Substituted 4-hydroxypyrimidine-5-carboxamides
View Patent ↗The present invention relates to substituted 4-hydroxypyrimidine-5-carboxamides useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
1. A compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:
R 1 is selected from —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, and —C 1-6 alkoxy, wherein in R 1 said alkyl, alkenyl, alkynyl, and alkoxy are each optionally substituted with 1, 2, or 3 R 8 substituents;
R 2 and R 3 are each independently selected from hydrogen, and —C 1-10 alkyl optionally substituted with 1, 2, or 3 substituents selected from halo, hydroxyl, and —OC 1-10 alkyl;
V, W, X, Y, and Z are each independently selected from N and CH, wherein V, W, X, Y or Z is substituted with one or two nitrogens, and at least one of V or W must be N; and
R 8 is selected from halogen, hydroxyl, —C 1-10 alkyl, —C 1-10 alkenyl, —C 1-10 alkynyl, cyano, oxo, C 2-6 -difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluorethoxy.
2. A compound of claim 1 wherein R 1 is selected from —C 1-10 alkyl and —C 1-6 alkoxy, said alkyl, and alkoxy are each optionally substituted with 1, 2, or 3 R 8 substituents.
3. A compound of claim 1 wherein R 1 is —C 1-6 alkoxy.
4. A compound of claim 1 wherein R 2 and R 3 are each independently selected from —C 1-10 alkyl optionally substituted with 1, 2, or 3 substituents selected from halo, hydroxyl, and —OC 1-10 alkyl.
5. A compound of claim 4 , wherein R 2 and R 3 are each methyl.
6. A compound of claim 1 , wherein W and X are each N, and V, Y and Z are each CH.
7. A compound of claim 1 , wherein V and W are each N, and X, Y, and Z are each CH.
8. A compound according to claim 1 , selected from 4-Hydroxy-N-{1-[6-(4-methoxyphenyl)pyridin-3-yl]-1-methylethyl}-2-pyridazin-3-ylpyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 selected from a pharmaceutically acceptable salt of 4-Hydroxy-N-{1-[6-(4-methoxyphenyl)pyridin-3-yl]-1-methylethyl}-2-pyridazin-3-ylpyrimidine-5-carboxamide.
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, and pharmaceutically acceptable carrier.