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 selected from 0 and 1;

each occurrence of A is independently selected from —CH═ and —N═, provided that at least one A is —CH═;

M is selected from —O—, —S— and —CR a R b —, each of R a and R b is independently selected from H, halogen, —OH, and —C 1-8 alkyl; or alternatively, R a and R b together with the carbon to which they are attached form a C 3-4 carbocyclic ring, optionally substituted with 1-2 substituents independently selected from halogen and C 1-4 alkyl;

R 1 is selected from:

(1) phenyl, and

(2) a 6-membered monocyclic heterocyclyl;

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) —C 3-8 cycloalkyl, optionally substituted with —OH,

(c) —CN,

(d) —O—C 1-8 alkyl, optionally substituted with 1-5 halogens,

(e) —O—C 3-8 cycloalkyl,

(f) —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,

(g) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,

(h) —C(O)—OH,

(i) aryl, optionally substituted with 1-3 halogens and

(j) heterocyclyl, optionally substituted with 1-3 substituents independently selected from halogen and —C 1-8 alkyl;

R 2 is selected from:

(1) C 3-8 carbocyclyl, and

(2) aryl,

wherein each of the C 3-8 carbocyclyl of (1), and the aryl 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.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein:

n is 1;

p is 0 or 1;

M is selected from —O— and —CR a R b —, each of R a and R b is independently selected from H, halogen, —OH and —C 1-6 alkyl;

R 1 is selected from:

(1) phenyl, and

(2) a 6-membered monocyclic heterocyclyl;

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

(c) —CN,

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

(e) —O—C 3-6 cycloalkyl,

(f) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, —NH 2 , NHC(O)R c , and —S(O) 2 —C 1-6 alkyl, wherein R c is selected from —C 1-6 alkyl and —C 3-6 cycloalkyl,

(g) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-6 alkyl and —C 3-6 cycloalkyl,

(h) —C(O)—OH, and

(i) heterocyclyl, optionally substituted with 1-3 substituents independently selected from halogen and —C 1-6 alkyl;

R 2 is selected from:

(1) C 3-6 carbocyclyl, and

(2) aryl,

wherein each of the C 3-6 carbocyclyl of (1), and the aryl 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, —OH, and —NH 2 ; and

R 3 is selected from H and halogen.

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

n is 1;

p is 0 or 1;

each A group is —CH═;

or alternatively, one A group is —N═ and the three other A groups are each —CH═; and

M is selected from —O—, —CH 2 —, —CF 2 —, and —CH(CH 3 )—.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H and halogen.

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

R 1 is selected from:

(1) phenyl, and

(2) a 6 membered monocyclic heterocyclyl containing one to three heteroatoms independently selected from N, O, and S;

wherein each of the phenyl of (1) and the mono-cyclic 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) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(e) —O—C 3-6 cycloalkyl,

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

(g) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-6 alkyl and —C 3-6 cycloalkyl,

(h) —C(O)—OH, and

(i) a 5-6 membered monocyclic ring containing one to three heteroatoms independently selected from N, O, and S, optionally substituted with —C 1-6 alkyl.

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

R 1 is a 6 membered monocyclic heterocyclyl selected from pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl; 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) —O—C 1-3 alkyl, optionally substituted with 1-3 halogens,

(f) —O-cyclopropyl,

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

(h) —C(O)—OH, and

(i) 1,2,4-oxadiazolyl, optionally substituted with —C 1-4 alkyl.

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

R 2 is selected from:

(1) C 3-6 carbocyclyl, and

(2) phenyl;

wherein each of the C 3-6 carbocyclyl of (2) and the phenyl of (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl,

(c) —CN, and

(d) —C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH.

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

R 2 is selected from:

(1) 5-6 membered bridged bicyclic carbocyclyl, and

(2) phenyl;

wherein each of the 5-6 membered carbocyclyl of (1) and the phenyl of (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —CN, and

(c) —C 1-4 alkyl, optionally substituted with 1-3 halogens.

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

n is 1;

p is 0 or 1;

each A group is —CH═;

or alternatively, one A group is —N═ and the three other A groups are each —CH═;

M is selected from —O—, —CH 2 —, —CF 2 —, and —CH(CH 3 )—;

R 1 is selected from:

(1) phenyl, and

(2) a 6 membered monocyclic heterocyclyl containing one to three heteroatoms independently selected from N, O, and S;

wherein each of the phenyl of (1) and the mono-cyclic 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) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(e) —O—C 3-6 cycloalkyl,

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

(g) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-6 alkyl and —C 3-6 cycloalkyl,

(h) —C(O)—OH, and

(i) a 5-6 membered monocyclic heterocyclyl containing one to three heteroatoms independently selected from N, O, and S, optionally substituted with —C 1-6 alkyl;

R 2 is selected from:

(1) C 3-6 carbocyclyl, and

(2) phenyl;

wherein each of the C 3-6 carbocyclyl of (2) and the phenyl of (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —C 3-6 cycloalkyl,

(c) —CN, and

(d) —C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH; and

R 3 is selected from H and halogen.

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

n is 1;

p is 0 or 1;

each A group is —CH═;

or alternatively, one A group is —N═ and the three other A groups are each —CH═;

M is selected from —O—, —CH 2 —, and —CH(CH 3 )—;

R 1 is a 6 membered monocyclic heterocyclyl selected from pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl; each of which 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) —O—C 1-3 alkyl, optionally substituted with 1-3 halogens,

(f) —O-cyclopropyl,

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

(h) —C(O)—OH, and

(i) 1,2,4-oxadiazolyl, optionally substituted with —C 1-4 alkyl;

R 2 is selected from:

(1) a 5-6 membered bridged bicyclic carbocyclyl, and (2) phenyl;

wherein each of the 5-6 membered carbocyclyl of (1) and the phenyl of (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) —CN, and

(c) —C 1-4 alkyl, optionally substituted with 1-3 halogens; and

R 3 is selected from H and halogen.

11. The compound of claim 1 having formula (Ii), or a pharmaceutically acceptable salt thereof,

wherein:

p is 0 or 1;

R 1 is selected from:

(1) phenyl, and

(2) a 6 membered monocyclic heterocyclyl containing one to three heteroatoms independently selected from N, O, and S;

wherein each of the phenyl of (1) and the mono-cyclic 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) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,

(e) —O—C 3-6 cycloalkyl,

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

(g) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-6 alkyl and —C 3-6 cycloalkyl,

(h) —C(O)—OH, and

(i) a 5-6 membered monocyclic heterocyclyl containing one to three heteroatoms independently selected from N, O, and S, optionally substituted with —C 1-6 alkyl;

R 3 is selected from H and halogen;

R a is selected from (a) H and (b) C 1-4 alkyl; and

R d is selected from:

(a) H,

(b) halogen, and

(c) —CN.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

p is 0 or 1;

R 1 is a 6 membered monocyclic heterocyclyl selected from pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl; each of which is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl,

(c) —CN,

(d) —O—C 1-3 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, —OH, and —S(O) 2 —C 1-4 alkyl,

(g) —NH—S(O) 2 —C 1-4 alkyl,

(h) —NH—S(O) 2 -cyclopropyl,

(i) —C(O)—OH, and

(j) 1,2,4-oxadiazolyl, optionally substituted with —C 1-4 alkyl;

R 3 is selected from H and halogen;

R c is selected from (a) H and (b) —CH 3 ; and

R d is selected from (a) halogen and (b) —CN.

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

4-cyano-N-(1-(4-(6-methoxy-4-methylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(difluoromethoxy)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropoxypyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropylpyridin-3-yl)-3-fluorophenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropyl-4-methylpyridin-3-yl)-3-fluorophenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(5-(cyclopropanesulfonamido)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(2-cyclopropylpyrimidin-5-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropyl-4-methylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyanopyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(1-hydroxyethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyano-4-methylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(hydroxymethyl)-4-methoxypyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-((methylsulfonyl)methyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(difluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

5-(4-(1-(4-cyanobenzamido)cyclobutyl)phenyl)picolinic acid,

4-cyano-N-(1-(4-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-cyclopropyl-2-(hydroxymethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(5-cyclopropylpyrazin-2-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(5-(2-fluoroethoxy)pyrazin-2-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-isopropylpyridazin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-methoxy-2-methylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

N-(1-(4-(4,6-bis(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)-4-cyanobenzamide,

4-cyano-N-(1-(4-(6-(2-fluoroethoxy)pyridazin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-methoxy-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide, cyano-N-(1-(4-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-cyano-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(6-(difluoromethoxy)-4-methylpyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-formyl-6-isopropoxypyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(4-(4-(difluoromethyl)-6-isopropoxypyridin-3-yl)phenyl)cyclobutyl)benzamide,

4-cyano-N-(1-(6′-cyclopropyl-4′-methyl-[3,3′-bipyridin]-6-yl)cyclobutyl)benzamide,

3-cyano-N-(1-(6′-(difluoromethoxy)-4′-methyl-[3,3′-bipyridin]-6-yl)cyclobutyl)bicyclo[1.1.1]-pentane-1-carboxamide,

3-cyano-N-(1-(6′-cyclopropyl-4′-methyl43,3′-bipyridin]-6-yl)cyclobutyl)bicyclo[1.1.1]pentane-1-carboxamide,

4-fluoro-N-(3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-yl)benzamide,

4-chloro-N-(1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)benzamide,

N-(1-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)cyclopropyl)-4-fluorobenzamide,

N-(1-(4-(6-cyclopropoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)cyclopropyl)-4-fluorobenzamide,

4-fluoro-N-(1-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)cyclopropyl)benzamide,

(S)-4-fluoro-N-(1-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)benzamide,

(R)-4-fluoro-N-(1-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclopropyl)benzamide, 2,2,2-trifluoroacetate salt,

4-fluoro-N-(1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutyl)benzamide, and

N-(1-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)cyclobutyl)-4-fluorobenzamide.

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