Inhibitors of protein kinases
View Patent ↗The present invention is directed to compounds of formula I-II and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
1. A compound having the formula:
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R 7c is halo;
wherein Y 2b is N, NH, C or CH; R 2d is H, C 1-8 alkylaminoC 1-8 alkylene, aminocarbonyl, aminocarbonylamino, aminocarbonylaminocarbonylamino, amino, oxo, aminoC 1-8 alkylene, aminocarbonylaminoC 1-8 alkylene, hydroxyC 1-8 alkylene, arylalkoxycarbonylamino; cyanoC 1-8 alkylenecarbonyl, cyanoC 1-8 alkylenecarbonylamino, hydroxyl, C 1-8 alkoxycarbonyl, alkoxycarbonylC 1-8 alkylene, optionally substituted by amino;
R 4g is selected from the group consisting of H, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonylamino, amino, aminocarbonylaminoC 1-8 alkylene, aminocarbonyl and aminosulfonyl; and
m is 0 or 1.
2. The compound of claim 1 , wherein R 7c is selected from the group consisting of F, Cl, and Br, cyano and aminocarbonyl.
3. The compound of claim 1 , wherein R 7c is F.
4. The compound of claim 1 , wherein R 7c is selected from the group consisting of F and Br.
5. A compound selected from the group consisting of:
1-(4-(4-(4-(2-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-yl amino)phenyl)piperazin-1-yl)ethanone; 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidine-3-carboxamide 1-(4-(4-(5-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, 4-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperazine-1-carboxamide, 2-(1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-yl)acetamide, benzyl 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl-)piperidin-4-ylcarbamate, 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, 1-(1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-yl)urea, N-(1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-yl)-2-cyanoacetamide, 3-(4-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperazin-1-yl)-3-oxopropanenitrile, tert-butyl 4-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)piperazine-1-carboxylate, and N-((4-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)piperazin-1-yl)carbamoyl)acetamide.
6. A composition comprising a compound of any one of the preceding claims in combination with a pharmaceutically acceptable carrier or diluent.
7. A kit comprising a composition of claim 6 , packaging and instructions for use.
8. A method for inhibiting syk, JAK kinase or a signal transduction pathway mediated at least in part by syk or JAK kinase activity comprising the step of contacting a cell with a compound of any one of the preceding claims.
9. A method for treating a condition or disorder mediated at least in part by syk or JAK kinase activity in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a composition of claim 6 .
10. The method of claim 9 , wherein the condition or disorder is selected from the group consisting of cardiovascular disease, inflammatory disease, immune-related disease and cell proliferative disorder.