Indole derivatives as efflux pump inhibitors

Patent metadata

Field	Value
Publication number	US-11993571-B2
Application number	US-201816492901-A
Country	US
Kind code	B2
Filing date	Mar 9, 2018
Priority date	Mar 10, 2017
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

Disclosed herein are compounds of formula (I): and salts thereof. Also disclosed are compositions comprising compounds of formula I and compounds of formula I for use in treating or preventing bacterial infections.

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 , or —O—R 1 , and B is hydrogen, halogen, or (C 1 -C 4 )alkyl;
each R 1 is independently:
(a) (C 2 -C 8 )alkyl substituted with two or more —NR b2 R c2 and wherein (C 2 -C 8 )alkyl is optionally substituted independently with one or more halo, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl; or
(b) pyrrolidinyl-(CH 2 ), (C 3 -C 7 )carbocyclyl-NR e —(C 1 -C 4 )alkyl- or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl- wherein each (C 3 -C 7 )carbocyclyl-NR e —(C 1 -C 4 )alkyl- is independently substituted with one or more Z 1 or Z 2 , and wherein each pyrrolidinyl-(CH 2 )— or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl- is independently substituted with one or more Z 1 or Z 2 , and wherein any pyrrolidinyl-(CH 2 ), (C 3 -C 7 )carbocyclyl NR e —(C 1 -C 4 )alkyl- or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl-of R 1 is independently optionally substituted with one or more halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 )alkyl, —C(═O)N((C 1 -C 4 )alkyl) 2 , —NHC(═O)(C 1 -C 4 )alkyl-NH 2 , or 3-7 membered monocyclic heterocyclyl wherein (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C 1 -C 4 )alkyl, —NH 2 , —NH(C 1 -C 4 )alkyl or —N((C 1 -C 4 )alkyl) 2 ;
R 2 is hydrogen or (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 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, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, methylenedioxy (—OCH 2 O—), and (C 3 -C 7 )carbocyclyl;
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, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, methylenedioxy (—OCH 2 O—), and (C 3 -C 7 )carbocyclyl;
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 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 Z 1 is independently selected from the group consisting

of —NR b3 R c3 , —NHNH 2 , —C(═NR a3 )(NR b3 R c3 ), —NR a3 C(═NR a3 )(R d3 ),
and —NR a3 C(═NR a3 )(NR b3 R c3 );
each Z 2 is independently —(C 1 -C 6 )alkyl substituted with one or more Z 1 and optionally substituted with one or more Z 3 ;
each Z 3 is independently halo or (C 3 -C 7 )carbocyclyl;
each R a1 is independently hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl or 3-7 membered monocyclic heterocyclyl optionally substituted with one or more halogen or (C 1 -C 4 )alkyl;
each R b2 and R c2 is independently hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl;
each R a3 is independently hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl;
each R b3 is hydrogen;
each R c3 is independently hydrogen, (C 1 -C 4 )alkyl, or (C 3 -C 7 )carbocyclyl;
R d3 is (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl; and
each R e is independently hydrogen, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl;
or a salt thereof; and
wherein any carbocyclyl is saturated or partially unsaturated.

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

3. A compound of formula Ia:

wherein:
R 1 is:
(a) (C 2 -C 8 )alkyl substituted with two or more —NR b2 R c2 and wherein (C 2 -C 8 )alkyl is optionally substituted independently with one or more halo, (C 1 -C 4 )alkyl or (C 3 -C 7 )carbocyclyl; or
(b) pyrrolidinyl-(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl-NR e —(C 1 -C 4 )alkyl- or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl- wherein each (C 3 -C 7 )carbocyclyl-NR e —(C 1 -C 4 )alkyl- is independently substituted with one or more Z 1 or Z 2 , and wherein each pyrrolidinyl-(C 1 -C 4 )alkyl- or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl- is independently substituted with one or more Z 1 or Z 2 , and wherein any pyrrolidinyl-(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl NR e —(C 1 -C 4 )alkyl- or 4-7 membered monocyclic heterocyclyl-NR e —(C 1 -C 4 )alkyl- of R 1 is independently optionally substituted with one or more halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 )alkyl, —C(═O)N((C 1 -C 4 )alkyl) 2 , —NHC(═O)(C 1 -C 4 )alkyl-NH 2 , or 3-7 membered monocyclic heterocyclyl wherein (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C 1 -C 4 )alkyl, —NH 2 , —NH(C 1 -C 4 )alkyl or —N((C 1 -C 4 )alkyl) 2 ;
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 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, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 1 -C 4 )alkyl-, (C 3 -C 7 )carbocyclyl(C 2 -C 4 )alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO 2 , —CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, methylenedioxy (—OCH 2 O—), and (C 3 -C 7 )carbocyclyl;
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, heteroaryl, aryl(C 1 -C 4 )alk

Assignees

• Univ Rutgers

Inventors

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

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07D401/04

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

• A61K45/06

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

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• C07D405/04

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