Modulators of 5′-nucleotidase, ecto and the use thereof

Patent metadata

Field	Value
Publication number	US-12459967-B2
Application number	US-202318516459-A
Country	US
Kind code	B2
Filing date	Nov 21, 2023
Priority date	Jan 8, 2016
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

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 thereof, wherein,
each R 1 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, and —C(R 2 R 2 )—O—C(O)—OR 3 , or two R 1 groups are optionally combined to form a 5- to 7-membered ring;
each R 2 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, and optionally substituted aryl;
R 5 is selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
X is selected from the group consisting of O, CH 2 , and S;
A is selected from the group consisting of:

each of which is optionally substituted with from 1 to 5 R 6 substituents, and wherein the subscript n is an integer from 0 to 3;

Z is selected from the group consisting of CH 2 , CHR 6 , NR 6 , and O;
each R 6 is independently selected from the group consisting of H, CH 3 , OH, CN, F, optionally substituted C 1 -C 6 alkyl, and OC(O)—C 1 -C 6 alkyl; and optionally two R 6 groups on adjacent ring vertices are 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, and wherein:
R a is selected from the group consisting of H, NH 2 , NHR 7 , NHC(O)R 7 , NR 7 R 7 , R 7 , OH, SR 7 , and OR 7 ;
R b is selected from the group consisting of H, halogen, NH 2 , NHR 7 , NR 7 R 7 , R 7 , OH, and OR 7 ;
R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 7 , NR 7 R 7 , R 7 , OH, OR 7 , SR 7 , SO 2 R 7 , —X 1 —NH 2 , —X 1 —NHR 7 , —X 1 —NR 7 R 7 , —X 1 —OH, —X 1 —OR 7 , —X 1 —SR 7 , and —X 1 —SO 2 R 7 ;
R e and R f are independently selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 7 is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkylC 1 -C 4 alkyl, optionally substituted 4-7 membered cycloheteroalkyl, optionally substituted 4-7 membered cycloheteroalkylC 1 -C 4 alkyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 alkyl, optionally substituted arylC 2 -C 4 alkenyl, optionally substituted arylC 2 -C 4 alkynyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1 -C 4 alkyl, optionally substituted heteroarylC 1 -C 4 alkenyl, optionally substituted heteroarylC 2 -C 4 alkynyl, and optionally, two R 7 groups attached to a nitrogen atom are joined together to form a 4- to 7-membered heterocyclic ring, optionally fused to an aryl ring.

2. The compound of claim 1 , wherein R 5 is H, X is O, each R 1 is H, R e is H, and R a is selected from the group consisting of NH 2 , NHR 7 , and N(R 7 ) 2 .

3. The compound of claim 1 , wherein R 5 is H, X is O, each R 1 is H, R e is H, R c is other than H, and R a is NHR 7 .

4. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein,
each R 1 is independently selected from the group consisting of hydrogen and —C(R 2 R 2 )—O—C(O)—OR 3 ;
each R 2 is H;
each R 3 is independently selected from the group consisting of H and C 1 -C 6 alkyl;
R 5 is H;
X is O;
A is

 optionally substituted with from 1 to 5 R 6 substituents;
Z is O;
each R 6 is independently selected from the group consisting of H, OH, and F;
Het is

 wherein the wavy line indicates the point of attachment to the remainder of the compound, and wherein:
R a is selected from the group consisting of NHR 7 and NR 7 R 7 ;
R b is H;
R c is H or halogen;
R e is H; and
each R 7 is independently selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered cycloheteroalkyl, and optionally substituted arylC 1 -C 4 alkyl; wherein the aryl is optionally substituted with halogen in a number up to the total number of open valences.

5. The compound of claim 4 , wherein A is selected from the group consisting of:

6. The compound of claim 4 , each R 1 is H.

7. The compound of claim 4 , wherein R a is N(R 7 ) 2 .

8. The compound of claim 4 , wherein R a is NHR 7 .

9. A compound which is:

10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignees

• Arcus Biosciences Inc

Inventors

• Debien Laurent Pierre Paul
• Jaen Juan Carlos
• Kalisiak Jaroslaw
• Lawson Kenneth V
• Leleti Manmohan Reddy
• Lindsey Erick Allen
• Miles Dillon Harding
• Newcomb Eric
• Powers Jay Patrick
• Rosen Brandon Reid
• Sharif Ehesan Ui

Classifications

• C07H19/14

  Pyrrolo-pyrimidine radicals · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• A61K31/7052

  having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides · CPC title

• A61K31/70

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title

• A61K45/06

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