Substituted biaryl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Patent metadata

Field	Value
Publication number	US-10995085-B2
Application number	US-202016819325-A
Country	US
Kind code	B2
Filing date	Mar 16, 2020
Priority date	Nov 14, 2017
Publication date	May 4, 2021
Grant date	May 4, 2021

Abstract

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof:

Also disclosed herein are uses of a compound disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. Further disclosed herein are uses of a composition in the potential treatment or prevention of an IDO-associated disease or disorder.

First claim

What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
n is 1;
p is 1;
each occurrence of A is independently selected from —CH═ and —N═, provided that one A group is —N═ and three other A groups are each CH═;
M is selected from —O and —S;
R 1 is selected from:
(1) aryl, and
(2) heterocyclyl;

wherein the aryl of (1) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-8 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) oxo,
(e) —O—C 1-8 alkyl, optionally substituted with 1-5 halogens,
(f) —O—C 3-8 cycloalkyl,
(g) —C 1-8 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, —NH 2 , NHC(O)R c and —S(O) 2 —C 1-8 alkyl, wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(h) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(i) —C(O)—R e , R e is selected from —OH and —C 1-8 alkyl,
(j) aryl, optionally substituted with 1-3 halogens and
(k) heterocyclyl, optionally substituted with 1-3 substituents independently selected from halogen and —C 1-8 alkyl;

wherein the heterocyclyl of (2) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-8 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) oxo,
(e) —O—C 1-8 alkyl, optionally substituted with 1-5 halogens,
(f) —O—C 3-8 cycloalkyl,
(g) —C 1-8 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, —NH 2 , NHC(O)R c and —S(O) 2 —C 1-8 alkyl, wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(h) —NH—S(O) 2 —R c , wherein R c is selected from —C 1-8 alkyl and —C 3-8 cycloalkyl,
(i) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-8 alkyl,
(j) aryl, optionally substituted with 1-3 halogens, and
(k) heterocyclyl, optionally substituted with 1-3 substituents independently selected from halogen and —C 1-8 alkyl;

R 2 is selected from:
(1) aryl, and
(2) heterocyclyl;

wherein each of the aryl of (1) and the heterocyclyl of (2) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-8 cycloalkyl,
(c) —CN,
(d) —O—C 1-8 alkyl, optionally substituted with 1-3 halogens and
(e) —C 1-8 alkyl, optionally substituted with 1-3 substituents independently selected from halogen, —OH and —NH 2 ; and

R 3 is selected from H, halogen and —C 1-8 alkyl, optionally substituted with —OH.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
M is —O;
R 1 is selected from:
(1) aryl, and
(2) heterocyclyl;

wherein the aryl of (1) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,
(e) —O—C3-6 cycloalkyl,
(f) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and
(g) —C(O)—R e , R e is selected from —OH and —C 1-6 alkyl;

wherein the heterocyclyl of (2) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) oxo,
(e) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,
(f) —O—C3-6 cycloalkyl,
(g) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, and —NH 2 ,
(h) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-6 alkyl, and
(i) phenyl, optionally substituted with 1-3 halogens;

R 2 is selected from:
(1) aryl, and
(2) a 4-7 membered mono-cyclic heterocyclyl;

wherein each of the aryl of (1), and the heterocyclyl of (2) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens and
(e) —C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from halogen and —OH; and

R 3 is selected from H, halogen and —C 1-6 alkyl, optionally substituted with —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from:
(1) phenyl,
(2) a 4-7 membered mono-cyclic heterocyclyl selected from a saturated, a partially unsaturated and an aromatic ring containing one to four heteroatoms independently selected from N, O and S, and
(3) a 7-10 membered fused bicyclic heterocyclyl containing one to three heteroatoms independently selected from N, O and S in either of the rings;

wherein the phenyl of (1) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,
(e) —O—C3-6 cycloalkyl,
(f) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and
(g) —C(O)—R e , R e is selected from —OH and —C 1-6 alkyl; and

wherein each of the mono-cyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) —C 3-6 cycloalkyl, optionally substituted with —OH,
(c) —CN,
(d) oxo,
(e) —O—C 1-6 alkyl, optionally substituted with 1-3 halogens,
(f) —O—C 3-6 cycloalkyl,
(g) —C 1-6 alkyl, optionally substituted with 1-4 substituents independently selected from halogen, —OH, and —NH 2 ,
(h) —C(O)—R f , R f is selected from —OH, —NH 2 and —NH—C 1-6 alkyl, and
(i) phenyl, optionally substituted with 1-3 halogens.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from:
(1) phenyl;
(2) a mono-cyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl; and
(3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazol[4,5-b]pyridinyl, imidazol[4,5-c]pyridinyl, indolyl, isoindolinyl;
wherein the phenyl of (1) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) cyclopropyl, optionally substituted with —OH,
(c) cyclobutyl, optionally substituted with —OH,
(d) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,
(e) —O-cyclopropyl,
(f) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and
(g) —C(O)—C 1-4 alkyl; and

wherein each of the mono-cyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,
(b) cyclopropyl, optionally substituted with —OH,
(c) cyclobutyl, optionally substituted with —OH,
(d) —CN,
(e) oxo,
(f) —O—C 1-4 alkyl, optionally substituted with 1-3 halogens,
(g) —O-cyclopropyl,
(h) —C 1-4 alkyl, optionally substituted with 1-4 substituents independently selected from halogen and —OH, and
(i) phenyl, optionally substituted with 1-3 halogens.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from:
(1) phenyl; and
(2) a 5-6 membered mono-cyclic heterocyclyl;

wherein each of the phenyl of (1), and the heterocyclyl of (4) is optionally substituted with 1-3 substituents independently selected from:
(a) halogen,

Assignees

• Merck Sharp & Dohme

Inventors

• Han Yongxin
• Achab Abdelghani
• Deng Yongqi
• Fradera Xavier
• Gibeau Craig
• Hopkins Brett A
• Li Derun
• Liu Kun
• Mcgowan Meredeth A
• Sciammetta Nunzio
• Sloman David
• White Catherine
• Zhang Hongjun
• Zhou Hua

Classifications

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D213/56

  Amides · CPC title

• A61K31/4245

  Oxadiazoles · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title