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

Patent metadata

Field	Value
Publication number	US-11034661-B2
Application number	US-201816495883-A
Country	US
Kind code	B2
Filing date	Mar 23, 2018
Priority date	Mar 29, 2017
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof. 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, 3 or 4; is 1, 2, or 3; p is 0, 1, 2 or 3;
W is selected from (a) —CR a R b — and (b) —NR a —; wherein each R a and R b is independently selected from the group consisting of (a) hydrogen, (b) halogen and (c) C 1-6 alkyl, optionally substituted with —OH or halogen;
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) —OH and (ii) —C 1-6 alkyl, optionally substituted with —OH;
(d) —(C═O)—(NH) q —R c , wherein q is 0 or 1; and R c 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, (3) —O-methyl, (4) —C 3-6 cycloalkyl, (5) —CN, (6) —S(O) 2 -C 1-6 alkyl and (7) heterocyclyl,
(iii) —O-C 1-6 alkyl,

(iv) —OH,
(v) —C 3-6 cycloalkyl, optionally substituted with —OH or —C 1-6 alkyl, and
(vi) a 4-, 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (1) halogen, (2) C 1-6 alkyl and (3) —OH;

(e) —S(O) 2 —NR d R e ; each of R d and R e is independently hydrogen or C 1-6 alkyl;
(f) —S(O) 2 —C 1-6 alkyl;
(g) C 4-5 cycloalkenyl, optionally substituted with one to four substituents independently selected from the group consisting of (i) oxo, (ii) —C 1-6 alkyl and (iii) —NH—C 1-6 alkyl; and
(h) 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 —OH;

each occurrence of R 1 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —CN, (d) C 1-6 alkyl, optionally substituted with 1 to 3 halogens, and (e) —O—C 1-6 alkyl, optionally substituted with one to three halogens;
each occurrence of R 2 is independently selected from the group consisting of (a) hydrogen, (b) halogen, (c) —OH and (d) C 1-6 alkyl, optionally substituted with —OH;
or, alternatively, two R 2 groups together with the carbon to which they are attached form a C 3-6 cycloalkyl or 4-, 5-, or 6-membered heterocycle;
or, alternatively, R 2 and R a of W together with the carbon and/or nitrogen atoms to which they are attached form a 4-, 5- or 6-membered carbocycle or heterocycle;
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 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein m is 1 or 2; n is 1 or 2; and p is 0, 1 or 2;
W is selected from (a) —CR a R b —and (b) —NR a —; wherein each occurrence of R a and R b is independently selected from the group consisting of (a) hydrogen and (b) C 1-6 alkyl, optionally substituted with —OH;
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 and (ii) halogen;
(c) C 3-6 cycloalkyl, optionally substituted with —OH;
(d) —(C═O)—(NH) q —R c , wherein q is 0 or 1; and R c 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, (3) —O—methyl and (4) —C 3-6 cycloalkyl,
(iii) —O—C 1-6 alkyl, and
(iv) a 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (1) halogen, (2) C 1-6 alkyl and (3) —OH;

(e) —S(O) 2 —NH 2;
(f) —S(O) 2 —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 —OH;

each occurrence of R 1 is independently selected from the group consisting of (a) hydrogen, (b) halogen, and (c) —CN;
each occurrence of R 2 is independently selected from the group consisting of (a) hydrogen and (b) —OH;
or alternatively, two R 2 groups together with the carbon to which they are attached form a C 3-6 cycloalkyl or a 4-, 5-, or 6-membered heterocycle;
or alternatively, R 2 and R a of W together with the carbon and/or nitrogen atoms to which they are attached form a 4-, 5- or 6-membered carbocycle or heterocycle;
each occurrence of R 3 is independently selected from the group consisting of (a) hydrogen and (b) C 1-6 alkyl; and
R 4 is selected from the group consisting of (a) hydrogen and (b) C 1-6 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of:
(a) hydrogen;
(b) C 1-6 alkyl, optionally substituted with one to three —OH;
(c) C 3-6 cycloalkyl, optionally substituted with —OH;
(d) —(C═O)—(NH) q —R c , wherein q is 0 or 1; and R c is selected from the group consisting of:
(i) hydrogen,
(ii) —C 1-6 alkyl, optionally substituted with one to three —OH,
(iii) —O—C 1-6 alkyl, and
(iv) a 5- or 6-membered heterocyclyl, optionally substituted with one to four substituents independently selected from the group consisting of (1) halogen, (2) C 1-6 alkyl and (3) —OH;

(e) —S(O) 2 —NH 2 ;
(f) —S(O) 2 —C 1-4 alkyl; and
(g) a 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 and (iii) oxo; and

each occurrence of R a and R b is independently selected from the group consisting of (a) hydrogen and (b) C 1-4 alkyl, optionally substituted with —OH.

4. 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, pyrrolidinyl, 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.

5. 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 and (b) halogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 2 is independently selected from the group consisting of (a) hydrogen and (b) —OH.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each occurrence of R 3 is independently selected from the group consisting of (a) hydrogen and (b) C 1-4 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; n is 1; and p is 0, 1 or 2;
W is selected from (a) —CR a R b —and (b) —NR a —; wherein each occurrence of R a and R b is independently selected from the group consisting of (i) hydrogen and (ii) C 1-4 alkyl;

Assignees

• Merck Sharp & Dohme
• Guo Liangqin
• Han Yongxin
• Liu Kun
• He Shuwen
• Kozlowski Joseph
• Nargund Ravi
• Yu Wensheng
• Zhang Hongjun
• Pu Qinglin
• Li Derun
• Achab Abdelghani
• Li Guoqing

Inventors

• Guo Liangqin
• Han Yongxin
• Liu Kun
• He Shuwen
• Kozlowski Joseph
• Nargund Ravi
• Yu Wensheng
• Zhang Hongjun
• Pu Qinglin
• Li Derun
• Achab Abdelghani
• Li Guoqing

Classifications

• C07D413/12

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

• C07D271/08 Primary

  1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles · CPC title

• A61P37/06

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

• A61P31/12

  Antivirals · CPC title

• A61P27/12

  for cataracts · CPC title