Substituted urea depsipeptide analogs as activators of the clpp endopeptidase

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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising an effective amount of 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 and 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 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, and a pharmaceutically acceptable carrier. 
       
     
     
         2 . The composition of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The composition of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The composition of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are covalently bonded, together with the intermediate atoms, comprise a piperazinyl ring substituted with 1 methyl group;
 wherein each of R 60a , R 60b , R 60c , R 60d , and R 60e  is independently selected from hydrogen, —F, —Cl, and methyl, provided that no more than three of R 60a , R 60b , R 60c , R 60d , and R 60e  are not hydrogen; and 
 
         wherein R 70a  is methyl. 
       
     
     
         7 . The composition of  claim 6 , wherein R 60a  is —F. 
     
     
         8 . The composition of  claim 6 , wherein R 60c  is —Cl or methyl. 
     
     
         9 . The composition of  claim 6 , wherein each of R 60b , R 60d , and R 60e  is hydrogen. 
     
     
         10 . The composition of  claim 6 , wherein R 60a  is —F, R 60c  is —Cl or methyl, and each of R 60b , R 60d , and R 60e  is hydrogen. 
     
     
         11 . The composition of  claim 1 , wherein the effective amount is a therapeutically effective amount. 
     
     
         12 . The composition of  claim 1 , wherein the effective amount is a prophylactically effective amount. 
     
     
         13 . The composition of  claim 1 , wherein the compound exhibits an EC 50  for activation of Sa-ClpP in a casein-BODIPY digestion assay of less than or equal to about 10 μM. 
     
     
         14 . 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 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 and 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 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, thereby enhancing the activity of ClpP protease activity in the at least one cell. 
       
     
     
         15 . The method of  claim 14 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are covalently bonded, together with the intermediate atoms, comprise a piperazinyl ring substituted with 1 methyl group;
 wherein each of R 60a , R 60b , R 60c , R 60d , and R 60e  is independently selected from hydrogen, —F, —Cl, and methyl, provided that no more than three of R 60a , R 60b , R 60c , R 60d , and R 60e  are not hydrogen; and 
 
         wherein R 70a  is methyl. 
       
     
     
         16 . The method of  claim 14 , 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 14 , wherein the cell is a fungus. 
     
     
         20 . The method of  claim 14 , wherein the contacting is via administration to a mammal.