NOVEL SULFONAMIDOMETHYLPHOSPHONATE INHIBITORS OF BETA-LACTAMASE

1 . A compound of Formula I:

or a pro-drug or pharmaceutically acceptable salt thereof, wherein:

W represents:

R a represents: (CH 2 ) n KR aa , or R aa ;

R aa represents:

J represents N or CR 1 ;

K represents O, S, or NR 1 ;

Het represents a 5-6 membered nitrogen containing heterocycle substituted with 0 to 4 groups of R 2 ;

T represents hydrogen, halogen, OR 1 or C 1-6 alkyl;

M is a negative charge, H, or a pharmaceutically acceptable metal or ammonium salt, and provided that when W contains a moiety with multiple positive charges, there is an appropriate number of L ⊖ present to provide overall neutrality;

R 1 independently represents hydrogen, or C 1-6 alkyl;

R 2 and R 5 independently represent hydrogen, halogen, cyano, —OR 1 or C 1-6 alkyl;

R 3 , R 4 , and R 7 independently represent hydrogen, halogen, cyano, —OR 1 C 1-6 alkyl, or —X m —Y m —Z* m —R 8 ;

X and Y independently are bond, O, (C═O), SO 2 , (CH 2 ) n , —(CH 2 ) n NR 1 C(O)—, —(CH 2 ) n S—, or —(CH 2 ) n NR x —;

Z* is (CH 2 ) n which may be substituted with one to four R b ,

R 6 represents C 6-10 aryl, or C 5-10 heteroaryl, said aryl and heteroaryl optionally substituted;

R 8 represents H, halogen, —N(R c ) 2 , —C(O)R 5 , —NR 1 (CH 2 ) n C 5-10 aryl, —NR 1 (CH 2 ) n C 5-10 heterocyclyl, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted with one to four R b ;

each R b independently represents halogen; —CN; —NO 2 ; phenyl; —NHSO 2 R c ; —OR c , —SR c ; —N(R c ) 2 ; —N + (R c ) 3 ; —C(O)N(R c ) 2 ; —SO 2 N(R c ) 2 ; heteroaryl; heteroarylium; —CO 2 R c ; —C(O)R c ; —OC(O)R c ; —NHC(O)R c ; —NHC(O) 2 R c ; guanidinyl; carbamimidoyl or ureido, said phenyl and heteroaryl optionally substituted;

each R c independently represents hydrogen, a —C 1-6 straight or branched-chain alkyl group, a —C 3 -C 6 cycloalkyl group or C 6-10 aryl, said aryl optionally substituted with one to four groups of halogen; —CN; —NO 2 ; phenyl; —NHSO 2 R j ; —OR 1 , —SR j ; —N(R j ) 2 ; —N + (R j ) 3 ; —C(O)N(R j ) 2 ; —SO 2 N(R j ) 2 ; heteroaryl; heteroarylium; formamidinyl, —CO 2 R j ; —C(O)R j ; —OC(O)R j , —NHC(O)R j , —NHC(O) 2 R j ; guanidinyl; carbamimidoyl or ureido, said phenyl and heteroaryl optionally substituted, wherein Rj is selected from the group consisting of hydrogen, a —C 1-6 straight or branched-chain alkyl group, a —C 3 -C 6 cycloalkyl group or C 6-10 aryl;

R x represents hydrogen or a C 1-8 straight- or branched-alkyl chain, optionally interrupted by one or two of O, S, SO, SO 2 , NR w , N + R c R w , or —C(O)—, said alkyl chain being unsubstituted or substituted with one to four of halogen, CN, NO 2 , —N 3 , OR w , SR w , SOR w , SO 2 R w , NR c R w , N + (R c ) 2 R w , Q, —C(O)—R w , C(O)NR c R w , SO 2 NR c R w , CO 2 R w , OC(O)R w , OC(O)NR c R w , NR c C(O)R w , NR c C(O)NR c R w , phenyl, napthyl, heteroaryl, or heterocyclic group said phenyl, heteroaryl, and heterocyclic group optionally substituted with from one to four R b groups or with one to two C 1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R b groups; and

each R w independently represents hydrogen; —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups, —C 3-6 cycloalkyl optionally substituted with one to four R b groups; phenyl optionally substituted with one to four R b groups, or heteroaryl optionally substituted with one to four R b groups;

m represents 0 to 1; n represents 0 to 6; wherein it is understood that when a value is zero, a bond exists.

2 . The compound according to claim 1 wherein at least one of R 3 , R 4 , and R 7 is —X m —Y m —Z* m —R 8 .

3 . The compound according to claim 2 wherein R 3 and R 4 , both are —X m —Y m —Z* m —R 8 .

4 . The compound according to claim 2 wherein X is O and Y is (CH 2 ) n NR 1 CO − , —(CH 2 ) n S—, or (CH 2 ) n NR x .

5 . The compound according to claim 1 of structural formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 2 , R 3 . R 4 , R 5 , R 6 are as previously described.

6 . A compound which is:

{2-[({[[4-cyano-3-(trifluoromethyl)phenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-difluoro-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-difluoro-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-dichloro-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-3,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-(trifluoromethyl)phenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[(6-cyanopyridin-3-yl)oxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy] (hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-(trifluoromethyl)phenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

2-(acetyloxy)-4-({[3-({6-(4-{[3,4-bis(acetyloxy)benzoyl]amino}butoxy)-2-[({[(4-cyano-3-fluorophenoxy)-(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothien-5-yl}oxy)propyl]amino}carbonyl)phenyl acetate;

2-(acetyloxy)-4-({[3-({6-(4-{[3,4-bis(acetyloxy)benzoyl]amino}propoxy)-2-[{([(4-cyano-3-fluorophenoxy)-(hydroxy)-phosphoryl]methyl}amino)sulfonyl]-1-benzothien-5-yl}oxy)butyl]amino}carbonyl)phenyl acetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-difluoro-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-3-methyl-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-3-ethyl-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-difluoro-3-ethyl-1-benzothiene-5,6-diyl}bis(oxypropane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

{2-[({[[4-cyano-3-fluorophenoxy](hydroxy)phosphoryl]methyl}amino)sulfonyl]-4,7-difluoro-3-ethyl-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

(4-{5-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-2-thienyl}-1,2-phenylene)bis(oxypropane-3,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

(4-{5-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-2-thienyl}-3-methyl-1,2-phenyl ene)bis(oxypropane-3,1-diyliminocarbonylbenzene-4,1,2-triyl)tetraacetate;

4-cyano-3-fluorophenyl hydrogen {[({5,6-bis[2-(1-naphthoylamino)ethoxy]-1-benzothien-2-yl}sulfonyl)amino]-methyl}phosphonate;

4-cyano-3-fluorophenyl hydrogen {[({5,6-bis[2-(2-naphthoylamino)ethoxy]-1-benzothien-2-yl}sulfonyl)amino]-methyl}phosphonate;

4-cyano-3-fluorophenyl hydrogen {[({5,6-bis[2-(benzoylamino)ethoxy]-1-benzothien-2-yl}sulfonyl)amino]-methyl}phosphonate;

4-cyano-3-fluorophenyl hydrogen {[({5,6-bis[2-(3,4-difluorobenzoylamino)ethoxy]-1-benzothien-2-yl}-sulfonyl)amino]methyl}phosphonate;

{2-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonyl-4,1-phenylene) diacetate;

{2-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis(oxyethane-2,1-diyliminocarbonyl-3,1-phenylene) diacetate;

{2-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothiene-5,6-diyl}bis[oxyethane-2,1-diylimino(2-oxoethane-2,1-diyl)benzene-4,1,2-triyl]tetraacetate;

4-(cyano-3-fluorophenyl hydrogen {5,6-bis[3-(3,4-dihydroxybenzamido)propoxy]benzo[d]thiazole-2-sulfonamido}-methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-4,7-difluoro-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-4,7-difluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-4,7-dichloro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(2,3-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen ({[(5,6-bis{2-[(2,3-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

3-fluoro-4-[(trifluoromethyl)sulfonyl]phenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

6-cyanopyridin-3-yl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]propoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]butoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen ({[(5,6-bis{2-[(2,3-dihydroxybenzoyl)amino]propoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(6-{4-[(3,4-dihydroxybenzoyl)amino]butoxy}-5-{3-[(3,4-dihydroxybenzoyl)amino]propoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5-{4-[(3,4-dihydroxybenzoyl)amino]butoxy}-6-{3-[(3,4-dihydroxybenzoyl)amino]propoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]propoxy}-4,7-dichloro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]propoxy}-4,7-difluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(4-hydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3-hydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[3,4-dihydroxybenzoyl)amino]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]propoxy}-3-ethyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]propoxy}-4,7-difluoro-3-ethyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen ({[(5,6-bis{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-4,7-difluoro-3-ethyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;

4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(2-{[(3,4-dihydroxyphenyl)acetyl]amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;

4-cyano-3-fluorophenyl hydrogen[({[5-(3,4-bis{3-[(3,4-dihydroxybenzoyl)amino]propoxy}phenyl)-2-thienyl]sulfonyl}amino)methyl]phosphonate;

4-cyano-3-fluorophenyl hydrogen[({[5-(3,4-bis{3-[(3,4-dihydroxybenzoyl)amino]propoxy}-2-methylphenyl)-2-thienyl]sulfonyl}amino)methyl]phosphonate;

4-Cyano-3-fluorophenyl hydrogen (5-{3,4-bis[3-(3,4-dihydroxybenzamido) propoxy]benzamido}-benzo[b]thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-((pyridin-2-ylthio)methyl)thiophene-2-sulfonamido)-methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(dimethylamino)benzo[b]thiophene-2-sulfonamido)-methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (7-cyano-6-(dimethylamino)benzo[b]thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (5-(3,4-dihydroxybenzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(2,3-dihydroxybenzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (5-(2,3-dihydroxybenzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(3,4-dihydroxybenzamido)benzo[b]thiophene-2-sulfonamido)-methylphosphonate;

Ammounium 4-cyano-3-(trifluoromethyl)phenyl (2-(3,4-dimethoxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-fluorophenyl (2-(3,4-dimethoxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (2-(3,4-dihydroxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (2-(3,4-dihydroxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-fluorophenyl (2-(2,3-dimethoxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-fluorophenyl (5-(3,4-dimethoxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-(trifluoromethyl)phenyl (5-(3,4-dimethoxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (5-(3,4-dihydroxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(3,4-dihydroxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-fluorophenyl (5-(6-methoxypyridin-3-yl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-(trifluoromethyl)phenyl (5-(6-methoxypyridin-3-yl)thiophene-2-sulfonamido)methylphosphonate;

6-cyanopyridin-3-yl hydrogen (5-(6-methoxypyridin-3-yl)thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (2-(2,3-dihydroxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (2-(2,3-dimethoxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (2-(2,3-dihydroxyphenyl)thiazole-5-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-fluorophenyl (5-(2,3-dimethoxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-(trifluoromethyl)phenyl (5-(2,3-dimethoxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-fluorophenyl hydrogen (5-(2,3-dihydroxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (5-(2,3-dihydroxyphenyl)thiophene-2-sulfonamido)methylphosphonate;

Ammonium 4-cyano-3-(trifluoromethyl)phenyl (5,6-dimethoxybenzofuran-2-sulfonamido)methylphosphonate;

4-cyano-3-(trifluoromethyl)phenyl hydrogen (5,6-dihydroxybenzofuran-2-sulfonamido)methylphosphonate; and

Ammonium 4-cyano-3-fluorophenyl(5-((3,4-dihydroxyphenylsulfonyl)methyl)thiophene-2-sulfonamido)methylphosphonate

or pharmaceutically acceptable salts thereof.

7 . A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

8 . The composition according to claim 7 in combination with a beta-lactam antibiotic selected from the group consisting of imipenem, Primaxin®, Amoxicillin, Ticarcillin, Ampicillin, Cefoperazone, Piperacillin, and ceftazidime.

9 . The composition of claim 8 wherein the beta-lactam antibiotic is Primaxin®.

10 . Use of a compound of formula I of claim 1 in combination with a beta lactam antibiotic in the manufacture of a medicament for treating bacterial infections or for inhibiting beta-lactamase.