IP Library › Granted Patent US 7,939,526

Granted Patent B2

US 7,939,526 · App. 10/596,117 · Granted May 10, 2011

Sulfone substituted imidazo ring ethers

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Quick Facts

Patent No.: US 7,939,526
App. No.: 10/596,117
Granted: May 10, 2011
Kind: B2

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Abstract

Imidazo ring compounds (e.g., imidazoquinolines, 6,7,8,9-tetrahydroimidazoquinolines, imidazonaphthyridines, and 6,7,8,9-tetrahydroimidazonaphthyridines) with a sulfide-, sulfinyl-, or sulfonyl-containing ether substituent at the 1-position, pharmaceutical compositions containing the compounds, intermediates, methods of making the compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases, are disclosed.

Claims (267)

1. A compound of the Formula Ia:

wherein:

X 1-1 and X 1-2 are independently selected from the group consisting of C 1-10 alkylene, C 4-10 alkenylene, and C 4-10 alkynylene; wherein the terminal carbon atoms of alkenylene and alkynylene are tetrahedral;

Z is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of:

C 1-10 alkyl,

C 2-10 alkenyl,

C 2-10 alkynyl,

aryl,

aryl-C 1-10 alkylenyl,

aryloxy-C 1-10 alkylenyl,

C 1-10 alkylarylenyl,

heteroaryl,

heteroaryl-C 1-10 alkylenyl,

heteroaryloxy-C 1-10 alkylenyl,

C 1-10 alkylheteroarylenyl,

heterocyclyl,

heterocyclyl-C 1-10 alkylenyl, and

C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, aryl-C 1-10 alkylenyl, aryloxy-C 1-10 alkylenyl, C 1-10 alkylarylenyl, heteroaryl, heteroaryl-C 1-10 alkylenyl, heteroaryloxy-C 1-10 alkylenyl, C 1-10 alkylheteroarylenyl, heterocyclyl, and heterocyclyl-C 1-10 alkylenyl substituted by one or more substituents independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, hydroxy-C 1-10 alkyl, halo-C 1-10 alkyl, halo-C 1-10 alkoxy, halogen, nitro, hydroxy, cyano, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, amino,

C 1-10 alkylamino, di(C 1-10 alkyl)amino, and in the case of C 1-10 alkyl, C 2-10 alkenyl,

C 2-10 alkynyl, and heterocyclyl, oxo; wherein heteroaryl,

C 1-10 alkylheteroarylenyl, and heterocyclyl are attached to Z through a carbon atom;

A″ is a fused benzene ring, wherein the benzene ring is unsubstituted or substituted by one or more R groups, or

A″ is a fused cyclohexene ring, wherein the ring is fully saturated except for the bond where the ring is fused, wherein the cyclohexene ring is unsubstituted or substituted by one or more R A groups;

each R is independently selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, and trifluoromethyl;

each R A is independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R 9 ) 2 ;

R 2 is selected from the group consisting of

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

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 or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, 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, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, 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 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

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

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 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;

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; or a pharmaceutically acceptable salt thereof.

2. A compound of the Formula IIa:

wherein:

Z is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of:

C 1-10 alkyl,

C 2-10 alkenyl,

C 2-10 alkynyl,

aryl,

aryl-C 1-10 alkylenyl,

aryloxy-C 1-10 alkylenyl,

C 1-10 alkylarylenyl,

heteroaryl,

heteroaryl-C 1-10 alkylenyl,

heteroaryloxy-C 1-10 alkylenyl,

C 1-10 alkylheteroarylenyl,

heterocyclyl,

heterocyclyl-C 1-10 alkylenyl, and

C 1-10 alkylamino, di(C 1-10 alkyl)amino, and in the case of C 1-10 alkyl, C 2-10 alkenyl,

C 2-10 alkynyl, and heterocyclyl, oxo; wherein heteroaryl,

C 1-10 alkylheteroarylenyl, and heterocyclyl are attached to Z through a carbon atom;

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

n is 0 to 4;

R 2 is selected from the group consisting of

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

Y is selected from the group consisting of:

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 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

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

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; or a pharmaceutically acceptable salt thereof.

3. A compound of the Formula IIa:

wherein:

Z is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of:

C 1-10 alkyl,

C 2-10 alkenyl,

C 2-10 alkynyl,

aryl,

aryl-C 1-10 alkylenyl,

aryloxy-C 1-10 alkylenyl,

C 1-10 alkylarylenyl,

heteroaryl,

heteroaryl-C 1-10 alkylenyl,

heteroaryloxy-C 1-10 alkylenyl,

C 1-10 alkylheteroarylenyl,

heterocyclyl,

heterocyclyl-C 1-10 alkylenyl, and

C 1-10 alkylamino, di(C 1-10 alkyl)amino, and in the case of C 1-10 alkyl, C 2-10 alkenyl,

C 2-10 alkynyl, and heterocyclyl, oxo; wherein heteroaryl,

C 1-10 alkylheteroarylenyl, and heterocyclyl are attached to Z through a carbon atom;

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

n is 0 to 4;

R 2 is selected from the group consisting of

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

Y is selected from the group consisting of:

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 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

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

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; or a pharmaceutically acceptable salt thereof.

4. A compound of the Formula IIIa:

wherein:

Z is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of:

C 1-10 alkyl,

C 2-10 alkenyl,

C 2-10 alkynyl,

aryl,

aryl-C 1-10 alkylenyl,

aryloxy-C 1-10 alkylenyl,

C 1-10 alkylarylenyl,

heteroaryl,

heteroaryl-C 1-10 alkylenyl,

heteroaryloxy-C 1-10 alkylenyl,

C 1-10 alkylheteroarylenyl,

heterocyclyl,

heterocyclyl-C 1-10 alkylenyl, and

C 1-10 alkylamino, di(C 1-10 alkyl)amino, and in the case of C 1-10 alkyl, C 2-10 alkenyl,

C 2-10 alkynyl, and heterocyclyl, oxo; wherein heteroaryl,

C 1-10 alkylheteroarylenyl, and heterocyclyl are attached to Z through a carbon atom;

R A is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

n is 0 to 4;

R 2 is selected from the group consisting of

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

Y is selected from the group consisting of:

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 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

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

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; or a pharmaceutically acceptable salt thereof.

5. A compound of the Formula IIIa:

wherein:

Z is selected from the group consisting of —S—, —S(O)—, and —S(O) 2 —;

R 1 is selected from the group consisting of:

C 1-10 alkyl,

C 2-10 alkenyl,

C 2-10 alkynyl,

aryl,

aryl-C 1-10 alkylenyl,

aryloxy-C 1-10 alkylenyl,

C 1-10 alkylarylenyl,

heteroaryl,

heteroaryl-C 1-10 alkylenyl,

heteroaryloxy-C 1-10 alkylenyl,

C 1-10 alkylheteroarylenyl,

heterocyclyl,

heterocyclyl-C 1-10 alkylenyl, and

C 1-10 alkylamino, di(C 1-10 alkyl)amino, and in the case of C 1-10 alkyl, C 2-10 alkenyl,

C 2-10 alkynyl, and heterocyclyl, oxo; wherein heteroaryl,

C 1-10 alkylheteroarylenyl, and heterocyclyl are attached to Z through a carbon atom;

R A is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

n is 0 to 4;

R 2 is selected from the group consisting of

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

Y is selected from the group consisting of:

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 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

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

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; or a pharmaceutically acceptable salt thereof.

6. The compound or salt of claim 2 wherein n is 0.

7. The compound or salt of claim 1 wherein R 2 is hydrogen, alkyl, hydroxyalkylenyl, or alkoxyalkylenyl.

8. The compound or salt of claim 7 wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, 2-hydroxyethyl, hydroxymethyl, 2-methoxyethyl, or ethoxymethyl.

9. The compound or salt of claim 1 wherein Z is —S(O) 2 —.

10. The compound or salt of claim 1 wherein Z is —S(O)—.

11. The compound or salt of claim 1 wherein Z is —S—.

12. The compound or salt of claim 1 wherein R 1 is linear or branched C 1-4 alkyl, aryl, or 5 to 10 membered heteroaryl containing one or two heteroatoms, wherein the alkyl, aryl, or heteroaryl group may be unsubstituted or substituted with one or more substituents.

13. The compound or salt of claim 12 wherein R 1 is methyl, ethyl, 1-propyl, 2-propyl, 2-methylpropyl, 2-hydroxy-2-methylpropyl, phenyl, -4-chlorophenyl, or 4-fluorophenyl.

14. The compound or salt of claim 1 wherein X 1-1 and X 1-2 are independently selected from C 2-7 alkylene groups.

15. The compound or salt of claim 14 wherein X 1-1 is —(CH 2 ) 2-4 —, —CH 2 —C(CH 3 ) 2 —, or —CH 2 -cyclic(CH 2 ) 3-6 —.

16. The compound or salt of claim 15 wherein X 1-2 is —(CH 2 ) 2 — or —(CH 2 ) 3 —.

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

18. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.

19. The compound or salt of claim 2 wherein R 2 is hydrogen, alkyl, hydroxyalkylenyl, or alkoxyalkylenyl.

20. The compound or salt of claim 19 wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, 2-hydroxyethyl, hydroxymethyl, 2-methoxyethyl, or ethoxymethyl.

21. The compound or salt of claim 2 wherein Z is —S(O) 2 —.

22. The compound or salt of claim 2 wherein R 1 is linear or branched C 1-4 alkyl, aryl, or 5 to 10 membered heteroaryl containing one or two heteroatoms, wherein the alkyl, aryl, or heteroaryl group may be unsubstituted or substituted with one or more substituents.

23. The compound or salt of claim 22 wherein R 1 is methyl, ethyl, 1-propyl, 2-propyl, 2-methylpropyl, 2-hydroxy-2-methylpropyl, phenyl, 4-chlorophenyl, or 4-fluorophenyl.

24. The compound or salt of claim 2 wherein X 1-1 and X 1-2 are independently selected from C 2-7 alkylene groups.

25. The compound or salt of claim 24 wherein X 1-1 is —(CH 2 ) 2-4 —, —CH 2 —C(CH 3 ) 2 —, or —CH 2 -cyclic(CH 2 ) 3-6 —.

26. The compound or salt of claim 25 wherein X 1-2 is —(CH 2 ) 2 — or —(CH 2 ) 3 —.

27. The compound or salt of claim 4 wherein n is 0.

28. The compound or salt of claim 4 wherein R 2 is hydrogen, alkyl, hydroxyalkylenyl, or alkoxyalkylenyl.

29. The compound or salt of claim 28 wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, 2-hydroxyethyl, hydroxymethyl, 2-methoxyethyl, or ethoxymethyl.

30. The compound or salt of claim 4 wherein Z is —S(O) 2 —.

31. The compound or salt of claim 4 wherein R 1 is linear or branched C 1-4 alkyl, aryl, or 5 to 10 membered heteroaryl containing one or two heteroatoms, wherein the alkyl, aryl, or heteroaryl group may be unsubstituted or substituted with one or more substituents.

32. The compound or salt of claim 31 wherein R 1 is methyl, ethyl, 1-propyl, 2-propyl, 2-methylpropyl, 2-hydroxy-2-methylpropyl, phenyl, 4-chlorophenyl, or 4-fluorophenyl.

33. The compound or salt of claim 4 wherein X 1-1 and X 1-2 are independently selected from C 2-7 alkylene groups.

34. The compound or salt of claim 33 wherein X 1-1 is —(CH 2 ) 2-4 —, —CH 2 —C(CH 3 ) 2 —, or —CH 2 -cyclic(CH 2 ) 3-6 —.

35. The compound or salt of claim 34 wherein X 1-2 is —(CH 2 ) 2 — or —(CH 2 ) 3 —.

36. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 2 in combination with a pharmaceutically acceptable carrier.

37. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 2 to the animal.

38. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 4 in combination with a pharmaceutically acceptable carrier.

39. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 4 to the animal.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2011

From: COLEY PHARMACEUTICAL GROUP, INC.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 025839/0772 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2007

From: 3M COMPANY; 3M INNOVATIVE PROPERTIES COMPANY

To: COLEY PHARMACEUTICAL GROUP, INC.

Reel/Frame 019945/0698 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 31, 2006

From: RADMER, MATTHEW R.; MOSER, WILLIAM H.; MOSEMAN, JOAN T.; DELLARIA, JOSEPH F. JR.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 017719/0543 →