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

Patent metadata

Field	Value
Publication number	US-11208407-B2
Application number	US-201816631191-A
Country	US
Kind code	B2
Filing date	Jul 30, 2018
Priority date	Aug 2, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: (I) Also disclosed herein are uses of the compounds 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 the compositions 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:
L is selected from (1) —NHC(O)—, (2) —C(O)NH—, (3) —NH— and (4) —NHC(O)O—;
one M is —N═ and the other M is selected from (1) —CR a ═ and (2) —N═; wherein R a is selected from (a) H, (b) halogen and (c) C 1-6 alkyl;
V is selected from (1) —CR b R b , (2) —NR c — and (3) —O—; wherein each occurrence of R b is independently selected from (a) H, (b) —OH, (c) halogen and (d) C 1-6 alkyl; and R c is selected from (a) H and (b) C 1-6 alkyl;
R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl;
wherein:
the C 1-6 alkyl of (1) is optionally substituted with —NH 2 ; and
each of the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) —CN, (c) —NH 2 , (d) C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —OH, (e) —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens and (f) C 3-6 cycloalkyl;

each occurrence of R 2 is independently selected from (1) H, (2) —OH, (3) halogen, (4) —CN and (5) C 1-6 alkyl; wherein the C 1-6 alkyl of (5) is optionally substituted with 1 to 3 substituents independently selected from (a) —OH and (b) halogen;
R 3 is selected from (1) H and (2) C 1-6 alkyl optionally substituted with (a) halogen or (b) —OH; and
R 4 is selected from (1) H, (2) halogen, (3) —CN, (4) alkenyl and (5) C 1-6 alkyl optionally substituted with —OH.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L is selected from (1) —NHC(O)— and (2) —C(O)NH—;
V is selected from (1) —CR b R b — and (2) —O—; wherein each occurrence of R b is independently selected from (a) H, (b) —OH and (c) halogen;
R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl; wherein the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl optionally substituted with —OH, (f) —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens and (g) C 3-6 cycloalkyl;
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN and (4) C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens;
R 3 is selected from (1) H and (2) C 1-6 alkyl; and
R 4 is selected from (1) H, (2) halogen, (3) —CN and (4) C 1-6 alkyl optionally substituted with —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
one M is —N═ and the other M is selected from (1) —CH═ and (2) —N═;
V is selected from (1) —CR b R b — and (2) —O—, wherein each occurrence of R b is independently selected from (a) H, (b) —OH and (c) halogen;
R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl; wherein the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl optionally substituted with —OH, (f) —O—CHF 2 and (g) C 3-6 cycloalkyl;
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN and (4) C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens;
R 3 is H; and
R 4 is selected from (1) H, (2) halogen, (3) —CN and (4) C 1-4 alkyl optionally substituted with —OH.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L is selected from (1) —NHC(O)— and (2) —C(O)NH—;
V is selected from (1) —CH 2 —, (2) —CHF—, (3) —CF 2 — and (4) —O—;
R 1 is selected from (1) C 1-4 alkyl, (2) C 3-6 cycloalkyl, (3) phenyl and (4) 5- or 6-membered heteroaryl selected from isoxazolyl, oxadiazolyl, oxazolyl, oxoimidazolidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrrolyl; wherein the phenyl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) C 1-6 alkyl optionally substituted with —OH, (f) —O—CHF 2 and (g) C 3-6 cycloalkyl; and
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN, (4) —CH 3 (5) ethyl and (6) —CF 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L is selected from (1) —NHC(O)— and (2) —C(O)NH—;
V is selected from (1) —CH 2 —, (2) —CHF—, (3) —CF 2 — and (4) —O—;
R 1 is selected from (1) C 1-4 alkyl, (2) cyclopropyl, (3) phenyl and (4) 5- or 6-membered heteroaryl selected from pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl and pyrimidinyl; wherein the phenyl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) —NH 2 , (e) —CH 3 , (f) —CH 2 OH, (g) —O—CHF 2 and (h) cyclopropyl; and
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN, (4) —CH 3 and (5) —CF 3 , and
R 4 is selected from (1) H, (2) halogen, (3) —CN, (4) —CH 3 and (5) —CH 2 OH.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of formula (Ia):

wherein:
L is selected from (1) —NHC(O)—, (2) —C(O)NH— and (3) —NHC(O)O—;
V is selected from (1) —CR b R b — and (2) —O—, wherein each occurrence of R b is independently selected from (a) H, (b) —OH and (c) halogen;
R 1 is selected from (1) C 1-6 alkyl, (2) C 3-6 cycloalkyl, (3) aryl and (4) 5- or 6-membered heteroaryl; wherein the aryl of (3) and the heteroaryl of (4) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —NH 2 , (d) C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and —OH, (e) —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens and (f) C 3-6 cycloalkyl;
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN and (4) C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted with 1 to 3 halogens; and
R 4 is selected from (1) H, (2) halogen, (3) —CN and (4) C 1-4 alkyl optionally substituted with —OH.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
L is selected from (1) —NHC(O)— and (2) —C(O)NH—;
V is selected from (1) —CR b R b — and (2) —O—; wherein each occurrence of R b is independently selected from (a) H and (b) halogen;
R 1 is selected from (1) C 3-6 cycloalkyl, (2) phenyl and (3) 5- or 6-membered heteroaryl selected from isoxazolyl, oxadiazolyl, oxazolyl, oxoimidazolidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl and pyrrolyl; wherein each of the phenyl of (2) and the heteroaryl of (3) is optionally substituted with 1 to 3 substituents independently selected from (a) halogen, (b) —CN, (c) —CF 3 , (d) C 1-6 alkyl optionally substituted with —OH, (e) —O—CHF 2 and (f) cyclopropyl;
each occurrence of R 2 is independently selected from (1) H, (2) halogen, (3) —CN, (4) —CH 3 and (5) —CF 3 ; and
R 4 is selected from (1) H, (2) halogen, (3) —CN, (4) —CH 3 and (5) —CH 2 OH.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
V is selected from (1) —CH 2 —, (2) —CHF—, (3) —CF 2 —

Assignees

• Merck Sharp & Dohme

Inventors

• Zhou Hua
• Achab Abdelghani
• Fradera Xavier
• Han Yongxin
• Li Derun
• Mcgowan Meredeth A
• Sciammetta Nunzio
• Sloman David L
• Yu Wensheng

Classifications

• C07D235/10

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D235/14

  Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10) · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title