10-(DI(PHENYL)METHYL)-4-HYDROXY-8,9,9A,10-TETRAHYDRO-7H-PYRROLO[1 ',2':4,5]PYRAZINO[1,2-B]PYRIDAZINE-3,5-DIONE DERIVATIVES AND RELATED COMPOUNDS AS INHIBITORS OF THE ORTHOMYXOVIRUS REPLICATION FOR TREATING INFLUENZAThe present disclosure refers to 10-(di(phenyl)methyl)-4- hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1';2':4,5]pyrazino[1,2- b]pyridazine-3,5-dione derivatives and related compounds of Formula (A) as inhibitors of the orthomyxovirus replication for treating influenza.(Formula A) (A) A preferred specific compound is e.g. (9aR, 10S)-10-((S)-(4- fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-4-hydroxy-8,9,9a,10- tetrahydro-7H-pyrrolo[1';2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione (example 1).A compound of formula (a):or a pharmaceutically acceptable salt thereof, wherein:y is a group of the formulawherein the dotted line represents a bond linking the group to formula (a);g is h or a group selected from: r0，–c(o)r0，–c(o)-or0，-c(rg)2-o-c(o)r0，–c(rg)2-o-c(o)-or0，-p(＝o)(or0)2，-(crg)2-o-p(＝o)(or0)2，–c(o)-n(r0)2and-c (r)g)2-o-c(o)n(r0)2，wherein each r0independently is h or a group selected from: c1-c6alkyl, phenyl, pyridyl, c3-c7cycloalkyl radicals, and containing one or twoa 3-6 membered heterocyclic ring having as ring members a heteroatom selected from n, o and s; and each r other than h0optionally substituted with one or two groups selected from: halogen, cn, -oh, amino, c1-4alkyl, coor, phenyl, c1-4alkoxy radical, c1-4haloalkyl, c1-4haloalkoxy, and a 3-6 membered heterocyclic ring containing one or two heteroatoms selected from n, o and s as ring members, and which is optionally substituted with one or two groups selected from: halogen, cn, -oh, oxo, amino, c1-4alkyl, phenyl, c1-4alkoxy radical, c1-4haloalkyl and c1-4a haloalkoxy group;and each rgindependently selected from h and c1-4an alkyl group;r1is h, halogen, cn, coor, -conr2or c optionally substituted by one or two groups selected from1-c6alkyl groups: halogen, -or and-nr2；r is independently at each occurrence h or optionally-or or-nr2substituted c1-c6an alkyl group;z1is n, and z2is c (r)2；or z1is ch, and z2is nr, o, s or ch2；z3is ch2，q，-ch2-ch2-，-q-ch2-，–ch2-q-，-ch2-q-ch2-，-ch2-ch2-ch2-or cx2wherein x is halogen;q is selected from-nr-, o, s, so and so2；r2selected from h, halogen, cn, c1-4alkyl radical, said c1-4alkyl is optionally substituted with up to three groups independently selected from: halogen, cn, c1-4alkyl, -or, c1-4haloalkoxy, -nr2and c and1-4a haloalkyl group;each r3is optionally present in a solvent containing z2and z3and is independently selected from halogen, -or, c1-4haloalkyl, c1-4haloalkoxy, oxo, cn, -nr2and c optionally substituted with up to three groups independently selected from1-4alkyl groups: halogen, cn, c1-4alkyl, -or, c1-4haloalkoxy, -nr2and c1-4a haloalkyl group;n is 0 to 2;ar1and ar2each independently represents phenyl or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from n, o and s as ring members, and ar1and ar2each independently substituted with up to three groups selected from: halogen, c1-4alkyl radical, c1-4haloalkyl, c1-4alkoxy radical, c1-4halogenoalkoxy, c2-4alkyne and cn;and ar1and ar2optionally by the formula-c (r)l)2bridges of-l-are joined together to form a tricyclic group, wherein ar1and ar2each optionally substituted with up to three groups independently selected from: halogen, c1-4alkyl radical, c1-4haloalkyl, c1-4alkoxy radical, c1-4halogenoalkoxy, c2-4alkyne and cn;r is independently at each occurrence h or c1-c4alkyl radical, said c1-c4alkyl is optionally substituted with up to three groups independently selected from: halogen, oh, oxo, c1-4alkyl radical, c1-4alkoxy radical, c1-4haloalkoxy and c1-4a haloalkyl group;l is selected from s, s ═ o, so2，o，nr，c(rl)2and cf2(ii) a and isand each rlindependently is h or c1-2an alkyl group; with the proviso that the compound is not a compound selected from the group consisting of:112-benzhydryl-4-hydroxy-7, 8,9, 10-tetrahydro-12h-dipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;212- (bis (3-fluorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-bipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;312- (bis (4-chlorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-bipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;412- (bis (3-chlorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-bipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;512- (bis (4-fluorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-bipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;613-benzhydryl-4-hydroxy-8, 9,10, 11-tetrahydro-7h, 13h-pyridazino [1',6':4,5][1,2,4]triazino [1,2-a][1,2]diaza derivatives-3, 5-diketones;713- (bis (3-fluorophenyl) methyl) -4-hydroxy-8, 9,10, 11-tetrahydro-7h, 13h-pyridazino [1',6':4,5][1,2,4]triazino [1,2-a][1,2]diaza derivatives-3, 5-diketones;8(r) -12- (bis (3-fluorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-dipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;9(s) -12- (bis (3-fluorophenyl) methyl) -4-hydroxy-7, 8,9, 10-tetrahydro-12h-dipyridazino [1,2-a:1',6' -d ] [1,2,4] triazine-3, 5-dione;10(9ar,10s) -10-benzhydryl-4-hydroxy-8, 9,9a, 10-tetrahydro-7h-pyrrolo [1',2':4,5] pyrazino [1,2-b ] pyridazine-3, 5-dione;11(9ar,10r) -10-benzhydryl-4-hydroxy-8, 9,9a, 10-tetrahydro-7h-pyrrolo [1',2':4,5] pyrazino [1,2-b ] pyridazine-3, 5-dione;12(9as,10r) -10-benzhydryl-4-hydroxy-8, 9,9a, 10-tetrahydro-7h-pyrrolo [1',2':4,5] pyrazino [1,2-b ] pyridazine-3, 5-dione;13(9as,10s) -10-benzhydryl-4-hydroxy-8, 9,9a, 10-tetrahydro-7h-pyrrolo [1',2':4,5] pyrazino [1,2-b ] pyridazine-3, 5-dione;14(9ar,10s) -10- ((r) - (3-fluorophenyl) (phenyl) methyl) -4-hydroxy-8, 9,9a, 10-te...
인플루엔자의 치료를 위한 오르토믹소바이러스 복제의 억제제로서의 10-(디(페닐)메틸)-4-히드록시-8,9,9A,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-B]피리다진-3,5-디온 유도체 및 관련 화합물본 개시내용은 인플루엔자의 치료를 위한 오르토믹소바이러스 복제의 억제제로서의 10-(디(페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1';2':4,5]피라지노[1,2-b]피리다진-3,5-디온 유도체 및 화학식 (A)의 관련 화합물에 관한 것이다. 바람직한 구체적 화합물은 예를 들어 (9aR, 10S)-10-((S)-(4-플루오로페닐)(3-(트리플루오로메틸)페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1';2':4,5]피라지노[1,2-b]피리다진-3,5-디온 (실시예 1)이다.[이미지]화학식 A의 화합물 또는 그의 제약상 허용되는 염:[이미지]여기서Y는 하기 화학식의 기:[이미지]이고, 여기서 파선은 화학식 A에 상기 기를 연결하는 결합을 나타내고;G는 H이거나 또는 R0, -C(O)R0, -C(O)-OR0, -C(RG)2-O-C(O)R0, -C(RG)2-O-C(O)-OR0, -P(=O)(OR0)2, -(CRG)2-O-P(=O)(OR0)2, -C(O)-N(R0)2, 및 -C(RG)2-O-C(O)N(R0)2로부터 선택된 기이고,여기서 각각의 R0은 독립적으로 H이거나 또는 C1-C6 알킬, 페닐, 피리딜, C3-C7 시클로알킬, 및 고리원으로서 N, O 및 S로부터 선택된 1 또는 2개의 헤테로원자를 함유하는 3-6원 헤테로시클릭 고리로부터 선택된 기이고; H가 아닌 각각의 R0은 할로, CN, -OH, 아미노, C1-4 알킬, COOR, 페닐, C1-4 알콕시, C1-4 할로알킬, C1-4 할로알콕시, 및 고리원으로서 N, O 및 S로부터 선택된 1 또는 2개의 헤테로원자를 함유하며 할로, CN, -OH, 옥소, 아미노, C1-4 알킬, 페닐, C1-4 알콕시, C1-4 할로알킬, 및 C1-4 할로알콕시로부터 선택된 1 또는 2개의 기로 임의로 치환된 3-6원 헤테로시클릭 고리로부터 선택된 1 또는 2개의 기로 임의로 치환되고;각각의 RG는 H 및 C1-4 알킬로부터 독립적으로 선택되고;R1은 H, 할로, CN, COOR*, -CONR*2, 또는 할로, -OR* 및 -NR*2로부터 선택된 1 또는 2개의 기로 임의로 치환된 C1-C6 알킬이고;R*는 각 경우에 독립적으로 H이거나 또는 -OR 또는 -NR2로 임의로 치환된 C1-C6 알킬이고;Z1은 N이고, Z2는 C(R)2이거나;또는 Z1은 CH이고, Z2는 NR, O, S, 또는 CH2이고;Z3은 CH2, Q, -CH2-CH2-, -Q-CH2-, -CH2-Q-, -CH2-Q-CH2-, -CH2-CH2-CH2- 또는 CX2이며, 여기서 X는 할로이고;Q는 -NR-, O, S, SO, 및 SO2로부터 선택되고;R2는 H, 할로, CN, 및 할로, CN, C1-4 알킬, -OR, C1-4 할로알콕시, -NR2 및 C1-4 할로알킬로부터 독립적으로 선택된 3개 이하의 기로 임의로 치환된 C1-4 알킬로부터 선택되고;각각의 R3은 Z2 및 Z3을 함유하는 고리의 임의의 탄소 원자 상에 임의로 존재하는 치환기이고, 할로, -OR, C1-4 할로알킬, C1-4 할로알콕시, 옥소, CN, -NR2, 및 할로, CN, C1-4 알킬, -OR, C1-4 할로알콕시, -NR2 및 C1-4 할로알킬로부터 독립적으로 선택된 3개 이하의 기로 임의로 치환된 C1-4 알킬로부터 독립적으로 선택되고;n은 0-2이고;Ar1 및 Ar2는 각각 독립적으로 페닐 또는 고리원으로서 N, O 및 S로부터 선택된 1-3개의 헤테로원자를 함유하는 5-6원 헤테로아릴 고리를 나타내고, Ar1 및 Ar2는 각각 할로, C1-4 알킬, C1-4 할로알킬, C1-4 알콕시, C1-4 할로알콕시, C2-4 알킨 및 CN으로부터 독립적으로 선택된 3개 이하의 기로 치환되고;Ar1 및 Ar2는 임의로 화학식 -C(RL)2-L-의 가교에 의해 함께 연결되어 트리시클릭 기를 형성하고, 여기서 Ar1 및 Ar2는 각각 할로, C1-4 알킬, C1-4 할로알킬, C1-4 알콕시, C1-4 할로알콕시, C2-4 알킨 및 CN으로부터 독립적으로 선택된 3개 이하의 기로 임의로 치환되고;R은 각 경우에 독립적으로 H이거나 또는 할로, OH, 옥소, C1-4 알킬, C1-4 알콕시, C1-4 할로알콕시 및 C1-4 할로알킬로부터 독립적으로 선택된 3개 이하의 기로 임의로 치환된 C1-C4 알킬이고;L은 S, S=O, SO2, O, NR, C(RL)2 및 CF2로부터 선택되고;각각의 RL은 독립적으로 H 또는 C1-2 알킬이고; 단 화합물은 하기로부터 선택된 화합물 및 이들 화합물의 제약상 허용되는 염이 아니다:1 12-벤즈히드릴-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;2 12-(비스(3-플루오로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;3 12-(비스(4-클로로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;4 12-(비스(3-클로로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;5 12-(비스(4-플루오로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;6 13-벤즈히드릴-4-히드록시-8,9,10,11-테트라히드로-7H,13H-피리다지노[1',6':4,5][1,2,4]트리아지노[1,2-a][1,2]디아제핀-3,5-디온;7 13-(비스(3-플루오로페닐)메틸)-4-히드록시-8,9,10,11-테트라히드로-7H,13H-피리다지노[1',6':4,5][1,2,4]트리아지노[1,2-a][1,2]디아제핀-3,5-디온;8 (R)-12-(비스(3-플루오로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;9 (S)-12-(비스(3-플루오로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;10 (9aR,10S)-10-벤즈히드릴-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;11 (9aR,10R)-10-벤즈히드릴-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;12 (9aS,10R)-10-벤즈히드릴-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;13 (9aS,10S)-10-벤즈히드릴-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;14 (9aR,10S)-10-((R)-(3-플루오로페닐)(페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;15 (9aR,10R)-10-(비스(3-플루오로페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;16 (9aR,10S)-10-(비스(3-플루오로페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;17 (9aS,10R)-10-((S)-(3-클로로페닐)(페닐)메틸)-4-히드록시-8,9,9a,10-테트라히드로-7H-피롤로[1',2':4,5]피라지노[1,2-b]피리다진-3,5-디온;18 (10aS,11R)-11-벤즈히드릴-4-히드록시-7,8,10a,11-테트라히드로-10H-피리다지노[1',6':4,5]피라지노[2,1-c][1,4]옥사진-3,5-디온;19A 12-벤즈히드릴-7-히드록시-3,4,12,12a-테트라히드로-2H-피리다지노[1',6':4,5]피라지노[2,1-b][1,3]옥사진-6,8-디온;19B 12-벤즈히드릴-7-히드록시-3,4,12,12a-테트라히드로-2H-피리다지노[1',6':4,5]피라지노[2,1-b][1,3]옥사진-6,8-디온;20 11-(비스(3-플루오로페닐)메틸)-4-히드록시-8,9-디히드로-7H,11H-피라졸로[1,2-a]피리다지노[1,6-d][1,2,4]트리아진-3,5-디온;21 12-(1,1-디페닐에틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;22 12-(비스(2-플루오로페닐)메틸)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;23A 12-벤즈히드릴-4-히드록시-10-메틸-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;23B 12-벤즈히드릴-4-히드록시-10-메틸-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;24 12-벤즈히드릴-4-히드록시-7-메틸-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;25A 12-벤즈히드릴-4-히드록시-7,10-디메틸-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;25B 12-벤즈히드릴-4-히드록시-7,10-디메틸-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;26A 12-(6,11-디히드로디벤조[b,e]티에핀-11-일)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;26B 12-(6,11-디히드로디벤조[b,e]티에핀-11-일)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;27A 12-(6,11-디히드로디벤조[b,e]옥세핀-11-일)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;27B 12-(6,11-디히드로디벤조[b,e]옥세핀-11-일)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;28A 12-(7,8-디플루오로-6,11-디히드로디벤조[b,e]티에핀-11-일)-4-히드록시-7,8,9,10-테트라히드로-12H-디피리다지노[1,2-a:1',6'-d][1,2,4]트리아진-3,5-디온;28B 12-(7,8-디플루오로...