IP Library › Granted Patent US 12,358,951
Granted Patent B2
US 12,358,951 · App. 17/447,361 · Granted Jul 15, 2025

Cyclic peptide antibiotics

Inventors: Guosheng Wu (Beijing, CN); Emily J. Hanan (Redwood City, CA); Marie-Gabrielle Braun (San Francisco, CA); Sharada S. Labadie (Sunnyvale, CA); Keira Garland (San Francisco, CA); Richard M. Pastor (San Francisco, CA); Paul Anthony Gibbons (San Francisco, CA); Yuhong Fu (Beijing, CN); Yun-Xing Cheng (Beijing, CN)
Assignee: Genentech, Inc.
C07K7/56A61K38/00
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Quick Facts
Patent No.
US 12,358,951
App. No.
17/447,361
Granted
Jul 15, 2025
Kind
B2
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.

Claims (64)

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

R 1a , R 2a , R 4a , R 5a , and R 6a are each independently hydrogen or optionally substituted C 1 -C 6 alkyl;

R 3a is hydrogen, 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 20 is hydroxyl or —NR 1 R 2 ;

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;

or, R 3a and R 8 are taken together with the atoms to which they are attached to form an optionally substituted heterocycloalkyl;

R 10 and R 11 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 20 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 12 and R 13 are each independently hydrogen, halogen, optionally substituted C 1 -C 20 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 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;

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;

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.

2. The compound of claim 1 , wherein R 20 is hydroxyl.

3. The compound of claim 1 , wherein R 20 is —NR 1 R 2 .

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

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

6. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 1a , R 2a , R 4a , R 5a , R 6a , R 9 , R 10 and R 11 are hydrogen.

7. The compound of claim 1 , wherein R 8 is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three halogen.

8. The compound of claim 1 , wherein R 3a and R 8 are taken together with the atoms to which they are attached to form an azetidinyl, a pyrrolidinyl, or a piperidinyl.

9. The compound of claim 1 , wherein R 6 is:

10. The compound of claim 1 , wherein R 6 is:

11. The compound of any one of claim 1 , wherein R 12 is C 1 -C 6 alkyl optionally substituted with one, two, or three halogen or —OCH 3 .

12. The compound of claim 1 , wherein R 12 is

13. The compound of claim 1 , wherein R 14 is C 1 -C 6 alkyl.

14. The compound of any claim 1 , wherein R 16 is:

15. The compound of claim 1 , wherein R 3a is

16. The compound of claim 1 , wherein each R a is independently C 1 -C 6 alkyl.

17. The compound of claim 1 , wherein each R b and R c is hydrogen.

18. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

19. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

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;

wherein the compound is selected from the group consisting of:

20. A pharmaceutical composition comprising the compound claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

21. A method of treatment of a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to the mammal at a frequency and for a duration sufficient to provide a beneficial effect to the mammal.

22. The method of claim 21 , wherein the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis , Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii , or Bacteroides splanchnicus.

Priority Claims (1)
WO PCT/CN2019/078189 · Mar 14, 2019 · international
Continuity (2)
Continuation PCTUS2020022272 · Mar 12, 2020
Related Publication 20230025834A1 · Jan 26, 2023
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