FUSED QUINOLINE DERIVATIVES USEFUL AS GABA MODULATORSThis invention relates to novel compounds having the structural formula (I) below: and their pharmaceutically acceptable salts, tautomers or in vivo-hydrolysable precursors, compositions and methods of use thereof, wherein R1, R2, R3, R4, R5, and R6 are defined in the specification. These novel compounds provide a treatment or prophylaxis of anxiety disorders, schizophrenia, cognitive disorders, and/or mood disorders.A compound of Formula I:I or a pharmaceutically acceptable salt, tautomer, atropisomer, or in vz'vo-hydrolysable precursor thereof, wherein:R1 is Ci_6 alkyl, C6-ioaryl, C2-5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl,C6-ioaryl-Ci_4alkyl, C2-5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl-Ci_4alkyl, wherein each of the Ci_6 alkyl, Cό-ioaryl, C2_5heteroaryl, C3_ γcycloalkyl, C2_5heterocycloalkyl, C6-ioaryl-Ci_4alkyl, C2-5heteroaryl-Ci_4alkyl, C3_ or C2-5heterocycloalkyl-Ci-4alkyl is optionally substituted by 1, 2, 3,4 or 5 R7;R2 is H, -C(=O)Rb, -C(=0)NRcRd, -C(=O)ORa, -S(=O)2Rb, Ci_6 alkyl, C6-i0aryl,C2-5heteroaryl, C3_7cycloalkyl, C2-5heterocycloalkyl, C6-ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_ 4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2-5heterocycloalkyl-Ci_4alkyl, wherein each of the Ci_6 alkyl, C6-ioaryl, C2-5heteroaryl, C3_7cycloalkyl, C2-5heterocycloalkyl, C6-ioaryl-Ci_4alkyl,C2-5heteroaryl-Ci-4alkyl, C3-7cycloalkyl-Ci-4alkyl or C2-5heterocycloalkyl-Ci-4alkyl is optionally substituted by 1, 2, 3, 4 or 5 R8;R3, R4 and R5 are each, independently, H, halo, -Si(Ci_iO alkyl)3, -CN, -NO2, -ORa, -SRa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb,-C(=O)NRcRd, -NRcRd, -NRcC(=O)Ra, -NRcC(=O)ORb, -NRcS(=O)2Rb, -S(=O)Ra,-S(=O)NRcRd, -S(=O)2Ra, -S(=O)2NRcRd, Ci_6 alkyl, C6-i0aryl, C2_5heteroaryl, C3-7cycloalkyl, C2_5heterocycloalkyl, C6-ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_4alkyl, C3.7cycloalkyl-Ci-4alkyl or C2-5heterocycloalkyl-Ci-4alkyl, wherein each of the Ci-6 alkyl, CO- loaryl, C2-sheteroaryl, C3-7cycloalkyl, C2-5heterocycloalkyl, C6-ioaryl-Ci-4alkyl, C2-5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl-Ci_4alkyl is optionally substituted by 1 , 2 or 3 R9; - 259 -R6 is Cό-ioaryl, C6-ioaryloxy, C2-5heteroaryloxy, or C2-5heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 A1;R7, R8 and R9 are each, independently, halo, Ci-4alkyl, Ci-4haloalkyl, Cό-ioaryl, C3-7cycloalkyl, C2-5heteroaryl, C2-5heterocycloalkyl, -CN, -NO2, -0Ra', -SRa', -C(=O)Rb', -C(=0)NRc Rd', -C(=O)ORa', -OC(=O)Rb', -0C(=0)NRc Rd', -NRc Rd', -NRc C(=O)Rb', -NRc C(=0)0Ra', -NRc S(=O)2Rb', -S(=O)Rb', -S(=O)NRc Rd', -S(=O)2Rb', or -S(=O)2NRc Rd';A1 is halo, -CN, -NO2, -0Ra, -SRa, -C(=O)Rb, -C(=0)NRcRd, -C(=O)ORa, - OC(=O)Rb, -0C(=0)NRcRd, -NRcRd, -NRcC(=O)Rd, -NRcC(=0)0Ra, -NRcS(=O)Rb, - NRcS(=O)2Rb, -S(=O)Rb, -S(=O)NRcRd, -S(=O)2Rb, -S(=O)2NRcRd, Ci-4 alkoxy, Ci-4 haloalkoxy, amino, Ci-4 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkyl, C6_ioaryl, C2_5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl, C6_ ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl- Ci_4alkyl, wherein each of the Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 alkyl, C6_ioaryl, C2_5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl, C6-ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_ 4alkyl, C3-7cycloalkyl-Ci-4alkyl or C2-5heterocycloalkyl-Ci-4alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-4 haloalkyl, C6-ioaryl, C3_7cycloalkyl, C2_5heteroaryl, C2_5heterocycloalkyl, -CN, -NO2, -0Ra', -SRa', -C(=O)Rb', -C(=0)NRc Rd', -C(=O)ORa', -OC(=O)Rb', - OC(=O)NRc Rd', -NRc Rd', -NRc C(=O)Rb', -NRc C(=O)ORa', -NRc S(=O)Rb', - NRc S(=O)2Rb', -S(=O)Rb', -S(=O)NRc Rd', -S(=O)2Rb', or -S(=O)2NRc Rd';Ra and Ra are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2. 6 alkynyl, Ci_6 alkyl, C6-ioaryl, C2_5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl, C6- ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl- Ci_4alkyl;Rb and Rb are each, independently, H, Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 alkyl, C6-ioaryl, C2_5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl, C6- ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl- C1_4alkyl; Rc and Rd are each, independently, H, Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 alkyl, C6_ioaryl, C2_5heteroaryl, C3_7cycloalkyl, C2_5heterocycloalkyl, C6_ ioaryl-Ci_4alkyl, C2_5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl- C1_4alkyl; - 260 - or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7-membered heterocycloalkyl group; andRc and Rd are each, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkyl, Cό-ioaryl, C2-5heteroaryl, C3-7cycloalkyl, C2-5heterocycloalkyl, CO- C2-5heteroaryl-Ci_4alkyl, C3_7cycloalkyl-Ci_4alkyl or C2_5heterocycloalkyl- Ci_4alkyl; or Rc and Rd together with the N atom to which they are attached form a A-, 5-, 6- or 7-membered heterocycloalkyl group; with the proviso that when R2, R3, R4 and R5 are each H, then R6 is not selected from unsubstituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, A- methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, and 4-N,N-dimethylaminophenyl .
ＧＡＢＡ 조절제로서 유용한 융합 퀴놀린 유도체본 발명은 하기 화학식 I의 구조를 갖는 신규 화합물 및 그의 제약상 허용되는 염, 호변이성질체 또는 생체내-가수분해가능한 전구체, 조성물 및 그의 사용 방법에 관한 것이다. 상기 신규 화합물은 불안 장애, 정신분열증, 인지 장애 및/또는 기분 장애의 치료 또는 예방을 제공한다. <화학식 I>  상기 식에서, R1, R2, R3, R4, R5 및 R6은 명세서에 정의되어 있다.하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염, 호변이성질체, 회전장애이성질체 또는 생체내-가수분해가능한 전구체.<화학식 I>상기 식에서,R1은 C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고, 여기서 각각의 C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬은 1, 2, 3, 4 또는 5개의 R7로 임의로 치환되고;R2는 H, -C(=O)Rb, -C(=O)NRcRd, -C(=O)ORa, -S(=O)2Rb, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고, 여기서 각각의 C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬은 1, 2, 3, 4 또는 5개의 R8로 임의로 치환되고;R3, R4 및 R5는 각각 독립적으로, H, 할로, -Si(C1-10알킬)3, -CN, -NO2, -ORa, -SRa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -NRcRd, -NRcC(=O)Ra, -NRcC(=O)ORb, -NRcS(=O)2Rb, -S(=O)Ra, -S(=O)NRcRd, -S(=O)2Ra, -S(=O)2NRcRd, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고, 여기서 각각의 C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬은 1, 2 또는 3개의 R9로 임의로 치환되고;R6은 1, 2, 3, 4 또는 5개의 A1로 각각 임의로 치환된 C6-10아릴, C6-10아릴옥시, C2-5헤테로아릴옥시 또는 C2-5헤테로아릴이고;R7, R8 및 R9는 각각 독립적으로, 할로, C1-4알킬, C1-4할로알킬, C6-10아릴, C3-7시클로알킬, C2-5헤테로아릴, C2-5헤테로시클로알킬, -CN, -NO2, -ORa', -SRa', -C(=O)Rb', -C(=O)NRc'Rd', -C(=O)ORa', -OC(=O)Rb', -OC(=O)NRc'Rd', -NRc'Rd', -NRc'C(=O)Rb', -NRc'C(=O)ORa', -NRc'S(=O)2Rb', -S(=O)Rb', -S(=O)NRc'Rd', -S(=O)2Rb' 또는 -S(=O)2NRc'Rd'이고;A1은 할로, -CN, -NO2, -ORa, -SRa, -C(=O)Rb, -C(=O)NRcRd, -C(=O)ORa, -OC(=O)Rb, -OC(=O)NRcRd, -NRcRd, -NRcC(=O)Rd, -NRcC(=O)ORa, -NRcS(=O)Rb, -NRcS(=O)2Rb, -S(=O)Rb, -S(=O)NRcRd, -S(=O)2Rb, -S(=O)2NRcRd, C1-4알콕시, C1-4할로알콕시, 아미노, C1-4알킬아미노, C2-8디알킬아미노, C1-6알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고, 여기서 각각의 C1-6알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬은, 할로, C1-6알킬, C2-6알케닐, C2-6알키닐, C1-4할로알킬, C6-10아릴, C3-7시클로알킬, C2-5헤테로아릴, C2-5헤테로시클로알킬, -CN, -NO2, -ORa', -SRa', -C(=O)Rb', -C(=O)NRc'Rd', -C(=O)ORa', -OC(=O)Rb', -OC(=O)NRc'Rd', -NRc'Rd', -NRc'C(=O)Rb', -NRc'C(=O)ORa', -NRc'S(=O)Rb', -NRc'S(=O)2Rb', -S(=O)Rb', -S(=O)NRc'Rd', -S(=O)2Rb' 또는 -S(=O)2NRc'Rd'으로부터 독립적으로 선택된 1, 2, 3, 4 또는 5개의 치환기로 임의로 치환되고;Ra 및 Ra'은 각각 독립적으로, H, C1-6알킬, C1-6할로알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고;Rb 및 Rb'은 각각 독립적으로, H, C1-6알킬, C1-6할로알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이고;Rc 및 Rd는 각각 독립적으로, H, C1-6알킬, C1-6할로알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이거나; 또는Rc 및 Rd는 이들이 부착된 N 원자와 함께 4-, 5-, 6- 또는 7-원 헤테로시클로알킬기를 형성하고;Rc' 및 Rd'은 각각 독립적으로, H, C1-6알킬, C1-6할로알킬, C2-6알케닐, C2-6알키닐, C1-6알킬, C6-10아릴, C2-5헤테로아릴, C3-7시클로알킬, C2-5헤테로시클로알킬, C6-10아릴-C1-4알킬, C2-5헤테로아릴-C1-4알킬, C3-7시클로알킬-C1-4알킬 또는 C2-5헤테로시클로알킬-C1-4알킬이거나; 또는Rc' 및 Rd'은 이들이 부착된 N 원자와 함께 4-, 5-, 6- 또는 7-원 헤테로시클로알킬기를 형성하며;단, R2, R3, R4 및 R5가 각각 H인 경우, R6은 비치환된 페닐, 4-플루오로페닐, 4-클로로페닐, 4-메톡시페닐, 4-메틸페닐, 3-메톡시페닐, 2-메톡시페닐 및 4-N,N-디메틸아미노페닐로부터 선택되지 않는다.