[1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors

Patent metadata

Field	Value
Publication number	US-11478461-B2
Application number	US-201917047247-A
Country	US
Kind code	B2
Filing date	Apr 15, 2019
Priority date	Apr 19, 2018
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme: (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. 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 1;
V is selected from

X is selected from a bond, O and N(R a ); where R a is selected from hydrogen and C 1-6 alkyl;
each occurrence of R 1 and R 2 is independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl, and
(iii) C 3-6 cycloalkyl;

or alternatively, le and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl or a 4-6 membered heterocyclyl; wherein the C 3-6 cycloalkyl is optionally substituted with C 1-6 alkyl; and
each occurrence of R 3 and R 4 is independently selected from:
(i) C 1-6 alkyl, optionally substituted with one to four substituents independently selected from halogen and phenyl,
(ii) C 3-6 cycloalkyl,
(iii) aryl, and
(iv) heterocyclyl;

wherein each of the phenyl of (i), aryl of (iii) and heterocyclyl of (iv) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) C 1-6 alkyl, optionally substituted with one to four halogens,
(c) —O—C 1-6 alkyl, optionally substituted with one to four halogens,
(d) C 3-6 cycloalkyl, optionally substituted with one to four halogens, and
(e) —CN.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each occurrence of R 1 and R 2 is independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl, and
(iii) C 3-6 cycloalkyl;

or alternatively, R 1 and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl or a 4-6 membered saturated heterocyclyl; wherein the C 3-6 cycloalkyl is optionally substituted with C 1-6 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen; and
R 2 is methyl;
or alternatively, R 1 and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl or oxetanyl; wherein the C 3-6 cycloalkyl is optionally substituted with methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:
(i) phenyl,
(ii) naphthyl and
(iii) pyridinyl;
wherein each of the phenyl of (i), naphthyl of (ii) and pyridinyl of (iii) is optionally substituted with one to four substituents independently selected from:
(a) halogen, and
(b) C 1-6 alkyl, optionally substituted with one to three halogens.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:
(i) phenyl, and
(ii) pyridinyl;
wherein each of the phenyl of (i) and pyridinyl of (ii) is optionally substituted with a halogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:
(i) phenyl,
(ii) naphthyl and
(iii) a heterocyclyl selected from furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazolyl, imidazo[1,5-a]pyridinyl, indolinyl, indolizinyl, isoquinolinyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, 4,5,6,7-tetrahydro-1,2-benzoxazolyl and triazolo[1,5-a]pyridinyl;
wherein each of the phenyl of (i), naphthyl of (ii) and heterocyclyl of (iii) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) C 1-6 alkyl, optionally substituted with one to four halogens,
(c) —O—C 1-6 alkyl, optionally substituted with one to four halogens,
(d) C 3-6 cycloalkyl, optionally substituted with one to four halogens, and
(e) —CN.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:
(i) phenyl, and
(ii) a heterocyclyl selected from isoxazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, imidazo[1,5-a]pyridinyl, indolinyl, indolizinyl, isoquinolinyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, 4,5,6,7-tetrahydro-1,2-benzoxazolyl and triazolo[1,5-a]pyridinyl;
wherein each of the phenyl of (i) and heterocyclyl of (ii) is optionally substituted with one to three substituents independently selected from:
(a) halogen,
(b) C 1-4 alkyl, optionally substituted with one to four halogens,
(c) —O—C 1-4 alkyl, optionally substituted with one to four halogens, and
(d) CN.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each occurrence of R 1 and R 2 is independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl, and
(iii) C 3-6 cycloalkyl;

or alternatively, R 1 and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl;
R 3 is selected from:
(i) phenyl,
(ii) naphthyl and
(iii) pyridinyl;

wherein each of the phenyl of (i), naphthyl of (ii) and pyridinyl of (iii) is optionally substituted with one to four substituents independently selected from:
(a) halogen, and
(b) C 1-6 alkyl; and

R 4 is selected from:
(i) phenyl,
(ii) naphthyl and
(iii) a heterocyclyl selected from isoxazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, imidazo[1,5-a]pyridinyl, indolinyl, indolizinyl, isoquinolinyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, 4,5,6,7-tetrahydro-1,2-benzoxazolyl and triazolo[1,5-a]pyridinyl;

wherein each of the phenyl of (i), naphthyl of (ii) and heterocyclyl of (iii) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) C 1-6 alkyl, optionally substituted with one to four halogens,
(c) —O—C 1-6 alkyl, optionally substituted with one to four halogens, and
(d) CN.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen;
R 2 is selected from:
(i) hydrogen, and
(ii) C 1-6 alkyl;

or alternatively, le and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl;
R 3 is selected from:
(i) phenyl, and
(ii) pyridinyl;

wherein each of the phenyl of (i) and pyridinyl of (ii) is optionally substituted with a halogen; and
R 4 is selected from:
(i) phenyl,
(ii) naphthyl and
(iii) a heterocyclyl selected from isoxazolyl, oxadiazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, imidazo[1,5-a]pyridinyl, indolinyl, indolizinyl, isoquinolinyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, 4,5,6,7-tetrahydro-1,2-benzoxazolyl and triazolo[1,5-a]pyridinyl;

wherein each of the phenyl of (i), naphthyl of (ii) and heterocyclyl of (iii) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) C 1-4 alkyl, optionally substituted with one to four halogens,
(c) —O—C 1-4 alkyl, optionally substituted with one to four halogens, and
(d) CN.

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

wherein:
R 1 is hydrogen;
R 2 is selected from:
(i) hydrogen, and
(ii) C 1-6 alkyl;

or alternatively, le and R 2 together with the carbon to which they are attached form a C 3-6 cycloalkyl or a 4-6 membered saturated heterocyclyl;
R 3 is selected from:
(i) phenyl, and
(ii) pyridinyl;

wherein each of the phenyl of (i) and pyridinyl of (i

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme Llc

Inventors

• Guo Liangqin
• Zhang Hongjun
• Chen Ping
• Clausen Dane
• Fradera Xavier
• Han Yongxin
• He Shuwen
• Huang Xianhai
• Pasternak Alexander
• Pu Qinglin
• Xiao Li
• Ye Feng

Classifications

• C07D213/81

  Amides; Imides · CPC title

• C07D237/28

  Cinnolines · CPC title

• C07D261/20

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/44 Primary

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/42

  Oxazoles · CPC title