Polycyclic guanine derivatives and use thereof

1. A compound having the formula:

or a pharmaceutically acceptable salt, thereof, wherein:

R 1 is —C 1 -C 6 alkyl or -alkylene-O—C 1 -C 6 alkyl;

R 2 is alkyl, aryl, -alkylene-aryl, heterocycloalkyl or heteroaryl, any of which may be optionally substituted with R 5 ;

R 3 is alkyl, -alkylene-aryl, cycloalkyl, -alkylene-cycloalkyl or -alkylene-heterocycloalkyl, wherein an aryl, cycloalkyl or heterocycloalkyl group can be optionally substituted with R 7 ;

each occurrence of R 4 is independently H or —C 1 -C 6 alkyl, or both R 4 groups together with the carbon atom to which they are attached, join to form a 3- to 7-membered cycloalkyl group, which can be optionally fused with a benzene ring;

R 5 represents from 1 to 3 groups, each independently selected from alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, halo, —CN, —C(O)OR 6 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —S(O) 2 NHR 6 , —OH, —O-alkyl, haloalkyl, —O-haloalkyl and —NHC(O)N(R 6 ) 2 , where an aryl, heterocycloalkyl or heteroaryl group may be optionally substituted with up to 3 groups, each independently selected from —C 1 -C 6 alkyl, halo, —C(O)OR 6 and —C(O)N(R 6 ) 2 ;

each occurrence of R 6 is independently H, —C 1 -C 6 alkyl, aryl or heterocycloalkyl, wherein an aryl or heterocycloalkyl group can be optionally substituted with up to 3 groups, each independently selected from alkyl, —O-alkyl, halo, —CN, haloalkyl, -alkylene-C(O)N(R 8 ) 2 , —C(O)N(R 8 ) 2 , —C(O)OR 8 , —C(O)-heterocycloalkyl, —C(O)-alkyl or —N(R 8 ) 2 ;

R 7 represents from 1 to 3 groups, each independently selected from —C 1 -C 6 alkyl, halo, aryl, —N(R 8 ) 2 , —C(O)OR 8 , —C(O)N(R 8 ) 2 and haloalkyl; and

each occurrence of R 8 is independently H, —C 1 -C 6 alkyl or aryl, provided that when one of R 4 is hydrogen, and the other is ethyl or propyl, and R 1 is ethyl, then R 2 and R 3 both cannot be benzyl.

2. The compound of claim 1 , wherein R 1 is —C 1 -C 6 alkyl.

3. The compound of claim 2 , wherein R 1 is methyl or ethyl.

4. The compound of claim 2 , wherein R 2 is phenyl, which can be optionally substituted with R 5 .

5. The compound of claim 2 , wherein R 2 is pyridyl, which can be optionally substituted with R 5 .

6. The compound of claim 2 , wherein R 2 is piperidinyl or piperazinyl, each of which can be optionally substituted with R 5 .

7. The compound of claim 2 , wherein R 3 is —CH 2 -phenyl, wherein the phenyl group can be optionally substituted with R 7 .

8. The compound of claim 2 , wherein each R 4 is independently selected from H, methyl, isopropyl, sec-butyl or t-butyl.

9. The compound of claim 8 , wherein one occurrence of R 4 is H and the other is C 1 -C 6 alkyl.

10. The compound of claim 9 , wherein one occurrence of R 4 is H and the other is isopropyl.

11. The compound of claim 8 , wherein each occurrence of R 4 is methyl.

12. The compound of claim 2 , wherein both R 4 groups, together with the carbon atom to which they are attached, join to form a 5- or 6-membered cycloalkyl group.

13. The compound of claim 12 , wherein the group formed is a 5-membered cycloalkyl group that is fused to a benzene ring.

14. The compound of claim 4 , wherein R 3 is —CH 2 -phenyl, and wherein the phenyl moiety of the R 3 group can be optionally substituted with R 7 .

15. The compound of claim 14 , wherein one occurrence of R 4 is H and the other is isopropyl.

16. The compound of claim 14 , wherein each occurrence of R 4 is methyl.

17. The compound of claim 15 , wherein R 2 is:

and R 3 is:

18. The compound of claim 16 , wherein R 2 is:

and R 3 is:

19. The compound of claim 1 , having the formula:

and pharmaceutically acceptable salts, solvates, esters and prodrugs thereof, wherein:

R 1 is —C 1 -C 6 alkyl;

R 2 is -A-B,

A is alkyl, aryl, -alkylene-aryl, heterocycloalkyl or heteroaryl, any of which may be optionally substituted with R 5 ;

B is alkyl, aryl, -alkylene-aryl, heterocycloalkyl or heteroaryl, any of which may be optionally substituted with R 5 such that at least one of A and B is heteroaryl;

R 3 is -alkylene-aryl, wherein the aryl moiety can be optionally substituted with R 7 ;

each occurrence of R 4 is independently H or —C 1 -C 6 alkyl, or both R 4 groups together with the carbon atom to which they are attached, join to form a 3- to 7-membered cycloalkyl group, which can be optionally fused with a benzene ring;

R 5 represents from 1 to 3 groups, each independently selected from aryl, heterocycloalkyl, heteroaryl, halo, —CN, —C(O)OR 6 , —C(O)R 6 , —C(O)N(R 6 ) 2 , —S(O) 2 NHR 6 , —OH, —O-alkyl, haloalkyl, —O-haloalkyl and —NHC(O)N(R 6 ) 2 , where an aryl, heterocycloalkyl or heteroaryl group may be optionally substituted with up to 3 groups, each independently selected from —C 1 -C 6 alkyl, halo, —C(O)OR 6 and —C(O)N(R 6 ) 2 ;

each occurrence of R 6 is independently H, —C 1 -C 6 alkyl, aryl or heterocycloalkyl;

R 7 represents from 1 to 3 groups, each independently selected from —C 1 -C 6 alkyl, halo, aryl, —N(R 8 ) 2 , —C(O)OR 8 , —C(O)N(R 8 ) 2 and haloalkyl; and

each occurrence of R 8 is independently H, —C 1 -C 6 alkyl or aryl.

20. The compound of claim 19 , wherein R 1 is methyl or ethyl.

21. The compound of claim 19 , wherein A is 6-membered heteroaryl.

22. The compound of claim 19 , wherein B is 6-membered heteroaryl.

23. The compound of claim 19 , wherein R 2 is:

24. The compound of claim 19 , wherein R 3 is benzyl.

25. The compound of claim 19 , wherein R 3 is:

26. The compound of claim 19 , wherein each occurrence of R 4 is independently, H, methyl or isopropyl.

27. The compound of claim 26 , wherein each occurrence of R 4 is methyl.

28. The compound of claim 26 , wherein one occurrence of R 4 is H and the other is isopropyl.

29. The compound of claim 20 , wherein R 2 is:

30. The compound of claim 29 , wherein R 3 is:

31. The compound of claim 30 , wherein each occurrence of R 4 is independently, H, methyl or isopropyl.

32. A compound being any of the compounds numbered 1 through 160 as set forth in the above specification, or a pharmaceutically acceptable salt, or ester thereof.

33. A composition comprising one or more compounds of claim 1 , or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier.

34. A composition comprising one or more compounds of claim 19 or a pharmaceutically acceptable salt, or ester or thereof, and a pharmaceutically acceptable carrier.