Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activities

1. A compound of Formula I,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein:

A is

wherein the “*” is connected to the R1-substituted phenyl ring and the “#” is connected to the amide carbonyl;

W is —(CH 2 ) n -pyrazole optionally substituted with —(R3) q ;

X1 is halogen or C1-C6 alkyl;

X2 is halogen or C1-C6 alkyl;

each R1 is individually and independently halogen, H, C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, branched C3-C6 alkoxy, or cyano;

each R2 is individually and independently C1-C6 alkoxy, C1-C6 alkylamino, H, halogen, C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, branched C3-C6 alkoxy, branched C3-C6 alkylamino, or cyano;

each R3 is individually and independently C1-C6 alkyl, branched C3-C8 alkyl, halogen, —(CH 2 ) r —CN, —(CH 2 ) r —OR6, —(CH 2 ) r —NR6(R7), —(CH 2 ) r —SO 2 —C1-C6-alkyl, —(CH 2 ) r —C(O)NR6(R7), —(CH 2 ) r —C(O)—C4-C6-heterocyclyl, or —(CH 2 ) r —C4-C6-heterocyclyl, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;

Z1 is CR4 or N;

Z2 is CR5 or N;

with the proviso that only one of Z1 and Z2 are simultaneously N;

R4 and R5 are independently and independently H, halogen, C1-C6 alkyl, C3-C8 branched alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, branched C3-C6 alkoxy, or cyano;

each R6 and R7 is individually and independently H, C1-C6 alkyl, or branched C3-C8 alkyl;

m is 0, 1, or 2;

n is 0, 1, or 2;

p is 1, 2, or 3;

q is 0, 1, or 2; and

r 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 W is

5. The compound of claim 4 , wherein R3 is C1-C6 alkyl or branched C3-C8 alkyl.

6. The compound of claim 4 , wherein R3 is methyl.

7. The compound of claim 3 wherein the A ring is

and R2 is C1-C6 alkoxy.

8. The compound of claim 7 wherein R2 is ethoxy.

9. The compound of claim 2 , wherein the compound has the Formula:

10. The compound of claim 1 , wherein the compound is of Formula Ic,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

11. The compound of claim 10 , wherein the compound is of Formula Id,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

12. The compound of claim 11 , wherein W is

13. The compound of claim 12 , wherein R3 is C1-C6 alkyl or branched C3-C8 alkyl.

14. The compound of claim 12 , wherein R3 is methyl.

15. The compound of claim 11 wherein the A ring is

and R2 is C1-C6 alkoxy.

16. The compound of claim 15 wherein R2 is ethoxy.

17. The compound of claim 11 , wherein the compound has the Formula:

18. The compound of claim 1 , wherein the compound is of Formula Ie,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

19. The compound of claim 18 , wherein the compound is of Formula If,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

20. The compound of claim 19 , wherein W is

21. The compound of claim 20 , wherein R3 is C1-C6 alkyl or branched C3-C8 alkyl.

22. The compound of claim 20 , wherein R3 is methyl.

23. The compound of claim 19 wherein the A ring is

and R2 is C1-C6 alkoxy.

24. The compound of claim 23 wherein R2 is ethoxy.

25. The compound of claim 19 , wherein the compound has the Formula

26. A compound selected from the group consisting of N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(2,5-difluoro-4-((2-(1-isopropyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, 4-ethoxy-N-(4-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, N-(4-((2-(1H-pyrazol-4-yl)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-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide, and N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

27. The compound N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

28. A pharmaceutical composition, comprising a compound of claim 27 and a pharmaceutically acceptable carrier.

29. The composition of claim 28 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

30. The compound 4-ethoxy-N-(4-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

31. A pharmaceutical composition, comprising a compound of claim 30 and a pharmaceutically acceptable carrier.

32. The composition of claim 31 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.

33. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

34. The pharmaceutical composition of claim 33 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.