Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
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Abstract
The present invention relates to a cyclic urea compound of formula I:
as defined herein. The invention is also directed to the process for its preparation, pharmaceutical composition comprising it and its pharmaceutical use, as an inhibitor on a protein kinase. Thus, it is useful for preventing or treating a physiological disorder capable of being modulated by inhibiting the activity of a protein kinase, such as a solid tumor.
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Citations
58 Claims
- 1. The compound of formula I:
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8. A compound of formula I wherein
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11. The compound of formula I:
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36. The compound of formula I:
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38. The compound of formula I:
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39. The compound of formula I:
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42. The compound of formula I:
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43. The compound of formula I:
- 48. The compound of formula (IC):
- 50. The compound of formula (IA):
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55. A compound selected from the group consisting of:
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(S)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (S)-5-methyl-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (S)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-methyl-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-methyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-4-methyl-3-quinol-4-ylmethyl-5-thioxo-1-(4-trifluoromethylsulfanylphenyl)imidazolidin-2-one trifluoroacetate; (R)-5-isopropyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-isopropyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-(4-hydroxybenzyl)-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-(4-hydroxybenzyl)-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-5-(1-hydroxyethyl)-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; (R)-1-(3-hydroxypyrid-4-ylmethyl)-5-methyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; 5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; 1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate; 1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate 1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate; {4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl} cyclopropanecarboxamide trifluoroacetate; 5,5-dimethyl-1-[2-(pyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;
compound with trifluoroacetic acid;N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}isobutyramide;
compound with trifluoroacetic acid;N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide;
compound with trifluoroacetic acid;1-(2-aminopyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione hydrochloride; {4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}pyridine-2-carboxamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-piperid-1-ylpropionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-[4-(2-hydroxyethyl)piperazin-1-yl]propionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-morpholin-4-ylpropionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-pyrrolidin-1-ylpropionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(4-methylpiperazin-1-yl)propionamide trifluoroacetate; 1-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-phenylurea; 1-[2-(6-ethylpyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 5,5-dimethyl-1-[2-(4-methylpyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 5,5-dimethyl-1-[2-(6-methylpyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 1-[2-(4,6-dimethylpyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethyl sulfanylphenyl)-imidazolidine-2,4-dione; 1-[2-(3,5-dichloropyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione; 5,5-dimethyl-1-[2-(pyrid-4-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 5,5-dimethyl-1-[2-(pyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(2-oxoazepan-1-yl)propionamide; 3-(benzylmethylamino)-N-{4-[5,5-dimethyl-2,4-di-oxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide; 4,5-diacetoxy-6-acetoxymethyl-2-(3-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)-imidazolidin-1-ylmethyl]pyrid-2-yl}thioureidoacetic acid; 5,5-dimethyl-1-[2-(5-methylpyrid-2-ylamino)pyridin-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3,5-dimethoxybenzamide trifluoroacetate; 5,5-dimethyl-1-[2-(pyrazin-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(3-methylpiperid-1-yl)propionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(3,5-dimethylpiperid-1-yl)propionamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-methoxybenzamide trifluoroacetate; {4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}pyrazine-2-carboxamide trifluoroacetate; {4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}thiophene-2-carboxamide trifluoroacetate; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-4-methylbenzamide;
compound with trifluoroacetic acid;1-isoquinolin-5-yl-5,5-dimethyl-3-(4-trifluoro-methylsulfanylphenyl)imidazolidine-2,4-dione; 3-(4-acetylpiperazin-1-yl)-N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide; 3-[4-(2-diethylaminoethyl)piperazin-1-yl]-N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(2,6-dimethylmorpholin-4-yl)propionamide; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(4-pyrrolidin-1-ylpiperid-1-yl)propionamide; N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-2-(4-pyrrolidin-1-ylpiperid-1-yl)acetamide; 5,5-dimethyl-1-[2-(4-methylpyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 5,5-dimethyl-1-[2-(6-morpholin-4-ylpyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 1-[2-(2,6-dimethylpyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione; methyl 5-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-ylamino}pyridine-2-carboxylate; 1-[2-(2,6-dimethoxypyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione; 1-[2-(6-fluoropyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione; and 1-[2-(6-methoxypyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione, or a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.
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Specification