Bacterial efflux pump inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2024350454-A1
Application number	US-202218294248-A
Country	US
Kind code	A1
Filing date	Jun 2, 2022
Priority date	Aug 2, 2021
Publication date	Oct 24, 2024
Grant date	—

Abstract

Disclosed herein are bacterial efflux inhibitor compounds and methods of using the compounds for treating bacterial infection.

First claim

1 . A compound of Formula (I)

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1, 2, or 3;
p is 1, 2, 3, 4, or 5;
m is 1, 2, 3, 4, or 5;
each R 1 is independently halo, alkyl, or haloalkyl;
R 2 is —H, alkyl, alkenyl, or alkynyl;
R 3 is —H, alkyl, alkenyl, or alkynyl;
R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more R 5 ;
or R 3 and R 4 are taken together to form a heterocyclyl, which is optionally substituted with one or more R 5 ,
R 5 is aryl, heteroaryl, alkyl, NH 2 , NHR A , or NR A R B , or alkyl-NH 2 ;
R A is alkyl, alkenyl, or alkynyl, each of which is optionally substituted with —OH or alkoxy; and
R B is alkyl, alkenyl, or alkynyl.

2 . The compound of claim 1 , wherein R 3 and R 4 are taken together to form a heterocyclyl, which is optionally substituted with one or more R 5 .

3 . A compound of claim 1 or 2 , having a structure of Formula (II):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1, 2, or 3;
p is 1, 2, 3, 4, or 5;
m is 1, 2, 3, 4, or 5;
q is 1, 2, or 3;
each R 1 is independently halo, alkyl, or haloalkyl;
R 2 is hydrogen, C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl;
A ring is heterocyclyl;
R 5 is aryl, heteroaryl, alky, NH 2 , NHR A , or NR A R B ;
R A is C 1-6 alkyl, C 1-6 alkenyl, or C 14 alkynyl, each of which is optionally substituted with —OH, or C 14 alkoxy; and
R B is C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl, each of which is optionally substituted with —OH, or C 1-6 alkoxy.

4 . The compound of claim 3 , wherein:
the A ring is a 5-8 membered heterocyclyl, optionally having 1, 2, or 3 heteroatoms selected from N, O, or S in addition to the ring N shown in Formula (II).

5 . The compound of claim 3 or 4 , wherein the A ring is a 5-6 membered heterocyclyl.

6 . The compound of any one of claims 3-5 , wherein:
R 5 is heteroaryl, NH 2 , NHR A , or NR A R B ; R A is C 1-6 alkyl optionally substituted with C 1-6 alkoxy; and R B is C 1-6 alkyl.

7 . The compound of any one of claims 3-6 , wherein:
p is 1 or 2.

8 . The compound of any one of claims 3-7 , wherein:
m is 1 or 2.

9 . The compound of any one of claims 3-8 , wherein:
q is 1.

10 . The compound of claim 1 , having a structure of Formula (III):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 2;
p is 1, 2, or 3;
m is 1, 2, or 3;
q is 1;
each R 1 is independently halo or haloalkyl;
A ring is a 5 or 6 membered heterocyclyl;
R 5 is heteroaryl or C 1-6 alkyl, substituted with —NH 2 , —NHR A , or —NR A R B ;
R A is C 1-6 alkyl which is optionally substituted with C 1-6 alkoxy; and
R B is C 1-6 alkyl.

11 . The compound of any one of claims 1-10 , wherein each R 1 is Cl.

12 . The compound of any one of claims 1-11 , having a structure of Formula (IV):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 2;
q is 1;
each R 1 is Cl or fluoroalkyl;
R 5 is alkyl, —NH 2 , or —NH 2 , —NHR A , or NR A R B ;
R A is C 1-6 alkyl which are optionally substituted with C 1-6 alkoxy;
R B is C 1-6 alkyl.

13 . The compound of claim 12 , wherein R 5 alkyl-NH 2 , or —NH 2 .

14 . The compound of claim 12 or 13 , having the following structure:

or a stereoisomer or pharmaceutically acceptable salt thereof.

15 . The compound of claim 14 , having the following structure:

or a pharmaceutically acceptable salt thereof.

16 . The compound of any one of claims 1-11 , having a structure of Formula (V):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 2;
q is 1 or 2;
each R 1 is Cl or fluoroalkyl;
R 5 is C 1-6 alkyl, heteroaryl, NH 2 , NHR A , or NR A R B ;
R A is C 1-6 alkyl optionally substituted with C 1-6 alkoxy;
R B is C 1-6 alkyl.

17 . The compound of claim 16 , wherein R 5 is a 5-7 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N or S.

18 . The compound of claim 16 or 17 , wherein R 5 is a 5 membered heteroaryl having 1 or 2 N heteroatoms.

19 . The compound of any one of claims 16-17 , wherein R 5 is imidazolyl.

20 . The compound of any one of claims 16-19 , having the following structure:

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 1 , wherein:
R 3 is —H or alkyl.

22 . The compound of claim 1 or 21 , wherein
R 4 is alkyl substituted with R 5 ; and R 5 is NH 2 .

23 . The compound of claim 1 or 21 , wherein:
R 4 is heterocyclyl.

24 . The compound of claim of 23 , wherein:
the R 4 is 5, 3 fused heterocyclyl.

25 . The compound of any one of claims 21-24 , wherein:
R 2 is H.

26 . The compound of any one of claims 21-25 , wherein:
n is 1 or 2, and R 1 is halo.

27 . The compound of any one of claims 21-26 , wherein:
m is 1 or 2.

28 . The compound of any one of claims 21-27 , wherein:
p is 1 or 2.

29 . The compound of any one of claims 21-28 , having one of the following structures:

or a pharmaceutically acceptable salt thereof.

30 . The compound of claim 1 having one of the following structures:

or a pharmaceutically acceptable salt thereof.

31 . A pharmaceutical composition comprising therapeutically effective amount of a compound of any one of claims 1-30 , and one or more pharmaceutically acceptable excipients.

32 . A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of any one of claims 1-30 .

33 . The method of claim 32 , wherein the bacteri

Assignees

• Univ Colorado Regents
• Crestone Inc

Inventors

• Detweiler Corrella S
• Crooks Amy L
• Ochsner Urs
• Sun Xicheng
• Graham James M
• Wong Christina

Classifications

• C07C217/34

  by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms · CPC title

• C07D209/52

  condensed with a ring other than six-membered · CPC title

• C07D207/09

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

• C07D401/04

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

• C07D211/58

  attached in position 4 · CPC title