# US 12,180,198 B2 · Ribocil C antibiotics effective for Gram-negative pathogens

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- Number: US 12,180,198 B2
- Document ID: US12180198B2
- Status: Granted
- Kind: B2
- Application number: 18/344,336
- Filed: 2023-06-29
- Published: 2024-04-11
- Granted: 2024-12-31
- Earliest claimed: 2018-03-12
- Assignees: The Board of Trustees of the University of Illinois
- Applicants: The Board of Trustees of the University of Illinois
- Inventors: Paul J. Hergenrother; Emily Jane Geddes; Bryon Shane Drown; Stephen E. Motika; Erica Nicole Parker
- Web page: https://patentgrep.com/patent/US12180198B2

## CPC

- C07D 409/14: containing three or more hetero rings
- A61P 31/04: Antibacterial agents
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are antibacterial compounds that accumulate in Gram-negative bacteria, methods of preparing the compounds, and methods of using the compounds to inhibit or kill microbes, and methods of treating microbial infections, such as Gram-negative bacterial infections. Compounds selected for conversion to potential Gram-negative antibacterial compounds were identified based on compounds having low globularity and low flexibility. Amine substituents were then strategically added to the selected compounds to provide compounds having antibacterial activity against Gram-negative bacteria.

## Claims

### Claim 1

A compound of Formula III:
or a pharmaceutically acceptable salt thereof;
wherein
X1 is selected from the group consisting of NR6 and C(R7a)(R7b);
X2 is selected from the group consisting of N and CR8;
X3 is selected from the group consisting of OR9, SR9 and N(R10a)(R10b);
each R1, R2, R4, and R5 is independently selected from the group consisting of halogen, hydroxyl, —O(C1-C6)alkyl, nitro, cyano, —(C1-C6)alkyl, N(R11a)(R11b), —((C1-C6)alkylene)N(R11a)(R11b), cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R3a and R3b are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, N(R11a)(R11b), and ((C1-C6)alkylene)N(R11a)(R11b); or R3a and R3b together form an oxo;
R6 is selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, —(C1-C6)alkyl, and ((C1-C6)alkylene)N(R11a)(R11b);
R7a and R7b are each independently selected from the group consisting of hydrogen, —(C1-C6)alkyl, N(R11a)(R11b), and ((C1-C6)alkylene)N(R11a)(R11b); or together R7a and R7b form an oxo;
R8 is selected from the group consisting of hydrogen, N(R11a)(R11b), —((C1-C6)alkylene)N(R11a)(R11b), and —(C1-C6)alkyl;
R9 is selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, and —(C1-C6)alkyl;
R10a and R10b are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, —(C1-C6)alkyl, C(O)(C1-C6)alkyl, and C(O)O(C1-C6)alkyl;
R11a and R11b are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, aralkyl, —(C1-C6)alkyl, C(O)(C1-C6)alkyl, and C(O)O(C1-C6)alkyl;
n and q are each independently an integer from 0-3;
m is an integer from 0-7; and
p is an integer from 0-2;
provided that:
a) at least one of R1, R2, R3a, R3b, R4, and R5 is N(R11a)(R11b) or ((C1-C6)alkylene)N(R11a)(R11b), and at least one of n, q, m and p is 1;
b) X1 is NR6 or C(R7a)(R7b), and at least one of R7a and R7b is N(R11a)(R11b); or
c) X2 is CR8 and R8 is N(R11a)(R11b) or ((C1-C6)alkylene)N(R11a)(R11b).

### Claim 2 (depends on 1)

The compound of claim 1 represented by formula IIIa
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R1 is ((C1-C6)alkylene)N(R11a)(R11b).

### Claim 4 (depends on 1)

The compound of claim 1 wherein X1 is NR6.

### Claim 5 (depends on 4)

The compound of claim 4 wherein R6 is hydrogen, —(C1-C6)alkyl, or —((C1-C6)alkylene)N(R11a)(R11b).

### Claim 6 (depends on 1)

The compound of claim 1 wherein X1 is C(R7a)(R7b).

### Claim 7 (depends on 6)

The compound of claim 6 wherein at least one of R7a and R7b is —N(R11a)(R11b).

### Claim 8 (depends on 6)

The compound of claim 6 wherein at least one of R7a and R7b is hydrogen.

### Claim 9 (depends on 1)

The compound of claim 1 wherein X2 is CR8.

### Claim 10 (depends on 9)

The compound of claim 9 wherein R8 is —N(R11a)(R11b) or —((C1-C6)alkylene)N(R11a)(R11b).

### Claim 11 (depends on 1)

The compound of claim 1 wherein R2 is N(R11a)(R11b) or ((C1-C6)alkylene)N(R11a)(R11b).

### Claim 12 (depends on 1)

The compound of claim 1 wherein at least one of R3a and R3b is ((C1-C6)alkylene)N(R11a)(R11b).

### Claim 13 (depends on 1)

The compound of claim 1 wherein at least one of R3a and R3b is hydrogen, or wherein at least one of R11a and R11b is hydrogen.

### Claim 14 (depends on 1)

The compound of claim 1 wherein R4 is ((C1-C6)alkylene)N(R11a)(R11b), or wherein R5 is ((C1-C6)alkylene)N(R11a)(R11b).

### Claim 15 (depends on 1)

The compound of claim 1 wherein at least one of R11a and R11b is —(C1-C6)alkyl, C(O)(C1-C6)alkyl, or C(O)O(C1-C6)alkyl.

### Claim 16 (depends on 1)

The compound of claim 1 wherein at least one of n, q, m, and p is 1.

### Claim 17 (depends on 1)

The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

A method of treating S. aureus or E. coli microorganisms comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of the microorganisms in the subject.

### Claim 20 (depends on 19)

The method of claim 19 wherein the microorganism is a Gram-negative bacterium.