Inhibitors of indoleamine 2,3-dioxygenase (IDO)

Patent metadata

Field	Value
Publication number	US-9675571-B2
Application number	US-201414776035-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

First claim

What is claimed is:

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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Balog James Aaron
• Huang Audris
• Chen Bin
• Chen Libing
• Seitz Steven P
• Hart Amy C
• Markwalder Jay A

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P25/24

  Antidepressants · CPC title