Bacterial efflux pump inhibitors

Patent metadata

Field	Value
Publication number	US-2021137881-A1
Application number	US-201816492908-A
Country	US
Kind code	A1
Filing date	Mar 9, 2018
Priority date	Mar 10, 2017
Publication date	May 13, 2021
Grant date	—

Abstract

Disclosed herein are compounds of formula I: and salts thereof. Also disclosed are compositions comprising compounds of formula I and methods using compounds of formula I.

First claim

1 . A compound of formula I:

wherein:
A is —C(═O)N(R a1 )—R 1 , —(C 1 -C 3 )alkyl-C(═O)N(R a1 )R 1 , —(C 1 -C 3 )alkyl-O —R 1 , —O—R 1 , —(C 1 -C 3 )alkyl-N(R a1 )—R 1 , or —N(R a1 )—R 1 ;
each R 1 is independently a (C 3 -C 7 )carbocyclyl, (C 3 -C 7 )carbocyclyl-(C 1 -C 4 )alkyl-, 4-7 membered monocyclic heterocyclyl, or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl-, wherein each (C 3 -C 7 )carbocyclyl or (C 3 -C 7 )carbocyclyl-(C 1 -C 4 )alkyl- is independently substituted with one or more groups selected from the group consisting of Z and —(C 1 -C 6 )alkyl substituted with one or more Z, and wherein each 4-7 membered monocyclic heterocyclyl or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl- is independently optionally substituted with one or more groups selected from the group consisting of Z and —(C 1 -C 6 )alkyl substituted with one or more Z, wherein each Z is independently selected from the group consisting of NR b2 R c2 , —NHNH 2 , —C(═NR a2 )(NR b2 R c2 ), —NR a2 C(═NR a2 )(R d2 ), and —NR a2 C(═NR a2 )(NR b2 R c2 ) and wherein each (C 3 -C 7 )carbocyclyl, (C 3 -C 7 )carbocyclyl-(C 1 -C 4 )alkyl-, 4-7 membered monocyclic heterocyclyl, or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl-, is independently optionally substituted independently with one or more (C 1 -C 4 )alkyl;
R 2 is hydrogen, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 3 is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 4 is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 5 is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 6 is hydrogen, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and C 1 -C 4 )haloalkoxy;
each R a1 is independently hydrogen, (C 1 -C 6 )alkyl or (C 3 -C 7 )carbocyclyl;
each R a2 is independently hydrogen, (C 1 -C 6 )alkyl or (C 3 -C 7 )carbocyclyl;
each R b2 and R c2 is independently hydrogen, (C 1 -C 6 )alkyl or (C 3 -C 7 )carbocyclyl; and
R d2 is (C 1 -C 6 )alkyl or (C 3 -C 7 )carbocyclyl;
or a salt thereof.

2 . The compound or salt of claim 1 , wherein A is —C(═O)N(R a1 )—R 1 , —(C 1 -C 3 )alkyl-C(═O)N(R a1 )R 1 , —(C 1 -C 3 )alkyl-O —R 1 , or —O—R 1 .

3 . The compound or salt of claim 1 , wherein A is —C(═O)N(R a1 )—R 1 .

4 . The compound or salt of claim 1 , wherein A is —(C 1 -C 3 )alkyl-C(═O)N(R a1 )R 1 .

5 . The compound or salt of any one of claims 1 - 4 , wherein R a1 is hydrogen.

6 . The compound or salt of claim 1 , wherein A is —O—R 1 .

7 . The compound or salt of any one of claims 1 - 6 , wherein R 2 is hydrogen, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, or (C 1 -C 4 )haloalkoxy.

8 . The compound or salt of any one of claims 1 - 6 , wherein R 2 is hydrogen.

9 . The compound or salt of any one of claims 1 - 8 , wherein R 3 is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy.

10 . The compound or salt of any one of claims 1 - 8 , wherein R 3 is phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy.

11 . The compound or salt of any one of claims 1 - 8 , wherein R 3 is 4-fluorophenyl or 4-trifluoromethyphenyl.

12 . The compound or salt of any one of claims 1 - 6 , wherein R 4 is hydrogen, halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy.

13 . The compound or salt of any one of claims 1 - 6 , wherein R 4 is hydrogen.

14 . The compound or salt of any one of claims 1 - 13 , wherein R 5 is aryl or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy.

15 . The compound or salt of any one of claims 1 - 13 , wherein R 5 is phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 4 )haloalkoxy.

16 . The compound or salt of any one of claims 1 - 13 , wherein R 5 is 4-fluorophenyl or 4-trifluoromethyphenyl.

17 . The compound or salt of any one of claims 1 - 16 , wherein R 6 is hydrogen, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, or (C 1 -C 4 )haloalkoxy.

18 . The compound or salt of any one of claims 1 - 16 , wherein R 6 is hydrogen.

19 . The compound or salt of any one of claims 1 - 6 , wherein the moiety:

of the compound of formula I is:

20 . The compound or salt of any one of claims 1 - 17 , wherein R 1 is a 4-7 membered monocyclic heterocyclyl or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl- is optionally substituted independently with one or more groups selected from the group consisting of Z and —(C 1 -C 6 )alkyl substituted with one or more Z, wherein each Z is NR b2 R c2 nd wherein the 4-7 membered monocyclic heterocyclyl or 4-7 membered monocyclic heterocyclyl-(C 1 -C 4 )alkyl- is optionally substituted with one or more (C 1 -C 4 )alkyl.

21 . The compound or salt of any one of claims 1 - 17 , wherein R 1 is a 4-7 membered monocyclic N-heterocyclyl or 4-7 membered monocyclic N-heterocyclyl-(C 1 -C 4 )alkyl-, wherein the 4-7 membered monocyclic N-heterocyclyl or 4-7 membered monocyclic N-heterocyclyl-(C 1 -C 4 )alkyl- is optionally substituted independently with one or more groups selected from the group consisting of Z and —(C 1 -C

Assignees

• Univ Rutgers
• Rutgers The State Univeristy Of New Jersey

Inventors

• Lavoie Edmond J
• Parhi Ajit
• Zhang Yongzheng

Classifications

• A61K31/40 Primary

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• A61K45/06

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

• C07D207/12

  Oxygen or sulfur atoms · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title