WO2005004799A2 - β-LACTAMASE INHIBITORS AND METHODS OF USE THEREOF - Google Patents

β-LACTAMASE INHIBITORS AND METHODS OF USE THEREOF Download PDF

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WO2005004799A2
WO2005004799A2 PCT/US2004/018624 US2004018624W WO2005004799A2 WO 2005004799 A2 WO2005004799 A2 WO 2005004799A2 US 2004018624 W US2004018624 W US 2004018624W WO 2005004799 A2 WO2005004799 A2 WO 2005004799A2
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hydrogen
compound
alkyl
effective amount
chloro
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PCT/US2004/018624
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French (fr)
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WO2005004799A3 (en
Inventor
Ernesto Freire
Patrick Ross
Yingxin Xiao
Raphael Ottenbrite
Irene Luque
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Fulcrum Pharmaceuticals, Inc.
The Johns Hopkins University
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Priority to JP2006533731A priority Critical patent/JP2007505950A/en
Priority to AU2004256841A priority patent/AU2004256841A1/en
Priority to CA002528587A priority patent/CA2528587A1/en
Priority to EP04776476A priority patent/EP1635812A2/en
Publication of WO2005004799A2 publication Critical patent/WO2005004799A2/en
Publication of WO2005004799A3 publication Critical patent/WO2005004799A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to inhibitors of -lactamase and methods of use thereof. Specifically, the invention relates to non-jS-lactam-based inhibitors of ⁇ - lactamase.
  • PBPs Penicillin Binding Proteins
  • 8-lactam drugs 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 ⁇ - lactam antibiotics (Sanders, Clinical Infectious Disease, 14, 1089-1099 (1992); Li et al., Antimicrob. Agents Chemolher., 39, 1948-1953 (1995)). Probably the most widespread is the hydrolysis of jS-lactarns by
  • /3-lactamases are endogenous bacterial enzymes that destroy j ⁇ -lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the /3-lactam ring.
  • the structures of many ⁇ -lactamases are known at the atomic level and available in the protein database. At least four classes of ⁇ -lactamases are known: Classes A, B, C and D. At the clinical level, the most important jS-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 Class A
  • 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 /3-lactamases is to use molecules that neutralize the action of /3-lactamase (known as /3-lactamase inhibitors or inhibitors of /3-lactamase) in combination with antibiotics.
  • the three ⁇ -lactamase inhibitors currently in clinical use are all transition state analogs that utilize the same -lactam core that is present in the antibiotics themselves .
  • the similarity between the /3-lactam antibiotics and /3-lactam-based ⁇ - lactamase inhibitors has proven to be a serious problem.
  • Resistance to such /3-lactam- based /3-lactamase inhibitors arises through modifications of previously susceptible mechanisms. Certain mutations in /3-lactamase, for example, reduce the effectiveness of (S-lactam-based jS-lactamase inhibitors while preserving the ability of the /3-lactamase to hydrolyze the antibiotic molecules.
  • /3-lactam binding to these sensors leads to transcriptional up- regulation of the /3-lactamase.
  • /3-lactam-based /3-lactamase inhibitors thus, can induce the production of the enzyme that they are meant to inhibit, preventing or reducing their efficacy.
  • ⁇ -lactamases have evolved mechanisms for, e.g., sensing and/or hydrolyzing such molecules.
  • Such novel inhibitors would also escape detection by ⁇ - lacta sensor proteins that up-regulate /3-lactamase transcription, and may be unaffected by porin mutations that limit the access of /3-lactams to PBPs. Such inhibitors would allow the current /3-lactam antibiotics to effectively work against bacteria where ⁇ - lactamases provide the dominant resistance mechanism. It has previously been reported that boric acid and certain phenyl boronic acids are inhibitors of certain /3-lactamases (Koehler and Lienhard, (1971); Kiener and Waley, Biochem.
  • m-(dansylamidophenyl)-boronic acid has been reported to inhibitor of the Enterobacter cloacae P99 /3-lactamase (Dryjanski and Pratt, Biochemistry, 34, 3561-3568 (1995)).
  • Strynadka and colleagues used the crystallographic shructure of a mutant TEM-1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [(lR)-l-acetamido-2-(3- carboxyphenyTjethane boronic acid] with high affinity for this enzyme. (Strynadka et al., Nat. Struc. Biol, 3, 688-695 (1996)).
  • the present invention provides compounds having the formula (A): (HO) 2 -B-T (A) wherein
  • T has one of the following structures:
  • Ri through R 12 are each independently (i) when connected to a carbon atom: hydrogen, Q- ⁇ alkyl, C 3 . 6 cycloalkyl, C ⁇ _ 3 alkoxy, «-butoxy, z-butoxy, sec-butoxy, R 13 R ⁇ 4 N- (wherein R 1 and R] are each independently hydrogen or C1.
  • the compounds of the present invention are represented by formula A(I):
  • Ri through R 9 are each independently (i) when connected to a carbon atom: hydrogen, C ⁇ . 6 alkyl, C 3 . 6 cycloalkyl, C ⁇ - 3 alkoxy, «-butoxy, z-butoxy, sec-butoxy, R ⁇ 3 R ⁇ N-,wherein R ⁇ 3 and Ru are each independently hydrogen or C1- 3 alkyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C].
  • Ri, R 3 and 4 are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C 3 .
  • Ri through R 12 are each independently hydrogen, C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, C ⁇ - 3 alkoxy, zz-butoxy, z-butoxy, _?ec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d- 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , -
  • Ri, R 3 , Ri, R , R 11 and R 12 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C M alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 8 are each independently hydrogen, CM alkyl, C 3 . 6 cycloalkyl, C ⁇ .
  • Ri, R 3 and R 4 are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C M alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl,
  • the present invention relates to compounds represented by fonnula A(III) wherein Ri through R 9 are each independently (i) when connected to a carbon atom: hydrogen, C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, C 1 - 3 alkoxy, zt-butoxy, z-butoxy, sec- butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ 4 are each independently hydrogen or C ⁇ - 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-
  • Ri, R 3 and t are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C M alkyl, C 3 .
  • the compounds of the present invention are represented by formula A(IV) wherein Ri through R 9 are each independently (i) when connected to a carbon atom: hydrogen, Ci- ⁇ alkyl, C . 6 cycloalkyl, C ⁇ .
  • the compounds of the present invention are represented by fonnula A(V):
  • Rj through R are each independently hydrogen, C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, C 1 - 3 alkoxy, zz-butoxy, i-butoxy, i'ec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ each independently represents hydrogen or C ⁇ - 3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci- 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , - SO 2 NHRi 5 (wherein R ⁇ 5 is hydrogen or C ⁇ - 3 alkyl), or -O(CH 2 —
  • Ri and R 4 are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R are each independently hydrogen, CM alkyl, C .
  • the compounds of the present invention are represented by formula A(V): wherein Rj through R 9 are each independently hydrogen, Ci- 6 alkyl, C 3 . 6 cycloalkyl, C 1 - 3 alkoxy, zz-butoxy, i-butoxy, jec-butoxy, R ⁇ 3 R ⁇ N- (wherein R[ and R ⁇ each independently represents hydrogen or C 1 - 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, -SO 3 H, -SO 2 CH 33 - SO 2 NHR 15 (wherein R15 is hydrogen or C
  • Ri and R 4 are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C M alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 9 are each independently hydrogen, C 1 -4 alkyl, C 3 .
  • the compounds of the present invention are represented by formula A (XI):
  • Ri is hydrogen, Ci- ⁇ alkyl, C 3 -6 cycloalkyl, C 1 - 3 alkoxy, «-butoxy, i- butoxy, sec-butoxy, R ⁇ 3 R ⁇ N- (wherein R ⁇ 3 and R 14 are each independently hydrogen or C 1 -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, -SO 3 H, -SO 2 CH 3 , -SO 2 NHR ⁇ 5 (wherein R 15 is hydrogen or d- 3 alkyl), or -O(CH 2 ) n ORi 6 - (wherein R ⁇
  • Ri is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d- alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and - SO 2 NH 2 .
  • the compounds of the present invention are represented by formula A(XI), wherein Ri is C ⁇ _ 6 alkyl, C 3 .
  • R ⁇ 3 and R i4 are each independently hydrogen or C M alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, C ⁇ _ 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , - SO NHR ⁇ 5 (wherein R ⁇ 5 is hydrogen or d_ 3 alkyl), or -O(CH 2 ) n OR ⁇ 6 - (wherein R 16 is hydrogen or C ⁇ _ 3 alkyl, and n is 1, 2 or 3).
  • Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, C ⁇ _ 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO NH 2 .
  • the compounds of the present invention are represented by formula A(XII):
  • Ri, R 3 and R 4 are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C1- 4 alkyl, C3-6 cycloalkyl, d- 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO
  • the compounds of the present invention are represented by formula A(XIII): wherein Ri through R ⁇ 2 are each independently hydrogen, C ⁇ _ 6 alkyl, C 3 . 6 cycloalkyl, C alkoxy, n-butoxy, z ' -butoxy, sec-butoxy, R 13 R ⁇ 4 N- (wherein R ⁇ 3 and R 14 are each independently hydrogen or d- 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR ⁇ 5 (wherein R 15 is hydrogen
  • Ri, R 3 , R 4 , R 9 , R ⁇ and R1 2 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C M alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 8 are each independently hydrogen, C M alkyl, C 3 .
  • the compounds of the present invention are represented by formula A(XfV): wherein Ri through R 9 are each independently hydrogen, C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, CM alkoxy, ⁇ -butoxy, i-butoxy, sec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ 4 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR ⁇ 5 (wherein R1 5 is hydrogen or C alkoxy, ⁇ -
  • Ri and R 4 are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 1 - 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through o are each independently hydrogen, C ⁇ - 4 alkyl, C 3 - 6 cycloalkyl, d- 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C M alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , -SO 2 NH 2 , or when any two Rs
  • the compounds of the present invention are represented by formula A(XV): wherein Ri through R ⁇ are each independently hydrogen, Ci- 6 alkyl, C 3 . 6 cycloalkyl, C alkoxy, ?z-butoxy, z-butoxy, sec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ 4 are each independently hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d- 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR 15 (wherein R 15 is hydrogen or C alkyl
  • Ri, R 3 , Ri, R 9 , Rn and R 12 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C M alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 8 are each independently hydrogen, C M alkyl, C 3 .
  • the invention is directed to compounds represented by formula A(XVI): wherein Ri through R ⁇ 2 are each independently hydrogen, C ⁇ _ 6 alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ 3 and R ⁇ 4 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR 15 (wherein R ⁇ 5 is hydrogen or Ci-3
  • R 3 , R 4 , R 9 , R ⁇ and R ⁇ 2 are each hydrogen;
  • R 2 and io are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, d- alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO H,
  • R 5 through Rg are each independently hydrogen, CM alkyl, C 3 - 6 cycloalkyl, C 1 - 3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C ⁇ - alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO 2 CH
  • the invention is directed to compounds represented by formula A(XVII): wherein R ! through Rj 2 are each independently hydrogen, Ci- ⁇ alkyl, C 3 . 6 cycloalkyl, d- 3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R ⁇ 3 R J4 N- (wherein R ⁇ 3 and R 14 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR 15 (wherein R 15 is hydrogen or C alky
  • the invention is directed to compounds represented by formula A(XVII) wherein, Ri, R 3 , R 4 , R 9 , R 11 and R 12 are each hydrogen; R 2 and io are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO H, -S0 2 CH 3 and -S0 2 NH 2 ; R 5 through R 8 are each independently hydrogen, CM alkyl, C 3 - 6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3
  • Rj through R 20 are each independently hydrogen, C ⁇ - 6 alkyl, C 3 - 6 cycloalkyl, C alkoxy, zz-butoxy, z ' -butoxy, see-butoxy, R ⁇ 3 R ⁇ 4 ⁇ - (wherein R ⁇ 3 and R 14 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO2 HR 15 (wherein Rj 5 is hydrogen or C alkyl), or -O(CH 2 ) n OR 16 - (wherein Rj
  • the invention is directed to compounds represented by formula A(XVILT) wherein, Ri, R 3 , 4, R 9 , R11, R12, R17.
  • R 1 9 and R20 are each hydrogen;
  • R 2 , Rio and R 18 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 7 are each independently hydrogen, d- alkyl, C 3 .
  • the invention relates to a method of inhibiting /3-lactamase comprising contacting the /3-lactamase with an effective amount of one or more compounds of formula A(I), A(II), A(III), A(1N), A(V), A(VI), A(NII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIN), A(XN), A(XNI), A(XNII) or A(XNIII).
  • the invention provides a method of treating bacterial infection, particularly j3-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(N), A(NI), A(NII), A(VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XrV), 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(ID, A(III), A(TV), A(V), A(VI), A(VII), A(VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVII), or A(XVIII); and an effective amount of /3-lactam-antibiotic, with or without one or more other antibacterial agent.
  • the invention further provides a method of overcoming bacterial resistances, particularly resistance to /3-lactam-antibiotic.
  • the method comprises administering a subject an effective amount of one or more compounds of formula A(I), A(II), A(I ⁇ ), A(IN), A(V), A(V ⁇ ), A(NII), A(VIII), A(IX), A(X), A(XI), A(XII),
  • the invention also provides a pharmaceutical composition comprising one or more compounds of formula A(I), A(II), A(HI), A(IV), A(V), A(VI), A(VII), A(VIII), A(K), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVH), 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(XTV), A(XV), A(XVI), A(XVII), or A(XVIII); a /3-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:
  • - N CH-S- or -O-CH 2 CH 2 -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(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 ⁇ -lactamase with an effective amount of one or more compounds of fonnula 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 jS-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(I ⁇ ), A(III), AOV), A(V), A(VI), A(VIi) 3 A(Vffl), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVI ⁇ ) 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 /3-lactam-antibiotic.
  • the invention further provides a method of overcoming bacterial resistances, particularly resistance to ⁇ -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(rV), A(V), A(VI), A(VII), A(VIII), A(IX), A(X), A(XI), A(XH), A(XIII), A(XTV), A(XV), A(XVI), A(XVII) or A(XV ⁇ i); and an effective amount of ⁇ - 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(N), A(NI), A(NII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), 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(fl), A(III), A(TV), A(V), A(VI), A(VII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIN), A(XV), A(XVI), A(XVII) or A(XNIII); a ⁇ -lactam-antibiotic or other antibacterial agent; and a pharmaceutically acceptable carrier.
  • Ri, R 3 and R are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C M alkyl, C 3 .
  • Ri through Rj 2 are each independently hydrogen, C ⁇ - 6 alkyl, C 3 . 6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, see-butoxy, R ⁇ R M N- (wherein R ⁇ 3 and R 14 are each independently hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cj- 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO H, -SO 2 CH 3 , - SO 2 NHRi 5 (wherein R 15 is hydrogen or C alkyl), or -O(CH 2 ) n OR ⁇ 6 - (wherein R ⁇ 6 is hydrogen
  • Ri, R 3 , R 4 , R 9 , R ⁇ and R ⁇ 2 are each hydrogen;
  • R 2 and Piio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C 1 - 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -S0 2 CH 3 and -SO 2 MH 2 ;
  • R 5 through R 8 are each independently hydrogen, CM alkyl, C 3 _ 6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO H, -SO 2 CH 3 , -SO
  • Ri, R 3 and R 4 are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C 3 - 6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO,
  • the present invention relates to compounds represented by formula A(III) wherein Ri through R 9 are each independently (i) when connected to a carbon atom: hydrogen, C alkyl, C 3 - 6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, sec- butoxy, R 1 3E.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound (compound F1001) is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2118).
  • the compound (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(1N): wherein R ⁇ tlirough R 9 are each independently (i) when connected to a carbon atom: hydrogen, d- 6 alkyl, C 3 .
  • Ri, R 3 and R 4 are each hydrogen;
  • R 5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C alkyl, C 3 .
  • Ri through R 9 are each independently hydrogen, C ⁇ _ 6 alkyl, d- 6 cycloalkyl, d-3 alkoxy, zz-butoxy, i-butoxy, see-butoxy, R 13 R 14 N- (wherein R13 and R 1 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, d- 6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO 2 CH3, - SO 2 NHRi5 (wherein R15 is hydrogen or C alkyl), or -0(CH 2 ) n OR ⁇ 6 - (wherein R ⁇ 6 is hydrogen or C
  • Ri and t are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C M alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 9 are each independently hydrogen, CM alkyl, C 3 .
  • R 13 and Ru each independently represents hydrogen or CM alkyl
  • R 13 and Ru each independently represents hydrogen or CM alkyl
  • trifluoromethyl trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl
  • Ri and R 4 are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 9 are each independently hydrogen, C alkyl, C 3 .
  • Formula AfV the compounds of the present invention are represented by formula A(VI): (Compound F1212). This compound is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2162).
  • Compound BB-1003 is commercially available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB2119).
  • Compound BB-1004 is commercially available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB2623).
  • Formula AfX In a tenth embodiment, the compounds of the present invention are represented by formula A(X):
  • Compound BB-1005 is commercially available from Combi-Blocks, Inc. (San Diego, California , Cat. No. BB3052).
  • Ri is hydrogen, C alkyl, C 3 - 6 cycloalkyl, C M alkoxy, zz-butoxy, z- butoxy, -ec-butoxy, R ⁇ 3 R ⁇ N- (wherein R 13 and R 14 are each independently hydrogen or d-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, -SO 3 H, -SO 2 CH 3 , -SO 2 NHR 15 (wherein R ⁇ 5 is hydrogen or C M alkyl), or -O(CH 2 )nORi 6 - (wherein Ri ⁇ is hydrogen or C alky
  • Ri is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C ⁇ - 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and - SO 2 NH 2 .
  • the compounds of the present invention are represented by formula A(XI), wherein Ri is C alkyl, C 3 .
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • R ⁇ 3 and R 14 are each independently hydrogen or C M alkyl
  • Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 .
  • Non-limiting specific compounds described by formula A(XI) are listed in Table 6. Table 6: Representative Compounds in Formula A(XI): NH 2 H OH CN Br
  • Ri, R 3 and R 4 are each hydrogen;
  • - Rs is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C 3 - 6 cycloalkyl, C M alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci- 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, - SO 2 CH 3 ,
  • Ri through R 12 are each independently hydrogen, C alkyl, € 3 , 5 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, s ⁇ c-butoxy, R1 3 R14N- (wherein R 13 and R ⁇ 4 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR 15 (wherein R 15 is hydrogen or C alkyl), or -O(CH 2 ) n ORi 6 - (wherein Rj ⁇ is hydrogen or
  • Ri, R 3 , i, R 9 , Ru and R 12 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C 1 - 4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 8 are each independently hydrogen, C alkyl, C 3 _ 6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 1 - 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO 2 CH 3 ,
  • the compounds of the present invention are represented by fonnula A(XIV): wherein Ri through R 9 are each independently hydrogen, d- 6 alkyl, C 3 - 6 cycloalkyl, C1- 3 alkoxy, zz-butoxy, i-butoxy, sec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R ⁇ and R 14 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR ⁇ 5
  • Ri and R 4 are each hydrogen;
  • R 2 and R 3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -S0 2 CH 3 and -S0 2 NH 2 ;
  • R 5 through R 9 are each independently hydrogen, CM alkyl, C 3 .6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , -SO NH 2 , or when any two Rs are located at the ortho position to
  • Ri through R 12 are each independently hydrogen, C alkyl, C 3 . 6 cycloalkyl, C 1 - 3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R ⁇ 3 R ⁇ 4 N- (wherein R 13 and R 14 are each independently hydrogen or d- 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, -SO 3 H, -SO 2 CH 3 , - SO2NHR 15 (wherein R 15 is hydrogen or C M alkyl), or -O(CH 2 ) n ORi 6 - (wherein R 15
  • Ri, R 3 , R 4 , R 9 , Ru and R ⁇ 2 are each hydrogen;
  • R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H,
  • R 5 through R 8 are each independently hydrogen, C M alkyl, C 3 _ 6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C ⁇ _ 4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO 2 CH 3 , -SO 2 NH 2 , or when any two Rs are located at the ortho position to each
  • the compounds of the present invention are represented by fo ⁇ nula A(XVI): wherein Ri through R 12 are each independently hydrogen, C alkyl, C 3 . 6 cycloalkyl, C alkoxy, zz-butoxy, z ' -butoxy, s ⁇ c-butoxy, R ⁇ 3 R 1 N- (wherein R ⁇ 3 and R 14 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHR 15 (wherein Ri through R 12 are each independently hydrogen, C al
  • Ri, R 3 , R 4 , R 9 , Ru and R 12 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R5 through Rg are each independently hydrogen, CM alkyl, C 3 - ⁇ cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO 3 H, -SO CH 3 , -SO2NH2, or when any two
  • Ri through R ⁇ are each independently hydrogen, C alkyl, C 3 -6 cycloalkyl, C M alkoxy, zz-butoxy, z ' -butoxy, sec-butoxy, R ⁇ R ⁇ N- (wherein R 13 and R 14 are each independently hydrogen or C ⁇ - 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, -SO H, -SO 2 CH 3 , - SO 2 NHRi 5 (wherein R 15 is hydrogen or C M alkyl), or -O(CH 2 ) n OR 16 - (wherein R 16 is hydrogen or
  • Ri, R 3 , i, R 9 , R ⁇ and R ⁇ 2 are each hydrogen;
  • R 2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 through R 8 are each independently hydrogen, d_ alkyl, C 3 .
  • R ⁇ through R 20 are each independently hydrogen, C alkyl, C 3 . 6 cycloalkyl, CM alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R 13 R 14 N- (wherein R ⁇ 3 and R 1 are each independently hydrogen or C 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, -SO 3 H, -SO 2 CH 3 , - SO 2 NHRi5 (wherein R15 is hydrogen or C alkyl), or -O(CH 2 ) n OR ⁇ 6 - (wherein Rj 6 is hydrogen or
  • Ri, R 3 , R4, R 9 , Ru, R12, R1 7 , R1 9 and R20 are each hydrogen;
  • R 2 , Rio and R ⁇ 8 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO 3 H, -SO 2 CH 3 and -SO 2 NH 2 ;
  • R 5 tlirough R 7 are each independently hydrogen, C alkyl, C 3 -6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3
  • jg-Lactamases The compounds of the present invention can be used to inhibit any ⁇ - lactamases.
  • /3-lactamases are endogenous bacterial enzymes that destroy /3-lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the /3-lactam ring.
  • the structures of many 3-lactamases are known at the atomic level and available in the protein database.
  • the /3-lactamase is a Class A, B, C or D ⁇ - lactamase. More preferably, it is a Class A (TEM) or Class C (AmpC) p actamase.
  • TEM Class A
  • AmpC Class C
  • 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, polymorphs, 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 in
  • 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, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate
  • a prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transfonnation. In vivo, 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.
  • 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.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
  • 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.
  • the can ⁇ er 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 may be employed.
  • Treatment methods of the present invention using fonnulations 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.
  • 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 microp articulate systems which are designed to target the compound to blood components or one or more organs. The fonnulations may be presented in unit-dose or multi-dose form.
  • Parenteral administration may comprise any suitable fonn 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., intraperitoiieal), 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
  • Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes.
  • formulations 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.
  • a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
  • 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.
  • /3-Laetam Antibiotics /3-lactam antibiotics are compounds with antimicrobial activities and contain the /3-lactam structure. Any /3-lactam antibiotic is suitable. Many suitable ⁇ - lactam antibiotics are known (See e.g., R. B. Morin and M. Gorin, M.Eds.; Academic Press, New York, 1982; vol. 1-3).
  • cephalosporins e.g., cephalothin
  • penicillins e.g., amoxicillin
  • monobactams e.g., aztreonam
  • carbapenems e.g., imipenem
  • carbacephems loracarbef
  • others /3-lactam antibiotics are effective (in the absence of resistance) against a wide range of bacterial infections.
  • bacteria of the genus Siaphylococcus such as Staphylococcus aureus and Staphylococcus epidermis
  • Streptococcus such as Streptococcus agalactine, Streptococcus penumoniae and Streptococcus faecalis
  • Micrococcus such as Micrococcus luteus
  • Bacillus such as Bacillus subtilis
  • Listerella such as Listerella monocytogenes
  • Escherichia such as Escherichia coli
  • Klebsiella such as Klebsiella pneumoniae
  • Proteus such as Proteus mirabilis and Proteus vulgaris
  • Salmonella such as Salmonella typhosa
  • Shigella such as Shigella sonne ⁇
  • Enterobacter such as Enterobacter aerogenes and Enterobacter faciurn
  • Serratia such as Serratia marcesc
  • Preferred /3-lactam antibiotics are those which preferentially deactivated by Class A and Class C /3-lactamase enzymes, for example, amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, and ceftazidime.
  • Effective doses and modes of administration of /3-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.
  • Prefened 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.
  • 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.
  • 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.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage fomis (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.
  • step i (COCl) 2 , DMF, CH 2 CI 2> rt, overnight step ii, Et 3 N, CH 2 C1 2 , rt, overnight
  • step (i) of general procedure A oxalyl chloride (35 ⁇ L, 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 CH 2 C1 2 . 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.
  • 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 CH 2 CI 2 was added dropwise to an ice-cold solution of (la), anhydrous triefhyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous CH 2 C1 2 .
  • 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 NaHCO 3 , saturated brine solution, dried (Na 2 SO 4 ) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10).
  • the product yielded from step (ii) is ( ⁇ b).
  • step (i) of general procedure B oxalyl chloride (35 ⁇ L, 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 CH 2 C1 2 .
  • 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.
  • 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 (Ila), anhydrous triethyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anliydrous 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 IN aqueous HCl, 10% aqueous NaHCOj, saturated brine solution, dried (Na 2 SO 4 ) and concentrated. The residue was recrystallized from ethyl acetate/hexane.
  • the product yielded from step (ii) is (lib).
  • step i (COCl) 2 , DMF, CH 2 C1 2 , rt, overnight step ii, Et 3 N, CH 2 C1 2 , rt, overnight
  • step (i) of general procedure C oxalyl chloride (35 ⁇ L, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boiOnic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH 2 C1 2 .
  • the reaction mixture was stined at room temperature overnight and then evaporated to dryness to afford acid chloride as a yellow solid, which was used without further purification.
  • 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 CH 2 C1 2 was added dropwise to an ice-cold solution of (Ilia), anhydrous triethyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous CH 2 C1 .
  • the reaction mixture was stined 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 NaHCO 3 , saturated brine solution, dried (Na 2 SO4) and then concentrated.
  • step (ii) is (IHb).
  • Compound (3a) (3-(2,6-Dichlorobenzyloxycarbonyl)-5-nitrophenylboronic)
  • step (i) oxalyl chloride (35 ⁇ L, 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 C ⁇ 2 C1 2. 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).
  • 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 chlorohydroquinone (11 mg, 0.075 mmol), anhydrous triethyl amine (42 ⁇ L, 0.3 mmol) and 10 mL of anhydrous THF.
  • the reaction mixture was stined 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 NaHCO 3 , saturated brine solution, dried (Na 2 S0 4 ) and then concentrated.
  • step (i) oxalyl chloride (35 ⁇ L, 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 CH 2 C1 2 . 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).
  • 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 ⁇ L, 0.3 mmol) and 10 mL of dried THF.
  • the reaction mixture was stined 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 (Na 2 SO 4 ) and concentrated.
  • step (i) oxalyl chloride (35 ⁇ L, 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 CH 2 C1 2 .
  • the reaction mixture was stined 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).
  • 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 ⁇ L, 0.3 mmol) and 10 mL of dried THF.
  • the reaction mixture was stined 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 NaHCO 3 , saturated brine solution, dried (Na 2 SO 4 ) and concentrated.
  • step (i) oxalyl chloride (35 ⁇ L, 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 C ⁇ 2 C1 2 .
  • the reaction mixture was stined 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).
  • 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 1,2- benzenedimethanol (10 mg, 0.075 mmol), anhydrous triethyl amine (42 ⁇ 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 IN aqueous HCl, 10% aqueous NaHCO 3 , saturated brine solution, dried (Na 2 SO 4 ) and then concentrated.
  • 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 ⁇ 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 IN aqueous HCl, 10% aqueous NaHCO , saturated brine solution, dried (Na SO ) and then concentrated.
  • EXAMPLE 13 Inhibition Assay The inhibition of TEM-1 (3-lactamase was determined spectrophotometrically. B-lactamase activity was followed by measuring the hydrolysis ofnitrocefin, [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, p ⁇ 7.0. The enzyme concentration was held at 5nM, with substrate at 167 ⁇ M and varying inhibitor concentrations.
  • Inhibitor was added to the enzyme and incubated for ten minutes before the addition of substrate.
  • Inhibition constants (Kj) for the inliibitors 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 /3-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.
  • 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.
  • 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 nonspecific 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).
  • EXAMPLE 15 Activity against Clavulanic Acid Resistant Mutants
  • /3-lactam-based /3-lactamase inhibitors have 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 cunently in clinical use (clavulanic acid, sulbactam, tazobactam) (Bonomo et al, 1997).
  • Three of the most important mutations are M69I, R244S and E104K.
  • methicillin resistant S. aureus ATCC 33591 MRSA-ATCC
  • This strain was obtained from American Type Culture Collection (ATCC), Manassas, MD; (2) methicillin resistant S. aureus 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.
  • Staphylococci are also resistant to all penicillins, and all cephalosporins, in addition to all /3-lactamase inhibitor combinations (including ampicillin/sulbactam, aii oxicillin clavulanic acid, piperacillin/tazobactam), imipenem, and meropenem; and (3) methicillin sensitive S. aureus ATCC 25923 (MSSA).
  • MSSA methicillin sensitive S. aureus ATCC 25923
  • 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).
  • MHA Mueller-Hinton agar plate
  • 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 10 7 colony forming unit (CFU)/ml. This cell suspension was then further diluted 10-fold (to 10 6 CFU/ml) by transferring the 2 ml cell suspension to 18 ml of MHB. Addition of 50 ⁇ l of this dilute cell suspension to 50 ⁇ l of growth medium yielded the desired cell density, namely about 5 x 10 4 CFU/well, or 5 x 10 5 CFU/ml.
  • MHB Mueller-Hinton broth
  • MIC Assays with Oxacillin The MIC experiments were perfonned in duplicate in 96-well micro titer 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 ( ⁇ g/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 was added 47.5 ⁇ l of MHB.
  • DMSO dimethylsulfoxide
  • a volume of 2.5 ⁇ l 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 ⁇ l of a diluted cell suspension to give a final volume of 100 ⁇ l and a final cell density of 5 x 10 4 CFU/well. The volume in the sterility control wells was adjusted to 100 ⁇ l 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).
  • 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 detennined to be the MIC value.
  • Matrix System The effect of the four compounds of the present invention on oxacillin resistance of the MRS A strains was detennined using a matrix system.
  • the /3-lactamase 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 ⁇ l/ml which was not bacterio toxic 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 ⁇ - lactamase inhibitors was added, 2.5 ⁇ l each, to the wells prior to addition of the test organisms.
  • the gene for AmpC ⁇ -lactamase was obtained from Escherichia coli K12 strain W3110 (American Type Culture Collection, Rockville, MD). E. coli was grown and plasmid (F- laclq lacPLS ampC:. ambdacI+) was isolated via Qiagen (Valencia, CA) mini prep.
  • the gene for AmpC was amplified in two pieces via polj ⁇ nerase 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).
  • Conect 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 OD ⁇ oo of 0.8 at 37 °C.
  • 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 ⁇ -lactamase was determined spectrophotometrically using a Varian (Walnut Creek, CA) Cary 100 UN- Visible spectrophotometer. ⁇ -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 ⁇ - lactamase preparations hydrolyze nitrocefin substrate from 50 to 150 s "1 . Under these conditions, the KM for AmpC ⁇ -lactamase is 250 ⁇ M and the k cat is 975 s "1 . Penicillin G (Sigma, St. Louis, MO) was also used as a substrate to determine KM and k cat . Lineweaver-Burk plots were used to determine the inhibition mechanism, and several compounds were found to inhibit competitively.
  • ⁇ -Lactamase solutions were titrated with inhibitors in 50 mM sodium phosphate, 2% DMSO, pH 7.0, with ⁇ - lactamase concentrations ranging from 15 to 25 ⁇ M and inhibitor concentrations ranging from 300 to 1000 ⁇ M.
  • 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 ⁇ -lactamase.
  • Phenyl -boronic acids have inhibitory activity against theTEM-1 and AmpC ⁇ -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 ⁇ -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 ⁇ -lactamase variant TEM-1. Table 20.
  • Ki units are ⁇ M.
  • ⁇ G, ⁇ and -T ⁇ S units are cal/mol.

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Abstract

The invention provides novel non-β-lactam inhibitors of β-lactamases. In particular, the invention provides boronic acid-based compounds set forth in the specification. These compounds may be used with β-lactam antibiotics to bacterial infection, particularly β-lactam-antibiotic-resistant bacterial infections. These compounds are also antibacterial agents by themselves. The invention further provides methods of using such compounds. Finally, the invention provides a pharmaceutical composition comprising these compounds.

Description

0-LACTAMASE INHIBITORS AND METHODS OF USE THEREOF
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 -lactamase and methods of use thereof. Specifically, the invention relates to non-jS-lactam-based inhibitors of β- lactamase.
BACKGROUND OF THE INVENTION Drug resistance to antibiotics, especially |S-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 j^ear 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. hi 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. β-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. /3-lactam antibiotics have been widely prescribed. In the absence of resistance, β-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 |8-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 β- lactam antibiotics (Sanders, Clinical Infectious Disease, 14, 1089-1099 (1992); Li et al., Antimicrob. Agents Chemolher., 39, 1948-1953 (1995)). Probably the most widespread is the hydrolysis of jS-lactarns by |8-lactamase enzymes. /3-lactamases are endogenous bacterial enzymes that destroy jβ-lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the /3-lactam ring. The structures of many β-lactamases are known at the atomic level and available in the protein database. At least four classes of β-lactamases are known: Classes A, B, C and D. At the clinical level, the most important jS-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 /3-lactamases is to use molecules that neutralize the action of /3-lactamase (known as /3-lactamase inhibitors or inhibitors of /3-lactamase) in combination with antibiotics. The three β-lactamase inhibitors currently in clinical use (clavulanic acid, sulbactam and tazobactam) are all transition state analogs that utilize the same -lactam core that is present in the antibiotics themselves . The similarity between the /3-lactam antibiotics and /3-lactam-based β- lactamase inhibitors has proven to be a serious problem. Resistance to such /3-lactam- based /3-lactamase inhibitors arises through modifications of previously susceptible mechanisms. Certain mutations in /3-lactamase, for example, reduce the effectiveness of (S-lactam-based jS-lactamase inhibitors while preserving the ability of the /3-lactamase to hydrolyze the antibiotic molecules. Certain point substitutions in j8-lactamases allow the enzymes to hydrolyze compounds designed to evade them (Philippon et al., Antimicrob. Agents Chemother., 33, 1131-1136 (1989)). Other substitutions reduce the affinity of β- 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 /3-lactams in the environment of the cell (Bennet and Chopra, Antimicrob. Agents Chemotherapy, 37, 153-158 (1993)). /3-lactam binding to these sensors leads to transcriptional up- regulation of the /3-lactamase. /3-lactam-based /3-lactamase inhibitors, thus, can induce the production of the 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 3-lactam-based inhibitors is that the mechanisms of action of the inhibitors are not, in fact, new, because β-lactamases have evolved mechanisms for, e.g., sensing and/or hydrolyzing such molecules. Accordingly, as long as medicinal chemistry focuses on /3-lactam-based molecules to overcome /3-lactamases, resistance can be expected to follow shortly. One way to avoid recapitulating this "arms race" between bacteria and β- lactams is to develop non-β-lactam inhibitors that have novel chemistries and are dissimilar to /3~lactams. Such non-/3-lactam inhibitors would not themselves be degraded by /3-lactamases, and mutations in the enzymes would not be expected render such inhibitors labile to hydrolysis. Such novel inhibitors would also escape detection by β- lacta sensor proteins that up-regulate /3-lactamase transcription, and may be unaffected by porin mutations that limit the access of /3-lactams to PBPs. Such inhibitors would allow the current /3-lactam antibiotics to effectively work against bacteria where β- lactamases provide the dominant resistance mechanism. It has previously been reported that boric acid and certain phenyl boronic acids are inhibitors of certain /3-lactamases (Koehler and Lienhard, (1971); Kiener and Waley, Biochem. J., 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-foπnylphenylboronate, 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 /3-lactamase (Dryjanski and Pratt, Biochemistry, 34, 3561-3568 (1995)). In addition, Strynadka and colleagues used the crystallographic shructure of a mutant TEM-1 enzyme-penicillin G complex to design a novel alkylboronic acid inhibitor [(lR)-l-acetamido-2-(3- carboxyphenyTjethane 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. 6,075,014 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-/3-lactam-based /3-lactamase inhibitors that are active against a wide variety of /3-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:
Figure imgf000006_0001
Figure imgf000007_0001
-6-
Figure imgf000008_0001
wherein Ri through R12 are each independently (i) when connected to a carbon atom: hydrogen, Q-β alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, «-butoxy, z-butoxy, sec-butoxy, R13Rι4N- (wherein R1 and R] are each independently hydrogen or C1.3 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 C1-3 alkyl, or - O(CH )nORi6-, wherein R16 is hydrogen or C1.3 alkyl, and n is 1, 2 or 3; or when any two R,s are located at the onho position to each other, they together form -Zι=Z2-Σ3=Z4- (wherein Zi tlrrough Z4 each independently represents CH or N), -S-CO-0-, -CH=CH- H-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH CH -O-; 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):
Figure imgf000009_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Cι.6 alkyl, C3.6 cycloalkyl, Cι-3 alkoxy, «-butoxy, z-butoxy, sec-butoxy, Rι3Rι N-,wherein Rι3 and Ru 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, -SO2NHRι5,wherein R15 is hydrogen or C1-3 alkyl, or - O(CH2)nORι6-, wherein Rι6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3; or when any two Rjs are located at the ortho position to each other, they together foπn -Z]=Z2-Z3 :=Z -, wherein Z1 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-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 first embodiment, Ri, R3 and 4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, 2, 4-dichlorophenoxy, 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 -Z1=Z2-Z3=Z - (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-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C alkyl, C .6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hyc oxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R6 are located at the ortho position to another R;, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z each independently represents CH orN), -S-CO-O-, -CH=CH-NH-, -GH 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, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=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-; R8 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, - SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=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. In a second embodiment, the compounds of the present invention are represented by formula A(II):
Figure imgf000011_0001
wherein Ri through R12 are each independently hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, Cι-3 alkoxy, zz-butoxy, z-butoxy, _?ec-butoxy, Rι3Rι4N- (wherein Rι3 and Rι are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, -
SO2NHRi5 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nORι6- (wherein R]6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (wherein i through Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-5 -CH=CH-O-, -N=CH-NH-, -CH2-N=N-3 -N=N-0-, -N=CH-S- or -O-CH2CH2-O-. In a preferred embodiment of the second embodiment, Ri, R3, Ri, R , R11 and R12 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, Cι.3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=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 third embodiment, the compounds of the present invention are represented by formula A(III):
Figure imgf000012_0001
wherein Ri through R are each independently (i) when connected to a carbon atom: hydrogen, CM alkyl, C3.6 cycloalkyl, C1.3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Ri3R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -ONOHCH3, -SO3H, -SO2CH3. -SO2MHR15 (wherein R,5 is hydrogen or C1.3 alkyl), or -O(CH2)nORι6- (wherein R16 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two R,s are located at the ortho position to each other, they together form - Z!=Z2-Z3=Z - (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-; 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, CM 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, CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z2-Z3=Z4- (wherein Zj through Z 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, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together foπn -Zι=Z2-Z3=Z4- (wherein Z\ through ∑a each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=CH-O-, -N=€H-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -0-CH2CH2-O-; R7 is: (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Ri5 they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -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, CM alkyl, C3.6 cycloalkyl, Cι-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=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. In one particular embodiment of the third embodiment, the present invention relates to compounds represented by fonnula A(III) wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, C1-3 alkoxy, zt-butoxy, z-butoxy, sec- butoxy, Rι3Rι4N- (wherein Rι3 and Rι4 are each independently hydrogen or Cι-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH-NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein Rι5 is hydrogen or Ci-3 alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or Cι- alkyl, and n is 1, 2 or 3); or when any two K;s are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z4- (wherein Zi through Z 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-0-, - N=CH-S- or -O-CH2CH2-O-; or (ii) when comiected to a nitrogen atom: absent; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when Rι=R3=R =R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon; R2 is not NH2, NO2;, or H. In another embodiment of the third embodiment, the invention relates to compounds described by formula A(III) wherein Ri, R3 and i are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; Rsis: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z2-Z3=Z4- (wherein Zi through Z 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, CM alkyl, C .6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together form -Zι=Z2-Z =Z - (wherein Zi through Z 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, CM alkyl, C3.6 cycloalkyl, Cι-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -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, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (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 Rι= R3= R^ R5= R6= R7= R8= R9=hydrogen, and X=Y=Z=carbon; R2 is not NH2, NO2j, or H. In a fourth embodiment, the compounds of the present invention are represented by formula A(IV):
Figure imgf000016_0001
wherein Ri through R are each independently (i) when connected to a carbon atom: hydrogen, Cι.6 alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, n-butoxy, z-butoxy, sec- butoxy, R13R1 N- (wherein R13 and Rι are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-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 Ci-3 alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or Cι.3 alkyl, and n is 1, 2 or 3); or when any two R,s are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z - (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-; 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, Ri, R3 and t are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - O=N0HCH3, -SO3H, -SO2CH3 and -SO2NH2; R5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=MOH, -C=MOHCH3, -S03H, -S02CH3, -S02NH2, or when R5 are located at the ortho position to another R;, they together form -Z1=Z2-Z3 :=Z - (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-; R6 is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, CM alkyl, C .6 cycloalkyl, Cj.3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together foπn -Zι=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -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, CM alkyl, C3_6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R;, they together form -Zι=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-; R8 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι- alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2- Z3=Z - (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. In one particular embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A(IV) wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Ci-β alkyl, C .6 cycloalkyl, Cι.3 alkoxy, π-butoxy, z-butoxy, sec- butoxy, Rι Rι4N- (wherein Rj3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci-β alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or Ci-3 alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two R,s are located at the ortho position to each other, they together form - Zι=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-; 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 Rι=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon; R7 is not CI, CN, OCH3, NO2, CF3, H, or COOCH ; when Rι=R2=R3=R =R5=R7=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 is not CN, NO2, or CF3; when Rι=R2=R3=R4=R5=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 and
R7 together is not -CH-CH-CH=CH-; when
Figure imgf000019_0001
R9=hydrogen, and X=Y=Z=carbon; R5 is not OCOCH3; when Rι=R3=R4=R5=Rg=R7=R8= R9 = hydrogen, and X=Y=Z=carbon; R2 is not COOH; and when Rι=R2=R3=R4 :=R5=R8= R9 = hydrogen, R6= CI, and X=Y=Z=carbon; R7 is not CI.
In a preferred embodiment of the fourth embodiment, the compounds of the present invention are represented by fomiula A(Fv ) wherein Ri, R3 and R are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C 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, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -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, C alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 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=€H-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, CM alkyl, C3. cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydiOxymethyl, -CHO, - CH-NOH, -C=NOHCH3, -SO3H, -S02CH3, -SO2NH2? or when R7 are located at the ortho position to another R, they together form -Zι=Z -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-; R8 through R are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2- Z3=Z4- (wherein Zi through Z 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=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon; R7 is not CI, CN, OCH3, NO2, CF3, H, or COOCH3; when Rι=R2=R3=R4=R5=R7=R8=R9 = hydrogen, and X=Y=Z=:carbon; R is not CN, NO2, or CF3; when Rι=R2=R3=:R4=R5=R8=R9 = hydrogen, and X=Y=Z=carbon; R6 and
R7 together is not -CH=CH-CH=CH-; when Rι=R2=R3=R =R6=R7=R8= R =hydrogen, and X=Y=Z=carbon; R5 is not OCOCH3; when Rι=R3=R4=R5 ::=R6=R7 :=R8= R =hydrogen, and X=Y=Z=carbon; R2 is not COOH; and when R1=R2=R3=R4=R5=R8=: R9=hydrogen, R6= CI, and X=Y=Z=carbon; R7 is not CI.
In a fifth embodiment, the compounds of the present invention are represented by fonnula A(V):
Figure imgf000021_0001
wherein Rj through R are each independently hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, C1-3 alkoxy, zz-butoxy, i-butoxy, i'ec-butoxy, Rι3Rι4N- (wherein Rι3 and Rι each independently represents hydrogen or Cι-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRi5 (wherein Rι5 is hydrogen or Cι-3 alkyl), or -O(CH2)nORι6- (wherein Riβ is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=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 fifth embodiment, Ri and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R are each independently hydrogen, CM alkyl, C .6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together fonn -Zι=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-. In one particular embodiment of the fifth embodiment, the compounds of the present invention are represented by formula A(V): wherein Rj through R9 are each independently hydrogen, Ci-6 alkyl, C3.6 cycloalkyl, C1-3 alkoxy, zz-butoxy, i-butoxy, jec-butoxy, Rι3Rι N- (wherein R[ and Rι each independently represents hydrogen or C1-3 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, -SO2CH33 - SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nORι6- (wherein R16 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (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-; with the proviso that when Rι=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, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 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, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS 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-; with the proviso that when
Figure imgf000023_0001
= hydrogen; R7 is not H, OH or C(CH3)3. In a sixth embodiment, the compounds of the present invention are represented by fonnula A(VI):
Figure imgf000023_0002
In a seventh embodiment, the compounds of the present invention are represented by formula A(VII):
Figure imgf000023_0003
wherein Q is oxygen or lone-pair electrons. In an eighth embodiment, the compounds of the present invention are represented by formula A(VIII):
Figure imgf000024_0001
In a ninth embodiment, the compounds of the present invention are represented by formula A(IX):
Figure imgf000024_0002
In a tenth embodiment, the compounds of the present invention are represented by formula A(X):
Figure imgf000024_0003
In an eleventh embodiment, the compounds of the present invention are represented by formula A (XI):
Figure imgf000024_0004
wherein Ri is hydrogen, Ci-β alkyl, C3-6 cycloalkyl, C1-3 alkoxy, «-butoxy, i- butoxy, sec-butoxy, Rι3Rι N- (wherein Rι3 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, -SO2NHRι5 (wherein R15 is hydrogen or d-3 alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or d-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, d- alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and - SO2NH2. In one particular embodiment of the eleventh embodiment, the compounds of the present invention are represented by formula A(XI), wherein Ri is Cι_6 alkyl, C3.6 cycloalkyl, d_3 alkoxy, 7ϊ-butoxy, z-butoxy, sec- butoxy, Rι3Rι4N- (wherein Rι3 and Ri4 are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, Cι_6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO NHRι5 (wherein Rι5 is hydrogen or d_3 alkyl), or -O(CH2)nORι6- (wherein R16 is hydrogen or Cι_3 alkyl, and n is 1, 2 or 3). In another embodiment of the eleventh embodiment, Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, Cι_4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO NH2. In a twelfth embodiment, the compounds of the present invention are represented by formula A(XII):
Figure imgf000025_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Cι.6 alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, Rι3Rι4N- (wherein Ro and Rι are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-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 -3 alkyl), or -O(CH )nOR16- (wherein Rι6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=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-; 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, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C 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, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z -Z3=Z4- (wherein Zj through Z 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, C alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=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-; R7is: (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, Ci-4 alkyl, C3.6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together form -Zι=Z2-Z =Z4- (wherein Z\ through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=€H-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, C alkyl, C3.6 cycloalkyl, Cι-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 any two R;s are located at the ortho position to each other, they together form -Zι=Z2- Z3=Z - (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, - CH=CH-NH-9 -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 thirteenth embodiment, the compounds of the present invention are represented by formula A(XIII):
Figure imgf000028_0001
wherein Ri through Rι2 are each independently hydrogen, Cι_6 alkyl, C3.6 cycloalkyl, C alkoxy, n-butoxy, z'-butoxy, sec-butoxy, R13Rι4N- (wherein Rι3 and R14 are each independently hydrogen or d-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, -SO3H, -SO2CH3, - SO2NHRι5 (wherein R15 is hydrogen or CM alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=€H-S- or -O-CH2CH2-O-. In a preferred embodiment of the thirteenth embodiment, Ri, R3, R4, R9, Rπ and R12 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -S03H, -SO2CH3, -SO2NH2, or when any two s are located at the ortho position to each other, they together form -Zι=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 fourteenth embodiment, the compounds of the present invention are represented by formula A(XfV):
Figure imgf000029_0001
wherein Ri through R9 are each independently hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, CM alkoxy, π-butoxy, i-butoxy, sec-butoxy, Rι3Rι4N- (wherein Rι3 and Rι4 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRι5 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein Rj6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z 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-. hi 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; R5 through o are each independently hydrogen, Cι-4 alkyl, C3-6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z 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):
Figure imgf000030_0001
wherein Ri through R^ are each independently hydrogen, Ci-6 alkyl, C3.6 cycloalkyl, C alkoxy, ?z-butoxy, z-butoxy, sec-butoxy, Rι3Rι4N- (wherein Rι3 and Rι4 are each independently hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nOR16- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -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, Ri, R9, Rn and R12 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z each independently represents CH or N), -S-CO-O-, -CH=CH- NH-, -CH=CH-S-, -CH=CH-O-, -N=€H-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):
Figure imgf000031_0001
wherein Ri through Rι2 are each independently hydrogen, Cι_6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Rι3Rι4N- (wherein Rι3 and Rι4 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2NHR15 (wherein Rι5 is hydrogen or Ci-3 alkyl), or -O(CH )nOR16- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form
Figure imgf000031_0002
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-. hi certain preferred embodiments of the invention is directed to compounds represente by fonnula A(XVI) wherein , Ri, R3, R4, R9, Rπ and Rι2 are each hydrogen; R2 and io are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, d- alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO H,
Figure imgf000031_0003
R5 through Rg are each independently hydrogen, CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι- alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=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 certain embodiments, the invention is directed to compounds represented by formula A(XVII):
Figure imgf000032_0001
wherein R! through Rj2 are each independently hydrogen, Ci-β alkyl, C3.6 cycloalkyl, d-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Rι3RJ4N- (wherein Rι3 and R14 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3 :=Z - (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 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 io are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO H, -S02CH3 and -S02NH2; R5 through R8 are each independently hydrogen, CM alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -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(XNIII):
Figure imgf000033_0001
wherein Rj through R20 are each independently hydrogen, Cι-6 alkyl, C3-6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, see-butoxy, Rι3Rι4Ν- (wherein Rι3 and R14 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2 HR15 (wherein Rj5 is hydrogen or C alkyl), or -O(CH2)nOR16- (wherein R^ is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein
Figure imgf000033_0002
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(XVILT) wherein, Ri, R3, 4, R9, 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, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R7 are each independently hydrogen, d- alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2. The invention relates to a method of inhibiting /3-lactamase comprising contacting the /3-lactamase with an effective amount of one or more compounds of formula A(I), A(II), A(III), A(1N), A(V), A(VI), A(NII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIN), A(XN), A(XNI), A(XNII) or A(XNIII). The invention provides a method of treating bacterial infection, particularly j3-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(N), A(NI), A(NII), A(VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XrV), 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(ID, A(III), A(TV), A(V), A(VI), A(VII), A(VIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVII), or A(XVIII); and an effective amount of /3-lactam-antibiotic, with or without one or more other antibacterial agent. The invention further provides a method of overcoming bacterial resistances, particularly resistance to /3-lactam-antibiotic. The method comprises administering a subject an effective amount of one or more compounds of formula A(I), A(II), A(Iιι), A(IN), A(V), A(Vι), A(NII), A(VIII), A(IX), A(X), A(XI), A(XII),
A(XIII), A(XrV), A(XN), A(XVI), A(XVII), or A(XVIII); and an effective amount of β- 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(HI), A(IV), A(V), A(VI), A(VII), A(VIII), A(K), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVH), 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(XTV), A(XV), A(XVI), A(XVII), or A(XVIII); a /3-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:
Figure imgf000035_0001
Figure imgf000036_0001
wherein Ri through R12 are each independently (i) when connected to a carbon atom: hydrogen, CM alkyl, C3_6 cycloalkyl, d_ alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Rι3Rι4N- (wherein Rι3 and RM are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHRι5 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein R16 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form - Zι=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-; 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(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 β-lactamase with an effective amount of one or more compounds of fonnula 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 jS-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(Iι), A(III), AOV), A(V), A(VI), A(VIi)3 A(Vffl), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), A(XV), A(XVI), A(XVIι) 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 /3-lactam-antibiotic. The invention further provides a method of overcoming bacterial resistances, particularly resistance to β-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(rV), A(V), A(VI), A(VII), A(VIII), A(IX), A(X), A(XI), A(XH), A(XIII), A(XTV), A(XV), A(XVI), A(XVII) or A(XVπi); and an effective amount of β- 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(N), A(NI), A(NII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XTV), 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(fl), A(III), A(TV), A(V), A(VI), A(VII), A(NIII), A(IX), A(X), A(XI), A(XII), A(XIII), A(XIN), A(XV), A(XVI), A(XVII) or A(XNIII); a β-lactam-antibiotic or other antibacterial agent; and a pharmaceutically acceptable carrier.
Formula Aff) In a first embodiment, the compounds of the present invention are represented by formula A(I):
Figure imgf000038_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Cι_6 alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, Rι3Rι Ν- (wherein Rι3 and Rι4 are each independently hydrogen or C 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, -SO2NHRι5 (wherein Rl5 is hydrogen or Cι-3 alkyl), or -O(CH2)nORι6- (wherein Rj6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z - (wherein Zi through Z4 each independently represents CH orN), -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 first embodiment, Ri, R3 and R are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, Ci-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -S03H, -SO2CH3, -SO2NH2, or when R5 are located at the ortho position to another R;, they together form - Zι=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=€H-S- or -O-CH2CH2-O-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, CM alkyl, C3-6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -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, C alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=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-; R8 through R9 are each independently hydrogen, Ci-4 alkyl, C3-6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH-NOH, -C=NOHCH3, -SO3H, - SO2CH3, -SO2NH2, or when any two R;s are located at the ortho position to each other, they together form -Zι=Z2~Z3=Z4- (wherein Zi through Z4 each independently represents CH or M), -C-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-0-, -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. Non-limiting specific compounds described by formula A(I) are listed in Table 1.
Table 1: Representative Compounds in Formula A(I):
Figure imgf000040_0001
Figure imgf000041_0001
Formula A(II) In a second embodiment, the compounds of the present invention are represented by formula A(II):
Figure imgf000042_0001
wherein Ri through Rj2 are each independently hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, see-butoxy, R^RMN- (wherein Rι3 and R14 are each independently hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cj-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO H, -SO2CH3, - SO2NHRi5 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or C 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
Figure imgf000042_0002
(wherein Zi through Z each independently represents CH orN), -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, Rπ and Rι2 are each hydrogen; R2 and Piio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C1-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -S02CH3 and -SO2MH2; R5 through R8 are each independently hydrogen, CM alkyl, C3_6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=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-s -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.
Figure imgf000043_0002
Formula A(III) hi a third embodiment, the compounds of the present invention are represented by formula A(III):
Figure imgf000043_0001
wherein Ri through R are each independently (i) when connected to a carbon atom: hydrogen, CM alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, sec- buloxy, Rι3Rι N- (wherein Ro and Rι4 are each independently hydrogen or CM alk l), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -O=N0HCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORι6- (wherein R16 is hydrogen or Cι-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z4- (wherein Zi tlirough 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 third embodiment, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM 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, CM alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -SO3H, -SO CH3, -SO2NH2, or when R5 are located at the ortho position to another R, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z4 each independently represents CH orN), -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: absenl, and (ii) when Y is carbon: hydrogen, d-4 alkyl, C3-6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d-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 R„ they together form -Zι=Z2-Z3=Z - (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=€H-NH-, -CH=CH-S-, - CH=CH-O-, -N=CH-NH-, -CH2-N=N-5 -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R7is: (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, d_4 alkyl, C3.6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 Rj, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=€H-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through R9 are each independently hydrogen, Cι-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z each independently represents CH orN), -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 R9 are each independently (i) when connected to a carbon atom: hydrogen, C alkyl, C3-6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, sec- butoxy, R13E.1-1N- (wherein R1 and R14 are each independently hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C-NOHCH3, -SO3H, -SO2CH3, -SO2NHRi5 (wherein R]5 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two R,s are located at the ortho position to each other, they together form - Zι=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-S -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 Rι=R3=:R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z=carbon; R2 is not NH2, NO2), or H. hi 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, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=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-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, CM alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together form -Zι=Z -Z3=Z4- (wherein Z\ through Z4 each independently represents CH orN), -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, CM alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R;, they together form -Zι=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-; R8 through R9 are each independently hydrogen, C alkyl, -6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH or M), -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-CH CH2-O-; and X, Y and Z are each independently carbon or nitrogen; with the proviso that when Rι= R3= R^= 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 lable 3.
Table 3: Representative Compounds in Formula A(III):
Figure imgf000047_0001
Figure imgf000048_0003
In a particular preferred embodiment, the compound is
Figure imgf000048_0001
The compound (compound F1001) is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2118).
The compound
Figure imgf000048_0002
(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(1N):
Figure imgf000049_0001
wherein R\ tlirough R9 are each independently (i) when connected to a carbon atom: hydrogen, d-6 alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, sec- butoxy, R1 R14N- (wherein R13 and R14 are each independently hydrogen or Ci-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -C =NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein Rι5 is hydrogen or Ci-3 alkyl), or -O(CH )nORι6- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z - (wherein Zi through Z4 each independently represents CH or N), -S-CO- O-, -CH=CH-NH-., -CT 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, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R 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-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z each independently represents CH or ), -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, CM alkyl, C3-6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -SO3H, -S02CH3, -SO2NH2, or when R7 are located at the ortho position to another R;, they together form -Z1=Z2-Z3=Z4- (wherein Zi tlirough Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=CH-O-, -N 3Ϊ-NH-, -CH2-N=N-, -NMN-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C1.3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two s are located at the ortho position to each other, they together form -Zι=Z2-
Figure imgf000051_0001
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 fourth embodiment, the compounds of the present invention are represented by formula A(Fv) wherein R\ through R9 are each independently (i) when comiected to a carbon atom: hydrogen, Cι-6 alkyl, C3_6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHRι5 (wherein R!5 is hydrogen or C1-3 alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or C alkyl, and 11 is 1, 2 or 3); or when any two s are located at the ortho position to each other, they together form - Zι=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-; 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
Figure imgf000051_0002
R is not CI, CN, OCH3, NO2, CF3, H, or COOCH3; when
Figure imgf000051_0003
= hydrogen, and X=Y=Z=carbon; R6
Figure imgf000051_0004
when Rι=R2=R3=R4 :=R5=R8 :=R9 = hydrogen, and X=Y=Z=carbon; R6 and R7 together is not -CH=CH-CH=CH-; when Rι=R2=R3=:R =:R6=R7=Rs== R9=hydrogen, and X=Y=Z=carbon; R5 is not OCOCH3; when
Figure imgf000051_0005
R2 is not COOH; and when R1=R2=R3=R4=R5=R8= R9 = hydrogen, R6= CI, and X=Y=Z=carbon; R7 is not CI. hi a preferred embodiment of the fourth embodiment, the compounds of the present invention are represented by formula A(1N) 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=ΝOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, C alkyl, C .6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=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-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together form -Zι=:Z2-Z3=Z - (wherein Zi tlirough Z 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, C alkyl, C3.6 cycloalkyl, d_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 Z each independently represents CH orN), -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, C alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Z1=Z2- Z3=Z4- (wherein Zi through Z 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=R2=R3=R4=R5=R6=R8=R9 = hydrogen, and X=Y=Z=carbon; R is not CI, CN, OCH3, NO2, CF3, H, or COOCH3; when R1=R2 :=R3=R4=R5 :=R =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-;
Figure imgf000053_0001
is not OCOCH3;
Figure imgf000053_0002
is not COOH; and when R1=R2=R3=R4=R5=R8=: R9=hydrogen, R6= CI, and X=Y=Z=carbon; R7 is not CI.
Table 4: Representative Compounds in Formula A(IV):
Figure imgf000054_0003
Formula A(V) In a fifth embodiment, the compounds of the present invention are represented by formula A(V):
Figure imgf000054_0001
wherein Ri through R9 are each independently hydrogen, Cι_6 alkyl, d-6 cycloalkyl, d-3 alkoxy, zz-butoxy, i-butoxy, see-butoxy, R13R14N- (wherein R13 and R1 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, d-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRi5 (wherein R15 is hydrogen or C alkyl), or -0(CH2)nORι6- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form
Figure imgf000054_0002
(wherein Zi through Z 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, Ri and t are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι_ alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (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-
Figure imgf000055_0001
In one particular embodiment of the fifth embodiment, the compounds of the present invention are represented by formula A(V): wherein Ri tlirough R are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, i-butoxy, sec-butoxy, R13R14N- (wherein R13 and Ru each independently represents hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRι (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORι6- (wherein R16 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=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-5 -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; with the proviso that when Rι=R =R3=R =R5=R6=Rs=: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, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R9 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z 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
Figure imgf000056_0001
- 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):
Figure imgf000056_0003
Compound
Figure imgf000056_0002
(compound F1002)is available from Combi-
Blocks, Inc. (San Diego, California, Cat. No. BB-2114).
Formula AfV ) In a sixth embodiment, the compounds of the present invention are represented by formula A(VI):
Figure imgf000057_0001
(Compound F1212). This compound is available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB-2162).
Formula ACVID In a seventh embodiment, the compounds of the present invention are represented by formula A(VII):
Figure imgf000057_0002
wherein Q is oxygen or lone-pair electrons. H
The compound
Figure imgf000057_0003
(compound F1012)is available from
Sigma-Aldrich, Inc. (St. Louis, MO, Cat. No. 51221-4.
Formnla ACYΪtt) In an eighth embodiment, the compounds of the present invention are represented by formula A(VIII) :
Figure imgf000057_0004
(compound BB-1003). Compound BB-1003 is commercially available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB2119).
Formula A(DQ In a ninth embodiment, the compounds of the present invention are represented by formula A(IX):
Figure imgf000058_0001
(compound BB-1004). Compound BB-1004 is commercially available from Combi-Blocks, Inc. (San Diego, California, Cat. No. BB2623). Formula AfX In a tenth embodiment, the compounds of the present invention are represented by formula A(X):
Figure imgf000058_0002
(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):
Figure imgf000058_0003
wherein Ri is hydrogen, C alkyl, C3-6 cycloalkyl, CM alkoxy, zz-butoxy, z- butoxy, -ec-butoxy, Rι3Rι N- (wherein R13 and R14 are each independently hydrogen or d-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, -SO2NHR15 (wherein Rι5 is hydrogen or CM alkyl), or -O(CH2)nORi6- (wherein Riβ is hydrogen or C 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, Cι-4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and - SO2NH2. In one particular embodiment of the eleventh embodiment, the compounds of the present invention are represented by formula A(XI), wherein Ri is C alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, Rι3R14N- (wherein Rι3 and R14 are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, d-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or C alkyl, and n is 1, 2 or 3). In another embodiment of the eleventh embodiment, Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2. Non-limiting specific compounds described by formula A(XI) are listed in Table 6. Table 6: Representative Compounds in Formula A(XI):
Figure imgf000059_0001
NH2 H OH CN Br
Formula A(XII) In a twelfth embodiment, the compounds of the present invention are represented by formula A(XII):
Figure imgf000060_0001
wherein Ri tlirough R9 are each independently (i) when connected to a carbon atom: hydrogen, C alkyl, C3-6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, R13R14N- (wherein Rj and Rj are each independently hydrogen or CM alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHRι5 (wherein R]5 is hydrogen or CM alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Z1=Z2-Z3=:Z4- (wherein Zi through Z 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; and X, Y and Z are each independently carbon or nitrogen. In a preferred embodiment of the twelfth embodiment, Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -
Figure imgf000060_0002
Rs is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3-6 cycloalkyl, CM 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 R5 are located at the ortho position to another R, they together form -Zι=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-; R6is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, CM alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d_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 R, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - Orϊ=CH-O-, -N=CH-NH-, -CH2-N=N-, --S N-O-, -N=CH-S- or -O-CH2CH2-O-; R7is: (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, C alkyl, C3-6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, - CH=CH-O-3 -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-; R8 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=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. Non-limiting specific compounds described by formula A(XII) are listed in Table 7. Table 7: Representative Compounds in Formula A(XII):
Figure imgf000062_0002
Formula ΛCXIII) In a thirteenth embodiment, the compounds of the present invention are represented by formula A(XIII):
Figure imgf000062_0001
wherein Ri through R12 are each independently hydrogen, C alkyl, €3,5 cycloalkyl, C alkoxy, zz-butoxy, z-butoxy, sβc-butoxy, R13R14N- (wherein R13 and Rι4 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein Rjβ is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z -Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -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 prefen-ed embodiment of the thirteenth embodiment, Ri, R3, i, R9, Ru 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 independently hydrogen, C alkyl, C3_6 cycloalkyl, C 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 Rs are located at the ortho position to each other, they together form -Zι=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):
Figure imgf000063_0001
Formula AfXiV) In a fourteenth embodiment, the compounds of the present invention are represented by fonnula A(XIV):
Figure imgf000064_0001
wherein Ri through R9 are each independently hydrogen, d-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, zz-butoxy, i-butoxy, sec-butoxy, Rι3Rι4N- (wherein Rι and R14 each independently represents hydrogen or C alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRι5 (wherein R15 is hydrogen or -3 alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form ~Zι=Z -Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -S-CO-O-, -CB=CH-NH-, -CH-CH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-. h 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, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -S02CH3 and -S02NH2; R5 through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=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(X1N) are listed in Table 9. Table 9: Representative Compounds in Formula A(XIV):
Figure imgf000065_0002
Formula A(XV) hi a fifteenth embodiment, the compounds of the present invention are represented by formula A(XV):
Figure imgf000065_0001
wherein Ri through R12 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Rι3Rι4N- (wherein R13 and R14 are each independently hydrogen or d-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, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or CM alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (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-. In a preferred embodiment of the fifteenth embodiment, Ri, R3, R4, R9, Ru and Rι2 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H,
Figure imgf000066_0001
R5 through R8 are each independently hydrogen, CM alkyl, C3_6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH Η-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):
Figure imgf000066_0002
Formula A(XVI) In a sixteenth embodiment, the compounds of the present invention are represented by foπnula A(XVI):
Figure imgf000067_0001
wherein Ri through R12 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C alkoxy, zz-butoxy, z'-butoxy, sβc-butoxy, Rι3R1 N- (wherein Rι3 and R14 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together foπn -Zι=Z2-Z3=Z4- (wherein Z\ through Z 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, Ru and R12 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through Rg are each independently hydrogen, CM alkyl, C3-β cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=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 10 A. Table 10A Representative Compounds in Formula A(XVI)
Figure imgf000068_0002
Formula A(XVII) In a seventeenth embodiment, the compounds of the present invention are represented by formula A(XVII):
Figure imgf000068_0001
wherein Ri through Rι are each independently hydrogen, C alkyl, C3-6 cycloalkyl, CM alkoxy, zz-butoxy, z'-butoxy, sec-butoxy, RπR^N- (wherein R13 and R14 are each independently hydrogen or Cι-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, -SO H, -SO2CH3, - SO2NHRi5 (wherein R15 is hydrogen or CM alkyl), or -O(CH2)nOR16- (wherein R16 is hydrogen or CM alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z -Z3=:Z4- (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-0-, -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, i, R9, Rπ and Rι2 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, d_ alkyl, C3.6 cycloalkyl, CM alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together form -Zι=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(XVII) are listed in Table 1 OB. Table 10B Representative Compounds in Formula A(XVII)
Figure imgf000069_0002
Formula A(XVIIT) In a eighteenth embodiment, the compounds of the present invention are represented by formula A(XVIII):
Figure imgf000069_0001
wherein R\ through R20 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, CM alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R13R14N- (wherein Rι3 and R1 are each independently hydrogen or C 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, -SO3H, -SO2CH3, - SO2NHRi5 (wherein R15 is hydrogen or C alkyl), or -O(CH2)nORι6- (wherein Rj6 is hydrogen or C alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position' to each other, they together form -Zι=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 eighteenth embodiment, Ri, R3, R4, R9, Ru, R12, R17, R19 and R20 are each hydrogen; R2, Rio and Rι8 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 tlirough R7 are each independently hydrogen, C alkyl, C3-6 cycloalkyl, C alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2. Non-limiting specific compounds described by formula A(XVIII) are listed in Table IOC.
Figure imgf000070_0001
jg-Lactamases The compounds of the present invention can be used to inhibit any β- lactamases. /3-lactamases are endogenous bacterial enzymes that destroy /3-lactam antibiotics and eliminate their efficacy. The name derives from their ability to cleave the /3-lactam ring. The structures of many 3-lactamases are known at the atomic level and available in the protein database. Preferably, the /3-lactamase is a Class A, B, C or D β- lactamase. More preferably, it is a Class A (TEM) or Class C (AmpC) p actamase. 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, polymorphs, 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, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succmate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate 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 transfonnation. In vivo, 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 /3-lactam antibiotics, are intimately admixed with a pharmaceutical carrier according to conventional phaπnaceutical 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 canϊer 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 may be employed. In some applications, it may be advantageous to utilize the active agent in a "vectorized" foπn, 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 fonnulations 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 microp articulate systems which are designed to target the compound to blood components or one or more organs. The fonnulations may be presented in unit-dose or multi-dose form. Parenteral administration may comprise any suitable fonn 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., intraperitoiieal), 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. hi 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. /3-Laetam Antibiotics /3-lactam antibiotics are compounds with antimicrobial activities and contain the /3-lactam structure. Any /3-lactam antibiotic is suitable. Many suitable β- 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. /3-lactam antibiotics are effective (in the absence of resistance) against a wide range of bacterial infections. These include those caused by gram-positive and/or gram-negative bacteria, for example, bacteria of the genus Siaphylococcus (such as Staphylococcus aureus and Staphylococcus epidermis), Streptococcus (such as Streptococcus agalactine, Streptococcus penumoniae and Streptococcus faecalis), Micrococcus (such as Micrococcus luteus), Bacillus (such as Bacillus subtilis), Listerella (such as Listerella monocytogenes), Escherichia (such as Escherichia coli), Klebsiella (such as Klebsiella pneumoniae), Proteus (such as Proteus mirabilis and Proteus vulgaris), Salmonella (such as Salmonella typhosa), Shigella (such as Shigella sonneϊ), Enterobacter (such as Enterobacter aerogenes and Enterobacter faciurn), Serratia (such as Serratia marcescens), Pseudomonas (such as Pseudomonas aeruginosa), Acinetobacter such as Acinetobacter anitratus), Nocardia (such as Nocardia autotrophica), or Mycobacterium (such as Mycobacterium fortuitum). Preferred /3-lactam antibiotics are those which preferentially deactivated by Class A and Class C /3-lactamase enzymes, for example, amoxicillin, piperacillin, ampicillin, ceftizoxime, cefotaxime, cefuroxime, cephalexin, cefaclor, cephaloridine, and ceftazidime. Effective doses and modes of administration of /3-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. Prefened 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 prefened embodiment of the present invention, the active agents are combined and administered in a single dosage form. In another pretended embodiment, the active agents are administered in separate dosage fomis (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-aryIoxycarbonyl-phenylboronic acid
Figure imgf000076_0001
step i, (COCl)2, DMF, CH2CI2> rt, overnight step ii, Et3N, CH2C12, rt, overnight In step (i) of general procedure A, 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 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 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 (la), anhydrous triefhyl amine (42 μL, 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 (ϊb).
Compound (la) (3-(4-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000076_0002
To make compound (la) ?-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, 6-DMSO): δl. 1-1. 6 [m, 2H, Ar-H], 8.30-8.35 [m, 2Η, Ar-H], 8.78-8.89 [m, 3Η, Ar-H]. Compound (lb) (3-(2-Nitroρhenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000077_0001
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. 1H-NMR(300MHz, -DMSO): 57.52-7.71 [m, 2H, Ar-H], 7.81-7.94 [m, 1Η, Ar-H], 58.13-8.24 [m, 1Η, Ar-H], 8J0-8.93 [m, 3Η, Ar-H].
Compound (lc (3-(3-Nitrophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000077_0002
To make compound (lc), z z-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, mp: 185- 187°C. Η-NMR(300MHz, rf6-DMSO): 57.72-7.81 [m, 2H, Ar-H], 58.15-8.29 [m, 2Η, Ar-H], 8.76-8.89 [m, 3Η, Ar-H].
Compound (Id) (3-(4-Methoxyphenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000077_0003
To make compound (ld),/?-Mefhoxyphenol (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-OMSO): 53.74 [s, 3H, OCH?], 6.93-6.99 [m, 2H, Ar-H], 7.19-7.24 [m, 2Η, Ar-H], 8.72-8.87 [m, 3Η, Ar-H].
Compound (1 e (3-(4-Ethoxvcarbonvlphenoxycarboιιyl)-5-nitroρhenylboronic acid)
Figure imgf000078_0001
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. 1H-NMR(400MHz, 6-DMSO): 5 1.31 [t, 2H, CH2CH3], 4.30 [q, 3H, CH2CH_,], 7.50 [d, 2H, Ar-H], 8.05 [d, 2Η, Ar-H], 8.78-8.90 [m, 3Η, Ar-H].
Compound (If) (3-(2-Oxo-benzo[l ,3]oxathiol-6-oxycarbonyl)-5- nitrophenylboronic acid)
Figure imgf000078_0002
To make compound (If), 6-Hydroxy-l,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 : 57.28-7.36 [m, 1H, Ar-H], 7.56-7.64 [m, 1Η, Ar-H], 7.78-7.86 [m, 1Η, Ar-H], 8.72-8.86 [m, 3Η, Ar-H].
Compound (lg) (3-(2-Cyanophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000078_0003
To make compound (lg), 2-Ηydroxybenzonitrile (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, p: 248-250°C. 1H-NMR(400MHz, 6-DMSO): 5 7.48-7.57 [m, IH, Ar-H], 7.62-7.69 [m, 1Η, Ar-H], 7.78-7.89 [m, 1Η, Ar-H], 7.96-8.01 [m, 1Η, Ar-H], 8.83-8.94 [m, 3Η, Ar-H]. Compound (lh) (3-(2-Chloro-6-nitrophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000079_0001
To make compoun (lh), 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. 1H-NMR(300MHz, 6-DMSO): 5 7.54-7.72 [m, IH, Ar-H], 8.01-8.24 [m, 2Η, Ar-H], 8.65-8.94 [m, 3Η, Ar-H].
Compound (li (3-(2-Ethoxycarbonyl-phenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000079_0002
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, _f6-DMSO): 1.24 [t, 2H, CH2CH3], 4.31 [q, 3H, CH2CH5], 7.41-7.57 [m, 2Η, Ar-H], 7.81-8.05 [m, 2Η, Ar-H],
8.67-8.93 [m, 3Η, Ar-H].
Compound (li) (3-(2-Chlorophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000079_0003
To make compound (lj), σ-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. 1H-NMR(300MHz, 6-DMSO): 57.38- 7.78 [m, 4H, Ar-H], 8.71-9.04 [m, 3Η, Ar-H].
Compound (Ik) (3-(2-Methylphenoxycarbonyl)-5-nitro-phenylboronic acid)
Figure imgf000080_0001
To make compound (Ik), σ-Cresol (16 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 40 mg (89%o yield) of the desired compound as a yellow powder, mp: 175°C(dec). 1H-NMR(300MHz, ti6-DMSO): 52.17 [t, 3H, CH5], 7.21-7.40 [m, 3Η, Ar-H], 8.15-8.22 [m, 1Η, Ar-H], 8.65-8.91 [m, 3Η, Ar- H .
Compound (11) (3-(2-Methoxylphenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000080_0002
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. 1H-NMR(300MHz, tf6-DMSO): 53.69[s, 3H, OCH3], 7.46-8.03 [m, 4Η, Ar-H], 8.64-8.97 [m, 3Η, Ar-H].
Compound (lnϊ) (3-(3-Methylphenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000080_0003
To make compound (lm), zzz-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, rf6-DMSO): 52.35 [t, 3H, CH}], 7.79-8.30 [m, 4Η, Ar-H], 8.71-8.91 [m, 3Η, Ar-H]. Compound (In) (3-(2,6-Dichlorophenoxycarbonyl)-5-nitrophenylboronic acid)
To make compound (In), 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): 57.39-7.44 [m, IH, Ar-H], 7.52-7.67 [m, 2Η, Ar-H], 8.83 [t, 1Η, Ar-H], 8.94- 8.96 [m, 2Η, Ar-H].
Compound (lo) (3-(2-Fluorophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000081_0002
To make compound (lo), 2-Fluorophenol (17 mg, 0.15 mmol) was treated according to general procedure A, step (ii), to give 39 mg (85% yield) of the desired compound as a white needle, mp: 144-146°C. 1H-NMR (400MΗz, d6-OMSO+ D2O): 5
7.29-7.53 [m, 4H, Ar-H], 8.80 [s, 1Η, Ar-H], 8.89-8.93 [m, 2Η, Ar-H].
Compound (lp) (3-(2,6-Difluorophenoxycarbonyl)-5-nitroρhenylboronic acid)
Figure imgf000081_0003
To make compound (lp), 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, d<_-
DMSO+D2O): 57.23-7.38 [m, 2H, Ar-H], 7.38-7.48 [m, 1Η, Ar-H], 8.81 [s, 1Η, Ar-H], 8.86-8.96 [m, 2Η, Ar-H].
Compound (lq) (3-(4-Fluorophenoxycarbonyl)-5-nitrophenylboroιιic acid)
Figure imgf000082_0001
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%>D2O in d6-DMSO): 57.21-7.42 [m, 4H, Ar-H], 8.76 [s, 1Η, Ar-H], 8.83-8.95 [m, 2Η, Ar-H].
Compound (If) (3-(4-pyridyloxycarbonyl)-5-nitro-phenylboronic acid)
Figure imgf000082_0002
To make compound (lr), 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-ΩMSO): 5 7.43-7.50 [m, IH, Ar-H], 8.67-8.72 [m, 1Η, Ar-H], 8.77-8.86 [m, 3Η, Ar-H], 8.86-8.97 [m, 1Η, Ar-H]. Compound (Is) (3-(2-Chloro-3-pyridyloxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000082_0003
To make compound (Is), 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 dβ- DMSO): 57.57-7.63 [m, IH, Ar-H], 8.05-8.09 [m, 1Η, Ar-H], 8.39-8.43 [m, 1Η, Ar-H], 8.81 [s, 1Η, Ar-H], 8.89-8.94 [m, 2Η, Ar-H].
Compound (It) (3-Phenoxycarbonyl-5-nitrophenylboronic acid)
Figure imgf000083_0001
To make compound (It), 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%D2O in 6-DMSO): 57.28-7.34 [m, 3H, Ar-H], 7.44-7.51 [m, 2Η, Ar-H], 8.78 [s, 1Η, Ar-H], 8.86-8.92 [m, 2Η, Ar-H].
Compound (lu) (3-(2-Bromophenoxycarbonyl)-5-nitro-phenylboronic acid)
Figure imgf000083_0002
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(400MΗz, 5%D2O in d6- DMSO): δl.26-135 [m, IH, Ar-H], 7.47-7.56 [m, 2Η, Ar-H], 7.76-7.81 [m, 1Η, Ar-H], 8.83-8.94 [m, 3Η, Ar-H].
Compound (lv (3-(3-Boronophenoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000083_0003
To make compound (lv), 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%D2O in ^6-DMSO): 57.30-7.36 [m, IH, Ar-H], 7.41-7.47 [m, 1Η, Ar-H], 7.60-7.63 [m, 1Η, Ar-H], 7.68-7.73 [m, 1Η, Ar-H], 8.76-8.79 [m, 1Η, Ar-H], 8.84-8.90 [m, 2Η, Ar- Compound (lw) (3-(2,4-Dichloro-6-nitro-ρhenoxycarbonyl)-5-nitro- phenylboronic acid)
Figure imgf000084_0001
To make compound (lw), 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%D2O in αVDMSO): 8.34-8.38 [m, IH, Ar-H], 8.82-8.84 [m, 1Η, Ar-H], 8.90-8.91 [m, 1Η, Ar-H], 8.94-8.96 [m, 1Η, Ar-H]. Compound (lx) (3 -(2,4-Dichloro-6-nitro-phenoxycarbonyl)-5 -nitro- phenylboronic acid)
Figure imgf000084_0002
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 (11% yield) of the desired compound as a pale yellow powder, mp: 193°C. 1H-NMR
(400MHz, 5%D2O in d6-DMSO): 56.61-6.94 [m, 3H, Ar-H], 7.15-8.07 [m, 3Η, Ar-H],
8.71-8.76 [m, 1Η, Ar-H], 8.84-8.89 [m, 1Η, Ar-H], 8.89-8.96 [m, 1Η, Ar-H].
Compound (ly) (3-(2,4,6-Trichlorophenoxycarboιιyl)-5-nitro-phenylboronic acid)
Figure imgf000084_0003
To make compound (ly), 2,4,6-TrichlorophenoI (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 (400MΗz, 5%D2O in d6-DMSO): 57.24 [s, 2Η, Ar-H], 8.77-8.80 [m, 1Η, Ar-H], 8.90-8.96 [m, 2Η, 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
Figure imgf000085_0001
i, (COCl)2, DMF, CH2C12, rt, overnight ii, Et3N, THF, rt, overnight
In step (i) of general procedure B, 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 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 (Ila), anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anliydrous 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 IN aqueous HCl, 10% aqueous NaHCOj, saturated brine solution, dried (Na2SO4) 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)
Figure imgf000085_0002
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. 1H-NMR(300MHz, d6- DMSO+D2O): 57.43 [s, 4H, Ar-H], 8.79 [t, 1Η, Ar-H], 8.84 [t, 1Η, Ar-H], 8.86 [d, 1Η, Ar-H].
Compound (2b) (3-Borono-5-nitrobenzoic acid 2-chloro-l,4-phenylene ester)
Figure imgf000086_0001
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. 1H-NMR(300MHz, d6-OMSO): 5 7.46-7.79 [m, 3H, Ar-H], 8.79 [d, 1Η, Ar-H], 8.88-8.92 [m, 2Η, Ar-H].
Compound (2c) (3-Borono-5-nitrobenzoic acid 2-chloro-l,4-phenylene ester)
Figure imgf000086_0002
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. 1Η-NMR(300MΗz, ^-DMSO): 5 8.71-8.75 [m, 2H, Ar-H], 8.93-8.99 [m, 4Η, Ar-H],
Compound (2d) (3-Borono-5-nitrobenzoic acid 2-chloro-l,4-phenylene ester)
Figure imgf000087_0001
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). 1H-NMR(300MHz, dβ- DMSO): 5 1.34[s, 9H, CH3], 7.02-7.27 [m, 3Η, Ar-H], 8.79-8.83 [m, 2Η, Ar-H], 8.86- 8.92 [m, 4Η, Ar-H].
EXAMPLE 3. Synthesis of Select Compounds In Formulation A(III) General procedure C: Synthesis of 3-aryloxycarbonyl-phenylboronic acid
Figure imgf000087_0002
step i, (COCl)2, DMF, CH2C12, rt, overnight step ii, Et3N, CH2C12, rt, overnight In step (i) of general procedure C, oxalyl chloride (35 μL, 0.4 mmol) was added to a suspension of (3-carboxyl-5-nitrophenyl)boiOnic acid (42 mg, 0.2 mmol), 1 drop of DMF and 5 mL of anhydrous CH2C12. The reaction mixture was stined 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 (Ilia), anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous CH2C1 . The reaction mixture was stined 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 (IHb). Compound (3a) (3-(2,6-Dichlorobenzyloxycarbonyl)-5-nitrophenylboronic)
Figure imgf000088_0001
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%D2O in c 6-DMSO): 55.62 [s, 2H, Ar-CH2], 7.26-7.62 [m, 3Η, Ar-H], 8.57-8.95 [m, 3Η, Ar-H].
Compound (3b) (3-(3-Nitrobenzyloxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000088_0002
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 dδ-DMSO): 55.46 [s, 2H, Ar-CH2], 7.65-7.70 [m, 1Η, Ar-H], 7.93-7.97 [m,
1Η, Ar-H], 8.09-8.12 [m, 1Η, Ar-H], 8.17-8.21 [m, 1Η, Ar-H], 8.62-8.94 [m, 3Η, Ar-H]. Compound (3c) (3-(3-Chlorobenzyloxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000088_0003
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). 1H-NMR(400MΗz, 5%>D2O in 6- DMSO): 55.41 [s, 2H, Ar-CH2], 7.41-7.61 [m, 4Η, Ar-H], 8.62-8.95 [m, 3Η, Ar-H]. Compound (3d) (3-(3-Boronobenzyloxycarbonyl)-5-nitrophenylboronic acid) H
Figure imgf000089_0001
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. 1H-NMR (400MHz, 5%D2O in dβ-
DMSO): 55.39 [s, 2H, Ar-CH2], 7.27-7.84 [m, 4Η, Ar-H], 8.79-8.90 [m, 3Η, Ar-H].
Compound (3e) (3-(l-Naphthalenemethoxycarbonyl)-5-nitrophenylboronic acid)
Figure imgf000089_0002
To make compound (3e), 1-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-DMSQ): 5 5.88 [s, 2H, Ar-CHJ, 7.50-8.24 [m, 7Η, Ar-H], 8.601-8.87 [m, 3Η, Ar-H].
Compound (3f) (3-(3-Boronobenzyloxycarbonyl)-5-aminophenylboronic acid) H
Figure imgf000089_0003
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/H2O to give 60 mg (38% yield) of the desired compound as a pale yellow semisolid. 1H-NMR(300MHz, 5%D2O in i6-DMSO): 55.25 [s, 2H, Ar-CH.], 6.56-6.97 [m, 2Η, Ar-H], 7.15-8.09 [m, 5Η, Ar-H]. Compound (3g) (3-(3-Boronobenzyloxycarbonyl)-5-hydroxylphenylboronic acid)
Figure imgf000090_0001
To make the compound (3g), 3-(3-boronobenzyloxycarbonyl)-5- aminophenylboronic acid (31 mg, 0.1 mmol) was suspended in 2 mL of 50% H2SO4 and treated at -5 °C with a solution of NaNO2 (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 Na2SO4. 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%D2O in _/6-DMSO): 5 5.39 [s, 2H, Ar-CH2], 7.07-7.64 [m, 3Η, Ar-H], 7.89-8.27 [m, 4Η, Ar-H]. EXAMPLE 4. Synthesis of Select Compounds In Formulation A(TV)
Compound (4a) 3-(2-Fluorobenzamido)-5-carboxylphenylboronic acid
Figure imgf000090_0002
To make compound (4a), 2-fluorobenzoyl chloride (60μL, 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) and NaHC03 (105 mg, 1.25 mmol) in 10 mL of water. The reaction mixture was kept at 0°C for lh and then stined at room temperature overnight. It was then extracted twice with 10 mL of ethyl ether. The aqueous solution was acidified with IN 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%D2O in i6-DMSO): 57.21-7.38 [m, 2H, Ar-H], 7.48-7.72 [m, 2Η, Ar-H], 8.12-8.33 [m, 3Η, Ar-H].
EXAMPLE 5. Synthesis of Select Compounds In Formulation A(XI)
Compound (5a) (3-amino-5-carboxylphenylboronic acid)
Figure imgf000091_0001
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). 1Η-NMR(400MΗz, 5%D2O in d6-DMSO): 57.06 [s, IH, Ar-H], 7.16 [s, 1Η, Ar-H], 7.55 [s, 1Η, Ar-H] (Torssell, K.; Meyer, Η.; 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) Η
Figure imgf000091_0002
To make compound (6a), a solution of 2,6-dichlorobenzoyl chloride (29 μL, 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 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stined 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 (Na2SO4) 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). 1H-NMR (400MHz, 5%D2O in rf6-DMSO): 57.08-7.19 [m, IH, Ar-H], 7.22-7.30 [m, 1Η, Ar-H], 7.22-7.30 [m, 1Η, Ar-H], 7.42-7.50 [m, 1Η, Ar-H], 7.54-7.60 [m, 1Η, Ar-H], 7.60-7.68 [m, 2Η, Ar-H], 7.73-7.78 [m, 3Η, Ar-H].
EXAMPLE 7. Synthesis of Select Compounds In Formulation A(XIII)
Compound (7a) 4-Borono-2-fluorobenzoic acid 2-chloro-l,4-phenylene ester
Figure imgf000092_0001
hi step (i), oxalyl chloride (35 μL, 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 CΗ2C12. 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 chlorohydroquinone (11 mg, 0.075 mmol), anhydrous triethyl amine (42 μL, 0.3 mmol) and 10 mL of anhydrous THF. The reaction mixture was stined 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 26 mg (74% yield) of the desired compound as a pale yellow powder, mp: 228-230°C. 1H-NMR (400MHz, 5%>D O in <i6- DMSO): 56.52-6.55 [m, IH, Ar-H], 6.68-6.76 [m, 2Η, Ar-H], 6.94-7.06 [m, 1Η, Ar-H], 7.21-7.34 [m, 1Η, Ar-H], 7.57-7.78 [m, 3Η, Ar-H], 7.99-8.11 [m, 1Η, Ar-H].
EXAMPLE 8. Synthesis of Select Compounds In Formulation A(XIV) Compound 8(a) (4-(2-Chloro-6-nitrophenoxvcarbonvl)-3-fluorophenylboronic acid)
Figure imgf000093_0001
hi step (i), oxalyl chloride (35 μL, 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 stined 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 (Na2SO4) 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. 1H-NMR (400MHz, 5%D2O in tf6-DMSO): 57.61-7.36 [m, IH, Ar-H], 7.71-7.74 [m, 1Η, Ar-H], 7.77-7.79 [m, 1Η, Ar-H], 8.07-8.11 [m, 2Η, Ar-H], 8.18-8.21 [m, 2Η, Ar- H\.
EXAMPLE 9. Synthesis of Select Compounds In Formulation AfXV)
Compound (9a) (3-Borono-5-nitrobenzoic acid 1,3-phenylene ester)
Figure imgf000093_0002
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 CH2C12. The reaction mixture was stined 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 stined 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 (Na2SO4) 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). 1H- NMR (400MHz, 5%D2O in 6-DMSO): 56.14-6.18 [m, 2H, Ar-H], 7.33-7.45 [m, 2Η, Ar-H], 8.75-8.82 [m, 2Η, Ar-H], 8.85-8.90 [m, 4Η, Ar-H].
EXAMPLE 10. Synthesis of Select Compounds In Formulation A(XVI)
Compound (10a) (3-Borono-5-nitrobenzoic acid 1,2-benzenedimethanol ester)
Figure imgf000094_0001
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 CΗ2C12. The reaction mixture was stined 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). hi 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 1,2- benzenedimethanol (10 mg, 0.075 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 (Na2SO4) 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%D2O in d6- DMSO): 55.64 [s, 4H, CH2], 6.14-6.18 [m, 2H, Ar-H], 7.33-7.45 [m, 2Η, Ar-H], 8.77- 8.84 [m, 2Η, Ar-H], 8.87-8.93 [m, 4Η, Ar-H].
EXAMPLE 11. Synthesis of Select Compounds In Formulation A(XVII) Compound (Ila) (1,4-Benzenedicarboxylic acid, di 3-boronophenyl ester)
Figure imgf000095_0001
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 stined 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 (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%D2O in c 6-DMSO): 57.28-7.34 [m, 2H, Ar-H], 7.38-7.46 [m, 2Η, Ar-H], 7.59-7.63 [m, 2Η, Ar-H], 7.68-7.73 [m, 2Η, Ar- H], 8.30 [s, 4H, Ar-H].
EXAMPLE 12. Synthesis of Select Compounds In Formulation A(XJIIi) Compound (12a) (Tris(3-borono-5-nitrobenzoic acid), 1,3,5-trihydroxybenzene ester)
Figure imgf000096_0001
In step (i), oxalyl chloride (79 μL, 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 stined 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 NaHCO , saturated brine solution, dried (Na SO ) and then concentrated. The residue was purified by flash cliromatography 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%D2O in -DMSO): 7.46 [s, IH, Ar-H], 8.72-8.76 [m, 1Η, Ar-H], 8.78-8.86 [m, 2Η, Ar-H].
EXAMPLE 13. Inhibition Assay The inhibition of TEM-1 (3-lactamase was determined spectrophotometrically. B-lactamase activity was followed by measuring the hydrolysis ofnitrocefin, [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, pΗ 7.0. The enzyme concentration was held at 5nM, with substrate at 167 μM and varying inhibitor concentrations. Inhibitor was added to the enzyme and incubated for ten minutes before the addition of substrate. Inhibition constants (Kj) for the inliibitors 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 /3-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 /3-Lactamase Inhibition Assay
Figure imgf000097_0001
Figure imgf000098_0001
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 nonspecific 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
Figure imgf000099_0001
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 very 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 /3-lactam-based /3-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 cunently 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 /3-Lactamase Mutants Expressed as the Ratio of the Inhibitory Constant Between Mutant and Wild Type (Potency wt/Potencymuta„t). *
Figure imgf000100_0001
*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 (compound F1201);
mpuond F1202);
Figure imgf000101_0001
(compound F1203); and
Figure imgf000101_0002
(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. aureus 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 /3-lactamase inhibitor combinations (including ampicillin/sulbactam, aii oxicillin 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 μl of this dilute cell suspension to 50 μl of growth medium yielded the desired cell density, namely about 5 x 104 CFU/well, or 5 x 105 CFU/ml. Broth Microdilutioή 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.
MIC Assays with Oxacillin The MIC experiments were perfonned in duplicate in 96-well micro titer 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 was added 47.5 μl of MHB. A volume of 2.5 μl 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 μl of a diluted cell suspension to give a final volume of 100 μl and a final cell density of 5 x 104 CFU/well. The volume in the sterility control wells was adjusted to 100 μl 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).
MIC Assays with Compounds of the Present Invention 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 μl of each dilution was delivered to appropriate wells. The initial doses used were (μg/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 detennined to be the MIC value.
Matrix System The effect of the four compounds of the present invention on oxacillin resistance of the MRS A strains was detennined using a matrix system. The /3-lactamase 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 μl/ml which was not bacterio toxic 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 β- lactamase inhibitors was added, 2.5 μl each, to the wells prior to addition of the test organisms.
RESULTS AND DISCUSSION MIC Evaluation of Oxacillin and the Four Compounds MIC assays were performed with oxacillin and the four compounds. Each of the compounds was tested at the following 8 doses (μg/ml): 512, 256, 128, 64, 32, 16, 8, and 4. Oxacillin was tested at the following 8 doses (μg/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
Figure imgf000104_0001
Matrix Study: Oxacillin and Compound FL201 with MRSA-ATCC The results are shown in Table 15.
Table 15.
-t> Compound F1201 Oxacillin
Figure imgf000104_0002
Figure imgf000105_0001
Matrix Study. -Oxacillin and Compound F 1202 with MRSA-ATCC
The results are shown in Table 16.
Table 16.
-o Compound F1202 Oxacillin
Figure imgf000105_0002
Figure imgf000106_0001
Matrix Study: Oxacillin and Compound FL201 with MRSA-SU The results are shown in Table 17.
Table 17.
Compound F1201 Oxacillin
Figure imgf000106_0002
Matrix Study: Oxacillin and Compound FL202 with MRSA-SU The results are shown in Table 18.
Table 18. Compound F1202 Oxacillin
Figure imgf000107_0001
EXAMPLE 17 COMPARISON OF ACTIVITIES AGAINST TEM-1 AND
Amp-C β-LACTAMASES
Materials and Methods The gene for AmpC β-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- laclq lacPLS ampC:. ambdacI+) was isolated via Qiagen (Valencia, CA) mini prep. The gene for AmpC was amplified in two pieces via poljαnerase 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). Conect 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 ODδoo of 0.8 at 37 °C. 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 β-lactamase was determined spectrophotometrically using a Varian (Walnut Creek, CA) Cary 100 UN- Visible spectrophotometer. β-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 β- lactamase preparations hydrolyze nitrocefin substrate from 50 to 150 s"1. Under these conditions, the KM for AmpC β-lactamase is 250 μM and the kcat is 975 s"1. Penicillin G (Sigma, St. Louis, MO) was also used as a substrate to determine KM and kcat. 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 μM 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 β-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). β-Lactamase solutions were titrated with inhibitors in 50 mM sodium phosphate, 2% DMSO, pH 7.0, with β- lactamase concentrations ranging from 15 to 25 μM and inhibitor concentrations ranging from 300 to 1000 μM. 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 β-lactamase. Results Kinetic measurements of the digestion of a natural substrate, penicillin G and a chemically available substrate, nitrocefin are shown in Table 19. kcatIKM, a measure of the catalytic efficiency, is larger with penicillin G as a substrate instead of nitrocefin.
Table 19. Kinetic characterization of the AmpC β-lactamase.
Figure imgf000109_0001
2' Units are μM. 3' Units are s^μM"1.
Phenyl -boronic acids have inhibitory activity against theTEM-1 and AmpC β-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 β-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 β-lactamase variant TEM-1. Table 20. Inhibition constants and thermodynamic parameters of compounds versus AmpC and TEM-1 β-lactamases AmpC Ki1 ΛG2 ΔH2 -TΔS2 TEM-1 Ki1 ΔG2 AH2 -TΔS2 (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 (In) 8.8 -5608 -1173 -4435 (8a) 0.913 -8190 -8486 296 (lh) 9.5 -6614 -1140 -5474 (3d) 1.03 -7442 -15637 8195 (10a) 9.7 -7183 -982 -6201 (Ila) 1.31 -7548 -3114 -4434 (lx) 10.4 -6655 -577 -6078 (6a) 1.53 -1151 -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) 12J -6409 -4554 -1855 (3g) 2.69 -7356 -3677 -3679 (2b) 15.2 -7864 -520 -7344 (2b) 2.92 -7736 -225 -7511 (iy) 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 dp) 19.8 -5916 -6715 799 (2d) 6.27 -7098 0 -7098 (2a) 227 -7451 274 -7725
Ki units are μM.
2. ΔG, Δ and -TΔS units are cal/mol.
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.

Claims

WHAT IS CLAIMED IS:
1. A method of treating bacterial infection comprises administering to a subject suffering from such an infection an effective amount of a compound having the fonnula: (HO)2-B-T (A) wherein B stands for boron, and T has one of the following structures:
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
wherein R] through R12 are each independently (i) when comiected to a carbon atom: hydrogen, d-6 alkyl, C .6 cycloalkyl, Cι_3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Rι3R14N- (wherein R13 and R1 are each independently hydrogen or Cι_3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenox}^, phenoxycarbonyl, 2, 4-dichlorophenoxy, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CE NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHR]5
(wherein R15 is hydrogen or d-3 alkyl), or -0(CH2)nORι6- (wherein ι6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form
Figure imgf000114_0002
tlirough 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; X, Y and Z are each independently carbon or nitrogen; and Q is oxygen or lone-pair electrons. 2. A compound having the formula A(I)
Figure imgf000115_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Cμ6 alkyl, C3-6 cycloalkyl, C1.3 alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, R13R14N- (wherein R13 and R14 are each independently hydrogen or d-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, -d=NOHCH3, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or d-3 alkyl), or -O(CH2)nOR16- (wherein Rie is hydrogen or Ci-3 alkyl, and n is 1, 2 or 3); or when any two Rs 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-NH-, -CH=CH-S-, -CH=CHO-, -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. 3. The compound of claim 2 wherein Ri , R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, d_4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, d-4 alkyl, C3.6 cycloalkyl, Ci-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, -4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, 2, 4-dichlorophenoxy, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when R5 are located at the ortho position to another Rj, they together form -Zι=Z2-Z3=Z - (wherein Z\ through Z 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, d-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 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, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-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 R, they together form -Zι=Z2-Z =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-; R8 through R9 are each independently hydrogen, d-4 alkyl, C3-6 cycloalkyl, Ci-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d_4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, - SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form
Figure imgf000117_0001
(wherein Zi through Z4 each independently represents CH orN), -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. 4. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 2. 5. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 2. 6. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 2 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 7. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 2 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 8. A phamiaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition comprising the compound of claim 2, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 10. A compound represented by formula A(II) :
Figure imgf000117_0002
wherein Ri through R12 are each independently hydrogen, Ci-6 alkyl, C3.6 cycloalkyl, Ci-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Rι3R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 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, -SO3H, -SO2CH , - SO2NHR15 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or C1.3 alkyl, and 11 is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=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-. 11. The compound of claim 10, wherein Ri, R3, i, R9, Rπ and Rι2 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -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, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs 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-, -CHOH-S-, -CH=CH-O-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-. 12. A method of inhibiting jδ-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 10. 13. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 10. 14. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 10 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent.
15. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 10 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 16. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising the compound of claim 10, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 18. A compound represented by formula A(III) :
Figure imgf000119_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Ci-6 alkyl, C3.6 cycloalkyl, Ci-3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, R13R14N- (wherein R13 and Rj4 are each independently hydrogen or C1.3 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, -SO2NHRι5 (wherein R15 is hydrogen or d-3 alkyl), or -0(CH2)nORι6- (wherein
Figure imgf000119_0002
is hydrogen or C1-3 alkyl, and 11 is 1, 2 or 3); or when any two R,s are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z - (wherein Z\ through Z4 each independently represents CH or N), -S-CO- O-, -CH=CH-NH-3 -CT 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. 19. The compound of claim 18 wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, d-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Rι3Rι4N- (wherein R13 and R14 are each independently hydrogen or Cι_3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NHRι5 (wherein R15 is hydrogen or d-3 alkyl), or -O(CH2)„ORi6- (wherein R16 is hydrogen or d-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=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-; 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 Rι=R3=R4=R5=R6=R7=R8=R9=hydrogen, and X=Y=Z:=carbon; R2 is not NH2, NO2)5 or H. 20. The compound of claim 18 wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, C alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - C=NOHCH3, -SO3H, -302CH3 and -SO2NH2; R5is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3-6 cycloalkyl, Cι_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 R;, they together form
Figure imgf000120_0001
(wherein Zi through Z4 each independently represents CH orN), -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-; Rόis: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, d-4 alkyl, C3-6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 form -Zι=Z2-Z3=Z4- (wherein Z\ through Z each independently represents CH orN), -S-CO-O-, -CH=CH-NH-, -CHK2Ϊ-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 alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together fonn -Zι=Z2-Z3=Z4- (wherein Zi tlirough 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-; Kg tlirough K9 are each independently hydrogen, -4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonjd, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two jS are located at the ortho position to each other, they together form -Zι=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
Figure imgf000122_0001
R9=hydrogen, and X=Y=Z=carbon; R2 is not H2, NO2,, or H. 21. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 18. 22. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 18. 23. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 18 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 24. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 18 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 25. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically acceptable canier. 26. A pharmaceutical composition comprising the compound of claim 18, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 27. A compound of represented by formula A(IV):
Figure imgf000122_0002
wherein R] through R are each independently (i) when connected to a carbon atom: hydrogen, Cι-6 alkyl, C3-6 cycloalkyl, d-3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Ri3Rι N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, -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 -3 alkyl), or -O(CH2)nOR]6- (wherein R16 is hydrogen or C1.3 alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z - (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-; or (ii) when connected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen. 28. The compound of claim 27 wherein, Ri, R3 and i are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, Cμ alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -CHO, -CH=NOH, - Q=NOHCH3, -SO3H, -SO2CH3 and -SO2NH2; R5 is: (i) when X is nitrogen: absent, and (ii) when X is carbon: hydrogen, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 -Zι=Z2-Z3=Z4- (wherein Z\ through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-5 - CH=CH-0-, -N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -0-CH2CH2-0- Re is: (i) when Y is nitrogen: absent, and (ii) when Y is carbon: hydrogen, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 form
Figure imgf000123_0001
(wherein Zi through Z4 each independently represents CH or ), -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, Cι-4 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C 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 R\, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH orN), -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 tlirough R9 are each independently hydrogen, CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -O=N0HCH3,-S03H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2- Zι=X \- (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. 29. The compound of claim 27, wherein Rj through R are each independently (i) when comiected to a carbon atom: hydrogen, Cι-6 alkyl, C3.6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z'-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, 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 C1-3 alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=Z2-Z3=Z4- (wherein Zi through Z 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
Figure imgf000125_0001
= hydrogen, and X=Y=Z=carbon; R is not CI, CN, OCH3, NO2, CF3, H, or COOCH3; when Rι=R2=R3=R4=R5=R =R8=R9 = hydrogen, and X=Y=Z=carbon; Rό is not CN, NO2, or CF3; when Rι=R2=R3=R4=R =R8=R9 = hydrogen, and X=Y=Z=carbon; R6 and R7 together is not -CH=CH-CH=CH-; when Rι=R2=R3=R4=R6=R7=Rs= R9=hydrogen, and X=Y=Z=carbon; R5 is not OCOCH3; when Rι=R3=R4=R5=R6=R7=R8= R9 = hydrogen, and X=Y=Z=carbon; R2 is not COOH; and when Rι=R2=R3=R4=R5= 8=π R9 = hydrogen, R6= CI, and X=Y=Z=carbon; R is not CI. 30. The compound of the claim 27 wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM 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, CM alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together form
Figure imgf000125_0002
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, CM alkyl, C3-6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d-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 R, they together form -Zι=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-; R7 is: (i) when Z is nitrogen: absent, and (ii) when Z is carbon: hydrogen, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 R, they together form -Zι=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-; Rg through R9 are each independently hydrogen, CM alkyl, C3.6 cycloalkyl, C1.3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3,-SO3H, -SO2CH3, -SO2NH2, or when any two R;s are located at the ortho position to each other, they together form -Zι=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- H-, -CH2-N=N-, -N=N-O-, -NICK¬
Figure imgf000126_0001
X, Y and Z are each independently carbon or nitrogen; with the proviso that when
Figure imgf000127_0001
= hydrogen, and X=Y=Z=carbon; R7 is not CI, CN, OCH3, NO2, CF3, H, or COOCH3; when
Figure imgf000127_0002
= hydrogen, and X=Y=Z=carbon; R6 is not CN, NO2, or CF3;
Figure imgf000127_0003
R7 together is not -CH=CH-CH=CH-; when
Figure imgf000127_0004
R5 is not OCOCH3; when Rι=R3=R4=R5=R6=R7=R8= R =hydrogen, and X=Y=Z=carbon; R2 is not COOH; and
Figure imgf000127_0005
R7 is not CI. 31. A method of inhibiting (3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 27. 32. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 27. 33. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 27 and an effective amount of a /3-lactam-a.ntibiotic or other antibacterial agent. 34. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 27 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 35. A pharmaceutical composition comprising the compound of claim 27 and a pham aceutically acceptable carrier. 36. A pharmaceutical composition comprising the compound of claim 27, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 37. A compound represented by fomiula A(V) :
Figure imgf000128_0001
wherein Ri through R9 are each independently hydrogen, Ci-6 alkyl, C3_6 cycloalkyl, Ci-3 alkoxy, zz-butoxy, i-butoxy, .sec-butoxy, Ri3Rι N- (wherein Rι3 and R1 each independently represents hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO CH3, - SO2NHRι5 (wherein R15 is hydrogen or C1-3 alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4- (wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CHOH-O-, -N=CH-NH-, -CH2-N=N-, -N-N-O-, -N=CH-S- or -O-CH2CH2-O-. 38. The compound of claim 37, wherein Ri and R4 are each hydrogen; R2 and R3 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -S02NH2; R5 through R9 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, C alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z =Z4- (wherein Z\ through Z each independently represents CH or N), -S-CO-O-, -CH=CH- NH-, -CH=CH-S-, -CH=CH-0-, -N=CH- H-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-.
39. The compound of claim 37 wherein Ri through R9 are each independently hydrogen, C.-6 alkyl, C3_6 cycloalkyl, Cι_3 alkoxy, zz-butoxy, i-butoxy, sec-butoxy, R13Ri N- (wherein R13 andR14 each independently represents hydrogen or d-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRi5 (wherein Rι5 is hydrogen or Cι-3 alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or Cι-3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (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-; with the proviso that when
Figure imgf000129_0001
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 R are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 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, d.4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO NH2, or when any two Rs are located at the ortho position to each other, they together form
Figure imgf000129_0002
(wherein Zi through Z4 each independently represents CH or N), -S-CO-O-, -CH=CH- NH-, -CH=CH-S-5 -CH=CH-0-, -N=CH- H-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O- CH2CH2-O-; with the proviso that when
Figure imgf000129_0003
hydrogen; R7 is not H, OH or
C(CH3)3. 40. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 37.
41. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 37. 42. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 37 and an effective amount of a (3-lactam-antibiotic or other antibacterial agent. 43. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 37 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 44. A pharmaceutical composition comprising the compound of claim 37 and a pharmaceutically acceptable carrier. 45. A pharmaceutical composition comprising the compound of claim 37, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 46. A compound represented by formula A(VI):
Figure imgf000130_0001
47. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 46. 48. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 46. 49. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 46 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 50. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 46 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 51. A pharmaceutical composition comprising the compound of claim 46 and a pharmaceutically acceptable canier.
52. A pharmaceutical composition comprising the compound of claim 46, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 53. A compound represented by formula A(VII):
Figure imgf000131_0001
wherein Q is oxygen or lone-pair electrons. 54. A method of inhibiting (3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 53. 55. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 53. 56. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 53 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 57. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 53 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 58. A pharmaceutical composition comprising the compound of claim 53 and a pharmaceutically acceptable carrier. 59. A pharmaceutical composition comprising the compound of claim 53, a /3- lactam-antibiotic; and a pharmaceutically acceptable carrier. 60. A compound represented by fonnula A(VIII):
Figure imgf000131_0002
61. A method of inliibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 60.
62. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 60. 63. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 60 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 64. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 60 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 65. A pharmaceutical composition comprising the compound of claim 60 and a pharmaceutically acceptable carrier. 66. A pharmaceutical composition comprising the compound of claim 60, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 67. A compound represented by formula A(IX):
Figure imgf000132_0001
68. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 67. 69. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 67. 70. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 67 and an effective amount of a (3-lactam-antibiotic or other antibacterial agent. 71. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 67 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 72. A pharmaceutical composition comprising the compound of claim 67 and a pharmaceutically acceptable canier.
73. A pharmaceutical composition comprising the compound of claim 67, a β- lactam-antibiotic; and a pharmaceutically acceptable canier. 74. A compound represented by formula A(X) : H
Figure imgf000133_0001
75. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 74. 76. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 74. 77. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 74 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 78. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 74 and an effective amount of a β- lactam-antibioti or other antibacterial agent c. 79. A pharmaceutical composition comprising the compound of claim 74 and a pharmaceutically acceptable canier. 80. A pharmaceutical composition comprising the compound of claim 2, a β- lactam-antibiotic; and a pharmaceutically acceptable canier. 81. A compound represented by formula A(XT):
Figure imgf000133_0002
wherein Ri is hydrogen, d-6 alkyl, C3_e cycloalkyl, C1-3 alkoxy, zz-butoxy, i- butoxy, sec-butoxy, R13R14N- (wherein R13 and Rι4 are each independently hydrogen or C1-3 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, -SO3H, -SO2CH3, -SO2NHR15 (wherein R15 is hydrogen or d.3 alkyl), or -O(CH2)nORi6- (wherein R16 is hydrogen or C1.3 alkyl, and n is 1, 2 or 3). 82. The compound of claim 81, wherein Ri is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and - SO2NH2. 83. The compound of claim 81 , wherein Ri is d-6 alkyl, C3.6 cycloalkyl, d-3 alkoxy, zz-butoxy, z'-butoxy, sec- butoxy, RπRι4N- (wherein R13 and R14 are each independently hydrogen or C1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, carboxyl, d-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)nORi6- (wherein Ri6 is hydrogen or Ci-3 alkyl, and n is 1, 2 or 3). 84. The compound of claim 81 wherein Ri is fluoro, chloro, bromo, cyano, acetyl, carboxyl, CM alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO CH3 and -SO2NH2. 85. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 81. 86. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim
81. 87. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim
81 and an effective amount of a /3-laetam-antibiotic or other antibacterial agent. 88. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 81 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 89. A pharmaceutical composition comprising the compound of claim 81 and a pharmaceutically acceptable carrier. 90. A phannaceutical composition comprising the compound of claim 81 , a β- lactam-antibiotic; and a pharmaceutically acceptable carrier.
91. A compound represented by formula A(XII) :
Figure imgf000135_0001
wherein Ri through R9 are each independently (i) when connected to a carbon atom: hydrogen, Ci-6 alkyl, C3.6 cycloalkyl, C1.3 alkoxy, zz-butoxy, z-butoxy, sec- butoxy, Rι3R14N- (wherein R13 and R14 are each independently hydrogen or C1-3 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, -SO2NHRι5 (wherein R15 is hydrogen or C1.-3 alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or C1-3 alkyl, and 11 is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form - Zι=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-, -NOH-NH-, -CH2-N=N-, -N=N-O-, - N=CH-S- or -O-CH2CH2-O-; or (ii) when coimected to a nitrogen atom; absent; and X, Y and Z are each independently carbon or nitrogen. 92. The compound of claim 91 wherein Ri, R3 and R4 are each hydrogen; R2 is hydrogen, fluoro, chloro, bromo, cyano, acetyl, amino, nitro, carboxyl, CM 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, CM alkyl, C3-6 cycloalkyl, Cι-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together form -Zι=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- H-, -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, CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM 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 Rj, they together form -Zι=Z2-Z3=Z4- (wherein Z\ through Z 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, d- alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, - CH=NOH, -C=NOHCH3, -SO3H, -S02CH3, -SO2NH2, or when R7 are located at the ortho position to another R, they together form -Zι=Z2-Z3=Z - (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-; R8 tlirough R9 are each independently hydrogen, C alkyl, C3.6 cycloalkyl, d-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d.4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -CHO, -CH=NOH, -C=NOHCH3, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=Z2-
Figure imgf000137_0001
through Z4 each independently represents CH or N), -S-CO-O-, - CH=CH-NH-, -CBXΗ-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. 93. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 91. 94. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 91. 95. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 91 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 96. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 91 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 97. A pharmaceutical composition comprising the compound of claim 91 and a pharmaceutically acceptable carrier. 98. A pharmaceutical composition comprising the compound of claim 91, a β- lactam-antibiotic; and a pharmaceutically acceptable carrier. 99. A compound represented by formula A(XIII) :
Figure imgf000137_0002
wherein Ri through R12 are each independently hydrogen, d-6 alkyl, C3_6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, R13Ri4N- (wherein R13 and R14 are each independently hydrogen or d_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, -SO3H, -SO2CH3, - SO2NHRι5 (wherein Rι5 is hydrogen or d-3 alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or d-3 alkyl, and n is 1, 2 or 3); or when any two Rs 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-. 100. The compound of claim 99 wherein Ri, R3, R4, R9, Ru and Rι2 are each hydrogen; R2 and Rio are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Cμ4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, d_4 alkyl, C3.6 cycloalkyl, Cι-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, Cι-4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two R;s are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z4-
(wherein Zi through Z 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-. 101. A method of inhibiting |3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 99. 102. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 99. 103. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 99 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 104. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 99 and an effective amount of a β- lactam-antibiotic or other antibacterial agent. 105. A pharmaceutical composition comprising the compound of claim 99 and a pharmaceutically acceptable canier. 106. A pharmaceutical composition comprising the compound of claim 99, a β- lactam-antibiotic; and a phamiaceutically acceptable carrier. 107. A compound represented by formula A(XIV) :
Figure imgf000139_0001
wherein Ri through R9 are each independently hydrogen, Ci-6 alkyl, C3_6 cycloalkyl, Cι-3 alkoxy, zz-butoxy, i-butoxy, sec-butoxy, Rι3R14N- (wherein Rι3 and Rι4 each independently represents hydrogen or Cι- alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Ci-6 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl, -SO3H, -SO2CH3, - SO2NHRi5 (wherein Rι5 is hydrogen or Cι-3 alkyl), or -O(CH2)nORι6- (wherein Rι6 is hydrogen or d-3 alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zi=Z2-Z3=Z - (wherein Z\ through Z4 each independently represents CH orN), -S-CO-O-, -CH=CH-NH-, -CH=CH-S-, -CH=CH-O-, -N=€H-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-. 108. The compound of claim 107 wherein 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 -SO2 H2; R5 through R9 are each independently hydrogen, CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, d.4 alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two RjS are located at the ortho position to each other, they together fonn
Figure imgf000139_0002
(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-.
109. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 107. 110. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 107. 111. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 107 and an effective amount of /3-lactam-antibiotic. 112. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 107 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 113. A phannaceutical composition comprising the compound of claim 107 and a pharmaceutically acceptable canier. 114. A pharmaceutical composition comprising the compound of claim 107, a /3-lactam-antibiotic; and a pharmaceutically acceptable carrier. 115. A compound represented by formula A(XV) :
Figure imgf000140_0001
wherein i through Rι2 are each independently hydrogen. CM alkyl, C3-6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Ri3Rι4N- (wherein R13 and R14 are each independently hydrogen or C1-3 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, -SO3H, -SO2CH3, - SO2NHR15 (wherein R15 is hydrogen or C1.3 alkyl), or -O(CH2)nORi6- (wherein Rι6 is hydrogen or C1-3 alkyl, and n is 1, 2 or 3); or when any two RjS are located at the ortho position to each other, they together form -Zι=Z2-Z3=Z - (wherein Zi through Z each independently represents CH or N), -S-CO-O-, -CH=CH-NH-, -CE CH-S-, -CH=CH-O-,
-N=CH-NH-, -CH2-N=N-, -N=N-O-, -N=CH-S- or -O-CH2CH2-O-. 116. The compound of claim 115, wherein Ri, R3, R4, R9, Ru and Rι2 are each hydrogen; R2 and Rι0 are each independently hydrogen, fluoro, chloro, bromo, cyano, acetyl, nitro, amino, borono, carboxyl, Cι_4 alkoxycarbonyl, phenoxycarbonyl, hydroxyl, -SO3H, -SO2CH3 and -SO2NH2; R5 through R8 are each independently hydrogen, Cι_ alkyl, C3.6 cycloalkyl, Cι_3 alkoxy, trifluoromethyl, fluoro, chloro, bromo, cyano, acetyl, amino, borono, nitro, carboxyl, CM alkoxycarbonyl, phenyl, phenoxy, phenoxycarbonyl, benzyloxy, hydroxyl, hydroxymethyl, -SO3H, -SO2CH3, -SO2NH2, or when any two Rs are located at the ortho position to each other, they together form -Zι=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-. 117. A method of inl ibiting (8-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 115. 118. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 115. 119. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 115 and an effective amount of a j8-lactam-antibiotic or other antibacterial agent. 120. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 115 and an effective amount of a
/3-lactam-antibiotic or other antibacterial agent. 121. A pharmaceutical composition comprising the compound of claim 115 and a pharmaceutically acceptable carrier. 122. A pharmaceutical composition comprising the compound of claim 115, a (3-lactam-antibiotic; and a pharmaceutically acceptable carrier. 123. A compound represented by formula:
Figure imgf000142_0001
124. A method of inhibiting /3-lactamase comprising contacting the β- lactamase with an effective amount of the compound of claim 123. 125. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of the compound of claim 123. 126. A method of treating bacterial infection comprising administering a subject suffering from such an infection an effective amount of the compound of claim 123 and an effective amount of a (3-lactam-antibiotic or other antibacterial agent. 127. A method of overcoming bacterial resistances comprising administering a subject an effective amount of the compound of claim 123 and an effective amount of a /3-lactam-antibiotic or other antibacterial agent. 128. A pharmaceutical composition comprising the compound of claim 123 and a pharmaceutically acceptable carrier. 129. A pharmaceutical composition comprising the compound of claim 123, a /3-lactam-antibiotic; and a pharmaceutically acceptable carrier. 130. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of a compound represented by fomiula A(XVI):
Figure imgf000142_0002
wherein Ri through Rι2 are each independently hydrogen, Cι-6 alkyl, C3_6 cycloalkyl, Cι-3 alkoxy, zz-butoxy, z'-butoxy, sec-butoxy, Rι3Rι4N- (wherein Rι and Rι 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, -SO3H, -SO CH3, - SO2NHRi5 (wherein Rι5 is hydrogen or Cι-3 alkyl), or -O(CH2)nOR16- (wherein Rι6 is hydrogen or Cι_3 alkyl, and n is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=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-. 131. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of a compound represented by formula A(XVII):
Figure imgf000143_0001
wherein Ri through Ri2 are each independently hydrogen, Ci-6 alkyl, C .6 cycloalkyl, d_3 alkoxy, zz-butoxy, z-butoxy, sβc-butoxy, R13Rι4N- (wherein R13 and R14 are each independently hydrogen or Cι-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, -SO H, -SO2CH , - Sθ2NHRι5 (wherein Rι5 is hydrogen or Ci-3 alkyl), or -0(CH2)nOKi6- (wherein R16 is hydrogen or d-3 alkyl, and n is 1, 2 or 3); or when any two KjS are located at the ortho position to each other, they together form -Zι=:Z2-Z =Z - (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-. 132. A method of treating bacterial infection comprising administering to a subject suffering from such an infection an effective amount of a compound represented by formula A(XVIII):
Ap vπi)
Figure imgf000144_0001
wherein Ri through R20 are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-3 alkoxy, zz-butoxy, z-butoxy, sec-butoxy, Ri3Rι4N- (wherein Ri3 and Rι4 are each independently hydrogen or C1-3 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, -SO3H, -SO2CH3, - SO2NHRi5 (wherein R15 is hydrogen or d-3 alkyl), or -O(CH2)nORi6- (wherein Ri6 is hydrogen or d-3 alkyl, and 11 is 1, 2 or 3); or when any two Rs are located at the ortho position to each other, they together form -Zι=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-.
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