Inhibitors of indoleamine 2,3-dioxygenase (IDO)

1. A compound of formula (I)

where

X is

E is NH or CH 2 ;

W is CR 10 ;

Y is CR 11 ;

V is CR 12 ;

is C 3 -C 8 cycloalkyl;

R 1 is C 1 -C 10 alkyl optionally substituted with halo or phenyl wherein said phenyl may be optionally substituted with halo;

R 2 is COOH, heteroaryl or CONHSO 2 R 14 ;

R 3 is H, C 1 -C 10 alkyl or halo;

R 4 is H, C 1 -C 10 alkyl, or halo;

R 6 is H;

R 7 and R 8 are independently selected from the group consisting of C 1 -C 10 alkyl optionally substituted with halo or phenyl, wherein said phenyl may be optionally substituted with halo, C 1 -C 10 alkoxy, C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, C 3 -C 8 cycloalkyl, aryl optionally substituted with halo;

R 9 is aryl, C 1 -C 10 alkylaryl, C 3 -C 8 cycloalkylaryl, C 1 -C 10 alkoxyaryl, C 1 -C 10 alkyl heteroaryl, heteroaryl, or

wherein R 9 may be substituted with at least one alkyl, halo, alkoxy, CN, or haloalkyloxy;

R 10 is H or halo;

R 11 is H or halo; and

R 12 is H, C 1 -C 10 alkyl, or C 2 -C 10 alkenyl;

R 14 is CF 3 , C 3 -C 8 cycloalkyl or C 1 -C 10 alkyl;

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein

X is NR 7 R 8 ;

E is NH;

R 2 is COOH,

 or CONHSO 2 R 14 ;

R 3 is H or C 1 -C 6 alkyl;

R 4 is H, C 1 -C 6 alkyl, or halo;

R 6 is H;

R 7 and R 8 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl;

R 10 is H;

R 11 is halo or H; and

R 12 is H;

R 14 is CF 3 C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl;

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein

E is NH;

X is

R 2 is COOH;

R 3 , R 4 , R 5 and R 6 are H;

R 7 and R 8 are independently selected from C 1 -C 10 alkyl;

R 9 is C 1 -C 10 alkylaryl;

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 wherein

R 7 and R 8 are each

 and

R 9 is

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein

X is OR 1 ;

E is NH;

R 2 is COOH,

 or —CONHSO 2 R 14 ;

R 3 , R 4 , R 5 and R 6 are H;

R 1 is aryl-C 1 -C 6 -alkyl or C 1 -C 6 alkyl wherein R 1 may be optionally substituted with halo;

R 9 is aryl or C 1 -C 6 alkylaryl wherein R 9 may be substituted with at least one alkyl, halo, alkoxy, CN, or haloalkyloxy;

R 12 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or halo;

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein E is CH 2 ;

X is —NR 7 R 8 ;

R 2 is COOH; and

R 7 and R 8 are independently selected from C 1 -C 6 alkyl;

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 wherein

R 2 is COOH;

R 7 and R 8 are each

 and

R 9 is

and/or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein the IC 50 in the HEK Human IDO-1 assay is <10 nM.

9. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

10. A method of inhibiting the activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

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

(1R,2S)-2-(4-(cyclohexyl(4,4,4-trifluoro-2-methylbutyl)amino)-3-(2-(p-tolypacetamido)phenyl)cyclopropanecarboxylic acid;

(1S,2R)-2-(4-(cyclohexyl(4,4,4-trifluoro-2-methylbutyl)amino)-3-(2-(p-tolypacetamido)phenyl)cyclopropanecarboxylic acid, mixture of diastereomers;

2-(4-(diisobutylamino)-3-(3-o-tolylureido)phenyl) cyclopropanecarboxylic acid;

(1S,2R)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)-N-(methylsulfonyl)cyclopropanecarboxamide;

(1S,2R)—N-(cyclopropylsulfonyl)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxamide;

(1S,2R)-2-(4-((S)-1-phenylpropoxy)-3-(3-(p-tolyl)ureido) phenyl)cyclopropanecarboxylic acid;

(1R,2S)-2-(4-((R)-1-phenylpropoxy)-3-(3-(p-tolyl)ureido) phenyl)cyclopropanecarboxylic acid;

(1R,2S)-2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenyl)cyclopropanecarboxylic acid; and

(1S,2R)-2-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)cyclopentanecarboxylic acid.