# US 11,993,571 B2 · Indole derivatives as efflux pump inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,993,571 B2
- Document ID: US11993571B2
- Status: Granted
- Kind: B2
- Application number: 16/492,901
- Filed: 2018-03-09
- Published: 2021-04-01
- Granted: 2024-05-28
- Earliest claimed: 2017-03-10
- Assignees: Rutgers, The State University of New Jersey
- Applicants: Rutgers, the State University of New Jersey
- Inventors: Edmond J. LaVoie; Ajit Parhi; Yi Yuan; Yongzheng Zhang; Yangsheng Sun
- Web page: https://patentgrep.com/patent/US11993571B2

## CPC

- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of formula I:
wherein:
A is —C(═O)N(Ra1)—R1, —(C1-C3)alkyl-C(═O)N(Ra1)R1, —(C1-C3)alkyl-O—R1, or —O—R1, and B is hydrogen, halogen, or (C1-C4)alkyl;
each R1 is independently:
(a) (C2-C8)alkyl substituted with two or more —NRb2Rc2 and wherein (C2-C8)alkyl is optionally substituted independently with one or more halo, (C1-C4)alkyl or (C3-C7)carbocyclyl; or
(b) pyrrolidinyl-(CH2), (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- wherein each (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein each pyrrolidinyl-(CH2)— or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein any pyrrolidinyl-(CH2), (C3-C7)carbocyclyl NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl-of R1 is independently optionally substituted with one or more halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, —C(═O)NH2, —C(═O)NH(C1-C4)alkyl, —C(═O)N((C1-C4)alkyl)2, —NHC(═O)(C1-C4)alkyl-NH2, or 3-7 membered monocyclic heterocyclyl wherein (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C1-C4)alkyl, —NH2, —NH(C1-C4)alkyl or —N((C1-C4)alkyl)2;
R2 is hydrogen or (C1-C4)alkyl;
R3 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)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, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
R4 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
R5 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
R6 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)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, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
each Z1 is independently selected from the group consisting
of —NRb3Rc3, —NHNH2, —C(═NRa3)(NRb3Rc3), —NRa3C(═NRa3)(Rd3),
and —NRa3C(═NRa3)(NRb3Rc3);
each Z2 is independently —(C1-C6)alkyl substituted with one or more Z1 and optionally substituted with one or more Z3;
each Z3 is independently halo or (C3-C7)carbocyclyl;
each Ra1 is independently hydrogen, (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl optionally substituted with one or more halogen or (C1-C4)alkyl;
each Rb2 and Rc2 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
each Ra3 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
each Rb3 is hydrogen;
each Rc3 is independently hydrogen, (C1-C4)alkyl, or (C3-C7)carbocyclyl;
Rd3 is (C1-C4)alkyl or (C3-C7)carbocyclyl; and
each Re is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
or a salt thereof; and
wherein any carbocyclyl is saturated or partially unsaturated.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein A is —C(═O)N(Ra1)—R1 or —(C1-C3)alkyl-C(═O)N(Ra1)R1, and B is hydrogen, halogen, or (C1-C4)alkyl.

### Claim 3

A compound of formula Ia:
wherein:
R1 is:
(a) (C2-C8)alkyl substituted with two or more —NRb2Rc2 and wherein (C2-C8)alkyl is optionally substituted independently with one or more halo, (C1-C4)alkyl or (C3-C7)carbocyclyl; or
(b) pyrrolidinyl-(C1-C4)alkyl-, (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- wherein each (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein each pyrrolidinyl-(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein any pyrrolidinyl-(C1-C4)alkyl-, (C3-C7)carbocyclyl NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- of R1 is independently optionally substituted with one or more halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, —C(═O)NH2, —C(═O)NH(C1-C4)alkyl, —C(═O)N((C1-C4)alkyl)2, —NHC(═O)(C1-C4)alkyl-NH2, or 3-7 membered monocyclic heterocyclyl wherein (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C1-C4)alkyl, —NH2, —NH(C1-C4)alkyl or —N((C1-C4)alkyl)2;
R3 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)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, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
R4 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
R5 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
R6 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)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, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
each Z1 is independently selected from the group consisting
of —NRb3Rc3, —NHNH2, —C(═NRa3)(NRb3Rc3); —NRa3 (═NRa3)(Rd3);
and —NRa3C(═NRa3)(NRb3Rc3);
each Z2 is independently —(C1-C6)alkyl substituted with one or more Z1 and optionally substituted with one or more Z3;
each Z3 is independently halo or (C3-C7)carbocyclyl;
each Rb2 and Rc2 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
each Ra3 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
each Rb3 is hydrogen;
each Rc3 is independently hydrogen, (C1-C4)alkyl, or (C3-C7)carbocyclyl;
Rd3 is (C1-C4)alkyl or (C3-C7)carbocyclyl; and
each Re is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
or a salt thereof; and
wherein any carbocyclyl is saturated or partially unsaturated.

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein R3 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or (C1-C4)haloalkoxy.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein R3 is hydrogen or phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy and (C1-C4)haloalkoxy.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein R4 is hydrogen, 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, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, methylenedioxy (—OCH2O—), and (C1-C4)haloalkoxy.

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein R4 is hydrogen, phenyl, or pyridinyl wherein the phenyl or pyridinyl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, methylenedioxy (—OCH2O—), and (C1-C4)haloalkoxy.

### Claim 8 (depends on 1)

The compound or salt of claim 1, wherein R5 is hydrogen or aryl wherein the aryl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, methylenedioxy (—OCH2O—), and (C1-C4)haloalkoxy.

### Claim 9 (depends on 1)

The compound or salt of claim 1 wherein R5 is hydrogen or phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, methylenedioxy (—OCH2O—), and (C1-C4)haloalkoxy.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein R6 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or (C1-C4)haloalkoxy.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein R6 is hydrogen or phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy and (C1-C4)haloalkoxy.

### Claim 12 (depends on 1)

The compound or salt of claim 1, wherein R1 is (C4-C8)alkyl substituted with two or more groups independently selected from —NRb2Rc2.

### Claim 13 (depends on 1)

The compound or salt of claim 1, wherein R1 is pyrrolidinyl-(CH2), (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- wherein each (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein each pyrrolidinyl-(CH2) or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein any pyrrolidinyl-(CH2), (C3-C7)carbocyclyl NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- of R1 is independently optionally substituted independently with one or more halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, —C(═O)NH2, —C(═O)NH(C1-C4)alkyl, —C(═O)N((C1-C4)alkyl)2, —NHC(═O)(C1-C4)alkyl-NH2, or 3-7 membered monocyclic heterocyclyl wherein (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C1-C4)alkyl, —NH2, —NH(C1-C4)alkyl or —N((C1-C4)alkyl)2.

### Claim 14 (depends on 1)

The compound or salt of claim 1, wherein R1 is a pyrrolidinyl-(CH2)—, wherein the pyrrolidinyl-(CH2) is substituted with one or more groups independently selected from the group consisting of Z and (C1-C6)alkyl substituted with one or more Z, wherein each Z is independently —NRb3Rc3 and wherein the pyrrolidinyl-(CH2) is optionally substituted with one or more (C1-C4)alkyl.

### Claim 15 (depends on 1)

The compound or salt of claim 1, wherein R1 is:

### Claim 16 (depends on 1)

The compound or salt of claim 1, wherein A is:

### Claim 17

A compound or salt thereof that is:
or a salt thereof.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

A method of inhibiting a bacterial efflux pump in an animal comprising administering to the animal a compound as described in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

A method of treating or preventing a bacterial infection in an animal comprising co-administering to the animal a compound as described in claim 1 or a pharmaceutically acceptable salt thereof and one or more antibacterial agents.

### Claim 22 (depends on 17)

A pharmaceutical composition comprising a compound as described in claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle.

### Claim 23 (depends on 17)

A pharmaceutical composition comprising a compound as described in claim 17 or a pharmaceutically acceptable salt thereof, one or more antibacterial agents and a pharmaceutically acceptable vehicle.

### Claim 24 (depends on 17)

A method of inhibiting a bacterial efflux pump in an animal comprising administering to the animal a compound as described in claim 17 or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 17)

A method of treating or preventing a bacterial infection in an animal comprising co-administering to the animal a compound as described in claim 17 or a pharmaceutically acceptable salt thereof and one or more antibacterial agents.

### Claim 26 (depends on 1)

The compound or salt of claim 1, wherein R2 is hydrogen.