Nitrophenyl-acrylamides and uses thereof

Patent metadata

Field	Value
Publication number	US-2025074894-A1
Application number	US-202218555505-A
Country	US
Kind code	A1
Filing date	Apr 15, 2022
Priority date	Apr 15, 2021
Publication date	Mar 6, 2025
Grant date	—

Abstract

Provided herein are nitrophenyl-acrylamide compounds, their preparation, and uses thereof.

First claim

The invention claimed is:

1 . A compound, having the following formula:

or a pharmaceutically acceptable salt thereof,
wherein
is a single or double bond;
R 1 is C 1-4 alkyl;
R 2 is C 1-4 alkylene;
R 3 is N, O, S, NH, CH, or N—(C 1-4 alkyl);
R 4 is H, C 1-4 alkyl, or (C 1-4 alkyl)-OH;
or R 3 and R 4 combine to form a C 2-6 heterocycloalkyl;
R 5 is C(O)N(H) (C 1-4 alkyl), C(O)N(H) (C 2-6 heterocycloalkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), C(O)H, CN, pyrrolidinonyl, C 1-4 alkyl, C 1-4 haloalkyl, C(O)O(C 1-4 alkyl), C(O)NH 2 , C(O)N(H) C(O)H, (C 1-4 alkyl)-OH, C 2-6 heterocycloalkyl-C(O) H, or O—(C 1-4 alkyl);
or R 4 and R 5 combine to form CO, C 3-7 cycloalkyl, C 2-6 heterocycloalkyl, pyrrolidinonyl, pyrrolidinonyl-(C 1-4 alkyl), or imidazolidinonyl-OH; and
R 6 is H, CN, C(O)H, C 1-4 alkyl, heteroaryl, O—(C 1-4 alkyl), O—(C 1-4 alkyl)-OH, N(H)—(C 1-4 alkyl), or N(H)—(C 1-4 alkyl)-OH.

2 . The compound of claim 1 , wherein R 1 is methyl or ethyl.

3 . The compound of claim 1 , wherein R 2 is methylene.

4 . The compound of claim 1 , wherein is a single bond, and R 3 is N, O, or S.

5 . The compound of claim 1 , wherein is a double bond, and R 3 is NH or CH.

6 . The compound of claim 1 , wherein R 4 is H or C 1-4 alkyl.

7 . The compound of claim 1 , wherein each instance of heteroaryl refers, independently, to furanyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, or imidazolyl.

8 . The compound of claim 1 , wherein R 3 and R 4 combine to form a C 2-6 heterocycloalkyl.

9 . The compound of claim 1 , wherein R 4 and R 5 combine to form CO, C 3-7 cycloalkyl, pyrrolidinonyl, pyrrolidinonyl-(C 1-4 alkyl), or imidazolidinonyl-OH.

10 . The compound of claim 1 , wherein:
R 3 is N, O, S, NH, CH, or N—(C 1-4 alkyl); R 4 is H, C 1-4 alkyl, or (C 1-4 alkyl)-OH; and R 5 is C(O)N(H)(C 1-4 alkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), C(O)H, CN, pyrrolidinonyl, C 1-4 alkyl, C 1-4 haloalkyl, C(O)O(C 1-4 alkyl), C(O)NH 2 , C(O)N(H)C(O)H, (C 1-4 alkyl)-OH, or O—(C 1-4 alkyl).

11 . The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof,
wherein
R 7 is

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

or a pharmaceutically acceptable salt thereof.

13 . A composition, comprising the compound of claim 1 .

14 . The composition of claim 13 , wherein the composition is a pharmaceutical composition further comprising a pharmaceutical acceptable carrier.

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

16 . The method of claim 15 , wherein the cancer comprises a brain tumor.

17 . The method of claim 15 , wherein the cancer comprises a glioblastoma or a diffuse intrinsic pontine glioma.

18 . The method of claim 15 , wherein the cancer comprises a brain cancer or tumor, a leukemia, a breast cancer, a lung cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a prostate cancer, or a kidney cancer.

19 . A method of inhibiting fat mass obesity-associated protein (FTO) or Notch1 activity in a cell, comprising contacting the cell with an effective amount of entacapone or a pharmaceutically acceptable salt thereof or the compound of claim 1 .

20 . The method of claim 19 , wherein:
the cell is a brain cell, a blood cell, a breast cell, a lung cell, a colon cell, a pancreatic cell, an ovarian cell, a prostate cell, or a kidney cell, and optionally the contacting is in a subject; or the contacting is in vitro, and optionally the cell is a brain cell, a blood cell, a breast cell, a lung cell, a colon cell, a pancreatic cell, an ovarian cell, a prostate cell, or a kidney cell.

21 . The method of claim 19 , wherein the cell is a glioma stem cell.

Assignees

• Univ Brown
• Rhode Island Hospital

Inventors

• Tapinos Nikolaos
• Zepecki John
• Karambizi David

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D307/22

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D295/125

  with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title