Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
The present disclosure provides methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds useful in the treatment of p38 kinase mediated diseases, such as lymphoma and auto-inflammatory disease, including rheumatoid arthritis, having the structure of Formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 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 selected from the group consisting of H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, or —CF 3 ;
R 2 is selected from the group consisting of H, methyl, cyano, or fluoro;
R 3 is selected from the group consisting of:
R 4 is selected from the group consisting of H, methyl, OH, and O—CH 3 ;
R 5 is H or C 1 -C 3 alkyl;
m is 1 or 2;
n is 0 or 1;
p is 1; and
q is 0 or 1.
2. The compound of claim 1 , wherein the compound has the structure of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, or —CF 3 ;
R 2 is selected from the group consisting of H, methyl, cyano, or fluoro;
R 3 is
R 4 is selected from the group consisting of H, methyl, OH, and —OCH 3 ;
R 5 is H or C 1 -C 3 alkyl;
m is 1 or 2; and
n is 0 or 1.
3. The compound of claim 2 , wherein R 3 is selected from the group consisting of 3,5-difluoropyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoro-3-methylpyridin-2-yl, 6-fluoropyridin-2-yl, 6-fluoro-4-methylpyridin-2-yl, 3-fluoro-5-methylpyridin-2-yl, and 5-fluoropyridin-2-yl.
4. The compound of claim 3 , wherein the compound has the structure 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. The compound of claim 4 , wherein the compound is selected from the group consisting of:
3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2″,2″-terpyridin]-2-one;
3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one.
6. The compound of claim 3 , wherein the compound is selected from the group consisting of:
3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.
7. The compound of claim 1 , wherein the compound has the structure of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, or —CF 3 ;
R 2 is selected from the group consisting of H, methyl, cyano, or fluoro;
R 4 is selected from the group consisting of H, methyl, OH, and —OCH 3 ;
R 5 is H or C 1 -C 3 alkyl;
m is 1 or 2; and
n is 0 or 1.
8. The compound of claim 7 , wherein the compound has the structure 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. The compound of claim 8 , wherein the compound is selected from the group consisting of:
3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.
10. The compound of claim 1 , wherein the compound has the structure of Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, or —CF 3 ;
R 2 is selected from the group consisting of H, methyl, cyano, or fluoro;
R 4 is selected from the group consisting of H, methyl, OH, and —OCH 3 ;
R 5 is H or C 1 -C 3 alkyl;
p is 1; and
q is 0 or 1.
11. The compound of claim 10 , wherein the compound has the structure of Formula (VII):
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.
12. The compound of claim 11 , wherein the compound is selected from the group consisting of:
3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;
3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;
3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and
3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.
13. 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.
14. The pharmaceutical composition of claim 13 , 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.