Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by VLA-4

1. A compound of formula I:

wherein:

R 1 is selected from the group consisting of C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, heteroaryl, and —NR 5 R 6 wherein R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1 to C 4 alkyl, or R 5 and R 6 together with the nitrogen atom pendent thereto form a heterocyclic ring;

R 2 is selected from the group consisting of C 1 to C 4 alkyl, C 2 to C 4 alkenyl, and C 2 to C 4 alkynyl; and

R 3 and R 4 are independently C 1 to C 3 alkyl or R 3 and R 4 together with the nitrogen atom pendent thereto join to form a heterocyclic ring;

or a pharmaceutically acceptable salt;

or an ester of the carboxylic acid alpha to the amino group thereof.

2. A compound of claim 1 , wherein the —OC(O)NR 3 R 4 group is in the para position of the phenyl ring.

3. A compound of claim 2 , wherein R 3 and R 4 together with the nitrogen atom pendent thereto form a heterocyclic ring.

4. A compound of claim 3 , wherein the heterocyclic ring is pyrrolidinyl.

5. A compound of claim 4 , wherein R 2 is C 1 to C 4 alkyl.

6. A compound of claim 5 , wherein R 2 is ethyl.

7. A compound of formula II:

wherein:

R 7 is C 1 to C 4 alkyl, C 1 to C 4 haloalkyl, or heteroaryl;

R 8 is C 1 to C 4 alkyl;

R 9 and R 10 are independently C 1 to C 3 alkyl, or R 9 and R 10 together with the nitrogen atom pendent thereto form a heterocyclic ring;

or a pharmaceutically acceptable salt;

or an ester of the carboxylic acid alpha to the amino group thereof.

8. A compound of claim 7 wherein the —OC(O)NR 9 R 10 group is in the para position of the phenyl ring.

9. A compound of claim 8 , wherein R 9 and R 10 together with the nitrogen atom pendent thereto form a heterocyclic ring.

10. A compound of claim 9 , wherein the heterocyclic ring is pyrrolidinyl.

11. A compound of claim 10 , wherein R 8 is C 1 to C 4 alkyl.

12. A compound of claim 11 , wherein R 8 is ethyl.

13. A compound of claim 12 , wherein R 7 is C 1 to C 4 alkyl.

14. A compound of claim 13 , wherein R 7 is selected from the group consisting of isopropyl and t-butyl.

15. A compound of claim 12 , wherein R 7 is C 1 to C 4 haloalkyl.

16. A compound of claim 15 , wherein R 7 is trifluoromethyl.

17. A compound of claim 12 , wherein R 7 is heteroaryl.

18. A compound of claim 17 , wherein R 7 is selected from the group consisting of furan-2-yl, furan-3-yl, thien-2-yl, and thien-3-yl.

19. A compound of formula III:

wherein:

R 11 and R 12 are independently C 1 to C 4 alkyl, or R 11 and R 12 together with the nitrogen atom pendent thereto form a heterocyclic ring;

R 13 is C 1 to C 4 alkyl; and

R 14 and R 15 are independently C 1 to C 3 alkyl or R 14 and R 15 together with the nitrogen atom pendent thereto form a heterocyclic ring;

or a pharmaceutically acceptable salt;

or an ester of the carboxylic acid alpha to the amino group thereof.

20. A compound of claim 19 wherein the —OC(O)NR 14 R 15 group is in the para position of the phenyl ring.

21. A compound of claim 20 , wherein R 14 and R 15 together with the nitrogen atom pendent thereto form a heterocyclic ring.

22. A compound of claim 21 , wherein the heterocyclic ring is pyrrolidinyl.

23. A compound of claim 22 , wherein R 13 is C 1 to C 4 alkyl.

24. A compound of claim 23 , wherein R 13 is ethyl.

25. A compound of claim 24 , wherein R 11 and R 12 are independently C 1 to C 4 alkyl.

26. A compound of claim 25 , wherein R 11 is ethyl and R 12 is isopropyl.

27. A compound of claim 24 , wherein R 11 and R 12 together with the nitrogen atom pendent thereto form a heterocyclic ring.

28. A compound of claim 27 , wherein said heterocyclic ring is selected from the group consisting of piperidin-1-yl and 3-thiapyrrolidin-1-yl.

29. A compound selected from the group consisting of:

N-[2-diethylamino-5-{N-ethyl-N-(trifluoroacetyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(iso-propylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(t-butylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(furan-2-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(piperidin-1-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(N-ethyl-N-iso-propylaminocarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(thien-3-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(thien-2-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(furan-3-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(3-thiapyrrolidin-1-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}phenylalanine;

N-[2-diethylamino-5-{N-ethyl-N-(thien-2-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}-phenylalanine t-butyl ester;

N-[2-diethylamino-5-{N-ethyl-N-trifluoromethylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}-phenylalanine t-butyl ester;

N-[2-diethylamino-5-{N-ethyl-N-t-butylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}-phenylalanine t-butyl ester; and

N-[2-diethylamino-5-{N-ethyl-N-furan-3-ylcarbonyl)amino}pyrimidin-4-yl]-L-4′-{(pyrrolidin-1-yl)carbonyloxy}-phenylalanine t-butyl ester;

or a pharmaceutically acceptable salt;

or an ester of the carboxylic acid alpha to the amino group thereof.

30. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of a compound according to claim 1 .