[发明专利]用于治疗肥胖症的大麻素受体拮抗剂/反向激动剂

摘要

本发明提供了用作大麻素受体拮抗剂的新型吡唑及其药物组合物和使用它们治疗肥胖症、糖尿病和/或心脏代谢病的方法。

主权项

1.一种下式I的化合物或其立体异构体或药学上可接受的盐：其中：X和Y独立选自H、卤素、C_1-6烷基、NO₂、CF₃、NR₂、OR、CO₂R、(CH₂)_nCO₂R、O(CH₂)_nCO₂R、OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、NR^a(CH₂)_nCO₂R、NR^a(CH₂)_nPO(OR)₂、NR^aCH₂CH＝CHCO₂R、NR^aSO₂CH₃、NR^aCO(CH₂)_nCO₂R、O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄(CH₂)_nCO₂R、CH₂O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄CONH₂、O(CH₂)_nC₆H₄(CH₂)_nCONH₂、CH₂O(CH₂)_nC₆H₄CONH₂、O(CH₂)_nC₆H₄-四唑、CH₂O(CH₂)_nC₆H₄-四唑、O(CH₂)_nC₆H₄(CH₂)_n-四唑、NR^a(CH₂)_nC₆H₄CO₂R、CH₂NR^a(CH₂)_nC₆H₄CO₂R、NR^a(CH₂)_nC₆H₄CONH₂、CH₂NR^a(CH₂)_nC₆H₄CONH₂、NR^a(CH₂)_nC₆H₄-四唑、CH₂NR^a(CH₂)_nC₆H₄-四唑、-CN、(CH₂)_mC(NH)NH₂、CONR₂、(CH₂)_nCONR₂、O(CH₂)_nCONR₂、CH₂O(CH₂)_nCONH₂、NR^a(CH₂)_nCONR₂、OCH₂CH＝CHCONR₂、CH₂OCH₂CH＝CHCONR₂、NR^aCH₂CH＝CHCONR₂、-四唑、O(CH₂CH₂O)_PR、NR^a(CH₂CH₂O)_pR和SO₂NR^aCH₃；X＇和Y＇独立选自H、卤素、C_1-6烷基、NO₂、CF₃、NR₂、OR、CO₂R、(CH₂)_nCO₂R、O(CH₂)_nCO₂R、OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、NR^a(CH₂)_nCO₂R、NR^a(CH₂)_nPO(OR)₂、NR^aCH₂CH＝CHCO₂R、NR^aSO₂CH₃、NR^aCO(CH₂)_nCO₂R、O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄(CH₂)_nCO₂R、CH₂O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄CONH₂、O(CH₂)_nC₆H₄(CH₂)_nCONH₂、CH₂O(CH₂)_nC₆H₄CONH₂、O(CH₂)_nC₆H₄-四唑、CH₂O(CH₂)_nC₆H₄-四唑、O(CH₂)_nC₆H₄(CH₂)_n-四唑、NR^a(CH₂)_nC₆H₄CO₂R、CH₂NR^a(CH₂)_nC₆H₄CO₂R、NR^a(CH₂)_nC₆H₄CONH₂、CH₂NR^a(CH₂)_nC₆H₄CONH₂、NR^a(CH₂)_nC₆H₄-四唑、CH₂NR^a(CH₂)_nC₆H₄-四唑、-CN、(CH₂)_mC(NH)NH₂、CONR₂、(CH₂)_nCONR₂、O(CH₂)_nCONR₂、CH₂O(CH₂)_nCONH₂、NR^a(CH₂)_nCONR₂、OCH₂CH＝CHCONR₂、CH₂OCH₂CH＝CHCONR₂、NR^aCH₂CH＝CHCONR₂、-四唑、O(CH₂CH₂O)_PR、NR^a(CH₂CH₂O)_pR和SO₂NR^aCH₃；A选自H、C_1-6烷基、(CH₂)_m-C_3-6-环烷基、(CH₂)_m-杂芳基和(CH₂)_m-芳基，其中每个芳基和杂芳基被0-1个选自CF₃、卤素、C_1-4烷基、-CN、CONR₂、NO₂、NR₂和OR的基团取代；R＇选自H、C_1-6烷基、CH(A)-(CH₂)_mCO₂R、CH(A)-(CH₂)_mCONH₂、CH(A)-(CH₂)_mC(NH)NH₂、(CH₂)_m-苯基-(CH₂)_mCO₂R、(CH₂)_m-吡啶基-(CH₂)_mCO₂R、(CH₂)_m-苯基-(CH₂)_mCONH₂、(CH₂)_m-吡啶基-(CH₂)_mCONH₂、(CH₂)_m-苯基-(CH₂)_mC(NH)NH₂、(CH₂)_m-吡啶基-(CH₂)_m(CN)NH₂、(CH₂)_m-苯基-(CH₂)_m-四唑和(CH₂)_m-吡啶基-(CH₂)_m-四唑；可选地，R＇是R＂选自H、C_1-6烷基、(CH₂)_0-6芳基和(CH₂)_0-6杂芳基；Z选自H、C_1-6烷基、芳基、NR₂、OR、-CN、(CH₂)_mC(NH)NH₂、CO₂R、(CH₂)_nCO₂R、O(CH₂)_nCO₂R、CH₂O(CH₂)_nCO₂R、NR^aCH(A)CO₂R、CH₂NR^aCH(A)CO₂R、NR^a(CH₂)_nCO₂R CH₂NR^a(CH₂)_nCO₂ROCH₂CH＝CHCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、O(CH₂)_nC₆H₄CO₂R、CH₂O(CH₂)_nC₆H₄CO₂R、CONR₂、(CH₂)_nCONR₂、O(CH₂)_nCONR₂、CH₂O(CH₂)_nCONR₂、OCH₂CH＝CHCONR₂、CH₂OCH₂CH＝CHCONR₂、CH₂NR^a(CH₂)_n四唑、CH₂O(CH₂)_n四唑和(CH₂)_m四唑；Q选自N、CH和CQ＇；Q＇选自H、CO₂R、(CH₂)_nCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nPO(OR)₂、CONR₂、(CH₂)_nCONR₂、CH₂O(CH₂)_nCONR₂、CH₂OCH₂CH＝CHCONR₂和(CH₂)_m四唑；V选自H、C_1-6烷基、C_2-6烯基、CF₃、芳基、-CN、(CH₂)_mC(NH)NH₂、(CH₂)_mCO₂R、(CH₂)_mCONR₂、(CH₂)_m-四唑、(CH₂)_mCONR^aCH(A)-(CH₂)_mCO₂R、(CH₂)_mCONR^a(CH₂)_m-苯基-(CH₂)_mCO₂R、(CH₂)_mCONR^a(CH₂)_m-苯基-(CH₂)_m-四唑、CH₂O(CH₂)_nCO₂R、CH₂NR^a(CH₂)_nCO₂R、CH₂O(CH₂)_nCONH₂、CH₂NR^a(CH₂)_nCONH₂和CH₂O(CH₂)_n四唑；R独立选自H、C_1-6烷基；R^a独立选自H、C_1-6烷基、C_2-6烯基和C_2-6炔基；m选自0、1、2、3和4；n选自1、2、3和4；且p选自1、2、3、4、5、6、7、8、9、10、11和12；只要符合至少一个下述条件：(a)至少一个X、Y、X＇和Y＇不是H、卤素、C_1-6烷基、NO₂、-CN、CF₃、OR和苯基；(b)R＇选自CH(A)-(CH₂)_mCO₂R、CH(A)-(CH₂)_mCONH₂、CH(A)-(CH₂)_mC(NH)NH₂、(CH₂)_m-苯基-(CH₂)_mCO₂R、(CH₂)_m-吡啶基-(CH₂)_mCO₂R、(CH₂)_m-苯基-(CH₂)_mCONH₂、(CH₂)_m-吡啶基-(CH₂)_mCONH₂、(CH₂)_m-苯基-(CH₂)_mC(NH)NH₂、(CH₂)_m-吡啶基-(CH₂)_m(CN)NH₂、(CH₂)_m-苯基-(CH₂)_m-四唑和(CH₂)_m-吡啶基-(CH₂)_m-四唑；(c)Z存在，且不是H、C_1-6烷基、芳基、NR₂和OR；(d)Q存在，且为CQ＇，其中Q＇不是H；和/或(e)V不是H、-CN、CF₃、C_2-6烯基、芳基和C_1-6烷基。