DPAGT1 inhibitors of capuramycin analogues and their antimigratory activities of solid tumors

Patent metadata

Field	Value
Publication number	US-12570684-B2
Application number	US-202118013403-A
Country	US
Kind code	B2
Filing date	Jun 30, 2021
Priority date	Jun 30, 2020
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

Provided herein are compounds and methods of using these compounds to treat disorders related to DPAGT1 function, including cancer and bacterial infections.

First claim

The invention claimed is:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof;
wherein
X is NH, O, or —(CH 2 ) m —;
Y is CH or N;
Z is CH or N;
A is absent, O, or NH;
R 1 is OR 7 or —(CH 2 ) n NHR 7 ;
R 2 is H or halo;
R 3 is selected from the group consisting of H, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl;
R 4 is H or halo;
R 5 and R 6 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, and C(O)C 1 -C 6 alkyl;
R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl, wherein the aryl and heteroaryl are each optionally substituted one, two, or three times with OC 1 —C 6 haloalkyl; and
m and n are, independently at each occurrence, 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 , wherein R 1 is OR 7 .

6 . The compound of claim 1 , wherein R 1 is —(CH 2 ) n NHR 7 .

7 . The compound of claim 1 , wherein the compound of Formula I is CPPB:

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 7 , wherein the compound of Formula I is CPPB1:

or a pharmaceutically acceptable salt thereof.

9 . A pharmaceutical composition comprising the compound of claim 1 , and at least one pharmaceutically acceptable carrier.

10 . The pharmaceutical composition of claim 9 , further comprising an additional therapeutic agent.

11 . The pharmaceutical composition of claim 10 , wherein the additional therapeutic agent is selected from the group consisting of paclitaxel, tunicamycin, capuramycin, erlotinib, capecitabine, fluorouracil, and gemcitabine.

12 . A method of inhibiting dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

13 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .

14 . The method of claim 13 , wherein the cancer is selected from the group consisting of pancreatic cancer, cervical cancer, brain cancer, colon cancer, ovarian cancer, breast cancer, carcinoma, and adenocarcinoma.

15 . The method of claim 14 , wherein the cancer is pancreatic cancer.

16 . The method of claim 13 , wherein the cancer is a solid tumor.

17 . A compound of Formula V:

or a pharmaceutically acceptable salt thereof;
wherein
X and Y are independently O or NH;
R1 is selected from the group consisting of H, OH, C(O)NH2, CO2H, C(O)H, and C(O)halo; and
R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl.

18 . A compound of Formula VI:

or a pharmaceutically acceptable salt thereof;
wherein
X and Y are independently O or NH;
R 1 and R 2 are each independently selected from H and OH; and
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl.

Assignees

• Univ Tennessee Res Found
• California Inst Of Techn

Inventors

• Kurosu Michio
• Mitachi Katsuhiko
• Clemons William M

Classifications

• A61K45/06

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

• C07H19/06

  Pyrimidine radicals · CPC title

• C07H19/067 Primary

  with ribosyl as the saccharide radical · CPC title