NZ500512A - Cephalosporin for treating beta-lactam antibiotic resistant bacteria (such as S. aureus, E. faecium or E. faecalis) or PBP2a-producing bacteria - Google Patents

Abstract

A compound of Formula (I) wherein the compound is useful in the treatment against methicillin-resistant, vancomycin-resistant or ampicillin-resistant bacteria bacterial infection. The compound of Formula (III) shows one of the preferred compounds. Wherein; R1 is selected from the group consisting of -NHC(O)ZR3, -NR4R5 and Formula (II); wherein Z is selected from the group consisting of -CH2(X)m-, -C(NOR6)-, -CH(OR7)-, -C(CHCO2R8)- and -CH(NR9R10)-; X is selected from oxygen and sulphur; m is 0 or 1; R3 is selected from the group consisting of cyano, C1-6alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, C1-6alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl and dibenzthienyl, C6-14aryl, heteroaryl, carboxyl, C1-6alkoxycarbonyl, C1-6alkyl, C1-6alkenyl, nitro, amino, C1-6alkoxyl and amido; C6-14aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, C1-6alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl and dibenzthienyl, C6-14aryl, heteroaryl, carboxyl, C1-6alkoxycarbonyl, C1-6alkyl, C1-6alkenyl, nitro, amino, C1-6alkoxyl and amido; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl and dibenzthienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, C1-6alkylthio, heterocycle, C6-14aryl, heteroaryl, carboxyl, oxo, C1-6alkoxycarbonyl, C1-6alkyl, C1-6alkenyl, nitro, amino, C1-6alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is C1-6alkyl, HetAr is an aromatic heterocycle), and (CH2)nT, n is 1 to 6, T is selected from the group consisting of amino (NRR' wherein R and R' may be C1-6alkyl, C6-14aryl or acyl C(O)R wherein R is C1-6alkyl), amidino (C- or N-linked), guanidino, and isothioureido, which may be substituted with C1-6alkyl, C6-14aryl, hydroxyl, or amino; R4-7 are independently selected from the group of hydrogen, C1-6alkyl, C6-14aryl and acyl; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen; R8 is selected from the group of hydrogen, C1-6alkyl and C6-14aryl; R9 and R10 are selected independently from the group consisting of hydrogen, C1-6alkyl, acyl and heterocyclecarbonyl (C(O)Het wherein Het is a heterocycle); R2 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, C1-6alkylthio, heterocycle, C6-14aryl, heteroaryl, carboxyl, C1-6alkoxycarbonyl, C1-6alkyl, C1-6alkenyl, nitro, amino, C1-6alkoxyl, and amido; C6-14aryl, a heterocycle, aralkyl (RAr wherein R is C1-6alkyl which may be substituted and Ar is C6-14aryl, heteroaralkyl and trialkylsilyl (RR'R" Si wherein R, R' and R" are C1-6alkyl groups); or R2 is not present and the CO2 group to which it would be attached bears a negative charge; The ring A, B, D, and E is a carbon, nitrogen and sulphur containing heterocycle selected from the group consisting of thienyl, imidazolyl, thiazolyl thiadiazolyl and pyrazolyl.

Description

5005 12 NEW ZEALAND PATENTS ACT, 1953 No: Divided out of NZ 321135 Date- Dated 11 October 1996 complete specification CEPHALOSPORIN ANTIBIOTICS We, MICROCIDE PHARMACEUTICALS, INC., a California Corporation of 850 Maude Avenue, Mountain View, California 94043, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: "followed by page - la-' -la-DESCRTPTTON CEPHALOSPORIN ANTIBIOTICS BACKGROUND OF THE INVENTION 1. Related Applications This application is related to provisional patent application Serial No. 60/005,389, filed on October 12, 1995, which is incorporated herein by-reference in its entirety, including any drawings. 2. Field of the Invention This is a divisional of New Zealand Patent Specification No. 321135.

The present invention and the invention of NZ 321135 relate to novel cephalosporin antibiotics and their methods of production and use. These compounds are expected to exhibit antibiotic activity against a wide spectrum of organisms, including organisms which are resistant to conventional P-lactam antibiotics. 3. Review of the Background Art The following review of the background of the invention is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.

Over the past three decades a large variety of antibiotics have become available for clinical use. One class of antibiotics which has seen remarkable growth are the cephalosporins, over 70 of which have entered clinical use for the treatment of bacterial infections in mammals since 1965. The cephalosporins exhibit their antibacterial activity by inhibiting bacterial peptidoglycan biosynthesis, and have been extremely effective in treating a wide variety of bacterial infections. Cephalosporins that are said to have antibacterial activity are described in U.S. Patent 3,992,377 and U.S. Patent 4,256,739.

Unfortunately, the wide-spread and indiscriminant use of these antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms which threaten to limit the utility of presently available cephalosporin antibiotics. In particular, resistant strains of Salmonella, S. pneumoniae, Enterobacteriaces, and Pseudomonas have emerged which threaten to undo many of the strides made in reducing mortality and morbidity from bacterial infections.

Bacterial resistance to cephalosporins follows three major pathways: (a) the development of S-lactamases capable of inactivating the fi-lactam ring of the cephalosporin; (b) decreased cephalosporin penetration into the bacteria due to changes in bacterial cell wall composition; and (c) poor binding to penicillin-binding proteins (PBPs). The latter pathway is especially important, as the binding of S-lactams to PBPs is essential for inhibiting bacterial cell-wall 3 biosynthesis. Certain Gram-positive bacteria, namely methicillin-resistant Staphylococcus aureus ("MRSA") and enterococci are highly resistant to E-lactam antibiotics. Resistance in MRSA is due to the presence 5 of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to £-lactam antibiotics. The activity of S-lactam antibiotics against PBP2a-containing organisms has been shown to correlate well with the binding affinity of the antibiotic to 10 PBP2a. Currently, the glycopeptides vancomycin and teicoplanin are primarily used for MRSA bacteremia. The guinolone antibacterials and some carbapenems, such as imipenem, have been reported to be active against a few MRSA strains, but their use is restricted due to 15 emerging resistant MRSA strains.

Experimental compounds which may possess utility as anti-MRSA or anti-enterococcal bactericides include the glycylcyclines (see. e.g.. P.-E. Sum si. al. . J Med Chem.. 37, (1994)), FK-037 (see. e q.. H. Ohki 20 St al., J. AntibigtiCS, 46:359-361 (1993)), RP-59,500 (see, e g , S.K. Spangler sLL ai- , Antimicro. Agents Chemother.. 36:856-9 (1992)), the everninomycin complex (see, e.g./ W.E. Sanders fit si., Antimicro. Agents Chemother. . 6: 232-8 (1974)), the 2-(biaryl)carbapenems 25 (see. e.g.. U.S. Patent No. 5,025,006), 3-(benzothiazolylthio)cephems (see, e.g.. EP Application No. 527686), 3 -(thiazolylthio)carbacephems (see. e.g., R.J. Ternansky aJL al. . J Med. Chem. . 36:1971 (1993) and U.S. Patent No. 5,077,287) and arbekacin (S. Kondo, 30 aJL. J. Antibiotics 46:531 (1993). 4 Recent advances in the compounds, compositions and methods useful for treating infections in mammals arising from B-lactam antibiotic resistant bacteria are described in commonly owned International Application No. WO 96/26966.

SUMMARY OF THE INVENTION In a first aspect the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of ,11- Z is selected from the group consisting of -CH2 (X) m-, -C (NOR6) -CH (OR7) -C(CHC02R3)- and -CH(NR9R10) X is selected from the group consisting of oxygen and sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cyano, C^-Cfi alkyl whxcn may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, Ci-C6 alkyltr.io, heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridmyl, thiadiazolyl, tniazolyl, piperazmyl, cioer.zfuranyl and dibenzthienyl, Cs-Cn aryl, heteroaryl, carooxyl, Ci-Cs alkoxycarbonyl, Ci~C6 alkyl, Ci-C^alkenyl, nitro, ammo, C;-Cs alkoxyl and amide; C6~Ci4 aryl which may be substituted with one or more substituents selected from the group consisting of hydroxvl, bromo, fluoro, c.ilcro, lodo, mercapto or thio, cyano, cyanoamido, C-.-C,s alkylthio, heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci-C6 alkyl, C;-C6 alkenyl, nitro, ammo, Ci~C6 alkoxyl and ami do ; a heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl 6 and dibenzthienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, cyanoamido, C:-C6 alkylthio, heterocycle, C^-Cu aryl, heteroaryl, carboxyl, oxo, Ci-C6 alkoxycarbonyl, Ci-C6 alkyl, Ci-Cs alkenyl, nitro, ammo, C-,-C6 alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is C:~C6 alkyl HetAr is an aromatic heterocyle as defined above), and (CK2)nT, n is 1 to 6, T is selected from the group consisting of ammo (NRR' wherein R and R1 may be C:-C6 alkyl, C6-Ci4 aryl or acvl C (0) R wherein R is C:-C6 alkyl), amidmo (C- or N-lmked) , guamdmo, and isothioureiao, which may be substituted with C:-C6 alkyl, Cs-Ci4 aryl, hydroxyl, or ammo as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci-Cs alkyl and C6-Ci4 aryl; 7 R9 and R10 are selected independently from the group consisting of hydrogen, Ci-C6 alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is heterocycle as defined above); R: is selected from the group consisting of hydrogen, C:-C6 alkyl which may be substituted as defined above, C;alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio cyano, C:-C6 alkylthio, heterocycle, C;-C:i aryl, heteroaryl, carboxyl, C:-C6 alkoxycarbonyl, C.-C6 alkyl, C:-C6 alkenyl, nitro, amino, C:-C^ alkoxyl, and amido; C6-C14 aryl whicn may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is O-Ce alkyl which may be substituted as defined above and Ar is Ce-C^ aryl which may be substituted as defined above), heteroaralkvl and trialkylsilyl (RR'R11 Si wherein R, R'and R'' are Ci-C6 alkyl groups) ; or R2 is not present and the C02 group to which it would be attached bears a negative charge; the ring A, B, D, and E is a carbon, nitrogen and sulphur containing heterocycle selected from the group consisting of thienyl, imidazolyl, thiazolyl thiadiazolyl and pyrazolyl; 8 R11 is selected from the group consisting of H, halogen, Ci-C6 alkyl, C;-C6 alkoxy, hydroxyl, amino as defmec above, cyano, C:-Ce hydroxyalkyl, C:-C6 carboxamicoal.-:yl, Ci-Ce aminoalkvl or C;-C, quaternary ammonium alkyl, ana quaternary heteroaryliumalkyl; alki and alk2 are C.-Ce alkyl groups which may be independently substituted with a substituent selec.ec from the group consisting of C;-C6 alkyl, hydroxyl, ammo as defined above, C-.-C.- alkoxy, C:-C* hydroxyalkyl ana carboxamiae; p is 0, 1, or 2; R99 is selected from the group consisting of sulfir, S3, S02, NH, C;-C6 N-alkyl, oxygen, C=C (cis or trans , ana CsC; q is 1; r is 0, 1, 2 or 3; 9 R^-R16 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, cycloalkyl, acyl as defined above, ammoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Ci-C6 alkyl; wherein alk2 and R1* taken together may form an 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

In a second aspect the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of Z is selected from the group consisting of -CH2(X)--, -C (NOR6) -, -CH (OR7) -, -C (CHC02R8) - and -CH (NR3R:0)-; cc5r2 KaikOpfR99)^!^13] 1-4 x is selected from the group consisting of oxygen ana sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cyano, C:-Co alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, Ci-C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci-C6 alkyl, Ci-C6alkenyl nitro, ammo, Ci-C* alkoxyl and amido; C^-C^ aryl wr.icn may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, cyanoamido, C:-Cs alkylthio, heterocycle selecrec from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C.-C., aryl heteroaryl, carboxyl, C-L-C6 alkoxycarbonyl, C.-C. al.-cyl, C:-C6 alkenyl, nitro, ammo, Ci-C6 alkoxyl ana amiac; a heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and diber.zmienyl which may be substituted with one or more suostizuer.ts selected from the group consisting of hyarox v' — / crcmo / fluoro, chloro, lodo, mercapto or thio, cyano, 11 cyanoamido, Ci-C6 alkylthio, heterocycle, C^-C- aryl, heteroaryl, carboxyl, oxo, Ci-C6 alkoxycarbonyl, C.-C6 alkyl, Ci-Cs alkenyl, nitro, ammo, C:-C; alkoxyl ana amido; or a heteroalkyl group (RHetAr wherein R is C:-C6 alkyl HetAr is an aromatic heterocyle as defmec above) , and (CH2)nT, n is 1 to 6, T is selected from the group consisting of ammo (NRR' wherein R and R' may be Ci~C6 alkyl, Cb-Ci4 aryl or acyl C(0)R wherein R is Ci-C6 alkyl), amidino (C-or N-lmked) , guanidmo, and isothioureido, which may be substituted with Ci-Cs alkyl, C6-Ci4 aryl, hydroxyl, or ammo as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, C-.-C, alkyl and C6-Ci4 aryl; R9 and R10 are selected independently from the group consisting of hydrogen, Ci-Cs alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is a heterocycle as defined above); 12 R2 is selected from the group consisting of hydrogen, Ci-C6 alkyl which may be substituted as defined above, Ci-Cs alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, Ci-C6 alkylthio, heterocycle, Cs-Cn aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci-Co alkyl, Ci-C6 alkenyl, nitro, amino, Ci-C6 alkoxyl, and amido; C6-Cn aryl which may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is Ci-C6 alkyl which may be substituted as defined above and Ar is C€-Cu aryl which may be substituted as defined above), heteroaralkyl and trialkylsilyl (RR'R'' Si wherein R, R'and R1' are C.-C6 alkyl groups); or R2 is not present and the C02 group to which it would be attached bears a negative charge; R11 is selected from the group consisting of H, halogen, Ci-C6 alkyl, Ci-C6 alkoxy, hydroxyl, ammo as defined above, cyano, Ci-C6 hydroxyalkyl, Ci~C6 carboxamicoalkyl, Ci-C6 aminoalkyl or C:-Ci quaternary ammonium alkyl, and quaternary heteroaryliumalkyl; alki and alk2 are C.-CU alkyl groups which may be independently substituted with a substituent selected from the group consisting of Ci-Ce alkyl, hydroxy!, ammo as defined above, C.-C6 alkoxy, Ci-C6 hydroxyalkyl and carboxamide; p is 0, 1, or 2; 13 R99 is selected from the group consisting of sulfur, SO, S02, NH, Ci-Cs N-alkyl, oxygen, C=C (cis or trans) , and CsC; q is 1; r is 0, 1, 2 or 3; T"R" vO",'5r" -VT -v I! R" is NR"R», m"* , NR» , NR» p •;( u o nr15r16 _ or + ^.4 R13-R16 are independently selected from the group consisting of H, hydroxy, ammo as defined above, amidmo, Ci-Cs alkyl, cycloalkyl, acyl as defined above, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Ci-Cs alkyl; wherein alk2 and R12 taken together may form a 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

In a third aspect the present invention provides a compound of the formula 14 CO2R2 [(ai^R99)^)^12]^ or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of -NHC(0)ZRJ, -NR4R5, and -NHC(° Z is selected from the group consisting of -CH:(X)~-, -C (NOR6) -, -CH (OR7) -/ -C(CHC02R8)- and -CH (NR3R:0) - ; X is selected from the group consisting of oxygen and sulphur; m is selected from the group consisting of 0 anc 1; RJ is selected from the group consisting of cyano, C:-C alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or chic cyano, C.-Ce alkylthio, heterocycle selected from the group comprising furyl, thienyl, lmidazolyl, maclyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl carboxyl, Ci-C6 alkoxycarbonyl, C:-C6 alkyl, C.-Csalkeny nitro, ammo, Ci-C6 alkoxyl and amido; C6-C14 aryl wmch may be substituted with one or more substituenrs selected from the group consisting of hydroxyl, bromo, fluoro, chloro, xodo, mercapto or thio, cyano, cyanoamido, Ci-C« alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, Cs-Ci4 aryl, heteroaryl, carboxyl, C-.-C. alkoxycarbonyl, C-.-C al.-:yl, C:-C6 alkenyl, nitro, ammo, C.-C* alkoxyl and amico; a heterocycle selected from tne group comprising furyl, thienyl, imidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenz~r.ier.yl which may be substituted witn one or more subst;:„er.:s selected from the group consisting of hydroxyl, broiro, fluoro, chloro, lodo, mercapto or thio, cyano, cyanoamido, C-.-C, alkylthio, r.eterocycle, C.--C., ar_*l, heteroaryl, carboxyl, oxo, C_-C.: alkoxycaroonyl, C -3 alkyl, C;-C^ alkenyl, nitro, ammo, C.-Ci alkoxyl ar.a amido; or a hereroalkvl group (RKetAr wnerem P 15 Z.-C( alkyl HetAr is an aromatic heterocyle as defined acove), and (CH:)nT, n is 1 to 6, T is selected from the group consisting of ammo vNRR' wherein R and R' may be C;-C.: alkyl, C,:-Ci4 aryl or acyl C(0)R wherein R is C:-C6 alkyl), amidmo (C- or N-lmked) , guanidmo, and isothioureido, which may oe substituted with C.-Cs alkyl, C£-C:4 aryl, hydroxy!, or ammo as defined above; 16 R4"7 are independently selected from the group consisting of hydrogen, C:-C6 alkyl, Ce~Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci-Cs alkyl and C6-Ci4 aryl; R9 and R10 are selected independently from the group consisting of hydrogen, Ci-C* alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is a heterocycle as defined above); R2 is selected from the group consisting of hydrogen, C-.-Cs alkyl which may be substituted as defined above, C:-Ci alkenyl which may be substituted with one cr more functional groups selected from tne group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, Ci-C6 alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, C:-C6 alkoxycarbonyl, C.-C6 alkvl, Ci-C6 alkenyl, nitro, amino, C:-C€ alkoxyl, and amido; C6-Cu aryl which may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is Ci-C6 alkyl which may be substituted as defined above and Ar is C6-Ci4 aryl which may be substituted as defined above), heteroaralkyl and trialkylsilyl (RR'R'' Si wherein R, R'and R1' are C:-C€ alkyl groups); or R2 is not present and the C02 group to which it would be attached bears a negative charge; 17 the ring A, B, D, and E is a carbon, nitrogen and sulphur containing heterocycle selected from the group consisting of thienyl, imidazolyl, thiazolyl thiadiazolyl and pyrazolyl; R11 is selected from the group consisting of H, halogen, Ci-C6 alkyl, C-,-Cs alkoxy, hydroxyl, ammo as defmec above, cyano, Ci~Cb hydroxyalkyl, C-.-C* carboxamicoal-:yl, C:-C6 ammoalkyl or C-.-C- quaternary ammonium alkyl, ar.c quaternary heteroaryliumalkvl; alki and alk2 are C-.-C, alkyl groups which may be independently substituted with a suostituent selected from the group consisting of C.-C-- alkyl, hydroxyl, ammo as defined above, C.-C,- alkoxy, C-.-C.- nycroxyal-:yl ar.a carboxamide; p is 0, 1, or 2; R" is selected from the group consisting of sulfur, SO, S02, NH, C-.-Ce N-alkyl, oxygen, C=C (cis or trans) , ar.a C=C; q is 1; r is 0, 1, 2 or 3; R13 N NR15R16 18 ♦ ,r n 1 *17 R13 , or + nr13r14 R13-R16 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, Ci-Cs cycloalkyl, acyl as defined above, ammoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Cj-Cs alkyl; wherein alk2 and R12 taken together may form a 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

In a fourth aspect the present invention provides a compound of the formula: co,r< . or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of -NHC(0)ZR3, r> -NR4R5, and -NHC(Of/^s . 19 Z is selected from the group consisting of -CH. (X}r-, -C (NOR6) -, -CH (OR7) -, -C(CHCO;R5)- and -CH (NR?R:r') - ; X is selected from the group consisting of oxygen ana sulphur; m is selected from the group consisting of 0 ana 1; R3 is selected from the group consisting of cyano, C-.-Cs alkyl which may be substituted with one or more substituents selectec from the group consisting of hyaroxyl, bromo, fluoro, c.iloro, lodo, mercapto or tmo, cyano, Ci-C6 alkyltnio, heterocycle selectea from tne group comprising furyl, tnienyl, imidazolyl, mcclyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dioenztnienyl, C6-C:, aryl, heteroaryl, carboxyl, Ci-Cs alkoxycarbonyl, C:-C6 alkyl, C.-C~alKenyl, nitro, ammo, Ci-C, alkoxyl and amido; C-.-Ci„ aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, lodo, mercapto or thio, cyano, cyanoamido, Ci-Cs alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, Cs-Ci„ aryl, heteroaryl, carboxyl, C:-Cs alkoxycarbonyl, Ci-Cs alkyl, Ci-C6 alkenyl, nitro, amino, Ci-C6 alkoxyl and amido; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, mdolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci~C6 alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, oxo, Ci-C6 alkoxycarbonyl, C:-C6 alkyl, Ci-C6 alkenyl, nitro, amino, Ci-C* alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is C.-C^ alkyl HetAr is an aromatic heterocyle as defined above), and (CH2)nT, n is 1 to 6, T is selected from the group consisting of ammo (NRR' wherein R and R' may be C:-Cs alkyl, C6-C14 aryl or acyl C (0) R wherein R is C:-C5 alkyl), amidmo (C- or N-lmked) , guanidmo, and isothioureido, wnich may be substituted with Ci-C6 alkyl, C6-Ci4 aryl, hydroxy!, or ammo as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci~C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci-C6 alkyl and C6-Ci4 aryl; 21 R9 and R1C are selected independently from the group consisting of hydrogen, C:-C6 alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is a heterocycle as defined above); R2 is selected from the group consisting of hydrogen, Ci-Cs alkyl which may be substituted as defined aoove, Ci-C6 alkenyl which may be substituted with one or mere functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or tr.io, cyano, Ci-C6 alkyltnio, heterocycle, C,-C_, aryl, heteroaryl, carboxyl, C:-C6 alkoxycarbonyl, C.-C. al-:yl, Ci-Cs alkenyl, nitro, amino, C:-C6 alkoxyl, anc amico; C6-Ci4 aryl which may oe substituted as defined aoove, a heterocycle which may be substituted as defined aoove, aralkyl (RAr wherein R is C:-Cs alkyl wnich may ce substituted as defined above and Ar is Cs-Ci, aryl wr.i:n may be substituted as defined above), heteroaral -:yl ar.o trialkylsilyl (RR' R' ' Si wherein R, R'and R'' are C-.-C. alkyl groups); or R" is not present and the CO; group to which it would be attached bears a negative charge; the ring G, H, J, L and M is a carbon, nitrogen or NR:: (quaternary ammonium heterocycle) containing heterocycle selected from the group consisting of pyridmyl piperazmyl, pynmidmyl and pyrazmyl; 22 R11 is selected from the group consisting of H, halogen, Ci-Ce alkyl, Ci~C6 alkoxy, hydroxyl, ammo as defined above, cyano, Ci~C6 hydroxyalkyl, Ci-Ce carboxamidoalkyl, Ci-C6 ammoalkyl or Ci-C6 quaternary ammonium alkyl, and quaternary heteroaryliumalkyl; alki and alk2 are Ci~C6 alkyl groups which may be independently substituted with a substituent selected from the group consisting of C-.-C5 alkyl, hydroxyl, ammo as defined above, Ci-C6 alkoxy, C:-Ci hydroxyalkyl and carboxamide; p is 0, 1, or 2; R99 is selected from the group consisting of sulfur, SO, S02, NH, Ci-C6 N-alkyl, oxygen, C=C (cis or trans) , and C=C; q is 1; r is 0, 1, 2 or 3; + nr13r14 R13-Rl0 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, C-.-C* cycloalkyl, acyl as aefmec above, ammoacyl, and phosphoryl and taken together -ay form a 5- or 6-membered ring; and R17 is H or C:-C6 alkyl; wherein alk: and R:~ taken together may form a 3 c: member non-aromatic neterocycle which may be sues" as defined above. ituted Described herein is a compound of the formula: PgiNH // .OP92 COjH CI wherein Pgi is hydrogen or a first protecting group and wherein Pg2 is a second protecting group.

In a fifth aspect the present invention provides the use of a compound of the first, second, third or fourth aspects of the invention or a salt thereof in the manufacture of a medicament for the treatment of a mammal suffering from a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection. intellectual ps office of i 1 1 JUN 21 RECEIV In a sixth aspect the present invention provides an antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillm-resistant bacterial infection, comprising a therapeutically effective amount of a compound or salt of the first, second, third or fourth aspects of the invention in a pharmaceutically acceptable carrier. 24 Described herein is a method for making the compound of the fifth aspect of the invention comprising the step of adding a chlorinating reagent to a solution or compositions and methods effective to treat infections in mammals arising from 6-lactam antibiotic resistant bacteria. Preferred compounds will have a minimum inhibitory concentration (MIC) that is less that 50%, more preferably less than 10%, and most preferably less than 1% of the MIC of cefotaxime or imipenem for a beta-lactam resistant organism, preferably a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism. Other preferred compounds will be able to prevent or reduce mortality in mice infected with the beta-lactam resistant organism to a greater extent than cefotaxime or imipenem.

Described herein are compounds of the structures II-VI N /OP® S Described herein are compounds intellectual property office of n.z. 1 1 JUN 2001 RECEIVED COjR2 [(a|k,)p(R99)q(al^)rR12]1_2 II r11jo-3 S' M' , CQ.R2 [(alk|)p(R99)q(al^)rR12]1_2 III fR11]i_4 ccfer2 [(alk,)p(R99)p(al^)rR12]lJ) IV ccfer2 [r1V3 ((alki)p(R99)p(al^)rR12]1.2 V :r1V3 CQ.R2 [(alk^R99)^1^12]^ VI and/or their pharmaceutically acceptable salts and/or prodrugs, wherein R1 is selected from the group consisting of -NHC (0) ZR3, -NR4R5' and "NHC(°) Z is selected from the group consisting of -CH2 (X) m- , -C (NOR6) - , - CH (OR7) - , -C(CHC02R8)- and -CH (NR9R10) X is selected from the group consisting of oxygen and sulphur; m is selected from the group consisting of 0 R3 is selected from the group consisting of cyano, alkyl, aryl, heterocycle (wherein said heterocycle is optionally substituted and preferably is disubstituted with NH2 and halogen (preferably chlorine)), heteroaralkyl and (CH2)nT, . and 1; 27 n is 1 to 6, T is selected from the group consisting of amino, amidino (C- or N-linked), guanidino, and isothioureido, optionally substituted by alkyl, aryl, hydroxyl, or amino; R4"7 are independently selected from the group consisting of hydrogen, alkyl, aryl and acyl; R8 is selected from the group of hydrogen, alkyl and aryl; R9 and R10 are selected independently from the group consisting of hydrogen, alkyl, acyl, and heterocyclecarbonyl; R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocycle, aralkyl, heteroaralkyl, and trialkylsilyl; or R2 is not present and the C02 group to which it would be attached bears a negative charge.

A, B, D, and E are selected from the group consisting of carbon, nitrogen and sulphur and the specific juxtaposition of groups A, B, D and E is limited to examples of heterocyclic groups known in the chemistry arts; 28 G, H, J, L and M are carbon, nitrogen or "NR11 (quaternary ammonium heterocycle) and the specific juxtaposition of groups G, H, J, L and M is limited to examples of heterocyclic groups known in the chemistry 5 arts; R11 is selected from the group consisting of H, halogen, alkyl, alkoxy, hydroxyl, amino, cyano, hydroxyalkyl, carboxamidoalkyl, optionally substituted aminoalkyl or quaternary ammonium alkyl, and quaternary 10 heteroaryliumalkyl; alkx and alk2 are alkyl groups and are independently and optionally substituted with a substitutent selected from the group consisting of alkyl, hydroxyl, optionally substituted amino, alkoxy, hydroxyalkyl and optionally 15 substituted carboxamide; p is 0, 1, or 2; R" is selected from the group consisting of sulfur, SO, S02, NH, N-alkyl, oxygen, C=C (cis or trans), and C=C; q is 0 or 1; r is 0, 1, 2 or 3; 29 ♦nr»r" j^7 .7 mr15R16 ^ I! 14 II 14 R12 is NR13R14, ^ NR R , NR , NR , .,1 fl ^ ^17 ■v^ nr13r14 l o nr15r16 ■Vif or + nr13r14 R13-R16 are independently selected from the group consisting of H, hydroxy, amino, amidino, alkyl, 5 cycloalkyl, acyl, aminoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or alkyl; wherein alk2 and R12 taken together may form an 10 optionally substituted 5 or 6 member non-aromatic heterocycle.

Specific examples of heterocyclic groups known in the chemistry arts include the following (shown linked to a sulfur atom in each case, as above): Structures IV, V and VI show a vinyl group linking the cephem nucleus to an arylthio or 5 heteroarylthio group. It is to be understood that each carbon atom of the vinyl group may optionally in addition be substituted by a lower alkyl group, such as a methyl or ethyl group.

Preferred compounds include those compounds 10 wherein R11 is H or halogen, R12 is NR13R14, 31 Ip" J>r'Sr" J£>' yV"^'6 NR'SR'6 ' Ur« ' [JR» tNpW / / I v-'-L p is 0 or 1, g is 0 or 1, r is 1, 2 or 3, R13-R16 are H or lower alkyl, and R17 is H or lower alkyl. Especially preferred compounds include those compounds wherein R11 11 N r\ II yy is hydrogen, R12 is NR13R14, ^ , NR , or ,13 ■V R ,17 NR 14 or p is 1, q is 1, r is 1, 2, or 3, R13-R16 are hydrogen, and R17 is hydrogen or lower alkyl. There are preferably one or two [ (CH2) p (S) q (CH2) rR12] groups present. There are preferably three or four R11 groups 10 present.

Preferred compounds include those wherein: (1) R1 is NHC(O) ZR3 Z is -CH2 (X) m-X is S m is 1 (2) R1 is NHC(O) ZR3 32 Z is -C (NOR6) -R5 is selected from the group consisting of hydrogen, methyl, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroallyl and cyclopentyl, and R3 is selected from 5 the group consisting of phenyl, 2-thienyl, 2-furyl, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl; (3) R11 is H or halogen + KtD13p14 r13 r13 n ^ri5R16 N^R17 "V I! K II \ip15p16 II M ''14 4) R12 is NR13R14, ^ , NR , NR , or c nr15r16 v ^ II + NR13R14 . (5) p is 0 or 1 g is 0 or 1 r is 1, 2 or 3; and/or (6) R13 - R17 are H or lower alkyl.

Preferred compounds include those wherein alk2 and R12 taken together an optionally substituted 5 or 6 member carbon ring containing a single nitrogen. In especially preferred embodiments, alk2 and R12 taken 33 together form a substitutent (shown below on a sulfur atom) selected from the group consisting of Other preferred examples are shown below linked through a sulfur atom to a .4-pyridyl substituent Without being bound to any particular theory regarding operation of the invention, it is noted that there are several novel structural features described herein are believed to contribute to the 34 substantially improved functional properties. In particular,, chlorine substituents on heterocyclic R3 groups appear to impact 2-4 fold improved MIC values compared to the compounds with non-chlorinated 5 heterocyclic R3 groups.

Preferred pharmaceutically acceptable salts include (1) inorganic salts such as chloride, bromide, iodide, nitrate, phosphate or sulfate; (2) carboxylate salts such as acetate, propionate, butyrate, maleate, or 10 fumarate; (3) alkylsulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethylsulfonate, n-propylsulfonate or iso-propylsulfonate; and (4) hydroxycarboxylates such as lactate, malate, and citrate.

Also described herein are compositions comprising an amount of a compound of Structure II, III, IV, V or VI effective to treat bacterial infections in mammals arising from bacteria resistant to S-lactam antibiotics.

Further described herein are methods for treating a bacterial infection in a mammal arising from bacteria resistant to S-lactam antibiotics comprising administering to a mammal suffering from such an infection a 25 therapeutically effective amount of a compound of Structure II, III, IV, V or VI. Of course, the compounds of the present invention also have utility in compositions and methods to treat mammals infected with bacteria that are sensitive to conventional p-lactam 30 antibiotics.

Still further described herein are compounds and methods for preparation of an intermediate VII, which is useful for preparing compounds having particularly potent activity against methicillin-resistant Staphylococci and ampicillin-resistant Enterococci.

/OPcfe N VII Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-5 show preferred synthetic schemes for producing compounds of the present invention.

Figure 1 shows preparation of the cephem.

Figure 2 shows preparation of the C(7)-substituent.

Figure 3 shows preparation of the 3-substituent.

Figure 4 shows the final assembly. 36 Figure 5 shows deprotection and salt formation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS I. Definitions 5 As used herein, the term "alkyl" denotes branched or unbranched hydrocarbon chains, preferably containing between one and six, more preferably one and four, carbon atoms, such as, e.g.. methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 10 tert-butyl, and 2-methylpentyl. These groups may be optionally substituted with one or more functional groups which are attached commonly to such chains, such as, e.a.. hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocycle, aryl, 15 heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and optionally substituted isothioureido, amidino, guanidino, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexy1, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, 2 0 4-cyanobutyl, 2-guanidinoethyl, 3-N,N'-dimethylisothiouroniumpropyl, and the like.

The term "alkenyl" denotes an alkyl group as defined above having at least one double bond, e.a.. allyl, 3-hydroxy-2-buten-l-yl, 1-methyl-2-propen-l-yl 25 and the like.

The term "aryl" denotes a chain of carbon atoms an which form an least one aromatic ring having preferably between about 6-14 carbon atoms, such as, e.g.. phenyl, naphthyl, indenyl, and the like, and which 37 may be substituted with one or more functional groups which are attached commonly to such chains, such as, e.g.. hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, cyanophenyl, pyridylphenyl, pyrrolylphenyl, pyrazolylphenyl, triazolylphenyl, tetrazolylphenyl and the like.

The term "heterocycle" denotes a chain of carbon and at least one non-carbon atoms which together form one or more aromatic or non-aromatic rings having preferrably between about 6-14 atoms, such as, e.g.. furyl, thienyl, imidazolyl, indolyl-, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl. These rings may be optionally substituted with one or more functional groups which are attached commonly to such rings, such as, e.a.. hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form rings such as, e.g.. 2-aminothiazol-4-yl, 2-amino- 38 -chlorothiazol-4-yl, 2-amino-thiadiazol-4-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzfuranyl and 3-hydroxy-4-dibenzthienyl and the like.

The term "heteroaromatic" or "heteroaryl" (HetAr) denotes an aromatic heterocycle as defined above.

The term "heterotricycle" denotes an aromatic heterocyclic substituent as defined above which comprises three aromatic rings.

The term "heterocyclecarbonyl" denotes the group -C(0)Het, where Het is heterocycle as defined above.

The term "alkoxyl" denotes the group -OR, where R is alkyl as defined above, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, trifluoromethoxy, 3-hydroxyhexyloxy, 2-carboxypropyloxy, 2-fluoroethoxy, carboxymethoxy and cyanobutyloxy and the like.

The term "alkylthio" denotes the group -SR, where R is alkyl as defined above, such as methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, sec-butylthio, iso-butylthio, tert-butylthio, trifluoromethylthio, 3-hydroxyhexylthio, 2-carboxypropylthio, 2 -fluoroethylthio, carboxymethylthio and cyanobutylthio and the like.

The term "acyl" denotes groups -C(0)R, where R is alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl. 39 The term "aryloxy" denotes groups -OAr, where Ar is an aryl group as defined above.

The term "aralkyl" denotes groups -RAr, where R is alkyl and Ar is aryl, both as defined above.

The term "heteroaralkyl" denotes groups -RHetAr where R is alkyl and HetAr is heteroaryl as defined above.

The term "trialkylsilyl" denotes the group RR1R"Si-, where R, R' and R" are alkyl as defined above.

The term "trialkylammonium" denotes the group [RR'R"N-]+, where R, R' and R" are alkyl as defined above.

The term "amino" denotes the group NRR', where R and R' may independently be alkyl, aryl or acyl as defined above, or hydrogen.

The term "carboxamido" denotes the group -C(0)NRR', where R and R' may independently be alkyl, aryl or acyl as defined above, or hydrogen.

The term "cyanoamido" refers to the group -NH-C=N.

The term "2-lactam resistant bacteria" refers to bacteria against which a 5-lactam antibiotic has an minimum inhibitory concentration (MIC) greater than 32 mg/ml.

The term "methicillin-resistant bacteria" refers to bacteria that are resistant to methicillin. Examples of such bacteria are provided in Table 1 and are identified MethR. The term "methicillin sensitive bacteria" refers to bacteria that are sensitive to 40 methicillin. Examples of such bacteria are provided in Table 1 and are identified Meths.

The term "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs may be easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable by oral administration but the parent is not, or the prodrug may improve solubility to allow for intravenous administration.

II. Compounds of the Invention The present invention together with its parent provide compounds, methods and compositions effective to treat bacterial infections, and, especially, infections arising from bacteria which have developed resistance to conventional S-lactam antibiotics. More importantly, the present invention together with its parent provide compounds, methods and compositions effective to treat bacterial infections arising from bacteria which have developed resistance to conventional cephalosporin antibiotics.

A. Synthesis of Compounds of Structure II The compounds of the present invention and its parent may be readily prepared in accordance with the following schemes. However, it will be appreciated that other synthetic pathways for forming the compounds of the invention are available and that the following is offered merely by way of example, and not limitation.

It will be further recognized that various protecting and deprotecting strategies will be employed which are 41 standard in the art (see. e.g.. Green and Wuts). Those of skill in the art will recognize that the selection of any particular protecting group (e.g.. a carboxy protecting group) will depend on the stability of the protected moiety with respect to subsequent reaction conditions.

Generally, the synthesis of the cephalosporins described herein may be achieved using well-known methods and readily available materials (see. e . ct . . March; Larock, Comprehensive Organic Transformations (VCH Publishers, 1989) ; and G.I. Georg, the organic chemistry of S-lactams, (VCH 1992), each of which is incorporated herein by reference). As shown below in Scheme 1, treatment of the cephem triflate 1 with the desired optionally protected thiolate nucleophile 2, using standard methods such as those described in Farina al., J. Org. Chem. 54:4962 (1989) and U.S. Patent No. 4,870,168 to Baker, ££. si., (both of which are incorporated herein by reference), provides the 3-thio derivative 3. Subsequent deprotection using procedures known to those skilled in the art affords the biologically active 4-carboxycephem 4. 42 [Ri1b-3 s "S Xa t(alk|)p(f^9)q(alk2)rR12-Pg]|.2 COJR2 [R111M [(alk,)p(Fe9)q(alKj)IR12-Pgll.2 R1X, / XC CCfeH [R1V3 A"B\ x[(alk,)p(R99)p(all%)rR12]1.2 Compound 1 is formed readily from commercially available starting materials, such as the reaction of (7R)-7-[(phenylacetyl)amino]-3-hydroxy-3-cephem-4-carbox 5 ylic acid (Otsuka Chemical Co., Ltd., Otsuka, Japan) with triflie anhydride (Aldrich, Milwaukee, WI), using known procedures (see. e.g.. Farina; and U.S. Patent No. 4,870,168 to Baker, al-) Other 3-hydroxy-3-cephems may be formed from the ozonolysis of 3-exomethylene 10 cephems using known procedures (see, e.g.. Farina).

Similarly, the thiolate nucleophile 2 may be formed 43 using known procedures and commercially available starting materials.

The substituent R1 may be any of the groups described above and are either available commercially 5 (e.g.. from Aldrich, Milwaukee, WI) or can be formed using known techniques and starting materials (see. e.g.. March; Larock). These groups can be substituted for those present on the starting material by variety of well known techniques (see. e . cr. . Barrett, J.C.S. Perkin 10 I, 1629 (1979) or Chauvette, J. Org. Chem. 36:1259 (1971), both of which are incorporated herein by reference), such as by transamination of an existing substituent for the desired substituent, or hydrolytic removal of the existing substituent followed by reaction 15 with a suitably reactive form of desired substituent, such as an acyl chloride. Again, the appropriate reagents and techniques will be apparent to those of skill in the art.

The carboxyl group R2 may be those protecting 2 0 groups amenable to reductive cleavage, such as benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl and the like. Alternatively, R2 may be a protecting group amenable to acidic cleavage, such as t-butyl, t-amyl, trityl, 25 4-methoxytrityl, 4,41-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, £-(trimethylsilyl)ethyl, benzyl, 4-(or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethy1, benzhydryl, or 30 3,3-dimethylallyl. Preferred protecting groups are p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl. Such groups may be attached to the unprotected carboxyl group of the cephalosporin starting material using known reagents and techniques, such as those described in Green and Wuts.

B. Synthesis of Compounds of Strueture ITT The compounds of general structure III are prepared similarly to those of general structure II. In most cases, a key step is the coupling of a substituted heteroarylthiolate with cephem triflate 1 or a functionally equivalent cephem having an alternative leaving group at C-(3). Compounds of structure III where the ring containing G, H, J, L and M is 4-pyridyl may also be prepared as exemplified in Figure 4.

C. Synthesis of Compounds of Structures IV. V and VI The compounds of general structure IV, V and VI are prepared by coupling an aromatic or heteroaromatic thiolate with tosylvinyl cephem sulfoxide 6. Compound 6 is formed readily from commercially available starting materials using known procedures (see, e.g.. Farge et al.. U.S. Patent No. 4,307,116). The requisite aromatic or heteroaromatic thiols are prepared by a variety of methods known in the literature, as described in the Examples. As shown below in Scheme 2, treatment of the cephem intermediate 6 with a desired optionally protected thiolate nucleophile, such as 5, using methods such as those described in Farge et al.. U.S. Patent No. 4,3 07,116 (which is incorporated herein by reference), provides the 3-thiovinyl derivative 7. Sulfoxide reduction and subsequent deprotection using procedures known to those skilled in the art affords the biologically active 4 -carboxycephem 8. o o CCfcR2 OTs CQ.R2 ,A II ,s. 6 7 1) Sulfoxide reduction 2) Deprotection H CCfeH i[(alkt)p(R99)q(all%)TR12]^ 8 46 D. Synthesis of Compounds of Stiructure VII A preferred synthetic route for preparation of these intermediates is set forth in Figure 2. In particular, the step of converting 6 to 7 shown in 5 Figure 2 and described in Example 18 is especially useful in providing compounds having substantially improved activity against methicillin-resistant and ampicillin-resistant bacteria.

III. Pharmaceutical Applications and Preparations 10 As described herein, a therapeutically or pharmaceutically effective amount of a cephalosporin and particularly, a compound of Structure II, III, IV, V or VI, is administered to a mammal suffering from an methicillin-resistant bacterial infection (or other p-15 lactam resistant bacterial infections, such as vancomycin-resistant or ampicillin-resistant infections) , especially resistant S. aureus, in an amount effective to at least partially relieve the infection. Especially important are infections 20 resulting from strains having similar activity to strains such as S. aureus Col (MethR) (lac") , S. aureus 16 (MethR) (lac+) , E. fsscium ATCC 35667, or E. f&calis ATCC 29212. Again, such compounds are also effective against bacteria sensitive to methicillin, vancomycin, and/or 25 ampicillin and therefore have utility in such compositions and methods.

The compositions containing the compound(s) of the invention and its parent can be administered for prophylactic and/or therapeutic treatments. In therapeutic 47 applications, the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the infection. 5 An amount adequate to accomplish this is defined as "therapeutically effective amount or dose." Amounts effective for this use will'depend on the severity and course of the infection, previous therapy, the patient's health status and response to the drugs, and the 10 judgment of the treating physician. In prophylactic applications, compositions containing the compounds of the invention and its parent are administered to a patient susceptible to or otherwise at risk of a particular infection. Such an amount is defined to be a "prophylactically effective 15 amount or dose." In this use, the precise amounts again depend on the patient's state of health, weight, and the like.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if 2 0 necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease. 25 Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of the disease symptoms.

In general, a suitable effective dose of the compound of the invention and its parent will be m the range of 0.1 to 3 0 1000 milligram (mg) per recipient per day, preferably in 48 the range of 1 to 100 mg per day. The desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form. Preferably, the compounds of the invention and its parent will be administered m amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.

While it is possible to administer the active ingredient of this invention alone, it is preferable to present it as part of a pharmaceutical formulation. The formulations described herein comprise at least one compound or inhibitor of this invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically or therapeutically acceptable carriers. Solid carriers inlcude, e.g., starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and kaolin, and optionally other therapeutic ingredients. Liquid carriers include, e.g., sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut and sesame oils. In addition, various adjuvants such as are commonly used in the art may be included. For example: flavoring agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA. Various other considerations are described, e.g., in Gilman et al. (eds) (1990) Goodman and Gilman's: The Pharmacological 49 Basis of Therapeutics, 8th Ed., Pergamon Press; and Remington's supra. Methods for administration are discussed therein, e.g., for oral, intravenous, intraperitoneal, or intramuscular administration, and 5 others. Pharmaceutically acceptable carriers will include water, saline, buffers, and other compounds described, e.g., in the Merck Index, Merck & Co., Rahway, NJ. Generally, preferred routes of administration are intravenous and intraperitoneal.

These pharmacological agents can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The 15 preferred form depends on the intended mode of administration and therapeutic application. Generally, a pharmacologically acceptable salt of the compound will be used to simplify preparation of the composition. Preferred salts include sodium, potassium, arginine, 20 glycine, alanine, threonine. These are prepared, preferably, in water suitably mixed with a surfactant such as hydroxypropylcellulose.

Depending on the specific conditions being treated, such agents may be formulated and administered 25 systemically or locally. Techniques for formulation and administration may be found in Remington1s Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990) . Suitable routes may include oral, rectal, transdermal, vaginal, transmucosal, or 3 0 intestinal administration; parenteral delivery, 50 including intramuscular subcutaneous, intramedullary injections, as well an intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, just to name a few.

For injection, the agents of the invention and its parent may be formulated m aqueous solutions, preferably m physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

IV. Biological Activity In Vitro Antibacterial Evaluation The compounds of the invention and its parent were evaluated against several S-lactam resistant (for example methicillin-resistant, vancomycin resistant, and/or ampicillin-resistant) bacteria strains by determining the minimum inhibitory concentration (MIC, ,ug/ml) of each compound with respect to each strain. The MIC, the lowest concentration of antibiotic which inhibits growth of the test organism, was determined by the agar dilution method. 51 To determine the MIC for bacterial isolates, the test compound was incorporated in a series of two-fold dilutions into liquified Mueller-Hinton agar. Upon solidification, a number of different bacterial strains were spot inoculated with a replicating device onto the agar surface. After overnight incubation, the MIC breakpoint was determined as the lowest drug concentration that completely inhibited growth, disregarding a single colony or a faint haze. The procedures used in these stuides have been standardized by the National Committee for Clinical Laboratory Standards (NCCLS), as per the NCCLS publication entitled Methods for Dilution Antimicrobial Susceptibility Tests (1991) , which is incorporated herein by reference.

Aliquots of antimicrobial agents were prepared in phosphate buffered saline (PBS) at pH 7.2. Tween 20 or DMSO was used as a solubilizing vehicle as needed. Standard methods of vortexing, sonicating and gentle heat were used to facilitate solubilizing the test agent. Typically, the concentration of the stock solution was 10X that of the highest drug concentration tested. A 1.28 mg/mL stock solution was used with a subsequent highest working concentration of 12 8 /zg/mL. Serial two-fold dilutions were done through s0.25//g/mL. Each drug level was tested in duplicate. Two-fold drug dilutions were done in sterile 50 mL tubes with a final drug volume of 5 mL. Upon the addition of 45 mL of molten agar, a 10-fold dilution resulted. Two, 25 mL. plates were then poured into 15x150 mm square Petri plates with grids and allowed to harden. 52 A control plate with a reference drug, either cefotaxime, vancomycin or imipenem, was used as the positive growth control. Stock concentrations of reference antibiotics were prepared and frozen at -80°C. Upon preparation, the control plates were sealed and stored in the refrigerator for up to 1 week prior to use; however, imipenem control plates had to be prepared just prior to use. All test plates were used within 24 hours of preparation.

Satisfactory results were obtained where the inoculum contained about 104 colony forming units (cfu) ± 0.5 logs. Starting with pure cultures of the test isolates on agar plates, a few isolated colonies were transferred to a tube of nutrient broth and allowed to grow 4-6 hours at 35-36°C to reach log-phase growth. Dropwise addition of the broth culture to PBS was done to match a 0.5 McFarland turbidity standard equal to 10® cfu/mL. This was further diluted ten-fold in PBS to reach a working inoculum concentration of 107 cfu/mL.

When 1/zL of the working inoculum was applied to the agar surface a concentration of about 10-4 cfu per spot was obtained.

Disposable sterile l^L loops were used to inoculate test plates, with each isolate in a designated grid on the agar plate. An alternate method of inoculation involved the use of a replica plater, a device with 48 steel pins allowing the simultaneous inoculation of multiple isolates. After the spots had dried, the plates were incubated at 35-36°C for 16-20 53 hours. Endpoints were assessed as the minimum inhibitory-concentration (MIC) of antimicrobial agent.

The novel agents of this invention are notable for their enhanced activity against S. aureus Col and 5 Enterococci (E. faecium and E. faecalis) . The S. aureus Col strain is a high-level PBP2a producer, whereas s. aureus Col 8A, its isogenic partner, lacks PBP2a.

Certain compounds show broad activity against both S. aureus Col and S. aureus Col 8A, as well as 10 Enterococci. The S. aureus Col 8A strain was highly responsive to all test agents including the Cefotaxime control. Thus, the compounds of the present invention and its parent are effective against PBP2a-producing bacteria. Certain compounds show potent activity against enterococci.

Certain other compounds of the present invention and its parent, are effective against E. coli in addition to Gram-positive organisms.

In Vivo Antibacterial Evaluation Compounds with superior activity in vitro when 20 compared to reference antibiotics, are further evaluated in a murine model for lethal bacteremic peritonitis.

Groups of 5 female Swiss-Webster mice (Simonsen, Gilroy, CA) each are challenged by the intraperitoneal (IP) route with tenfold increments of a 25 bacterial inoculum. This permits calculation of the mean lethal dose (LDS0) and the LD100. For preliminary evaluation of a new antibiotic, mice are challenged IP with an LD100 titer of bacteria. In two equal doses administered at the time of bacterial -challenge and 2 54 hours later, groups of 10 mice each are treated subcutaneously with two-fold increments of the test drug and an antibiotic of known efficacy in mice and humans (i.e., positive control). Mice are observed for 72h. Those alive at 72h are considered long term survivors. The total drug dose in mg/kg that protects 50% of mice in a group from death is termed the mean protective dose (PD50) . PD50s are similarly determined for several pathogens. The quantitative endpoints for the new drug are then compared with those obtained with reference antibiotics.

Six ten-fold dilutions of inoculum suspended in 0.5 mL of sterilized 7% hog gastric mucin (Sigma) are injected IP in groups of 5 mice each. A control group of 5 mice receive mucin alone. Mice are observed for 72h. Those alive at 72h are considered long term survivors. The mean lethal dose (LD50) and 100% lethal dose (LD100) are determined by the probit test.

For antibiotic efficacy studies, mice are challenged IP with bacterial titers that will afford an LD100 for the test strain. In two equal doses administered at the time of bacterial challenge and 2 hours later, groups of 10 mice each are treated by the subcutaneous route (SC) with twofold increments of the test antibiotic; another group is treated similarly with a reference antibiotic of known efficacy in animals and man. Drug doses can range from 0.01 to 512 mg/kg. If the drug is poorly soluble, Tween 2 0 or propylene glycol will be employed to solubilize the drug. Animals are observed for 72h. The 50% protective dose (PD50) is 55 calculated in mg/kg by the probit method. The PD50 is the same as the 50% effective dose (EDS0) and the 50% curative dose (CD50) . Samples of blood from the hearts of all animals that die and from half the mice that survive 5 are cultured on brain-heart infusion agar. Animals that received a protective dosage of the test drug will be alive at 72h, although they may appear moderately ill to very ill during the observation period. Infected, placebo-treated control mice and those receiving 10 non-effective i.e. lower dosages of the test drug will demonstrate a high rate of mortality. Most of these mice will die within 6 to 48 h. Those alive at 72h will be considered long term survivors. 56 Table 1. Antimicrobial Properties of 7-(Acvlamido)-3-(arvlthiokephems Organism ImiDenem I 2 3 4 6 S aureus ATCC 29213 £0.25 0.13 ^0.06 0.5 0.25 0 13 0.25 aureus Col8A(Meths)(lac') £0.25 £0.06 £0.06 0.5 0.25 £0.06 0.13 aureus PC 1 (Meths)(lac*) £0.25 1 0.5 0.5 0.25 0.25 0.5 aureus ATCC 13709 (Meths) £0.25 — - 0.5 0.25 £0.06 £0 06 S aureus Col (MethR)(lac') 32 4 1 8 8 8 2 S aureus 76 (MethR)(lac'f) 32 8 4 8 8 16 8 S aureus ATCC 33593(MethR) 32 8 4 8 4 16 8 S aureus Spain #356 (MethR) 32 8 4 8 8 16 8 S haemolyticus 05 (MethR) 64 16 4 8 8 16 16 £ faecaiis ATCC 29212 £0.25 1 0.5 0.5 0.5 2 05 £ faecium ATCC 35667 4 2 1 2 2 4 2 E faecium VanA (Van") 4 8 4 8 4 32 8 £ faecahs VanB (VanR) 0.5 4 0.5 1 4 4 8 £ faecium A491 (Amp") >128 >32 >32 >32 >32 >32 >32 £ coh ATCC25992 £0.25 >32 16 2 4 >32 >32 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 Table 1. Antimicrobial Properties of 7-(AcvlamidoV3-(arvlthioteephems Organism Imipenem 2 8 9 11 11 S aureus ATCC 29213 £0.25 0.5 1 0.25 0.5 05 0.5 S aureus Col8A(Meths)(lac') £0.25 0.5 1 0 13 05 1 05 S aureus PCI (Meths)(lacf) £0.25 2 1 1 0.5 1 0.5 S aureus ATCC 13709 (Meths) £0.25 0.5 1 £0 06 0.5 0.5 0.25 aureus Col (MethR)(lac") 32 8 2 1 2 4 2 aureus 76 (MethR)(lac*) 32 8 4 4 2 8 2 aureus ATCC 33593(MethR) 32 8 4 4 2 4 2 S aureus Spain #356 (MethR) 32 8 4 4 2 8 2 S haemolyticus 05 (MethR) 64 32 4 16 4 4 2 £ faecahs ATCC 29212 £0 25 1 0.5 1 05 0.25 0 25 £ faecium ATCC 35667 4 4 2 1 2 2 1 £ faecium VanA (VanR) 4 16 8 4 4 4 4 £ faecahs VanB (VanR) 05 2 05 2 1 05 05 £ ybecjumA491 (AmpR) >128 >32 32 >32 >32 >32 >32 £ co/i ATCC25992 £0 25 4 2 >32 4 8 8 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 45 Table 1. Antimicrobial Properties of 7-(AcvlamidoV3-(arvlthiokephems Organism Immenem 13 14 16 12 18 S aureus ATCC 29213 £0.25 2 0.5 1 0.25 0.25 1 aureus Col8A(Meths)(lac') £0.25 2 0.5 1 0.25 0.5 1 S aureus PCI (Meths)(lac^) £0.25 2 05 1 0 25 0.25 1 aureus ATCC 13709 (Meths) £0.25 2 0.25 0.5 0 13 0.25 I aureus Col (MethR)(lac') 32 4 4 4 0.5 2 44 S aureus 76 (MethR)(lac+) 32 8 4 4 1 4 8 aureus ATCC 33593(MethR) 32 8 2 4 1 2 4 S aureus Spain #356 (MethR) 32 8 4 4 I 4 8 haemolyticus 05 (Meth") 64 8 4 8 2 8 8 £ faecahs ATCC 29212 £0.25 1 0.25 2 £0.06 0.13 0.25 £ faecium ATCC 35667 4 4 1 2 0.5 1 2 £ faecium VanA (VanR) 4 8 2 4 0.25 0.25 2 £ faecahs VanB (VanR) 0.5 2 0.25 0.5 0.13 0.5 05 £ faecium A491 (AmpR) >128 >32 >32 >32 8 >32 >32 £ coh ATCC25992 £0.25 8 4 8 8 2 8 .P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 40 45 50 57 Table 1. Antimicrobial Properties of 7-fAcvlamidoV3-<arvlthiofcephems Organism ImiDenem 12 21 22 23 24 aureus ATCC 29213 £0.25 05 0.5 0.25 0.25 I 1 S aureus Col8A(Meths)(lac") £0.25 0.5 0.5 0.25 0.5 05 1 S aureus PCI (Meths)(lac>) £0.25 0.5 05 0.5 1 0.5 1 S aureus ATCC 13709 (Meths) sO.25 0.5 0.5 1 1 0.5 1 S aureus Col (MethR)(lac') 32 8 2 I 2 2 8 aureus 76 (MethR)(lac+) 32 8 4 1 2 4 8 aureus ATCC 33593(Meth*) 32 8 2 1 2 4 4 S aureus Spain #356 (MethR) 32 8 4 1 2 4 4 S haemolyticus 05 (MethR) 64 16 4 2 2 4 8 E faecalis ATCC 29212 £0.25 1 1 0 13 0 13 05 0.25 £ faecium ATCC 35667 4 1 1 0.5 1 2 2 £ faecium VanA (VanR) 4 2 2 1 2 4 4 £ faecalis VanB (VanR) 05 0.5 05 0 13 05 1 05 £ faecium A491 (Amp11) >128 >32 >32 8 lb >32 >32 £ coh ATCC25992 £0.25 8 4 32 8 2 8 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 Table 1. Antimicrobial Properties of 7-(Acvlamido^-3-(arvlthio>cephems Oreanism ImiDenem 26 27 28 29 aureus ATCC 29213 £0.25 0.25 0 13 0.25 1 0.25 0.25 S aureus Col8A(Meths)(iac') £0 25 0 25 0 13 0 13 0 25 0.25 0 13 S aureus PCI (Meths)(lac^) £0 25 0.25 0 13 0 25 0.5 0.25 £0.25 aureus ATCC 13709 (Meths) £0.25 0 25 £0 06 0 13 0.13 0.13 £0.25 aureus Col (MethR)(lac') 32 1 05 05 2 I 05 S aureus 76 (MethR)(laO 32 2 1 1 2 1 2 aureus ATCC 33593(MethR) 32 I 1 1 4 2 1 S aureus Spain #356 (MethR) 32 2 I I 2 2 1 S haemolyticus 05 (MethR) 64 2 2 2 4 2 1 £ faecahs ATCC 29212 £0.25 0 13 £0 06 £0 06 0 13 £0 06 £0 06 £ faecium ATCC 35667 4 1 0 25 0 25 I 0 25 0.5 £ faecium VanA (VanR) 4 2 05 0.5 4 05 1 £ faecahs VanB (VanR) 05 0 13 0 13 £0 06 0 25 £0 06 £0 06 £ faecium A491 (AmpR) >128 32 8 4 16 4 8 £ co/; ATCC25992 £0 25 4 >32 8 2 8 8 P aeruginosa ATCC 27853 1 >32 >32 32 32 >32 >32 Table 1. Antimicrobial Properties of 7-(Acvlamido)-3-(arvlthiokephems Organism Imipenem 21 32 33 34 36 S aureus ATCC 29213 £0.25 0.25 0.25 0.25 £0 06 0.25 05 S aureus Col8A(Meths)(lac") £0.25 0.25 0.25 0 25 £0.06 0.25 0 25 S aureus PCI (Meths)(lac*) £0.25 0.25 05 0.25 0 13 05 0.25 S aureus ATCC 13709 (Meths) £0 25 0.25 0 13 0 13 £0 06 0.25 0.25 S aureus Col (MethR)(lac-) 32 2 1 1 1 2 1 S aureus 76 (MethR)(lac*) 32 2 2 1 1 2 2 •S aureus ATCC 33593(MethR) 32 2 2 2 1 2 1 S aureus Spain #356 (MethR) 32 2 2 1 1 2 1 S haemolyticus 05 (MethR) 64 4 4 2 2 4 2 £ faecahs ATCC 29212 £0.25 0.5 £0.06 0 13 £0.06 £0 06 0.25 £ faecium ATCC 35667 4 0.5 05 0.5 0.25 0.25 05 £ faecium VanA (VanR) 4 1 1 2 0.5 0.5 1 E faecahs VanB (VanR) 0.5 0.25 0.13 0.13 £0.06 0.25 0.13 £ faecium A491 (AmpR) >128 8 8 8 4 4 8 £ coh ATCC25992 £0.25 8 8 1 4 8 16 P aeruginosa ATCC 27853 1 >32 >32 32 >32 >32 >32 58 Table 1. Antimicrobial Properties of 7-^Aevlamido>-3-(arvlthioteephems Orpanism ImiDenem 22 28 22 40 41 42 S. aureus ATCC 29213 £0.25 0.5 0 13 0.25 0.25 0.13 0 13 •S aureus Col8A(Meths)(lac") £0.25 £0.06 0.13 0.5 05 0.25 0.25 S aureus PCI (Meths)(lacT) £0.25 1 0.25 0.5 0 13 0 25 0.13 aureus ATCC 13709 (Meths) £0.25 £0.06 0.13 0.25 0.25 0.13 0 13 S aureus Col (MethR)(lac") 32 0.5 1 2 2 1 0.5 S aureus 76 (MethR)(lac+) 32 4 1 4 2 1 1 aureus ATCC 33593(MethR) 32 16 1 4 2 1 1 S aureus Spain #356 (MethR) 32 8 1 4 2 1 1 S haemolyticus 05 (MethR) 64 8 2 8 4 1 2 £ faecahs ATCC 29212 £0 25 0.25 0.13 0.25 0 13 £0 06 £0 06 £ faecium ATCC 35667 4 0.5 1 1 1 0 25 0.25 £ faecium VanA (VanR) 4 2 2 2 2 1 0.5 £ faecahs VanB (Van") 05 0.5 0.13 0.25 0.25 £0.06 £0 06 £ Jaecium A4V1 (Amp"} ->128 ->32 --32 32 16 S H £ coh ATCC25992 £0.25 >32 2 8 8 4 2 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 32 32 Table 1. Antimicrobial Properties of 7-(AcvlamidoV-3-(arvlthioteephems Organism ImiDenem 43 44 45 46 47 48 S aureus ATCC 29213 £0.25 05 0.5 1 1 1 05 S aureus Col8A(Meths)(lac") £0 25 0.5 0.5 1 0.5 0.5 0.5 S aureus PCI (Meths)(lac*) £0.25 1 2 2 2 2 0.5 S aureus ATCC 13709 (Meths) £0.25 0.5 2 2 2 2 0.25 S aureus Col (MethR)(iac") 32 2 4 4 2 2 4 S aureus 76 (MethR)(lac'') 32 2 4 4 4 2 8 S aureus ATCC 33593(MethR) 32 2 4 4 2 2 4 aureus Spajn #356 (MethR) 32 2 4 4 4 2 8 S haemolyticus 05 (MethR) 64 4 8 8 8 4 16 £ faecahs ATCC 29212 £0 25 0.13 0 13 0 13 0.13 0 13 0 25 £ faecium ATCC 35667 4 1 4 2 2 2 1 £ faecium VanA (Van") 4 1 2 4 2 2 4 £ faecahs VanB (VanR) 05 0 25 — — — — 05 £ faecium A491 (AmpR) >128 8 16 16 16 16 32 £ coh ATCC25992 £0 25 8 8 16 8 8 4 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 40 45 50 Table 1. Antimicrobial Properties of 7-(Acfvlamido>-3-(arvlthiokephems Organism Jmipentfp 49 50 51 51 53 54 S aureus ATCC 29213 £0.25 0.25 0 13 0.25 0.5 05 0.25 aureus Col8A(Meths)(lac") £0 25 0.5 0.25 0.5 0.25 05 0 25 S aureus PCI (Meths)(lac*) £0.25 0.5 0.25 05 0.5 1 0.25 S aureus ATCC 13709 (Meths) £0 25 0.25 0.13 0.5 0.5 0.25 0 25 S aureus Col (MethR)(lac") 32 2 2 2 2 4 2 S aureus 76 (MethR)(lac*) 32 2 2 4 2 4 2 S aureus ATCC 33593(MethR) 32 2 2 2 2 2 1 S aureus Spain #356 (MethR) 32 2 2 2 2 4 2 S haemolyticus 05 (MethR) 64 4 4 2 2 4 2 £ faecahs ATCC 29212 £0.25 0.13 0.13 0.13 £0.06 0.13 0 13 £ faecium ATCC 35667 4 1 1 0.13 £0.06 1 0.5 £ faecium VanA (VanR) 4 2 2 1 1 2 1 £ faecalis VanB (VanR) 0.5 0 13 0.5 0.25 0.13 0.25 0.25 £ faecium A491 (AmpR) >128 16 16 8 4 16 8 £ coh ATCC25992 £0.25 8 4 8 2 4 8 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 59 t Table 1. Antimicrobial Properties of 7-fAcvlamido)-3-('arvlthio)cephems • Organism ImiDenem 2£ 56 57 M 59 60 S aureus ATCC 29213 £0.25 0.5 0.5 1 0.5 0.5 0.25 S aureus Col8A(Meths)(lac') £0.25 0.5 0.5 I 0.5 0.25 0.25 aureus PC] (Meths)(lac+) £0.25 1 0.5 I 1 05 0.25 aureus ATCC 13709 (Meths) £0.25 0.25 0.25 0.5 0.5 0.13 0 13 S aureus Col (MethR)(lac") 32 4 2 4 4 2 2 aureus 76 (MethR)(lac>) 32 4 2 4 4 2 1 S aureus ATCC 33593(MethR) 32 2 2 4 2 2 2 aureus Spain #356 (MethR) 32 4 2 4 4 4 2 S haemolyticus 05 (MethR) 64 4 4 8 4 4 4 £ faecalis ATCC 29212 £0.25 0.25 0 13 0 13 0.5 0.5 05 £ faecium ATCC 35667 4 0.5 1 1 1 I 1 £ faecium VanA (VanR) 4 2 1 2 2 2 2 E faecalis VanB (VanR) 0.5 0.5 2 4 05 05 0.25 t. jaecium A491 (Amp"; >i2S io 8 io io io £ coh ATCC25992 £0 25 8 8 4 8 8 8 P aeruginosa ATCC 27853 1 >32 >32 >32 >32 >32 >32 Table 1. Antimicrobial Properties of 7-<AcvlamidoV3-(arvlthiolcephems Organism ImiDenem 61 £2 63 64 65 S aureus ATCC 29213 £0.25 1 0.5 0.25 0.25 0.5 S aureus Col8A(Meths)(lac") £0 25 1 0.5 0 13 0.25 0.5 aureus PC 1 (Meths)(lac+) £0 25 1 0.5 0.25 05 1 aureus ATCC 13709 (Meths) £0.25 1 0.5 0.25 0 25 0.5 aureus Col (MethR)(lac') 32 4 4 2 2 2 S aureus 76 (MethR)(lac'') 32 4 4 2 4 4 aureus ATCC 33 593(MethR) 32 4 4 2 2 4 S aureus Spain #356 (MethR) 32 4 4 4 4 4 S haemolyticus 05 (MethR) 64 8 4 2 4 4 £ faecahs ATCC 29212 £0 25 0 25 0 13 0 13 0.25 0.25 £ faecium ATCC 35667 4 1 1 0.5 1 — £ faecium VanA (VanR) 4 2 2 1 2 2 £ faecahs VanB (VanR) 05 0 25 0 25 0 25 05 05 £ faecium A491 (AmpR) >128 16 16 16 16 16 £ coh ATCC25992 £0.25 16 8 16 8 16 P aeruginosa ATCC 27853 I >32 >32 >32 >32 >32 40 45 Cmpd 1 (7i?)-7-[ (phenylacetyl) amino] -3-(3-isothioureido methylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 2 (7R)-7-[(phenylacetyl)amino]-3-(4-isothioureido methyl-1,2,3-thiadiazol-5-ylthio)-3-cephem-4-ca rboxylate, trifluoroacetic acid salt Cmpd 3 (7J?)-7- [ (Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(3-isothioureidomethylpyrid-4-y lthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 60 (1R) -7- [ (Z) -2- (aminothiazol-4-yl) -2- (hydroxyimi no)acetamido]-3-(4-isothioureidomethyl-l,2,3-th iadiazol-5-ylthio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(phenylacetyl)amino]-3-(4-isothioureido methylthiazol-5-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(phenylacetyl)amino]-3-[4-(3-pyrrolidin othiomethyl)-1,2,3-thiadiazol-5-ylthio]-3-cephe m-4-carboxylate, trifluoroacetic acid salt (1R) -7- [ (Z) -2- (aminothiazol-4-yl) -2- (hydroxyimi no)acetamido]-3-(4-isothioureidomethylthiazol-5 -ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(cyclopenty loxyimino)acetamido]-3-(3-isothioureidomethylpy rid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(phenylacetyl)amino]-3-(3-aminoethylthi omethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (1R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(3-aminoethylthiomethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2 -(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-[(methylaminoethylaminoethylthi omethyl)-1,2,3-thiadiazol-5-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 61 Cmpd 12 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-[(guanidinoethylaminoethylthiom ethyl)-1,2,3-thiadiazol-5-ylthio]-3-cephem-4-ca rboxylate, trifluoroacetic acid salt 5 Cmpd 13 (7J?)-7-[ (Z)-2-(aminothiazol-4-yl)-2-(cyclopenty loxyimino)acetamido]-3-(3-aminoethylthiomethylp yrid-4-ylthio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 14 (1R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi 10 no)acetamido]-3-(3-guanidinoethylthiomethylpyri d-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 15 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(3-methylaminoethylthiomethylpy 15 rid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 16 (7i?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-aminoethylthiomet hylpyrid-4-ylthio)-3-cephem-4-carboxylate, 20 trifluoroacetic acid salt Cmpd 17 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-[3-(3-pyrrolidinothiomethyl)pyr id-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 25 Cmpd 18 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no) acetamido]-3-[3-(N-methylglycyl)aminoethylth iomethylpyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 62 Cmpd 19 (7J?)-7-[ (Z) -2-(aminothiazol-4-yl) -2-(hydroxyimi no)acetamido]-3-[3-(2-amino-l,1-dimethylethylth iomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate , trifluoroacetic acid salt 5 Cmpd 20 (7R)-7-[ (Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(3-aminoethylthiopyrid-4-ylthio )-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 21 (7J?)-7-[ (Z)-2-(2-amino-5-bromothiazol-4-yl)-2-( 10 hydroxyimino)acetamido]-3-(3-aminoethylthiometh ylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 22 (7J2)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(methylaminoethylam 15 inoethylthiomethyl)-1,2,3-thiadiazol-5-ylthio]- 3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 23 (7i?) -7- [ (Z) -2- (aminothiazol-4-yl) -2- (2-fluoroet hoxyimino)acetamido]-3-(3-aminoethylthiomethylp 20 yrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt • Cmpd 24 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no) acetamido] -3- [3- (glycyl) arninoethylthiomethyl pyrid-4-ylthio]-3-cephem-4-carboxylate, 25 trifluoroacetic acid salt Cmpd 25 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(3-(N-formamidoyl)aminoethylthi omethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 63 Cmpd 26 (72?) -7- [ (Z) -2-phenyl-2- (hydroxyimino) acetamido] -3-(3-aminoethylthiomethylpyrid-4-ylthio)-3-cep hem-4-carboxylate, trifluoroacetic acid salt Cmpd 27 (7R) -7-[(Z) -2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- [3-(3-aminopropyl)th iomethylpyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 28 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[(methylamino ethylaminoethylthiomethyl)-1,2,3-thiadiazol-5-y lthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 29 (7R) -7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- [3-(glycyl)aminoethy 1thiomethylpyrid-4-ylthio]-3 -cephem-4-carboxyla te, trifluoroacetic acid salt Cmpd 30 (7J?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-aminoethylthiopyr id-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 31 [7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(N-formamidinoyl) aminoethylthiomethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 32 (7J?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(3-amino-2-hydrox yprop-1-ylthiomethyl)pyrid-4-ylthio]-3-cephem-4 -carboxylate, trifluoroacetic acid salt 64 Cmpd 33 (7R) -7-[(Z) -2-(2-amino-5-chlorothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-(3-aminoethyl thiomethylpyrid-4-ylthio)-3-cephem-4-carboxylat e, trifluoroacetic acid salt 5 Cmpd 34 (7i?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(3-N-formamidoyla minopropylthiomethyl)pyrid-4-ylthio)-3-cephem-4 -carboxylate, trifluoroacetic acid salt Cmpd 35 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-10 (hydroxyimino)acetamido]-3-[3-(glycyl)aminoprop ylthiomethylpyrid-4-ylthio]-3-cephem-4-carboxyl ate, trifluoroacetic acid salt Cmpd 36 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2-aminoprop-1-yl 15 thiomethyl)pyrid-4-ylthio)-3-cephem-4-carboxyla te, trifluoroacetic acid salt Cmpd 3 7 (7R)-7-[(phenylacetyl)amino]-3-(4-(2-aminoethyl thiomethyl)-1,2,3 -thiadiazol-5-ylthio)- 3-cephem -4-carboxylate, trifluoroacetic acid salt 20 Cmpd 38 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimi no)acetamido]-3-(4-(2-aminoethylthiomethyl)-1,2 ,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 39 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-25 (hydroxyimino)acetamido]-3-(3-carboxamidomethyl thiomethylpyrid-4-ylthio)-3-cephem-4-carboxylic acid o 65 Cmpd 40 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2-aminoethoxymet hyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 5 Cmpd 41 (7J2)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2-N-methylaminoe thylthiomethyl)pyrid-4-ylthio)-3-cephem-4-carbo xylate, trifluoroacetic acid salt Cmpd 42 (7J?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-10 (hydroxyimino)acetamido]-3-(3-(pyrrolidin-3-ylt hiomethyl)pyrid-4-ylthio)-3-cephem-4-carboxylat e, trifluoroacetic acid salt Cmpd 43 (7R) -7-[(Z) -2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(N-methylglycyl)a 15 minoethylthiomethylpyrid-4-ylthio]-3-cephem-4-c arboxylate, trifluoroacetic acid salt Cmpd 44 (7R) -7-[(Z) -2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(5-aminopentyloxy methyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, 20 trifluoroacetic acid salt Cmpd 45 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-aminoethylsulfony lmethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 25 Cmpd 46 (7R)-7- [ (Z)-2-(2-ammo-5-chlorothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-(3-(4-aminobutyloxym ethyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt n 66 Cmpd 47 (7R) -7-[ (Z)-2-(2-arnino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(3-aminopropyloxy methyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 5 Cmpd 48 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(4-amino-2-butyn-1-yl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 49 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-10 (hydroxyimino)acetamido]-3-(3-(2-aminopropyloxy methyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 50 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(4-amino-2-Z-bute 15 n-l-yl)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 51 (7R) -7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(3-aminopropylthi o)pyrid-4-ylthio)-3-cephem-4-carboxylate, 20 trifluoroacetic acid salt Cmpd 52 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(piperidine-4-ylt hiomethyl)pyrid-4-ylthio)-3-cephem-4-carboxylat e, trifluoroacetic acid salt 25 Cmpd 53 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-(3-aminoethylsulfiny lmethylpyrid-4-ylthio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt n 67 Cmpd 54 (7J?)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-(3-(N-acetamidinoyl) aminoethylthiomethylpyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt 5 Cmpd 55 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(5S-5-N,N-dimethy Icarboxamidopyrrolidin-3-ylthiomethyl)pyrid-4-y lthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 56 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2- (hydroxyimino) acetamido] -3- [3- (2RS-2-amino-3-hy droxyprop-l-ylthiomethyl)pyrid-4-ylthio] - 3-ceph em-4-carboxylate, trifluoroacetic acid salt Cmpd 57 (7jR)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl) -2-15 (hydroxyimino)acetamido]-3-(3-(N-methylaminoeth ylaminoethylthiomethyl)pyrid-4-ylthio)-3-cephem -4-carboxylate, trifluoroacetic acid salt Cmpd 58 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2R-2-N,N-dimethy 20 lcarboxamido-2-aminoethylthiomethyl)pyrid-4-ylt hio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 59 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2R-2-carboxamido 25 -2-aminoethylthiomethyl)pyrid-4-ylthio)-3-cephe m-4-carboxylate, trifluoroacetic acid salt Cmpd 60 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-isothioureidometh ylpyrid-4-ylthio)-3 -cephem-4-carboxylate, 3 0 trifluoroacetic acid salt # 68 Cmpd 61 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(N,N-dimethylcarb oxamidomethylaminoethylthiomethyl)pyrid-4-ylthi o)-3-cephem-4-carboxylate, trifluoroacetic acid 5 salt Cmpd 62 (7J?)-7- [ (Z) -2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-(2-amino-2-methyl propylthiomethyl)pyrid-4-ylthio)-3-cephem-4-car boxylate, trifluoroacetic acid salt 10 Cmpd 63 (7J?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-(3-(N-formylaminoeth ylthiomethyl)pyrid-4-ylthio)-3 -cephem-4-carboxy late, trifluoroacetic acid salt Cmpd 64 (71?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-15 (hydroxyimino)acetamido]-3-(3-(N-formylaminoeth ylthio)pyrid-4-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt Cmpd 65 (7J?)-7-[ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino) acetamido] -3- [3- (2i?-2-amino-3-hyd 20 roxyprop-1-ylthiomethyl)pyrid-4-ylthio]-3-cephe m-4-carboxylate, trifluoroacetic acid salt (Compound numbers correspond to those in MIC tables; data reported for challenge with methicillin-susceptible S. aureus strain ATCC 13709.) 69 # " | Survivors Compound: Vancomycin Imroenem 1 3 Dose mg/kg /10 mg/kg /10 2.5 mg/kg 4/10 /10 9/10 1.25 mg/kg 2/10 8/10 7/10 /10 0 . 625 mg/kg 2/10 /10 6/10 8/10 8/10 0.3125 mg/kg /10 /10 /10 2/10 0.156 mg/kg /10 2/10 0/10 2/10 0 . 07R mg/kg 6/1 0 2/10 0 . 039 mg/kg 3/10 1.29 ED50 (mg/kg) 1 . 94 0 . 06 0 .39 0 .42 Survivors Compound: 11 14 13. 16 17 Dose 40 mg/kg mg/kg mg/kg mg/kg /10 /10 6/10 2.5 mg/kg 6/10 9/10 /10 8/10 3/10 1.25 mg/kg /10 3/10 2/10 /9 /10 0 . 625 mg/kg 3/10 3/10 0/10 3/10 2/10 0.3125 mg/kg 1/10 1/10 2/10 1/10 2/10 0 .156 mg/kg 1/10 2/10 EDS0 (mg/kg) 0 . 96 1.13 4 . 63 1. 00 3 . 59 Survivors Compound: 11 26 27 28 22 Dose mg/kg 6/10 9/10 7/10 7/10 7/10 2 . 5 mg/kg 2/10 7/10 6/10 3/10 9/10 1.25 mg/kg 2/10 /10 2/10 4/10 9/10 0 . 625 mg/kg 2/10 /10 0/10 1/10 /10 0.3125 mg/kg 3/10 1/10 0/10 1/10 2/10 ED50 (mg/kg) 4 .44 1. 06 2 . 64 3 . 01 1.26 70 Survivors Compound: M 12 11 12 Dose mg/kg /10 8/10 8/10 /10 8/10 2.5 mg/kg /10 /10 9/10 6/10 8/10 1.25 mg/kg 4/10 /10 /10 6/10 3/10 0.625 mg/kg 2/10 1/10 4/10 3/10 3/10 0.3125 mg/kg 0/10 0/10 0/10 1/10 2/10 ED„ (mg/kg) 1.14 2 . 00 1.19 1.15 1.23 Su-*-""' Compound: 57 58 59 64 65 Dose mg/kg 9/10 /10 /10 8/10 8/10 2.5 mg/kg /10 /10 4/10 4/10 3/10 1.25 mg/kg 4/10 2/10 4/10 4/10 1/10 0.625 mg/kg 4/10 1/10 6/10 1/10 2/10 0.3125 mg/kg 4/10 1/10 4/10 1/10 1/10 ED50 (mg/kg) H O 00 H O 0 . 81 2.27 3 .10 71 EXAMPLES The present invention will be more fully described in conjunction with the following specific examples which are not to be construed in any way as limiting the scope of the invention.

Example 1 (7R)-7 -t(phenylacetyl)amino]-3 -(4-hydroxymethyl-i,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirred solution of 1,3-dichloroacetone (6.85 g, 54 mmol) and ethyl 3-mercaptopropionate (13.9 mL, 108 mmol) in anhydrous tetrahydrofuran (150 mL) was dropwise added triethylamine (15.0 mL, 108 mmol) at 0 °C and stirred at room temperature for 24 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate phase was washed with 5% hydrochloric acid and then brine, dried over sodium sulfate, and concentrated to dryness, affording 17.4 g of the crude 1,3-bis(2-ethoxycarbonylethylthio)acetone.

A solution of 1,3-bis [ (2-ethoxycarbonylethyl)thio]acetone (6.22 g, 19.3 mmol), ethyl carbazate (2.40 g, 23.1 mmol) and a catalytic amount of p-toluenesulfonic acid in anhydrous acetonitrile (50 mL) containing molecular sieve was stirred for 2 days at room temperature. The reaction was quenched with water / ethyl acetate and filtered. The filtrate was extracted with ethyl acetate. The 72 organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was triturated with hexane, affording 7.2 g of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone ethoxycarbonylhydrazone. 1H NMR (CDC13) 5 2.2-2.4 (m, 9H) , 2.6-2.8 (m, 8H) , 3.42 (s, 2H) , 3.54 (s, 2H) , 4.1-4.3 (m, 6H), 8.82 (br s, 1H).

To a solution of the hydrazone (7.2 g, 17.6 mmol) in 1,2-dichloroethane (20 mL) was added thionyl chloride (3.9 mL, 53 mmol) at 0 °C and stirred overnight at room temperature. The mixture was concentrated to a volume of 10 mL, diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and then concentrated to dryness, affording 6.47 g of - [ (2-ethoxycarbonylethyl) thio],-4- [ (2-ethoxycarbonylethy 1)thiomethyl]-1,2,3-thiadiazole. 1H NMR (CDC13) 5 1.2-1.3 (m, 6H), 2.60 (t, 2H, J=7), 2.68 (t, 2H, J=7), 2.77 (t, 2H, J=7), 3.24 (t, 2H, J=7), 4.07 (s, 2H), 4.1-4.2 (m, 4H) .

To a solution of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethy 1)thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmol) in dichloromethane (4 0 mL) was added m-chloroperoxybenzoic acid in several portions at 0 °C until the starting material was disappeared. The mixture was then sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, 73 and was concentrated to dryness. The oxidized product was treated with trifluoroacetic anhydride (2 mL) for 3 0 min at room temperature. After removal of trifluoroacetic anhydride under the reduced pressure, 5 the mixture was stirred in ethyl acetate / 1% sodium hydroxide (3 0 ml / 3 0 mL) for 3 0 min. The ethyl acetate layer was concentrated to a volume of 5 mL and methanol (10 mL) was added. Excess sodium borohydride (200 mg) was added in portions at 0 °C while stirring. After 3 0 10 min, the reaction was quenched with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol / dichloromethane) to provide 225 mg of 15 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-l,2, 3-th ladiazole. 1H NMR (CDC13) 6 1.27 (t, 3H, J=8), 2.71 (t, 2H, J=7), 3.27 (t, 2H, J=7), 4.16 (q, 2H, J=8), 5.03 (s, 2H) .

To a solution of 20 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-l,2,3-th iadiazole (225 mg, 0.91 mmol) in anhydrous ethanol (20 mL) was added 0.5M sodium methoxide in methanol (1.6 mL). After 10 min, the mixture was concentrated, and was triturated with dichloromethane to obtain the sodium 25 thiolate. A solution of the sodium thiolate and (7R)-7-[(phenylacetyl)amino]-3-trifluoromethanesulfonylo xy-3-cephem-4-carboxylate, 4-methoxybenzyl ester (500 mg, 0.85 mmol) in tetrahydrofuran (10 mL) was stirred at 0 °C for 3 0 min, and water (50 ml) was added. The 74 reaction mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (2% methanol / dichloromethane), affording 407 mg of the title compound. 1H NMR (CDC13) 5 5 3.22 (d, 1H, J=18), 3.46 (d, 1H, J=18), 3.61 (d, 1H, J=16), 3.67 (d, 1H, J=16), 3.81 (s, 3H) , 4.95 (d, 1H, J=5) , 5.02 (s, 2H) , 5.23 (d, 1H, J=12), 5.28 (d, 1H, J=12), 5.83 (dd, 1H, J=5, 8), 6.14 (d, 1H, J=8), 6.86 (d, 2H, J=9), 7.2-7.4 (m, 7H).

Example 2 (7R)-7-[(phenylacetyl)amino]-3-(4-chloromethyl-l,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To DMF (5 mL) was added thionyl chloride (85 15 mL, 1.71 mmol) and stirred for 30 min at room temperature. A solution of (7R)-7-[(phenylacetyl)amino]-3-(4-hydroxymethyl-l,2,3-th iadiazol-5-ylthio)- 3-cephem-4-carboxylate, 4-methoxybenzyl ester (400 mg, 0.684 mmol) in DMF (1 mL) 20 was added and stirred for an additional 3 0 min. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic extract was washed with water and concentrated. The residue was purified by silica gel chromatography (0.5% methanol / 25 dichloromethane), affording 322 mg of the title compound. 1H NMR (CDC13) 5 3.20 (d, 1H, J=18), 3.47 (d, 1H, J=18), 3.60 (d, 1H, J=16), 3.66 (d, 1H, J=16), 3.79 (s, 3H), 4.95 (m, 3H), 5.22 (d, 1H, J=12), 5.25 (d, 1H, 75 J=12) , 5.85 (dd, 1H, J=5, 8), 6.53 (d, 1H, J=8) , 6.84 (d, 2H, J=9), 7.2-7.4 (m, 7H).

Example 3 (7J2) -7- [ (phenylacetyl) amino] -3- (4-isothioureidomethyl-l, 5 2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt A solution of (7R)-7-[(phenylacetyl)amino]-3-(4-chloromethyl-l,2, 3-thi adiazol-5-ylthio)-3 -cephem-4-carboxylate, 10 4-methoxybenzyl ester (70 mg, 0.12 mmol), thiourea (7.6 mg, 0.1 mmol) and sodium iodide (15 mg, 0.1 mmol) in dry acetonitrile (3 mL) was stirred at room temperature overnight. The mixture was concentrated and triturated with dichloromethane to remove the unreacted starting 15 material. The residue was redissolved in acetone (2 mL) and filtered. The filtrate was concentrated to dryness, affording 60 mg of (7R)-7-[(phenylacetyl)amino]-3 -(4-isothioureidomethyl-l, 2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 20 4-methoxybenzyl ester, iodide salt as a yellowish solid. 1H NMR (acetone-d6) 5 3.56 (d, 1H, J=18) , 3.66 (d, 1H, J=16), 3.72 (d, 1H, J=16), 3.80 (s, 3H), 3.86 (d, 1H, J=18) , 5.06 (d, 1H, J=15), 5.10 (d, 1H, J=15) , 5.28 (m, 3H), 5.88 (dd, 1H, J=5, 8), 6.91 (d, 2H, J=9), 7.2-7.4 25 (m, 7), 8.32 (d, 1H, J=8).

A mixture of {7R)-7-[(phenylacetyl)amino]-3-(4-isothioureidomethyl-l, 2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 76 4-methoxybenzyl ester, iodide salt (60 mg), anisole (0.1 mL) and trifluoroacetic acid (1 mL) was stirred at 0 °C for 3 0 min, and then concentrated to dryness. The residue was sequentially triturated with dichloromethane 5 (40 mL) and water (0.5 mL) to afford 38 mg of the title compound. 1H NMR (DMSO-d6) 8 3.41 (d, 1H, J=18) , 3.48 (d, 1H, J=14), 3.55 (d, 1H, J=14), 3.69 (d, 1H, J=18), 4.86 (d, 1H, J=15) , 4.94 (d, 1H, J=15) , 5.14 (d, 1H, J=5) , 5.72 (dd, 1H, J=5, 8), 7.1-7.3 (m, 7H) , 9.18 (d, 1H, 10 J=8) Example 4 (7R)-7-amino-3 -(4-chloromethyl-l,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a solution of 15 (7R) -7- [ (phenylacetyl) ammo] - 3- (4-chloromethyl-l, 2, 3-thi adiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (6 04 mg, 1.6 8 mmol) and pyridine (0.271 mL, 3.36 mmol) in dichloromethane (20 mL) was dropwise added a solution of phosphorous pentachloride 20 (208 mg, 2.68 mmol) in dichloromethane (10.7 mL) and stirred at -10 °C for 2 h. After cooling to -40 °C, isobutanol (1.55 mL) was added, and the resulting mixture was stirred at -10 °C for 4 h. The reaction was quenched with water, and the mixture was extracted with 25 dichloromethane. The organic extract was washed with saturated aqueous sodium bicarbonate and concentrated. The residue was purified by silica gel chromatography (10% methanol / dichloromethane), affording 599mg of the 77 title compound. 1H NMR (CD3OD) d 3.45 (d, 1H, J=18), 3.65 (d, 1H, J=18), 3.76 (s, 3H), 4.75 (1H, overlapped with water), 4.98 (s, 2H), 5.05 (d, 1H, J=5), 5.23 (s, 2H), 6.82 (d, 2H, J=9), 7.26 (d, 2H, J=9) .

Example 5 4-chloro-3-hydroxymethylpyridine To a solution of 4-chloro-3-pyridyl carboxyaldehyde (140 mg, 1.0 mmol) in THF (1 mL) at 0 °C was added methanol (lmL) followed by portionwise 10 addition of sodium borohydride (75 mg, 2.0 mmol). After 1 hr, acetic acid (0.15 ml) was added and the reaction mixture was evaporated to dryness with rotary evaporator at room temperature. The solid residue was chromatographed on silica gel column (1% MeOH / 15 dichloromethane) to afford 60 mg (42 %) of the title compound. 1H NMR (CDC13) 5 4.30 (br s, 1H), 4.80 (s, 2H), 7.30 (d, 1H, J=5), 8.34 (d, 1H, J=5), 8.62 (s, 1H).

Example 6 (7R)-7-[(phenylacetyl)amino]-3-(3-hydroxymethylpyrid-4-20 ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a solution of 4-chloro-3-hydroxymethylpyridine (60 mg, 0.42 mmol) in DMF (1 mL) at room temperature under nitrogen was added potassium thioacetate (71 mg, 0.63 mmol). After 25 overnight stirring, the solvent was removed with rotary evaporator. The residue was washed with ethyl ether and taken up in 10% MeOH / dichloromethane. The insoluble 78 material was filtered off and the filtrate was concentrated with rotary evaporator. The residual material was dissolved in MeOH (3 mL) and aqueous sodium hydroxide was added (0.5 mL, 3 M). After an overnight 5 reaction at room temperature the reaction was acidified with 1 M hydrochloric acid, evaporated to dryness with rotary evaporator, and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried with sodium sulfate and the 10 solvent was removed with rotary evaporator. The residue was dissolved in MeOH and (7R)-7- [ (phenylacetyl)amino]-3-trifluoromethanesulfonylo xy-3-cephem-4-carboxylate, 4-methoxybenzyl ester(240 mg, 0.42 mmol) was added followed by addition of 15 dichloromethane. After an overnight reaction at room temperature the reaction was partitioned between 5% sodium bicarbonate solution and ethyl acetate. Purification on silica gel (Chromatotron, 2% MeOH / dichloromethane) afforded the title compound (60 mg, 20 25%). 1H NMR (CDCl3) 5 3.15 (d, 1H, J=18), 3.55 (d, 1H, J=18) , 3.63 (d, 1H, J=18) , 3.68 (d, 1H, J=18), 3.78 (s, 3H), 4.61 (d, 1H, J=13), 4.66(d, 1H, J=13), 5.05 (d, 1H, J=5) , 5.08 (d, 1H, J=13) , 5.25 (d, 1H, J=13) , 5.89 (dd, 1H, J=9, 5), 6.76 (d, 2H, J=8), 7.05 (m, 2H), 7.16 25 (d, 21H, J=8), 7.32 (m, 5H), 8.40 (d, 1H, J=5), 8.48 (s, 1H) . 79 Example 7 (7R)-7-[(phenylacetyl) amino]-3-(3-chloromethylpyrid-4-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a solution of 5 (7R)-7-[(phenylacetyl)amino]-3-(3-hydroxymethylpyrid-4-y lthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (112 mg, 0.194 mmol) and lithium chloride (14 mg, 0.581 mmol) in DMF at 0 °C was added diisopropylethylamine (0.101 mL, 0.581 mmol) and methanesulfonyl chloride 10 (0.045 mL, 0.581 mmol). After 45 min, the reaction mixture was partitioned between water and ethyl acetate / hexane (v/v, 3/1). Purification on silica gel (Chromatotron, 2% MeOH / dichloromethane) afforded the title compound (52 mg, 45%) . 1H NMR (CDC13) 5 3.17 (d, 15 1H, J=18), 3.59 (d, 1H, J=18), 3.63 (d, 1H, J=18), 3.68 (d, 1H, J=18), 3.77 (s, 3HH), 4.54 (d, 1H, J=13), 4.66 (d, 1H, J=13) , 5.06 (d, 1H, J=5), 5.08 (d, 1H, J=13), 5.22 (d, 1H, J=13), 5.90 (dd, 1H, J=9, 5), 6.76 (d, 2H, J=8) , 6.95 (d, 1H, J=9) , 7.07 (d, 1H, J=5), 7.15 (d, 20 2H, J=8), 7.30 (m, 5H), 8.41 (d, 1H, J=5), 8.45 (s, 1H).

Example 8 (7R)-7-[(phenylacetyl)amino]-3 -(3 -isothioureidomethylpyrid-4-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester, hydrochloride salt To a solution of (7R)-7-[(phenylacetyl)amino]-3-(3-chloromethylpyrid-4-yl thio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (52 mg, 0.087 mmol) in ethanol (0.4 mL) and dichloromethane 80 (0.1 mL) was added thiourea (7 mg, 0.095 mmol) at room temperature. After overnight reaction the solvents were removed with rotary evaporator and the residue was triturated with ethyl ether. The solid precipitate was 5 then dried in vacuum to afford the title compound (56mg, 96%). 1H NMR (CDC13 / cd3od) 5 3.14 (d, 1H, J=10), 3.53 (d, 1H, J=10), 3.58 (s, 2H), 3.73 (s, 3H), 4.40 (s, 2H), 5.03 (d, 1H, J=5), 5.12 (d, 1H, J=9), 5.15 (d, 1H, J=9), 5.75 (d, 1H, J= 5), 6.74 (d, 2H, J=10), 7.10 (d, 1H, 10 J=5), 7.14 (d, 2H, J=10), 7.25 (m, 5H), 8.30 (d, 1H, J=5) , 8.45 (s, 1H) .

Example 9 (7R)-7-[(phenylacetyl)amino]-3-(3-isothioureidomethylpyrid-4-ylthio)-3-cephem-4-15 carboxylate, trifluoroacetic acid salt To a solution of (7R)-7-[(phenylacetyl)amino]-3-(3-isothioureidomethylpyr id-4-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester hydrochloride (56mg, 0.083 mmol) in 20 dichloromethane (1 mL) was added anisole (0.1 ml) followed by addition of trifluoroacetic acid (1 mL). After 3 0 min, the reaction mixture was concentrated with rotary evaporator and the residue was triturated with ethyl ether. The precipitate was repeatedly washed by 25 decantation with fresh portions of ethyl ether and dried in vacuum to afford the title compound (49mg, 79%). 1H NMR (cd3od) 8 3.20 (d, 1H, J=18), 3.58 (d, 1H, J=13), 3.62 (d, 1H, J=13), 3.83 (d, 1H, J=18), 4.56 (d, 1H, 81 J=10), 4.60 (d, 1H, J=10), 5.25 (d, 1H, J=5), 5.78 (d, 1H, J=5) , 7.28 (m, 5H) , 7.43 (d, 1H, J=5) , 8.45 (d, 1H, J=5) , 8.55 (s, 1H) .

Example 10 (7R)-7- [ (Z)-2-(N-triphenylmethylaminothiazol-4-yl) -2-(triphenylmethoxyimino) acetamido]-3-(4-chloromethyl-l,2, 3 -thiadiazol-5-ylthio)-3 -cephem-4-carboxylate, 4-methoxybenzyl ester To a suspension of (Z)-2-(N-triphenylmethylaminothiazol-4-yl)-2-(triphenylm ethoxyimino)acetate sodium salt (2.11 g, 3.05 mmol) in DMF (4 mL) was added methanesulfonyl chloride (0.28 mL) at -60 °C and stirred at the same temperature for 1.5 h. The solution was then added to a solution of (7R)-7-ammo-3-(4-chloromethyl-l,2,3-thiadiazol-5-yl)thi o-3-cephem-4-carboxylate, 4-methoxybenzyl ester hydrochloride (920 mg, 1.8 8 mmol) and diisopropylethylamine (0.4 mL) in DMF (2 mL) at -10 °C and stirred for 1 h. The reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration. The filter cake was purified by silica gel column chromatography (0.5% methanol / dichloromethane), affording 558 mg of the title compound. 1H NMR (CDC13) 8 3.07 (d, 1H, J=18), 3.44 (d, 1H, J=18), 3.81(2H), 4.96 (2H), 5.06 (1H), 6.07 (1H), 6.43 (s, 1H), 6.80 (br s, 1H), 6.88 (1H), 7.25-7.45 (40H) . 82 Example 11 (7R) -7- [(Z) -2- (aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-(4-isothioureidomethyl-l,2,3 -thiadiazol-5-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt A solution of (1R)-7-[(Z)-2-(N-triphenylmethylaminothiazol-4-yl)-2-(tr iphenylmethoxyimino)acetamido]-3-(4-chloromethyl-l, 2, 3-t hiadiazol-5-ylthio)-3 -cephem-4-carboxylate, 4-methoxybenzyl ester(221mg, 0.19 mmol), sodium iodide (34 mg, 0.23 mmol) and thiourea (14 mg, 0.18 mmmol) in acetonitrile (10 mL) was stiired at 45 °C for 3 h. The resulting mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water and concentrated. The residue was triturated to obtain the isothiouronium salt, which was subjected to the substantially the same conditions for deprotection as used in Example 9, affording 27 mg of the title compound. 1H NMR (D20) 8 3.48 (d, 1H, J=18), 3.84 (d, 1H, J=18), 5.39 (s, 1H), 5.90 (s, 1H), 7.16 (s, 1H).

Example 12 4-ethoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio]thiazole To a solution of potassium tert-butoxide (496 mg, 4.4 mmol) in 10 ml of THF was added a solution of ethyl isocyanoacetate (0.48 ml, 4.4 mmol) in 5 ml of THF at -40 °C and the reaction mixture was continued to stir for 10 min. After the reaction was cooled down to -60 °C, a solution carbon disulfide in 5 ml of THF was added. 83 The resulting mixture was allowed to warm up to 0 °C and 2-iodoethyl phenyl sulfone (4.4 mmol) was added. The mixture was then stirred at refluxed condition for 5 hours. After it was cooled down to room temperature, 5 water and ethyl acetate were added. The aqueous layer was adjusted to acidic condition with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced 10 pressure. The crude residue was purified by chromatography to give the title compound (890 mg, 56%). 1H NMR (CDC13) 6 1.40 (t, 3H, J=7), 3.3-3.5 (m, 4H), 4.40 (q, 2H, J=7) , 7.6 (t, 2H, J=8), 7.70 (t, 1H, J=8), 7.93 (d, 2H, J=8), and 8.64 (s, 1H).

Example 13 4-hydroxymethyl-5-[2-(phenylsulfonyl)ethylthio]thiazole To a solution of 4-ethoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio] thiazole (702 mg, 2 mmol) in 2 0 ml of THF was added lithium 20 borohydride (2M, 1 ml) and methanol (0.16 ml, 4 mmol) at -3 0 °C. The reaction mixture was allowed slowly warm up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the crude residue was subjected to chromatography by using dichloromethane 25 and methanol as the eluent to give the title compound (400 mg, 65%). 1H NMR (CDCl3) 5 2.55 (s, 1H) , 3.00 (t, 2H, J=6), 3.40 (t, 2H, J=6), 4.71 (s, 2H), 7.6 (t, 2H, 84 J=7) , 7.68 (t, 1H, J=7) , 7.82 (d, 2H, J=7) , and 8.80 (s, 1H) .

Example 14 (7R)-7-[(Z)-2-(N-triphenylmethylaminothiazol-4-yl)-2 -(triphenylmethoxyimino)acetamido]-3-(4-hydroxymethylthiazol-5-ylthio)-3 -cephem-4-carboxylate, 4-methoxybenzyl ester To a solution of 4-hydroxymethyl-5-[2-(phenylsulfonyl)ethylthio]thiazole (3 9 mg) in 1 ml of DMF was added potassium t-butoxide (14 mg) and the resulting mixture was continued to stir for 2 hours. After the reaction solution was cooled down to -4 0 °C, a solution of (7R) -7- [ (z) -2- (N-triphenylmethylammothiazol-4-yl) -2- (tr iphenylrnethoxyimino) acetamido] -3-trifluoromethanesulfony loxy-3-cephem-4-carboxylate, 4-methoxybenzyl ester (104 mg) in 1.5 ml of DMF was added. The mixture was allowed slowly warm up to 0 °C, quenched with dilute aqueous ammonium chloride, and extracted with ethyl acetate and hexane. The solvent was removed under reduced pressure and the crude residue was purified by chromatography to give the title compound (61 mg). 1H NMR (CDC13) 5 3.28 (q, 2H, J=8), 3.82 (s, 3H), 4.72 (q, 2H, J=8 Hz), 4.98 (d, 1H, J=4) , 5.25 (q, 2H, J=8), 5.96 (q, 1H, J=4) , 6.42 (s, 1H), 6.85 (s, 1H), 6.93 (d, 2H, J=7), 7.20-7.42 (m, 33H), and 8.8 (s, 1H). 85 Example 15 (712) -7- [ (Z) -2- (N-triphenylmethylaminothiazol-4-yl) -2- (triphenylmethoxyimino) acetamido] -3- (4-chloromethylthiazol-5-ylthio)-3 -cephem-4-carboxylate, 4-methoxybenzyl ester To DMF (l ml) was added thionyl chloride (0.016 ml) at 0 °C and the resulting mixture was continued to stir at the same temperature for 3 0 min. The resulting solution was canulated to a solution of (72?) -7- [ (Z) -2- (N-triphenylmethylaminothiazol-4-yl) -2- (tr iphenylmethoxyimino)acetamido]-3-(4-hydroxymethylthiazol -5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (61 mg) in 1 ml of DMF and continued to stir at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and hexane, and was washed with water. The solvent was removed under reduced pressure and the crude residue was purified by chromatography to give the title compound (43 mg). 1H NMR (CDC13) 5 3.22 (q, 2H, J=12), 3.80 (s, 3H) , 4.78 (q, 2H, J=8), 5.04 (d, 1H, J=4), 5.30 (q, 2H, J=5), 6.00 (q, 1H, J=4), 6.42 (s, 1H) , 6.72 (s, 1H) , 6.92 (d, 2H, J=7) , 7.08 (d, 1H, J=4), 7.20-7.45 (m, 32H), and 8.95 (s, 1H). 86 Example 16 (7J2) -7- [ (Z) -2- (N-triphenylmethylaminothiazol-4-yl) -2-(triphenylmethoxyimino) acetamido] -3-(4-isothioureidomethylthiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (7R)-7-[(Z)-2-(N-triphenylmethylaminothiazol-4-yl)-2-(tr iphenylmethoxyimino)acetamido]-3-(4-chloromethylthiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (43 mg) was dissolved in 2 ml of acetonitrile, to which was added thiourea (4.5 mg) and sodium iodide (13 mg). The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography to give the title compound(40 mg). 1H NMR (CDC13 / CD3OD) 5 3.2 (q, 2H, J=12), 3.80 (s, 3H), 4.4 (q, 2H, J=12), 5.02 (d, 1H, J=4 5.25 (q, 2H, J=5), 5.85 (d, 1H, J=4) , 6.45 (s, 1H) , 6.90 (d, 2H, J=7) , 7.2-7.4 (m, 32H), and 9.00 (s, 1H).

Example 17 (7,R)-7-[(Z)-2- (amino thiazol-4-yl) -2-(hydroxyimino)acetamido]-3-(4-isothioureidomethylthiazol-5-ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2-(N-triphenylmethylaminothiazol-4-yl)-2-(tr iphenylmethoxyimino)acetamido]-3-(4-isothioureidomethylt hiazol-5-ylthxo)-3-cephem-4-carboxylate, 4-methoxybenzyl 87 ester(40 mg) was dissolved in 0.1 ml of anisole and 0.9 ml of dichloroacetic acid. The resulting mixture was stirred at room temperature for 3 hours and then precipitated by addition of diethyl ether (100 ml). The 5 precipitate was filtered and subjected to HP-20 reverse phase chromatography to give the title compound. 1H NMR (D20) 5 3.60 (q, 2H, J=6), 4.60 (q, 2H, J=10), 5.20 (d, 1H, J=4), 5.80 (d, 1H, J=4), 6.90 (s, 1H), and 9.13 (s, 1H). IR (KBr) 997, 1042, 1180, 1349, 1386, 1533, 1615, 10 1655, and 1768 cm"1.

Example 18 (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(triphenylmethoxyimino) acetic acid To a solution of 15 (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino) ace tic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature (lmL) was added N-chlorosuccinimide (1.80 g, 13.47 mmol). After overnight reaction the reaction mixture was poured into water (about 500 mL) and the 2 0 resulting precipitate was filtered, washed with water and then with ethyl acetate and dried in vacuum to afford 4.43 g (71%) of the title compound. 13C NMR (CDC13) 5 108.5 , 125.6 ,126.2 , 126.6 , 12.3 , 134.7 , 141.8 , 146.5 , 162.1 , 163.3. 88 Example 19 (7fi)-7-[(Z)-2- (2-amino-5-chloro thiazol-4-yl) - 2 -(triphenylmethoxyimino) acetamido] -3-chloro-3-cephem-4-carboxylate diphenylmethyl ester To a solution of 7-amino-3-chlorocephalosporanic acid diphenylmethyl ester toluenesulfonic acid salt (5.0g, 8.72 mmol) in dry THF (lOOml)was added pyridine (0.63g. 10.0 mmol) at room temperature followed by addition of (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxy imino)acetic acid (5.81 g, 13.47 mmol). The resulting slurry was cooled to -15 °C and additional pyridine (1.42 g, 22.5 mmol) was added followed by dropwise addition of phosphorous oxychloride(1.64 g, 17.5 mmol) while maintaining reaction temperature below -10 °C. After 30 min. reaction ethyl acetate (200 mL) was added followed by addition of water (150 mL). Aqueous layer was thoroughly extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate and concentrated in vacuum to yield crude product which was purified by flash column chromatography on silica gel (ethyl acetate / hexane-3/l) to afford the title compound (5.37 g, 65%). 1H NMR (CDC13 /CD30D) 5 3.35 (d, 1H, J=18) , 3.68 (d, 1H, J=18), 5.07 (d, 1H, J=5) , 5.80 (br s, 2H), 6.04 (dd, 1H, J=9, 5), 7.03 (s, 1H), 7.06 (d, 1H, J=9) , 7.22-7-50 (m, 25H) . 89 Example 20 (712) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(triphenyImethoxyimino) acetamido] -3 -mercapto-3 -cephem-4-carboxylate diphenylmethyl ester To a solution of (7R) -7- [ (Z) -2- (2-arnino-5-chlorothiazol-4-yl) -2- (tripheny Imethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate diphenylmethyl ester (4.0 g , 4.72 mmol) in DMF (30 mL) cooled to -20 °C was added in one portion powdered sodium 10 hydrogen sulfide hydrate (1.1 g, 19.6 mmol). After 15 min the reaction mixture was poured into 0.5 M monosodium phosphate (about 100 mL), extracted with ethyl acetate and the organic layer was washed thoroughly with water. After concentrating in vacuum 15 the crude title product was obtained as yellow foam 3.8 g (95%). 1H NMR (CDC13 / CD30D) 6 3.38 (d, 1H, J=15), 4.43 (d, 1H, J=15), 5.03 (d, 1H, J=5), 5.80 (d, 1H, J=5), 5.99 (br s, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H).

Example 21 3-chloromethyl-4-chloropyridine hydrochloride Thionyl chloride (0.714 mL, 9.78 mmol) was added at room temperature to dry DMF (7 mL). After 3 0 min the above solution was cannulated into the solution of 3-hydroxymethyl-4-chloropyridine (700 mg, 4.89 mmol) 25 in DMF (3 mL). After 45 min, the product was precipitated by addition of dry ether (100 ml), washed with ether, and dried in vacuum to yield 813 mg (84%) of 90 the title compound. 1H NMR (CD3OD) 5 5.00 (s, 2H) , 8.31-(d, 1H, J=5) , 8.99 (d, 1H, J=5) , 9.18 (s, 1H) .

Example 22 3- (N-fcer-t-butoxycarbonylaminoethyl thiomethyl) -4- chloropyridine To a solution of 3-chloromethyl-4-chloropirydine hydrochloride (513 mg, 2.59 mmol) in DMF (6 mL) at room temperature were added sodium iodide (386 mg, 2.59 mmol), diisopropylethylamine (1.12 mL, 6.4 7 mmol) and 2-(N-tert-butoxycarbonylamino)ethanethiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCl and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated to yield 750 mg of the oily product (96%), which was used for the next step without further purification. 1H NMR (CDC13) 6 1.43 (s, 9H) , 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (br s, 1H), 7.35 (d, 1H, J=4) , 8.40 (d, 1H, J=4) , 8.57 (s, 1H) .

Example 23 (7J2) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(tripheny Imethoxyimino) acetamido] -3- (3 -N-tei-t-butoxycarbonylaminoethyl thiomethylpyrid-4 -yl thio) -3 -cephem-4-carboxylate diphenylmethyl ester To a solution of (71?) -1- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (tripheny Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla 91 te diphenylmethyl ester (650 mg, 0.777 mmol) in DMF (3 mL) was added 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropy ridine (242 mg, 0.80 mmol) at room temperature. After overnight reaction the reaction mixture was partitioned between water and ethyl acetate. The organic layer was thoroughly washed with water, dried over sodium sulfate, and concentrated to yield the crude product which was purified by radial chromatography on silica gel (dichloromethane / methanol; v/v, 50/1) to afford 220 mg of the title compound (26%). 1H NMR (CDCl3/CD3OD) 5 1.23 (s, 9H), 2.32 (t, 2H, J=6), 2.98 (d, 1H, J=18), 3.06 (m, 2H), 3.40 (d, 1H, J=18), 3.46 (s, 2H), 5.03 (d, 1H, J=5), 5.52 (br s, 1H), 5.94 (d, 1H, J= 5), 6.80 (s, 1H), 6.90 (d, 1H, J=6), 7.00-7.22 (m, 25H), 8.01 (d, 1H, J=6), 8.08 (s, 1H).

Example 24 (7J?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino) acetamido] -3- (3-aminoethylthiomethylpyrid-4-ylthio)-3-cephem-4-carboxylate, methanesulfonic acid salt To a solution of (7J?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (tripheny Imethoxyimino)acetamido]-3-(3-N-tert-butoxycarbonylamino ethylthiomethylpyrid-4-ylthio)-3-cephem-4-carboxylate diphenylmethyl ester(1.0 g, 0.907 mmol) in dichloromethane (10 mL) and anisole (1.0 mL) was added at 0 °C trifluoroacetic acid (13 mL). After 1.5 hr the 92 reaction mixture was concentrated in vacuum at room temperature and the oily residue was dissolved in 98% formic acid (20 mL). After 4 hr at room temperature formic acid was removed in vacuum and the residue was dissolved in water ( 25 mL). The insoluble material was removed by centrifugation and the supernatant was purified on HP20 column by elution with water followed by 0.1 M ammonium acetate, water and finally eluting the product with acetonitrile / water (1/4). The eluate was concentrated to about 1/10 original volume and the resulting precipitate was filtered, washed with water and dried in vacuum to yield zwitterionic product (260 mg). The methanosulfonate salt was prepared by suspending the above material in water (15 mL) followed by addition of methanesulfonic acid (1.0 M in water, 0.98 eq) and acetonitrile (5 mL). After evaporation of the resulting solution to dryness the residue was dissolved in water (3 0 mL), centrifuged to remove insoluble material and the supernatant was lyophilized to produce the title compound (274 mg, 44%). 1H NMR (D20) 8 3.11 (s, 3H), 3.19 (m, 2H), .3.52 (m, 2H), 3.67 (d, 1H, J=17) , 4.22 (d, 1H, J=17) , 4.33 (s, 2H) , 5.76 (d, 1H, J=4) , 6.29 (d, 1H, J=4) , 7.93 (d, 1H, J=4), 8.78 (d, 1H, J=4) , 8.87 (s, 1H) . 93 Example 25 3- (N- tert-butoxycarbonylaminoethylthio) -4-chloropyridine To a suspension of 4-chloropyridine hydrochloride (2 g) in 4 0 mL of dry THF was added a 5 freshly prepared LDA (2.5eq.) at -70 °C and the resulting mixture was continued to stir at the same temperature for 4 hours. A solution of N, N'-di(tert-butoxycarbonyl)cystamine (2.5 g, 0.5eq.) in 10 ml of THF was cannulated to the above solution. The 10 reaction mixture was allowed to warm up to 0 °C, quenched with water and then extracted with ethyl acetate. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography to give of the title compound(0.95 g, 50%) as a white solid. 1H NMR 15 (CDC13) 6 1.42 (s, 9H), 3.15 (t, 2H, J=7), 3.38 (t, 2H, J=7) , 4.95 (s, 1H) , 7.32 (d, 1H, J=6), 8.35 (d, 1H, J=6), and 8.60 (s, 1H).

Example 2 6 (7J?) -7- [ (Z) -2- (2-amino-5-chloro thiazol-4-yl) -2-20 (triphenylmethoxyimino) acetamido] -3- [3- (N-fcert- butoxycarbonylaminoethylthio) pyridyl - 4 - thio] - 3-cephem-4-carboxylate, diphenylmethyl ester To a stirring solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny 25 Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla te, diphenylmethyl ester (6.7 g, 7.8 mmol) in 20 ml of dry DMF was added 3-(N-tert-butoxycarbonylaminoethylthio)-4-chloropyridine 94 (2.3 g, 7.8 mmol) at -20 °C. The reaction mixture was allowed to slowly warm up to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and hexane and washed with water.

The solvent was removed under reduced pressure and the crude residue was purified by chromatography to give the title compound (6 g, 68%) as a yellow solid. 1H NMR (CDC13) 8 1.40 (s, 9H), 2.75 (t, 2H, J=7), 3.10 (t, 2H, J=7), 3.15 (d, 1H, J=14), 3.60 (d, 1H, J=14), 4.95 (s, 10 1H) , 5.20 (d, 1H, J=4) , 5.90 (s, 2H) , 6.25 (q, 1H, J=4), 6.85 (d, 1H, J=4), 6.90 (s, 1H), 7.15-7.4 (m, 26H), 8.1 (s, 1H) , 8.21 (d, 1H, J=7).

Example 27 (7R)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-15 (hydroxyimino)acetamido] -3-(3-aminoethylthiopyrid-4- ylthio)-3-cephem-4-carboxylate, trifluoroacetic acid salt To a solution of (7R)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny 2 0 Imethoxyimino)acetamido]-3-[3-(N-tert-butoxycarbonylamin oethylthio)pyridyl-4-thio] -3-cephem-4-carboxylate, diphenylmethyl ester (6 g) in 10 ml of dichloromethane and 1 ml of anisole was added 10 ml of trifluoroacetic acid at 0 °C and the resulting solution was stirred at 25 room temperature for 1 hour. After the solvent was removed, the residue was redissolved in 20 ml formic acid and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue 95 was dried over high vacuum and then triturated with ethyl acetate. The resulting solid was subjected to reverse phase chromatography on Amberchrom column (0.1% aqueous trifluoroacetic acid / acetonitrile) to give the 5 title compound(1.5 g, 48%). 1H NMR (D20) 8 3.5-3.7 (m, 4H) , 3.8 (d, 1H, J=14) , 4.4 (d, 1H, J=14) , 5.84 (d, 1, J=4) , 6.4 (d, 1H, J=4) , 7.65 (d, 1H, J=6) , 8.82 (d, 1H, J=6), and 9.02 (s, 1H) . IR (KBr) 778, 1042, 1173, 1541, 1610, 1780, 3187 cm*1.

Example 2 8 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(triphenylmethoxyoxyimino)acetamido]-3-(4-(2-fcert-butoxycarbonylaminoethylthiomethyl)-1,2,3 -thiadiazol-5-ylthio)-3-cephem-4-carboxylate, benzhydryl ester 15 To a solution of 4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-5-(2-eth oxycarbonylethyl)thio-1,2,3--1,2,3-thiadiazole (181 mg, 0.44 mmol) in ethanol ( 5 mL) was added sodium methoxide in methanol ( 0.55M, lmL), and concentrated. The 20 residue was triturated with hexane-ethyl acetate(9:1), mixed with (7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxy imino)acetyl]amino]-3-chloro-3-cephem-4-carboxylate, diphenylmethyl ester (200 mg, 0.25 mmol), and dissolved 25 in a mixed solvent of ethanol and dichloromethane. The solution was stirred at room temperature for 16 h, and concentrated. The crude was purified by silica gel column chromatography (3% methanol / dichloromethane), 96 affording 100 mg of the title compound. 1H NMR (CDC13) 5 1.46 (9H), 2.68 (2H), 3.19 (d, 1H, J=18), 3.33 (2H + 1H), 4.03(2H), 4.88 (br s, 1H), 5.09 (1H), 5.93 (br s, 2H), 6.44 (s, 1H) , 7.03 (1H), 7.20-7.45 (25H).

Example 29 (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2 -(hydroxyimino) acetamido] -3- (4- (2-aminoethylthiomethyl) -1,2, 3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, dichloroacetic acid salt (7J?) -7 - [ (Z) -2- (aminothiazol-4-yl) -2- (triphenylmethoxyoxy imino)acetamido]-3-(4-(2-aminoethylthiomethyl)-1,2,3-thi adiazol-5-ylthio)-3-cephem-4-carboxylate, diphenylmethyl ester (82 mg, 0.076 mmol) was dissolved in 0.8 mL of 15 dichloroacetic acid containing 5% anisole and stirred at room temperature overnight. Excess diethyl ether was added and the resulting precipitate was collected by filtration. The filter cake was purified by HP-20 reverse phase column chromatography, affording 16 mg of 20 the title compound. 1H NMR (DMSO-d6) 5 2.64(2H), 2.90 (2H), 3.4 (1H, overlapped with water), 3.82 (d, 1H, J=17), 4.04 (d, 1H, J=15), 4.14 (d, 1H, J=15), 5.17 (d, 1H, J=5 ), 5.74 (dd, 1H, J=5, 8), 6.64 (s, 1H) , 7.08 (s, 1H) , 9.50 (d, 1H, J=8) . 97 Example 30 3- (2-N-fcerfc-butoxycarbonylaminoethoxymethyl) -4- chloropyridine A diphasic mixture of 4-chloro-3-chloromethylpyridine hydrochloride (3 96 mg, 2 mmol), N-tert-butoxycarbonylaminoethanol (132 mg, 2 mmol)and benzyl triethyl ammonium bromide (544 mg, 2 mmol) in toluene (20 mL) and 50% sodium hydroxide aqueous solution was vigorously stirred at room temperature for 24 h. The organic layer was taken and concentrate to afford 490 mg of the title compound. 1H NMR (CDC13) 8 1.46 (s, 9H) , 3.39 (2H), 3.65 (2H) , 4.64 (s, 2H), 4.90 (br s, 1H), 7.33 (d, 1H, J=5), 8.46 (d, 1H, J=5) , 8.64 (s, 1H) .

Example 31 (72?) -7- [ (Z) -2- (2-amino-5- chloro thiazol-4-yl) -2-(triphenyImethoxyimino)acetamido]-3-(3-(2-tert-butoxycarbonylaminoethoxymethyl)pyrid-4-ylthio)-3 -cephem-4-carboxylate, diphenylmethyl ester Under substantially the same conditions as used in Example 26, (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (tripheny Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla te, diphenylmethyl ester was reacted with 3-(2-N-tert-butoxycarbonylaminoethoxymethyl)-4-chloropyr idine to afford the title compound. 1H NMR (CDC13) 8 1.42 (9H), 3.11 (d, 1H, J=18), 3.24 (2H), 3.40 (2H), 3.46 (d, 1H, J=18), 4.30 (2H), 4.83 (br s, 1H), 5.17 (1H), 5.72 98 (br s, 2H), 6.20 (1H), 6.99 (s, 1H), 7.25-7.45 (25H), 8 . 28 (1H) , 8.33 (1H) .

Example 32 (7R) -7- [ (Z) -2- (2-amino-5-cb.loroth.iazol-4-yl) -2- (hyd.roxyi.mino) acetamido] - 3- (3- (2-aminoethoxymethyl)pyrid-4-ylthio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-(3-(2-tert-butoxycarbonylamin oethoxymethyl)pyrid-4-ylthio)-3-cephem-4-carboxylate, diphenylmethyl ester was subjected to deprotection under substantially the same conditions as used in Example 27, affording the title compound. 1H NMR (D20) 5 3.35 (2H) , 3.45 (d, 1H, J=18), 3.91 (2H), 4.00 (d, 1H, J=18), 5.52 (d, 1H, J=5) , 6.04 (d, 1H, J=5)_, 7.73 (d, 1H, J=6) , 8.57 (d, 1H, J=6) , 8.65 (s, 1H) .

Example 33 3-(N-1ert-butoxycarbonylami noethy1sulfonylmethyl)-4- chloropyridine To a solution of 3-(N-tert-butoxycarbonylaminoethyl)thiomethyl)-4-chlorop yridine (3 02 mg, 1 mmol) in a mixed solvents of ethyl acetate (10 mL) and methanol (5 mL) was added methanesulfonic acid (144 mg, 1.5 mmol). 3-chloroperoxybenzoic acid (700 mg) was added and stirred at room temperature for 5 h. The reaction was 99 quenched with saturated sodium thiosulfate aqueous solution. The solution was neutralized with 10 % sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and concentrated to dryness, affording 286 mg of the title compound. 1H NMR (CDC13) 5 1.44 (9H) , 3.22 (2H) , 3.66 (2H) , 4.50 (s, 2H) , 5.21 (br S,1H), 7.42 (d, 1H, J=5) , 8.54 (s,1H, J=5), 8.72 (1H).

Example 34 (7R) - 7- [(Z) -2 - (2-amino-5-chlorothiazol-4-yl) -2-(tripheny Imethoxyimino) acetamido] -3- (3-N-tert-butoxycarbonylaminoethylsulfonylmethylpyrid-4-ylthio) - 3-cephem-4-carboxylate, diphenylmethyl ester Under substantially the same conditions as used in Example 26, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla te, diphenylmethyl ester was reacted with 3-(N-tert-butoxycarbonylaminoethylsulfonylmethyl) -4-chlo ropyridine to afford the title compound. 1H NMR (CDC13) 5 1.44 (9H), 3.20(3H), 3.66 (3H), 4.48 (s, 2H), 5.19 (1H), 7.25-7.45 (25H), 8.50 (s,lH, J=5), 8.70 (1H). 100 Example 35 (7R)-7- [ (Z)- 2 -(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(3-aminoe thy1sulfony lmethylpyrid-4-y1thio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-(3-N-tert-butoxycarbonylamino ethylsulfonylomethylpyrid-4-ylthio)-3-cephem-4-carboxyla te, diphenylmethyl ester was subjected to deprotection under substantially the same conditions as used in Example 27, affording the title compound. 1H NMR (D20) 5 3.47 (d, 1H, J=18), 3.3.70 (2H), 3.85 (2H), 4.02 (d, 1H, J=18) , 5 . 07 (s, 2H) , 5.52 (d, 1H, J=5), 6.03 (d, 1H, J=5) , 7.79 (d, 1H, J=6) , 8.64 (d, 1H, J=6), 8.76 (s, 1H) .

Example 36 3-(4-N-tert-butoxycarbonylaminobutyn-1-yl)-4- chloropyridine 4-chloro-3-chloromethylpyridine hydrochloride was reacted with 3-t-BOC-amino-l-propyne under the phase transfer condition described in Example 30, affording the title compound. 1H NMR (CDC13) 6 1.4-1.6 (9H, rotomeric mixture), 4.0-4.2 (2H), 7.32 (d, 1H, J=5) , 8.43 (d, 1H, J=5) , 8.53 (s, 1H) . 101 Example 37 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(triphenyImethoxyimino) acetamido] -3- (3- (4-N-te.rt-butoxycarbonylaminobutyn-1-yl)pyrid-4-ylthio)-3 -cephem-4-carboxylate, diphenylmethyl ester Under substantially the same conditions as used in Example 26, (1R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla te, diphenylmethyl ester was reacted with 3-(4-N-tert-butoxycarbonylaminobutyn-l-yl)-4-chloropyrid ine to afford the title compound. 1H NMR (CDC13) 5 1.4-1.8 (9H), 3.10 (d, 1H, J=18), 3.47 (d, 1H, J=18), 3.85 (2H), 5.16 (1H), 5.62 (br s, 2H), 6.13 (1H), 7.00 (1H), 7.2 -7.5 (25H), 8.35 (2H).

Example 38 (712) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-(3-(4-amino-2-butyn-1-yl)pyrid-4-ylthio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt (71?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (tripheny Imethoxyimino)acetamido]-3-(3-(4-N-tert-butoxycarbonylam inobutyn-1-yl)pyrid-4-ylthio)-3-cephem-4-carboxylate, diphenylmethyl ester was subjected to deprotection under substantially the same conditions as used in Example 27, affording the title compound. 1H NMR (D20) 5 3.46 (d, 1H, J=18), 4.02 (d, 1H, J=18), 4.16 (2H), 4.70 (2H), 5.52 102 (d, 1H, J=5), 6.03 (d, 1H, J=5), 7.76 (d, 1H, J=6), 8.66. (d, 1H, J=6), 8.78 (S, 1H).

Example 39 (7J2) -7- [ (Z) -2 - (2 -ami no-5- chloro thiazol - 4 -yl) -2 -5 (hydroxyimino)acetamido]-3-(3-(4-ami no-2 -(Z)-buten-1- yl)pyrid-4-y1thio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenyl 10 methoxyimino)acetamido] -3-(3-(4-tert-butoxycarbonylamino -2-(Z)-buten-l-yl)pyrid-4-ylthio)-3-cephem-4-carboxylate, diphenylmethyl ester was subjected to deprotection under substantially the same conditions as used in Example 27, affording the title compound, as a 15 mixture with the 1-butenyl isomer. 1H NMR (D20) 5 3.46 (d, 1H, J=18} , 3.91 (2H) , 4.02 (d, 1H, J=18), 4.56 (2H) , 5.52 (d, 1H, J=5) , 5.63 (2H) , 6.03 (d, 1H, J=5), 7.76 (d, 1H, J=6) , 8.65 (d, 1H, J=6) , 8.76 (s, 1H) .

Example 40 2 0 3-(N-fcert-butoxycarbonylami noethylsulfenylmethyl)- 4-chloropyridine To a solution of 3-(N-tert-butoxycarbonylaminoethyl)thiomethyl)-4-chlorop yridine (687mg ,2.26 mmol) in methylene chloride ( 10 25 mL) at 0 °C was added 3-chloroperoxybenzoic acid (467, 2.72 mmol). After overnight reaction at room temperature reaction mixture was partitioned between 103 dichloromethane and diluted sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. Crystallization of the crude from ethyl acetate/hexane afforded the title compound. 1H NMR (CDCI3) 5 1.40 (s, 9H), 2.90 (m, 1H), 3.01 (m, 1H), 3.59 (m, 2), 4.00 (d, 1H, J=13), 4.22 (d, 1H, J=13), 5.30 (br. s, 1H) , 7.40 (d, 1H, J=4), 8.45 (d, 1H, J-4), 8.57 (s, 1H) Example 41 (720 -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2 -(hydroxyimino)acetamido]-3-(3-aminoe thylsulf enylmethylpyrid-4-y1thio)-3 -cephem-4-carboxylate, trifluoroacetic acid salt Under substantially the same conditions as used in Example 43, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-mercapto-3-cephem-4-carboxyla te, diphenylmethyl ester was reacted with 3-(N-tert-butoxycarbonylaminoethylsulfenylmethyl)-4-chlo ropyridine to afford (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(tripheny Imethoxyimino)acetamido]-3-(3-N-tert-butoxycarbonylamino ethylsulfenylmethylpyrid-4-ylthio)-3-cephem-4-carboxylat e, diphenylmethyl ester, which was then subjected to deprotection under substantially the same conditions as used in Example 35, affording the title compound. 1H 104 NMR (D20) 6 2.90 (s, 3H), 3.20-3.35 (m, 1H), 3.50-3.70 (m, 4H), 4.00 (dd, 1H, J=18, 3), 4.55 (dd, 1H, J=13, 3), 4.65 (dd, 1H, J=13, 3), 5.51 (m, 1H) , 6.02 (m, 1H) , 7.75 (m, 1H), 8.60 (m, 2H).

Example 42 (7R) -7-{ [2- [N,N' -bis- (t-butoxycarbonyl) guadinino] ethylthio] acetyl] ami no}-3- (4-chlorome thyl-1,2,3-thiadiazo1-5-y1thio)-3 -c ephem-4-carboxylate, 4-methoxybenzyl ester To a solution of (7R)-7-amino-3-(4-chloromethyl-l,2,3 -1,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylat e, 4-methoxybenzyl ester (485 mg, 0.794 mmol) and {2 - [N", N*' -bis- (t -butoxycarbonyl) guadinino] ethyl} t:hioacet ic acid (329 mg, 0.873 mmol) were added phosphorous oxychloride (0.103 mL, 1.11 mmol) and diisopropylethyl amine (0.55 mL, 3.18 mmol), and was stirred at -10 °C for 16 h. Water was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate and then concentrated. The residue was purified by silica gel chromatography (1% methanol / dichloromethane), affording 44 0 mg of the title compound. XH NMR (CD3OD) d 1.44 (s, 9), 1.47 (s, 9), 2.79 (m, 2), 3.30 (2, overlapped with solvent), 3.35 (d, 1, J=18), 3.57 (m, 2), 3.64 (d, 1, J=18), 3.77 (s, 3), 4.96 (s, 2), 5.15(d, 1, J=5), 5.20 (d, 1, J=12), 5.23 (d, 1, J=12) , 5.77 (d, 1, J=5) 6.81 (d, 2, J=9), 7.25 (d, 1, J=8) . 105 Example 43 (7R) -7-{ [2- [N,N' -bis- (t-butoxycarbonyl) guadinino] ethylthio] acetyl] amino}-3- (4-isothiouroniummethylthiomethyl-1,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester, iodide salt A solution of (7R)-7-{[2-[N,N'-bis-(t-butoxycarbonyl)guadinino]ethylth io]acetyl]amino}-3 -(4-chloromethyl-l,2,3--1,2,3-thiadiaz ol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (200 mg, 0.24 mmol), thiourea (18 mg, 0.24 mmol) and sodium iodide (35 mg, 0.24 mmol) in acetonitrile (3 mL) was stirred at room temperature overnight. The mixture was concetrated and triturated with dichloromethane. The residue was redissolved in acetone (2 mL) and filtered. The filtrate was concentrated to dryness, affording 200 mg of the title compound. 1H NMR (CDC13) d 1.45 (s, 18), 2.81 (m, 2), 3.15 (d, 1, J=18), 3.36 (d, 1, J=15), 3.55 (d, 1, J=15), 3.62 (m, 2), 3.80 (s, 3), 3.83 (d, 1, J=18), 4.80 (d, 1, J=15), 4.86 (d, 1, J=15) , 5.08 (d, 1, J=5) , 5.23 (d, 1, J=12), 5.27 (d, 1, J=12) , 5.58 (dd, 1, J=5, 8) 6.85 (d, 2, J=9) , 7.37 (d, 2, J=9) , 8.24 (d, 1, J=8) . 106 Example 44 (7R)-7-{[(2-guadininoethylthio)acetyl]amino}-3-(4- i so thi our oniunnne thyl thiomethyl -1,2,3-thiadiazol-5-ylthio)-3-cephem-4- carboxylic acid, 5 2,2-dichloroacetate salt A solution of (7R)-7-{[2-[N,N'-bis-(t-butoxycarbonyl)guadinino]ethylth io]acetyl]amino}-3-(4-isothiouroniummethylthiomethyl-l,2 ,3--1,2,3-thiadiazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester, iodide salt (200 mg) and anisole (0.1 mL) in dichloroacetic acid (2 mL) was stirred at room temperature for 16 h. The mixture was precipitated with diethylether/hexane, filtered, and vacuum-dried to afford 70 mg of the title compound.

Using substantially the same methods as described in the Examples above, the following additional compounds were prepared: Example 45 (7R)-7- [ (Z)-2-(2-aminothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-[3-(2-aminoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 46 (7R)-7- [ (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethy 1 thio) pyrid-4 -y 1 thio] - 3 - cephem- 4 - 3 0 carboxylate, trifluoroacetic acid salt 107 Example 47 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2-N-5 (iminomethyl) aminoethyl thio) pyrid-4-ylthio] -3-cephem-4-carboxylate, trifluoroacetic acid salt Example 48 (1R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-10 (hydroxyimino) acetamido] -3- [3- (2 - am i nopr opy 1 thio) pyr i d -4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 49 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-[3-(2-guani dinopropy1thio)pyrid-4-y1thio]-3 -cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 50 (7J2)-7-[(Z)-2 - (2-aminothiazol-4-yl) - 2-(hydroxyimino)acetamido] -3-[3-(2-N-(iminomethyl) aminopropy 1 thio) pyrid-4-ylthio] -3-cephem-4-carboxylate, trifluoroacetic acid salt 108 Example 51 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido] -3-[3-(2-amino-2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 52 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-guanidino-2-c arb oxami doe thy1thio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 53 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino 2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 54 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-amino-3-hydroxyp ropy1thio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 55 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2 -guanidino-3 -hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4- • carboxylate, trifluoroacetic acid salt 109 Example 56 (7R)-7- [ (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino 3 -hydroxypropylthio) pyrid-4-ylthio] -3 -cephem-4-5 carboxylate, trifluoroacetic acid salt Example 57 (7R)-7 - [(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-10 aminoethylthiomethyl)pyrid-4-ylthio] -3-cephem-4- carboxylate, trifluoroacetic acid salt Example 58 (7R)-7- [ (Z)-2- (2-aminothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 59 (7R)-7- [ (Z)-2- (2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-N-(iminomethyl)aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 60 (7R)-7 - [(Z)-2 - (2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminopropyl thiomethyl) pyrid-4 -ylthio] - 3 - cephem-4 - 3 0 carboxylate, trifluoroacetic acid salt 110 Example 61 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyiTni.no) acetami do] -3- [3- (2-guanidinopr opy 1 thi ome thyl) pyr id - 4 - y 1 thi o ] - 3 - c ephem- 4 ■ 5 carboxylate, trifluoroacetic acid salt Example 62 (722)-7- [ (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2 -N-10 (iminomethyl)aminopropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 63 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-15 (hydroxyimino) acetamido] - 3- [3- (2 - amino-2 - carboxami doethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt 2 0 Example 64 (72?) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-guanidino-2-carboxamidoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt Example 65 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino) acetami do] - 3- [3- (2-N- (iminomethyl) amino 2-carboxamidoethylthiomethyl)pyrid-4-ylthio]-3-cephem 3 0 4-carboxylate, trifluoroacetic acid salt Ill Example 66 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-amino-3-hydroxypropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 67 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2-10 (hydroxyimino)acetamido]-3-[3-(2 -guanidino-3 - hydroxypropylthiomethyl)pyrid-4-ylthio]-3 -cephem-4-carboxylate, trifluoroacetic acid salt Example 68 (722) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino)acetamido]-3-[3-(2-N-(iminomethyl)amino 3-hydroxypropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 69 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthio)pyrid 4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 70 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino)acetamido]-3-[3-(2-guani dinoe thylthio)pyrid-4-ylthio]-3-cephem-4-3 0 carboxylate, trifluoroacetic acid salt 112 Example 71 (722) -7- [ (Z) -2 - (2-amino-5-chlorothiazol-4-yl) -2-(hydroxy!mino)acetamido]-3-[3-(2-N-(iminomethyl) aminoethyl thio) pyr id-4-ylthio] -3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 72 (722) -7 - [(Z) -2 - (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-aminopropylthio)pyrid-10 4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 73 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (hydroxyimino)acetamido]-3-[3-(2-guanidinopropyl thio) pyrid-4-ylthio] -3 - cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 74 (722) - 7- [(Z) -2 - (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetami do]-3-[3-(2-N-(iminomethyl) aminopropylthio) pyrid-4-ylthio] -3-cephem-4-carboxylate, trifluoroacetic acid salt Example 75 (722) -7 - [(Z) - 2- (2-amino-5-chlorothiazol-4-yl) - 2-(hydroxyimino)acetamido]-3- [3-(2-amino-2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4- 3 0 carboxylate, trifluoroacetic acid salt 113 Example 76 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-guanidino-2-carboxamidoethylthio)pyrid-4-ylthio] -3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 77 (7R)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-N-(iminomethyl) amino 10 2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4- carboxylate, trifluoroacetic acid salt Example 78 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-15 (hydroxyimino)acetamido]-3-[3-(2-amino-3 - hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 79 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-guanidino-3-hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 80 (722) -7 - [ (Z) - 2- (2-amino-5-chloro thiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-N-(iminomethyl)amino 3 -hydroxypropylthio)pyrid-4-y1thio]-3-c ephem-4- 3 0 carboxylate, trifluoroacetic acid salt 114 Example 81 (7R) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3- [3-(2-aminoethylthiomethyl)pyrid-4-ylthio] -3- cephem-4-5 carboxylate, trifluoroacetic acid salt Example 82 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl) -2-10 (hydroxyimino)acetamido]-3-[3-(2- guanidino e thylthi ome thyl)pyrid-4-y1thio]-3 -c ephem-4-carboxylate, trifluoroacetic acid salt Example 83 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2- (hydroxyimino)acetamido]-3-[3-(2-N-(iminome thyl) aminoethyl thiomethyl) pyrid-4-ylthio] -3-cephem-4-carboxylate, trifluoroacetic acid salt Example 84 {7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminopropy1thiome thyl)pyrid-4-y1thio]-3 -c ephem- 4 -carboxylate, trifluoroacetic acid salt Example 85 (7R)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-3 0 guanidinopropylthiomethyl)pyrid-4-ylthio] -3-cephem-4-carboxylate, trifluoroacetic acid salt 115 Example 86 (7R) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido]-3-[3-(2-N-(iminomethyl)ami nopropy1thiomethyl)pyrid-4-y1thio]-3 cephem-4-carboxylate, trifluoroacetic acid salt Example 87 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-amino-2 -carboxamidoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt Example 88 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidino-2-c arboxami do e thylthiome thyl)pyrid-4-y1thio]-3 -c ephem-4 carboxylate, trifluoroacetic acid salt Example 89 (7R)-7 - [(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino 2 -carboxamidoe thy1thiomethyl)pyrid-4-y1thio]-3 -cephem 4-carboxylate, trifluoroacetic acid salt Example 90 (7 R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-amino-3 -hydroxypropylthiomethyl)pyrid-4-y1thio]-3 -cephem-4-carboxylate, trifluoroacetic acid salt 116 Example 91 (7J2) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-(hydroxyimino)acetamido] -3-[3-(2-guanidino-3-hydroxypropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 92 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino) acetamido] -3- [3- (2-N- (iminomethyl) amino-3 -hydroxypropy1thiomethy1)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 93 {7R)-7-[(Z)-2 -(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-aminoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 94 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2 -(2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidinoethy1thio)pyrid-4-y1thio]-3-c ephem-4-carboxylate, trifluoroacetic acid salt Example 95 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl) aminoethyl thio) pyrid-4-yl thio] -3-cephem-4-carboxylate, trifluoroacetic acid salt 117 Example 96 (7R) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-aminop ropy1thio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 97 (7R)-7-[(Z)-2 -(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidinopropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 98 (7R)-7 - [(Z)-2 - (2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl)aminopropylthio)pyrid-4-ylthio]-3-cephem 4-carboxylate, trifluoroacetic acid salt Example 99 (7R)-7 - [(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-amino-2 -carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Excuz^)le 100 (7R)-7- [ (Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidino-2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 118 Example 101 (7J2) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxyimi.no) acetamido] -3- [3- (2-N-(iminome thyl) amino - 2 - c arboxami do e thyl thi o) pyr i d - 4 -ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 102 (7JR) -7- [ (Z) -2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-amino-3 -hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 103 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2 -guanidino-3 -hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 104 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminome thyl) amino - 3 - hydroxyp r opy 1 thi o) pyr i d - 4 -ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 119 Example 105 (7i?)-7-[(Z)-2- (2-aminothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 106 (7J?) -7- t (Z) -2- (2-aminothiazol-4-yl) -2- (2- f luoroethoxyimino) acetamido] - 3- [3- (2- guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt Example 107 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2- fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl) aminoethylthiomethyl)pyrid-4-ylthio]-3 cephem-4-carboxylate, trifluoroacetic acid salt Example 108 (7JR) -7- [ (Z) -2- {2-aminothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-aminopropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 109 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2- guanidinopropylthiomethyl)pyrid-4-ylthio] -3-cephem-4 carboxylate, trifluoroacetic acid salt 120 Example 110 (722)-7-[(Z)-2- (2-aminothiazol-4-yl) -2- (2-f luoroethoxyimino) acetamido] -3- [3- (2-N-(iminomethyl) auninopropyl thiomethyl) pyrid-4-ylthio] -3 cephem-4-carboxylate, trifluoroacetic acid salt Example 111 (7R)-7- [ (Z)-2- (2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-amino-2 -c arboxami do e thyl thi ome thyl) pyr i d - 4 - y 1 thi o ] -3-c ephem - 4 carboxylate, trifluoroacetic acid salt Example 112 (7R)-7-[(Z)-2-(2-ami nothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2 -guanidino-2 -carboxamidoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt Example 113 (722)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl) amino- 2 -carboxami do ethyl thi ome thyl) pyrid 4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 114 (722) -7- [ (Z) -2- (2 - aminothiazol - 4 -yl) -2- (2-fluoroethoxyimino) acetamido] -3- [3- (2 -amino-3 -hydroxypropyl thi ome thyl) pyrid - 4 - y 1 thi o ] -3-c ephem- 4 -carboxylate, trifluoroacetic acid salt # 121 Example 115 (722)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidino-3-hydroxypropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 116 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-N-10 (iminomethyl)am i no-3 -hydroxypropylthiome thyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 117 (712) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2- fluoroethoxyimino)acetamido]-3-[3-(2-aminoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 118 (722)- 7-[(Z)-2- (2-amino-5-chloro thiazol-4-yl) -2- (2- fluoroethoxyimino)acetamido]-3-[3-(2-guanidinoethylthio)pyrid-4-ylthio]-3 -cephem-4-carboxylate, trifluoroacetic acid salt Example 119 (722) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2- fluoroethoxyimino) acetamido] -3- [3- (2-N-(iminomethyl)aminoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 122 Example 120 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2 -(2-fluoroethoxyi mino)acetamido]-3-[3-(2-aminopropy1thio)pyrid-4-ylthio]-3-cephem-4-5 carboxylate, trifluoroacetic acid salt Example 121 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2-10 fluoroethoxyimino)acetamido]-3-[3-(2- guanidinopropy1thio)pyrid-4-ylthio]-3 -cephem-4-carboxylate, trifluoroacetic acid salt Example 122 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2- fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl) aminopropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 123 (7J2)-7-[(Z)-2 - (2-amino-5-chlorothiazol-4-yl) - 2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-amino-2-carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 124 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2-f luoroethoxyimino) acetamido] -3- [3- (2-guanidino-2 -30 carboxamidoethylthio)pyrid-4-ylthio]-3-cephem-4- carboxylate, trifluoroacetic acid salt a 123 Example 125 (7R) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2 fluoroethoxyimino)acetamido]-3-[3-(2 -N-(iminomethyl) amino-2 -carboxamidoethylthio) pyrid-4 5 ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 126 (7 R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2 10 fluoroethoxyimino)acetamido]-3-[3-(2 -amino-3 - hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 127 (7R)-7- [ (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidino-3-hydroxypropylthio)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Example 12 8 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimi.no) acetamido] -3- [3- (2-N-(iminome thyl) amino-3 - hydroxypropyl thio) pyrid-4-25 ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 124 Example 129 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2- fluoroethoxyimino)acetamido]-3-[3-(2-aminoe thy1thiomethyl)pyrid-4-y1thio]-3 -cephem-4-5 carboxylate, trifluoroacetic acid salt Example 13 0 (72?) -7 - [(Z) -2 - (2-amino-5-chlorothiazol-4-yl) - 2- (2-10 fluoroethoxyimino)acetamido]-3 -[3 -(2 - guani dino e thylthiome thyl)pyrid-4-ylthio]-3-c ephem-4 carboxylate, trifluoroacetic acid salt Example 131 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2- fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl)aminoethylthiomethyl)pyrid-4-ylthio]-3 cephem-4-carboxylate, trifluoroacetic acid salt 2 0 Example 132 (72?) -7- [ (Z) -2- (2- amino-5-chlorothiazol-4-yl) -2- (2- fluoroethoxyimino)acetamido]-3-[3-(2-aminop ropy1thiomethyl)pyrid-4-y1thio]-3-c ephem-4-carboxylate, trifluoroacetic acid salt Example 133 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2- 3 0 guanidinopropylthiomethyl)pyrid-4-ylthio] -3-cephem-4 carboxylate, trifluoroacetic acid salt 125 Example 134 (72?) -7- [ (Z) -2 - (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2 -N-(iminomethyl)aminopropylthiomethyl)pyrid-4-ylthio] -3 cephem-4-carboxylate, trifluoroacetic acid salt Example 13 5 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2 -amino-2-carboxamidoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4 carboxylate, trifluoroacetic acid salt Example 13 6 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidino-2-carboxamidoethyl thiomethyl) pyrid-4-ylthio] -3 -cephem-4 carboxylate, trifluoroacetic acid salt Example 137 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyimino)acetamido]-3-[3-(2-N-(iminomethyl) amino-2 -carboxamidoethyl thi ome thyl) pyrid 4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt 126 Example 138 (72?) -7-[(Z)-2 - (2-amino-5-chlorothiazol-4-yl) -2- (2-fluoroethoxyl.Tni.no) acetamido] -3- [3- (2-amino-3-hydroxypropyl thiomethyl) pyrid-4 -yl thio] - 3 - cephem-4 -5 carboxylate, trifluoroacetic acid salt Example 13 9 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) - 2 - (2-fluoroethoxyimino)acetamido]-3-[3-(2-guanidino-3-10 hydroxypropyl thiomethyl) pyrid-4-ylthio] -3-cephem-4- carboxylate, trifluoroacetic acid salt Example 140 (72?) -7- [ (Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (2-15 fluoroethoxyimino)acetamido]-3-[3-(2-N- (iminomethyl)amino-3 -hydroxypropylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylate, trifluoroacetic acid salt Thus, it will be appreciated that the compounds, methods and compositions of the invention and its parent are effective against various S-lactam resistant strains of bacteria which pose an increasing health risk to society.

Although certain embodiments and examples have been used to describe the present invention, it will be apparent to those skilled in the art that changes to the embodiments and examples shown may be made without departing from the scope or spirit of the 3 0 invention. 127 Those references not previously incorporated herein by reference, including both patent and non-patent references, are expressly incorporated herein by reference for all purposes.

Other embodiments are within the following claims. 128

Claims (53)

WHAT WE CLAIM IS:

1. A compound of the formula: r111o-3 CCfcR2 "Kall^fAWrR12]^ or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of -NHC (0) ZR3, -NR4R5' and -NHC(or^s . Z is selected from the group consisting of -CH2(X)m-, -C (NOR6) -CH (OR7) -, -C(CHC02R8)- and -CH(NR9R10) X is selected from the group consisting of 129 oxygen and sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cyano, Ci~C6 alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, Ci-Ce alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Cn aryl, heteroaryl, carboxyl, Ci~C6 alkoxycarbonyl, Ci-C6 alkyl, Ci-Csalkenyl, nitro, ammo, Ci~C6 alkoxyl and amido; C6-C14 aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-Cs alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, C:-C6 alkyl, Ci-C6 alkenyl, nitro, amino, Ci-C6 alkoxyl and amido; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl 130 and dibenzthienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-C6 alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, oxo, Ci-C6 alkoxycarbonyl, Ci-C6 alkyl, Ci-C6 alkenyl, nitro, amino, Cx-C* alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is Ci-C6 alkyl HetAr is an aromatic heterocyle as defined above), and (CH2)nT, n is 1 to 6, T is selected from the group consisting of amino (NRR' wherein R and R' may be Ci-C6 alkyl, C6-Ci4 aryl or acyl C(0)R wherein R is Ci~C6 alkyl), amidino (C- or N-lmked) , guanidino, and isothioureido, which may be substituted with Ci~C6 alkyl, Cg-Cn aryl, hydroxyl, or amino as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci~C6 alkyl and C6-Ci4 aryl; 131 R9 and R10 are selected independently from the group consisting of hydrogen, Ci-C6 alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is heterocycle as defined above); R2 is selected from the group consisting of hydrogen, C-.-Ce alkyl which may be substituted as defined above, Ci-Cs alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio cyano, Ci-Cs alkylthio, heterocycle, C-;-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, C:-C6 alkyl, C-,-C6 alkenyl, nitro, ammo, C:-Cs alkoxyl, and amido; C6-Ci4 aryl which may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is Ci~C6 alkyl which may be substituted as defined above and Ar is Cs-Cn aryl which may be substituted as defined above), heteroaralkyl and trialkylsilyl (RR'R'1 Si wherein R, R'and R'1 are Ci~C6 alkyl groups); or R2 is not present and the C02 group to which it would be attached bears a negative charge; the ring A, B, D, and E is a carbon, nitrogen and sulphur containing heterocycle selected from the group consisting of thienyl, imidazolyl, thiazolyl thiadiazolyl and pyrazolyl; 132 Rn is selected from the group consisting of H, halogen, Ci-C6 alkyl, C:-C6 alkoxy, hydroxyl, amino as aefmea above, cyano, Ci-Ce hydroxyalkyl, Ci-C6 carboxamidoal.-:yl, C1-C6 ammoalkyl or Ci-Cr quaternary ammonium alkyl, ana quaternary heteroaryliumalkyl; alki and alk2 are Ci-C6 alkyl groups which may be independently substituted with a substituent selec~ec from the group consisting of Ci-C6 alkyl, hydroxyl, arr.mo as defined above, C:-Cf alkoxy, Ci-C6 hydroxyalkyl ar.a carboxamide; p is 0, 1, or 2; R99 is selected from the group consisting of sulfur, 50, S02, NH, Ci-Cs N-alkyl, oxygen, C=C (cis or trans', and C=C; q is 1; r is 0, 1, 2 or 3; 133 R13-R16 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, cycloalkyl, acyl as defined above, aminoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Ci-C6 alkyl; wherein alk2 and R12 taken together may form an 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

2. The compound or salt of claim 1, wherein R: is -NHC(0)ZR3

3. The compound or salt of claim 2, wherein R3 is C6-Ci4 aryl or heterocycle, which may be substituted, as defined m claim 1.

4. The compound or salt of claim 3, wherein R3 is selected from the group consisting of phenyl, thienyl or furanyl, which may be substituted, as defined m claim 1, 2-aminothiazol-4-yl, 2-ammo-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl.

5. The compound or salt of claim 4, wherein Z is -C(N0R6)-, and R6 is selected from the group consisting of hydrogen and Ci-C6 alkyl, which may be substituted, as defined m claim 1. 134

6. The compound or salt of claim 5, wherein R" is selected from the group consisting of hydrogen, 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroallyl and cyclopentyl, and RJ is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-aminothiazol-4-yl, 2-ammo-5-chlorothiazol-4-yl, ana 2-ammothiadiazol-4-yl.

7. The compound or salt of claim 6, wherein R' is hydrogen or 2-fluoroethyl and RJ is 2-aminothiazoi-4-vl or 2-amino-5-chlorothiazol-4-yl.

8. The compound or salt of claim 7, wherein said compound is active against methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacteria, as demonstrated by a lower minimum inhibitory concentration than cefotaxime or imipenem.

9. A compound of claim 1 of the formula: NOf^ R5^ // [R11]0-3 "r34 o' S E co2!?2 [(alk1)p(R99)q(alk2)rR12]1_ or a pharmaceutically acceptable salt thereof wherein R34 is halogen or hydrogen; 135 R33 is selected from the group consisting of NH2, NH3" and protected amino; R2, R6, A, B, D, E, R11, alki, p, R99, q, alk2, r, and R12 are as defined in claim 1 above.

10. The compound of salt or claim 9, wherein R34 is chlorine; R2 is hydrogen, or is not present and the CO; to which it would be attached bears a negative charge; R6 is hydrogen; A, B, D, and E are selected to form thiazole and thiadiazole; R11 is hydrogen, halogen or Ci-C6 alkyl; alki is CH2; p is 0 or 1; R99 is sulfur; alk2 is CH2; 136 r is 2 or 3; and R12 is NH2 or NH3+.

11. The use of a compound according to any of claims 1 to 10 or a salt thereof m the manufacture of a medicament for the treatment of a mammal suffering from a methicillin-resistant, vancomycm-resistani, or ampicillin-resistant bacterial infection.

12. The use of claim 11, wherein said mammal is infected with a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

13. An antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection, comprising a therapeutically effective amount of a compound or salt of any one of claims 1-10 m a pharmaceutically acceptable carrier.

14. The composition of claim 13, wherein said bacteria is a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism. 137

15. A compound of the formula: [R11]m CQjR2 Kal^R99)^!^12] 1-4 or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of Z is selected from the group consisting of -CH2(X)r-, -C (NOR6) -CH (OR7) -C(CHC02R8)- and -CH (NR9R10) -; X is selected from the group consisting of oxygen and sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cyano, C:-C6 alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, Ci~C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci~C6 alkyl, Ci-C6alkenyl, 138 nitro, amino, Ci-C6 alkoxyl and amido; C6-C14 aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci~C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl and dibenzthienyl, C.--C-., aryl, heteroaryl, carboxyl, Ci-Cs alkoxycarbonyl, C.-C. alKyl, C:-C6 alkenyl, nitro, amino, Ci-C6 alkoxyl and amido; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridmyl, thiaaiazolvl, thiazolyl, piperazmyl, dibenzfuranyl and dibenztnienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, cromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-C6 alkylthio, heterocycle, C6-C;4 aryl, heteroaryl, carboxyl, oxo, Ci-C6 alkoxycarbonyl, C;-C6 alkyl, Ci-C6 alkenyl, nitro, ammo, Ci-Cg alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is C:-C6 alkyl HetAr is an aromatic heterocyle as defined above), and (CH2)nT, n is 1 to 6, T is selected from the group consisting of ammo (NRR1 wherein R and R' may be Ci-C6 alkyl, C*-Cu aryl or acyl C(0)R wherein R is Ci-C6 alkyl), amidino (C-or N-linked), guanidino, and isothioureido, which may be substituted 139 with Ci~C6 alkyl, C^-Cu aryl, hydroxyl, or amino as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci-Ce alkyl and Co-Cn aryl; R9 and R10 are selected independently from the group consisting of hydrogen, Ci-C6 alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is a heterocycle as defined above); R2 is selected from the group consisting of hydrogen, Ci-C6 alkyl which may be substituted as defined above, Ci~C6 alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, Ci~C6 alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-Cs alkoxycarbonyl, Ci~C6 alkyl, Ci-C6 alkenyl, nitro, amino, Ci~C6 alkoxyl, and amido; C6-Ci4 aryl which may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is Ci-C6 alkyl which may be substituted as defined above and Ar is C6-Ci4 aryl which may be substituted as defined above), heteroaralkyl and 140 trialkylsilyl (RR'R'' Si wherein R, R'and Rf' are C;-Cs alkyl groups); or R2 is not present and the C02 group to which it would be attached bears a negative charge; R11 is selected from the group consisting of H, halogen, Ci-C6 alkyl, Ci~C6 alkoxy, hydroxyl, amino as defined above, cyano, Ci-C6 hydroxyalkyl, Ci-C6 carboxamiaoalkyl, Ci-C6 aminoalkyl or Ci-Cs quaternary ammonium alkyl, and quaternary heteroaryliumalkyl; alki and alk2 are Ci-Cs alkyl groups which may be independently substituted with a substituent selected from the group consisting of Ci-C6 alkyl, hydroxyl, ammo as defined above, Ci-Cs alkoxy, Ci-C6 hydroxyalkyl and carboxamide; p is 0, 1, or 2; R99 is selected from the group consisting of sulfur, SO, S02, NH, Ci-C6 N-alkyl, oxygen, C=C (cis or trans), and C=C; q is 1; r is 0, 1, 2 or 3; 141 *nr13ru r13 nr15r16 s13 r17 ii vv^ Jx Y If -YT r12 is nr"r", -R"R", nr" , MR" , fl J nr15r16 ^ f "R" Y if ■\ nr13r14^ r,3 f or +nr13r14 ri3_r16 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, cycloalkyl, acyl as defined above, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Ci~C6 alkyl; wherein alk2 and R12 taken together may form a 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

16. The compound or salt of claim 15, wherein R1 is -NHC(0)ZR3.

17. The compound or salt of claim 16, wherein R3 is C6-Ci4 aryl or heterocycle, which may be substituted, as defined in claim 15.

18. The compound or salt of claim 17, wherein R3 is selected from the group consisting of phenyl, thienyl or 142 furanyl, which may be substituted, as defined m claim 15, 2-ammothiazol-4-yl, 2-ammo-5-chlorothiazol-4-yl, and 2-ammothiadiazol-4-yl.

19. The compound or salt of claim 18, wherein Z is -C(NOR6) -, and R6 is selected from the group consisting of hydrogen and Ci-C6 alkyl, which may be substituted, as defined in claim 15.

20. The compound or salt of claim 19, wnerem RD is selected from the group consisting of hydrogen, 2-fluoroethyl, cyclopropylmethyl, allyl, aichloroallyl and cyclopentyl, and R3 is selected from tne group consisting of phenyl, 2-thienyl, 2-furyl, 2-ammothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-ammothiadiazol-4-yl.

21. The compound or salt of claim 20, wherein R6 is hydrogen or 2-fluoroethyl and RJ is 2-ammothiazol-4-yl or 2-amino-5-chlorothiazol-4-yl.

22. The compound or salt of claim 21, wherein said compound is active against methicillin-resistant vancomycin-resistant, or ampicillin-resistant bacteria, as demonstrated by a lower minimum inhibitory concentration than cefotaxime or imipenem.

23. The use of a compound according to any of claims 15 to 22 or a salt thereof m the manufacture of 143 a medicament for the treatment a mammal suffering from a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection.

24. The use of claim 23, wherein said mammal is infected with a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

25. An antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection, comprising a therapeutically effective amount of a compcunc or salt of any one of claims 15-22 m a pharmaceutically acceptable carrier.

26. The composition of claim 25, wherein saic bacteria is a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

27. A compound of the formula or a pharmaceutically acceptable salt thereof wherein CO2R2 [(al^yR^all^R12]^ R1 is selected from the group consisting of -NHC(0)ZR3, 144 s -nhc(oj ""s -NR4R5, and Z is selected from the group consisting of -CH:(X)m-, -C (NOR6) -, -CH (OR7) -C(CHC02R8)- and -CH (NRSR10) -; X is selected from the group consisting of oxygen and sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cyano, C-.-C* alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, Ci-C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl, heteroaryl, carboxyl, Ci~C6 alkoxycarbonyl, C-,-C6 alkyl, Ci-C6alkenyl nitro, amino, Ci-C6 alkoxyl and amido; C6-Ci4 aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C6-Ci4 aryl 145 heteroaryl, carboxyl, C-.-C,- alkoxycarbonyl, C-.-C al.-:yl, Ca-Ce alkenyl, nitro, ammo, C.-Cs alkoxyl and amicc; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenztr.ienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-C.- alkylthio, neterocycle, C.--Ci, aryl, heteroaryl, carboxyl, oxo, C.-C.- alkoxycarbonyl, C.-C alkyl, Cj-Ce alkenyl, nitro, ammo, C.-C6 alkoxyl ar.c amido; or a heteroalkyl group (RHetAr wherein R is C.-C£ alkyl HetAr is an aromatic heterocyle as defined acove), and (CH?) nT, n is 1 to 6, T is selected from the group consisting of ammo iNRR' wherein R and R' may be Ci-C£ alkyl, C„:-Ci4 aryl or acyl C(0)R wherein R is Ci~Cs alkyl), amidmo (C- or N-lmked) , guanidmo, and isothioureido, which may be substituted with Ci~C6 alkyl, C£-Ci4 aryl, hydroxyl, or ammo as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci~C6 alkyl, C6-Ci4 aryl and acyl as defined above; wherein Rs may also be a group that forms a protected hydroxy group with the adjacent oxygen 146 Ra is selected from the group of hydrogen, Ci~C6 alkyl and C6-Ci< aryl; R9 and R10 are selected independently from the group consisting of hydrogen, C:-C6 alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Het is heterocycle as defined above); R2 is selected from the group consisting of hydrogen, Cj.-C6 alkyl which may be substituted as defined above, Ci-Cs alkenyl which may be substituted with one or more functional groups selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio cyano, Ci-C6 alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci-Cs alkyl, Ci~C6 alkenyl, nitro, amino, C-_-C5 alkoxyl, and amido; C6-Ci4 aryl which may be substituted as defined above, a heterocycle which may be substituted as defined above, aralkyl (RAr wherein R is Ci-Cs alkyl which may be substituted as defined above and Ar is C6-Ci4 aryl which may be substituted as defined above), heteroaralkyl and trialkylsilyl (RR1R11 Si wherein R, R'and R'' are Ci-C6 alkyl groups) ; or R2 is not present and the C02 group to which it would be attached bears a negative charge; the ring A, B, D, and E is a carbon, nitrogen and sulphur containing heterocycle selected from the group consisting of thienyl, imidazolyl, thiazolyl 147 thiadiazolyl and pyrazolyl; R11 is selected from the group consisting of H, halogen, Cx-C6 alkyl, C-L-Ce alkoxy, hydroxyl, ammo as defmec above, cyano, Ci-CD hydroxyalkyl, C:-C6 carboxamidoal>:vl, Ci-Cs ammoalkyl or C-,-C„ quaternary ammonium alkyl, ar.c quaternary heteroaryliumalkyl; alki and alk2 are C-.-C, alkyl groups which may be independently substituted with a substituent selected from the group consisting of C.-C.- alkyl, hydroxy!, arr.mo as defined above, C.-C.; alkoxy, C:-Cs nydroxyalkvl ar.c carboxamide; p is 0, 1, or 2; R99 is selected from the group consisting of sulfur, SO, S02, NH, Ci-Cs N-alkyl, oxygen, C=C (cis or trans), ar.a C=C; q is 1; r is 0, 1, 2 or 3/ 148 X .yYr,Sr'6 ■v^nr13r14 ^ jj13 ^ or +Nr13R14 R13-R16 are independently selected from the group consisting of H, hydroxy, ammo as defined above, amidino, Cj-Ce alkyl, Ci-C6 cycloalkyl, acyl as defined above, aminoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or C:-C6 alkyl; wherein alk2 and R12 taken together may form a 5 or 6 member non-aromatic heterocycle which may be substituted as defined above.

28. The compound or salt of claim 27, wherein R1 is -NHC (0) ZR3.

29. The compound or salt of claim 28, wherein R3 is Ce-Cn aryl or heterocycle which may be substituted as defined in claim 27 .

30. The compound or salt of claim 29, wherein R3 is selected from the group consisting of phenyl, thienyl or furanyl, which may be substituted, as defined m claim 27, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl. 149

31. The compound or salt of claim 30, wherein Z is -C(NOR6)-, and R6 is selected from the group consisting of hydrogen and C;-Cr- alkyl, which may be substituted, as defined m claim 27.

32. The compound or salt of claim 31, wnereir. R' is selected from the group consisting of hydrogen 2-fluoroethyl, cyclopropylmethyl, allyl, dicnlcrcallvl and cyclopentyl, and RJ is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-ammothiazol-4-yl, 2-amino-5-chlorothiazcl-4-yl, ar.d 2-ammothiadiazol-4-yl.

33. The compound or salt of claim 32, wr.erem R' is hydrogen or 2-fluoroethyl and R3 is 2-aminotr.iazcl-4-yl or 2-ammo-5-chlorothiazol-4-yl.

34. The compound or salt of claim 33, wnereir. said compound is active against methicillin-resistant vancomycin-resistant, or ampicillin-resistant bacteria, as demonstrated by a lower minimum inhibitory concentration than cefotaxime or imipenem.

35- The use of a compound according to any of claims 27 to 34 in the manufacture of a medicament for the treatment of a mammal suffering from a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection. 150

36. The use of claim 37, wherein said mammal is infected with a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

37. An antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection, comprising a therapeutically effective amount of a compound or salt of any one of claims 27-34 m a pharmaceutically acceptable carrier.

38. The composition of claim 37, wherein said bacteria is a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

39. A compound of the formula: or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of -NHC(0)ZR3, CCfcR2 [(3lk1)p(R99)q(aMrR12]i.2 151 Z is selected from the group consisting of -CH:(X)r-, -C (NOR5) -CH (OR7) -, -C(CHCO;R5)- and -CH (NR3R:n) -; X is selected from the group consisting of oxygen ana sulphur; m is selected from the group consisting of 0 and 1; R3 is selected from the group consisting of cvano, C:-C6 alkyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or tnio, cyano, Ci-C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, mdolyl, pyridmyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C^-C- aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci-C6 alkyl, C:-C*alkenyl, nitro, amino, Ci~Ct- alkoxyl and amido; C^-Cn aryl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-C6 alkylthio, heterocycle selected from the group comprising furyl, thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl, C—C^ aryl, heteroaryl, carboxyl, Ci-C6 alkoxycarbonyl, Ci~C6 alkyl, Ci~C6 alkenyl, nitro, amino, Ci-C6 alkoxyl and amido; a heterocycle selected from the group comprising furyl, thienyl, imidazolyl, mdolyl, pyridmyl, thiadiazolyl, 152 thiazolyl, piperazmyl, dibenzfuranyl and dibenzthienyl which may be substituted with one or more substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, Ci-Ce alkylthio, heterocycle, C6-Ci4 aryl, heteroaryl, carboxyl, oxo, Ci-Cs alkoxycarbonyl, C:-C6 alkyl, Ci~C6 alkenyl, nitro, ammo, Ci-C* alkoxyl and amido; or a heteroalkyl group (RHetAr wherein R is C:-C6 alkyl HetAr is an aromatic heterocyle as defined above), and (CH2)nT, n is 1 to 6, T is selected from the group consisting of ammo (NRR' wherein R and R' may be Ci-C5 alkyl, C6-Ci4 aryl or acyl C(0)R wherein R is Ci-C6 alkyl), amidmo (C- or N-lmked) , guanidmo, and isothioureido, which may be substituted with Ci-C6 alkyl, C6-Ci4 aryl, hydroxyl, or ammo as defined above; R4"7 are independently selected from the group consisting of hydrogen, Ci-C6, alkyl, C6-Ci4 aryl and acyl as defined above; wherein R6 may also be a group that forms a protected hydroxy group with the adjacent oxygen R8 is selected from the group of hydrogen, Ci~C6 alkyl and C6-Ci4 aryl; 153 R9 and R10 are selected independently from the group consisting of hydrogen, C]-Cs alkyl, acyl as defined above, and heterocyclecarbonyl (C(O)Het wherein Ket is heterocycle as defined above); R2 is selected from the group consisting of hyarogen, Ci-Cs alkyl which may be substituted as defined acove, Ci-C6 alkenyl which may be substituted with one or mere functional groups selected from the group consisting cf hydroxyl, bromo, fluoro, chloro, iodo, mercapto or tr.io cyano, Ci~C6 alkylthio, heterocycle, Cs-C., aryl, heteroaryl, carboxyl, C:-Cs alkoxycarbonyl, C.-C, alkyl, C:-Cs alkenyl, nitro, amino, C:-Cs alkoxyl, and amiao; C6-Ci4 aryl which may be substituted as aefinec above, a heterocycle which may be substituted as aefinec above, aralkyl (RAr wherein R is C1-C6 alkyl which may be substituted as defined above and Ar is C^-Ci, aryl wmch may be substituted as defined above), heteroaralkyl and trialkylsilyl (RR'R'' Si wherein R, R'ana R'' are C:-C, alkyl groups); or R~ is not present and the C0: group to which it would be attached bears a negative charge; the ring G, H, J, L and M is a carbon, nitrogen or NR11 (quaternary ammonium heterocycle) containing heterocycl selected from the group consisting of pyridinyl piperazinyl, pyrimidmyl and pyrazmyl; 154 Rn is selected from the group consisting of H, halogen, Ci~C6 alkyl, Ci~C6 alkoxy, hydroxyl, ammo as defined above, cyano, Ci~C6 hydroxyalkyl, Ci~C6 carboxamidoalkyl, Cx-C6 aminoalkyl or Ci-C6 quaternary ammonium alkyl, and quaternary heteroaryliumalkyl; alki and alk2 are Ci-C6 alkyl groups which may be independently substituted with a substituent selected from the group consisting of Ci-Cs alkyl, hydroxyl, ammo as defined above, Ci-C6 alkoxy, C:-C6 hydroxyalkyl and carboxamide; p is 0, 1, or 2; R99 is selected from the group consisting of sulfur, SO, S02, NH, Ci~C6 N-alkyl, oxygen, C=C (cis or trans) , and C=C; q is 1; r is 0, 1, 2 or 3; + kid13D^ R12 is NR"R", NR'5R'6, NR" , NR'4 , fi JJ - NR,SR18 (I ,yV •\ NR,3R" 1,3 ^ or + ^,4 155 R13-R16 are independently selected from the group consisting of H, hydroxy, amino as defined above, amidmo, Ci-C6 alkyl, C:-C6 cycloalkyl, acyl as defined above, aminoacyl, and phosphoryl and taken together may form a 5- or 6-membered ring; and R17 is H or Ci-Ce alkyl; wherein alk2 and R"~ taken together may form a 5 or c member non-aromatic heterocycle which may be substituted as defined above.

40. The compound or salt of claim 39, where R" is is -NHC(0)ZR3.

41. The compound or salt of claim 40, wherein R" is C6-C14 aryl or heterocycle, wnich may be substituted, as defined m claim 39.

42. The compound or salt of claim 41, wherein R3 is selected from the group consisting of phenyl, thienyl or furanyl, which may be substituted, as defined m claim 39, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-aminothiadiazol-4-yl.

43. The compound or salt of claim 42, wherein Z is -C(NOR6)-, and R6 is selected from the group consisting of hydrogen and Ci~C6 alkyl which may be substituted as defined in claim 39. 156

44. The compound or salt of claim 43, wherein R° is selected from the group consisting of hydrogen 2-fluoroethyl, cyclopropylmethyl, allyl, dichloroallyl and cyclopentyl, and R3 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, and 2-ammothiadiazol-4-yl.

45. The compound of claim 44, wherein R° is hydrogen or 2-fluoroethyl and R3 is 2-ammothiazol-4-yl or 2-amino-5-chlorothiazol-4-yl.

46. The compound or salt of claim 45, wherein said compound is active against methicillin-resistant vancomycin-resistant, or ampicillin-resistant bacteria, as demonstrated by a lower minimum inhibitory concentration than cefotaxime or imipenem.

47. The use of a compound according to any of claims 39-46 or a salt thereof in the manufacture of a medicament for the treatment of a mammal suffering from a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection.

48. The use of claim 47, wherein said mammal is infected with a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism. 157

49. An antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection, comprising a therapeutically effective amount of a compound or salt of any one of claims 39-46 m a pharmaceutically acceptable carrier.

50. The composition of claim 49, wherein said bacteria is a methicillin-resistant Staphylococcal or ampicillin-resistant Enterococcal organism.

51 • A compound as defined in any one of claims 1, 15, 27, or 39, substantially as herein described with reference to any example thereof and/or the accompanying drawings.

52. The use of a compound as claimed in any one of claims -11, 23, 35 or 47 substantially as herein described with reference to any example thereof and/or the accompanying drawings.

53. An antibacterial composition for treating a methicillin-resistant, vancomycin-resistant, or ampicillin-resistant bacterial infection substantially as herein described with reference to any example thereof and/or the accompanying drawings. By the authorised agents INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 1 JUN 2001 RECEIVED