Substituted phenyloxetane and phenyltetrahydrofuran compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Patent metadata

Field	Value
Publication number	US-11319295-B2
Application number	US-201816753043-A
Country	US
Kind code	B2
Filing date	Oct 4, 2018
Priority date	Oct 9, 2017
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof: (Formula (I)). 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:
n is selected from 1, 2 and 3;
p is selected from 0 and 1;
each occurrence of A is independently selected from —CH═ or —N═, provided not all A groups are —N═;
L is selected from —NHC(O)— and —C(O)NH—;
M is selected from —O— and —S—;
W is selected from —C(O)NH— and —NHC(O)—;
R 1 is aryl; wherein the aryl is optionally substituted with 1-3 substituents independently selected from (a) halogen, (b) —CN, (c) C 1-6 alkyl, and (d) —O—C 1-6 alkyl;
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; and

R 3 is selected from (1) H, (2) halogen, and (3) C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
n is selected from 1 and 2;
each occurrence of A is —CH═; and
M is —O—.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
n is selected from 1 and 2;
one occurrence of A is —N═; three occurrences of A are —CH═; and
M is —O—.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN.

5. 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 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, and
(3) phenyl, 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 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) cyclopropyl,
(2) cyclopropyl, optionally substituted with C 1-4 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
n is selected from 1 and 2;
each occurrence of A is —CH═;
L is selected from —NHC(O)— and —C(O)NH—;
M is —O—;
W is selected from —C(O)NH— and —NHC(O)—;
R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN;
R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) C 1-6 alkyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from:
(1) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) cyclopropyl,
(2) cyclopropyl, optionally substituted with C 1-4 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) methyl.

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

wherein:
n is selected from 1 and 2;
p is selected from 0 and 1;
M is —O—;
R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN;
R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) C 1-6 alkyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
M is —O—;
R 1 is phenyl, optionally substituted with (a) halogen or (b) —CN;
R 2 is selected from:
(1) C 1-4 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) cyclopropyl,
(2) cyclopropyl, optionally substituted with C 1-4 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) methyl.

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

wherein:
n is selected from 1 and 2;
p is selected from 0 and 1;
M is —O—;
R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN;
R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) C 1-6 alkyl.

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

wherein:
n is 1 or 2;
p is 1;
M is —O—;
R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) —CN;
R 2 is selected from:
(1) C 1-6 alkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 3-6 cycloalkyl,
(2) C 3-6 cycloalkyl, optionally substituted with 1-3 substituents independently selected from (a) halogen and (b) C 1-6 alkyl, and
(3) phenyl, optionally substituted with 1-3 halogens; and

R 3 is selected from (1) H and (2) C 1-6 alkyl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
R 1 is phenyl, optionally substituted with (a) chloro or (b) —CN;
R 2 is phenyl, optionally substituted with fluoro; and
R 3 is selected from H and methyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
N-(4-(3-butyramidooxetan-3-yl)phenyl)-3-chlorobenzamide,
3-(4-(3-chlorobenzamido)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-{4-[(3-chloro-2-fluorobenzene-1-carbonyl)amino]phenyl}-N-(4-fluorophenyl)oxetane-3-carboxamide,
3-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}-N-(2-methylcyclopropyl)oxetane-3-carboxamide,
3-{4-[(3-chlorobenzene-1-carbonyl)amino]phenyl}-N-propyloxetane-3-carboxamide,
3-{4-[(3-chlorobenzene-1-carbon

Assignees

• Merck Sharp & Dohme
• White Catherine M
• Mcgowan Meredeth Ann
• Han Yongxin
• Sciammetta Nunzio

Inventors

• White Catherine M
• Mcgowan Meredeth Ann
• Han Yongxin
• Sciammetta Nunzio

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D305/08 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms · CPC title

• C07D405/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D307/22

  Nitrogen atoms not forming part of a nitro radical · CPC title