Hetero-bicyclic crf antagonists

本发明提供了包括立体异构体、前药和其可药用盐或溶剂化物的式(I)化合物、其制备方法、含有所述式(I)化合物的药物组合物及其在治疗促肾上腺皮质激素释放因子(CRF)介导的疾病中的用途，其中，R是芳基或杂芳基，各自可被1-4个下述基团取代：卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R#-[5]、硝基、-NR#-[6]R#-[7]、氰基和R#-[8]；R#-[1]是氢、C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤素、NR#-[6]R#-[7]或氰基；R#-[2]是氢、C3-C7环烷基或R#-[9]；R#-[3]是C3-C7环烷基或R#-[9]；或R#-[2]和R#-[3]与N一起形成5-14元杂环，且该杂环可以被1-3个R#-[10]取代；R#-[4]是氢、C1-C6烷基、卤素或卤代C1-C6烷基；R#-[5]是C1-C4烷基、-OR#-[6]或-NR#-[6]R#-[7]；R#-[6]是氢或C1-C6烷基；R#-[7]是氢或C1-C6烷基；R#-[8]是5-6元杂环，该杂环可以是饱和杂环或可以含有1-3个双键，且可被一个或多个R#-[11]取代；R#-[9]是C1-C6烷基，其可以被一个或多个下述基团取代：C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基、卤代C1-C6烷基；R#-[10]是R#-[8]、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基、C(O)NR#-[6]R#-[7]、可以被1-4个R#-[11]取代的苯基；R#-[11]是C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基或C(O)NR#-[6]R#-[7]；X是碳或氮；n是1或2。 The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof wherein R is aryl or heteroaryl, each of which may be substituted by I to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, -C(O)R 5 , nitro, -NR 6 R 7 , cyano, and a group R 8 ; R 1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7 or cyano; R 2 and R 3 corresponds to; R 4 is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R 5 is a C1-C4 alkyl, -OR 6 or -NR 6 R 7 ; R 6 is hydrogen or C1-C6 alkyl; R 7 is hydrogen or C1-C6 alkyl; R 8 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11 groups; R 11 is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).