IDO inhibitors

Patent metadata

Field	Value
Publication number	US-10689331-B2
Application number	US-201615737798-A
Country	US
Kind code	B2
Filing date	Jun 27, 2016
Priority date	Jun 26, 2015
Publication date	Jun 23, 2020
Grant date	Jun 23, 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 is:

1. A compound of Formula (I)

wherein:
W is CR X ,
V is CR X ,
Y is CR X ;
Z is —O—;
R x is hydrogen;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl or C 1 -C 4 alkoxy;
R 2 is hydrogen or methyl, or
R 1 and R 2 are taken together with the carbon to which they are attached to form a 3-6 membered cycloakyl ring;
R 4 is —COZR 3 ; wherein when Z is —O—, R 3 is H or C 1 -C 4 alkyl;
R 5 is hydrogen;
R 6 is —COR 10 or CONR 5 R 9 ;
R 7 and R 8 are independently optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted 5- to 7-membered monocyclic heterocyclyl, optionally substituted 8- to 10-membered bicyclic heterocyclyl, optionally substituted aryl C 1 -C 6 alkyl, or optionally substituted C 2 -C 6 alkenyl; R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; wherein the optional substituents are 1-4 R y ;
R y is hydrogen, halogen, CN, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy or aryloxy;
R 10 is optionally substituted aryl; wherein the optional substituents are 1-4 R z ;
R z is hydrogen, halogen, CN, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy or aryloxy;
R 11 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, trifluoromethyl, phenyl or optionally substituted heterocyclyl;
R 12 is hydrogen or optionally substituted C 1 -C 6 alkyl;
R 13 is hydrogen or optionally substituted C 1 -C 6 alkyl;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R 1 and R 2 are independently H, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, or join together to form cyclopropyl or cyclobutyl.

3. The compound according to claim 1 wherein Z is O and R 3 is H.

4. The compound according to claim 1 wherein R 4 is —CO 2 R 3 .

5. The compound according to claim 1 wherein R 5 is H and R 6 is —COR 10 or —CONR 9 R 10 ; R 9 is H, and R 10 is phenyl, pyridyl, isoxazolyl, thiadiazolyl, indolinyl, or benzyl, wherein R 10 may optionally be substituted with from 1 to 3 substituents selected from the group consisting of halo, amino, phenoxy, benzoxy, isoxalyl, C 1 to C 4 alkoxy, C 1 to C 4 alkyl, halo-C 1 to C 4 alkyl, and CN.

6. The compound according to claim 1 wherein R 7 is C 3 to C 7 cycloalkyl optionally substituted with halo, —OH or C 1 to C 4 alkoxy; C 1 to C 4 alkyl optionally substituted with halo, —OH or phenyl, wherein said phenyl is optionally substituted with C 1 to C 4 haloalkyl, C 1 to C 4 alkoxy, halo or C 1 to C 4 alkyl; C 1 to C 4 alkenyl; C 1 to C 4 alkoxy; or benzyl optionally substituted with C 1 to C 4 alkyl, halo, C 1 to C 4 alkoxy, or haloalkyl.

7. The compound according to claim 1 wherein R is a C 3 to C 7 heterocycloalkyl containing from 1 to 4 heteroatoms selected from O, N or S.

8. The compound according to claim 7 wherein R is furanyl, oxetanyl, piperidinyl optionally substituted with C 1 to C 4 alkenyl.

9. The compound according to claim 7 wherein R 7 is cyclohexyl optionally substituted with halo, —OH or C 1 to C 4 alkoxy or C 1 to C 4 alkenyl.

10. The compound according to claim 1 wherein R 8 is C 1 to C 4 alkyl or alkenyl wherein said alkyl is optionally substituted with halo, C 1 to C 4 alkoxy, C 3 to C 6 or cycloalkyl.

11. The compound according to claim 1 wherein W, V, and Y are —CR X wherein R X is H.

12. A compound having the following Formula I, or a pharmaceutically acceptable salt thereof:

wherein
R 1 H, C 1 to C 4 alkyl, or C 3 to C 6 cycloalkyl;
R 2 is H, C 1 to C 4 alkyl, or C 1 to C 2 alkoxy;
R 3 is H, C 1 to C 4 alkyl;
R 4 is —COZR 3 ;
R 5 is H;
R 6 is —COR 10 or —CO R 9 R 10 ;
R 7 is C 1 to C 4 alkyl; C 1 to C 4 alkenyl; cyclohexl; morpholinyl; oxetanyl; pipendinyl; furanyl; or benzyl; any of which may be optionally substituted with halo, —OH, alkyenyl, C 1 to C 4 alkyl, methoxy, ethoxy, haloalkyl;
R 8 is C 1 to C 4 alkyl, C 1 to C 4 alkoxy-C 1 to C 4 alkyl; —C 1 to C 4 alkyl-C 3 to C 6 cycloalkyl;
R 9 is H;
R 10 is phenyl, optionally substituted with halo, amino, C 1 to C 4 alkyl, haloalkyl, alkoxy, haloalkoxy, CN, isoxazolyl, benzoxy, phenoxy;
Z is O and R 3 is H or C 1 to C 4 alkyl.

13. A compound selected from the group consisting of:
2-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(pyrimidin-5-yl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(pyridin-3-yl)ureido) phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(pyridin-4-yl)ureido) phenoxy)acetic acid;
2-(3-(3-(1,3,4-thiadiazol-2-yl)ureido)-4-(cyclohexyl(isobutyl) amino)phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)ureido)phenoxy) acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(4-(dimethylamino) phenyl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(isoxazol-3-yl)ureido) phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(thiazol-2-yl)ureido) phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(4-phenoxyphenyl)ureido) phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(4-(oxazol-5-yl)phenyl) ureido)phenoxy)acetic acid;
2-(3-(3-(4-(benzyloxy)phenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(indoline-1-carboxamido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(4-fluorophenyl)ureido) phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2-fluorophenyl)ureido) phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2,6-difluorophenyl)ureido) phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2,5-difluorophenyl)ureido) phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2,4-difluorophenyl)ureido) phenoxy)acetic acid; 2-(3-(3-(5-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2-fluoro-4-methylphenyl)ureido)phenoxy)acetic acid;
2-(3-(3-(3-chloro-2,4-difluorophenyl)ureido)-4-(cyclo-hexyl(isobutyl)amino)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2-fluoro-4-methoxyphenyl) ureido)phenoxy)acetic acid;
2-(3-(3-(3-chloro-2-fluorophenyl)ureido)-4-(cyclo-hexyl(isobutyl)amino)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2-fluoro-3-(trifluoromethyl)phenyl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(3-fluoro-2-methylphenyl) ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(2,5-difluoro-4-methoxy-phenyl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(5-fluoro-2-methylphenyl)ureido)phenoxy)acetic acid;
2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(3,4-difluorophenyl) ureido)phenoxy)acetic acid; 2-(4-(cyclohexyl(isobutyl)amino)-3-(3-(3,5-difluorophe

Assignees

• Bristol Myers Squibb Co

Inventors

• Balog James Aaron
• Cherney Emily Charlotte
• Markwalder Jay A
• Shan Weifang
• Williams David K

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

• C07C311/49

  to nitrogen atoms · CPC title

• C07C275/40

  being further substituted by nitrogen atoms not being part of nitro or nitroso groups · CPC title

• C07C233/44

  having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton · CPC title

• C07C311/51

  Y being a hydrogen or a carbon atom · CPC title