Small molecule inhibitors of ULK1

Patent metadata

Field	Value
Publication number	US-12473284-B2
Application number	US-202017790091-A
Country	US
Kind code	B2
Filing date	Dec 29, 2020
Priority date	Dec 30, 2019
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

The present technology is directed to compounds, compositions, and methods related to inhibition of ULK1 and treatment of cancers therefrom.

First claim

What is claimed is:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt and/or solvate thereof, wherein
R 1 and R 2 are each independently H, or R 1 and R 2 together are a bond;
R 3 and R 4 are each independently H, or R 3 and R 4 together are a bond;
R 5 and R 6 are each independently H, alkyl, O-alkyl, CO 2 H, CO 2 -alkyl, halogen, or cyano;
X 1 is H, Me, CO 2 -alkyl, or heteroaryl;
X 2 is H or Me;
X 3 is H or Me;
X 4 is NH or O;
X 5 is CH or N; and
X 6 is aryl or heteroaryl.

2 . The compound of claim 1 , wherein X 6 is substituted phenyl, unsubstituted phenyl, or heteroaryl.

3 . The compound of claim 1 , wherein X 6 is

where W 1 , W 2 , and W 3 are each independently H, Cl, Br, F, Me, cyclopropyl, CF 3 , OMe, or CN.

4 . The compound of claim 1 , wherein R 1 and R 2 are each independently H.

5 . The compound of claim 1 , wherein R 3 and R 4 are each independently H.

6 . The compound of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each independently H.

7 . The compound of claim 1 , wherein the compound is of Formula IA

or a pharmaceutically acceptable salt and/or solvate thereof.

8 . The compound of claim 1 , wherein the compound is of Formula IB

or a pharmaceutically acceptable salt and/or solvate thereof, wherein X 1 is Me, CO 2 -alkyl, or heteroaryl.

9 . The compound of claim 1 , wherein the compound is of Formula IC

or a pharmaceutically acceptable salt and/or solvate thereof, wherein X 1 is Me, CO 2 -alkyl, or heteroaryl.

10 . The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt and/or solvate thereof.

11 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 for treating cancer in a subject, and a pharmaceutically acceptable carrier.

13 . A method comprising administering an effective amount of a compound of claim 1 for treating cancer to a subject in need thereof, wherein the subject is suffering from one or more of nasopharyngeal carcinoma, oesophageal squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, glioblastoma, lung cancer, non-small cell lung cancer, renal carcinoma, renal clear cell carcinoma, pancreatic cancer, and breast cancer.

14 . The method of claim 13 , wherein the administering further comprises administration of an effective amount of a MEK inhibitor.

15 . The method of claim 13 , wherein the administering further comprises administration of an effective amount of trametinib, cobimetinib, binimetinib, selumetinib, or a combination of any two or more thereof.

16 . A method of inhibiting ULK1, the method comprising contacting ULK1 with a compound of claim 1 .

17 . The method of claim 16 , wherein the contacting comprises contacting a cell not within a patient.

18 . The method of claim 17 , wherein the cell is a nasopharyngeal carcinoma cell, oesophageal squamous cell carcinoma cell, colorectal cancer cell, hepatocellular carcinoma cell, glioblastoma cell, lung cancer cell, non-small cell lung cancer cell, renal carcinoma cell, renal clear cell carcinoma cell, pancreatic cancer cell, or breast cancer cell.

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Jiang Xuejun
• Tan Derek
• Liang Deguang
• Wong Pui-Mun
• Suzuki Takao

Classifications

• A61K45/06

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/437

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

• A61P35/00

  Antineoplastic agents · CPC title