Inhibitors of syk and JAK protein kinases
View Patent ↗The present invention is directed to compounds of formula I-V and tautomers thereof or pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk 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 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 kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
1. A method for inhibiting syk or JAK kinase or a signal transduction pathway mediated at least in part by syk kinase activity comprising the step of contacting a cell with a compound
having the formula:
or a tautomer thereof or a pharmaceutically acceptable salt thereof,
wherein
each X and Y is independently selected from the group consisting of: CH 2 and O;
each E 1 is independently selected from the group consisting of C 1-8 alkyl, heteroaryl, heterocyclyl, halo, C 1-8 haloalkyl, C 1-8 alkoxy, cyano, C 1-8 acyl, aminoC 1-8 alkyl, aminosulfonyl, C 1-8 alkylsulfonyl and acylamino; and
R 5 is heteroaryl; and
the subscript n is 0, 1, 2, 3 or 4.
2. A method for treating a condition or disorder selected from the group consisting of Non-Hodgkin's Lymphoma, Burkett's lymphoma, T-cell leukemia, thrombocytopenia and rheumatoid arthritis in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound having the formula:
or a tautomer thereof or a pharmaceutically acceptable salt thereof,
wherein
each X and Y is independently selected from the group consisting of: CH 2 and O;
each E 1 is independently selected from the group consisting of C 1-8 alkyl, heteroaryl, heterocyclyl, halo, C 1-8 haloalkyl, C 1-8 alkoxy, cyano, C 1-8 acyl, aminoC 1-8 alkyl, aminosulfonyl, C 1-8 alkylsulfonyl and acylamino; and
R 5 is heteroaryl; and
the subscript n is 0, 1, 2, 3 or 4.
3. The method of claim 2 , wherein said disease is selected rheumatoid arthritis, Non Hodgkin's Lymphoma.
4. The method of claim 2 , wherein said disease is selected from the group consisting of thrombocytopenia.
5. The method of claim 2 , wherein said inflammatory disease is rheumatoid arthritis.
6. The method of claim 2 , wherein said disease is Burkitt's lymphoma.
7. The method of claim 2 , wherein said disease is T-cell leukemia.
8. The method of claim 1 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
10. The method of claim 2 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
11. The method of claim 2 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
12. The method of claim 3 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
13. The method of claim 3 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
14. The method of claim 4 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
15. The method of claim 4 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
16. The method of claim 5 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
17. The method of claim 5 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
18. The method of claim 6 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
19. The method of claim 6 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
20. The method of claim 7 wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.
21. The method of claim 7 , wherein said compound has the formula:
or a tautomer or a pharmaceutically acceptable salt thereof.