FIELD OF INVENTION
This invention relates to certain tricyclic 6-alkylidene penems which act as a broad
spectrum ?-lactamase inhibitors. ?-Lactamases hydrolyze ?-lactam antibiotics, and
as such serve as the primary cause of bacterial resistance. The compounds of the
present invention when combined with P-lactam antibiotics will provide an effective
treatment against life threatening bacterial infections.
BACKGROUND OF THE INVENTION
Penicillins and cephalosporins are the most frequently and widely used p-lactam
antibiotics in the clinic. However, the development of resistance to p-lactam
antibiotics by different pathogens has had a damaging effect on maintaining the
effective treatment of bacterial infections. (Coleman, K. Expert Opin. Invest. Drugs
1995,4, 693; Sutherland, R. Infection 1995,23 (4) 191; Bush, K, Cur. Pharm. Design
1999, 5, 839-845). The most significant known mechanism related to the
development of bacterial resistance to the ?-lactam antibiotics is the production of
class-A, class-B and class-C serine ?-lactamases. These enzymes degrade the
?-lactam antibiotics, resulting in the loss of antibacterial activity. Class-A enzymes
preferentially hydrolyze penicillins where as Class-C lactamases have a substrate
profile favoring cephalosporin hydrolysis. (Bush, K.; Jacoby, G.A.; Medeiros, A.A.
Antimicrob. Agents Chemother. 1995, 39, 1211). To date over 250 different
?-lactamases have been reported (Payne, D.J,: Du, W and Bateson, J.H. Exp. Opin.
Invest. Drugs 2000, 247) and there is a need for a new generation of broad
spectrum p-lactamase inhibitors. Bacterial resistance to these antibiotics could be
greatly reduced by administering the ?-lactam antibiotic in combination with a
compound which inhibits these enzymes.
The commercially available ?-lactamase inhibitors such as clavulanic acid,
sulbactam and tazobactam are all effective against class-A producing pathogens.

Clavulanic acid is clinically used in combination with amoxicillin and ticarcillin;
similarly sulbactam with ampicillin and tazobactam with piperacillin. However, these
compounds are ineffective against class C producing organisms. The mechanism of
inactivation of class-A ?-lactamases (such as PCI and TEM-1) has been elucidated.
(Bush, K.; Antimicrob. Agents Chemother. 1993, 37, 851; Yang, Y.; Janota, K.;
Tabei, K.; Huang, N.; Seigal, M.M.; Lin, Y.I.; Rasmussen, B.A. and Shlaes, D.M. J.
Biol. Chem. 2000, 35, 26674-26682).
In 1981, the Beecham group disclosed 6-alkylidine penems of general structure 1 as
inhibitors of ?-lactamases. [N.F. Osborne, U.S.patent 4, 485, 110 (1984); N.F.
Osborne, Eur. Pat Appl. 81 301683.9.]

R1 and R2 are independently hydrogen or a C1-10 hydrocarbon group or mono
heterocyclic, and R3 represents a hydrogen or an organic group. Subsequently, the
same group disclosed compounds of the general formula 1, wherein R1 comprises a
1,2,3-triazole moiety. [N.F. Osborne, Eur. Pat Appl. 84301255.0]. The following
year, the same group filed three patent applications of the structure 1, wherein R1 is
an optionally substituted six membered or five membered mono aromatic ring
system. [N.F. Osborne, Eur. Pat Appl. 85100520.7; Eur. Pat Appl. 85100521.5
and Eur. Pat Appl. 85300456.2]. European patent application No. 86305585.1
discloses the synthesis and the utility of (Z)-6-(1-rnethy1,2,3-triazol-4-ylmethylene)-
penem-3-carboxylate 2 as a class-A and class-C ?-lactamase inhibitor.
>

Eur. Pat Appl. 86305584.4 disclosed the preparation of compounds of general
formula ±, wherein R1 = non-aromatic heterocyclic group and a PCT application [N.J.
Broom; P.D. Edwards, N.F. Osborne and S. Coulton PCT WO 87/00525] disclosing
R1 = fused bicyclic hetero-aromatic group was published. Similarly patent
applications [N.J. Broom; G. Brooks; S. Coulton, Eur.Pat Appl. 88311786.3; N.J.
Broom; G. Brooks; B.P. Clarke, Eur. Pat Appl. 88311787.1) disclosed the
preparation and use of compounds of general structure 1, wherein R1 is a substituted
five membered hetero-aromatic ring. A process for the preparation of compounds of
general formula 1 has been disclosed by Coulton, et al. [S. Coulton; J.B. Harbridge;
N.F. Osborne and G. Walker Eur. Pat Appl. No 87300193.7]
In the year 1993, Beecham disclosed [A.V. Stachulski and R. walker, PCT WO
93/03042] the preparation and the use of compounds of general formula 1, in which
R1= (C1-6) alkyl and R2 = CH2X or COY wherein X = halogen or CONR2.
During the last decade three patents have been filed by Beecham describing
compounds of general formula 3. [N.J. Broom; F.P. Harrington, PCT WO 94/10178;
K. Coleman; J.E. Neale PCT WO 95/28935; K. Coleman; J.E. Neale PCT WO
95/17184] wherein Ra = hydrogen or an organic group, and Rd and Re may be both
hydrogen or one or more substituents replacing hydrogen atoms in the ring system
shown below.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel, low molecular weight broad spectrum
?-lactam compounds and in particular to a class of tricyclic heteroaryl substituted 6-
alkylidene penems which have ?-lactamase inhibitory and antibacterial properties.
The compounds are therefore useful in the treatment of antibacterial infections in
humans or animals, either alone or in combination with other antibiotics.
In accordance with the present invention there are provided compounds of general
formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof:

wherein:
One of A and B denotes hydrogen and the other an optionally substituted fused
tricyclic heteroaryl group;
X is S or O, preferably S;
R5 is H, an in vivo hydroryzable ester such as C1 -C6 alkyl, C5 - C6 cycloalkyl,
CHR3OCOC1-C6 or salts such as Na, K, Ca; preferable R5 groups are H or salts.
The expression "Fused tricyclic heteroaryl group" is used in the specification and
claims to mean:
a group comprising three fused rings in which at least one ring has aromatic
character (i.e meets Huckel's rule (4n+2)). The fused tricyclic heteroaryl group
contains 1-6 heteroatoms selected from the group consisting of O, S, N and N-R1-
The fused tricyclic heteroaryl must be bonded through a carbon preferably in one of

the at least one aromatic rings to the remainder of the formula I molecule. The fused
tricyclic heteroaryl group may contain 1-3 aromatic rings and 0-2 non-aromatic rings.
Each aromatic ring(s) in the fused tricyclic heteroaryl group may contain 5 to 7 ring
atoms (including the bridgehead atoms) selected from CR2,O, S, N, and N-R1. Each
of the aromatic ring(s) of the fused tricyclic heteroaryl group may contain 0 to 3
heteroatoms selected from O, S, N or N-R1. The non-aromatic ring(s), if any, of the
fused tricyclic heteroaryl group may contain 5-8 ring atoms (including bridgehead
atoms) and contain CM heteroatoms selected from N, N-R1, O or S(O)n, wherein n is
0-2. In each non-aromatic ring of the fused tricyclic heteroaryl group, one or two of
the non-bridgehead carbon atoms may each be optionally substituted with one or two
R4, and each R4 may be independently the same or different. Examples of fused
tricyclic heteroaryl are optionally substituted ring systems such as imidazo[2,1-
b][1,3]benzothiazole optionally substituted e.g.,by for example C1-C6alkyl, C1-
C6alkoxy or halo (such as chlorine or fluorine); imidazo[1,2-a]quinoline; 6,7-dihydro-
5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazole; imidazo[1,2-a]quinoxaline; 5,6,7,8-
tetrahydro-[1,2,4]tria2olo[1,5-a]pyridine dibenzo[b,f][1,4]-oxazepin-11 (10H)-one
optionally substituted e.g., by arylalkyl such as benzyl; 7,8-dihydro-6H-3,4,8b-triaza-
as-indacene optionally substituted by C1-C6 alkoxy; 4H,10H-pyrazolo[5,1-
c][1,4]benzoxazepine optionally substituted e.g., by C1-C6 alkoxy; 5H-lmidazo[2,1-
a]isoindole; 5,8-dihydro-6H-imidazo[2,1 -b]pyrano[4,3-d][1,3]thiazole; imidazo[2,1 -
b]benzothiazole; [1,3]thiazolo[3,2-a]benzimidazole; 7,8-dihydro-6H-
cyclopenta[3,4]pyrazolo['5,1-b][1,3]thiazole; 5,6,7,8-tetrahydroimidazo[2,1-b][1,3]-
benzothiazole; 9H-imidazo[1,2-a]benzimidazole optionally substituted e.g., by C1-
C6alkyl;4H-thieno[2',3':4,5]thiopyrano[2,3-b]pyridine; 7,8-dihydro-6H-
cyclopenta[e][1,2,4]-triazolo[1,5-a]pyrimidine optionally substituted e.g., by C1-
C6alkyl; 6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine optionally
substituted e.g., by C2-C7alkoxycarbonyl; 8,,9,-dihydro-6'H-spiro[1,3-dioxolane-2,7'-
[1,2,4]triazolo[1,5-a]-quinazoline; 6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazoline
optionally substituted e.g., by C1-C6alkyl; 7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-
a]pyrimidine optionally substituted e.g., by C1-C6alkoxy; 7,8-dihydro-6H-
cyclopenta[e]imidazo[1,2-a]pyrimidinyl optionally substituted e.g., by
arylalkyloxyalkyloxy; 3-dihydro[1,3]thiazolo[3,2-a]-benzimidazole; 2,3-
dihydro[1,3]thiazolo[3,2-a]benzimidazole; 4-dihydro-2H-[1,3]thiazino[3,2-a]-

benzimidazole; 11,3]thiazolol3,2-a]benzimidazole; 7,8-dihydro-5H-pyrano[4,3-
d]pyrazolo[5,1-b][1,3]-oxazole; 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole;
and 5,6,7,8-tetrahydropyrazolo[5',1 ':2,3][1,3]oxazolo[5,4-c]pyridine optionally
substituted e.g., by C2-C7alkoxycarbonyl.
R1 is H, optionally substituted -C1-C6 alkyl, optionally substituted -aryl, optionally
substituted -heteroaryl or mono or bicyclic saturated heterocycles, optionally
substituted -C3-C7 cycloalkyl, optionally substituted -C3-C6 alkenyl, optionally
substituted -C3-C6 alkynyl with the proviso that both the double bond and the triple
bond should not be present at the carbon atom which is directly linked to N;
optionally substituted -C1-C6 per fluoro alkyl, -S(O)p optionally substituted alkyl or
aryl where p is 2, optionally substituted -C=Oheteroaryl, optionally substituted -
C=Oaryl, optionally substituted -C=O (C1-C6) alkyl, optionally substituted -C=O (C3-
C6) cycloalkyl, optionally substituted -C=O mono or bicyclic saturated heterocycles,
optionally substituted C1-C6 alkyl aryl, 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, -CONReRy, -SO2NR6R7, optionally
substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally
substituted -alkyt-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally
substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally
substituted aryloxyheteroaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally
substituted C1-C6 alkyl aryloxyheteroaryl , optionally substituted alkyl aryloxy
alkylamines, optionally substituted alkoxy carbonyl, optionally substituted aryloxy
carbonyl, optionally substituted heteroaryloxy carbonyl. Preferred R1 groups are H,
optionally substituted alkyl, optionally substituted aryl, -C=O(C1-C6)alkyl, C3-
C6alkenyl, C3-C6alkynyl, optionally substituted cycloalkyl, SO2alkyl, SO2aryl,
optionally substituted heterocycles, -CONR7R7, and optionally substituted heteroaryl.
R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6
alkenyl having 1 to 2 double bonds, optionally substituted C2-C6 alkynyl having 1 to
2 triple bonds, halogen, cyano, N-R6R7, optionally substituted C1-C6 alkoxy, hydroxy;
optionally substituted aryl, optionally substituted heteroaryl, COOR6, 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 akyi, S(O)q- optionally substituted aryl where q is 0, 1 or
2, CONR6R7, guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl,
optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryi,
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, SO2NR6R7, optionally substituted arylalkyloxyalkyl, optionally
substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally
substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted
heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally
substituted C1-C6 alkylaryloxyheteroaryl , optionally substituted aryloxyalkyl,
optionally substituted heteroaryloxyalkyl, optionally substituted
alkylaryloxyalkylamines, optionally substituted C3-C7 cycloalkyl, optionally
substituted C3-C7 saturated or partially saturated heterocycle. Preferred R2 groups
are H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted
heteroaryl, halogen, CN, hydroxy, optionally substituted heterocycle, -CONR6R7,
COOR6, optionally substituted aryl, S(O)q-alkyl, and S(O)q-aryl.
R3 is hydrogen, C1-C6 alkyl, C3 - C6 cycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl. Preferred R3 groups are H or C1-C6 alkyl.
R4 is H, optionally substituted C1-C6 alkyl, one of R4 is OH, C1-C6 alkoxy, -S-C1-C6
alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may together be =O or R4R4 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 N, O, S=(O)n (where
n =0 to 2), N-R1; preferred R4 groups are H, C1-C6 alkyl, NR6R7, or R4R4 together
with the carbon to which they are attached forming a spiro system of five to eight
members.

R6 and R7 are independently H, optionally substituted C1-C6 alkyt, optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl
aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally
substituted C1-C6 alkyl heteroaryl, R6 and R7 can together with the nitrogen to which
they are attached form a 3-7 membered saturated ring system optionally having one
or two heteroatoms such as N-R1, O, S=(O)n n = 0-2. Preferred R6 and R7 groups
are H, C1-C6 alkyl, arylalkyl, heteroarylalkyl, or R6 and R7 together with the nitrogen
to which they are attached forming a 3-7 membered saturated ring system.
Chemical Definitions
The term alkyl means both straight and branched chain alkyl moieties of 1-12
carbons, preferably of 1-6 carbon atoms.
The term alkenyl means both straight and branched alkenyl moieties of 2-8 carbon
atoms containing at least one double bond, and no triple bond, preferably the alkenyl
moiety has 1 or two double bonds. Such alkenyl moieties may exist in the E or Z
conformations; the compounds of this invention include both conformations. In the
case of alkenyl, hetero atoms such as O, S or N-R1 should not be present on the
carbon that is bonded to a double bond;
The term alkynyl includes both straight chain and branched alkynyl moieties
containing 2-6 carbon atoms containing at least one triple bond, preferably the
alkynyl moiety has one or two triple bonds. In the case of alkynyl, hetero atoms such
as O, S or N-R, should not be present on the carbon that is bonded to a double or
triple bond;
The term cycloalkyl refers to a alicyclic hydrocarbon group having 3-7 carbon atoms.
The term perfluoroalkyl is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having at least one carbon atom and two or
more fluorine atoms. Examples include CF3, CH2CF3, CF2CF3 and CH(CF3)2.
The term halogen is defined as CI, Br, F, and I.

If alkyl, alkenyl, alkynyl, or cycloalkyl is "optionally substituted", one or two of the
following are possible substituents: nitro, -aryl, -heteroaryl, aikoxycarbonyl-, -alkoxy,
-alkoxy-alkyl, alkyl-O-C2-C4alkyl-O-, -cyano, -halogen, -hydroxy, -N-R6R7, -COOH,
-COO-alkyl, -trifluoromethyl, -trifluoromethoxy, arylalkyl, alkylaryl, R6R7N-alkyl-,
HO-C1-C6-alkyl-, alkoxyalkyl-, alkyl-S-, -SO2N-R6R7. -SO2NHR6, -CO2H, CONR6R7,
aryl-O-, heteroaryl-O, -S(O)s-aryl (where s = 0 -2), -alkyl-O-alkyl-NR6R7, -alkyl-aryl-
O-alkylN-R6R7. C1-C6alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy-alkyl-O, R6R7N-alkyl-,
and -S(O)s-heteroaryl (where s = 0 -2); Preferred substitutents for alkyl, alkenyl,
alkynyl, and cycloalkyl include: halogen, nitro, aryl, heteroaryl, aikoxycarbonyl-,
alkoxy, -alkoxy-alkyl, -cyano, hydroxy, and -N-R6R7-
Aryl is defined as an aromatic hydrocarbon moiety selected from the group: phenyl,
a-naphthyl, ?-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl,
biphenylenyl, acenaphthenyl, groups. Preferred aryl groups are phenyl and
biphenyl.
Heteroaryl is defined as a aromatic heterocyclic ring system (monocyclic or bicyclic)
where the heteroaryl moieties are selected from: (1) furan, thiophene, indole,
azaindole, oxazole, thiazole, Isoxazole, isothiazole, imidazole, N-methylimidazole,
pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-
methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-
tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole,
benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline,
quinoline, and isoquinoline; (2) a bicyclic aromatic heterocycle where a phenyl,
pyridine, pyrimidine or pyridizine ring is: (a) fused to a 6-membered aromatic
(unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5 or 6-
membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c)
fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen
atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-
membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected
from O, N or S. Preferred heteroaryl groups are furan, oxazole, thiazole, isoxazole,
isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-
methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-

methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, quinoline, isoquinoline, and
naphthyridine.
If aryl or heteroaryl is 'optionally substituted', one or two of the following are possible
substituents: nitro, -aryl, -heteroaryl, alkoxycarbonyl -alkoxy, -alkoxy-alkyl, alkyl-O-
C2-C4alkyl-O-, -cyano, -halogen, -hydroxy, -N-R6R7, -trifluoromethyl,
trifluoromethoxy, arylalkyl, alkylaryl, R6R7N-alkyl-, HO-C1-C6-alkyl alkoxyalkyl-,
alkyl-S-, -SO2N-R6R7. -SO2NHR6. -CO2H, CONR6R7, aryl-O, heteroaryl-O-, -S(O)s-
aryl (where s = 0 -2), -alkyl-O-alkyl-NR6R7, -alkyl-aryl-O-alkylN-R6R7. C1-C6alkyl,
alkenyl, alkynyl, cycloalkyl, alkoxy-alkyl-O-, R6R7N-alkyl-, and -S(O)s-heteroaryl
(where s = 0 -2); Preferred substituents for aryl and heteroaryl include: .alkyl,
halogen, -N-R6R7, trifluoromethyl, -trifluoromethoxy, arylalkyl, and alkylaryl.
Arylalkyl is defined as Aryl-C1-C6alkyl—; Arylalkyl moieties include benzyl, 1-
phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. The term
'optionally substituted' refers to unsubstituted or substituted with 1 or 2 substituents
on the alkyl or aryl moiety as defined above.
Alkylaryl is defined as C1-C6alkyl-aryl-. The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents on the aryl or alkyl moiety as
defined above.
Heteroaryl-C1-C6- alkyl is defined as a heteroaryl substituted alkyl moiety wherein
the alkyl chain is 1-6 carbon atoms (straight or branched). Alkyl heteroaryl moieties
include Heteroaryl-(CH2)1-6- and the like. The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents on the alkyl or heteroaryl moiety
as defined above;
C1-C6 alkylheteroaryl is defined an alkyl chain of 1-6 carbon atoms (straight or
branched) attached to a heteroaryl moiety, which is bonded to the rest of the
molecule. For example C1-C6-alkyl-Heteroaryl-. The term 'optionally substituted'
refers to unsubstituted or substituted with 1 or 2 substituents on the alkyl or
heteroaryl moiety as defined above;

Saturated or partially saturated heterocycles groups are defined as heterocyclic
rings selected from the moieties; aziridinyl, azetidinyl, 1,4-dioxanyl,
hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl,
dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,
dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydro-1,4-
dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, and
tetrahydroisoquinolinyl. Preferred saturated or partially saturated heterocycles
include: aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,
piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, dihydroimidazolyl, and dihydroisooxazolyl.
C1-C6 alkyl mono or bicyclic saturated or partially saturated heterocycles is defined
as an alkyl group (straight or branched) of C1-C6 attached to a heterocycles (which
is defined before) through a carbon atom or a nitrogen atom and the other end of the
alkyl chain attached to the rest of the molecule. The terms 'optionally substituted'
refers to unsubstituted or substituted with 1 or 2 substituents present on the alkyl or
heterocyclic portion of the molecule, as defined before;
Arylalkyloxyalkyl is defined as Aryl-C1-C6alkyl-0-C1-C6alkyl—.The term 'optionally
substituted' refers to unsubstituted or substituted with 1 or 2 substituents present on
the alkyl and/or aryl portions as defined before;
Alkyloxyalkyl is defined as C1-C6 alkyl-O-C1-C6alkyl—. The term 'optionally
substituted' refers to unsubstituted or substituted with 1 or 2 substituents present at
the alkyl moiety as defined before;

Aryloxyalkyl is defined as Aryl-0-C1-C6 alkyl—. The term 'optionally substituted'
refers to unsubstituted or substituted with 1 or 2 substituents present at the alkyl or
aryl moiety as defined before;
Heteroarylalkyloxyalkyl is defined as Heteroaryl-C1-C6alkyl-O-C1-C6alkyl—.The
term 'optionally substituted' refers to unsubstituted or substituted with 1 or 2
substituents present on the alkyl or heteroaryl moiety as defined before;
Aryloxyaryl is defined as Aryl-O-Aryl—-.. The term 'optionally substituted' refers to
unsubstituted or substituted withl or 2 substituents present on the aryl moiety as
defined before;
Aryloxyheteroaryl is defined as Aryl-O-Heteroaryl- or -Aryl-O-Heteroaryl; In this
definition either the aryl moiety or the heteroaryl moiety can be attached to the
remaining portion of the molecule; The term 'optionally substituted' refers to
unsubstituted or substituted withl or 2 substituents present on the aryl moiety or on
the heteroaryl moiety as defined before;
Alkyl aryloxyaryl is defined as Aryl-O-Aryl-C1-C6alkyl—; The term 'optionally
substituted' refers to unsubstituted or substituted withl or 2 substituents present at
the aryl moiety as defined before;
Alkylaryloxyheteroaryl is defined as Heteroaryl-O-Aryl-C1-C6alkyl-; The term
'optionally substituted' refers to unsubstituted or substituted with 1 or 2 substituents
present on the aryl moiety or on the hetroaryl moiety as defined before;
Alkylaryloxyalkylamine is defined as R6R7N-C1-C6alkyl-O-Aryl-C1C6alkyl—; The
terms 'optionally substituted' refers to unsubstituted or substituted with 1 or 2
substituents present on the alkyl or aryl moiety as defined before; R5 and R7 as
defined before;
Alkoxycarbonyl is defined as C1-C6alkyl-O-C=O-; The term 'optionally substituted'
refers to unsubstituted or substituted with 1 or 2 substituents present on the alkyl

portion of the alkoxy moiety as defined before;
Aryloxycarbonyl is defined as Aryl-O-OO-; The term 'optionally substituted' refers
to unsubstituted or substituted with 1 or 2 substituents present at the aryl moiety as
defined before;
Heteroaryloxy carbonyl is defined as Heteroaryl-O-C=O-; The term 'optionally
substituted' refers to unsubstituted or substituted with 1 or 2 substituents present at
the heteroaryl moiety as defined before;
Alkoxy is defined as C1-C6alkyl-O-; The terms 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the alkyl moiety as
defined before;
Aryloxy is defined as Aryl-O-; The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the aryl moiety as
defined before;
Heteroaryloxy is defined as Heteroaryl-O-; The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the heteroaryl moiety
as defined before;
Alkenyloxy is defined as C3-C6 alkene-O—; Example allyl-O-, but-2-ene-O or like
moieties; The term 'optionally substituted' refers to unsubstituted or substituted with
1 or 2 substituents present at the alkene moiety as defined before, with the proviso
that no hetero atom such as O, S or N-R1 is present on the carbon atom, which is
attached to a double bond;
Alkynyloxy is defined as C3-C6alkyne-O-; Example CH triple bond C-CH2-O-, or like
moieties; The term 'optionally substituted' refers to unsubstituted or substituted with
1 or 2 substituents present at the alkyne moiety as defined before, with the proviso
that no hetero atom such as O, S or N-R1 is present on a carbon atom which is
attached to a double or triple bond;

Alkyiaminoalkoxy is defined as R6R7N-C1-C6-alkyl-O-C1-C6-alkyl—, where the
terminal alky! group attached to the oxygen is connected to the rest of the molecule;
The terms R6 and R7 are defined above; The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the alkyl moiety as
defined before;
Alkylenedioxy is defined as-O-CH2-O- or -O—(CH2)2-O—;
Aryloxyalkylamine is defined as R6R7N-C1-C6-alkyl-O-Aryl- where the aryl is
attached to the rest of the molecule; The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the alkyl or aryl
moiety as defined before;
Arylalkenyl is defined as Aryl-C2-C8alkene—, with the proviso that no hetero atom
such as O, S or N-R1 is present on the carbon atom, which is attached to a double
bond; The term 'optionally substituted' refers to unsubstituted or substituted with 1 or
2 substituents present on the alkene or aryl moiety as defined before;
Heteroaryloxyalkyl is defined as Heteroaryl-O-C1-C6alkyl—; The term 'optionally
substituted' refers to unsubstituted or substituted with 1 or 2 substituents present at
the heteroaryl moiety as defined before;
Heteroaryloxyaryl is defined as Heteroaryl-O-aryl—, where the aryl moiety is
attached to the rest of the molecule; The term 'optionally substituted' refers to
unsubstituted or substituted with 1 or 2 substituents present at the heteroaryl moiety
or the aryl moiety as defined before;
Alkoxy, alkoxyalkyl, alkoxyalkyloxy and alkylthioalkyloxy are moieties wherein the
alkyl chain is 1-6 carbon atoms (straight or branched). Aryloxy, heteroaryloxy,
arylthio and heteroarylthio are moieties wherein the aryl and heteroaryl groups are as
herein before defined. Arylalkyloxy, heteroarylalkyloxy, arylalkylthio and
heteroarylalkylthio are moieties wherein the aryl and heteroaryl groups are as herein
before defined and wherein the alkyl chain is 1-6 carbons (straight or branched).

Aryloxyalkyl, heteroaryloxyalkyl, aryloxyalkyloxy and heteroaryloxyalkyloxy are
subsiituents wherein the alkyl radical is 1-6 carbon atoms. - The terms
monoalkylamino and dialkylamino refer to moieties with one or two alkyl groups
wherein the alkyl chain is 1-6 carbons and the groups may be the same or different.
The terms monoalkylaminoalkyl and dialkylaminoalkyl refer to monoalkylamino and
dialkylamino moieties with one or two alkyl groups (the same or different) bonded to
the nitrogen atom which is attached to an alkyl group of 1-3 carbon atoms.
Pharmaceutically acceptable salts are those salts which may be administered or
provided to a warm blooded animal, preferably sodium, potassium or calcium
alkaline earth metal salts.
Preferably the formula I compound has the following stereochemistry:

Examples of tricyclic heteroarylgroup A and B:
Ring size and arrangements: (5-5-5)

In both formula 1-A and 1-B Z1, Z2,Z3, Z4, Z5, Z6 and Z7 are independently selected
from CR2, N, O, S or N-R1 and as mentioned above one of Z1 - Z7 is a carbon atom
to which the remainder of the molecule is attached. Y1, Y2 , Y3 and Y4 may
independently be C or N.
Ring size and arrangement: (5-5-6)

In both formula 2-A and 2-B Z1 , Z2, Z3, Z4, Z5 , Z6 , Z7 and Z8 are independently
selected from CR2, N, O, S or N-R1 and as mentioned above one of the Z1 - Z8 is a
carbon atom to which the remainder of the molecule is attached. Y1, Y2 , Y3 and Y4
may be independently be C or N.
Ring size and arrangement: (5-6-5)

In both formula 3-A and 3-B Z1 , Z2, Z3, Z4, Z5 , Z6 , Z7 and Z8 are independently
selected from CR2, N, O, S or N-R1 and as mentioned above one of Z1 - Z8 is a
carbon atom to which the remainder of the molecule is attached. Y1, Y2, Y3 and Y4
may be C or N.
Ring size and arrangements: (5-6-6)

In formula 4-A , 4-B and 4=C Z1 , Z2, Z3, Z4, Z5 , Z6 , Z7 and Z8 are independently
selected from CR2, N, O, S or N-R1 and as mentioned above one of the Z1 - Z8 is a
carbon atom to which the remainder of the molecule is attached. Y1, Y2, Y3 and Y4
are independently C or N.
Ring size and arrangements: [5-5-(non-aromatic)]

In both formula 5-A and 5-B Z1 , Z2, Z3 and Z4 are indpendently selected from CR2,
N, O, S or N-R1 and as mentioned above one of the Z1 - Z4 is a carbon atom to
which the remainder of the molecule is attached; Y1, Y2, Y3 and Y4 are independently
C or N. W1, W2 and W3 are independently selected from CR4R4, S(O)r (r = 0 -2),
5 O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; and t = 1 to 3.
Ring size and arrangement: [5-6-(non-aromatic)]

In formulae 6-A. 6-B and 6-C Z1, Z2,Z3,Z4 and Z5 are indepedently selected from
CR2, N, O, S or N-R1 and as mentioned above one of the Z1 - Z5 is a carbon atom to
which the remainder of the molecule is attached. Y1, and Y2 are independently C or
N. W1, W2 and W3 are independently CR4R4, S(O)r (r = 0 -2), O, or N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
and t = 1 to 3.
Ring size and arrangement: [5-(non-aromatic)-5]

In formulae 7-A and 7-B Z1 , Z2, Z3, Z4, Z5 and Z6 are independently selected from
CR2 , N, O, S, and N-R1; one of Z1 - Z6 is a carbon atom to which the remainder of
the molecule is attached. Y1,Y2, Y3 and Y4 are independently C or N. W1 and W2 are
independently selected from CR4R4 , S(O)r (r = 0 -2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; and t = 1 to
3.
Ring size and arrangement: [5-(non-aromatic)-6]

In formulae 8-A and 8-B Z1 , Z2, Z3, Z4, Z5 , Z6 and Z7 are indepdently selected from
CR2, N, O, S and N-R1 and as mentioned above one of the Z1 - Z7 is a carbon atom
to which the remainder of the molecule is attached. Y1,,Y2, Y3 and Y4 are
independently C or N. W1 and W2 are independently CR4R4, S(O)r (r = 0 -2), O, or
N-R1 with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; and t = 0-3.
Ring size and arrangement [5-(non-aromatic)-(non-aromatic)]

In formulae 9-A and 9-B Z1 , Z2 and Z3 are independently selected from CR2 N, O,
S or N-R1; one of Z1 - Z3 is a carbon atom to which the remainder of the molecule is
attached. Y1 and Y4 are independently C or N; Y2 and Y3 are independently CH or
N; W1, W2 W3, W4 and W5 are independently CR4R4, S(O)r (r = 0 -2), O, or N-R1
with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 0 to 2 and u = 1 to 3.
Ring size and arrangement (6-5-6)

In formula 10-A and 10-B Z1, Z2, Z3, Z4, Z5 , Z6, Z7, Z8 and Z9 are independently
selected from CR2, N, O, S or N-R1 and as mentioned above one of the Z1 - Z9 is a
carbon atom to which the remainder of the molecule is attached. Y1, Y2, Y3 and Y4
are independently C or N.
Ring size and arrangement (6-6-6)

In formula 11-A. 11-B and 11-C Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 and Z10 are
independently CR2 , N, O, S or N-R1; one of the Z1 - Z10 is a carbon atom to which
the remainder of the molecule is attached. Y1, Y2, Y3 and Y4 are independently C or
N.

Ring size and arrangement [6-5-(non-aromatic)]

In formula 12-A and 12-B Z1, Z2, Z3, Z4 and Z5 are independently CR2 , N, O, S or
N-R1 with the proviso that one of Z1 - Z5 is a carbon atom to which the remainder of
the molecule is attached. Y1, Y2 , Y3 and Y4 are independently C or N; W1, W2, W3
are independently CR4R4 O, N-R1 or S=(O)r (r = 0-2) with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; and t =1-4.
Ring size and arrangement [6-6-(non-aromatic)]

In formula 13-A. 13-B and 13-C Z1, Z2, Z3, Z4, Z5 and Z6 are independently CR2,
N, O, S or N-Ri; one of Z1 - Z6 is a carbon atom to which the remainder of the
molecule is attached. Y1, Y2, Y3 and Y4 are independently C or N; W1, W2 and W3
are independently CR4R4, S(O)r (r = 0 -2), O, or N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; and t = 1 to 3.
Ring size and arrangement [6-(non-aromatic)-6]

In formula 14-A. 14-B and 14-C Z1, Z2, Z3, Z4, Z5, Z6, Z7 and Z8 are independently
CR2, N, O, S or N-R1; one of Z1 - Z8 is a carbon atom to which the remainder of the
molecule is attached. Y1, Y2 , Y3 and Y4 are independently C or N; W1, and W2 are
independently CR4R4 , S(O)r ( r = 0 -2), O, or N-R1 with the proviso that no S-S, S-
O or OO bond formation can occur to form a saturated ring; and t = 1 to 2.
Ring size and arrangement [6-(non-aromatic)-(non-aromatic)]

In formula 15-A. 15-B and 15-C Z1, Z2, Z3 and Z4 are independently CR2, N, O, S
or N-R1; one of Z1 - Z4 is a carbon atom to which the remainder of the molecule is
attached. Y1, Y2 . Y3 and Y4 are independently C or N; W1, W2 , W3, W4 and W5 are
independently CR4R4 , S(O)r ( r = 0 -2), O, or N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; t = 1 to 3 and u = 1 to
3.
The preferred embodiments of formula 1-A are:
1. Z1 is O, S, or N-R1; Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2, or N ; Y1,
Y2, Y3, Y4 are C; any one of Z2, Z3, Z4, Z5, Z6, Z7 is a carbon to which the
remainder of the molecule is attached.

2. Z1 is O, S, or N-R1; Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2; Y1, Y2, Y3,
and Y4 are C; one of Z2, Z3, Z3, Z4, Z5, Z7 is a carbon to which the remainder
of the molecule is attached.
3. Z2 is O, S, or N-R1; Z1, Z3, Z4, Z5, Z6 and Z7 are independently CR2, or N ; Y1,
Y2, Y3, Y4 are C; one of Z1, Z3, Z4, Z5, Z6, Z7 is a carbon to which the
remainder of the molecule is attached.
4. Z2 is O, S, or N-R1; Z1, Z3, Z4, Z5, Z6 and Z7 are independently CR2; Y1, Y2,
Y3, Y4 are C; one of Z1, Z3, Z4, Z5, Z6, Z7 is a carbon to which the remainder of
the molecule is attached.

5. Z3 is O, S, or N-R1; Z1, Z2, Z4, Z5, Z6, Z7 are independently CR2. or N ; Y1, Y2,
Y3, Y4 are C; one of Z1, Z2, Z4, Z5, Z6, Z7 is a carbon to which the remainder of
the molecule is attached.
6. Z3 is O, S, or N-R1; Z1, Z3, Z4, Z5, Z6, Z7 are independently CR2; Y1, Y2, Y3, Y4
are C; one of Z1, Z3, Z4, Z5, Z6, Z7 is a carbon to which the remainder of the
molecule is attached.
7. Z7 is O, S, or N-R1; Z1, Z2, Z3, Z4, Z5 and Z6 are independently CR2 or N; Y1,
Y2, Y3, Y4 are C; one of Z1, Z2, Z3, Z4, Z5 and Z6 is a carbon to which the
remainder of the molecule is attached.

8. Z7 is O, S, or N-R1; Z1, Z2, Z3, Z4, Z5 and Z6 are independently CR2; Y1, Y2,
Y3, Y4 are C; any of Z1, Z2, Z3, Z4, Z5 and Z6 is a carbon to which the
remainder of the molecule is attached.
9. Z1, Z4, and Z8 are independently O, S, or N-R1; Z2, Z3, Z5, Z7 are
independently CR2, or N; Y1, Y2, Y3, Y4 are C; any one of Z2, Z3, Z5, or Z7 is a
carbon to which the remainder of the molecule is attached.
10. Z1, Z4, and Z5 are independently O, S, or N-R1; Z2, Z3, Z5, Z7 are
independently CR2; Y1, Y2, Y3, Y4 are C; any one of Z2, Z3, Z5, or Z7 is a
carbon to which the remainder of the molecule is attached.

11. Z3, Z4, and Z6 are independently O, S, or N-R1; Z1, Z2, Z5, Z7 are
independently CR2, or N; Y1, Y2, Y3, Y4 are C; any one of Z1, Z2, Z5, or Z7 is a
carbon to which the remainder of the molecule is attached.
12. Z3, Z4, and Z6 are independently O, S, or N-R1; Z2, Z3, Z5, Z7 are
independently CR2; Y1, Y2, Y3, Y4 are C; any one of Z1, Z2, Z5, or Z7 is a
carbon to which the remainder of the molecule is attached.

13. Z1 is O, S, or N-R1; Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2, or N ; Y2
is N; Y1, Y3, Y4 are C; any one of Z2, Z3, Z4, Z5, Z6, or Z7 is a carbon to which
the remainder of the molecule is attached.
14. Z1 is O, S, or N-R1; Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2 ; Y2 is N;
Y1, Y3, Y4 are C; one of Z2, Z3, Z4, Z5, Z6, or Z7 is a carbon to which the
remainder of the molecule is attached.
15. Z2 and Z4 are independently O, S, or N-R1; Z1, Z3, Z5, Z6 , Z7 are
independently CR2, N ; Y1 is N; Y2, Y3, Y4 are C; any one of Z1, Z3, Z5, Z6, or
Z7 is a carbon to which the remainder of the molecule is attached.

16. Z2 and Z4 are independently O, S, or N-R,; Z1, Z3, Z5, Z6 , Z7 are
independently CR2 ; Y1 is N; Y2, Y3, Y4 are C; any one of Z1, Z3, Z5, Z6, or Z7
is a carbon to which the remainder of the molecule is attached
17. Z3 and Z5 are independently O, S, or N-R1; Z1, Z2, Z4, Z5 , Z7 are
independently CR2, or N ; Y1 is N; Y2, Y3, Y4 are C; any one of Z1, Z3, Z5, Z6,
or Z7 is a carbon to which the remainder of the molecule is attached.
18. Z3 and Z5 are independently O, S, or N-R,; Z1, Z2, Z4, Z6 , Z7 are
independently CR2 ; Y1 is N; Y2, Y3, Y4 are C; any one of Z1, Z3, Z5, Z6, or Z7
is a carbon to which the remainder of the molecule is attached.

19. Z1 and Z5 are independently O, S, or N-R1; Z2, Z3, Z4, Z5 , Z7 are
independently N, or CR2; Y1 is N; Y2, Y3, Y4 are C; any one of Z2, Z3, Z4, Z6,
Z7 is a carbon to which the remainder of the molecule is attached.
20. Z, and Z5 are independently O, S, or N-R,; Z2, Z3, Z4, Z6 , Z7 are
independently CR2 ; Y, is N; Y2, Y3, Y4 are C; any one of Z2, Z3, Z4, Z6, or Z7
is a carbon to which the remainder of the molecule is attached.
21. Z3 and Z7 are independently O, S, or N-R,; Z1, Z2, Z4, Z5 , Z6 are
independently N, or CR2 ; Y1 is N; Y2, Y3, Y4 are C; any one of Z1, Z2, Z4, Z5,
or Z6 is a carbon to which the remainder of the molecule is attached.

22. Z3 and Z7 are independently O, S, N-R1; Z1, Z2, Z4, Z5 , Z6 are independently
CR2 ; Y1 is N; Y2, Y3, Y4 are C; Any one of Z1, Z2, Z4, Z5, or Z6 is a carbon to
which the remainder of the molecule is attached.
23. Z3 and Z7 are independently O, S, N-R1; Z1, Z2, Z4,Z5,Z6 are independently
N, or CR2 ; Y2 is N; Y1, Y3, Y4 are C; any one of Z1, Z2, Z4, Z5, or Z6 is a
carbon to which the remainder of the molecule is attached.

24. Z3 and Z7 are independently O, S, or N-R1; Z1, Z2, Z4, Z5, Z6 are independently
CR2 ; Y2 is N; Y1, Y3, Y4 are C; any one of Z1, Z2, Z4, Z5, or Z6 is a carbon to
which the remainder of the molecule is attached.
25. Z3 and Z5 are independently O, S, N-R1; Z1, Z2, Z4, Z6, Z7 are independently
N, or CR2 ; Y2 is N; Y1, Y3, Y4 are C; any one of Z1, Z2, Z4, Z6, or Z7 is a
carbon to which the remainder of the molecule is attached.
26. Z3 and Z5 are independently O, S, or N-R-1; Z1, Z2, Z4, Z6 , Z7 are
independently CR2; Y2 is N; Y1, Y3, Y4 are C; any one of Z1, Z2, Z4, Z6, or Z7
is a carbon to which the remainder of the molecule is attached.
The preferred embodiment of formula 1-B is:
27. Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2.
The preferred embodiments of formula 2-A are:
28. Z1 is CR2; Z2 is the carbon to which the remainder of the molecule is
attached; Z3 is N or CR2 ; Z4 is O, S, CR2 or N-R1; Z5, Z6, Z7, Z8 are
independently CR2 or N ; Y1 is N; Y2, Y3 and Y4 are C.
29. Z2 is CR2; Z1is carbon to which the remainder of the molecule is attached; Z3
is N or CR2; Z4 is O, S, CR2 or N-R1; Z5,Z6, Z7, Z8 are independently CR2 or N
; Y1 is N; Y2, Y3 and Y4 are C.
30. Z1 is N, Z2is carbon to which the remainder of the molecule is attached; Z3 is
N or CR2 ; Z4 O, S, CR2 or N-Rn; Z5, Z6, Z7, Z8 are independently CR2 or N; Y,
is N; Y2, Y3 and Y4 are C.

31. Z1, Z2, Z3 are independently CR2 or N; Z4 is O, S, CR2 or N-R1; Z5, Z6, Z7, Z8
are independently CR2 or N and one of Z5, Z6, Z7, or Z8 is a carbon to which
the remainder of the molecule is attached; Y1 is N; Y2, Y3 and Y4 is C.
32. Z1 is CR2 or N; Z2 is CR2: Z3 is O, S or N-R1; Z4 is N or CR2; Z5. Z6, Z7, Z8 are
independently CR2; Y1 is N, or C; Y2, Y3 and Y4 are C.
33. Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8 are independently N or CR2; Y1, Y2, Y3, Y4 are C.
34. Z1, Z2 , Z5, Z6 , Z7, Z8 are independently N or CR2; Z3 and Z4 are
independently O, S, or N-R,; Y1, Y2, Y3, and Y4 are C.
35. Zn, Z2, and Z3 are independently CR2 or N; Z4 is O, S, CR2 or N-R,; Z5, Z6, Z7,
and Z8 are independently CR2 or N; Y1 is N; Y2, Y3 and Y4 are C.

36. Z1 is N; Z2 is CR2; Z3 is the carbon atom to which remainder of the molecule
is attached; Z4 is N; Z5, Z6, Z7, Z8 are independently N or CR2; Y1, Y2, Y3, Y4
are independently N or C.
The preferred embodiment of formula 2-B is:
37. Z1 and Z4 are independently CR2 or N; Z2 and Z3 are CR2; Z5, Z6, Z7 are
independently CR2 or N; Y1 is C and Y2 is N.
38. Z1 is O, S, or N-R1; Z2is CR2; Z3 is CR2, or N; Z, is O, S, N-R1, or CR2: Z5, Z6,
Z7, Z8 are independently N or CR2; Y1, Y2, Y3 , and Y4 are C; one of Z2, Z3, Z5,
Z6, Z7, or Z8 is a carbon atom to which the remainder of the molecule is
attached.
The preferred embodiments of formula 3-A are:
39. Z1 is O, S, or N-R1; Z2 is N, or CR2; Z3 is CR2; Z5, Z6, and Z7 are independently
N or CR2; Z4 and Z8 are independently O, S, or N -R1; Y1, Y2, Y3, and Y4 are
C and one of Z2, Z5, Zs, or Z7 is a carbon atom to which the remainder of the
molecule is attached.
- 40. Z3 is O, S, or N-R1; Z2 is N, CR2; Z1 is CR2; Z5, Z6, and Z7 are independently N
or CR2; Z4 and Z8 are independently O, S, or N -R1, Y1, Y2, Y3, and Y4 are C
and one of Z2, Z5, Z6, or Z7 is a carbon atom to which the remainder of the
molecule is attached.
The preferred embodiments of formula 3-B are:
41. Z1 is O, S, or N-R1; Z2 is N or CR2; Z3 is CR2; Z4, Z5, Z6, Z7, and Z8 are
independently N or CR2; Y1, Y2, Y3, and Y4 are C; and one of Z2, Z5, Z6, Z7 is
a carbon atom to which the remainder of the molecule is attached.
42. Z1 is N or CR2; Z2 is CR2; Z3 is O, S, N-R, or CR2; Z7 is CR2 or N; Z6, and Z8
are independently N or CR2; Z4 and Z5 are CR2 or N; Y1, Y2, and Y3 are C; Y4
is N and one of Z2, Z4, Z5, Z6 is a carbon atom to which the remainder of the
molecule is attached.
43. Z1 is N, or CR2 ; Z2 is CR2; Z3 is O, S, N-Rt or CR2; Z6 is CR2 or N; Z7, and Z8
are independently N or CR2; Z4 and Z5 are independently CR2 or N; Y1, Y2, Y3

are C; Y4 is N and one of Z2, Z4, Z5, Z6 is a carbon atom to which the
remainder of the molecule is attached.
44. Z1 is O, S, or N-R1; Z2 is N, or CR2; Z3 is CR2; Z6, Z7, and Z8 are N; Z4 and Z5
are independently CR2 or N; Y1, Y2, Y4 are C; Y3 is N and one of Z2, or Z3 is a
carbon atom to which the remainder of the molecule is attached.
45. Z1 is N or CR2; Z2 is CR2; Z3 is O, S, N-R1 or CR2; Z6, Z7, and Z8 are N; Z4,
and Z5 are independently CR2 or N; Y1, Y2, Y4 are C; Y3 is N and one of Z1, Z2
is a carbon atom to which the remainder of the molecule is attached.
46. Z1 is N or CR2; Z2 is CR2; Z3 is O, S, N-R1 or CR2; Z6, Z7. and Z8 are N; Z4
and Z5 are independently CR2 or N; Y1, Y2, Y4 are C; Y3 is N and one of Z1,
Z2, is a carbon atom to which the remainder of the molecule is attached.

47. Z1 is N; Z2, Z3, Z4 and Z5 are independently CR2; Ze, Z7, and Z8 are
independently O, S, N, N-R1 or CR2; Y2, Y3, and Y4 are C; Y1 is N; one of Z2,
Z3, Z6, Z6, Z7, Z8 is a carbon atom to which the remainder of the molecule is
attached.
48. Z3 is N; Z2 and Z1 are independently CR2; Z4, and Z5 are independently CR2;
Z6, Z7, Z8 are independently O, S, N, N-R1 or CR2; Y2, Y3, and Y1 are C; Y4 is
N; one of Z2, Z1, Z6, Z6, Z7, Z8 is a carbon atom to which the remainder of the
molecule is attached.
49. Z1 is N, or CR2; Z2 is CR2; Z3 is O, S, or N-R1; Z4 and Z5 are independently
CR2; Z6, Z7, Z8 are independently O, S, N, N-R1, or CR2; Y1, Y2, Y3, and Y4 are
C; one of Z1, Z2, Z3, Z6, Z7, Z8 is a carbon atom to which the remainder of the
molecule is attached.
The Preferred embodiments of formula 4-A
50. Z1 and Z3 are independently O, S, N-R1, N, or CR2; Z2 is CR2; Z4, Z5, Z6, Z7,
Z8, Z9, are independently CR2; Y1, Y2, Y3, Y4, are C.
51. Z1 and Z3 are independently O, S, N-R1, N, or CR2; Z2 is CR2; Z4, and Z9 are
independently CR2, or N; Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4,
are C; One of Z1, Z2, Z3, Z5, Z6, Z7, Z8 is a carbon atom to which the remainder
of the molecule is attached.
52. Z1is S, O, or N-R1; Z2, Z3, Z4, Z5, Z6, Z7, Z8 are independently CR2; Z9 is N; Y1,
Y2.Y3,Y4, are C.

53. Z1, and Z3 are independently O, S, N-R1, N, or CR2; Z4, and Z9, are
independently N or CR2; Z5, Z6, Z7, Z8 are independently CR2 or N; Y1, Y2, Y3,
Y4, are C; Z2 is the carbon to which the remainder of the molecule is
attached.
54. Z1 is N; Z2, Z3, and Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently
N or CR2; Z9 is CR2 or N; Y1 is N; Y2, Y3, and Y4, are C; Z2 or Z3 is the carbon
to which the remainder of the molecule is attached.
55. Z3 is N; Z1, Z2, and Z4 are independently CR2; Z5, Z6, Z7, and Z8 are
independently CR2, or N; Z9 is CR2, or N; Y4 is N; Y1, Y2, and Y3 are C.
The Preferred embodiments of formula 4-B
56. Z1 is N; Z2, Z3, Z4, Z5, Z6, Z7, Z8, and Z9 are independently CR2; Y1 is N; Y2, Y3,
and Y4 are C; one of Z2, Z3, Z6, Z7, Z8, Z9 is the carbon atom to which the
remainder of the molecule is attached.
57. Z3 is N; Z1, Z2, and Z4 are independently CR2; Z5, Z6, Z7, Z8, and Z9 are
independently CR2 or N; Y1, Y3, Y4 are C; Y2 is N.

58. Z1 is O, S, or N-R1; Z2, Z3, and Z4 are independently CR2; Z5 is CR2 or N; Z6,
Z7, Z8, and Z9 are independently CR2, or N; one of Z6, Z7, Z8, Z9 is a carbon
atom to which the remainder of the molecule is attached.
59. Z1 and Z3 are independently O, S, N-R1, N, or CR2; Z4 is CR2 or N; Z5 is CR2;
Z6, Z7, Z8, and Z9 are independently CR2, or N; Y1, and Y2 are independently
C or N; Y3 and Y4 are C.
The Preferred embodiments of formula 4-C
60. Z1 and Z2 are independently N or CR2; Z3, Z4, Z5, Z6, Z7, and Z8 are
independently CR2; Y1 is C.
61. Z1, and Z2 are independently CR2; Z3, Z4, Z5, Z6, Z7, and Z8 are independently
N or CR2; Y1 is C.
62. Z1, Z2, Z3, Z4, Z5, Z6, Z7, and Z8 are independently N or CR2; Y1 is C.
The Preferred embodiments of formula 5-A

63. Z, is O, S, or N-R1; Z2, and Z3 are independently CR2; Z4 is O, S, N-R1, or
CR2; Y1, and Y2 are C; Y4, and Y3 are independently C, or N; W1, W2, W3 are
independently CR4R4; t = 1 or 2.
64. Z1 is O, S, or N-R1; Z2 and Z3 are independently CR2; Z4 is O, S, N-R1, or
CR2; Y1, and Y2 are C; Y4, and Y3 are independently C, or N; W1, and W3 are
independently CR4R4; t = 1 to 2; W2 is O, S (O)r (r = 0-2), N-R1 or CR4R4.
65. Z3 is N; Z2 is CR2; Z1 is CR2, or N; Z4 is O, S, N-R1, W1, W2, and W3 are
independently CR4R4; t = 1 to 3; Y1,Y3, and Y4 are C; Y2 is N; one of Z1, Z2 or
Z4 is the carbon atom to which the remainder of the molecule is attached.

66. Z, is N; Z2 is CR2; Z3 is CR2, or N; Z4 is O, S, or N-R1; W1, W2, and W3 are
independently CR4R4; t = 1 to 3; Y2, Y3, and Y4 are C; Y1 is N; one of Z2, Z3,
Z4 is the carbon atom to which the remainder of the molecule is attached.
67. Z3 is N; Z2 is CR2; Z1 is CR2. or N; Z4 is O, S, or N-R,; Y1, Y3, and Y4 are C; Y2
is N; W1, W2, and W3 are independently CR4R4, O S(O)r (r = 0-2), or N-R1
with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1 to 3; one of Z1, Z2 or Z4 is the carbon atom to which the
remainder of the molecule is attached.

68. Z1 is N; Z2 is CR2; Z3 is CR2, or N; Z4 is O, S, or N-R1; Y2, Y3, and Y4 are C; Y1
is N; W1, W2, and W3 are independently CR4R4, O, S = (O)r (r = 0-2); or N-R1,
with the proviso that no S-S, S=O or O-O bond formation can occur to form a
saturated ring; t = 1 - 3; one of Z2, Z3, Z4 is a carbon atom to which the
remainder of the molecule is attached.
69. Z1 is CR2; Z2 is the carbon atom to which the remainder of the molecule is
attached; Z3 is N; Z4 is O, S, or N-R,; Y1 is C; Y2 is N; Y3, and Y4 are C; W1,
W2, and W3 are independently CR4R4, O, S = (O)r (r = 0-2), or N-R1 with the
proviso that no S-S, S=O or O-O bond formation can occur to form a
saturated ring; t = 1 to 3.
70. Z, is the carbon atom to which the remainder of the molecule is attached; Z2
is CR2; Z3 is N; Z4 is O, S, N-R1; Y1 is C; Y2 is N; Y3, and Y4 are C; W1, W2,
and W3 are independently CR4R4, O, S=(O)r (r = 0-2), or N-R1 with the
proviso that no S-S, S=O or O-O bond formation can occur to form a
saturated ring;t= 1-3.

71. Z1, Z2, and Z3 are independently CR2, or N; Z4 is CR2; Y1, Y2 are C; Y3, Y4 are
N; W1, W2, and W3 are independently CR4R4, O, S = (O)r (r = 0-2), or N-R1
with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3.
The Preferred embodiments of formula 5-B
72. Z1, Z2, Z3, Z4 are independently CR2; Y1, Y2 are N; W1, W2 are independently
O,S,N-R1, or CR4R4;t=1-2.
73. Z1, Z2 are independently N, or CR2; Z3 is CR2; Z4 is O, S, or N-R1; W1, and W2
are independently O, S, N-R1, CR4R4; t = 1-2.
The preferred embodiments of formula 6-A are:
74. Z1 is O, S, N-R1; Z2, Z3, Z4, Z5 are independently CR2; W1, W2, W3 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2 are C; t = 1-3; one
of Z2, Z3 is the carbon atom to which the remainder of the molecule is
attached.
75. Z1 is O, S, or N-R1; Z3 is N, O, or S ; Z2, Z4, Z5 are independently CR2; W1,
W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, and Y2 are
C; t = 1-3; Z2 is the carbon atom to which the remainder of the molecule is
attached.
76. Z1 is CR2; Z3 is N ; Z2, Z4, and Z5 are independently CR2; W1, W2, and W3 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1 is N; Y2 is C; t = 1-3; Z1,
or Z2 is the carbon atom to which the remainder of the molecule is attached.
77. Z1 is N; Z2, Z3, Z4, Z5 are independently CR2; W1, W2, W3 are independently
N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1 is C; Y2 is N; t = 1-3; Z2, or Z3 is the
carbon atom to which the remainder of the molecule is attached.
78. Z1 is O, S, or N-R1; Z2 is N, O, or S ; Z3, Z4, and Z5 are independently CR2;
W1, W2, and W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1,
and Y2 are C; t= 1-3; one of Z3 is a carbon atom to which the remainder of the
molecule is attached.
79. Z1 is O, S, or N-R1; Z2, and Z3 are independently CR2; Z4, and Z5 are
independently CR2, or N; W1, W2, and W3 are independently N-R,, O, S=(O)r

(r = 0-2), or CR4R4; Y1, Y2 are C; t = 1-3; Z2 or Z3 is the carbon atom to which
the remainder of the molecule is attached.
80. Z1 is O, S, or N-R1; Z3 is N, O, or S ; Z2 is CR2; Z4, Z5 are independently CR2,
or N; W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1,
Y2 are C; t = 1-3; Z2 is the carbon atom to which the remainder of the
molecule is attached.
81. Z1 is CR2; Z3 is N ; Z2 is CR2; Z4, Z5 are independently N, or CR2; W1, W2, W3
are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1 is N; Y2 is C; t = 1-
3; Z1 or Z2 is the carbon atom to which the remainder of the molecule is
attached.

82. Z1 is N; Z2, and Z3 are independently CR2; Z4, Z5 are independently N or CR2;
W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1 is C; Y2
is N; t = 1-3; Z2 or Z3 is the carbon atom to which the remainder of the
molecule is attached.
83. Z1 is O, S, or N-R1; Z2 is N, O, or S ; Z3 is CR2; Z4, and Z5 are independently
N, or CR2; W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; Y1, Y2 are C; t = 1-3; Z3 is the carbon atom to which the remainder of
the molecule is attached.
The preferred embodiments of formula 6-B are:
84. Z1 is O, S, or N-R1; Z2, Z3, Z4, and Z5 are independently CR2; W1, W2, W3 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2,Y3, and Y4 are C; t =
1-3; Z2 or Z3 is the carbon atom to which the remainder of the molecule is
attached.
85. Zt is O, S, or N-R1; Z3 is N, O, or S ; Z2, Z4, Z5 are independently CR2; W1,
W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2, Y3, Y4
are C; t = 1-3; Z2 is the carbon atom to which the remainder of the molecule
is attached.
86. Z1 is CR2; Z3 is N ; Z2, Z4, and Z5 are independently CR2; W1, W2, W3 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y3 is N; Y1, Y2, Y4 are C; t =
1-3; Z1, or Z2 is the carbon atom to which the remainder of the molecule is
attached.

87. Z1 is N; Z2, Z3, Z4, Z5 are independently CR2; W1, W2, W3 are independently
N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2, Y3 are C; Y4 is N; t = 1-3; Z2 or Z3
is the carbon atom to which the remainder of the molecule is attached.
88. Z1 is O, S, or N-R1; Z2 is N, O, or S ; Z3, Z4, and Z5 are independently CR2;
W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2, Y3,
and Y4 are C; t - 1-3; Z3 is the carbon atom to which the remainder of the
molecule is attached.

89. Z1 is O, S, or N-R1; Z2, and Z3 are independently CR2; Z4, and Z5 are
independently CR2, or N; W1, W2, W3 are independently N-R1, O, S=(O)r (r =
0-2), or CR4R4; Y1, Y2 , Y3, Y4 are C; t = 1-3; Z2 or Z3 is the carbon atom to
which the remainder of the molecule is attached.
90. Z1 is O, S, or N-R1; Z3 is N, O, or S ; Z2 is CR2; Z4, and Z5 are independently
CR2 or N; W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4;
Y1, Y2, Y3, Y4 are C; t = 1-3; Z2 is the carbon atom to which the remainder of
the molecule is attached.

91. Z1 is CR2; Z3 is N ; Z2 is GR2; Z4, and Z5 are independently N, CR2; W1, W2,
W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y3 is N; Y1, Y2, Y4
are C; t = 1-3; Z1 or Z2 is the carbon atom to which the remainder of the
molecule is attached.
92. Z1 is N; Z2, Z3 are independently CR2; Z4, Z5 are independently N, or CR2;
W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1, Y2, Y3
are C; Y4 is N; t = 1-3; Z2, or Z3 is the carbon atom to which the remainder of
the molecule is attached.
93. Z1 is O, S, or N-R1; Z2 is N, O, or S; Z3 is CR2; Z4, Zs are independently N, or
CR2; W1, W2, W3 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; Y1,
Y2, Y3, Y4 are C; t = 1-3; Z3 is the carbon atom to which the remainder of the
molecule is attached.
The preferred embodiments of formula 6-C are:
94. Z1, Z3. Z4, and Z5 are independently N or CR2; Z2 is O, S, or N-R1; Y1, Y2 are
C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2.
95. Z1, Z3. Z4. Z5 are independently CR2; Z2 is O, S, or N-R,; Y1, Y2 are C; W1, W2
are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2.

96. Z1,Z3,Z5 are independently CR2; Z2 is O, S, N-R1; Z4 is N; Y1, Y2 are C; W1,
W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1 -2.
97. Z1, Z2, Z3, Z4, and Z5 are independently CR2; Y1 is C; Y2 is N; W1, W2 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t= 1-2.
98. Z1, Z2, Z3, Z5 are independently CR2; Z4 is N; Y1 is C; Y2 is N; W1, W2 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2.
The preferred embodiments of formula 7-A are:
99. Z3, Z6 are independently O, S, or N-R1; Z1, Z2, Z4, Z5 are independently CR2;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2.
100. Z3, Z6 are independently O, S, or N-R1; Z1, Z4 are N; Z2, Z5 are independently
CR2; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;
Z2 or Z5 is the carbon atom to which the remainder of the molecule is
attached.

101. Z1, Z4 are independently O, S, or N-R1; Z2, Z3, Z5, Z6 are independently CR2;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2.
102. Z1, Z4 are independently O, S, or N-R1; Z3, Z6 are N; Z2, Z5 are independently
CR2; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;
Z2 or Z5 is the carbon atom to which the remainder of the molecule is
attached.
103. Z2, Z5 are independently O, S, or N-R1; Z1, Z3, Z4, Z5 are independently CR2;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2.
104. Z2, Z5 are independently O, S, N-R1; Z1, Z3, Z4, Z6 are independently CR2, N,
S; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2; One of
Z1, Z3, Z4, Z6 is the carbon atom to which the remainder of the molecule is
attached.

105. Z1 is CR2, N; Z2 is CR2; Z3 is N; Z4, Z5 are independently CR2; Z6 is N; Y1, Y3
are independently CR2; Y2, Y4 are N; W1, W2 are independently N-R1, O,
S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5 is the carbon atom to
which the remainder of the molecule is attached.
106. Z1 is CR2, or N; Z2 is CR2; Z3 is O, S, N-R1; Z4, Z5 are independently CR2; Z5
is N; Y1, Y4, Y3 are independently CR2; Y2 is N; W1, W2 are independently N-

R1, O, S=(O)f (r = 0-2), CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5 is the carbon
atom to which the remainder of the molecule is attached.
107. Z1 is CR2, or N; Z2 is CR2; Z3 is N; Z4, Z5 , Z6 are independently N, or CR2; Y1,
and Y3 are N; Y2, Y4 are independently CR2; W1, W2 are independently N-R1
O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6 is the carbon
atom to which the remainder of the molecule is attached.
The preferred embodiments of formula 7-B are:
108. Z1, Z2, Z4 , Z5, Z6 are independently CR2; Z3 is O, S, or N-R1; Y1, Y2, Y4 are C;
Y3 is N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-
2.
109. Z1, Z2, Z4,Z5,Z6 are independently CR2 or N; Z3 is O, S, or N-R1; Y1, Y2, Y4
are C; Y3 is N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4;
t = 1-2; One of Z1, Z2, Z4, Z5, Z6 is the carbon atom to which the remainder of
the molecule is attached.
110. Z1, Z2, Z3,Z5,Z6 are independently CR2; Z4 is O, S, or N-R1; Y1, Y2, Y3 are C;
Y4 is N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-
2; One of Z1, Z2, Z3, Z5, Z6 is the carbon atom to which the remainder of the
molecule is attached.

111. Z1, Z2, Z3 , Z5, Z6 are independently CR2 or N; Z4 is O, S, or N-R1; Y1, Y2, Y3
are C; Y4 is N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4;
t = 1-2; One of Z1, Z2, Z3, Z5, Z6 is the carbon atom to which the remainder of
the molecule is attached.
112. Z1, Z2, Z3, Z4. Z5, Z6 are independently CR2; Y1, Y3 are N; Y2, Y4 are C; W1, W2
are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z1, Z2,
Z3, Z4, Z5, Z6 is the carbon atom to which the remainder of the molecule is
attached.

113. Z1, Z2, Z3 , Z4, Z5, Z6 are independently CR2 or N; Y1, Y3 are N; Y2, Y4 are C;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of
Z1, Z2, Z3, Z4, Z5, Z6 is the carbon atom to which the remainder of the
molecule is attached.
114. Z1, Z3, Z4, Z5, Z6 are independently CR2; Z2 is O, S, or N-R1; Y1, Y2, Y4 is C;
Y3is N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;

One of Z1, Z3, Z4, Z5, Z6 is the carbon atom to which the remainder of the
molecule is attached.
115. Z1, Z3 , Z4, Z5, Z6 are independently CR2, or N; Z2 is O, S, or N-Rr, Y1, Y2, Y4
are C; Y3= N; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t
= 1-2; One of Z1, Z3, Z4, Z5, Z6 is the carbon atom to which the remainder of
the molecule is attached.
116. Z1, Z2, Z4, Z6 are independently CR2; Z3, Z5 are independently O, S, or N-R1;
Y1, Y2, Y3. Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z2, Z4, Z6 is the carbon atom to which the
remainder of the molecule is attached.

117. Z1, Z2, Z4, Z6 are independently CR2, or N; Z3. Z5 are independently O, S, or
N-R1; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z6 is the carbon atom to which the
remainder of the molecule is attached.
118. Z1, Z2,Z4,Z5 are independently CR2; Z3, Z6 are independently O, S, or N-R1;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5 is the carbon atom to which the
remainder of the molecule is attached.
119. Z1, Z2, Z4, Z5 are independently CR2. or N; Z3, Z6 are independently O, S, or
N-R1; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5 is the carbon atom to which the
remainder of the molecule is attached.

120. Z1, Z2, Z5, Z6 are independently CR2; Z3, Z4 are independently O, S, or N-R1;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z2, Z5, Z6 is the carbon atom to which the
remainder of the molecule is attached.
121. Z1, Z2, Z5, Z6 are independently CR2 or N; Z3, Z4 are independently O, S, or
N-R1; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), or CR4R4; t = 1-2; One of Z1, Z2, Z5, Z6 is the carbon atom to which the
remainder of the molecule is attached.
122. Z1, Z2 , Z4, Z5 are independently CR2; Z3, Z6 are independently O, S, or N-R1;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1,, O, S=(O)r (r = 0-2), or

CR4R4; t = 1-2; One of Z1, Z2, Z5, Z6 is the carbon atom to which the
remainder of the molecule is attached.
123. Z1, Z2 , Z4, Z5 are independently CR2, or N; Z3, Z6 are independently O, S, or
N-R1; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), or CR4R4; t = 1-2; One of Z1, Z2, Z5, Z6 is the carbon atom to which the
remainder of the molecule is attached.
124. Z1, Z2, Z3, Z4, Z6 are independently CR2; Z5 is O, S, or N-R1; Y, is N; Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;
One of Z1, Z2, Z3, Z4, Z6 is the carbon atom to which the remainder of the
molecule is attached.

125. Z1, Z2, Z3, Z4, Z6 are independently CR2, or N; Z5 is O, S, or N-R1; Y1 is N; Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t
= 1-2; One of Z1, Z2, Z3, Z4, Z6 is the carbon atom to which the remainder of
the molecule is attached.
126. Z1, Z3, Z4, Z6 are independently CR2; Z2, Z5 are independently O, S, or N-R1;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z3, Z4, Z6 is the carbon atom to which the
remainder of the molecule is attached.
127. Z1, Z3, Z4, Z6 are independently CR2 or N; Z2, Z5 are independently O, S, or
N-R1; Y1, Y2, Y3. Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), or CR4R4; t = 1-2; One of Z1, Z3, Z4, Z6 is the carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 8-A are:
128. Z1 is O, S, or N-R1; Z2, Z4, Z5, Z6, Z7 are independently CR2; Z3 is CR2, or N;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z2, Z3, 24, Z6 is the carbon atom to which the
remainder of the molecule is attached.
129. Z1 is O, S, or N-R1; Z2, Z4, Z5, Z6, Z7 are independently CR2; Z3 is CR2; Y1, Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or C4R4; t
= 1-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder
of the molecule is attached.

130. Z1 is O, S, or N-R1; Z2, Z4, Z5, Z6, Z7 are independently CR2; Z3 is N; Y1, Y2, Y3.
Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-
2; One of Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
131. Z1 is O, S, or N-R1; Z3, Z4, Z5, Z6, Z7 are independently CR2; Z2 is CR2, or N;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O. S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.

132. Z1 is O, S, or N-R1; Z3, Z4, Z5, Z6, Z7 are independently CR2; Z2 is N; Y1, Y2,
Y3. Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t
= 1-2; One of Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of
the molecule is attached.
133. Z1 is O, S, or N-R1; Z3, Z4, Z5, Z6, Z7 are independently CR2; Z2 is CR2; Y1, Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t
= 1-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder
of the molecule is attached.

134. Z1 is O, S, or N-R1; Z2, Z3, Z4, Z5, Z6, Z7 are independently N or CR2; Y1, Y2, Y3.
Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-
2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of
the molecule is attached.
135. Z1 is O, S, or N-R1; Z2 is CR2; Z4, Z5, Z6, Z7 are independently N or CR2; Z3 is
CR2; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
or CR4R4; t = 1-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.

136. Z1 is O, S, or N-R1; Z2 is CR2; Z4, Z5, Z6, and Z7 are independently N or CR2;
Z3 is N; Y1, Y2, Y3, Y4 are C; W1, and W2 are independently N-R1, O, S=(O)r (r
= 0-2), or CR4R4; t = 1-2; One of Z2, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
137. Z1 is O, S, or N-R1; Z4 , Z5, Z6, and Z7 are independently N or CR2; Z2 and Z3
are independently CR2 or N; Y1, Y2, Y3, Y4 are C; W1 and W2 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z2, Z3, Z4,
Z5, Z6, Z7 is the carbon atom to which the remainder of the molecule is
attached.

138. Z1 is O, S, or N-R1; Z3 is CR2; Z4, Z5, Z6, and Z7 are independently N or CR2;
Z2 is N; Y1, Y2, Y3, and Y4 are C; W1 and W2 are independently N-R1, O,
S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z3, Z4 , Z5, Z6, Z7 is the carbon
atom to which the remainder of the molecule is attached.
139. Z1 is O, S, N-R1;Z4, Z5, Z6, and Z7 are independently N or CR2; Z2 and Z3 are
independently CR2; Y1, Y2, Y3, Y4 are C; W1 and W2 are independently N-R1,
O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z2. Z3, Z4, Z5, Z6, Z7is the
carbon atom to which the remainder of the molecule is attached.

140. Z3 is O, S, or N-R1; Z2, Z4, Z5, Z6, and Z7 are independently CR2; Z1 is CR2 or
N; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2).
or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7is the carbon atom to which the
remainder of the molecule is attached.
141. Z3 is O, S. or N-Rt; Z1, Z2, Z4, Z5, Z6, Z7 are independently CR2; Y1, Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;
One of Z1, Z2, Z4, Z5, Z6, Z7is the carbon atom to which the remainder of the
molecule is attached.

142. Z3 is O, S. or N-R1; Z2, Z4, Z5, Z6, and Z7 are independently CR2; Z1 is N; Y1,
Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
143. Z3 is O, S, or N-R1; Z1, Z4, Z5, Z6, Z7 are independently CR2; Z2 is CR2 or N;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.

144. Z3 is O, S, or N-R1; Z1, Z4 , Z5, Z6, Z7 are independently CR2; Z2 is N; Y1, Y2,
Y3, Y4 are C; W1 and W2 are independently N-R1, O, S=(O)r (r = 0-2), or
CR4R4; t = 1-2; One of Z1, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
145. Z3 is O, S, or N-R1; Z1, Z2, Z4, Z5, Z6. Z7 are independently CR2; Y1, Y2, Y3. Y4
are C; W1 and W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t =
1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of
the molecule is attached.

146. Z3 is O, S, or N-R1; Z2, Z4 , Z5, Z6, Z7 are independently N or CR2; Z1 is CR2,
or N; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-
2), CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
147. Z3 is O, S, or N-R1; Z2 is CR2; Z4, Z5, Z6, Z7 are independently N or CR2; Z1 is
CR2; Y1, Y2, Y3, Y4 are C; W1 and W2 are independently N-R1, O, S=(O)r (r =
0-2), or CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to
which the remainder of the molecule is attached.
148. Z3 is O, S, or N-R1; Z2 is CR2; Z4, Z5, Z6, and Z7 are independently N or CR2;
Z1 is N; Y1, Y2, Y3, Y4 are C; W1 and W2 are independently N-R1, O, S=(O)r (r
= 0-2), or CR4R4; t = 1-2; One of Z2, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.

149. Z3 is O, S, or N-R1; Z4, Z5, Z6, and Z7 are independently N or CR2; Z2 and Z1
are independently CR2 or N; Y1, Y2, Y3, Y4 are C; W1 and W2 are
independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z1, Z2, Z4 ,
Z5, Z6. Z7 is the carbon atom to which the remainder of the molecule is
attached.
150. Z3 is O, S, N-R1; Z1 is CR2; Z4, Z5, Z6, Z7 are independently N or CR2; Z2 is
N; Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4; t = 1-2; One of Z1, Z4 , Z5, Z6, and Z7 is the carbon atom to which the
remainder of the molecule is attached.

151. Z3 is O, S, N-R1;Z4, Z5, Z6. and Z7 are independently N or CR2; Z1 and Z2 are
independently CR2; Y1, Y2, Y3. Y4 are C; W1 and W2 are independently N-R1,
O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One of Z1, Z2, Z4 , Z5, Z6, and Z7 is the
carbon atom to which the remainder of the molecule is attached.
152. Z1, Z2, Z3, Z4, Z5, Z6, and Z7are independently CR2; Y4 is N; Y1, Y2, Y3 are C;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t = 1-2; One
of Z1, Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
153. Z1 is N; Z2, Z3, Z4 , Z5, Z6, and Z7 are independently CR2; Y4 is N; Y1, Y2. Y3
are C; W1 and W2 are independently N-R1, O, S=(O)r (r = 0-2), or CR4R4; t =
1-2; One of Z2, Z3, Z4 , Z5, Z6, and Z7 is the carbon atom to which the
remainder of the molecule is attached.

154. Z2 is N; Z1, Z3, Z4, Z5, Z6, Z7 are independently CR2; Y4 is N; Y1, Y2, Y3 are C;
W1 and W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2; One
of Z1, Z3, Z4, Z5, Z6, and Z7 is the carbon atom to which the remainder of the
molecule is attached.
155. Z3 is N; Z1, Z2, Z4 , Z5, Z6, and Z7 are independently CR2; Y4 is N; Y1, Y2, Y3
are C; W1, W2 are independently N-R1,O, S=(O)r (r = 0-2), or CR4R4; t = 1-2;
One of Z1, Z2, Z4 , Z5, Z6, and Z7 is the carbon atom to which the remainder of
the molecule is attached.

156. Z1 and Z2 are N; Z3, Z4 , Z5, Z6, Z7 are independently CR2; Y4 is N; Y1, Y2, Y3
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2;
One of Z3, Z4 , Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
157. Z1, Z3 are N; Z2, Z4 , Z5, Z6, Z7 are independently CR2; Y4 is N; Y1, Y2, Y3 are
C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2; One
of Z1, Z2, Z4 , Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

158. Z1, Z2, Z3 are N; Z4, Z5, Z6, Z7 are independently CR2; Y4 is N; Y1, Y2, Y3 are
C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2; One
of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the molecule is
attached.
159. Z1, Z2, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N, CR2; Y4
is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4', t = 1-2; One of Z1, Z2, Z4 , Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.

160. Z1 is N; Z2, Z3are independently CR2; Z4 , Z5, Z6, Z7 are independently N, CR2;
Y4 is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4; t = 1-2; One of Z1, Z2, Z4 , Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
161. Z2 is N; Z1, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N, CR2;
Y4 is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4; t = 1-2; One of Z1, Z3, Z4 , Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.

162. Z3 is N; Z1, Z2 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 1-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
163. Z1, Z2 are N; Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 1-2; One of Z3, Z4 , Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
164. Z1, Z3 are N; Z2 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y1, Y2, Y3 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 1-2; One of Z1, Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to
which the remainder of the molecule is attached.
165. Z1, Z2, Z3 are N; Z4, Z5, Z6, Z7 are independently N, CR2; Y4 is N; Y1, Y2, Y3
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 1-2;
One of Z4 , Z5, Z6. Z7 is the carbon atom to which the remainder of the
molecule is attached.
The preferred embodiments of formula 8-B are:
166. Z1 is O, S, N-R1; Z2, Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z2, Z4 , Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
167. Z1 is O, S, N-R,; Z2, Z3, Z4, Z5, Z6, Z7 are CH2; Y1, Y2, Y3, Y4 are C; W1, W2
are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; One of Z2, Z3, Z4,
Z5, Z6, Z7 is the carbon atom to which the remainder of the molecule is
attached.
168. Z1 is O, S, N-R1; Z2 is N; Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2.
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
169. Z1 is O, S, N-R1; Z2, Z3 areN; Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =

0-2; One of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
170. Z1 is O, S, N-R1; Z2, Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z3 isN; Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of
the molecule is attached.
171. Z2 is O, S, N-R1; Z1, Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z1, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

172. Z2 is O, S, N-R1; Z1, Z3, Z4, Z5, Z6, Z7 are independently CR2; Y1, Y2, Y3, Y4 are
C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; One of
Z1, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
173. Z2 is O, S, N-R1; Z1 isN; Z3 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4; t = 0-2; One of Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.

174. Z2 is O, S, N-R,; Z1, Z3 areN; Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2,
Y3, Y4 are C; W1,W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
175. Z3 is O, S, N-R1; Z1, Z2, Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

176. Z3 is O, S, N-R,; Z1, Z2, Z4, Z5, Z6, Z7 are independently CR2; Y1, Y2, Y3, Y4 are
C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; One of
Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
177. Z3 is O, S, N-R1; Z1 isN; Z2 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2;
Y1, Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),

CR4R4; t = 0-2; One of Z2, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
178. Z3 is O, S, N-R1; Z1, Z2 isN; Z4, Z5, Z6, Z7 are independently N, CR2; Y1, Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
179. Z1, Z2, Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y1 isN; Y2, Y3, Y4 are C;
Wt, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; One of
Z1, Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

180. Z1 is N; Z2, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N, CR2;
Y1 isN; Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2),
CR4R4; t = 0-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the
remainder of the molecule is attached.
181. Z1, Z2 are N; Z3 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2; Y1 is N; Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

182. Z1, Z2, Z3 are N; Z4, Z5, Z6, Z7 are independently N, CR2; Y1 is N; Y2, Y3, Y4
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
183. Z2 is N; Z1, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y1 is N; Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 0-2; One of Z1, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
184. Z2,Z3 are N; Z1 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2; Y1 is N; Y2,
Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z1, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
185. Z3 is N; Z1, Z2 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y1, is N; Y2, Y3, Y4 are C; W1, W2 are independently N-R1, O, S=(O)r (r =

0-2), CR4R4; t = 0-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
186. Z1, Z2, Z3, Z4, Z5, Z6, Z7 are independently N, CR2; Y4 is N; Y2, Y3, Y1 are C;
W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; One of
Z1, Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
187. Z1 is N; Z2, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y2, Y3, Y1 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 0-2; One of Z2, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.

188. Z1, Z2 are N; Z3 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2; Y4 is N; Y2,
Y3, Y1 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z3, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of
the molecule is attached.
189. Z1, Z2, Z3 are N; Z4, Z5, Z6, Z7 are independently N, CR2; Y4 is N; Y2, Y3, Y1
are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2;
One of Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.

190. Z2 is N; Z1, Z3 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y2, Y3, Y1 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 0-2; One of Z1, Z3, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
191. Z2, Z3 are N; Z1 is CR2; Z4, Z5, Z6, Z7 are independently N, CR2; Y4 is N; Y2,
Y3, Y1 are C; W1, W2 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t =
0-2; One of Z1, Z4, Z5, Z6, Z7 is the carbon atom to which the remainder of the
molecule is attached.
192. Z3 is N; Z1, Z2 are independently CR2; Z4, Z5, Z6, Z7 are independently N,
CR2; Y4 is N; Y2, Y3, Y1 are C; W1, W2 are independently N-R1, O, S=(O)r (r =
0-2), CR4R4; t = 0-2; One of Z1, Z2, Z4, Z5, Z6, Z7 is the carbon atom to which
the remainder of the molecule is attached.
The preferred embodiments of formula 9-A are:

193. Z1is O, S, N-R1; Z2, Z3 are independently CR2; Y1, Y4 are C; Y2, Y3 are
independently N, C, CH (in between a double bond might be present); W1t
W2, W3, W4, W5 are independently N-R1, O, S=(O), (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.
194. Z1is O, S, N-R1; Z2 is N; Z3 is CR2; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.

195. Z1is O, S, N-R1; Z3 is N Z2 is CR2; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
196. Z2 is O, S, N-R1; Z1, Z3 are independently CR2; Y1, Y4 are C; Y2, Y3 are
independently C, CH, N (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.

197. Z2 is O, S, N-R1; Z1 is N; Z3 is CR2; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.
198. Z2 is O, S, N-R1; Z3 is N Z1 is CR2; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z1 is the
carbon atom to which the remainder of the molecule is attached.

199. Z3 is O, S, N-R1; Z1, Z2 are independently CR2; Y1, Y4 are C; Y2, Y3 are
independently C, CH, N (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z1, Z2 is the carbon atom to which the remainder of the
molecule is attached.
200. Z3 is O, S, N-R1; Z1 is N; Z2 is CR2; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are

independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
201. Z3 is O, S, N-R1; Z1 is CH2; Z2 is N; Y1, Y4 are C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z1 is the
carbon atom to which the remainder of the molecule is attached.
202. Z1, Z2, Z3 are independently CR2; Y1 is N; Y4 is C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR1R4; t = 0-2; u = 1-3; One of Z1,
Z2, Z3 is the carbon atom to which the remainder of the molecule is attached.

203. Z1 is N; Z2, Z3 are independently CR2; Y1 is N; Y4 is C; Y2, Y3 are
independently C, CH. N (in between a double bond might be present); W1(
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.
204. Z1, Z2 is N; Z3 is CR2; Y1 is N; Y4 is C; Y2, Y3 are independently C, CH, N (in
between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.

205. Z1, Z3 are N; Z2 is CR2; Y1 is N; Y4 is C; Y2, Y3 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O), (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
206. Z1, Z2, Z3 are independently CR2; Y4 is N; Y1 is C; Y2, Y3 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; One of Z1,
Z2, Z3 is the carbon atom to which the remainder of the molecule is attached.
207. Z1 is N; Z2, Z3 are independently CR2; Y4 is N; Y1 is C; Y2, Y3 are
independently C, CH. N (in between a double bond might be present); W,,
W2, W3, W4, W5 are independently N-R1, O, S=(O)f (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.

208. Z1, Z2 are N; Z3 is CR2; Y4 is N; Y1 is C; Y2, Y3 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.
209. Z1, Z3 are N; Z2 is CR2; Y4 is N; Y1 is C; Y2, Y3 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O), (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
The preferred embodiments of formula 9-B:
210. Z1 is O, S, N-R1; Z2, Z3 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently N, C, CH (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t - 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.
211. Z1 is O, S, N-R1; Z2 is N; Z3 is CR2; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.

212. Z1 is O, S, N-R1; Z3 is N Z2 is CR2; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
213. Z2 is O, S, N-R1; Z1, Z3 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently C, CH, N (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.
214. Z2 is O, S, N-R1; Z1 is N; Z3 is CR2; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.

215. Z2 is O, S, N-R1; Z3 is N Z1 is CR2; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z1 is the
carbon atom to which the remainder of the molecule is attached.
216. Z3 is O, S, N-R1; Z1, Z2 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently C, CH, N (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z1, Z2 is the carbon atom to which the remainder of the
molecule is attached.

217. Z3 is O, S, N-R1; Z1 is N; Z2 is CR2; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
218. Z3 is O, S, N-R1; Z1 is CH2; Z2 is N; Y1, Y2 are C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z1 is the
carbon atom to which the remainder of the molecule is attached.

219. Z1, Z2, Z3 are independently CR2; Y1 is N; Y2 is C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; One of Z1,
Z2, Z3 is the carbon atom to which the remainder of the molecule is attached.
220. Z1is N; Z2, Z3 are CR2; Y1 is N; Y2 is C; Y3, Y4 are independently C, CH. N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; One of Z2,
Z3 is the carbon atom to which the remainder of the molecule is attached.

221. Z1, Z2 are N; Z3 is CR2; Y, is N; Y2 is C; Y3, Y4 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.
222. Z1, Z3 are N; Z2 is CR2; Y1 is N; Y2 is C; Y3, Y4 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.

223. Z1, Z2, Z3 are independently CR2; Y2 is N; Y1 is C; Y3, Y4 are independently C,
CH, N (in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; One of Z1
Z2, Z3 is the carbon atom to which the remainder of the molecule is attached.
224. Z1 is N; Z2, Z3 are independently CR2; Y2 is N; Y1 is C; Y3, Y4 are
independently C, CH. N (in between a double bond might be present); W1,
W2, W3, W4, W5 are independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u
= 1-3; One of Z2, Z3 is the carbon atom to which the remainder of the
molecule is attached.

225. Z1, Z2 are N; Z3 is CR2; Y2 is N; Y1 is C; Y3, Y4 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z3 is the
carbon atom to which the remainder of the molecule is attached.
226. Z1, Z3 are N; Z2 is CR2; Y2 is N; Y1 is C; Y3, Y4 are independently C, CH, N
(in between a double bond might be present); W1, W2, W3, W4, W5 are
independently N-R1, O, S=(O)r (r = 0-2), CR4R4; t = 0-2; u = 1-3; Z2 is the
carbon atom to which the remainder of the molecule is attached.
The preferred embodiments of formula 10-A:
227. Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1; Y1, Y2,
Y3, Y4 are C; one of Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.
228. Z1 is N; Z2, Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1; Y1,
Y2, Y3, Y4 are C; one of Z2, Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.
229. Z1, Z2 are N; Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1;
Y1, Y2, Y3, Y4 are C ; one of Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.
230. Z1, Z3 are N; Z2, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1;
Y1, Y2, Y3, Y4 are C; one of Z2, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.

231. Z1, Z4 are N; Z3, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1; Y1,
Y2, Y3, Y4 are C; one of Z3, Z6, Z7, Z8, Z9 must be a carbon atom to which the
remainder of the molecule is attached.
232. Z1 is N; Z2, Z3, Z4 are independently CR2; Z6, Z7, Z8, Z9 are independently N,
CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z2, Z3, Z4, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.
233. Z1, Z2 are N; Z3, Z4 are independently CR2; Z6, Z7, Z8, Z9 are independently
N, CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z3, Z4, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.

234. Z1, Z3 are N; Z2, Z4 are independently CR2; Z6, Z7, Z8, Z9 are independently
N, CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z2, Z4, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.
235. Z1, Z4 are N; Z2, Z3 are independently CR2; Z6, Z7, Z8, Z9 are independently
N, CR2; Zs is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z2, Z3, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.
236. Z2 is N; Z1, Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1; Y1,
Y2, Y3, Y4 are C; one of Z1, Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.

237. Z2, Z3 are N; Z1, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1;
Y1, Y2, Y3, Y4 are C ; one of Z1, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.
238. Z2, Z4 are N; Z1, Z3, Z6, Z7, Z8, Z9 are independently CR2; Z5 is O, S, N-R1;
Y1, Y2, Y3, Y4 are C; one of Z1, Z3, Z6, Z7, Z8, Z9 must be a carbon atom to
which the remainder of the molecule is attached.
239. Z2 is N; Z1, Z3, Z4 are independently CR2; Z6, Z7, Z8, Z9 are independently N,
CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z1, Z3, Z4, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.
240. Z2, Z3 are N; Z1, Z4 are independently CR2; Z6, Z7, Z8, Z9 are independently
N, CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z1, Z4, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.
241. Z2, Z4 are N; Z1, Z3 are independently CR2; Z6, Z7, Z8, Z9 are independently
N, CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C; one of Z1, Z3, Z6, Z7, Z8, Z9
must be a carbon atom to which the remainder of the molecule is attached.*********

The preferred embodiments of formula 11-A:
242. Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Z5, Z10 are independently
O, S, N-R1; Y1, Y2, Y3, Y4 are C; Any one of Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 must
be a carbon atom to which the remainder of the molecule is attached.
243. Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 are independently N, CR2; Z5, Z10 are
independently O, S, N-R1; Y1, Y2, Y3, Y4 are C ; Any one of Z1, Z2, Z3, Z4, Z6,
Z7, Z8, Z9 must be a carbon atom to which the remainder of the molecule is
attached.
The preferred embodiments of formula 11-B:
244. Z1, Z2, Z3, Z4,Z7, Z8, Z9, Z10 are independently CR2; Z5, Z6 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; Any one of Z1, Z2, Z3, Z4, Z7, Z8, Z9, Z10 must be
a carbon atom to which the remainder of the molecule is attached.
245. 163.Z1, Z2, Z3, Z4 are independently CR2, N; Z5, Z6,. Z7, Z8, Z9 , Z10 are
independently CR2; Y1, Y2, Y3, Y4 are C; Any one of Z1, Z2, Z3, Z4, Z7, Z8, Z9,
Z10 must be a carbon atom to which the remainder of the molecule is
attached.
The preferred embodiments of formula 11-C:
246. Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 are independently CR2; Y1 is N; Y2is C; Any one of
Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to which the remainder of
the molecule is attached.
247. Z1, Z2, Z3, Z4, Z7, Z8, Z9 are independently CR2; Z6 is O, S, N-R,; Y, is C; Y2 is
N; Any one of Z1, Z2, Z3, Z4, Z6, Z7, Z8, Z9 must be a carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 12-A:
248. Z1, Z2, Z3, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,

Y3, Y4 are C; Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
249. Z1, Z2. Z3, Z4 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which
the remainder of the molecule is attached.
250. Z1, Z2, Z3, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

251. Z1 is N; Z2, Z3, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 —4; Y1, Y2,
Y3, Y4 are C; Any one of Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
252. Z1 ,Z2 are N; Z3, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-Rt with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t - 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
253. Z1, Z3 are N; Z2, Z4 are independently CR2; Z5 is O, S, N-R1; Z1 ,Z2 are N;
Z3, Z4 are independently CR2; Z5 is N, CR2; W1, W2, W3 are independently
CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-O or O-O
bond formation can occur to form a saturated ring; In the ring formed by W1,
W2, W3 one double bond might be present; t = 1 -4; Y1, Y2, Y3 are C; Y4 is
N; Any one of Z2, Z4 must be a carbon atom to which the remainder of the
molecule is attached.

254. Z1, Z4 are N; Z2, Z3 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z2, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
255. Z1 is N; Z2, Z3, Z4 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z2, Z3, Z4 must be a carbon atom to which
the remainder of the molecule is attached.
256. Z1, Z3 are N; Z2, Z4 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4. S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

257. Z1 ,Z4 are N; Z2, Z3 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z2, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
258. Z1, Z2 are N; Z3, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
259. Z1, Z3 are N; Z2, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring

formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
260. Z1, Z4 are N; Z2, Z3 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z2, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
261. Z2 is N; Z1, Z3, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

262. Z2, Z3 are N; Z1, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1t W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
263. Z2, Z4 are N; Z1, Z3 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
264. Z2 is N; Z1, Z3, Z4 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

265. Z2, Z3 are N; Z1, Z4 are independently CR2; Z5 is N, CR2; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
266. Z2, Z4 are N; Z1, Z3 are independently CR2; Zs is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
267. Z2 is N; Z1, Z3, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
268. Z2, Z3 are N; Z1, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by Wi, W2l W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

269. Z2, Z4 are N; Z1, Z3 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
270. Z3 is N; Z1, Z2, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring

formed by \N1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
271. Z3, Z4 are N; Z1, Z4 are independently CR2; Z5 is O, S, N-R1; W1, W2, W3 are
independently CR4R4, S(O)r (r - 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z2 must be a carbon atom to which the
remainder of the molecule is attached.
272. Z3 is N; Z1, Z3, Z4 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4 S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.

273. Z3, Z4 are N; Z1, Z2 are independently CR2; Z5 is N, CR2 ; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z2 must be a carbon atom to which the
remainder of the molecule is attached.
274. Z3 is N; Z1, Z3, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
275. Z3, Z4 are N; Z1, Z4 are independently CR2; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1-3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z2 must be a carbon atom to which the
remainder of the molecule is attached.

276 Z1, Z2, Z3 are independently CR2; Z4 is N; Z5 is O, S, N-R1, W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring. In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3, Y4 are C; Any one of Z1, Z2, Z3, must be a carbon atom to which the
remainder of the molecule is attached.
277. Z1, Z2, Z3 are independently CR2; Z4 is N; Z5 is N, CR2; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S, S-
O or O-O bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1 -4; Y1, Y2,
Y3 are C; Y4 is N; Any one of Z1, Z2, Z3 must be a carbon atom to which the
remainder of the molecule is attached.
278. Z1, Z2, Z3 are independently CR2; Z4 is N; Z5 is O, S. N; W1, W2, W3 are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or OO bond formation can occur to form a saturated ring; In the ring
formed by W1, W2, W3 one double bond might be present; t = 1- 3; Y1, Y2, Y3
are C; Y4 is N; Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 12-B:
279. Z1, Z2, Z3,Z4 are independently CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4 are C;
W1, W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z4 must be a carbon atom to which the remainder
of the molecule is attached.
280. Z1 is N; Z2, Z3, Z4 are independently CR2; Z5 is O, S, N-R1; Y1,Y2,Y3,Y4
are C; W1, W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z3, Z4 must be a carbon atom to which
the remainder of the molecule is attached.
281. Z1, Z2 are N; Z3,Z4 are independently CR2; Z5 is O, S, N-R1; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a

saturated ring; t = 1-3. Any one of Z3,Z4 must be a carbon atom to which the
remainder of the molecule is attached.
282. Z1, Z3 are N; Z2, Z4 are independently CR2; Z5 is O, S, N-R1; Y1,Y2, Y3,Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
283. Z2 is N; Z1, Z3, Z4 are independently CR2; Z5 is O, S, N-R1; Y1,Y2,Y3,Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z3, Z4 must be a carbon atom to which
the remainder of the molecule is attached.

284. Z2, Z3 are N; Z1, Z4 are independently CR2; Z5 is O, S, N-R,; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
285. Z3 is N; Z1, Z2,Z4 are independently CR2; Z5 is O, S, N-R1; Y1,Y2,Y3,Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z2, Z4 must be a carbon atom to which
the remainder of the molecule is attached.

286. Z1, Z2, Z3,Z5 are independently CR2; Z4 is O, S, N-R1; Y1, Y2, Y3, Y4 are C;
W1, W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z5 must be a carbon atom to which the remainder
of the molecule is attached.
287. Z1 is N; Z2, Z3, Z5 are independently CR2; Z4 is O, S, N-R1; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z3, Z5 must be a carbon atom to which
the remainder of the molecule is attached.

288. Z1, Z2 are N; Z3,Z5 are independently CR2; Z4 is O, S, N-R1; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z3, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
289. Z1, Z3 are N; Z2,Z5 are independently CR2; Z4 is O, S, N-R1; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z5 must be a carbon atom to which the
remainder of the molecule is attached.

290. Z2 is N; Z1,Z3,Z5 are independently CR2; Z4 is O, S, N-R1; Y1, Y2, Y3, Y4
are C; W1, W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z3,Z5 must be a carbon atom to which
the remainder of the molecule is attached.
291. Z2, Z3 are N; Z1, Z5 are independently CR2; Z4 is O, S, N-R1, Y1, Y2, Y3, Y4
are C; \N1, W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z5 must be a carbon atom to which the
remainder of the molecule is attached.

292. Z3 is N; Z1, Z2, Z5 are independently CR2; Z4 is O, S, N-R1; Y1,Y2,Y3,Y4
are C; W1, W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z2, Z5 must be a carbon atom to which
the remainder of the molecule is attached.
293. Z1, Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1, W2are
independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no S-S,
S-O or 0-0 bond formation can occur to form a saturated ring; t = 1-3. Any
one of Z1, Z2, Z3, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
294. Z1 is N; Z2, Z3,Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.

Any one of Z2, Z3, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
295. Z1, Z2 are N; Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z3, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
296. Z1, Z3 are N; Z2, Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.
Any one of Z2, Z4, Z5 must be a carbon atom to which the remainder of the
molecule is attached.

297. Z2 is N; Z1, Z3,Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.
Any one of Z1, Z3, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
298. Z2, Z3 are N; Z1, Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.
Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the remainder of the
molecule is attached.
299. Z3 is N; Z1, Z2, Z4, Z5 are independently CR2; Y1, Y2, Y3 are C; Y4 is N; W1,
W2 are independently CR4R4, S(O)r (r - 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.
Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the remainder of the
molecule is attached.
The preferred embodiments of formula 13-A:
300. Z1, Z2, Z3, Z4, Z5, Z6 are independently N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-

3. Any one of Z1, Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
301. Z1 is N; Z2, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
302. Z1, Z2 are N; Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

303. Z1, Z3 are N; Z2, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
304. Z1, Z4 are N; Z2, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r - 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

305. Z1, Z5 are N; Z2, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
306. Z1, Z6 are N; Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z2, Z3, Z5 must be a carbon atom to which the remainder
of the molecule is attached.

307. Z2 is N; Z1, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
308. Z2, Z3 are N; Z1, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z4, Z5, Z6 must be a carbon atom to which the remainder of
the molecule is attached.

309. Z2, Z4 are N; Z1, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r - 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1t Zs, Zs, Zs must be a carbon atom to which the
remainder of the molecule is attached.
310. Z2, Z5 are N; Z1, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

311. Z2, Z5 are N; Z1,Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
312. Z2, Z6 are N; Z1, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2l W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
313. Z3 is N; Z1, Z2, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1t
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t

= 1-3. Any one of Z1, Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
314. Z3, Z4 are N; Z1, Z2, Z6. Z are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
315. Z3, Z5 are N; Z1, Z2, Z4, Z6 are independently CR2; Y1, Y2, Y3 Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.

316. Z3,. Z6 are N; Z1, Z2, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4. S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
317. Z4 is N; Z1, Z2, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that no
S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-3.
Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the remainder
of the molecule is attached.

318. Z4, Z5 are N; Z1,Z2, Z3, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
319. Z5 is N;Z1, Z2, Z3, Z4, Z6 are independently CR2;Y1,Y2,Y3,Y4 are C;W1, W2
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1, Z2, Z4, Z6, Z6 must be a carbon atom to which the remainder
of the molecule is attached.

320. Z5, Z6 are N; Z1, Z2, Z3, Z4 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
321. Z5 is N; Z1, Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 13-B:
322. Z1, Z2, Z3,Z4, Z5, Z6 are independently N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2 ,
W3 are independently CR4R4, S(O)r (r = 0-2). O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1, Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
323. Z1 is N; Z2, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R= with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

324. Z1, Z2 are N; Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
325. Z1, Z3 are N; Z2, Z4, Z5, Z3 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

326. Z1, Z4 are N; Z2,Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
327. Z1, Z5 are N; Z2, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

328. Z1, Z6 are N; Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
329. Z2 is N; Z1, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1,Z3, Z4, Z5, Z6 must be a carbon atom to which the remainder
of the molecule is attached.

330. Z2, Z3 are N; Z1, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z4, Z5, Z6 must be a carbon atom to which the remainder
of the molecule is attached.
331. Z2, Z4 are N; Z1, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
332. Z2, Z5 are N; Z1, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;

t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
333. Z2, Z5 are N; Z1, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
334. Z2, Z6 are N; Z1,Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.

335. Z3 is N; Z1, Z2, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
336. Z3, Z4 are N; Z1, Z2, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

337. Z3, Z5 are N; Z1, Z2, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
338. Z3, Z6 are N; Z1, Z2, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.

339. Z4 is N; Z1, Z2, Z3, Z5, Z6 are independently CR2;Y1,Y2,Y3,Y4 are C;W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
340. Z4, Z5 are N; Z1, Z2, Z3, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

341. Z5 is N; Z1, Z2, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
342. Z5, Z6 are N; Z1, Z2, Z3, Z4 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
343. Z6 is N; Z1, Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 13-C:
344. Z1, Z2, Z3, Z4, Z5, Z6 are independently N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso that
no S-S, S-O or 0-0 bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1, Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

345. Z1 is N; Z2, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1, W2,
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z2, Z3, Z4, Z5, Z6 must be a carbon atom to which the remainder
of the molecule is attached.
346. Z1, Z2 are N; Z3, Z4, Z5, 2% are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

347. Z1, Z3 are N; Z2, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
348. Z1, Z4 are N; Z2, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

349. Z1, Z5 are N; Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
350. Z1, Z6 are N; Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
351. Z2 is N; Z1, Z3, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t

= 1-3. Any one of Z1, Z3, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
352. Z2, Z3 are N; Z1, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z4, Z5, Z6 must be a carbon atom to which the remainder
of the molecule is attached.
353. Z2, Z4 are N; Z1, Z3, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

354. Z2, Z5 are N; Z1,Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
355. Z2, Z5 are N; Z1,Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4 S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

356. Z2, Z6 are N; Z1, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
357. Z3 is N; Z1, Z2, Z4, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z4, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

358. Z3, Z4 are N; Z1, Z2, Z5, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
359. Z3, Z5 are N; Z1, Z2, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4. S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.

360. Z3, Z6 are N; Z1, Z2, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
361. Z4 is N; Z1, Z2, Z3, Z5, Z6 are independently CR2;Y1,Y2, Y3, Y4 are C; W1, W2
W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
3. Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
362. Z4, Z5 are N; Z1, Z2, Z3, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4 S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
t= 1-3. Any one of Z1, Z2, Z3, Z5, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
363. Z5 is N; Z1, Z2, Z3, Z4, Z6 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4, Z6 must be a carbon atom to which the
remainder of the molecule is attached.
364. Z5, Z6 are N; Z1, Z2, Z3, Z4 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the proviso
that no S-S, S-O or 0-0 bond formation can occur to form a saturated ring;

t= 1-3. Any one of Z1, Z2, Z3, Z4 must be a carbon atom to which the
remainder of the molecule is attached.
365. Z6 is N; Z1, Z2, Z3, Z4, Z5 are independently CR2; Y1, Y2, Y3, Y4 are C; W1,
W2, W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring; t
= 1-3. Any one of Z1, Z2, Z3, Z4, Z5 must be a carbon atom to which the
remainder of the molecule is attached.
The preferred embodiments of formula 14-A and 14-B;
366. Z1 is N; Z2, Z3, Z4, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z3, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
367. Z1, Z2 are N; Z3, Z4, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z3, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
368. Z1, Z3 are N; Z2, Z4, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
369. Z1, Z4 are N; Z2, Z3, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z2, Z3, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
370. Z1, Z2 are N; Z3, Z4, Z5, Z3, Z7, Za are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a

saturated ring; t = 1-3. Any one of Z3, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
371. Z1 is N; Z2, Z3, Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently N,
CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4. S(O)r (r = 0-
2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z2, Z3, Z4, Z5, Z6, Z7, Z8
must be a carbon atom to which the remainder of the molecule is attached.
372. Z1, Z2 are N; Z3, Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or OO bond formation can
occur to form a saturated ring; t - 1-3. Any one of Z3, Z4, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.

373. Z1, Z3 are N; Z2, Z4 are independentlyCR2; Z5, Z6, Z7, Z8 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z2, Z4, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.
374. Z1, Z4 are N; Z2, Z3 are independently CR2; Z5, Z6, Z7, Z6 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z2, Z3, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.

375. Z1, Z2 are N; Z3, Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z3, Z4, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.
376. Z2 is N; Z1, Z3, Z4, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2),- O, N-R, with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z3, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.

377. Z2, Z3 are N; Z1, Z4, Z5, Z6, Z7, Z8, are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R, with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z4, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
378. Z2, Z4 are N; Z1, Z3, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently CR4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1, Z3, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
379. Z2 is N; Z1, Z3, Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently N,
CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r = 0-
2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z1, Z3, Z4, Z5, Z6, Z7, Z8
must be a carbon atom to which the remainder of the molecule is attached.

380. Z2, Z3 are N; Z1, Z4 are independentlyCR2; Z5, Z6, Z7, Z8 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently CR4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z1, Z4, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.
381. Z2, Z4 are N; Z1, Z3 are independently CR2; Z5, Z6, Z7, Z8 are independently
N, CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently C4R4, S(O)r (r =
0-2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z1, Z3, Z5, Z6, Z7, Z8 must
be a carbon atom to which the remainder of the molecule is attached.

382. Z3 is N; Z1, Z2, Z3, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently C4R4, S(O)r (r = 0-2), O, N-R, with the
proviso that no S-S, S-O or 0-0 bond formation can occur to form a
saturated ring; t = 1-3. Any one of Z1f Z2, Z4l Z5, Ze, Z7l Z8 must be a carbon
atom to which the remainder of the molecule is attached.
383. Z3, Z4 are N; Z1, Z2, Z5, Z6, Z7, Z8 are independently CR2; Y1, Y2, Y3, Y4 are C;
W1, W2 , W3 are independently C4R4, S(O)r (r = 0-2), O, N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a

saturated ring; t = 1-3. Any one of Z1, Z2, Z5, Z6, Z7, Z8 must be a carbon
atom to which the remainder of the molecule is attached.
384. Z4 is N; Z1, Z3, Z4 are independently CR2; Z5, Z6, Z7, Z8 are independently N,
CR2; Y1, Y2, Y3, Y4 are C; W1, W2, W3 are independently C4R4, S(O)r (r = 0-
2), O, N-R1 with the proviso that no S-S, S-O or O-O bond formation can
occur to form a saturated ring; t = 1-3. Any one of Z1, Z3, Z4, Z5, Z6, Z7, Z8
must be a carbon atom to which the remainder of the molecule is attached.
The preferred embodiments of formula 15-A:
385. Z1 is N; Z2, Z3, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z2, Z3, Z4
must be a carbon atom to which the remainder of the molecule is attached.
386. Z1 ,Z2 are N; Z3, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1.; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z3, Z4 must
be a carbon atom to which the remainder of the molecule is attached.

387. Z1, Z3 are N; Z2, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or 0-0 bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z2, Z4 must
be a carbon atom to which the remainder of the molecule is attached.
388. Z1 ,Z4 are N; Z2, Z3 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4 N-R1 with the proviso that no S-S, S-O or O- bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z2, Z3 must
be a carbon atom to which the remainder of the molecule is attached.

389. Z2 is N; Z1, Z3, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R, with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z1, Z3, Z4
must be a carbon atom to which the remainder of the molecule is attached.
390. Z2 ,Z3 are N; Z1, Z4 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z1, Z4 must
be a carbon atom to which the remainder of the molecule is attached.
391. Z2 ,Z4 are N; Z1, Z3 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r - 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z1, Z3 must
be a carbon atom to which the remainder of the molecule is attached.
392. Z3 is N; Z1, Z2, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independenUy CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4. N-R1,; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring ; u = 1-3; Any one of Z1, Z2, Z4
must be a carbon atom to which the remainder of the molecule is attached.
3 393. Z3 ,Z4 are N; Z1, Z2 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4. N-R1; t = 0-2; W3, W4, W5 are independently O, S
(O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S, S-O or 0-0 bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z1, Z2 must
be a carbon atom to which the remainder of the molecule is attached.
394. Z4 is N; Z1, Z2 Z3 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W, is O, S (O)r (r = 0-2), CR4R4, N-R1, a bond; W2 is
O, S (O)r (r = 0-2), CR4R4, N-R1; t = 0-2; W3, W4, W5 are independently O, S

(O)r (r - 0-2), CR4R4, N-R, with the proviso that no S-S, S-O or O-O bond
formation can occur to form a saturated ring; u = 1-3; Any one of Z1, Z2, Z3
must be a carbon atom to which the remainder of the molecule is attached.
The preferred embodiments of formula 15-B
395. Z1 is N; Z2, Z3 Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one of Z2, Z3, Z4 must be a carbon atom to which the remainder of
the molecule is attached.
396. Z1, Z2 are N; Z3, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one of Z3, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
397. Z1, Z3 are N; Z2, Z4 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one of Z2, Z4 must be a carbon atom to which the remainder of the
molecule is attached.

398. Z1, Z4 are N; Z2, Z3 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one of Z2, Z3 must be a carbon atom to which the remainder of the
molecule is attached.
399. Z2 is N; Z1, Z3 Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R, with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =

1-3; Any one of Z1, Z3, Z4 must be a carbon atom to which the remainder of
the molecule is attached.
400. Z2, Z3 are N; Z1, Z4 are independently CR2; Y1, Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one of Z1, Z4 must be a carbon atom to which the remainder of the
molecule is attached.
401. Z2, Z4 are N; Z1, Z3 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring ; t = 1-2; u =
1-3; Any one of Z1, Z3 must be a carbon atom to which the remainder of the
molecule is attached.

402. Z3 is N; Z1, Z2, Z4 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R, with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one Z1, Z2, Z4 of must be a carbon atom to which the remainder of
the molecule is attached.
403. Z3, Z4 are N; Z1, Z2 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W1 is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1 -2; u =
1-3; Any one of Z1, Z2 must be a carbon atom to which the remainder of the
molecule is attached.
404. Z4 is N; Z1, Z2, Z3 are independently CR2; Y1 , Y2 are C; Y3, Y4 are
independently CH, N; W, is O, S (O)r (r = 0-2), CR4R4, N-R1; W2, W3, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-3; Any one Z1, Z2, Z3 of must be a carbon atom to which the remainder of
the molecule is attached.

The preferred embodiments of formula 15-C:
405. Z1, Z2, Z3 are independently CR2; Y1, Y2, Y4 are C; Y2 is N; W1, W2,, W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-2; Any one Z1, Z2, Z3 of must be a carbon atom to which the remainder of
the molecule is attached.
406. Z1 is N; Z2, Z3 are independently CR2; Y1, Y2, Y4 are C; Y2 is N; W1, W2,,
W4 are independently O, S (O)r (r = 0-2), CR4R4, NR1 with the proviso that
no S-S, S-O or O-O bond formation can occur to form a saturated ring; t = 1-
2; u = 1-2; Any one Z2, Z3 of must be a carbon atom to which the remainder
of the molecule is attached.
407. Z1, Z3 are N; Z3 is CR2; Y1, Y2, Y4 are C; Y2 is N; W1, W2, , W4 are
independently O, S (O)r (r = 0-2), CR4R4, N-R1 with the proviso that no S-S,
S-O or O-O bond formation can occur to form a saturated ring; t = 1-2; u =
1-2; Z3 is the carbon atom to which the remainder of the molecule is attached.
The preferred tricyclic heteroarylgroup A and B are one of the following formulae: 1-
A, 1-B, 2-A, 3-B, 4-B, 5-A, 5-B, 6-B, 6-C, 7-B, 8-B, 9-A, 10-A, 12-A, 12-B, 13-B, 14-
A, 14-B, and 15-B.
The most preferred compounds of the present invention are:
1. (5R,6Z)-6-(lmidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
2. (5R,6Z)-6-[(7-methoxyimidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-
thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
3. (5R,6Z)-6-[(7-chloroimidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-
1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
4. (5R),(6Z)-6-lmidazol1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
5. (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-
ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
6. (5R),(6Z)-6-(lmidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0] hepto-2-ene-2-carboxylic acid, sodium salt;

7. (5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-
1-azabicydo[3.2.0]hept-2-ene-2-carboxylicadd;
8. (5R), (6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cycIopenta[a]indene-2-
ylmethylene)-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
sodium salt;
9. (5R,6E)-6-[(10-benzyl-11-0X0-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-
yl)methylenel-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
10.6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-
thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
11. (5R,6E&Z)-7-oxo-6-(4H, 10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-
thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt; and
12. (5R), (62)-6-(5H-lmidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt
A compound's structural formula includes any tautomers, any stereoisomers (except
where stereochemistry is clearly noted) and any crystalline forms.
The compounds according to the present invention have ?-lactamase inhibitory and
antibacterial properties and are useful for the treatment of infections in humans and
animals. It should be noted that the compounds of the present invention, when used
in combination with ?-lactam antibiotics will result in the increased antibacterial
activity (synergistic effect) against class-A and class-C producing organisms, ?-
Lactam antibiotics include penicillin antibiotics such as piperacillin, amoxycillin,
ticarcillin, benzylpenicillins, ampicillin, sulbenicillin, other known penicillins and
cephalosporins such as cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin,
cephradine, other known cephalosporins, aztreonam and latamoxef (Moxalactam).
Most preferably compounds of this present invention are used with piperacillin, and
Amoxicillin which has a broad spectrum of activity against Gram positive and Gram
negative pathogens.
The administration of the compounds of the present invention may be provided in
conjunction with prior, simultaneous or subsequent administration of a p-lactam
antibiotic ("co-administration"). By "provided", it is intended to include direct

administration as well as in vivo, e.g. pro-drugs. When the compounds of the
present invention are co-administered with a ?-lactam antibiotic, the ratio of the
amount of the compound to the amount of the p-lactam antibiotic may vary in a wide
range. The ratio of ?-lactam antibiotic to ?-lactamase inhibitor may vary from 1:1 to
100:1. Preferably the ratio of the ?-lactam antibiotic to the ?-lactamase inhibitor is
less than 10:1. The composition of the present invention may be in a form suitable
for oral (PO), intravenous (IV) or topical administration. The compositions of the
invention may be in a form of tablets, capsules, creams, syrups, suspension, sterile
solutions suitable for injection or infusion. Preferably, the compounds of the present
invention are co-administered with piperacillin intravenously or Amoxicillin orally or
intravenously.
IC50 Determination for the Penem Inhibitor
?-Lactamase inhibitory activity of the penem inhibitors was determined
spectrophotometrically as described by Bush et a/., [Bush, K., Macalintal, C,
Rasmussen, B. A., Lee, V. and Yang, Y. Antimicrobial Agents and Chemotherapy
1993, 37, 851]. Homogeneously purified class A ?-lactamases TEM-1 from E. coli
and lmi-1 from Enterobacter cloacae, class B enzyme CcrA from Bacteroides fragilis
and class C enzyme AmpC from Enterobacter cloaca were employed in the assay.
The enzyme concentrations for TEM-1, lmi-1, CcrA and AmpC were 4.3, 7.1,1.2 and
2.1 nM, respectively. A wide range of inhibitor concentrations were prepared in 50
mM PO4, pH 7.0 to include the possible IC50 values. The substrate used to initiate
the enzyme reaction was nitrocefin at 50 µg/ml in the same buffer as the inhibitor.
Initially the enzyme and inhibitor (20 µl each) were preincubated for 10 minutes at
25°C prior to the addition of 160 µl volume of nitrocefin. Initial rates of hydrolysis
were monitored for 5 minutes at 495 nm using a Molecular Devices Spectra Max 250
with kinetic protocol of SoftMax Program. Readings from the Spectra Max 250 were
exported and transferred to Microsoft Excel. The percent of inhibition of each
inhibitor concentration was calculated based on the control enzyme activity. The
inhibitor concentration that caused a 50% reduction in the enzymatic activity (IC50)
was determined graphically.

Antimicrobial susceptibility testing. The in vitro activities of the antibiotics were
determined by the microbroth dilution method as recommended by the National
Committee for Clinical Laboratory Standards (NCCLS). (NCCLS. 2000. Methods for
Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;
Approved Standards: M7-A5, vol. 19. National Committe for Clinical Laboratory
Standards, Villanova, PA). Mueller-Hinton II broth (MHBII)(BBL Cockeysville, MD),
was used for the testing procedure. Microtiter plates containing 50 µl per well of two-
fold serial dilutions of piperacillin combined with a constant amount (4µg/ml) of a B-
lactamase inhibitor (final concentration) were inoculated with 50 µl of inoculum to
yield the appropriate density (105 CFU/ml) in 100 µl. The plates were incubated for
18-22 hours at 35°C in ambient air. The minimal inhibitory concentration (MIC) for
all isolates was defined as the lowest concentration of antimicrobial agent that
completely inhibits the growth of the organism as detected by the unaided eye. The
MIC data obtained by the above said procedure are listed in Table 2.

In Vivo Antibacterial Protection
MATERIALS:
ANIMALS:
Female mice strain CD-1, approximately 18-22 grams, were received from Charles
River Laboratories and quarantined 7 days prior to use. In addition, mice may be
rendered neutropenic using Cytoxan for particular studies.
INFECTIONS:
Clinical isolates that have been adapted to cause infection in mice, are used in the
experiment, including infections with strains of E. coli, K. pneumoniae, M. morganii,.
E. cloacae, S. marcescens, C. freundii, staphylococci, streptococci, P. aemginosa
and N. gonorrhoeae.
PREPARATION: Animals are housed five to a cage with free access to food and
water, in accordance with NIH guidelines.
EXPERIMENTAL PROTOCOL:
Mice are challenged by injecting 0.5 ml intraperitoneally or 0.05 ml intranasally of a
predetermined bacterial inoculum suspended in broth, saline or hog gastric mucin
(supplemented with dried bovine hemoglobin for N. gonorrhoeae). The bacterial
inoculum is equivalent to 10 -100 LD50s of the specific infecting strain and will result
in death of the non-treated control animals within 7 days: "Bacterial Virulence in
Mice". Antibacterial doses (dose concentration prepared by two fold serial dilutions
of the antibiotic) are dissolved or suspended in 0.2% aqueous agar or methocel,
phosphate buffered saline or an adjuvant are administered orally, subcutaneously or
intravenously in the following manner
a) Orally or subcutaneously: Dose volume of 0.5 ml administered 1/2 hr after
infection. A second dose may be administered 3 hr. after infection for treatment of
infections with more virulent organisms.
b) Intravenously: Dose volume of 0.2 ml, administered 1/2hr. after infection.

For the treatment of infections with more virulent organisms, more doses, up to 48 hr
may be administered. (Intravenous dosing will not exceed 3 doses/24 hr period.)
c) Oral pretreatment: Under special circumstances, the pH of the stomach
needs to be adjusted in order to increase the gastric stability of the antibiotic. For
this purpose, 0.5 ml of phosphate buffered saline (pH7.8, 0.06M) (or specific
approved adjuvant) is administered orally 1/2 hr after infection, followed 5 minutes
later by 0.5ml of antibiotic (also orally) contained in phosphate buffered saline
(pH7.8,0.06M).
ANIMAL SPECIES
A detailed explanation as to the number of animals needed for the determination, of
in vivo efficacy follows:
A) Novel antibiotics are tested at 5 different dose levels with 5 mice per dose level
at each of three routes of administration (oral, subcutaneous and intravenous).
Initially the three routes of administration should be investigated so as to
determine if the drug is orally absorbed and/or which is the most effective
route. This would require 25 mice / route with 3 routes / antibiotic or 75 mice
per novel compound tested. One to two novel antibiotics will be tested per
experiment (75-150 mice)
B) The effectiveness of the new compound must be compared to that of a
standard, or antibiotic of known effectiveness. Known or previously tested
antibiotics are tested at 5 dose levels with 5 mice per dose level by a single
route of administration, for a total of 25 mice / antibiotic. Usually 3-6
antibiotics will be tested per experiment. (75-150 mice).
C) Untreated controls - in each of the above tests, untreated animals are infected
with 3 different concentrations of bacterial inoculum with 10 mice per
concentration (30 mice total in each and every test). These untreated controls
are used to determine and maintain the infection level between 10-100 LD50s
as required for test to test comparison and validity.

DETERMINATION OF PROTECTIVE EFFECTS OF ANTIBACTERIAL AGENTS:

The protective effects of the antibacterial agent(s) are measured by the survival of
the infected untreated as compared to the treated animals. For this determination,
animals are observed for 7 days after treatment. A census of survivors is taken
twice daily and at that time dead as well as moribund animals are removed. The 7
day survival ratio from three separate tests are pooled for estimation of median
effective dose (ED50) by computerized program for probit analysis (Cleeland, R. and
E. Squires. 1991. Evaluation of New Antimicrobials in Vitro and in Experimental
Animal Infections. In Antibiotics in Laboratory Medicine", 3rd. ed., edited by Victor
Lorian. Willams and Wilkins Baltimore, Maryland, pp. 752 - 783). The test is
performed three times on separate days to provide a statistically valid number of
animals and to minimize variation in test results on a day to day and test to test
basis.

This invention also provides a process for preparing the compounds of general
formula I, which process comprises subjecting to reductive elimination a compound
of fomula II:

wherein A' is A or B as defined above, X is O or S, P is an ester leaving group,
(e.g.,an acetate, mesylate, triflate or tosylate) and R is a protecting group, followed if
necessary by removal of the protecting group, to give a compound of formula I
wherein R5 is hydrogen; and if desired converting to a pharmaceutically acceptable

salt or tc-an ester wherein R5 is C1 -C6 alkyl, C5 - C6 cycloalkyl, or CHR3OCOC1-
C6alkyl.
For example compounds of the general formula I can be prepared by a novel, mild
and a facile way, by condensing an appropriately substituted aldehyde 4 with a 6-
bromo-penem derivative of structure ± (Scheme 1) in the presence of anhydrous
MgBr2 or MgBr2: etherate and a base such as triethylamine, DMAP or DBU,
preferably at -20°C to -40°C. The intermediate aldol product 5 can be functionalized
with acid chlorides or anhydrides to an acetate, triflate or a tosylate 6. Compound 6
can be smoothly converted to the desired product by a reductive elimination process
using a metal such as activated zinc and phosphate buffer at 20°C to 35°C at a pH of
6.5 to 8.0. If the protecting group on the carboxylate oxygen is a para-nitrobenzyl
substitiuent then the reductive elimination and deprotection can be achieved by a
single step. However, if the protecting group is other than a para-nitrobenzyl
substituent, a two step
SCHEME 1

procedure can be followed depending up on the nature of the protecting
group. In an alternate procedure, the intermediate 6 can be hydrogenated at 40Psi
pressure in the presence of 10% Pd/C. The product can be isolated as a free acid or
as an alkali metal salt. The above mentioned two step procedure can be carried out
in one step by carrying out the entire process without isolating the intermediate 6.
This is a very general, relatively simple and efficient procedure in terms of yield and
economic feasibility. This procedure can be adopted to large scale synthesis and is
amenable to a variety of aldehydes. The above mentioned aldol condensation
reaction is very versatile and it can be applied to any bromopenem derivative, where
the carboxy group is protected other than 4-nitrobenzyl moiety. Example of other
protecting group include benzyl, para-methoxy benzyl derivative, benzyhydrol, trityl,
alkyl and allyl derivatives. However, when the protecting group is other than 4-
nitrobenzyl group, a separate deprotection step need to be carried out after the
reductive elimination procerdure. The chemistry involved in the deprotection step is
well known to people who are skilled in that art.
The required aldehydes 4 for the above mentioned transformations can be prepared
from their respective alcohol derivatives by MnO2 oxidation or by Swem oxidation. In
some cases the required aldehyde functionality can be introduced directly in the
heterocyclic moiety by a Vilsmier Haack reaction using DMF/POCI3. The aldehydes
required for the present investigation may be prepared as depicted in Schemes 2 to
8. This procedure can be adopted to any system where there is an amino
functionality adjacent to the -N= system. For example, the aldehyde required to
synthesize compound in Example 12, was prepared starting from 2-aminophenyl
acetonitrile (Scheme 6).

2-Amino- condensed thiazole ring systems (Exemplified with the preparation of
ethyl6,7-dihydrc-5H-cyclopenta[d]imidazo[2,1 -b]thiazole-2-carboxylate, Example 5)
can be prepared by reacting cyclic a-halo ketones with thiourea. Scheme 7)

The aldehyde required to prepare example 10, can be synthesized by following the
procedure outlined in Scheme 8. This procedure can be adopted to prepare a
variety of condensed tricyclic imidazolo pyrimidine ring systems. The other examples
that are enlisted here Examples 13 to 33 were prepared by the route enlisted in
Schemes 9 to 16.

EXPERIMENTALS
Example 1
Preparation of (5R,6Z)-6-(imidazo[2,1 -b][1,3]benzothiazol-2-
ylmethylene)-7-oxo-
4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Step 1: Ethyl imidazor2.1-b1-benzthiazole-2-carboxylate:
Ethyl bromopyruvate (9.8 g, 50 mmol) was added dropwise to a stirred solution of 2-
aminobenzothiazole (7.5 g, 50 mmol) in DMF (100 ml) at room temperature. After
the addition, the reaction mixture was heated to reflux for 6 h. The reaction mixture
was cooled to room temperature and quenched with ice cold water. The aqueous
layer was neutralized with NH4OH and the separated solid was fitered. It was
washed well with water and dried. The crude product obtained was taken to next

step without purification.
Brown solid; Yield: 10 g, 81%; M+H 248. mp 97° C
Step 2: imidazo[2,1-b]-benzthiazole-2-methanol:
To a stirred slurry of LiAlH4 (2.0 g, excess) in dry THF, ethyl imidazo[2,1-b]-
benzthiazole-2-carboxylate (4.9 g, 20 mmol) was slowly added in THF (100 ml) at 0°
C. After the addition, the reaction mixture was stirred at room temperature for 1 h
and quenched with saturated NH4CI/ NH4OH. The separated solid was diluted with
Chloroform/ MeOH (3:1) and filtered through a pad of celite. The organic layer was
washed once with saturated NaCI and dried over anhydrous MgSO4. It was filtered
and concentrated. The brown solid obtained was taken to next step with out
purification. Yield: 3.8 g, 93%; M+H 205; mp 131°C.
Step 3: 2-Formyl-imidazo[2,1-b]-benzthiazole:
To a stirred solution of imidazo[2,1-b]-benzthiazole-2-methanol (2.04 g, 10 mmol) in
methylene chloride (200 ml), activated MnO2 ( 15 g, excess) was added. The
reaction mixture was stirred at room temperature for 24 h and filtered through a pad
of celite. The reaction mixture was concentrated and the product was purified by
silica gel column chromatography by eluting it with 75% ethyl acetate; hexane.
Brown solid; Yield: 800 mg, 40%; M+H 203.
Step 4: 4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1-b][1,3]benzothiazol-2-
yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[32.0]hept-2-ene-2-carboxylate:
2-Formyl-lmidazo[2,1-b]-benzthiazole (444 mg, 2.2 mmol) and a dry THF solution (20
mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic
acid 4-nitro-benzyl ester (772 mg, 2 mmol) were added successively to a dry
acetonitrile (15 mL) solution of anhydrous MgBr2:etherate (619 mg 2.4 mmol) under
an argon atmosphere at room temperature. After cooling to -20 °C, Et3N (2.0 mL)
was added in one portion. The reaction vessel was covered with foil to exclude light.
The reaction mixture was stirred for 2 h at -20 °C and treated with acetic anhydride
(1.04 mL) in one portion. The reaction mixture was warmed to 0 °C and stirred for
15 h at 0 °C. The mixture was diluted with ethyl acetate and washed with 5% citric
acid aqueous solution, saturated sodium hydrogen carbonate, and brine. The

organic layer was dried (MgSO4) and filtered through a pad of Celite. The pad was
washed with ethyl acetate. The filtrate was concentrated under reduced pressure.
The residue was applied to a silica gel column, then the column was eluted with ethyl
acetate: hexane (1:1). Collected fractions were concentrated under reduced
pressure and the mixture of diastereo isomers were taken to the next step. Pale
yellow amorphous solid; Yield: 850 mg, 67%; mp 69°C; M+H 630
Step 5: (5R),(6Z)-6-(imidazo[1,2-b][1,3]benzothlazol-2-ylmethylene) -7-oxo-4-
thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1 -b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-
oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 500 mg, 0.79 mmol) was
dissolved in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn dust (5.2 g)
was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vessel
was covered with foil to exclude light. The reaction mixture was vigorously stirred for
2 h at room temperature. The reaction mixture was filtered, cooled to 3 °C, and 1 N
NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate
and the aqueous layer was separated. The aqueous layer was concentrated under
high vacuum at 35 °C to give a yellow precipitate. The precipitate was dissolved in
acetonitrile and loaded on a HP-21 reverse phase column. It was eluted with
deionized water (2 L) and latter eluted with 10% acetonitrile:water. Yield: 105 mg,
35%; as yellow crystals; mp 233°C; M+H 356.
1H NMR (DMSO-d6) ? 6.51 (s, 1H), 6.53(s, 1H), 7.09(s, 1H), 7.47(t, 1H, J =
7.5 Hz), 7.54(t, 1H, J= 7.5 Hz), 8,06(t, 1H), 8.62(s, 1H).
Example 2
Preparation of (5R,6Z)-6-[(7-methoxyimidazo[2,1-b][1,3benzothiazol-2-
ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0hept-2-ene-2-carboxylic acid.
) Step 1: Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate:
Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according
to the procedure as outlined in Example 1, (Step 1). Starting from 6-methoxy-2-
amino benzothiazole (27 g, 0.15 mol) and ethyl bromopyruvate (39.9 g, 0.2 mol), 24

g (43% Yield) of ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was
isolated as a brown solid. (M+H) 277.
Step 2: 7-methoxy imidazo[2.1-b]-benzthiazole-2-methanol:
7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol was prepared according to the
procedure outlined in Example 1, (Step 2). Starting from- ethyl 7-
methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate (12.5 g, 43.5 mmol) and LiAIH4
solution (43.5 ml, 0.5 M solution in THF), 4.0 g (40% yield) of the alcohol derivative
was isolated as a brown solid. (M+H) 235.
Step 3: 2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole:
2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole was prepared according to the
procedure outlined in Example 1, (Step 3). Starting from 7-methoxy imidazo[2,1-b]-
benzthiazole-2-methanol (4.0 g 17 mmol) in methylene chloride/ DMF(300 mL: 50
mL) and active MnO2 (12 g, excess), 822 mg (21% Yield) of the aldehyde derivative
was isolated as brown solid. (M+H) 233.
Step 4: 4-Nitrobenzyl-6-[(acetyloxy) (7-methoxyimidazo[2,1-
b][1,3]benzothiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3,2.0]hept-
2-ene-2-carboxylate:
2-Formyl-7-methoxyimidazo[2I1-b]-ben2thiazole (822 mg, 3.5 mmol) and the dry THF
solution (40 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-a2a-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (1.364, 3.54 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2:etherate (1.3 g, 5mmol)
under an argon atmosphere at room temperature. After cooling to -20 °C, Et3N (2.0
mL) was added in one portion. The reaction vessel was covered with foil to exclude
light. The reaction mixture was stirred for 2 h at -20 °C and treated with acetic
anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C and
stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed with
5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and brine.
The organic layer was dried (MgSO4) and filtered through a pad of Celite. The pad
was washed with ethyl acetate. The filtrate was concentrated under reduced
pressure. The residue was applied to a silica gel column, then the column was

eluted with ethyl acetate: hexane (1:1). Collected fractions were concentrated under
reduced pressure and the mixture of diastereo isomers were taken to next step.
Pale yellow amorphous solid; Yield: 2.24 g, 95%; M+H 660.
Step 5: (5R),(6Z)-6-[(7-methoxyimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]
-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy) (7-methoxyimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-
6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 659 mg, 1.0
mmol) was dissolved in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn
dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The
reaction vessel was covered with foil to exclude light. The reaction mixture was
vigorously stirred for 2 h at room temperature. The reaction mixture was filtered,
cooled to 3 °C, and 1 N NaOH was added to adjust pH to 8.5. The filtrate was
washed with ethyl acetate and the aqueous layer was separated. The aqueous layer
was concentrated under high vacuum at 35 °C to give yellow precipitate. The
precipitate was filtered and washed with H2O, MeCN, acetone to give the title
compound. Yield: 68 mg, 23%; as yellow crystals; mp 284; M+H 386.
1H NMR (DMSO-d6) ? 3.89 (s, 3H), 6.58(s, 1H), 6.64(s, 1H), 7.14(s, 1H),
7.2(dd, 1H, J = 6.0 Hz), 7.75(d, 1H, J = 3.0 Hz), 8,03(d, J = 6.0 Hz 1H), 8.62(s, 1H).
Example 3
Preparation of (5R,6Z)-6-[(7-chloroimidazo[2,1-b][1.3]benzothiazol-2-
ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate:
Ethyl 7-chloroimidazol2,1-b]-benzthiazole-2-carboxylate was prepared according to
the procedure as outlined in Example 1, (Step 1). Starting from 6-chloro-2-amino
benzothiazole (9.2 g, 50 mmol) and ethyl bromopyruvate (11.6 g, 60 mmol), 8.5 g
(60% Yield) of ethyl 7-chloroimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated
as brown solid. (M+H) 281.
Step 2: 7-chloroimidazo[2,1-b]-benzthiazole-2-methanol:

7-chloro imidazo[2,1-b]-benzthiazole-2-methanol was prepared according to the
procedure outlined in Example 1, (Step 2). Starting from ethyl 7-chloroimidazo[2,1-
b]-benzthiazole-2-carboxylate (9.0 g, 32.1 mmol) and LiAIH4 (4.0 g, excess), 5.5 g
(72% yield) of the alcohol derivative was isolated as brown solid, mp 166°C(M+H)
239.
Step 3: 2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole:
2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole was prepared according to the
procedure outlined in Example 1, (Step 3). Starting from 7-chloroimidazo[2,1-b]-
benzthiazole-2-methanol (4.0 g 16.8mmol) in methylene chloride/ MeOH (300 mL:
50 mL) and active MnO2 (20 g, excess), 2.2 g (55% yield) of the aldehyde derivative
was isolated as brown solid. (M+H) 236.
Step 4: 4-Nitrobenzyl-6-[(acetyloxy) (7-chloroimidazor2.1 -b][1.3]benzothiazol-2-
yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
2-Formyl-7-chloroimidazo[2,1-b]-benzthiazole (270 mg, 1.14 mmol) and the dry THF
solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (500 mg, 1.14 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2: O(Et)2 (390 mg, 1.5
mmol)under an argon atmosphere at room temperature. After cooling to -20 °C,
Et3N (2.0 mL) was added in one portion. The reaction vessel was covered with foil to
exclude light The reaction mixture was stirred for 2 h at -20 °C and treated with
acetic anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C
and stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed
with 5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and
brine. The organic layer was dried (MgSO4) and filtered through a pad of Celite.
The pad was washed with ethyl acetate. The filtrate was concentrated under
reduced pressure. The residue was applied to silica gel column chromatography,
then the column was eluted with ethyl acetate: hexane (1:1). Collected fractions
i were concentrated under reduced pressure and the mixture of diastereomers were
taken to the next step. Pale yellow amorphous solid; Yield: 495 mg, 65%; M+H 665.

Step 5: (5R),(6Z)-6-[(7-chloroimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)] -
7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy)(7-chloroimidazo[2,1-b][1,3]benzothiazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 450 mg, 0.67
mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn
dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The
reaction vessel was covered with foil to exclude light. The reaction mixture was
vigorously stirred for 2 h at room temperature. The reaction mixture was filtered,
cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was
washed with ethyl acetate and the aqueous layer was separated. The aqueous layer
was concentrated under high vacuum at 35 °C to give a yellow precipitate. The
product was purified by HP21 resin reverse phase column chromatography. Initially
the column was eluted with deionized water (2 L) and latter with 10%
acetonitrilerwater. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 80 mg, 18%; as yellow crystals; mp
240°C;(M+H+Na)412.
1H NMR (DMSOd6) ? 6.6 (s, 2H), 7.1 (s, 1H), 7.62 (dd, 1H), 8.11 (d, 1H), 8.2
(s, 1H),8.6(s,1H).
Example 4
Preparation of (5R),(6Z)-6-imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
lmidazo[1,2-a]quinoline-2-carbaldehyde
lmidazo[1,2-a]quinoline-2-carbaldehyde was prepared by the method of Westwood
and co-workers (J. Med. Chem. 1988, 31,1098-1115).
Step 1: (5R, 6RS)-6-[(RS)-Acetoxyimidazo[1,2-a]quinolin-2-ylmethyn-6-bromo-
7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl
ester:
lmidazo[1,2-a]quinoline-2-carbaldehyde (1.09 g) and a dry THF solution (75.5 mL)

of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-
nitro-benzyl ester (2.22 g) were added successively to a dry acetonitrile (75.5 mL)
solution of anhydrous MgBr2 (2.5 g) under an argon atmosphere at room
temperature. After cooling to -20 °C, Et3N (1.85 mL) was added in one portion. The
reaction vessel was covered with foil to exclude light. The reaction mixture was
stirred for 2 h at -20 °C and treated with acetic anhydride (1.04 mL) in one portion.
The reaction mixture was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture
was diluted with ethyl acetate and washed with 5% citric acid aqueous solution,
saturated sodium hydrogen carbonate, and brine. The organic layer was dried
(MgSO4) and filtered through a pad of Celite. The pad was washed with ethyl
acetate. The filtrate was concentrated under reduced pressure. The residue was
applied to a silica gel column, then the column was eluted with CHCI3-acetone(1/0 ~
95/5). Collected fractions were concentrated under reduced pressure followed by
recrystallization from CHCI3-Et2O to give the title compound as one isomer, (pale
yellow crystals, yield: 1.3 g, 38%).
1H NMR (CDCI3) ? 2.37(s, 3H), 5.29(d, 1H. J = 13.5 Hz), 5.45(d, 1H, J = 13.5 Hz),
6.22(s, 1H), 7.14(s, 1H), 7.46 - 7.52(m, 3H), 7.56(d, 1H, J= 9.6 Hz), 7.62(d, 2H, J =
8.6 Hz), 7.64 - 7.69(m, 1H), 7.83(dd, 1H, J = 1.1, 7.9 Hz), 7.93(d, 1H, J = 8.3 Hz),
. 7.99(s, 1H), 8.25(d, 2H, J= 8.6 Hz).
Step 2: (5R),(6Z)-6-imidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:
(5R,6RS)-6-[(RS)-Acetoxyimidazo[1,2-a]quinolin-2-ylmethyl]-6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (1.3 g) was
dissolved in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn dust (5.2 g)
was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The reaction vessel
was covered with foil to exclude light. The reaction mixture was vigorously stirred for
2 h at room temperature. The reaction mixture was filtered, cooled to 3 °C, and 1 N
NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate
and the aqueous layer was separated. The aqueous layer was concentrated under
high vacuum at 35 °C to give a yellow precipitate. The precipitate was filtered and
washed with H2O, acetonitrile, and acetone to give the title compound, yield 297 mg,
38%, as yellow crystals mp 205°C.

1H NMR (D2O) d 6.19(s, 1H), 6.36 (s, 1H), 6.87 (s, 1H), 6.96 (d, 1H, J = 9.5
Hz),7.32 (d, 1H, J = 9.5 Hz), 7.33 (s, 1H), 7.44 ~ 7.57 m, 4H).
Example 5
Preparation of (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-
b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.20]hept-2-ene-2-
carboxylic acid
Step 1: Preparation of ethyl 6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-
b][1,3]thiazole-2-carboxylate.
A mixture of 2-chlorocyclopentanone (11.8 g, 100 mmol) and thiourea (8.0 g 101
mmol) was refluxed in ethanol: THF (1:2) for 16 hrs. The reaction mixture was
cooled to room temperature and the separated white solid was filtered. (9.0 g
separated) This was dissolved in anhydrous ethanol (100 ml) and sodium methoxide
(2.7 g, 51 mmol). To this ethyl bromopyruvate (10 .0 g) was added and stirred at
room temperature for 2 hrs. Then it was refluxed for 48 hrs. At the end reaction
mixture was cooled to room temperature and concentrated. The residue was
extracted with chloroform and washed well with water. The product was purified by
silica-gel column chromatography by eluting it with 50% ethyl acetae: hexane. Red
semi-solid; Yield: 3.0 g; M+H 237.
The ester was reduced with LiAIH4 and the resultant alcohol was oxidized with active
MnO2. The aldehyde obtained was taken to next step.
Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(6,7-dihydro-5H-
cyclopenta[d]imidazo[2,1-b][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
2-Formyl-6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazole (600 mg, 3.1
mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.2 g, 3 mmol) were
added successively to the dry acetonitrile (15 mL) solution of anhydrous MgBr2:
O(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature. After

cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel was
covered with foil to exclude light The reaction mixture was stirred for 2 h at -20 °C
and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 850
mg, 45%; M+H 620.
Step 4: Preparation of (5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-
b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
4-nitrobenzyl (5R)-6-[(acetyloxy)(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-
b][1,3lthiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
(850 mg, 1.37 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL).
Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH
6.5, 28 mL). The reaction vessel was covered with foil to exclude light. The reaction
mixture was vigorously stirred for 2 h at room temperature. The reaction mixture
was filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5.
The filtrate was washed with ethyl acetate and the aqueous layer was separated.
The aqueous layer was concentrated under high vacuum at 35 °C to give a yellow
precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 138 mg, 29%; as yellow crystals; mp
192°C; (M+H+Na) 367 .1H NMR (DMSO-d6) ? 2.51 (m, 4H), 3.01 (m, 2H), 8.2 (s, 1H),
7.1 (s, 1H), 6.55 (s, 1H), 6.4 (s, 1H).

Example 6
Preparation of (5R),(6Z)-6-(imidazo[1 ,2-a]quinoxaline-2-ylmethylene)-7-oxo-4-
thia-1-azabicyclo[3.2.0] hepto-2-ene-2-carboxylic acid, sodium salt
lmidazo[1,2-a]quinoxaline-2-carboxaldehyde
lmidazo[1,2-a]quinoxaline-2-carboxaldehyde was prepared by the method, of
Westwood and co-workers (J. Med. Chem. 1998, 31, 1098-1115).
Step 1: (5R, 6RS)-6-((RS)-Acetoxy imidazo[1,2-a]quinoxalin-2-ylmethyl)-6-
bromo-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid p-
nitrobenzyl ester:
A dry acetonitrile (33 mL) solution of imidazo[1,2-a]quinoxaline-2-carboxaldehyde
(505 mg) was added to a dry acetonitrile (20 mL) solution of MgBr2 (1.1 g) under an
nitrogen atmosphere at room temperature, and the mixture was stirred for 10 min.
After addition of the dry THF (25 mL) solution of (5R, 6S)-6-bromo-7-oxo-4-thia-1-
aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (931 mg), the
mixture was cooled to -20 °C then triethylamine (0.8 mL) was added in one portion.
The reaction vessel was covered with foil to exclude light. The reaction mixture was
stirred for 4 h at -20 °C and treated with 4,4-dimethylamino pyridine (58 mg) and
acetic anhydride (0.44 mL) in one portion. The reaction mixture was warmed to 0 °C
and stirred for 16 h at 0 °C. 10% Citric acid aqueous solution (200 mL) was added to
the reaction mixture and the aqueous layer was extracted with ethyl acetate (3 x 100
mL). The organic layer was washed with water, saturated sodium hydrogen
carbonate and brine, dried (MgSO4) and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column chromatography,
eluted with CH2CI2 - acetone (50:1), and the title compound was obtained as a
diastereomeric mixture (78: 22, pale brown foamy amorphous, 1.0 g, 68.9%).
1H NMR (CDCI3) 5 2.07 (s, 0.66H), 2.38 (s, 2.34H), 5.30 (d, 1H, J = 13.5 Hz),
5.45 (d, 0.78H, J = 13.5 Hz), 5.48 (d, 0.22H, J = 13.5 Hz), 6.24 (s, 0.78H), 6.46 (s,
0.22H), 6.63 (s, 0.22H), 7.18 (s, 0.78H), 7.50 (s, 0.78H), 7.52 (s, 0.22H), 7.61 (d,
1.56H, J= 8.7 Hz), 7.63 (d, 0.44H, J= 8.8 Hz), 7.64-7.67 (m, 1H), 7.68-7.73 (m, 1H),

7.92-7.95 (m, 1H), 8.08 (s, 0.78H), 8.13-8.16 (m, 1H), 8.24 (d, 1.56H, J = 8.7 Hz),
8.25 (d, 0.44H, J = 8.8 Hz), 8.33 (s, 0.22H), 9.05 (s, 0.78H), 9.09 (s, 0.22H).
Step 2: (5R),(6Z)-(imidazo[1,2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0] hepto-2-ene-2-carboxylic acid, sodium salt;
(5R, 6RS)-6-((RS)-Acetoxy imidazo[1,2-a]quinoxalin-2-ylmethyl)-6-bromo-7-oxo-4-
thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (951 mg)
and 10% Pd-C (50% wet, 477 mg) were added to a mixture of THF (48 mL) and 0.5
mol/L phosphate buffer (pH 6.5, 48 mL). The mixture was hydrogenated at 400 kPa
at room temperature for 4 h. The reaction solution was filtered and Pd-C was
washed with water and n-butanol. The reaction mixture was cooled to 0°C and IN
NaOH was added to adjust the ph to 8.5. The aqueous layer was separated and then
the organic layer was extracted with water. The combined aqueous layer was
concentrated to 57 g and applied to Diaion HP-21 resin (60 mL, Mitsubishi Kasei Co.
Ltd.) column chromatography. After adsorbing, the column was eluted with water
and then 5,10,15 and 20% aceton'rtrile:water solution (each 60 mL). The combined
fractions were concentrated under high vacuum at 35 °C and lyophilized to give the
title compound as a yellow amorphous solid, yield 148 mg (26.1%), mp 300 °C (dec).
1H NMR (D2O) ? 5.92 (s, 1H), 6.23 (s, 1H), 6.66 (s, 1H), 7.11-7.22 (m, 3H), 7.25 (d,
1H. J = 7.9 Hz), 7.50 (s, 1H), 8.03 (s, 1H); IR (KBr) 3413,1748,1592,1553 cm-1; Imax
(H2O) 340, 293, 237, 218 nm.
Example 7
Preparation of (5R,6Z)-6-[(7-methylimidazo[2,1-b][1,3]benzothiazol-2-
ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Ethyl 7-methylimidazo[2.1-b]-benzthiazole-2-carboxylate:
Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to
the procedure as outlined in Example 1, (Step 1). Starting from 6-methyl-2-amino
I benzothiazole (3.2 g, 20 mmol) and ethyl bromopyruvate (4.0 g, 20.4 mmol), 3.0 g
(57% Yield) of ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated
as brown solid. (M+H) 261.

Step 2: 2-Formyl-7-methylimidazo[2,1-b]-benzthiazole:
To a stirred solution of Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxyIate (4.0
g, 15.38 mmol) in dry THF at -78°C, DIBAL (1M. solution in toluene) (16.0 ml, 16
mmol) was added. The reaction mixture was stirred at -78°C and slowly elevated to
room temperature. The reaction mixture was stirred at room temperature for 30
minutes and quenched with saturated NH4CI. The reaction mixture was extracted
with chloroform and washed well with water. The organic layer was dried over
anhydrous MgSO4; filtered and concentrated. The residue was purified bt SiO2
column chromatography by eluting it with chloroform: metrhanol (20:1). Brown solid;
(M+H) 217; Yield: 800 mg (24%)
Step 3: 4-Nitrobenzyl-6-[(acetyloxy) (7-methylimidazo[2,1-b][1,3]benzothiazol-
2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
2-Formyl-7-methylimidazo[2,1-b]-benzthiazole (432 mg, 2.0 mmol) and the dry THF .
solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (772 mg, 2.0 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2: O(Et)2 (566 mg, 2.0 mmol)
under an argon atmosphere at room temperature. After cooling to -20 °C, Et3N (2.0
mL) was added in one portion. The reaction vessel was covered with foil to exclude
light. The reaction mixture was stirred for 2 h at -20 °C and treated with acetic
anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C and
stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed with
5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and brine.
The organic layer was dried (MgSO4) and filtered through a pad of Celite. The pad
was washed with ethyl acetate. The filtrate was concentrated under reduced
pressure. The residue was applied to silica gel column chromatography, then the
column was eluted with ethyl acetate: hexane (1:1). Collected fractions were
concentrated under reduced pressure and the mixture of diastereomers were taken
to the next step. Pale yellow amorphous solid; Yield: 400 mg, 31%; M+H 645.
Step 4: (5R),(6Z)-6-[(7-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)]-
7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy)(7-methylimidazo[2,1 -b][1,3]benzothiazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 350 mg, 0.54

mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly activated Zn
dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The
reaction vessel was covered with foil to exclude light. The reaction mixture was
vigorously stirred for 2 h at room temperature. The reaction mixture was filtered,
cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was
washed with ethyl acetate and the aqueous layer was separated. The aqueous layer
was concentrated under high vacuum at 35 °C to give a yellow precipitate. The
product was purified by HP21 resin reverse phase column chromatography. Initially
the column was eluted with deionized water (2 L) and latter with 10%
acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 110 mg, 55%; as yellow crystals; mp
178°C (Dec); (M+H+Na) 392.
1H NMR (DMSO-d6) ? 8.56 (s, 1H), 7.93 (d, 1H), 7.83 (s, 1H), 7.38 (d, 1H),
7.07 (S, 1H), 6.51 (s, 2H), 2.42 (s, 3H).
Step 4: (5R),(6Z)-6-[(7-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)] -
7-oxo-4-thia-1-azabicyclo [3,2,0]hept-2-ene-2-carboxylic acid: (Procedure B)
4-Nitrobenzyl-6-[(acetyloxy)(7-methylimidazo[2,1 -b][1,3]benzothiazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyIate ( 350 mg, 0.54
mmol) was dissolved in THF (40 mL) and 6.5 pH phosphate buffer (40 ml) and
hydrogenated over Pd/C (10% , 200 mg) at 40 psi pressure for 3 hrs at room
temperature. At the end , reaction mixture was filtered through a pad of celite and
washed with acetonitrile. The reaction mixture was concentrated to 40 ml and
cooled to 0° C and pH was adjusted to 8.5 by adding 1N NaOH. The product was
directly loaded over HP21 resin reverse phase column chromatography. Initially the
column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water.
The fractions were concentarated and the yellow solid was washed with acetone,
filtered and dried. Yield: 110 mg, 55% as yellow solid.

Example 8
Preparation of (5R), (6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-
cyclopenta[a]indene-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3,2,0]hept-2-
ene-2-carboxylic acid sodium salt
Step 1:5.6.7.8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine
The 12.7% solution of HCI in ethanol (5.35 mL) and 10% Pd-C (50% wet)
(2.5 g) were added to the mixture of [1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.5 g) in
ethanol (72 mL). The reaction mixture was hydrogenated at 400 KPa of H2 for 3
days at room temperature. The mixture was filtered and concentrated under
reduced pressure. The residue was treated with saturated potassium carbonate
solution and extracted with chloroform. The organic layer was dried (Na2SO4) and
concentrated under reduced pressure. The title compound was obtained as a pale
yellow solid (2.31 g, 90%). 1H-NMR (400 MHz, CDCI3) ? 1.88-1.94 (m, 2H), 1.98-
2.05 (m, 2H), 2.77 (t, 2H, J = 6.2 Hz), 3.95 (t, 2H, J - 6.2 Hz), 4.09 (brs, 2H).
Step 2: 4.5.6.7-Tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carboxylic
acid ethyl ester
Ethyl bromopyruvate (10.23 g) was added to the mixture of 5,6,7,8-
tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (5.8 g) in 1,2-dimethoxyethane (320
mL). The reaction mixture was stirred for 5 hours at room temperature and
concentrated to 100 mL under reduced pressure. The precipitate was obtained by
an addition of diethyl ether (200 mL), followed by filtration. The precipitate was
dissolved in ethanol (175 mL) and stirred for 20 hours at 110 °C in shield tube. The
reaction mixture was cooled to room temperature and concentrated under reduced
pressure. The residue was treated with saturated potassium carbonate solution and
extracted with chloroform. The organic layer was dried (Na2SO4) and concentrated
under reduced pressure. The residue was applied to silica gel column
chromatography, then eluted with ethyl acetate - methanol (1/1). The title
compound was obtained as a pale yellow solid (7.56 g, 77%). 1H-NMR (400 MHz,

CDCl3) ? 1.42 (t, 3H, J = 7.1 Hz), 2.14-2.25 (m, 4H), 3.11 (t, 2H, J = 6.1 Hz), 4.37 (t,
2H, J = 5.7 Hz), 4.41 (q, 2H, J = 7.1 Hz), 7.57 (s, 1H).
Step 3:4,5,6,7-Tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-
carbaldehyde
1.01 M Diisobutylalminium hydride in toluene (1.06 mL) was added dropwise
to the solution of 4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-
carboxylic acid ethyl ester (100 mg) in dry THF (5 mL) at -78 °C under a nitrogen
atmosphere. The reaction mixture was stirred for 30 minutes at -78 °C and treated
with ethanol (ca. 1 mL). The mixture was warmed to 0 °C and stirred for 1 h at 0 °C.
The reaction solution was diluted with ethyl acetate (20 mL), treated with 0.5 mL
saturated ammonium chloride solution, and sonicated for ca. 5 minutes (until a
precipitate was deposited enough). The mixture was dried (Na2SO4) and filtered
through a pad of Celite. The filtrate was concentrated under reduced pressure.
The residue was crystallized from dichloromethane and diethyl ether to give the title
compound (47.4 mg, 58%). 1H-NMR (400 MHz, CDCI3) ? 2.16-2.27 (m, 4H), 3.14
(t, 2H, J = 6.1 Hz), 4.39 (t, 2H, J = 5.7 Hz), 7.53 (s, 1H), 10.01 (s, 1H).
Step 4: (5R, 6RS)-6-[(RS)-Acetoxy-[4,5,6,7-tetrahydro-1,3a,3b.8-tetraaza-
cyclopenta[a] indene-2-yl]-methyl]-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester
4,5,6,7-Tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-carbaldehyde
(2.97 g) was added to the dry acetonitrile (110 mL) solution of anhydrous MgBr2
(4.45 g) under a nitrogen atmosphere at room temperature. The dry THF solution
(110 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (2.97 g) was added to the reaction mixture,
cooled to -20 °C, and triethylamine (6.45 mL) was added in one portion. The
reaction vessel was covered with foil to exclude light. After the mixture was stirred
for 1.2 h at -20 °C, acetic anhydride (2.9 mL) was added in one portion. The
reaction mixture was warmed to 0 °C and stirred for 16.5 h at 0 °C. The mixture
was diluted with ethyl acetate and washed with H2O and brine. The organic layer
was dried (MgSO4) and filtered through a pad of Celite. The pad was washed with
ethyl acetate. The filtrate was concentrated under reduced pressure. The residue

was applied to silica gel column chromatography, eluted with ethyl acetate - n-
hexane (3/1) and then with ethyl acetate - methanol (5/1). The title compound was
obtained as a brown amorphous solid (651.6 mg, 13%). 1H-NMR (400 MHz, CDCI3)
? 2.10-2.24 (m, 4H), 2.29 (s, 3H), 3.04-3.07 (m, 2H), 4.28-4.32 (m, 2H), 5.27 (d, 1H,
J= 13.7 Hz), 5.43 (d, 1H, J= 13.7 Hz), 6.19 (s, 1H), 6.91 (s, 1H), 7.01 (s, 1H), 7.49
(s, 1H), 7.59-7.62 (m, 2H), 8.23-8.25 (m, 2H).
Step 5: (5R), (6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-
2-ylmethylene)-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
sodium salt
(5R, 6RS)-6-{(RS)-Acetoxy-[4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-
cyclopenta[a]indene-2-yl]-methyl}-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-
ene-2-carboxylic acid 4-nitro-benzyl ester (643.6 mg) was dissolved in THF (9 mL)
and acetonitrile (4.2 mL). Freshly activated Zn dust (2.57 g) and 0.5 M phosphate
buffer (pH 6.4,13.2 mL) were added to the reaction mixture. The reaction vessel
was covered with foil to exclude light. The mixture was vigorously stirred for 2 h at
room temperature. The mixture was cooled to 3 °C, and 1 N NaOH aqueous
solution was added to adjust pH to 7.5. The reaction solution was mixed with ethyl
acetate and filtered through a pad of Celite. The pad was washed with water. The
aqueous layer was concentrated to 20 mL under high vacuum at 35 °C. The
concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin
column chromatography. After adsorbing, the column was eluted with water and
then with 2.5-10% acetonitrile-water. The combined fractions was concentrated
under high vacuum at 35 °C and lyophilized to give the title compound as a yellow
amorphous solid (68 mg, 18%, pH 7.4). Mp 175 °C (dec); 1H-NMR (400 MHz,
D2O) ? 1.85-2.03 (m, 4H), 2.85-2.99 (m, 2H), 4.07-4.14 (m, 2H), 6.34 (s, 1H), 6.74 (s,
1H),6.76(s, 1H),7.28(s, 1H).

Example 9
Preparation of (5R,6E)-6-[(10-benzyl-11-oxo-10,11-
dihydrodibenzo[b,f][1,4]oxazepin-8-yl)methylene]-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic
Acid
Step 1: Preparation of 8-(hydroxymethy)dibenzo[b,f][1,4]oxazepin-11(10H)-
one.
Lithium aluminum hydride (11 mL, 11 mmole) was slowly added to the solution of 11-
Oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carboxylic acid methyl ester (1.346
g, 5 mmole) in THF under N2 at room temperature. The reaction mixture was stirred
for 1hour and 45 minutes then quenched with 2N of HCi until the pH value reaches
2-3. Removed all the THF by rotary evaporation, and extracted the reaction mixture
with ethyl acetate for five times, dried the organic layer with sodium sulfate and
filtered and concentrated. Obtained the desired compound (white solid) in 46% yield.
Step 2; Preparation of 11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-
carbaldehyde.
8-(hydroxymethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (0.241 g, 1 mmole) in
acetonitrile was added to the molecular sieves (1 g) under N2 at room temperature
then 4-methylmorpholine N-oxide (0.175 g, 1.5 mmole) was also added into the
reaction mixture. After stirring the mixture for 10 minutes, tetrapropylammonium
perruthenate (0.0176 g, 0.05 mmole) was added and the reaction followed by t.l.c.
until complete. Dilute the reaction mixture with 10ml of ethyl acetate and flashed it
through a small silica gel column. Collected all the ethyl acetate that contains
desired material, extracted the organic layer with 1N HCI and also washed it with
brine. Dried the organic layer over sodium sulfate and filtered and concentrated.
Obtained the desired.compound (white solid) in 83% yield.
Step 3: Preparation of 10-benzyl-11-oxo-10,11-dihydro-
dibenzo[b,f][1,4]oxazepine-8-carbaldehyde:

Potassium carbonate anhydrous (0.207g, 1.5 mmole) and benzyl bromide (0.205 g,
1.2 mmole) were added to a solution of the 11-oxo-
10,11dihydrodibenzo[b,f][1,4]oxazepine-8-carbaidehyde (0.240 g, 1 mmole) in
acetonitrile under N2 at room temperature. The reaction mixture then was refluxed
for 4 hours, and cooled to room temperature. Diluted the reaction mixture with ethyl
acetate and filtered through a magnesol pad and concentrated. Purified with silica
gel column and 50% ethyl acetate in hexane. Obtained the desired compound (light
yellow oil) in 63% yield.
Step 4: Preparation of 6-[acetoxy-(10-benzyl-11-oxo-10,11-dihydro-
dibenzo[b,f][1,4]oxazepin-8-yl)-methyl]-6-bromo-7oxo-4-thia-1 -aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester;
10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carbaldehyde (0.250 g,
0.759 mmole) in acetonitrile was added to magnesium bromide (0.419 g,
2.28mmole) under N2 at room temperature. The dry THF solution of (5R,6S)-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl
ester (0.292 g, 0.758 mmole) then was added to the mixture. After 15 minutes the
reaction mixture was cooled to -20°C, and triethylamine (0.317 mL, 2.27 mmole)
was added. The reaction flask was covered with foil to exclude light After 4 hours
at -20°C, treated with acetic anhydride (0.358 mL, 3.795 mmole) and DMAP
(0.00927 g, 0.0759 mmole). Warmed up the reaction mixture to 0°C and placed it in
freezer overnight. Reaction solution was concentrated and dissolved with ethyl
acetate and washed with 5% of citric acid aqueous solution, saturated NaHCO3,
water and brine. Organic layer was dried in.sodium sulfate and filtered and
concentrated. Purified with silica gel column and 1:15 ethyl acetate/CH2CI2.
Obtained the desired compound (light yellow oil) in 41% yield.
Step 5; Preparation of 6-(10-benzyl-11-oxo-10,11-dihydro-
dibenzo[b,f][1,4]oxazepin-8-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-
2-ene-2-carboxylic acid, sodium salt;
A 0.5M phosphate buffer solution (pH 6.5) was added to a solution of 6-[acetoxy-( 10-
benzyM 1 -oxo-10,11 -dihydro-dibenzo[b,f][1,4]oxazepin-8-yl)-methyl]-6-bromo-7oxo-
4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (0.210 g,

0.273 mmole) in THF, followed by 10% Pd-C (0.0546 g). The reaction mixture then
was hydrogenated at 40psi for three hours. Filtered through a celite pad and
removed the THF by rotary evaporation, extracted the mixture with ethyl acetate and
washed with water and brine. Dried the organic layer with sodium sulfate and filtered
and concentrated. Dissolved the NaHCO3 with minimal amount of distal water and
added it to the reaction mixture along with a small amount of ethyl acetate until the
pH value reaches 7-8, evaporated the ethyl acetate. Purified with reverse phase
column (MCI Gel CHP20P) with varying amounts of acetonitrile (0%-20%) in water.
Removed the acetonitrile and water by rotary evaporation, and freeze-dried the
compound. Obtained the desired material (yellow solid) in 24% yield.Mp: 179°C. 1H
NMR (DMSO) ? 1.755-1.825 (s, 1H), 2.497-2.506 (d, 2H), 5.243-5.434 (m, 2H),
6.516-6.770 (m, 1H), 7.039-7.792 (m, 11H).
Example 10
Preparation of 6-(5-ethoxy-7,8-dihydro-6H-3.4.8b-triaza-as-indacen-2-
ylmethylene)-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Preparation of 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine
(SM:Ross, L O.; Goodman, L; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108)
5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved
in 200ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodium ethoxide was
added and the mixture was refluxed for 3 hours. Then the solvent was removed in
vacuo and 100ml water was added to the residue. Filter and wash the cake with
water (50ml). The solid was further vacuumed to dry for several hours. The desired
product weighed 5.3 gram (98% yield). Mp: 133.8-134.9 oC.
H-NMR: (300 MHz, CDCI3) ?. 6.23(s, NH2), 4.28(quartet, 2H, J= 6.9 Hz), 2.6 (m, 2H),
1.93 (m, 2H), 1.27 (t, CH3, J=6.9 Hz); MS: 180.0 (M+H)
Step 2: Preparation of 5-Ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carboxylic acid ethyl ester

5.2 gram (29mmol) 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was
dissolved in 100 ml dry THF. Bromopyruvate (5.4ml,) was then added dropwise with
in five minutes. The mixture was stirred at 23oC for one hour. It was then filtered
and washed with ether to give 8.7 gram of solid. This solid was then dissolved in
50ml ethanol and refluxed for two hours. The reaction mixture was cooled to room
temperature and partitioned between 350ml chloroform and 200 ml saturated sodium
bicarbonate. The organic layer was separated and dried over magnesium sulfate.
Filter off the drying agent and concentrate to give 6.5 gram of product.
MP: 168.6-168.7 oC.
H-NMR: (300 MHz, CDCI3) ?. 7.69(s, 1H), 4.50 (qartet, 2H, J=7.2 Hz), 4.40 (qartet,
2H, J=7.2 Hz), 3.11 (t, 2H, J=9.6 Hz), 2.88 (t, 2H, J=9.6 Hz). 2.88 (m, 2H), 1.43 (t,
2H, J=7.2 Hz).; MS: 276.2(M+H)
Step 3: Preparation of 5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carbaldehyde
1.925 grams 5-ethoxy-7, 8-dihydro-6H-3,4,8b-triaza-as-indacene-2-carboxylic acid
ethyl ester was dissolved in 40 ml dichloromethane and then cooled to -78oC.
DIBAL (1 M, 21 ml, 3 eq.) was then added within five minutes. The reaction media
was then quenched with 2ml ethanol and partitioned between 350ml
dichloromethane and 100 ml 1 N sodium hydroxide. The aqueous layer was washed
with another 150ml chloroform and the combined organic layer was dried over.
magnesium sulfate and filtered and concentrated to give the corresponding alcohol.
The alcohol is then dissolved in 150ml dichloromethane and 10 grams of manganese
dioxide is then added. The mixture was stirred at 23 oC for two hours. The reaction
mixture was then filtered through a pad of celite and concentrated to give 1.1 gram
(68%) of the desired aldehyde.
MP: 237.2-237.3° C
H-NMR: (300 MHz, CDCI3) ?. 9.94(s, 1H, CHO), 8.39 (s, 1H), 4.46 (quartet, 2H, J=
7.2Hz), 3.2 (m, 2H, CH2), 2.85 (m, 2H, CH2), 2.24 (m, 2H, CH2), 1.38 (t, 3H, CH3,
J=7.2Hz); MS: 232.1(M+H)

Step 4: Preparation of 6-[acetoxy-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-
fndacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bIcyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester
A 30 ml acetonitrile solution of 5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carbaldehyde (693 mg, 3mmol) was added 1.03 gram of magnesium bromide
etherate. The mixture was stirred at 23oC for half an hour. Then a 30ml dry THF
solution of the 6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitro-benzyl ester (1.155 gram, 1 eq.) was injected within a minute and the reaction
mixture was then cooled to -20oC. Triethylamine (0.7 ml, eq.) was then injected and
the reaction mixture was stirred for five hours at -20oC. Then acetic anhydride
(0.377 ml, eq.) was injected and the reaction mixture was left at zero degree for 18
hours. The reaction media was then diluted with 400ml ethyl acetate and washed
with 100 ml 5% citric acid, 100 ml saturated sodium bicarbonate, and 100ml brine.
The organic layer was then dried over magnesium sulfate, filtered and concentrated.
Rash column chromatography using 20% ethyl acetate in hexane gave 1.1 gram
product.
MP: 118.7-119.1 °C
H-NMR: (300 MHz, CDCI3) ?. 8.35(d, 2H, J=11Hz), 7.63 (m, 2H), 7.41 (d, 1H,
J=6.9Hz), 7.08 (d, 1H, J=11Hz), 6.47(s, 1H), 5.55 (4H, CH2), 4.54 (m, 2H), 3.09 (m,
2H), 2.93 (m, 2H), 2.32 (m, 2H), 1.41 (t, J=9.6Hz); MS: 660.1 (M+H)
Step 5: Preparation of 6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-
ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
6-[acetoxy-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-
7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester
(1.03 gram, 1.565 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous
phosphate buffer. The mixture was then subjected to 45psi hydrogen for two hours.
Then it was filtered through a pad of celite and concentrated in vacuo to remove
most of the THF. The solution was then cooled to zero degree and basified to pH=8
with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1
liter of water followed by 5% ~25% acetonitrile and water. Water was then removed

through concentrate in vacuo and 100 mg of product was collected.
MP: >250° C
H-NMR: (300 MHz, CDCI3) ?. 7.52 (s, 1H), 6.95(s, 1H), 6.54(s, 1H), 4.73 (m, 2H),
3.06(m, 2H), 2.84 (m, 2H), 2.27 (m, 2H), 1.43 (t, 3H); MS: 383.2 (M+H).
Example 11
(5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1 -c][1,4]benzoxazepin-2-ylmethylene)-4-
thia-1-azablcyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1: Preparation of 1-(2-fluorobenzyl-1H-pyrazole-3,5-dicarboxylate
2-fluorobenzyl bromide (2.0 ml, 16.58 mmol) was added to a mixture of diethyl 3,5-
pyrazoledicarboxylate (3.01 g, 14.18 mmol), Cs2CO3 (5.57 g, 17.1 mmol), and
acetonitrile (140 ml) under N2. Heated to 60°C for two hours and then cooled to room
temperature. Filtered and concentrated the reaction solution. Added water (~200mL)
to the resulting residue and extracted with EtOAc. Washed organics with water and
brine. Dried organics over sodium sulfate and filtered and concentrated. Obtained
diethyl 1-(2-fluorobenzyl)-1H-pyrazole-3,5-dicarboxylate (light-yellow oil) in
quantitative yield.
Step 2: Preparation of 1-(2-fluorobenzyl)-1H-pyrazole-3,5-methanediol
A 1M solution of DIBAL-H in THF (90 ml, 90 mmol) was added to a solution of diethyl
1-(2-fluorobenzyl)-1H-pyrazole-3,5-dicarboxylate (4.80 g, 14.99 mmol) in CH2CI2 (90
ml) at 0°C under N2. After two hours quenched with NH4CI(aq) and suspension was
formed. Filtered and extracted with EtOAc and washed with brine. Dried organics
over sodium sulfate and filtered and concentrated. Purified with silica gel column and
5% MeOH in CH2CI2. Obtained 3.4 g of the diol compound (clear oil) in 96% yield.
Step 3: Preparation of 4H,10H-pvrazolo[5,1-c][1.4]benzoxazepine-2-
carbaldehyde
The diol compound (3.83 g, 16.21 mmol) in HMPA (24 ml) was added to a
suspension of NaH (60%, 1.34 g, 33.5 mmol) in toluene (330 ml) under N2. Rapidly
heated to 95°C for three hours and cooled to room temperature. Quenched with

water and extracted with EtOAc. Washed organics with water and brine. Dried
organics over sodium sulfate and filtered and concentrated. Purified with silica gel
column and 2% MeOH in CH2CI2. Obtained 4H,10H-pyrazolo[5,1-
c][1,4]benzoxazepin-2-ylmethanol (white solid). Yield: 0.71 g 20%.
4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (0.71 g, 3.28 mmol), 4-
methylmorpholine N-oxide (1/198g, 10.23 mmol), molecular sieves (powder, 4
angstroms) (3.32 g), and acetonitrile (0.07M) were placed together under N2.
Tetraptopylamrnoniumperruthenate (0.113 g, 0.322 mmol) was added and after
three hours the reaction solution was filtered through celite and concentrated.
Purified with silica gel column and 1:1 EtOAc/Hexane. Obtained 4H,10H-
pyrazoto[5,1-cl[1,4]benzoxazepine-2-carbaldehyde (white solid). Yield: 0.31 g 44%.
Step 4: Preparation of Preparation of 6-[acetoxy-(4H,10H-pyrazolo[5,1-
c][1,4]benzoxazepine-8-yl)-methyl]-6-bromo-7oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester:
4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde (0.19 g, 0.887 mmol) in
acetonitrile (14 ml) was added to MgBr2 (0.49g, 2.66 mmol) under N2. After 25
minutes 6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-
nitro-benzyl ester (0.342g, 0.888 mmol.) in THF (14 ml) was added. After 15
minutes the reaction was cooled to -20°C. Ten minutes later added Et3N (3eq) and
placed reaction in the dark. After 6.5 hours added Ac2O (0.42 ml, 4.45 mmol) and
DMAP (0.011g, 0.0900 mmol). Warmed to 0°C and placed in freezer overnight.
Reaction solution was concentrated and resulting residue was taken up in EtOAc
Washed with 5% citric acid(aq) and saturated NaHCO3(aq). Further washed with water
and brine. Dried organics over sodium sulfate and filtered and concentrated. Purified
with silica gel prep plates and 1:2 EtOAc/Hexane. Obtained the condensation
product (yellow gum/solid). Yield: 0.31 g, 54% yield.
Step 5: (5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-
ylmethylene)-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium
salt:
Step 6: A 0.5M phosphate buffer solution (pH 6.5) (18mL) was added to a solution of

the condensation product (5) (0.300g, 0.468mmol) in THF (18mL). The Pd on
Carbon (0.102g) was added and the reaction mixture was hydrogenated at 40psi for
two hours. Filtered through celite and removed THF by rotary evaporation. Extracted
with EtOAc. Dried organics over sodium sulfate and filtered and concentrated.
NaHCO3 (0.08g, 0.952mmol) was dissolved in a minimal amount of water and added
to the concentrated organics along with a small amount of EtOAc. Filtered and
removed EtOAc by rotary evaporation. Purified with reverse phase column (MCI Gel
CHP20P) and varying amounts of acetonitrile (0% to 15%) in water. Removed the
acetonitrile and most of the water from the collected fractions by rotary evaporation.
Freeze-dried the rest to obtain 41mg of (5R,6E)-7-oxo-6-(4H,10H-pyrazolo[5,1-
c][1,4]benzoxazepin-2-ylmethylene)-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt (6) (yellow solid) in 22% yield. HPLC found the purity to
be 77% and the E/Z isomer ratio to be 3:2.1H-NMR (?, DMSO-d6) 5.366 (m, 4H),
5.649 (m, 4H), 6.326 (t, 2H), 6.444 (s, 2H), 6.551 (s, 2H), 6.640 (s, 2H), 6.810 (s,
2H), 6.974 (m, 2H), 7.249 (m, 2H), 7.355 (m, 2H). m/z (M+H)390.0
Example 12-
(5R), (6Z)-6-(5H-imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt
Step 1: Preparation of 5H-imidazo[2,1-a]isoindole-2-carbaldehyde
The solution of 2-bromo-3-isopropoxy-propenal (4.97 g) in dry acetonitrile (3
mL) was added to the mixture of 3-amino-1H-isoindole (3.4 g) in dry acetonitrile (100
mL). The reaction mixture was stirred for 3.25 h at room temperature. Then
triethylamine (3.6 mL) was added to the mixture and heated to reflux for 2 h. The
mixture was cooled to room temperature, diluted with ethyl acetate, and washed with
20% potassium hydrogen carbonate. After filtration through a pad of Celite, the
organic layer was dried (MgSO4) and concentrated under reduced pressure. The
residue was applied to silica gel column chromatography, then eluted with ethyl
acetate - hexane (3/1 ~ 4/1). The crude compound was crystallized from ethyl
acetate and n-hexane to give the title compound (1.04 g, 22%). 1H NMR (400 MHz,
CDCI3) ? 5.01 (s, 2H), 7.28-7.52 (m, 3H), 7.90 (s, 1H), 7.91-7.93 (m, 1H), 9.92 (s,
1H).

Step 2: Preparation of (5R, 6RS)-6-[(RS)-acetoxy-[5H-imidazo[2,1-a]isoindol-2-
yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclor3.2.01hept-2-ene-2-carboxylic
acid 4-nitro-benzyl esten
5H-imidazo[2,1-a]isoindole-2-carbaldehyde (736.8 mg) was added to the
dry acetonitrile (50 mL) solution of anhydrous MgBr2 (1.8 g) under a nitrogen
atmosphere at room temperature. The dry THF solution (50 mL) of (5R, 6S)-6-
bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-ntoro-benzyl
ester (1.55 g) was added to the reaction mixture, cooled to -20 °C, and
triethylamine (1.34 mL) was added in one portion. The reaction vessel was covered
with foil to exclude light. The mixture was stirred for 2 h at -20 °C and treated with
acetic anhydride (0.76 mL) in one portion. The reaction mixture was warmed to 0
°C and stirred for 18 h at 0 °C. The mixture was diluted with ethyl acetate and
washed with H2O, saturated sodium hydrogen carbonate, and brine. The organic
layer was dried (MgSO4) and filtered through a pad of Celite. The pad was washed
with ethyl acetate. The filtrate was concentrated under reduced pressure. The
residue was applied to silica gel column chromatography, then eluted with ethyl
acetate - hexane (2/3 ~ 1/1). The title compound was obtained as two diastereo
mixture (5/1, a pale yellow amorphous solid, 1.8 g, 73%). 1H NMR (400 MHz,
CDCI3) ? 2.02 (s, 0.84 x 3H), 2.27 (s, 0.16 x 3H), 4.89-4.94 (m, 2H), 5.29 (d, 1H, J =
13.6 Hz), 5.47 (d, 1H, J= 13.6 Hz), 6.18 (s, 0.16 x 1H), 6.40 (s, 0.84 x 1H), 6.42 (s,
0.84 x 1H), 6.94 (d, 0.16 x 1H, J = 0.9 Hz), 7.18 (d, 0.16 x 1H, J = 0.7 Hz), 7.35-7.48
(m, 3H), 7.51 (s, 0.84 x 1H), 7.60-7.64 (m, 2H), 7.79-7.83 (m, 1H), 8.23-8.27 (m,
2H).
Step 3: (5R), (6Z)-6-(5H-imidazo[2,1-a]isoindol-2-ylmethylene)-7-oxo-4-thia-1-
aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt
(5R, 6RS)-6-[(RS)-Acetoxy-(5H-imidazo[2,1 -a]isoindol-2-yl)-methyl]-6-
bromo-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl
ester (1.5 g) was dissolved in THF (21 mL) and acetonitrile (9.8 mL). Freshly
activated Zn dust (6 g) and 0.5 M phosphate buffer (pH 6.4, 30.8 mL) were added to
the reaction mixture. The reaction vessel was covered with foil to exclude light.
The mixture was vigorously stirred for 2 h at room temperature. The mixture was

cooled to 9 °C, and 1 M NaOH aqueous solution was added to adjust pH to 7.5.
The reaction solution was mixed with ethyl acetate and filtered through a pad of
Celite. The pad was washed with water and the aqueous layer was separated.
The aqueous layer was concentrated to 25 mL under high vacuum at 35 °C. The
concentrate was applied to Diaion HP-21 (100 mL, Mitsubishi Kasei Co. Ltd.) resin
column chromatography. After adsorbing, the column was eluted with water and
then with 5-15% acetonitrile-water. The combined fractions was concentrated under
high vacuum at 35 °C and lyophilized to give the title compound as a yellow
amorphous solid (527 mg, 58%). Mp 170 °C (dec); 1H NMR (400 MHz, D2O) ? 4.62
(s, 2H), 6.27 (s, 1H), 6.56 (s, 1H), 6.78 (s, 1H), 7.22-7.31 (m, 4H), 7.52 (d, 1H, J =
6.7 Hz).
Example 13
Preparation of (5R,6Z)-6-[(5-methylimidazo[2,1-b][1,3]benzothiazol-2-
ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Step 1: Ethyl 5-methylimidazo[2.1-b]-benzthiazole-2-carboxylate:
Ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to
the procedure as outlined in Example 1, (Step 1). Starting from 4-methly-2-amino
benzothiazole (8.0 g, 48.7 m.mol) and ethyl bromopyruvate (14.0 g, 71.7 mmol), 6.0
g (45% Yield) of ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was
isolated as a brown solid. (M+H) 261.
Step 2: 5-methyl imidazo[2.1-b]-benzthiazole-2-methanol:
5-methyl imidazo[2,1-bl-benzthiazole-2-methanol was prepared according to the
procedure outlined in Example 1, (Step 2). Starting from ethyl 5-methylimidazo[2,1-
b]-benzthiazole-2-carboxylate (5.2 g, 20 mmol) and LiAIH4 solution (22 ml, 0.5 M
solution in THF), 3 g (69% yield) of the alcohol derivative was isolated as a brown
solid. (M+H) 219.
Step 3: 2-Formyl-5-methylmidazo[2.1-b]-benzthiazole:
2-Formyl-5-methylimidazo[2,1-b]-benzthiazole was prepared according to the
procedure outlined in Example 1, (Step 3). Starting from 5-methyl imidazo[2,1-b]-

benzthiazole-2-methanol (2.0 g 9.1 mmol) in methylene chloride/ DMF(300 mL: 50
mL) and active MnO2 (12 g, excess), 700 mg (35% Yield) of the aldehyde derivative
was isolated as brown solid. (M+H) 217.
Step 4: 4-Nitrobenzyl-6-[(acetyloxy) (5-methylimidazo[2,1-b][1,3]benzothiazol-
2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
2-Formyl-5-methylimidazo[2,1-b]-benzthiazole (432 mg, 2.0 mmol) and the dry THF
solution (40 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (770 mg, 2 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2:etherate (1.3 g, 5mmol)
under an argon atmosphere at room temperature. After cooling to -20 °C, Et3N (2.0
mL) was added in one portion. The reaction vessel was covered with foil to exclude
light. The reaction mixture was stirred for 2 h at -20 °C and treated with acetic .
anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C and
stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed with
5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and brine.
The organic layer was dried (MgSO4) and filtered through a pad of Celite. The pad
was washed with ethyl acetate. The filtrate was concentrated under reduced
pressure. The residue was applied to a silica gel column, then the column was
eluted with ethyl acetate: hexane (1:1). Collected fractions were concentrated under
reduced pressure and the mixture of diastereo isomers were taken to next step.
Pate yellow amorphous solid; Yield: 270 mg, 20%; M+H 644.
Step 5: (5R).(6Z)-6-[(5-methylimidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)] -
7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy) (5-methylimidazo[2,1 -b][1,3]benzothiazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 400 mg, 0.62
mmol) was dissolved in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn
dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The
reaction vessel was covered with foil to exclude light. The reaction mixture was
vigorously stirred for 2 h at room temperature. The reaction mixture was filtered,
cooled to 3 °C, and 1 N NaOH was added to adjust pH to 8.5. The filtrate was
washed with ethyl acetate and the aqueous layer was separated. The aqueous layer

was concentrated under high vacuum at 35 °C to give yellow precipitate. The
precipitate was filtered and washed with H2O, MeCN, acetone to give the title
compound. Yield: 60 mg, 24%; as yellow crystals; mp 192; M+Na 392.
1H NMR (DMSO-d6) ? 2.1 (s, 3H), 6.53(s, 2H), 7.1(s, 1H), 7.34-7.36 (m, 2H),
7.85(m, 1H),8,58(s,1H).
Example 14
Preparation of (5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-
ylmethylene)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-
Step 1: Ethyl 7-fluoroimidazo[2,1-b]-benzthiazole-2-carboxylate:
Ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to
the procedure as outlined in Example 1, (Step 1). Starting from 6-fluoro-2-amino
benzothiazole (10.0 g, 59.5 m.mol) and ethyl bromopyruvate (17.4 g, 89.2 mmol), 3.0
g (19% Yield) of ethyl 7-fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate was
isolated as a brown semi-solid. (M+H) 265.
Step 2: 7-fluoro- imidazo[2,1-b]-benzthiazole-2-methanol:
7-Fluoro-imidazo[2,1-b]-benzthiazole-2-methanol was prepared starting from Ethyl 7-
fluoro-imidazo[2,1-b]-benzthiazole-2-carboxylate (2.64 g, 0.01 mol) and LiBH4 (50
mg) in THF at refluxing temperature for 2 hrs. at the end, reaction mixture was
quenched with ice cold water and acidified with 10 N. HCI. Reaction mixture was
stirred for 1 hr and nuetralized with K2CO3. The separated residue was extracted
with chloroform: methanol (3:1) and dried over anhydrous MgSO4. It was filtered and
concentrated. The crude reaction mixture was found to be pure and taken to next
step with out any purification. Yeild: 1.5 g (68%) Semi solid; M+H 223.
Step 3: 2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole:
2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole was prepared according to the
procedure outlined in Example 1, (Step 3). Starting from 7-fluoro-imidazo[2,1-b]-
benzthiazole-2-methanol (1.5 g 6.7 mmol) in methylene chloride/ DMF(300 mL: 50
mL) and active MnO2 (12 g, excess), 1.1 g (78% Yield) of the aldehyde derivative
was isolated as brown solid. (M+H) 221.

Step 4: 4-Nitrobenzyl-6-[(acetyloxy) (7-fluoro-midazo[2,1-b][1,3]benzothiazol-2-
yl)methyn-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole (500 mg, 2.3 mmol) and the dry THF
solution (40 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxyiic acid 4-nitro-benzyl ester (875 mg, 2.3 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2:etherate (1.3 g, 5mmol)
under an argon atmosphere at room temperature. After cooling to -20 °C, Et3N (2.0
mL) was added in one portion. The reaction vessel was covered with foil to exclude
light. The reaction mixture was stirred for 2 h at -20 °C and treated with acetic
anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C and
stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed with
5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and brine.
The organic layer was dried (MgSO4) and filtered through a pad of Celite. The pad
was washed with ethyl acetate. The filtrate was concentrated under reduced
pressure. The residue was applied to a silica gel column, then the column was
eluted with ethyl acetate: hexane (1:1). Collected fractions were concentrated under
reduced pressure and the mixture of diastereo isomers were taken to next step.
Pale yellow amorphous solid; Yield: 330 mg, 22%; M+H 649.
Step 5: (5R),(6Z)-6-[(7-fluoro-imidazo[1,2-b][1,3]benzothiazol-2-ylmethylene)] -
7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl-6-[(acetyloxy) (7-fluoro-imidazo[2,1 -b][1,3]benzothiazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 710 mg, 1.07
mmol) was dissolved in THF (17 mL) and acetonitrile (36 mL). Freshly activated Zn
dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28 mL). The
reaction vessel was covered with foil to exclude light. The reaction mixture was
vigorously stirred for 2 h at room temperature. The reaction mixture was filtered,
cooled to 3 °C, and 1 N NaOH was added to adjust pH to 8.5. The filtrate was
washed with ethyl acetate and the aqueous layer was separated. The aqueous layer
was concentrated under high vacuum at 35 °C to give yellow precipitate. The
precipitate was filtered and washed with H2O, MeCN, acetone to give the title
compound. Yield: 80 mg, 19%; as yellow crystals; mp 200 (dec); M+Na 396.

1H NMR (DMSO-d6) ? 6.53(s, 1H), 6.63(s, 1H), 7.1(s, 1H), 7.45 (t, 1H), 8.04
(m, 1H), 8,13-8.10 (m, 1H), 8.61 (s,1H).
Example 15
Preparation of (5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2.1-b]pyrano[4,3-
d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1 - azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
Step 1: Preparation of ethyl 5.8-dihydro-6H-lmidazo[2.1-b]pyrano[4,3-
d][1.3]thiazole-2-carboxylate
A mixture oftetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in CCl4 (100 ml) at 0°C,
SO2CI2 (7.4 g, 55 mmol) was slowly added. After the addition, reaction mixture was
stirred at room temperature for 4 hrs and carefully quenched with ice cold water.
Recation mixture was washed well and dried over anhydrous MgSO4. The organic
layer was filtered and concentrated. The coluriess oil obtained was diisoolved in
THF/EtOH containing thiourea (4.0 g, 52 mmol) and refluxed for 8 hrs. At the end,
reaction mixture was cooled to room temperature and the separated, 6,7-dihydro-
4H-pyrano[4,3-d][1,3]thiazol-2-amine hydrochloride white solid was filtered. Yield.
4.5 g (47%); M.Pt. 115°C, (M+H) 157.
To a stirred mixture of, 6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-amine
hydrochloride (4.0 g, 20.8 mmol) was dissolved in anhydrous ethanol (100 ml) and
sodium methoxide (1.1 g, 21 mmol). This was stirred at room temperature for 30
minutes and to this ethyl bromopyruvate (10 .0 g) was added and stirred at room
temperature for 2 hrs. Then it was refluxed for 48 hrs. At the end reaction mixture
was cooled to room temperature and concentrated. The residue was extracted with
chloroform and washed well with water. The product was purified by silica-gel
column chromatography by eluting it with 50% ethyl acetae: hexane. Red semi-solid;
Yield: 3.1 g, (59%) M+H 253.
The ester was reduced with LiBH4 and the resultant alcohol was oxidized with active
MnO2. The aldehyde obtained was taken to next step.

Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(5,8-dihydro-6H-
imidazo[2,1 -b][1,3]pyrano[4,3-d][1,3]thiazol-2-yl-6-bromo-7-oxo-4-thia-1 -
azablcyclor3.2.01hept-2-ene-2-carboxylate:
2-Formyl-5,8- dihydro-6H-imidazo[2.1-b]pyrano[4,3-d][1,3]thiazoIe (208 mg, 1.0
mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicydo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (400 mg, 1.1 mmol)
were added successively to the dry acetonitrile (15 mL) solution of anhydrous MgBr2:
0(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature. After
cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel was
covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20 °C
and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 400
mg, 62%; M.Pt. 78°C; M+H 636.
Step 4; Preparation of (5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-
d][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-1- azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
4-nitrobenzyl (5E)-6-[(acetyloxy)(5,8-dihydro-6H-imidazo[2,1-b][1,3]pyrano[4,3-
d][1,3]thiazol-2-yl)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
(500 mg, 0.79 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL).
Freshly activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH
6.5, 28 mL). The reaction vessel was covered with foil to exclude light. The reaction
mixture was vigorously stirred for 2 h at room temperature. The reaction mixture
was filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5.
The filtrate was washed with ethyl acetate and the aqueous layer was separated.

The aqueous layer was concentrated under high vacuum at 35 oC to give a yellow
precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrilerwater. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 85 mg, 30%; as yellow crystals; mp
205°C; (M+H+Na) 383 .1H NMR (DMSO-d6) ? 2.8 (m, 2H), 4.0 (m,2H), 4.6(s,2H), 6.4
(S.1H), 6.5 (s,1H), 7.0(s,1H), 8.1 (s,1H).
Example 16
Preparation of (5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-
thia-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Preparation of imidazo[2,1-b][1,3]benzothiazol-7-ylmethanol: A solution
of ethyl imidazo[2,1-b][1,3]benzothizole-7-carboxylate (1.1 g, 4.5 mmol) in THF (50
ml) was slowly added to to a stirred solution of LiBH4 (1 g) in THF (100 ml) at 0°C .
The reaction mixture was refluxed for 2 hrs and cooled to room temperature. It was
quenched with ice cold water andf carefully nuetralized with Con. HCI. The soltion
was stirred at room temperature for 2 hrs and basified with K2CO3 (solid). At the
end, reaction mixture was extracted with chloform: methanol (3:1) and dried over
anhydrous MgSO4. It was filtered and concentrated. The product was pue enough
and taken to next step with out purification. Brown solid. M.t. 75°C; (M+H) 205. Yield;
800 mg, (87%).
Step 2: Preparation of 7-fomyl- imidazo[2,1-b][1,3]benzothiazol:
lmidazo[2,1-b][1,3]benzothiazol-7-ylmethanol ( 700 mg, 3.4 mmol) obtained by the
above mentioned process was oxidiazed with active MnO2 (2 g) in CH2Cl2= under
refluxing condition. The reaction mixture was stirred for 6 hrs and cooled to room
temperature. It was filtered and through celite and concentrated. The separated
brown color solid was triturated with diethyl ether and filtered. It was found to be pure
enough and taken to next step with out purification. Yield. 400 mg (58%); (M+H) 203.

Stag 3: 4-Nitrobenzyl-64(acetyloxy) (imidazo[2,1 -b][1,3]benzothiazol-7-
ylmethyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
7-fomyl- imidazo[2,1-b][1,3]benzothiazol (260 mg, 1.3 mmol) and the dry THF
solution (20 m) of (5R, 6S)-6-bromo-7-oxo-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyi ester (500 mg, 1.14 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2: 0(Et)2 (390 mg, 1.5
mmol)under an argon atmosphere at room temperature. After cooling to -20 °C,
Et3N (2.0 mL) was added in one portion. The reaction vessel was covered with foil to
exclude light. The reaction mixture was stirred for 2 h at -20 °C and treated with
acetic anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C
and stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed
with 5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and
brine. The organic layer was dried (MgSO4) and filtered through a pad of Celite.
The pad was washed with ethyl acetate. The filtrate was concentrated under
reduced pressure. The residue was applied to silica gel column chromatography,
then the column was eluted with ethyl acetate: hexane (1:1). Collected fractions
were concentrated under reduced pressure and the mixture of diastereomers were
taken to the next step. Pale yellow amorphous solid; Yield: 750 mg, 91%; M.pt.
82°C; M+H 630.
Step 5:5R),(6Z)-6-(imidazor2.1 -b1bebzothiazol-7-ylmethylenel-7-oxo-4-thia-1 -
azabicyclor3.2.01hept-2-ene-2-carboxylicacid:
4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1 -b][1,3]benzothiazol-7-yl)methyl]-6-bromo-7-
oxo-4-thia-1-azabicyclo{3.2.0]hept-2-ene-2-carboxylate (900 mg, 1.4 mmol) was
dissolved in THF (20 mL) and acetonitrile (20 mL) and 0.5 M phosphate buffer (pH
6.5, 20 mL) and hydrogenated over Pd/C (10%) at 40 psi pressure for 6 hrs. The
reaction vessel was covered with foil to exclude light. The reaction mixture was
filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The
filtrate was concentarted and the aqueous layer was washed with ethyl acetate. The
aqueous layer was separated. The aqueous layer was concentrated under high
vacuum at 35 °C to give a yellow precipitate. The product was purified by HP21
resin reverse phase column chromatography. Initially the column was eluted with

deinonized water (2 L) and latter with 10% acetonitrile:water. The fractions containing
the product were collected and concentrated under reduced pressure at room
temperature. The yellow solid was washed with acetone, filtered and dried. Yield:
180 mg, 36%; as yellow crystals; mp 235°C; (M+H+Na) 378.
1H NMR (DMSO-d6) ? (s, 1H), 6.6 (s,1H), 7.1 (s, 1H), 7.52 (s, 1H), 8.1-8.5
(m,3H), 8.7 (s, 1H).
Example 17
Preparation of (5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-
ylmethylene)-4-thia-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Preparation of benzo[4,5]imidazo[2,1-b]thazole-2-carbaldehyde: To a
stirred solution of 2-mercapto benzimidazole (5.0 g, 33.3 mmol) and K2CO3 (4.59 g,
33.3 mmol) in anhydrous DMF (100 mL) bromomalonaldehyde (4.99 g, 33.3) was
added and heated fo 8 hrs at 80°C. At the end, reaction mixture was concentrated to
dryness and ice cold water was added.and nuetralzed with 1N HCI. The product was
extarcted with chloroform and washed with water and dried over anhydrous MgSO4.
It was filterd and concentrated. The residue was taken in DMF/ acetic acid mixture
(1:1) (100 ml) and heated at 120°C for 6 hrs. The reaction mixture was
concentarted and extracted with chloroform; washed well with water and dried over
anhydrous MgSO4. It was filtered and concentarted. The separated solid was
triturated with diethyl ether and filtered. Yield: 4.2 g (62%); (M+H) 203.
Step 2: 4-Nitrobenzyl (5R)-6-[(acetyloxy) ([1,3]thiazolo[3,2-a]benzimidazol-2-
yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
Benzo[4,5]imidazo[2,1-b]thazole-2-carbaldehyde (404 mg, 2 mmol) and the dry THF
solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester (772 mg, 2 mmol) were added successively to
the dry acetonitrile (15 mL) solution of anhydrous MgBr2: O(Et)2 (1.65 g,
excess)under an argon atmosphere at room temperature. After cooling to -20 °C,
Et3N (2.0 mL) was added in one portion. The reaction vessel was covered with foil to
exclude light. The reaction mixture was stirred for 2 h at -20 °C and treated with
acetic anhydride (1.04 mL) in one portion. The reaction mixture was warmed to 0 °C
and stirred for 15 h at 0 °C. The mixture was diluted with ethyl acetate and washed

with. 5% citric acid aqueous solution, saturated sodium hydrogen carbonate, and
brine. The organic layer was dried (MgSO4) and filtered through a pad of Celite.
The pad was washed with ethyl acetate. The filtrate was concentrated under
reduced pressure. The residue was applied to silica gel column chromatography,
then the column was eluted with ethyl acetate: hexane (1:1). Collected fractions
were concentrated under reduced pressure and the mixture of diastereomers were
taken to the next step. Pale yellow amorphous solid; Yield: 800 mg 63%; M.pt. 78°C;
(M+H) 630.
Step 3: (5R),(6Z)-7-oxo-6-([1,3]thiazolo[3.2-a]benzimidazol-2-ylmethylene0-4-
thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid:
4-Nitrobenzyl (5R)-6-[(acetyloxy) ([1,3]thiazolo[3,2-a]benzimidazol-2-yl)methyl]-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate: (630 mg, 1.0 mmol)
was dissolved in THF (20 mL) and acetonitrile (20 mL) and 0.5 M phosphate buffer
(pH 6.5, 20 mL) and hydrogenated over Pd/C (10%) at 40 psi pressure for 6 hrs. The
reaction vessel was covered with foil to exclude light. The reaction mixture was
filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The
filtrate was concentarted and the aqueous layer was washed with ethyl acetate. The
aqueous layer was separated. The aqueous layer was concentrated under high
vacuum at 35 °C to give a yellow precipitate. The product was purified by HP21
resin reverse phase column chromatography. Initially the column was eluted with
deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing
the product were collected and concentrated under reduced pressure at room
temperature. The yellow solid was washed with acetone, filtered and dried. Yield:
190 mg, 50%; as yellow crystals; mp 240°C (Dec); (M+H+Na) 378 .
1H NMR (DMSO-d6) ? 6.3 (s, 1H), 6.4 (s,1H), 6.6 (d, 2H), 7.29-7.39 (m, 2H),
7.69-7.73 (t,1H), 8.1-8.19 (m, 1H), 8.84 (s,1H).
Example 18
Preparation of (5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1 -
b][1,3]thiazol-2-ylmethylene)-7-oxo-6-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid

Step 1: Preparation of 7,9-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-
b][1,3]thiazole-2-carbaldehyde:
To a stirred solution of 1,4,5,6-tetrahydrocycIopenta[c]pyrazole-3(H)-thione
[Prepared by the procedure of T.takeshima, N. Oskada, E.Okabe and F. mineshima,
J. Chem. Soc. Perkin. Trans. 1,1277-1279, (1975)] (5.3 g, 37.85 mmol) and K2CO3 (
10.4 g, 75 mmol) in anhydrous DMF (100 mL) bromomalonaldehyde (5.7 g, 37.85)
was added and heated fo 8 hrs at 80°C. At the end, reaction mixture was
concentrated to dryness and ice cold water was added.and nuetralzed with 1N HCI.
The product was extarcted with chloroform and washed with water and dried over
anhydrous MgSO4. It was filterd and concentrated. The residue was taken in DMF/
acetic acid mixture (1:1) (100 ml) and heated at 120°C for 6 hrs. The reaction
mixture was concentarted and extracted with chloroform; washed well with water and
dried over anhydrous MgSO4. It was filtered and concentarted. The product was
purified by SiO2 column chromatography by eluting it with 75% ethyl acetate: hexane.
Yield: 2.2 g (30%); M.PL 112°C; (M+H) 193.
Step 2:4-Nitrobenzyl-(5R)-6-[(acetyloxy) (7,8-dihydro-8H-
cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-yl)methyl]-6-bromo-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylate
7,9-dihydro-6H-cyclopenta[3,4]pyra20lo[5,1-b][1,3]thiazole-2-carbaldehyde (576 mg,
3 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.16 g, 3 mmol) were
added successively to the dry acetonitrile (15 mL) solution of anhydrous MgBr2:
0(Et)2 (165 g, excess)under an argon atmosphere at room temperature. After
cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel was
covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20 °C
and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).

Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 1.5
g, 83%; M.pt. 69°C; (M+H) 620.
Step 3: (5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]Pyrazolo[5,1-b][1,3]thiazol-2-
ylmethylene)7-oxo-4-thia-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-Nitrobenzyl-(5R)-6-[(acetyloxy) (7,8-dihydro-8H-cyclopenta[3,4]pyrazolo[5,1 -
b][1,3lthiazol-2-yl)methynyl]-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxyiate (1.2 g, 1.9 mmol) was dissolved in THF (30 mL) and acetonitrite (30 mL)
and 0.5 M phosphate buffer (pH 6.5,30 mL) and hydrogenated over Pd/C (10%) at
40 psi pressure for 6 hrs. The reaction vessel was covered with foil to exclude light.
The reaction mixture was filtered, cooled to 3 °C, and 0.1 N NaOH was added to
adjust the pH to 8.5. The filtrate was concentarted and the aqueous layer was
washed with ethyl acetate. The aqueous layer was separated. The aqueous layer
was concentrated under high vacuum at 35 °C to give a yellow precipitate. The
product was purified by HP21 resin reverse phase column chromatography. Initially
the column was eluted with deionized water (2 L) and latter with 10%
acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 420 mg, 38%; as yellow crystals; mp
190°C (Dec); (M+H+Na) 368 .
1H NMR (DMSO-d6) 1H NMR (DMSO-d6) ? 2.38 -2.42 (m, 2H), 2.69-2.89 (m,
4H), ,6.57 (s, 1H), 6.58 (s,1H), 7.36 (s, 1H), 8.53 (s,1H).
Example 19
Preparation of (5R),(6Z)-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-
b][1,3]benzothiazol-2-ylmethylene)- 4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
Step 1: Preparation of ethyl 5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-
2-carboxylate.
A mixture of 2-chlorocyclohexanone (13.2 g, 100 mmol) and thiourea (8.0 g 101
mmol) was refluxed in ethanol: TH,F (1:2) for 16 hrs. The reaction mixture was
cooled to room temperature and the separated white solid was filtered. (12.0 g

separated) This was dissolved in anhydrous ethanol (100 ml) and sodium methoxide
(3.3 g, 63 mmol). To this ethyl bromopyruvate (15.0 g) was added and stirred at
room temperature for 2 hrs. Then it was refluxed for 48 hrs. At the end reaction
mixture was cooled to room temperature and concentrated. The residue was
extracted with chloroform and washed well with water. The product was purified by
silica-gel column chromatography by eluting it with 50% ethyl acetae: hexane. Red
semi-solid; Yield: 6.2 g (39%); M+H 251.
The ester was reduced with LiBH4 and the resultant alcohol was oxidized with active
MnO2. The aldehyde obtained was taken to next step.
Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(5,6,7,8-
tetrahydroimidazo[2,1 -b][1.3]benzothiazol-2-yl)methyl]- 6-bromo-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-2-carbaldehyde (412 mg, 2.0
mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (770 mg, 2 mmol)
were added successively to the dry acetonitrile (15 mL) solution of anhydrous MgBr2:
0(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature. After
cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel was
covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20 °C
and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Ceiite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 980
mg, 77%; M+H 634.
Step 4: Preparation of (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-

b][1,3]benzothiazol-2-ylmethylene)- 4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
4-nitrobenzyl (5R)-6H(acetyloxy)(5,6,7,8-tetrahydroimidazo[2, 1 -b][1,3]benzothiazol-2-
yl)methyl]- 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (980
mg, 1.55 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly
activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28
mL). The reaction vessel was covered with foil to exclude light The reaction mixture
was vigorously stirred for 2 h at room temperature. The reaction mixture was
filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The
filtrate was washed with ethyl acetate and the aqueous layer was separated. The
aqueous layer was concentrated under high vacuum at 35 °C to give a yellow
precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 120 mg, 20%; as yellow crystals; mp
250°C (Dec); (M+H+Na) 382 .1H NMR (DMSO-d6) 5 1.9 (m,2H), 2.5 (m, 2H), 3.2-3.4
(m, 4H), 6.6 (s, 1H), 7.1 (s, 1H), 7.5 (s, 1H), 8.1 (s. 1H).
Example 20
Preparation of (5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-
yl)methylene]-7-oxo- 4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Step 1: Preparation of 9-methyl-9H-imidazon[1,2-a]benzimidazole-2-
carbaldehyde.
To stirred solution of LiBH4 (1.79 g, 82 mmol) in THF at 0°C, ethyl 9-methyl-9H-
imidazo[1,2-a]benzimidazole-2-carboxylate (2.5 g, 10.3 mmol) was added drop wise.
The reaction mixture was refluxed for 2 hrs and cooled to room temperature. Ti was
carefully quenched with icve cold water and acidified with Con. HCI to pH 4. The
reaction mixture was stirred at room temperature for 1 hr and basified with K2CO3.
The residue was extracted with chloroform; methanol (3:1) and dried over anhydrous
MgSO4. It was filtered and concentrated. Yield. 1.3 g (65%). (M+H) 202.
The resdue (1.3 g, 6.4 mmol) was oxidised with MnO2 (5.0 g) in CH2CI2 under
refluxing condition. After the completion, reaction mixture was filtered and

concentrated. It was purified by Si02 column chromatography by eluting it with 1:1
ethyl acetate: hexane. Brown solid. Yield. 330 mg (25%); (M+H) 200.
Step 2: Preparation of 4-nitrobenzyl (5R)-6-(acetyloxy)(9-methyl-9H-
imidazo[1,2-a]benzimidazole-2-)methyl]- 6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
9-methyl-9H-imidazo[1,2-a]benzimidazole-2-carbaldehyde. (330 mg, 1.65 mmol) and
the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (770 mg, 2 mmol)
were added successively to the dry acetonitrile (15 mL) solution of anhydrous MgBr2:
O(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature. After
cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel was
covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20 °C
and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture was
warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 330
mg, 31%; (M+H) 628.
Step 3: Preparation of (5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-
yl)methylenel-7-oxo- 4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitrobenzyl(5R)-6-[(acetyloxy)(9-methyl-9H-imida2o[1,2-a]benzimidazole-2-
)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:
(1 g, 1.6 mmol) was dissolved in THF (20 mL) and acetonitrile (10 mL). Freshly
activated Zn dust (5.2 g) was added rapidly with 0.5 M phosphate buffer (pH 6.5, 28
mL). The reaction vessel was covered with foil to exclude light. The reaction mixture
was vigorously stirred for 2 h at room temperature. The reaction mixture was
filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The

filtrate was washed with ethyl acetate and the aqueous layer was separated. The
aqueous layer was concentrated under high vacuum at 35 °C to give a yellow
precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 140 mg, 23%; as yellow crystals; mp
220°C (Dec); (M+H+Na) 375 .1H NMR (DMSO-d6) ? 3.4 (s,3H), 6.54 (s, 1H), 6.56 (s,
1H), 7.01 (s, 1H), 7.21 (t, 1H), 7.3 (t, 1H), 7.56 (d, 1H), 7.85 (d,1H), 8.1 (s,1H).
Example 21
Preparation off (5R,6Z)-7-oxo-6-(4H-thieno[2',3':4,5]thiopyrano[2,3-b]pyridin-2-
ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Sodium
salt)
Step 1:2,3 dihydro-4H-thiopyrano[2,3-b]pyridin-4-one:
A solution of 14 g. (61.6 mmol) 3-(3-Carboxy-2-pyridylthio)propionic Acid [prepared
as described in lit.:J.Heterocyclic Chem.,37.379(2000)] and 15 g.(185 mmol,3 eqs) of
anhydrous sodium acetate, in 200 mL. of acetic anhydride was refluxed (160° C)
under stirring, N2 atm, dry conditions, for 2 hours. Cooled, diluted with 300 mL of
water.bas'rfied with 30% ammonium hydroxide solution to pH 8-9, extracted with
3x200 mL chloroform. Combined organics washed with 2x60 mL Sodium bicarbonate
(satn.sol), water.dried, evaporated, gave 2.8g. (27%) of the title compound, reddish
solid, m.p.66-8° C, (M+H)+=166.2.
Step 2: 4-chloro-2H-thiopyrano[2,3b]pyridine-3-carbaldehyde:
A solution of 6.6g.(43 mmol,1 eq) of phosphorous oxychloride in 30 mL methylene
chloride was dropwise added to 3.95g (43 mmol, 1.25 eqs) of anhydrous
dimetylformamide (0° C, stirring, N2 atm, dry conditions) with such a rate to maintain
temperature between 0-5° C; RM was stirred at RT for 2 hours, cooled to 0° C, and
a solution of 8.9 g.(54 mmol, 1.25 eqs.) of 2,3 dihydro-4H-thiopyrano[2,3-b]pyridin-4-
one in 30 mL of methylene chloride was dropwise added over a 20 min. period. RM

stirred at RT for 2 hours, poured over crushed ice:sodium acetate 4:1 mixture,
extracted with 4x 150 mL methylene chloride, combined organics washed with water,
dried, evaporated, gave 7.76g (68%) of the title compound, brownish solid,m.p.56-8°
C,(M+H)+=212.6.
Step 3: Ethyl 4H-thieno[2'3':4,5]thiopyrano[2,3b]pyridine-2 carboxylate:
To a solution of 7.5g. (35 mmol, 1 eq.) of 4-chloro-2H-thiopyrano[2,3b]pyridine-3-
carbaldehyde in 25o mL of methylene chloride were added (under stirring, N2 atm,
dry conditions): 4.7 g.(39 mmol, 1.1 eqs) of ethyl mercaptoacetate, and 7.2 g. (71
mmol,2 eqs) of triethylamine in 30 mL of methylene chloride. RM was refluxed for 2
hours,quenched with 100 mL of water, organics separated, waters extracted with
4x150 mL of methylene chloride, combined organics dried, evaporated. Residue
purified on a silicagel column, using hexanerethyl acetate 3:1 as a solvent, gave
7.6g. (78%) of the title compound, yellow crystals, m.p. 113-5° C, (M+H) += 278.3.
Step 4; 4H-thieno[2',3':4,5]thiopyrano[2,3b]pyridin-2-ylmethanol:
To a cold solution of 7.5g.(27 mmol) of Ethyl 4H-
thieno[2'3':4,5]thiopyrano[2,3b]pyridine-2 carboxylate in 300 mL of dry
tetrahydrofuran (0° C, N2 atm.dry condition) was dropwise added 60 mL (60 mmol,
2.1 eqs) of 1M cold solution of Lithium Aluminum Hydride in tetrahydrofuran, and RM
stirred at RT untill the SM disappeared (monitored by TLC/MS). Cooled to 0° C, RM
was quenced with aquous 2N formic acid solution to neutral pH=8, and stirred at RT
for 2 hours, filtered, filtrate extracted 4x 200 mL methylene chloride, combined
organics dried, evaporated gave 6.0 g. (94%) of the desired compound, yellow
crystals, m.p.112-4°C, (M+H)+= 236.4.
Step 5: 4H-thieno[2',3':4,5]thiopyrano[2,3b]pyridin-2-carbaldehyde:
To a solution of 3.0 g.(12.8 mmol) of 4H-thieno[2',3':4,5]thiopyrano[2,3b]pyridin-2-
ylmethanol in 200 mL of chloroform, was added 9.0 g.(80 mmol, 7 eqs) of activated
manganese(IV)oxide, and RM refluxed under stirring, N2 atm., for 12 hours. Filtered
trough a celite pad, filtrate evaporated, and residue purified on a silicagel column,
gave 2.5 g.(86%) of the title compound, yellow crystals, m.p. 93-5° C, (M+H)+=
234.4.

Step-6: 4-nitrobenzyl(5R)-6-[(acetyloxy)(4H-
thieno[2',3':4,5]thiopyrano[2,3b]pyridin-2-yl) methyl]-6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0.]hept-ene-2carboxylate
In a sealed dry r.b. flask, flushed with N2, were added: 4H-
thieno[2',3':4,5]thiopyrano[2,3b]- pyridin-2-carbaldehyde 0.6g. (2.57 mmol.1 eq),
anhydrous THF (15 mL), anhydrous ACN (15 mL), 0.520 g.(2.8 mmol, 1.1 eqs)
anhydrous MgBr2, and RM stirred at RT for 30 min. To the RM was added 2.5 mL(14
mmol.5.4 eqs) of anhydrous triethylamine, 10 mL of anhydrous THF, RM cooled at (-
20° C), and 0.95 g.(2.5 mmol,1 eq) of bromopenam was added. RM stirred at (-20°
C) for 6 hours. At the same temperature, 3 mL (3 mmol, 1.15 eqs) of acetic anhydride
was added, RM stirred for 15 min and kept at 0° C for 12 hours, evaporated to
dryness, residue extracted with 5x 80 mL ethyl acetate. Organic solvent evaporated,
and residue purified an a silicagei column (solvent hexanerethyl acetate 4:1), gave
0.880 g.(52%) of the title compound, yellowish crystals, m.p.141-3° C,
(M+H)+=661.6.
Step 7: (5R,6Z)-7-oxo-6-(4H-thieno[2',3':4,5]thiopyrano[2,3-b]pyridin-2-
ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Sodium
salt
A solution of 4-nitrobenzyl(5R)-6-t(acetyloxy)(4H-
thieno[2', 3':4,5]thiopyrano[2,3b]pyridin-2-yl) methyl]-6-bromo-7-oxo-4-thia-1 -
azabicyclo[3.2.0.]hept-ene-2carboxylate 0.8g.(1.21 mmol, 1 eq) in 40 mL THF and
40 mL phosphate buffer solution (pH=6.36) was hydrogenated at 40 psi for 3 hours
in the presence of 0.4g. Palladium on Carbon 10% catalyst RM filtrated trough celite
pad, filtrate adjusted to pH=8.0, concentrated in vacuo, residue purified on a reverse-
phase column (amberiite), using 5%.. 10% ACN/water mixture as solvent, gave
0.103g.(21%) of the title compound, reddish crystals, m.p.362.4° C, (M+H) += 409.5.
1H NMR: (DMSO-d6) ? 4.12(s,2H), 6.49 (s,1H), 6.53(s,1H);7.22(d,1H);7.34
(s,1H);7.41 9s, 1H). 7.76 (t,1H);8.28 (d,1H).

Example 22
Preparation of (5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-
cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-
1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1; Preparation of (8-methyl-6,7-dihydro-5H-
cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol
To a round bottomed flask was loaded 3.78 grams of 2-acetylcyclopentanone, 3.52
grams of (5-Amino-1H-[1,2,4ltriazol-3-yl)-methanol and 50ml 2-methoxyethanol. The
mixture was refluxed for 18 hours. Then it was cooled down to 23°C and
concentrated to 5ml. Then 50ml ethyl ether was added and the precipitate was
filtered and vacuum dried to yielded 2.0 grams of product. This compound was used
directly for the next step. MS: 205.2(M+H). H-NMR(DMSO): ? 5.55(t, 1H, OH, J=
6.2Hz), 4.63(d, 2H, J= 6.2Hz), 3.28 (m, 2H), 3.02 (t, 2H, CH2, J= 6.8Hz), 2.51 (s, 3H,
CH3), 2.27 (m, 2H, CH2).
Step 2: Preparation of 8-methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4]triazolo[1,5-
a]pyrimidine-2-carbaldehyde
To a round bottomed flask was loaded 0.17ml of DMSO and 1 ml dichloromethane.
The mixture was cooled to -50~-60°C. Then a mixture of 0.1 ml oxallyl chloride and
2ml dichloromethane was injected in into the flask all at once. The mixture was
stirred at the same temperature for another 5 minutes. Then 0.174 grams of (8-
Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4] triazolo [1,5-a]pyrimidin-2-yl)-methanol in
2 ml dichloromethane was added within 2 minutes. The mixture was stirred at -50~-
60°C for fifteen minutes and 0.7 ml triethylamine was next added. After another five
minutes the reaction media was warmed up to 23°C and a mixture of 20ml water and
200ml dichloromethane was added. The organic layer was dried over magnesium
sulfate. Filter off the drying agent and concentrate the filtrate yielded 0.153 grams of
product (89%). MS: 203.1(M+H). H-NMR(CDCI3): ? 10.24(s, 1H), 3.49(m, 2H),
3.15(m, 2H), 2.67 (s, 3H, CH3), 2.44 (m, 2H, CH2).

Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-
6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-
thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate
8-Methyl-6,7-dihyclro-5H-cyclopenta[cl][1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde
(153 mg, 0.75 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-
thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (385 mg, 1
mmol) were added successively to the dry acetonitrile (15 mL) solution of anhydrous
MgBr2: 0(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature.
After cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel
was covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20
°C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture
was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 200
mg,42%;(M+H)631.
Step 4; Preparation of (5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-
cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methylene1-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-n'rtrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-
cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg, 0.31 mmol) was dissolved in
THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and
hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction
mixture was filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to
8.5. The filtrate was washed with ethyl acetate and the aqueous layer was

separated. The aqueous layer was concentrated under high vacuum at 35 °C to give
a yellow precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 15 mg, 13%; as yellow crystals; mp
250°C (Dec); (M+H+Na) 378 .1H NMR (DMSO-d6) ? 6.80 (s, 1H), 6.76(s, 1H), 6.25(s,
1H), 3.24(m, 2H), 2.96 (m, 2H), 2.49(s, 3H), 2.25(m, 2H).
Example 23
Preparation of (5R,6Z)-6-([7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[3,4-
e][1,2,4]triazolo[1,5-a]pyrimidin-2-ynmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1: Preparation of 2-hydroxymethyl-8.9-dihydro-6H-1,3,4,7,9b-pentaaza-
cyclopenta[a]naphthalene-7-carboxylic acid ethyl ester
To a round bottomed flask was loaded 8.56 grams of 4-oxo-piperidine-1-carboxylic
acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture was
refluxed at 90°C for two hours. Then it was poured into 75 ml water and extracted
with 2x250ml dichloromethane. The combined organic layers was washed with 50ml
brine and dried over magnesium sulfate. Filter off the drying agent and concentrate
gave 28 grams of 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid
ethyl ester. This material (12.8 grams) was then loaded into a round bottomed flask
along with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-rnethanol and 100ml 2-
methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to
23°C and concentrated to 5ml. Then 50ml ethyl ether was added and the precipitate
was filtered and vaccum dried to yielded 1.5 grams of product. MS: 278.1 (M+H). H-
NMR(CDCL3): 8 8.60(s, 1H), 4.98(s, 2H), 4.78(s, 2H, CH2), 4.22(q, 2H, J= 4.8Hz),
3.75 (t, 2H, CH2, J= 4Hz), 3.51 (t, 2H, J= 4Hz), 1.32 (m, 3H, CH3, J= 4.8Hz).

Step 2; Preparation of 2-Formyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-
yclopenta[a]naphthalene-7-carboxylic acid ethyl ester
Z-Hydroxymethyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-cyclopentalalnaphthalene-7-
carboxylic acid ethyl ester (831 mg, 3 mmol) was converted to 2-formyl-8,9-dihydro-
6H-1,3,4,7,9b-pentaaza-yclopenta[a]naphthalene-7-carboxylic acid ethyl ester (690
mg, 89% Yield) by the procedure outlined in example 22, (step 2).
MS: 276.1(M+H). H-NMR(CDCI3): ? 10.24(s, 1H), 8.76(s. 1H), 4.86(s, 2H), 4.23 (q,
2H, CH2, J= 7.2Hz), 4.13 (t, 2H, CH2, J= 7.2Hz) 3.39 (t, 2H, CH2, J= 5.7Hz), 1.34 (t,
3H,CH3,J= 7.2Hz).
Step 3; ethyl 2-[(acetyloxy)((5R)-6-bromo-2-[(4-nitrobenzyl)oxy]carbonyl-7-
oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8,9-dihydropvridol3.4-
e][1,2,4]triazolo[1,5-a]pyrimidine-7(6H)-carboxylate
2-formyl-8,9-dihydro-6H-1,3,4,7,9b-pentaaza-yclopenta[a]naphthalene-7-carboxylic
acid ethyl ester (550 mg, 2 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-
bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl
ester (770 mg, 2 mmol) were added successively to the dry aceton'rtrile (15 mL)
solution of anhydrous MgBr2: O(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at
room temperature. After cooling to -20 °C, Et3N (2.0 mL) was added in one portion.
The reaction vessel was covered with foil to exclude light. The reaction mixture was
stirred for 2 h at -20 °C and treated with acetic anhydride (1.04 mL) in one portion.
The reaction mixture was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture
was diluted with ethyl acetate and washed with 5% citric acid aqueous solution,
saturated sodium hydrogen carbonate, and brine. The organic layer was dried
(MgSO4) and filtered through a pad of Celite. The pad was washed with ethyl
acetate. The filtrate was concentrated under reduced pressure. The residue was
applied to silica gel column chromatography, then the column was eluted with ethyl
acetate: hexane (1:1). Collected fractions were concentrated under reduced
pressure and the mixture of diastereomers were taken to the next step. Pale yellow
amorphous solid; Yield: 220 mg, 1(5%; (M+H) 703.

Step 4: Preparation of (5R,6Z)-6-{[7-(ethoxycarbonyn-6,7,8,9-
tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl]methylene)-7-oxo-4-
thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
ethyl 2-[(acetyloxy)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8,9-dihydropyrido[3,4-e][1,2,4]tri-
a]pyrimidine-7(6H)-carboxylate (220 mg, 0.28 mmol) was dissolved in THF (20 mL)
and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over
Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was
filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to 8.5. The
filtrate was washed with ethyl acetate and the aqueous layer was separated. The
aqueous layer was concentrated under high vacuum at 35 °C to give a yellow
precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 15 mg, 2%; Yellow crystals; mp
>250°C (Dec); (M+H+Na) 449.1H NMR (DMSO-d6) ? 8.61 (s, 1H), 7.01 (s, 1H),
6.90(s, 1H), 6.44(s, 1H), 4.74(m, 2H, CH2), 4.13 (q, 2H, J= 5.4Hz), 3.84(s, m, 2H,
CH2), 1.22(t, 3H, CH3, J= 5.7Hz).
Example 24
Preparation of (5R,6Z)-6-(8',9'-dihydro-6'H-spiro[ .3-dioxolane-2.7'-
[1,2,4]triazolo[1,5-a]quinazolin]-2'-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1: Preparation of 2-hydroxymethyl-8.9-dihydro-6H-[1,2,4]triazolo[1,5-
a]auinazolin-7-ethylene ketal
To a round bottomed flask was loaded 15.6 g of 1,4-cyclohexadione mono-ethylene
ketal, 11.9 g of dimethylformamide dimethylacetal, and the mixture was refluxed at
90°C for two hours. Then it was poured into 75 ml water and extracted with 2x250ml
dichloromethane. The combined organic layers was washed with 50ml brine and

dried over magnesium sulfate. Filter off the drying agent and concentrate gave 28
grams of 3-Dimethylaminomethylene-4-oxo-cyclohexane. The crude product was
then loaded into a round bottomed flask along with 11.9 grams of (5-Amino-1H-
[1,2,4]triazol-3-yl)-methanol and 100ml 2-methoxyethanol. The mixture was refluxed
for 18 hours. Then it was cooled down to 23°C and concentrated to 5ml. Then 50ml
ethyl ether was added and the precipitate was filtered and vaccum dried to yielded
2.0 grams (8% Yield) of product MS: 263 (M+H). H-NMR(CDCL3): ? 8.51 (s, 1H),
5.17(s, 2H, CH2), 4.08(s, 4H, OCH2CH2O), 3.42(t, 2H, CH2, J= 5.1Hz), 3.07 (s, 2H,
CH2), 2.15 (t, 3H, CH3, J= 5.1Hz).
Step 2: Preparation of 7-ethyleneketal-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-
a]quinazoline-2-carbaldehyde
To a round bottomed flask was loaded 5ml of DMSO and 5 ml dichloromethane. The
mixture was cooled to -50~-60°C. Then a mixture of 1 ml oxallyl chloride and 5ml
dichloromethane was injected in into the flask all at once. The mixture was stirred at
the same temperature for another 5 minutes. 2-Hydroxymethyl-8,9-dihydro-6H-
[1,2,4]triazolo[1,5-a]quinazolin-7-ethylene ketal (1.31 g, 5 mmol) in 20 ml
dichloromethane was added within 2 minutes. The mixture was stirred at -50~-60°C
for fifteen minutes and 0.7 ml triethylamine was next added. After another five
minutes the reaction media was warmed up to 23°C and a mixture of 20ml water and
200ml dichloromethane was added. The organic layer was dried over magnesium
sulfate. Filter off the drying agent and concentrate the filtrate yielded 910 mg of
product (70%). MS: 261 (M+H). H-NMR(CDCI3): ? 10.26(s, 1H), 8.66(s, 1H), 4.08(s,
4H, OCH2CH20), 3.49(t, 2H, J= 6.9Hz), 3.11(s, 2H), 2.18 (t, 3H, CH3, J= 6.9Hz),
2.44 (m, 2H, CH2).
Step 3: Preparation of 4-nitrobenzyl (5-6-[(acetyloxy)(8',9'-dihydro-6'H-
spiro[1,3-dioxolane-2,7'-[1,2,4]triazolo[1,5-a]quinazolin]-2'-yl)methyl]-6-bromo-
7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
7-Ethyleneketal-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde
(780 mg, 3 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-
thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.15g g, 3

mmol) were added successively to the dry acetonitrile (15 mL) solution of anhydrous
MgBr2: O(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature.
After cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel
was covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20
°C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture
was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1). .
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 300
mg, 15%; (M+H) 688.8.
Step 4: Preparation of Preparation of (5R,6Z)-6-(8',9'-dihydro-6'H-spiro[1,3-
dioxolane-2,7'-[1,2,4]triazolo[1,5-a]quinazolin]-2'-ylmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitrobenzyl (5R)-6-[(acetyloxy)(8',9'-dihydro-6'H-spiro[1,3-dioxolane-2,7'-
[1,2,4]triazolo[1,5-a]quinazolin]-2'-yl)methyl]-6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg, 0.43 mmol) was dissolved in
THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and
hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction
mixture was filtered, cooled to 3 °C, and 0.1 N NaOH was added to adjust the pH to
8.5. The filtrate was washed with ethyl acetate and the aqueous layer was
separated. The aqueous layer was concentrated under high vacuum at 35 °C to give
a yellow precipitate. The product was purified by HP21 resin reverse phase column
chromatography. Initially the column was eluted with deionized water (2 L) and latter
with 10% acetonitrile:water. The fractions containing the product were collected and
concentrated under reduced pressure at room temperature. The yellow solid was
washed with acetone, filtered and dried. Yield: 15 mg, 9%; Yellow crystals; mp
>250°C (Dec); (M+H+Na) 435.9 .1H NMR (DMSO-d6) ? 8.50 (s, 1H), 6.97(s, 1H),
6.85(s, 1H), 6.38(s, 1H), 4.05 (s, 4H, OCH2CH20), 3.28(m, 2H), 3.07 (s, 2H), 2.13(t,

Example 25
Preparation of (5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-
a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt
Step 1: Preparation of (5-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-
a]quinazolin-2-yl)-methanol:
To a round bottomed flask was loaded 4.2 grams of 2-acetylcyclohexanone, 3.52
grams of (5-Amino-1H-[1,2,41triazol-3-yl)-methanol and 50ml 2-methoxyethanol. The
mixture was refluxed for 18 hours. Then it was cooled down to 23°C and
concentrated to 5ml. Then 50ml ethyl ether was added and the precipitate was
filtered and vacuum dried to yielded 3.32 grams of product Yield. 49%. This
compound was used directly for the next step. MS: 219.2(M+H). H-NMR(DMSO): ?
5.49(t, 1H, OH, J= 6Hz), 4.61 (d, 2H, J= 6Hz), 3.24 (m, 2H), 2.93 (m, 2H), 2.69 (s,
3H), 2.52 (s, 2H), 1.84 (m, 4H).
Step 2: Preparation of 5-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-
a]quinazoline-2-carbaldehyde
To a round bottomed flask was loaded 1 ml of DMSO and 5 ml dichloromethane. The
mixture was cooled to -50~-60°C. Then a mixture of 1 ml oxallyl chloride and 2ml
dichloromethane was injected in into the flask all at once. The mixture was stirred at
the same temperature for another 5 minutes. Then 0.218 grams of (5-Methyl-
6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-methanol in 2 ml
dichloromethane was added within 2 minutes. The mixture was stirred at -50~-60°C
for fifteen minutes and 0.7 ml triethylamine was next added. After another five
minutes the reaction media was warmed up to 23°C and a mixture of 20ml water and
200ml dichloromethane was added. The organic layer was dried over magnesium
sulfate. Filter off the drying agent and concentrate the filtrate yielded 0.216 grams of
product (99%). MS: 217.1 (M+H). H-NMR(CDCI3): ? 10.20(s, 1H), 3.23(m, 2H), 2.78
(m, 2H) 2.63 (s, 3H, CH3), 2.00 (m, 4H),

Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-
tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methyl-6-bromo-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate
5-Methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[1,5-a]quinazoline-2-carbaldehyde
(432 mg, 2 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-
thia-1-aza-bicydo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (770 mg, 2
mmol) were added successively to the dry acetonitrile (15 mL) solution of anhydrous
MgBr2: O(Et)2 (1.2 g, 3.0 mmol)under an argon atmosphere at room temperature.
After cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction vessel
was covered with foil to exclude light The reaction mixture was stirred for 2 h at -20
°C and treated with acetic anhydride (1.04 mL) in one portion. The reaction mixture
was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was diluted with ethyl
acetate and washed with 5% citric acid aqueous solution, saturated sodium
hydrogen carbonate, and brine. The organic layer was dried (MgSO4) and filtered
through a pad of Celite. The pad was washed with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was applied to silica gel column
chromatography, then the column was eluted with ethyl acetate: hexane (1:1).
Collected fractions were concentrated under reduced pressure and the mixture of
diastereomers were taken to the next step. Pale yellow amorphous solid; Yield: 600
mg, 47%; (M+H) 644.7.
Step 4: Preparation of Preparation of (5R,6Z)-6-[(5-methyl-6,7,8,9-
tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-yl)methylene]-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-
a]quinazolin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate (600 mg, 0.93 mmol) was dissolved in THF (20 mL) and acetonitrile (20
mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200
mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3 °C,
and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with
ethyl acetate and the aqueous layer was separated. The aqueous layer was
concentrated under high vacuum at 35 °C to give a yellow precipitate. The product

was purified by HP21 resin reverse phase column chromatography. Initially the
column was eluted with deionized water (2 L) and latter with 10% acetonitrile.water.
The fractions containing the product were collected and concentrated under reduced
pressure at room temperature. The yellow solid was washed with acetone, filtered
and dried. Yield: 37 mg, 11%; as yellow crystals; mp 250°C (Dec); (M+H+Na) 392
1H NMR (DMSO-d6) ? 6.90 (s, 1H), 6.85(s, 1H), 6.28(s, 1H), 2.98(m, 2H), 2.77 (m,
2H), 2.55(m, 3H), 1.78(m, 4H).
Example 26
Preparation of (5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-
a]pyrimidin-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt
Step 1: Preparation of 4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-
ylamine
(SM:Ross, L. O.; Goodman, L; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108)
5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved
in 200ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodium methoxide
was added and the mixture was refluxed for 3 hours. Then the solvent was removed
in vacuo and 100ml water was added to the residue. Filter and wash the cake with
water (50ml). The solid was further vacuumed to dry for several hours. The desired
product weighed 4.8 gram (98% yield). Mp: 133.8-134.9° C; MS: 166.2.0 (M+H)
Step 2: Preparation of 5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carboxylic acid ethyl ester
4.8 gram (29mmol) 4-ethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was
dissolved in 100 ml dry THF. Bromopyruvate (5.4ml,) was then added dropwise with
in five minutes. The mixture was stirred at 23oC for one hour. It was then filtered
and washed with ether to give 8.7 gram of solid. This solid was then dissolved in
50ml ethanol and refluxed for two hours. The reaction mixture was cooled to room

temperature and partitioned between 350ml chloroform and 200 ml saturated sodium
bicarbonate. The organic layer was separated and dried over magnesium sulfate.
Filter off the drying agent and concentrate to give 5.3 gram of product (70% Yield).
MP: 105-106°C. (M+H) 262.
Step 3: Preparation of 5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carbaldehyde
5.2 grams (19.8 mmol) 5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-2-
carboxylic acid ethyl ester was dissolved in 40 ml dichloromethane and then cooled
to -78oC. DIBAL (1 M, 30 ml, 1.5 eq.) was then added within five minutes. The
reaction media was then quenched with 2ml ethanol and partitioned between 350ml
dichloromethane and 100 ml 1 N sodium hydroxide. The aqueous layer was washed
with another 150ml chloroform and the combined organic layer was dried over
magnesium sulfate and filtered and concentrated to give the corresponding alcohol.
The alcohol is then dissolved in 150ml dichloromethane and 10 grams of manganese
dioxide is then added. The mixture was stirred at 23 oC for two hours. The reaction
mixture was then filtered through a pad of celrte and concentrated to give 1.1 gram
(68%) of the desired aldehyde. MP: 235.2-236.3° C; MS: 218.1 (M+H)
Step 4: Preparation of 6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-
indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-nitro-benzyl ester
A 30 ml acetonitrile solution of 5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacene-
2-carbaldehyde (660 mg, 3mmol) was added 1.03 gram of magnesium bromide
etherate. The mixture was stirred at 23oC for half an hour. Then a 30ml dry THF
solution of the 6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitro-benzyl ester (1.155 gram, 1 eq.) was injected within a minute and the reaction
mixture was then cooled to -20oC. Triethylamine (0.7 ml, eq.) was then injected and
the reaction mixture was stirred for five hours at -20oC. Then acetic anhydride
(0.377 ml, eq.) was injected and the reaction mixture was left at zero degree for 18
I hours. The reaction media was then diluted with 400ml ethyl acetate and washed
with 100 ml 5% citric acid, 100 ml saturated sodium bicarbonate, and 100ml brine.
The organic layer was then dried over magnesium sulfate, filtered and concentrated.
Flash column chromatography using 20% ethyl acetate in hexane gave 1.8gram

product. (93% Yield); MP: 118.7~119.1 °C; MS: 645.9(M+H)
Step 5: Preparation of 6-(5-methoxy-7.8-dihydro-6H-3,4,8b-triaza-as-indacen-2-
ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carpoxylic acid
6-[acetoxy-(5-methoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-
bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl
ester (966 mg, 1.4 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous
phosphate buffer. The mixture was then subjected to 45psi hydrogen for two hours.
Then it was filtered through a pad of celite and concentrated in vacuo to remove
most of the THF. The solution was then cooled to zero degree and basified to pH=8
with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1
liter of water followed by 5% ~25% acetonitrile and water. Water was then removed
through concentrate in vacuo and 100 mg of product was collected.
MP:>250°C
H-NMR: (300 MHz, D2O) ? 10.12 (s, 1H), 9.29(s, 1H), 8.81(s, 1H), 8.78(s, 1H), 6.19
(s, 3H), 5.36(m, 2H), 5.05 (m, 2H), 4.43 (m, 2H).; MS: 371.2 (M+H).
Example 27
Preparation of (5R,6Z)-6-({5-[2-(benzyloxy)ethoxyl-7,8-dihydro-6H-
cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1: Preparation of 4-benzyioxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-
2-ylamine
(SM.Ross, L O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108)
To stirred suspension of NaH (60% 552 mg) in THF 2-benzyloxyethanol (3.38 g, 20
mmol) was slowly added at room temperature. After the addition,, 3.28 grams (19.4
mmol) of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in
200ml THF and added to it and the mixture was refluxed for 3 hours. Then the
solvent was removed in vacuo and 100ml water was added to the residue. The

product was extracted with chloroform; washed well with water and dried over
anhydrous MgSO4. It was filtered and concentrated. Low melting solid; Yield: 4.2
gram (73%); (M+H) 286.1
Step 2: Preparation of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-
indacene-2-carboxylic acid ethyl ester
6.0 gram (21mrnol) of 4-benzyloxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-
ylamine was dissolved in 100 ml dry THF. Bromopyruvate (8 ml,) was then added
dropwise with in five minutes. The mixture was stirred at 23oC for one hour. It was
then filtered and washed with ether to give a solid. This solid was then dissolved in
50ml ethanol and refluxed for two hours. The reaction mixture was cooled to room
temperature and partitioned between 350ml chloroform and 200 ml saturated sodium
bicarbonate. The organic layer was separated and dried over magnesium sulfate.
Filter off the drying agent and concentrate to give 5.36 gram of product (67% Yield).
(M+H) 382.1
Step 3: Preparation of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-
indacene-2-carbaidehyde
3.81 grams (10 mmol) 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-.
indacene-2-carboxylic acid ethyl ester was dissolved in 40 ml dichloromethane and
then cooled to -78oC. DIBAL (1 M, 30 ml, 1.5 eq.) was then added within five
minutes. The reaction media was then quenched with 2ml ethanol and partitioned
between 350ml dichloromethane and 100 ml 1 N sodium hydroxide. The aqueous
layer was washed with another 150ml chloroform and the combined organic layer
was dried over magnesium sulfate and filtered and concentrated to give the
corresponding alcohol. The alcohol is then dissolved in 150ml dichloromethane and
10 grams of manganese dioxide is then added. The mixture was stirred at 23 oC for
two hours. The reaction mixture was then filtered through a pad of celite and
concentrated to give 2.25 gram (67%) of the desired aldehyde. MS: 338(M+H)
Step 4: Preparation of 6-[acetoxy-(5-[2-(benzyloxy)emethoxy-7,8-dihydro-6H-
3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester

A 30 ml acetonitrile solution of 5-benzyloxyethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-
indacene-2-carbalsdehyde (676 mg, 2mmol) was added 1.03 gram of magnesium
bromide etherate. The mixture was stirred at 23oC for half an hour. Then a 30ml
dry THF solution of the 6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-
carboxylic acid 4-n*itro-benzyl ester (770 mg, 2 mmol) was injected within a minute
and the reaction mixture was then cooled to -20oC. Triethylamine (0.7 ml, eq.) was
then injected and the reaction mixture was stirred for five hours at -20oC. Then
acetic anhydride (0.377 ml, eq.) was injected and the reaction mixture was left at
zero degree for 18 hours. The reaction media was then diluted with 400ml ethyl
acetate and washed with 100 ml 5% citric acid, 100 ml saturated sodium
bicarbonate, and 100ml brine. The organic layer was then dried over magnesium
sulfate, filtered and concentrated. Flash column chromatography using 20% ethyl
acetate in hexane gave 1.05 gram product. (68% Yield); MS: 765.8(M+H)
Step 5: Preparation of Preparation of (5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-
dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-yl)methylene)-7-oxo-4-thia-
1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
6-[acetoxy-(5-[2-(benzyloxy)emethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-
methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-
nitro-benzyl ester (966 mg, 1.2 mmol) was suspended in 20 ml THF and 20 ml
pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45psi
hydrogen for two hours. Then it was filtered through a pad of celite and
concentrated in vacuo to remove most of the THF. The solution was then cooled to
zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified
via reverse phase HPLC using 1 liter of water followed by 5% -25% acetonitrile and
water. Water was then removed through concentrate in vacuo and 100 mg of
product was collected. MP: >250° C; H-NMR(DMSO): ? 7.66(s, 1H), 7.36(s, 1H),
7.08(m, 5H), 6.87(s, 1H), 6.85(s, 1H), 4.37 (m, 2H), 4.29 (m, 2H, CH2), 3.65 (m, 2H,
CH2), 2.73 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.02 (m, 2H, CH2).
MS: 491.1 (M+H).

Example 28
Preparation of (5R,6Z)-6-(2,3-dihydror[1,3]thiazolo[3,2-a]benzimidazol-6-
ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
sodium salt
Step 1: Preparation of (2,3-Dihydro-benzo[4,5]imidazo[2.1-b]thiazol-7-yl)-
methanol
To a round bottomed flask was added 2.83 grams of 2-Thioxo-2,3-dihydro-1H-
benzoimidazole-5-carboxylic acid methyl ester, 2.55 grams of dibromoethane and
50ml DMF and 50ml ethanol. The mixture was refiuxed for 10 hours. Then it was
concentrated to dry on a rotary evaporator. The solid was next dissolved in 100ml
THF and 20 ml of 1M LiAIH4 (in THF) was next injected within five minutes. The
reaction media was stirred at room temperature for one hour. Ethanol was next
added (~10ml), followed by 50ml 2N HCI. The aqueous layer was adjusted to basic
Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2x500ml ethyl
acetate. The combined organic layers was dried over magnesium sulfate. Filter off
the drying agent and cocentrate yielded 2.04 grams (60%) product. MS: 207.0(M+H).
H-NMR(DMSO): ? 7.34(m, 2H), 7.08 (m, 1H), 5.15(m, 1H, OH), 4.53 (m, 2H, CH2),
4.34 (m, 2H, CH2), 4.00 (m, 2H, CH2).
Step 2: Preparation of 2.3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazole-7-
carbaldehyde
To a pre-cooled (-50~-60oC) mixture of 1.7ml DMSO and 5ml dichloromathane was
injected a 20ml dichloromethane solution of 1ml oxallyl chloride within five minutes.
The mixture was stirred for another five minutes at the same temperature. Then 1.9
grams of 2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thia2ol-7-yl)-methanol in a mixture of
20ml dichloromethane and 20 ml THF was injected within 2 minutes. The mixture
was kept stirred at -50~-60°C for 15 minutes. Then 7ml triethylamine was injected
all at once and after another 5minutes the cooling bath was removed and the
reaction was warmed up to room temperature by itself. Water (100ml) was next
added and the reaction media was extracted with 2x200ml ethyl acetate. The
combined organic layers was dried over magnesium sulfate. Filter off the drying

agent and concentrate gave 1.2 grams product (64%). MS: 205.0(M+H). H-
NMR(CDCI3): D 9.98(m, 1H), 7.67 (m, 2H), 7.17 (m, 1H), 4.33(m, 2H), 3.99 (m, 2H,
CH2).
Step 3: Preparation of 6-[Acetoxy-(2,3-dihdyro-benzo[4,5]imidazo[2,1-b]thiazol-
6-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic
acid 4-nitro-benzyl ester
A 30 ml acetonitrile solution of 2,3-Dihydro-benzo[4,5]imidazo[2,1-b]thiazole-7-
carbaldehyde (610 mg, 2mmol) was added 1.03 gram of magnesium bromide
etherate. The mixture was stirred at 23oC for half an hour. Then a 30ml dry THF
solution of the 6-Bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitro-benzyl ester (770 mg, 2 mmol) was injected within a minute and the reaction
mixture was then cooled to -20oC. Triethylamine (0.7 ml, eq.) was then injected and
the reaction mixture was stirred for five hours at -20oC. Then acetic anhydride
(0.377 ml, eq.) was injected and the reaction mixture was left at zero degree for 18
hours. The reaction media was then diluted with 400ml ethyl acetate and washed
with 100 ml 5% citric acid, 100 ml saturated sodium bicarbonate, and 100ml brine.
The organic layer was then dried over magnesium sulfate, filtered and concentrated.
Rash column chromatography using 20% ethyl acetate in hexane gave 690 mg
product. (54% Yield); MS: 630.8(M+H)
Step 4: Preparation of (5R,6Z)-6-(2,3-dihydror[1,3]thiazolo[3,2-a]benzimidazol-6-
ylmethylene)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
6-[Acetoxy-(2,3-dihydro-benzo[4,5]imidazo[2,1-b]thiazol-6-yl)-methyl]-6-bromo-7-oxo-
4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (690 mg,
1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate
buffer. The mixture was then subjected to 45psi hydrogen for two hours. Then it
was filtered through a pad of celite and concentrated in vacuo to remove most of the
THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N
sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of
water followed by 5% -25% acetonitrile and water. Water was then removed
through concentrate in vacuo and 32 mg of product (Yield 3%) was collected. MP:
>250° C; H-NMR(D2O): ? 7.08(m, 6H), 7.36(s, 1H), 4.05(m, 2H), 3.90(b, 1H); MS:

Example 29
Preparation of (5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-
ylmethylene)-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
sodium salt
Step 1: Preparation of (3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol
To a round bottomed flask was added 4.06 grams of 2-Thioxo-2,3-dihydro-1 H-
benzoimidazole-5-carboxylic acid methyl ester, 4.04 grams of 1,3-dibromopropane
and 50ml DMF and 50ml ethanol. The mixture was refluxed for 10 hours. Then it
was concentrated to dry on a rotary evaporator. The solid was next dissolved in
100ml THF and 20 ml of 1M LiAIH4 (in THF) was next injected within five minutes.
The reaction media was stirred at room temperature for one hour. Ethanol was next
added (~10ml), followed by 50ml 2N HCI. The aqueous layer was adjusted to basic
Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2x500ml ethyl
acetate. The combined organic layers was dried over magnesium sulfate. Filter off
the drying agent and cocentrate yielded 3 grams (68%) product. NMR(DMSO): ?
7.91 (m, 3H), 4.13 (m, 2H), 3.93(s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS:
221.0(M+H).
Step 2: Preparation of 3,4-Dihydro-2H-1-thia-4a,9-diaza-fluorene-6-
carbaldehyde
To a round bottomed flask was loaded 1.1 grams of (3,4-Dihydro-2H-1-thia-4a,9-
diaza-fluoren-6-yl)-methanol, 6 grams of manganese dioxide and 250 ml chloroform.
The mixture was stirred for one hour at room temperature and then filtered through a
pad of celite. This yielded 0.67 grams of product (61%). MS: 219.0(M+H). H-
NMR(CDCI3): ? 10.04(s, 1H), 7.67 (m, 3H), 4.25 (m, 2H), 3.27(m, 2H), 2.50 (m, 2H).
Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-
[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-

azabicyclo[3.2.0]hept-2-ene-2-carboxylate
A 30 ml acetonitrile solution of 3,4-Dihydro-2H-1-thia-4a,9-diaza-fluorene-6-
carbaldehyde (660 mg, 3mmol) was added 1.03 gram of magnesium bromide
etherate. The mixture was stirred at 23oC for half an hour. Then a 30ml dry THF
solution of the 6-Bromo-7-oxo-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitro-benzyl ester (1.15 g, 3 mmol) was injected within a minute and the reaction
mixture was then cooled to -20oC. Triethylamine (0.7 ml, eq.) was then injected and
the reaction mixture was stirred for five hours at -20oC. Then acetic anhydride
(0.377 ml, eq.) was injected and the reaction mixture was left at zero degree for 18
hours. The reaction media was then diluted with 400ml ethyl acetate and washed
with 100 ml 5% citric acid, 100 ml saturated sodium bicarbonate, and 100ml brine.
The organic layer was then dried over magnesium sulfate, filtered and concentrated.
Flash column chromatography using 20% ethyl acetate in hexane gave 690 mg
product. (36% Yield); MS: 644.9(M+H)
Step 4: Preparation of (5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-
a]benzimldazol-7-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid
4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-
yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
(700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous
phosphate buffer. The mixture was then subjected to 45psi hydrogen for two hours.
Then it was filtered through a pad of celite and concentrated in vacuo to remove
most of the THF. The solution was then cooled to zero degree and basified to pH=8
with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1
liter of water followed by 5% ~25% acetonitrile and water. Water was then removed
through concentrate in vacuo and 75 mg of product (Yield 18%) was collected. MP:
>250° C; H-NMR(D2O): ? 7.08(m, 6H), 3.70(m, 2H), 4.05(m, 2H), 3.13(m, 2H),
2.22(m, 2H); MS: 372.1(M+H).

Example 30
Preparation of (5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-
ylmethylene)-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic
acid, sodium
salt
Step 1: Preparation of Benzo[4.5]imidazo[2.1-b]thiazole-6-carboxylic acid
methyl ester
To a round bottomed flask was loaded with 3.3 grams of 2-Thioxo-2,3-dihydro-1H-
benzoimidazole-5-carboxylic acid methyl ester, 4.5ml alpha-bromodiethylacetal, 50ml
DMF. The mixture was refluxed for 10 hours. Then is was poured into 10% sat
sodium bicarbonate (100ml) and extracted with 2x100ml ethyl acetate. The
combined organic layers were dried over magnesium sulfate. Filter off the drying
agent, concentrate to dry, flash column chromatography using 10-30% ethyl
acetate/hexane yielded 1.16 grams (32%) crude product. MS: 233.1 (M+H). H-
NMR(DMSO): 8 7.78(m, 5H), 2.04 (s, 3H, CH3).
Step 2: Preparation of Benzo[4,5]imidazo[2,1-b]thiazole-6-carbaldehyde
To a round bottomed flask was loaded 1.16 grams of (3,4-Dihydro-2H-1-thia-4a,9-
diaza-fluoren-6-yl)-methanol, 25 grams of manganese dioxide and 250 ml
chloroform. The mixture was stirred for one hour at room temperature and then
filtered through a pad of celite. This yielded 0.42 grams of product (42%). MS:
203.0(M+H). H-NMR(CDCI3): ? 10.10(ss, 1H), 8.24 (ss, 1H), 7.85 (m, 3H), 6.96 (m,
1H).
Step 3: Preparation of 4-nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-
a]benzimidazol-6-yl)methyl-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-
ene-2-carboxylate
A 30 ml acetonitrile solution of benzo[4,5]imidazo[2,1-b]thiazole-6-carbaldehyde (404
mg, 2mmol) was added 1.03 gram of magnesium bromide etherate. The mixture
was stirred at 23oC for half an hour. Then a 30ml dry THF solution of the 6-Bromo-

7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester
(770 mg, 2 mmol) was injected within a minute and the reaction mixture was then
cooled to -20oC. Triethylamine (0.7 ml, eq.) was then injected and the reaction
mixture was stirred for five hours at -20oC. Then acetic anhydride (0.377 ml, eq.)
was injected and the reaction mixture was left at zero degree for 18 hours. The
reaction media was then diluted with 400ml ethyl acetate and washed with 100 ml
5% citric acid, 100 ml saturated sodium bicarbonate, and 100ml brine. The organic
layer was then dried over magnesium sulfate, filtered and concentrated. Rash
column chromatography using 20% ethyl acetate in hexane gave 630 mg product.
(50% Yield); MS: 631.9(M+H)
Step 4: Preparation of (5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-
ylmethylene)-4-thia-1-azablcyclo[3.2.0]hept-2-ene-2-carboxylic acid
4-nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-6-yl)methyl}-6-
bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (630 mg, 1 mmol)
was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The
mixture was then subjected to 45psi hydrogen for two hours. Then it was filtered
through a pad of celite and concentrated in vacuo to remove most of the THF. The
solution was then cooled to zero degree and basified to pH-8 with 1 N sodium
hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water
followed by 5% ~25% acetonitrile and water. Water was then removed through
concentrate in vacuo and 33 mg of product (Yield 8%) was collected. MP: >250° C;
H-NMR(D2O): ? 6.89(m, 8H), 5.22(s, 2H), 5.02(s, 2H), 4.81 (s, 2H).
MS: 378.1(M+H+Na).
Example 31
Preparation of (5R,6Z)-6-[7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-
b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt
Step 1: Preparation of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy)-1H-
pyrazole-3-carboxylate:

To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (7.0 g, 45
mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0
g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction
mixture was allowed to cool to room temperature, then filtered, the solid was
washed with acetonitrile. The filtrate was concentrated to an oil. The residue was
dissolved in ethyl acetate and extracted with water. The organic phase was dried
over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was
obtainedas a white solid. M.Pt. 121-123°C; (M+H) 255.
Step 2: Preparation of ethyl 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-
b][1,3]oxazole-2-carboxylate:
A mixture of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate
(254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of acetic acid and
toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water.
The reaction mixture was allowed to cool to room temperature. The reaction mixture
was filtered. The filtrate was concentrated to an oil. The residue was dissolved in
ethyl acetate aqueous bicarbonate solution. The organic layer was washed with
water and dried over MgSO4. After removal of the ethyl acetate, the residue was
purified by silica gel chromatography eluting with ethyl acetate/hexane to give 120
mg (51%) of the desired product as white solid. Mp; 116-118° C; Electrospray-MS
m/z 237.0 (M+H)+
Step 3: Preparation of 7,8-dihydro-5H-Pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-
2-ylmethanol:
To the stirred solution of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazole-2-
carboxylate (1.5 g, 6.3 mmol) of in 100 ml of THF was added 1.05 g of lithium
borohydride and 1.54 g of methanol. The solution was heated at 40C for 2.5 hour.
The reaction was quenched by 1N HCI, and adjusted to pH 1.3 and stirred at room
temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The
reaction mixture was extracted with ethyl acetate. The organic layer was dried over
MgSO4, and concentrated to an oil and column chromatographyed to give 0.74 g of
the desired product (60%). (M+H) 196.

Step A: Preparation of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-
2-carbaldehyde:
To the stirred solution of 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-
ylmethanol (1.0 g, 5.1 mmol) in 60 ml of CHCI3 was added 8 g of Mn02. Th
suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction
mixture was filtered through a pad of Celite. The filtrate was concentrated to give
yellow oil. The product was purified by chromatography. 0.79 g of the product was
obtained (80%); (M+H) 193
Step 5:4-Nitrobenzyl (5R)-6-[(acetyloxy)(7,8-dihydro-5H-
pyrano[4,3]pyrazolo[5,1 -b][1,3]oxazol-2-yllmethyl] -6-bromo-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylate
7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-carbaldehyde (600 mg,
3.1 mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-
aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.54 g, 4.6
mmol) were added successively to the dry acetonitrile (15 mL) solution of
anhydrous MgBr2: O(Et)2 (2.21 g , 8.5 mmol)under an argon atmosphere at room
temperature. After cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The
reaction vessel was covered with foil to exclude light. The reaction mixture was
stirred for 2 h at -20 °C and treated with acetic anhydride (1.04 mL) in one portion.
The reaction mixture was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture
was diluted with ethyl acetate and washed with 5% citric acid aqueous solution,
saturated sodium hydrogen carbonate, and brine. The organic layer was dried
(MgSO4) and filtered through a pad of Celite. The pad was washed with ethyl
acetate. The filtrate was concentrated under reduced pressure. The residue was
applied to silica gel column chromatography, then the column was eluted with ethyl
acetate: hexane (1:1). Collected fractions were concentrated under reduced
pressure and the mixture of diastereo isomers were taken to next step. Pale yellow
amorphous solid; Yield: 1.35 g, 70%; (M+H) 619.

Step 6: Preparation of (5R, 6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-
b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt & (5R,6E)-6-(7,8-dihydro-5H-pyrano[4,3-
d]pvrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-oxo-4-thia-1-
azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid, sodium salt
4-Nitrobenzy(5R)-6-[(acetyloxy)(7,8-dihyclro-5H-pyrano[4,3]pyrazolo[5,1-
b][1,3]oxazol-2-yl)methyl] -6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate (1.2 g, 1.9 mmol) was dissolved in THF (20 ml), acetonitrile (10 mL) and
0.5 M phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% Pd/C at 40 psi
pressure. After 4 hrs the reaction mixture was filtered, cooled to 3 °C, and 0.1 M
NaOH was added to adjust pH to 8.5. The filtrate was washed with ethyl acetate and
the aqueous layer was separated. The aqueous layer was concentrated under high
vacuum at 35 °C to give yellow precipitate. The product was purified by HP21 resin
reverse phase column chromatography. Initially the column was eluted with
deionized water (2 lits) and latter with 10% acetonitrile: Water. The fractions
containing the product were collected and concentrated at reduced pressure at room
temperature. The yellow solid was washed with acetone and filtered. In this reaction
both E and Z isomers were formed and they were separated by prep. HPLC.
(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxazol-2-ylmethylene)7-
oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt: Yield 87
mg, (25%); Yellow solid; (M+H+Na) 368.2.
H-NMR (D2O): 7.04 (1H, s), 7.01 (1H, s), 6.45 (1H, s), 6.09 (1H, s), 4.76 (2H, m),
4.12 (2H,m), 2.96 (2H,m).
(5R,6E)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]oxa2ol-2-ylmethylene)7-
oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt: Yield 75
mg, (21%); Yellow solid; (M+H+Na) 368.2.
H-NMR (D2O): 7.08 (1H, s), 6.81 (1H, s), 6.71 (1H, s), 6.40 (1H, s), 4.68 (2H, m),
4.03 (2H, m), 2.87 (2H, m).

Example 32
Preparation of (5R,6Z)-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-
b][1,3]benzoxazol-2-ylmethylene)-thia--1 -azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt
Step 1: Preparation of ethyl-5-[(2oxocyclohexyl)oxy]-1H-pyrazole-3-
carboxylate;
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (6.25 g, 40
mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35
g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was
allowed to cool to room temperature, then filtered, the solid was washed with
acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in
ethyl acetate and extracted with water. The organic phase was dried over MgSO4
and evaporated to dryness. The product was purified by silics-gel column
chromatography by eluting it with 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the
desired product was obtained as a white solid. M.Pt. 122-124°C; (M+H) 253.
Step 2: Preparation of ethyl 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-
2-carboxylate:
A mixture of ethyl-5-[(2-oxocyclohexyl)oxy]-1 H-pyrazole-3-carboxylate
(127.6 mg, 0.5 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid and
toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water.
The reaction mixture was allowed to cool to room temperature. The reaction mixture
was filtered. The filtrate was concentrated to an oil. The residue was dissolved in
ethyl acetate and aqueous bicarbonate solution. The organic layer was washed with
water and dried over MgSO4. After removal of the ethyl acetate, the residue was
purified by silica gel chromatography eluting with 1:1 ethyl acetate/hexane to give
69.7 mg (59%) of the desired product as white solid. Mp; 55-57° C; Electrospray-MS
m/z 235.0 (M+H)+

Step 3: Preparation of 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazol-2-
ylmethanol:
To the stirred solution of ethyl 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-
carboxylate (3.84 g, 16.4 mmol) of in 100 ml of THF was added 3.05 g of lithium
borohydride and 3 ml of methanol. The solution was heated at 40C for 2.5 hour.
The reaction was quenched by 1N HCI, and adjusted to pH 1.3 and stirred at room
temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The
reaction mixture was extracted with ethyl acetate. The organic layer was dried over
MgSO4, and concentrated to an oil and column chromatographyed to give 2.62 g of
the desired product (83%). Mpt. 82-84°C; (M+H) 193.
Step 4: Preparation of 5,6,7,8-tetrahydropvrazolo[5,1-b][1,3]benzoxazole-2-
carbaldehyde:
To the stirred solution of 5,6,7,8-tetraihydropyrazolo[5,1-b][1,3]benzoxazol-2-
ylmethanol (2.30 g, 11.97 mmol) in 60 ml of CHCI3 was added 10 g of MnO2. Th
suspension was refluxed for 1.5 hour under a nitrogen atmosphere. The reaction
mixture was filtered through a pad of Celite. The filtrate was concentrated to give
yellow solid. The product was purified by chromatography. 1.95 g of the product
was obtained (85.5%); (M+H) 191
Step 5: 4-Nitrobenzy (5R)-6-[(acetyloxy)(5,67,8-tetrahydropyrazolo[5,1-
b][1,3]benzoxazol-2-yl)methyl-6-bromo-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-
ene-2-carboxylate
5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole-2-carbaldehyde (589 mg, 3.1
mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-bromo-7-oxo-4-thia-1-aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.54 g, 4.6 mmol)
were added successively to the dry acetonitrile (15 mL) solution of anhydrous
MgBr2: O(Et)2 (2.21 g , 8.5 mmol)under an argon atmosphere at room temperature.
After cooling to -20 °C, Et3N (2.0 mL) was added in one portion. The reaction
vessel was covered with foil to exclude light. The reaction mixture was stirred for 2
h at -20 °C and treated with acetic anhydride (1.04 mL) in one portion. The

reaction mixture was warmed to 0 °C and stirred for 15 h at 0 °C. The mixture was
diluted with ethyl acetate and washed with 5% citric acid aqueous solution,
saturated sodium hydrogen carbonate, and brine. The organic layer was dried
(MgSO4) and filtered through a pad of Celite. The pad was washed with ethyl
acetate. The filtrate was concentrated under reduced pressure. The residue was
applied to silica gel column chromatography, then the column was eluted with ethyl
acetate: hexane (1:1). Collected fractions were concentrated under reduced
pressure and the mixture of diastereo isomers were taken to next step. Pale yellow
amorphous solid; Yield: 792 mg, 42%; M.pt 160-162°C; (M+H) 618.
Step 6: Preparation of (5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1-
b][1.3]benzoxazol-2-ylmethylene)-4-thia- -1 -azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid, sodium salt
4-Nitrobenzy(5R)-6-[(acetyloxy)(5,67,8-tetrahydropyra2olo[5,1-b][1,3]benzoxazol-2-
yl)methyl-6-bromo-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylate (318
mg, 0.5 mmol) was dissolved in THF (20 mL), acetonitrile (10 mL) and 0.5 M
phosphate buffer (pH 6.5,28 mL) and hydrogenated over 10% Pd/C (100 mg) at 40
psi pressure. After 4 hrs the reaction mixture was filtered, cooled to 3 °C, and 0.1 M
NaOH was added to adjust pH to 8.5. The filtrate was washed with ethyl acetate and
the aqueous layer was separated. The aqueous layer was concentrated under high
vacuum at 35 °C to give yellow precipitate. The product was purified by HP21 resin
reverse phase column chromatography. Initially the column was eluted with
deionized water (2 lits) and latter with 10% acetonitrile: Water. The fractions
containing the product were collected and concentrated at reduced pressure at room
temperature. The yellow solid was washed with acetone and filtered. Yield 150 mg,
(76%); Yellow solid; (M+H+Na) 365.2.
H-NMR (D2O): ? 6.92 (1H, s), 6.91 (1H, s), 6.32 (1H, s), 5.85 (1H, s), 2.59 (4H, m),
1.80 (4H,m).

Example 33
Preparation of (5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-
tetrahydropyrazolo[5',1':2.3][1,3]oxazolo[5,4-c]pyridin-2-yl]methvlene)-7-oxo-4-
thia--1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Step 1: Preparation of ethyl 3-{[3-ethoxycarbonyl)-1H-pyrazol-5-yl]oxy]-4-
oxopiperidine-1-carboxylate:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (19.5 g,
127 mmol) and 50.0 g of potassium carbonate in 500 ml of acetonitrile was added
3-bromo-4-oxo-piperidine-1-carboxylic acid ethyl ester (37.45 g, 149 mmol), and
refluxed for 16 hours. The reaction mixture was allowed to cool to room
temperature, then filtered, the solid was washed with acetonitrile. The filtrate was
concentrated to an oil. The residue was dissolved in ethyl acetate and extracted
with water. The organic phase was dried over MgSO4 and evaporated to dryness.
The product was purified by silics-gel column chromatography by eluting it with 1:1
ethyl acetaet;hexane. 8.5 g (19%) of the desired product was obtained as an
yellow oil. (M+H) 326.
Step 2: Preparation of diethyl 7.8-tetrahydropyrazolo[5'
,1 ':2,3][1,3]oxazolo[5,4-c]pyridine-2,6(5H)-dicarboxylate:
A mixture of ethyl 3-{[3-ethoxycarbonyl)-1H-pyrazol-5-yl]oxy}-4-oxopiperidine-1-
carboxylate (325 mg, 1 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic
acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to
remove water. The reaction mixture was allowed to cool to room temperature. The
reaction mixture was filtered. The filtrate was concentrated to an oil. The residue
was dissolved in ethyl acetate and aqueous bicarbonate solution. The organic layer
was washed with water and dried over MgSO4. After removal of the ethyl acetate, the
residue was purified by silica gel chromatography eluting with 1:1 ethyl
acetate/hexane to give 175 mg (57%) of the desired product as an yellow oil
Electrospray-MS m/z 308.0 (M+H)+

Step 3: Preparation of ethyl 2-(hydroxymethyl)-7,8-dihydropyrazolo [5'
.1':2,3][1,3]oxazolo[5,4-c]pyridine-6(5H-carboxylate
To the stirred solution of diethyl 7,8-tetrahydropyrazolo[5' ,1':2,3][1,3]oxazolo[5,4-
c]pyridine-2,6(5H)-dicarboxylate (307 mg, 1 mmol) of in 40 ml of THF was added
305 mg of lithium borohydride and 1 ml of methanol. The solution was heated at
40C for 2.5 hour. The reaction was quenched by 1N HCI, and adjusted to pH 1.3
and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH
to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic
layer was dried over MgSO4, and concentrated to an oil and column
chromatographyed to give 172 mg of the desired product (65%); (M+H) 266.
Step 4; Preparation of ethyl 2-formvl-7.8-dihydropyrazolo [5'
.1':2.3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate
To the stirred solution of ethyl 2-(hydroxymethyl)-7,8-dihydropyrazolo [5'
,1':2,3][1,3loxazolo[5,4-c]pyridine-6(5H)-carboxylate (1.76 g, 6.6 mmol) in 60 ml of
CHCI3 was added 10 g of MnO2. Th suspension was refluxed for 1.5 hour under a
nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite.
The filtrate was concentrated to give yellow solid. The product was purified by
chromatography. 1.43 g of the product was obtained (82%); M.pt: 97-99°C (M+H)
264.
Step 5: Preparation of ethyl 2-[(acetyloxy)(5R)-6-bromo-2-Z{(4-
nitrobenzyl)oxylcarbonyl) -7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-en-6-
yl)methyl]-7,8-dihydropyrazolo[5',1':2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-
carboxylate
Ethyl 2-formyl-7,8-dihydropyrazolo [5' ,1':2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-
carboxylate (790 mg, 3. mmol) and the dry THF solution (20 mL) of (5R, 6S)-6-
bromo-7-oxo-4-thia-1 -aza-bicyclo[3.2.01hept-2-ene-2-carboxylic acid 4-nitro-benzyl
ester (1.54 g, 4.6 mmol) were added successively to the dry acetonitrile (15 mL)
solution of anhydrous MgBr2: O(Et)2 (2.21 g , 8.5 mmoi)under an argon atmosphere
at room temperature. After cooling to -20 °C, Et3N (2.0 mL) was added in one
portion. The reaction vessel was covered with foil to exclude light. The reaction
mixture was stirred for 2 h at -20 °C and treated with acetic anhydride (1.04 mL) in

one portion. The reaction mixture was warmed to 0 °C and stirred for 15 h at 0 °C.
The mixture was diluted with ethyl acetate and washed with 5% citric acid aqueous
solution, saturated sodium hydrogen carbonate, and brine. The organic layer was
dried (MgSO4) and filtered through a pad of Celite. The pad was washed with ethyl
acetate. The filtrate was concentrated under reduced pressure. The residue was
applied to silica gel column chromatography, then the column was eluted with ethyl
acetate: hexane (1:1). Collected fractions were concentrated under reduced
pressure and the mixture of diastereo isomers were taken to next step. Pale yellow
amorphous solid; Yield: 1.67 g, 81%; (M+H) 690.
Step 6: Preparation of (5R,6Z)-6-{[6-(ethoxycarbonyl-5,6,7,8-
tetrahydropyrazolo[5',1':2,3][1,3]oxazolo[5,4-c]pyridin-2-yl]methylene)-7-oxo-4-
thia--1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt
Ethyl 2-[(acetyloxy)(5R)-6-bromo-2-Z{I(4-nitrobenzyl)oxy]carbonyl} -7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-en-6-yl)methyll-7,8-
dihydropyrazolo[5',1 ':2,3][1,3]oxazolo[5,4-c]pyridine-6(5H)-carboxylate
(828 mg, 0.5 mmol) was dissolved in THF (20 mL), acetonitrile (10 mL) and 0.5 M
phosphate buffer (pH 6.5, 28 mL) and hydrogenated over 10% Pd/C (200 mg) at 40
psi pressure. After 4 hrs the reaction mixture was filtered, cooled to 3 °C, and 0.1 M
NaOH was added to adjust pH to 8.5. The filtrate was washed with ethyl acetate and
the aqueous layer was separated. The aqueous layer was concentrated under high
vacuum at 35 °C to give yellow precipitate. The product was purified by HP21 resin
reverse phase column chromatography. Initially the column was eluted with
deionized water (2 lits) and latter with 10% acetonitrile: Water. The fractions
containing the product were collected and concentrated at reduced pressure at room
temperature. The yellow solid was washed with acetone and filtered. Yield 375 mg,
(71%); Yellow solid; (M+H+Na) 438.4.
H-NMR (D2O): ? 6.96 (1H, s), 6.94 (1H, s), 6.41 (1H, s), 6.00 (1H, s), 4.53 (2H, m),
4.13 (2H,q), 3.78 (2H,m), 2.78 (2H, m), 1.21 (3H, t).

WE CLAIM:
1. A process for preparing a compound of formula I

wherein:
one of A and B denotes hydrogen and the other an optionally substituted fused
tricyclic heteroaryl group;
X is S or O;
R5 is H, C1 -C6 alkyl, C5 - C6 cycloalkyl, or CHR3OCOC1-C6alkyl; and
R3 is hydrogen, C1-C6 alkyl, C5 - C6 cycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof;
which comprises subjecting to reductive elimination a compound of fomula II:

wherein A' is A or B as defined above, X is O or S, P is an ester leaving group, and
R is a protecting group, group, followed if necessary by removal of the protecting
group, to give a compound of formula I wherein R5 is hydrogen; and if desired
converting to a pharmaceutically acceptable salt or to an ester wherein R5 is C1 -C6
alkyl, C5 - C6 cycloalkyl, or CHR3OCOC1-C6alkyl.
2. A process according to claim 1 wherein the tricyclic heteroarylgroup has the
formula

wherein Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are independently CR2 , N, O, S or N-R1
provided one of Z1 - Z7 is a carbon atom to which the remainder of the molecule is
attached;
R1 is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted
heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted
cycloalkyl, optionally substituted alkenyl, optionally substituted 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
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=Oalkyl, optionally substituted -
C=Ocycloalkyl, optionally substituted -C=O mono or bicyclic saturated
heterocycles, optionally substituted C1-C6 alkylaryl, optionally substituted C1-
C6 alkylheteroaryl, optionally substituted aryl-C1-C6alkyl, optionally
substituted heteroaryl-C1-C6alkyl, optionally substituted C1-C6 alkyl mono or
bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16
carbon atoms, -CONR6R7, -SO2NR6R7, 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;

R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6
alkenyl, optionally substituted C2-C6 alkynyl, halogen, cyano, N-R6R7,
optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl,
optionally substituted heteroaryl, COOR6, optionally substituted
alkylaryloxyalkylamines, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted
C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylenedioxy, 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,
CONR6R7, guanidino or cyclic guanidino, optionally substituted 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, SO2NR6R7, optionally substituted
arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted
heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted
aryloxyheteroaryl, optionally substituted heteroaryloxyaryl, optionally
substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6
alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally
substituted heteroaryloxyalkyl, or optionally substituted
alkylaryloxyalkylamine;
R6 and R7 are independently H, optionally substituted C1-C6 alkyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted C1-
C6 alkyl aryl, optionally substituted arylalkyl, optionally substituted
heteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, or R6 and R7
can be together to form a 3-7 membered saturated ring system optionally
having one or two heteroatoms selected from N-R,, O, and S(O)n n = 0-2;
and
Y1, Y2, Y3 and Y4 may independently be C or N.
3. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4, Z5 , Z6, Z7 and Z8 are independently CR2 , N, O, S or N-R1
provided one of the Z1 - Z8 is a carbon atom to which the remainder of the molecule
is attached; and R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2.
4. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4, Z5 , Z6, Z7 and Z8 are independently CR2, N, O, S or N-R1
provided one of Z1 - Z8 is a carbon atom to which the remainder of the molecule is
attached; and R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2.
5. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1 , Z2, Z3, Z4, Z5, Z6, Z7, Z8 and Z9 are independently CR2, N, O, S or N-R1
provided one of the Z1 - Z9 is a carbon atom to which the remainder of the molecule
is attached;and R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2.
6. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1 , Z2 , Z3 and Z4 are independently CR2, N, O, S or N-R provided one of Z1
- Z4 is a carbon atom to which the remainder of the molecule is attached;
W1, W2 and W3 are independently CR4R4, S(O)r ( r = 0 -2) , O, or N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;

and
= 1 to 3.
7. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4 and Z5 are independently CR2, N, O, S or N-R1 provided one
of Z1 - Z5 is a carbon atom to which the remainder of the molecule is attached;
Y1, and Y2 are independently C or N;
W1, W2 and W3 are independently CR4R4 , S(O)r ( r = 0 -2) , O, or N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring; R1, R2, R6, and R7, are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t = 1 to 3.
8. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1 , Z2, Z3, Z4, Z5 and Z6 are independently CR2 , N, O, S, and N-R1;
provided one of Z1 - Z6 is a carbon atom to which the remainder of the molecule is
attached;
W1 and W2 are independently CR4R4 , S(O)r ( r = 0 -2) , O, N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t = 1 to 3.
9. A
process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1 , Z2, Z3, Z4, Z5, Z6 and Z7 are indepdently CR2, N, O, S or N-R1 provided
one of the Z1 - Z7 is a carbon atom to which the remainder of the molecule is
attached;
W1 and W2 are independently CR4R4 , S(O)r (r = 0 -2), O, or N-R1 with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
or optionally R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are
not OH), C1-C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7; or R4R4
may together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t = 0-3.
10. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2 and Z3 are independently CR2 N, O, S or N-R1 provided one of Z1 -
Z3 is a carbon atom to which the remainder of the molecule is attached;
Y1 and Y4 are independently C or N;
Y2 and Y3 are independently CH or N;
W1, W2 W3, W4 and W5 are independently CR4R4, S(O)r (r = 0 -2), O, or N-R1 with
the proviso that no S-S, S-0 or O-O bond formation can occur to form a
saturated ring;
R1, R2, R6, and R7 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may

together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
t = 0 to 2; and
u = 1 to 3.
11. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8 and Z9 are independently CR2, N, O, S or N-R1
provided one of the Z1 - Z9 is a carbon atom to which the remainder of the molecule
is attached; R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2.
12. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2,Z3, Z4, Z5, Z6, Z7, Z8, Z9 and Z10 are independently CR2, N, O, S or N-
R1 provided one of Z1 - Z10 is a carbon atom to which the remainder of the molecule
is attached; and R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2.

13. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4 and Z5 are independently CR2, N, O, S or N-R1 provided that
one of Z1- Z5 is a carbon atom to which the remainder of the molecule is attached;
W1, W2, W3 are independently CR4R4 O, N-R1, or S=(O)r (r = 0-2) with the proviso
that no S-S, S-O or O-O bond formation can occur to form a saturated ring;
and R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t=1-4.
14. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3, Z4, Z5 and Z6 are independently CR2, N, O, S or N-R1 provided
one of Z1 - Z6 is a carbon atom to which the remainder of the molecule is attached;

W1, W2 and W3 are independently CR4R4 , S(O)r ( r = 0 -2) , O, or N-R1 with the
proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring;
R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COORe, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t = 1 to 3.
15. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1 , Z2, Z3, Z4, Z5, Z6, Z7 and Z8 are independently CR2, N, O, S or N-R1
provided one of Z1 - Z8 is a carbon atom to which the remainder of the molecule is
attached;
W1, and W2 are independently CR4R4 , S(O)r (r = 0 -2), O, or N-R1 with the proviso
that no S-S, S-O or 0-0 bond formation can occur to form a saturated ring;
R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COORe, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
and
t = 1 to 2.

16. A process according to claim 1 wherein the tricyclic heteroaryl group is

wherein Z1, Z2, Z3 and Z4 are independently CR2, N, O, S or N-R1 provided one of
Z1 - Z4 is a carbon atom to which the remainder of the molecule is attached;
W1, W2 , W3, W4 and W5 are independently CR4R4 , S(O)r (r = 0 -2) , O, or N-R1
with the proviso that no S-S, S-O or O-O bond formation can occur to form a
saturated ring;
R1, R2, R6, R7, Y1, Y2, Y3 and Y4 are as defined in claim 2;
R4 is H, optionally substituted C1-C6 alkyl, OH (provided both R4 are not OH), C1-
C6 alkoxy, -S-C1-C6 alkyl, COOR6, -NR6R7, -CONR6R7 ; or R4R4 may
together be =O or R4R4 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 N, O, S(O)n (where n =O to 2), N-R1;
t = 1 to 3; and
u = 1 to 3.
17. A process according to any one of claim 1 to 16 wherein the compound has the
formula

18. A process according to any one of claims 1 to 17 wherein X is S.
19. A process according to claim 1in which the product is selected from one of the
following:
(5R,6Z)-6-(lmidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6Z)-6-[(7-methoxyimidazo[2,1 -b][1,3lbenzothiazol-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6Z)-6-[(7-chloroimidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-6-lmidazo[1,2-a]quinolin-2-ylmethylene-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-6-(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1 -b][1,3]thiazol-2-ylmethylene)-
7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-6-(lmidazo[1.2-a]quinoxaline-2-ylmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0] hepto-2-ene-2-carboxylic acid, sodium salt;
(5R,6Z)-6-[(7-methylimidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.01hept-2-ene-2-carboxylic acid;
(5R), (6Z)-6-(4,5,6,7-tetrahydro-1,3a,3b,8-tetraaza-cyclopenta[a]indene-2-
ylmethylene)-7-oxo-4-thia-1 -aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium
salt;
(5R,6E)-6-[(10-benzyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-8-
yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic
Acid;
6-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-ylmethylene)-7-oxo-4-thia-1-
aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6E&Z)-7-oxo-6-(4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethylene)-4-thia-
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
(5R), (6Z)-6-(5H-lmidazo[2,1 -a]isoindol-2-ylmethylene)-7-oxo-4-thia-1 -aza-
bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt;
(5R,6Z)-6-[(5-methylimidazo[2,1 -b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1 -
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6Z)-6-[(7-fluoroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-7-oxo-4-thia-1-

azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-6-(imidazo[2,1-b]bebzothiazol-7-ylmethylene)-7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-2-ylmethylene)-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-8-[(9-methyl-9H-imidazo[1,2-a]benzimidazol-2-yl)methylene]-7-oxo-4-thia-
1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6Z)-7-oxo-6-(4H-thieno[2',3':4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Sodium salt);
(5R,6Z)-7-oxo-6-(4H-thieno[2',3,:4,5]thiopyrano[2,3-b]pyridin-2-ylmethylene)-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Sodium salt);
(5R,6Z)-6-[(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-
yl)methylene]-7-oxo-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium
salt;
(5R,6Z)-6-{(7-ethoxycarbonyl)6,7,8, 9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-
a]pyrimidin-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic
acid, sodium salt;
(5R,6Z)-6-(8',9'-dihydro-6'H-spiro[1,3-dioxolane-2,7'-[1,2,4]triazolo[1,5-a]quinazolin]-
2'-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium
salt;
(5R,6Z)-6-[(5-methyl-6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazolin-2-
yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium
salt;
(5R,6Z)-6-[(5-methoxy-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidin-2-
yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium
salt;
(5R,6Z)-6-({5-[2-(benzyloxy)ethoxy]-7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-
a]pyrimidin-2-yl}methylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic
acid, sodium salt;
(5R,6Z)-6-(2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-7-oxo-4-thia-
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
(5R,6Z)-6-(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-ylmethylene)-7-oxo-4-
thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

(5R,6Z)-7-oxo-6-([1,3]thiazolo[3,2-a]benzimidazol-6-ylmethylene)-4-thia-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt.
20. A compound according to claim 1 selected from the group consisting of
(5R),(6Z)-6-(7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazol-2-
ylmethylene)-7-oxo-6-4-thia-1 - azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazol-2-ylmethylene)-
4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;
(5R,6Z)-6-(7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1 -b][1,3]oxazol-2-ylmethylene)7-
oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;
(5R,6Z)-7-oxo-6-(5,6,7,8-tetrahydropyrazolo[5,1 -b][1,3]benzoxazol-2-ylmethylene)-4-
thia- -1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt; and
(5R,6Z)-6-{[6-(ethoxycarbonyl)-5,6,7,8-tetrahydropyrazolo[5',1':2,3][1,3]oxazolo[5,4-
c]pyridin-2-yl]methylene}-7-oxo-4- thia- -1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic
acid, sodium salt.
21. A process according to claim 1 which is which is carried out to prepare
(5R),(6Z)-6-(5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazol-2-ylmethylene)-
7-oxo-4-thia-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
22. A process according to claim 1 which is carried out to prepare (5R),(6Z)-6-
(6,7-dihydro-5H-cyclopenta[d]imidazo[2,1 -b][1,3]thiazol-2-ylmethylene)-7-oxo-4-thia-
1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
23. Use of a compound of formula I as illustrated and defined in claim 1
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the
preparation of a medicament for the treatment of bacterial infection or disease.
24. Use according to claim 23 wherein the compound is to be co-administered
with a betalactam antibiotic.
25. Use according to claim 24 wherein the ratio of ?-lactam antibiotic to the
compound is in a range from about 1:1 to about 100:1.

26. Use according to claim 25 wherein the ratio of the ?-lactam antibiotic to the
compound is less than 10:1.
27. A process for the preparation of a pharmaceutical composition which
comprises bringing a pharmaceutically acceptable carrier into association with a
compound of formula I as illustrated and defined in claim 1 or a pharmaceutically
acceptable salt or in vivo hydrolysable ester
thereof.

A process for preparing a compound of formula I
wherein:
one of A and B denotes hydrogen and the other an optionally substituted fused
tricyclic heteroaryl group;
X is S or O;
R5 is H, C1 -C6 alkyl, C5 - C6 cycloalkyl, or CHR3OCOC1-C6alkyl; and
R3 is hydrogen, C1-C6 alkyl, C5 - C6 cycloalkyl, optionally substituted aryl, or
optionally substituted heteroaryl;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof;
which comprises subjecting to reductive elimination a compound of fomula II:
wherein A' is A or B as defined above, X is O or S, P is an ester leaving group, and
R is a protecting group, group, followed if necessary by removal of the protecting
group, to give a compound of formula I wherein R5 is hydrogen; and if desired
converting to a pharmaceutically acceptable salt or to an ester wherein R5 is C1 ~C6
alkyl, C5 - C6 cycloalkyl, or CHR3OCOC1-C6alkyl.