Indazole derivativesThis invention relates to compounds, pharmaceutical compositions and methods for the treatment of a condition mediated by CB1 receptor activity in a mammalian subject including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula (I) wherein R1, R2 and R3 are as defined in this specification.Chemical compound with formula ior its pharmaceutically-acceptable salts, wherein:x is ch or n;r 1be r 41-5-aryl-(ch 2) n-or r 51-5-heteroaryl-(ch 2) n-; wherein each r 4be h, halogen, cyano group, nh independently 2-c (o)-, c 1-c 6alkoxyl-, trifluoromethyl or c 1-c 6alkoxy-c (o)-; each r 5be h or c independently 1-c 6alkyl; r 2be nr 11r 12-c(o)-r 13ch-、 r 14-c(o)-nr 15-(ch 2) n-r 13ch-、 r 16-c(o)-r 13ch-、 c 1-c 6alkoxy-c (o)-(ch 2) n-nr 15-c (o)-r 13ch-, nr 17r 18-c(o)-(ch 2) n-nr 19-c(o)-r 13ch-、 r 20-so 2-nr 21-(ch 2) n-r 13ch-、 r 22r 23ch-、 r 241-5-heteroaryl, r 241-5-heteroaryl-r 13ch-, r 241-5-heteroaryl-nr 15-c (o)-r 13ch-, r 251-5-heterocyclic radical, r 251-5-heterocyclic radical-(ch 2) n-, r 261-5-c 3-c 7cycloalkyl, nr 27r 28-(ch 2) n-nr 29-c(o)-r 13ch-、 r 30-so 2-nr 31-(ch 2) n-nr 15-c(o)-r 13ch-、 r 30-so 2-(ch 2) n-nr 31-c(o)-r 13ch-、 r 32-c(o)-r 33ch-nr 34-c(o)-r 13ch-、 r 32-c(o)-(ch 2) n-nr 34-c(o)-r 13ch-、 r 351-5-heteroaryl-(ch 2) n-nr 36-c (o)-r 13ch-, r 371-5-heterocyclic radical-(ch 2) n-nr 36-c (o)-r 13ch-, r 371-5-heterocyclic radical-c (o)-r 13ch-, r 381-5-aryl-r 39c-nr 40-c (o)-r 13ch-, r 381-5-aryl-(ch 2) n-nr 40-c (o)-r 13ch-, r 411-5-aryl-(ch 2) n-, nr 17r 18-c (o)-ch (r 42)-nr 19-c (o)-r 13ch-or r 43-ch (oh)-ch 2-nr 19-c (o)-r 13ch-; whereinr 11and r 12be h, oh, c independently 1-c 6alkyl, c 1-c 6haloalkyl, oh-c 1-c 6alkyl, (oh) 2-c 1-c 6alkyl, (oh) 3-c 4-c 6alkyl, c 1-c 6alkoxyl-(ch 2) n-, c 3-c 7cycloalkyl, benzo-fused c 3-c 7cycloalkyl, cyano group-c 1-c 6alkyl, nh 2-c (nh)-c 1-c 6alkyl, (oh-c 1-c 6alkyl) 2-c 1-c 6alkylidene, oh-c 3-c 7cycloalkyl-(ch 2) n-, oh-(ch 2) n-c 3-c 7cycloalkyl-, oh-c 3-c 7cycloalkyl-, c 1-c 6alkoxy-c (o)-c 3-c 7cycloalkyl-, (c 1-c 6alkoxyl-aryl)-c 3-c 7cycloalkyl-, nh 2-c (o)-c 3-c 7cycloalkyl-, oh-aryl or r 241-5-heteroaryl-o-(ch 2) n-; r 13be h, c 1-c 6alkyl, oh-c 1-c 6alkyl, aryl, aryl-(ch 2) n-or c 3-c 7cycloalkyl; r 14be (c 1-c 6alkyl) 2n-, aryl, c 1-c 6alkyl or c 3-c 7cycloalkyl; r 15, r 21, r 29, r 31, r 34and r 40be h or c independently 1-c 6alkyl; r 16be oh or c 1-c 6alkoxyl; r 17and r 18be h, c independently 1-c 6alkyl, c 3-c 7cycloalkyl, oh-c 1-c 6alkyl, (oh) 2-c 1-c 6alkyl or r 241-5-heteroaryl-; each r 19be h or c independently 1-c 6alkyl; r 20be c 1-c 6alkyl, c 1-c 6haloalkyl or (c 1-c 6alkyl) 2n-; r 22and r 23be c independently 1-c 6alkyl, c 3-c 7cycloalkyl-(ch 2) n-, oh-c 1-c 6alkyl, aryl or aryl-oh-c 1-c 6alkylidene; each r 24be h, c independently 1-c 6alkyl, c 3-c 7cycloalkyl, c 1-c 6haloalkyl, oxo, oh, nh 2, c 1-c 6alcoxyl base-c (o)-, nh 2-c (o)-(ch 2) n-, nh 2-c (o)-, nh 2-c(o)-nh-、oh-c(o)-、 nh 2-c (o)-(ch 2) n-nh-c (o)-, (oh) 2-c 1-c 6alkane base-nh-c (o)-, oh-c 1-c 6alkyl-nh-c (o)-or c 3-c 7cycloalkyl-c (o)-nh-; each r 25be h or oxo independently; each r 26be h, oh, oh-c independently 1-c 6alkyl, virtue base-(ch 2) n-o-, nh 2-c (o)-or c 1-c 6alkoxy-c (o)-; r 27and r 28be h, nh independently 2-c (o)-, c 3-c 7cycloalkanes base-c (o)-or r 241-5-heteroaryl-; r 30be c 1-c 6alkyl, c 3-c 7cycloalkyl, nh 2, c 1-c 6alkyl-nh-, c 3-c 7cycloalkyl-(ch 2) n-nh-, morpholine-4-base or r 381-5-phenyl; r 32be oh or c 1-c 6alkoxyl-; each r 33be h, c independently 1-c 6alkyl or oh-c 1-c 6alkyl; each r 35be h, c independently 1-c 6alkyl, nh 2-c (o)-, c 1-c 6alkoxy-c (o)-, c 3-c 7cycloalkyl, oh, phenyl or heteroaryl, or two be adjacent to r 35group can form-(ch together 2) 3-6-; each r 36be h, c independently 1-c 6alkyl, c 1-c 6alkoxyl-or nh 2-c (o)-; each r 37be h, nh independently 2c (o)-, oh, halogen, cyano group, oxo, oh-c 1-c 6alkyl, (oh) 2-c 1-c 6alkyl, nh 2c(o)-(ch 2) n-、nh 2c(o)-(ch 2) n-c(o)-、 nh 2c (o)-nh-(ch 2) n-, c 1-c 6alkyl-nh-c (o)-o-, (oh)-c 1-c 6alkyl-nh-c (o)-, (oh) 2-c 1-c 6alkane base-nh-c (o)-, c 1-c 6alkyl-c (o)-, c 1-c 6alcoxyl base-c (o)-, c 3-c 7cycloalkyl-c (o)-nh-(ch 2) n-, c 1-c 6alkyl-so 2-, c 3-c 7cycloalkyl-so 2-or c 3-c 7cycloalkanes base-so 2--nh-(ch 2) n-; each r 38be h, nh independently 2so 2-, cyano group, heteroaryl, oh, halogen, c 1-c 6alkoxyl, oh-c (o)-or c 1-c 6alkoxy-c (o)-; each r 39be h, c independently 1-c 6alkyl or oh-c 1-c 6alkyl; each r 41be h, c independently 1-c 6alkoxy or halogen; r 42be h, c 1-c 6alkyl, oh-c 1-c 6alkyl, aryl, aryl-(ch 2) n-or nh 2-c (o)-ch 2r 43be oh-c (o)-, c 1-c 6alkoxy-c (o)-, nh 2-c (o)-or r 44r 45nch 2-; with r 44and r 45be c independently 1-c 6alkyl or oh-c 1-c 6alkyl, or r 44and r 45the nitrogen-atoms that connects with them forms pyrrolidine ring, piperidine ring or morpholine ring; n is 1 to 6 integer; andeach r 3be h, halogen, c independently 1-c 6alkyl, aryl, nh 2-c (o)-, c 1-c 6alkoxyl or heteroaryl.
인다졸 유도체본 발명은 치료 유효량의 하기 화학식 I의 화합물을 칸나비노이드(CB)1 수용체 활성에 의해 매개되는 증상의 치료가 필요한 인간을 포함하는 포유동물에게 투여함을 포함하는, 상기 포유동물에서 CB1 수용체 활성에 의해 매개되는 증상의 치료를 위한 화합물, 약학 조성물 및 방법에 관한 것이다: 화학식 I  상기 식에서, R1, R2 및 R3은 본 명세서에 정의된 바와 같다.하기 화학식 I의 화합물 또는 이의 약학적으로 허용가능한 염:화학식 I[이미지]상기 식에서, X는 CH 또는 N이고;R1은 R41-5-아릴-(CH2)n- 또는 R51-5-헤테로아릴-(CH2)n-이며; 이때, R4는 각각 독립적으로 H, 할로, 시아노, NH2-C(O)-, C1-C6알콕시-, 트라이플루오로메틸 또는 C1-C6알콕시-C(O)-이고; R5는 각각 독립적으로 H 또는 C1-C6알킬이며;R2는 NR11R12-C(O)-R13CH-, R14-C(O)-NR15-(CH2)n-R13CH-, R16-C(O)-R13CH-, C1-C6알콕시-C(O)-(CH2)n-NR15-C(O)-R13CH-, NR17R18-C(O)-(CH2)n-NR19-C(O)-R13CH-, R20-SO2-NR21-(CH2)n-R13CH-, R22R23CH-, R241-5-헤테로아릴, R241-5-헤테로아릴-R13CH-, R241-5-헤테로아릴-NR15-C(O)-R13CH-, R251-5-헤테로사이클릴, R251-5-헤테로사이클릴-(CH2)n-, R261-5-C3-C7사이클로알킬, NR27R28-(CH2)n-NR29-C(O)-R13CH-, R30-SO2-NR31-(CH2)n-NR15-C(O)-R13CH-, R30-SO2-(CH2)n-NR31-C(O)-R13CH-, R32-C(O)-R33CH-NR34-C(O)-R13CH-, R32-C(O)-(CH2)n-NR34-C(O)-R13CH-, R351-5-헤테로아릴-(CH2)n-NR36-C(O)-R13CH-, R371-5-헤테로사이클릴-(CH2)n-NR36-C(O)-R13CH-, R371-5-헤테로사이클릴-C(O)-R13CH-, R381-5-아릴-R39C-NR40-C(O)-R13CH-, R381-5-아릴-(CH2)n-NR40-C(O)-R13CH-, R411-5-아릴-(CH2)n-, NR17R18-C(O)-CH(R42)-NR19-C(O)-R13CH-, 또는 R43-CH(OH)-CH2-NR19-C(O)-R13CH-이고;이때, R11 및 R12는 독립적으로 H, OH, C1-C6알킬, C1-C6할로알킬, OH-C1-C6알킬, (OH)2-C1-C6알킬, (OH)3-C4-C6알킬, C1-C6알콕시-(CH2)n-, C3-C7사이클로알킬, 벤조-융합된 C3-C7사이클로알킬, 시아노-C1-C6알킬, NH2-C(NH)-C1-C6일킬, (OH-C1-C6알킬)2-C1-C6알킬렌, OH-C3-C7사이클로알킬-(CH2)n-, OH-(CH2)n-C3-C7사이클로알킬-, OH-C3-C7사이클로알킬-, C1-C6알콕시-C(O)-C3-C7사이클로알킬-, (C1-C6알콕시-아릴)-C3-C7사이클로알킬-, NH2-C(O)-C3-C7사이클로알킬-, OH-아릴 또는 R241-5-헤테로아릴-O-(CH2)n-이고;R13은 H, C1-C6알킬, OH-C1-C6알킬, 아릴, 아릴-(CH2)n- 또는 C3-C7사이클로알킬이며;R14는 (C1-C6알킬)2N-, 아릴, C1-C6알킬 또는 C3-C7사이클로알킬이고;R15, R21, R29, R31, R34 및 R40은 독립적으로 H 또는 C1-C6알킬이며;R16은 OH 또는 C1-C6알콕시이고;R17 및 R18은 독립적으로 H, C1-C6알킬, C3-C7사이클로알킬, OH-C1-C6알킬, (OH)2-C1-C6알킬 또는 R241-5-헤테로아릴-이며;R19는 각각 독립적으로 H 또는 C1-C6알킬이고;R20은 C1-C6알킬, C1-C6할로알킬 또는 (C1-C6알킬)2N-이며;R22 및 R23은 독립적으로 C1-C6알킬, C3-C7사이클로알킬-(CH2)n-, OH-C1-C6알킬, 아릴 또는 아릴-OH-C1-C6알킬렌이고;R24는 각각 독립적으로 H, C1-C6알킬, C3-C7사이클로알킬, C1-C6할로알킬, 옥소, OH, NH2, C1-C6알콕시-C(O)-, NH2-C(O)-(CH2)n-, NH2-C(O)-, NH2-C(O)-NH-, OH-C(O)-, NH2-C(O)-(CH2)n-NH-C(O)-, (OH)2-C1-C6알킬-NH-C(O)-, OH-C1-C6알킬-NH-C(O)- 또는 C3-C7사이클로알킬-C(O)-NH-이며;R25는 각각 독립적으로 H 또는 옥소이고;R26은 각각 독립적으로 H, OH, OH-C1-C6알킬, 아릴-(CH2)n-O-, NH2-C(O)- 또는 C1-C6알콕시-C(O)-이고;R27 및 R28은 독립적으로 H, NH2-C(O)-, C3-C7사이클로알킬-C(O)- 또는 R241-5-헤테로아릴-이며;R30은 C1-C6알킬, C3-C7사이클로알킬, NH2, C1-C6알킬-NH-, C3-C7사이클로알킬-(CH2)n-NH-, 모르폴린-4-일 또는 R381-5-페닐이고;R32는 OH 또는 C1-C6알콕시-이며;R33은 각각 독립적으로 H, C1-C6알킬 또는 OH-C1-C6알킬이고;R35는 각각 독립적으로 H, C1-C6알킬, NH2-C(O)-, C1-C6알콕시-C(O)-, C3-C7사이클로알킬, OH, 페닐 또는 헤테로아릴이거나, 2개의 인접한 R35 기는 함께 -(CH2)3-6-을 형성하고;R36은 각각 독립적으로 H, C1-C6알킬, C1-C6알콕시- 또는 NH2-C(O)-이며;R37은 각각 독립적으로 H, NH2C(O)-, OH, 할로, 시아노, 옥소, OH-C1-C6알킬, (OH)2-C1-C6알킬, NH2C(O)-(CH2)n-, NH2C(O)-(CH2)n-C(O)-, NH2C(O)-NH-(CH2)n-, C1-C6알킬-NH-C(O)-O-, (OH)-C1-C6알킬-NH-C(O)-, (OH)2-C1-C6알킬-NH-C(O)-, C1-C6알킬-C(O)-, C1-C6알콕시-C(O)-, C3-C7사이클로알킬-C(O)-NH-(CH2)n-, C1-C6알킬-SO2-, C3-C7사이클로알킬-SO2- 또는 C3-C7사이클로알킬-SO2--NH-(CH2)n-이고;R38은 각각 독립적으로 H, NH2SO2-, 시아노, 헤테로아릴, OH, 할로, C1-C6알콕시, OH-C(O)- 또는 C1-C6알콕시-C(O)-이며;R39는 각각 독립적으로 H, C1-C6알킬 또는 OH-C1-C6알킬이고;R41은 각각 독립적으로 H, C1-C6알콕시 또는 할로이며;R42는 H, C1-C6알킬, OH-C1-C6알킬, 아릴, 아릴-(CH2)n- 또는 NH2-C(O)-CH2이고;R43은 OH-C(O)-, C1-C6알콕시-C(O)-, NH2-C(O)- 또는 R44R45NCH2-이며;R44 및 R45는 독립적으로 C1-C6알킬 또는 OH-C1-C6알킬이거나, R44와 R45는 이들이 부착된 질소 원자와 함께 피롤리딘, 피페리딘 또는 모르폴린 고리를 형성하고;n은 1 내지 6의 정수이며;R3은 각각 독립적으로 H, 할로, C1-C6알킬, 아릴, NH2-C(O)-, C1-C6알콕시 또는 헤테로아릴이다.