Substituted n′-hydroxycarbamimidoyl-1,2,5-oxadiazole compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Patent metadata

Field	Value
Publication number	US-10988487-B2
Application number	US-201716326408-A
Country	US
Kind code	B2
Filing date	Aug 24, 2017
Priority date	Aug 29, 2016
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: Formula (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:
m is 0, 1, 2, or 3; n is 1, 2, or 3,
X is —S— or —NH—;
R is selected from the group consisting of:
(a) hydrogen,
(b) C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of (i) —OH, (ii) halogen, and (iii) —NH 2 ,
(c) C 3-6 cycloalkyl, optionally substituted with one to three substituents independently selected from the group consisting of (i) NH 2 , (ii) —NH—S(O) 2 —NH 2 and (iii) —NH—C(O)—C 1-6 alkyl, optionally substituted with —OH,
(d) C 4-6 cycloalkenyl, optionally substituted with an oxo,
(e) —(C═O)—NH—R a , wherein R a is selected from the group consisting of:
(i) hydrogen,
(ii) —C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of (1) halogen, (2) —OH and (3) —S(O) 2 —C 1-6 alkyl,
(iii) —C 1-6 alkoxy, and
(iv) —C 3-6 cycloalkyl,

(f) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of:
(i) hydrogen,
(ii) —(C═O)—R a , wherein R a is selected from the group consisting of (1) hydrogen, and (2) —C 1-6 alkyl, optionally substituted with one to three substituents independently selected from halogen and —CN, (3) —NH 2 , (4) —NH—C 1-6 alkyl, optionally substituted with —OH, —O-methyl, or —CN, (5) —NH—C 3-6 cycloalkyl, and (6) heterocyclyl, optionally substituted with —OH,
(iii) —S(O) 2 —NH 2 ,
(iv) —S(O) 2 —CH 3 , and
(v) C 4-5 cycloalkenyl, optionally substituted with one to four substituents independently selected from the group consisting of (1) oxo, (2) —C 1-6 alkyl, and (3) —NH—C 1-6 alkyl,

(g) a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (i) halogen, (ii) C 1-6 alkyl, (iii) oxo, (iv) —C(O)—C 1-6 alkyl, optionally substituted with one to three groups independently selected from —OH and —O—C 1-6 alkyl, (v) —S(O) 2 —NH 2 and (vi) —S(O) 2 —NH—C 1-6 alkyl, optionally substituted with —OH,
(h) —S(O) 2 —C 1-6 alkyl, optionally substituted with one to three —OH groups,
(i) —O—S(O) 2 —NH 2 ;
(j)

(k) a 7-, 8-, 9- or 10-membered bi-cyclic heterocyclyl, optionally substituted with one to three substituents independently selected from the group consisting of (i) halogen, (ii) C 1-6 alkyl and (iii) oxo, and
(l) aryl, optionally substituted with one to three substituents independently selected from the group consisting of (i) halogen and (ii) —B(OH) 2 ;
each occurrence of R 1 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —CN, and (d) C 1-6 alkyl, optionally substituted with 1 to 3 halogens;
each occurrence of R 2 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —OH, (d) —NH 2 and (e) C 1-6 alkyl, optionally substituted with —OH;
each occurrence of R 3 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) C 1-6 alkyl, and (d) —O—C 1-6 alkyl; and
R 4 is selected from the group consisting of (a) hydrogen and (b) C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein: m is 0, 1, 2, or 3; n is 1, 2, or 3;
X is —S— or —NH—;
R is selected from the group consisting of:
(a) hydrogen,
(b) C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of (i) —OH, (ii) halogen, and (iii) —NH 2 ,
(c) C 3-6 cycloalkyl, optionally substituted with one to three substituents independently selected from the group consisting of (i) NH 2 , (ii) —NH—S(O) 2 —NH 2 and (iii) —NH—C(O)—C 1-6 alkyl, optionally substituted with —OH,
(d) C 4-6 cycloalkenyl, optionally substituted with an oxo,
(e) —(C═O)—NH—R a , wherein R a is selected from the group consisting of:
(i) hydrogen,
(ii) —C 1-6 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of (1) halogen, (2) —OH and (3) —S(O) 2 —C 1-6 alkyl,
(iii) —C 1-6 alkoxy, and
(iv) —C 3-6 cycloalkyl,

(f) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of:
(i) hydrogen,
(ii) —(C═O)—R a , wherein R a is selected from the group consisting of (1) hydrogen, and (2) —C 1-6 alkyl, optionally substituted with one to three substituents independently selected from halogen and —CN, (3) —NH 2 , (4) —NH—C 1-6 alkyl, optionally substituted with —OH, —O-methyl, or —CN, and (5) —NH—C 3-6 cycloalkyl,
(iii) —S(O) 2 —NH 2 ,
(iv) —S(O) 2 —CH 3 , and
(v) C 4-5 cycloalkenyl, optionally substituted with one to four substituents independently selected from the group consisting of (1) oxo, (2) —C 1-6 alkyl, and (3) —NH—C 1-6 alkyl, and

(g) a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (i) halogen, (ii) C 1-6 alkyl, (iii) oxo and (iv) —C(O)—C 1-6 alkyl, optionally substituted with one to three —OH groups;
each occurrence of R 1 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —CN, and (d) C 1-6 alkyl, optionally substituted with 1 to 3 halogens;
each occurrence of R 2 is independently selected from the group consisting of (a) hydrogen, (b) halogen, and (c) —OH;
each occurrence of R 3 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) C 1-6 alkyl, and (d) —O—C 1-6 alkyl; and
R 4 is selected from the group consisting of (a) hydrogen and (b) C 1-4 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; and n is 1 or 2.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of:
(a) C 1-4 alkyl, optionally substituted with one to two —OH groups,
(b) C 3-4 cycloalkyl,
(c) —(C═O)—NH—R a , wherein R a is selected from the group consisting of:
(i) hydrogen,
(ii) —C 1-6 alkyl,
(iii) —C 1-6 alkoxy, and
(iv) —C 3-6 cycloalkyl,

(d) —NR x R y , wherein each of R x and R y is independently selected from the group consisting of:
(i) hydrogen,
(ii) —(C═O)—C 1-6 alkyl,
(iii) —S(O) 2 —NH 2 , and
(iv) cyclobutenyl, optionally substituted with one to three substituents independently selected from the group consisting of (1) oxo, (2) —C 1-4 alkyl, and (3) —NH—C 1-4 alkyl, and

(e) a 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (i) C 1-6 alkyl, and (ii) oxo.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is a 5- or 6-membered heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, piperidinyl, triazolyl, and thiazolyl;
wherein the 5- or 6-membered heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of (i) C 1-6 alkyl, and (ii) oxo.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 1 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —CN, and (d) C 1-4 alkyl, optionally substituted with 1 to 3 halogens.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 2 is independently selected from the gr

Assignees

• Merck Sharp & Dohme

Inventors

• Liu Kun
• Achab Abdelghani
• Biju Purakkattle
• Cernak Timothy A
• Deng Yongqi
• Fradera Xavier
• Guo Liangqin
• Han Yongxin
• He Shuwen
• Kozlowski Joseph
• Li Derun
• Li Guoqing
• Pu Qinglin
• Shi Zhi-Cai
• Yu Wensheng
• Zhang Hongjun

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P31/12 Primary

  Antivirals · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title