Bacterial efflux pump inhibitors

Patent metadata

Field	Value
Publication number	US-11180459-B2
Application number	US-201816492907-A
Country	US
Kind code	B2
Filing date	Mar 9, 2018
Priority date	Mar 10, 2017
Publication date	Nov 23, 2021
Grant date	Nov 23, 2021

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

The invention claimed is:

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 , —N(R a1 )—R 1 , or R 1 ;
R 2 is hydrogen, (C 1 -C 6 )alkyl or phenyl(C 1 -C 6 )alkyl-, wherein the phenyl is optionally substituted with one or more (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, halo or —NO 2 ;
R 1 is:

R 3 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 the group consisting of NR a3 R b3 , halo, —OH, —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 4 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 the group consisting of NR a3 R b3 , halo, —OH, —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 5 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 the group consisting of NR a3 R b3 , halo, —OH, —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 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 the group consisting of NR a3 R b3 , halo, —OH, —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 4 )alkyl or (C 3 -C 7 )carbocyclyl;
and
each R a3 and R b3 is independently hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl;
or a salt thereof.

2. The compound 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 , or R 1 .

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

4. The compound of claim 1 , wherein R 2 is hydrogen, (C 1 -C 6 )alkyl, or phenyl(C 1 -C 6 )alkyl-, wherein the phenyl is optionally substituted with one or more (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, halogen or —NO 2 .

5. The compound of claim 1 , wherein R 3 is hydrogen, (C 1 -C 4 )haloalkyl, or aryl wherein the aryl is optionally substituted with one or more groups independently selected from the group consisting of NR a3 R b3 , halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkoxy.

6. The compound of claim 1 , wherein R 3 is hydrogen, trifluoromethyl or 4-fluorophenyl.

7. The compound of claim 1 , wherein R 4 is hydrogen or phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of NR a3 R b3 , halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkoxy.

8. The compound of claim 1 , wherein R 4 is hydrogen, 4-fluorophenyl, 4-aminophenyl, 4-nitrophenyl, 3,4-difluorophenyl, or 4-methoxyphenyl.

9. The compound of claim 1 wherein R 5 is hydrogen or phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of NR a3 R b3 , halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )haloalkoxy.

10. The compound of claim 1 , wherein R 5 is hydrogen, 4-fluorophenyl, 4-trifluormethylphenyl, 4-methoxyphenyl, 3-cyanophenyl, bromo, 4-nitrophenyl, or 3,4-difluorophenyl.

11. The compound of claim 1 , wherein R 6 is hydrogen, halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )alkoxy.

12. The compound of claim 1 , wherein R 6 is hydrogen.

13. The compound of claim 1 , wherein A is:

14. The compound of claim 1 that is:

or a salt thereof.

15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in claim 1 , and a pharmaceutically acceptable vehicle.

16. A pharmaceutical composition comprising 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 , —N(R a1 )—R 1 , or R 1 ;
R 2 is hydrogen, (C 1 -C 6 )alkyl or phenyl(C 1 -C 6 )alkyl-, wherein the phenyl is optionally substituted with one or more (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, halo or —NO 2 ;
R 1 is:
(a) (C 1 -C 16 )alkyl substituted with one or more groups 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 ); or
(b) (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 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 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 3 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 the group consisting of NR a3 R b3 , halo, —OH, —NO 2 , —CN, (C 1 -C 4

Assignees

• Univ Rutgers

Inventors

• Lavoie Edmond J
• Parhi Ajit
• Zhang Yongzheng
• Yuan Yi
• Sun Yangsheng

Classifications

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K9/4866

  Organic macromolecular compounds · CPC title

• C07D235/24 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2 · CPC title

• A61K45/06

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

• A61K9/28

  Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)} · CPC title