Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: Also disclosed herein are uses of a compound 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 a composition in the potential treatment or prevention of an IDO-associated disease or disorder.
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
n is 1;
p is 1;
each occurrence of A is —CH═;
M is selected from —O— and —S—;
R 1 is
pyridinyl;
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-8 cycloalkyl, optionally substituted with OH,
(c) —CN,
(d) oxo,
(e) —O—C 1-8 alkyl, optionally substituted with 1-5 halogens,
(f) —O—C 3-8 cycloalkyl,
(g) —C 1-8 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, —NH 2 , NHC(O)R c and —S(O) 2 —C 1-8 alkyl, wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(h) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(i) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-8 alkyl,
(j) aryl, optionally substituted with 1-3 halogens, and
(k) heterocyclyl, optionally substituted with 1-3 substituents independently selected from halogen and —C 1-8 alkyl;
R 2 is
phenyl;
wherein the phenyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-8 cycloalkyl,
(c) —CN,
(d) —O—C 1-8 alkyl, optionally substituted with 1-3 halogens and
(e) —C 1-8 alkyl, optionally substituted with 1-3 substituents independently selected from halogen, —OH and —NH 2 ; and
R 3 is selected from H, halogen and —C 1-8 alkyl, optionally substituted with —OH.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
M is —O—;
and
R 3 is H.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is pyridinyl;
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) cyclopropyl, optionally substituted with —OH,
(c) cyclobutyl, optionally substituted with —OH,
(d) —CN,
(e) oxo,
(f) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,
(g) —O-cyclopropyl,
(h) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and
(i) phenyl, optionally substituted with 1-3 halogens.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is phenyl;
wherein the phenyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens, and
(e) —C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is phenyl;
wherein the phenyl is-optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —CN,
(c) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens and
(d) —C 1-4 alkyl, optionally substituted with 1-3 halogens.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
M is —O—;
R 1 is
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) cyclopropyl, optionally substituted with —OH,
(c) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens, and
(d) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH;
and
R 2 is phenyl;
wherein the phenyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —CN,
(c) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens and
(d) —C 1-4 alkyl, optionally substituted with 1-3 halogens.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is pyridinyl;
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen, and
(b) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH; and
R 2 is phenyl;
wherein the phenyl is optionally substituted with 1-3 halogens; and
R 3 is H.
8. The compound of claim 1 of formula (Ia), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is pyridinyl;
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,
(c) —O-cyclopropyl, and
(d) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH; and
R 2 is phenyl, optionally substituted with 1-3 halogens.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is pyridinyl, optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —CH 3 ,
(c) —CHF 2 ,
(d) —CF 3 , and
(e) —C(CH 3 ) 2 OH; and
R 2 is phenyl, optionally substituted with 1-2 halogens.
10. The compound of claim 1 of formula (Ii), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is pyridinyl;
wherein the pyridinyl is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —CN,
(c) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,
(d) —O-cyclopropyl, and
(e) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH; and
R d is selected from:
(a) halogen,
(b) —CN,
(c) —O—C 1-3 alkyl, optionally substituted with 1-3 halogens, and
(d) C 1-3 alkyl, optionally substituted with 1-3 halogens.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is pyridinyl, optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —CH 3 ,
(c) —CHF 2 ,
(d) —CF 3 ,
(e) —CH 2 OH, and
(f) —C(CH 3 ) 2 OH;
and
R d is selected from:
(a) a halogen selected from F, Cl and Br,
(b) —CH 3 , and
(c) —CF 3 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3-(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(6-cyclopropyl-4-fluoropyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(6-cyclopropyl-4-methylpyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(4-(6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(6-(difluoromethoxy)-4-methylpyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-[4-[3-(2-hydroxyethyl)-5-(trifluoromethyl)-2-pyridyl]phenyl]oxetane-3-carboxamide,
(R or S)—N-(4-fluorophenyl)-3-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-[4-[6-(difluoromethoxy)-4-(1-hydroxy-1-methyl-ethyl)pyridin-1-ium-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide;
N-(4-chlorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-chlorophenyl)-3-[4-[4-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide,
N-(4-chlorophenyl)-3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide,
3-[4-[6-cyclopropyl-2-(hydroxmethyl)pyridin-1-ium-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3- carboamide,
N-(4-fluorophenyl)-3-[4-[6-(trifluoromethyl)pyridin-1-ium-3-yl]phenyl]oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-[4-[2-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(4-(4-(fluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)oxetane-3-carboxamide,
N-(4-bromophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethyl)phenyl)oxetane-3-carboxamide,
N-(3,4-difluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-cyanophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-(difluoromethoxy)phenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(4-(6-cyclopropoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
5-(4-(3-((4-flurophenyl)carbamoyl)oxetan-3-yl)phenyl)-N-methyl-2-(trifluoromethyl)isonicotinamide,
5-(4-(3-((4-flurophenyl)carbomoyl)oxetan-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide,
(R)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
(S)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetane-3-carboxamide,
3-(4-(5-cyclopropoxy-3-(hydroxymethyl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(5-cyclopropoxy-3-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(4-(6-(2,2-difluoroethoxy)-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)oxetane-3-carboxamide,
3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-(4-(6-ethoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, and
N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetane-3-carboxamide.
13. A composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
14. A compound which is N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetane-3 -carboxamide, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 which is N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetane-3-carboxamide.
16. The compound of claim 14 which is a pharmaceutically acceptable salt of N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetane-3-carboxamide.