Boron-containing small molecules as antiprotozoal agents

Abstract

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.

What is claimed is: 
     
         1 . A compound having a structure according to formula (I) and/or (II): 
       
         
           
           
               
               
           
         
         wherein Y substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 3 -C 5  cycloalkyl or substituted or unsubstituted C 1 -C 3  alkyloxy, and R 1  and R 2  are each independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and wherein R 1  and R 2 , along with the nitrogen to which they are attached, can be optionally joined to form a substituted or unsubstituted 3 to 8 membered ring, or a salt, prodrug, or a hydrate, or a solvate thereof. 
       
     
     
         2 . The compound of  claim 1  having a structure according to formula (Ia) and/or (IIa): 
       
         
           
           
               
               
           
         
         wherein Y is substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 3 -C 5  cycloalkyl or substituted or unsubstituted C 1 -C 3  alkyloxy, A is a substituted or unsubstituted 3 to 8 membered ring, or a salt, prodrug, or a hydrate, or a solvate thereof. 
       
     
     
         3 . The compound of  claim 2 , wherein the compound is according to formula (Ia). 
     
     
         4 . The compound of  claim 2 , wherein the compound is according to formula (IIa). 
     
     
         5 . The compound of  claim 1 , wherein Y is substituted or unsubstituted C 1 -C 3  alkyl. 
     
     
         6 . The compound of  claim 1 , wherein Y is substituted or unsubstituted methyl. 
     
     
         7 . The compound of  claim 2 , wherein the group and 
       
         
           
           
               
               
           
         
       
       wherein R 8  is H or substituted or unsubstituted alkyl and R 4  or R 5  or R 6  are each independently selected from H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and wherein R 4  and R 5 , along with the atoms to which they are attached, can be optionally joined to form a substituted or unsubstituted 3 to 8 membered ring, and wherein R 5  and R 6 , along with the atoms to which they are attached, can be optionally joined to form a substituted or unsubstituted 3 to 8 membered ring, wherein R 6  and R 8 , along with the atoms to which they are attached, can be optionally joined to form a substituted or unsubstituted 3 to 8 membered ring. 
     
     
         8 . The compound of  claim 7 , wherein R 8  is H. 
     
     
         9 . The compound of  claim 7 , wherein R 6  is unsubstituted C 1 -C 4  alkyl or halosubstituted C 1 -C 4  alkyl or unsubstituted C 3 -C 5  cycloalkyl. 
     
     
         10 . The compound of  claim 7 , wherein R 6  is methyl or ethyl or propyl or isopropyl or trifluoromethyl or difluoromethyl or trifluoroethyl or cyclopropyl. 
     
     
         11 . The compound of  claim 7 , wherein R 5  is H. 
     
     
         12 . The compound of  claim 7 , wherein R 4  is H. 
     
     
         13 . The compound of  claim 1 , selected from the following group:
 5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(2-hydroxyethyl) pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-methoxyethyl)pyrazine-2-carboxamide;   N-(1-hydroxy-2-methylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   N-(2-hydroxy-2-methylpropyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N,N-bis(2-hydroxyethyl)pyrazine-2-carboxamide;   N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   N-(1-hydroxy-4-methylpentan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydroxypropyl) pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(2-hydroxyethyl)-N-methylpyrazine-2-carboxamide;   ((R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypropan-2-yl)pyrazine-2-carb oxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypropan-2-yl)pyrazine-2-carboxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypentan-2-yl)pyrazine-2-carboxamide;   N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(1-(hydroxymethyl)cyclopropyl)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybutan-2-yl)pyrazine-2-carboxamide;   N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (S)—N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(1-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(2-hydroxy-1-phenylethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(1-hydroxy-3-phenylpropan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy) pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxyhexan-2-yl) pyrazine-2-carboxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxybut-3-en-2-yl)pyrazine-2-carboxamide;   (S)—N-(1-cyclopropyl-2-hydroxyethyl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (S)—N-(1-hydroxy-3-methoxypropan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)pyrazine-2-carboxamide;   (S)—N-(1-hydroxy-3-(methylthio)propan-2-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;   (S)—N-(1-hydroxy-3-(methylsulfonyl)propan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide;   (S)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(5,5,5-trifluoro-1-hydroxypentan-2-yl)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(3-hydroxybutan-2-yl)pyrazine-2-carboxamide;   (3-hydroxy-3-methylpyrrolidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-methylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-((1R,2R)-2-hydroxycyclopentyl)pyrazine-2-carboxamide;   (R)—N-(2-hydroxy-2-methylhexan-3-yl)-5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazine-2-carboxamide;   (S)—N-(2-hydroxy-2-methylhexan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-((1S,2S)-2-hydroxycyclopentyl)pyrazine-2-carboxamide;   (S)—N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (R)—N-(3-hydroxy-3-methylbutan-2-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-N-(cis-2-hydroxycyclopentyl)pyrazine-2-carboxamide;   (S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;   (R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;   (R)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-N-(1-hydroxypentan-2-yl)-N-methylpyrazine-2-carboxamide;   (S)—N-(2-hydroxy-2-methylpentan-3-yl)-5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxamide;   (3-ethyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-cyclopropyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-propylazetidine-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-isopropylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; and   (3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone, or a salt, prodrug, or a hydrate, or a solvate thereof.   
     
     
         14 . The compound of  claim 2 , selected from the following group:
 (3-hydroxy-3-methylpyrrolidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-methylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (S)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;   (R)-(5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazin-2-yl)(2-(hydroxymethyl)piperazin-1-yl)methanone;   (3-ethyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-cyclopropyl-3-hydroxyazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-propylazetidine-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone;   (3-hydroxy-3-isopropylazetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; and   (3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)(5-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)pyrazin-2-yl)methanone; or a salt, prodrug, or a hydrate, or a solvate thereof.   
     
     
         15 . A pharmaceutical formulation comprising:
 a) the compound of  claim 1 ; and   b) a pharmaceutically acceptable excipient.   
     
     
         16 . A combination comprising the compound of  claim 1 , together with at least one additional therapeutic agent. 
     
     
         17 . The combination of  claim 16 , wherein said at least one additional therapeutic agent is an antimalarial. 
     
     
         18 . The combination of  claim 16 , wherein said antimalarial is artemisinin or an artemisinin derivative selected from artesunate or artemether or artemotil or dihydroartemisinin or lumefantrine, artemether-lumefantrine, amodiaquine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine/pyrimethamine, atovaquone-proguanil, quinine, chloroquine, cotrifazid, doxycycline, mefloquine, primaquine, proguanil, sulfadoxine-pyrimethamine, hydroxychloroquine, sulfalene-pyrimethamine, dapsone, proguanil-dapsone, chloroproguanil-dapsone, halofantrine, dihydroartemisinin-piperaquine, piperaquine, pyronaridine and tetracycline. 
     
     
         19 . A method of killing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of  claim 1 , thereby killing the growth of the protozoa. 
     
     
         20 . The method of  claim 19 , wherein the protozoa is a member of the  Plasmodium  genus, in particular  Plasmodium falciparum.    
     
     
         21 . The method of  claim 19 , wherein the disease is malaria. 
     
     
         22 . A method for preparing a compound according to  claim 1 , wherein said method comprises reacting an intermediate of formula: 
       
         
           
           
               
               
           
         
       
       under amide formation conditions with an intermediate of formula 
       
         
           
           
               
               
           
         
       
       to lead to a compound of Formula (I) or (II): 
       
         
           
           
               
               
           
         
       
     
     
         23 . An intermediate for the preparation of a compound of  claim 1 , said intermediate having the following formula: 
       
         
           
           
               
               
           
         
       
       in particular 5-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)pyrazine-2-carboxylic acid.