Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones

1. A compound of the formula:

wherein

X 1 is O, S(O) n , or C═O;

wherein

n is 0, 1 or 2;

Ar 1 is aryl or heteroaryl;

R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hydroxyalkyl, or hydroxycycloalkyl; and

R 2 is hydroxyalkyl.

2. The compound of claim 1 , wherein Ar 1 is aryl.

3. The compound of claim 2 , wherein Ar 1 is optionally substituted phenyl.

4. The compound of claim 3 , wherein Ar 1 is phenyl optionally substituted one or more time with alkyl, halo, haloalkyl or alkoxy.

5. The compound of claim 4 , wherein Ar 1 is 2,4-disubstituted phenyl.

6. The compound of claim 5 , wherein Ar 1 is 2,4-di-halophenyl.

7. The compound of claim 6 , wherein Ar 1 is 2,4-difluorophenyl.

8. The compound of claim 2 , wherein X 1 is O.

9. The compound of claim 8 , wherein R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl.

10. The compound of claim 9 , wherein R 1 is tetrahydropyranyl, 1-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, iso-propyl, cyclohexyl, 1-(2-hydroxyethyl)-3-hydroxypropyl, 1-hydroxymethyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-1-methylethyl, 1-(2-methoxyethyl)-3-methoxypropyl, N-methanesulfonyl piperidinyl, ethyl, methyl, 2-hydroxypropyl, neopentyl, 1,1-dimethyl-2-hydroxyethyl, 1-(hydroxymethyl)propyl, 2-methylpropyl, cyclopropylmethyl, cyclobutyl, 1,2-dimethyl-2-hydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl.

11. The compound of claim 10 , wherein R 2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-(2-hydroxyethyl)-3-hydroxypropyl.

12. The compound of claim 11 , wherein:

R 1 is (R)-2-hydroxy-1-methylethyl or (S)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl or (S)-2-hydroxypropyl.

13. The compound of claim 8 , wherein R 1 is hydroxyalkyl.

14. The compound of claim 13 , wherein R 2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, or 1-(2-hydroxyethyl)-3-hydroxypropyl.

15. The compound of claim 14 , wherein:

R 1 is (R)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl;

R 1 is (R)-2-hydroxy-1-methylethyl and R 2 is (S)-2-hydroxypropyl;

R 1 is (S)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl; or

R 1 is (S)-2-hydroxy-1-methylethyl and R 2 is (S)-2-hydroxypropyl.

16. The compound of claim 1 , wherein R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl.

17. The compound of claim 16 , wherein R 1 is hydroxyalkyl.

18. The compound of claim 16 , wherein X 1 is O.

19. The compound of claim 18 , wherein Ar 1 is aryl.

20. The compound of claim 19 , wherein Ar 1 is 2,4-dihalophenyl.

21. The compound of claim 20 , wherein Ar 1 is 2,4-di-fluorophenyl.

22. The compound of claim 21 , wherein R 1 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, or 1-(2-hydroxyethyl)-3-hydroxypropyl.

23. The compound of claim 1 , wherein said compound is of the formula:

wherein:

m is from 0 to 4;

each R 3 independently is: alkyl; alkoxy; halo; or haloalkyl; and

R 1 and R 2 are as defined in claim 1 .

24. The compound of claim 23 , wherein R 1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or heterocyclyl.

25. The compound of claim 24 , wherein R 1 is tetrahydropyranyl, 1-methyl-2-methoxyethyl, cyclopentyl, cyclopropyl, iso-propyl, cyclohexyl, 1-(2-hydroxyethyl)-3-hydroxypropyl, 1-hydroxymethyl-2-hydroxypropyl, 1-hydroxymethyl-3-hydroxypropyl, 1-methylpropyl, 2-hydroxy-1-methylethyl, 1-(2-methoxyethyl)-3-methoxypropyl, N-methanesulfonyl piperidinyl, ethyl, methyl, 2-hydroxypropyl, neopentyl, 1,1-dimethyl-2-hydroxyethyl, 1-(hydroxymethyl)propyl, 2-methylpropyl, cyclopropylmethyl, cyclobutyl, 1,2-dimethyl-2-hydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl.

26. The compound of claim 25 , wherein R 2 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-(2-hydroxyethyl)-3-hydroxypropyl.

27. The compound of claim 26 , wherein:

R 1 is (R)-2-hydroxy-1-methylethyl or (S)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl or (S)-2-hydroxypropyl.

28. The compound of claim 23 , wherein R 1 is hydroxyalkyl.

29. The compound of claim 28 , wherein:

R 1 is (R)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl;

R 1 is (R)-2-hydroxy-1-methylethyl and R 2 is (S)-2-hydroxypropyl;

R 1 is (S)-2-hydroxy-1-methylethyl and R 2 is (R)-2-hydroxypropyl; or

R 1 is (S)-2-hydroxy-1-methylethyl and R 2 is (S)-2-hydroxypropyl.

30. The compound of claim 28 , wherein n is 1 and R 3 is halo.

31. The compound of claim 28 , wherein n is 2 and R 3 is halo.

32. The compound of claim 1 , wherein said compound is selected from:

6-(2,4-Difluoro-phenoxy)-8-(2-hydroxy-ethyl)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-(3-hydroxy-propyl)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-(2-hydroxy-propyl)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-[3-hydroxy-1-(2-hydroxy-ethyl)-propyl]-2-((S)-2-methoxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-Cyclopentylamino-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-Cyclopropylamino-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-isopropylamino-8H-pyrido[2,3-d]pyrimidin-7-one;

2-Cyclohexylamino-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-[3-hydroxy-1-(2-hydroxy-ethyl)-propylamino]-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((1R,2R)-2-hydroxy-1-hydroxymethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((S)-3-hydroxy-1-hydroxymethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((R)-3-hydroxy-1-hydroxymethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-((S)-sec-Butylamino)-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-((S)-sec-Butylamino)-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-((R)-sec-Butylamino)-6-(2,4-difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-((S)-2-methoxy-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-[3-methoxy-1-(2-methoxy-ethyl)-propylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-(1-methanesulfonyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-Cyclopropylamino-6-(2,4-difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-isopropylamino-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-ethylamino-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one;

2-((S)-sec-Butylamino)-6-(2,4-difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-((R)-sec-Butylamino)-6-(2,4-difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-((R)-2-hydroxy-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((S)-2-hydroxy-propyl)-2-((S)-2-hydroxy-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-(2,2-dimethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((S)-1-hydroxymethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((R)-1-hydroxymethyl-propylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-((S)-2-hydroxy-propylamino)-8H-pyrido [2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-((R)-2-hydroxy-propylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((R)-1-hydroxymethyl-propylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-2-isobutylamino-8H-pyrido[2,3-d]pyrimidin-7-one;

2-(Cyclopropylmethyl-amino)-6-(2,4-difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-Cyclobutylamino-6-(2,4-difluoro-phenoxy)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-(2,2-dimethyl-propylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

6-(2,4-Difluoro-phenoxy)-2-((S)-2-hydroxy-1,2-dimethyl-propylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one; and

6-(2,4-Difluoro-phenoxy)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-(

6-(2,4-Difluoro-phenoxy)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one.

33. A composition comprising:

(a) a pharmaceutically acceptable excipient; and

(b) a compound of claim 1 .

34. A method for treating arthritis, comprising administering to a patient a therapeutically effective amount of a compound of claim 1 .