Arylpropionyl-alpha-pyrone antibacterial agents

1. A compound of formula I:

wherein:

R 1 is one of aryl and heteroaryl, and optionally is substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR a R b ;

R 2 is one of H, halo, hydroxy, carboxy, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NR c R d , wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy or —NR c R d ;

R 3 is one of H, halo, hydroxy, carboxy, cyano, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, or —NR e R f , wherein any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, and heteroaryl, and is optionally substituted with one or more halo, hydroxy, carboxy, cyano, nitro, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy or —NR e R f ;

R 4 is (C 2 -C 6 )alkyl or (C 2 -C 6 )alkenyl, which (C 2 -C 6 )alkyl or (C 2 -C 6 )alkenyl is optionally substituted with one or more groups independently selected from oxo, halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR g R h ;

R a and R b are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 ) alkyl; or R a and R b together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino;

R c and R d are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 ) alkyl; or R c and R d together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino;

R e and R f are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 ) alkyl; or R e and R f together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino; and

R g and R h are each independently H, (C 1 -C 6 )alkyl, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, or heteroaryl(C 1 -C 6 ) alkyl; or R g and R h together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino;

or a salt thereof.

2. The compound of claim 1 wherein R 2 is H or methyl; and R 3 is H or methyl.

3. The compound of claim 1 wherein R 1 is phenyl which is optionally substituted with one or more groups independently selected from halo, hydroxy, carboxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR a R b .

4. The compound of claim 1 wherein R 1 is phenyl.

5. The compound of claim 1 wherein R 4 is n-butyl, or i-pentyl.

6. The compound of claim 1 which is:

or a salt thereof.

7. A composition comprising a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

8. A method for inhibiting a bacterial RNA polymerase comprising contacting the bacterial RNA polymerase with a compound of formula I as described in claim 1 , or a salt thereof.

9. A method for inhibiting the growth of a bacterium comprising contacting the bacterium with a compound of formula I as described in claim 1 , or a salt thereof.

10. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the bacteria is selected from Mycobacterium tuberculosis, Staphylococcus aureus MSSA and MRSA, Enterococcus faecalis, Enterococcus faecium , and Escherichia coli D21f21tolC.