IDO inhibitors

Patent metadata

Field	Value
Publication number	US-9624188-B2
Application number	US-201414775976-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	Apr 18, 2017
Grant date	Apr 18, 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 autoimmune diseases utilizing the compounds of the invention. Formula (I).

First claim

What is claimed is:

1. A compound of formula I

wherein
X is

W is N or CR 10 ;
Y is N or CR 11 ;
V is N or CR 12 ;
R 1 is optionally substituted aryl-C 1 -C 10 -alkyl, or optionally substituted aryl;
R 2 is —CO 2 H, optionally substituted heterocyclyl, optionally substituted —CONHSO 2 R 14 , optionally substituted —CONHCOR 13 , optionally substituted —SO 2 NHCOR 13 or optionally substituted —NHSO 2 R 14 ;
R 13 is optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;
R 14 is CF 3 or optionally substituted C 1 -C 10 alkyl;
R 3 is H, halo, CN, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;
R 4 is H or optionally substituted C 1 -C 10 alkyl;
R 5 and R 6 are independently H, optionally substituted C 1 -C 10 alkyl or OH, or
R 5 and R 6 are taken together with the carbon to which they are attached to form

R 7 and R 8 are independently H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted aryl, optionally substituted aryl-C 1 -C 10 -alkyl, optionally substituted 5- to 8-membered heteroaryl, or optionally substituted C 3 -C 8 cycloalkyl;
R 9 is optionally substituted aryl, optionally substituted C 1 -C 10 alkylaryl, optionally substituted C 1 -C 10 alkoxyaryl, optionally substituted heteroaryl, optionally substituted C 1 -C 10 -alkyl heteroaryl, optionally substituted aryl-C 1 -C 10 -alkylaryl, optionally substituted aryloxyaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 10 , R 11 and R 12 are H;

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

2. The compound according to claim 1 of formula II

wherein
X is

R 1 is optionally substituted aryl-C 1 -C 10 -alkyl, or optionally substituted aryl;
R 2 is —CO 2 H, optionally substituted heterocyclyl, optionally substituted —CONHSO 2 R 14 , optionally substituted —CONHCOR 13 , optionally substituted —SO 2 NHCOR 13 or optionally substituted —NHSO 2 R 14 ;
R 13 is optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;
R 14 is CF 3 or optionally substituted C 1 -C 10 alkyl;
R 3 is H, halo, CN, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;
R 4 is H or optionally substituted C 1 -C 10 alkyl;
R 5 and R 6 are independently H, optionally substituted C 1 -C 10 alkyl or OH, or
R 5 and R 6 are taken together with the carbon to which they are attached to form

R 7 and R 8 are independently H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted aryl, optionally substituted aryl-C 1 -C 10 -alkyl, optionally substituted 5- to 8-membered heteroaryl, or optionally substituted C 3 -C 8 cycloalkyl;
R 9 is optionally substituted aryl, optionally substituted C 1 -C 10 alkylaryl, optionally substituted C 1 -C 10 alkoxyaryl, optionally substituted heteroaryl, optionally substituted C 1 -C 10 -alkyl heteroaryl, optionally substituted aryl-C 1 -C 10 -alkylaryl, optionally substituted aryloxyaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 10 , R 11 and R 12 are H;

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

3. The compound according to claim 2 wherein X is NR 7 R 8 and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 wherein X is OR 1 and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3 wherein
X is NR 7 R 8 ;
R 2 is CO 2 H or

R 3 is H or C 1 -C 6 alkyl;
R 4 is H or C 1 -C 6 alkyl;
R 5 and R 6 are independently H, C 1 -C 6 alkyl, CF 3 or OH,
or R 5 and R 6 are taken together with the carbon to which they are attached to form

R 7 and R 8 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 -alkoxy-C 1 -C 10 alkyl, C 1 -C 6 alkoxy, or optionally substituted aryl-C 1 -C 6 -alkyl;
R 9 is aryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkoxyaryl, or optionally substituted heteroaryl;

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

6. The compound according to claim 4
wherein
X is OR 1 ;
R 1 is aryl-C 1 -C 6 -alkyl or aryl(C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl;
R 2 is CO 2 H;
R 3 is H;
R 4 is H;
R 5 and R 6 are independently selected from H or C 1 -C 6 alkyl;
R 9 is C 1 -C 6 alkylaryl or haloaryl;

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

7. The compound according to claim 1 which is 3-(4-(diisobutylamino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenyl)butanoic acid, and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

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

9. 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.

10. The compound of claim 1 that is
3-(4-(diisobutylamino)-3-(3-(p-toly)ureido)phenyl)-2-methylpropanoic acid;
2-(3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)oxetan-3-yl)acetic acid;
3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid;
3-(4-(diisobutylamino)-3-(3-(2-fluorophenyl)ureido)phenyl)butanoic acid;
3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)phenyl)butanoic acid;
3-(4-(diisobutylamino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)butanoic acid;
3-(4-(diisobutylamino)-3-(3-(6-methylpyridin-3-yl)ureido)phenyl)butanoic acid;
3-(4-((4-chlorobenzyl)(2-methoxyethyl)amino)-3-(3-(p-toly)ureido)phenyl)butanoic acid;
3-(3-(3-(2-fl

Assignees

• Bristol Myers Squibb Co

Inventors

• Balog James Aaron
• Huang Audris
• Chen Bin
• Chen Libing
• Shan Weifang

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/12

  Antivirals · CPC title