Inhibitors of beta-lactamase
View Patent ↗This invention provides novel β-lactamase inhibitors of the aryl- and heteroaryl-sulfonamidomethylphosphonate monoester class having nitrogen-based cations or quarternary ammomium groups. The compounds inhibit three classes of β-lactamases and synergize the antibacterial effects of β-lactam antibiotics (e.g., imipenem and ceftazimdime) against those micro-organisms normally resistant to the β-lactam antibiotics as a result of the presence of the β-lactamases.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
W represents:
wherein
R 3 independently represents fluorine, cyano, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-tert-butyl, —O-isobutyl, —O-pentyl, —O-hexyl, C 1-6 alkyl, —X m —Y m —Z* m —R 8 or —X m —Y m —Z* m -Q + ; R 4 independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; and R 8 represents hydrogen, halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted;
or
R 3 independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; R 4 independently represents fluorine, cyano, —O-propyl, —O-isopropyl, —O-butyl, —O-tert-butyl, —O-isobutyl, —O-pentyl, —O-hexyl, C 1-6 alkyl, —X m —Y m —Z* m —R 8 or —X m —Y m —Z* m -Q + ; and R 8 represents, halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted;
or W represents
wherein
R 3 and R 4 independently represent hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; and R 8 represents hydrogen, halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted;
or W represents
R a represents: (CH 2 ) n R aa ;
R aa represents:
wherein
R 3 in R aa independently represents halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; R 4 in Raa independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
R 7 -independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; and R 8 represents hydrogen, halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted;
or
R 3 in R aa independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; R 4 in Raa independently represents halogen, cyano, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-tert-butyl, —O-isobutyl, —O-pentyl, —O-hexyl, C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
R 7 independently represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ; and R 8 represents halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, or (CH 2 ) n C 5-10 heterocyclyl, said heterocyclyl optionally substituted;
provided at least one of R 3 , R 4 , and R 7 is —X m —Y m —Z* m Q+;
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;
R 1 independently represents hydrogen, 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 2 and R 5 independently represent hydrogen, halogen, cyano, —OR 1 , or C 1-6 alkyl;
X and Y independently are O, NR x , (C═O), SO 2 , (CH 2 ) n , —(CH 2 ) n NR 1 C(O)—, —(CH 2 ) n S—, or —(CH 2 ) n N(R x ) 2 —;
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;
Q is selected from the group consisting of:
wherein Z represents N + or carbon; and A is O, CH 2 , S(O) 0-2 , NR x , or N + (R x ) 2 ;
+ represents a positive charged ion;
L ⊖ represents a pharmaceutically acceptable counterion that is present as needed to provide charge balance on the molecule;
a and b are 1, 2 or 3;
α represents O, S or NR s ;
β, δ, λ, μ and σ represent CR t , N or N ⊖ R s , provided that no more than one of β, δ, λ, μ and σ is N ⊖ R s ;
each R b independently represents halo; —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; formamidinyl, —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;
each R s independently represents hydrogen; phenyl or —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
each R t independently represents hydrogen; halo; phenyl; —CN; —NO 2 ; —NR u R v ; —OR u ; —SR u ; —C(O)NR u R v ; —COOR c ; —SOR u ; —SO 2 R u ; —SO 2 NR u R v ; —NR u SO 2 R v ; —C(O)R u ; —NR u C(O)R v ; —OC(O)R u ; —OC(O)NR u R v ; —NR u CO 2 R v ; —NR u C(O)NR v R w ; —OCO 2 R v ; —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
R u and R v represent hydrogen or —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
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;
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 halo, 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(NH)NH 2 , NR c C(NH)H, NR c C(O)NR c R w , phenyl, naphthyl, 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;
R y and R z represent hydrogen; phenyl; —C 1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R b groups, and optionally interrupted by O, S, N w , N + R c R w or —C(O)—; and
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 one of R 3 and R 4 is —X m —Y m —Z* m -Q + and the other is —X m —Y m —Z* m —R 8 .
3. The compound according to claim 1 wherein X is O; and Y is (CH 2 ) n NR 1 CO—, a bond, —(CH 2 ) n S—, or (CH 2 ) n N(R x ) 2 .
4. A compound which is:
4-cyano-3-fluorophenyl-[({[5-(2-pyridiniumethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]-phosphonate;
4-cyano-3-fluorophenyl-[({[6-(2-pyridiniumethoxy)-4,5,7-trifluoro-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[6-(2-pyridiniumethoxy)-4-fluoro-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[6-(4-pyridiniumbutoxy)-4-fluoro-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[4-chloro-3-methyl-5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[7-chloro-3-methyl-5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-{[({5-[4-(2-pyridinium-1-ylethoxy)phenyl]-1,3,4-thiadiazol-2-yl}-sulfonyl)amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-{[({5-[4-(3-pyridinium-1-ylpropoxy)phenyl]-1,3,4-thiadiazol-2-yl}sulfonyl)amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-pyridinium-1-ylethoxy)-6-(2-chloroethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[6-(2-pyridinium-1-ylethoxy)-5-(2-chloroethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[6-(4-pyridinium-1-ylbutoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[6-(5-pyridinium-1-ylpentoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[6-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[6-(6-pyridinium-1-ylhexoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[4-chloro-3-methyl-5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[4,5,7-trifluoro-6-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[7-chloro-3-methyl-5-(2-pyridinium-1-ylethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-{[({5-[4-(2-pyridinium-1-ylethoxy)phenyl]-1,3,4-thiadiazol-2-yl}sulfonyl)amino]methyl}phosphonate;
Ammonium 4-cyano-3-fluorophenyl[({[5-(morpholin-4-yl-methyl)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-Cyano-3-fluorophenyl-({[(4,7-dichloro-5-{[(3-(pyridinium-1-ylpropyl)thio]methyl}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-({[(4,7-dichloro-5-{[(3-(pyridinium-1-ylpropyl)thio]methyl}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(aminomethyl)-thieno[3,2-b]thien-2-yl]sulfonyl}amino)methyl]phosphonate; 4-cyano-3-fluorophenyl-({[(5-{[(3-aminopropyl)thio]methyl}thieno[3,2-b]thien-2-yl)sulfonyl]amino}methyl)phosphonate;
Ammonium-4-cyano-3-fluorophenyl-[({[5-(aminomethyl)thieno[2,3-b]thien-2-yl)sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5,6-bis(2-ammonioethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
3-fluoro-4-[(trifluoromethyl)sulfonyl]phenyl-[({[5,6-bis(2-ammonioethoxy)-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-2-yl-[({[5,6-bis(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino)-methyl]-phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-ammoniopropoxy)-1-benzothien-2-yl]sulfonyl}amino)-methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(4-ammoniobutoxy)-1-benzothien-2-yl]sulfonyl}amino)-methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5,6-bis(3-ammoniopropoxy)-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-4,7-dichloro-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5,6-bis(2-ammonioethoxy)-4,7-dichloro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
3-fluoro-4-[(trifluoromethyl)sulfonyl]phenyl-[({[5,6-bis(2-ammonioethoxy)-4,7-dichloro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-4,7-difluoro-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5,6-bis(2-ammonioethoxy)-4,7-difluoro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl[({[5,6-bis(3-ammoniopropoxy)-4,7-difluoro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-ammoniopropoxy)-3-methyl-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-ammoniopropoxy)-4,7-difluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]-phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino) methyl]phosphonate;
6-cyanopyridin-3-yl-[({[5-(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-methylsulfonylpyridin-3-yl-[({[5-(2-ammonioethoxy)-1-benzothien-2-yl]sulfonyl}amino) methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-4-chloro-1-benzothien-2-yl]sulfonyl}amino) methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-7-chloro-1-benzothien-2-yl]sulfonyl}amino) methyl]phoshonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-ammonioethoxy)-7-chloro-1-benzothien-2-yl]-sulfonyl}amino)methyl]phoshonate;
3-fluoro-4-[(trifluoromethyl)sulfonyl]phenyl-[({[5-(ammonioethoxy)-7-chloro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-4-chloro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-ammonioethoxy)-4-chloro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(ammonioethoxy)-7-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
3-fluoro-4-(trifluoromethyl)phenyl-[({[5-(ammonioethoxy)-7-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
3-fluoro-4-[(trifluoromethyl)sulfonyl]phenyl-[({[5-(ammonioethoxy)-7-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-[(trifluoromethyl)sulfonyl]-phenyl-[({[5-(2-ammonioethoxy)-4-chloro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-7-chloro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-ammonioethoxy)-7-chloro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-[({[6-(2-ammonioethoxy)-4,5,7-trifluoro-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-{[({5-[4-(2-ammonioethoxy)phenyl]-1,3,4-thiadiazol-2-yl}sulfonyl)-amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-{[({5-[3,4-bis(3-ammoniopropoxy)phenyl]thiophen-2-yl}sulfonyl)-amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-{[({5-[3,4-bis(3-ammoniopropoxy)-2-methylphenyl]thiophen-2-yl}sulfonyl)amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-{[({5-[4,5-bis(3-ammoniopropoxy)-2-methylphenyl]thiophen-2-yl}-sulfonyl)amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-[({[6-(2-ammonioethoxy)-5-(2-{[2,3-bis(benzyloxy)benzoyl]amino}-ethoxy-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl-[({[5-(2-ammonioethoxy)-6-(2-{[2,3-bis(benzyloxy)benzoyl]amino}-ethoxy)-1-benzothien-2-yl)-sulfonyl]amino}methyl)phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[6-(2-ammonioethoxy)-5-(2-{[3,4-bis(benzyloxy)benzoyl]-amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-ammonioethoxy)-6-(2-{[3,4-bis(benzyloxy)benzoyl]-amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl({[(6-(2-ammonioethoxy)-5-{2-[(2,3-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl({[(5-(2-ammonioethoxy)-6-{2-[(2,3-dihdroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-({[(6-(2-ammonioethoxy)-5-{2-[(3,4-dihydroxybenzoyl)-amino]ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-({[(5-(2-ammonioethoxy)-6-{2-[(3,4-dihydroxybenzoyl)amino]ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl {[({5-[2-dimethylammonio-ethoxy]-1-benzothien-2-yl}sulfonyl)amino]methyl}phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-({[(5-{2-[(iminiomethyl)amino]ethoxy}-1-benzothien-2-yl)sulfonyl]-amino}methyl)phosphonate;
4-cyano-3-fluorophenyl[({[5-(2-{[(dimethyliminio)-methyl]amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]-phosphonate;
4-cyano-3-fluorophenyl-{[({5-(2-(4-aza-1-azoniabicyclo[2.2.2]oct-1-yl)ethoxy)-1-benzothien-2-yl}sulfonyl)-amino]methyl}phosphonate;
4-cyano-3-fluorophenyl-{[({6-(2-(4-aza-1-azoniabicyclo[2.2.2]oct-1-yl)ethoxy)-4,5,7-trifluoro-1-benzothien-2-yl}sulfonyl)amino]methyl}phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-[({[5-(2-(4-methyl-1,4-diazoniabicyclo[2.2.2]oct-1-yl)ethoxy)-1-benzothien-2-yl]sulfonyl}-amino)methyl]-phosphonate;
4-cyano-3-fluorophenyl-({[(5-{2-[4-(3-azidopropyl)-1,4-diazoniabicylco[2.2.2]oct-1-yl]ethoxy}-1-benzothien-2-yl)sulfonyl]-amino}methyl)phosphonate;
4-cyano-3-fluorophenyl-({[(6-{2-[4-(3-azidopropyl)-1,4-diazoniabicylco[2.2.2]oct-1-yl]ethoxy}-4-fluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl-({[(6-{2-[4-(3-azidopropyl)-1,4-diazoniabicylco[2.2.2}oct-1-yl]ethoxy}-4,5,7-trifluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-{2-[bis(2-cyanoethyl)amino]ethoxy}-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5-(2-{4-[3-(1,4-diazoniabicyclo[2.2.2]oct-1-yl)propyl]-1,4-diazoniabicyclo[2.2.2]oct-1-yl}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl-{[({6-[2-(4-{3-[(2,3-dihydroxybenzoyl)amino]propyl}-1,4-diazoniabicyclo[2.2.2]oct-1-yl)ethoxy]-4,5,7-trifluoro-1-benzothien-2-yl}sulfonyl)-amino]methyl}phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-{2-[bis(3-ammoniopropoxy)amino]ethoxy}-1-benzothien-2-yl]-sulfonyl}amino)methyl]phoshonate;
4-cyano-3-fluorophenyl hydrogen({[(5-{3-[bis(3-aminopropyl)amino]propoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen({[(5-{3-[(4-aminobutyl)-(3-aminopropyl)amino]propoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen({[(5-{3-[bis(3-aminopropyl)amino]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(3-{bis[3-({[(4-methoxybenzyl)oxy]carbonyl}amino)propyl]-amino}propoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(3-{[4-({[(4-methoxybenzyl)oxy]carbonyl}amino)butyl][3-({[(4-methoxybenzyl)oxy]carbonyl}amino)propyl]amino}propoxy)-1-benzothien-2-yl]-sulfonyl}amino)-methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(3-{bis[3-({[(4-methoxybenzyl)oxy]carbonyl}amino)propyl]-amino}propoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(3-{[4-({[(4-methoxybenzyl)oxy]carbonyl}amino)butyl][3-({[(4-methoxybenzyl)oxy]carbonyl}amino)propyl]amino}propoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen({[(5-{3-[4-aminobutyl]-(3-aminopropyl)amino]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl-({[(5-{2-[4-(3-ammoniopropyl)-1,4-diazoniabicylco[2.2.2}oct-1-yl]-ethoxy}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate trifluoroacetate trifluoromethanesulfonate;
4-cyano-3-fluorophenyl-({[(6-{2-[4-(3-ammoniopropyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]-ethoxy}-4-fluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl-({[(6-{2-[4-(3-ammoniopropyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]-ethoxy}-4,5,7-trifluoro-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-{[4-({2-[({(4-cyano-3-fluorophenoxy)(hydroxyl)-phosphoryl]methyl}amino)sulfonyl]-1-benzothien-6-yl}-oxy)butyl]thio}-1-methylpyridinium;
4-Cyano-3-fluorophenyl-({[(5-{[(3-(pyridinium-1-ylpropyl)thio]methyl}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-(trifluoromethyl)phenyl-({[(5-{[(3-(pyridinium-1-ylpropyl)thio]methyl}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-Cyano-3-fluorophenyl-({[(5-{[(3-(pyridinium-1-ylpropyl)sulfonyl]methyl}-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-ammoniopropoxy)-3-ethyl-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[6-(4-ammoniobutoxy)-5-(3-ammoniopropoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(4-ammoniobutoxy)-6-(3-ammoniopropoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-3-methyl-4,7-difluoro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-3-ethyl-4,7-difluoro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-ammoniopropoxy)-4,7-difluoro-3-ethyl-1-benzothien-2-yl]-sulfonyl}amino)methyl]phosphonate;
N′2′,N′2′-bis(2-aminoethyl)-N-{2-[({[(4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl]-methyl}amino)sulfonyl]-1-benzothien-5-yl}glycinamide;
2-(2-(N-(((4-cyano-3-fluorophenoxy)(hydroxy)phosphoryl)methyl)sulfamoyl)benzo[b]thiophen-5-ylamino)-N,N,N-trimethyl-2-oxoethanaminium;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-{[amino(iminio)methyl]amino}propoxy)-4,7-difluoro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-{[amino(iminio)methyl]amino}propoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-{[amino(iminio)methyl]amino}propoxy)-4,7-dichloro-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
N′2′,N′2′-bis{2-[(tert-butoxycarbonyl)amino]ethyl}-N-{2-[({[(4-cyano-3-fluorophenoxy)-(hydroxy)phosphoryl]methyl}amino)sulfonyl]-1-benzothien-5-yl}glycinamide;
4-cyano-3-fluorophenyl hydrogen[({[5-(2-{bis[3-({[(4-methoxybenzyl)oxy]carbonyl}amino)-propyl]amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[5-(2-{[(8-hydroxyquinolin-5-yl)methyl](methyl)amino}-acetamido)-benzo[b]thiophene-2-sulfonamido]methyl phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-{[amino(iminio)methyl]amino}propoxy)-3-ethyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(3-{[amino(iminio)methyl]amino}propoxy)-4,7-fluoro-3-ethyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl[({[5,6-bis(2-ammonioethoxy)-3-ethyl-1-benzothien-2-yl]sulfonyl}-amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[5-((S)-2,6-diaminohexanamido)benzo[b]thiophene-2-sulfonamido]methylphosphonate;
4-cyano-3-fluorophenyl-hydrogen-{5-[(S)-2-amino-3-(1H-imidazol-4-yl)propanamido]-benzo[b]thiophene-2-sulfonamido}methylphosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5-(2-{bis[3-({[(4-methoxybenzyl)oxy]-carbonyl}amino)-propyl]amino}ethoxy)-1-benzothien-2-yl]sulfonyl}amino)methyl]-phosphonate;
4-cyano-3-fluorophenyl(5-((3-(pyridinium-1-yl)propylthio)methyl)benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl(5-((3-(pyridinium-1-yl)propylsulfonyl)methyl)benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl aminooxy((7-cyano-6-(dimethylamino)benzo[b]thiophene-2-sulfonamido)methyl)phosphinate;
4-cyano-3-fluorophenyl hydrogen(5-(2-(bis(2-(3,4-dimethoxybenzamido)ethyl)-amino)acetamido)-benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl hydrogen(5-(2-(bis(2-(3,4-dihydroxybenzamido)ethyl)-amino)acetamido)-benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl hydrogen(5-(3,4-bis(3-aminopropoxy)benzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl hydrogen(5-(3,4,5-tris(3-aminopropoxy)benzamido)-benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl hydrogen(5-(3,5-bis(3-aminopropoxy)benzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-aminopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen({[(5,6-bis{3-[(iminomethyl)amino]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-{[amino(imino)methyl]amino}propoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-aminopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl hydrogen({[(5,6-bis{3-[(iminomethyl)amino]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-{[amino(imino)methyl]amino}propoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl[({[5,6-bis(3-ammoniopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-aminopropoxy)-4-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-aminopropoxy)-7-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-aminopropoxy)-4,7-difluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-aminopropoxy)-4-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-aminopropoxy)-7-fluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl hydrogen[({[5,6-bis(3-aminopropoxy)-4,7-difluoro-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate;
4-cyano-3-fluorophenyl({[(5-{3-[4-(3-ammoniopropyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl({[(5-{3-[4-(3-{[(Z)-iminomethyl]amino}propyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
4-cyano-3-fluorophenyl({[(5-{3-[4-(3-{[(Z)-amino(imino)methyl]amino}propyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
6-cyanopyridin-3-yl({[(5-{3-[4-(3-ammoniopropyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
6-cyanopyridin-3-yl({[(5-{3-[4-(3-{[(Z)-iminomethyl]amino}propyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate; and
6-cyanopyridin-3-yl({[(5-{3-[4-(3-{[(Z)-amino(imino)methyl]amino}propyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl]propoxy}-3-methyl-1-benzothien-2-yl)sulfonyl]amino}methyl)phosphonate;
or pharmaceutically acceptable salts thereof.
5. A compound according to claim 4 wherein the pharmaceutically acceptable salts are selected from one or more of the groups consisting of chloride, trifluoroacetate, iodide, trifluoromethanesulfonate, acetate, phosphate, or a mixture thereof.
6. A compound according to claim 1 , which is
4-cyano-3-fluorophenyl hydrogen(5-(3,4-bis(3-aminopropoxy)benzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate trifluoroacetate;
4-cyano-3-fluorophenyl hydrogen(5-(3,4,5-tris(3-aminopropoxy)benzamido)-benzo[b]thiophene-2-sulfonamido)methylphosphonate trifluoroacetate;
4-cyano-3-fluorophenyl hydrogen(5-(3,5-bis(3-aminopropoxy)benzamido)benzo[b]thiophene-2-sulfonamido)methylphosphonate trifluoroacetate;
6-cyanopyridin-3-yl[({[5,6-bis(3-ammoniopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate chloride;
6-cyanopyridin-3-yl[({[5,6-bis(3-ammoniopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate trifluoroacetate; or
4-cyano-3-fluorophenyl[({[5,6-bis(3-ammoniopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate trifluoroacetate.
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.
9. The composition according to claim 8 wherein the beta-lactam antibiotic is selected from the group consisting of imipenem, Primaxin®, Amoxicillin, Ticarcillin, Ampicillin, Cefoperazone, Piperacillin, and ceftazidime.
10. The composition of claim 9 wherein the beta-lactam antibiotic is Primaxin®.
11. A method of treating bacterial infections or inhibiting beta-lactamase in a mammal, the method comprising administering a therapeutically effect amount of a compound according to claim 1 .
12. A compound according to claim 1 , which is 6-cyanopyridin-3-yl hydrogen[({[5,6-bis(3-aminopropoxy)-3-methyl-1-benzothien-2-yl]sulfonyl}amino)methyl]phosphonate or a pharmaceutically acceptable salt thereof.
13. A compound which is 4-cyano-3-fluorophenyl(5-((triethylammonio)methyl)thiophene-2-sulfonamido)methylphosphonate or a pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 :
or a pharmaceutically acceptable salt thereof, wherein:
W represents:
and
R 3 and R 4 independently represent cyano, C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
or W represents
and
R 3 and R 4 independently represent hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
or W represents
R a represents: (CH 2 ) n R aa ;
Raa represents:
and
R 3 and R 4 independently represent halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
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;
R 1 independently represents hydrogen, 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 2 and R 5 independently represent hydrogen, halogen, cyano, —OR 1 , or C 1-6 alkyl;
R 7 represents hydrogen, halogen, cyano, —OR 1 , C 1-6 alkyl, —X m —Y m —Z* m —R 8 , or —X m —Y m —Z* m -Q + ;
X and Y independently are O, NR x , (C═O), SO 2 , (CH 2 ) n , —(CH 2 ) n NR 1 C(O)—, —(CH 2 ) n S—, or —(CH 2 ) n N(R x ) 2 —;
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 halo, N(R c ) 2 , —C(O)R 5 , NR c C(NH)NH 2 , NR c C(NH)H, (CH 2 ) n C 5-10 heterocyclyl, or (CH 2 ) n C 5-10 aryl, said heterocyclyl and aryl optionally substituted;
Q is selected from the group consisting of:
wherein Z represents N + or carbon; and A is O, CH 2 , S(O) 0-2 , NR x , or N + (R x ) 2 ;
+ represents a positive charged ion;
L ⊖ represents a pharmaceutically acceptable counterion that is present as needed to provide charge balance on the molecule;
a and b are 1, 2 or 3;
α represents O, S or NR s ;
β, δ, λ, μ and σ represent CR t , N or N ⊖ R s , provided that no more than one of β, δ, λ, μ and σ is N ⊖ R s ;
each R b independently represents halo; —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; formamidinyl, —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;
each R s independently represents hydrogen; phenyl or —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
each R t independently represents hydrogen; halo; phenyl; —CN; —NO 2 ; —NR u R v ; —OR u ; —SR u ; —C(O)NR u R v ; —COOR c ; —SOR u ; —SO 2 R u ; —SO 2 NR u R v ; —NR u SO 2 R v ; —C(O)R u ; —NR u C(O)R v ; —OC(O)R u ; —OC(O)NR u R v ; —NR u CO 2 R v ; —NR u C(O)NR v R w ; —OCO 2 R v ; —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
R u and R v represent hydrogen or —C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R b groups;
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;
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 halo, 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(NH)NH 2 , NR c C(NH)H, NR c C(O)NR c R w , phenyl, naphthyl, 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;
R y and R z represent hydrogen; phenyl; —C 1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R b groups, and optionally interrupted by O, S, N w , N + R c R w or —C(O)—; and
m represents 0 to 1; n represents 0 to 6; wherein it is understood that when a value is zero, a bond exists.
15. The compound of claim 1 wherein W represents:
16. The compound of claim 15 wherein J is CR 1 and K is S.
17. The compound of claim 1 wherein R 3 and R 4 are —X m —Y m —Z* m -Q + .
18. The compound of claim 1 wherein X is O.
19. The compound of claim 18 wherein Y is a bond and Z* is (CH 2 ).
20. The compound of claim 1 wherein R 6 is C 6-10 aryl, C 5-10 heteroaryl, said aryl and heteroaryl optionally substituted with 1-4 groups selected from halogen, cyano, nitro, C 1-6 alkyl, OR 1 , N(R 1 ) 2 , COOR 1 , and CON(R 1 ) 2 .
21. The compound of claim 1 wherein Q + is
and L − is present if needed to provide neutrality.