There are provided inter alia metalloenzyme inhibitors, such as inhibitors of influenza A RNA dependent RNA polymerase PA subunit endonuclease, and methods of synthesis and use of the same.

The present invention includes novel polycationic amphiphilic compounds useful as antimicrobial agents. The present invention further includes methods useful for removing microorganisms and/or biofilm-embedded microorganisms from a surface. The present invention further includes compositions and methods useful for preventing or reducing the growth or proliferation of microorganisms and/or biofilm-embedded microorganisms on a surface.

The present invention includes novel polycationic amphiphilic compounds useful as antimicrobial agents. The present invention further includes methods useful for removing microorganisms and/or biofilm-embedded microorganisms from a surface. The present invention further includes compositions and methods useful for preventing or reducing the growth or proliferation of microorganisms and/or biofilm-embedded microorganisms on a surface.

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalkyl and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This includes synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalkyl and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This includes synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalkyl and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This includes synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

Improved methods of synthesizing 6-aryl-4-aminopicolinates, such as arylalkyl and alkyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates and arylalkyl and alkyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylates, are described herein. The improved methods include a direct Suzuki coupling step, which eliminates the protection/de-protection steps in the current chemical process, and therefore eliminates or reduces various raw materials, equipment and cycle time as well as modification of other process conditions including use of crude AP, use of ABA-diMe, and varying pH, catalyst concentration, solvent composition, and/or workup procedures. This includes synthesis of 2-aryl-6-aminopyrimidine-4-carboxylates.

A compound, or a protonate or salt thereof, of formula I:

##STR00001## wherein Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; n is 1 or 2; each R.sup.10 is independently alkyl, substituted alkyl, a polyether moiety, carboxyl, substituted carboxyl, alkoxy, substituted alkoxy, haloalkyl, halogen, nitro, amino, aryloxy, aryl, substituted aryl, cyano, hydroxyl, carbonylamino, aminocarbonyl, acyl, sulfonyl, or substituted sulfonyl; a is 0 to 4;

##STR00002## is an aryl or heteroaryl ring; and each R is independently halogen, carbonylamino, sulfonamide, carboxylic acid or hydrogen, provided at least one R is a halogen; and provided that if Y is

##STR00003## are not

##STR00004## respectively.

A compound, or a protonate or salt thereof, of formula I:

##STR00001## wherein Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; n is 1 or 2; each R.sup.10 is independently alkyl, substituted alkyl, a polyether moiety, carboxyl, substituted carboxyl, alkoxy, substituted alkoxy, haloalkyl, halogen, nitro, amino, aryloxy, aryl, substituted aryl, cyano, hydroxyl, carbonylamino, aminocarbonyl, acyl, sulfonyl, or substituted sulfonyl; a is 0 to 4;

##STR00002## is an aryl or heteroaryl ring; and each R is independently halogen, carbonylamino, sulfonamide, carboxylic acid or hydrogen, provided at least one R is a halogen; and provided that if Y is

##STR00003## are not

##STR00004## respectively.

Disclosed are compounds of formula (I) below and pharmaceutically acceptable salts thereof, in which each of variables R.sub.1, R.sub.2, L, and Z is defined herein. Also disclosed are methods for reducing the glycemic level and treating glucagon-associated disorders with a compound of formula (I) or a salt thereof and a pharmaceutical composition containing same.