# US 12,215,104 B2 · Anti-biofilm compounds

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- Number: US 12,215,104 B2
- Document ID: US12215104B2
- Status: Granted
- Kind: B2
- Application number: 17/263,126
- Filed: 2019-07-19
- Published: 2021-06-24
- Granted: 2025-02-04
- Earliest claimed: 2018-07-27
- Assignees: University of Louisville Research Foundation, Inc.
- Applicants: University of Louisville Research Foundation, Inc.
- Inventors: Donald R. Demuth; Frederick A. Luzzio
- Web page: https://patentgrep.com/patent/US12215104B2

## CPC

- C07D 419/14: containing three or more hetero rings
- A61K 9/0063: {Periodont}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- C07D 419/12: linked by a chain containing hetero atoms as chain links
- 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

The present invention provides non-peptide compounds that mimic the streptococcal SspB Adherence Region (BAR) and function as inhibitors of P. gingivalis adherence to streptococci. The invention also provides methods of making and using the inhibitors.

## Claims

### Claim 1

A compound of formula I:
wherein:
X is —(CH2)S(═O)nphenyl-; or
X is phenyl and (a) at least one of R1 or R2 is an optionally substituted 5-6 membered heteroaryl; or (b) Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein the heteroaryl, (C3-C7)carbocycle, or aryl is substituted with at least one —NRjRk wherein at least one of Rj or Rk is optionally substituted phenyl and wherein the heteroaryl, (C3-C7)carbocycle, or aryl is further optionally substituted with one or more Z1 groups;
n is 1 or 2;
Y is heteroaryl, (C3-C7)carbocycle, or aryl wherein any heteroaryl, (C3-C7)carbocycle, or aryl of Y is optionally substituted with one or more Z1 groups;
R1 is (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORa, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc;
R2 is (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2, halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg;
each Ra is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, and aryl;
Rb and Rc are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle and aryl, or Rb and Rc together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
Rd is independently selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, and aryl;
each Re is independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, and aryl;
Rf and Rg are each independently selected from the group consisting of H, (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle and aryl, or Rf and Rg together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle;
Rh is selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle and aryl;
each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C1-C6)haloalkyl, —ORi, —NRjRk and —NRiORm;
Ri is H, (C1-C6)alkyl, (C1-C6)haloalkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
Rj and Rk are each independently selected from H, (C1-C8)alkyl or phenyl wherein phenyl is optionally substituted with one or more halogen or (C1-C6)alkyl;
Rm is (C1-C6)alkyl
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, halo (C1-C3)alkyl, —CN, NO2, halogen, —ORa, —SRa, —S(O)2NRbRc, —NRbRc, —NRaCORd, —C(O)Ra, —C(O)ORa, and —C(O)NRbRc.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is phenyl or 5-6 membered heteroaryl wherein the phenyl or 5-6 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of (C1-C8)alkyl, halo(C1-C3)alkyl, and halogen.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is phenyl wherein the phenyl is optionally substituted with one or more groups independently selected from the group consisting of halogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is aryl, or 5-6 membered heteroaryl wherein the aryl or 5-6 membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of (C1-C8)alkyl, (C2- C8)alkenyl, (C2- C8)alkynyl, (C3-C7)carbocycle, halo(C1-C3)alkyl, —CN, NO2,
halogen, —ORe, —SRe, —S(O)2NRfRg, —NRfRg, —NReCORh, —C(O)Re, —C(O)ORe, and —C(O)NRfRg.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Y is heteroaryl or aryl wherein any heteroaryl, or aryl of Y is optionally substituted with one or more Z1 groups.

### Claim 7 (depends on 1)

The compound of claim 1, wherein each Z1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C1-C6)haloalkyl, and —ORi.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Y is pyridinyl, fluorophenyl, methoxyphenyl, trifluoromethylphenyl, methoxynaphthyl, pentylphenyl, phenoxyphenyl, or di-(trifluoromethy)phenyl.

### Claim 9 (depends on 1)

The compound of claim 1 that is selected from the group consisting of
or a salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein each Z1 is independently selected from —NRjRk.

### Claim 11 (depends on 1)

The compound of claim 1 that is selected from the group consisting of
or a salt thereof.

### Claim 12 (depends on 1)

A composition comprising a compound of formula I as described in claim 1 or a salt thereof and a physiologically acceptable carrier.