Alkoxy substituted imidazoquinolines

1. A compound of the formula (II):

wherein:

R 3 is selected from the group consisting of

—Z—Y—R 4 ,

—Z—Y—X—Y—R 4 ,

—Z—R 5 ,

—Z-Het,

—Z-Het′-R 4 , and

—Z-Het′-Y—R 4 ;

Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;

n is 0 or 1;

R 1 is selected from the group consisting of alkyl, alkoxyalkylenyl, aminoalkylenyl, hydroxyalkylenyl, dihydroxyalkylenyl and alkyl substituted by a group selected from the group consisting of —NH—C(O)-alkyl, —NH—S(O) 2 -alkyl, —NH—C(O)—NH-alkyl, —NH—C(O)—O-alkyl, phenoxy, tetrahydropyranyl, 1,1-dioxidoisothiazolidin-2-yl, and 2,2-dimethyl-1,3-dioxolan-4-yl;

R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, and alkoxyalkylenyl;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of

—S(O) 2 —N(R 8 )—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryloxy, arylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

Het is a non-aromatic heterocyclyl containing at least one nitrogen atom which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;

Het′ is a non-aromatic heterocyclylene containing at least one nitrogen atom which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo;

Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, and —C(R 6 )—O—;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;

and a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7;

with the proviso that Z can also be a bond when:

R 3 is —Z-Het, —Z-Het′-R 4 , or —Z-Het′-Y—R 4 ; or

R 3 is —Z—Y—R 4 or —Z—Y—X—Y—R 4 , and Y is selected from —S(O) 2 —N(R 8 )—,

—C(R 6 )—N(R 8 )—,

R 3 is —Z—R 5 and R 5 is

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 wherein R 3 is —Z—Y—R 4 or —Z—Y—X—Y—R 4 .

3. The compound or salt of claim 2 wherein Y is selected from the group consisting of

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

wherein Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, and —S(O) 2 —N(R 8 )—; W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; R 6 is selected from the group consisting of ═O or ═S; R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and alkoxyalkylenyl; and R 10 is selected from the group consisting of C 4-6 alkylene;

X is selected from the group consisting of alkylene, arylene, heterocyclylene, and heteroarylene; and

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and heterocyclyl, and wherein arylalkylenyl and heteroarylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, and alkoxy.

4. The compound or salt of claim 1 wherein R 3 is —Z—R 5 .

5. The compound or salt of claim 4 wherein R 5 is selected from the group consisting of

wherein R 7 is C 3-5 alkylene; R 10 is C 4-6 alkylene; and a and b are each independently 1 to 3.

6. The compound or salt of claim 1 wherein R 3 is —Z-Het, —Z-Het′-R 4 , or—Z-Het′-Y—R 4 .

7. The compound or salt of claim 6 wherein Z is a bond.

8. The compound or salt of claim 1 wherein R 3 is —Z—N(R 8 )—C(R 6 )—R 4 .

9. The compound or salt of claim 8 wherein R 8 is hydrogen, R 6 is ═O, and R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, cyano, aryloxy, arylalkyleneoxy, nitro, dialkylamino, heterocyclyl, trifluoromethyl, trifluoromethoxy, and in the case of alkyl, oxo.

10. The compound or salt of claim 1 wherein R 3 is —Z—N(R 8 )—S(O) 2 —R 4 .

11. The compound or salt of claim 10 wherein R 8 is hydrogen, and R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, cyano, aryloxy, arylalkyleneoxy, nitro, dialkylamino, heterocyclyl, trifluoromethyl, trifluoromethoxy, and in the case of alkyl, oxo.

12. The compound or salt of claim 11 wherein Z is ethylene or propylene, R 8 is hydrogen, and R 4 is C 1-3 alkyl.

13. The compound or salt of claim 1 wherein R 3 is

14. The compound or salt of claim 13 wherein R 7 is C 3-5 alkylene.

15. The compound or salt of claim 1 wherein R 3 is

16. The compound or salt of claim 15 wherein Z is a bond.

17. The compound or salt of claim 16 wherein R 6 is ═O or ═S, R 8 is hydrogen or C 1-4 alkyl, R 10 is C 4-6 alkylene, W is a bond, —C(O)—, or —S(O) 2 —, and R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, alkoxy, cyano, aryloxy, arylalkyleneoxy, nitro, dialkylamino, heterocyclyl, trifluoromethyl, trifluoroethoxy, and in the case of alkyl, oxo.

18. The compound or salt of claim 17 wherein R 3 is

19. A compound of the formula (VI):

wherein:

R 3-4 is selected from the group consisting of

—Z a —C(R 6 )—N(R 8 )—R 4 , and

Z a is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;

R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;

n is 0 or 1;

R 1 is selected from the group consisting of alkyl, alkoxyalkylenyl, aminoalkylenyl, hydroxyalkylenyl, dihydroxyalkylenyl and alkyl substituted by a group selected from the group consisting of —NH—C(O)-alkyl, —NH—S(O) 2 -alkyl, —NH—C(O)—NH-alkyl, —NH—C(O)—O-alkyl, phenoxy, tetrahydropyranyl, 1,1-dioxidoisothiazolidin-2-yl, and 2,2-dimethyl-1,3-dioxolan-4-yl;

R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, and alkoxyalkylenyl;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryloxy, arylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R 6 is selected from the group consisting of ═O and ═S;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;

A′ is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, —N(R 4 )—, and —CH 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a +b is ≦7;

or a pharmaceutically acceptable salt thereof.

20. The compound or salt of claim 19 wherein R 3-4 is

21. The compound or salt of claim 20 wherein R 6 is ═O or ═S, a and b are each independently 1 to 3, and A′ is selected from the group consisting of —CH 2 —, —S(O) 2 —, and —O—.

22. The compound or salt of claim 21 wherein Z a is methylene, R 6 is ═O, a is 1 or 2, b is 2, and A′ is —CH 2 —.

23. The compound or salt of claim 21 wherein Z a is methylene, R 6 is ═O, a and b are each 2, and A′ is —O—.

24. The compound or salt of claim 19 wherein Z a is a bond or alkylene.

25. The compound or salt of claim 1 wherein:

R 3 is selected from the group consisting of

with the proviso that Z can also be a bond when R 3 is

26. The compound or salt of claim 1 wherein n is 0.

27. The compound or salt of claim 1 wherein Het or Het′ is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, aziridinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl.

28. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of alkyl, hydroxyalkylenyl , dihydroxyalkylenyl, and alkyl substituted by a group selected from the group consisting of: —NH—C(O)-alkyl, —NH—S(O) 2 -alkyl, —NH—C(O)—NH-alkyl, tetrahydropyranyl, and 1,1-dioxidoisothiazolidin-2-yl.

29. The compound or salt of claim 28 wherein R 1 is selected from the group consisting of 4-[(methylsulfonyl)amino]butyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 2-(acetylamino)-2-methylpropyl, 2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl, 4-{[(isopropylamino)carbonyl]amino}butyl, 4-(1,1)-dioxidoisothiazolidin-2-yl)butyl, and tetrahydro-2H-pyran-4-ylmethyl.

30. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of alkyl, alkoxyalkylenyl, and hydroxyalklenyl.

31. The compound or salt of claim 30 wherein R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl, 2-methyoxyethyl, hydroxymethyl, and 2-hydroxyethyl.

32. The compound or salt of claim 1 wherein Z is alkylene.

33. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.

34. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 1 to the animal.

35. The compound or salt of claim 19 wherein R 1 is selected from the group consisting of alkyl, hydroxyalkylenyl, dihydroxyalkylenyl, and alkyl substituted by a group selected from the group consisting of: —NH—C(O)-alkyl, —NH—S(O) 2 -alkyl, —NH—C(O)—NH—alkyl, tetrahydropyranyl, and 1,1-dioxidoisothiazolidin-2-yl.

36. The compound or salt of claim 19 wherein R 2 is selected from the group consisting of alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.

37. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 8 in combination with a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 10 in combination with a pharmaceutically acceptable carrier.

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 13 in combination with a pharmaceutically acceptable carrier.

40. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 15 in combination with a pharmaceutically acceptable carrier.

41. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 19 in combination with a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 20 in combination with a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 20 in combination with a pharmaceutically acceptable carrier.

44. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 25 in combination with a pharmaceutically acceptable carrier.

45. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 8 to the animal.

46. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 10 to the animal.

47. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 13 to the animal.

48. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 15 to the animal.

49. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 19 to the animal.

50. A method of modulating cytokine biosynthesis in an animal by inducing the production of at least one of interferon-alpha or tumor necrosis factor-alpha, the method comprising administering an effective amount of a compound or salt of claim 20 to the animal.

51. The compound or salt of claim 4 , wherein R 1 is an alkyl group substituted with amino, —NH—S(O) 2 -alkyl, —NH—C(O)-alkyl, —NH—C(O)—NH-alkyl or 1,1-dioxidoisothiazolidin-2-yl.

52. The compound or salt of claim 1 , wherein R 1 is alkyl substituted with —NH—S(O) 2 -alkyl.

53. The compound or salt of claim 52 , wherein —NH—S(O) 2 -alkyl is —NH—S(O) 2 —CH 3 .

54. The compound or salt of claim 19 , wherein R 1 is an alkyl group substituted with amino, —NH—S(O) 2 -alkyl, —NH—C(O)-alkyl, —NH—C(O)—NH-alkyl or 1,1-dioxidoisothiazolidin-2-yl.

55. The compound or salt of claim 19 , wherein R 1 is alkyl substituted with —NH—S(O) 2 -alkyl.

56. The compound or salt of claim 55 , wherein —NH—S(O) 2 -alkyl is —NH—S(O) 2 —CH 3 .

57. The compound or salt of claim 1 , wherein

R 1 is alkyl substituted with —NH—S(O) 2 -alkyl;

R 2 is alkoxyalkylenyl;

R 3 is —Z—Y—R 4 ;

Z is alkylene;

Y is —N(R 8 )-Q-;

R 8 is H; Q is —C(R 6 )—;

R 6 is ═O; and

R 4 is alkyl substituted by mercapto.

58. The compound or salt of claim 1 selected from the group consisting of:

59. The compound or salt of claim 1 , wherein R 1 is hydroxyalkylenyl, dihydroxyalkylenyl, alkyl, or tetrahydro-2H-pyran-4-ylmethyl.

60. The compound or salt of claim 19 , wherein R 1 is hydroxyalkylenyl, dihydroxyalkylenyl, alkyl, or tetrahydro-2H-pyran-4-ylmethyl.