[发明专利]新噻吩－吡啶和噻吩－嘧啶衍生物及其作为mGluR2受体的正性别构调节剂的用途

摘要

本发明涉及新化合物，具体是根据通式(I)的新噻吩－吡啶和噻吩－嘧啶衍生物，其中所有的基团均在申请文件中限定。根据本发明的化合物是代谢型受体亚型2(“mGluR2”)的正性别构调节剂，用于治疗或预防与涉及代谢型受体mGluR2亚型的谷氨酸功能功能障碍和疾病有关的神经学和精神病学病症。具体而言，这些疾病是选自焦虑症、精神分裂症、偏头痛、抑郁症和癫痫症的中枢神经系统病症。本发明同时也涉及药物组合物、制备这些化合物和组合物的方法以及这些化合物用于预防和治疗涉及mGluR2的疾病的用途。

主权项

1.一种通式(I)的化合物其药学上可接受的酸或碱加成盐，其立体化学异构体形式和其N-氧化物形式，其中：Y选自-N-和-C(R²)-；X选自-S-、-S(O)-、-S(O)₂-、-O-和-N(R³)-；R¹、R²和R³各自独立地选自氢、卤素、-CN、-OH、-NO₂、-CF₃、-NH₂、-SH、-C(＝NR⁴)NR⁵R⁶、-C(＝O)R⁴、-C(＝NR⁴)R⁵、-C(＝O)OR⁴、-C(＝O)NR⁴R⁵、-SR⁴、-S(O)R⁴、-S(O)₂R⁴、-NR⁴R⁵、-NR⁴C(＝O)R⁵、-NR⁴C(＝NR⁵)R⁶、-NR⁴C(＝NR⁵)NR⁶R⁷、-NR⁴C(＝O)OR⁵、-NR⁴C(＝O)NR⁵R⁶、-NR⁴S(O)₂R⁵、-S(O)₂NR⁴R⁵、-C(＝S)NR⁴R⁵、-OC(＝O)R⁴、-OC(＝O)NR⁴R⁵、-OR⁴、选自-(C₁-C₆)烷基、-(C₁-C₆)卤烷基、-(C₂-C₆)炔基、-(C₂-C₆)烯基、-(C₃-C₇)环烷基、-(C₃-C₈)环烯基、-(C₁-C₆)氰烷基、-(C₁-C₆)烷芳基、-(C₁-C₆)烷基杂芳基、芳基和杂芳基的任意取代的基团、以及描述为-V₁-T₁-M₁的基团；Z₁、Z₂、Z₃和Z₄各自独立地选自共价键、C、S、N和O，前提是形成5元或6元杂芳基环或芳基环，其可被1到4个Aⁿ基团任意取代；Aⁿ基团各自独立地选自氢、卤素、-CN、-OH、-NO₂、-CF₃、-SH、-NH₂、选自-(C₁-C₆)烷基、-(C₁-C₆)卤烷基、-(C₂-C₆)炔基、-(C₂-C₆)烯基、-(C₃-C₇)环烷基、-(C₁-C₆)氰烷基、-O-(C₁-C₆)烷基、-O-(C₁-C₆)卤烷基，-O-(C₁-C₆)氰烷基，-O-(C₃-C₆)炔基、-O-(C₃-C₇)环烷基、-O-(C₂-C₆)烯基、-O-(C₂-C₆)烷基-OR⁸、-O-(C₁-C₆)烷基-杂芳基、-O-(C₀-C₆)烷芳基、-(C₀-C₆)烷基-OR⁸、-(C₃-C₇)环烷基-(C₁-C₆)烷基、-O-(C₃-C₇)环烷基-(C₁-C₆)烷基、-O-杂芳基、杂芳基、-(C₁-C₆)烷基-杂芳基、芳基、-O-芳基、-(C₁-C₆)烷芳基、-(C₁-C₆)卤烷基-OR⁸、-(C₃-C₆)炔基-OR⁸、-(C₃-C₆)烯基-OR⁸、-(C₀-C₆)烷基-SR⁸、-O-(C₂-C₆)烷基-SR⁸、-(C₁-C₆)烷基-S(＝O)-R⁸、-O-(C₁-C₆)烷基-S(＝O)-R⁸、-(C₀-C₆)烷基-S(＝O)₂-R⁸、-O-(C₁-C₆)烷基-S(＝O)₂-R⁸、-(C₀-C₆)烷基-NR⁸R⁹、-O-(C₂-C₆)烷基-NR⁸R⁹、-(C₀-C₆)烷基-S(＝O)₂NR⁸R⁹、-(C₀-C₆)烷基-NR⁸-S(＝O)₂R⁹、-O-(C₁-C₆)烷基-S(＝O)₂NR⁸R⁹、-O-(C₁-C₆)烷基-NR⁸-S(＝O)₂R⁹、-(C₀-C₆)烷基-C(＝O)-NR⁸R⁹、-(C₀-C₆)烷基-NR⁸C(＝O)-R⁹、-O-(C₁-C₆)烷基-C(＝O)-NR⁸R⁹、-O-(C₁-C₆)烷基-NR⁸C(＝O)-R⁹、-(C₀-C₆)烷基-OC(＝O)-R⁸、-(C₀-C₆)烷基-C(＝O)-OR⁸、-O-(C₁-C₆)烷基-OC(＝O)-R⁸、-O-(C₁-C₆)烷基-C(＝O)-OR⁸、-(C₀-C₆)烷基-C(＝O)-R⁸、-O-(C₁-C₆)烷基-C(＝O)-R⁸、-(C₀-C₆)烷基-NR⁸-C(＝O)-OR⁹、-(C₀-C₆)烷基-O-C(＝O)-NR⁸R⁹、-(C₀-C₆)烷基-NR⁸-C(＝NR⁹)-NR¹⁰R¹¹、-(C₀-C₆)烷基-NR⁸-C(＝O)-NR⁹R¹⁰、-(C₀-C₆)烷基-NR⁸-C(＝S)-NR⁹R¹⁰的任意取代的基团和-V₂-T₂-M₂基团；n是从1到4的整数；T₁、V₁、T₂和V₂各自独立地选自共价键、-O-、-C(＝O)-、-C(＝O)O-、-C(＝O)NR¹²-、-S-、-S(O)-、-S(O)₂-、-S(O)₂NR¹²-、-NR¹²-、-NR¹²C(＝O)-、-NR¹²C(＝O)NR¹³-、-NR¹²S(O)₂-、-NR¹²C(＝S)NR¹³-、-OC(＝O)-、-OC(＝O)NR¹²、-NR¹²C(＝O)O-，和选自-(C₁-C₆)烷基-、-(C₂-C₆)炔基-、-(C₂-C₆)烯基-、-(C₃-C₇)环烷基-、-(C₃-C₈)环烯基-、-(C₁-C₆)卤烷基-、-(C₁-C₆)氰烷基-、-(C₀-C₆)烷基-O-(C₁-C₆)烷基-、-(C₀-C₆)烷基-O-(C₂-C₆)炔基-、-(C₀-C₆)烷基-O-(C₂-C₆)烯基-、-(C₀-C₆)烷基-O-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-O-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-C(＝O)-(C₁-C₆)烷基-、-(C₀-C₆)烷基-C(＝O)-(C₂-C₆)炔基-、-(C₀-C₆)烷基-C(＝O)-(C₂-C₆)烯基-、-(C₀-C₆)烷基-C(＝O)-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-C(＝O)-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-C(＝O)O-(C₁-C₆)烷基-、-(C₀-C₆)烷基-C(＝O)O-(C₂-C₆)炔基-、-(C₀-C₆)烷基-C(＝O)O-(C₂-C₆)烯基-、-(C₀-C₆)烷基-C(＝O)O-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-C(＝O)O-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-C(＝O)NR¹²-(C₁-C₆)烷基-、-(C₀-C₆)烷基-C(＝O)NR¹²-(C₂-C₆)炔基-、-(C₀-C₆)烷基-C(＝O)NR¹²-(C₂-C₆)烯基-、-(C₀-C₆)烷基-C(＝O)NR¹²-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-C(＝O)NR¹²-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-S-(C₁-C₆)烷基-、-(C₀-C₆)烷基-S-(C₂-C₆)炔基-、-(C₀-C₆)烷基-S-(C₂-C₆)烯基-、-(C₀-C₆)烷基-S-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-S-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-S(O)-(C₁-C₆)烷基-、-(C₀-C₆)烷基-O-(C₂-C₆)炔基-、-(C₀-C₆)烷基-S(O)-(C₂-C₆)烯基-、-(C₀-C₆)烷基-S(O)-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-S(O)-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-S(O)₂-(C₁-C₆)烷基-、-(C₀-C₆)烷基-S(O)₂-(C₂-C₆)炔基-、-(C₀-C₆)烷基-S(O)₂-(C₂-C₆)烯基-、-(C₀-C₆)烷基-S(O)₂-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-S(O)₂-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-S(O)₂NR¹²-(C₁-C₆)烷基-、-(C₀-C₆)烷基-S(O)₂NR¹²-(C₂-C₆)炔基-、-(C₀-C₆)烷基-S(O)₂NR¹²-(C₂-C₆)烯基-、-(C₀-C₆)烷基-S(O)₂NR¹²-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-S(O)₂NR¹²-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝O)-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝O)-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)NR¹³-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)NR¹³-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝O)NR¹³-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝O)NR¹³-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)NR¹³-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²S(O)₂-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²S(O)₂-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²S(O)₂-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²S(O)₂-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²S(O)₂-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²C(＝S)NR¹³-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝S)NR¹³-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝S)NR¹³-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝S)NR¹³-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝S)NR¹³-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-OC(＝O)-(C₁-C₆)烷基-、-(C₀-C₆)烷基-OC(＝O)-(C₂-C₆)炔基-、-(C₀-C₆)烷基-OC(＝O)-(C₂-C₆)烯基-、-(C₀-C₆)烷基-OC(＝O)-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-OC(＝O)-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-OC(＝O)NR¹²-(C₁-C₆)烷基-、-(C₀-C₆)烷基-OC(＝O)NR¹²-(C₂-C₆)炔基-、-(C₀-C₆)烷基-OC(＝O)NR¹²-(C₂-C₆)烯基-、-(C₀-C₆)烷基-OC(＝O)NR¹²-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-OC(＝O)NR¹²-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)O-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)O-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝O)O-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝O)O-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝O)O-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)NR¹⁴-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)NR¹⁴-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)NR¹⁴-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)NR¹⁴-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)NR¹⁴-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)-(C₁-C₆)烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)-(C₂-C₆)炔基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)-(C₂-C₆)烯基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)-(C₃-C₇)环烷基-、-(C₀-C₆)烷基-NR¹²C(＝NR¹³)-(C₄-C₁₀)烷基环烷基-、-(C₀-C₆)烷基-C(＝NR¹²)NR¹³-(C₁-C₆)烷基-、-(C₀-C₆)烷基-C(＝NR¹²)NR¹³-(C₂-C₆)炔基-、-(C₀-C₆)烷基-C(＝NR¹²)NR¹³-(C₂-C₆)烯基-、-(C₀-C₆)烷基-C(＝NR¹²)NR¹³-(C₃-C₇)环烷基-和-(C₀-C₆)烷基-C(＝NR¹²)NR¹³-(C₄-C₁₀)烷基环烷基；M₁和M₂各自独立地选自氢、-CN、-OH、-NO₂、-CF₃、-NH₂、-SH、-C(＝O)R¹⁵、-C(＝NR¹⁵)R¹⁶、-C(＝O)OR¹⁵、-C(＝O)NR¹⁵R¹⁶、-SR¹⁵、-S(O)R¹⁵、-S(O)₂R¹⁵、-NR¹⁵R¹⁶、-NR¹⁵C(＝O)R¹⁶、-NR¹⁵C(＝NR¹⁶)R¹⁷、-NR¹⁵C(＝NR¹⁶)NR¹⁷R¹⁸、-NR¹⁵C(＝O)OR¹⁶、-NR¹⁵C(＝O)NR¹⁶R¹⁷、-NR¹⁵S(O)₂R¹⁶、-C(＝S)NR¹⁵R¹⁶、-OC(＝O)R¹⁵、-OC(＝O)NR¹⁵R¹⁶、-OR¹⁵、-S(O)₂NR¹⁵R¹⁶，和选自-(C₁-C₆)烷基、-(C₂-C₆)炔基、-(C₂-C₆)烯基、-(C₃-C₇)环烷基和-(C₃-C₈)环烯基的任意取代的基团，以及选自芳基、杂芳基、杂环和环烷基环的任意取代的3到10元环；R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷和R¹⁸各自独立地是氢或选自-(C₁-C₆)卤烷基、-(C₁-C₆)烷基、-(C₁-C₆)氰烷基、-(C₂-C₆)炔基、-(C₂-C₆)烯基、-(C₃-C₇)环烷基、-(C₄-C₁₀)烷基环烷基、杂芳基、-(C₁-C₆)烷基杂芳基、芳基、-(C₁-C₆)烷基芳基、-(C₂-C₆)炔基-(C₃-C₇)环烷基、-(C₂-C₆)炔基-杂芳基、-(C₂-C₆)炔基-芳基、-(C₂-C₆)烯基-(C₃-C₇)环烷基、-(C₂-C₆)烯基-杂芳基和-(C₂-C₆)烯基-芳基的任意取代的基团；R⁴、R⁵、R⁶和R⁷可以组合在一起形成任意取代的3到10元非芳香性杂环或任意取代的5到10元芳香杂环；R⁸、R⁹、R¹⁰和R¹¹可以组合在一起形成任意取代的3到10元非芳香性杂环或任意取代的5到10元芳香杂环；R¹²、R¹³和R¹⁴可以组合在一起形成任意取代的3到10元非芳香性杂环或任意取代的5到10元芳香杂环；和R¹⁵、R¹⁶、R¹⁷和R¹⁸可以组合在一起形成任意取代的3到10元非芳香性杂环或任意取代的5到10元芳香杂环。