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

Patent metadata

Field	Value
Publication number	US-11066392-B2
Application number	US-201816612076-A
Country	US
Kind code	B2
Filing date	May 10, 2018
Priority date	May 12, 2017
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

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 or formula III

wherein
X is CH, CR 4 , or N;
R 1 is C 1-6 alkyl, C 0-6 alk-O—C 1-6 alkyl, C 0-6 alk-O—C 1-6 alk-O—C 1-6 alkyl, C 0-6 alk-CN, or C 0-6 alk-heterocycloalkyl;
R 2 is H, —NH 2 ; —NH(C 1-6 alkyl); —N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, halo, heterocycloalkyl, or heteroaryl;
R 3 is pyridyl; pyrimidinyl; quinolinyl; or naphthyridinyl, wherein the pyridyl, pyrimidinyl, quinolinyl, or naphthyridinyl is optionally substituted on any atom with 1, 2 or 3 R substituents that are independently C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, or halo;
R 4 is NH 2 ; —NH(C 1-6 alkyl); —N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl; C 1-6 alkoxy, OH, halo, heterocycloalkyl, or heteroaryl;
or a stereoisomer thereof or a tautomer thereof;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 that is a compound of formula I, or a stereoisomer thereof or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein X is CH or CR 4 .

4. The compound of claim 2 , wherein X is N.

5. The compound of claim 1 that is a compound of formula II, or a stereoisomer thereof or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 1 is C 1-6 alkyl.

7. The compound of claim 1 , wherein R 1 is C 0-6 alk-O—C 1-6 alkyl.

8. The compound of claim 1 , wherein R 1 is C 0-6 alk-O—C 1-6 alk-O—C 1-6 alkyl.

9. The compound of claim 1 , wherein R 1 is C 0-6 alk-CN.

10. The compound of claim 1 , wherein R 1 is C 0-6 alk-heterocycloalkyl.

11. The compound of claim 1 , wherein R 2 is H.

12. The compound of claim 1 , wherein R 2 is —NH 2 ; —NH(C 1-6 alkyl); or —N(C 1-6 alkyl)(C 1-6 alkyl).

13. The compound of claim 1 , wherein R 2 is C 1-6 alkyl or C 1-6 alkoxy.

14. The compound of claim 1 , wherein R 2 is d 1 -d 13 -C 1-6 alkyl or d 1 -d 13 -C 1-6 alkoxy.

15. The compound of claim 1 , wherein R 2 is OH.

16. The compound of claim 1 , wherein R 2 is halo.

17. The compound of claim 1 , wherein R 2 is heterocycloalkyl.

18. The compound of claim 1 , wherein R 2 is heteroaryl.

19. The compound of claim 1 , wherein R 3 is pyridyl optionally substituted on any atom with 1, 2 or 3 R substituents that are independently C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, or halo.

20. The compound of claim 1 , wherein R 3 is pyrimidinyl optionally substituted on any atom with 1, 2 or 3 R substituents that are independently C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, or halo.

21. The compound of claim 1 , wherein R 3 is quinolinyl optionally substituted on any atom with 1, 2 or 3 R substituents that are independently C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, or halo.

22. The compound of claim 1 , wherein R 3 is naphthyridinyl optionally substituted on any atom with 1, 2 or 3 R substituents that are independently C 1-6 alkyl, d 1 -d 13 -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy, d 1 -d 13 -C 1-6 alkoxy, OH, or halo.

23. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

24. 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 ; wherein the cancer is brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer or bone cancer.

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D213/85 Primary

  in position 3 · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title