Arginase inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12195485-B2
Application number	US-202217812736-A
Country	US
Kind code	B2
Filing date	Jul 15, 2022
Priority date	Feb 17, 2018
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

Disclosed are compounds of formula (Ia) or a pharmaceutically acceptable salt thereof pharmaceutical compositions comprising compounds of formula (Ia) and methods of using the same for treating cancer or a respiratory inflammatory disease and inhibiting arginase:

wherein
R 1 is —NHR 1a ; R 1a is —H or —C(O)CH(R 1b )NHR 1c ; and R 1b is selected from —H, —(C 1 -C 4 ) alkyl and CH 2 OR 1d and R 1c is —H; or R 1b and R 1c , together with the atom to which they are attached, form a 5-membered heterocyclic ring; and R 1d is H or —CH 3 .

First claim

The invention claimed is:

1. A method of treating a respiratory inflammatory disease associated with Arginase 1 or Arginase 2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein
R 2 is —OH or —NHR 2a :
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .

2. The method of claim 1 , wherein the compound is represented by formula (III), or a pharmaceutically acceptable salt thereof:

wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .

3. A method of treating a respiratory inflammatory disease associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IIb), or a pharmaceutically acceptable salt thereof:

wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .

4. The method of claim 3 , wherein the compound is represented by formula (IIIb), or a pharmaceutically acceptable salt thereof:

wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .

5. The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound has the following structure:

8. The method of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound has the following structure:

10. The method of claim 3 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

11. The method of claim 3 , wherein the compound has the following structure:

12. The method of claim 1 , wherein the inflammatory respiratory disease is selected from idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease and chemically-induced lung fibrosis.

13. The method of claim 1 , wherein the inflammatory respiratory disease is idiopathic pulmonary fibrosis.

14. The method of claim 3 , wherein the inflammatory respiratory disease is selected from idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease and chemically-induced lung fibrosis.

15. The method of claim 3 , wherein the inflammatory respiratory disease is idiopathic pulmonary fibrosis.

16. A method of treating a cancer associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .

17. The method of claim 16 , wherein the compound is represented by formula (III), or a pharmaceutically acceptable salt thereof:

wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .

18. A method of treating a cancer associated with Arginase 1 or Arginase 2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (IIb), or a pharmaceutically acceptable salt thereof:

wherein
R 2 is —OH or —NHR 2a ;
R 2a is —H or —C(O)CH(R 2b )NH 2 ; and
R 2b is —CH 3 or —CH(CH 3 ) 2 .

19. The method of claim 18 , wherein the compound is represented by formula (IIIb), or a pharmaceutically acceptable salt thereof:

wherein R 3 is —CH 3 or —CH(CH 3 ) 2 .

20. The method of claim 16 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

21. The method of claim 16 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 16 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

23. The method of claim 18 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.

Assignees

• Astrazeneca Ab

Inventors

• Mlynarski Scott Nathan
• Grebe Tyler
• Kawatkar Sameer
• Finlay Maurice Raymond Verschoyle
• Simpson Iain
• Wang Jianyan
• Cook Steve
• Wu Dedong

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/69

  Boron compounds · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title