5-substituted indazoles as kinase inhibitors
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Abstract
The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts,
wherein A, R1, R2, R3 and m, are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), Cdc7, AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.
37 Citations
7 Claims
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1. A compound of formula (I)
- View Dependent Claims (2, 3, 4, 5, 6, 7)
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2. The compound according to claim 1, wherein
R2 is hydrogen, or ReRfN-alkyl-C(O)— - ;
R4 is alkyl, alkoxyalkyl, aryl, cycloalkyl, RjRkN—
or RjRkN-alkyl-;R5 is alkyl, aryl or heteroaryl; Rj and Rk are each independently hydrogen, alkyl, or aryl; Rii is alkoxyalkyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, ZaZbNalkyl-, or ZcZdNC(O)—
;Za and Zb are each independently hydrogen or alkyl; Zc and Zd are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkylalkyl or heterocyclealkyl; m is 0; and b is 1 or 2.
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3. The compound according to claim 1, wherein
R2 is hydrogen; -
R4 is alkyl, alkoxyalkyl or aryl; R5 is alkyl or aryl; Rii is aryl, arylalkyl, cycloalkyl, cycloalkylalkyl or halogen; b is 1 or 2; and m is 0.
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4. The compound according to claim 1, wherein
R4 is alkoxyalkyl, alkyl, aryl, or RjRkN— - ;
R5 is alkyl, aryl, or heteroaryl; Rj and Rk are alkyl; Rii is alkoxyalkyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, ZaZbNalkyl or ZcZdNC(O)—
;Za and Zb are each independently hydrogen or H2Nalkyl-C(O)—
;Zc and Zd are each independently hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, or heterocyclealkyl; b is 1; and m is 0.
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5. The compound according to claim 1, wherein
R2 is hydrogen, heterocyclecarbonyl, or arylcarbonyl; -
R4 is alkyl, alkoxyalkyl, aryl, RjRkN—
or RjRkN-alkyl-;R5 is alkyl, or aryl; Rj and Rk are each independently hydrogen, alkyl, aryl, or arylalkyl; Rii is aryl, arylalkyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, halogen, heteroaryl, heterocyclealkyl, heterocyclecarbonyl, or ZcZdNC(O)—
;Zc and Zd are each independently hydrogen, alkyl, alkoxyalkyl, aryl; m is 0; and b is 1 or 2.
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6. The compound of claim 1, that is selected from the group consisting of:
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5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazole; 5-[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 2-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile; 3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile; 4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzonitrile; 5-{1-[2-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{1-[3-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{1-[3-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; methyl 3-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate; methyl 4-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}benzoate; 5-[1-(2,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3,5-dimethylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2,3-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(2,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-(3,5-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine; 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-[(1-methylpiperidin-4-yl)carbonyl]-1H-indazol-3-amine; 5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazole; 5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazole; 5-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazole; 5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole; 5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine; 5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl)-1H-indazol-3-amine; 5-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine; 2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol; 5-[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole; 1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]-1-phenylethanol; 1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-2-ol; 3-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]propan-1-ol; 1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-1,2,3-benzotriazole; 5-{4-[(phenylthio)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole; 5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole; 5-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole; 5-[4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole; 5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole; 1-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]cyclohexanol; 5-[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]-1H-indazole; 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole; 5-[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]-1H-indazole; [1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](phenyl)methanone; N,N-diethyl-N-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}amine; 5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazole; 5-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine; 5-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-1H-indazol-3-amine; N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}-N′
-(3-methylphenyl)urea;[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](3-chlorophenyl)methanone; [1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl](cyclopropyl)methanone; 5-[5-cyclopropyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; N1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]methyl}glycinamide; (4-fluorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone; (4-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone; (3-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone; (2-chlorophenyl)[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone; cyclopentyl[4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl]methanone; 1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid; 5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl)benzyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine; 5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; [4-(1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-5-yl](tetrahydro-2H-pyran-4-yl)methanone; 5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-{1-benzyl-5-[(4-methylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-ol; 1-acetyl-5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 1-benzyl-4-(1H-indazol-5-yl)-N,N-dimethyl-1H-1,2,3-triazole-5-carboxamide; N,1-dibenzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; 5-[1-benzyl-5-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 2-{2-[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]ethyl}-1H-isoindole-1,3(2H)-dione; 5-{4-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole; 5-{4-[(2,6-dichlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-1H-indazole; 5-[5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 1-{[1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazole; 5-[1-benzyl-5-(piperidin-1-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[5-(2-methylphenyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 5-[1-benzyl-5-(morpholin-4-ylcarbonyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; 5-[1-benzyl-5-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 5-{1-benzyl-5-[3-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine; 5-{1-benzyl-5-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine; N-{3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide; N-{4-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenyl}acetamide; 5-{1-benzyl-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine; 5-[1-benzyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-phenylbenzamide; 3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]-N-benzylbenzamide; 5-[1-benzyl-5-(1-methyl-1H-indol-5-yl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 5-[1-benzyl-5-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 5-[1-benzyl-5-(3-morpholin-4-ylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-amine; 1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-4-amine; 3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]phenol; 3-[4-(3-amino-1H-indazol-5-yl)-1-benzyl-1H-1,2,3-triazol-5-yl]benzamide; 5-{1-benzyl-5-[4-(methylsulfonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-amine; 1-benzyl-4-(1H-indazol-5-yl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-(2-isopropoxyethyl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethyl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-cyclopentyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-(cyclopentylmethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-ethyl-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-(2-methoxyethyl)-N-methyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-phenyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-(4-chlorophenyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-4-(1H-indazol-5-yl)-N-(2-morpholin-4-ylethyl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-[2-(dimethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-N-propyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-[3-(dimethylamino)propyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-[2-(diethylamino)ethyl]-4-(1H-indazol-5-yl)-N-methyl-1H-1,2,3-triazole-5-carboxamide; N,1-dibenzyl-N-ethyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; N,1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; (3R)-1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidin-3-ol; 1-{[1-benzyl-4-(1H-indazol-5-yl)-1H-1,2,3-triazol-5-yl]carbonyl}piperidine-4-carboxamide; 5-{1-benzyl-5-[(2,6-dimethylmorpholin-4-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1-benzyl-1H-1,2,3-triazol-4-yl}-1H-indazole; 5-{1-benzyl-5-[(4-phenylpiperazin-1-yl)carbonyl]-1H-1,2,3-triazol-4-yl}-1H-indazole; 1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; 1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide; and 1-benzyl-N-[3-(1H-imidazol-1-yl)propyl]-4-(1H-indazol-5-yl)-1H-1,2,3-triazole-5-carboxamide.
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7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, in combination with a pharmaceutically suitable carrier.
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2. The compound according to claim 1, wherein
Specification
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Current AssigneeAbbvie Incorporated
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Original AssigneeAbbvie Incorporated
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InventorsAkritopoulou-Zanze, Irini, Wakefield, Brian D., Mack, Helmut, Turner, Sean C., Gasiecki, Alan F., Sarris, Kathy A., Kalvin, Douglas M., Michmerhuizen, Melissa J., Shuai, Qi, Patel, Jyoti R., Bakker, Margaretha, Teusch, Nicole, Kovar, Peter J., Djuric, Stevan W., Long, Andrew J., Vasudevan, Anil, George, Dawn, Wang, Lu, Li, Biqin, Moore, N. St. John, Hobson, Adrian D., Woods, Keith W., Miyashiro, Julie M., Penning, Thomas D., Gracias, Vijaya J., Johnson, Eric F., Swann, Steven L. Jr.
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Primary Examiner(s)Otton, Alicia L
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Application NumberUS12/327,991Publication NumberTime in Patent Office1,895 DaysField of SearchNoneUS Class Current514/228.2CPC Class CodesA61P 25/28 for treating neurodegenerat...A61P 35/00 Antineoplastic agentsC07D 401/14 containing three or more he...C07D 403/04 directly linked by a ring-m...C07D 403/14 containing three or more he...C07D 405/04 directly linked by a ring-m...C07D 405/14 containing three or more he...C07D 409/14 containing three or more he...C07D 413/04 directly linked by a ring-m...C07D 413/14 containing three or more he...C07D 417/04 directly linked by a ring-m...C07D 417/14 containing three or more he...C07D 471/04 Ortho-condensed systemsC07D 487/04 Ortho-condensed systemsC07D 513/04 Ortho-condensed systems