CN113549058A - 一种哒嗪酮类化合物及其制备和用途 - Google Patents
一种哒嗪酮类化合物及其制备和用途 Download PDFInfo
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- CN113549058A CN113549058A CN202110318824.3A CN202110318824A CN113549058A CN 113549058 A CN113549058 A CN 113549058A CN 202110318824 A CN202110318824 A CN 202110318824A CN 113549058 A CN113549058 A CN 113549058A
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- alkyl
- deuterium
- compound
- cycloalkyl
- radical
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- 238000002360 preparation method Methods 0.000 title abstract description 12
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Abstract
本发明公开一种式(I)的化合物及其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或含它们的药物组合物、制备方法,以及其在制备治疗由甲状腺激素受体介导的相关疾病的药物中的用途,式(I)中各基团与说明书定义一致。
Description
技术领域
本发明属于药物领域,涉及一种哒嗪酮类化合物及其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药以及其药物组合物、制备方法,以及在制备由甲状腺激素受体介导的疾病的药物中的用途。
背景技术
甲状腺激素对于正常生长和发育以及维持代谢平衡是关键的(Paul M.Yen,生理学评论(Physiological review)),81(3)卷:1097-1126页(2001))。甲状腺激素由甲状腺产生并且以下面的两种不同的形式分泌到循环系统中:3,5,3’,5’-四-碘-L-甲状腺原氨酸(T4)和3,5,3’-三-碘-L-甲状腺原氨酸(T3)。尽管T4是由甲状腺分泌的主要形式,但是T3是生理上更活跃的形式。T4通过组织特异性脱碘酶被转化成T3,组织特异性脱碘酶存在于所有组织中,但是主要在肝和肾中。甲状腺激素的生物活性由甲状腺激素受体(TRs)介导(M.A.Lazar,内分泌评论(Endocrine Reviews),14卷:348-399页(1993))。TR属于已知为核受体的超家族。甲状腺激素受体源自两个分开的基因,α和β。这些不同的基因产物通过差别的RNA加工而产生多种形式的它们各自的受体。主要的甲状腺受体同工型是α1、α2、β1和β2。甲状腺激素受体α1、β1和β2结合甲状腺激素。已经显示,甲状腺激素受体亚型在它们对于特殊生理响应的贡献方面可以不同。最近的研究表明,TRβ1在肝中在介导TRH(促甲状腺激素释放激素)和介导甲状腺激素的作用中起重要作用。TRβ2在介导TSH(甲状腺刺激激素)方面起主要作用(Abel等,临床研究杂志(J.Clin.Invest.),104卷:291-300页(1999))。TRβ1在介导心率方面起重要作用(B.Gloss等,内分泌学(Endocrinology),142卷:544-550页(2001);C.Johansson等,美国生理学杂志(Am.J.Physiol.),275卷:R640-R646页(1998))。
甲状腺激素的另一在治疗上的有益效果是降低血清低密度脂蛋白(LDL)(EugeneMorkin等,分子和细胞心脏病学杂志(Journal of MolecularandCellularCardiology),37卷:1137-1146页(2004))。已经发现,甲状腺机能亢进与低的总血清胆固醇有关,这归因于甲状腺激素增加肝LDL受体表达并且刺激胆固醇向胆汁酸的代谢(J.J.Abrams等,脂类研究杂志(J.Lipid Res.),22卷:323-38页(1981))。甲状腺功能减退又与高胆固醇血症有关,并且已知甲状腺激素替代疗法降低了总胆固醇(M.Aviram等,临床生化(Clin.Biochem.),15卷:62-66页(1982);J.J.Abrams等,脂类研究杂志(J.LipidRes.),22卷:323-38页(1981))。
避免甲状腺机能亢进和甲状腺功能减退的不良效果同时保持甲状腺激素的有益效果的甲状腺激素类似物的开发将打开治疗以下疾病患者的新的途径:代谢疾病如肥胖,高脂血症,高胆固醇血症,糖尿病和其它病症和疾病如肝脂肪变性和NASH,动脉粥样硬化,心血管疾病,甲状腺功能减退,甲状腺癌,甲状腺疾病,以及相关病症和疾病。迄今,天然存在的甲状腺激素的治疗用途受到与甲状腺机能亢进、特别是心血管毒性有关的不利副作用的限制。
因此,具有甲状腺激素的有益效果同时又避免不良副作用的新型甲状腺激素模拟物仍然亟需。
发明内容
本发明提供一种新的具有甲状腺激素模拟物,具有活性高,生物利用度高,具有良好的药代动力学特征,不良副作用小。
本发明提供了一种式(I)所示的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,
C1-C2、C2-C3、C3-C4三个化学键不同时为单键;
C1、C2、C3、C4位置上的氢任选被1-3个氘取代;
R1选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;在某些实施方案中,R1选自H、氘、卤素、-CN;在某些实施方案中,R1选自氘、-CN;在某些实施方案中,R1选自氘;在某些实施方案中,R1选自-CN;
R2、R7各自独立地选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C3-8环烷基、3-8元杂环烷基、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c;在某些实施方案中,R2、R7各自独立地选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基;在某些实施方案中,R2、R7各自独立地选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基;在某些实施方案中,R2、R7各自独立地选自H、氘、C1-6烷基、C1-6氘代烷基;在某些实施方案中,R2、R7各自独立地选自H、氘、C1-6烷基;在某些实施方案中,R2、R7各自独立地选自H、氘;在某些实施方案中,R2、R7各自独立地选自H;在某些实施方案中,R2、R7各自独立地选自氘;
R3、R4、R5、R6各自独立地选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;在某些实施方案中,R3、R4、R5、R6各自独立地选自H、氘、卤素、C1-6烷基,所述的烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R3、R4、R5、R6各自独立地选自H、氘、卤素;在某些实施方案中,R3、R6各自独立地选自H、氘,R4、R5各自独立地选自H、氘、卤素;在某些实施方案中,R3、R6各自独立地选自H,R4、R5各自独立地选自卤素;
R1a选自C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代;在某些实施方案中,R1a选自C1-6烷基、C3-8环烷基,所述的烷基、环烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R1a选自C1-6烷基,所述的烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R1a选自C1-6烷基,所述的烷基任选地被一个或多个氘取代;
R1b、R1c各自独立地选自H、氘、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代;在某些实施方案中,R1b、R1c各自独立地选自H、氘、C1-6烷基、C3-8环烷基、3-8元杂环烷基,所述的烷基、环烷基、杂环烷基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基取代;在某些实施方案中,R1b、R1c各自独立地选自H、氘、C1-6烷基、C3-8环烷基、3-8元杂环烷基,所述的烷基、环烷基、杂环烷基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基取代;在某些实施方案中,R1b、R1c各自独立地选自H、氘、C1-6烷基、C3-8环烷基、3-8元杂环烷基,所述的烷基、环烷基、杂环烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R1b、R1c各自独立地选自H、氘、C1-6烷基,所述的烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R1b、R1c各自独立地选自H、C1-6烷基,所述的烷基任选地被一个或多个氘、卤素取代;在某些实施方案中,R1b、R1c各自独立地选自H、C1-6烷基,所述的烷基任选地被一个或多个卤素取代。
本发明方案一,本发明提供了一种式(I)所示的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,
C1-C2、C2-C3、C3-C4三个化学键不同时为单键;
C1、C2、C3、C4位置上的氢任选被1-3个氘取代;
R1选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;
R2、R7各自独立地选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C3-8环烷基、3-8元杂环烷基、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c;
R3、R4、R5、R6各自独立地选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;
R1a选自C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代;
R1b、R1c各自独立地选自H、氘、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代。
本发明方案二涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R1选自H、氘或-CN;
其他基团定义与方案一一致。
本发明方案三涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R1选自-CN;
其他基团定义与方案一一致。
本发明方案四涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R2选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基;
其他基团定义与方案一一致。
本发明方案五涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R2选自H、氘;
其他基团定义与方案一一致。
本发明方案六涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R2选自H;
其他基团定义与方案一一致。
本发明方案七涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R7选自H、氘、C1-6烷基;
其他基团定义与方案一一致。
本发明方案八涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R7选自H、氘;
其他基团定义与方案一一致。
本发明方案九涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R7选自H;
其他基团定义与方案一一致。
本发明方案十涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R1选自H、氘或-CN;
R2选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基;
R7选自H、氘、C1-6烷基;
其他基团定义与方案一一致。
本发明方案十一涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R3、R6各自独立地选自H、氘、卤素或-CN;
其他基团定义与方案一一致。
本发明方案十二涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R3、R6各自独立地选自H、氘;
其他基团定义与方案一一致。
本发明方案十三涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R4、R5各自独立地选自H、氘、卤素、-CN、C1-6卤代烷基、C1-6氘代烷基或羟基取代的C1-6烷基;
其他基团定义与方案一一致。
本发明方案十四涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R4、R5各自独立地选自H、氘、卤素;
其他基团定义与方案一一致。
本发明方案十五涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R4、R5各自独立地选自卤素;
其他基团定义与方案一一致。
本发明方案十六涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R3、R6各自独立地选自H、氘、卤素或-CN;
R4、R5各自独立地选自H、氘、卤素、-CN、C1-6卤代烷基、C1-6氘代烷基或羟基取代的C1-6烷基;
其他基团定义与方案一一致。
本发明方案十七涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R3、R6各自独立地选自H、氘;
R4、R5各自独立地选自卤素;
其他基团定义与方案一一致。
本发明方案十八涉及式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,具有式(II)所示的结构,
本发明方案十九涉及式(II)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其化合物选自
本发明还涉及一种药物组合物,其特征在于,含有本发明前面任意一项所述的式(I)或(II)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,以及药学上可接受的辅料和/或载体。
本发明还涉及本发明前面任意一项所述的式(I)或(II)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或者所述的组合物在制备治疗由甲状腺激素受体介导的疾病的药物中的用途。所述的甲状腺激素受体介导的疾病为肥胖、高脂血症、高胆固醇血症、糖尿病、NASH(非酒精性脂肪性肝)、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌,特别是高胆固醇血症、NASH。
本发明还涉及一种治疗由甲状腺激素受体介导的疾病的方法,所述方法包括给药本发明任意一项所述的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或者所述的组合物。其中,所述的甲状腺激素受体介导的疾病为肥胖、高脂血症、高胆固醇血症、糖尿病、NASH、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌,特别是高胆固醇血症、NASH。
合成路线
专利文献WO2019240938A1中介绍了一类甲状腺激素受体化合物的制备方法,本领域技术人员可以结合该文献以及已知的有机合成技术制备本发明的化合物,其起始原料为市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的,供应商包括:泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
本领域的参考书和专著,详细介绍了可用于制备本文所述化合物的反应物的合成,或提供了描述该制备方法的文章以供参考。这些参考书和专著包括:“SyntheticOrganic Chemistry”,John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,“OrganicFunctional Group Preparations,”2nd Ed.,Academic Press,New York,1983;H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,NewYork,1992;J.March,“Advanced Organic Chemistry:Reactions,Mechanisms andStructure”,4th Ed.,Wiley-Interscience,New York,1992;Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised andEnlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5;Hoffman,R.V.“OrganicChemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.“Comprehensive Organic Transformations:A Guide toFunctional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4thEdition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModernCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2ndEdition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial OrganicChemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55 volumes;and“Chemistry of FunctionalGroups”John Wiley&Sons,in 73 volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引,可以选择性地识别特定和类似的反应物,这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备,其中许多标准化学供应工厂(例如,上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,VerlagHelvetica Chimica Acta,Zurich,2002.
术语
在本发明未特殊说明的情况下,本发明的术语具有以下含义:
“卤素”在本文中是指F、Cl、Br、I、或者它们的同位素。
“卤代”或“卤素取代”是指被一个以上选自F、Cl、Br、I、或者它们的同位素取代,卤素取代基数量的上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代。
“烷基”是指一价的直链或支链饱和脂肪族烃基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;所述的烷基可以进一步被任意取代基取代。
“氘代”是指烷基、环烷基、亚烷基、芳基、杂芳基、烯基、炔基等基团上的氢原子被至少一个同位素氘取代的情形,氘代的数量上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,氘代数量为1至该上限之间的任意整数,优选1-20个氘原子取代,更优选为1-10个氘原子取代,更优选为1-6个氘原子取代,进一步优选为1-3个氘原子取代。
“环烷基”是指一价饱和的、不饱和的非芳香环的碳环烃基,可以是单环、双环、螺环、桥环、并环,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、 等。所述的环烷基可以任选进一步被任意取代基所取代。
“杂环烷基”是指取代或未取代、饱和或不饱和的、含有至少一个杂原子的非芳香环,未特殊限定时,包含1至3个选自N、O、P、S、Si的杂原子及各种氧化形式,可以是单环、双环、桥环、并环、螺环,未特殊限定时,为3至12元杂环,更优选为4-12元杂环,更优选为4-10元杂环。杂环基的环中选择性取代的N、S、P可被氧化成各种氧化态。非限制性实施例包括杂环丙基、氧杂环丙基、硫杂环丙基、氮杂环丁基、氮杂环戊基、哌啶、氧杂环丁基、氧杂环戊基、氧杂环己基、硫杂环丁基、吡咯烷基、吡唑烷基、四氢呋喃基、四氢噻吩基、氮杂金刚烷基和氧杂螺[3.3]庚烷基、 等。所述的杂环烷基可以任选进一步被任意取代基所取代。
“芳基”是指取代的或未取代的、5至15元具有芳香性的碳环,包括单环芳香基和稠环芳香基。优选5至10元芳香环,进一步优选5至8元芳香环,其非限制性实例包括苯基、萘基、蒽基和菲基等。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
“杂芳基”是指取代或未取代的、5至15元的具有芳香性的环,且含有1至5个选自N、O、S、P、Si杂原子及其杂原子各种氧化形式,优选5至10元杂芳香环,进一步优选5至8元。杂芳基的非限制性实施例包括但不限于呋喃基、恶唑基、呋喃基、噻吩基、N-烷基吡咯基、吡嗪基、哒嗪基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含所述的杂芳基可以任选进一步被任意取代基所取代。
“炔基”是指直链或支链的、含有一个以上碳碳三键的一价不饱和烃基,除非特殊说明,炔基含有2-6个碳原子,优选含有2-4个碳原子,非限制性地的实施例为乙炔基、丙炔基、炔丙基等。
“烯基”是指直链或支链的、含有一个以上碳碳双键的一价不饱和烃基,除非特殊说明,炔基含有2-6个碳原子,优选含有2-4个碳原子,非限制性地的实施例为乙烯基、丙烯基、烯丙基、2-丁烯基、1-丁烯基等。
“烷氧基”或“烷基氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基等。
“卤代烷氧基”是指-O-卤代烷基。非限制性实施例包括一氟甲氧基、二氟甲氧基、三氟甲氧基、二氟乙基氧基等。
“烷基氨基”或“烷氨基”是指被单个或两个烷基取代的氨基,也写作-N-(烷基)2或-NH-烷基,后者也写作单烷基氨基。非限制实施例包括二甲氨基、单甲基氨基、二乙氨基、单乙氨基等。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指可以但不必须被F取代,说明包括被F取代的情形和不被F取代的情形。
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐或共晶,与其他组成成分的混合物,其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是:不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性,并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是:其本身并非治疗剂,用作稀释剂、辅料、粘合剂和/或媒介物,用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的,药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠);(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液(Ringer’s solution);(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;及(22)其他用于药物制剂中的无毒相容物质。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时,则为水合物。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的,按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明,但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
测试方法
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
2-(3,5-二氯-4-((7-亚甲基-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈
2-(3,5-dichloro-4-((7-methylene-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
第一步:2-(吡咯烷基-1-基)环戊-2-烯甲酸甲酯(1-B)
methyl 2-(pyrrolidin-1-yl)cyclopent-2-enecarboxylate
将2-甲氧羰基环戊酮(1-A)(45.0g,316.57mmol)溶于无水甲苯(280mL)中,加入四氢吡咯(20.26g,284.91mmol)和对甲苯磺酸(5.45g,31.66mmol),升温至130℃,回流分水1小时后,无需反应监控,浓缩干,得到红色油状物1-B(56g,粗品),直接下一步。
第二步:1,4-二氯-6,7-二氢-5H-环戊[d]哒嗪-5-羧酸甲酯(1-C)
methyl 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine-5-carboxylate
将二氯均四嗪(15.0g,99.37mmol)溶于二氯甲烷(300mL)中,-78℃下滴加上一步产品2-(吡咯烷基-1-基)环戊-2-烯甲酸甲酯(1-B)(56g,粗品),反应10min后,控制温度30℃以下,浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=10:1~4:1),得到黄色油状物1-C(9.0g,产率36.7%)。
LCMS m/z=247.1[M+1]
第三步:1-(4-氨基-2,6-二氯苯氧基)-4-氯-6,7-二氢-5H-环戊[d]哒嗪-5-羧酸甲酯(1-D)
Methyl 1-(4-amino-2,6-dichlorophenoxy)-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazine-5-carboxylate
将1,4-二氯-6,7-二氢-5H-环戊[d]哒嗪-5-羧酸酯(1-C)(4.0g,16.19mmol)溶于二甲亚峰(50mL)中,依次加入碳酸钾(3.36g,24.29mmol),4-胺基-2,6-二氯苯酚(2.88g,16.19mmol),碘化亚酮(1.54g,8.1mmol),氮气保护下,90℃反应1小时后,加入乙酸乙酯(90mL)和水(80mL),过滤,分液,水相用乙酸乙酯(50mL*3)萃取,合并有机相,水(80m L)洗,饱和氯化钠(80mL)洗,无水硫酸钠干燥,浓缩干,加入二氯甲烷(30mL)打浆,过滤,得到棕红色固体1-D(1.1g,产率17.48%)
LCMS m/z=388.0[M+1]
第四步:4-(4-乙酰氨基-2,6-二氯苯氧基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-7-羧酸甲酯(1-E)
Methyl 4-(4-acetamido-2,6-dichlorophenoxy)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazine-7-carboxylate
将1-(4-氨基-2,6-二氯苯氧基)-4-氯-6,7-二氢-5H-环戊[d]哒嗪-5-羧酸甲酯(1-D)(1.1g,2.83mmol)溶于乙酸(25mL)中,加入乙酸钠(0.81g,9.91mmol),100℃反应1小时后,浓缩除去乙酸,加入水(50mL),乙酸乙酯(50mL*3)萃取,水(30mL)洗,饱和氯化钠(30mL)洗,无水硫酸钠干燥,浓缩干,加入二氯甲烷(30mL)打浆,过滤,得到褐色固体1-E(0.74g,产率63.43%)。
LCMS m/z=412.0[M+1]
第五步:N-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)乙酰胺(1-F)
N-(3,5-dichloro-4-((7-(hydroxymethyl)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)acetamide
将4-(4-乙酰氨基-2,6-二氯苯氧基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-7-羧酸甲酯(1-E)(0.7g,1.70mmol)溶于四氢呋喃(15mL)中,0℃下加入硼氢化锂的四氢呋喃溶液(2.6mL,4mol/L),反应2小时,滴加甲醇淬灭,加入水(50mL),乙酸乙酯(30mL*3)萃取,水(30mL)洗,饱和氯化钠(30mL)洗,无水硫酸钠干燥,浓缩干,得到棕色固体1-F(0.54g,产率82.68%)。
LCMS m/z=386.0[M+1]
第六步:4-(4-氨基-2,6-二氯苯氧基)-7-(羟甲基)-2,5,6,7-四氢-1H-环戊二烯并[d]哒嗪-1-酮(1-G)
4-(4-amino-2,6-dichlorophenoxy)-7-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one
将N-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)乙酰胺(1-F)(0.5g,1.30mmol)溶于甲醇(8mL)中,加入氢氧化钠水溶液(8mL,2mol/L),80℃反应16小时,加入水(50mL),乙酸乙酯(30mL*3)萃取,水(30mL)洗,饱和氯化钠(30mL)洗,无水硫酸钠干燥,浓缩干,得到棕色固体1-G(0.42g,产率94.42%)。
LCMS m/z=342.1[M+1]
第七步:(E)-乙基(2-氰基-2-(2-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)肼基)乙酰基氨基甲酸酯(1-H)
(E)-ethyl(2-cyano-2-(2-(3,5-dichloro-4-((7-(hydroxymethyl)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)hydrazono)acetylcarbamate
将4-(4-氨基-2,6-二氯苯氧基)-7-(羟甲基)-2,5,6,7-四氢-1H-环戊二烯并[d]哒嗪-1-酮(1-G)(0.45g,1.32mmol)加入到单口瓶(S1)中,然后加入水(10mL),浓盐酸(8mL),0℃下加入亚硝酸钠(0.12g,1.72mmol),搅拌30min;在单口瓶(S2)中加入N-氰基乙酰尿烷(0.23g,1.45mmol),水(15mL),吡啶(8mL),0℃下,将单口瓶S1中的溶液滴入第二个单口瓶S2中,搅拌30min,加水(30mL),EA(20mL*3)萃取,饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到橙红色固体1-H(0.67g,粗品)。
LCMS m/z=509.0[M+1]
第八步:2-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(1-I)
2-(3,5-dichloro-4-((7-(hydroxymethyl)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
将(E)-乙基(2-氰基-2-(2-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊][d]哒嗪-4-基)氧基)苯基)肼基)乙酰基氨基甲酸酯(1-H)(0.25g,0.5mmol)溶于乙酸(10mL)中,加入乙酸钠(0.21g,2.5mmol),120℃反应1.5小时,浓缩干,残留物用液相制备柱分离提纯(液相制备条件:制备柱:Sunfire C18 5μm,19*250mm;流动相:乙腈(A),含0.1%三氟乙酸的去离子水(B);梯度洗脱,A含量=20%~75%,洗脱时间15min,流速15mL/min;保留时间14min),得到白色固体1-I(0.15g,产率64.76%)。
LCMS m/z=463.0[M+1]
第九步:(4-(2,6-二氯-4-(6-氰基-3,5-二氧代-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-7-基)甲磺酸甲酯(1-J)
(4-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-7-yl)methyl methanesulfonate
将2-(3,5-二氯-4-((7-(羟甲基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(1-I)(0.14g,0.3mmol)溶于四氢呋喃(10mL)中,加入三乙胺(0.09g,0.9mmol),DMAP(0.02g,0.15mmol),甲基磺酰氯(0.07g,0.6mmol),室温反应1小时,加水(30mL),EA(20mL*3)萃取,饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到白色固体1-J(0.12g,产率73.89%)。
LCMS m/z=543.1[M+1]
第十步:2-(3,5-二氯-4-((7-亚甲基-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-腈(1)
2-(3,5-dichloro-4-((7-methylene-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
将(4-(2,6-二氯-4-(6-氰基-3,5-二氧代-4,5-二氢-1,2,4-三嗪-2(3H)-基)苯氧基)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-7-基)甲磺酸甲酯(1-J)(0.12g,0.22mmol)溶于N-甲基吡咯烷酮(10mL)中,加入无水乙酸甲(0.11g,1.1mmol),130℃反应1小时,加水(30mL),EA(20mL*3)萃取,饱和氯化钠洗,无水硫酸钠干燥,浓缩,残留物用液相制备柱分离提纯(液相制备条件:制备柱:Sunfire C18 5μm,19*250mm;流动相:乙腈(A),含0.1%三氟乙酸的去离子水(B);梯度洗脱,A含量=25%~85%,洗脱时间20min,流速15mL/min;保留时间18min),得到化合物1(0.02g,产率20.42%)。
LCMS m/z=443.0[M+1]
1H NMR(400MHz,CDCl3)δ13.26(s,1H),12.31(s,1H),7.79(s,2H),6.24(s,1H),5.40(s,4H),3.07-3.03(m,2H),2.92-2.84(m,2H).
生物测试
1、THR共激活剂招募测定
化合物与THRβ或THR a受体的结合导致配体结合域中螺旋12周围的构象变化,从而对共激活肽产生更高的亲和力。用LanthaScreenTM TR-FRET-TR共激活试剂盒(ThermoFisher)进行共激活子招募试验(coactivator recruitment assay)。在TR-FRET共调节缓冲液C中,使用液体分配器(Tecan D300e)以最终试验浓度的2倍制备甲状腺激素T3(最高剂量500nm)的10:1~5稀释系列和试验化合物(最高剂量6250nm)的9:1~4稀释系列。将THRβ-FBD(配体结合域)或THRα-FBD以2.5nM的最终浓度添加到试验化合物中,然后添加荧光素-共激活肽和铽结合抗GST抗体的混合物。将稀释的试验化合物与相同体积的其他试剂(10μL:10μL)混合。在室温下孵育2小时后,使用Envison读板仪(PerkinElmer)在520nm和495nm波长下读取。计算了520:495的TR-FRET比值,并利用该比值从受试化合物的剂量-反应曲线确定了EC50。实验结果见表1。
表1 本发明化合物对THRβ或THR a的激动活性
化合物编号 | THRβEC50(μM) | THR a EC50(μM) |
化合物1 | >10 | 10.27 |
2.大鼠药代动力学测试
实验目的:通过单剂量静脉和灌胃给予受试物于SD大鼠,测定大鼠血浆中受试物的浓度,评价受试物在大鼠体内药代特征和生物利用度。
实验对象:本发明实施例化合物1。
试验动物:雄性SD大鼠,220g左右,6~8周龄,6只/化合物。购于成都达硕实验动物有限公司。
试验方法:试验当天,6只SD大鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。按照表2给药。
表2 给药信息
*剂量以游离碱计。
取样
于给药前及给药后异氟烷麻醉经眼眶取血0.1ml,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。
G1组采集血浆时间点:0,5,15,30min,1,2,4,6,8,24h。
G2组采集血浆时间点:0,15,30min,1,2,4,6,8,24h。
分析检测前,所有样品存于-80℃。
样品前处理
取30μL血浆样品、标曲和质控样品,加入200μL的含内标乙腈溶液,涡旋混匀之后,4℃,12000rpm离心10min。取170μL上清于96孔板中,LC-MS/MS分析,进样量为6μL。
主要药代动力学参数用WinNonlin 8.0软件非房室模型分析。实验结果如表3所示。
表3 化合物1大鼠药代动力学
结论:本发明化合物具有较好的生物利用度,具有良好的药代动力学特征。
Claims (10)
1.一种式(I)所示的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,
C1-C2、C2-C3、C3-C4三个化学键不同时为单键;
C1、C2、C3、C4位置上的氢任选被1-3个氘取代;
R1选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;
R2、R7各自独立地选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基、氨基取代的C1-6烷基、C3-8环烷基、3-8元杂环烷基、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c;
R3、R4、R5、R6各自独立地选自H、氘、卤素、-CN、-OH、-NO2、-OR1a、-NR1bR1c、-SR1b、-S(O)R1a、-S(O)2R1a、-S(O)2NR1bR1c、-NHS(O)2R1a、-C(O)R1a、-OC(O)R1a、-C(O)OR1b、-C(O)NR1bR1c、-NH1cC(O)R1a、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、-OR1a、-NR1bR1c、-C(O)R1a、-C(O)OR1b、-C(O)NR1bR1c或C1-6卤代烷基取代;
R1a选自C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代;
R1b、R1c各自独立地选自H、氘、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环烷基、C5-6芳基或5-6元杂芳基,所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基任选地被一个或多个氘、卤素、-CN、-OH、氧代、氨基、-NHCH3、C1-6烷氧基、C1-6烷基、-C(O)CH3、-C(O)OCH3、-C(O)NH2或C1-6卤代烷基取代。
2.根据权利要求1所述的式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R1选自H、氘或-CN;
R2选自H、氘、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、羟基取代的C1-6烷基;
R7选自H、氘、C1-6烷基。
3.根据权利要求1所述的式(I)化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,其中,
R3、R6各自独立地选自H、氘、卤素或-CN;
R4、R5各自独立地选自H、氘、卤素、-CN、C1-6卤代烷基、C1-6氘代烷基或羟基取代的C1-6烷基。
6.一种药物组合物,其特征在于,含有权利要求1-5任意一项所述的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,以及药学上可接受的辅料和/或载体。
7.权利要求1-5任意一项所述的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或者权利要求6所述的组合物在制备治疗由甲状腺激素受体介导的疾病的药物中的用途。
8.根据权利要求7所述的用途,所述甲状腺激素受体介导的疾病为肥胖、高脂血症、高胆固醇血症、糖尿病、NASH、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌。
9.一种治疗由甲状腺激素受体介导的疾病的方法,所述方法包括给药权利要求1-5任意一项所述的化合物,其立体异构体、氘代化合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药,或者权利要求6所述的组合物。
10.根据权利要求9所述的方法,其中,甲状腺激素受体介导的疾病为肥胖、高脂血症、高胆固醇血症、糖尿病、NASH、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌。
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WO2022099060A3 (en) * | 2020-11-06 | 2022-06-16 | Aligos Therapeutics, Inc. | Bicyclic pyridazinones as thyroid hormone receptor beta (tr-beta) agonists |
WO2022127699A1 (zh) * | 2020-12-15 | 2022-06-23 | 中国科学院上海药物研究所 | 甲状腺素受体β选择性激动剂化合物、其药物组合物和用途 |
WO2023147779A1 (zh) * | 2022-02-07 | 2023-08-10 | 四川海思科制药有限公司 | 一种哒嗪酮衍生物制备方法及其中间体 |
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WO2022099060A3 (en) * | 2020-11-06 | 2022-06-16 | Aligos Therapeutics, Inc. | Bicyclic pyridazinones as thyroid hormone receptor beta (tr-beta) agonists |
US11858913B2 (en) | 2020-11-06 | 2024-01-02 | Aligos Therapeutics, Inc. | Bicyclic pyridazinones and methods of use thereof |
WO2022127699A1 (zh) * | 2020-12-15 | 2022-06-23 | 中国科学院上海药物研究所 | 甲状腺素受体β选择性激动剂化合物、其药物组合物和用途 |
WO2023147779A1 (zh) * | 2022-02-07 | 2023-08-10 | 四川海思科制药有限公司 | 一种哒嗪酮衍生物制备方法及其中间体 |
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