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

Patent metadata

Field	Value
Publication number	US-10696648-B2
Application number	US-201716098239-A
Country	US
Kind code	B2
Filing date	May 4, 2017
Priority date	May 4, 2016
Publication date	Jun 30, 2020
Grant date	Jun 30, 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 or formula II

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—, —C(C 1 -C 6 alkyl)-, or N;
n is 0, 1, 2, 3, or 4;
Z is a bond or C 1 -C 6 alkylene optionally substituted with one, two, or three R 4 substituents independently selected from C 1 -C 6 alkyl;
R 2 is -alkaryl optionally substituted with —OC 1 -C 6 alkyl, —C 1 -C 6 alkCOOH, or —C 1 -C 6 alkCOOC 1 -C 6 alkyl;
R 3 is H or C 1 -C 6 alkyl;
B is aryl optionally substituted with 1, 2, or 3 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 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;

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 that is a compound of formula II.

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

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 Z is a bond.

10. The compound of claim 1 , wherein Z is C 1 alkylene substituted with one C 1 -C 6 alkyl.

11. The compound of claim 1 , wherein B is aryl optionally substituted with 1, 2, or 3 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 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 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. A compound that is
3-(4-Chlorophenyl)-1-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)-1-methylurea;
3-(4-Butylphenyl)-1-(1-(6-fluoroquinolin-4-yl)piperidin-4-yl)-1-methylurea;
1-(1-(6-Fluoroquinolin-4-yl)piperidin-4-yl)-1-methyl-3-(4-(trifluoromethoxy)phenyl)urea;
3-(4-Chlorophenyl)-1-(4-methoxybenzyl)-1-((1r,4r)-4-phenylcyclohexyl)urea;
3-(2,4-difluorophenyl)-1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)urea;
3-(4-chloro-2-fluorophenyl)-1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)urea;
1-(4-methoxybenzyl)-3-(3-phenoxyphenyl)-1-(trans-4-phenylcyclohexyl)urea;
3-(3,4-difluorophenyl)-1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)urea;
3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)urea;
1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea;
1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)-3-(p-tolyl)urea;
1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)-3-(4-(trifluoromethyl)phenyl)urea;
3-(4-ethoxyphenyl)-1-(4-methoxybenzyl)-1-(trans-4-phenylcyclohexyl)urea;
3-(4-Chlorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-1-methylurea;
3-(4-chlorophenyl)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-1-methylurea;
3-(4-Chlorophenyl)-1-ethyl-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
3-(4-chlorophenyl)-1-ethyl-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-(4-chlorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-(4-fluorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-3-(p-tolyl)urea;
1-benzyl-3-(4-chloro-2-fluorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-(4-cyanophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-(4-chlorophenyl)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-(4-chloro-2-fluorophenyl)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
2-(4-((3-(4-chlorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)ureido)methyl)phenyl)acetic acid;
2-(4-((3-(4-chloro-2-fluorophenyl)-1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)ureido)methyl)phenyl) acetic acid;
2-(4-((1-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-3-phenylureido)methyl) phenyl)acetic acid;
2-(4-((3-(4-chlorophenyl)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl) ureido)methyl)phenyl)acetic acid;
2-(4-((3-(4-chloro-2-fluorophenyl)-1-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)ureido)methyl)phenyl)acetic acid;
3-(4-cyanophenyl)-1-(4-methoxybenzyl)-1-((1 r,4r)-4-phenylcyclohexyl)urea 3-((S)-1-(4-chlorophenyl)ethyl)-1-(4-methoxybenzyl)-1-((1 r,4 S)-4-phenyl cyclohexyl)urea;
3-(4-fluorobenzyl)-1-(4-methoxybenzyl)-1-((1r,4r)-4-phenylcyclohexyl)urea;
3-((R)-1-(4-fluorophenyl)ethyl)-1-(4-methoxybenzyl)-1-((1r,4R)-4-phenylcyclohexyl)urea;
1-((S)-1-(4-chlorophenyl)ethyl)-3-((1 r,4 S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-((S)-1-(4-chlorophenyl)ethyl)-3-((1 s,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
3-((S)-1-(4-chlorophenyl)ethyl)-1-((1 r,4 S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-1-methylurea;
3-((S)-1-(4-chlorophenyl)ethyl)-1-ethyl-1-((1 r,4 S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
3-((S)-1-(4-chlorophenyl)ethyl)-1-ethyl-1-((1 s,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-((S)-1-(4-chlorophenyl)ethyl)-1-((1 r,4 S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
1-benzyl-3-((R)-1-(4-fluorophenyl)ethyl)-1-((1r,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl)urea;
2-(4-((3-((R)-1-(4-fluorophenyl)ethyl)-1-((1r,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ureido)methyl)phenyl)acetic acid;
3-((R)-1-(4-fluorophenyl)ethyl)-1-((1r,4R)-4-(6-fluoroquinolin-4-yl)cyclohexyl)-1-((R)-1-phenylethyl)urea;
3-cyclohexyl-1-(4-methoxybenzyl)-1-((1r,4r)-4-phenylcyclohexyl)urea;
3-cyclopentyl-1-(4-methoxybenzyl)-1-((1r,4r)-4-phenylcyclohexyl)urea; or
3-cyclopropyl-1-(4-methoxybenzyl)-1-((1r,4r)-4-phenylcyclohexyl)urea;

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 .

18. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier.

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

20. 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 14 .

Assignees

• Bristol Myers Squibb Co

Inventors

• Williams David K
• Shan Weifang
• Balog James Aaron

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07C275/32

  being further substituted by singly-bound oxygen atoms · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/14

  The ring being saturated · CPC title