Substituted cyclobutylpyridine and cyclobutylpyrimidine compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

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

wherein:

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

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

W is selected from —C(O)NH— and —NHC(O)—;

R 1 is selected from:

(1) C 1-6 alkyl,

(2) —O—C 1-6 alkyl,

(3) C 3-6 cycloalkyl,

(4) aryl, and

(5) heterocyclyl;

wherein each of the C 1-6 alkyl of (1) and (2) is optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl; and

wherein each of the C 3-6 cycloalkyl of (3), aryl of (4), and heterocyclyl of (5) is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, (c) —O—C 1-6 alkyl, and (d) C 1-6 alkyl optionally substituted with 1-3 halogens;

R 2 is selected from:

(1) C 1-6 alkyl,

(2) C 3-6 cycloalkyl,

(3) aryl, and

(4) heterocyclyl;

wherein the C 1-6 alkyl of (1) is optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl; and

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

R 3 is selected from H, halogen, —OH, and C 1-6 alkyl optionally substituted with —OH; and each of R 4 and R 5 is independently selected from H, halogen, and C 1-6 alkyl.

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

wherein:

one A is —N═ and the three other A groups are each —CH═;

R 3 is selected from (1) H, (2) —OH, and —CH 3 , optionally substituted with —OH; and

each of R 4 and R 5 is H.

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

two A groups are each —N═ and the two other A groups are each —CH═;

R 3 is H; and

each of R 4 and R 5 is H.

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

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,

(2) —O—C 1-6 alkyl,

(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) 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.

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

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,

(2) —O—C 1-4 alkyl,

(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl 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.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,

(3) phenyl, optionally substituted with 1-3 halogens, and

(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with a halogen,

(3) phenyl, optionally substituted with 1-2 halogens, and

(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens.

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

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,

(2) —O—C 1-6 alkyl,

(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,

(3) phenyl, optionally substituted with 1-3 halogens, and

(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 3 , optionally substituted with —OH; and each of R 4 and R 5 is H.

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

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,

(2) —O—C 1-4 alkyl,

(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with a halogen,

(3) phenyl, optionally substituted with 1-2 halogens, and

(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 2 —OH; and each of R 4 and R 5 is H.

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

two A groups are each —N═ and the two other A groups are each —CH═;

R 1 is phenyl, optionally substituted with 1-2 halogens;

R 2 is phenyl, optionally substituted with 1-2 halogens;

R 3 is H; and

each of R 4 and R 5 is H.

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

wherein:

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,

(2) —O—C 1-6 alkyl,

(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,

(3) phenyl, optionally substituted with 1-3 halogens, and

(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 3 , optionally substituted with —OH; and each of R 4 and R 5 is H.

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

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,

(2) —O—C 1-4 alkyl,

(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with a halogen,

(3) phenyl, optionally substituted with 1-2 halogens, and

(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 2 —OH; and each of R 4 and R 5 is H.

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

wherein:

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,

(2) —O—C 1-6 alkyl,

(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,

(3) phenyl, optionally substituted with 1-3 halogens, and

(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 3 , optionally substituted with —OH; and each of R 4 and R 5 is H.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:

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

R 1 is selected from:

(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,

(2) —O—C 1-4 alkyl,

(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,

(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and

(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl 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;

R 2 is selected from:

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

(2) C 3-6 cycloalkyl, optionally substituted with a halogen,

(3) phenyl, optionally substituted with 1-2 halogens, and

(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 2 —OH; and each of R 4 and R 5 is H.

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

3-chloro-N-(5-(1-(4-chlorobenzamido)cyclobutyl)pyridin-2-yl)benzamide,

3-chloro-N-(5-(1(4-fluorophenyl)carbamoyl)cyclobutyl)pyridin-2-yl)benzamide,

3-chloro-N-(5-{1-[(3 ,3,3-trifluoropropyl)carbamoyl]cyclobutyl) pyridin-2-yl)benzamide, 3-chloro-N- {5-(propylcarbamoyl)cyclobutyl]pyridin-2-yl}benzamide, N-(4-fluorophenyl)-1-(6-(4,4,4-trifluorobutanamido)pyridin-3-yl)cyclobutane-1-carboxamide, 6-chloro-N-(5-{1-[(6-fluoropyridin-3-yl)carbamoyl] cyclobutyl}pyridin-2-yl)pyridine-2-carboxamide, N-(5-{1-[(6-fluoropyridin-3-yl)carbamoyl]cyclobutyl}pyridin-2-yl)cyclohexanecarboxamide, N-(5-{1-[(6-fluoropyridin-3-yl)carbamoyl]cyclobutyl}pyridin-2-yl)-6-methylpyridine-2-carboxamide, 4,4-difluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)cyclohexane-1-carboxamide, (1 S,3R)-3-cyano-N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)cyclohexane-1-carboxamide, 1-{6-[(4,4-dimethylpentanoyl)amino]pyridin-3-yl}-N-(4-fluorophenyl)cyclobutane-1-carboxamide, 1-{6-[(3-cyclopropylpropanoyl)amino]pyridin-3-yl}-N-(6-fluoropyridin-3-yl)cyclobutane-1-carboxamide, (1R,3R)-3-cyano-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)cyclohexane-1-carboxamide, 3-chloro-2-fluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)benzamide, N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)cyclohexanecarboxamide, 5-chloro-2-fluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)benzamide, 3,3-difluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)cyclohexane-1-carboxamide, 1-{6-[(3-cyclopropylpropanoyl)amino]pyridin-3-yl}-N-(4-fluorophenyl)cyclobutane-1-carboxamide, tert-butyl (5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)carbamate, N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)oxane-4-carboxamide, 3-chloro-2,6-difluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)benzamide, N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)oxane-3-carboxamide, 3-fluoro-N-(5-(1-((4-fluorophenyl)carbamoyl)cyclobutyl)pyridin-2-yl)benzamide, 3-cyano-N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)benzamide, 5-chloro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)pyridine-3-carboxamide, 4-chloro-N-(5-{1-[(4-fluorophenyl)carbamoyl] cyclobutyl}pyridin-2-yl)pyridine-2-carboxamide, N-(4-fluorophenyl)-1- {64(3-methylbutanoyl)amino]pyridin-3-yl} cyclobutane- 1-carboxamide, 5-fluoro-N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)pyridine-3-carboxamide, N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)-2-(trifluoromethyl)pyridine-4-carboxamide, 1- {6-[(cyclopropylacetyl)amino]pyridin-3-yl}-N-(4-fluorophenyl)cyclobutane-1-carboxamide, N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)pyrrolidine-1-carboxamide, 5-cyano-N-(5-{1-[(4-fluorophenyl)carbamoyl]cyclobutyl}pyridin-2-yl)pyridine-3-carboxamide, 5-chloro-N-(5-(1-((4,4-difluorocyclohexyl)carbamoyl)cyclobutyl)pyridin-2-yl)nicotinamide, 5-chloro-N-(5-{1-[(5-fluoropyridin-2-yl)carbamoyl] cyclobutyl}pyridin-2-yl)pyridine-3-carboxamide, N-cyclohexyl-5-(1-((4-fluorophenyl)carbamoyl)cyclobutyl)picolinamide, 3-chloro-N-(6-((4(4-fluorophenyl)carbamoyl)cyclobutyl)pyridin-3-yl)benzamide, 3-chloro-N-(6-{1-[(5-fluoropyridin-2-yl)carbamoyl] cyclobutyl}pyridin-3-yl)benzamide, 3-chloro-N-(2-((4-fluorophenyl)carbamoyl)cyclobutyl)pyrimidin-5-yl)benzamide, N-(6-(1-(6-chloronicotinamido)cyclobutyl)pyridin-3-yl)oxazole-2-carboxamide, 6-chloro-N-(1-{5-[(1,3-thiazole-2-carbonyl)amino]pyridin-2-yl} cyclobutyl)pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(3 , 5-difluorobenzene-1-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(3-chlorobenzene-1-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(2-chloropyridine-4-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, 5-chloro-N-(6-{1-[(6-chloropyridine-3-carbonyl)amino]cyclobutyl}pyridin-3-yl)pyridine-3-carboxamide, 6-chloro-N-[1-(5-{[2-(trifluoromethyl)pyridine-4-carbonyl]amino}pyridin-2-yl)cyclobutyl]pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(2-methylpyridine-4-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(4-cyanobenzene-1-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, 6-chloro-N-(1-{5-[(3-cyanobenzene-1-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, N-(6- {1-[(6-chloropyridine-3-carbonyl)amino]cyclobutyl}pyridin-3-yl)-5-cyanopyridine-3-carboxamide, N-(6- {1-[(6-chloropyridine-3-carbonyl)amino]cyclobutyl}pyridin-3-yl)pyrimidine-2-carboxamide, 6-chloro-N-(1-{5-[(3-fluorobenzene-1-carbonyl)amino]pyridin-2-yl}cyclobutyl)pyridine-3-carboxamide, bromo-N-(1-(5-(3-chlorobenzamido)pyridin-2-yl)cyclobutyl)benzo[d]thiazole-2-carboxamide, 3-chloro-N-(6-(1-(propylcarbamoyl)cyclobutyl)pyridin-3-yl)benzamide, 3-cyano-N-(6-(14(4-fluorophenyl)carbamoyl)cyclobutyl)-2-hydroxypyridin-3-yl)benzamide, and 3-chloro-N-(6-(14(4-fluorophenyl)carbamoyl)cyclobutyl)-2-(hydroxymethyl)pyridin-3-yl)benzamide.

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

17. 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.

18. 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.

19. The method of claim 1 , 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.

20. The method of claim 19 , 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.