8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression

1. A compound of formula I

wherein

Q is selected from the group consisting of CX and nitrogen;

X is selected from the group consisting of hydrogen, halogen and an electron-withdrawing group;

Z is selected from the group consisting of oxygen, sulfur, and NR 2 ;

p is zero or one;

A is chosen from the group consisting of alkyl, pyridinyl, pyrimidinyl, benzimidazolyl, imidazolyl, furanyl, pyrrolyl, thiazolyl, quinolinyl, morpholinyl, cyclopentyl, aryl, substituted alkyl, substituted pyridinyl, substituted pyrimidinyl, substituted benzimidazolyl, substituted imidazolyl, substituted furanyl, substituted pyrrolyl, substituted thiazolyl, substituted quinolinyl, substituted morpholinyl, substituted cyclopentyl, substituted aryl, cyano and halogen;

W is (C 1 -C 6 )alkylene;

q is zero or one;

y is zero or an integer selected from 1, 2 and 3;

R 2 and R 3 are selected independently for each occurrence from the group consisting of hydrogen and (C 1 -C 6 )alkyl;

R 4 is selected from the group consisting of alkyl, alkoxy, pyranyl, benzopyranyl, pyridinyl, furanyl, cyclohexyl, aryl, substituted alkyl, substituted pyranyl, substituted benzopyranyl, substituted pyridinyl, substituted furanyl, substituted cyclohexyl, substituted aryl, and C(O)NHR 7 ; and

R 7 is selected from the group consisting of alkyl and haloalkyl.

2. A compound according to claim 1 wherein p is equal to one.

3. A compound according to claim 1 where in p is equal to zero, q is equal to zero, and A is cyano, CF 3 or a halogen.

4. A compound in which p is zero and q is zero of formula II according to claim 1

wherein

Q is selected from the group consisting of CX and nitrogen;

X is selected from the group consisting of hydrogen, halogen and an electron-withdrawing group;

A is chosen from the group consisting of alkyl, pyridinyl, pyrimidinyl, benzimidazolyl, imidazolyl, furanyl, pyrrolyl, thiazolyl, quinolinyl, morpholinyl, cyclopentyl, aryl, substituted alkyl, substituted pyridinyl, substituted pyrimidinyl, substituted benzimidazolyl, substituted imidazolyl, substituted furanyl, substituted pyrrolyl, substituted thiazolyl, substituted quinolinyl, substituted morpholinyl, substituted cyclopentyl, and substituted aryl;

y is zero or an integer selected from 1, 2 and 3;

R 2 and R 3 are selected independently for each occurrence of (CR 2 R 3 ) from the group consisting of hydrogen and (C 1 -C 6 )alkyl; and

R 4 is selected from the group consisting of alkyl, alkoxy, pyranyl, benzopyranyl, pyridinyl, furanyl, cyclohexyl, aryl, substituted alkyl, substituted pyranyl, substituted benzopyranyl, substituted pyridinyl, substituted furanyl, substituted cyclohexyl, and substituted aryl.

5. A compound according to claim 1 wherein Q is nitrogen of formula:

6. A compound according to claim 1 wherein Q is CX of formula:

7. A compound according to claim 6 wherein X is chosen from H, F, Cl, CN, CF 3 and OCF 3 .

8. A compound according to claim 1 wherein y is 1 or 2 and R 2 and R 3 are independently selected from hydrogen and methyl.

9. A compound according to claim 1 wherein y is zero and R 4 is a residue selected from a monocycle, a bicycle, a substituted monocycle and a substituted bicycle said residue containing at least one oxygen atom.

10. A compound according to claim 9 wherein R 4 is chosen from pyranyl, benzopyranyl, furanyl, optionally substituted with halogen, and a hydroxyl- or alkoxy-substituted carbocycle optionally substituted with halogen.

11. A compound according to claim 9 wherein R 4 is chosen from

wherein R 6 in each occurrence is hydrogen or fluorine, R 8 is selected from hydrogen, lower alkyl, a halogen, and CF 3 , and “a” and “b” represent stereogenic centers.

12. A compound according to claim 11 wherein R 4 is chosen from

13. A compound according to claim 11 wherein the carbon marked with an “a” is of the (R)— absolute configuration.

14. A compound according to claim 13 wherein R 4 is

15. A compound according to claim 13 wherein R 4 is

16. A compound according to claim 1 wherein R 4 is C(O)NHR 7 .

17. A compound according to claim 1 wherein p and q are both zero and A is chosen from pyridinyl, pyrimidinyl, benzimidazolyl, imidazolyl, furanyl, pyrrolyl, thiazolyl, quinolinyl, morpholinyl, cyclopentyl, substituted pyridinyl, substituted pyrimidinyl, substituted benzimidazolyl, substituted imidazolyl, substituted furanyl, substituted pyrrolyl, substituted thiazolyl, substituted quinolinyl, substituted morpholinyl, substituted cyclopentyl, aryl, substituted aryl, (C 1 -C 6 )alkyl and substituted (C 1 -C 6 )alkyl.

18. A compound according to claim 17 wherein A is chosen from piperidinyl, morpholinyl, pyrimidinyl, methyl, pyridinyl, 2-aminopyrimidinyl, acetamidophenyl, propyl, hydroxyphenyl, carboxyphenyl, methanesulfonamidophenyl, halopyridinyl, methoxypyridinyl, methylpyridinyl, chloromethyl, furanyl, pyrrolyl, ethyl, butyl, imidazolyl, N-methylimidazolyl, phenyl, (aminosulfonyl)phenyl, (dialkylamino)pyrimidinyl, mono- and di-hydroxypyrimidinyl, (trifluoromethyl)pyridinyl, oxopyridinyl, (alkylthio)pyrimidinyl, (trifluoromethyl)phenyl, cyanophenyl, pyridine-N-oxide, methoxyphenyl, methylpyrrolyl, methylfuranyl, tetrahydrofuranyl, methylphenyl, cyclopentyl, thiazolyl, halophenyl, benzyl, (methoxycarbonyl)phenyl, indolyl, quinolinyl, and (trifluoromethoxy)phenyl.

19. A compound according to claim 1 wherein Z is sulfur, p is one, q is zero and A is an optionally substituted alkyl.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1 .