Methods and materials for increasing level of phosphorylated AMPK protein

Patent metadata

Field	Value
Publication number	US-12428378-B2
Application number	US-202017641606-A
Country	US
Kind code	B2
Filing date	Sep 9, 2020
Priority date	Sep 10, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

This document provides methods and materials for increasing the level of phosphorylated AMPK. For example, compounds (e.g., organic compounds) having the ability to increase the level of phosphorylated AMPK within cells, formulations containing compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for making formulations containing compounds having the ability to increase the level of phosphorylated AMPK within cells, methods for increasing the level of phosphorylated AMPK within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in the level of phosphorylated AMPK are provided.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a group of formula

L 1 is C 1-4 alkylene optionally substituted with halo or OR 4 ;
L 2 is C 1-4 alkylene or L 2 is absent;
X is selected from CR 7 (OR 4 ) and C═O; or X is absent;
R 7 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 2 is —CH 2 -phenyl, wherein said phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy1 ;
R 3 is —CH 2 -(5-10 membered monocyclic or bicyclic heteroaryl), wherein said heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy1 ;
R 4 is selected from H, C(O)R b1 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R g ;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, or 3;
each R 5 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —SH, C 1-6 alkylthio, carboxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino;
each R Cy1 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered monocyclic or bicyclic heteroaryl, and 4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy2 ;
each R Cy2 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
each R a1 , R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered monocyclic or bicyclic heteroaryl, 4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered monocyclic or bicyclic heteroaryl)-C 1-4 alkylene, and (4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl)-C 1-4 alkylene, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered monocyclic or bicyclic heteroaryl, 4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered monocyclic or bicyclic heteroaryl)-C 1-4 alkylene, and (4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl)-C 1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R g ;
or any R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R g ;
each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkylene, HO—C 1-3 alkylene, C 6-10 aryl, C 6-10 aryloxy, C 3-10 cycloalkyl, 5-10 membered monocyclic or bicyclic heteroaryl, 4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl, C 6-10 aryl-C 1-4 alkylene, C 3-10 cycloalkyl-C 1-4 alkylene, (5-10 membered monocyclic or bicyclic heteroaryl)-C 1-4 alkylene, (4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl)-C 1-4 alkylene, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, —SH, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino; wherein
each 5-10 membered monocyclic or bicyclic heteroaryl independently has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen; and
each 4-10 membered monocyclic or fused or spiro bicyclic heterocycloalkyl and each 4-7 membered monocyclic heterocycloalkyl independently has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, oxygen, and sulfur and contains 0 to 3 double bonds.

2. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Chen Beibei
• Finkel Toren
• Liu Yuan

Classifications

• C07D417/04

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D277/28

  Radicals substituted by nitrogen atoms · CPC title

• C07D239/26

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

• C07D233/24

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title