Inhibitors of CD73-mediated immunosuppression

Patent metadata

Field	Value
Publication number	US-11267845-B2
Application number	US-201716461649-A
Country	US
Kind code	B2
Filing date	Nov 17, 2017
Priority date	Nov 18, 2016
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
R 1a and R 1b are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted —C(R 2a R 2b )-aryl, —C(R 2a R 2b )—O—C(O)—OR 3 , —C(R 2a R 2b )—O—C(O)R 3 , and —C(R 2a R 2b )C(O)OR 3 ; or, R 1a and R 1b groups are combined to form a 5- to 6-membered heterocyclic ring;
each R 2a and R 2b is independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 4 )alkyl and optionally substituted aryl;
R 5a and R 5b are independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, —C(O)OR 3 , C 3 -C 6 cycloalkyl(C 1 -C 6 )alkyl aryl(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl and aryl;
each X is selected from the group consisting of O, NH, and S;
A is:

which is optionally substituted with from 1 to 5 R 6 substituents;

Z is selected from the group consisting of NH, NR 6 , and O;
each R 6 is independently selected from the group consisting of CH 3 , OR g , CN, F, and optionally substituted C 1 -C 6 alkyl; or two R 6 groups on adjacent ring vertices are optionally joined together to form a 5- to 6-membered ring having at least one heteroatom as a ring vertex; and
Het is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to the remainder of the compound,
wherein each G, when present, is independently selected from the group consisting of N and CR e , and wherein:
R a is selected from the group consisting of NHR 7a , NHC(O)R 7a , NR 7a R 7b , R 7a , SR 7a and OR 7a ;
R b is selected from the group consisting of H, halogen, NH 2 , NHR 7a , NR 7a R 7b , R 7a , OH, and OR 7a ;
R c and R d are independently selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 7a , NR 7a R 7b , R 7a , OH, OR 7a , SR 7a ,
SO 2 R 7a , —X 1 —NH 2 , —X 1 —NHR 7a , —X 1 —NR 7a R 7b , —X 1 —OH, —X 1 —OR 7a , —X 1 —SR 7a
and —X 1 —SO 2 R 7a ;

each R e is independently selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each R g is independently selected from the group consisting of H and —C(O)—C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 7a and R 7b is independently selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, 4-7 membered cycloheteroalkyl, 4-7 membered cycloheteroalkylC 1 -C 4 alkyl, aryl, arylC 1 -C 4 alkyl, arylC 2 -C 4 alkenyl, arylC 2 -C 4 alkynyl, heteroaryl, heteroarylC 1 -C 4 alkyl, heteroarylC 1 -C 4 alkenyl, and heteroarylC 2 -C 4 alkynyl; or R 7a and R 7b when attached to the same nitrogen atom are optionally joined together to form a 4- to 7-membered heterocyclic ring, optionally fused to an aryl ring.

2. The compound of claim 1 , wherein A is selected from the group consisting of:

3. The compound of claim 1 , wherein Het is:

4. The compound of claim 3 , wherein R c is other than hydrogen.

5. The compound of claim 4 , having a formula selected from the group consisting of:

6. The compound of claim 5 , wherein each X is oxygen.

7. The compound of claim 6 , wherein R e is hydrogen.

8. The compound of claim 7 , wherein each R g is hydrogen.

9. The compound of claim 5 , having the formula:

10. The compound of claim 9 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.

11. The compound of claim 9 , having the formula:

12. The compound of claim 5 , having the formula:

13. The compound of claim 12 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.

14. The compound of claim 12 , having the formula:

15. The compound of claim 5 , having the formula:

16. The compound of claim 15 , wherein R 1a and R 1b are H; each X is O; R g is H; and R g is Cl.

17. The compound of claim 15 , having the formula:

18. The compound of claim 5 , having the formula:

19. The compound of claim 18 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.

20. The compound of claim 18 , having the formula:

21. The compound of claim 1 , wherein R 5a is selected from the group consisting of H, optionally substituted C 1-4 alkyl, —C(O)OR 3 , C 3 -C 6 cycloalkyl(C 1 -C 4 )alkyl and aryl(C 1 -C 4 )alkyl, and R 5b is H.

22. The compound of claim 1 , wherein Het is selected from

23. The compound of claim 22 , wherein R 5a is selected from the group consisting of optionally substituted C 1-3 alkyl, —C(O)OH, C 3 -C 6 cycloalkyl(C 1 -C 2 )alkyl and phenyl(C 1 -C 2 )alkyl, R 5b is H, each X is O, R 1a and R 1b are H, R e is H, R c is other than H, and R a is NHR 7a .

24. The compound of claim 23 , wherein R 7a is C 3 -C 7 cycloalkyl, or 4-7 membered cycloheteroalkylC 1 -C 4 alkyl.

25. The compound of claim 24 , wherein R 7a is cyclopentyl.

26. A compound selected from the group consisting of

Assignees

• Arcus Biosciences Inc

Inventors

• Kalisiak Jaroslaw
• Lawson Kenneth V
• Leleti Manmohan Reddy
• Lindsey Erick Allen
• Miles Dillon Harding
• Newcomb Eric
• Powers Jay Patrick
• Sharif Ehesan Ul

Classifications

• A61K45/06 Primary

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

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P21/02

  Muscle relaxants, e.g. for tetanus or cramps · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P19/10

  for osteoporosis · CPC title