Substituted urea depsipeptide analogs as activators of the clpp endopeptidase

Patent metadata

Field	Value
Publication number	US-2016200770-A1
Application number	US-201414914449-A
Country	US
Kind code	A1
Filing date	Aug 30, 2014
Priority date	Aug 30, 2013
Publication date	Jul 14, 2016
Grant date	—

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

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 alkylamino, C1-C3 dialkylamino, and C1-C3 aminoalkyl;
wherein R 3 is C1-C6 alkyl;
wherein R 4 is C1-C6 alkyl;
or wherein R 3 and R 4 are covalently bonded, 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 , and —(C1-C3 alkyl)-(C═O)NR 32a R 32b ;
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 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 , having a structure represented by a formula:

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

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

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

6 . A method for the treatment of an infectious disease in a mammal, the method comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, thereby treating the infectious disease in the mammal.

7 . The method of claim 6 , wherein the mammal is a human.

8 . The method of claim 7 , wherein the human has been diagnosed with an infectious disease.

9 . The method of claim 6 , wherein the mammal has been diagnosed with a need for treatment of the infectious disease prior to the administering step.

10 . The method of claim 6 , further comprising the step of identifying a mammal in need of treatment of the infectious disease.

11 . The method of claim 7 , wherein the human has been diagnosed with a biofilm mediated disease.

12 . (canceled)

13 . The method of claim 11 , further comprising the step of identifying a mammal in need of treatment of the biofilm mediated disease.

14 . The method of claim 6 , further comprising administering to the mammal a therapeutically effective amount of at least one antibacterial agent.

15 . A method for enhancing the activity of ClpP protease activity in at least one cell, the method comprising the step of contacting the at least one cell with an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, thereby enhancing the activity of ClpP protease activity in the at least one cell.

16 . The method of claim 15 , wherein the cell is a bacterial cell.

17 . The method of claim 16 , wherein the bacterial cell is a gram positive bacterial cell.

18 . The method of claim 16 , wherein the bacterial cell is a gram negative bacterial cell.

19 . The method of claim 15 , wherein the cell is a fungus.

20 . The method of claim 15 , wherein the contacting is via administration to a mammal.

21 . The method of claim 20 , wherein the mammal has been diagnosed with a need for treatment of an infectious disease prior to the administering step.

22 . The method of claim 20 , wherein the mammal has been diagnosed with a need for enhancing the activity of ClpP protease activity prior to the administering step.

23 . (canceled)

24 . (canceled)

25 . (canceled)

Assignees

• St Jude Childrens Res Hospital

Inventors

• Lee Richard E
• Zhao Ying
• Griffith Elizabeth
• Zheng Zhong
• Singh Aman P

Classifications

• C12N9/52 Primary

  derived from bacteria {or Archaea} · CPC title

• A61P31/00

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

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K11/02 Primary

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

• C12Y304/21

  Serine endopeptidases (3.4.21) · CPC title