IDO inhibitors

Patent metadata

Field	Value
Publication number	US-9765018-B2
Application number	US-201414897668-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Jul 1, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

There are disclosed compounds of formula (I) 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)

wherein:
W is CR 4 or N;
V is CR 5 or N, and
Y is CR 6 or N;
{circle around (A)} is optionally substituted phenyl or optionally substituted 5 to 7-membered monocyclic heteroaryl;
R 1 is COOH, tetrazol-5-yl, —NHSO 2 R 20 ,

—CONHSO 2 R 21 , —CONHCOOR 22 , or —SO 2 NHCOR 23 ;
R 2 and R 3 are independently H, hydroxy, optionally substituted C 1 -C 6 alkyl, halo, N(C 1 -C 6 alkyl) 2 or optionally substituted C 1 -C 6 alkoxy;
R 4 , R 5 and R 6 are independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, C 1 -C 6 alkanoyl, halo, CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 -alken-dienyl, dihydroindenyl, optionally substituted C 1 -C 6 alkoxy, or OH,
wherein the optional substituents, where possible, are 1-3 groups selected from halo, C 3 -C 8 cycloalkyl, aryl, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di-C 1 -C 6 -alkylamino or cyano;
R 7 is H, optionally substituted aryl, optionally substituted bicyclic carbocyclyl, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 5- to 7-membered monocyclic heterocyclic, optionally substituted C 1 -C 6 alkoxy, optionally substituted arylalkyl, optionally substituted C 1 -C 9 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 5 -C 8 cycloalkenyl,
wherein the optional substituents, where possible, are 1-3 groups selected from H, C 1 -C 6 alkyl, aryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 5- to 7-membered monocyclic heterocyclic, C 2 -C 6 alkynyloxy(C 1 -C 6 alkyl) 0-1 , halo, halo-substituted aryl, oxo, trihalo-C 1 -C 6 -alkyl, or OR 19 ,
where R 19 is H, C 1 -C 6 alkyl, C 2 -C 6 alkyl, or C 2 -C 6 alkynyl;
R 8 is optionally substituted aryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclic, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted C 1 -C 6 alkoxycarbonyl 5- to 7-membered monocyclic heteroaryl, R 24 CO—, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl or optionally substituted C 5 -C 8 cycloalkenyl,
wherein the optional substituents, where possible, are 1-2 groups selected from H, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, halo, optionally substituted C 1 -C 6 -alkoxy, cyano, 5 to 7-membered monocyclic heteroaryl, NH 2 CO—, di-C 1 -C 6 -alkylamino, aminosulfonyl, 5 to 7-membered monocyclic heterocyclo, hydroxy, C 1 -C 6 alkylsulfonyl, azido, or aryl;
R 19 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 20 is optionally substituted C 1 -C 6 alkyl, optionally substituted phenyl, CF 3 , CF 2 CF 3 or CH 2 CF 3 ;
R 21 is optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 8 cycloalkyl;
R 22 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 23 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 24 is optionally substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 alkylaryl, aryl-C 1 -C 6 -alkyl(hydroxy), or optionally substituted C 1 -C 6 alkyl;
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

2. The compound as defined in claim 1 wherein:
W is CR 4 ;
V is CR 5 ;
Y is CR 6 or N;
R 4 is H;
R 5 is H; and
R 6 is H, halo, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 alken-dienyl, C 3 -C 8 cycloalkyl or C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl;
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

3. The compound as defined in claim 1 wherein {circle around (A)} is phenyl, and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

4. The compound as defined in claim 1 wherein:
R 1 is COOH, tetrazol-5-yl, —NHSO 2 R 20 or CONHSO 2 R 21 ;
R 2 is H, halo, hydroxy, optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 alkoxyl; and
R 3 is H or C 1 -C 6 alkoxy;
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

5. The compound as defined in claim 1 wherein:
R 7 is aryl, optionally substituted C 1 -C 9 -alkyl, optionally substituted C 1 -C 6 alkylaryl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, C 3 -C 8 cycloalkylaryl, optionally substituted C 3 -C 8 -cycloalkyl or optionally substituted aryl C 1 -C 6 -alkyl,
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

6. The compound as defined in claim 1 wherein:
R 8 is optionally substituted C 1 -C 6 alkylaryl, optionally substituted aryl, optionally substituted C 3 -C 8 cycloalkylaryl, optionally substituted C 3 -C 8 -cycloalkyl-C 1 -C 6 alkyl, optionally substituted 5- to 7-membered heterocyclic, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl-C 1 -C 6 -alkyl, C 1 -C 6 alkoxyaryl, C 1 -C 6 -alkoxy(C 1 -C 6 -alkyl)aryl, C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 6 -alkyl-C 3 -C 8 -cycloalkyl, optionally substituted C 1 -C 6 alkanoyl, di-C 1 -C 6 -alkylaminophenyl or C 2 -C 6 alkenyl,
and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

7. A compound of Formula (II)

wherein:
Y is CR 6 or N;
R 1 is COOH, tetrazol-5-yl,

R 2 is H, optionally substituted C 1 -C 6 alkyl, OH, optionally substituted C 1 -C 6 alkoxy or CF 3 ;
R 3 is H, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 4 is H;
R 5 is H;
R 6 is H, optionally substituted aryl C 1 -C 6 -alkyl, optionally substituted aryl-C 2 -C 6 -alkenyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl or optionally substituted C 2 -C 6 -alken-dienyl,
R 7 is selected from optionally substituted aryl, optionally substituted C 1 -C 6 alkylaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 8 alkyl, optionally substituted aryl-C 1 -C 6 -alkyl, C 3 -C 8 cycloalkylaryl, 2,2-C 1 -C 6 -dialkyldihydrobenzofuran

optionally substituted C 1 -C 6 -alkyl(aryl)-C 1 -C 6 -alkyl, C 2 -C 6 alkynyloxy(C 1 -C 6 alkyl)aryl, optionally substituted 5 to 7-membered monocyclic heterocyclic or optionally substituted C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl;
R 8 is optionally substituted C 1 -C 6 alkylaryl, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted aryl-C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 alkoxyaryl, optionally substituted C 1 -C 6 -alkoxy(C 1 -C 6 -alkyl)aryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkylaryl, optionally substituted C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclic, optionally substituted C 1 -C 6 -alkyl-C 3 -C 8 -cycloalkyl, optionally substituted C 1 -C 6 alkanoylaryl, C 1 -C 6 dialkylaminoa

Assignees

• Bristol Myers Squibb Co
• Syngene Int Ltd

Inventors

• Markwalder Jay A
• Seitz Steven P
• Balog James Aaron
• Huang Audris
• Mandal Sunil Kumar
• Williams David K
• Hart Amy C
• Inghrim Jennifer

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07D257/04

  Five-membered rings · CPC title