Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

n is 1;

p is 1;

each occurrence of A is independently selected from —CH═ and —N═, provided that one A group is —N═ and three other A groups are each CH═;

M is selected from —O and —S;

R 1 is selected from:

(1) aryl, and

(2) heterocyclyl;

wherein the aryl of (1) 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 e , R e is selected from —OH and —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;

wherein the heterocyclyl of (2) 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 selected from:

(1) aryl, and

(2) heterocyclyl;

wherein each of the aryl of (1) and the heterocyclyl of (2) 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;

R 1 is selected from:

(1) aryl, and

(2) heterocyclyl;

wherein the aryl of (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl, optionally substituted with —OH,

(c) —CN,

(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(e) —O—C3-6 cycloalkyl,

(f) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

(g) —C(O)—R e , R e is selected from —OH and —C 1-6 alkyl;

wherein the heterocyclyl of (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl, optionally substituted with —OH,

(c) —CN,

(d) oxo,

(e) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(f) —O—C3-6 cycloalkyl,

(g) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, and —NH 2 ,

(h) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-6 alkyl, and

(i) phenyl, optionally substituted with 1-3 halogens;

R 2 is selected from:

(1) aryl, and

(2) a 4-7 membered mono-cyclic heterocyclyl;

wherein each of the aryl of (1), and the heterocyclyl of (2) 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; and

R 3 is selected from H, halogen and —C 1-6 alkyl, optionally substituted with —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from:

(1) phenyl,

(2) a 4-7 membered mono-cyclic heterocyclyl selected from a saturated, a partially unsaturated and an aromatic ring containing one to four heteroatoms independently selected from N, O and S, and

(3) a 7-10 membered fused bicyclic heterocyclyl containing one to three heteroatoms independently selected from N, O and S in either of the rings;

wherein the phenyl of (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl, optionally substituted with —OH,

(c) —CN,

(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(e) —O—C3-6 cycloalkyl,

(f) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

(g) —C(O)—R e , R e is selected from —OH and —C 1-6 alkyl; and

wherein each of the mono-cyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl, optionally substituted with —OH,

(c) —CN,

(d) oxo,

(e) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(f) —O—C 3-6 cycloalkyl,

(g) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, and —NH 2 ,

(h) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-6 alkyl, and

(i) phenyl, optionally substituted with 1-3 halogens.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from:

(1) phenyl;

(2) a mono-cyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl; and

(3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazol[4,5-b]pyridinyl, imidazol[4,5-c]pyridinyl, indolyl, isoindolinyl;

wherein the phenyl of (1) 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) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,

(e) —O-cyclopropyl,

(f) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

(g) —C(O)—C 1-4 alkyl; and

wherein each of the mono-cyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) 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.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is selected from:

(1) phenyl; and

(2) a 5-6 membered mono-cyclic heterocyclyl;

wherein each of the phenyl of (1), and the heterocyclyl of (4) 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.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is selected from:

(1) phenyl, and

(2) a 5-6 membered mono-cyclic heterocyclyl selected from oxazolyl, pyridinyl, and thiazolyl;

wherein each of the phenyl of (1), and the heterocyclyl of (2) 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 1 , or a pharmaceutically acceptable salt thereof, wherein:

M is —O;

R 1 is selected from:

(1) phenyl;

(2) a mono-cyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl; and

(3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazol[4,5-b]pyridinyl, imidazol[4,5-c]pyridinyl, indolyl, isoindolinyl;

wherein the phenyl of (1) 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) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,

(e) —O-cyclopropyl,

(f) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

(g) —C(O)—C 1-4 alkyl; and

wherein each of the mono-cyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) 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;

R 2 is selected from:

(1) phenyl, and

(2) a 5-6 membered mono-cyclic heterocyclyl selected from oxazolyl, pyridinyl, and thiazolyl;

wherein each of the phenyl of (1), and the heterocyclyl of (2) 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; and

R 3 is selected from H, halogen and —CH 2 —OH.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:

M is —O—;

R 1 is selected from:

(1) phenyl; and

(2) a mono-cyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl;

wherein the phenyl of (1) 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,

(d) —O-cyclopropyl, and

(e) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

wherein the mono-cyclic heterocyclyl of (2) 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;

R 2 is selected from:

(1) phenyl, and

(2) pyridinyl;

wherein each of the phenyl of (1), and the pyridinyl of (2) is optionally substituted with 1-3 halogens; and

R 3 is H.

9. The compound of claim 1 of formula (Ik), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is selected from:

(1) phenyl; and

(2) a mono-cyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl;

wherein the phenyl of (1) 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,

(d) —O-cyclopropyl, and

(e) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and

wherein the mono-cyclic heterocyclyl of (2) 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.

10. The compound of claim 9 , 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,

(f) —C(CH 3 ) 2 OH, and

(g) cyclopropyl, and

R d is selected from:

(a) a halogen selected from F, Cl and Br,

(b) —CN,

(c) —CH 3 , and

(d) —CF 3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

N-(4-fluorophenyl)-3-(4′-(hydroxymethyl)-6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide,

3-(6′-(difluoromethoxy)-4′-(hydroxymethyl)-[3,3′-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide,

3-(6′-(difluoromethoxy)-4′-(2-hydroxypropan-2-yl)-[3,3′-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(4′-(2-hydroxypropan-2-yl)-6′-(trifluoromethyl)[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(4′-(hydroxymethyl)-6′-(trifluoromethyl)[2,3′-bipyridin]-5-yl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(6-(2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(4′-(2-hydroxypropan-2-yl)-6′-(trifluoromethyl)[2,3′-bipyridin]-5-yl)oxetane-3-carboxamide,

3-(6′-cyclopropoxy-4′-(hydroxymethyl)-[2,3′-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(4-(hydroxymethyl)-6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide,

N-(6-chloropyridin-3-yl)-3-(4′-(hydroxymethyl)-6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide,

N-(4-fluorophenyl)-3-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxetane-3-carboxamide,

N-(6-chloropyridin-3-yl)-3-(4′-(2-hydroxypropan-2-yl)-6′-(trifluoromethyl)-[3 3′-bipyridin]-6-yl)oxetane-3-carboxamide,

N-(6-fluoropyridin-3-yl)-3-hydroxypropan-2-yl)-6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide, and

N-(4-chlorophenyl)-3-(4′-(2-hydroxypropan-2-yl)-6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)oxetane-3-carboxamide.

12. A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.