GCN2 and perk kinase inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12577249-B2
Application number	US-202218073886-A
Country	US
Kind code	B2
Filing date	Dec 2, 2022
Priority date	Dec 3, 2021
Publication date	Mar 17, 2026
Grant date	Mar 17, 2026

Abstract

Described herein are compounds that are inhibitors of GCN2 kinase or PERK kinase, and methods of treating diseases, including diseases associated with GCN2 kinase or PERK kinase, with said compounds.

First claim

What is claimed is:

1 . A compound represented by Formula I-A:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
X 1 and X 3 are each independently selected from the group consisting of CH and N;
X 2 is selected from the group consisting of NR 6 , O, and S;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of H, halogen, cyano, and alkoxy;
R 4 is selected from the group consisting of halogen, alkoxy and alkyl;
R 5 is selected from the group consisting of H, halogen and alkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl; and
R 7 is selected from the group consisting of H, alkyl, and acyl.

2 . The compound of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is halogen.

3 . The compound of claim 1 , wherein at least one of R 1 , R 2 , and R 3 is fluoro.

4 . The compound of claim 1 represented by Formula I-B:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
X 1 and X 3 are each independently selected from the group consisting of CH and N;
X 2 is selected from the group consisting of NR 6 , O, and S;
R 2 and R 3 are each independently selected from the group consisting of H, halogen, cyano, and alkoxy;
R 4 is selected from the group consisting of halogen, alkoxy and alkyl;
R 5 is selected from the group consisting of H, halogen and alkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl; and
R 7 is selected from the group consisting of H, alkyl, and acyl.

5 . The compound of claim 1 represented by Formula I-C:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
X 2 is selected from the group consisting of NR 6 , O, and S;
X 3 is selected from the group consisting of CH and N;
R 2 and R 3 are each independently selected from the group consisting of H, halogen, cyano, and alkoxy;
R 4 is selected from the group consisting of halogen, alkoxy, and alkyl;
R 5 is selected from the group consisting of H, halogen, and alkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl; and
R 7 is selected from the group consisting of H, alkyl, and acyl.

6 . The compound of claim 1 represented by Formula I-D:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
R 2 and R 3 are each independently selected from the group consisting of H, halogen, cyano, and alkoxy;
R 4 is selected from the group consisting of halogen, alkoxy and alkyl;
R 5 is selected from the group consisting of H, halogen and alkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, alkenylalkyl, alkynyl, alkynylalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl; and
R 7 is selected from the group consisting of H, alkyl, and acetate.

7 . The compound of claim 4 , wherein R 2 is H and R 3 is H.

8 . The compound of claim 4 , wherein R 2 is F and R 3 is H.

9 . The compound of claim 4 , wherein R 2 is H and R 3 is F.

10 . The compound of claim 1 , wherein R 6 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkenyl-(C 1 -C 4 )alkyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )alkynyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 4 )alkyl, (C 3 -C 8 )alkoxy-(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )cycloalkenyl-(C 1 -C 4 )alkyl, heterocyclyl, heterocyclyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, and heteroaryl-(C 1 -C 4 )alkyl.

11 . The compound of claim 1 , wherein R 6 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )alkoxy-(C 1 -C 4 )alkyl, heterocyclyl, and heteroaryl.

12 . The compound of claim 1 , wherein R 6 is selected from the group consisting of

13 . The compound of claim 1 , wherein R 4 is selected from the group consisting of halogen, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkyl.

14 . The compound of claim 1 , wherein R 4 is selected from the group consisting of chloro, fluoro, methoxy, and methyl.

15 . The compound of claim 1 , wherein R 5 is selected from the group consisting of H, halogen, and (C 1 -C 6 )alkyl.

16 . The compound of claim 1 , wherein R 5 is selected from the group consisting of chloro, fluoro, and methyl.

17 . The compound of claim 1 , wherein R 7 is H.

18 . A compound selected from the group consisting of:

and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

19 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

20 . A method of treating a disease caused by a dysregulation of the integrated stress response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21 . The method of claim 20 , wherein the dysregulation of the integrated stress response and/or an unfolded protein response is caused by PERK kinase and/or GCN2 kinase.

22 . A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

23 . The method of claim 22 , wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer, mesothelioma, pancreatic cancer, pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric, duodenal cancer, small intestinal cancer, breast cancer, ovarian cancer, testis tumor, prostate, liver cancer, thyroid cancer, renal cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin canc

Assignees

• Deciphera Pharmaceuticals Llc

Inventors

• Ahn Yu Mi
• Al-Ani Gada
• Flynn Daniel L
• Javed Salim
• Kearney Patrick
• Lebourdonnec Bertrand
• Stoltz Kristen
• Zwicker Jeffery

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title