US2006217361A1PendingUtilityA1
Bicyclic 6-alkylidene-penems as beta-lactamase inhibitors

Assignee: WYETH CORPPriority: May 1, 2002Filed: Jun 6, 2006Published: Sep 28, 2006
Est. expiryMay 1, 2022(expired)· nominal 20-yr term from priority
Inventors:Aranapakam Mudumbai Venkatesan Tarek Suhayl Mansour Takao Abe Itsuki Yamamura Tsuyoshi Takasaki Atul Agarwal Osvaldo Dos Santos Fuk-Wah Sum Yang-I Lin
C07D 499/88C07D 503/00A61P 43/00A61P 31/04C07D 499/861C07D 519/00C07D 499/881
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Claims
Abstract

The present invention provides a compound of formula I, pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof.
Claims

exact text as granted — not AI-modified
1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;  
 X is O or S;  
 R 5  is H, C1-C6 alkyl, C5-C6 cycloalkyl, or CHR 3 OCOC1-C6alkyl; and  
 R 3  is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The compound according to  claim 1  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein 
 Z1, Z2 and Z3 are independently CR 2 , N, O, S or N—R 1  provided one of Z1-Z3 is carbon and is bonded to the remainder of the molecule;  
 W 1 , W 2  and W 3  are independently CR 4 R 4 , S, SO, SO 2 , O, or N—R 1 ; with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;  
 t=1 to 4;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR 6 , optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q -optionally substituted C1-C6 akyl, S(O) q — optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       3 . The compound according to  claim 1  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein 
 Z1, Z2 and Z3 are independently CR 2 , N, O, S or N—R 1  provided one of Z1-Z3 is carbon and is bonded to the remainder of the molecule;  
 W 1 , W 2  and W 3  are independently CR 4 R 4 , S, SO, SO 2 , O, or N—R 1 ;  
 t=1 to 4;  
 Y 1  and Y 2  are independently N or C; with the proviso that if the aromatic ring portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C 1 -C 6  alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR 6 , optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q -optionally substituted C1-C6 akyl, S(O) q — optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       4 . The compound according to  claim 1  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein  
     Z1, Z2, Z3 and Z4 are independently CR 2  or N provided one of Z1-Z4 is carbon and is bonded to the remainder of the molecule; 
 W 1 , W 2  and W 3  are independently CR 4 R 4 , S, SO, SO 2 , O, or N—R 1 ; with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;  
 t=1 to 4;  
 Y 1  and Y 2  are independently C or N;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR 6 , optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q -optionally substituted C1-C6 akyl, S(O) q — optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       5 . The compound according to  claim 2  wherein one of Z1-Z3 is CR 2 .  
   
   
       6 . The compound according to  claim 2  wherein one of Z2 or Z3 is N, O, or S.  
   
   
       7 . The compound according to  claim 5  wherein one of Z2 or Z3 is N, O, or S.  
   
   
       8 . The compound according to  claim 2  wherein at least one of W 1 , W 2  and W 3  is CR 4 R 4 .  
   
   
       9 . The compound according to  claim 8  wherein W 1 , W 2  and W 3  are independently CR 4 R 4 .  
   
   
       10 . The compound according to  claim 2  wherein t=1-3.  
   
   
       11 . The compound according to  claim 3  wherein t=3.  
   
   
       12 . The compound according to  claim 3  wherein at least two of Z 1 , Z 2 , Z 3 , Y 1 , and Y 2  are N.  
   
   
       13 . The compound according to  claim 12  wherein three of Z 1 , Z 2 , Z 3 , Y 1 , and Y 2  are N.  
   
   
       14 . The compound according to  claim 3  wherein two of W 1 , W 2 , and W 3  are independently CR 4 R 4 .  
   
   
       15 . The compound according to  claim 14  wherein R 4  is H.  
   
   
       16 . The compound according to  claim 3  wherein one of Y 1  and Y 2  is C and the other is N.  
   
   
       17 . The compound according to  claim 3  wherein two of Z 1 , Z 2 , and Z 3  are independently CR 2 .  
   
   
       18 . The compound according to  claim 4  wherein three of Z 1 -Z 4  are independently CR 2  and the other is C.  
   
   
       19 . The compound according to  claim 4  wherein at least one of Z 1 -Z 4  is N.  
   
   
       20 . The compound according to  claim 19  wherein Z 1  is N.  
   
   
       21 . The compound according to  claim 19  wherein two of Z 1 -Z 4  are N.  
   
   
       22 . The compound according to  claim 19  wherein three of Z 1 -Z 4  are N.  
   
   
       23 . The compound according to  claim 1  selected from the group consisting of 
 a. (5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methylene]-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    b. (5R),(6Z)-6-(7-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    c. (5R),(6Z)-7-Oxo-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    d. (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    e. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    f. (5R),(6Z)-6-(6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    g. (5R), (6Z)-6-(5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    h. (5R),(6Z)-6-(5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    i. (5R)(6Z)-7-Oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    j. (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt;    k. (5R)(6Z)-6-(6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    l. (5R)(6Z)-7-Oxo-6-(4H-5-thia-1,6a-diazapentalen-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    m. (5R)(6Z)-6-(7H-Imidazo[1,2-c]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    n. (5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    o. 6-(6,7-Dihydro-4H-thieno[3,2-c]pyran-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    p. 6-(6,7-Dihydro-4H-thieno[3,2-c]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    q. 6-(5-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    r. 2-(2-Carboxy-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-en-6-ylidenemethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid ethyl ester;    s. 7-Oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene) 4 -thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    t. (5R),(6Z)-6-(7-Benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    u. (5R,6Z)-7-oxo-6-{[5-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    v. (5R,6Z)-7-oxo-6-{[5-(pyridin-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    w. (5R,6Z)-7-oxo-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)]methylene}-7oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    x. (5R),(6Z)-6-(5,5-Dioxo-4,5,6,7-tetrahydro-5λ 6 -pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    y. (5R),(6Z)-7-Oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    z. (5R)(6Z)-6-(5,5-Dimethyl-4H-1,6a-diazapentalen-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt 5,5-Dimethyl-2-piperidone;    aa. (5R),(6Z)-6-(5,6-Dihydro-4H-cyclopenta[b]furan-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    bb. (5R)(6Z)-6-(4,5-Dihydro-6-thia-1,7a-diazainden-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    cc. (5R),(6Z)-6-(6,6-Dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrizin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    dd. (5R),(6Z)-6-(5,6-Dihydro-8-H-imidazo[2,1-c][1,4]thiazin-3-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    ee. (5R)(6Z)-7-Oxo-6-(4H-5-thia-1,6a-diazapentalen-2-ylmethylene) 4 -thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    ff. (5R)(6Z)-6-(2,3-Dihydropyrazolo[5,1-b]thiazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    gg. (5R)(6Z)-6-(2,3-Dihydropyrazolo[5,1-b]oxazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    hh. (5R,6Z)-6-[(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)methylene]-oxo-4-thia-1-azabicyclo[3.2.0.]hept-2-ene-2-carboxylic acid (E+Z Isomers mixture, Sodium salt);    ii. (5R,6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;    jj. (5R)(6Z)-6-(6,7-5H—Dihydropyrazolo[5,1-b]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    kk. (5R),(6Z)-6-[5-(3-carboxypropionyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, disodium salt;    ll. (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, sodium salt;    mm. (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, sodium salt; and    nn. (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid, sodium salt.    
   
   
       24 . The compound according to  claim 23  selected from the group consisting of 
 i. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    ii. (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;    iii. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt; and    iv. (5R)(6Z)-7-Oxo-6-(4H-5-thia-1,6a-diazapentalen-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.    
   
   
       25 . The compound according to  claim 24:  (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.  
   
   
       26 . A method for the treatment of bacterial infection or disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;  
 X is O or S;  
 R 5  is H, C1-C6 alkyl, C5-C6 cycloalkyl, CHR 3 OCOC1-C6alkyl; and  
 R 3  is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       27 . The method according to  claim 26  wherein the compound is co-administered with a betalactam antibiotic.  
   
   
       28 . The method according to  claim 27  wherein the ratio of β-lactam antibiotic to the compound is in a range from about 1:1 to 100:1.  
   
   
       29 . The method according to  claim 28  wherein the ratio of the β-lactam antibiotic to the compound is less than 10:1.  
   
   
       30 . The method according to  claim 28  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein 
 Z1, Z2 and Z3 are independently CR 2 , N, O, S or N—R, provided one of Z1-Z3 is carbon and is bonded to the remainder of the molecule;  
 W 1 , W 2  and W 3  are independently CR 4 R4, S, SO, SO 2 , O, or N—R 1 ; with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;  
 t=1 to 4;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR 6 , optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q -optionally substituted C1-C6 akyl, S(O) q — optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       31 . The method according to  claim 27  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein 
 Z1, Z2 and Z3 are independently CR 2 , N, O, S or N—R 1  provided one of Z1-Z3 is carbon and is bonded to the remainder of the molecule;  
 W 1 , W 2  and W 3  are independently CR 4 R 4 , S, SO, SO 2 , O, or N—R 1 ;  
 t=1 to 4;  
 Y 1  and Y 2  are independently N or C; with the proviso that if the aromatic ring portion of the bicyclic heteroaryl group is imidazole, the nonaromatic ring portion may not contain a S adjacent to the bridgehead carbon;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR 6 , optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q — optionally substituted C1-C6 akyl, S(O) q — optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       32 . The method according to  claim 27  wherein the bicyclic heteroaryl group is  
     
       
         
         
             
             
         
       
     
     wherein 
 Z1, Z2, Z3 and Z4 are independently CR 2  or N provided one of Z1-Z4 is carbon and is bonded to the remainder of the molecule;  
 W 1 , W 2  and W 3  are independently CR 4 R 4 , S, SO, SO 2 , O, or N—R 1 ; with the proviso that no S—S or O—O or S—O bond formation can occur to form the saturated ring system;  
 t=1 to 4;  
 Y 1  and Y 2  are independently C or N;  
 R 1  is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C5-C7 cycloalkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl with the proviso that neither the double bond nor the triple bond should be present at the carbon atom which is directly linked to N; optionally substituted C1-C6 perfluoroalkyl,  
 —S(O) p  optionally substituted alkyl or aryl where p is 0-2, optionally substituted —C═Oheteroaryl, optionally substituted —C═Oaryl, optionally substituted —C═O (C1-C6) alkyl, optionally substituted —C═O(C5-C6)cycloalkyl, optionally substituted —C═O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, —CONR 6 R 7 , —SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkylaryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted alkylaryloxyalkylamines, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, or optionally substituted heteroaryloxy carbonyl;  
 R 2  is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N—R 6 R 7 , optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COORS, optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O) q -optionally substituted C1-C6 akyl, S(O) q , optionally substituted aryl where q is 0, 1 or 2, CONR 6 R 7 , guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO 2 NR 6 R 7 , optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, or optionally substituted alkylaryloxyalkylamine;  
 R 4  is H, optionally substituted C1-C6 alkyl, one of R 4  is OH, C1-C6 alkoxy, —S—C1-C6 alkyl, COOR 6 , —NR 6 R 7 , —CONR 6 R 7 ; or R 4 R 4  may together be ═O or R 4 R 4  together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected from N, O, S═(O)n (where n=0 to 2), and N—R 1 ; and  
 R 6  and R 7  are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkylheteroaryl, or R 6  and R 7  can be together to form a 3-7 membered saturated ring system optionally having one or two heteroatoms selected from N, O, or S.  
 
   
   
       33 . The method according to  claim 27  wherein the betalactam antibiotic is selected from the group consisting of a penicillin antibiotic and a cephalosporin antibiotic.  
   
   
       34 . The method according to  claim 33  wherein the betalactam antibiotic is selected from the group consisting of piperacillin, amoxycillin, ticarcillin, benzylpenicillins, ampicillin, sulbenicillin, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephradine, aztreonam, and latamoxef.  
   
   
       35 . The method according to  claim 34  wherein the betalactam antibiotic is piperacillin or amoxycillin.  
   
   
       36 . The method according to  claim 35  wherein the betalactam antibiotic is piperacillin and is provided to the patient intravenously.  
   
   
       37 . The method according to  claim 35  wherein the betalactam antibiotic is amoxycillin and is provided to the patient orally.  
   
   
       38 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 one of A and B is hydrogen and the other is an optionally substituted fused bicyclic heteroaryl group;  
 X is O or S;  
 R 5  is H, C1-C6 alkyl, C5-C6 cycloalkyl, CHR 3 OCOC1-C6alkyl; and  
 R 3  is hydrogen, C1-C6 alkyl, C5-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       39 . The composition according to  claim 36  further comprising a betalactam antibiotic.
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