mg/kg至10 mg/kg。然而,剂量也可以根据患者的需求、所治疗疾病的严重程度和所采用的化合物而变化。对特定情况的合适剂量由医生确定。治疗可以从小于所述化合物的最佳剂量的较小剂量开始。此后,剂量以少量增加,直至达到最佳效果。如果需要,为方便起见,总的日剂量可以在一天内分多份并分批施用。
类似类型的固体组合物还可以填充到用乳糖或奶糖以及高分子量的聚乙二醇等作为载体的软和硬的明胶胶囊中。
片剂、糖衣丸、胶囊、丸剂和颗粒剂的固体剂型可以用包衣和壳例如肠溶衣和其它药物制剂领域中熟知的包衣来制备。它们可以任选含有遮光剂,也可以是组合物,使得它们仅在或优先在肠道的某一部分中任选地以延迟方式释放活性成分。可使用的包埋组合物的实例包括聚合物和蜡。
如果合适,可以将活性化合物与一种或多种上述载体一起制成微囊化形式。
用于口服施用的液体剂型包括可药用的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性化合物外,液体剂型可含有在本领域通常使用的惰性稀释剂,例如,水或其它溶剂,增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨糖醇的脂肪酸酯及它们的混合物。
除惰性稀释剂外,口服组合物还可包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
悬浮液,除了活性化合物外,还可含有悬浮剂,例如,乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、西黄蓍胶和它们的混合物。
用于直肠或阴道施用的组合物优选是栓剂,其可通过混合本发明化合物与合适的非刺激性载体如可可脂、聚乙二醇或栓剂用蜡制备,其在室温下是固体但在体温下是液体并因此在直肠中或阴道腔融化并释放活性化合物。
式I化合物还可以以脂质体的形式施用。脂质体通常可以由磷脂或其它脂质物质制备。脂质体通过分散在水性介质中的单或多层水合液晶形成。任何无毒的、生理学上可接受和可代谢的能够形成脂质体的脂质都可以使用。除了式(I)化合物之外,脂质体形式的本发明组合物还可含有稳定剂、防腐剂、赋形剂等。脂质的实例包括,但不限于,天然和合成的磷脂和磷脂酰胆碱(卵磷脂),单独或一起使用。
形成脂质体的方法已描述于,例如Prescott,编辑,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y. (l976),p. 33 et seq。
本文所述化合物的局部施用的剂型包括粉剂、喷雾剂、软膏剂和吸入剂。该活性化合物可在无菌条件下与药学上可接受的载体和可能需要的任何所需防腐剂、缓冲剂或抛射剂进行混合。眼用制剂、眼用软膏、粉剂和溶液也涵盖在本发明的范围之内。
使用方法
式I化合物,或其药学上可接受的盐,以及包含式I化合物或其药学上可接受的盐的药物组合物,可以施用于患有布罗莫结构域介导的病症或疾病的患者。术语“施用”是指给患者服用化合物的方法。因此,式I化合物可以通过注射施用,即静脉内、肌内、皮内、皮下、十二指肠内、胃肠外或腹膜内。并且,本文所述化合物可以通过吸入,例如鼻内施用。另外,式I化合物可以经皮、局部、经由植入、经皮施用。在某些实施方案中,式I化合物可以口服递送。所述化合物还可以经直肠、经颊、阴道内、经眼、经肛门或通过吹入递送。布罗莫结构域介导的病症和疾病可以使用式I化合物预防性、急性和慢性治疗,这取决于病症或疾病的性质。通常,每个这些方法中的宿主或患者是人,虽然其它哺乳动物也可以受益于式I化合物的施用。
“布罗莫结构域介导的疾病或病症”的特征为一个或多个布罗莫结构域(例如BRD4)参与病症或疾病的一种或多种症状或疾病标志物的开始、表现、严重性或进展。
因此,式I化合物可以用于治疗癌症,包括但不限于:听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞白血病(单核细胞的、成髓细胞的、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞的和早幼粒细胞的)、急性t细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管源性癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞(粒细胞)白血病、慢性粒细胞白血病、结肠癌、结肠直肠癌、颅咽管癌、囊腺癌、弥漫性大B细胞淋巴癌、异常增生(dysproliferative)变化(发育不良症和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因癌、纤维肉瘤、滤泡性淋巴瘤、睾丸生殖细胞癌、神经胶质瘤、胶质母细胞瘤、神经胶质肉瘤、重链病、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤(lympagiendotheliosarcoma)、淋巴管肉瘤、淋巴母细胞白血病、淋巴瘤(霍奇金型和非霍奇金型),膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性疾病和增生病变,T细胞或B细胞源的恶性淋巴增殖性疾病、白血病、淋巴癌、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓源性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突胶质细胞瘤、口腔癌、成骨肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体肿瘤(细胞癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、良性滑膜瘤、汗腺癌、辐射诱发的甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。
此外,式I化合物可以用于治疗炎性疾病、炎性病症和自身免疫性疾病,包括但不限于:阿狄森氏病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特氏病、大疱性皮肤病、慢性阻塞性肺部疾病(COPD)、克罗恩病、皮炎、湿疹、巨细胞动脉炎、肾小球肾炎、肝炎、垂体炎、炎性肠道疾病、川崎症、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、高安氏动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、脉管炎和韦格纳氏肉芽肿病。
式I化合物或其药学可接受的盐可用于治疗艾滋病。
式I化合物可以联合施用于患者。术语“联合施用”是指两种或更多种不同的药剂或治疗(例如,放射性治疗)联合施用于患者,其在相同的药物组合物中或在不同的药物组合物中。因此,联合施用涉及同时施用含有两种或更多种药剂的单个药物组合物,或给同一患者同时或不同时施用两种或更多种不同的组合物。
本发明化合物可以与治疗有效量的一种或多种治疗癌症的药剂联合施用,其中所述药剂的实例包括:例如辐射、烷基化试剂、血管生成抑制剂、抗体、抗代谢剂、抗有丝分裂药、抗增殖药、抗病毒药、奥罗拉激酶抑制剂、细胞凋亡促进剂(例如、Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体通道的激活剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞桥联体)抗体、抗体药物偶联物、生物反应调节剂、细胞周期激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVDs(双变量域抗体)、白血病病毒致癌基因同系物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂、激素疗法治疗剂、免疫药物、凋亡蛋白抑制剂(IAPs)的抑制剂、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、哺乳动物雷帕霉素靶抑制剂、mRNA、丝裂原活化细胞外信号调节激酶抑制剂、多价结合蛋白、非甾体抗炎药(NSAIDs)、聚ADP(腺苷二磷酸酯)-核糖聚合酶(PARP)抑制剂、铂类化疗药物、保罗样激酶(Plk)抑制剂、磷脂酰肌醇-3-激酶(布罗莫结构域)抑制剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、etinoids/deltoids植物生物碱、小核糖核酸抑制剂 (siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂,等等,或一种或多种所述药剂联合使用。
BiTE抗体是双特异性抗体,其通过同时结合T-细胞与癌细胞,导引T-细胞攻击癌细胞。于是T细胞攻击目标癌细胞。BiTE抗体的实例包括阿德木单抗(Micromet MT201)、blinatumomab(Micromet MT103)等。不受理论的限制,T细胞引起目标癌细胞凋亡的机制之一是溶细胞颗粒组分(包括穿孔蛋白和颗粒酶B)的胞吐作用。在这方面,Bcl-2已显示出减弱由穿孔蛋白和颗粒酶B诱发的细胞凋亡。这些数据表明,抑制Bcl-2能增强靶向癌细胞时的T细胞引起的细胞毒性作用(V. R. Sutton,D. L. Vaux和J. A. Trapani,J. ofImmunology 1997,158 (12),5783)。
SiRNAs是具有内源性RNA碱基或化学改性核苷酸的分子。所述的改性不消除细胞活性,而是赋予提高的稳定性和/或增强的细胞效能。化学改性的实例包括硫代磷酸基团、2’-脱氧核苷酸、含有2’-OCH3的核糖核苷酸、2’-F-核糖核苷酸、2’-甲氧基乙基核糖核苷酸,它们的组合等。siRNA可以有变化的长度(例如,10-200 bps)和结构(例如,发夹形、单/双链、凸起、缺口/裂隙、错配),并且在细胞中被加工以提供活性基因沉默。双链siRNA(dsRNA)在每条链(平端)或不对称端(突出端)上可以有相同数目的核苷酸。1-2个核苷酸的突出端可存在于正义链和/或反义链上,以及存在于给定链的5’-端和/或3’-端。
多价结合蛋白是含有两个或更多抗原结合位点的结合蛋白。多价结合蛋白被设计成具有三个或更多的抗原结合位点并且通常是非天然存在的抗体。术语“多特异性结合蛋白”是指能结合两个或更多的相关或不相关靶标的结合蛋白。双可变域(DVD)结合蛋白是含有两个或多个抗原结合位点的四价或多价结合蛋白。这种DVD可以是单特异性的(即,能结合一种抗原)或多特异性的(即,能结合两种或更多种抗原)。含两个重链DVD多肽和两个轻链DVD多肽的DVD结合蛋白被称作DVD Ig。DVD Ig的每一半都含一个重链DVD多肽、一个轻链DVD多肽和两个抗原结合位点。每个结合位点含有一个重链可变域和一个轻链可变域,每个抗原结合位点有总计6个参与抗原结合的CDR。多特异性DVD包括结合DLL4和VEGF,或C-met和EFGR或ErbB3和EGFR的DVD结合蛋白。
烷基化试剂包括六甲蜜胺、AMD-473、AP-5280、阿帕齐醌(apaziquone)、苯达莫司汀、brostallicin、白消安、卡波醌、卡莫司汀(BCUN)、苯丁酸氮芥、CLORETAZINE®(拉罗莫司汀(laromustine),VNP 40101M)、环磷酰胺、达卡巴嗪(decarbazine)、雌莫司汀、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、洛莫司汀(CCNU)、马磷酰胺、苯丙氨酸氮芥、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、塞替哌、TREANDA®(苯达莫司汀)、曲奥舒凡、rofosfamide,等等。
血管生成抑制剂包括内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、表皮生长因子受体(EGFR)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板衍生的生长因子受体(PDGFR)抑制剂、凝血酶敏感蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂,等等。
抗代谢药包括ALIMTA®(培美曲塞二钠、LY 231514,MTA)、5-阿扎胞苷、XELODA®(卡培他滨)、卡莫氟、LEUSTAT®(克拉屈滨)、氯法拉滨、阿糖胞苷、阿糖胞苷十八碳磷酸酯钠、胞嘧啶阿糖胞苷、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、依诺他滨、ethnylcytidine、氟达拉滨、5-氟尿嘧啶本身或与甲酰四氢叶酸组合、GEMZAR®(吉西他滨)、羟基脲、ALKERAN®(苯丙氨酸氮芥)、巯基嘌呤、6-巯基嘌呤类核苷、甲氨蝶呤、麦考酚酸、奈拉滨、洛拉曲塞、十八碳磷酸酯钠(ocfosfate)、吡利曲索(pelitrexol)、喷司他丁、雷替曲塞、利巴韦林、triapine、三甲曲沙、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、UFT,等等。
抗病毒药包括利托那韦、羟氯喹等。
奥罗拉激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、奥罗拉A-特异性激酶抑制剂、奥罗拉B特异性激酶抑制剂和潘-奥罗拉激酶抑制剂等。
Bcl-2蛋白抑制剂包括AT-101 ((-)棉酚)、GENASENSE® (G3139或奥利美生(oblimersen)( 靶向Bcl-2的反义寡核苷酸))、IPI 194、IPI-565、N-(4-(4-((4'-氯(1,1'-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-硝基苯磺酰胺) (ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-环己-1-烯-1-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(吗啉-4-基)-1-((苯基硫烷基)甲基)丙基)氨基)-3-((三氟甲基)磺酰基)苯磺酰胺(ABT-263)、GX-070 (obatoclax)、ABT-199,等等。
Bcr-Abl激酶抑制剂包括DASATINIB®(BMS-354825)、GLEEVEC® (伊马替尼),等等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT 2584、flavopyridol、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib (CYC-202、R-细胞周期蛋白B激酶抑制剂)、ZK-304709,等等。
COX-2抑制剂包括ABT-963、ARCOXIA® (依托昔布)、BEXTRA® (伐地昔布)、BMS347070、CELEBREX® (塞来昔布)、COX 189 (罗美昔布)、CT-3、DERAMAXX® (地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰苯基-1H-吡咯)、MK-663 (依托昔布)、NS-398、帕瑞昔布、RS-57067、SC 58125、SD-8381、SVT 2016、S-2474、T-614、VIOXX® (罗非昔布),等等。
EGFR抑制剂包括EGFR抗体、ABX-EGF、抗EGFR免疫脂质体、EGF疫苗、EMD-7200、ERBITUX® (西妥昔单抗)、HR3、IgA抗体、IRESSA® (吉非替尼)、TARCEVA® (厄洛替尼或OSI-774)、TP-38、EGFR融合蛋白、TYKERB® (拉帕替尼),等等。
ErbB2受体抑制剂包括CP-724-714、CI-1033 (卡奈替尼)、HERCEPTIN® (曲妥珠单抗)、TYKERB® (拉帕替尼)、OMNITARG® (2C4,帕妥珠单抗)、TAK-165、GW-572016(ionafarnib)、GW-282974、EKB-569、PI-166、dHER2 (HER2疫苗)、APC-8024 (HER-2疫苗)、抗 HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三官能双特异性抗体、mAB AR-209、mAB2B-1,等等。
组蛋白去乙酰化酶抑制剂包括缩酚肽、LAQ-824、MS-275、trapoxin、辛二酰苯胺异羟肟酸(SAHA)、TSA、丙戊酸,等等。
HSP-90抑制剂包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MYCOGRAB® (HSP-90的人重组抗体)、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090 VER49009,等等。
细胞凋亡蛋白抑制剂的抑制剂包括HGS1029、GDC-0145、GDC-0152、LCL-161、LBW-242,等等。
抗体药物偶联物包括抗-CD22-MC-MMAF、抗-CD22-MC-MMAE、抗-CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19Am SGN-35、SGN-75,等等。
死亡受体通道的激活剂包括TRAIL,以TRAIL或死亡受体(例如DR4和DR5)为靶标的抗体或其它试剂,例如Apomab、可那木单抗(conatumumab)、ETR2-ST01、GDC0145、(来沙木单抗)、HGS-1029、LBY-135、PRO-1762和曲妥珠单抗。
驱动蛋白抑制剂包括Eg5抑制剂,例如AZD4877、ARRY-520;CENPE抑制剂,例如GSK923295A,等等。
JAK-2抑制剂包括CEP-701(lesaurtinib)、XL019和INCB018424,等等。
MEK抑制剂包括ARRY-142886、ARRY-438162、PD-325901、PD-98059,等等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、坦罗莫司、ATP-竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30、Torin 1,等等。
非甾体抗炎药包括AMIGESIC® (双水杨酸酯)、DOLOBID® (二氟尼柳)、MOTRIN®(布洛芬)、ORUDIS® (酮洛芬)、RELAFEN® (萘丁美酮)、FELDENE® (吡罗昔康)、布洛芬乳膏、ALEVE® (萘普生)和NAPROSYN® (萘普生)、VOLTAREN® (双氯芬酸)、INDOCIN® (吲哚美辛)、CLINORIL® (舒林酸)、TOLECTIN® (托美丁)、LODINE® (依托度酸)、TORADOL® (酮咯酸)、DAYPRO® (奥沙普秦),等等。
PDGFR抑制剂包括C-451、CP-673、CP-868596,等等。
铂类化疗药物包括顺铂、ELOXATIN® (奥沙利铂)、依铂、洛铂、奈达铂、PARAPLATIN® (卡铂)、沙铂、吡铂,等等。
保罗样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶(PI3K)抑制剂包括渥曼青霉素、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765,等等。
凝血酶敏感蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1,等等。
VEGFR抑制剂包括AVASTIN® (贝伐珠单抗)、ABT-869、AEE-788、ANGIOZYMETM (抑制血管生成的核酶(Ribozyme Pharmaceuticals (Boulder、CO.)和Chiron (Emeryville,CA))、阿昔替尼(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN (pegaptamib)、NEXAVAR® (索拉非尼,BAY43-9006)、帕唑帕尼(GW-786034)、伐他拉尼(PTK-787、ZK-222584)、SUTENT® (舒尼替尼、SU-11248)、VEGF trap、ZACTIMATM (凡德他尼,ZD-6474)、GA101、奥法木单抗、ABT-806 (mAb-806)、ErbB3特异性抗体、BSG2特异性抗体、DLL4特异性抗体和C-met特异性抗体,等等。
抗生素包括嵌入抗生素阿柔比星、放线菌素D、氨柔比星、annamycin、阿霉素、BLENOXANE® (博来霉素)、柔红霉素、CAELYX®或MYOCET® (多柔比星脂质体)、依沙芦星、epirbucin、glarbuicin、ZAVEDOS® (伊达比星)、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、stimalamer、链脲霉素、VALSTAR® (戊柔比星)、净司他丁,等等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、贝特卡令(becatecarin)、贝洛替康、BN-80915、CAMPTOSAR® (盐酸伊立替康)、喜树碱、CARDIOXANE®(dexrazoxine)、二氟替康(diflomotecan)、艾特咔林(edotecarin)、ELLENCE®或PHARMORUBICIN® (表柔比星)、伊托泊苷、伊沙替康、10-羟基喜树碱、gimatecan、勒托替康、米托蒽醌、orathecin、pirarbucin、 pixantrone、鲁比替康、索布佐生、SN-38、他氟泊苷(tafluposide)、托泊替康,等等。
抗体包括AVASTIN® (贝伐珠单抗)、CD40-特异性抗体、chTNT-1/B、德尼单抗、ERBITUX®(西妥昔单抗)、HUMAX CD4®(扎木单抗)、IGF1R-特异性抗体、林妥珠单抗、PANOREX®(依决洛单抗)、RENCAREX®(WX G250)、RITUXAN®(利妥昔单抗)、替昔木单抗(ticilimumab)、曲妥珠单抗(trastuzimab)、CD20抗体I型和II型,等等。
激素治疗剂包括ARIMIDEX® (阿那曲唑)、AROMASIN® (依西美坦)、阿佐昔芬、CASODEX® (比卡鲁胺)、CETROTIDE® (西曲瑞克)、地加瑞克、地洛瑞林、DESOPAN® (曲洛司坦)、地塞米松、DROGENIL® (氟他胺)、EVISTA® (雷洛昔芬)、AFEMATM (法倔唑)、FARESTON®(托瑞米芬)、FASLODEX® (氟维司群)、FEMARA® (来曲唑)、福美坦、肾上腺糖皮质激素、HECTOROL® (度骨化醇)、RENAGEL® (碳酸司维拉姆)、拉索昔芬、醋酸亮丙瑞林、MEGACE®(megesterol)、MIFEPREX® (米非司酮)、NILANDRONTM (尼鲁米特)、NOLVADEX® (枸橼酸他莫昔芬)、PLENAXISTM (阿巴瑞克)、泼尼松、PROPECIA® (非那雄胺)、rilostane、SUPREFACT®(布舍瑞林)、TRELSTAR® (促性腺激素释放激素(LHRH))、VANTAS® (组氨瑞林植入剂)、VETORYL® (曲洛司坦或modrastane)、ZOLADEX® (fosrelin、戈舍瑞林),等等。
Deltoids和retinoids包括西奥骨化醇(EB1089、CB1093)、lexacalcitrol(KH1060)、芬维A胺、PANRETIN® (aliretinoin)、ATRAGEN® (维甲酸脂质体)、TARGRETIN®(贝沙罗汀)、LGD-1550,等等。
PARP抑制剂包括ABT-888 (veliparib)、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231,等等。
植物生物碱包括但不限于长春新碱、长春花碱、长春地辛、长春瑞滨,等等。
蛋白酶体抑制剂包括VELCADE® (硼替佐米)、MG132、NPI-0052、PR-171,等等。
免疫药物的实例包括干扰素和其它免疫增强剂。干扰素类包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ACTIMMUNE® (干扰素γ-1b)或干扰素γ-n1,它们的组合,等等。其它药剂包括ALFAFERONE® (IFN-α)、BAM-002 (氧化谷胱甘肽)、BEROMUN®(他索纳明)、BEXXAR® (托西莫单抗)、CAMPATH® (阿仑珠单抗)、CTLA4 (细胞毒性淋巴细胞抗原4)、decarbazine、denileukin、依帕珠单抗、GRANOCYTE® (来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫德、MDX 010 (抗-CTLA-4)、黑素瘤疫苗、米妥莫单抗、莫拉司亭、MYLOTARGTM (吉妥珠单抗奥佐米星)、NEUPOGEN® (非格司亭)、OncoVAC-CL、OVAREX®(oregovomab)、pemtumomab (Y muHMFG1)、PROVENGE® (sipuleucel-T)、sargaramostim、西佐喃、替西白介素、THERACYS® (卡介苗菌)、乌苯美司、VIRULIZIN® (免疫治疗药,LorusPharmaceuticals)、Z-100 (Maruyama的特异物质(SSM))、WF-10 (Tetrachlorodecaoxide(TCDO))、PROLEUKIN® (阿地白介素)、ZADAXIN® (胸腺法新)、ZENAPAX® (达利珠单抗)、ZEVALIN® (90Y-替伊莫单抗),等等。
生物响应调节剂是调节活的有机体的防御机制或生物响应(例如组织细胞的存活、生长或分化)以引导其具有抗肿瘤活性的药剂,包括云芝多糖、香菇多糖、西佐糖、溶链菌制剂PF-3512676 (CpG-8954)、乌苯美司,等等。
嘧啶类似物包括阿糖胞苷(ara C或阿糖胞苷 C)、胞嘧啶阿糖胞苷、去氧氟尿苷、FLUDARA® (氟达拉滨)、5-FU (5-氟尿嘧啶)、氟尿苷、GEMZAR® (吉西他滨)、TOMUDEX®(ratitrexed)、TROXATYLTM (三乙酰尿苷油沙他滨),等等。
嘌呤类似物包括LANVIS® (硫鸟嘌呤)和PURI-NETHOL® (巯基嘌呤)。
抗有丝分裂药包括巴他布林(batabulin)、埃坡霉素D (KOS-862)、N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS 247550)、紫杉醇、TAXOTERE®(多西他赛)、PNU100940 (109881)、帕土匹隆、XRP-9881 (洛他赛)、长春氟宁、ZK-EPO (合成的埃坡霉素),等等。
泛素连接酶抑制剂包括MDM2抑制剂,例如nutlins、NEDD8抑制剂如MLN4924,等等。
本发明化合物也可用作增强放疗效力的放射增敏剂。放疗的实例包括体外放射治疗、远距离放射治疗、近距离放射治疗和封闭源放疗及非封闭源放疗等。
另外,式(I)化合物可以与其它的化疗药物组合,例如ABRAXANETM (ABI-007)、ABT-100 (法呢基转移酶抑制剂)、ADVEXIN® (Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR® (洛伐他汀)、AMPLIGEN® (poly I:poly C12U、合成的RNA)、APTOSYN® (依昔舒林)、AREDIA® (帕米膦酸)、阿格拉滨(arglabin)、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄-1,4-二烯)、AVAGE® (他扎罗汀)、AVE-8062 (风车子抑碱(combreastatin)衍生物)、BEC2 (米托莫单抗)、恶液质素或cachexin(肿瘤坏死因子)、康维辛(疫苗)、CEAVAC® (癌症疫苗)、CELEUK®(西莫白介素)、CEPLENE® (组胺二盐酸盐)、CERVARIX® (人乳头瘤病毒疫苗)、CHOP® (C:CYTOXAN® (环磷酰胺);H: ADRIAMYCIN® (羟基多柔比星);O: 长春新碱(ONCOVIN®);P: 泼尼松)、CYPATTM (醋酸环丙孕酮)、卡贝塔汀A4P、DAB(389)EGF(通过His-Ala连接与人表皮生长因子融合的白喉毒素的催化域和转运域)或TransMID 107RTM (白喉毒素)、达卡巴嗪、放线菌素D、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、尿嘧啶、EVIZONTM (角鲨胺乳酸盐)、DIMERICINE®(T4N5脂质体洗剂)、discodermolide、DX-8951f (甲磺酸伊喜替康)、enzastaurin、EPO906 (epithilone B)、GARDASIL®(四价人乳突状瘤病毒(6、11、16、18型)重组疫苗)、GASTRIMMUNE®、GENASENSE®、GMK (神经节苷酯结合物疫苗)、GVAX® (前列腺癌疫苗)、哌喹酮、组氨瑞林(histerelin)、羟基脲、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekin besudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JUNOVAN™或MEPACT™(米伐木肽)、洛那法尼、5,10-亚甲基四氢叶酸、米替福新(十六烷基磷酸胆碱)、NEOVASTAT®(AE-941)、NEUTREXIN®(葡糖醛酸三甲曲沙)、NIPENT®(喷司他丁)、ONCONASE®(核糖核酸酶)、ONCOPHAGE®(黑色素瘤疫苗治疗)、ONCOVAX®(IL-2疫苗)、ORATHECIN™(鲁比替康)、OSIDEM®(基于抗体的细胞药物)、OVAREX® MAb(小鼠单克隆抗体)、紫杉醇、PANDIMEX™(包含20(S)-原人参二醇(aPPD)和20(S)-原人参三醇(aPPT)的来自人参的糖苷配基皂苷)、帕尼单抗、PANVAC®-VF(研究中的癌症疫苗)、培门冬酶、PEG干扰素A、苯妥帝尔(phenoxodiol)、丙卡巴肼、瑞马司他(rebimastat)、REMOVAB®(卡妥索单抗)、REVLIMID®(来那度胺)、RSR13(乙丙昔罗)、SOMATULINE® LA(兰瑞肽)、SORIATANE®(依曲替酸)、星孢菌素(链霉菌星状孢子)、talabostat(PT100)、TARGRETIN®(贝沙罗汀)、TAXOPREXIN®(DHA-紫杉醇)、TELCYTA®(坎磷酰胺(canfosfamide),TLK286)、temilifene、TEMODAR®(替莫唑胺)、替米利芬、沙利度胺、THERATOPE®(STn-KLH)、诺拉屈西二氢氯组胺(2-氨基-3,4-二氢-6-甲基-4-氧代-5-(4-吡啶基硫基)喹唑啉二盐酸盐)、TNFERADE™(腺病毒载体: 含有肿瘤坏死因子-α的基因的DNA载体)、TRACLEER®或ZAVESCA®(波生坦)、维甲酸(Retin-A)、粉防己碱、TRISENOX®(三氧化二砷)、VIRULIZIN®、ukrain(来自白屈菜植物的生物碱衍生物)、整合素拮抗剂(vitaxin)(抗-αvβ3抗体)、XCYTRIN®(莫特沙芬钆)、XINLAY™(阿曲生坦)、XYOTAX™(聚谷氨酸紫杉醇)、YONDELIS®(曲贝替定)、ZD-6126、ZINECARD®(右丙亚胺)、ZOMETA®(唑来膦酸(zolendronic acid))、佐柔比星等。
本发明化合物也可与治疗有效量的一种或多种制剂一起施用来治疗炎性疾病或病症,或自身免疫疾病,其中所述制剂的实例包括例如氨甲喋呤、6-巯基嘌呤类、硫唑嘌呤、柳氮磺胺吡啶、美沙拉嗪、奥沙拉秦氯喹/羟氯喹、青霉胺、硫代苹果酸金(肌内和口服)、硫唑嘌呤、秋水仙碱、皮质类固醇类药物(口服、吸入和局部注射)、β2肾上腺素受体激动剂(沙丁胺醇、特布他林、沙美特罗)、黄嘌呤(茶碱、氨茶碱)、色甘酸盐、萘多罗米、酮替芬、异丙托铵和氧托溴铵、环孢菌素、FK506、雷帕霉素、霉酚酸酯、来氟洛米、非甾体抗炎药,例如布洛芬、皮质类固醇类药物,例如强的松龙、磷酸二酯酶抑制剂、腺苷激动剂、抗凝剂、补体抑制剂、肾上腺素能药、干扰经由促炎细胞因子例如TNFα或IL-1的信号传导的试剂(例如NIK、IKK、p38或MAP激酶抑制剂)、IL-1β转化酶抑制剂、T细胞信号传导抑制剂例如激酶抑制剂、金属蛋白酶抑制剂、柳氮磺胺吡啶、6-巯基嘌呤类、血管紧张素转化酶抑制剂、可溶性细胞因子受体及其衍生物(例如,可溶性p55或p75 TNF受体和衍生物p75TNFRIgG(依那西普)和p55TNFRIgG(来那西普)、sIL-1RI、sIL-1RII、sIL-6R)、抗炎细胞因子(例如,IL-4、IL-10、IL-11、IL-13和TGFβ)、塞来昔布、叶酸、硫酸羟氯喹、洛芬昔布、依那西普、英夫利昔单抗、萘普生、伐地考昔、柳氮磺胺吡啶、甲基强的松龙、美洛昔康、乙酸甲基强的松龙、硫代苹果酸金钠、阿司匹林、曲安奈德、萘磺酸右丙氧芬/扑热息痛、叶酸盐、萘丁美酮、双氯芬酸、吡罗昔康、依托度酸、双氯酚酸钠、奥沙普嗪、盐酸羟考酮、重酒石酸氢可酮/扑热息痛、双氯酚酸钠/米索前列醇、芬太尼、阿那白滞素(anakinra)、盐酸曲马多、双水杨酸酯、舒林酸、氰钴胺素/fa/吡哆醇、扑热息痛、阿仑膦酸钠、强的松龙、硫酸吗啡、盐酸利多卡因、吲哚美辛、硫酸葡糖胺(glucosamine sulf)/软骨素、盐酸阿米替林、磺胺嘧啶、盐酸羟考酮/扑热息痛、盐酸奥洛他定、米索前列醇、萘普生钠、奥美拉唑、环磷酰胺、利妥昔单抗、IL-1 TRAP、MRA、CTLA4-IG、IL-18 BP、抗IL-12、抗IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、罗氟司特(Roflumilast)、IC-485、CDC-801、S1P1激动剂(例如FTY720)、PKC 家族抑制剂(例如鲁伯斯塔或AEB-071)和美苏帕玛(Mesopram)。在某些实施方案中,组合包括氨甲喋呤或来氟米特,并且在中度或严重类风湿性关节炎的情况下,组合包括上述环孢霉素和抗-TNF抗体。
可以与本发明的式(I)的化合物共同施用的炎症性肠病治疗剂的非限制性实例包括如下:布地奈德;表皮生长因子;皮质类固醇类药物;环孢菌素、柳氮磺胺吡啶;氨基水杨酸盐;6-巯基嘌呤类;硫唑嘌呤;甲硝唑;脂氧合酶抑制剂;美沙拉嗪;奥沙拉嗪;巴柳氮;抗氧化剂;血栓烷抑制剂;IL-1受体拮抗剂;抗-IL-1β单克隆抗体;抗-IL-6单克隆抗体;生长因子;弹性蛋白酶抑制剂;吡啶基-咪唑化合物;抗体或其它人细胞因子或生长因子的拮抗剂,例如,TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-12、IL-15、IL-16、IL-23、EMAP -II、GM-CSF、FGF和PDGF;细胞表面分子如CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、CD90或它们的配体;甲氨蝶呤;环孢菌素;FK506;雷帕霉素;霉酚酸酯;来氟米特;非甾体抗炎药类,例如,布洛芬、皮质类固醇类药物如强的松龙;磷酸二酯酶抑制剂;腺苷激动剂;抗血栓形成剂;补体抑制剂;肾上腺素能剂;通过促炎细胞因子如TNFα或IL-1干扰信号传递的药剂(例如,NIK、IKK或MAP激酶抑制剂);IL-1β转化酶抑制剂;TNFα转化酶抑制剂;T-细胞信号抑制剂如激酶抑制剂;金属蛋白酶抑制剂;柳氮磺胺吡啶;硫唑嘌呤;6-巯基嘌呤类;血管紧张素转化酶抑制剂;可溶性细胞因子受体及其衍生物(例如可溶性p55或p75 TNF受体、sIL-1RI、sIL-1RII、sIL-6R)和抗炎细胞因子(如IL-4、IL-10、IL-11、IL-13和TGFβ)。可以与式(I)的化合物组合的克罗恩氏病治疗剂优选的实例包括下列:TNF拮抗剂,例如,抗TNF抗体、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、p75TNFRIgG(依那西普)和p55TNFRIgG(LenerceptTM)抑制剂和PDE4抑制剂。式(I)化合物可以组合皮质类固醇类药物,例如布地奈德和地塞米松;柳氮磺胺吡啶、5-氨基水杨酸;奥沙拉嗪;和干扰促炎细胞因子如IL-1的合成和作用的药剂,例如,IL-1β转化酶抑制剂和IL-1ra;T细胞信号传递抑制剂,例如,酪氨酸激酶抑制剂;6-巯基嘌呤类;IL-11;美沙拉嗪;强的松;硫唑嘌呤;巯嘌呤;英夫利昔单抗;甲泼尼龙琥珀酸钠;地芬诺酯/硫酸阿托品;盐酸洛哌丁胺;氨甲喋呤;奥美拉唑;叶酸盐;环丙沙星/葡萄糖水;重酒石酸氢可酮/扑热息痛;盐酸四环素;醋酸氟轻松;甲硝唑;硫柳汞/硼酸;消胆胺/蔗糖;盐酸环丙沙星;硫酸莨菪碱;盐酸哌替啶;盐酸咪达唑仑;盐酸羟考酮/对乙酰氨基酚;盐酸异丙嗪;磷酸钠;磺胺甲噁唑/甲氧苄啶;塞来昔布;聚卡波非;丙氧芬萘磺酸盐;氢化可的松;多维生素;巴柳氮二钠;磷酸可待因/扑热息痛;盐酸考来维仑;氰钴胺;叶酸;左氧氟沙星;甲强龙;那他珠单抗和干扰素-γ。
可以与式(I)的化合物共同施用的用于多发性硬化症的治疗剂的非限制性实例包括下列:皮质类固醇类药物;泼尼松龙;甲泼尼龙;硫唑嘌呤;环磷酰胺;环孢菌素;甲氨蝶呤;4-氨基吡啶;替扎尼定;干扰素-β1a(Avonex®;Biogen);干扰素-β1b(Betaseron ®;Chiron/Berlex);干扰素α-n3)(Interferon Sciences/Fujimoto),干扰素-α (AlfaWassermann/J&J),干扰素β1A-IF(Serono/Inhale Therapeutics),聚乙二醇干扰素α2b(Enzon/Schering-Plough),共聚物1(Cop-1;Copaxone®,Teva PharmaceuticalIndustries,Inc.);高压氧;静脉注射免疫球蛋白;克拉屈滨;其他人细胞因子或生长因子及其受体(例如,TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-12、IL-23、IL-15、IL-16、EMAP-Ⅱ、GM-CSF、FGF和PDGF)的抗体或拮抗剂。式(I)化合物可以与细胞表面分子(例如CD2、CD3、CD4、CD8、CD19、CD20、CD25、CD28、CD30、CD40、CD45、CD69、CD80、CD86、CD90)的抗体或它们的配体组合。式(I)化合物还可以与下列药剂组合:如氨甲喋呤、环孢菌素、FK506、雷帕霉素、霉酚酸酯、来氟洛米、S1P1激动剂、非甾体类抗炎药例如布洛芬、皮质类固醇类药物例如强的松龙、磷酸二酯酶抑制剂、腺苷激动剂、抗血栓剂、补体抑制剂、肾上腺素能剂、通过促炎细胞因子如TNFα或IL-1干扰信号传递的药剂(例如NIK、IKK、p38或MAP激酶抑制剂)、IL-1β转化酶抑制剂、TACE抑制剂、T-细胞信号抑制剂如激酶抑制剂、金属蛋白酶抑制剂、柳氮磺胺吡啶、硫唑嘌呤、6-巯基嘌呤类、血管紧张素转化酶抑制剂、可溶性细胞因子受体及其衍生物(例如,可溶性p55或p75 TNF受体、sIL-1RI、sIL-1RII、sIL-6R)和抗炎细胞因子(如IL-4、IL-10、IL-13和TGFβ)。
式(I)的化合物,也可以与下列药剂共同施用:如阿仑单抗、屈大麻酚、达利珠单抗、米托蒽醌、扎利罗登盐酸盐、氨吡啶、格拉默乙酸盐、那他珠单抗、辛纳比道(sinnabidol)、α-immunokine NNSO3、ABR-215062、AnergiX.MS、趋化因子受体拮抗剂、BBR-2778、卡拉古林(calagualine)、CPI-1189、LEM(脂质体封装的米托蒽醌)、THC.CBD(大麻素激动剂)、MBP-8298、苏帕玛(mesopram)(PDE4抑制剂)、MNA-715、抗-IL-6受体抗体、neurovax、吡非尼酮allotrap1258(RDP-1258)、sTNF-R1、他仑帕奈、特立氟胺、TGF-β2、替利莫肽(tiplimotide)、VLA-4拮抗剂(例如TR-14035、VLA4 Ultrahaler、Antegran-ELAN/Biogen)、干扰素γ拮抗剂和IL-4激动剂。
可以与式(I)的化合物共同施用的强直性脊柱炎治疗剂的非限制性的实例包括下列:布洛芬、双氯芬酸、米索前列醇、萘普生、美洛昔康、吲哚美辛、双氯芬酸、塞来昔布、罗非昔布、柳氮磺胺吡啶、甲氨蝶呤、硫唑嘌呤、米诺环素、泼尼松、和抗-TNF抗体、D2E7(HUMIRA®)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、(p75TNFRIgG(ENBREL®)和p55TNFRIgG(LENERCEPT®)。
可以与式(I)的化合物共同施用的哮喘治疗剂的非限制性的实例包括下列:沙丁胺醇、沙美特罗/氟替卡松、孟鲁司特钠、丙酸氟替卡松、布地奈德、泼尼松、沙美特罗昔萘酸酯、左旋沙丁胺醇盐酸、硫酸沙丁胺醇/异丙托铵、强的松龙磷酸钠、曲安奈德、二丙酸氯地米松、异丙托溴铵、阿奇霉素、醋酸吡布特罗、泼尼松龙、无水茶碱、甲基强的松龙琥珀酸钠、克拉霉素、扎鲁司特、富马酸福莫特罗、流感病毒疫苗、阿莫西林三水合物、氟尼缩松、变态反应注射剂、色甘酸钠、盐酸非索非那定、氟尼缩松/薄荷醇、阿莫西林/克拉维酸、左氧氟沙星、吸入器辅助装置、愈创甘油醚、地塞米松磷酸钠、莫西沙星盐酸、盐酸强力霉素、愈创甘油醚/d-甲吗喃、p-麻黄素/cod/扑尔敏、加替沙星、盐酸西替利嗪、糠酸莫米松、羟萘酸沙美特罗、苯佐那酯、头孢氨苄、PE/氢可酮/扑尔敏、盐酸西替利嗪/伪麻黄碱、去氧肾上腺素/cod/异丙嗪、可待因/异丙嗪、头孢丙烯、地塞米松、愈创甘油醚/伪麻黄碱、氯苯那敏/氢可酮、奈多罗米钠、硫酸特布他林、肾上腺素、甲基强的松龙、抗IL-13抗体、和奥西那林硫酸盐。
可以与式(I)的化合物共同施用的COPD治疗剂的非限制性的实例包括下列:硫酸沙丁胺醇/异丙托铵,异丙托溴铵、沙美特罗/氟替卡松、沙丁胺醇、羟萘酸沙美特罗、丙酸氟替卡松、泼尼松、无水茶碱、甲基强的松龙琥珀酸钠、孟鲁司特钠、布地奈德、富马酸福莫特罗、曲安奈德、左氧氟沙星、愈创甘油醚、阿奇霉素、二丙酸氯地米松、盐酸左旋沙丁胺醇、氟尼缩松、头孢曲松钠、阿莫西林三水合物、加替沙星、扎鲁司特、阿莫西林/棒酸、氟尼缩松/薄荷醇、氯苯那敏/氢可酮、硫酸奥西那林、甲泼尼龙、糠酸莫米松、p-麻黄素/cod/扑尔敏、醋酸吡布特罗、p-麻黄素/氯雷他定、硫酸特布他林、噻托溴铵、(R,R)-福莫特罗、TgAAT、西洛司特和罗氟司特。
可以与式(I)的化合物共同施用的银屑病治疗剂的非限制性的实例包括下列:卡泊三醇、丙酸氯氟美松、曲安奈德、丙酸卤倍他索、他扎罗汀、甲氨蝶呤、醋酸氟轻松、倍他米松diprop augmented、肤轻松、阿维A、焦油香波、倍他米松戊酸酯、糠酸莫米松、酮康唑、普莫卡因/肤轻松、戊酸氢化可的松、氟氢缩松、尿素、倍他米松、氯倍他索丙酸酯/emoll、丙酸氟替卡松、阿奇霉素、氢化可的松、湿润配方、叶酸、地奈德、吡美莫司、煤焦油、二氟拉松双乙酸酯、依那西普叶酸盐、乳酸、甲氧沙林、hc/bismuth subgal/znox/resor、醋酸甲基强的松龙、泼尼松、防晒剂、哈西奈德、水杨酸、蒽林、氯可托龙新戊酸酯、煤提取物、煤焦油/水杨酸、煤焦油/水杨酸/硫、去羟米松、地西泮、润肤剂、醋酸肤轻松/润肤剂、矿物油/蓖麻油/na lact、矿物油/花生油、石油/肉豆蔻酸异丙酯、补骨脂素、水杨酸、皂/三溴沙仑、硫柳汞/硼酸、塞来考昔、英夫利昔单抗、环孢霉素、阿来塞普、依法利珠单抗、他克莫司、吡美莫司、 PUVA 、UVB、柳氮磺胺吡啶、ABT-874和ustekinamab。
可以与式(I)的化合物共同施用的银屑病关节炎治疗剂的非限制性的实例包括下列:氨甲蝶呤、依那西普、罗非昔布、塞来昔布、叶酸、柳氮磺胺吡啶、萘普生、来氟米特、醋酸甲基强的松龙、吲哚美辛、硫酸羟氯喹、强的松、舒林酸、倍他米松diprop augmented、英夫利昔单抗、甲氨蝶呤、叶酸、曲安奈德、双氯芬酸、二甲基亚砜、吡罗昔康、双氯芬酸钠、酮洛芬、美洛昔康、甲基强的松龙、萘普酮、托美丁钠、卡泊三醇、环孢菌素、双氯芬酸钠/米索前列醇、醋酸氟轻松、氨基葡萄糖硫酸盐、金硫丁二钠、重酒石酸氢可酮/扑热息痛、布洛芬、利塞膦酸钠、磺胺嘧啶、硫鸟嘌呤、伐地考昔、阿来塞普、D2E7(阿达木单抗)和依法利珠单抗。
可以与式(I)的化合物共同施用的SLE (狼疮)治疗剂的优选的实例包括下列:非甾体类抗炎药,例如,双氯芬酸、萘普生、布洛芬、吡罗昔康、吲哚美辛;COX2抑制剂、例如塞来昔布、罗非昔布、伐地昔布;抗疟药、例如,羟氯喹;类固醇,例如,强的松、强的松龙、布地奈德(budenoside)、地塞米松;细胞毒性药物,例如、硫唑嘌呤、环磷酰胺、霉酚酸酯、氨甲蝶呤;PDE4抑制剂或嘌呤合成抑制剂,例如骁悉®。式(I)的化合物还可以与药剂例如柳氮磺胺吡啶、5-氨基水杨酸、奥沙拉嗪、依木兰®和干扰促炎细胞因子如IL-1的合成、产生或作用的药剂,例如半胱天冬酶抑制剂如IL-1β转化酶抑制剂和IL-1ra合用。式(I)的化合物还可以与T细胞信号传递抑制剂,例如,酪氨酸激酶抑制剂一起使用;或靶向T细胞活化分子的分子,例如,CTLA-4-IgG或抗B7家族抗体、抗PD-1家族抗体一起使用。式(I)化合物可以与IL-11或抗细胞因子抗体,例如,fonotolizumab(抗-IFNg的抗体),或抗受体受体抗体,例如抗-IL-6受体抗体和B细胞表面分子抗体合用。式(I)化合物也可与LJP394(阿贝莫司)、耗尽或灭活B细胞的试剂,例如利妥昔单抗(抗CD20抗体)、lymphostat-B(抗BlyS抗体)、TNF拮抗剂,例如抗-TNF抗体、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、(p75TNFRIgG(依那西普)和p55TNFRIgG(LenerceptTM) 一起使用。
本发明化合物也可与治疗有效量的用于预防或治疗AIDS的一种或多种药剂共同施用,其中所述药剂的实例包括HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、免疫调节剂以及其它逆转录病毒药物。逆转录酶抑制剂的实例包括但不限于,阿巴卡韦、阿德福韦、去羟肌苷、阿德福韦酯地拉韦啶、依法韦仑、拉米夫定、奈韦拉平、司他夫定扎西他滨和齐多夫定。蛋白酶抑制剂的实例包括,但不限于,安泼那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦和沙奎那韦。
式(I)的化合物,也可以与胰岛素一起施用,用于I型糖尿病的治疗。
本发明化合物也可与一种或多种治疗有效量的在AIDS的预防或治疗中使用的药剂共同施用,其中所述药剂的实例包括HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、免疫调节剂以及其它逆转录病毒药物。逆转录酶抑制剂的实例包括但不限于,阿巴卡韦、阿德福韦、去羟肌苷、阿德福韦酯地拉韦啶、依法韦仑、恩曲他滨、拉米夫定、奈韦拉平、利匹韦林、司他夫定、替诺福韦、扎西他滨和齐多夫定。蛋白酶抑制剂的实例包括,但不限于,安泼那韦、阿扎那韦、地瑞那韦、茚地那韦、福沙那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和替拉那韦。其他逆转录病毒药物的例子包括,但不限于,埃替拉韦、恩夫韦地、马拉韦罗和雷特格韦。
本发明化合物也可与一种或多种治疗有效量的在肥胖治疗中使用的药剂共同施用,其中所述药剂的实例包括奥利斯他。
本发明化合物也可与一种或多种治疗有效量的在II型糖尿病治疗中使用的药剂共同施用,其中所述药剂的实例包括α-葡萄糖苷酶抑制剂、胰岛素、二甲双胍、磺酰脲类(例如,氨磺丁脲、醋磺环已脲、氯磺丙脲、格列本脲、格列波脲、格列齐特、格列美脲、格列吡嗪、格列喹酮、格列派特、格列吡脲、甲苯磺丁脲和妥拉磺脲)、非磺酰脲类(例如,那格列奈和瑞格列奈)和噻唑烷二酮类(例如,吡格列酮)。
本发明化合物也可以与治疗有效量的一种或多种预防或治疗II型糖尿病、肝脂肪变性、胰岛素抗性、代谢综合征和相关病症的药剂共同施用,其中所述药剂的实例包括,但不限于,胰岛素和被修饰以改善在体内的作用持续时间的胰岛素;刺激胰岛素分泌的药剂,如醋磺环已脲、氯磺丙脲、格列本脲、格列美脲、格列吡嗪、格列齐特(glicazide)、glycopyramide、格列喹酮、rapaglinide、nataglinide、妥拉磺脲和甲苯磺丁脲;胰高血糖素样肽激动剂的药剂如exanatide、利拉鲁肽和他司鲁肽;抑制二肽基肽酶IV的药剂,例如维格列汀、西他列汀、沙格列汀、利拉利汀、allogliptin和septagliptin;结合到过氧化物酶体增殖物激活受体γ的药剂,例如罗格列酮和吡格列酮;降低胰岛素抗性的药剂,例如二甲双胍;减少葡萄糖在小肠中吸收的药剂,例如阿卡波糖,米格列醇与伏格列波糖。
本发明化合物也可以与治疗有效量的一种或多种预防或治疗急性肾功能障碍和慢性肾脏疾病的药剂共同施用,其中所述药剂的实例包括,但不限于,多巴胺、利尿药如呋塞米、布美他尼、噻嗪等、甘露醇、葡萄糖酸钙、碳酸氢钠、沙丁胺醇、帕立骨化醇、度骨化醇以及西那卡塞。
下面的实施例可以用于说明性目的,不应被认为限制本发明的范围。
实施例
实施例 1.5-(2-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 1a
2-乙酰基-4-(2-硝基苯基)-4-氧代丁酸叔丁基酯
在N2气氛、0℃下,向氢化钠(60%矿物油分散体,2.95 g,73.8 mmol)的无水四氢呋喃(120 mL)悬浮液中滴加3-氧代丁酸叔丁基酯(10.12 mL,61.5 mmol)。在5℃下搅拌形成的混合物20分钟,滴加2-溴-2'-硝基苯乙酮(15 g,61.5 mmol)的四氢呋喃 (60 mL)溶液进行处理并在环境温度下搅拌24小时。然后使反应混合物在乙酸乙酯和饱和的氯化铵水溶液之间分配,有机层经盐水洗涤,干燥(无水Na2SO4),过滤并浓缩。残余物经闪式色谱法纯化(硅胶,5-45% 乙酸乙酯/己烷)得到标题化合物(15.8 g,80%)。
实施例 1b
2-甲基-5-(2-硝基苯基)-1H-吡咯-3-甲酸叔丁基酯
在80℃下加热实施例 1a (15.8 g,49.2 mmol)和乙酸铵(37.9 g,492 mmol) 的乙酸(50 mL)混合物1.5 小时,冷却并用200 mL 冰水稀释产生固体。搅拌该混合物十分钟并过滤收集固体,用水反复洗涤并干燥至恒重得到标题化合物(14.3 g,96%)。
实施例 1c
2-甲基-5-(2-硝基苯基)-1H-吡咯-3-甲酸
向实施例 1b (7.4 g,24.1 mmol)的1,4-二噁烷 (50 mL)溶液中添加4 M HCl 的二噁烷溶液(36 mL,144 mmol)。在环境温度下搅拌形成的混合物16 小时并浓缩。将残余物与甲苯共沸蒸馏3 x 25 mL 并干燥至恒重得到标题化合物(6.23 g,100%)。
实施例 1d
2-甲基-5-(2-硝基苯基)-1H-吡咯-3-甲酰胺
在二甲基甲酰胺 (40.6 mL)中混合实施例 1c (3.0 g,12.18 mmol)、1-羟基苯并三唑(2.8 g,18.28 mmol)、N 1 -((乙基亚氨基)亚甲基)-N 3 ,N 3 -二甲基丙烷-1,3-二胺盐酸盐(3.5 g,18.28 mmol)和氯化铵(3.26 g,60.9 mmol)的混合物,用N,N-二异丙基乙胺(12.77mL,9.45 mmol)处理并在40℃加热24 小时。将混合物冷却并在乙酸乙酯和水之间分配,用乙酸乙酯萃取水层两次。合并的乙酸乙酯萃取液(400 mL)依次地用各100 mL饱和碳酸氢钠水溶液、水、1 M 盐酸溶液和盐水洗涤,干燥(无水Na2SO4),过滤并浓缩。残余物用最小体积的二氯甲烷研制,过滤收集形成的固体得到标题化合物(2.09 g,70%)。
实施例 1e
5-(2-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺
在乙醇、四氢呋喃、水 (21 mL,21 mL,7 mL)的溶剂混合物中,在95℃、剧烈搅拌下加热实施例 1d (2.09 g,8.52 mmol)、铁(2.38 g,42.6 mmol)和氯化铵(0.684 g,12.78mmol)的混合物1.5 小时。将反应混合物冷却并通过密实的硅藻土塞过滤,用乙醇和四氢呋喃反复冲洗。浓缩滤液并将残余物溶于乙酸乙酯中,用盐水洗涤,干燥(无水Na2SO4)、过滤并浓缩得到标题化合物(2.0 g,定量收率)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.00 (s, 1H),7.17 (dd, J=7.80, 1.36 Hz, 1H), 7.12 (s, 1H), 6.95 (m, 1H), 6.73 (dd, J=7.97,1.19 Hz, 1H), 6.64 (d, J=2.71 Hz, 1H), 6.60 (td, J=7.38, 1.19 Hz, 1H), 6.51(s, 1H), 5.00 (s, 2H), 2.43 (s, 3H)。MS (ESI+) m/z 216.0 (M+H)+。
实施例 2.5-[2-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用乙酸酐(0.094 mL, 1.000 mmol)处理实施例 1e (0.022 g, 0.1 mmol)并在环境温度下搅拌5 小时。将反应混合物浓缩至一半体积,然后用2 mL乙醚稀释,过滤收集固体并用另外的乙醚洗涤。将所述固体加到乙酸乙酯中, 用饱和碳酸氢钠溶液 (2x)、水和盐水洗涤, 干燥(无水MgSO4),过滤, 浓缩并在真空干燥箱中于80℃干燥得到标题化合物(0.0188g, 73%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 9.08 (s, 1H), 7.60(d, J=6.74 Hz, 1H), 7.40 (m, 1H), 7.18 (m, 3H), 6.71 (d, J=2.78 Hz, 1H), 6.58(s, 1H), 2.46 (s, 3H), 2.05 (s, 3H)。MS (ESI+) m/z 257.9 (M+H)+。
实施例 3.2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酰胺
实施例 3a
2-乙酰基-4-(3-硝基苯基)-4-氧代丁酸乙基酯
用3-氧代丁酸乙基酯代替3-氧代丁酸叔丁基酯和用2-溴-3'-硝基苯乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 3a, 得到标题化合物(0.594 g, 40%)。
实施例 3b
2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酸乙基酯
用实施例 3a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例 3b,得到标题化合物(0.125 g, 96%)。
实施例 3c
2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酸
向实施例 3b (0.130 g, 0.475 mmol)的四氢呋喃(2 mL)混合物中添加氢氧化锂单水合物(0.199 g, 4.75 mmol)和水(0.500 mL)。在60℃加热反应混合物过夜,冷却至环境温度,用 2 N 的盐酸水溶液酸化并用乙酸乙酯萃取。有机层用盐水洗涤,干燥(无水MgSO4),过滤, 浓缩并在真空干燥箱中于80℃干燥得到标题化合物(0.117, 90%)。
实施例 3d
2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酰胺
将实施例 3c (3 g, 12.18 mmol), 氯化铵(1.304 g, 24.37 mmol), 六氟磷酸(苯并三唑-1-基-氧基三吡咯烷子基鏻(9.51 g, 18.28 mmol)和1-羟基苯并三唑(2.80 g,18.28 mmol)于二甲基甲酰胺(48.7 mL)中混合,用N,N-二异丙基乙胺 (8.51 mL, 48.7mmol)处理并在环境温度下搅拌过夜。将反应混合物在乙酸乙酯和水之间分配,有机相用1N HCl溶液、水、饱和碳酸氢钠水溶液和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物用甲醇研制,过滤收集形成的固体得到标题化合物(1.5 g, 50%)。1H NMR (300 MHz, DMSO- d 6 ) δ 11.67 (s, 1H), 8.43 (t, J=2.03 Hz, 1H), 7.97 (m, 2H), 7.65 (t, J=7.97Hz, 1H), 7.17 (s, 1H), 7.13 (d, J=2.71 Hz, 1H), 6.68 (s, 1H), 2.48 (s, 3H)。MS(ESI+) m/z 246.1 (M+H)+。
实施例 4.5-(3-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 3d代替实施例 1d并通过闪式色谱法纯化(硅胶, 0至14% 甲醇/二氯甲烷),按照制备实施例 1e所用的步骤制备了实施例 4,得到标题化合物(0.193, 90%)。1HNMR (300 MHz, DMSO-d 6 ) δ 11.13 (s, 1H), 7.11 (s, 1H), 6.99 (m, 1H), 6.73 (m,2H), 6.70 (d, J=2.78 Hz, 1H), 6.54 (s, 1H), 6.39 (m, 1H), 5.01 (s, 2H), 2.43(s, 3H)。MS (ESI+) m/z 216.1 (M+H)+。
实施例 5.5-[3-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用实施例 4代替实施例 1e,按照制备实施例 2所用的步骤制备了实施例 5,得到标题化合物(0.347 g, 98%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 9.90 (s,1H), 7.83 (s, 1H), 7.27 (m, 3H), 7.20 (m, J=10.51 Hz, 1H), 6.78 (d, J=2.71Hz, 1H), 6.56 (s, 1H), 2.45 (s, 3H), 2.05 (s, 3H)。LCMS m/z 258.1 (M+H)+。
实施例 6.2-甲基-5-{3-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺
将实施例 4 (0.022 g, 0.1 mmol)溶于吡啶(1.0 mL)中,用甲烷磺酰氯(0.016mL, 0.200 mmol)处理并在环境温度下搅拌1 小时10分钟。浓缩反应混合物,加入乙酸乙酯,用水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法纯化(硅胶, 2至20% 甲醇/二氯甲烷)得到标题化合物(0.02 g, 68%)。1H NMR (300 MHz, DMSO-d 6 ) δ11.34 (s, 1H), 9.71 (s, 1H), 7.38 (m, 1H), 7.32 (m, 2H), 7.19 (s, 1H), 6.99(m, 1H), 6.82 (d, J=2.78 Hz, 1H), 6.59 (s, 1H), 3.01 (s, 3H), 2.46 (s, 3H)。MS(ESI+) m/z 294.0 (M+H)+。
实施例 7.2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酰胺
实施例 7a
2-乙酰基-4-(4-硝基苯基)-4-氧代丁酸乙基酯
用3-氧代丁酸乙基酯代替3-氧代丁酸叔丁基酯和用2-溴-4'-硝基苯乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 7a,得到标题化合物(8.0 g, 83%)。
实施例 7b
2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酸乙基酯
用实施例 7a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例 7b,得到标题化合物(7.3 g, 97%)。
实施例 7c
2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酸
用实施例 7b代替实施例 3b,按照制备实施例 3c所用的步骤制备了实施例 7c,得到标题化合物(2.38 g, 88%)。
实施例 7d
2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酰胺
用实施例 7c代替实施例 3c并通过闪式色谱法纯化(硅胶, 0-25% 甲醇/二氯甲烷),按照制备实施例 3d所用的步骤制备了实施例 7d,得到标题化合物(1.8 g, 76%)。1HNMR (300 MHz, DMSO-d 6 ) δ 11.72 (s, 1H), 8.24 (m, 2H), 7.77 (m, 2H), 7.22 (m,J=2.71 Hz, 2H), 6.73 (s, 1H), 2.49 (s, 3H)。MS (ESI-) m/z 244.2 (M-H)-。
实施例 8.5-(4-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 7d代替实施例 1d并通过闪式色谱法纯化(硅胶, 1-14% 甲醇/二氯甲烷),按照制备实施例 1e所用的步骤制备了实施例 8,得到标题化合物(0.202, 47%)。1HNMR (300 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 7.24 (m, 2H), 6.98 (s, 1H), 6.56 (m,3H), 6.49 (s, 1H), 5.03 (s, 2H), 2.42 (s, 3H)。LCMS m/z 216.2 (M+H)+。
实施例 9.2-甲基-5-{4-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺
用实施例8代替实施例 4,按照制备实施例 6所用的步骤制备了实施例 9,得到标题化合物(0.0333 g, 57%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.23 (s, 1H), 9.65 (s,1H), 7.51 (d, J=8.48 Hz, 2H), 7.19 (d, J=8.48 Hz, 2H), 7.08 (s, 1H), 6.80 (d,J=2.71 Hz, 1H), 6.57 (s, 1H), 2.98 (s, 3H), 2.45 (s, 3H)。MS (ESI+) m/z 294.0(M+H)+。
实施例 10.5-[4-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用实施例8代替实施例 1e,按照制备实施例 2所用的步骤制备了实施例 10,得到标题化合物(0.032 g, 62%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 9.90 (s,1H), 7.55 (m, 2H), 7.46 (m, 2H), 7.07 (s, 1H), 6.76 (d, J=2.71 Hz, 1H), 6.57(s, 1H), 2.45 (s, 3H), 2.04 (s, 3H)。MS (ESI+) m/z 258.1 (M+H)+。
实施例 11.5-{2-[(4-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
将实施例 1e (0.022 g, 0.1 mmol)和4-氯苯甲醛(0.015 g, 0.110 mmol) 与二氯甲烷 (1.0 mL)和乙酸 (5.72 µL, 0.100 mmol)混合,在环境温度下搅拌20分钟并用三乙氧基硼氢化钠 (0.032 g, 0.150 mmol) 处理。在环境温度下搅拌反应混合物3天,缓慢地用饱和碳酸氢钠水溶液碱化,然后用二氯甲烷萃取,干燥合并的萃取液(无水MgSO4),过滤并浓缩。残余物经闪式色谱法纯化(硅胶, 1-5% 甲醇/二氯甲烷) 得到标题化合物(0.017 g, 50%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.40 (m, 4H), 7.16(m, J=7.54, 1.59 Hz, 2H), 6.97 (td, J=7.74, 1.19 Hz, 1H), 6.72 (d, J=2.38 Hz,1H), 6.61 (t, J=7.54 Hz, 2H), 6.42 (d, J=7.93 Hz, 1H), 5.74 (s, 1H), 4.37 (s,2H), 2.45 (s, 3H)。MS (ESI+) m/z 340.0 (M+H)+。
实施例 12.5-[2-(苄基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
向微波小瓶中加入搅拌子、实施例 1e (0.02 g, 0.093 mmol)的二氯甲烷/甲醇(1:1 v/v) (0.5 mL)溶液、苯甲醛(0.0197 g, 0.186 mmol)的二氯甲烷/甲醇 (1:1 v/v)(0.619 mL)溶液和乙酸(0.558 mmol, 0.032 mL)。将小瓶密封并在50℃ 加热/搅拌1 小时,将小瓶打开,加入MP-氰基硼氢化物(大孔三乙基铵甲基聚苯乙烯氰基硼氢化物)树脂(0.206 g, 2.25 mmol/g 载体),重新将将小瓶密封并在60℃加热/搅拌过夜。完成后,过滤反应混合物,将滤液浓缩至干并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(0.019 g, 49%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ11.09 (s, 1H), 7.37 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 7.16 (dd, J=7.63,1.53 Hz, 1H), 6.98 (m, 1H), 6.73 (d, J=2.75 Hz, 1H), 6.61 (m, 1H), 6.49 (d, J=8.24 Hz, 1H), 4.38 (s, 2H), 2.45 (s, 3H)。MS (ESI+) m/z 306.0 (M+H)+。
实施例 13.2-甲基-5-{2-[(四氢呋喃-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺
向实施例 1e (0.041 g, 0.19 mmol)的甲醇/二氯甲烷(1:1 混合物)(0.5 mL)溶液中依次加入四氢呋喃-2-甲醛(0.038 g, 0.38 mmol)的甲醇/二氯甲烷(1:1 混合物)(0.96mL)溶液、乙酸(0.066 mL, 1.14 mmol)和MP-氰基硼氢化物(大孔三乙基铵甲基聚苯乙烯氰基硼氢化物)树脂(0.425 g, 2.25 mmol/g 载体)。在60℃振摇所得混合物过夜。将反应混合物浓缩至干并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1%TFA/水) 纯化得到标题化合物(0.0027 g, 5%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.14(m, 2H), 6.69 (m, 2H), 6.63 (s, 1H), 4.91 (m, 2H), 4.06 (m, 1H), 3.63 (m,2H), 2.44 (s, 3H), 1.97 (m, 1H), 1.80 (m, 4H), 1.62 (m, 1H)。MS (ESI+) m/z 300(M+H)+。
实施例 14.5-{2-[(环戊基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用环戊烷甲醛代替四氢呋喃-2-甲醛, 按照制备实施例 13所用的步骤制备了实施例 14,得到标题化合物(0.0024 g, 4%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.13 (m,2H), 6.65 (m, 2H), 6.62 (s, 1H), 3.02 (d, J=7.78 Hz, 2H), 2.44 (s, 3H), 2.17(m, 1H), 1.61 (m, 6H), 1.23 (m, 2H)。MS (ESI+) m/z 298 (M+H)+。
实施例 15.5-(2-{[(4-溴噻吩-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用4-溴噻吩-2-甲醛代替四氢呋喃-2-甲醛, 按照制备实施例 13所用的步骤制备了实施例 15,得到标题化合物(0.0275 g, 37%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.44(d, J=1.53 Hz, 1H), 7.18 (dd, J=7.63, 1.53 Hz, 1H), 7.05 (m, 2H), 6.67 (m,3H), 4.55 (s, 2H), 2.45 (s, 3H)。MS (ESI+) m/z 392 (M+H)+。
实施例 16.2-甲基-5-{2-[(3,4,5-三甲氧基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺
用3,4,5-三甲氧基苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 16,得到标题化合物(0.0079 g, 10%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ7.17 (dd, J=7.63, 1.53 Hz, 1 H), 7.04 (m, 1H), 6.73 (s, 1H), 6.68 (s, 2H),6.63 (m, 2H), 4.29 (s, 2H), 3.72 (s, 6H), 3.62 (s, 3H), 2.45 (s, 3H)。MS (ESI+) m/z 396 (M+H)+。
实施例 17.2-甲基-5-{2-[(四氢呋喃-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺
用四氢呋喃-3-甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 17,得到标题化合物(0.0095 g, 17%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.13(m, 2H), 6.70 (m, 2H), 6.61 (s, 1H), 3.77 (m, 2H), 3.63 (q, J=7.83 Hz, 1H),3.49 (dd, J=8.54, 5.19 Hz, 1H), 3.09 (dd, J=7.02, 3.66 Hz, 2H), 2.58 (m, 1H),2.44 (s, 3H), 1.99 (m, 1H), 1.62 (m, 1H)。MS (ESI+) m/z 300 (M+H)+。
实施例 18.2-甲基-5-(2-{[(3R)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺
将实施例 17的产物进行色谱分离(SFC CO2 , Chiralpak AD-H 柱, 10%-50% 异丙醇和0.1 % 二乙胺缓冲液,洗脱时间= 4.44分钟)得到标题化合物,任意指定立体化学(0.046 g, 38%)。1H NMR (300 MHz, DMSO-d 6) δ 11.05 (s, 1 H) 7.05 -7.19 (m, 3 H)6.54 -6.72 (m, 4 H) 4.98 (t, J=5.75 Hz, 1 H) 3.68 -3.81 (m, 2 H) 3.62 (q, J=7.80 Hz, 1 H) 3.49 (dd, J=8.53, 5.35 Hz, 1 H) 3.05 -3.12 (m, 2 H) 2.56 (d, J=6.35 Hz, 1 H) 2.43 (s, 3 H) 1.90 -2.04 (m, 1 H) 1.53 -1.68 (m, 1 H)。MS (ESI-)m/z 298 (M-H)+。
实施例 19.2-甲基-5-(2-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺
将实施例 17的产物进行色谱分离(SFC CO2 , Chiralpak AD-H 柱, 10%-50% 异丙醇和0.1 % 二乙胺缓冲液,洗脱时间= 4.64分钟)得到标题化合物,任意指定立体化学(0.036 g, 30%)。1H NMR (300 MHz, DMSO-d 6) δ 11.05 (s, 1 H) 7.05 -7.19 (m, 3 H)6.54 -6.72 (m, 4 H) 4.98 (t, J=5.75 Hz, 1 H) 3.68 -3.81 (m, 2 H) 3.62 (q, J=7.80 Hz, 1 H) 3.49 (dd, J=8.53, 5.35 Hz, 1 H) 3.05 -3.12 (m, 2 H) 2.56 (d, J=6.35 Hz, 1 H) 2.43 (s, 3 H) 1.90 -2.04 (m, 1 H) 1.53 -1.68 (m, 1 H)。MS (ESI-)m/z 298 (M-H)+。
实施例 20.5-(2-{[(4,5-二甲基呋喃-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用4,5-二甲基呋喃-2-甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 20,得到标题化合物(0.0033 g, 5%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ7.16 (dd, J=7.63, 1.53 Hz, 1H), 7.08 (m, 1H), 6.74 (d, J=8.24 Hz, 1H), 6.68(t, J=7.48 Hz, 1H), 6.64 (s, 1H), 6.04 (s, 1H), 4.25 (s, 2H), 2.44 (s, 3H),2.11 (s, 3H), 1.83 (s, 3H)。MS (ESI+) m/z 324 (M+H)+。
实施例 21.5-(2-{[3,5-二(三氟甲基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用3,5-二(三氟甲基)苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 21,得到标题化合物(0.0378 g, 45%)。1H NMR (400 MHz, DMSO-d 6 /D2O)δ 8.05 (s, 2H), 7.95 (s, 1H), 7.20 (dd, J=7.63, 1.53 Hz, 1H), 7.00 (m, 1H),6.76 (s, 1H), 6.68 (td, J=7.48, 0.92 Hz, 1H), 6.46 (d, J=7.93 Hz, 1H), 4.58(s, 2H), 2.47 (s, 3H)。MS (ESI+) m/z 442 (M+H)+。
实施例 22.5-{2-[(2,6-二氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用2,6-二氟苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 22,得到标题化合物(0.013 g, 20%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.35(m, 1H), 7.15 (dd, J=7.63, 1.53 Hz, 1H), 7.07 (m, 3H), 6.78 (d, J=7.93 Hz,1H), 6.68 (t, J=7.02 Hz, 1H), 6.62 (s, 1H), 4.46 (s, 2H), 2.43 (s, 3H)。MS(ESI+) m/z 342 (M+H)+。
实施例 23.5-{2-[(4-氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-氟苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 23,得到标题化合物(0.0076 g, 12%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.41 (dd,J=8.54, 5.49 Hz, 2H), 7.15 (m, 3H), 6.98 (m, 1H), 6.73 (s, 1H), 6.63 (t, J=7.48 Hz, 1H), 6.48 (d, J=7.32 Hz, 1H), 4.36 (s, 2H), 2.46 (s, 3H)。MS (ESI+)m/z 324 (M+H)+。
实施例 24.2-甲基-5-{2-[(2-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺
用2-甲基苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 24,得到标题化合物(0.0048 g, 8%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.17 (m,5H), 7.02 (m, 1H), 6.71 (s, 1H), 6.65 (t, J=7.48 Hz, 1H), 6.46 (d, J=7.63 Hz,1H), 4.33 (s, 2H), 2.46 (m, 3H), 2.31 (s, 3H)。MS (ESI+) m/z 320 (M+H)+。
实施例 25.2-甲基-5-{2-[(3-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺
用3-甲基苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 25,得到标题化合物(0.005 g, 8%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.18 (m,4H), 7.01 (m, 2H), 6.73 (s, 1H), 6.63 (t, J=7.02 Hz, 1H), 6.51 (d, J=7.93 Hz,1H), 4.34 (s, 2H), 2.45 (s, 3H), 2.28 (s, 3H)。MS (ESI+) m/z 320 (M+H)+。
实施例 26.5-{2-[(环丙基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用环丙烷甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 26,得到标题化合物(0.005 g, 10%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.12 (m,2H), 6.68 (dd, J=10.38, 7.93 Hz, 2H), 6.64 (s, 1H), 2.98 (d, J=6.71 Hz, 2H),2.45 (s, 3H), 1.09 (m, 1H), 0.45 (m, 2H), 0.22 (m, 2H)。MS (ESI+) m/z 270 (M+H)+。
实施例 27.5-[2-(丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用丁醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 27,得到标题化合物(0.0057 g, 11%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.14 (m, 2H),6.66 (dd, J=7.63, 3.97 Hz, 2H), 6.62 (s, 1H), 3.09 (m, 2H), 2.44 (m, 3H),1.53 (m, 2H), 1.34 (m, 2H), 0.92 (m, 3H)。MS (ESI+) m/z 272 (M+H)+。
实施例 28.2-甲基-5-(2-{[4-(三氟甲基)苄基]氨基}苯基)-1H-吡咯-3-甲酰胺
用4-(三氟甲基)苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 28,得到标题化合物(0.0194 g, 27%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ7.68 (m, 2H), 7.60 (m, 2H), 7.18 (dd, J=7.63, 1.53 Hz, 1H), 6.98 (m, 1H),6.76 (s, 1H), 6.64 (t, J=7.48 Hz, 1H), 6.43 (d, J=7.63 Hz, 1H), 4.48 (s, 2H),2.47 (s, 3H)。MS (ESI+) m/z 274 (M+H)+。
实施例 29.2-甲基-5-{2-[(4-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺
用4-甲基苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 29,得到标题化合物(0.0029 g, 5%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.25 (d,J=7.93 Hz, 2 H), 7.14 (m, 3H), 6.99 (m, 1H), 6.72 (s, 1H), 6.62 (m, 1H), 6.50(d, J=7.63 Hz, 1H), 4.33 (s, 2H), 2.45 (s, 3H), 2.26 (s, 3H)。MS (ESI+) m/z320 (M+H)+。
实施例 30.5-{2-[(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-甲氧基苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 30,得到标题化合物(0.0021 g, 3%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.29(d, J=8.85 Hz, 2H), 7.15 (dd, J=7.63, 1.53 Hz, 1H), 7.00 (m, 1H), 6.88 (m,2H), 6.71 (s, 1H), 6.62 (t, J=7.48 Hz, 1H), 6.53 (d, J=8.24 Hz, 1H), 4.30 (s,2H), 3.72 (s, 3H), 2.45 (s, 3H)。MS (ESI+) m/z 336 (M+H)+。
实施例 31.5-{2-[(4-氰基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-甲酰基苄腈代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 31,得到标题化合物(0.0058 g, 9%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.77 (d,J=8.24 Hz, 2H), 7.57 (d, J=8.54 Hz, 2H), 7.18 (dd, J=7.63, 1.53 Hz, 1H), 6.97(m, 1H), 6.76 (s, 1H), 6.64 (t, J=7.48 Hz, 1H), 6.39 (d, J=7.63 Hz, 1H) ,4.48(s, 2H), 2.47 (s, 3H)。MS (ESI+) m/z 331 (M+H)+。
实施例 32.5-{2-[(4-溴苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-溴苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 32,得到标题化合物(0.0173 g, 24%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.50 (d, J=8.24 Hz, 2H), 7.34 (d, J=8.24 Hz, 2H), 7.17 (dd, J=7.63, 1.53 Hz, 1H), 6.99(m, 1H), 6.74 (s, 1H), 6.63 (t, J=7.02 Hz, 1H), 6.44 (d, J=7.93 Hz, 1H), 4.35(s, 2H), 2.46 (s, 3H)。MS (ESI+) m/z 384 (M+H)+。
实施例 33.5-{2-[(3,4-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用3,4-二氯苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 33,得到标题化合物(0.0017 g, 2%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.58(m, 2H), 7.37 (dd, J=8.24, 1.83 Hz, 1H), 7.18 (dd, J=7.63, 1.53 Hz, 1H), 7.00(m, 1H), 6.75 (s, 1H), 6.65 (t, J=7.48 Hz, 1H), 6.42 (d, J=7.63 Hz, 1H), 4.39(s, 2H), 2.46 (s, 3H)。MS (ESI+) m/z 374 (M+H)+。
实施例 34.5-{2-[(2-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用2-氯苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 34,得到标题化合物(0.0169 g, 26%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.46 (m,1H), 7.38 (m, 1H), 7.29 (m, 2H), 7.19 (dd, J=7.32, 1.53 Hz, 1H), 7.02 (m,1H), 6.75 (s, 1H), 6.66 (t, J=7.02 Hz, 1H), 6.38 (d, J=7.63 Hz, 1H), 4.45 (s,2H), 2.46 (s, 3H)。MS (ESI+) m/z 340 (M+H)+。
实施例 35.5-{2-[(3-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用3-氯苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 35,得到标题化合物(0.0255 g, 39%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.40 (s,1H), 7.35 (m, 2H), 7.28 (m, 1H), 7.18 (dd, J=7.63, 1.53 Hz, 1H), 7.00 (m,1H), 6.75 (s, 1H), 6.64 (t, J=7.02 Hz, 1H), 6.45 (d, J=7.63 Hz, 1H), 4.40 (s,2H), 2.47 (s, 3H)。MS (ESI+) m/z 340 (M+H)+。
实施例 36.5-{2-[(环己基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用环己烷甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 36,得到标题化合物(0.0043 g, 7%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.09 (m,2H), 6.63 (m, 3H), 2.96 (d, J=6.71 Hz, 2H), 2.44 (s, 3H), 1.64 (m, 6H), 1.15(m, 3H), 0.89 (m, 2H)。MS (ESI+) m/z 312 (M+H)+。
实施例 37.5-(2-{[4-(二甲基氨基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用4-(二甲基氨基)苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 37,得到标题化合物(0.0036 g, 5%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ7.06 (m, 1H), 6.94 (dd, J=7.63, 1.53 Hz, 1H), 6.82 (d, J=8.85 Hz, 2H), 6.74(d, J=7.93 Hz, 1H), 6.60 (m, 1H), 6.55 (d, J=8.85 Hz, 2H) 3.73 (m, 2 H), 2.78(m, 6 H), 2.34 (s, 3H)。MS (ESI+) m/z 349 (M+H)+。
实施例 38.2-甲基-5-{2-[(噻吩-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺
用噻吩-2-甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 38,得到标题化合物(0.005 g, 8%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.33 (dd,J=5.19, 1.22 Hz, 1H), 7.17 (dd, J=7.63, 1.53 Hz, 1H), 7.06 (m, 2H), 6.96 (dd,J=5.19, 3.36 Hz, 1H), 6.69 (m, 3H), 4.56 (s, 2H), 2.44 (s, 3H)。MS (ESI+) m/z312 (M+H)+。
实施例 39.5-{2-[(3,5-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用3,5-二氯苯甲醛代替四氢呋喃-2-甲醛,按照制备实施例 13所用的步骤制备了实施例 39,得到标题化合物(0.0069 g, 10%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.42(m, 3H), 7.19 (dd, J=7.63, 1.53 Hz, 1H), 7.03 (m, 1H), 6.75 (s, 1H), 6.66 (t,J=7.48 Hz, 1H), 6.42 (d, J=7.63 Hz, 1H), 4.40 (s, 2H), 2.47 (s, 3H)。MS (ESI+)m/z 374 (M+H)+。
实施例 40.3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)吡咯烷-1-甲酸叔丁基酯
将实施例 1e (86 mg, 0.40 mmol)、3-甲酰基吡咯烷-1-甲酸叔丁基酯 (88 mg,0.44 mmol)、三乙酰氧基硼氢化钠(136 mg, 0.64 mmol)和乙酸 (0.023 mL, 0.40 mmol)在二氯甲烷 (2 mL)中混合。在环境温度下搅拌反应混合物1 小时,用二氯甲烷稀释,用饱和碳酸氢钠溶液和盐水洗涤。有机层用无水硫酸钠干燥、过滤并浓缩。残余物经闪式色谱法(硅胶, 2-4% 甲醇/二氯甲烷)纯化得到标题化合物(124 mg, 78%)。1H NMR (300 MHz,DMSO-d 6) δ 11.05 (s, 1 H) 7.01 -7.23 (m, 3 H) 6.49 -6.74 (m, 4 H) 4.97 (s,br, 1 H) 3.33 -3.45 (m, 2 H) 3.16 -3.25 (m, 1 H) 3.07 -3.16 (m, 2 H) 2.91 -3.02 (m, 1 H) 2.43 (s, 3 H) 1.87 -1.97 (m, 1 H) 1.52 -1.67 (m, 1 H) 1.31 -1.42 (m, 10 H)。MS (ESI+) m/z 399 (M+H)+。
实施例 41.4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)哌啶-1-甲酸叔丁基酯
用4-甲酰基哌啶-1-甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 41,得到标题化合物(128 mg, 78%)。1H NMR (300MHz, DMSO-d 6) δ 11.04 (s, 1 H) 7.00 -7.22 (m, 3 H) 6.53 -6.70 (m, 4 H) 4.97(t, J=5.95 Hz, 1 H) 3.94 (d, J=13.09 Hz, 2 H) 3.01 (t, J=6.35 Hz, 2 H) 2.59 -2.73 (m, 2 H) 2.43 (s, 3 H) 1.63 -1.83 (m, 3 H) 1.38 (s, 9 H) 0.93 -1.10 (m,2 H)。MS (ESI+) m/z 413 (M+H)+。
实施例 42.2-甲基-5-{2-[(吡咯烷-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺
向实施例 40的产物(119 mg, 0.299 mmol)/二噁烷(2 mL)中添加 4.0 M 盐酸/二噁烷 (2 mL, 8 mmol)并在环境温度下搅拌反应混合物30分钟。浓缩反应混合物并用二噁烷共沸蒸馏,残余物用二氯甲烷研制得到标题化合物(99 mg, 89%),为盐酸盐。1H NMR(300 MHz, DMSO-d 6) δ 11.11 (s, 1 H) 9.17 (s, 1 H) 9.03 (s, 1 H) 7.04 -7.30(m, 2 H) 6.56 -6.84 (m, 3 H) 3.05 -3.31 (m, 5 H) 2.88 -3.03 (m, 1 H) 2.58 -2.67 (m, 1 H) 2.44 (s, 3 H) 1.94 -2.10 (m, 1 H) 1.53 -1.75 (m, 1 H)。MS (ESI+)m/z 299 (M+H)+。
实施例 43.2-甲基-5-{2-[(哌啶-4-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺
用实施例 41的产物代替实施例 40的产物,按照制备实施例 42所用的步骤制备了实施例 43,得到标题化合物(89 mg, 77%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ11.11 (s, 1 H) 8.71 -8.88 (m, 1 H) 8.43 -8.69 (m, 1 H) 7.04 -7.21 (m, 2 H)6.54 -6.77 (m, 3 H) 3.25 (d, J=11.90 Hz, 2 H) 3.05 (d, J=6.35 Hz, 2 H) 2.71 -2.91 (m, 2 H) 2.44 (s, 3 H) 1.75 -1.96 (m, 3 H) 1.28 -1.47 (m, 2 H)。MS (ESI+)m/z 313 (M+H)+。
实施例 44.4-(2-{[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}乙基)哌啶-1-甲酸叔丁基酯
用4-(2-氧代乙基)哌啶-1-甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 44,得到标题化合物(94 mg, 55%)。1H NMR(300 MHz, DMSO-d 6) δ 11.04 (s, 1 H) 6.99 -7.20 (m, 3 H) 6.50 -6.71 (m, 4 H)4.80 (t, J=5.59 Hz, 1 H) 3.85-3.96 (m, 2 H) 3.08-3.16 (m, 2 H) 2.60 -2.75 (m,2 H) 2.43 (s, 3 H) 1.61-1.71 (m, 2 H) 1.46-1.58 (m, 3 H) 1.38 (s, 9 H) 0.92 -1.10 (m, 2 H)。MS (ESI+) m/z 427 (M+H)+。
实施例 45.[顺式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯
用(1s,4s)-4-甲酰基环己基氨基甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯, 按照制备实施例 40所用的步骤制备了实施例 45, 得到标题化合物(137 mg,80%)。1H NMR (300 MHz, DMSO-d 6) δ 11.04 (s, 1 H) 7.03 -7.20 (m, 3 H) 6.49 -6.73(m, 5 H) 4.87 (t, J=5.59 Hz, 1 H) 3.43 -3.51 (m, 1 H) 3.00 (t, J=6.27 Hz, 2H) 2.43 (s, 3 H) 1.63 -1.72 (m, 1 H) 1.40 -1.59 (m, 8 H) 1.38 (s, 9 H)。MS(ESI+) m/z 427 (M+H)+。
实施例 46.[反式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯
用(1r,4r)-4-甲酰基环己基氨基甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯, 按照制备实施例 40所用的步骤制备了实施例 46,得到标题化合物(131 mg, 77%)。1H NMR (300 MHz, DMSO-d 6) δ 11.04 (s, 1 H) 7.01 -7.20 (m, 3 H) 6.46 -6.71 (m,5 H) 4.93 (t, J=5.76 Hz, 1 H) 3.10 -3.21 (m, 1 H) 2.95 (t, J=6.27 Hz, 2 H)2.43 (s, 3 H) 1.71 -1.82 (m, 4 H) 1.45 -1.54 (m, 1 H) 1.36 (s, 9 H) 0.87 -1.19 (m, 4 H)。MS (ESI+) m/z 427 (M+H)+。
实施例 47.2-甲基-5-(2-{[2-(哌啶-4-基)乙基]氨基}苯基)-1H-吡咯-3-甲酰胺
用实施例 44的产物代替实施例 40的产物,按照制备实施例 42所用的步骤制备了实施例 47,得到标题化合物(49 mg, 61%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ11.18 (s, 1 H) 8.70 -8.83 (m, 1 H) 8.41 -8.58 (m, 1 H) 7.09 -7.26 (m, 2 H)6.71 -6.87 (m, 2 H) 6.66 (d, J=2.78 Hz, 1 H) 3.23 (d, J=12.29 Hz, 2 H) 3.13(t, J=7.34 Hz, 2 H) 2.72 -2.89 (m, 2 H) 2.44 (s, 3 H) 1.81 (d, J=13.48 Hz, 2H) 1.47 -1.66 (m, 3 H) 1.22 -1.41 (m, 2 H)。MS (ESI+) m/z 327 (M+H)+。
实施例 48.5-(2-{[(顺式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 45的产物代替实施例 40的产物,按照制备实施例 42所用的步骤制备了实施例 48,得到标题化合物(119 mg, 99%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ11.11 (s, 1 H) 7.89 (s, 2 H) 7.04 -7.21 (m, 2 H) 6.55 -6.76 (m, 3 H) 3.12 -3.24 (m, 1 H) 3.04 (d, J=7.14 Hz, 2 H) 2.44 (s, 3 H) 1.73 -1.84 (m, 1 H) 1.59-1.69 (m, 4 H) 1.46 -1.58 (m, 4 H)。MS (ESI+) m/z 327 (M+H)+。
实施例 49.5-(2-{[(反式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 46的产物代替实施例 40的产物,按照制备实施例 42所用的步骤制备了实施例 49,得到标题化合物(109 mg, 95%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ11.16 (s, 1 H) 7.94 (s, 2 H) 7.01 -7.27 (m, 2 H) 6.68 -6.79 (m, 2 H) 6.64 (d,J=2.78 Hz, 1 H) 2.85 -3.00 (m, 3 H) 2.44 (s, 3 H) 1.95 (d, J=10.31 Hz, 2 H)1.82 (d, J=11.90 Hz, 2 H) 1.49 -1.62 (m, 1 H) 1.18 -1.36 (m, 2 H) 0.93 -1.09(m, 2 H)。MS (ESI+) m/z 327 (M+H)+。
实施例 50.[4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯
用4-甲酰基苯基氨基甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 50,得到标题化合物(119 mg, 71%)。1H NMR(300 MHz, DMSO-d 6) δ 11.06 (s, 1 H) 9.23 (s, 1 H) 7.34 -7.40 (m, 2 H) 7.22 -7.27 (m, 2 H) 7.11 -7.18 (m, 2 H) 6.92 -7.02 (m, 1 H) 6.70 (d, J=2.71 Hz, 1H) 6.54 -6.64 (m, 2 H) 6.49 (d, J=8.14 Hz, 1 H) 5.56 (t, J=5.93 Hz, 1 H) 4.29(d, J=5.76 Hz, 2 H) 2.45 (s, 3 H) 1.46 (s, 9 H)。MS (ESI+) m/z 421 (M+H)+。
实施例 51.[3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯
用3-甲酰基苯基氨基甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 51,得到标题化合物(103 mg, 61%)。1H NMR(300 MHz, DMSO-d 6) δ 11.07 (s, 1 H) 9.29 (s, 1 H) 7.48 (s, 1 H) 7.29 (d, J=8.33 Hz, 1 H) 7.13 -7.20 (m, 2 H) 7.09 (s, 1 H) 6.92 -7.01 (m, 2 H) 6.72 (d,J=2.78 Hz, 1 H) 6.56 -6.65 (m, 2 H) 6.45 (d, J=7.54 Hz, 1 H) 5.65 (t, J=6.15Hz, 1 H) 4.32 (d, J=5.95 Hz, 2 H) 2.45 (s, 3 H) 1.45 (s, 9 H)。MS (ESI+) m/z421 (M+H)+。
实施例 52.5-{2-[(4-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用实施例 50代替实施例 40,按照制备实施例 42所用的步骤制备了实施例 52,得到标题化合物(92 mg, 87%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ 11.13 (s, 1 H)10.17 (s, 2 H) 7.49 (d, J=8.48 Hz, 2 H) 7.32 (d, J=8.48 Hz, 2 H) 7.17 (dd, J=7.46, 1.36 Hz, 1 H) 6.92 -7.01 (m, 1 H) 6.76 (d, J=2.37 Hz, 1 H) 6.62 (t, J=7.12 Hz, 1 H) 6.44 (d, J=8.14 Hz, 1 H) 4.41 (s, 2 H) 2.46 (s, 3 H)。MS (ESI+)m/z 321 (M+H) +。
实施例 53.5-{2-[(3-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用实施例 51代替实施例 40,按照制备实施例 42所用的步骤制备了实施例 53,得到标题化合物(65 mg, 72%),为盐酸盐。1H NMR (300 MHz, DMSO-d 6) δ 11.12 (s, 1 H)10.04 (s, 2 H) 7.35 -7.49 (m, 3 H) 7.14 -7.24 (m, 2 H) 6.92 -7.00 (m, 1 H)6.78 (d, J=2.38 Hz, 1 H) 6.62 (t, J=6.94 Hz, 1 H) 6.42 (d, J=7.54 Hz, 1 H)4.44 (s, 2 H) 2.46 (s, 3 H)。MS (ESI+) m/z 321 (M+H)+。
实施例 54.5-{2-[(4-羟基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-羟基苯甲醛代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 54。通过闪式色谱法(硅胶, 4-5% 甲醇/二氯甲烷)纯化得到标题化合物(55 mg, 43%)。1H NMR (300 MHz, DMSO-d 6) δ11.06 (s, 1 H) 9.21 (s, 1 H) 7.09-7.22 (m, 4 H) 6.93 -7.02 (m, 1 H) 6.44 -6.77 (m, 6 H) 5.48 (t, J=5.93 Hz, 1H) 4.24 (d, J=6.10 Hz, 2 H) 2.44 (s, 3 H)。MS (ESI+) m/z 322 (M+H)+。
实施例 55.5-[2-({[5-(羟基甲基)呋喃-2-基]甲基}氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用5-(羟基甲基)呋喃-2-甲醛代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 55。通过闪式色谱法(硅胶, 4-5% 甲醇/二氯甲烷)纯化得到标题化合物(39 mg, 30%)。1H NMR (300 MHz, DMSO-d 6) δ11.06 (s, 1 H) 7.00 -7.22 (m, 3 H)6.54 -6.79 (m, 4 H) 6.08 -6.28 (m, 2 H) 5.40 (t, J=6.10 Hz, 1 H)5.12 (t, J=5.76, 1 H) 4.26 -4.39 (m, 4 H) 2.44 (s, 3 H)。MS (ESI-) m/z 324 (M-H)+。
实施例 56.5-{2-[(1H-吲哚-5-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
实施例 56a
5-((2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基氨基)甲基)-1H-吲哚-1-甲酸叔丁基酯
用5-甲酰基-1H-吲哚-1-甲酸叔丁基酯代替3-甲酰基吡咯烷-1-甲酸叔丁基酯,按照制备实施例 40所用的步骤制备了实施例 56a,得到标题化合物(113 mg, 64%)。
实施例 56b
5-{2-[(1H-吲哚-5-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用实施例 56a代替实施例 40,按照制备实施例 42所用的步骤制备了实施例56b。通过反相HPLC (C18, 20-95% 乙腈/10mM 乙酸铵/水)纯化得到标题化合物(21 mg,25%)。1H NMR (300 MHz, DMSO-d 6) δ 11.08 (s, 1 H) 10.99 (s, 1 H) 7.52 (s, 1 H)7.26 -7.35 (m, 2 H) 7.06 -7.19 (m, 3 H) 6.89 -7.00 (m, 1 H) 6.73 (d, J=2.38Hz, 1 H) 6.50 -6.64 (m, 3 H) 6.33 -6.36 (m, 1 H) 5.58 (t, J=5.75 Hz, 1 H)4.42 (d, J=5.55 Hz, 2 H) 2.44 (s, 3 H)。MS (ESI+) m/z 345 (M+H)+。
实施例 57.5-{2-[(环戊基甲基){4-[3-(二甲基氨基)丙氧基]苄基}氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
将实施例 14 (30 mg, 0.1 mmol )、4-(3-(二甲基氨基)丙氧基)苯甲醛(41 mg,0.2 mmol)和乙酸 (0.058 mL, 1.0 mmol )在甲醇/二氯甲烷 (1:1, 1.7 mL)混合物中混合。在50℃振摇反应混合物40分钟,加入MP-氰基硼氢化物(大孔三乙基铵甲基聚苯乙烯氰基硼氢化物)树脂(163 mg, 0.35 mmol),在50℃振摇所得混合物过夜,过滤并浓缩。残余物经反相HPLC(C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(14 mg, 19%),为三氟乙酸盐。1H NMR (400 MHz, DMSO-d 6) δ 7.47 (d, J=7.32 Hz, 1H) 7.09 -7.28 (m, 3 H) 7.08 (d, J=8.54 Hz, 2 H) 6.85 -6.96 (m, 1 H) 6.82 (d,J=8.54 Hz, 2 H) 3.92 -4.13 (m, 4 H) 3.15 -3.24 (m, 2 H) 2.75 -2.92 (m, 8 H)2.44 -2.48 (m, 3 H) 2.01 -2.14 (m, 2 H) 1.89 -1.99 (m, 1 H) 1.32 -1.59 (m, 6H) 0.94 -1.04 (m, 2 H)。MS (ESI+) m/z 489 (M+H)+。
实施例 58.5-(2-{[(1-乙酰基-1H-吲哚-3-基)甲基](环戊基甲基)氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用1-乙酰基-1H-吲哚-3-甲醛代替4-(3-(二甲基氨基)丙氧基)苯甲醛,按照制备实施例 57所用的步骤制备了实施例 58,得到标题化合物(9.7 mg, 17%),为三氟乙酸盐。1H NMR (400 MHz, DMSO-d 6) δ 8.24 (d, J=8.24 Hz, 1 H) 7.53 (s, 1 H) 7.48 (dd, J=7.17, 1.68 Hz, 1 H) 7.08 -7.34 (m, 6 H) 6.87 -6.94 (m, 1 H) 4.24 (s, 2 H)2.97 (s, 2 H) 2.54 (s, 3 H) 2.34 (s, 3 H) 1.99 -2.09 (m, 1 H) 1.33 -1.67 (m,6 H) 1.02 -1.14 (m, 2 H)。MS (ESI+) m/z 469 (M+H)+。
实施例 59.5-(2-{[4-(乙酰基氨基)苄基](环戊基甲基)氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用N-(4-甲酰基苯基)乙酰胺代替4-(3-(二甲基氨基)丙氧基)苯甲醛,按照制备实施例 57所用的步骤制备了实施例 59,得到标题化合物(11.6 mg, 21%),为三氟乙酸盐。1HNMR (400 MHz, DMSO-d 6) δ 7.41 -7.52 (m, 3 H) 7.09 -7.32 (m, 3 H) 7.07 (d, J=8.54 Hz, 3 H) 3.97 -4.15 (m, 2 H) 2.87 (s, 2 H) 2.45 (s, 3 H) 2.02 (s, 3 H)1.88 -1.97 (m, 1 H) 1.31 -1.59 (m, 6 H) 0.95 -1.05 (m, 2 H)。MS (ESI+) m/z 445(M+H)+。
实施例 60.5-{2-[(环戊基甲基)(噻吩-2-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用噻吩-2-甲代替4-(3-(二甲基氨基)丙氧基)苯甲醛,按照制备实施例 57所用的步骤制备了实施例 60,得到标题化合物(14 mg, 27%),为三氟乙酸盐。1H NMR (400 MHz,DMSO-d 6) δ 7.52 (dd, J=7.78, 1.68 Hz, 1 H) 7.39 (d, J=3.97 Hz, 1 H) 7.09 -7.23 (m, 3 H) 6.94 (dd, J=5.04, 3.51 Hz, 2 H) 6.88 (d, J=3.05 Hz, 1 H) 4.25(s, 2 H) 2.88 (d, J=6.41 Hz, 2 H) 2.48 (s, 3 H) 1.89 -2.02 (m, 1 H) 1.31 -1.64 (m, 6 H) 1.01 -1.11 (m, 2 H)。MS (ESI-) m/z 392 (M-H) +。
实施例 61.5-{2-[(环戊基甲基)(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-甲氧基苯甲醛代替4-(3-(二甲基氨基)丙氧基)苯甲醛,按照制备实施例 57所用的步骤制备了实施例 61,得到标题化合物(9.4 mg, 18%),为三氟乙酸盐。1H NMR(400 MHz, DMSO-d 6) δ 7.47 (d, J=7.32 Hz, 1 H) 7.01 -7.40 (m, 5 H) 6.76 -7.01(m, 3 H) 3.97 -4.15 (m, 2 H) 3.70 (s, 3 H) 2.87 (s, 2 H) 2.45 (s, 3 H) 1.93(s, 1 H) 1.29 -1.62 (m, 6 H) 0.95 -1.05 (m, 2 H)。MS (ESI+) m/z 418 (M+H) +。
实施例 62.5-[2-(环己基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用环己酮代替4-氯苯甲醛,按照制备实施例 11所用的步骤制备了实施例 62。通过制备HPLC (C8(2) 5 µm 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.043 g, 73%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 7.11 (m, 3H), 6.65(m, 4H), 4.69 (s, 1H), 3.29 (m, 1H), 2.43 (s, 3H), 1.93 (m, 2H), 1.62 (m,3H), 1.27 (m, 5H)。MS (ESI+) m/z 298.0 (M+H)+。
实施例 63.2-甲基-5-[2-(四氢呋喃-3-基氨基)苯基]-1H-吡咯-3-甲酰胺
用二氢呋喃-3(2H)-酮代替4-氯苯甲醛,按照制备实施例 11所用的步骤制备了实施例 63,得到标题化合物(0.0138 g, 24%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.07 (s,1H), 7.13 (m, 3H), 6.68 (m, 2H), 6.63 (d, J=2.78 Hz, 1H), 6.58 (s, 1H), 4.82(d, J=6.74 Hz, 1H), 4.08 (m, 1H), 3.91 (dd, J=8.72, 5.95 Hz, 1H), 3.81 (q, J=7.27 Hz, 1H), 3.70 (td, J=8.23, 5.75 Hz, 1H), 3.56 (dd, J=8.72, 3.57 Hz, 1H),2.44 (s, 3H), 2.24 (m, 1H), 1.78 (m, 1H)。MS (ESI+) m/z 286.0 (M+H)+。
实施例 64.2-甲基-5-[2-(吡咯烷-3-基氨基)苯基]-1H-吡咯-3-甲酰胺
实施例 64a
3-((2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基)氨基)吡咯烷-1-甲酸叔丁基酯
用3-氧代吡咯烷-1-甲酸叔丁基酯代替4-氯苯甲醛,按照制备实施例 11所用的步骤制备了实施例 64a,得到标题化合物。
实施例 64b
2-甲基-5-[2-(吡咯烷-3-基氨基)苯基]-1H-吡咯-3-甲酰胺
将实施例 64a 在1,4-二噁烷(5 mL)和甲醇(1 mL)中用盐酸溶液 (4 N于1,4-二噁烷中)(1 mL, 4.00 mmol)处理并在环境温度下搅拌1.5 小时。浓缩反应混合物至干并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.0316 g, 40%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.72 (s, 1H),7.16 (m, 3H), 6.68 (m, 4H), 4.98 (m, 1H), 4.20 (m, 1H), 3.33 (m, 2H), 3.18(m, 2H), 2.45 (s, 3H), 2.30 (m, 1H), 1.93 (m, 1H)。MS (ESI+) m/z 285.0 (M+H)+。
实施例 65.2-甲基-5-[2-(哌啶-4-基氨基)苯基]-1H-吡咯-3-甲酰胺
实施例 65a
4-((2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基)氨基)哌啶-1-甲酸叔丁基酯
用4-氧代哌啶-1-甲酸叔丁基酯代替4-氯苯甲醛,按照制备实施例 11所用的步骤制备了实施例 65a,得到标题化合物(0.05 g, 62%)。
实施例 65b
2-甲基-5-[2-(哌啶-4-基氨基)苯基]-1H-吡咯-3-甲酰胺
用实施例65a代替实施例64a,按照制备实施例 64b所用的步骤制备了实施例65b,得到标题化合物(0.047 g, 91%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.09 (s, 1H),8.50 (m, 1H), 8.19 (m, 1H), 7.14 (m, 3H), 6.77 (d, J=7.93 Hz, 1H), 6.66 (m,3H), 4.67 (s, 1H), 3.62 (m, 1H), 3.29 (d, J=13.09 Hz, 2H), 3.03 (m, 2H), 2.44(s, 3H), 2.10 (d, J=11.50 Hz, 2H), 1.54 (m, 2H)。MS (ESI+) m/z 299.0 (M+H)+。
实施例 66.5-[2-(环丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用环丁酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 66,得到标题化合物(0.0066 g, 13%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.15 (m, 2H), 6.69(m, 2H), 6.58 (d, J = 7.5 Hz, 1H), 3.91 (m, 1H), 2.72 (d, J = 18.2 Hz, 2H),2.40 (d, J = 34.4 Hz, 3H), 1.75 (d, J = 8.4 Hz, 2H), 1.22 (m, 2H)。MS (ESI+)m/z 270 (M+H)+。
实施例 67.5-[2-(2,3-二氢-1H-茚-1-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用2,3-二氢-1H-茚-1-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 67,得到标题化合物(0.0106 g, 17%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.32(m, 3H), 7.16 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H),6.60 (s, 1H), 5.04 (t, J = 7.3 Hz, 1H), 2.92 (m, 2H), 2.62 (m, 1H), 2.40 (m,3H), 1.80 (m, 1H)。MS (ESI+) m/z 332 (M+H)+。
实施例 68.2-甲基-5-[2-(四氢-2H-噻喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺
用二氢-2H-噻喃-4(3H)-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 68,得到标题化合物(0.0137 g, 23%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.17(m, 2H), 6.79 (m, 2H), 6.64 (s, 1H), 3.35 (ddd, J = 10.3, 7.0, 3.3 Hz, 1H),2.77 (m, 2H), 2.64 (d, J = 13.9 Hz, 2H), 2.46 (d, J = 10.0 Hz, 3H), 2.20 (m,2H), 1.54 (m, 2H)。MS (ESI+) m/z 316 (M+H)+。
实施例 69.5-[2-(2,3-二氢-1H-茚-2-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用1H-茚-2(3H)-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 69,得到标题化合物(0.0082 g, 13%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.27 (m,1H), 7.20 (m, 2H), 7.12 (m, 3H), 6.88 (d, J = 8.1 Hz, 1H), 6.75 (dd, J =10.7, 4.2 Hz, 1H), 6.57 (s, 1H), 4.35 (p, J = 6.7 Hz, 1H), 3.35 (dd, J =15.9, 7.2 Hz, 2H), 2.87 (dd, J = 15.9, 5.7 Hz, 2H), 2.42 (s, 3H)。MS (ESI+) m/z 332 (M+H)+。
实施例 70.2-甲基-5-[2-(四氢-2H-吡喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺
用二氢-2H-吡喃-4(3H)-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 70,得到标题化合物(0.0209 g, 38%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.18(m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.80 (dd, J = 10.9, 4.1 Hz, 1H), 6.66 (s,1H), 3.86 (dd, J = 8.3, 3.1 Hz, 2H), 3.53 (m, 1H), 3.41 (m, 2H), 2.45 (s,3H), 1.90 (d, J = 12.5 Hz, 2H), 1.52 (m, 2H)。MS (ESI+) m/z 300 (M+H)+。
实施例 71.5-[2-(1-氮杂双环[2.2.2]辛烷-3-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用奎宁环-3-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例71,得到标题化合物(0.0105 g, 16%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.22 (dd, J =7.5, 1.5 Hz, 1H), 7.12 (m, 1H), 6.75 (dd, J = 23.0, 15.4 Hz, 1H), 6.67 (d, J= 9.1 Hz, 2H), 3.88 (s, 1H), 3.26 (m, 4H), 3.05 (d, J = 12.4 Hz, 1H), 2.57(s, 1H), 2.46 (d, J = 2.0 Hz, 3H), 2.37 (d, J = 7.8 Hz, 1H), 2.27 (d, J =12.7 Hz, 1H), 1.94 (d, J = 8.5 Hz, 2H), 1.79 (s, 1H)。MS (ESI+) m/z 325 (M+H)+。
实施例 72.2-甲基-5-{2-[三环[3.3.1.13,7]癸烷-2-基氨基]苯基}-1H-吡咯-3-甲酰胺
用金刚烷酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 72,得到标题化合物(0.0105 g, 16%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.12 (m, 2H),6.69 (dd, J = 11.8, 4.5 Hz, 3H), 3.55 (s, 1H), 2.45 (s, 3H), 1.95 (s, 2H),1.83 (s, 4H), 1.74 (d, J = 13.1 Hz, 4H), 1.70 (s, 2H), 1.53 (d, J = 12.0 Hz,2H)。MS (ESI+) m/z 350 (M+H)+。
实施例 73.5-[2-(环庚基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用环庚酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 73,得到标题化合物(0.0145 g, 25%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.19 (m, 2H), 6.79(m, 2H), 6.63 (s, 1H), 3.42 (d, J = 3.9 Hz, 1H), 2.45 (s, 3H), 1.90 (dd, J =13.1, 3.6 Hz, 2H), 1.54 (m, 10H) MS (ESI+) m/z 312 (M+H)+。
实施例 74.2-甲基-5-[2-(1,2,3,4-四氢萘-2-基氨基)苯基]-1H-吡咯-3-甲酰胺
用3,4-二氢萘-2(1H)-酮代替2-氟环己酮,按照制备实施例 75所用的步骤制备了实施例 74,得到标题化合物(0.0095 g, 15%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.18(dt, J = 12.2, 4.1 Hz, 2H), 7.09 (m, 5H), 6.86 (t, J = 8.5 Hz, 1H), 6.76 (m,1H), 6.58 (s, 1H), 3.11 (dd, J = 16.1, 4.6 Hz, 1H), 2.87 (m, 2H), 2.75 (dt, J= 18.1, 10.4 Hz, 2H), 2.43 (s, 3H), 2.13 (t, J = 12.1 Hz, 1H), 1.72 (m, 1H)。MS (ESI+) m/z 346 (M+H)+。
实施例 75.5-{2-[(2-氟环己基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
向4 mL小瓶中加入搅拌子、实施例 1e (0.04 g, 0.18 mmol)的二氯甲烷 (1 mL)溶液、2-氟环己酮(0.025 g, 0.22 mmol)的二氯甲烷(1 mL)溶液和乙酸(0.053 mL, 0.92mmol)和三乙氧基硼氢化钠(0.06 g, 0.27 mmol)。将小瓶密封并在环境温度下搅拌16 小时。完成后,过滤粗制材料、干燥并通过反相HPLC(C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(0.0023 g, 4%)。1H NMR (400 MHz, DMSO-d 6 /D2O)δ 7.13 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 6.60 (s,1H), 4.85 (d, J = 52.2 Hz, 1H), 3.55 (d, J = 18.3 Hz, 1H), 2.45 (d, J = 7.9Hz, 3H), 1.97 (s, 1H), 1.77 (m, 4H), 1.47 (m, 4H)。MS (ESI+) m/z 316 (M+H)+。
实施例 76.2-甲基-5-{2-[(苯基乙酰基)氨基]苯基}-1H-吡咯-3-甲酰胺
向实施例 1e (0.065 g, 0.3 mmol)和二异丙基乙胺 (0.105 mL, 0.6 mmol)的四氢呋喃(1.5 mL)溶液中滴加苯乙酰氯(phenacyl chlorid)(0.048 mL, 0.36 mmol),搅拌1 小时并在乙酸乙酯和盐水之间分配。分离出有机层并浓缩。通过反相HPLC (C8(2), 5µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.035 g, 35%) 1HNMR (300 MHz, DMSO-d 6) δ 11.09 -11.13 (m, 1 H) 9.15 -9.20 (m, 1 H) 7.57 -7.65(m, 1 H) 7.36 -7.42 (m, 1 H) 7.15 -7.35 (m, 7 H) 6.98 (s, 1 H) 6.66 (d, J=2.71 Hz, 1 H) 6.59 -6.63 (m, 1 H) 3.64 -3.74 (m, 2 H) 2.43 -2.46 (m, 3 H)。MS(ESI-) m/z 332 (M-H)+。
实施例 77.2-甲基-5-[2-(苯基氨基)苯基]-1H-吡咯-3-甲酰胺
向实施例 1e (0.043 g, 0.2 mmol)、苯基硼酸(0.037 g, 0.300 mmol)、乙酸铜(II)(7.27 mg, 0.040 mmol)和肉豆蔻酸 (0.018 g, 0.080 mmol)的混合物中添加甲苯(1.0 mL)和2,6-二甲基吡啶 (0.047 mL, 0.400 mmol)。将反应混合物暴露于空气并在环境温度下剧烈搅拌过夜。用乙酸乙酯稀释反应混合物,用饱和碳酸氢钠水溶液、水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 3% 甲醇/二氯甲烷)纯化得到标题化合物(0.33 g, 57%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 7.39(dd, J=7.63, 1.53 Hz, 1H), 7.19 (m, 5H), 6.99 (m, 4H), 6.81 (m, 1H), 6.75 (d,J=2.71 Hz, 1H), 6.53 (s, 1H), 2.43 (s, 3H)。MS (ESI+) m/z 291.9 (M+H)+。
实施例 78.2-甲基-5-{2-[(苯基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺
向实施例 1e (0.20g, 0.929 mmol)和DMAP (0.114 g, 0.929 mmol)在二噁烷(10 mL)中的混合物中添加苯磺酰氯(0.164 g, 0.929 mmol)。在60℃加热反应混合物4 小时。反应混合物直接经制备型薄层色谱(硅胶, 二氯甲烷/甲醇, 12/1) 纯化得到标题化合物(0.056 g, 17%收率)。1H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1 H), 9.35 (s, 1H), 7.64-7.56 (m, 3 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.32 (dd, J = 7.6, 1.2 Hz,1 H), 7.22-7.18 (m, 1 H), 7.15-7.11 (m, 1 H), 7.03-7.01 (m, 1 H), 6.94 (s, 1H), 6.64 (d, J = 2.4 Hz, 2 H), 2.42 (s, 3 H)。MS (ESI+) m/z 356.8 (M +H)。
实施例 79.5-{2-[(环己基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用环己烷磺酰氯代替苯磺酰氯,按照制备实施例 78所用的步骤制备了实施例79,得到标题化合物。1H NMR (400 MHz, DMSO-d 6) δ 11.13 (s, 1 H), 8.53 (s, 1 H),7.40-7.36 (m, 2 H), 7.30-7.26 (m, 2 H), 7.01 (s, 1 H), 6.71 (d, J = 2.4 Hz, 2H), 2.62-2.56 (m, 1 H), 2.45 (s, 3 H), 1.78-1.75 (m, 2 H), 1.64-1.61 (m, 2H), 1.52-1.49 (m, 1 H), 1.21-0.95 (m, 5H)。MS (ESI+) m/z 362.2 (M +H)。
实施例 80.2-甲基-5-{2-[(吡啶-3-基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺
在THF (10 mL)中搅拌实施例 1e (0.10 g, 0.465 mmol)和三乙胺 (0.097 mL,0.70 mmol)的混合物。向该混合物中添加吡啶-3-磺酰氯(0.082 g, 0.465 mmol)。在60℃加热反应混合物3 小时。通过添加盐水 (10 mL)淬灭反应,用水稀释并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。将残余物溶于二氯甲烷并通过闪式色谱法(硅胶, 0.5-10 % 甲醇/二氯甲烷梯度洗脱)纯化得到标题化合物(0.036 g, 22 %收率)。1HNMR (400 MHz, DMSO-d 6) δ 11.12 (s, 1 H), 9.67 (s, 1 H), 8.68 (d, J = 1.6 Hz,2 H), 7.93-7.90 (m, 1 H), 7.42-7.39 (m, 1 H), 7.35-7.32 (m, 1 H), 7.13-7.06(m, 3 H), 6.94 (s, 1 H), 6.65 (d, J = 2.0 Hz, 2 H), 2.40 (s, 3 H)。MS (ESI+):m/z 357.1 (M +H)。
实施例 81.5-(2-{[(4-氯苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用4-氯苯-1-磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 81,得到标题化合物。1H NMR (400 MHz, DMSO-d 6) δ 10.81 (s, 1 H), 7.54 (s,1 H), 7.53-7.50 (m, 2 H), 7.47-7.44 (m, 2 H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.26-7.22 (m, 1 H), 7.20-7.16 (m, 1 H), 7.09 (dd, J= 8.0, 1.2 Hz, 1 H),6.90 (s, 1 H), 6.62 (d, J = 2.4 Hz, 2 H), 2.41 (s, 3 H)。MS (ESI+) m/z 390.0(M +H)。
实施例 82.2-甲基-5-(2-{[(3,3,3-三氟丙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺
用3,3,3-三氟丙烷-1-磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 82,得到标题化合物。1H NMR (400 MHz, DMSO-d 6) δ 11.25 (s, 1 H),9.14 (s, 1 H), 7.44-7.41 (m, 1 H), 7.38-7.35 (m, 1 H), 7.28-7.26 (m, 2 H),6.99 (s, 1 H), 6.79 (d, J = 2.4 Hz, 1 H), 6.63 (s, 1 H), 3.11-3.07 (m, 2 H),2.44 (s, 5 H)。MS (ESI+) m/z 376.1 (M +H)。
实施例 83.5-{2-[(苄基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用苯基甲烷磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 83,得到标题化合物。1H NMR (400 MHz,DMSO-d 6) δ 11.30 (s, 1 H), 8.67 (s, 1H), 7.42-7.39 (m, 1 H), 7.32-7.31 (m, 4 H), 7.26-7.25 (m, 2 H), 7.19-7.18 (m,2 H), 7.04 (s, 1 H), 6.75 (d, J = 1.6 Hz, 1 H), 6.63 (s, 1 H), 4.30 (s, 2 H),2.44 (s, 3 H)。MS (ESI+) m/z 370.0 (M +H)。
实施例 84.5-(2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
在1,4-二噁烷 (10 mL)中搅拌实施例 1e (0.30 g, 1.39 mmol)和二甲基氨基吡啶(0.255 g, 2.09 mmol)的混合物。向该混合物中添加2,4-二氟苯-1-磺酰氯(0.326 g,1.53 mmol)。在60℃加热反应混合物3 小时,然后冷却至环境温度。添加盐水淬灭反应,用水稀释并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。将残余物溶于二氯甲烷并通过闪式色谱法(硅胶, 0.5-10 % 甲醇/二氯甲烷梯度洗脱)纯化得到标题化合物(0.35 g, 13%收率)。1H NMR (400 MHz, DMSO-d 6) δ 10.84 (s, 1 H), 9.65 (s, 1 H),7.46 (q, J = 8.4 Hz, 1 H), 7.30-7.12 (m, 5 H), 7.06-7.02 (m, 1 H), 6.78-6.69(m, 1 H), 6.61 (s, 1 H), 6.50 (d, J = 2 Hz, 1 H), 2.40 (s, 3 H)。MS (ESI) m/z392.0 (M +H)。
实施例 85.5-(2-{[(4-氯苄基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
用(4-氯苯基)甲烷磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 85,得到标题化合物。1H NMR (400 MHz, DMSO-d 6) δ 11.21 (s, 1 H), 8.68(s, 1 H), 7.41-7.33 (m, 4 H), 7.26 (d, J = 8.4 Hz, 2 H), 7.21-7.19 (m, 2 H),7.04 (s, 1 H), 6.75 (d, J = 2.4 Hz, 1 H), 6.65 (s, 1 H), 4.35 (s, 2 H), 2.44(s, 3 H)。MS (ESI+) m/z 404.0 (M +H)。
实施例 86.2-甲基-5-(2-{[(2,2,2-三氟乙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺
用2,2,2-三氟乙烷磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 86,得到标题化合物。1H NMR (400 MHz, DMSO-d 6) δ 11.16 (s, 1 H), 9.52(s, 1 H), 7.46-7.39 (m, 2 H), 7.31-7.25 (m, 2 H), 6.99 (s, 1 H), 6.76 (d, J =2.8 Hz, 1 H), 6.64 (s, 1 H), 4.24-4.16 (q, J = 10.0 Hz, 2 H), 2.45 (s, 3 H)。MS (ESI+) m/z 362.0 (M +H)。
实施例 87.5-{2-[(环戊基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用环戊烷磺酰氯代替吡啶-3-磺酰氯,按照制备实施例 80所用的步骤制备了实施例 87,得到标题化合物。1H NMR 400 MHz, CDCl3) δ 9.13 (s, 1 H), 7.51 (d, J = 7.6Hz, 1 H), 7.38-7.30 (m, 2 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.17 (s, 1 H), 6.42(d, J = 2.8 Hz, 1 H), 5.63 (s, 2 H), 3.65-3.61 (m, 1 H), 2.57 (s, 3 H), 2.08-1.97 (m, 4 H), 1.87-1.77 (m, 2 H), 1.67-1.60 (m, 2 H)。MS (ESI) m/z 348.0 (M +H)。
实施例 88.5-(2-{[(4-羟基苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺
在THF (10 mL)中搅拌实施例 1e (0.10 g, 0.465 mmol)和三乙胺 (0.097 mL,0.697 mmol)的混合物。向该混合物中添加4-羟基苯-1-磺酰氯(0.089 g, 0.465 mmol)。在60℃加热反应混合物3 小时。通过添加盐水(10 mL)淬灭反应,用水稀释并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。将残余物溶于二氯甲烷并通过闪式色谱法(硅胶, 0.5-10 % 甲醇/二氯甲烷梯度洗脱)纯化得到标题化合物(0.12 g, 8.6% 收率)。1H NMR (400 MHz, CD3OD) δ 7.28-7.22 (m, 3 H), 7.14-7.05 (m, 3 H), 6.62 (d,J = 8.8 Hz, 2 H), 6.41 (s, 1 H), 2.39 (s, 3 H), 2.05 (s, 1 H)。MS (ESI+) m/z372.0 (M +H)。
实施例 89.2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酰胺
实施例 89a
2-乙酰基-4-氧代-4-(2-苯氧基苯基)丁酸叔丁基酯
用2-溴-1-(2-苯氧基苯基)乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 89a,得到标题化合物(0.338 g, 89%)。
实施例 89b
2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酸叔丁基酯
用实施例 89a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例89b,得到标题化合物(0.285 g, 89%)。
实施例 89c
2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酸
用实施例 89b代替实施例 1b,按照制备实施例 1c所用的步骤制备了实施例89c,得到标题化合物(0.26 g, 100%)。
实施例 89d
2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酰胺
用实施例 89c代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例89d,得到标题化合物(0.026 g, 55%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.13 (s, 1H),7.69 (m, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 7.08 (m, 2H), 6.97 (m, 2H), 6.91(m, 2H), 6.54 (s, 1H), 2.43 (s, 3H)。MS (ESI+) m/z 293.1 (M+H)+。
实施例 90.5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 90a
2-乙酰基-4-(2,4-二甲基苯基)-4-氧代丁酸叔丁基酯
用2-溴-1-(2,4-二甲基苯基)乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 90a,得到标题化合物(0.609 g, 91%)。
实施例 90b
5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酸叔丁基酯
用实施例 90a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例90b,得到标题化合物(0.581 g, 99%)。
实施例 90c
5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酸
用实施例 90b代替实施例 1b,按照制备实施例 1c所用的步骤制备了实施例90c,得到标题化合物(0.43 g, 93%)。
实施例 90d
5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 90c代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例90d,得到标题化合物(0.03 g, 60%)。1H NMR (300 MHz, DMSO-d 6 ) δ 10.99 (s, 1H),7.27 (d, J=7.80 Hz, 1H), 7.11 (s, 1H), 7.04 (m, 2H), 6.57 (d, J=3.05 Hz, 1H),6.52 (s, 1H), 2.44 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H)。MS (ESI+) m/z 229.1 (M+H)+。
实施例 91.5-(2-氨基-6-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 91a
2-(1-乙氧基乙烯基)-1-氟-3-硝基苯
将2-溴-1-氟-3-硝基苯 (1.364 g, 6.20 mmol)和二氯二(三苯基膦)钯(II)(0.435 g, 0.620 mmol)的混合物脱气并用氮气吹扫。在氮气氛下依次加入1,4-二噁烷(15.5 mL)和三丁基(1-乙氧基乙烯基)锡(2.51 mL, 7.44 mmol),在95℃加热所得混合物4.5 小时,然后冷却至环境温度,加入氟化钾溶液(1.4 g 在12 mL 水中),然后加入乙酸乙酯。搅拌该混合物过夜,然后通过硅藻土过滤,用500 mL乙酸乙酯洗涤,用水和盐水洗涤滤液,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 2-20% 乙酸乙酯/己烷)纯化得到标题化合物(0.91 g, 70%)。
实施例 91b
1-(2-氟-6-硝基苯基)乙酮
用盐酸溶液(2 M 水溶液)(4.31 mL, 8.62 mmol)处理实施例 91a (0.91 g,4.31 mmol)/四氢呋喃(21.54 mL)并在环境温度下搅拌过夜。用乙酸乙酯稀释反应混合物,用饱和碳酸氢钠溶液中和,用水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 2-15% 乙酸乙酯/己烷)纯化得到标题化合物(0.775 g, 98%)。
实施例 91c
1-(2-硝基-6-苯氧基苯基)乙酮
将实施例 91b、苯酚(0.029 g, 0.310 mmol)和碳酸铯(2.76 g, 8.46 mmol)与二甲基甲酰胺(21 mL)混合,在50℃加热三小时,然后在环境温度下搅拌过夜。将反应混合物在乙酸乙酯和水之间分配,有机层经盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 1-10% 乙酸乙酯/己烷)纯化得到标题化合物(1.06 g, 97%)。
实施例 91d
2-溴-1-(2-硝基-6-苯氧基苯基)乙酮
向实施例 91c(0.99 g, 3.86 mmol)的乙酸(5.14 mL)溶液中加入溴(0.238 mL,4.63 mmol)的乙酸(5.14 mL)溶液。在100℃加热所得混合物4 小时。添加另外的溴(0.238mL, 4.63 mmol)并在100℃继续加热2 小时。将反应混合物冷却至环境温度,在乙酸乙酯和水之间分配,有机相用碳酸钠水溶液和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 0-12% 乙酸乙酯/己烷)纯化得到单-溴代和二溴代产物的混合物。将该产物混合物溶于四氢呋喃(5 mL)中,用亚磷酸二乙酯(0.523 mL, 4.05 mmol)和三乙胺(0.565 mL, 4.05 mmol)处理并在环境温度下搅拌2 小时20分钟。将反应混合物在乙酸乙酯和水之间分配,有机层经盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 2-14% 乙酸乙酯/己烷)纯化得到标题化合物(0.695 g, 54%)。
实施例 91e
2-乙酰基-4-(2-硝基-6-苯氧基苯基)-4-氧代丁酸叔丁基酯
在0℃下,向氢化钠(60%油分散体)(0.079 g, 1.971 mmol)的四氢呋喃(6.16 mL)悬浮液中滴加3-氧代丁酸叔丁基酯(0.300 mL, 1.806 mmol)并搅拌30分钟,然后将所得混合物用实施例 91d (0.69 g, 1.642 mmol)的四氢呋喃(2.053 mL)溶液处理并搅拌,使温度缓慢升至环境温度。9 小时后。将反应混合物冷却至0℃并加入另外的3-氧代丁酸叔丁基酯(0.300 mL, 1.806 mmol)和氢化钠(60%油分散体)(0.079 g, 1.971 mmol),搅拌混合物过夜。将反应混合物在乙酸乙酯和饱和的氯化铵水溶液之间分配并用盐水洗涤有机层,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法 (硅胶, 5-10% 乙酸乙酯/己烷)纯化。合并含有标题化合物的纯的级分,浓缩并通过闪式色谱法进行第二次纯化(硅胶, 2-12%乙酸乙酯/己烷)得到标题化合物(0.466 g, 69%)。
实施例 91f
2-甲基-5-(2-硝基-6-苯氧基苯基)-1H-吡咯-3-甲酸叔丁基酯
用实施例 91e代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例91f,得到标题化合物(0.253 g, 94%)。
实施例 91g
2-甲基-5-(2-硝基-6-苯氧基苯基)-1H-吡咯-3-甲酸
用实施例 91f代替实施例 1b,按照制备实施例 1c所用的步骤制备了实施例91g,得到标题化合物(0.375 g, 99%)。
实施例 91h
2-甲基-5-(2-硝基-6-苯氧基苯基)-1H-吡咯-3-甲酰胺
用实施例 91g代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例91h,得到标题化合物(0.155 g, 42%)。
实施例 91i
5-(2-氨基-6-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 91h代替实施例 1d,按照制备实施例 1e所用的步骤制备了实施例91i,通过闪式色谱法(硅胶, 0-5% 甲醇/二氯甲烷)纯化得到标题化合物(0.105 g, 76%)。1H NMR (300 MHz, DMSO-d 6 ) δ 10.85 (s, 1 H), 7.28 (m, 2H), 7.00 (m, 3H), 6.89(m, 2H), 6.53 (dd, J=8.14, 1.02 Hz, 1H), 6.43 (m, J=2.71 Hz, 2H), 6.06 (dd, J=7.80, 1.02 Hz, 1H), 5.01 (s, 2H), 2.37 (s, 3H)。MS (ESI+) m/z 308.0 (M+H)+。
实施例 92.5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
实施例 92a
2-乙酰基-4-(4-溴苯基)-4-氧代丁酸乙基酯
用3-氧代丁酸乙基酯代替3-氧代丁酸叔丁基酯并用2-溴-1-(4-溴苯基)乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 92a,得到标题化合物(5.05 g, 77%)。
实施例 92b
5-(4-溴苯基)-2-甲基-1H-吡咯-3-甲酸乙基酯
用实施例 92a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例92b,得到标题化合物(4.27 g, 90%)。
实施例 92c
5-(4-溴苯基)-2-甲基-1H-吡咯-3-甲酸
用实施例 92b代替实施例 3b,按照制备实施例 3c所用的步骤制备了实施例92c,得到标题化合物(2.65 g, 90%)。
实施例 92d
5-(4-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 92c代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例92d,得到标题化合物(2.37 g, 90%)。
实施例 92e
5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
将实施例 92d (0.028 g, 0.1 mmol)、3,5-二甲基异噁唑-4-基硼酸(0.0202 g,0.143 mmol)和氯化二(三苯基膦)钯(II)(7.02 mg, 10.00 µmol)在装有磁搅拌子微波小瓶中混合,将小瓶密封,脱气并用氮气吹扫。在氮气氛下经注射器加入1,4-二噁烷(0.667mL)、乙醇(0.333 mL)和2 M 碳酸钠水溶液(0.1 mL, 0.2 mmol)。在微波反应器中,在130℃加热反应混合物20分钟。然后将反应混合物在乙酸乙酯和水之间分配,有机相用水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法 (硅胶, 0-10% 甲醇/二氯甲烷)纯化得到标题化合物(0.02 g, 68%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.39 (s, 1H),7.64 (d, J=8.33 Hz, 2H), 7.38 (d, J=8.33 Hz, 2H), 7.15 (s, 1H), 6.94 (d, J=2.78 Hz, 1H), 6.65 (s, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H)。MS (ESI+) m/z 296.1 (M+H)+。
实施例 93.N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)-β-丙氨酸甲基酯
实施例 93a
5-(4-(3,5-二甲基异噁唑-4-基)苯基)-2-甲基-1H-吡咯-3-甲酸乙基酯
用实施例 92b代替实施例 92d,按照制备实施例 92e所用的步骤制备了实施例93a,得到标题化合物(0.09 g, 37%)。
实施例 93b
5-(4-(3,5-二甲基异噁唑-4-基)苯基)-2-甲基-1H-吡咯-3-甲酸
用实施例 93a代替实施例 3b,按照制备实施例 3c所用的步骤制备了实施例93b,得到标题化合物(0.284 g, 86%)。
实施例 93c
N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)-β-丙氨酸甲基酯
用实施例 93b代替实施例 1c和用3-氨基丙酸甲基酯盐酸盐代替氯化铵,按照制备实施例 1d所用的步骤制备了实施例 93c,通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.034 g, 53%)。1H NMR (300 MHz,DMSO-d 6 ) δ 11.39 (s, 1H), 7.71 (t, J=5.75 Hz, 1H), 7.65 (m, J=8.33 Hz, 2H),7.38 (m, J=8.73 Hz, 2H), 6.90 (d, J=2.78 Hz, 1H), 3.61 (s, 3H), 3.42 (q, J=6.74 Hz, 2H), 2.55 (t, J=7.14 Hz, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 2.25 (s,3H)。MS (ESI+) m/z 382.0 (M+H)+。
实施例 94.N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)甘氨酸甲基酯
用实施例 93b代替实施例 1c和用2-氨基乙酸甲基酯盐酸盐代替氯化铵,按照制备实施例 1d所用的步骤制备了实施例 94,通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(0.029 g, 47%)。1H NMR (300 MHz,DMSO-d 6 ) δ 11.46 (s, 1H), 8.10 (t, J=5.75 Hz, 1H), 7.66 (m, J=8.33 Hz, 2H),7.39 (m, J=8.33 Hz, 2H), 6.96 (d, J=2.38 Hz, 1H), 3.93 (d, J=5.55 Hz, 2H),3.65 (s, 3H), 2.48 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H)。MS (ESI+) m/z 367.9 (M+H)+。
实施例 95.5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-N-羟基-2-甲基-1H-吡咯-3-甲酰胺
将实施例 93b(0.05 g, 0.169 mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(0.071 g, 0.186 mmol)和N,N-二异丙基乙胺 (0.059 mL, 0.337mmol)混合并溶于二甲基甲酰胺(0.422 mL)中。加入羟胺盐酸盐 (0.023 g, 0.337 mmol)和N,N-二异丙基乙胺(0.059 mL, 0.337 mmol)的二甲基甲酰胺(0.422 mL)溶液并在40℃搅拌混合物过夜。将反应混合物在乙酸乙酯和水之间分配,有机相用饱和碳酸氢钠水溶液、水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经反相HPLC (C8(2), 5 µM 100 Å柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(0.017 g, 32%)。1H NMR (400MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 10.38 (s, 1H), 7.63 (m, J=8.54 Hz, 2H), 7.38(m, J=8.24 Hz, 2H), 6.80 (d, J=2.75 Hz, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.25(s, 3H)。
实施例 96.N-苄基-N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)-β-丙氨酸乙基酯
用实施例 93b代替实施例 1c和用3-(苄基氨基)丙酸乙基酯代替氯化铵,按照制备实施例 1d所用的步骤制备了实施例 96,通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.041 g, 45%)。1H NMR (300 MHz,DMSO-d 6 ) δ 11.42 (s, 1H), 7.63 (m, 2H), 7.33 (m, 7H), 6.53 (s, 1H), 4.71 (s,2H), 4.03 (q, J=7.12 Hz, 2H), 3.56 (t, J=6.27 Hz, 2H), 2.60 (t, J=7.12 Hz,2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 1.15 (t, J=7.12 Hz, 3H)。MS(ESI+) m/z 486.0 (M+H)+。
实施例 97.2-甲基-5-{4'-[(4-甲基哌嗪-1-基)甲基]联苯-4-基}-1H-吡咯-3-甲酰胺
向微波小瓶中加入搅拌子、实施例 92d (0.020 g, 0.072 mmol)的乙醇 (1.0mL)溶液、1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪(0.027 g,0.086 mmol)的乙醇(0.287 mL)溶液、1 M碳酸铯水溶液(0.215 mL, 0.215mmol)和Siliacat-DPP固定化的Pd催化剂(0.0265 g, 0.27 mmol/g 载体)。将反应小瓶密封并置于微波反应器中在120℃加热20分钟。完成后,过滤反应混合物,浓缩至干并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水) 纯化得到标题化合物(0.019 g, 43%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.54 (d, J=1.83 Hz, 1H), 7.80(d, J=8.24 Hz, 2H), 7.72 (q, J=8.54 Hz, 4H), 7.57 (d, J=8.24 Hz, 2H), 6.95(d, J=2.44 Hz, 1H), 4.25 (s, 2H), 3.93 (m, 2H), 3.37 (m, J=46.38 Hz, 6H),2.87 (s, 3H), 2.49 (s, 3H)。MS (ESI+) m/z 389.1 (M+H)+。
实施例 98.5-(3'-羟基联苯-4-基)-2-甲基-1H-吡咯-3-甲酰胺
用3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯酚代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 98,得到标题化合物(0.0137, 39%)。1H NMR (400 MHz, DMSO-d 6 /D2O)δ 11.46 (s, 1H), 7.64 (m, 4H), 7.28 (t, J=7.78 Hz, 1H), 7.12 (d, J=7.63 Hz,1H), 7.07 (m, J=1.83 Hz, 1H), 6.93 (d, J=2.44 Hz, 1H), 6.77 (dd, J=7.93, 2.14Hz, 1H), 2.48 (s, 3H)。MS (ESI+) m/z 292.9 (M+H)+。
实施例 99.2-甲基-5-(3',4',5'-三甲氧基联苯-4-基)-1H-吡咯-3-甲酰胺
用3,4,5-三甲氧基苯基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 99,得到标题化合物(0.0143 g, 32%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.68 (m, 4H), 6.94 (s,3H), 3.87 (s, 6H), 3.70 (m, 3H), 2.49 (s, 3H)。MS (ESI+) m/z 367 (M+H)+。
实施例 100.5-[4-(呋喃-3-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用呋喃-3-基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 100,得到标题化合物(0.0025 g, 8%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 8.16 (s, 1H), 7.72 (s, 1H),7.60 (m, 4H), 6.96 (s, 1H), 6.89 (s, 1H), 2.47 (s, 3H)。MS (ESI+) m/z 267 (M+H)+。
实施例 101.2-甲基-5-[4-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺
用噻吩-3-基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 101,得到标题化合物(0.0104 g, 30%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.84 (d, J=2.75 Hz, 1H), 7.73(d, J=8.24 Hz, 2H), 7.61 (m, 4H), 6.91 (s, 1H), 2.48 (s, 3H)。MS (ESI+) m/z283 (M+H)+。
实施例 102.2-甲基-5-[4-(吡啶-4-基)苯基]-1H-吡咯-3-甲酰胺
用吡啶-4-基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 102,得到标题化合物(0.010 g, 21%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 8.84 (d, J=6.41 Hz, 2H), 8.38(d, J=6.41 Hz, 2H), 8.07 (d, J=8.55 Hz, 2H), 7.82 (d, J=8.24 Hz, 2H), 7.12(d, J=1.83 Hz, 1H), 2.51 (s, 3H)。MS (ESI+) m/z 278 (M+H)+。
实施例 103.2-甲基-5-[4-(1-甲基-1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺
用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 103,得到标题化合物(0.0086 g, 25%)。1H NMR (400MHz, DMSO-d 6 /D2O) δ 11.39 (s, 1H), 7.57 (m, 3H), 7.37 (t, J=7.63 Hz, 2H), 7.18(t, J=7.48 Hz, 1H), 6.86 (t, J=3.05 Hz, 1H), 2.57 (s, 3H), 2.46 (s, 3H)。MS(ESI+) m/z 281 (M+H)+。
实施例 104.5-[3'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺
用N,N-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酰胺代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 104,得到标题化合物(0.024 g, 57%)。1H NMR (400MHz, DMSO-d 6 /D2O) δ 11.49 (s, 1H), 7.78 (d, J=7.93 Hz, 1H), 7.71 (m, 5H), 7.55(t, J=7.78 Hz, 1H), 7.37 (d, J=7.63 Hz, 1H), 6.96 (d, J=1.53 Hz, 1H), 3.03(s, 3H), 2.96 (s, 3H), 2.49 (s, 3H)。MS (ESI+) m/z 348 (M+H)+。
实施例 105.2-甲基-5-[3'-(吗啉-4-基)联苯-4-基]-1H-吡咯-3-甲酰胺
用3-吗啉代苯基硼酸盐酸盐代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 105,得到标题化合物(0.007 g, 15%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.67 (m, 4H), 7.37 (m,1H), 7.23 (s, 1H), 7.18 (d, J=7.63 Hz, 1H), 6.99 (dd, J=8.09, 1.98 Hz, 1H),6.93 (s, 1H), 3.80 (m, 4H), 3.22 (m, 4H), 2.48 (s, 3H)。MS (ESI+) m/z 362 (M+H)+。
实施例 106.5-{3'-[(呋喃-2-基甲基)氨基甲酰基]联苯-4-基}-2-甲基-1H-吡咯-3-甲酰胺
用3-(呋喃-2-基甲基氨基甲酰基)苯基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例106,得到标题化合物(0.0201 g, 41%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 8.17 (s,1H), 7.86 (dd, J=15.87, 7.63 Hz, 2H), 7.77 (m, 2H), 7.71 (m, 2H), 7.58 (m,2H), 6.96 (d, J=2.44 Hz, 1H), 6.42 (s, 1H), 6.33 (d, J=3.05 Hz, 1H), 4.52 (s,2H), 2.49 (s, 3H)。MS (ESI+) m/z 400 (M+H)+。
实施例 107.5-{4-[(1E)-3-甲氧基丙-1-烯-1-基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用(E)-2-(3-甲氧基丙-1-烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 107,得到标题化合物(0.0053, 16%)。1H NMR (400MHz, DMSO-d 6 /D2O) δ 7.61 (m, 2H), 7.46 (m, 2H), 6.89 (d, J=2.14 Hz, 1H), 6.59(d, J=15.87 Hz, 1H), 6.34 (m, 1H), 4.05 (d, J=6.10 Hz, 2H), 3.29 (s, 3H),2.46 (s, 3H)。MS (ESI+) m/z 271 (M+H)+。
实施例 108.5-[4'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺
用(4-(二甲基氨基甲酰基)苯基)硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例108,得到标题化合物(0.0011 g, 3%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.74 (m, 6H),7.50 (d, J=7.93 Hz, 2H), 6.96 (s, 1H), 3.00 (m, 6H), 2.48 (s, 3H)。MS (ESI+)m/z 348.0 (M+H)+。
实施例 109.2-甲基-5-[4-(嘧啶-5-基)苯基]-1H-吡咯-3-甲酰胺
用嘧啶-5-基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 109,得到标题化合物(0.0052 g, 15%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 9.17 (m, 3H), 7.84 (d, J=8.24Hz, 2H), 7.74 (d, J=8.24 Hz, 2H), 7.00 (d, J=2.44 Hz, 1H), 2.49 (s, 3H)。MS(ESI+) m/z 279 (M+H)+。
实施例 110.2-甲基-5-{4'-[(甲基磺酰基)氨基]联苯-4-基}-1H-吡咯-3-甲酰胺
用N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)甲烷磺酰胺代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 110,得到标题化合物(0.0062 g, 14%)。1H NMR (400MHz, DMSO-d 6 /D2O) δ 7.68 (m, 6H), 7.31 (m, 2H), 6.92 (s, 1H), 3.02 (m, 3H),2.48 (s, 3H)。MS (ESI+) m/z 370 (M+H)+。
实施例 111.5-[4-(1-苄基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用1-苄基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 111,得到标题化合物(0.0023 g, 5%)。1H NMR (400 MHz,DMSO-d 6 /D2O) δ 8.27 (s, 1H), 7.92 (s, 1H), 7.57 (m, 4H), 7.34 (m, 5H), 6.86(d, J=1.83 Hz, 1H), 5.35 (s, 2H), 2.47 (s, 3H)。MS (ESI+) m/z 357 (M+H)+。
实施例 112.5-[4-(3,5-二甲基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 112,得到标题化合物(0.0041 g, 11%)。1H NMR (400MHz, DMSO-d 6 /D2O) δ 7.62 (d, J=8.24 Hz, 2H), 7.31 (d, J=8.24 Hz, 2H), 6.89 (d,J=1.53 Hz, 1H), 2.48 (s, 3H), 2.25 (s, 6H)。MS (ESI+) m/z 295 (M+H)+。
实施例 113.2-甲基-5-[4-(喹啉-6-基)苯基]-1H-吡咯-3-甲酰胺
用6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)喹啉代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 113,得到标题化合物(0.0066 g, 12%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 9.07 (d, J=4.88 Hz, 1H), 8.85 (d, J=8.24 Hz, 1H), 8.52 (s, 1H), 8.38(d, J=8.85 Hz, 1H), 8.23 (d, J=8.85 Hz, 1H), 7.92 (d, J=8.24 Hz, 2H), 7.85(dd, J=8.39, 4.73 Hz, 1H), 7.77 (d, J=8.24 Hz, 2H), 7.01 (d, J=1.53 Hz, 1H),2.50 (s, 3H)。MS (ESI+) m/z 328 (M+H)+。
实施例 114.2-甲基-5-{4'-[(4-甲基哌嗪-1-基)羰基]联苯-4-基}-1H-吡咯-3-甲酰胺
用4-(4-甲基哌嗪-1-羰基)苯基硼酸代替1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪,按照制备实施例 97所用的步骤制备了实施例 114,得到标题化合物(0.0087 g, 14%)。1H NMR (400 MHz, DMSO-d 6 /D2O) δ 7.82 (d, J=7.93Hz, 2H), 7.73 (m, 4H), 7.56 (d, J=8.24 Hz, 2H), 6.96 (d, J=2.14 Hz, 1H), 3.32(m, 8H), 2.85 (s, 3H), 2.49 (s, 3H)。MS (ESI+) m/z 401 (M+H)+。
实施例 115.5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 115a
2-溴-1-(2-溴苯基)乙酮
用10分钟向1-(2-溴苯基)乙酮 (21.35 g, 107 mmol)/苯 (101 mL)中滴加溴(5.25 mL, 102 mmol)的苯(33.5 mL)溶液进行处理,加完后浓缩至干。残余物经闪式色谱法 (硅胶, 1-7% 乙酸乙酯/己烷)纯化得到标题化合物和未反应的1-(2-溴苯基)乙酮,为不可分离的混合物(87:13) (25.3 g, 74%)。
实施例 115b
2-乙酰基-4-(2-溴苯基)-4-氧代丁酸叔丁基酯
用实施例 115a代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 115b,得到标题化合物(8.66 g, 75%)。
实施例 115c
5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酸叔丁基酯
用实施例 115b代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例115c,得到标题化合物(8.63 g, 99%)。
实施例 115d
5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酸
用实施例 115c代替实施例 1b,按照制备实施例 1c所用的步骤制备了实施例115d,得到标题化合物(1.61 g, 82%)。
实施例115e
5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 115d代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例115e,得到标题化合物(1.08 g, 75%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.21 (s, 1H),7.68 (dd, J=7.93, 1.19 Hz, 1H), 7.47 (m, 1H), 7.41 (td, J=7.54, 1.19 Hz, 1H),7.18 (m, 2H), 6.88 (d, J=2.78 Hz, 1H), 6.58 (s, 1H), 2.45 (s, 3H)。MS (ESI+)m/z 279.0 (M+H)+。
实施例 116.5-[2-(4-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
将实施例 115e (0.028 g, 0.1 mmol)、4-氯苯酚(0.026 g, 0.200 mmol)、碘化铜(I)(1.905 mg, 10.00 µmol)、2-吡啶甲酸 (2.462 mg, 0.020 mmol)、磷酸三钾(0.042g, 0.200 mmol)和二甲基亚砜 (0.4 mL)混合、用氮气吹扫并在95℃加热22 小时。将反应混合物冷却至环境温度,在乙酸乙酯和水之间分配,有机相用饱和碳酸氢钠水溶液、水和盐水洗涤, 干燥(无水MgSO4),过滤并浓缩。残余物经反相HPLC纯化(C8(2), 5 µM 100 Å 柱,10-100% 乙腈和0.1% TFA/水) 得到标题化合物(0.010 g, 31%)。1H NMR (300 MHz,DMSO-d 6 ) δ 11.15 (s, 1H), 7.70 (m, 1H), 7.37 (m, 2H), 7.23 (m, 2H), 7.07 (s,1H), 6.97 (m, 3H), 6.89 (d, J=2.78 Hz, 1H), 6.55 (s, 1H), 2.43 (s, 3H)。MS(ESI+) m/z 327.1 (M+H)+。
实施例 117.5-[2-(2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用2-氟苯酚代替4-氯苯酚,按照制备实施例 116所用的步骤制备了实施例 117,得到标题化合物(0.036 g, 58%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 7.68(m, 1H), 7.39 (m, 1H), 7.16 (m, 6H), 6.97 (d, J=2.78 Hz, 1H), 6.72 (m, 1H),6.55 (s, 1H), 2.47 (s, 3H)。MS (ESI+) m/z 311.1 (M+H)+。
实施例 118.5-[2-(1H-吲哚-6-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
向含有磁搅拌子的微波小瓶中添加实施例 115e (0.028 g, 0.1 mmol)、1H-吲哚-6-酚(0.027 g, 0.200 mmol)、碘化铜(I)(0.0019 g, 0.010 mmol)、磷酸三钾(0.064g, 0.300 mmol)和2-吡啶甲酸 (2.462 mg, 0.020 mmol),密封,脱气并用氮气吹扫。在氮气氛下经注射器加入二甲基亚砜 (0.8 mL)并在微波反应器中于120℃加热反应混合物25分钟。将反应混合物在乙酸乙酯和水之间分配,有机相用饱和碳酸氢钠水溶液、水和盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 87:10:3 二氯甲烷/乙酸乙酯/甲醇)纯化,并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)进一步纯化得到标题化合物(0.011 g, 16%)。1H NMR (400 MHz, DMSO-d 6 ) δ 11.11(s, 1H), 10.97 (s, 1H), 7.67 (m, 1H), 7.52 (d, J=8.24 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.13 (m, 2H), 7.08 (s, 1H), 6.98 (d, J=2.44 Hz, 1H), 6.94 (d, J=1.53 Hz, 1H), 6.84 (m, 1H), 6.80 (dd, J=8.54, 2.14 Hz, 1H), 6.53 (s, 1H),6.40 (m, 1H), 2.45 (s, 3H)。MS (ESI+) m/z 331.9 (M+H)+。
实施例 119.5-[2-(4-氨基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
实施例 119a
(4-(2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯氧基)苯基)氨基甲酸叔丁基酯
用4-羟基苯基氨基甲酸叔丁基酯代替1H-吲哚-6-酚,按照制备实施例 118所用的步骤制备了实施例 119a,得到标题化合物(0.061 g, 75%)。
实施例 119b
5-[2-(4-氨基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用实施例 119a代替实施例 64a,按照制备实施例 64b所用的步骤制备了实施例119b,得到标题化合物(0.04 g, 64%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.15 (s, 1H),9.10 (s, 2H), 7.70 (m, 1H), 7.22 (m, 4H), 6.98 (m, 4H), 6.88 (d, J=2.78 Hz,1H), 6.56 (s, 1H), 2.43 (s, 3H)。MS (ESI-) m/z 306.2 (M-H)-。
实施例 120.2-甲基-5-[2-(吡啶-4-基氧基)苯基]-1H-吡咯-3-甲酰胺
用吡啶-4-酚代替1H-吲哚-6-酚,按照制备实施例 118所用的步骤制备了实施例120,得到标题化合物(0.029 g, 36%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.37 (s, 1H),8.32 (d, J=7.54 Hz, 2H), 7.68 (m, 2H), 7.58 (m, 1H), 7.49 (m, 1H), 6.97 (d, J=7.14 Hz, 2H), 6.91 (s, 1H), 6.60 (s, 1H), 5.79 (d, J=2.78 Hz, 1H), 2.40 (s,3H)。MS (ESI+) m/z 294.0 (M+H)+。
实施例 121.5-[2-(4-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
向微波小瓶中加入搅拌子、实施例 115e(0.02 g, 0.072 mmol)的二甲基亚砜(0.5 mL)溶液、4-苄基苯酚(0.0268 g,0.143 mmol)的二甲基亚砜(0.477 mL)溶液、碘化铜(I)(0.00273 g, 0.00144 mmol)、2-吡啶甲酸 (0.00265 g, 0.00216 mmol)和粉状磷酸三钾(0.0304 g,0.144 mmol)。将反应小瓶密封,用氮气吹扫并在微波反应器中于140℃加热30分钟。完成后,过滤反应混合物,将残余物浓缩至干并通过反相HPLC (C8(2), 5 µM 100Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.0064 g, 23%)。1H NMR (500MHz, DMSO-d 6 /D2O) δ 7.66 (m, 1H), 7.29 (t, J=7.63 Hz, 2H), 7.23 (m, 3H), 7.19(m, 4H), 6.91 (m, 3H), 6.88 (m, 1H), 3.90 (s, 2H), 2.43 (s, 3H)。MS (ESI+) m/z383.0 (M+H)+。
实施例 1222-甲基-5-[2-(4-苯氧基苯氧基)苯基]-1H-吡咯-3-甲酰胺
用4-苯氧基苯酚代替 4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 122,得到标题化合物(0.0024 g, 9%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.67 (dd,J=7.48, 1.98 Hz, 1H), 7.39 (t, J=7.78 Hz, 2H), 7.21 (m, 2 H), 7.12 (t, J=7.32Hz, 1H), 7.03 (s, 4H), 6.98 (d, J=8.54 Hz, 2H), 6.92 (m, 2H), 2.45 (s, 3H)。MS(ESI+) m/z 385.0 (M+H)+。
实施例 123.5-[2-(4-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-羟基苄腈代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例123,得到标题化合物(0.0025 g, 11%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.81 (d, J=8.24 Hz, 2H), 7.32 (d, J=8.54 Hz, 2H), 7.07 (m, 2H), 6.73 (t, J=7.48 Hz, 1H),6.65 (m, 2H), 2.34 (s, 3H)。MS (ESI+) m/z 318.0 (M+H)+。
实施例 124.5-[2-(4-环戊基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-环戊基苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例124,得到标题化合物(0.005 g, 19%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.67 (m, 1H),7.23 (d, J=8.54 Hz, 2H), 7.19 (m, 2H), 6.91 (m, 4H), 2.93 (m, 1H), 2.44 (s,3H), 1.99 (m, 2H), 1.75 (m, 2H), 1.63 (m, 2H), 1.49 (m, 2H)。MS (ESI+) m/z361.0 (M+H)+。
实施例 125.5-[2-(异喹啉-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用异喹啉-5-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例125,得到标题化合物(0.0065 g, 26%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.35 (s,1H), 9.71 (s, 1H), 8.63 (m, 2H), 8.10 (d, J=8.24 Hz, 1H), 7.79 (t, J=8.09 Hz,1H), 7.75 (dd, J=7.93, 1.53 Hz, 1H), 7.35 (m, 1H), 7.30 (td, J=7.63, 1.53 Hz,1H), 7.19 (d, J=7.93 Hz, 1H), 7.06 (d, J=7.93 Hz, 1H), 6.90 (d, J=2.75 Hz,1H), 2.38 (s, 3H)。MS (ESI+) m/z 344.0 (M+H)+。
实施例 126.2-甲基-5-[2-(吡啶-3-基氧基)苯基]-1H-吡咯-3-甲酰胺
用吡啶-3-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例126,得到标题化合物(0.007 g, 33%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.33 (s,1H), 8.41 (d, 2H), 7.74 (dd, J=7.48, 1.68 Hz, 1H), 7.62 (m, 2H), 7.32 (m,2H), 7.10 (m, 1H), 6.90 (d, J=2.75 Hz, 1H), 2.43 (s, 3H)。MS (ESI+) m/z 293.9(M+H)+。
实施例 127.5-[2-(3-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用3-羟基苄腈代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例127,得到标题化合物(0.0015 g, 7%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.72 (dd, J=7.32, 1.83 Hz, 1H), 7.53 (m, 2H), 7.39 (s, 1H), 7.29 (m, 3H), 7.06 (d, J=7.32Hz, 1H), 6.88 (d, J=2.14 Hz, 1H), 2.43 (s, 3H)。MS (ESI+) m/z 317.9 (M+H)+。
实施例 128.2-甲基-5-[2-(喹啉-5-基氧基)苯基]-1H-吡咯-3-甲酰胺
用喹啉-5-酚代替 4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例128,得到标题化合物(0.006 g, 24%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.33 (s,1H), 9.07 (m, 1H), 9.00 (d, J=8.54 Hz, 1H), 7.78 (m, 4H), 7.30 (m, 2H), 7.02(d, J=7.93 Hz, 1H), 6.91 (d, J=2.75 Hz, 1H), 6.86 (d, J=7.63 Hz, 1H), 2.38(s, 3H)。MS (ESI+) m/z 343.9 (M+H)+。
实施例 129.5-[2-(4-氯-2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-氯-2-氟苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 129,得到标题化合物(0.006 g, 24%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.25 (s,1H), 7.68 (m, 1H), 7.60 (dd, J=10.68, 2.14 Hz, 1H), 7.29 (d, J=8.54 Hz, 1H),7.19 (d, J=4.27 Hz, 2H), 7.11 (t, J=8.85 Hz, 1H), 6.94 (d, J=2.44 Hz, 1H),6.81 (m, 1H), 2.46 (s, 3H)。MS (ESI+) m/z 344.9 (M+H)+。
实施例 130.5-[2-(1H-吲哚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用1H-吲哚-5-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例130,得到标题化合物(0.0031 g, 13%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.17 (s,1H), 7.64 (dd, J=7.17, 1.68 Hz, 1H), 7.43 (d, J=8.54 Hz, 1H), 7.36 (d, J=2.44Hz, 1H), 7.16 (d, J=2.14 Hz, 1H), 7.11 (m, 2H), 6.99 (d, J=2.44 Hz, 1H), 6.88(dd, J=8.70, 1.98 Hz, 1H), 6.76 (m, 1H), 6.40 (d, J=3.05 Hz, 1H), 2.46 (s,3H)。MS (ESI+) m/z 332.0(M+H)+。
实施例 131.2-甲基-5-[2-(吡啶-2-基氧基)苯基]-1H-吡咯-3-甲酰胺
用吡啶-2-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例131,得到标题化合物(0.0035 g, 17%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.63 (d, J=7.93 Hz, 1H), 7.54 (m, 2H), 7.41 (m, 2H), 7.28 (d, J=7.63 Hz, 1H), 6.48 (d, J=9.46 Hz, 1H), 6.35 (t, J=6.56 Hz, 1H), 5.83 (s, 1H), 2.39 (s, 3H)。MS (ESI-)m/z 291.9 (M+H)+。
实施例 132.2-甲基-5-{2-[4-(甲基磺酰基)苯氧基]苯基}-1H-吡咯-3-甲酰胺
用4-(甲基磺酰基)苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 132,得到标题化合物(0.0053 g, 20%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.88(d, J=8.54 Hz, 2 H), 7.40 (d, J=8.54 Hz, 2H), 7.06 (dd, J=7.48, 1.98 Hz, 2H),6.74 (m, 1H), 6.66 (d, J=7.93 Hz, 1H), 6.64 (s, 1H), 3.21 (s, 3H), 2.35 (s,3H)。MS (ESI+) m/z 371.0 (M+H)+。
实施例 133.3-{2-[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯氧基]苯基}丙酸甲基酯
用3-(2-羟基苯基)丙酸甲基酯代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 133,得到标题化合物(0.0015 g, 5.5%)。1H NMR (500 MHz, DMSO-d 6 /D2O)δ 11.21 (s, 1H), 7.69 (m, 1H), 7.35 (d, J=7.63 Hz, 1H), 7.23 (m, 1H), 7.13(m, 3H), 6.95 (d, J=2.44 Hz, 1H), 6.78 (d, J=8.24 Hz, 1H), 6.67 (m, 1H), 3.53(s, 3H), 2.89 (t, J=7.63 Hz, 2H), 2.64 (t, J=7.63 Hz, 2H), 2.47 (s, 3H)。MS(ESI+) m/z 379.0 (M+H)+。
实施例 134.2-甲基-5-[2-(3-甲基苯氧基)苯基]-1H-吡咯-3-甲酰胺
用间-甲酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 134,得到标题化合物(0.0049 g, 22%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.20 (s, 1H),7.68 (m, 1H), 7.22 (m, 3H), 6.92 (m, 3H), 6.78 (m, 2H), 2.44 (s, 3H), 2.26(s, 3H)。MS (ESI+) m/z 306.9 (M+H)+。
实施例 135.5-{2-[4-(1H-咪唑-1-基)苯氧基]苯基}-2-甲基-1H-吡咯-3-甲酰胺
用4-(1H-咪唑-1-基)苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 135,得到标题化合物(0.0112 g, 44%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ9.49 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.75 (dd, J=7.32, 2.14 Hz, 1H),7.71 (d, J=8.85 Hz, 2H), 7.33 (m, 2H), 7.13 (m, 3H), 6.92 (d, J=2.14 Hz, 1H),2.43 (s, 3H)。MS (ESI+) m/z 359.0 (M+H)+。
实施例 136.2-甲基-5-[2-(5,6,7,8-四氢萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺
用5,6,7,8-四氢萘-1-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 136,得到标题化合物(0.0023 g, 9%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.66(dd, J=7.17, 2.29 Hz, 1H), 7.11 (m, 3H), 6.97 (s, 1H), 6.93 (d, J=7.63 Hz,1H), 6.64 (d, J=7.93 Hz, 1H), 6.60 (m, 1H), 2.76 (m, 2H), 2.61 (m, 2H), 2.47(s, 3H), 1.70 (m, 4H)。MS (ESI+) m/z 347.0 (M+H)+。
实施例 137.5-[2-(4-甲氧基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-甲氧基苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例137,得到标题化合物(0.0071 g, 31%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.18 (s,1H), 7.64 (dd, J=7.17, 1.98 Hz, 1H), 7.16 (m, 2H), 6.95 (m, 4H), 6.80 (m,1H), 3.73 (m, 3H), 2.45 (s, 3H)。MS (ESI+) m/z 322.9 (M+H)+。
实施例 138.5-[2-(2-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用2-苄基苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例138,得到标题化合物(0.0062 g, 23%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.13 (s,1H), 7.66 (dd, J=7.32, 1.83 Hz, 1H), 7.29 (d, J=7.63 Hz, 1H), 7.18 (m, 9H),6.93 (d, J=2.75 Hz, 1H), 6.80 (d, J=7.93 Hz, 1H) 6.56 (m, 1H), 3.97 (s, 2H),2.44 (s, 3H)。MS (ESI+) m/z 383.0 (M+H)+。
实施例 139.2-甲基-5-[2-(萘-2-基氧基)苯基]-1H-吡咯-3-甲酰胺
用萘-2-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 139,得到标题化合物(0.0069 g, 28%)。1H NMR (500 MHz, DMSO-d 6 /D2O)。δ 11.26 (s, 1H),7.95 (d, J=8.85 Hz, 1H), 7.89 (d, J=7.93 Hz, 1H), 7.74 (m, 2H), 7.45 (m, 2H),7.36 (dd, J=9.00, 2.29 Hz, 1H), 7.26 (m, 3H), 7.03 (m, 1H), 6.96 (d, J=2.44Hz, 1H), 2.43 (s, 3H)。MS (ESI+) m/z 343.0(M+H)+。
实施例 140.2-甲基-5-[2-(萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺
用萘-1-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 140,得到标题化合物(0.003.8 g, 16%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 8.18 (d, J=7.93Hz, 1H), 7.98 (d, J=7.93 Hz, 1H), 7.72 (m, 2H), 7.57 (m, 2H), 7.45 (t, J=7.93Hz, 1H), 7.20 (m, 2H), 7.01 (s, 1H), 6.87 (d, J=7.63 Hz, 1H), 6.79 (d, J=8.24Hz, 1H), 2.42 (s, 3H)。MS (ESI+) m/z 343.0 (M+H)+。
实施例 141.5-[2-(4-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-氟苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例141,得到标题化合物(0.0065 g, 29%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.67 (m,1H), 7.20 (m, 4H), 7.02 (m, 2H), 6.92 (s, 1H), 6.89 (m, 1H), 2.44 (s, 3H)。MS(ESI+) m/z 310.9 (M+H)+。
实施例 142.5-[2-(3-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用3-氯苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例142,得到标题化合物(0.0054 g, 23%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.26 (s,1H), 7.71 (m, 1H), 7.35 (t, J=8.09 Hz, 1H), 7.28 (m, 2H), 7.12 (d, J=7.93 Hz,1H), 7.05 (m, 1H), 6.98 (s, 1H), 6.91 (m, 2H), 2.43 (s, 3H)。MS (ESI+) m/z326.9 (M+H)+。
实施例 143.5-[2-(4-乙基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用4-乙基苯酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例143,得到标题化合物(0.0041 g, 18%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 11.19 (s,1H), 7.67 (dd, J=6.87, 2.29 Hz, 1H), 7.19 (m, 4H), 6.90 (m, 4H), 2.57 (m,2H), 2.44 (s, 3H), 1.16 (t, J=7.48 Hz, 3H)。MS (ESI+) m/z 321.0 (M+H)+。
实施例 144.5-[2-(2,3-二氢-1H-茚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
用2,3-二氢-1H-茚-5-酚代替4-苄基苯酚,按照制备实施例 121所用的步骤制备了实施例 144,得到标题化合物(0.007 g, 29%)。1H NMR (500 MHz, DMSO-d 6 /D2O) δ 7.66(m, 1H), 7.18 (m, 3H), 6.92 (d, J=2.14 Hz, 1H), 6.88 (m, 1H), 6.81 (s, 1H),6.76 (m, 1H), 2.80 (t, J=7.32 Hz, 4H), 2.44 (s, 3H), 2.01 (m, 2H)。MS (ESI+)m/z 333.0 (M+H)+。
实施例 145.5-[2-(6-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
向含有磁搅拌子的微波小瓶中加入实施例 115e (0.056 g, 0.2 mmol)、1H-苯并[d]咪唑-6-酚(0.040 g, 0.300 mmol)、碘化铜(I)(0.0038 g, 0.02 mmol)、磷酸三钾(0.127 g, 0.600 mmol)和2-吡啶甲酸 (0.0049 mg, 0.040 mmol),密封,脱气并用氮气吹扫。在氮气氛下经注射器加入二甲基亚砜 (1.6 mL)并在微波反应器中于120℃ 加热所得混合物25分钟。在50℃、高真空下除去二甲基亚砜,将残余物在甲醇中浆化并通过10 g硅藻土塞过滤,用另外的甲醇洗涤。浓缩滤液,然后通过闪式色谱法 (硅胶, 0-20% 甲醇/二氯甲烷)纯化得到实施例145和146的混合物。实施例145和146经反相HPLC (C8(2), 5 µM 100Å 柱, 10-100% 乙腈和0.1% TFA/水)分离。1H NMR (500 MHz, DMSO-d 6 ) δ 11.31 (s,1H), 9.80 (s, 1H), 9.00 (s, 1H), 7.78 (dd, J=7.93, 1.22 Hz, 1H), 7.68 (m,2H), 7.58 (m, 1H), 7.51 (td, J=7.55, 1.37 Hz, 1H), 6.93 (dd, J=8.85, 2.14 Hz,1H), 6.72 (s, 1H), 6.50 (s, 1H), 6.43 (d, J=1.83 Hz, 1H), 5.63 (d, J=2.75 Hz,1H), 2.34 (s, 3H)。LCMS m/z 333.2 (M+H)+。
实施例 146.5-[2-(5-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
如在实施例 145中所述制备实施例 146。1H NMR (500 MHz, DMSO-d 6 ) δ 11.28(d, J=1.22 Hz, 1H), 9.91 (s, 1H), 9.20 (s, 1H), 7.77 (dd, J=7.93, 1.22 Hz,1H), 7.69 (td, J=7.55, 1.37 Hz, 1H), 7.60 (dd, J=7.78, 1.07 Hz, 1H), 7.52(td, J=7.55, 1.37 Hz, 1H), 7.13 (d, J=2.14 Hz, 1H), 6.98 (d, J=8.85 Hz, 1H),6.87 (dd, J=9.00, 2.29 Hz, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 5.69 (d, J=2.75Hz, 1H), 2.33 (s, 3H)。LCMS m/z 333.2 (M+H)+。
实施例 147.5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 147a
2-乙酰基-4-(2,6-二氟苯基)-4-氧代丁酸叔丁基酯
在0℃、氮气氛下,向氢化钠(60%矿物油分散体, 0.204 g, 5.11 mmol)的无水四氢呋喃(21 mL)悬浮液中滴加乙酰乙酸叔丁基酯(0.7 mL, 4.25 mmol)。在5℃搅拌混合物20分钟并滴加2-溴-1-(2,6-二氟苯基)乙酮 (SynQuest 1.0 g, 4.25 mmol) 的2 mL 四氢呋喃溶液进行处理。在环境温度下搅拌混合物24 小时,并在乙酸乙酯和饱和氯化铵之间分配。乙酸乙酯层用盐水洗涤,干燥(无水Na2SO4),过滤并浓缩。通过色谱法(硅胶, 0-20% 乙酸乙酯/己烷)纯化得到标题化合物(1.07 g, 81%)。
实施例 147b
5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酸叔丁基酯
将实施例147a的产物 (1.0 g, 3.2 mmol)和乙酸铵 (2.47 g, 32 mmol)在乙酸(10 mL)中的混合物于80℃加热1.5 小时。浓缩混合物并用水和乙酸乙酯稀释残余物,并用5% NaHCO3水溶液处理至pH 恒定为8。用盐水洗涤乙酸乙酯层,干燥(无水Na2SO4),过滤并浓缩得到标题化合物(1.0 g, 99%)。
实施例 147c
5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酸
将实施例 147b的产物 (1.07 g, 3.65 mmol)的二噁烷(10 mL)溶液用4M HCl /二噁烷(9.12 mL, 36.5 mmol)处理并在环境温度下搅拌24 小时。浓缩该琥珀色溶液并用甲苯3 X 20 mL共沸蒸馏得到标题化合物(0.83 g 96%)。
实施例 147d
5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酰胺
将实施例147c的产物 (0.25 g, 1.05 mmol)、HOBT (0.24 g 1.58 mmol)、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(0.30 g, 1.58 mmol)和氯化铵(0.28 g, 5.27mmol)在二甲基甲酰胺(5.3 mL)中混合,用二异丙基乙胺(1.47 mL, 8.4 mmol)处理并在40℃加热24 小时。将混合物冷却并在乙酸乙酯和水之间分配。有机层用盐水反复洗涤,干燥(无水Na2SO4),过滤并浓缩。通过反相HPLC(C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1%TFA/水)纯化得到标题化合物(0.120 g, 48%)。1H NMR (300 MHz, DMSO-d 6) δ 9.02 (s, 1H) 7.07 -7.21 (m, 1 H) 6.83 -7.05 (m, 3 H) 5.72 (s, 2 H) 2.64 (s, 3 H)。MS(ESI+) m/z 237 (M+H)+。
实施例 148.5-(2-苄基苯基)-2-甲基-1H-吡咯-3-甲酰胺
在装有磁搅拌子的微波小瓶中混合实施例115e (0.028 g, 0.1 mmol)、乙酸钯(II)(0.0022 g, 0.01 mmol)和2-二环己基膦基-2',6'-二甲氧基联苯(0.0082 g, 0.020mmol)。将小瓶密封并用氮气吹扫。在氮气氛下经注射器加入四氢呋喃(0.2 mL) 并搅拌形成的混合物10分钟。在氮气氛下经注射器加入溴化苄基锌(II) (0.800 mL, 0.400 mmol),并在环境温度下搅拌该混合物过夜。将反应混合物在乙酸乙酯和水之间分配,有机层经盐水洗涤,干燥(无水MgSO4),通过硅藻土塞过滤并浓缩。残余物经反相HPLC (C8(2), 5 µM100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物。1H NMR (300 MHz, DMSO- d 6 ) δ 11.11 (s, 1H), 7.35 (dd, J=7.34, 1.39 Hz, 1H), 7.21 (m, 5H), 7.07 (m,4H), 6.59 (d, J=2.78 Hz, 1H), 6.55 (s, 1H), 4.14 (s, 2H), 2.45 (s, 3H)。MS(ESI+) m/z 291.0 (M+H)+。
实施例 149.2-甲基-5-(3,4,5-三甲氧基苯基)-1H-吡咯-3-甲酰胺
实施例 149a
2-甲基-1H-吡咯-3-甲酸
将氢氧化锂(1.563 g, 65.3 mmol)/水 (20 mL)加入到2-甲基-1H-吡咯-3-甲酸乙基酯(2.0 g, 13.06 mmol)/二噁烷 (20 mL)中。在回流温度下加热反应混合物4时,冷却并在乙酸乙酯和1 M HCl之间分配,有机层用盐水洗涤,用无水硫酸钠干燥,过滤蒸发得到标题化合物(1.513 g, 93%)。
实施例 149b
2-甲基-1H-吡咯-3-甲酰胺
将实施例 149a (0.86 g, 6.87 mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(HATU, 3.14 g, 8.25 mmol)、N,N-二异丙基乙胺 (3.60 mL,20.62 mmol)和0.5 M 氨/二噁烷 (27.5 mL, 13.8 mmol)在二甲基甲酰胺 (15 mL)中混合。在环境温度下搅拌反应混合物1 小时并浓缩。残余物经闪式色谱法 (硅胶, 5-10% 甲醇/二氯甲烷)纯化得到标题化合物(628 mg, 74%)。
实施例 149c
5-碘-2-甲基-1H-吡咯-3-甲酰胺
将实施例 149b (470 mg, 3.79 mmol)/四氢呋喃 (10 mL)冷却至-78℃并加入N-碘代琥珀酰亚胺(852 mg, 3.79 mmol)的四氢呋喃(5 mL)溶液。在该温度下搅拌反应混合物30分钟并在0℃下浓缩。残余物经闪式色谱法 (硅胶, 5% 甲醇/二氯甲烷)纯化得到标题化合物(670 mg, 71%)。
实施例 149d
2-甲基-5-(3,4,5-三甲氧基苯基)-1H-吡咯-3-甲酰胺
将实施例 149c(100 mg, 0.400 mmol)、3,4,5-三甲氧基苯基硼酸(93 mg, 0.440mmol)、氯化二(三苯基膦)钯(II) (14.04 mg, 0.020 mmol)和2 M 碳酸钠(0.60 mL, 1.20mmol)于1,2-二甲氧基乙烷 (1 mL)/乙醇 (1 mL)中混合。用氮气吹扫反应混合物5分钟并通过微波在100℃加热30分钟。将反应混合物在乙酸乙酯和水之间分配,有机层用盐水洗涤,用无水硫酸钠干燥,过滤并蒸发,残余物用甲醇/二氯甲烷(5%)研制得到标题化合物(13mg, 11%)。1H NMR (300 MHz, DMSO-d 6)δ 11.23 (s, 1 H) 7.06 (s, 1 H) 6.81 -6.91(m, 3 H) 6.59 (s, 1 H) 3.82 (s, 6 H) 3.65 (s, 3 H) 2.47 (s, 3 H)。MS (ESI+) m/z 291 (M+H)+。
实施例 150.5-(联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 150a
2-乙酰基-4-(3-溴苯基)-4-氧代丁酸叔丁基酯
用2-溴-1-(3-溴苯基)乙酮代替2-溴-2'-硝基苯乙酮,按照制备实施例 1a所用的步骤制备了实施例 150a,通过闪式色谱法(硅胶, 10-20% 乙酸乙酯/己烷)纯化得到标题化合物(21.4 g, 86%)。
实施例 150b
5-(3-溴苯基)-2-甲基-1H-吡咯-3-甲酸叔丁基酯
用实施例 150a代替实施例 1a,按照制备实施例 1b所用的步骤制备了实施例150b,得到标题化合物(18.3 g, 91%)。
实施例 150c
5-(3-溴苯基)-2-甲基-1H-吡咯-3-甲酸
向实施例150b (9.41 g, 28 mmol)中添加4 M 盐酸/二噁烷 (80 mL, 320mmol)。在环境温度下搅拌反应混合物28 小时并浓缩。残余物用甲苯共沸蒸馏两次,并用二氯甲烷/己烷(1:2)研制得到标题化合物(7.19 g, 92%)。
实施例 150d
5-(3-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 150c代替实施例 1c,按照制备实施例 1d所用的步骤制备了实施例150d,通过研制(二氯甲烷)纯化得到标题化合物(2.12 g, 76%)。
实施例 150e
5-(联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺
将实施例150d (30 mg, 0.10 mmol)、苯基硼酸(15 mg, 0.13 mmol)、碳酸铯(70mg, 0.21 mmol)和Silicat 树脂 (40 mg, 0.01 mmol)在乙醇 (2 mL)和水(0.2 mL)中混合。在120℃加热该混合物30分钟。过滤粗产物,浓缩洗涤液并通过反相HPLC (C8(2), 5 µM100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(5.4 mg, 18%)。1H NMR(400 MHz, DMSO-d 6) δ 11.50 (s, 1H), 7.89 (s, 1H), 7.67 -7.79 (m, 2H), 7.56 -7.65 (m, 1H), 7.44 -7.55 (m, 4H), 7.35 -7.43 (m, 1H), 6.99 (d, J = 2.7 Hz,1H), 2.49 (s, 3H)。MS (ESI+) m/z 277 (M+H)+。
实施例 151.5-(3'-甲氧基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺
用3-甲氧基苯基硼酸代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 151,得到标题化合物(7.2 mg, 22%)。1H NMR (400 MHz, DMSO-d 6) δ 7.88 (s, 1H),7.52 -7.63 (m, 1H), 7.44 -7.51 (m, 2H), 7.43 (t, J = 5.7 Hz, 1H), 7.30 (d, J= 8.1 Hz, 1H), 7.19 -7.28 (m, 1H), 6.86 -7.04 (m, 2H), 3.85 (s, 3H), 2.49 (s,3H)。MS (ESI+) m/z 307 (M+H)+。
实施例 152.2-甲基-5-[3-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺
用3-噻吩硼酸代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例152,得到标题化合物(3.6 mg, 12%)。1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H),7.93 (d, J = 1.5 Hz, 1H), 7.87 (dd, J = 2.9, 1.3 Hz, 1H), 7.67 (dd, J = 5.0,2.9 Hz, 1H), 7.61 (dd, J = 5.0, 1.3 Hz, 1H), 7.47 -7.54 (m, 2H), 7.41 (t, J =7.7 Hz, 1H), 2.49 (s, 3H)。MS (ESI+) m/z 283 (M+H)+。
实施例 153.5-(2'-乙酰基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺
用2-乙酰基苯基硼酸代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 153,得到标题化合物(3.4 mg, 10%)。1H NMR (400 MHz, DMSO-d 6) δ 11.46 (s,1H), 7.63 (t, J = 6.0 Hz, 2H), 7.60 (d, J = 7.5 Hz, 1H), 7.54 (dd, J = 3.7,1.4 Hz, 1H), 7.51 (dd, J = 7.9, 1.4 Hz, 1H), 7.45 -7.49 (m, 1H), 7.43 (d, J =7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 2.47 (s,3H), 2.18 (s, 3H)。MS (ESI+) m/z 319 (M+H)+。
实施例 154.2-甲基-5-[3-(吡啶-3-基)苯基]-1H-吡咯-3-甲酰胺
用3-吡啶硼酸代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例154,得到标题化合物(2.9 mg, 10%)。1H NMR (400 MHz, DMSO-d 6) δ 11.53 (s, 1H),9.12 (d, J = 1.9 Hz, 1H), 8.77 (dd, J = 5.3, 1.2 Hz, 1H), 8.60 (d, J = 8.2Hz, 1H), 7.99 (s, 1H), 7.91 (dd, J = 8.1, 5.3 Hz, 1H), 7.70 (d, J = 7.5 Hz,1H), 7.50 -7.63 (m, 2H), 7.02 (d, J = 2.5 Hz, 1H), 2.50 (s, 3H)。MS (ESI+) m/z278 (M+H)+。
实施例 155.2-甲基-5-[3-(1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺
用4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 155,得到标题化合物(1.4 mg, 5%)。1HNMR (400 MHz, DMSO-d 6) δ 11.41 (s, 1H), 8.08 (s, 2H), 7.83 (s, 1H), 7.22 -7.60 (m, 3H), 6.94 (d, J = 1.5 Hz, 1H), 2.49 (s, 3H)。MS (ESI+) m/z 267 (M+H)+。
实施例 156.2-甲基-5-[3-(1-甲基-1H-吲哚-5-基)苯基]-1H-吡咯-3-甲酰胺
用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 156,得到标题化合物(13.6 mg,38%)。1H NMR (400 MHz, DMSO-d 6) δ 11.47 (d, J = 15.7 Hz, 1H), 7.88 (t, J = 18.5Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H), 7.50 (t, J = 7.3 Hz, 2H), 7.40 -7.47 (m,1H), 7.36 (s, 1H), 6.97 (t, J = 5.2 Hz, 1H), 3.83 (s, 3H), 2.46 -2.51 (m,3H)。MS (ESI+) m/z 330 (M+H)+。
实施例 157.2-甲基-5-{3-[(E)-2-苯基乙烯基]苯基}-1H-吡咯-3-甲酰胺
用(E)-4,4,5,5-四甲基-2-苯乙烯基-1,3,2-二氧杂硼杂环戊烷代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 157,得到标题化合物(8.1 mg, 25%)。1HNMR (400 MHz, DMSO-d 6) δ 11.46 (s, 1H), 7.84 (s, 1H), 7.59 (dd, J = 29.3, 4.5Hz, 2H), 7.47 -7.51 (m, 1H), 7.36 -7.46 (m, 5H), 7.25 -7.34 (m, 3H), 6.95 (d,J = 2.6 Hz, 1H), 2.49 (s, 3H)。MS (ESI+) m/z 303 (M+H)+。
实施例 158.2-甲基-5-{3'-[(4-甲基哌嗪-1-基)甲基]联苯-3-基}-1H-吡咯-3-甲酰胺
用1-甲基-4-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)哌嗪代替苯基硼酸,按照制备实施例 150e所用的步骤制备了实施例 158,得到标题化合物(11mg, 17%),为三氟乙酸盐。1H NMR (400 MHz, DMSO-d 6) δ 11.50 (s, 1H), 7.88 (s, 1H),7.76 (d, J = 7.4 Hz, 2H), 7.51 -7.63 (m, 2H), 7.47 (dd, J = 17.8, 6.3 Hz,3H), 6.98 (d, J = 2.5 Hz, 1H), 4.05 (s, 2H), 3.32 (s, 4H), 2.82 (s, 4H), 2.49(s, 3H)。MS (ESI+) m/z 389 (M+H)+。
实施例 159.5-(4'-{[2-(二甲基氨基)乙基]氨基甲酰基}联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺
用4-(2-(二甲基氨基)乙基氨基甲酰基)苯基硼酸代替苯基硼酸,按照制备实施例150e所用的步骤制备了实施例 159,得到标题化合物(9.5 mg, 18%),为三氟乙酸盐。1HNMR (400 MHz, DMSO-d 6) δ 11.52 (s, 1H), 7.97 (t, J = 9.7 Hz, 3H), 7.88 (d, J= 8.5 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.46 -7.58 (m, 2H), 6.99 (d, J = 2.7Hz, 1H), 3.66 (t, J = 5.9 Hz, 1H), 3.30 (t, J = 6.0 Hz, 2H), 2.87 (s, 6H),2.50 (s, 3H)。MS (ESI+) m/z 391 (M+H)+。
实施例 160.5-[3-(1,3-苯并二氧杂环戊烯-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
将实施例 150 d (40 mg, 0.143 mmol)、苯并[d][1,3]二氧杂环戊烯-5-酚(240mg, 0.859 mmol)、碘化铜(I)(27.3 mg, 0.143 mmol)、2-吡啶甲酸 (21.2 mg, 0.172mmol)和磷酸三钾(91.3 mg, 0.430 mmol)在DMSO (3 mL)中混合。通过微波于150℃加热反应混合物45分钟。过滤粗产物,浓缩洗涤液并通过反相HPLC (C8(2), 5 µM 100 Å 柱, 10-100% 乙腈和0.1% TFA/水)纯化得到标题化合物(0.0237 g, 49%)。1H NMR (400 MHz,DMSO-d 6) δ 7.30 -7.37 (m, 2 H), 7.20 (s, 1 H), 6.92 (d, J=8.54 Hz, 1 H), 6.87(d, J=2.75 Hz, 1 H), 6.71 -6.75 (m, 2 H), 6.51 (dd, J=8.54, 2.44 Hz, 1 H),6.03 (s, 2 H), 2.45 (s, 3 H)。MS (ESI+) m/z 337 (M+H)+。
实施例 161.5-(5-氨基-2-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺
实施例 161a
5-(2-氟-5-硝基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 149c代替实施例 92d和用2-氟-5-硝基苯基硼酸代替3,5-二甲基异噁唑-4-基硼酸,按照制备实施例 92e所用的步骤制备了实施例 161a,得到标题化合物(0.059 g, 45%)。
实施例 161b
2-甲基-5-(5-硝基-2-苯氧基苯基)-1H-吡咯-3-甲酰胺
用实施例 161a代替实施例 91b,按照制备实施例 91c所用的步骤制备了实施例161b,得到标题化合物(0.060 g, 80%)。
实施例 161c
5-(5-氨基-2-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺
用实施例 161b代替实施例 1d,按照制备实施例 1e所用的步骤制备了实施例161c,得到标题化合物(0.0533 g, 54%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.15 (s, 1H),7.32 (m, 3H), 7.06 (m, 3H), 6.92 (m, 5H), 6.58 (s, 2H), 2.42 (s, 3H)。MS (ESI+) m/z 308.3 (M+H)+。
实施例 162.2-甲基-5-{5-[(甲基磺酰基)氨基]-2-苯氧基苯基}-1H-吡咯-3-甲酰胺
将实施例 161c (0.031 g, 0.1 mmol)/二氯甲烷 (1.0 mL)依次地用甲烷磺酰氯(0.017 mL, 0.220 mmol)和三乙胺 (0.035 mL, 0.250 mmol)处理, 在环境温度下搅拌1小时,然后浓缩至干。将残余物溶于1,4-二噁烷(1.0 mL), 用1N 氢氧化钠水溶液(1.0 mL)处理并在50℃加热1 小时,然后将反应混合物冷却至环境温度并用2 N盐酸水溶液中和。将所得混合物在乙酸乙酯和水之间分配,有机层用盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法(硅胶, 0-10% 甲醇/二氯甲烷)纯化,并通过反相HPLC (C8(2), 5 µM100 Å 柱, 10-100% 乙腈和0.1% TFA/水)进一步纯化得到标题化合物(0.0173 g, 45%)。1H NMR (300 MHz, DMSO-d 6 ) δ 11.14 (s, 1H), 9.62 (s, 1H), 7.46 (d, J=2.78 Hz,1H), 7.33 (m, 2H), 7.05 (m, 3H), 6.95 (m, 3H), 6.86 (d, J=2.78 Hz, 1H), 6.55(s, 1H), 3.02 (s, 3H), 2.43 (s, 3H)。LCMS m/z 386.2 (M+H)+。
实施例 163.5-(1H-苯并咪唑-4-基)-2-甲基-1H-吡咯-3-甲酰胺
向装有搅拌子的5 mL微波反应小瓶中加入实施例 149c (0.055 g, 0.220mmol)、1H-苯并[d]咪唑-4-基硼酸(0.062 g, 0.383 mmol)、2 M碳酸钠水溶液(1.6 mL,3.20 mmol)和二氯化双(三苯基膦)钯(II)(0.010 g, 0.014 mmol)/乙醇 (1.4 mL)/DME(1.4 mL),并密封小瓶,在Biotage Initiator 2 单模式微波反应器中于120℃加热混合物30分钟,然后冷却至环境温度。在分液漏斗中将该混合物与75 mL 乙酸乙酯和50 mL 水一起振摇,有机相经无水硫酸钠干燥,过滤并浓缩。残余物经反相HPLC (C18, 0-100 %CH3CN/10 mM 乙酸铵/水)纯化得到标题化合物。1H NMR (300 MHz, CDCl3) δ ppm 7.52(m, 1H), 7.31 (m, 2H), 6.91 (s, 1H), 6.85 (s, 1H), 2.61 (s, 3H)。MS (DCI+) m/z241.1 (M+H)+, 258.2 (M+NH4)+。
实施例 164.5-(1H-吲哚-7-基)-2-甲基-1H-吡咯-3-甲酰胺
用1H-吲哚-7-基硼酸代替1H-苯并[d]咪唑-4-基硼酸,按照制备实施例 163所用的步骤制备了实施例 164,得到标题化合物。1H NMR (300 MHz, CDCl3) δ ppm 7.60 (m1H), 7.19-7.16 (m, 3H), 6.91 (s, 1H), 6.64 (m, 1H), 2.66 (s, 3H)。MS (DCI+) m/z 240.1 (M+H)+, 257.1 (M+NH4)+。
实施例 165.[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸乙基酯
实施例 165a
2-(3-溴-4-羟基苯基)乙酸乙基酯
将2-(4-羟基苯基)乙酸乙基酯 (2.70 g, 15 mmol)/乙酸 (20 mL)用溴 (0.773mL, 15.00 mmol)的乙酸(15 mL)溶液处理15分钟。在环境温度下搅拌反应混合物30分钟并浓缩。残余物经闪式色谱法(硅胶, 10-20% 乙酸乙酯/己烷)纯化得到标题化合物(3.66 g,94%)。
实施例 165b
2-(4-(苄基氧基)-3-溴苯基)乙酸乙基酯
将实施例 165a (3.65 g, 14.1 mmol)、(溴甲基)苯 (2.01 mL, 16.9 mmol)和碳酸钾(5.84 g, 42.3 mmol)在乙醇(100 mL)中混合。在回流温度下加热反应混合物2 小时并浓缩。将残余物在乙酸乙酯和水之间分配,有机层用盐水洗涤,用无水硫酸钠干燥,过滤并蒸发。残余物经闪式色谱法(硅胶, 0-20% 乙酸乙酯/己烷)纯化得到标题化合物(4.84g, 98%)。
实施例 165c
2-(4-(苄基氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)乙酸乙基酯
将实施例 165b的产物 (1.048 g, 3.0 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷) (0.990 g, 3.90 mmol)、PdCl2(dppf) (0.220 g, 0.30mmol)和乙酸钾(0.883 g, 9.0 mmol)在二甲基甲酰胺 (15 mL)中混合。用氮气吹扫反应混合物30分钟并在85℃加热20 小时。将反应混合物在乙酸乙酯和水之间分配,有机层用盐水洗涤两次,用无水硫酸钠干燥,过滤并蒸发得到标题化合物,未经纯化直接应用。
实施例 165d
[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸乙基酯
将实施例 149c (0.750 g, 3.00 mmol)、实施例 165c (1.189 g, 3.00 mmol),Pd2(dba)3 (0.069 g, 0.075 mmol)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷杂金刚烷(phosphaadamante)在二噁烷 (12 mL)/水 (3 mL)中混合。用氮气吹扫反应混合物30分钟并在60℃加热6 小时。将反应混合物在乙酸乙酯和水之间分配,有机层用盐水洗涤两次,用无水硫酸钠干燥,过滤并蒸发。残余物经闪式色谱法(硅胶, 0-2% 甲醇/二氯甲烷)纯化得到标题化合物(318 mg, 27%)。1H NMR (300 MHz, DMSO-d 6) δ 10.91 (s, 1 H) 7.46 -7.51 (m, 2 H) 7.26 -7.43 (m, 4 H) 6.97 -7.05 (m, 3 H) 6.95 (d, J=2.78 Hz, 1H) 6.57 (s, 1 H) 5.26 (s, 2 H) 4.07 (q, J=7.14 Hz, 2 H) 3.57 (s, 2 H) 2.44(s, 3 H) 1.18 (t, J=7.14 Hz, 3 H)。MS (ESI+) m/z 393 (M+H)+。
实施例 166.[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸
将实施例 165d (305 mg, 0.777 mmol)和1 M氢氧化钠水溶液(2.33 mL, 2.33mmol)在四氢呋喃(10 mL)/水 (5 mL)中混合。在回流温度下加热反应混合物3 小时,冷却至环境温度并在乙酸乙酯和水之间分配,水层用1M HCl酸化并过滤产生的固体,用水洗涤并干燥得到标题化合物(267 mg, 94%)。1H NMR (300 MHz, DMSO-d 6) δ 10.90 (s, 1 H)7.46 -7.51 (m, 2 H) 7.26 -7.43 (m, 4 H) 6.96 -7.05 (m, 3 H) 6.95 (d, J=2.71Hz, 1 H) 6.54 (s, 1 H) 5.26 (s, 2 H) 3.48 (s, 2 H) 2.44 (s, 3 H)。MS (ESI+) m/z 365 (M+H)+。
实施例 167.5-[2-(苄基氧基)-5-(2-羟基乙基)苯基]-2-甲基-1H-吡咯-3-甲酰胺
将实施例 166 (51.0 mg, 0.14 mmol)/四氢呋喃 (2 mL)用1.0 M 甲硼烷四氢呋喃配合物(0.280 mL, 0.280 mmol)处理。在环境温度下搅拌反应混合物20 小时,用甲醇(2mL)处理并在50℃加热30分钟。浓缩反应混合物,残余物经闪式色谱法(硅胶, 0-4% 甲醇/二氯甲烷)纯化得到标题化合物(32 mg, 65%)。1H NMR (300 MHz, DMSO-d 6) δ 10.87 (s,1 H) 7.43 -7.53 (m, 2 H) 7.25 -7.41 (m, 4 H) 6.87 -7.04 (m, 4 H) 6.55 (s, 1H) 5.23 (s, 2 H) 4.60 (t, J=5.09 Hz, 1 H) 3.52 -3.65 (m, 2 H) 2.66 (t, J=7.29Hz, 2 H) 2.44 (s, 3 H)。MS (ESI+) m/z 351 (M+H)+。
实施例 168.5-[2-(2,4-二氟苯氧基)-5-氨磺酰基苯基]-2-甲基-1H-吡咯-3-甲酰胺
实施例 168a
4-(2,4-二氟苯氧基)-3-硝基苯磺酰胺
在10℃、氮气氛下,向2,4-二氟苯酚(5.39 g, 41.4 mmol)的二甲基甲酰胺 (34.5mL)溶液中分多份添加氢化钠(60%, 1.657 g, 41.4 mmol),搅拌15分钟,然后分多份添加4-氟-3-硝基苯磺酰胺 (2.28 g, 10.36 mmol)。在环境温度下搅拌该溶液1.5 小时,用乙酸乙酯稀释并小心地用0.5 M HCl淬灭反应至pH恒定为6。有机层用盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物用3:1 己烷/乙酸乙酯研制并通过过滤收集标题化合物 (3.24g, 95%)。
实施例 168b
3-氨基-4-(2,4-二氟苯氧基)苯磺酰胺
将实施例168a的产物(3.24 g, 9.81 mmol)、铁粉 (2.74 g, 49.1 mmol)和氯化铵(0.787 g, 14.72 mmol)在四氢呋喃(21 mL)、乙醇 (21 mL)和水(7 mL)的溶剂混合物中混合并在95℃剧烈搅拌3小时。将混合物冷却并通过硅藻土塞过滤以除去固体,用甲醇和四氢呋喃反复冲洗该塞,浓缩滤液并将残余物在乙酸乙酯和水之间分配。用盐水洗涤乙酸乙酯层,干燥(无水Na2SO4),过滤、浓缩得到标题化合物(2.81 g, 95%)。
实施例 168c
4-(2,4-二氟苯氧基)-3-碘苯磺酰胺
在0℃下,将实施例 168b的产物(2.8 g, 9.32 mmol)的二噁烷(20 mL)溶液用浓盐酸(40 mL, 9.32 mmol)处理,在0℃下搅拌15分钟并用亚硝酸钠(0.772 g, 11.19 mmol)的水(10 mL)溶液处理。在0℃下搅拌混合物1 小时,用碘化钾(3.10 g, 18.65 mmol)的水(10 mL)溶液处理,搅拌1 小时并在乙酸乙酯和水之间分配。有机层经饱和硫代硫酸钠、水、盐水洗涤,干燥(无水MgSO4),过滤并浓缩。残余物经闪式色谱法 (硅胶, 0-60% 乙酸乙酯/己烷)纯化得到标题化合物(2.24 g, 58%)。
实施例 168d
2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡咯-3-甲酸乙基酯
将2-甲基-1H-吡咯-3-甲酸乙基酯 (3.06 g, 20.0 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(2.54 g, 10 mmol)、(1,5-环辛二烯)(甲氧基)铱(I)二聚物(0.099 g, 0.15 mmol)和4,4'-二-叔丁基-2,2'-联吡啶(0.081 g,0.30 mmol)在己烷(100 mL)中的混合物用氩气吹扫15分钟,在氮气氛下搅拌24 小时并在乙酸乙酯和水之间分配。有机层用盐水洗涤,干燥(无水Na2SO4), 用巯基丙基二氧化硅(Aldrich catalog 538086, 约1.0 g)处理30分钟并过滤,浓缩滤液得到标题化合物(5.55g, 98%)。
实施例 168e
5-(2-(2,4-二氟苯氧基)-5-氨磺酰基苯基)-2-甲基-1H-吡咯-3-甲酸乙基酯
将实施例 168d的产物(0.167 g, 0.6 mmol)、实施例 168c的产物 (0.206 g,0.5 mmol)、三(二苄叉基丙酮)二钯(0)(0.014 g, 0.015 mmol)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷杂金刚烷 (PA-Ph, CAS 97739-46-3, 0.015 g, 0.05 mmol)和磷酸三钾(0.318 g, 1.5 mmol)混合并用氩气吹扫30分钟。同时用氮气将二噁烷 (2.3 mL)和水(0.57 mL)的溶液脱气30分钟并在氩气氛下转移至固体中。在60℃加热混合物3 小时,冷却,在乙酸乙酯和水之间分配并通过硅藻土塞过滤。分离滤液层,乙酸乙酯层经饱和盐水洗涤, 干燥(无水Na2SO4),用巯基丙基二氧化硅(Aldrich catalog 538086, 约1.0 g)处理三十分钟,过滤并浓缩。通过研制(10% 乙酸乙酯/己烷)纯化得到标题化合物(0.177 g,81%)。
实施例 168f
5-(2-(2,4-二氟苯氧基)-5-氨磺酰基苯基)-2-甲基-1H-吡咯-3-甲酸
将实施例168e的产物(0.177 g, 0.406 mmol)和氢氧化锂(0.097 g, 4.06 mmol)在水(2 mL)、乙醇(2 mL)和二噁烷(2 mL)中混合,在90℃加热5 小时,冷却至环境温度并浓缩。将残余物在乙酸乙酯和水之间分配并用1M HCl处理至 pH恒定为2。用盐水洗涤有机层,干燥(无水Na2SO4),过滤并浓缩得到标题化合物(0.15 g, 91%)。
实施例 168g
5-[2-(2,4-二氟苯氧基)-5-氨磺酰基苯基]-2-甲基-1H-吡咯-3-甲酰胺
用实施例 168f的产物代替实施例 147c的产物,按照实施例 147d的步骤制备了实施例 168g,通过在二氯甲烷中研制进行纯化得到标题化合物(0.114 g, 82%)。1H NMR(300 MHz, DMSO-d 6) δ 11.41 (s, 1 H) 8.14 (d, J=2.03 Hz, 1 H) 7.48 -7.59 (m, 2H) 7.35 -7.45 (m, 1 H) 7.27 (s, 2 H) 7.16 -7.24 (m, 2 H) 7.11 (d, J=2.03 Hz,1 H) 6.82 (d, J=8.48 Hz, 1 H) 6.58 (s, 1 H) 2.51 (s, 3 H)。MS (ESI+) m/z 408(M+H)+。
生物实施例
布罗莫结构域结构域结合测定
用时间分辨荧光共振能量转移(TR-FRET)分析确定表1所列出的实施例化合物对每个BRD4的布罗莫结构域的亲和力。表达和纯化His-标签的BRD4的第一(BD1:氨基酸K57-E168)和第二(BD2:氨基酸E352-E168)布罗莫结构域。在该测试中,用Alexa647-标记的BET-抑制剂作为荧光探针。
Alexa647-标记的布罗莫结构域抑制剂化合物的合成
2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酸。将2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酸甲酯(参见例如WO2006129623)(100.95mg,0.243mmol)悬浮在1mL甲醇中,向其中加入新鲜制备的氢氧化锂一水合物(0.973mL,0.5 M,0.487mmol),并在环境温度下振摇3小时。蒸去甲醇,并用盐酸水溶液(1M,0.5毫升,0.5毫摩尔) 调节pH,用乙酸乙酯萃取四次。将合并的乙酸乙酯层经硫酸镁干燥并蒸发,得到2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酸(85.3mg,87.0%);ESI-MS m/z = 401.1 [(M+H)+],将其直接用于下一步反应。
N-(2-(2-(2-氨基乙氧基)乙氧基)乙基)-2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺双(2,2,2-三氟乙酸盐)。将2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酸(85.3mg,0.213mmol)与2,2'-(乙烷-1,2-二基双(氧基))二乙胺(Sigma-Aldrich, 0.315 mg, 2.13 mmol)在5mL无水二甲基甲酰胺中合并。添加(1H-苯并[d][1,2,3]三唑-1-基氧基)三吡咯烷-1-基鏻六氟磷酸盐(V)(PyBOB, CSBio,Menlo Park CA; 332 mg, 0.638 mmol),并在环境温度下振摇反应16小时。用二甲基亚砜:水(9:1,v:v)将反应物稀释至6mL,分两次进样,用时间采集Waters Deltapak C18 200 x25 mm柱纯化,用含0.1%三氟乙酸(v/v)的水和乙腈梯度洗脱。将含有两种纯化产物的级分进行冷冻干燥,得到N-(2-(2-(2-氨基乙氧基)乙氧基)乙基)-2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺双(2,2,2-三氟乙酸盐)(134.4mg,82.3%);ESI-MS m/z = 531.1 [(M+H)+]; 529.1 [(M-H)-]和(S,Z)-N,N'-(2,2'-(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺)双(2,2,2-三氟乙酸盐)(3.0 mg, 1.5%);ESI-MS m/z = 913.2 [(M+H)+];911.0[(M-H)-]。
N-(2-(2-(2-酰氨基-(Alexa647)-乙氧基)乙氧基)乙基)-2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺(2,2,2-三氟乙酸盐)。将N-(2-(2-(2-氨基乙氧基)乙氧基)乙基)-2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺双(2,2,2-三氟乙酸盐)(5.4mg,0.0071mmol)与Alexa Fluor®647羧酸琥珀酰亚胺酯(Life Technologies, Grand Island, NY; 3 mg, 0.0024 mmol)合并于1mL含二异丙基乙胺(1%v/v)的无水二甲亚砜中,并在室温下振摇16小时。用二甲基亚砜:水(9:1,v:v)将反应物稀释至3mL,并通过一次进样用时间采集Waters Deltapak C18 200 x 25 mm柱纯化,用含0.1%三氟乙酸的水和乙腈梯度洗脱(v/v)。将含有纯化产物的级分冷冻干燥,得到N-(2-(2-(2-酰氨基(Alexa647)-乙氧基)乙氧基)乙基)-2-((6S,Z)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂䓬-6-基)乙酰胺(2,2,2-三氟乙酸盐)(1.8mg),为深蓝色粉末。MALDI-MS m/z = 1371.1, 1373.1 [(M+H)+]。
测定
通过3倍连续稀释制备化合物在DMSO中的系列稀释溶液:2.5 mM至42 nM。然后将化合物按6:100比例用测定缓冲液(20 mM磷酸钠,pH 6.0,50 mM氯化钠,1 mM 乙二胺四乙酸,0.01% Triton X-100,1 mM DL-二硫苏糖醇)稀释以获得3X工作溶液。然后将6微升(μL)的工作液转移至白色的小体积测定板(Costar#3673)。还制备含His-标记的布罗莫结构域、铕缀合的抗His抗体(Invitrogen PV5596)和Alexa-647-缀合的探针分子的1.5X测定混合物。将12 μL的此溶液添加到测定板以达到18 μL的终体积。最终浓度1X测试缓冲液含有2% DMSO、50 μM -0.85 nM 化合物、8 nM His-标记的布罗莫结构域、1 nM铕缀合的抗His标记抗体和100 nM或30 nM 探针(分别对于BDI或BDII)。在室温下孵育一小时后,用Envision多标记读板器(Ex 340, Em 495/520)确定TR-FRET比。
TR-FRET数据归一化到24个无化合物对照(“高”)的平均值和含有1 μM未标记的探针的8个对照(“低”)的平均值。将抑制百分比作为化合物浓度的函数进行绘图,并用4参数对数公式对数据进行拟合以获得IC50。由 IC50、探针Kd和探针浓度计算抑制常数(Ki)。典型的Z’值在0.65和0.75之间。测定最低显著性比以评价测定方法的重现性(Eastwood 等,(2006) J Biomol Screen, 11: 253-261)。对于BDI,MSR的测定值是2.03,对于BDII,MSR的测定值是1.93,并且对于BDI和BDII的移动MSR(last six run MSR overtime)通常<3。Ki值列于表1中。
MX-1细胞系增殖测定
使用乳腺癌细胞系MX-1 (ATCC),在3天增殖测试中测定实施例化合物对癌细胞增殖的影响,数据列于表1中。在37℃和5% CO2气氛中,用含10% FBS的RPMI 1640培养基(Sigma)培养MX-1细胞。测试化合物时,将MX-1细胞以5000细胞/孔的密度接种在每孔含有90µL培养基的96孔黑底板中,在37℃孵育过夜使细胞粘附和铺展。通过从3 mM到0.1 μM的3倍连续稀释制备化合物在DMSO中的系列稀释溶液。然后用磷酸盐缓冲液将所述DMSO系列稀释溶液以1:100比例稀释,并且将10 μL所得溶液添加到MX-1细胞板的相应孔中。孔中最终化合物浓度为3、1、0.3、0.1、0.03、0.01、0.003、0.001、0.0003和0.0001 μM。加入化合物后,再孵育细胞72小时,使用Cell Titer Glo测定试剂盒(Promega),按照制造商建议的方案测定存活细胞的量。
相对于DMSO处理的细胞,将由Cell Titer Glo测定的发光读数进行归一化,用GraphPad Prism软件分析,用S形曲线拟合得到EC50。测定最低显著性比(MSR)以评价测定方法的重现性(Eastwood 等, (2006) J Biomol Screen, 11: 253-261)。测得总MSR为2.1,移动MSR (last six run MSR overtime) <2。
表1
实施例# | TR-FRET结合Ki:BRD4 (BDI_K57-E168)(μM) | TR-FRET结合Ki:BRD4 (BDII_E352-M457)(μM) | 细胞增殖:EC50 (μM) |
1 | 2.54 | 6.21 | ND |
2 | 2.92 | 21.5 | ND |
3 | 2.33 | 7.2 | ND |
4 | 5.19 | 4.44 | ND |
5 | 8.09 | 6.43 | ND |
6 | 3.16 | 5.01 | ND |
7 | 1.63 | 6.89 | ND |
8 | 2.68 | 3.72 | ND |
9 | 2.88 | 3.14 | ND |
10 | 3.47 | 5.57 | ND |
11 | 2.87 | 2.51 | ND |
12 | 0.935 | 3.9 | 3.44 |
13 | 0.774 | 4.54 | 3.3 |
14 | 0.209 | 0.722 | 0.465 |
15 | 2.58 | 2.31 | ND |
16 | 1.18 | 2.02 | ND |
17 | 0.248 | 1.87 | 1.5 |
18 | 0.183 | 2.34 | 2.85 |
19 | 0.131 | 1.83 | 2.36 |
20 | 1.19 | 3.29 | ND |
21 | 9.69 | 21.5 | ND |
22 | 2.98 | 3.66 | ND |
23 | 3.52 | 3.53 | ND |
24 | 1.06 | 1.19 | ND |
25 | 1.26 | 2.16 | ND |
26 | 0.86 | 7.53 | ND |
27 | 0.384 | 1.48 | 1.3 |
28 | 9.45 | 13.6 | ND |
29 | 2.77 | 4.41 | ND |
30 | 3.06 | 3.48 | ND |
31 | 1.4 | 6.23 | ND |
32 | 5.17 | 10.3 | ND |
33 | 9.63 | 13.1 | ND |
34 | 1.4 | 3.45 | ND |
35 | 2.7 | 3.26 | ND |
36 | 0.521 | 1.16 | ND |
37 | 4.68 | 3.58 | ND |
38 | 0.622 | 1.14 | 3.8 |
39 | 3.82 | 4.98 | ND |
40 | 0.212 | 5.58 | >10 |
41 | 0.48 | 16.5 | ND |
42 | 0.446 | 14.55 | >10 |
43 | 0.469 | 10.99 | >10 |
44 | 0.322 | 1.79 | >10 |
45 | 0.434 | 9.29 | 5.44 |
46 | 0.426 | 16.26 | 4.95 |
47 | 0.498 | 7.83 | >10 |
48 | 0.224 | 6.22 | 9.58 |
49 | 0.313 | 5.6 | >10 |
50 | 5.04 | 22.2 | ND |
51 | 6.7 | 22.2 | ND |
52 | 3.08 | 16.4 | ND |
53 | 0.659 | 3.19 | 4.17 |
54 | 0.585 | 3.88 | 0.19 |
55 | 0.722 | 4.94 | ND |
56 | 1.63 | 2.69 | >10 |
57 | 0.392 | 1.9 | >3 |
58 | 4.68 | 22.2 | ND |
59 | 2.13 | 3.31 | ND |
60 | 5.1 | 20.5 | ND |
61 | 8.28 | 22.2 | ND |
62 | 0.197 | 1.24 | 0.52 |
63 | 0.352 | 6.9 | 2.46 |
64 | 1.04 | 22.2 | ND |
65 | 0.634 | 12.2 | ND |
66 | 1.76 | 6.15 | ND |
67 | 0.452 | 0.81 | >3 |
68 | 0.151 | 2.59 | 1.13 |
69 | 0.663 | 2.34 | ND |
70 | 0.434 | 4.29 | >3 |
71 | 0.628 | 22.2 | ND |
72 | 0.0781 | 0.416 | 0.167 |
73 | 0.862 | 3.83 | ND |
74 | 0.526 | 1.65 | ND |
75 | 0.0376 | 0.225 | 0.433 |
76 | 4.5 | 2.98 | 13.4 |
77 | 0.172 | 0.983 | 6.91 |
78 | 3.99 | 0.712 | ND |
79 | 0.904 | 2.65 | ND |
80 | 9.39 | 13.4 | ND |
81 | 9.29 | 22.2 | ND |
82 | 2.96 | 8.72 | ND |
83 | 0.237 | 0.653 | >3 |
84 | 10.6 | 22.2 | ND |
85 | 1.85 | 13.2 | >3 |
86 | 3.03 | 2.6 | ND |
87 | 0.366 | 0.465 | >3 |
88 | 8.48 | 22.2 | ND |
89 | 0.122 | 0.351 | 0.965 |
90 | 2.5 | 5.18 | 6.3 |
91 | 0.331 | 3.35 | >3 |
92 | 1.69 | 2.43 | ND |
93 | 5.09 | 6.42 | ND |
94 | 4.82 | 21.5 | ND |
95 | 5.07 | 5.62 | ND |
96 | 3.19 | 21.5 | ND |
97 | 1.41 | 1.87 | 15.3 |
98 | 11.3 | 7.01 | ND |
99 | 2.3 | 2.32 | ND |
100 | 8.36 | 5.32 | ND |
101 | 7.37 | 5.33 | ND |
102 | 5.68 | 4.37 | ND |
103 | 4.66 | 3.48 | ND |
104 | 2.38 | 2.34 | ND |
105 | 6.78 | 5.34 | ND |
106 | 6.01 | 4.87 | ND |
107 | 4.02 | 1.98 | 8.6 |
108 | 11.0 | 4.49 | ND |
109 | 9.24 | 4.42 | ND |
110 | 4.03 | 5.9 | ND |
111 | 6.9 | 5.74 | ND |
112 | 5.43 | 4.31 | ND |
113 | 4.64 | 4.22 | ND |
114 | 3.96 | 3.68 | ND |
115 | 1.85 | 7.12 | ND |
116 | 0.182 | 0.639 | 1.18 |
117 | 0.391 | 0.725 | 1.35 |
118 | 0.529 | 1.73 | 1.32 |
119 | 0.249 | 1.1 | 0.998 |
120 | 4.41 | 22.2 | ND |
121 | 0.776 | 10.21 | >10 |
122 | 1.96 | 7.04 | ND |
123 | 1.97 | 12.6 | ND |
124 | 4.6 | 13.14 | ND |
125 | 0.18 | 0.192 | 1.6 |
126 | 0.0834 | 1.14 | 1.3 |
127 | 0.233 | 1.04 | 2.0 |
128 | 0.0273 | 0.318 | 0.40 |
129 | 0.281 | 2.24 | 2.25 |
130 | 0.471 | 1.22 | 1.77 |
131 | 9.4 | 22.2 | ND |
132 | 10.91 | 22.2 | ND |
133 | 0.31 | 0.576 | 1.83 |
134 | 0.493 | 1.17 | >10 |
135 | 0.355 | 1.86 | >10 |
136 | 0.564 | 1.98 | ND |
137 | 0.218 | 1.02 | 4.88 |
138 | 1.48 | 1.82 | ND |
139 | 0.728 | 1.19 | 8.56 |
140 | 0.607 | 1.3 | ND |
141 | 0.123 | 1.6 | 2.42 |
142 | 0.357 | 0.775 | 2.13 |
143 | 0.259 | 2.11 | ND |
144 | 0.446 | 1.23 | ND |
145 | 1.19 | 3.92 | >10 |
146 | 0.0749 | 0.326 | 1.61 |
147 | 11.9 | 12.2 | ND |
148 | 0.355 | 0.605 | 4.32 |
149 | 0.884 | 3.88 | 2.32 |
150 | 10.7 | 9.69 | ND |
151 | 10.4 | 22.2 | ND |
152 | 4.7 | 7.87 | ND |
153 | 2.22 | 7.32 | ND |
154 | 2.99 | 7.12 | ND |
155 | 2.57 | 5.46 | ND |
156 | 8.49 | 21.9 | ND |
157 | 7.41 | 22.2 | ND |
158 | 1.5 | 2.14 | 7.75 |
159 | 1.08 | 2.1 | 28.6 |
160 | 11.5 | 22.2 | ND |
161 | 0.109 | 0.658 | 0.694 |
162 | 0.0591 | 0.754 | 1.03 |
163 | 0.912 | 2.81 | ND |
164 | 1.0 | 2.03 | ND |
165 | 0.595 | 7.49 | ND |
166 | 0.63 | 10.5 | ND |
167 | 0.627 | 2.25 | >3 |
168 | 0.106 | 0.757 | >3 |
ND = 未测定。
应当理解,前面的详细描述和所附实施例仅仅是说明性的,并且不应视为对本发明的范围的限制,本发明的范围仅由所附权利要求及其等同物来限定。对所公开的实施方案的各种变化和修饰对于本领域技术人员将是显而易见的。可以进行这些变化和修饰(非限制性地包括那些涉及本发明的化学结构、取代基、衍生物、中间体、合成、组合物和/或使用方法的变化和修饰),而不偏离其精神和范围。本文引用的所有出版物、专利和专利申请就各方面而言以引用方式整体并入本文中。
Claims (28)
1.式(I)化合物或其可药用盐
其中
R1是甲基;
R2是氢;
R3是-C(O)NR8R9;
R8和R9是选自下述之一:
(i)R8和R9都是H;
(ii)R8是H和R9是C1-C3亚烷基-C(O)O-C1-C3烷基或OH;和
(iii)R8是C1-C3亚烷基-芳基和R9是C1-C3亚烷基-C(O)-C1-C3烷基;
R10是苯基,其被一个取代基R41取代和任选进一步被1或2个指定为R40和R42的取代基取代;其中R40、R41和R42独立地选自:
NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12,
其中L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;
R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至8元杂环烷基、5至12元杂芳基和芳基,其可被一、二或三个指定为R15、R16和R17的取代基取代,
R15、R16和R17独立地选自:
OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,
其中R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基;
R26是C1-C3亚烷基-C3-C6环烷基;
R20和R22独立地选自H和C1-C6烷基;和
R30和R32独立地选自H和C1-C4烷基。
2.权利要求1的化合物或其可药用盐,其中R8和R9都是H。
3.权利要求2的化合物或其可药用盐,其中R10是苯基,其可被1至3个指定为R40、R41和R42的取代基取代并且独立地选自:
NO2、NR20R22、卤素、C1-C6烷基、C1-C6卤代烷基、-O-C1-C6烷基、-O-C1-C6卤代烷基、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、C2-C3亚烯基-O-C1-C3烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基、-SO2-NH2、-C(O)-NR20R22和-L-R12、
其中L不存在或者是-C1-C3亚烷基-、-C2-C3亚烯基-、-NH-、-NH-C1-C3亚烷基-、-NR26-、-NHS(O)2-、NHS(O)2-C1-C3亚烷基-、-NH-C(O)-C1-C3亚烷基-、-C(O)-、-C(O)-NH-C1-C3亚烷基-和-O-;
R12选自:C1-C6烷基、C1-C6卤代烷基、C3-C10环烷基、3至8元杂环烷基、5至12元杂芳基和芳基,其可被一、二或三个指定为R15、R16和R17的取代基取代,
R15、R16和R17独立地选自:
OH、CN、卤素、C1-C3烷基、C1-C3卤代烷基、-O-C1-C3烷基、-O-C1-C3卤代烷基、-C1-C3亚烷基-OH、-C1-C3亚烷基-C(O)O-C1-C3烷基、-C(O)-C1-C4烷基、-C(O)OC1-C4烷基、-C(O)NH-C1-C3亚烷基-NR30R32、-C(O)NR30R32、-O-C1-C4烷基-NR30N32、-NR30R32、-NHC(O)O-C1-C4烷基、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基、-S(O)2-C1-C3烷基、芳基、-O-芳基、-C1-C3亚烷基-芳基、C3-C6环烷基、杂环烷基、-C1-C3亚烷基-杂环烷基、-C(O)-杂环烷基、5至12元杂芳基和-C(O)NH-C1-C3亚烷基-杂芳基,
其中R15、R16和R17上的所述杂环烷基、杂芳基或芳基可被1至3个独立地选自下述的取代基取代:C1-C3-烷基、C1-C3-卤代烷基、-O-C1-C3-烷基、-O-C1-C3-卤代烷基、卤素、-NH-S(O)2-C1-C3烷基、-NH-S(O)2-C1-C3卤代烷基和-S(O)2-C1-C3烷基。
4.权利要求3的化合物或其可药用盐,其中所述苯基被指定为R41并且具体为:
的一个取代基取代。
5.权利要求2的化合物或其可药用盐,其中R10是苯基,其被一个取代基R41取代和任选进一步被1或2个指定为R40和R42的取代基取代;其中
R41是-L-R12;
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2;和
R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中L不存在和R12是任选被取代的环丙基。
6.权利要求2的化合物或其可药用盐,其中R10是苯基,其被一个取代基R41取代和任选进一步被1或2个指定为R40和R42取代基取代;其中
R41是-L-R12;
L不存在或者是-C2-C3亚烯基、-NH-、-NHS(O)2-、-NH-C(O)-C1-C3亚烷基或O;
R12是C3-C10环烷基、3至8元杂环烷基、5至12元杂芳基或芳基,其中每一个是任选被取代的;或者R12是被选自下述的取代基取代的C1-C6烷基:C3-C6环烷基、3至8元杂环烷基、5至12元杂芳基和芳基;其中C3-C6环烷基、3至8元杂环烷基、5至12元杂芳基和芳基的每一个是任选被取代的;
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NHC(O)-C1-C3烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2;和R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中L不存在和R12是任选被取代的环丙基。
7.权利要求2的化合物或其可药用盐,其中R10是
其中
L是-NH-或O;
R12是苯基、C3-C6环烷基、5-元杂环烷基或6-元杂环烷基;其中每一个是任选被取代的;或者R12是被选自下述取代基取代的C1-C3烷基:苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基;其中所述苯基、C3-C6环烷基、5-元杂环烷基和6-元杂环烷基的每一个是任选被取代的;
m是0或1;
R42是C1-C6烷基、C1-C6卤代烷基、卤素或-L-R12;其中L不存在和R12是任选被取代的环丙基,和
R40是NR20R22、卤素、C1-C3亚烷基-OH、C1-C3亚烷基-C(O)OH、C1-C3亚烷基-C(O)O-C1-C4烷基、-NH-SO2-C1-C3烷基、-NH-SO2-C1-C3卤代烷基或-SO2-NH2。
8.权利要求1的化合物或其可药用盐,其中所述化合物选自:
5-(2-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3-硝基苯基)-1H-吡咯-3-甲酰胺;
5-(3-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[3-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{3-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(4-硝基苯基)-1H-吡咯-3-甲酰胺;
5-(4-氨基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{4-[(甲基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-[4-(乙酰基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(苄基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(四氢呋喃-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-溴噻吩-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(3,4,5-三甲氧基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(四氢呋喃-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3R)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3S)-四氢呋喃-3-基甲基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-(2-{[(4,5-二甲基呋喃-2-基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[3,5-二(三氟甲基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(2,6-二氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氟苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(2-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(3-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(环丙基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[4-(三氟甲基)苄基]氨基}苯基)-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(4-甲基苄基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-氰基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-溴苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3,4-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(2-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3-氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环己基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[4-(二甲基氨基)苄基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(噻吩-2-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
5-{2-[(3,5-二氯苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)吡咯烷-1-甲酸叔丁基酯;
4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)哌啶-1-甲酸叔丁基酯;
2-甲基-5-{2-[(吡咯烷-3-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(哌啶-4-基甲基)氨基]苯基}-1H-吡咯-3-甲酰胺;
4-(2-{[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}乙基)哌啶-1-甲酸叔丁基酯;
[顺式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯;
[反式-4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)环己基]氨基甲酸叔丁基酯;
2-甲基-5-(2-{[2-(哌啶-4-基)乙基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-(2-{[(顺式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(反式-4-氨基环己基)甲基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
[4-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯;
[3-({[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]氨基}甲基)苯基]氨基甲酸叔丁基酯;
5-{2-[(4-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(3-氨基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(4-羟基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-({[5-(羟基甲基)呋喃-2-基]甲基}氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(1H-吲哚-5-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)(噻吩-2-基甲基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基甲基)(4-甲氧基苄基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(环己基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢呋喃-3-基氨基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡咯烷-3-基氨基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(哌啶-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(环丁基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-1-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢-2H-噻喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-2-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(四氢-2H-吡喃-4-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(1-氮杂双环[2.2.2]辛烷-3-基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[三环[3.3.1.13,7]癸烷-2-基氨基]苯基}-1H-吡咯-3-甲酰胺;
5-[2-(环庚基氨基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(1,2,3,4-四氢萘-2-基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-{2-[(2-氟环己基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(苯基乙酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(苯基氨基)苯基]-1H-吡咯-3-甲酰胺;
5-(2-{[(4-氯苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-{2-[(环己基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(苯基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[(吡啶-3-基磺酰基)氨基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(3,3,3-三氟丙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-{2-[(苄基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(2,4-二氟苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-氯苄基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-{[(2,2,2-三氟乙基)磺酰基]氨基}苯基)-1H-吡咯-3-甲酰胺;
5-{2-[(环戊基磺酰基)氨基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-{[(4-羟基苯基)磺酰基]氨基}苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(2-苯氧基苯基)-1H-吡咯-3-甲酰胺;
5-(2,4-二甲基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-氨基-6-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)-β-丙氨酸甲基酯;
N-({5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-2-甲基-1H-吡咯-3-基}羰基)甘氨酸甲基酯;
5-[4-(3,5-二甲基-1,2-噁唑-4-基)苯基]-N-羟基-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(4-甲基哌嗪-1-基)甲基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-(3'-羟基联苯-4-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3',4',5'-三甲氧基联苯-4-基)-1H-吡咯-3-甲酰胺;
5-[4-(呋喃-3-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(吡啶-4-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(1-甲基-1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺;
5-[3'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3'-(吗啉-4-基)联苯-4-基]-1H-吡咯-3-甲酰胺;
5-{3'-[(呋喃-2-基甲基)氨基甲酰基]联苯-4-基}-2-甲基-1H-吡咯-3-甲酰胺;
5-{4-[(1E)-3-甲氧基丙-1-烯-1-基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
5-[4'-(二甲基氨基甲酰基)联苯-4-基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(嘧啶-5-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(甲基磺酰基)氨基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-[4-(1-苄基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[4-(3,5-二甲基-1H-吡唑-4-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[4-(喹啉-6-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{4'-[(4-甲基哌嗪-1-基)羰基]联苯-4-基}-1H-吡咯-3-甲酰胺;
5-(2-溴苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(1H-吲哚-6-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-氨基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-4-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(4-苯氧基苯氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-环戊基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(异喹啉-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-3-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(3-氰基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(喹啉-5-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氯-2-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(1H-吲哚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(吡啶-2-基氧基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{2-[4-(甲基磺酰基)苯氧基]苯基}-1H-吡咯-3-甲酰胺;
3-{2-[2-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯氧基]苯基}丙酸甲基酯;
2-甲基-5-[2-(3-甲基苯氧基)苯基]-1H-吡咯-3-甲酰胺;
5-{2-[4-(1H-咪唑-1-基)苯氧基]苯基}-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(5,6,7,8-四氢萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-甲氧基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2-苄基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(萘-2-基氧基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[2-(萘-1-基氧基)苯基]-1H-吡咯-3-甲酰胺;
5-[2-(4-氟苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(3-氯苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(4-乙基苯氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(2,3-二氢-1H-茚-5-基氧基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(6-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-[2-(5-羟基-1H-苯并咪唑-1-基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;
5-(2,6-二氟苯基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(2-苄基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-(3,4,5-三甲氧基苯基)-1H-吡咯-3-甲酰胺;
5-(联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(3'-甲氧基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(噻吩-3-基)苯基]-1H-吡咯-3-甲酰胺;
5-(2'-乙酰基联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(吡啶-3-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(1H-吡唑-4-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-[3-(1-甲基-1H-吲哚-5-基)苯基]-1H-吡咯-3-甲酰胺;
2-甲基-5-{3-[(E)-2-苯基乙烯基]苯基}-1H-吡咯-3-甲酰胺;
2-甲基-5-{3'-[(4-甲基哌嗪-1-基)甲基]联苯-3-基}-1H-吡咯-3-甲酰胺;
5-(4'-{[2-(二甲基氨基)乙基]氨基甲酰基}联苯-3-基)-2-甲基-1H-吡咯-3-甲酰胺;
5-(5-氨基-2-苯氧基苯基)-2-甲基-1H-吡咯-3-甲酰胺;
2-甲基-5-{5-[(甲基磺酰基)氨基]-2-苯氧基苯基}-1H-吡咯-3-甲酰胺;
[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸乙基酯;
[4-(苄基氧基)-3-(4-氨基甲酰基-5-甲基-1H-吡咯-2-基)苯基]乙酸;
5-[2-(苄基氧基)-5-(2-羟基乙基)苯基]-2-甲基-1H-吡咯-3-甲酰胺;和
5-[2-(2,4-二氟苯氧基)-5-氨磺酰基苯基]-2-甲基-1H-吡咯-3-甲酰胺。
9.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗癌症的药物中的用途。
10.权利要求9的用途,其中所述癌症选自:听觉神经瘤、急性白血病、、基底细胞癌、胆小管癌、膀胱癌、脑癌、乳腺癌、支气管源性癌、宫颈癌、软骨肉瘤、脊索瘤、绒膜癌、慢性白血病、结肠癌、结直肠癌、颅咽管癌、囊腺癌、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、原发性血小板增多、尤因肉瘤、纤维肉瘤、胚细胞睾丸癌、神经胶质瘤、恶性胶质瘤、神经胶质肉瘤、重链病、成血管细胞瘤、肝脏肿瘤、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴管肉瘤、成淋巴细胞白血病、Hodgkin型淋巴瘤和非Hodgkin型淋巴瘤,淋巴癌、髓样癌、成髓细胞瘤、黑素瘤、脑膜瘤、间皮瘤、髓源性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌、少突胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、松果体瘤、真性红细胞增多、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、和维尔姆斯瘤。
11.权利要求10的用途,其中所述急性白血病选自:急性淋巴细胞白血病、急性髓细胞白血病、急性t细胞白血病。
12.权利要求11的用途,其中所述急性髓细胞白血病选自:单核细胞白血病、成髓细胞白血病、腺癌白血病、血管肉瘤白血病、星形细胞瘤白血病、髓细胞单核细胞白血病和原髓细胞白血病。
13.权利要求10的用途,其中所述慢性白血病选自:慢性淋巴细胞白血病、慢性髓细胞白血病、慢性粒性白血病。
14.权利要求10的用途,其中所述乳腺癌是雌激素受体阳性乳腺癌。
15.权利要求10的用途,其中所述淋巴癌选自滤泡性淋巴瘤、弥散性大B细胞淋巴癌、T细胞或B细胞源的淋巴癌。。
16.权利要求10的用途,其中所述骨髓瘤是多发性骨髓瘤。
17.权利要求10的用途,其中所述肺癌选自小细胞肺癌和非小细胞肺癌。
18.权利要求10的用途,其中所述淋巴管肉瘤是淋巴管内皮肉瘤。
19.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗疾病或病症的药物中的用途,其中所述疾病或病症选自:阿狄森氏病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特氏病、大疱性皮肤病、心肌病、心脏肥大、慢性阻塞性肺病、克罗恩病、皮炎、湿疹、巨细胞动脉炎、心脏衰竭、肝炎、垂体炎、炎性肠道疾病、川崎症、狼疮性肾炎、多发性硬化、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、高安氏动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳氏肉芽肿病。
20.权利要求19的用途,其中所述心肌病是心肌炎。
21.权利要求19的用途,其中所述肾炎是肾小球肾炎。
22.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗慢性肾脏疾病或病症的药物中的用途,其中所述疾病或病症选自:糖尿病肾病、高血压肾病、HIV相关性肾病、肾小球肾炎、狼疮性肾炎、IgA肾病、局灶节段性肾小球硬化、微小病变肾病、多囊性肾病和肾小管间质性肾炎。
23.权利要求22的用途,其中所述肾小球肾炎是膜性肾小球肾炎。
24.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗急性肾脏疾病或病症的药物中的用途,其中所述急性肾脏疾病或病症选自:缺血-再灌注引起的肾脏疾病、心脏和大型手术引起的肾脏疾病、经皮冠状动脉介入治疗引起的肾脏疾病、放射造影剂引起的肾脏疾病、脓毒症引起的肾脏疾病、肺炎引起的肾脏疾病以及药物毒性引起的肾脏疾病。
25.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗获得性免疫缺陷综合症(AIDS)的药物中的用途。
26.根据权利要求1的式(I)化合物或其可药用盐在制备用于在需要的患者中治疗疾病或病症的药物中的用途,其中所述疾病或病症选自:肥胖、血脂异常、高胆固醇血症、阿尔茨海默氏病、代谢综合征、脂肪肝、II型糖尿病、胰岛素抗性、糖尿病性视网膜病和糖尿病性神经病变。
27.根据权利要求1的式(I)化合物或其可药用盐在制备用于雄性患者避孕的药物中的用途。
28.药物组合物,其包含可药用载体和治疗有效量的权利要求1的化合物或其可药用盐。
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CA2905426A1 (en) | 2014-10-09 |
US20140275079A1 (en) | 2014-09-18 |
AU2014248647A1 (en) | 2015-10-01 |
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