Substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof (I). Also disclosed herein are uses of the compounds disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.
1. A compound of formula (Ia), formula (If), or formula (Ig), or a pharmaceutically acceptable salt thereof:
wherein:
A is phenyl, optionally substituted with 1-3 halogens;
X is selected from (1)-NHC(O)— and (2)—C(O)NH—;
each of R 1 and R 2 is independently selected from:
(1) H, and
(2) C 1-4 alkyl, optionally substituted with 1-3 halogens;
or alternatively, R 1 and R 2 together with the carbon to which they are attached form a 3-5 membered ring selected from:
(1) cyclopropyl, optionally substituted with 1-3 halogens,
(2) cyclobutyl, optionally substituted with 1-3 halogens,
(3) oxiranyl, and
(4) oxetanyl;
R 3 is selected from:
(1) phenyl, optionally substituted with 1-3 halogens, and
(2) a 4-6 membered monocyclic aromatic heterocyclyl selected from oxadiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, thiazolyl, and triazolyl, each of which is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b)—CH 3 , optionally substituted with 1-3 halogens,
(c)—O—CH 3 , and
(d) cyclopropyl; and
each of R 4 and R 5 is H.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl, optionally substituted with 1-3 halogens;
each of R 1 and R 2 is independently selected from:
(1) H, and
(2) C 1-4 alkyl, optionally substituted with 1-3 halogens;
or alternatively, R 1 and R 2 together with the carbon to which they are attached form a 3-5 membered ring selected from:
(1) cyclopropyl, optionally substituted with 1-3 halogens, and
(2) cyclobutyl, optionally substituted with 1-3 halogens; and
R 3 is selected from:
(1) phenyl, optionally substituted with 1-3 halogens, and
(2) a 4-6 membered monocyclic aromatic heterocyclyl selected from pyridinyl and pyrimidinyl, each of which is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b)—CH 3 , optionally substituted with 1-3 halogens, and
(c) cyclopropyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
4-chloro-N-((1-(3-chlorobenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzamide;
3-chloro-N-((1-(3-chlorobenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzamide;
4-chloro-N-{1-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]ethyl}benzamide;
2-{1-[4-(difluoromethyl)pyridine-2-carbonyl]-1,2,3,4-tetrahydroquinolin-6-yl}-N-(4-fluorophenyl)propanamide;
N-(4-fluorophenyl)-2-[1-(5-methyl-1,3-thiazole-2-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(3-methyl-1H-1,2,4-triazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl] propanamide;
N-(4-fluorophenyl)-2-[1-(3-methyl-1,2,4-oxadiazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(5-methyl-1,3,4-oxadiazole-2-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(2-methyl-1,3-oxazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(5-methyl-1,2-oxazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(5-methyl-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(1-methyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]propanamide;
N-(4-fluorophenyl)-2-[1-(1,3-oxazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl] propanamide;
2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)propanamide;
2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-chlorophenyl)propanamide;
(2S)-2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)propanamide;
(2R)-2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)propanamide;
(2S)-2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-chlorophenyl)propanamide;
(2R)-2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-chlorophenyl)propanamide;
N-(4-fluorophenyl)-1-[1-(5-methyl-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]cyclobutane-1-carboxamide;
N-(5-fluoropyridin-2-yl)-1-[1-(5-methyl-1,2,4-oxadiazole-3-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]cyclobutane-1-carboxamide;
N-(4-fluorophenyl)-1-[1-(3-methyl-1H-1,2,4-triazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]cyclobutane-1-carboxamide;
N-(4-fluorophenyl)-1-{1-[5-(trifluoromethyl)-4H-1,2,4-triazole-3-carbonyl]-1,2,3,4-tetrahydroquinolin-6-yl}cyclobutane-1-carboxamide;
1-[1-(1,5-dimethyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)cyclobutane-1-carboxamide;
1-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)cyclobutane-1-carboxamide;
N-(4-fluorophenyl)-1-{1-[3-(trifluoromethyl)-1H-pyrazole-5-carbonyl]-1,2,3,4-tetrahydroquinolin-6-yl}cyclobutane-1-carboxamide;
1-[1-(3-cyclopropyl-1H-pyrazole-5-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-fluorophenyl)cyclobutane-1-carboxamide;
4-chloro-N-{1-[5-(3-chlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}benzamide;
4-fluoro-N-{1-[5-(1-methyl-1H-pyrazole-3-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}benzamide;
N-{1-[5-(2-chlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}-4-fluorobenzamide;
N-{(1R)-1-[5-(1-cyclopropyl-1H-pyrazole-3-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}-4-fluorobenzamide;
N-{1-[5-(2,3-dichlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}-4-fluorobenzamide;
N-{1-[5-(3,5-dichlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}-4-fluorobenzamide;
N-{1-[5-(2,6-dichlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl] ethyl}-4-fluorobenzamide;
2-[5-(3-chlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl]-N-(4-fluorophenyl)propanamide;
4-chloro-N-(1-(1-(3-chlorobenzoyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl) ethyl)benzamide;
N-{1-[5-(3-chlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl]cyclopropyl}-4-fluorobenzamide;
4-fluoro-N-{1-[5-(1-methyl-1H-pyrazole-4-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl]cyclopropyl}benzamide;
2-[1-(3-chlorobenzene-1-carbonyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-(4-chlorophenyl)-2-methylpropanamide;
2-[5-(3-chlorobenzene-1-carbonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl]-N-(4-fluorophenyl)-2-methylpropanamide; and
3-(5-(3-chlorobenzoyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)-N-(4-fluorophenyl) oxetane-3-carboxamide.
4. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
5. A composition which comprises an inert carrier and the compound of claim 1 or a pharmaceutically acceptable salt thereof.