Cytokine inhibitors
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Abstract
A compound of Formula I:
Each variable is defined in the specification. This invention relates to a method of decreasing a level of a cytokine (e.g., TNFα or interlukine such as IL-1β) in a subject with a compound of Formula I. It also relates to a method of treating a disorder mediated by an overproduction of a cytokine with such a compound.
8 Citations
16 Claims
- 1. A compound of the formula:
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7. A compound chosen from
2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; -
1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(2-morpholinoethyl)urea; 1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(2-methoxyethy)urea; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyethanamine; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-morpholinoethanamine; 2-(3-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N, N-dimethylmethanamine; 2-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl) methylamino)ethanol; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl) methyl)ethanamine; 2-(3-(5-((4-fluorophenoxy)methyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl acetate; 2-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methanol; 2-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; N-methyl-2-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazin-6-amine; ethyl 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxylate; ethyl 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetate; 3-(3-(imidazo[1,2-b]pyridazin-2-yOphenyl)-1,2,4-oxadiazole-5-carboxylic acid; 3-(3-(imidazo[1,2-b]pyridazin-2-yOphenyl)-1,2,4-oxadiazole-5-carboxamide; 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetic acid; 2-(3-(5-(methylthiomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(methylsulfonylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; (3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine; 2-(3-(2-methoxyethoxy)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(2-methoxyethoxy)-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(2-methmethoxy)-5-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2-(3-(5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl)-5-(2-methoxyethoxy)phenyl)imidazo[1,2-b]pyridazine; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazol-5-yl)methanol; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylic acid; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(pyridin-2-yl)-1,2,4-oxadiazole-5-carboxamide; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)-N-(2,2,2-trifluoroethyl)-1,2,4-oxadiazole-5-carboxamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)acetamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2,2,2-trifluoroacetamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-chloroacetamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-chlorobenzamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-nitrobenzenesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-cyanobenzamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-bromobenzamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-fluorobenzenesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-3-chlorobenzenesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-4-methylbenzenesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzyl)-2-fluorobenzenesulfonamide; N-(2-(diethylamino)ethyl)-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide; N-butyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide; 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(2-tetrahydrofuran-2-yl)methyl)acetamide; N-cyclopentyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide; 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-N-(2-methoxyethyl)acetamide; 2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)-1-morpholinoethanone; N-cyclopropyl-2-(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)acetamide; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(2-morpholinoethyl)-1,2,4-oxadiazol-5-carboxamide; N-ethyl-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide; N-cyclopentyl-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)(morpholino)methanone; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(2-methoxyethyl)-1,2,4-oxadiazole-5-carboxamide; N-(2-(dimethylamino)ethyl)-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide; (4-ethylpiperazin-1-yl)(3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methanone; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-(thiophen-2-ylmethyl)-1,2,4-oxadiazole-5-carboxamide; N-(2-hydroxyethyl)-3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazole-5-carboxamide; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N,N-dimethyl-1,2,4-oxadiazole-5-carboxamide; (3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)(pyrrolidin-1-yl)methanone; 3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide; 2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide; (2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(pyrrolidin-1-yl)methanone; N-(2-hydroxyethyl)-2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide; ethyl 2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinate; N-cyclopropyl-2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)nicotinamide; (2-(3-(imidazo[1,2-b]pyridazin-2-yl)phenylamino)pyridin-3-yl)(morpholino)methanone; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-((2-methoxyethylamino)methyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3-(5-((2-(dimethylamino)ethylamino)methyl)-1,2,4-oxadiazol-3-yl)-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)-5-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanesulfonamide; N-(3-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide; 2-(3-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazol[1,2-b]pyridazine; N1-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)ethane-1,2-diamine; N1-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-N2,N2-dimethylethane-1,2-diamine; 2-(3-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine; 2,2,2-trifluoro-N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acetamide; ethyl 2-((3-(3-(imidazo[1,2-b]pyridazin-2-yl) phenyl)-1,2,4-oxadiazol-5-yl)methyl-amino) -2-oxoacetate; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methoxyacetamide; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopentanecarboxamide; ethyl 3-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl-amino) -3-oxopropanoate; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)-phenyl)-1,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)isobutyramide; 3-((3-(imidazo[1 ,2-b]pyridazin-2-yl)benzylamino)methyl)benzonitrile; N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-4-chlorobenzamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-2-methoxyacetamide; N-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-cyanobenzenesulfonamide; and 1-(3-(imidazo[1,2-b]pyridazin-2-yl)benzyl)-3-(thiophen-2-ylmethyl)urea; and
/or at least one pharmaceutically acceptable salt thereof. - View Dependent Claims (14)
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- 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula:
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15. A compound that is 2-(3-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine, and/or at least one pharmaceutically acceptable salt thereof.
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16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and 2-(3-(5-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine, and/or at least one pharmaceutically acceptable salt thereof.
Specification