Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activities
View Patent ↗Compounds useful in the treatment of mammalian cancers and especially human cancers according to Formula I are disclosed. Pharmaceutical compositions and methods of treatment employing the compounds disclosed herein are also disclosed.
1. A compound of Formula I,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:
X1 is halogen;
X2 is halogen;
Y is O, —NH;
each R1 is individually and independently halogen or H;
each R2 is individually and independently C1-C6 alkyl, deuteroC1-C6alkyl wherein the alkyl moiety can be partially or fully deuterated, C3-C8 branched alkyl, deuteroC3-C8 branched alkyl wherein the alkyl moiety can be partially or fully deuterated, or C3-C8 cycloalkyl;
R3 is C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, —NR6(R7), or —R4, wherein each alkyl, branched or cycloalkyl may be optionally substituted with cyano, C1-C6alkoxy, or hydroxy;
each R4 is independently and individually selected from the group consisting of
and wherein the symbol (##) is the point of attachment of the R4 moiety;
R5 is C1-C6 alkyl;
each R6 and R7 is individually and independently H, C1-C6 alkyl, or branched C3-C8 alkyl;
n is 0, 1, or 2.
2. The compound of claim 1 , wherein the compound is a compound of Formula Ia,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.
3. The compound of claim 2 , wherein the compound is a compound of Formula Ib,
or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
4. The compound of claim 3 , wherein the compound is a compound of Formula Ic,
or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
5. The compound of claim 4 , wherein R3 is C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
6. The compound of claim 4 , wherein R3 is —NR6(R7) or R4, or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
7. A compound of any one of claims 1 - 6 wherein R1 is fluoro or H and n is 1.
8. A compound of claims any one of 1 - 7 wherein R2 is C1-C6 alkyl or C3-C8 branched alkyl.
9. The compound of claim 1 , wherein the compound is a compound of Formula Id,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.
10. The compound of claim 9 , wherein the compound is a compound of Formula Ie,
or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
11. The compound of claim 10 , wherein the compound is a compound of Formula If,
or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
12. The compound of claim 11 , wherein R3 is C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
13. The compound of claim 11 , wherein R3 is —NR6(R7) or R4 or a pharmaceutically acceptable salt, enantiomer stereoisomer or tautomer thereof.
14. A compound of any one of claims 9 - 13 wherein R1 is fluoro or H and n is 1.
15. A compound of claims any one of 9 - 14 wherein R2 is C1-C6 alkyl or C3-C8 branched alkyl.
16. A compound selected from the group consisting of N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-isobutyramidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide, 1-(4-(2,5-difluoro-4-(1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-3-methylurea, N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(5-chloro-2-fluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(5-chloro-4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, and N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-(ethoxy-d5)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
17. The compound N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
18. The compound N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
19. The compound N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
20. The compound N-(4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
21. The compound N-(2,5-difluoro-4-((2-isobutyramidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, or tautomer thereof.
22. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
23. The composition of claim 22 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.