1-alkoxy 1H-imidazo ring systems and methods
View Patent ↗Imidazo-containing compounds (e.g., imidazonaphthyridines, imidazopyridines, imidazoquinolines, and imidazote-trahydroquinolines) with an alkoxy substituent at the 1-position, pharmaceutical compositions containing 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.
1. A compound of the following Formula II:
wherein:
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X″—C(R 7 )—N(R 9 )—R 4 ,
—X—O—C(R 7 )—N(R 6 )—R 4 ,
—X—S(O) 2 —N(R 6 )—R 4 , and
—X—R 4 ;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
alkyl-Z-alkylenyl,
aryl Z-alkylenyl,
alkenyl-Z-alkylenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
hydroxy,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl,
—C(O)-heteroaryl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 -aryl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl, and
—O—C(R 7 )—N(R 6 )-aryl;
R A and R B are each independently selected from the group consisting of:
hydrogen,
halogen,
alkyl,
alkenyl,
alkoxy,
alkylthio, and
—N(R 12 ) 2 ;
or when taken together, R A and R B form a fused benzene or pyridine ring which is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group, or substituted by one R 3 group and two R groups;
or when taken together, R A and R B form a fused cyclohexene or tetrahydropyridine ring which is unsubstituted or substituted by one or more R groups;
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R 12 ) 2 ;
R 3 is selected from the group consisting of:
-Z′R 4 ′,
-Z′-X′—R 4 ′,
-Z′-X′—Y′—R 4 ′, and
-Z′-X′—R 5 ′,
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the oxygen atom to which R 1 is bonded;
R 5 is selected from the group consisting of:
X is C 2-20 alkylene;
X″ is C 1-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—;
Z is selected from the group consisting of —O— and —S(O) 0-2 —;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
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:
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 by arylene, heteroarylene, or heterocyclylene and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
Z′ is a bond or —O—;
A′ is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 ′)—;
Q is selected from the group consisting of a bond, —C(R 7 )—, —C(R 7 )—C(R 7 )—, —S(O) 2 —, —C(R 7 )—N(R 11 )—W—, —S(O) 2 —N(R 11 )—, —C(R 7 )—O—, and —C(R 7 )—N(OR 12 )—;
V is selected from the group consisting of —C(R 7 )—, —O—C(R 7 )—, —N(R 11 )—C(R 7 )—, and —S(O) 2 —;
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
c and d are independently integers from 1 to 6 with the proviso that c+d is ≦7, and when A′ is —O— or —N(R 4 ′)— then c and d are independently integers from 2 to 4;
R 6 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
R 7 is selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
R 10 is C 3-8 alkylene;
R 11 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkylenyl, and arylC 1-10 alkylenyl; and
R 12 is selected from the group consisting of hydrogen and alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound of the following Formula IV:
wherein:
R 1 is selected from the group consisting of:
—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X″—C(R 7 )—N(R 9 )—R 4 ,
—X—O—C(R 7 )—N(R 6 )—R 4 ,
—X—S(O) 2 —N(R 6 )—R 4 , and
—X—O—R 4 ;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
alkyl-Z-alkylenyl,
aryl-Z-alkylenyl,
alkenyl-Z-alkylenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
hydroxy,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl,
—C(O)-heteroaryl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 -aryl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl, and
—O—C(R 7 )—N(R 6 )-aryl;
R is selected from the group consisting of:
halogen,
hydroxyl,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R 12 ) 2 ;
R 3 is selected from the group consisting of:
-Z′R 4 ′,
-Z′-X′—R 4 ′,
-Z′-X′—Y′—R 4 ′, and
-Z′-X′—R 5 ′,
n is an integer from 0 to 4;
m is 0 or 1, with the proviso that when m is 1, n is 0, 1, or 2;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, akynyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the oxygen atom to which R 1 is bonded;
R 5 is selected from the group consisting of:
X is C 2-20 alkylene;
X″ is C 1-20 alkylene,
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 N(R 6 )—, and —C(R 7 )—N(R 9 )—;
Z is selected from the group consisting of —O— and —S(O) 0-2 —;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
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:
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 by arylene, heteroarylene, or heterocyclylene and optionally interrupted by one or more —O— groups,
Y′ is selected from the group consisting of:
Z′ is a bond or —O—;
A′ is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 ′)—;
Q is selected from the group consisting of a bond, —C(R 7 )—, —C(R 7 )—C(R 7 )—, —S(O) 2 —, —C(R 7 )—N(R 11 )—W—, —S(O) 2 —N(R 11 )—, —C(R 7 )—O—, and —C(R 7 )—N(OR 12 )—;
V is selected from the group consisting of —C(R 7 )—, —O—C(R 7 )—, —N(R 11 )—C(R 7 )—, and S(O) 2 —.
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
c and d are independently integers from 1 to 6 with the proviso that c+d is ≦7, and when A′ is —O— or —N(R 4 ′)— then c and d are independently integers from 2 to 4;
R 6 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
R 7 is selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
R 10 is C 3-8 alkylene;
R 11 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkylenyl, and arylC 1-10 alkylenyl; and
R 12 is selected from the group consisting of hydrogen and alkyl;
or a pharmaceutically acceptable salt thereof.
3. The compound or salt of claim 2 wherein n is 0.
4. The compound or salt of claim 2 wherein m is 0.
5. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and alkoxyalkylenyl.
6. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
7. The compound or salt of claim 1 wherein R 1 is —R 4 , —X—N(R 6 )—Y—R 4 , or —X″—C(R 7 )—N(R 9 )—R 4 .
8. The compound or salt of claim 7 wherein —R 4 is alkyl, aryl, or arylalkylenyl.
9. The compound or salt of claim 8 wherein R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, 2-nitrobenzyl, and 2-phenoxyethyl.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.
11. The compound or salt of claim 2 wherein R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and alkoxyalkylenyl.
12. The compound or salt of claim 2 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
13. The compound or salt of claim 2 wherein R 1 is —R 4 , —X—N(R 6 )—Y—R 4 , or —X″—C(R 7 )—N(R 9 )—R 4 .
14. The compound or salt of claim 13 wherein —R 4 is alkyl, aryl, or arylalkylenyl.
15. The compound or salt of claim 14 wherein R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, 2-nitrobenzyl, and 2-phenoxyethyl.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 2 in combination with a pharmaceutically acceptable carrier.