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

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

wherein:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

=M- is ═N—;

each occurrence of =M- is independently selected from (1)═CR a —, (2) —CR a R a — and (3)═N—;

wherein each occurrence of R a is independently selected from:

(a) H,

(b) —OH,

(c) halogen,

(d) —CN,

(e) C 1-6 alkyl,

(f) —O—C 1-6 alkyl,

(g) —C(O)—R 5 , wherein R 5 is selected from (a) —OH, (b) —O—C 1-6 alkyl and (c) a 5- or 6-membered heterocyclyl, optionally substituted with —OH, and

(h) 5- or 6-membered heteroaryl;

wherein each of the C 1-6 alkyl of (e) and (f) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH, (b) —C(O)OH and (c) halogen;

each dotted bond “═” is independently selected from (1) a double bond and (2) a single bond;

one Z is ═CH— and the other Z is ═N—;

R 1 is selected from:

(1) C 1-6 alkyl,

(2) C 3-6 cycloalkyl,

(3) aryl and

(4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —NH 2 , (d) C 1-6 alkyl, optionally substituted with 1 to 3 halogens, (e) —O—C 1-6 alkyl and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from:

(1) H,

(2) —OH,

(3) halogen,

(4) —CN,

(5) C 1-6 alkyl,

(6) —O—C 1-6 alkyl,

(7) —C(O)—R 5 , wherein R 5 is selected from (a) —OH, (b) —O—C 1-6 alkyl and (c) a 5- or 6-membered heterocyclyl, optionally substituted with —OH, and

(8) 5- or 6-membered heteroaryl;

wherein each of the C 1-6 alkyl of (5) and (6) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH, (b) —C(O)OH and (c) halogen;

or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic ring comprising 1 to 2 hetero atoms independently selected from O, S and NH, wherein the 5- or 6-membered heterocyclic ring is optionally substituted with an oxo;

R 3 is selected from (1) H and (2) C 1-6 alkyl optionally substituted with a halogen or —OH; and

one R 4 is H and the other R 4 is selected from (1) —OH, (2) C 1-6 alkyl and (3) —O—C 1-6 alkyl;

or alternatively, two R 4 groups together with the carbon to which they are attached form a 3-5 membered cycloalkyl ring or a 4-5 membered heterocyclic ring containing one oxygen atom; each ring is optionally substituted with —OH, halogen or C 1-6 alkyl.

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

wherein:

the =M- in the five membered ring is ═N— and each occurrence of the other two =M- is independently selected from (1)═CR a — and (2)═N—;

R 1 is selected from:

(1) C 1-6 alkyl,

(2) C 3-6 cycloalkyl,

(3) phenyl and

(4) pyridinyl;

wherein each of the aryl of (3) and the pyridinyl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —NH 2 , (d) —CH 3 , (e) —CF 3 , (f) —O—CH 3 and (g) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from:

(1) H,

(2) —OH,

(3) halogen,

(4) —CN,

(5) C 1-6 alkyl,

(6) —O—C 1-6 alkyl,

(7) —C(O)—R 5 , wherein R 5 is selected from (a) —OH, (b) —O—C 1-6 alkyl and (c) a 5- or 6-membered heterocyclyl, optionally substituted with —OH, and

(8) 5- or 6-membered heteroaryl;

wherein each of the C 1-6 alkyl of (5) and (6) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH, (b) —C(O)OH and (c) halogen or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic group comprising 1 to 2 hetero atoms independently selected from O, S and N, wherein the 5- or 6-membered heterocyclic group is optionally substituted with an oxo;

R 3 is selected from (1) H and (2) C 1-6 alkyl optionally substituted with a halogen or —OH; and

one R 4 is H and the other R 4 is selected from (1) —OH, (2) C 1-4 alkyl and (3) —O—C 1-4 alkyl;

or alternatively, two R 4 groups together with the carbon to which they are attached form a cyclobutyl ring or an oxetanyl ring; each ring is optionally substituted with —OH, halogen or C 1-6 alkyl.

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

wherein:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

the =M- in the five membered ring is ═N— and the other =M- is selected from (1)═CR a — and (2) ═N—;

V is selected from (1) —CR b R b —, (3) —O—; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from:

(1) C 1-6 alkyl,

(2) C 3-6 cycloalkyl,

(3) aryl and

(4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from:

(1) H,

(2) —OH,

(3) halogen,

(4) —CN,

(5) C 1-6 alkyl,

(6) —O—C 1-6 alkyl, and

(7) 5- or 6-membered heteroaryl;

wherein each of the C 1-6 alkyl of (5) and (6) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH, (b) —C(O)OH and (c) halogen;

or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic group which is optionally substituted with an oxo; and

R 3 is selected from (1) H and (2) C 1-6 alkyl optionally substituted with halogen or —OH.

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

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

V is selected from (1) a bond and (2) —CR b R b —; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from (1) C 1-6 alkyl, (b) C 3-6 cycloalkyl, (c) aryl and (d) 5- or 6-membered heteroaryl;

wherein each of the aryl of (c) and the heteroaryl of (d) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN, (5) C 1-6 alkyl, (6) —O—C 1-6 alkyl and (7) 5- or 6-membered heteroaryl; wherein each of the C 1-6 alkyl of (5) and (6) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen;

or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic group which is optionally substituted with an oxo; and

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

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

each M is ═N—;

V is a bond or —CR b R b —; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from (1) H, (2)halogen, (3) —CN and (4) C 1-6 alkyl;

wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens; and

R 3 is selected from (1) H and (2) C 1-6 alkyl optionally substituted with —OH.

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

the =M- in the five membered ring is ═N— and the other =M- is ═CR a —;

V is a bond or CR b R b ; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from (1) H, (2)halogen, (3) —CN and (4) C 1-6 alkyl;

wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens; and

R 3 is H.

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

wherein:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

V is selected from (1) a bond and (2) —CR b R b wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl; and

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN, (5) C 1-6 alkyl, (6) —O—C 1-6 alkyl and (7) 5- or 6-membered heteroaryl; wherein each of the C 1-6 alkyl of (5) and (6) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen;

or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic group which is optionally substituted with an oxo.

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

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

V is selected from (1) —CH 2 — and (3) —CF 2 —;

R 1 is selected from (1) C 3-6 cycloalkyl, (2)aryl and (3) 5- or 6-membered heteroaryl; wherein each of the aryl of (2) and the heteroaryl of (3) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) C 1-6 alkyl and (e) C 3-6 cycloalkyl; and

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN, (5) C 1-6 alkyl, (6) —O—C 1-6 alkyl and (7) tetrazolyl; wherein each of the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen.

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

R 1 is selected from (1) phenyl and (2)pyridinyl; wherein each of the phenyl and the pyridinyl is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 and (d) C 1-6 alkyl; and

each occurrence of R 2 is independently selected from (1) H, (2)halogen, (3) —CN, (4) C 1-6 alkyl and (5) —O—C 1-6 alkyl; wherein each of the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen.

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

wherein:

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

V is selected from (1) a bond and (2) —CR b R b ; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl;

R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl;

wherein each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl and (f) C 3-6 cycloalkyl; and

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN, (5) C 1-6 alkyl, (6) —O—C 1-6 alkyl and (7) 5- or 6-membered heteroaryl; wherein each of the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen;

or alternatively, two adjacent R 2 groups together with the carbons to which they are attached form a 5- or 6-membered heterocyclic group which is optionally substituted with an oxo.

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

L is selected from (1) —NHC(O)— and (2) —C(O)NH—;

V is selected from (1) —CH 2 — and (3) —CF 2 —;

R 1 is selected from (1) C 3-6 cycloalkyl, (2)aryl and (3) 5- or 6-membered heteroaryl; wherein each of the aryl of (2) and the heteroaryl of (3) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) C 1-6 alkyl and (e) C 3-6 cycloalkyl; and

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN, (5) C 1-6 alkyl, (6) —O—C 1-6 alkyl and (7) tetrazolyl; wherein each of the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen.

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

R 1 is selected from (1) phenyl and (2)pyridinyl; wherein the phenyl and the pyridinyl is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 and (d) C 1-6 alkyl; and

each occurrence of R 2 is independently selected from (1) H, (2)halogen, (3) —CN, (4) C 1-6 alkyl and (5) —O—C 1-6 alkyl; wherein each of the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen.

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

N-(5-(1-(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl)pyridin-2-yl)-3-chlorobenzamide,

3-chloro-N-(5-(1-(6-cyano-1H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl)pyridin-2-yl)benzamide,

N-(5-(1-(1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl)-3-chlorobenzamide,

N-(5-(1-(6-cyano-1H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl)pyridin-2-yl)-5-fluoronicotinamide,

3-Cyano-N-(5-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl)benzamide,

3-chloro-N-(5-(1-(5-cyano-1H-pyrrolo[2,3-b]pyridin-2-yl)cyclobutyl)pyridin-2-yl)benzamide,

3-chloro-N-(5-{1-[6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl]cyclobutyl}pyridin-2-yl)benzamide,

3-chloro-N-{5-[1-(5,7-dimethyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(5-chloro-7-methyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(6,7-dimethyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(7-methyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

N-{5-[1-(6-tert-butyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}-3-chlorobenzamide,

3-chloro-N-{5-[1-(6-methyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(6-methoxy-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(4-methoxy-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(5,6-difluoro-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(5,7-difluoro-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(7-oxo-3,6,7,8-tetrahydroimidazo[4,5-g][1,4]benzoxazin-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-(5-{1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl)benzamide,

3-chloro-N-(5-{1-[5-(1H-tetrazol-1-yl)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl) benzamide,

3-chloro-N-{5-[1-(6-chloro-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-(5-{1-[6-(trifluoromethoxy)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl) benzamide,

3-chloro-N-(5-{1-[6-(difluoromethoxy)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl) benzamide,

3-chloro-N-(5-{1-[7-(hydroxymethyl)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl) benzamide,

3-chloro-N-{5-[1-(7-fluoro-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(5,6-dimethyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-chloro-N-{5-[1-(6-fluoro-5-methyl-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

3-cyano-N-(5-{1-[6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]cyclobutyl}pyridin-2-yl)benzamide,

3-cyano-N-{5-[1-(6-cyano-3H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl]pyridin-2-yl}benzamide,

N-{5-[1-(5-chloro-1H-benzimidazol-2-yl)cyclobutyl]pyridin-2-yl}-3-cyanobenzamide,

3-Chloro-N-(5-(1-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl)benzamide,

3-Chloro-N-(5-(1-(7-(3-hydroxypropyl)-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl)benzamide,

2-(2-(1-(6-(3-Chlorobenzamido)pyridin-3-yl)cyclobutyl)-1H-benzo[d]imidazol-7-yl)acetic acid,

3-Cyano-N-(5-(1-(7-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)cyclobutyl) pyridin-2-yl)benzamide,

methyl 2-(1-(6-(3-cyanobenzamido)pyridin-3-yl)cyclobutyl)-1H-benzo[d]imidazole-7-carboxylate,

2-(1-(6-(3-Cyanobenzamido)pyridin-3-yl)cyclobutyl)-1H-benzo[d]imidazole-7-carboxylic acid,

3-Cyano-N-(5-(1-(7-(4-hydroxypiperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl) benzamide,

3-cyano-N-(5-{1-[7-(pyrrolidine-1-carbonyl)-1H-benzimidazol-2-yl]cyclobutyl}pyridin-2-yl)benzamide,

3-Cyano-N-(5-(methoxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

(S)-3-cyano-N-(5-(methoxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

(R)-3-cyano-N-(5-(methoxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

3-cyano-N-(5-(hydroxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

(S)-3-cyano-N-(5-(hydroxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

(R)-3-cyano-N-(5-(hydroxy(6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)pyridin-2-yl)benzamide,

3-Cyano-N-(6-(1-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclobutyl)pyridin-3-yl)benzamide,

N-(6-(1-(1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-3-yl)-3-cyanobenzamide,

3-chloro-N-(6-(1-(6-cyano-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-3-yl) benzamide, and

3-Chloro-N-(5-(1-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)cyclobutyl)pyridin-2-yl)benzamide.

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

15. A method for treating an IDO-associated disease or disorder in a mammalian subject which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating an IDO-associated disease or disorder in a mammalian subject which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with another anti-cancer agent.

17. The method of claim 16 , wherein the IDO-associated disease or disorder is a cancer, viral infection, HCV infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplantation, and autoimmune diseases.

18. The method of claim 17 , wherein the cancer is a cancer of the colon, pancreas, breast, prostate, lung, brain, ovary, cervix, testes, renal, head and neck, lymphoma, leukemia, and melanoma.