Cyclic peptide antibiotics

Patent metadata

Field	Value
Publication number	US-11279735-B2
Application number	US-202016816969-A
Country	US
Kind code	B2
Filing date	Mar 12, 2020
Priority date	Sep 15, 2017
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

Abstract

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

First claim

What is claimed is:

1. A compound of Formula (I):

wherein:
X 1 is —O— or —NR 1a —;
X 2 is —O— or —NR 2a —;
X 3 is —O— or —NR 3a —;
X 4 is —O— or —NR 4a —;
X 5 is —O— or —NR 5a —;
X 6 is —O— or —NR 6a —;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , or X 6 is —O—;
R 1a , R 2a , R 3a , R 4a , R 5a , and R 6a are each independently hydrogen or optionally substituted C 1 -C 6 alkyl;
R 1 and R 2 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, optionally substituted (C 1 -C 6 alkyl)heteroaryl, —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , or —(C═NR b )NR b R c ;
or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
R 3 and R 4 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R 3 and R 4 are taken together with the carbon atom to which they are attached to form an oxo;
R 5 is hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
R 6 and R 7 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
R 8 and R 9 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
R 10 and R 11 are each independently hydrogen, halogen, optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 2 -C 20 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
R 12 and R 13 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
or R 10 and R 12 are taken together to form an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl;
R 14 and R 15 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
or R 14 and R 4a are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl;
R 16 and R 17 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
R 18 and R 19 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted (C 1 -C 6 alkyl)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted (C 1 -C 6 alkyl)heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 alkyl)aryl, optionally substituted heteroaryl, or optionally substituted (C 1 -C 6 alkyl)heteroaryl;
or R 18 and R 19 are taken together with the carbon atom to which they are attached to form an oxo;
each R a is independently optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R b and R c is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R b and R c are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound of claim 1 , wherein R 18 and R 19 are taken together with the carbon atom to which they are attached to form an oxo.

3. The compound of claim 1 , wherein R 18 and R 19 are hydrogen.

4. The compound of claim 1 , having the structure of Formula (Ia):

5. The compound of claim 1 , wherein R 1 , R 2 , R 5 , R 7 , R 9 , R 11 , R 13 , R 15 and R 17 are hydrogen.

6. The compound of claim 1 , having the structure of Formula (Ib):

7. The compound of claim 1 , wherein R 1a , R 2a , R 5a and R 6a are hydrogen.

8. The compound of claim 1 , having the structure of Formula (Ic):

Assignees

• Genentech Inc

Inventors

• Hanan Emily J
• Castanedo Georgette
• Braun Marie Gabrielle
• Garland Keira
• Smith Peter Andrew
• Pastor Richard
• Gibbons Paul
• Cheng Yunxing
• Wu Guosheng
• Fu Yuhong
• Yuen Po-Wai

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title

• C07D273/00

  Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 · CPC title

• A61P31/00 Primary

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title