Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
The present disclosure provides methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds useful in the treatment of p38 kinase mediated diseases, such as lymphoma and auto-inflammatory disease, having the structure of Formula (I): wherein R 1 , R 2 , R 3 and X are as defined in the detailed description; pharmaceutical compositions comprising at least one of the compounds; and methods for treating p38 kinase mediated diseases using the compound.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is chloro or bromo;
R 2 is —H or methyl; and
R 3 is selected from the group consisting of 2,4-difluoro-3-methylphenyl, 2,4-difluoro-5-methylphenyl, 5-methylpyridin-3-yl, and 4-methylpyrimidin-2-yl.
2. Compound according to claim 1 of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is chloro or bromo; and
R 2 is —H or methyl.
3. Compound according to claim 2 selected from the group consisting of:
3-chloro-4-((2,4-difluoro-3-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((2,4-difluoro-3-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((2,4-difluoro-3-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((2,4-difluoro-3-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((2,4-difluoro-3-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5″,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((2,4-difluoro-3-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one; and
3-chloro-4-((2,4-difluoro-3-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((2,4-difluoro-3-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.
4. Compound according to claim 1 of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is chloro or bromo; and
R 2 is —H or methyl.
5. Compound according to claim 4 selected from the group consisting of:
3-chloro-4-((2,4-difluoro-5-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((2,4-difluoro-5-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((2,4-difluoro-5-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((2,4-difluoro-5-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((2,4-difluoro-5-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((2,4-difluoro-5-methylbenzyl)oxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((2,4-difluoro-5-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-4-((2,4-difluoro-5-methylbenzyl)oxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.
6. Compound according to claim 1 of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is chloro or bromo; and
R 2 is —H or methyl.
7. Compound according to claim 6 selected from the group consisting of:
3-chloro-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-bromo-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-chloro-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-bromo-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-chloro-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-4-((5-methylpyridin-3-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one.
8. Compound according to claim 1 of Formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is chloro or bromo; and
R 2 is —H or methyl.
9. Compound according to claim 8 selected from the group consisting of:
3-bromo-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-chloro-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-chloro-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-bromo-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′-bipyridin]-2-one;
3-chloro-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-4-((4-methylpyrimidin-2-yl)methoxy)-2H-[1,4′:2′,2″-terpyridin]-2-one.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , further comprising a therapeutically effective amount of an active pharmaceutical ingredient selected from the group consisting of anti-inflammatory drugs, anti-atherosclerotic drugs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, kinase inhibitors, cytokine blockers and inhibitors of cell adhesion molecules.
12. A method for treating lymphoma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof.
13. The method of claim 12 , wherein the subject is a mammal selected from a canine and a humane.