7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors

1. A compound of formula (I):

wherein:

R 1 and R 2 are each independently hydrogen, (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkanoyl, (C 1 -C 10 )alkanoyloxy, (C 1 -C 10 )alkoxycarbonyl, aryl, heterocycle, halo, cyano, nitro, —COOR e , —C(═O)NR f R g ,—OC(═O)NR f R g , NR f R g , or —S(O) n R h ;

R 3 is —CH═CHC(═O)NR m R p ;

R 4 is hydrogen;

A is thio, sulfinyl, or sulfonyl;

each n is independently 0,1, or 2;

each R e is independently hydrogen, or (C 1 -C 10 )alkyl;

each R f and R g is independently hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, phenyl, benzyl, phenethyl, (C 1 -C 10 )alkanoyl, or —C(═O)NQ; wherein Q and the N atom to which it is attached forms a ring containing 2-20 carbon atoms, optionally containing a nitrogen atom in the ring —NR e —;

each R h is independently (C 1 -C 10 )alkyl, phenyl, aryl(C 1 -C 6 )alkyl, heteroaryl, heterocycle, or heterocycle(C 1 -C 6 )alkyl; and

R i is hydrogen or (C 1 -C 6 )alkyl; and

R m is hydrogen, and R p is NH 2 , OH, (C 3 -C 10 )cycloalkyl, or —(C 2 -C 10 )alkyl-NH 2 ; or R m and R p together with the nitrogen to which they are attached form a piperidine, morpholine, thiomorpholine, pyrrolidine, or a piperazine ring;

wherein any (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkanoyl, (C 1 -C 10 )alkanoyloxy, or (C 1 -C 10 )alkoxycarbonyl of R 1 or R 2 is optionally substituted with one or more, substituents independently selected from halo, hydroxy, cyano, cyanato, nitro, mercapto, oxo, aryl, heterocycle, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, aryl(C 1 -C 6 )alkanoyloxy, halo(C 1 -C 6 )alkanoyloxy, heterocycle(C 1 -C 6 )alkanoyloxy, aryloxy, (heterocycle)oxy, (C 3 -C 8 )cycloalkyl, —COOR e , —C(═O)NR f R g ,—OC(═O)NR f R g , —NR h R i , or —S(O) n R h ; and

wherein any aryl is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, trifluoromethyl, nitro, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl,—COOR e , —C(═O)NR f R g , —OC(═O)NR f R g , NR h R i , or —S(O) n R h ; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is aryl, heterocycle, or —COOR e .

3. The compound of claim 1 wherein R 1 is 2-pyridyl, or —COOR e .

4. The compound of claim 1 wherein R 2 is hydrogen.

5. The compound of claim 1 wherein R h is methyl or phenyl.

6. The compound of claim 1 wherein A is sulfonyl.

7. The compound of claim 1 wherein A is sulfonyl; R 1 is 2-pyridyl, carboxy or tert-butoxy carbonyl; and R 2 is hydrogen; or a pharmaceutically acceptable salt.

8. A pharmaceutical composition comprising a compound of claim 1 ; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

9. The composition of claim 8 further comprising a β-lactam antibiotic.

10. A method comprising inhibiting a β-lactamase by contacting said β-lactamase with an effective amount of a compound of claim 1 .

11. A therapeutic method comprising inhibiting a β-lactamase in a mammal in need of such therapy, by administering an effective inhibitory amount of a compound of claim 1 .

12. A therapeutic method comprising enhancing the activity of a β-lactam antibiotic, by administering the β-lactam antibiotic to a mammal in need thereof, in combination with an effective β-lactamase inhibiting amount of a compound of claim 1 .

13. A therapeutic method comprising treating a β-lactam resistant bacterial infection in a mammal, by administering to the mammal an effective amount of a β-lactam antibiotic, in combination with an effective β-lactamase inhibiting amount of a compound of claim 1 .