Substituted chiral fused [1,2]imidazo[4,5-
View Patent ↗Substituted fused [1,2]imidazo[4,5-c] ring compounds (e.g., imidazo[4,5-c]quinolines, 6,7,8,9-tetrahydroimidazo[4,5-c]quinolines, imidazo[4,5-c]naphthyridines, and 6,7,8,9-tetrahydroimidazo[4,5-c]naphthyridines) with a —CH(—R 1 )— group in the fused ring at the 1-position of the imidazo ring, wherein R 1 includes a functional group, for example, an amide, sulfonamide, urea, carbamate, ester, ketone, ether, a thio analog of the forgoing, sulfone, oxime, or hydroxylamine, 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.
1. A compound of the Formula IIa:
wherein:
X is a bond;
X′ is a methylene;
Z is —O—;
R 1 is selected from the group consisting of:
—X 1 —Y′—R 4 ,
—X 1 —Y′—X″—Y′—R 4 , and
—X 1 —R 5 ;
when taken together, R A1 and R B1 form a fused benzo ring wherein the fused benzo ring 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 when taken together, R A1 and R B1 form a fused 5 to 7 membered saturated carbocyclic ring, 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 9 ) 2 ;
R 3 is selected from the group consisting of:
—Z′—R 4 ,
—Z′—X″—R 4 ,
—Z′—X″—Y′—R 4 ,
—Z′—X″—Y′—X″—Y′—R 4 , and
—Z′—X″—R 5 ;
X 1 is selected from the group consisting of alkylene and alkenylene, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups, and optionally substituted by a hydroxy or methoxy group;
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—;
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, heteroarylalkylayl, 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, C 1-10 alkyl, C 2-10 alkenyl, hydroxy-C 1-10 alkylenyl, C 1-10 alkoxy-C 1-10 alkylenyl, aryl-C 1-10 alkylenyl, and heteroaryl-C 1-10 alkylenyl;
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 —CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(-Q-R 4 )—;
A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
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—, —C(R 6 )—S—, 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;
with the proviso that X 1 can also be a bond when:
Y′ is bonded to X 1 and Y′ is —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—, —C(R 6 )—N(OR 9 )—, —C(═N—O—R 8 )—, —CH(—N(—O—R 8 )-Q-R 4 )—,
wherein V is —C(R 6 )—, or
R 5 is bonded to X 1 and R 5 is
wherein V is —C(R 6 )— or
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 wherein X 1 is selected from the group consisting of alkylene and alkenylene, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups.
3. A compound of the Formula III:
wherein:
X is a bond;
X′ is a methylene;
Z is —O—;
R 1 is selected from the group consisting of:
—X 1 —Y′—R 4 ,
—X 1 —Y′—X″—Y′—R 4 , and
—X 1 —R 5 ;
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R 9 ) 2 ;
R 3 is selected from the group consisting of:
—Z′—R 4 ,
—Z′—X″—R 4 ,
—Z′—X″—Y′—R 4 ,
—Z′—X″—Y′—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, then n is 0 or 1;
X 1 is selected from the group consisting of alkylene and alkenylene, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups, and optionally substituted by a hydroxy or methoxy group;
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—;
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, C 1-10 alkyl, C 2-10 alkenyl, hydroxy-C 1-10 alkylenyl, C 1-10 alkoxy-C 1-10 alkylenyl, aryl-C 1-10 alkylenyl, and heteroaryl-C 1-10 alkylenyl;
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 —CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(-Q-R 4 )—;
A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
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—, —C(R 6 )—S—, 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;
with the proviso that X 1 can also be a bond when:
Y′ is bonded to X 1 and Y′ is —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—, —C(R 6 )—N(OR 9 )—, —C(═N—O—R 8 )—, —CH(—N(—O—R 8 )-Q-R 4 )—,
wherein V is —C(R 6 )—, or
R 5 is bonded to X 1 and R 5 is
wherein V is —C(R 6 )— or
or a pharmaceutically acceptable salt thereof.
4. The compound or salt of claim 3 wherein X 1 is selected from the group consisting of alkylene and alkenylene, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups.
5. The compound or salt of claim 3 wherein n is 0.
6. The compound or salt of claim 3 wherein n and m are 0.
7. The compound or salt of claim 1 wherein R 3 is benzyloxy.
8. The compound or salt of claim 1 wherein R is halogen or hydroxy.
9. The compound or salt of claim 1 wherein R 1 is —X 1 —Y′—R 4 .
10. The compound or salt of claim 1 wherein R 1 is —X 1 —R 5 .
11. The compound or salt of claim 1 wherein X 1 is C 1-4 alkylene.
12. The compound or salt of claim 9 wherein Y′ is —S—, —S(O) 2 —, or N(R 8 )-Q- wherein Q is a bond, —S(O) 2 —, —C(O)—, —C(O)—O—, —C(O)—N(R 8 )—, —C(S)—N(R 8 )—, or —S(O) 2 —N(R 8 )—; each R 8 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkyl; and R 4 is hydrogen, alkyl, aryl, arylalkylenyl, heteroaryl, or heterocyclyl wherein alkyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, alkoxy, alkyl, haloalkyl, and dialkylamino.
13. The compound or salt of claim 10 wherein R 5 is
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 3 and a pharmaceutically acceptable carrier.
16. The compound or salt of claim 3 wherein R 1 is —X 1 —Y′—R 4 .
17. The compound or salt of claim 16 wherein Y′ is —S—, —S(0) 2 —, or N(R 8 )-Q- wherein Q is a bond, —S(0) 2 —, —C(0)—, —C(0)—0—, —C(0)—N(R 8 )—, —C(S)—N(R 8 )—, or —S(0) 2 —N(R 8 )—; each R 8 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkyl; and R 4 is hydrogen, alkyl, aryl, arylalkylenyl, heteroaryl, or heterocyclyl wherein alkyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, alkoxy, alkyl, haloalkyl, and dialkylamino.
18. The compound or salt of claim 3 wherein R 1 is —X 1 —R 5 .
19. The compound or salt of claim 18 wherein R 5 is
20. The compound or salt of claim 3 wherein X 1 is C 1-4 alkylene.