Fused imidazole derivatives useful as IDO inhibitors

1. A compound of the formula,

or a pharmaceutically acceptable salt thereof, wherein

bond a is a single bond or a double bond;

n is 0 or 1;

each R 1 is independently halogen, —OR, —N(R) 2 , or —SR;

m is 0, 1, or 2;

p is 0 or 1;

when a is a single bond, then Z is —C(R 36 ) 2 — or —C(═R 32 )—,

when a is a double bond, then Z is —C(R 36 )═;

each R 36 is independently hydrogen or R 31 ;

each R 31 is independently halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 alkyl-R 33 , C 1-6 haloalkyl, —OR, —N(R) 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , wherein R 33 is —OR, —N(R) 2 , or —SR;

R 32 is oxo, ═C(R 34 ) 2 , =(spiro-C 3-8 cycloalkyl), or =(spiro-(3-10 membered heterocyclyl)), wherein each R 34 is independently hydrogen, halogen, C 1-6 alkyl, or C 3-8 cycloalkyl;

R C is hydrogen or C 1-6 alkyl; and

each R is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocyclyl, benzyl, (5- or 6-membered heteroaryl)C 1-6 alkyl-, C 3-8 cycloalkylC 1-6 alkyl-, C 3-8 cycloalkenylC 1-6 alkyl-, or (3-8 membered heterocyclyl)C 1-6 alkyl-.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein bond a is a single bond and Z is —C(R 36 ) 2 —.

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

m is 0;

bond a is a single bond; and

each R 36 is independently hydrogen, halogen, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, or —OH, and

R 32 is oxo, =C(R 34 ) 2 , =(spiro-C 3-8 cycloalkyl), or =(spiro-(3-8 membered heterocyclyl)), wherein each R 34 is independently hydrogen, halogen, C 1-6 alkyl, or C 3-8 cycloalkyl.

4. The compound of claim 1 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein

the stereoisomeric configuration of carbon-1 (C-1) and carbon-3 (C-3) are respectively (R, R), and wherein R 3 is

5. The compound of claim 1 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (R, S) , and wherein R 3 is

6. The compound of claim 1 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R) , and wherein R 3 is

7. The compound of claim 1 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, S), and wherein R 3 is

8. The compound of claim 1 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R) or (S,S), and wherein R 3 is cyclohexyl and R 31 is OR.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R), and R 1 is fluoro or chloro.

10. The compound of claim 6 , of the formula,

or a pharmaceutically acceptable salt thereof, wherein

the stereoisomeric configuration of carbon-1 and carbon-3 are respectively (S, R);

R 1 is fluoro or chloro;

R C is hydrogen;

a is a single bond;

m is 0;

p is 0 or 1;

Z is —C(R 36 ) 2 −;

each R 31 is independently halogen, C 1-6 alkyl, —C 1-6 alkyl-R 33 , C 1-6 haloalkyl, —OR, —N(R) 2 , —C(O)OR, —C(O)N(R) 2 , —N(R)C(O)R, wherein R 33 is —OR, or —N(R) 2 ; and

each R is independently hydrogen or C 1-6 alkyl.

11. The compound of claim 1 , that is

2-(6-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1-cyclohexylethanol;

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

1-cyclohexyl-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

2-(7-chloro-5H-imidazo[5,1-a]isoindol-5-yl)-1-cyclohexylethanol;

1-cyclopentyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanone;

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylenecyclohexyl)ethanol;

1-(cyclohex-3-en-1-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

1-(4-(hydroxymethyl)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylenecyclohexyl)ethanol;

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol;

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(iodomethylene)cyclohexyl)ethanol;

1-(4,4-difluorocyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

1-(4,4-difluorocyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

1-(4-(cyclopropylmethylene)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(propan-2-ylidene)cyclohexyl)ethanol;

2-(9-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-methylcyclohexyl)ethanol;

1-(cyclohex-3-en-1-yl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(R)-1-cyclohexyl-2((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(S)-1-cyclohexyl-2((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

cyclohexyl(4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)piperidin-1-yl)methanone;

methyl 4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl) ethyl) cyclohexanecarboxylate;

4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexanol;

1-(4-(2-hydroxyethylidene)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(1R,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl) cyclohexyl benzoate;

(1R,4s)-4-(2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl) cyclohexanol;

1-((1s,4s)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(1r,4r)-4-(2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

(1S,4s)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

(1R,4s)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

(1S,4r)-4-((S)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

(1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

N-((1s,4s)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide;

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

1-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

N-((1r,4r)-4-(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl)cyclohexyl)benzamide;

2-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol;

2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(4-(trifluoromethyl)cyclohexyl)ethanol;

or a pharmaceutically acceptable salt thereof.

12. A compound selected from the group consisting of

1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(S)-1-cyclohexyl-2((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol;

(1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

14. A pharmaceutical composition comprising the compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

15. A pharmaceutical composition comprising the compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

16. A pharmaceutical composition comprising the compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

17. A pharmaceutical composition comprising the compound of claim 12 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

18. A compound that is (S)-1-cyclohexyl-2((S)-5H -imidazo[5,1-a]isoindol-5-yl)ethanol, or a pharmaceutically acceptable salt thereof.

19. A compound that is (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of claim 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

21. A pharmaceutical composition comprising the compound of claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

22. A compound that is a hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, or acetic acid salt of (S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol.

23. A compound that is a phosphoric acid salt of (S)-1-cyclohexyl-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethanol.

24. A compound that is a hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, or acetic acid salt of (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol.

25. A compound that is a phosphoric acid salt of (1R,4r)-4-((R)-2-((S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-1-hydroxyethyl)cyclohexanol.

26. A pharmaceutical composition comprising the compound of claim 22 and a pharmaceutically acceptable diluent, excipient, or carrier.

27. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable diluent, excipient, or carrier.

28. A pharmaceutical composition comprising the compound of claim 24 and a pharmaceutically acceptable diluent, excipient, or carrier.

29. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable diluent, excipient, or carrier.