Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Patent metadata

Field	Value
Publication number	US-10633342-B2
Application number	US-201716098288-A
Country	US
Kind code	B2
Filing date	May 4, 2017
Priority date	May 4, 2016
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

First claim

What is claimed:

1. A compound of formula I

wherein
X is CH or N;
T is CH or N;
R 1 is H, halo, or C 1 -C 6 haloalkyl;
R 1A is H, halo, or C 1 -C 6 haloalkyl;
Y is CH or N;
W is CH—, or —C(C 1 -C 6 alkyl)-;
n is 0, 1, 2, 3, or 4;
V is C 1 -C 6 alkylene optionally substituted with one, two, or three substituents independently selected from C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
R 2 is H or C 1 -C 6 alkyl;
Z is a bond or C 1 -C 6 alkylene optionally substituted with one, two, or three substituents independently selected from C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
B is aryl optionally substituted with 1, 2, or 3R substituents independently selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —OC 1 -C 6 alkyl, —CN, aryl, or —Oaryl; or
C 3 -C 12 cycloalkyl optionally substituted with 1, 2, or 3 R substituents independently selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —OC 1 -C 6 alkyl, —CN, aryl, or —Oaryl;

or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.

2. The compound of claim 1 that is a compound of formula I.

3. The compound of claim 1 , wherein R 1 is H, F, or —CF 3 .

4. The compound of claim 1 , wherein R 1 is F.

5. The compound of claim 1 , wherein R 1A is H.

6. The compound of claim 1 , wherein Y is CH and W is CH.

7. The compound of claim 1 , wherein Y is N and W is CH.

8. The compound of claim 1 , wherein n is 2.

9. The compound of claim 1 , wherein V is unsubstituted C 1 alkylene or C 1 alkyklene substituted with C 1 -C 6 alkyl.

10. The compound of claim 1 , wherein Z is C 1 alkylene optionally substituted one substituent selected from C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.

11. The compound of claim 1 , wherein B is aryl optionally substituted with 1, 2, or 3 R substituents independently selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, —CN, aryl, or —Oaryl.

12. The compound of claim 11 , wherein B is phenyl optionally substituted with 1 or 2 R substituents independently selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, —CN, aryl, or —Oaryl.

13. The compound of claim 1 , wherein B is C 3 -C 12 cycloalkyl optionally substituted with 1, 2, or 3 R substituents independently selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, —CN, aryl, or —Oaryl.

14. The compound of claim 1 that is
N-((1-(6-Fluoroquinolin-4-yl)piperidin-4-yl)methyl)-2-(p-tolyl)acetamide;
2-(4-Fluorophenyl)-N-((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)acetamide;
2-(2-Fluorophenyl)-N-((1-(6-fluoroquinolin-4-yl)piperidin-4-yl)methyl)acetamide;
4-chloro-N—((R)-2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propyl)benzamide;
2-(4-chlorophenyl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)acetamide;
2-(2-chlorophenyl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)acetamide;
2-(3-chlorophenyl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)acetamide;
(S)—N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-phenylpropanamide;
(R)—N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-phenylpropanamide;
N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-(4-methoxyphenyl)acetamide;
(R)—N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-2-methoxy-2-phenylacetamide;
2-(2-fluorophenyl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)acetamide;
1-(4-chlorophenyl)-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclobutanecarboxamide;
4-chloro-N—((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)bicyclo [2.2.2]octane-1-carboxamide;
N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclohexanecarboxamide;
N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclopropanecarboxamide;
3,3-difluoro-N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclobutanecarboxamide;
(1r,3R)-3-fluoro-N—((R)-1-((1 s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclobutanecarboxamide;
(1s,3S)-3-fluoro-N—((R)-1-((1 s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclobutanecarboxamide;
N—((R)-1-((1 s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)cyclobutanecarboxamide;
(1s,4S)—N—((R)-1-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-hydroxycyclohexanecarboxamide; or
(1 r,4R)—N—((R)-1-((1 s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)-4-hydroxycyclohexanecarboxamide;
or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , further comprising ipilimumab, nivolumab, or pembrolizumab, or a combination thereof.

17. A method of treating cancer in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 .

Assignees

• Bristol Myers Squibb Co

Inventors

• Cherney Emily Charlotte
• Shan Weifang
• Zhang Liping
• Williams David K
• Guo Weiwei
• Huang Audris
• Balog James Aaron

Classifications

• C07C255/50

  to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61K31/451

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine · CPC title

• C07C233/65

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title