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

Patent metadata

Field	Value
Publication number	US-2021198190-A1
Application number	US-201917057921-A
Country	US
Kind code	A1
Filing date	May 28, 2019
Priority date	May 31, 2018
Publication date	Jul 1, 2021
Grant date	—

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

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:
X is selected from a bond and —CH(R a )—; where R a is selected from hydrogen and C 1-6 alkyl;
R b is selected from: (i) hydrogen and (ii) C 1-6 alkyl;
each occurrence of R 1 and R 2 is independently selected from: (i) hydrogen and (ii) C 1-6 alkyl; and
each occurrence of R 3 and R 4 is independently selected from:
(i) aryl, and
(ii) heterocyclyl;

wherein each of the aryl of (i) and heterocyclyl of (ii) 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, and
(c) —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) methyl and (iii) ethyl.

3 . The compound of claim 2 , 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 one to four substituents independently selected from:
(a) halogen,
(b) C 1-6 alkyl, optionally substituted with one to three halogens, and
(c) —CN.

4 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, optionally substituted with a halogen.

5 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:
(i) phenyl, and (ii) a heterocyclyl selected from furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, naphthyridinyl, phthalazinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, quinazolinyl and a fused bicyclic ring moiety wherein a 6-membered heterocyclic ring comprising 2 nitrogen atoms and a 5-membered carbocyclic ring are connected through two atoms; wherein each of the phenyl of (i) and heterocyclyl of (ii) 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, and
(c) —CN.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:
(i) phenyl, and (ii) a heterocyclyl selected from naphthyridinyl, phthalazinyl, pyridinyl, pyrimidinyl, quinazolinyl and a fused bicyclic ring moiety wherein a 6-membered aromatic heterocyclic ring comprising 2 nitrogen atoms and a 5-membered carbocyclic ring are connected through two carbon atoms wherein each of the phenyl of (i) and heterocyclyl of (ii) 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, and
(c) —CN.

7 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen; R 2 is selected from:
(i) hydrogen,
(ii) methyl, and
(iii) ethyl;
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 one to four substituents independently selected from:
(a) halogen,
(b) C 1-6 alkyl, optionally substituted with one to four halogens, and
(c) —CN; and
R 4 is selected from:
(i) phenyl, and
(ii) a heterocyclyl selected from naphthyridinyl, phthalazinyl, pyridinyl, pyrimidinyl, quinazolinyl and a fused bicyclic ring moiety wherein a 6-membered aromatic heterocyclic ring comprising 2 nitrogen atoms and a 5-membered carbocyclic ring are connected through two carbon atoms;
wherein each of the phenyl of (i) and heterocyclyl of (ii) 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, and
(c) —CN.

8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen; R 2 is selected from:
(i) methyl, and
(ii) ethyl;
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 one to four substituents independently selected from:
(a) halogen, and
(b) C 1-6 alkyl, optionally substituted with one to four halogens; and
R 4 is selected from:
(i) phenyl, and
(ii) a heterocyclyl selected from 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, 1,7-naphthyridinyl, phthalazinyl, pyridinyl, pyrimidinyl and quinazolinyl;
wherein each of the phenyl of (i) and heterocyclyl of (ii) 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, and
(c) —CN.

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

wherein:
R b is selected from (i) hydrogen and (ii) methyl;
R 3 selected from:
(i) phenyl, and
(ii) pyridinyl;

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

R 4 is selected from:
(i) phenyl, and
(ii) a heterocyclyl selected from naphthyridinyl, phthalazinyl, pyridinyl, pyrimidinyl, quinazolinyl and a fused bicyclic ring moiety wherein a 6-membered aromatic heterocyclic ring comprising 2 nitrogen atoms and a 5-membered carbocyclic ring are connected through two carbon atoms;
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 1-6 alkyl, optionally substituted with one to three halogens, and
(c) —CN.

10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof:
wherein: R b is hydrogen; R 3 is phenyl, optionally substituted with one to three substituents independently selected from:
(a) halogen, and
(b) C 1-4 alkyl, optionally substituted with one to three halogens; and
R 4 is phenyl, optionally substituted with one to three substituents independently selected from:
(a) halogen, and
(b) C 1-4 alkyl, optionally substituted with one to three halogens.

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

wherein:
R b is selected from:
(i) hydrogen,
(ii) methyl, and
(iii) ethyl;

R 3 selected from:
(i) phenyl, and
(ii) pyridinyl;

wherein each of the phenyl of (i) and pyridinyl of (ii) 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, and
(c) —CN; and

R 4 is selected from:
(i) phenyl, and
(ii) a heterocyclyl selected from naphthyridinyl, phthalazinyl, pyridinyl, pyrimidinyl, quinazolinyl and a fused bicyclic ring moiety wherein a 6-membered aromatic heterocyclic ring comprising 2 nitrogen atoms and a 5-membered carbocyclic ring are connected through two carbon atoms;
wherein each of the phenyl of (i) and heterocyclyl of (ii) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b)

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• A61P31/12 Primary

  Antivirals · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title