Substituted cyclobutylpyridine and cyclobutylpyrimidine compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Patent metadata

Field	Value
Publication number	US-11111232-B2
Application number	US-201816753050-A
Country	US
Kind code	B2
Filing date	Oct 4, 2018
Priority date	Oct 9, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 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:
each occurrence of A is independently selected from —CH═ and N═; provided that at least one A group is —N═ and at least one A group is —CH═;
L is selected from —NHC(O)— and —C(O)NH—;
W is selected from —C(O)NH— and —NHC(O)—;
R 1 is selected from:
(1) C 1-6 alkyl,
(2) —O—C 1-6 alkyl,
(3) C 3-6 cycloalkyl,
(4) aryl, and
(5) heterocyclyl;

wherein each of the C 1-6 alkyl of (1) and (2) is optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl; and
wherein each of the C 3-6 cycloalkyl of (3), aryl of (4), and heterocyclyl of (5) is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, (c) —O—C 1-6 alkyl, and (d) C 1-6 alkyl optionally substituted with 1-3 halogens;
R 2 is selected from:
(1) C 1-6 alkyl,
(2) C 3-6 cycloalkyl,
(3) aryl, and
(4) heterocyclyl;

wherein the C 1-6 alkyl of (1) is optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl; and
wherein each of the C 3-6 cycloalkyl of (2), aryl of (3), and heterocyclyl of (4) is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, and (c) C 1-6 alkyl optionally substituted with 1-3 halogens;

R 3 is selected from H, halogen, —OH, and C 1-6 alkyl optionally substituted with —OH; and each of R 4 and R 5 is independently selected from H, halogen, and C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
one A is —N═ and the three other A groups are each —CH═;
R 3 is selected from (1) H, (2) —OH, and —CH 3 , optionally substituted with —OH; and
each of R 4 and R 5 is H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
two A groups are each —N═ and the two other A groups are each —CH═;
R 3 is H; and
each of R 4 and R 5 is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,
(2) —O—C 1-6 alkyl,
(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,
(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and
(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, and (c) C 1-4 alkyl, optionally substituted with 1-3 halogens.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,
(2) —O—C 1-4 alkyl,
(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,
(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and
(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, and (c) C 1-4 alkyl, optionally substituted with 1-3 halogens.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 halogens,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,
(3) phenyl, optionally substituted with 1-3 halogens, and
(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 halogens,
(2) C 3-6 cycloalkyl, optionally substituted with a halogen,
(3) phenyl, optionally substituted with 1-2 halogens, and
(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
one A group is —N═ and the three other A groups are each —CH═;
R 1 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) C 3-6 cycloalkyl,
(2) —O—C 1-6 alkyl,
(3) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,
(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and
(5) a heterocyclyl selected from (a) a saturated 4-7 membered monocyclic heterocyclyl and (b) an aromatic 4-7 membered monocyclic heterocyclyl, wherein each heterocyclyl of (a) and (b) is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, and (c) C 1-4 alkyl, optionally substituted with 1-3 halogens;

R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 halogens,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 halogens,
(3) phenyl, optionally substituted with 1-3 halogens, and
(4) a heterocyclyl selected from (a) an aromatic 4-7 membered monocyclic heterocyclyl and (b) a 6-9 membered fused bicyclic ring containing one or more heteroatoms selected from N, O and S in either of the rings, wherein the heterocyclyl is optionally substituted with 1-3 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 3 , optionally substituted with —OH; and each of R 4 and R 5 is H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
one A group is —N═ and the three other A groups are each —CH═;
R 1 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) fluoro and (b) cyclopropyl,
(2) —O—C 1-4 alkyl,
(3) cyclohexyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN,
(4) phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN, and
(5) a heterocyclyl selected from pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydropyranyl, and thiazolyl, wherein the heterocyclyl is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, and (c) C 1-4 alkyl, optionally substituted with 1-3 halogens;

R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 halogens,
(2) C 3-6 cycloalkyl, optionally substituted with a halogen,
(3) phenyl, optionally substituted with 1-2 halogens, and
(4) a heterocyclyl selected from (a) pyridinyl and (b) benzo[d]thiazolyl, wherein the heterocyclyl is optionally substituted with 1-2 halogens;

R 3 is selected from (1) H, (2) —OH, and (3) —CH 2 —OH; and each of R 4 and R 5 is H.

10. The compound of claim 1 , or a pharmaceutically acc

Assignees

• Merck Sharp & Dohme

Inventors

• White Catherine M
• Achab Abdelghani
• Bharathan Indu T
• Fradera Xavier
• Han Yongxin
• Li Derun
• Lim Jongwon
• Liu Kun
• Mcgowan Meredeth Ann
• Sciammetta Nunzio
• Yu Wensheng
• Zhang Hongjun
• Zhou Hua

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D213/82

  in position 3 · CPC title

• C07D213/81

  Amides; Imides · CPC title