Substituted urea depsipeptide analogs as activators of the ClpP endopeptidase

Patent metadata

Field	Value
Publication number	US-10822377-B2
Application number	US-201916588738-A
Country	US
Kind code	B2
Filing date	Sep 30, 2019
Priority date	Mar 4, 2015
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

In one aspect, the invention relates to substituted urea depsipeptide analogs, derivatives thereof, and related compounds, which are useful as activators the ClpP endopeptidease; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating infectious disease using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein q is an integer selected from 0 and 1;
wherein L is moiety selected from —CH 2 —, —(CH 2 ) 2 —, —CH═CH—, and -(cyclopropyl)-;
wherein each of R 1a and R 1b is independently selected from hydrogen, halogen, hydroxyl, cyano, and C1-C3 alkyl; or
wherein R 1a and R 1b are optionally covalently bonded, and together with the intermediate carbon comprise an optionally substituted 3- to 7-membered spirocycloalkyl;
wherein R 2 is selected from hydrogen, halogen, —NH 2 , —OH, —NO 2 , C1-C3 alkyl, —C1-C3 hydroxyalkyl, —C1-C3 alkylamino, C1-C3 dialkylamino, and C1-C3 aminoalkyl;
or wherein R 2 is —(C0-C6)-G;
wherein R 3 is selected from C1-C6 alkyl and C1-C6 hydroxyalkyl;
wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, and C1-C6 alkylamino;
or wherein R 4 is —(C0-C6)-G, provided at least one of R 2 and R 4 is —(C0-C6)-G;
or wherein R 3 and R 4 are covalently bonded and, together with the intermediate atoms, comprise a 3- to 10-membered heterocycle having 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein the heterocycle is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —NO 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 hydroxyalkyl, —(C═O)OR 30 , —(C═O)NR 32a R 32b , —(C1-C3 alkyl)-(C═O)OR 30 , —(C1-C3 alkyl)—(C═O)NR 32a R 32b ), and —(C0-C6)-G; provided that the heterocycle is substituted with at least one group that is —(C0-C6)-G when R 2 is not —(C0-C6)-G;
wherein R 30 , when present, is selected from hydrogen and C1-C3 alkyl;
wherein each of R 32a and R 32b , when present, is independently selected from hydrogen and C1-C3 alkyl;
wherein G has a structure represented by a formula selected from:

wherein each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, difluoromethoxy, and trifluoromethoxy;
wherein each of R 70a and R 70b is independently selected from hydrogen, methyl, and ethyl;
wherein Ar 1 is selected from aryl and heteroaryl; and wherein Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —NO 2 , difluoromethoxy, trifluoromethoxy, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, —S(O) n R 40 , —S(O) n NR 41a R 41b , —(C═O)NR 42a R 42b , —NR 43 (C═O)NR 44a R 44b , —NR 43 (C═O)R 45 , —(C═O)OR 46 , Ar 2 , —(C1-C3 alkyl)—S(O) n R 40 , —(C1-C3 alkyl)—S(O) n NR 41a R 41b , —(C1-C3 alkyl)—(C═O)NR 42a R 42b , —(C1-C3 alkyl)—NR 43 (C═O)NR 44a R 44b , —NR 43 (C═O)R 45 , —(C1-C3 alkyl)—(C═O)OR 46 , and —(C1-C3 alkyl)-Ar 2 ;
wherein each n is an integer independently selected from 0, 1, and 2;
wherein each occurrence of R 40 , when present, is independently selected from hydrogen, C1-C6 alkyl, phenyl, benzyl, naphthyl, and monocyclic heteroaryl;
wherein each occurrence of R 41a and R 41b when present, is independently selected from hydrogen, C1-C6 alkyl, phenyl, benzyl, naphthyl, and monocyclic heteroaryl;
wherein each occurrence of R 42 , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each occurrence of R 43 , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each occurrence of R 44a and R 44b , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each occurrence of R 45 , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each occurrence of R 46 , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each Ar 2 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar 2 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1a is hydrogen or methyl; and wherein R 1b is hydrogen.

3. The compound of claim 1 , wherein R 2 is hydrogen, hydroxyl, or methyl.

4. The compound of claim 1 , wherein each of R 5a and R 5c is fluoro; and wherein R 5b is hydrogen.

5. The compound of claim 1 , wherein R 70a is hydrogen or methyl; and wherein R 70b is hydrogen.

6. The compound of claim 1 , wherein R 80 has a structure represented by a formula:

7. The compound of claim 1 , wherein Ar 1 has a structure represented by a formula:

wherein each of R 60a , R 60b , R 60c , R 60d , and R 60e is independently selected from hydrogen, —F, —Cl, —Br, —NH 2 , —OH, —NO 2 , difluoromethoxy, trifluoromethoxy, methyl, ethyl, —CH 2 F, —CH 2 Cl, —OCH 2 CH 3 , —OCH 3 , N(CH 3 ) 2 , NHCH 3 , NHCH 2 CH 3 , and —N(CH 3 )CH 2 CH 3 , provided that no more than three of R 60a , R 60b , R 60c , R 60d , and R 60e are not hydrogen.

8. The compound of claim 1 , having a structure represented by a formula:

9. The compound of any one of claim 1 , having a structure represented by a formula:

wherein Z is O, NH, NCH 3 , or CH 2 .

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 , further comprising an antibacterial agent.

12. A method for the treatment of a bacterial infection in a mammal or bird, the method comprising the step of administering to the mammal or bird a therapeutically effective amount of at least one compound of claim 1 , thereby treating the bacterial infection in the mammal or bird.

13. The method of claim 12 , wherein the bacterial infection is associated with a gram positive bacterial infection.

14. The method of claim 12 , wherein the bacterial infection is associated with a gram negative bacterial infection.

15. The method of claim 12 , wherein the bacterial infection is selected from urinary tract infection, skin infection, intestinal infection, lung infection, ocular infection, otitis, sinusitis, pharyngitis, osteo-articular infection, genital infection, dental infection, oral infection, septicemia, nocosomial infection, bacterial meningitis, gastroenteritis, gastritis, diarrhea, ulcer, endocarditis, sexually transmitted disease, tetanus, diphtheria, leprosy, cholera, listeriosis, tuberculosis, salmonellosis , dysentery, and soft tissue.

16. The method of claim 12 , further comprising administering to the mammal or bird a therapeutically effective amount of at least one antibacterial agent.

17. The compound of claim 1 , wherein the compound has a structure represented by a formula:

Assignees

• St Jude Childrens Res Hospital

Inventors

• Lee Richard E
• Zhao Ying
• Jiuyu Liu

Classifications

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C07K11/02 Primary

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

• C07D498/14

  Ortho-condensed systems · CPC title