Hydroxylamine substituted imidazoquinolines
View Patent ↗Imidazo ring compounds (e.g., imidazoquinolines, 6,7,8,9-tetrahydroimidazoquinolines, imidazonaphthyridines, and imidazopyridines) with a hydroxylamine substituent at the 2-position, pharmaceutical compositions containing the compounds, intermediates, 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.
1. A compound of the Formula II:
wherein:
X is C 1-10 alkylene;
R A1 and R B1 are taken together to form a fused aryl ring, wherein the aryl ring is unsubstituted or substituted by one R 3 group;
R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X′—R 4 , and
—Z—X′—Y—R 4 ;
Y′ is selected from the group consisting of:
a bond,
—C(O)—,
—S(O) 2 —,
—S(O) 2 —N(R 8 )—,
—C(O)—O—,
—C(O)—N(R 8 )—,
—C(S)—N(R 8 )—,
—C(O)—N(R 8 )—C(O)—, and
R 1 is selected from the group consisting of:
—R 4 ,
—X′—R 4 , and
—X′—Y—R 4 ;
R 2 and R 2a are independently selected from the group consisting of:
hydrogen,
alkyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
alkyl,
haloalkyl,
alkoxy,
halogen, and
aryl;
X′ is selected from the group consisting of alkylene and arylene;
Y is selected from the group consisting of:
—C(R 6 )—,
—N(R 8 )-Q-, and
—C(R 6 )—N(R 8 )—;
Z is a bond;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl, wherein the alkyl, alkenyl, alkynyl, and aryl 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, amino, alkylamino, and dialkylamino;
R 6 is ═O;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogen and C 1-10 alkyl;
R 10 is C 3-8 alkylene;
Q is selected from the group consisting of a bond, —C(R 6 )—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—W—; and
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the Formula IIIa:
wherein:
X is C 1-10 alkylene;
Y′ is selected from the group consisting of:
a bond,
—C(O)—,
—S(O) 2 —,
—S(O) 2 —N(R 8 )—,
—C(O)—O—,
—C(O)—N(R 8 )—,
—C(S)—N(R 8 )—,
—C(O)—N(R 8 )—C(O)—, and
R 1 is selected from the group consisting of:
—R 4 ,
—X′—R 4 , and
—X′—Y—R 4 ;
R 2 and R 2a are independently selected from the group consisting of:
hydrogen,
alkyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or
heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
alkyl,
haloalkyl,
alkoxy,
halogen, and
aryl;
R 3 is selected from the group consisting of:
—Z—R 4 ,
—Z—X′—R 4 , and
—Z—X′—Y—R 4 ;
n is 0;
m is 0 or 1;
X′ is selected from the group consisting of alkylene and arylene;
Y is selected from the group consisting of:
—C(R 6 )—, and
—N(R 8 )-Q-;
Z is a bond;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl wherein the alkyl, alkenyl, alkynyl, and aryl 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, amino, alkylamino, and dialkylamino;
R 6 is ═O;
R 7 is C 2-7 alkylene;
R 8 is selected from the group consisting of hydrogenand C 1-10 alkyl;
R 10 is C 3-8 alkylene;
Q is selected from the group consisting of a bond, —C(R 6 )—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—W—; and
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 of the Formula IIIaa:
wherein:
X is C 1-10 alkylene;
Y′ is selected from the group consisting of:
a bond,
—C(O)—,
—S(O) 2 —,
—S(O) 2 —N(R 8 )—,
—C(O)—O—,
—C(O)—N(R 8 )—,
—C(S)—N(R 8 )—,
—C(O)—N(R 8 )—C(O)—, and
R 2 and R 2a are independently selected from the group consisting of:
hydrogen,
alkyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
alkyl,
haloalkyl,
alkoxy,
halogen, and
aryl;
R 1 is selected from the group consisting of:
—R 4 ,
—X′—R 4 , and
—X′—Y—R 4 ;
X′ is selected from the group consisting of alkylene and arylene
Y is selected from the group consisting of:
—C(R 6 )—,
—N(R 8 )-Q-, and
—C(R 6 )—N(R 8 )—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and aryl wherein the alkyl, alkenyl, alkynyl, and aryl 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, amino, alkylamino, and dialkylamino;
R 6 is ═O;
R 8 is selected from the group consisting of hydrogenand C 1-10 alkyl;
R 10 is C 3-8 alkylene;
Q is selected from the group consisting of a bond, —C(R 6 )—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—W—; and
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
or a pharmaceutically acceptable salt thereof.
4. The compound or salt of claim 2 wherein m and n are 0.
5. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of alkyl, arylalkylenyl, hydroxyalkyl, and —X′—Y—R 4 ; wherein X′ is alkylene; Y is —N(R 8 )—C(O)—, —N(R 8 )—S(O) 2 —, —N(R 8 )—C(O)—N(R 8 )—, or —N(R 8 )—C(O)—N(R 8 )—C(O)—, and R 4 is hydrogen, alkyl, alkenyl, or aryl, wherein alkyl and alkenyl are optionally substituted by aryl and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen.
6. The compound or salt of claim 5 wherein R 1 is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or —X′—Y—R 4 ; X′ is ethylene, propylene, or butylene; Y is —NH—C(O)—, —NH—S(O) 2 —, —NH—C(O)—N(R 8 )—, or —NH—C(O)—NH—C(O)—;
and R 8 is hydrogen or methyl.
7. The compound or salt of claim 1 wherein X is C 1-4 alkylene.
8. The compound or salt of claim 7 wherein X is methylene.
9. The compound or salt of claim 1 wherein Y′ is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(O)—N(R 8 )—, —C(S)—N(R 8 )—, —C(O)—N(R 8 )—C(O)—, and
10. The compound or salt of claim 9 wherein Y′ is selected from the group consisting of —C(O)—, —S(O) 2 —, and —C(O)—N(R 8 )—.
11. The compound or salt of claim 1 wherein R 2 and R 2a are independently selected from the group consisting of: hydrogen, alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: alkyl, haloalkyl, alkoxy, halogen, and aryl.
12. The compound or salt of claim 1 wherein R 2a is hydrogen.
13. The compound or salt of claim 1 wherein R 2 and R 2a are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, wherein the alkyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of C 1-10 alkyl, aryl, C 1-10 alkoxy, and halogen.
14. The compound or salt of claim 1 wherein R 2 is alkyl or substituted alkyl, and R 2a is hydrogen.
15. The compound or salt of claim 14 wherein R 2 is methyl or cyclopropyl, and R 2a is hydrogen.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.
17. The compound or salt of claim 2 wherein R 1 is selected from the group consisting of alkyl, arylalkylenyl, hydroxyalkyl, and —X′—Y—R 4 ; wherein X′ is alkylene; Y is —N(R 8 )—C(O)—, —N(R 8 )—S(O) 2 —, N(R 8 )—C(O)—N(R 8 )—, or —N(R 8 )—C(O)—N(R 8 )—C(O)—; and R 4 is hydrogen, alkyl, alkenyl, or aryl, wherein alkyl and alkenyl are optionally substituted by aryl and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen.
18. The compound or salt of claim 17 wherein R 1 is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or —X′—Y—R 4 ; X′ is ethylene, propylene, or butylene; Y is —NH—C(O)—, —NH—S(O) 2 —, —NH—C(O)—N(R 8 )—, or —NH—C(O)—NH—C(O)—; and R 8 is hydrogen or methyl.
19. The compound or salt of claim 2 wherein X is C 1-4 alkylene.
20. The compound or salt of claim 19 wherein X is methylene.
21. The compound or salt of claim 2 wherein Y′ is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(O)—N(R 8 )—, —C(S)—N(R 8 )—, —C(O)—N(R 8 )—C(O)—, and
22. The compound or salt of claim 21 wherein Y′ is selected from the group consisting of —C(O)—, —S(O) 2 —, and —C(O)—N(R 8 )—.
23. The compound or salt of claim 2 wherein R 2 and R 2a are independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: alkyl, haloalkyl, alkoxy, dialkylamino, halogen, and aryl.
24. The compound or salt of claim 2 wherein R 2a is hydrogen.
25. The compound or salt of claim 2 wherein R 2 and R 2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, wherein the alkyl, alkenyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of C 1-10 alkyl, aryl, C 1-10 alkoxy, and halogen.
26. The compound or salt of claim 2 wherein R 2 is alkyl or substituted alkyl, and R 2a is hydrogen.
27. The compound or salt of claim 26 wherein R 2 is methyl or cyclopropyl, and R 2a is hydrogen.
28. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 2 in combination with a pharmaceutically acceptable carrier.
29. The compound or salt of claim 3 wherein R 1 is selected from the group consisting of alkyl, arylalkylenyl, and —X′—Y—R 4 ; wherein X′ is alkylene; Y is —N(R 8 )—C(O)—, —N(R 8 )—S(O) 2 —, —N(R 8 )—C(O)—N(R 8 )—, or —N(R 8 )—C(O)—N(R 8 )—C(O)—, and R 4 is hydrogen, alkyl, alkenyl, or aryl, wherein alkyl and alkenyl are optionally substituted by aryl and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen.
30. The compound or salt of claim 29 wherein R 1 is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or —X′—Y—R 4 ; X′ is ethylene, propylene, or butylene; Y is —NH—C(O)—, —NH—S(O) 2 —, —NH—C(O)—N(R 8 )—, or —NH—C(O)—NH—C(O)—; and R 8 is hydrogen or methyl.
31. The compound or salt of claim 3 wherein X is C 1-4 alkylene.
32. The compound or salt of claim 31 wherein X is methylene.
33. The compound or salt of claim 3 wherein Y′ is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(O)—N(R 8 )—, —C(S)—N(R 8 )—, —C(O)—N(R 8 )—C(O)—, and
34. The compound or salt of claim 33 wherein Y′ is selected from the group consisting of —C(O)—, —S(O) 2 —, and —C(O)—N(R 8 )—.
35. The compound or salt of claim 3 wherein R 2 and R 2a are independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: alkyl, haloalkyl, alkoxy, dialkylamino, halogen, and aryl.
36. The compound or salt of claim 3 wherein R 2a is hydrogen.
37. The compound or salt of claim 3 wherein R 2 and R 2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, wherein the alkyl, alkenyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of C 1-10 alkyl, aryl, C 1-10 alkoxy and halogen.
38. The compound or salt of claim 3 wherein R 2 is alkyl or substituted alkyl, and R 2a is hydrogen.
39. The compound or salt of claim 38 wherein R 2 is methyl or cyclopropyl, and R 2a is hydrogen.
40. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 3 in combination with a pharmaceutically acceptable carrier.