Substituted urea depsipeptide analogs as activators of the CLPP endopeptidase
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.
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 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 , 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. The compound of claim 1 , wherein each q is an integer with a value of 0.
7. The compound of claim 1 , wherein R 1a is hydrogen and R 1b is C1-C3 alkyl.
8. The compound of claim 1 , wherein R 1a is hydrogen and R 1b is methyl.
9. The compound of claim 1 , wherein R 3 is methyl.
10. The compound of claim 1 , wherein R 4 is methyl.
11. The compound of claim 1 , wherein R 3 is C1-C6 alkyl and R 4 is C1-C6 alkyl.
12. The compound of claim 1 , wherein R 3 is methyl and R 4 is methyl.
13. The compound of claim 1 , wherein R 70b is hydrogen and R 70a is methyl.
14. The compound of claim 1 , wherein Ar 1 is substituted with 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 , and Ar 2 .
15. The compound of claim 1 , wherein Ar 1 is substituted with 1 or 2 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 , and Ar 2 .
16. The compound of claim 1 , having a structure represented by a formula:
17. The compound of claim 1 , having a structure represented by a formula:
18. The compound of claim 1 , having a structure represented by a formula:
19. The compound of claim 1 , having a structure selected from:
20. The compound of claim 1 , having a structure selected from: