Pharmaceutically active pyrazolo-pyridone modulators of DCN1/2-mediated cullin neddylation

Patent metadata

Field	Value
Publication number	US-12409171-B2
Application number	US-202017618952-A
Country	US
Kind code	B2
Filing date	Jun 22, 2020
Priority date	Jun 20, 2019
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

A DCN1/2-mediated cullin neddylation modulator; a method for treating disorders associated with dysfunctional DCN1 and/or UBC12, Alzheimer's disease, other neurodegenerative diseases, bacterial infections, or viral infections; and a method for treating cancers are provided. The DCN1/2-mediated cullin neddylation modulator includes a compound according to Formula I disclosed herein. The methods include administering to a mammal a therapeutically effective amount of a compound according to Formula I. Also provided herein is a pharmaceutical composition including a therapeutically effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

First claim

What is claimed is:

1. A DCN1/2-mediated cullin neddylation modulator according to Formula I:

wherein;
R 1 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, haloaryl, alkyl ester, alkyl carboxylic acid, alkyl amide, or cyanomethyl;
R 2 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, haloaryl, or cyanomethyl;
R 3 is selected from —NHC(═O)—R 6 , —NHC(═O)—NH—R 6 , —NHSO 2 —R 6 , —C(═O)—NH—R 6 , or —CH 2 C(═O)—R 6 ;
R 4 is selected from alkyl, acyl, aryl, or heteroaryl;
R 5 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxylic acid, nitrile, or —(CH 2 ) n —X—R 7 ,
R 6 is selected from alkyl, alkenyl, acyl, aryl, or heteroaryl;
R 7 is selected from H, alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycle, heterocycloalkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, alkyl ester, alkyl carboxylic acid, alkyl amide, cyanomethyl, or —Y—Z—Y—R 8 ;
R 5 is H or biotin;
X is selected from O, NH, S, or Linker;
each Y is independently selected from CH 2 , NH, O, or S;
Z is —(OCH 2 CH 2 ) n —, alkyl linker, or aminoalkyl linker;
Linker is selected from —(OCH 2 CH 2 ) n —(PEG), alkyl linker, or aminoalkyl linker; and
each n is independently an integer from 0 to 20.

2. The modulator of claim 1 , wherein R 1 , R 2 , and R 4 are not the same.

3. The modulator of claim 1 , wherein at least two of R 1 , R 2 , and R 4 are the same.

4. The modulator of claim 1 , wherein each of R 1 , R 2 , and R 4 are the same.

5. The modulator of claim 1 , wherein R 1 is an aryl.

6. The modulator of claim 1 , wherein R 2 is an alkyl.

7. The modulator of claim 1 , wherein R 4 is a haloaryl.

8. The modulator of claim 1 , wherein R 3 and R 4 comprise a cis geometry.

9. The modulator of claim 1 , wherein R 1 is an aryl and R 4 is a haloaryl.

10. The modulator of claim 1 , wherein R 1 is an aryl, R 2 is an alkyl, and R 4 is a haloaryl.

11. The modulator of claim 1 , wherein R 5 is —(CH 2 ) n —X—R 7 .

12. The modulator of claim 1 , wherein R 5 is —(CH 2 ) n —X—R 7 ; R 7 is —Y—Z—Y—R 8 ; and
R 8 is biotin.

13. The modulator of claim 12 , wherein R 3 and R 4 comprise a cis geometry.

14. The modulator of claim 12 , wherein R 1 is an aryl.

15. The modulator of claim 12 , wherein R 2 is an alkyl.

16. The modulator of claim 12 , wherein R 4 is a haloaryl.

17. The modulator of claim 12 , wherein R 1 is an aryl, R 2 is an alkyl, and R 4 is a haloaryl.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method for ameliorating disorders associated with dysfunctional DCN1 and/or UBC12, Alzheimer's disease, ether neurodegenerative diseases, bacterial infections, or viral infections, the method comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 .

20. A method for ameliorating cancers, the method comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1 .

Assignees

• Univ Kentucky Res Found
• Memorial Sloan Kettering Cancer Center
• St Jude Childrens Res Hospital Inc

Inventors

• Kim Hoshin
• Guy Rodney Kiplin
• Hammill Jared T
• Scott Daniel Charles
• Schulman Brenda Arlene
• Singh Bhuvanesh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title