CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority under 35 U. S. C. § 119 (e) of provisional application 60/477,636, filed June 10,2003, which is hereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to inhibitors of F-lactamase and methods of use thereof. Specifically, the invention relates to non-ß-lactam-based inhibitors of ß- lactamase.

BACKGROUND OF THE INVENTION Drug resistance to antibiotics, especially 0-lactam antibiotics such as penicillin, cephalosporin and related compounds is one of the most serious problems in the treatment of infectious diseases (Neu, Science, 257,1064-1073 (1992) ). It represents not only a significant medical problem but a major public health and economic burden.

Between 1980 and 1992, the death rate, due to infectious diseases as the underlying cause of death, increased 58%, from 41 to 65 deaths per 100,000 population in the U. S.

Age adjusted mortality from infectious diseases increased 39% during the same period.

Infectious disease mortality increased 25% among those aged 65 years and older (from 271 to 338 per 100, 000) and 6. 3 times among 25-44 year olds (from 6 to 38 per 100, 000). Mortality due to respiratory tract infections increased 20% (from 25 to 30 deaths per 100,000). Reports from the Center for Disease Control (CDC) indicate that two million Americans acquire infections in hospitals each year, the cost of which runs to an estimated $4.5 billion. Of these infections, 70% are due to microbes that are resistant to one or more antibiotics and in 30-40% of the infections the causative microbe is resistant to first line treatment. The rate at which patients acquire infections in

hospitals rose by 36% in 1995 compared with 1975. In 1995,35. 9 million patients entered hospitals in the U. S. compared with 37.7 million patients in 1975. For the same period, lengths of hosptial stays dropped to an average of 5.3 days from 7.9 days due to managed health care guidelines. However, the number of infections per 1,000 patient days rose to 9.77 from 7.18.

Without being limited to any particular theory or mechanism of action, it is believed that evolutionary selection and genetic transformation have made this problem pressing. Most antibiotic drugs are derivatives of naturally occurring bactericides (Davies, Science, 264,375-382 (1994) ), and many resistance mechanisms evolved long ago. Human use of antibiotics has refined these mechanisms and promoted their spread through gene transfer (Davies, Science, 264,375-382 (1994) ). A resistance mechanism originating in one species of bacteria can be expected to spread throughout the biosphere. fol-lactam antibiotics inhibit bacterial cell wall biosynthesis (Tomasz, Rev.

Infect. Dis., 8, S270-S278 (1986) ). They form covalent complexes with and consequently inactivate a group of transpeptidases/carboxypeptidases called the Penicillin Binding Proteins (PBPs). PBP inactivation disrupts cell wall biosynthesis, leading to self-lysis and death of the bacteria. 0-lactam antibiotics have been widely prescribed. In the absence of resistance, fl-lactams are the first choice for treatment in 45 of 78 common bacterial infections (Goodman & Gilman's The Pharmacological Basis of Therapeutics (Hardman et al. , eds. , McGraw-Hill, New York, 1996) ).

Bacterial adaptations to 0-lactam drugs (e. g., amoxicillin, cephalothin, clavulanate, and aztreonam) are among the best studied and most pernicious forms of antibiotic resistance. Without being limited to any particular theory or mechanism of action, it is believed that bacteria use several different mechanisms to escape from ß- lacta, m antibiotics (Sanders, Clinical Itifectious Disease, 14., 1089-1099 (1992) ; Li et al., Antimicrob. Agents Chemother., 39, 1948-1953 (1995)). Probably the most widespread is the hydrolysis of ß-lactams by ß-lactamase enzymes.

ß-lactamases are endogenous bacterial enzymes that destroy fol-lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the ß-lactam ring. The structures of many ß-lactamases are known at the atomic level and available in the protein database. At least four classes of ß-lactamases are known: Classes A, B, C and D. At the clinical level9 the most important ß-lactamases belong to Class A (TEM) and Class C (AmpC). TEM and Amp-C are serine hydrolases and have a

critical serine in their catalytic site. TEM and AmpC) among different bacterial species share high sequence identity and structural similarity (Galleni, et al., Biochem. J., 250, 753-760 (1988) ; Galleni, et al., Biochem. J., 250,753-760 (1988) ; Usher et al., Biochemistry, 30,16082-16092 (1998) ).

One way to overcome the negative effects of ß-lactamases is to use molecules that neutralize the action of ß-lactamase (known as ß-lactamase inhibitors or inhibitors of ß-lactamase) in combination with antibiotics. The three ß-lactamase inhibitors currently in clinical use (clavulanic acid, sulbactam and tazobactam) are all transition state analogs that utilize the same 0-lactam core that is present in the antibiotics themselves.

The similarity between the ß-lactam antibiotics and ß-lactam-based ß lactamase inhibitors has proven to be a serious problem. Resistance to such 0-lactam- based 0-lactamase inhibitors arises through modifications of previously susceptible mechanisms. Certain mutations in 0-lactamase, for example, reduce the effectiveness of 0-lactam-based 0-lactamase inhibitors while preserving the ability of the (3-lactamase to hydrolyze the antibiotic molecules. Certain point substitutions in ß-lactamases allow the enzymes to hydrolyze compounds designed to evade them (Philippon et al., Antifnicrob.

Agents Chemother., 33,1131-1136 (1989)). Other substitutions reduce the affinity ouf 0- lactam inhibitors for the enzymes (Saves, et al., J Biol. Chem., 270, 18240-18245 (1995) ) or allow the enzymes to simply hydrolyze them. Furthermore, several gram- positive bacteria (e. g., Staph. Aureus) have acquired sensor proteins that detect ß-lactams in the environment of the cell (Bennet and Chopra, Antimicrob. Agents Chemotherapy, 37,153-158 (1993) ). fol-lactam binding to these sensors leads to transcriptional up- regulation of the j6-lactamase. ß-lactam-based j6-lactamase inhibitors, thus, can induce the production of the he enzyme that they are meant to inhibit, preventing or reducing their efficacy.

Without being limited to any particular theory or mechanism of action, it is believed that one reason that bacteria have been able to respond rapidly with"new" resistance mechanisms to ß-lactam-based inhibitors is that the mechanisms of action of the inhibitors are not, in fact, new, because p-lactamases have evolved mechanisms for, e. g. , sensing and/or hydrolyzing such molecules. Accordingly, as long as medicinal chemistry focuses on 0-lactam-based molecules to overcome 0-lactaniases, resistance can be expected to follow shortly.

One way to avoid recapitulating this"arms race"between bacteria and lactams is to develop non-p-lactam inhibitors that have novel chemistries and are dissimilar to ß-lactams. Such non-ß-lactam inhibitors would not themselves be degraded by ß-lactamases, and mutations in the enzymes would not be expected render such inhibitors labile to hydrolysis. Such novel inhibitors would also escape detection by ß- lactam sensor proteins that up-regulate 0-lactamase transcription, and may be unaffected by porin mutations that limit the access of (3-lactams to PBPs. Such inhibitors would allow the current ß-lactam antibiotics to effectively work against bacteria where/3- lactamases provide the dominant resistance mechanism.

It has previously been reported that boric acid and certain phenyl boronic acids are inhibitors of certain ß-lactamases (Koehler and Lienhard, (1971) ; Kiener and Waley, Biochenz. A, 169,197-204 (1978) (boric acid, phenylboronic acid and m- aminophenylboronate); Beesley et al., Biochem. J., 209,229-233 (1983) (twelve substituted phenylborinic acids, including 2-fonnylphenylboronate, 4- formylphenylboronate, and 4-methylphenylboronate ; and Amicosante et al., J.

Chemotherapy, 1, 394-398 (1989) (boric acid, phenylboronic acid, m- aminophenylboronate and tetraphenylboronic acid) ). m-(dansylamidophenyl)-boronic acid has been reported to inhibitor of the Enterobacter cloacae P99 ß-lactamase (Dryjanski and Pratt, Biochemistry, 34,3561-3568 (1995) ). In addition, Strynadka and colleagues used the crystallographic structure of a mutant TEM-1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [ (1R)-1-acetamido-2- (3- carboxyphenyl) ethane boronic acid] with high affinity for this enzyme. (Strynadka et al., Nat. Struc. Biol., 3, 688-695 (1996) ).

Additional boronic acid-based compounds with demonstrated or potential ability to inhibit b-lactamases have been reported in Tondi et al. (Chemistry & Biology, 8, 593-610 (2001), Martin et al. (Bioorganic & Medicinal Chemistry Letters, 4(10), 1229-1234 (1994), , Weston et al. (J. Med. Chem., 41, 4577-4586 (1998) and U. S. Patents No. 6, 0759014 and 6, 184,363 Many of the compounds described above are peptide derivatives or peptidyl mimetics which are not desirable as orally available pharmaceutical drugs due to their rapid degradation by digestive enzymes (Ness et al, 2000 ; Morandi et al, 2003, Rudgers et al, 2001).

Hence, there remains a need for new non-ß-lactam-based ß-lactamase inhibitors that are active against a wide variety of ß-lactamases, particularly those that are resistant to clavulanic acid, sulbactam and tazobactam.

* * * * * Citation or identification of any references in the "Background of the Invention"or anywhere in the specification of this application is not an admission that such references available as prior art to the present invention.

SUMMARY OF THE INVENTION The present invention provides compounds having the formula (A): (HO) 2-B-T (A) wherein B stands for boron, and T has one of the following structures:

wherein R1 through Ru are each independently (i) when connected to a carbon atom: hydrogen, C16 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or Cl-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl9 Cl-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO,-CH=NOH,- C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15, wherein R15 is hydrogen or Cl 3 alkyl, or- O (CH2)nOR16-, wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3 ; or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z ; through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- <BR> NH-,-CH=CH-S-,-CH==CH-0-,-N=CH-MH-,-CH2-N=N-,-N=N-0-,-N=CH-S -or-0-<BR> <BR> <BR> <BR> -;<BR> or (ii) when connected to a nitrogen atom: absent; X, Y and Z are each independently carbon or nitrogen; and Q is oxygen or lone-pair electrons.

In a first embodiment, the compounds of the present invention are represented by formula A (I) :

wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, C1 6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N-,wherein R13 and R14 are each independently hydrogen or Cl-3 alkyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO,-CH=NOH,- C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15, wherein R15 is hydrogen or C1-3 alkyl, or- O (CH2)nOR16-,wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3; or when any two Ris are located at the ortho position to each other, they together form-ZI=Z2-Z3==Z4-, wherein Zl through Z4 each independently represents CH or N, -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CHO-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-0- ; or (ii) when connected to a nitrogen atom: absent ; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the first embodiment, Ri, Et3 and R4 are each hydrogen ; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, Cl 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; R5 is : (i) when X is nitrogen : absent, and

(ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, 2,4-dichlorophenoxy, benzyloxy, hydroxyl, hydroxymethyl, -CHO,-CH=NOH,-C=NOHCH3,-SO3H,-SO2CH3,-SO2NH2, or when Rs are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,- <BR> <BR> CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O- <BR> <BR> CH2CH2-0- ; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R6 are located at the ortho position to another Ri, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-0-O ; R7 is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, ammo, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R7 are located at the ortho position to another Ri, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O- ; Rs through Rg are each independently hydrogen, CI-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl,

benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,- SO2CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2- N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen.

In a second embodiment, the compounds of the present invention are represented by formula A (II) : wherein Ri through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, Cl-3 alkoxy, n-butoxy, i-butoxy, see-butoxy, R13Rl4N- (wherein Ri3 and Ri are each independently hydrogen or Cl-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxyvarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SOzNHRjs (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Rje is hydrogen or C1-3 alkyl, and n is 1, 2 or 3) ; or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In a preferred embodiment of the second embodiment, Ri, R3, R4, R9, Rl and Ri2 are each hydrogen; R2 and RIO are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2;

Rs through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, Ci-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,-S02CH3,-S02NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-.

In a third embodiment, the compounds of the present invention are represented by formula A (III) : wherein Ri through Rg are each independently (i) when connected to a carbon atom: hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, Cl-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, Ry3R14N- (wherein Rl3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or Cl alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3) ; or when any two Ris are located at the ortho position to each other, they together form - Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independelltly represents CH or 9-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the third embodiment, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C1 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-SO2CH3 and-SO2NH2 ; Rs is : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when Rs are located at the ortho position to another R ;, they together form-Zi=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl ; 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R6 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-0-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; rois : (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, 1-4 alkyi, 3-6 cycloalkyi, 1-3 alkoxy, triiluoromethyl, iluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-

CH--NOH,-C=NOHCH3,-SO3H,-SO2CH3,-S02NH2, or when R7 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; R8 through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CH-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, - N=N-O-,-N=CH-S-or-O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen.

In one particular embodiment of the third embodiment, the present invention relates to compounds represented by formula A (III) wherein R1 through R9 are each independently (i) when connected to a carbon atom : hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13R14N- (wherein Ru and Roi4 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NHRISs (wherein Rl5 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form - Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO- 0-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-0-,-N=CH-NH-,-CH2-N==N-,-N=N- 0-,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom: absent; and X, Y and Z are each independently carbon or nitrogen; with the proviso that

when R1=R3=R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon ; Ra is not NH2, N02,, or H.

In another embodiment of the third embodiment, the invention relates to compounds described by formula A (III) wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; R5 is : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-SO2NH2, or when Rs are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Æ4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R6 are located at the oi-tli. position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; R7is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon: - 14-

hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R7 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O- ; R8 through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH <BR> <BR> or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N= N-,- N=N-O-,-N=CH-S-or-O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen ; with the proviso that when Ri== R3= R4= Rs= R6= Ry= Rg= R9=hydrogen, and X=Y=Z=carbon ; R2 is not NH2, N02,, or H.

In a fourth embodiment, the compounds of the present invention are represented by formula A (IV) : wherein R1 through Ru are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or CI-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl,

amino, borono, nitro, carboxyl, CI-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or Cl-3 alkyl), or-O (CH2)"ORt6- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3) ; or when any two Ris are located at the ortho position to each other, they together form- Z1=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO- 0-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -, N=CH-S- or -O-CH2CH2-O-; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the fourth embodiment, Rl, R3 and R4 are each hydrogen ; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; 5iS : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R5 are located at the ortho position to another Ri, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=CH-O-,-N=CH-NH-,-CH2-N=TT-,-N=N-O-,-N=CH-S-or-0-CH2CH2-0- ; R6 is : (i) when Y is nitrogen : absent, and (ii) when Y is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C]-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl,

phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R6 are located at the ortl7o position to another Ri, they together fonn-Zl=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7 is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-SO2NH2, or when R7 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; Rg through Ru are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-SO3H,-S02CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-ZI=ZZ- Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,- <BR> <BR> CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N =CH- S- or -O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen.

In one particular embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A (IV) wherein Ri through Rg are each independently (i) when connected to a carbon atom : hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, Ci-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13R14N- (wherein RI 3 and R14 are each independently hydrogen or C1 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl9 C1-6 alkoxycarbonyl, phenyl9 phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO,

- CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-S02NHRl5 (wherein Rls is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl-3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form- Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S- or -O-CH2CH2-O-; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when Ri=R2=R3=R4=Rs=R6==Rs=R9 = hydrogen, and X=Y=Z=carbon ; R7 is not Cl, CN, OCH3, NO2 CF3, H, or COOCH3; when R1=R2=R3=R4=R5=R7=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 is not CN, NO2, or CF3 ; when R1=R2=R3=R4=R5=R8=R9 = hydrogen, and X=Y=Z=carbon ; R6 and R7 together is not-CH=CH-CH=CH- ; when R1=R2=R3=R4=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon ; R5 is not OCOCH3 ; when R1=R3=R4=R5=R6=R7=R8= R9 = hydrogen, and X=Y=Z=carbon ; R2 is not COOH and when R1=R2=R3=R4=R5=R8= Rg = hydrogen, R6= C1, and X=Y=Z=carbon ; R7 is not Cl.

In a preferred embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A(IV) wherein RI, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, anino, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; R5 is : (i) when X is nitrogen: absent, and (ii) when X is carbon :

hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R5 are located at the ortho position to another R ;, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O- ; R6 is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-SO3H,-SO2CH3,-SO2NH2, or when R6 are located at the ortho position to another Ri, they together ibrm-Z} =Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; Ryis : (i) when Z is nitrogen : absent, and (ii) when Z is carbon: hydrogen, Cl alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl ;, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2. or when Ry are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form 2-

Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,- CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N =CH- S-or-0-CH2CH2-0- ; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when Rl=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon ; R7 is not Cl, CN, OCH3, NO2, CF3, H, or COOCH3 ; when RI=R2=R3=R4=Rs=R7=Rs=R9 = hydrogen, and X=Y=Z=carbon ; R6 is not CN, NO2, or CF3 ; when R1=R2=R3=R4=R5=R8=R9=hydrogen, and X=Y=Z=carbon; R6 and R7 together is not-CH=CH-CH=CH- ; when Ri=R2=R3=R4=Rg=R7=Rs= R9=hydrogen, and X=Y=Z=carbon; Rs is not OCOCH3 ; when Ri=R3=R4=R5=Rs=R7==Rs= R9=hydrogen, and X=Y=Z=carbon ; R2 is not COOH; and when R1=R2=R3=R3=R4=R5=R8=R9=hydrogen, R6= Cl, and X=Y=Z=carbon ; R7 is not Cl.

In a fifth embodiment, the compounds of the present invention are represented by formula A (V) : wherein RI through Rg are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyi, 1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and Ri4 each independently represents hydrogen or CI-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl,

trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-SOsH,-SOzCHs,- SOzNHRis (wherein Ris is hydrogen or Cl 3 alkyl), or-O (CH2) nORI6- (wherein RI 6 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, - N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-0-CH2CH2-0-.

In a preferred embodiment of the fifth embodiment, Ri and R4 are each hydrogen ; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2 ; Rs through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, Cl 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CI-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together fonn-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- <BR> <BR> NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S- or-O-<BR> <BR> CH2CH2-0-.

In one particular embodiment of the fifth embodiment, the compounds of the present invention are represented by formula A (V): wherein R through R9 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N-(wherein R13 and R14 each independently represents hydrogen or Ci-3 allcyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy9 diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3,- S02NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; with the proviso that

when R1=R2=R3=R4=R5=R6=R8=R9 = hydrogen; R7 is not H, OH or C (CH3) 3.

In another embodiment of the fifth embodiment, Ri and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, - S03H,-S02CH3 and-SO2NH2 ; Rs through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- <BR> <BR> NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S- or-O- CH2CH2-O-; with the proviso that when R1=R2=R3=R4=R5=R6=R8=R9 = hydrogen ; R7 is not H, OH or C (CH3) 3.

In a sixth embodiment, the compounds of the present invention are represented by formula A (VI) : In a seventh embodiment, the compounds of the present invention are represented by formula A (0 wherein Q is oxygen or lone-pair electrons.

In an eighth embodiment, the compounds of the present invention are represented by formula A (VIII):

In a ninth embodiment, the compounds of the present invention are represented by formula A (IX): In a tenth embodiment, the compounds of the present invention are represented by formula A (X):

In an eleventh embodiment, the compounds of the present invention are represented by formula A(XI);

wherein R, is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i- butoxy, sec-butoxy, R13Rl4N- (wherein Rig and Ri4 are each independently hydrogen or <BR> <BR> CI-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy,

phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-SO3H,-SO2CH3,-SO2NHRl5 (wherein Ris is hydrogen or Cl-3 alkyl), or -O (CH2) nORl6- (wherein R16 is hydrogen or Cl-3 alkyl, and n is 1,2 or 3).

In a preferred embodiment of the eleventh embodiment, Rl is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H,-S02CH3 and- S02NH2.

In one particular embodiment of the eleventh embodiment, the compounds of the present invention are represented by formula A (XI), wherein R1 is C1-6 alkyl, C3-6 cycloalkyl, CI-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13Rl4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, C1_6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3,- SO2NHRI5 (wherein Ris is hydrogen or CI-3 alkyl), or-O (CH2) nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3).

In another embodiment of the eleventh embodiment, Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, Cl-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and-S02NH2.

In a twelfth embodiment, the compounds of the present invention are represented by formula A (XII): wherein R1 through Rg are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, Rl3Rl4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl),

trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NHRis (wherein RI5 is hydrogen or Cl 3 alkyl), or-O (CH2) nORo6- (wherein Rl6 is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form- Zi=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the twelveth embodiment, Rl, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; Rosis : (i) when X is nitrogen : absent, and (ii) when X is carbon: hydrogen, Ci-4 alkyl, C3-6 cycloalkyl, CI-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R5 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH orN),-S-CO-0-,-CH=CH-MH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon :

hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1. 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R6 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7 is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R7 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH==CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-0-CH2CH2-0- ; R8 through Ru are each independently hydrogen, C1-4 alyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH-NOH,-C=NOHCH3,-S03H,-SO2CH3,-SO2NH2, or when any two Ris are located at the ortlio position to each other, they together form -Z1=Z2- Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-0-,- CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH- S-or-0-CH2CH2-0- and Y Y and Z are each independently carbon or nitrogen.

In a thirteenth embodiment, the compounds of the present invention are represented by formula A (XIII) :

wherein R1 through RIZ are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, Rl3Rs4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- S02NHR15 (wherein Ris is hydrogen or C1-3 alkyl), or-O (CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zi=Z2-Z3==Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-, In a preferred embodiment of the thirteenth embodiment, Ri, R3, R4, R9, R11 and Ruz are each hydrogen ; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through Rs are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyi, 1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Z, =Z2-Z3=Z4- (wherein Zt through Z4 each independently represents CH or,-S-CO-Q-,-CH=CH- <BR> <BR> <BR> <BR> <BR> NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S- or-0- CH2CH2-O-.

In a fourteenth embodiment, the compounds of the present invention are represented by formula A (XIV) :

wherein R1 through Rg are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13Rl4N- (wherein R13 and R14 each independently represents hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3,- SO2NHRI5 (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R ; 6 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In a preferred embodiment of the fourteenth embodiment, Ri and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; Rs through Rq are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chlor, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the oi-tlio position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- NH-, -CH=CH-S-, -CH=CH-O-,-N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-.

In a fifteenth embodiment, the compounds of the present invention are represented by formula A (XV) :

wherein R1 through RIZ are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, Rl3Rz4N- (wherein Ri3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-SO2CH3,- S02NHRis (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)n OR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O--N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the fifteenth embodiment, R1, R3, R4, R9, R11 and R12 are each hydrogen ; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; Rs through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SOI2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- <BR> <BR> <BR> <BR> NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S- or-O- CH2CH2-O-.

In certain embodiments, the invention is directed to compounds represented by formula A (XVI) :

wherein R1 through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, liydroxymet11yl,-S03H,-SO2CH3,- S02NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Rie is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In certain preferred embodiments of the invention is directed to compounds represente by formula A (XVI) wherein, Ri, R3, R4, R9, Ri and R12 are each hydrogen ; R2 and RIO are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, - SO2CH3 and -SO2NH2; Rs 5 through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RiS are located at the ortho position to each other, they together form-ZI=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, - N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In certain embodiments, the invention is directed to compounds represented by formula A (XVII) :

wherein Ri through RIZ are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13Rl4N- (wherein Rig and Ri4 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form-ZI=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In ertain preferred embodiments the invention is directed to compounds represented by formula A (XVII) wherein, RI, R3, R4, R9, R11 and R12 are each hydrogen ; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, SO2CH3 and -SO2NH2; R5 through R8 are each each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 <BR> <BR> <BR> <BR> alkoxy, trifluorometlyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,-SO2CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a certain embodiments, the invention is directed to compounds represented by formula A (XVIII) :

wherein Ri through R20 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein Ri3 and Ihm are each independently hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- S02NHRi5 (wherein R15 is hydrogen or 1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In ertain preferred embodiments the invention is directed to compounds represented by formula A (XVIII) wherein, Ri, R3, h9 Pug R11, R12, R17, R19 and R20 are each hydrogen; R2, Rio and R18 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2 ; Rs through R7 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,-S02CH3,-S02NH2.

The invention relates to a method of inhibiting 0-lactamase comprising contacting the ß-lactamase with an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII).

The invention provides a method of treating bacterial infection, particularly (3-lactam-antibiotic-resistant bacterial infection. The method comprises administering to a subject suffering from such an infection an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII), or A (XVIII).

The invention also provides a method of treating bacterial infection, particularly ß-lactam-antibiotic-resistant bacterial infection. The method comprises administering a subject suffering from such an infection an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII), or A (XVIII) ; and an effective amount of ß-lactam-antibiotic, with or without one or more other antibacterial agent.

The invention further provides a method of overcoming bacterial resistances, particularly resistance to 0-lactam-antibiotic. The method comprises administering a subject an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII), or A (XVIII); and an effective amount off6- lactam-antibiotic, with or without one or more other antibacterial agent.

The invention also provides a pharmaceutical composition comprising one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIV), A(XV), A(XVI), A(XVII), or A (XVIII) and a pharmaceutically acceptable carrier.

The invention further provides a pharmaceutical composition comprising one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII), or A (XVIII); a ß-lactam-antibiotic, and optionally comprising one or more other antibacterial agent; and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION The present invention provides compounds having the formula : (HO) 2-B-T (A) wherein B stands for boron, and T has one of the following structures:

wherein Ri through R12 are each independently

(i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13Rl4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, -CH=NOH,-C=NOHCH3,-SO3H,-SO2CH3,-SO2NHRos (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl-3 alkyl, and n is 1,2 or 3) ; or when any two Ris are located at the ortho position to each other, they together form- Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S- or -O-CH2CH2-O-; or (ii) when connected to a nitrogen atom: absent; and X, Y and Z are each independently carbon or nitrogen.

The compounds of the present invention are specifically described by formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII) A A(XIV), A(XV), A(XVI), A (XVII) and/or A (XVIII) below.

The invention relates to a method of inhibiting (3-lactamase comprising contacting the ß-lactamase with an effective amount of one or more compounds of <BR> <BR> formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI),<BR> <BR> A (XII), A (XIII), A (XIV), A (XV), A(XVI), A (XVII) or A (XVIII).

The invention provides a method of treating bacterial infection, particularly ß-lactam-antibiotic-resistant bacterial infection. The method comprises administering to a subject suffering from such an infection an effective amount of one or more compounds of formula A (I), A (II), A (III) , A(IV), A(V), A(VI), A (VII), A (VIII) g A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII).

The invention also provides a method of treating bacterial infection, particularly (3-lactam-antibiotic-resistant bacterial infection. The method comprises administering a subject suffering from such an infection an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII),

A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII); and an effective amount of ß-lactam-antibioic.

The invention further provides a method of overcoming bacterial resistances, particularly resistance to 13-lactam-antibiotic. The method comprises administering a subject an effective amount of one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII) ; and an effective amount of ß- lactam-antibiotic or other antibacterial agent.

The invention also provides a pharmaceutical composition comprising one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII); and a pharmaceutically acceptable carrier.

The invention further provides a pharmaceutical composition comprising one or more compounds of formula A (I), A (II), A (III), A (IV), A (V), A (VI), A (VII), A (VIII), A (IX), A (X), A (XI), A (XII), A (XIII), A (XIV), A (XV), A (XVI), A (XVII) or A (XVIII); a 0-lactam-antibiotic or other antibacterial agent; and a pharmaceutically acceptable carrier.

Formula A (I) In a first embodiment, the compounds of the present invention are represented by formula A (I): wherein Ri through Rg are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, Rl3Rl4Ar- (wherein R13 and R14 are each independently hydrogen or Cl 3 alkyl),

trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, - CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-SO2NHRIS (wherein R15 is hydrogen or C1-3 alkyl), or-O (CH2) nORl6- (wherein RI6 is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form- ZI=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the first embodiment, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, Ci-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-S02NH2 ; R5 is : (i) when X is nitrogen : absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO,- CH=NIH,-C=NOHCH3,-S03H,-SO2CH3,-S02NI2, or when R5 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each ch independently represents CH or N), -S-CO-O-, -CH=CH-NH-, _CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N--N=N-O-,-N=CH-S-or-O-CH2CH2-O-; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon :

hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-SO3H,-S02CH3,-S02NH2, or when R6 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R7 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, Cl 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C14 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,- S02CH3,-S02NH2, or when any two Ris are located at the ortho position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-MH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2- N=N-, -N=N-O-,-N=CH-S- or -O-CH2CH2-O-; and S9 Y and Z are each independently carbon or nitrogen.

Non-limiting specific compounds described by formula A (I) are listed in Table 1.

Table 1: Representative Compounds in Formula A (I) : Ri R2 R3 R4 R5 R6 R7 R8 H HHHNOzHHC C C H HNOzHHHHC C C H NO2 H H H NO2 H H H C C C H NO2 H H H H OCH3 H H C C C H NO2 H H H H COOCH2CH H H C C C 3 H NO2 H H H [1, 3] oxathiol-2-one H H C C C H NO2 H H CN H H H H C C C H NO2 H H Cl H H H NO2 C C C H NOz H H COOCH2CH3 H H H H C C C H NO2 H H Cl H H H H C C C H NO2 H H CH3 H H H H C C C H NO2 H H OCH3 H H H H C C C H NO2 H H H CH3 H H H C C C H NO2 H H Cl H H H Cl C C C H HFHHHHC C C H NO2 H H F H H H F C C C H HHHFHHC C C H NO2 H H H H -- H H C C N H NO2 H H Cl -- H H H C N C H NO2 H H H H H H H C C C H NO2 H H Br H H H H C C C H NO2 H H H B(OH)2 H H H C C C H NO2 H H Cl H Cl H NO2 C C C H COOH H H Cl H H H Cl C C C H NO2 H H COCH3 H H H C C C NO2 H H -CH=CH-CH=CH- H H C C C H NO2 H H H H COOH H H C C C H HOHHHHHC C C H NO2 H H NH2 H H H C C C H NO2 H H CHO H H H H H NO2 H H CH=NOH H H H H C C C H NO2 H H C=NOHCH3 H H H H C C C H H NO2 H Cl H H H Cl H H Cl H Cl H H H Cl C C C H H H H Cl H H H Cl C C C 2,4-dichloro- H NO2 H H H H Cl H C C C phenoxyl H NO2 H H Cl H Cl H Cl C C C Formula AID In a second embodiment, the compounds of the present invention are represented by formula A (II) :

wherein R1 through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Ri6 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-ZI=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the second embodiment, Ri, R3, R4, Rg, Rll and R12 are each hydrogen; R2 and R10 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino9 borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H, -SO2CH3 and -SO2NH2; R5 through Rg are each independently hydrogen, Cl-4 alkyl, C3-6 cycloalkyl, C1_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,-SO2CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

Non-limiting specific compounds described by formula A (II) are listed in Table 2.

Table 2 : Representative Compounds in Formula A (II) :

Ri Rz R3 R Rs R6 R7 R8 R9 R10 R11 R12 H NOZ H H H H H H H NO2 H H H NOZ H H ci H H H H NO2 H H H H NO2 H Cl H H H NO2 H H H H H H H Cl H H H H H H H H NO2 H H Cl Cl Cl Cl H NO2 H H H N02H H t-butylH H H H N02 H H Formula A (III) In a third embodiment, the compounds of the present invention are represented by formula A (III): wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- tuboxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Ri6 is hydrogen or C1-3 alky, and n is 1,2 or 3) ; or when any two Ris are located at the ol tho position to each other, they together form- Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-

O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the third embodiment, Rl, R3 and R4 are each hydrogen ; Ra is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CI-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and -SO2NH2 ; R5 is : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-SO3H,-SO2CH3,-S02NH2, or when R5 are located at the ortlio position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is : (i) when Y is nitrogen : absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyans, acetyl, amino, borono, nitro, carboxyl, Ci_4 alloxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R6 are located at the ortho position to another Ri, they together form-Zt=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-0-CH2CH2-0- ; R7 is :

(i) when Z is nitrogen : absent, and (ii) when Z is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH--NOH,-C=NOHCH3,-SO3H,-SO2CH3,-SO2NH2, or when R7 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CN2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; Rs through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Zj through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N= N-,- N=N-O-, -N=CH-S- or -O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen.

In one particular embodiment of the third embodiment, the present invention relates to compounds represented by formula A (III) wherein Ri through Rg are each independently (i) when connected to a carbon atom : hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano9 acetyl, amino, borono, nitro, carboxyl, Cl alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, - CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-S02NHRI5 (wherein Rls is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form- Zi=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO- N=CH-S- or -O-CH2CH2-O-; or

(ii) when connected to a nitrogen atom: absent; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when R1=R3=R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon; R2 is not NH2, N02,, or H.

In another embodiment of the third embodiment, the invention relates to compounds described by formula A (III) wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-S03H,-S02CH3 and-SO2NH2 ; R5is : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1 4 alkyl, C3-6 cycloalkyl, C13 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when Rs are located at the ortho position to another Ri, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; R6 is: (i) when Y is nitrogen : absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C13 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R6 are located at the oi-t7io position to another Ri, they together form -Z1=Z2-Z3=Z4-(wherein Z1 through Z4

each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7 is : (i) when Z is nitrogen : absent, and (ii) when Z is carbon: hydrogen, Cl-4 alkyl, C3-6 cycloallcyl, Cl-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-SO2NH2, or when R7 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3-Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-S02CH3, -S02NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein ZI through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N= N-,- N=N-O-, -N=CH-S- or -O-CH2CH2-O-; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when R1=R3=R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon ; R2 is not NH2, NO2,, or H.

Non-limiting specific compounds described by formula A (III) are listed in Table 3.

Table 3: Representative Compounds in Formula A (III) : Ri R2 R3 R4 R5 R7 R R9 Rs R9 X Y Z H H H H H H H H H C C C H NO2 H H H H H H H C C C H N02 H H ci H H H ci C C C H N02 H H H N02 H H H C C C H NO2 H H H Cl H H H C C C H N02 H H H B (OH) 2 H H H C C C H NO2 H H H COCH3 H H H C C C H NO2 H H H OH H H H C C C H NO2 H H H COOH H H H C C C H H H H H Cl H H H C C C H N02 H H-CH=CH-CH=CH-H H H C C C H NH2 H H H B (OH) 2 H H H C C C H OH H H H B (OH) 2 H H H C C C In a particular preferred embodiment, the compound is

HOOH 02N) 0 0 O HQ. OH \/ B 6 The compound 0 (compound F1001) is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2118). HO, OH D 02N X The compound 0 (compound F1201) is also available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2188).

Formula A (IV) In a fourth embodiment, the compounds of the present invention are represented by formula A (IV) :

wherein R1 through Rg are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, butoxy, i-butoxy, sec- butoxy, R13Rl4N- (wherein Rl3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C)-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortho position to each other, they together form- ZI=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N--N=N-O- ,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom ; absent ; and and Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the fourth embodiment Ri, R3 and R4 are each hydrogen ; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3,-S03H,-S02CH3 and-SO2NH2 ; R5 is : (i) when X is nitrogen : absent, and (ii) when X is carbon:

hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R5 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-SO2CH3,-S02NHz, or when R6 are located at the ortho position to another R ;, they together form-Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7 is : (i) when Z is nitrogen : absent, and (ii) when Z is carbon: hydrogen, CI-4 alkyi, 3-6 cycloalkyi, 1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R7 are located at the oríllo position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O- ; R8 through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-

Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,- <BR> <BR> <BR> <BR> CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N =CH- S-or-0-CH2CH2-0- ; and X, Y and Z are each independently carbon or nitrogen.

In one particular embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A (IV) wherein R1 through Rg are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, RI 3R, 4N- (wherein RI 3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NHRIS (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Rig is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortlio position to each other, they together form- Zl=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO- O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O -,- N=CH-S-or-0-CH2CH2-0- ; or (ii) when connected to a nitrogen atom ; absent; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when R1=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon; R7 is not Cl, CN, OCH3, OCH3, NO2, CF3, H, or COOCH3 ; when R1=R2=R3=R4=R5=R7=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 is not CN, NO2, or CF3 ; when R1=R2=R3=R4=R5=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 and R7 together is not-CH=CH-CH=CH- ; when R1=R2=R3=R4=R6=R7=R8= R9=hydrogen, and X=Y=Z=carbon; Rs is not OCOCH3 ; when R1=R3=R4=R5=R6=R7=R8= R9 = hydrogen, and X=Y=Z=ca ; R2 is not COOH; and

when R1=R2=R3=R4=R5=R8= Rg = hydrogen, R6= Cl, and X=Y=Z=carbon ; R7 is not Cl.

In a preferred embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A (IV) wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,- C=NOHCH3,-SO3H,-SO2CH3 and-SO2NH2 ; R5 is : (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when Rs are located at the ortho position to another Ri, they together form-Zl=Z2-Z3--Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon : hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R6 are located at the ortho position to another Ri, they together form-ZI=Z2-Z3=Z4- (wherein Z through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7is : (i) when Z is nitrogen : absent, and

(ii) when Z is carbon: hydrogen, Cl alkyl, C3-6 cycloalkyl, Cl 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R7 are located at the ortho position to another Ri, they together form -Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O- ; R8 through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2- Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,- <BR> <BR> <BR> CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N =CH- S-or-0-CH2CH2-0- ; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when R1=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon ; R7 is not Cl, CN, OCH3, NO2, CF3, H, or COOCH3 ; when R1=R2=R3=R4=R5=R7=R8=R9 = hydrogen, and X=Y=Z=carbon ; R6 is not CN, N02, or CF3 ; when R1=R2=R3=R4=R5=R8=R9= hydrogen, and X=Y=Z=carbon ; R6 and R7 together is not-CH=CH-CH=CH- ; when R1=R2=R3=R4=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon; R5 is not OCOCH3 ; when R1=R3=R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon; R2 is not COOH ; and when R1=R2=R3=R4=R5=R8=R9=hydrogen, R6= Cl, and X=Y=Z=carbon ; R7 is not Cl.

Table 4 : Representative Compounds in Formula A(IV): Ri R2 R3 R4 Rs Re R ? Rs R9 X Y Z H COOH H H F H H H H C C C H COOH H H Cl H H H ci C C C H NOz H H Cl H H H Cl C C C H H H H Cl H H H Cl C C C Formula A (V) In a fifth embodiment, the compounds of the present invention are represented by formula A (V):

wherein Ri through Rg are each independently hydrogen, CI-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N-(wherein R13 and R14 each independently represents hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo9 cyano, acetyl, nitro, amino, borono, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3,- SO2NHR15 (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)nOR16-(wherein R16 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Ris are located at the ortlio position to each other, they together form -Z1=Z2-Z3=Z4-(wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the fifth embodiment, Rl and R4 are each hydrogen;

R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C13 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, 1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris* are located at the ortho position to each other, they together form-Z1=Z2-Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-.

In one particular embodiment of the fifth embodiment, the compounds of the present invention are represented by formula A (V): wherein R1 through Rs are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13Rl4N- (wherein R13 and R14 each independently represents hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro9 chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Cl 6 alkoxyearbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein Ri6 is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CTI-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; with Lhe proviso that when R1=R2-R3=R4=R5=R6=R8=R9= hydrogen; R7 is not H, OH or C(CH3)3.

In another embodiment of the fifth embodiment, Ri and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO2H, -SO2CH3 and -SO2NH2 ; Rs through Rg are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, 1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino,

borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH- NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S- or-O- CH2CH2-O-; with the proviso that when R1=R2=R3=R4=R5=R6=R8=R9 = hydrogen; R7 is not H, OH or C (CH3) 3 Non-limiting specific compounds described by formula A (V) are listed in Table 5.

Table 5 : Representative Compounds in Formula A (V) : Ri R2 R3 R4 Rs R6 R7 R8 R9 H H H H H H H H H H F H H H NO2 H H H H F H H H Cl H H H H H H H H Cl H H P H H H H N02HH H

HO OH I oo ! Compound W (compound F1002) is ava. llable from Combi- p (P) C b

Blocks7 Inc. (San Diego, California, Cat. No. BB-2114).

Formula A (VI) In a sixth embodiment, the compounds of the present invention are represented by formula A (VI): HO, OH b A (VI) I O (Compound F1212).

This compound is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2162).

Formula A (VII) In a seventh embodiment, the compounds of the present invention are represented by formula A (VII) : wherein Q is oxygen or lone-pair electrons.

HOU OH B The compound (compound F1012) is available from Sigma-Aldrich, Inc. (St. Louis, MO, Cat. No. 51221-4.

Formula A(VIII) In an eighth embodiment, the compounds of the present invention are represented by formula A (VIII) : HO OH B I A (VIII) w°/ 0 (compound BB-1003).

Compound BB-1003 is commercially available from Combi-Blocks, Inc.

(San Diego, California, Cat. No. BB2119).

Formula A (IX) In a ninth embodiment, the compounds of the present invention are represented by formula A (IX): HO OH B A (IX) 1 0 6""o Ok (compound BB-1004).

Compound BB-1004 is commercially available from Combi-Blocks, Inc.

(San Diego, California, Cat. No. BB2623).

Formula A(X) In a tenth embodiment, the compounds of the present invention are represented by formula A (X): HOU WON B A (X) B A (X) W)/NX o (compound BB-1005).

Compound BB-1005 is commercially available from Combi-Blocks, Inc.

(San Diego, California, Cat. No. BB3052).

Formula A(XI) In an eleventh embodiment, the compounds of the present invention are represented by formula A (XI) : wherein Rl is hydrogen, Cl alkyl, C3-6 cycloalkyl, Cl 3 alkoxy, zl-butoxy i- butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or

C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1_6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, -SO2NHR15 (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl-3 alkyl, and n is 1,2 or 3).

In a preferred embodiment of the eleventh embodiment, Ri is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H,-S02CH3 and- S02NHz.

In one particular embodiment of the eleventh embodiment, the compounds of the present invention are represented by formula A (XI), wherein R1 is Cl 6 alkyl, C3-6 cycloalkyl, Cl 3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, R13Rl4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-SO2CH3,- S02NHRls (wherein R15 is hydrogen or Cl-3 alkyl), or-O (CH2) nORt6- (wherein Ri6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3).

In another embodiment of the eleventh embodiment, Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, 1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H,-S02CH3 and -SO2NH2.

Non-limiting specific compounds described by formula A (XI) are listed in Table 6.

Table 6 : Representative Compounds m Formula A (XI) : R1 NH2 H OH ON Br Formula A(XII) In a twelfth embodiment, the compounds of the present invention are represented by formula A (XII) :

wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec- butoxy, Rl3RI4N- (wherein R13 and Ri4 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or Cl-3 alkyl), or-O (CH2) nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two : s are located at the ortho position to each other, they together form- Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO- O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-,- N=CH-S- or -O-CH2CH2-O- ; or (ii) when connected to a nitrogen atom ; absent; and X, Y and Z are each independently carbon or nitrogen.

In a preferred embodiment of the twelfth embodiment, Rl, R3 and R4 are each hydrogen ; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, Cul-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,- SO2CH3 and-SO2NH2 ; R5 is :

(i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,- S02CH3,-S02NH2, or when R5 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH <BR> <BR> <BR> <BR> or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N= N-,- N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R6 is : (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-SO2NH2, or when R6 are located at the ortho position to another R ;, they together form -Z1=Z2-Z3 = Z4- (wherein Z, through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-,- CH=CH-O-, -N=CH=NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R is : (i) when Z is nitrogen: absent, and (ii) when Z is carbon; hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,- CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when R7 are located at the ortho position to another Ri, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,- CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-; R8 through R9 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro,

carboxyl, Cl 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-CHO,-CH=NOH,-C=NOHCH3,-S03H,-S02CH3,-S02NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2- Z3=Z4- (wherein Zl through Z4 each independently represents CH or N),-S-CO-O-,- <BR> <BR> CH=CH-NH-,-CH=CH-S-,-CH=CH-O-,-N=CH-NH-,-CH2-N=N-,-N=N-O-,-N =CH- S-or-0-CH2CH2-0- ; and X, Y and Z are each independently carbon or nitrogen.

Non-limiting specific compounds described by formula A (XII) are listed in Table 7.

Table 7: Representative Compounds in Formula A (XII) : Ri R2 R3 R4 R5 R6 R7 R8 R9 X Y Z H H H H Cl H H H Cl C C C H H H H Cl H Cl H Cl C C C H H H H H H H H H C N C H NOZ H H Cl H H H Cl C C C

Formula A (XIII) In a thirteenth embodiment, the compounds of the present invention are represented by formula A (XIII) :

wherein Ri through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is

hydrogen or CI-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the thirteenth embodiment, Ri, R3, R4, Rg, R11 and R13 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H, -SO2CH3 and -SO2NH2 ; Rs through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-S03H,-SO2CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

Non-limiting specific compounds described by formula A (XIII) are listed in Table 8.

Table 8 : Representative Compounds in Formula A (XIII) : R3 EDX2 R3 R4 lR5 R8 R9 R10 R11 R12 H F H H Cl H H H F H H H H F H H H H H H F H H H H H H H Cl H H H H H H H H H H H H H H H H H H H Formula A(XIV) In a fourteenth embodiment, the compounds of the present invention are represented by formula A (XIV) :

wherein Ri through R9 are each independently hydrogen, Cl-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13Rl4N- (wherein R13 and R14 each independently represents hydrogen or Cl-3 alkyl), trifluoromethyl, trifluoromethoxy, difluorometlioxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- S02NHRis (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or Cl 3 alkyl, and n is 1,2 or 3); or when any two RiS are located at the ortho position to each other, they together form -Z=Z2-Z3=Z4-(wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, - N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-0-CH2CH2-0-.

In a preferred embodiment of the fourteenth embodiment, R, and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R9 are each independently hydrogen, 1-4 alkyi, 3-6 cycloalkyi, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

Non-limiting specific compounds described by formula A (XIV) are listed in Table 9.

Table 9: Representative Compounds in Formula A (XIV) : Ri R2 R3 R4 R5 R6 R Rs R9 Rio Rm Ri2 H F H H Cl H H H NO2 H H H H F H H Cl H H H Cl H H H H H H H Cl H H H ci H H H

Formula A (XV) In a fifteenth embodiment, the compounds of the present invention are represented by formula A (XV): wherein Ri through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, c1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein Ri3 and Rl4 are each independently hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or CI-3 alkyl, and n is 1, 2 or 3) ; or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, - N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the fifteenth embodiment, Ri, R3, R4, Rg, Rll and Ri2 are each hydrogen ;

R2 and Rlo are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and-SO2NH2 ; R5 through R8 are each independently hydrogen, C1-4 alkyl, C1-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

Non-limiting specific compounds described by formula A (XV) are listed in Table 10.

Table 10: Representative Compounds in Formula A (XV) : Ri R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 H NOZ H H H H H H H NO2 H H H NO2 H H H Br H H H N02H H H NO2 H H COCH3 H H H H NOz H H H NO2 H H H H COOH H H NOz H H H H H H H H H H H H H H H H H H H Br H H H H H H H H H H COCH3 H H H H H H H H H H H H H COOH H H H H H Formula A (XVI) In a sixteenth embodiment, the compounds of the present invention are represented by fonnula A (XVI) :

wherein R11 through R12 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13Rl4N- (wherein Rig and R14 are each independently hydrogen or CI-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - S02NHRi5 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-.

In a preferred embodiment of the sixteenth embodiment, Ri, R3, R4, R9, R11 and R12 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; PS5 through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxy, hydroxymethyl,-S03H,-S02CH3,-S02NH2, or when any two RjS are located at the ortho position to each other, they together form-Zi=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-, Non-limiting specific compounds described by formula A (XVI) are listed in Table 10A.

Table 10A Representative Compounds in Formula A (XVI) Ri R2 R3 R4 Ra R6 R6 R7 R8 R9 R10 R11 R12 H N02 H H H H H H H N02 H H H H H H H H H H H H H H Formula A (XVII) In a seventeenth embodiment, the compounds of the present invention are represented by formula A (XVII):

wherein Ri through Rl2 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy9 Rl3Rl4N- (wherein R13 and R14 are each independently hydrogen or Cl 3 alkyl), trifluoromethyl9 trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-S02CH3,- SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1,2 or 3) 9 or when any two R ; s are located at the ortho position to each other, they together form -Z1=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, N=CH-S- or -O-CH2CH2-O-.

In a preferred embodiment of the sixteenth embodiment, Ri, R3, R4, R9, R11 and Ri2 are each hydrogen ; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 allcoxycarbonyl, phenoxycarbonyl, hydroxyl,-S03H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro,

carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,-SO3H,-SO2CH3,-SO2NH2, or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

Non-limiting specific compounds described by formula A (XVII) are listed in Table 10B.

Table 10B Representative Compounds in Formula A (XVII) Ri R2 R3 R4 Rs Rs R7 R8 R9 R10 R11 R12 H N02 H H H H H H H NOz H H H H H H H H H H H H H H

Formula A (XVIII) In a eighteenth embodiment, the compounds of the present invention are represented by formula A (XVIII):

wherein Ri through R20 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or Cl 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cl 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl,-S03H,-SO2CH3,- SOzNHRis (wherein Ris is hydrogen or C1-3 alkyl), or -O(CH2)nOR16-(wherein R16 is

hydrogen or C1-3 alkyl, and n is 1,2 or 3); or when any two Ris are located at the ortho position to each other, they together form-Zl=Z2-Z3=Z4- (wherein Z1 through Z4 each independently represents CH or N),-S-CO-O-,-CH=CH-NH-,-CH=CH-S-,-CH=CH-O-, - N=CH-NH-,-CH2-N=N-,-N=N-O-,-N=CH-S-or-O-CH2CH2-O-.

In a preferred embodiment of the eighteenth embodiment, Ri, R3, R4, R9, Rll, Riz, Ri7, Rig and R2o are each hydrogen ; R2, Rio and Rig are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Cl 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R7 are each independently hydrogen, C1-5 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C1-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2.

Non-limiting specific compounds described by formula A (XVIII) are listed in Table 10C.

Table 10C Representative Compounds in Formula A R1 R2 R3 R4 R5 R6 R7 R9 R10 R11 R12 R17 R18 R19 R20 H NO2 H H H H H H NO2 H H H NO2 H H H H H H H H H H H H H H H H H

S-Lactamases The compounds of the present invention can be used to inhibit any lactamases.

ß-lactamases are endogenous bacterial enzymes that destroy ß-lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the j6-lactam ring. The structures of many ß-lactamases are known at the atomic level and available in the protein database. Preferablyp the ß-lactamase is a Class A B, C or D 0- lactamase. More preferably, it is a Class A (TEM) or Class C (AmpC) ß-lactamase.

Salts and Derivatives Various pharmaceutically acceptable salts, ether derivatives, ester derivatives, acid derivatives, and aqueous solubility altering derivatives of the active compound also are encompassed by the present invention. The present invention further includes all individual enantiomers, diastereomers, racemates, and other isomer of the

compound. The invention also includes all polymorphs and solvates, such as hydrates and those formed with organic solvents, of this compound. Such isomers, polyrnorphs, and solvates may be prepared by methods known in the art, such as by regiospecific and/or enantioselective synthesis and resolution, based on the disclosure provided herein.

Suitable salts of the compound include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p- toluene sulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts formed with organic or inorganic ligands, such as quaternary ammonium salts.

Additional suitable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleat, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerat salts of the compound of the present invention.

Prodrugs and active metabolites of compounds disclosed herein are also within the scope of the invention.

A prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. I7z OS a prodrug is acted on by naturally occurring enzyme (s) resulting in liberation of the pharmacologically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

An active metabolite is a compound which results from metabolism of another compound after administration of the latter to a subject. Metabolites can be identified by techniques well-known in the art.

Formulation and Administration Suitable dosage forms include but are not limited to oral, rectal, sub- lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterille administration, and other dosage forms for systemic delivery of active ingredients.

To prepare such pharmaceutical dosage forms, one or more of the aforementioned compounds of formula (1), alone or in combination with 0-lactam antibiotics, are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.

In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents maybe employed.

In some applications, it may be advantageous to utilize the active agent in a"vectorized"form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e. g. , by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets,

tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules. Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient (s). Such accessory ingredient (s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration usually comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e. g. , physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

Parenteral administration may comprise any suitable form of systemic delivery or delivery directly to the CNS. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra- abdominal (e. g., intraperitoneal), etc. , and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.

Nasal and other mucosal spray formulations (e. g. inhalable forms) can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may

be delivered by any suitable means or method, e. g. , by nebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e. g. , methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of this invention may further include one or more accessory ingredient (s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

The formulation of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.

SLactam Antibiotics ß-lactam antibiotics are compounds with antimicrobial activities and contain the 0-lactam structure. Any ß-lactam antibiotic is suitable. Many suitable ß lactam antibiotics are known (See e. g. , R. B. Morin and M. Gorin, M. Eds.; Academic Press, New York, 1982 ; vol. 1-3). These include but not limited to cephalosporins (e. g., cephalothin), penicillins (e. g., amoxicillin), monobactams (e. g., aztreonam), carbapenems (e. g. , imipenem), carbacephems (loracarbef), and others. 0-lactam antibiotics are effective (in the absence of resistance) against a wide range of bacterial infections. These These include those caused by gram-positive and/or gram-negative bacteria, for example9 bacteria of the genus Staphylococcus (such as Staphylococcus aureus and Staphylococcus epidermis), Streptococcus (such as Streptococcus agalactine, Streptococcus penumoniae and Streptococcus faecalis), Micrococcus (such as Mcrococcus luteus), Bacillus (such as Bacillus su : btils), Listerella (such as Listerella mosaocytogefaes), Escherichia (such as Escherichia coli), Klebsiella (such as Klebsiella pneumoniae), Proteus (such as Proteus mirablis and Proteus vulgaris), Salmonella (such as Salmonella typhosa), Shigella (such as Shigella sonnei), Eiiterobacter (such as Enterobacter aerogenes and Enterobacter facium), Serratia (such as Sel-ratina marcescens), Pseudomonas (such as Pseudomonas aeruginosa), Acinetobacter such as

Acinetobacter anitratus), Nocardia (such as Nocardia autotrophica), or Mycobacterium (such as Mycobacterium fortuitum). Preferred ßlactam antibiotics are those which preferentially deactivated by Class A and Class C ß-lactamase enzymes, for example, amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, and ceftazidime. Effective doses and modes of administration of fol-lactam antibiotics, alone or in combination with 3-lactamase inhibitors), are known in the art or may be determined empirically by one skilled on the art.

Combination Treatments The compounds disclosed herein may be used in combination with with one or more other antibacterial agent for any of the aforementioned methods, including without limitation, any of the aforementioned methods of treatment. Preferred classes of antibacterial agents for use in combination with the compounds disclosed herein are, without limition, (3-lactam antibiotics, described supra, fluoroquinolones, quinolones, macrolides, and tetracyclines. Examples of fluoroquinolones include, without limitation, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, moxifloxacin, gemifloxacin, grepafloxacin, levofloxacin, norfloxacin, sparfloxacin, and trovafloxacin.

Examples of quinolones include, without limitation, cinoxacin, garenoxacin, and nalidixic acid. Examples of macrolides include, without limitation, azithromycin, clarithromycin, dirithromycin, erythromycin, and lincomycin. Examples of tetracyclines include, without limitation, doxycycline, minocycline, and tetracycline.

The term"in combination"refers to the concomitant administration of two (or more) active agents for the treatment of a, e. g., single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one preferred embodiment of the present invention, the active agents are combined and administered in a single dosage form. In another preferred embodiment, the active agents are administered in separate dosage forms (e. g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the disease state.

EXAMPLES The following examples illustrates the invention, but are not limiting.

EXAMPLE 1. Synthesis of Select Compounds In Formulation A (I) General procedure A: Synthesis of 3-aryloxycarbonyl-phenylboronic acid

step i, (COCI) 2, DMF, CH2Cl2, rt, overnight step ii, Et3N, CH2C12, rt, overnight In step (i) of general procedure A, oxalyl chloride (35 pL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl) boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CEI2Ck. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification.

In step (ii) of general procedure A, a solution of the acid chloride (0.2 mmol, obtained from step (i) above) in 5 mL of anhydrous CH2CI2 was added dropwise to an ice-cold solution of (Ia), anhydrous triethyl amine (42 uL, 0.3 mmol) and 10 mL of anhydrous CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1 : 10). The product yielded from step (ii) is (Ib).

Compound (1a) (3-(4-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (la) p-Nitrophenol (21 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to yield 42 mg (84% yield) of 3- (4-

Nitrophenoxycarbonyl)-5-nitrophenylboronic acid as a white powder, mp: 205-207°C.

1H-NMR (300MHz, d6-DMSO) : # 7. 61-7.66 [m, 2H, Ar-H], 8.30-8. 35 [m, 2H, Ar-H], 8. 78-8. 89 [m, 3H, Ar-H].

Compound (lb) (3- (2-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid) To make the compound (lb) o-Nitrophenol (21 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 36 mg (72% yield) of 3- (2- Nitrophenoxycarbonyl)-5-nitrophenylboronic acid as a pale yellow powder, mp: 128- 130°C. IH-NMR (300MHz, d6-DMSO) : # 7. 52-7.71 [m, 2H, Ar-H], 7.81-7. 94 [m, 1H, Ar-, t58. 13-8.24 [m, IH, Ar-H], 8. 70-8. 93 [m, 3H, Ar-H].

Compound (1c) (3- (3-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (1c) 7 m-Nitrophenol (21 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 41 mg (82% yield) of 3- (3- Nitrophenoxycarbonyl)-5-nitrophenylboronic acid as a light yellow crystal, nip : 185- 187°C. 1H-NMR(300MHz, d6-DMSO) : 57. 72-7. 81 [m, 2H, Ar-H], # 8.15-8. 29 [m, 2H, Ar-H] 8. 76-8. 89 [m, 3H, Ar-H].

Compound (ld) (3- (4-Methoxyphenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (ld), p-Methoxyphenol (19 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 39 mg (81% yield) of 3- (4- Methoxyphenoxycarbonyl)-5-nitrophenylboronic acid as a white needle, mp : 67°C. 1H-

NMR (300MHz, d6-DMSO) : # 3. 74 [s, 3H, OCH3], 6. 93-6 99 [m, 2H, Ar-H], 7.19-7. 24 [m, 2H, Ar-H], 8.72-8. 87 [m, 3H, Ar-H].

Compound (le) (3- (4-Ethoxycarbonylphenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (le), ethyl 4-hydroxybenzoate (25 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 51 mg (94% yield) of the desired compound as a white powder, mp : 230-232°C. IH-NMR (400MHz, d6-DMSO) : (5 1. 31 [t, 2H, CH2CH3], 4.30 [q, 3H, CH2CH3], 7.50 [d, 2H, Ar-H], 8.05 [d, 2H, Ar-H], 8.78-8. 90 [m, 3H, Ar-H].

Compound (1f) (3- (2-Oxo-benzo [1, 3] oxathiol-6-oxycarbonyl)-5- nitrophenylboronic acid) To make compound (lf), 6-Hydroxy-1, 3-benzoxathiol-2-one (25 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 50 mg (92% yield) of the desired compound as a white powder, mp : 145-147°C. 1H-NMR(300MHz, d6- DMSO) # 7.28-7.36 [m, 1H, Ar-H], 7.56-7.64 [m, 1H, Ar-H], 7.78-7.86 [m, 1H, Ar-H], 8. 72-8. 86 [m, 3H, Ar-H].

Compound (1g) (3-(2-Cyanophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (1g), 2-Hydroxybenzonitrile (18 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 43 mg (92% yield) of the

desired compound as a white powder, mp: 248-250°C. 1H-NMR(400MHz, d6-DMSO) : # 7.48-7. 57 [m, 1H, Ar-H], 7.62-7. 69 [m, 1H, Ar-H], 7.78-7. 89 [m, 1H, Ar-Hl, 7.96-8. 01 [m, 1H, Ar-H], 8.83-8. 94 [m, 3H, Ar-H].

Compound (lh) (3-(2-Chloro-6-nitrophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (1h), 2-Chloro-6-nitrophenol (26 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 39 mg (71% yield) of the desired compound as a yellow needle, mp: 179°C. IH-NMR (300MHz, d6-DMSO) : 8 7.54-7. 72 [m, 1H, Ar-H], 8.01-8. 24 [m, 2H, Ar-H], 8. 65-8. 94 [m, 3H, Ar-H].

Compound (li) (3-(2-Ethoxycarbonyl-phenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (li), ethyl salicylate (25 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 35 mg (64% yield) of the desired compound as a yellow semisolid. 1H-NMR(300MHz, d6-DMSO): # 1. 24 [t, 2H, CH2CH3], 4. 31 [q, 3H, CH2CH3], 7.41-7. 57 [m, 2H, Ar-Hl, 7. 81-8. 05 [m, 2H, Ar-H], 8.67-8.93 [m, 3H, Ar-H].

Compound (1j) (3-(2-Chlorophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (1j), o-Chlorophenol (19 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 44 mg (90% yield) of the desired compound as a white powder, mp: 138-140°C. IH-NMR (300MHz, d6-DMSO) : (5 7. 38- 7.78 [m, 4H, Ar-H], 8.71-9. 04 [m, 3H, Ar-H].

Compound (1k) (3- (2-Methylphenoxycarbonyl)-5-nitro-phenylboronic acid)

To make compound (1k), o-Cresol (16 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 40 mg (89% yield) of the desired compound as a yellow powder, mp : 175°C (dec). IH-NMR (300MHz, d6-DMSO) : # 2. 17 [t, 3H, CH3], 7.21-7. 40 [m, 3H, Ar-H], 8.15-8. 22 [m, 1H, Ar-H], 8.65-8. 91 [m, 3H, Ar- H1.

Compound (11) (3- (2-Methoxylphenoxycarbonyl)-5-nitrophenylboronic acid)

To make compound (11), guaiacol (19 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 44 mg (92% yield) of the desired compound as a yellow semisolid. IH-NMR (300MHz, d6-DMSO) : # 3. 69 [s, 3H, OCH3], 7.46-8. 03 [m, 4H9 Ar-FI], 8. 64-8. 97 [m, 3H, Ar-H].

Compound (1m) (3-(3-Methylphenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (lm), m-Cresol (16 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 41 mg (91% yield) of the desired compound as a yellow semisolid. 1H-NMR(300MHz, d6-DMSO) : 82. 35 [t, 3H, CH3], 7.79-8. 30 [m, 4H, Ar-H], 8.71-8. 91 [m, 3H, Ar-H].

Compound (1n) (3-(2, 6-Dichlorophenoxycarbonyl) -5-nitrophenylboronic acid)

To make compound (1n), 2,6-Dichlorophenol (25 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 43 mg (80% yield) of the desired compound as a pale yellow powder, mp: 167-169°C. 1H-NMR(300MHz, d6- DMSO): # 7. 39-7.44 [m, 1H, Ar-Ill, 7.52-7. 67 [m, 2H, Ar-H], 8. 83 [t, 1H, Ar-H], 8.94- 8.96 [m, 2H, Ar-H].

Compound 1o) (3- (2-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (lo), 2-Fluorophenol (17 mg, 0.15 mmol) was treated according to general procedure A9 step (ii), to give 39 mg (85% yield) of the desired compound as a white needle, mp: 144-146°C. 1H-NMR (400MHz, d6-DMSO+ D2O): # 7.29-7. 53 [m, 4H, Ar-Hl, 8. 80 [s, 1H, Ar-FI], 8.89-8. 93 [m, 2H, Ar-H].

Compound (1p) (3- (2, 6-Difluorophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (1p), 2,6-Difluorophenol (20 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 39 mg (81% yield) of the desired compound as a white powder, mp : 124-126°C. 1H-NMR(400MHz, d6- DMSO+D20) : # 7. 23-7. 38 [m, 2H, Ar-X71, 7.38-7. 48 [m, 1H, Ar-H], 8.81 [s, 1H, Ar-H], 8.86-8. 96 [m, 2H, Ar-H].

Compound (Iq) (3- (4-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid)

To make compound (lq), 4-Fluorophenol (17 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 41 mg (89% yield) of the desired compound as a white powder, mp: 233-235°C. 1H-NMR(400MHz, 5% D20 in d6-DMSO) : (57. 21-7.42 [m, 4H, Ar-H], 8.76 [s, 1H, Ar-H], 8. 83-8.95 [m, 2H, Ar-H].

Compound (lr) (3- (4-pyridyloxycarbonyl)-5-nitro-phenylboronic acid) To make compound (1r), 4-Pyridinol (14 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 34 mg (79% yield) of title compound as a pale yellow powder, mp : 165°C (dec). 1H-NMR (400MHz, 5% D2O in d6-DMSO): # 7.43-7. 50 [m, 1H, Ar-H], 8. 67-8. 72 [m, 1H, Ar-H], 8. 77-8. 86 [m, 3H, Ar-H], 8. 86-8. 97 [m, 1H, Ar-H].

Compound (Is) (3- (2-Chloro-3-pyridyloxycarbonyl)-5-nitrophenylboronic acid) To make compound (1s), 2-Chloro-3-pyridinol (19 mg, 0.15 mmol), was treated according to general procedure A, step (ii), to give 37 mg (77% yield) of the desired compound as a white powder, mp : 146-148°C. 1H-NMR(400MHz, 5%D2O in d6- DMSO) : # 7. 57-7.63 [m, 1H, Ar-H], 8. 05-8. 09 [m, 1H, Ar-H], 8. 39-8.43 [m, 1H, Ar-H], 8. 81 [s, 1H, Ar-H], 8.89-8.94 [m, 2H, Ar-H].

Compound (1t) (3-Phenoxycarbonyl-5-nitrophenylboronic acid)

To make compound (1t), phenol (14 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 39 mg (91% yield) of the desired compound as a white needle, mp: 139-141°C. 1H-NMR(400MHz, 5% D20 in d6-DMSO) : # 7. 28-7.34 [m, 3H, Ar-H], 7.44-7. 51 [m, 2H, Ar-H], 8.78 [s, 1H, Ar-H], 8. 86-8. 92 [m, 2H, Ar-H].

Compound (lu) (3- (2-Bromophenoxycarbonyl)-5-nitro-phenylboronic acid) To make compound (lu), 2-Bromophenol (26 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 49 mg (90% yield) of the desired compound as a pale yellow powder, mp: 128-130°C. 1H-NMR (400MHz, 5% D20 in d6- DMSO) : # 7.26-7. 35 [m, 1H, Ar-H], 7.47-7. 56 [m, 2H, Ar-H], 7.76-7. 81 [m, 1H, Ar-H], 8.83-8. 94 [m, 3H, Ar-H].

Compound (lv) (3- (3-Boronophenoxycarbonyl)-5-nitrophenylboronic acid) To make compound (lv) s 3-Hydroxyphenylboronic acid (21 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 32 mg (64% yield) of the desired compound as a pale yellow powder, mp: 228-230°C. 1H-NMR (400MHz, 5% D20 in d6-DMSO) : # 7. 30-7.36 [m, 1H, Ar-H], 7.41-7. 47 [m, 1H, Ar-H], 7.60-7. 63 [m, 1H, Ar-H], 7.68-7.73 [m, 1H, Ar-H], 8.76-8.79 [m, 1H, Ar-H], 8.84-8.90 [m, 2H, Ar- H]. Compound (lw-phenoxycarbonyl)-5-nitro- phenylboronic acid)

To make compound (1w), 2, 4-Dichloro-6-nitrophenol (80%) (39 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 52 mg (87% yield) of the desired compound as a pale yellow powder, mp: 184-186°C. 1H-NMR (400MHz, 5% D20 in d6-DMSO) : 8.34-8. 38 [m, 1H, Ar-H], 8. 82-8. 84 [m, 1H, Ar-, 8. 90-8. 91 [m, 1H, Ar-H], 8. 94-8. 96 [m, 1H, Ar-H].

Compound (1x) (3- (2, 4-Dichloro-6-nitro-phenoxycarbonyl) -5-nitro- phenylboronic acid) To make compound (lx), 5-Chloro-2- (2,4-dichlorophenoxy)phenol (43 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 51 mg (71% yield) of the desired compound as a pale yellow powder, mp: 193°C. 1H-NMR (400MHz, 5% D20 in d6-DMSO) : # 6. 61-6.94 [m, 3H, Ar-H], 7.15-8. 07 [m, 3H, Ar-H], 8. 71-8. 76 [m, 1H, Ar-H], 8. 84-8. 89 [m, 1H, Ar-H], 8.89-8. 96 [m, 1H, Ar-H].

Compound (1y) (3-(2,4,6-Trichlorophenoxycarbonyl)-5-nitro-phenylboronic acid) To make compound (ly), 2,4, 6-Trichlorophenol (30 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 45 mg (77% yield) of the desired compound as a white powder, mp: 217°C(dec). 1H-NMR (400MHz, 5% D20 in d6-DMSO) : # 7. 24 [s, 2H, Ar-H] 8. 77-8. 80 [m, 1H, Ar-H], 8. 90-8. 96 [m, 2H, Ar-H].

EXAMPLE 2. Synthesis of Select Compounds In Formulation A (II) General procedure B: Synthesis of 3-borono-5-nitrobenzoic acid 1,4- phenylene ester HO. B. OH HO. B. OH /, OH) 2 w )---"-- 02N"\-°Y) 0 O O R ii ON O R _ O I i O w NOz HO oH (zIb) BoH>Z (IIa) i, (COCI) 2, DMF, CH2CI2, rt, overnight ii, Et3N, THF, rt, overnight

In step (i) of general procedure B, oxalyl chloride (35 pL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl) boronic acid (42 mg, 0.2 mmol), I drop of DMF and 5 mL of anhydrous CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification.

In step (ii) of general procedure B, a solution of the acid chloride (0.2 mmol, obtained above in step (i)) in 5 mL of anhydrous THF was added dropwise to an ice-cold solution of 0.075 mmol of (IIa), anhydrous triethyl amine (42 I1L, 0*3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2S04) and concentrated. The residue was recrystallized from ethyl acetate/hexane.

The product yielded from step (ii) is (lib).

Compound (2a) (3-Borono-5-nitrobenzoic acid 1,4-phenylene ester)

To make the compound (2a), hydroquinone (9 mg, 0.075 mmol) was treated according to general procedure B, step (ii), to give 32 mg (86% yield) of the desired compound as a white powder, mp: 271-273°C. IH-NMR (300MHz, d6- DMSO+D20) : # 7. 43 [s, 4H, Ar-H], 8.79 [t, 1H, Ar-H], 8.84 [t, 1H, Ar-H], 8.86 [d, 1H, Ar-H].

Compound (2b) (3-Borono-5-nitrobenzoic acid 2-chloro-1, 4-phenylene ester) To make compound (2b), chlorohydroquinone (11 mg, 0.075 mmol) was treated according to general procedure B, step (ii), to give 31 mg (78% yield) of the deisred compound as a white powder, mp: 264-266°C. IH-NMR (300MHz, d6-DMSO) : # 7.46-7. 79 [m, 3H, Ar-H], 8.79 [d, 1H, Ar-H], 8.88-8. 92 [m, 2H, Ar-B].

Compound (2c) (3-Borono-5-nitrobenzoic acid 2-chloro-1, 4-phenylene ester) To make compound (2c), tetrachlorohydroquinone (19 mg, 0. 075 mmol) was treated according to general procedure B, step (ii), to give 33 mg (69% yield) of the desired compound as a white powder, mp: 252°C. 1H-NMR(300MHz, d6-DMSO) : 6 8. 71-8. 75 [m, 2H, Ar-R], 8. 93-8. 99 [m, 4H, Ar-H].

Compound (2d) (3-Borono-5-nitrobenzoic acid 2-chloro-1, 4-phenylene ester)

To make compound (2d), t-butylhydroquinone (12 mg, 0.075 mmol) was treated according to general procedure B, step (ii), to give 54 mg (65% yield) of the desired compound as a pale yellow powder, mp: 104°C (dec). IH-NMR (300MHz, d6- DMSO): # 1. 34 [s, 9H, CH3], 7.02-7. 27 [m, 3H, Ar-H], 8.79-8. 83 [m, 2H, Ar-H], 8. 86- 8.92 [m, 4H, Ar-H].

EXAMPLE 3. Synthesis of Select Compounds In Formulation A (III) General procedure C: Synthesis of 3-aryloxycarbonyl-phenylboronic acid step i, (COCI) 2, DMF, CH2C12, rt, overnight step ii, Et3N, CH2Cl2, rt, overnight In step (i) of general procedure C, oxalyl chloride (35 L, 0. 4 mmol) was added to a suspension of (3-carboxyl-5-1litrophenyl) boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification.

In step (ii) of general procedure C, a solution of the acid chloride (0.2 mmol, obtained from step (i) above) in 5 mL of anhydrous CH2C12 was added dropwise to an ice-cold solution of (IIIa), anhydrous triethyl amine (42 I1L, 0.3 mmol) and 10 mL of anhydrous CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was then dissolved in 25 mL of ethyl acetate and

washed with IN aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1: 10). The product yielded from step (ii) is (IIIb).

Compound (3a) (3- (2, 6-Dichlorobenzyloxycarbonyl)-5-nitrophenylboronic) To make compound (3a), 2,6-Dichlorobenzyl alcohol (27 mg, 0.15 mmol) was treated according to general procedure C, step (ii), to give 49 mg (89% yield) of the desired compound as a pale yellow semisolid. 1H-NMR(400MHz, 5% D20 in d6-DMSO) : # 5. 62 [s, 2H, Ar-CH2], 7.26-7. 62 [m, 3H, Ar-H], 8. 57-8.95 [m, 3H, Ar-Ill.

Compound (3b) (3- (3-Nitrobenzyloxycarbonyl)-5-nitrophenylboronic acid) To make compound (3b), 3-Nitrobenzyl alcohol (23 mg, 0.15 mmol) was treated according to general procedure C, step (ii), to give 43 mg (82% yield) of the desired compound as a pale yellow powder, mp : 142-144°C. 1H-NMR (400MHz, 5%D2O in d6-DMSO) : # 5. 46 [s, 2H, Ar-CH2], 7. 65-7. 70 [m, 1H, Ar-H], 7.93-7. 97 [m, 1H, Ar-H], 8. 09-8.12 [m, 1H, Ar-H], 8. 17-8. 21 [m, 1H, Ar-H], 8.62-8. 94 [m, 3H, Ar-H].

Compound f3c) (3- (3-Chlorobenzyloxycarbonyl)-5-nitrophenylboronic acid) To make compound (3c), 3-Chlorobenzyl alcohol (22 mg, 0. 15 mmol) was treated according to general procedure C, step (ii), to give 44 mg (88% yield) of the desired compound as a white powder, mp: 91°C (dec). IH-NMR (400MHz, 5% D20 in d6- DMSO) : # 5.41 [s, 2H, Ar-CH2], 7. 41-7.61 [m, 4H, Ar-H], 8. 62-8. 95 [m, 3H, Ar-H].

Compound (3d) (3- (3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid)

To make compound (3d), 3-Hydroxymethylphenylboronic acid (23 mg, 0.15 mmol) was treated according to general procedure C, step (ii), to give 35 mg (68% yield) of the desired compound as a yellow semisolid. lH-NMR (400MHz, 5% D20 in d6- DMSO): # 5. 39 [s, 2H, Ar-CH2], 7.27-7. 84 [m, 4H, Ar-H], 8. 79-8. 90 [m, 3H, Ar-H].

Compound 3e ? (3- (l-Naphthalenemethoxycarbonyl)-5-nitrophenylboronic acid) To make compound (3e), l-Naphthalenemethanol (24 mg, 0.15 mmol) was treated according to general procedure C, step (ii), to give 31 mg (59% yield) of the desired compound as a yellow semisolid. 1H-NMR (300MHz, 5%D2O in d6-DMSO) : # 5. 88 , Ar-CH2], 7.50-8.24 [m, 7H, Ar-H], 8.601-8.87 [m, 2H, Ar-H].

Compound (3f) (3- (3-Boronobenzyloxycarbonyl)-5-aminophenylboronic acid) To make the compound (3f) a solution of 3-(3-boronobenzyloxycarbonyl) -5-nitrophenylboronic acid (172 mg, 0.5 mmol) in absolute ethanol (10 ml) was hydrogenated in the presence of Raney Nickel (80 mg) for 4 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was recrystallized from ethanol/H20 to give 60 mg (38% yield) of the desired compound as a pale yellow semisolìd. lH-NMR (300MHz, 5% D20 in d6-DMSO) : 65. 25 [s, 2H9 Ar-CH2], 6. 56-6. 97 [m, 2H, Ar-H], 7. 15-8. 09 [in, 5H, Ar-H].

Compound (3g) (3- (3-Boronobenzyloxycarbonyl)-5-hydroxylphenylboronic acid)

To make the compound (3g), 3- (3-boronobenzyloxycarbonyl)-5- aminophenylboronic acid (31 mg, 0.1 mmol) was suspended in 2 mL of 50% H2S04 and treated at-5 °C with a solution of NaN02 (8 mg, 0. 1 mmol) in 1 mL of water. After the mixture had been stirred for 1 h at this temperature, water (10 mL) was added and the mixture was warmed to 60 °C until the evolution of gas ceased. The dark brown solution was extracted twice with ethyl acetate, and the extracts were washed with water and brine and dried with Na2S04. The solvent was evaporated to dryness, then the residue was recrystallized from methanol to give 10 mg (32% yield) of the desired compound as a pale yellow powder, mp : 217°C(dec). 1H-NMR(300MHz, 5% D20 in d6-DMSO) : a 5.39 [s, 2H, Ar-CH2], 7.07-7. 64 [m, 3H, Ar-H], 7.89-8. 27 [m, 4H, Ar-H].

EXAMPLE 4. Synthesis of Select Compounds In Formulation A (IV) Compound (4a) 3-(2-Fluorobenzamido)-5-carboxylphenylboronic acid To make compound (4a), 2-fluorobenzoyl chloride (60, L, 0.5 mmol) was added dropwise over a period of 30 min to an ice-cold solution of 3-amino-5- carboxylphenylboronic acid (91 mg, 0.5 mmol) al1d NaHCO3 (105 mg, 1.25 mmol) in 10 mL of water. The reaction mixture was kept at 0°C for lh and then stirred at room temperature overnight. It was then extracted twice with 10 mL of ethyl ether. The aqueous solution was acidified with 1N aqueous HCl and extracted twice with 10 mL of ethyl acetate. The combined organic layers were washed with water and saturated brine solution, dried (Na2SO4) and concentrated. The residue was recrystallized from ethyl

acetate/hexane to give 94 mg (62% yield) of the desired compound as a white powder, mp: 224-225°C. 1H-NMR (300MHz, 5% D20 in d6-DMSO) : 57. 21-7.38 [m, 2H, Ar-H], 7.48-7. 72 [m, 2H, Ar-H], 8. 12-8. 33 [m, 3H, Ar-Hl.

EXAMPLE 5. Synthesis of Select Compounds In Formulation A (XI) Compound (5a) (3-amino-5-carboxylphenylboronic acid)

To make the compound (5a), a solution of 3-carboxyl-5- nitrophenylboronic acid (422 mg, 2 mmol) in absolute ethanol (5 ml) was hydrogenated in the presence of Raney Nickel (150 mg) for 6 hours. The catalyst was removed by filtration and the solvent was evaporated to dryness, then the residue was recrystallized from water to give 257 mg (71% yield) of the desired compound as a pale yellow powder, mp: 210-212°C (Ref. mp: 212-214°C). 1H-NMR(400MHz, 5% D20 in d6-DMSO) : # 7. 06 [s, 1H, Ar-H], 7016 [s, 1H, Ar-Hl, 7.55 [s, 1H, Ar-H] (Torssell, K. ; Meyer, H. ; Zacharias, B. Arkiv Kemi 1957, 10, 497-505).

EXAMPLE 6. Synthesis of Select Compounds In Formulation A (XII) Compound (6a) (3- (2, 6-Dichlorophenylcarbonyloxy) phenyl boronic acid)

To make compound (6a), a solution of 2, 6-dichlorobenzoyl chloride (29 pL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3- hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (42 ut, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2S04)

and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1: 10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238°C (dec). lH-NMR (400MHz, 5% Da0 in d6-DMSO) : 057. 08-7.19 [m, 1H, Ar-H], 7.22-7. 30 [m, 1H, Ar-H], 7.22-7. 30 [m, 1H, Ar-H], 7.42-7. 50 [m, 1H, Ar-H], 7.54-7. 60 [m, 1H, Ar-H], 7.60-7. 68 [m, 2H, Ar-H], 7.73-7. 78 [m, 3H, Ar-H].

EXAMPLE 7. Synthesis of Select Compounds In Formulation A (XIII) Compound (7a) 4-Borono-2-fluorobenzoic acid 2-chloro-1, 4-phenylene ester In step (i), oxalyl chloride (35 uL, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of dried CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).

In step (ii), a suspension of the above acid chloride (002 mmol, obtained from step (ii) ) in 5 mL of dried THF was added dropwise to an ice-cold solution of chlorohydroquinone (11 mg, 0.075 mmol), anhydrous triethyl amine (42 u, L, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 26 mg (74% yield) of the desired compound as a pale yellow powder, mp : 228-230°C. 1H-NMR (400MHz, 5% D20 in d6- DMSO) : # 6. 52-6.55 [m, 1H, Ar-FI], 6. 68-6. 76 [m, 2H, Ar-FIJ, 6.94-7. 06 [m, 1H, Ar-H], 7.21-7. 34 [m, 1H, Ar-H], 7.57-7. 78 [m, 3H, Ar-H], 7.99-8. 11 [m, 1H, Ar-H].

EXAMPLE 8. Synthesis of Select Compounds In Formulation A (XIV) Compound 8 (a) (4- (2-Chloro-6-nitrophenoxycarbonyl)-3-fluorophenylboronic acid)

In step (i), oxalyl chloride (35 1L, 0.4 mmol) was added to a suspension of 3-fluoro-4-carboxylphenylboronic acid (37 mg, 0.2 mmol), 1 drop of DMF and 5 mL of dried CH2C12. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).

In step (ii), a suspension of the above acid chloride (0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 2-chloro-6-nitrophenol (26 mg, 0.15 mmol), dried triethyl amine (42 µL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2S04) and concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1: 10) to give 40 mg (79% yield) of the desired compound as a pale yellow powder, mp: 174- 175°C. IH-NMR (400MHz, 5% D20 in d6-DMSO) : 67. 61-7.36 [m, 1H, Ar-H], 7. 71-7. 74 [m, 1H, Ar-Hl, 7.77-7. 79 [m, 1H, Ar-Hl, 8. 07-8. 11 [m, 2H, Ar-H], 8. 18-8. 21 [m, 2H, Ar- H].

EXAMPLE 9. Synthesis of Select Compounds In Formulation A(XV) Compound (9a) (3-Borono-5-nitrobenzoic acid 1, 3-phenylene ester) In step (i), oxalyl chloride (35 µL, 0.4 mmol) was added to a suspension of 3-carboxyl-5-nitrophenylboronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of dried CH2CI2. The reaction mixture was stirred at room temperature overnight and then

evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).

In step (ii), a solution of the above acid chloride (0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of resorcinol (9 mg, 0.075 mmol), dried triethyl amine (42 µL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHC03, saturated brine solution, dried (Na2S04) and concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1: 10) to give 26 mg (70% yield) of the desired compound as a pale yellow powder, mp: 134°C (dec). lH- NMR (400MHz, 5% D20 in d6-DMSO) : eS6. 14-6. 18 [m, 2H, Ar-H], 7.33-7. 45 [m, 2H, Ar-H], 8. 75-8.82 [m, 2H, Ar-H], 8.85-8. 90 [m, 4H, Ar-Hl.

EXAMPLE 10. Synthesis of Select Compounds In Formulation A (XVI) Compound (l0a) (3-Borono-S-nitrobenzoic acid 1, 2-benzenedimethanol ester) In step (i), oxalyl chloride (35 µL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl) boronic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of dried CH2Cl2. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).

In step (ii) a suspension of the above acid chloride (0. 2 mmol, obtained from step (ii)) in 5 mL of dried THF was added dropwise to all ice-cold solution of 1,2- benzenedimethanol (10 mg, 0.075 mmol), anhydrous triethyl amine (42 p. L, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HC1, 10% aqueous NaHCO39 saturated brine solution, dried (Na2S04) and then concentrated. The residue was purified by flash chromatography

eluting with MeOH-ethyl acetate (1: 10) to give 21 mg (53% yield) of the desired compound as a pale yellow powder, mp : 142°C (dec). 1H-NMR (400MHz, 5% D20 in d6- DMSO): # 5. 64 [s, 4H, CH2], 6.14-6. 18 [m, 2H, Ar-H], 7. 33-7. 45 [m, 2H, Ar-H], 8.77- 8.84 [m, 2H, Ar-H], 8.87-8. 93 [m, 4H, Ar-H].

EXAMPLE 11. Synthesis of Select Compounds In Formulation A (XVII) Compound (lia) (1, 4-Benzenedicarboxylic acid, di 3-boronophenyl ester) To make compound (12a), a solution of terephthaloyl chloride (21mg, 0.1 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3- hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (28 µL, 0.2 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HC19 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1: 10) to give 16 mg (51% yield) of the desired compound as a white powder, mp : 214°C(dec). 1H-NMR (400MHz, 5% D20 in d6-DMSO) : # 7.28-7. 34 [m, 2H, Ar-H], 7. 38-7. 46 [m, 2H, Ar-H], 7.59-7. 63 [m, 2H, Ar-H], 7. 68-7. 73 [m, 2H, Ar- H], 8. 30 [s, 4H, Ar-H].

EXAMPLE 12. Synthesis of Select Compounds In Formulation A(XVIII) Compound ound (12a) (Tris(3-borono-5-nitrobenzoic acid), 1,3,5-trihydroxybenzene ester)

In step (i), oxalyl chloride (79 I1L, 0.9 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl) boronic acid (95 mg, 0.45 mmol), 1 drop of DMF and 10 mL of dried CH2C12 The reaction mixture was stirred at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification in step (ii).

In step (ii), a suspension of the above acid chloride (0.2 mmol, obtained from step (ii) ) in 5 mL of dried THF was added dropwise to an ice-cold solution of phloroglucinol (13 mg, 0.1 mmol), anhydrous triethyl amine (42 µL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with IN aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2S04) and then concentrated. The residue was purified by flash cluomatography eluting with MeOH-ethyl acetate (1 : 10) to give 17 mg (24% yield) of the desired compound as a pale yellow powder, mp: 274°C(dec). 1H-NMR (400MHz, 5% D20 in d6-DMSO) : 67. 46 [s, 1Hn, 8. 72-8. 76 [m, 1H, Ar-Hl, 8. 78-8. 86 [m, 2H9 Ar-Hl.

EXAMPLE 13. Inhibition Assay The inhibition of TEM-1 ß-lactamase was determined spectrophotometrically. B-lactamase activity was followed by measuring the hydrolysis of nitrocefin, [3-(2,4-dinitrostyryl)-(6R, 7R)-7-(2-thienylacetamido)-ceph-3-em-4- carboxylic acid, E-isomer], (Calbiochem, San Diego, CA, USA) at 486 nm. Inhibition assays were performed at 25°C in 50 mM sodium phosphate, 5 % DMSO, pH 7.0. The enzyme concentration was held at 5nM, with substrate at 167 LM and varying inhibitor concentrations. Inhibitor was added to the enzyme and incubated for ten minutes before the addition of substrate. Inhibition constants (F ;) for the inhibitors are obtained at the

desired temperature and solvent conditions by measuring the rate of substrate hydrolysis at increasing amounts of inhibitors.

Table 11 shows the ß-lactamase inhibition data of the compounds of the present invention obtained using inhibition assay described above. The Ki values in the parenthesis obtained from a Lineweaver-Burke analysis.

Table 11 Results of TEM-1 ß-Lactamase Inhibition Assay Ki (AM) Compound (Ki from Lineweaver- Burke Analysis) (1a) 80~9 12~3 (Ib) (1.18) (1c) 39~7 (1d) 42~7 (le) >1000 (1f) 33~4 37A3 (1.37) 9. 50. 8 (1h) (0. 65) (li) 101i4 28A2 (1.31) (1k) 130~18 (11) 116~7 (1m) 114i12 (2a) 22. 7~1. 3 (2b) 15. 2~1. 4 8. 8~0. 5 (in) (0. 62) (lo) 49. 34. 6 (lp) 19. 81. 3 (4a) 1439 (lq) 1008 34~2. 9 (4. 97) (1r) 138~2. 7 (5a) 72749 (1s) 42. 32. 4 958. 7 (It) (6. 54) 27~3. 4 (3b) (2. 76) 25~1. 5 (2. 35) 25~2. 5 (1.68) (6a) 28~2. 1 (lv) 32~1. 1 (3d) 55. 7~4. 3 (7a) 122i10 (8a) 43~1.6 (9a) 16~1. 5 (1w) 131. 1 F1001 104 F1002 148 F1012 113 F1201 27 F1212 95 BB-1003 231 BB-1004 297 BB-1005 392 EXAMPLE 14. Binding Energetics of Inhibitors

The binding of the compounds of the present invention to (3-lactamase was also measured by isothennal titration calorimetry. Isothermal titration calorimetry does not only measure the binding affinity of inhibitors but also dissects the enthalpic and entropic components to binding, thus allowing identification of the forces involved in the association reaction. In general a binding reaction characterized by a favorable enthalpy change indicates that the inhibitor establishes strong interactions with the target, whereas an inhibitor characterized by unfavorable binding enthalpy is driven by non- specific hydrophobic interactions, i. e. , a tendency to escape water rather than a strong attraction to the target (Velazquez-Campoy et al., (2001) Arch. Biochim. Biophys. 390, 169-175 ; and Ohtaka et al., (2002) Protein Science 11,1908-1916).

Table 12. Binding Enthalpy of Selected Compounds AHwt AHM69I AHE104K AHR244S Compound cal/mol cal/mol cal/mol cal/mol (lb)-3800-2000-3900-9500 F1201-3200-2400-3500-6500 F1212-4700-3300-4500-8900 (1h)-1140-953-1896-11931 (lj)-2145-1693-2756-6877 (1g)-5520-2460-6397-8200 These experiments, in combination with the inhibition assays, indicate that the compounds identified in this disclosure bind to the wild type as well as drug resistant beta lactamases with favorable binding enthalpies. This is a vtry important characteristic from the point of view of further optimization since it facilitates the achievement of extremely high affinities and low susceptibilities to drug resistant mutations and naturally occurring polymorphisms.

EXAMPLE 15. Activity Against Clavulanic Acid Resistant Mutants As discussed above, the use of ß-lactam-based ß-lactamase inhibitors has led to the appearance of infectious microorganisms that carry mutated versions of the beta lactamase enzyme that are not efficiently inhibited by beta lactamase inhibitors

currently in clinical use (clavulanic acid, sulbactam, tazobactam) (Bonomo et al, 1997).

Three of the most important mutations are M69I, R244S and E104K. The mutations M69I and R244S significantly lower the affinity of clinically used beta lactamase inhibitors whereas the mutation E104K does not have a direct effect on the affinity of those molecules but increases the hydrolysis rates of extended spectrum antibiotics.

Compounds of the present invention were tested against these mutations as shown in Table 13. As shown in Table 13, while the existing clinical inhibitors lose potency between one to over two orders of magnitude, compounds of the present invention maintain equivalent potency against wild type and drug resistant mutants, and in many cases exhibit better potency against drug resistant mutants.

Table 13. Loss of Potency Against ß-Lactamase Mutants Expressed as the Ratio of the Inhibitory Constant Between Mutant and Wild Type (Potencywt/Potencymutant)-* Compound M69I R244S E104K Clavulanic 163 38 0.67 Sulbactam 15 93 1 Tazobactam 31 105 1 (1h) 1. 2 0. 86 0. 77 (lb) 1.0 1.2 0.92 F1201 0. 52 0. 86 0. 48 (1j) 0.33 0.37 0.15 (TO047042037 (lg) 040026032 (Id) 060062055 (lc) 1.0 0.52 0.56 (la) a) 0.43 0.44 0.39 (il) 050034036 *A number higher than 1 reflects a loss of potency against mutant Example 16 Recovery of Antibiotic Potency in Antibacterial Assay The following four compounds

HO.. OH D 02N > (compound F1201) ; 02N) OH B on (compuond F1202) ; HCk., OH HOB'OH /OH o (compound F1203) ; and HO. OH I tiN°e ON ° (compound F1204) were tested against three different strains: (1) methicillin resistant S. aureus ATCC 33591 (MRSA-ATCC).

This strain was obtained from American Type Culture Collection (ATCC), Manassas, MD ; (2) methicillin resistant S. atreus from Stanford University Hospital Clinical Microbiology/Virology Laboratory (MRSA-SU). This strain was isolated from a blood culture and was found to be resistant to nafcillin and oxacillin. Such Staphylococci are also resistant to all penicillins, and all cephalosporins, in addition to all ß-lactamase inhibitor combinations (including ampicillin/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam), imipenem, and meropenem; and (3) methicillin sensitive S. aureus ATCC 25923 (MSSA). This strain was obtained from ATCC and was used as a control.

Oxacillin (Lot # 11OK1041) was purchased from Sigma Chemical Company, St. Louis, MO.

EXPERIMENTAL PROCEDURES Cultivation and Maintenance of Test Organisms

The strains were processed according to procedures recommended by ATCC, or procedures that are routinely used. Single colonies of each organism were picked for purification to generate pure working cultures. Prior to each experiment each strain was subcultured on a fresh Mueller-Hinton agar plate (MHA).

Inoculum Inocula for the MIC assays were prepared by transferring a tiny portion of one colony from a MHA plate to 2 ml of Mueller-Hinton broth (MHB) such that the estimated cell density was about 107 colony forming unit (CFU) /ml. This cell suspension was then further diluted 10-fold (to 106 CFU/ml) by transferring the 2 ml cell suspension to 18 ml of MHB. Addition of 50 Al of this dilute cell suspension to 50 ul of growth medium yielded the desired cell density, namely about 5 x 104 CFU/well, or 5 x 105 <BR> <BR> <BR> <BR> CFU/ml.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Broth lVlicrodilutioh Procedure The MIC value of oxacillin was determined using the broth microdilution procedure recommended by the National Committee of Clinical Laboratory Standards (NCCLS, 2000). This procedure was also used to determine whether any of the inhibitors exhibited antimicrobial activity.

ALICAssays with Oxacillin The MIC experiments were performed in duplicate in 96-well microtiter plates using MHB. A stock solution of 2.6 mg/0.5 ml was prepared in dimethylsulfoxide (DMSO). A total of 8 two-fold serial dilutions were made with DMSO. Initial oxacillin doses used were (µg/ml): 64, 32, 16, 8, 4, 2, 1, and 0.5. Doses were adjusted in the confirmatory experiment, if needed, in order to establish an actual MIC value.

To each well of a 96 well microtiter plate te was added 47.5 µl of MHB. A volume ouf 2. 5 il of each dilution of oxacillin was then transferred to appropriate wells containing the medium. All wells, except the sterility control wells, were then inoculated with 50 y1 of a diluted cell suspension to give a final volume of 100 itl and a final cell density of 5 x 104 CFU/well. The volume in the sterility control wells was adjusted to 100 ul with MHB. A sterile pipette tip was used to mix the contents of each well (one tip was used going from the low to the high concentration in the same column). The

microtiter plates were covered with the lids and were placed in large Stratagene Big Blue plates (Cat. # 400041). Four large kimwipes moistened with tap water were placed near the edges of the Stratagene plates to prevent evaporation of the medium. The microtiter plates were incubated for at least 24 hours at 35°C. The plates were then evaluated for growth in each well. Controls included: medium sterility and negative control (medium and bacteria only).

MICylssays with Compounds of the Present Inventon The procedure used to determine the antimicrobial activity of the compounds of the present invention was identical to the broth microdilution procedure described above with the exception of the preparation of the stock solutions. Stock solution at concentration of 40.96 mg/0. 5 ml was prepared in DMSO for each of the compounds. A total of 8 two-fold dilutions were then made in DMSO. A volume of 2.5 Itl of each dilution was delivered to appropriate wells. The initial doses used were (, ug/ml) : 512,256, 128, 64,32, 16,8, and 4.

Criteria for MIC determination A numerical code was used to evaluate the extent of growth as indicated below.

0: absence of growth 1: barely visible (faint) growth 2: fair growth but less than the negative solvent control 3: growth is equivalent to the negative solvent control.

The lowest dose at which no visible growth is observed was determined to be the MIC value. at7 ix SsteXz The effect of the four compounds of the present invention on oxacillin resistance of the MRSA strains was determined using a matrix system. The ß-lactanzase inhibitors were tested at 5 doses against up to eleven concentrations of oxacillin. The highest dose of oxacillin and inhibitors used were at least one dose above the MIC value, with the exception of compound FL203 which was tested at a high dose of 512 jU, l/ml which was not bacteriotoxic to any of the strains used. A 96-well microtiter plate was used for the matrix system. The procedure was identical to that described above for the

MIC determination, with the exception that both oxacillin and one each of the 0- lactamase inhibitors was added, 2. 5 ul each, to the wells prior to addition of the test organisms.

RESULTS AND DISCUSSION MIC Evaluation of Oxacillin and the Four Coinpounds MIC assays were performed with oxacillin and the four compounds. Each of the compounds was tested at the following 8 doses (llg/ml) : 512,256, 128,64, 32,16, 8, and 4. Oxacillin was tested at the following 8 doses (g/ml) : 64,32, 16,8, 4,2, 1, and 0.5. The MIC values obtained were tabulated in Table 14. These MIC data indicate that these four compounds have antibacterial activities.

Table 14 Test Compound Compound Compound Compound OxacHMn Organism F1201 F1202 F1203 F1204 MRSA- 32 16 > 512 256 32 ATCC MSSA 32 128 > 512 512 0. 25 MRSA-SU 32 256 >512 512 > 64 Matrix Study:Oxacillin and Compound FL201 with MRSA-ATCC The results are shown in Table 15.

Table 15. 0771FOU71 Fi ? ou Oxacillin jig/ml0168421 0 3 0 1 2 3 3 64 0 0 0 0 0 0 32200000 16 2 0 0 0 0 0 8 300001 4 3 0 0 0 0 1 2300001 1 3 0 0 0 1 1 0. 5 3 0 0 0 1 1 0. 25 3 0 0 1 1 0. 125 3 0 0 1 1 1 0. 064 3 0 0 1 1 1 MIC 64 N/A < 0. 064 0.5 2 16 Stg/Xl

Matrix Study:Oxacillin and Compound F1202 with MRSA-ATCC The results are shown in Table 16.

Table 16. Compound FI 202 Oxacillin , ug/ml O 16 4 1 0 3 1 1 2 2 3 64000000 32200000 16 2 0 0 0 Q 2 is300012 $ 3 0 0 0 1 2 2 3 300022 3 0 0 3 U 0 0 2' ? 1 3 0 0 0 2 3 0. 5 3 0 0 1 2 3 0. 25 3 0 0 1 2 3 0. 125 3 0 0 2 3 3 0. 064, 3 0 1 2 3 3 MIC 32 < 0. 064 0.125 1 16 32 µg/ml

Matrix Study : Oxacillin and Compound FL201 with MRSA-SU The results are shown in Table 17.

Table 17. Compound F1201 Oxacillin Cg/ml 0 32 16 8 4 2 0 3 0 1 2 2 3 256000000 128 1 0 0 0 0 0 64 2 0 0 0 0 0 16300001 4300011 2300011 1 3 0 0 0 1 1 0. 5 3 0 0 0 1 2 0. 25 3 0 0 1 1 2 0. 125 3 0 0 1 2 2 0. 064 3 0 0 1 2 2 256 N/A <0. 064 0. 5 t6 64 jg/mt

Matrix Study:Oxacillin and Compound FL202 with MRSA-SU The results are shown in Table 18.

Table 18. Compound F1202 Oxacillin 256 128 64 32 16 0 3 0 1 3 3 3 256 0 0 0 0 0 0 128200000 64 2 0 0 0 0 0 16 3 0 0 0 0 4 3 0 0 0 0 2 3 0 0 0 1 1 1 3 0 0 0 1 1 1 3 0 0 0 1 0. 5 3 0 0 1 1 1 0. 25 3 0 0 1 1 0. 125 3 Q 1 1 1 1 0. 064 3 0 1 1 1 MIC 256 N/A 0. 25 1 4 64 FLg/Xl

EXAMPLE 17 COMPARISON OF ACTIVITIES AGAINST TEM-1 AND Amp-C ß-LACTAMASES Materials and Methods The gene for AmpC p-lactamase (accession number P00811) was obtained from Escherichia coli K12 strain W3110 (American Type Culture Collection, Rockville, MD). E. coli was grown and plasmid (F- lacIq lacPL8 ampc : :lambdacI+) was isolated via Qiagen (Valencia, CA) mini prep. The gene for AmpC was amplified in two pieces via polymerase chain reaction, ligated and purified by agarose gel electrophoresis. The ligated gene was inserted into a pET200 vector via a TOPO reaction (Invitrogen, Carlsbad, CA). Correct gene and plasmid sequence was verified by standard DNA sequencing.

BL21 (DE3) (Invitrogen) cells were transformed by heat-shock with the prepared plasmid. These cells were grown to an OD600 of 0.8 at 37 °C. <BR> <BR> <BR> <P>Isopropylthiogalactoside (IPTG) was added to 1 mM, incubation temperature decreased to 25 °C and the cells were grown for an additional 18 hours. After 18 hours, the E. coli

was pelleted by centrifugation, and discarded. The growth media was concentrated and dialyzed versus 100 mM Tris, pH 7.0. This solution was run through an equilibrated Q- resin column, and washed with excess 100 mM Tris, pH 7.0. AmpC was eluted and purity was found to be > 95% by SDS-PAGE.

The competitive inhibition of ß-lactamase was determined spectrophotometrically using a Varian (Walnut Creek, CA) Cary 100 UV-Visible spectrophotometer. (3-lactamase activity was followed by measuring the hydrolysis of nitrocefin, [3- (2, 4-dinitrostyryl)- (6R, 7R)-7- (2-thienylacetamido)-ceph-3-em-4- carboxylic acid, E-isomer], (Calbiochem, San Diego, CA) at 486 nm. Inhibition assays were performed at 25 °C in 50 mM sodium phosphate, 5 % DMSO, pH 7.0. Typical p- lactamase preparations hydrolyze nitrocefin substrate from 50 to 150 s-1. Under these conditions, the KM for AmpC (3-lactamase is 250 uM and the k,, t is 975 s-. Penicillin G (Sigma, St. Louis, MO) was also used as a substrate to determine Km and Lineweaver-Burk plots were used to determine the inhibition mechanism, and several compounds were found to inhibit competitively. For determination of compound inhibition constants, protein was held at 5 nM, with nitrocefin substrate at 167 I1M and a varying inhibitor concentration. Inhibitor was added to protein and incubated for ten minutes before the addition of substrate. Inhibition constants were determined by measuring the loss of p-lactamase activity with increasing inhibitor concentrations and fitting the data to standard equations for competitive inhibition.

Isothermal titration calorimetry was performed on a high-precision VP- ITC titration calorimeter (Microcal Inc., Northampton, MA). ß-Lactamase solutions were titrated with inhibitors in 50 mM sodium phosphate, 2% DMSO, pH 7. 0, with p- lactanase concentrations ranging from 15 to 25 p, M and inhibitor concentrations ranging from 300 to 1000 j. The heat evolved from each injection was obtained by integrating the calorimetric signal. Heat of binding was obtained as the difference between the heat of reaction and the heat of inhibitor dilution. Data were analyzed using Origin 7. 0 (OriginLab Corporation, Northampton, MA).

These methods can also be used to express and assay recombinant TEM-1 variant of ß-lactamase.

Results Kinetic measurements of the digestion of a natural substrate, penicillin G and a chemically available substrate, nitrocefin are shown in Table 19. kcat/KM, a measure of the catalytic efficiency, is larger with penicillin G as a substrate instead of nitrocefin.

Table 19. Kinetic characterization of the AmpC ß-lactamase.

Substrate kcat1 KM2 kcat/KM penicillin G 198~4 28~3 7.2~0. 6 nitrocefin 976~46 253~28 3. 9~0. 6 1'Units are s-l.

2 Units are I1M.

3 Units are s-1µM-1.

Phenyl-boronic acids have inhibitory activity against theTEM-1 and AmpC P-lactamases. Lineweaver-Burk inhibition plots indicate competitive inhibition.

Screening of compounds for inhibitory activity showed several compounds with inhibitory activity in the high nanomolar to low micromolar range. Isothermal titration calorimetry was undertaken to determine the thermodynamic characteristics of binding to AmpC p-lactamase. Most compounds tested bound with favorable enthalpic contributions, although the magnitude of the enthalpic contribution varied greatly between the compounds. Several compounds bound with nM affinity.

The compounds with the highest inhibitory activity and the thermodynamic components of binding to Amp-C are shown in Table 20. Also shown are the results obtained for ß-lactamase variant TEM-I. Table 20. Inhibition constants and thermodynamic parameters of compounds versus AmpC and TEM-1 P-lactamases AmpC Ki1 #G2 #H2 -T#S2 TEM-1 (10a) 0.457-8590-4149-4441 (2c) 6. 7-5814-1648-4166 (3f) 0.724-8151-9325 1174 (12a) 6.9-6468-690-5778 (7a) 0.873-7314-9936 2622 (ln) 8.8-5608-1173-4435 (8a) 0.913-8190-8486 296 (1h) 9.5-6614-1140-5474 (3d) 1.03-7442-15637 8195 (10a) 9.7-7183-982-6201 (11a) 1.31 -7548 -3114 -4434 (1x) 10. 4-6655-577-6078 (6a) 1. 53-7757-6538-1219 (2d) 10.9-6513-859-5654 F1001 1.79-6830-644-6186 (lb) 12-6420-4011-2409 (12a) 1.94-7231-1470-5761 (lw) 12.7-6409-4554-1855 (3g) 2. 69-7356-3677-3679 (2b) 15. 2-7864-520-7344 (2b) 2. 92-7736-225-7511 (ly) 15. 8-6550 0-6550 (2c) 3.68-7115-473-6642 (9a) 16.2-7864 446-8310 F1201 4.45-6566-5084-1482 (3e) 17.1-6164 224-6388 (lv) 5.01-7221-10412 3191 (lp) 19. 8-5916-6715 799 (2d) 6.27-7098 0-7098 (2a) 22.7-7451 274-7725

1 Ki units are MM <BR> <BR> <BR> <BR> 2. JG, AH and-TJS units are cal/mol.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> * * * * * * * The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Numerous references, including patents, patent applications, protocols and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is"prior art"to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety and to the same extent as if each reference was individually incorporated by reference.