GYRASE INHIBITORS AND USES THEREOF

Abstract: Disclosed herein are compounds comprising the pharmacophore features HBA, HBD, Grpl, and at least two features selected from Grp2, Grp3 or Grp4 in which HBA is a hydrogen bond acceptor, HBD is a hydrogen bond donor, and Grps 1-4 are as described in the specification. The compounds are inhibitors of bacterial DNA gyrase and are useful in treating bacterial infections. The pharmacophore features may be used to identify and design new inhibitors.

Description: GYRASE INHIBITORS AND USES THEREOF This application claims the benefit of US Provisional Application serial number 60/176,675, filed January 18, 2000 and US Provisional Application serial number 60/176,671 filed January 18, 2000 and US Provisional Application serial number 60/254,331 filed December 8, 2000. Technical Field of the Invention This invention is in the field of medicinal chemistry and relates to novel compounds, and pharmaceutical compositions thereof, that inhibit DNA gyrases . The invention also relates to methods of using the compounds and pharmaceutical compositions of this invention to treat bacterial infections, including nosocomial infections, that are susceptible to gyrase inhibition. Background of the Invention Bacterial resistance to antibiotics has long been recognized, and it is today considered to be a serious worldwide health problem. As a result of resistance, some bacterial infections are either difficult to treat with antibiotics or even untreatable. This problem has become especially serious with the recent development of multiple drug resistance in certain strains of bacteria, such as Streptococcus pneumoniae (SP) , Mycobacterium tuberculosis, and Enterococcus . The appearance of vancomycin resistant enterococcus was particularly alarming because vancomycin was formerly the only effective antibiotic for treating this infection, and had been considered for many infections to be the drug of "last resort" . While many other drug-resistant bacteria do not cause life-threatening disease, such as enterococci, there is the fear that the genes which induce resistance might spread to more deadly organisms such as Staphylococcus aureus, where methicillin resistance is already prevalent (De Clerq, et al . , Current Opinion in Anti -infective Invest igational Drugs, 1999, 1, 1; Levy, "The Challenge of Antibiotic Resistance", Scientific American, March, 1998). Another concern is how quickly antibiotic resistance can spread. For example, until the 1960 's SP was universally sensitive to penicillin, and in 1987 only 0.02% of the SP strains in the U.S. were resistant. However, by 1995 it was reported that SP resistance to penicillin was about seven percent and as high as 30% in some parts of the U.S. (Lewis, FDA Consumer magazine (September, 1995) ; Gershman in The Medical Reporter, 1997) . Hospitals, in particular, serve as centers for the formation and transmission of drug-resistant organisms. Infections occurring in hospitals, known as nosocomial infections, are becoming an increasingly serious problem. Of the two million Americans infected in hospitals each year, more than half of these infections resist at least one antibiotic. The Center for Disease Control reported that in 1992, over 13,000 hospital patients died of bacterial infections that were resistant to antibiotic treatment (Lewis, "The Rise of Antibiotic-Resistant Infections", FDA Consumer magazine, Sept, 1995) . As a result of the need to combat drug- resistant bacteria and the increasing failure of the available drugs, there has been a resurgent interest in discovering new antibiotics. One attractive strategy for developing new antibiotics is to inhibit DNA gyrase, a bacterial enzyme necessary for DNA replication, and therefore, necessary for bacterial cell growth and division. Gyrase activity is also associated with events in DNA transcription, repair and recombination. Gyrase is one of the topoisomerases, a group of enzymes which catalyze the interconversion of topological isomers of DNA (see generally, Kornberg and Baker, DNA Replication, 2d Ed., Chapter 12, 1992, W.H. Freeman and Co.; Drlica, Molecular Microbiology, 1992, 6, 425; Drlica and Zhao, Microbiology and Molecular Biology Reviews, 1997, 61, 377). Gyrase itself controls DNA supercoiling and relieves topological stress that occurs when the DNA strands of a parental duplex are untwisted during the replication process. Gyrase also catalyzes the conversion of relaxed, closed circular duplex DNA to a negatively superhelical form which is more favorable for recombination. The mechanism of the supercoiling reaction involves the wrapping of gyrase around a region of the DNA, double strand breaking in that region, passing a second region of the DNA through the break, and rejoining the broken strands. Such a cleavage mechanism is characteristic of a type II topoisomerase . The supercoiling reaction is driven by the binding of ATP to gyrase. The ATP is then hydrolyzed during the reaction. This ATP binding and subsequent hydrolysis cause conformational changes in the DNA-bound gyrase that are necessary for its activity. It has also been found that the level of DNA supercoiling (or relaxation) is dependent on the ATP/ADP ratio. In the absence of ATP, gyrase is only capable of relaxing supercoiled DNA. Bacterial DNA gyrase is a 400 kilodalton protein tetramer consisting of two A (gyrA) and two B subunits (gyrB) . Binding and cleavage of the DNA is associated with gyrA, whereas ATP is bound and hydrolyzed by the gyrB protein. GyrB consists of an amino-terminal domain which has the ATPase activity, and a carboxy- terminal domain which interacts with gyrA and DNA. By contrast, eukaryotic type II topoisomerases are homodimers that can relax negative and positive supercoils, but cannot introduce negative supercoils. Ideally, an antibiotic based on the inhibition of bacterial DNA gyrase would be selective for this - enzyme and be relatively inactive against the eukaryotic type II topoisomerases . The widely-used quinolone antibiotics inhibit bacterial DNA gyrase. Examples of the quinolones include the early compounds such as nalidixic acid and oxolinic acid, as well as the later, more potent fluoroquinolones such as norfloxacin, ciprofloxacin, and gatifloxacin. These compounds bind to gyrA and stabilize the cleaved complex, thus inhibiting overall gyrase function, leading to cell death. However, drug resistance has also been recognized as a problem for this class of compounds (WHO Report, "Use of Quinolones in Food Animals and Potential Impact on Human Health", 1998) . With the quinolones, as with other classes of antibiotics, bacteria exposed to earlier compounds often quickly develop cross-resistance to more potent compounds in the same class. There are fewer known inhibitors that bind to gyrB. Examples include the coumarins, novobiocin and coumermycin Al, cyclothialidine, cinodine, and clerocidin. The coumarins have been shown to bind to gyrB very tightly. For example, novobiocin makes a network of hydrogen bonds with the protein and several hydrophobic contacts. While novobiocin and ATP do appear to bind within the ATP binding site, there is minimal overlap in the bound orientation of the twq compounds. The overlapping portions are the sugar unit of novobiocin and the ATP adenine (Maxwell, Trends in Microbiology, 1997, 5, 102) . For coumarin-resistant bacteria, the most prevalent point mutation is at a surface arginine residue that binds to the carbonyl of the coumarin ring (Argl36 in E. coli gyrB) . While enzymes with this mutation show lower supercoiling and ATPase activity, they are also less sensitive to inhibition by coumarin drugs (Maxwell, Mol . Microbiol . , 1993, 9, 681). Despite being potent inhibitors of gyrase supercoiling, the coumarins have not been widely used as antibiotics. They are generally not suitable due to their low permeability in bacteria, eukaryotic toxicity, and poor water solubility (Maxwell, Trends in Microbiology, 1997, 5, 102). It would be desirable to have a new, effective gyrB inhibitor that overcomes these drawbacks. Such an inhibitor would be an attractive antibiotic candidate, without a history of resistance problems that plague other classes of antibiotics. As bacterial resistance to antibiotics has become an important public health problem, there is a continuing need to develop newer and more potent antibiotics. More particularly, there is a need for antibiotics that represent a new class of compounds not previously used to treat bacterial infection. Such compounds would be particularly useful in treating nosocomial infections in hospitals where the formation and transmission of resistant bacteria are becoming increasingly prevalent. DESCRIPTION OF THE INVENTION It has now been found that compounds possessing certain pharmacophore features as described below are inhibitors of bacterial DNA gyrase and are therefore useful as antibiotics. • These compounds, when complexed with bacterial DNA gyrase, are comprised of the following features: (a) HBA, (b) HBD, (c) Grpl and/or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 : wherein HBA is a hydrogen bond acceptor; HBD is a hydrogen bond donor; Grpl is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40-160 (A) 2 ; Grpla is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (A) 2 and a buried polar surface area in the range of about 0-110 (A) 2 ; Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0-150 (A) 2 ; Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25-140 (A) 2 ; Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0-100 (A) 2 , provided that Grp4 is other than a coumarin ring; and the distances in angstroms between the features are in the following ranges: The applicants have identified these pharmacophore features by studying crystallographic complexes of compounds in the ATP binding site of bacterial DNA gyrase subunit B. In particular, Grpl and Grpla are novel features of the present compounds . These features provide additional binding interactions within the ATP binding site of the gyrase. Relative to previously known, non-natural product, gyrase inhibitors (see H.J. Boehm et al . , J " . Med. Chem. 43(14), 2664-2674, (2000) ) , new and improved gyrase inhibitors can now be provided that possess Grpl and/or Grpla, in addition to the other pharmacophore features described herein. The term "buried surface area" is the surface area of the inhibitor compound that is lost upon binding to the gyrase B subunit. The term "polar surface area" is that portion of the buried surface area corresponding to all of the present nitrogen and oxygen atoms . The term "non-polar surface area" is that portion of the buried surface area corresponding to all other atoms. The calculation of these surface areas is known in the computational chemistry literature. See F. Eisenhaber, P. Lijnzaad, P. Argos, and M. Scharf, "The Double Cubic Lattice Method: Efficient Approaches to Numerical Integration of Surface Area and Volume and to Dot Surface Contouring of Molecular Assemblies", J. Computational Chemistry, 16(3), 273-284, (1995) and F. Eisenhaber and P. Argos, "Improved Strategy in Analytical Surface Calculation for Molecular Systems: Handling of Singularities and Computational Efficiency" , J. Computational Chemistry, 14(11), 1272-1280, (1993). The term "substitute" refers to the replacement of a hydrogen atom in a compound with a substituent group. The term "substitute" does not include those hydrogen atoms which form a part of a hydrogen bonding moiety which is capable of. forming a hydrogen bond with a suitable hydrogen bond acceptor, such as a carbonyl oxygen, of an amino acid residue in the gyrase binding site. The term "strain energy" is used in this application to refer to the difference between the conformational energy of the unbound (or free) compound and that of the compound when bound to gyrase . The strain energy can be determined by the following steps: Evaluate the energy of the molecule when it has the conformation necessary for binding to gyrase . Then minimize and reevaluate the energy -- this is the strain energy. A more comprehensive definition of strain energy can be found in Bostrom, J. , Norrby, P.-O.; Liljefors, T., "Conformational Energy Penalties of Protein-Bound Ligands", J " . Comput. Aided Mol . Design, 1998, 383. The strain energy for binding of a potential inhibitor to gyrase is the difference between the free conformation energy and the bound conformation energy. In a preferred embodiment, the strain energy of an inhibitor of the present invention is less than about 10 kcal/mol. The term "hydrophobic" refers to a moiety which tends not to dissolve in water and is fat-soluble. Hydrophobic moieties include, but are not limited to, hydrocarbons, such as alkanes, alkenes, alkynes, cycloalkanes, cycloalkenes, cycloalkynes and aromatic compounds, such as aryls, certain saturated and unsaturated heterocycles and moieties that are substantially similar to the side chains of hydrophobic natural and unnatural -amino acids, including valine, leucine, isoleucine, methionine, phenylanine, α-amino isobutyric acid, alloisoleucine, tyrosine, and tryptophan. The term "hydrogen bond" refers to a favorable interaction that occurs whenever a suitable donor atom, X, bearing a proton, H, and a suitable acceptor atom, Y, have a separation of between 2.5A and 3.5A and where the angle X-H - - - Y is greater than 90 degrees. Suitable donor and acceptor atoms are well understood in medicinal chemistry (G.C. Pimentel and A.L. McClellan, The Hydrogen Bond, Freeman, San Francisco, I960; R. Taylor and 0. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984)). The compounds of this invention were designed to bind to bacterial DNA gyrase subunit B at the ATP binding site of the enzyme. The structure of this binding site has been described, and is known to be fairly well conserved across different strains of bacteria (Lewis, R.J. et al . , EMBO J. , 15, 1412 (1996); Holdgate, G.A. et al . , Biochemistry, 36, 9663 (1997); Brino, L. et al . , J. Biol . Chem. , 275, 9468 (2000); Tsai, F.T. et al., Proteins, 28(1), 41. (1997); Wigley, D.B. et al., Nature, 351, 624 (1991)). The structure of bacterial DNA grase subunit B is available from The Protein Data Bank (PDB™) . This is an international repository for three dimensional structures that can be located at www.rcsb.org/pdb/. Using the ATP binding site of the DNA gyrase of Staphylococcus aureus and E. coli , applicants have now found that effective gyrase inhibitors may be designed that orient in the binding site in a manner different than that of the aforementioned prior art inhibitors . • The practitioner skilled in the art will appreciate that there are a number of means to design the inhibitors of the present invention. These same means may be used to select a candidate compound for screening as a gyrase inhibitor. This design or selection may begin with selection of the various moieties which fill binding pockets . There are a number of ways to select moieties to fill individual binding pockets. These include visual inspection of a physical model or computer model of the active site and manual docking of models of selected moieties into various binding pockets. Modeling software that is well known and available in the art may be used. These include QUANTA [Molecular Simulations, Inc., San Diego, CA, 1992] , SYBYL [Molecular Modeling Software, Tripos Associates, Inc., St. Louis, MO, 1992]. This modeling step may be followed by energy minimization with standard molecular mechanics forcefields such as CHARMM and AMBER. [AMBER: (S. J. Weiner, P. A. Kollman, D. A. Case, U. C. Singh, C. Ghio, G. Alagona, and P. Weiner, J " . Am. Chem. Soc , 1984, 106, 765); CHARMM: (B. R. Brooks, R. E. Bruccoleri, B. D. Olafson, D. J. States, S Swaminathan, and M. Karplus, J. Comp . Chem. 1983, 4, 187) . In addition, there are a number of more specialized computer programs to assist in the process of optimally placing either complete molecules or molecular fragments into the protein binding site. These include: 1. GRID (Goodford, P. J. A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules. J. Med. Chem. 1985, 28, 849-857) . GRID is available from Oxford University, Oxford, UK. 2. MCSS (Miranker, A.; Karplus, M. Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method. Proteins: Structure, Function and Genetics 1991, 11, 29-34) . MCSS is available from Molecular Simulations, Inc., San Diego, CA. 3. DOCK (Kuntz, I. D.; Blaney, J. M. ; Oatley, S. J. ; Langridge, R. ; Ferrin, T. E. A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol. Biol. 1982, 161, 269-288) . DOCK is available from the University of California, San Francisco, CA. Once suitable binding orientations have been selected, complete molecules can be chosen for biological evaluation. In the case of molecular fragments, they can be assembled into a single inhibitor. This assembly may be accomplished by connecting the various moieties to a central scaffold. The assembly process may, for example, be done by visual inspection followed by manual model building, again using software such as Quanta or Sybyl. A number of other programs may also be used to help select ways to connect the various moieties. These include: 1. CAVEAT (Bartlett, P. A.; Shea, G. T.; Telfer, S. J. ; Waterman, S. CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules. In "Molecular Recognition in Chemical and Biological Problems," Special Pub., Royal Chem. Soc. 1989, 78, 182-196) . CAVEAT is available from the University of California, Berkeley, CA and Molecular Simulations, Inc., San Diego, CA. 2. 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif.). This area has been recently reviewed by Martin (Martin, Y.C. 3D Database Searching in Drug Design. J. Med. Chem. 1992, 35, 2145). 3. HOOK (available from Molecular Simulations, Inc., San Diego, CA.) In addition to the above computer assisted modeling of inhibitor compounds, the inhibitors of this invention may be constructed "de novo" using either an empty active site or optionally including some portions of a known inhibitor. Such methods are well known in the art. They include, for example: 1. LUDI (Bohm, H. J. The Computer Program LUDI : A New Method for the De Novo Design of Enzyme Inhibitors. J. Comp. Aid. Molec. Design. 1992, 6, 61-78) . LUDI is available from Molecular Simulations, San Diego, CA. 2. LEGEND (Nishibata, Y., Itai, A., Tetrahedron, 1991, 47, 8985) . 3. LeapFrog (available from Tripos Associates, St. Louis, MO.) A number of techniques commonly used for modeling drugs may be employed (For a review, see: Charifson, P.S., editor, Practical Application of Computer-Aided Drug Design, Marcel Dekker, Inc., 1997; Cohen, N. C; Blaney, J. M. ; Humblet, C. ; Gund, P.; Barry, D. C, "Molecular Modeling Software and Methods for Medicinal Chemistry", J. Med. Chem. , 1990, 33, 883). There are likewise a number of examples in the chemical literature of techniques that can be applied to specific drug design projects. For a review, see: Navia, M. A. and Murcko, M. A. , Current Opinions in Structural Biology, 1992, 2, 202. Some examples of these specific applications include: Baldwin, J. J. et al . , J. Med. Chem. , 1989, 32, 2510; Appelt, K. et al . , J. Med . Chem . , 1991, 34, 1925; and Ealick, S. E. et al . , Proc. Nat . Acad. Sci . USA, 1991, 88, 11540. Using the novel combination of steps of the present invention, the skilled artisan can advantageously reduce time consuming and expensive experimentation to determine enzymatic inhibition activity of particular compounds. The method also is useful to facilitate rational design of gyrase inhibitors and therapeutic and prophylactic agents against bacterial infections. Accordingly, the present invention relates to such inhibitors . A variety of conventional techniques may be used to carry out each of the above evaluations as well as the evaluations necessary in screening a candidate compound for gyrase inhibiting activity. Generally, these techniques involve determining the location and binding proximity of a given moiety, the occupied space of a bound inhibitor, the amount of complementary contact surface between the inhibitor and protein, the deformation energy of binding of a given compound and some estimate of hydrogen bonding strength and/or electrostatic interaction energies. Examples of conventional techniques useful in the above evaluations include: quantum mechanics, molecular mechanics, molecular dynamics, Monte Carlo sampling, systematic searches and distance geometry methods [G. R. Marshall, Ann. Rev. Pharmacol . Toxicol . , 1987, 27, 193]. Specific computer software has been developed for use in carrying out these methods. Examples of programs designed for such uses include: Gaussian 92, revision E.2 [M. J. Frisch, Gaussian, Inc., Pittsburgh, PA. ©1993]; AMBER, version 4.0 [P. A. Kollman, University of California at San Francisco, ©1993] ; QUANTA/CHARMM [Molecular Simulations, Inc., San Diego, CA. ©1992]; and Insight II/Discover . [Molecular Simulations, Inc., San Diego, CA. ©1992]. These programs may be implemented, for instance, using a Silicon Graphics workstation or personal computer network. Other hardware systems and software packages will be known and of evident applicability to those skilled in the art. Different classes of active gyrase inhibitors, according to this invention, may interact in similar ways with the various binding regions of the gyrase active site. The spatial arrangement of these important groups is often referred to as a pharmacophore. The concept of the pharmacophore has been well described in the literature [D. Mayer, C. B. Naylor, I. Motoc, and G. R. Marshall, J " . Comp . Aided Molec. Design, 1987, 1, 3; A. Hopfinger and B. J. Burke, in Concepts and Applications of Molecular Similarity, 1990, M. A. Johnson and G. M. Maggiora, Ed. , Wiley] . Different classes of gyrase inhibitors of this invention may also use different scaffolds or core structures, but all of these cores will allow the necessary moieties to be placed in the active site such that the specific interactions necessary for binding may be obtained. These compounds are best defined in terms of their ability to match the pharmacophore, i.e., their structural identity relative to the shape and properties of the active site of bacterial DNA gyrase. Distances to or from any given group are calculated from the center of mass of that group. The term "center of mass" refers to a point in three- dimensional space which represents a weighted average position of the masses that make up an object. Distances between groups may be readily determined using any modeling software and other suitable chemical structure software. In addition, specialized, commercially- available pharmacophore modeling software enables one to determine pharmacophore models from a variety of structural information and data. The software may also be used to search a database of three-dimensional structures in order to identify compounds that meet specific pharmacophore requirements. Examples of this software include: 1. DISCO (Martin, Y.C., Bures, M.G., Danaher, E.A., DeLazzer, J. , Lico, A., Pavlik, P.A. , J " . Comput . Aided Mol . Design, 1993, 7, 83). DISCO is available from Tripos Associates, St. Louis, MO. 2. CHEM-X which is developed and distributed by Chemical Design Ltd, Oxon, UK and Mahwah, NJ. 3. APEX-3D which is part of the Insight molecular modeling program, distributed by Molecular Simulations, Inc., San Diego, CA. 4. CATALYST (Sprague, P.W. , Perspectives in Drug Discovery and Design, 1995, 3, 1; Mϋller, K. , Ed., ESCOM, Leiden) CATALYST is distributed by Molecular Simulations, Inc., San Diego, CA. 5. UNITY which is available from Tripos Associates, St. Louis, MO. A typical hydrogen bond acceptor (HBA) is an oxygen or nitrogen, especially an oxygen or nitrogen that is sp 2 -hybridized or an ether oxygen. A typical hydrogen bond donor (HBD) is an oxygen or nitrogen that bears a hydrogen. Examples of substructures or moieties containing a hydrogen bond acceptor and hydrogen bond donor that are separated by up to 4.0 A include, but are not limited to, those substructures listed in Table 1. The dotted lines indicate that either a single or double bond may be present . Table 1. HBA/HBD Moieties (X = 0,S or NH; Y = N or CH) b d m n P q t u v w aa ab ac ad ae af ag ah ai a: ak al am an ao When bound to a bacterial DNA gyrase subunit B, compounds of this invention bind to the ATP binding site of the enzyme. During such binding, the pharmacophore features of the compounds will occupy certain regions or pockets of the ATP binding site. In the gyrB subunit of Staphylococcus aureus , Grpl will occupy a region of the ATP binding site bounded by the following amino acids (with the corresponding E. coli amino acids shown in parenthesis): Ile51 (Val43), Asn5 ' 4 (Asn46) , Ser55 (Ala47) , Vall74 (Metl66) , Ilel75 (Vall67) , Val79 (Val71) , Asp81 (Asp73), Thrl73 (Thr 165 ) and Thr80 (Gln72) . For amino acid numbering, see Brockbank, S.M.V. et al . , J " . Bacteriol . , 1993, . 175, 3269). In this relatively small region, the interaction of Grpl with its surrounding environment is primarily of a hydrophobic nature. Therefore, Groupl (Grpl) is typically a small, relatively hydrophobic group containing up to about six carbons. The binding interaction may be enhanced using a Grpl moiety that is able to form a direct hydrogen bond with one or more of the following: the backbone carbonyl oxygen of Ile51, the sidechain oxygen or nitrogen of Asn54, the backbone carbonyl oxygen of Val79, a sidechain carboxyl oxygen of Asp81, the backbone carbonyl oxygen of Thrl73, or the backbone amide nitrogen of Ilel75. Grpl is separated from HBA by a distance between about 2.9 to about 6.4 A and is separated from HBD by a distance between about 1.8 to about 5.0 A; however, Grpl is closer in distance to HBD than it is to HBA.- • Examples of suitable Grpl moieties include -CH(R 4 ) 2 , -C0 2 (Cι -6 aliphatic) , -C0N(R) 2 , -CONH-OR, -S0 2 R, and -S0 2 N(R) 2/ where each R is independently selected from hydrogen or a Cι -6 aliphatic group, and each R 4 is independently selected from hydrogen, an optionally substituted Cι -6 aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring. Grpla, when present, will occupy a region of the ATP binding site bounded by the following S . aureus amino acids (corresponding E. coli amino acids) : Ile51 (Val43) , Asn54 (Asn46) , Leul03 (Met95) , Serl29 (Vall20) , Vall31 (Vall23), Leul38 (Leul30) , Vall40 (Leul32) , Ilel75 (Vall67) , and Phel77 (Phel69) . The binding interaction may be enhanced using a Grpla moiety that is able to form a direct hydrogen bond with the side chain oxygen or nitrogen of Asn54 (Asn46) . Examples of suitable Grpla moieties include a Cι- 6 aliphatic group, -CH 2 (CH 2 ) n NRC0R, -CH 2 (CH 2 ) n NRC0 2 (C 1 -s aliphatic), -CH 2 (CH 2 ) n C0N (R) 2 , -CH 2 (CH 2 ) n S0 2 N(R) 2 , -CH 2 (CH 2 ) n NRS0 2 (C 1 - 6 aliphatic) , -CH=N- OR, -CH=N-OC(=0) (Cι. 6 aliphatic) , -CH=NNRC0 2 (C 1-6 aliphatic), -CH=NNRCOR, and -CH=NN(R) 2 , where n is zero or one. The pharmacophore features of the present compounds are not limited to distinct chemical moieties within the same compound. A chemical moiety may serve as parts of two pharmacophore features. As an illustration, when Grpl and Grpla are both present, the two groups may share the first carbon as a common branch point. One skilled in the art, by reference to the above preferred Grpl and Grpla moieties, would recognize the following hybrid moieties as containing features of both groups : -C(R 4 ) 2 (CH 2 ) n NRCOR, -C (R 4 ) 2 (CH 2 ) n NRC0 2 (C 1-6 aliphatic), -C(R 4 ) 2 (CH 2 ) n CON(R) 2 , -C (R 4 ) _ (CH 2 ) n S0 2 N (R) _ , -C(R ) 2 (CH 2 ) n NRS0 2 (C 1-6 aliphatic), -C(R 4 )=N-0R, -C(R 4 )=N-OC(=0) (Cι- 6 aliphatic), -C (R 4 ) =NNRC0 2 (C 1-6 aliphatic), -C (R 4 ) =NNRCOR, and -C (R 4 ) =NN (R) 2 , where n is zero or one and R 4 is as defined above. Grp2 , when present, will occupy a region of the ATP binding site bounded by the following amino acids in S. aureus gyrase (E. coli gyrase) : Asp57 (Asp49) , Glyl09 (GlylOl) , GlyllO (Glyl02) Asn54 (Asn46) , Ilel02 (Ile94) , Leul03 (Met95) and Serl29 (Vall20) . The interaction of Grp2 with this surrounding environment will be primarily hydrophobic in nature; however, the interaction may be enhanced using a Grp2 moiety that is able to form a direct hydrogen bond with the sidechain oxygen or nitrogen of Asn54. Grp2 is substantially equidistant to HBA and HBD (the distances being within about 0.5A of each other) . Examples of suitable Grp2 moieties include hydrogen, -C 1-4 aliphatic, -CONHR, -CN, -halo, -C0 2 R, -S0 2 R, -COR, -CON(R) 2 , -S0 2 N(R) 2 , -NRS0 2 R, -NRS0 2 N(R) 2 , -Q, -COQ, -S0 2 Q, -CONHQ, -S0 2 NRQ, -NRS0 2 Q, and -NRS0 2 NRQ, where .R is a C 1-3 aliphatic group and Q is a three to five-membered heterocyclyl or a five- or six-membered heteroaryl ring. Grp3, when present, ' will occupy a region of the ATP binding site bounded by the following S. aureus gyrase amino acids (E. coli amino acids) : Asn54 (Asn46) , Glu58 (Glu50) , Arg84 (Arg76) , Gly85 (Gly77) , Ile86 (Ile78), Ilel02 (Ile94) , Alal08 (AlalOO) , Glyl09 (GlylOl) , GlyllO (Glyl02), Lyslll (Lysl03) , Phell2 (Phel04) , and Hisl24 (Hisllδ) . The interaction of Grp3 with this surrounding environment will be primarily hydrophobic in nature; however, the interaction may be enhanced using a Grp3 moiety that is able to form a direct hydrogen bond with one or more of the following: the sidechain oxygen or nitrogen of Asn54, a sidechain carboxyl oxygen of Glu58, a sidechain nitrogen of Arg84, the backbone carbonyl oxygen of Gly85. Examples of suitable Grp3 moieties include R, -SR, -S0 2 R, -S0 2 NHR, -CONHR, -CONR 2 , -COR, -NHS0 2 R, -NHR, -halo, aryl, heteroaryl or heterocyclyl, where each R is a hydrogen or a Cι- 6 aliphatic group optionally substituted by one or more halogens, =0 or Cι_ 6 alkyl. A preferred Grp3 is Ring A : where X and Y are heteroatoms, Z is C-R 3 or N-R 3 ; R 3 is - (CH 2 ) P N(R 5 ) 2 or an optionally substituted group selected from Cι- 8 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; p is an integer from zero to four when Z is C-R 3 or an integer from one to four when Z is N-R 3 ; and each R 5 is independently selected from hydrogen, an optionally subtituted Cι- 4 aliphatic group, or two R 5 taken al¬ together with the nitrogen to which they are attached form a five or six membered heterocyciic ring. The bond extending from Y in Ring A is in the direction of Grp4. Examples of suitable Ring A moieties include a thiazole, oxazole, i idazole and pyrazole. Grp4, when present, will occupy a region of the ATP binding site bounded by the following gyrase amino acids of S . aureus (E. coli) : Arg84 (Arg76) , Gly85 (Gly77) , Pro87 (Pro79) , Lyslll (Lysl03), Phell2 (Phel04) , Glyll3 (Aspl05) , Glyll4 (Aspl06) , and Argl44 (Argl36) . The interaction of Grp4 with this surrounding environment can be either hydrophobic or polar in nature. Grp4 may optionally contain or be an acidic group such as a carboxylic acid, sulfate, sulfonic acid, phosphate or phosphonic acid.. Grp4 may also optionally form π-π stacking interactions with Arg84 or Argl44 or may form hydrogen bonds to these same amino acids. Interaction of Grp4 with Pro87 would be primarily of a hydrophobic nature. Interaction of Grp4 with its surrounding environment may be further enhanced by using a Grp4 moiety that is able to form a hydrogen bond with the backbone carbonyl oxygen of Gly85. Examples of suitable Grp4 moieties include -R, -SR, -S0 2 R, -S0 2 NHR, -CN, -CONHR, -C0NR 2 , -COR, -NHS0 2 R, -NHR, -halo, and Ar; where R is a hydrogen or a Cι- 6 aliphatic group optionally substituted by one or more halogens, =0 or Cχ_ 6 alkyl; and Ar is an optionally substituted aryl, heteroaryl, or heterocyclyl ring. Preferred Ar groups include phenyl, pyridyl and pyri idinyl rings. With reference to a moiety containing HBA and HBD, Groups 1-4 may be attached to such a moiety by a suitable attachment means such as a valence bond, a suitable linker group or by a ring fusion. Suitable linker groups include an alkylidene chain, an aliphatic or aryl ring, -S-, -0-, -C0NH-, -S0 2 NH-, -NHC0-, -CO-, -NH-, or -NHS0 2 -, or a combination thereof. Selected examples of substructures where Grpl (and/or Grpla) , HBA and HBD are all contained within the substructure and Grpl is attached to the HBA/HBD moiety by a valence bond are shown in Table 2 below. Table 2. Examples of Substructures of HBA, HBD and Grpl Shown immediately below is one possible arrangement of the pharmacophore features where the HBA/HBD-containing moiety is a pyrazole ring: PYR-A. The compounds of this invention will usually have a molecular weight of less than about 1000 Daltons, preferably less than about 700 Daltons, and more preferably between about 300 and 600 Daltons. The present compounds form favorable binding interactions within the ATP binding site of the bacterial DNA gyrB subunit. Accordingly, one embodiment of the present invention relates to an enzyme-inhibitor complex comprising a bacterial DNA gyrase and a bacterial DNA gyrase inhibitor wherein the inhibitor is comprised of the following features: (a) HBA, (b) HBD, (c) Grpl and/or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 , and the distances between the features is as described above. A general process for designing a gyrase inhibitor that embodies the present invention comprises the following steps. First, one selects a moiety that contains HBA and HBD separated by up to 4.0 A. Ideally, the moiety is chosen such that HBD would be capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Asp81 and/or HBA would be in the vicinity of the sidechain oxygen of Thrl73 and is capable of forming a water-bridged hydrogen bond with one of the side chain carboxyl oxygens of Asp81. Examples of such moieties are listed in Table 1. Second, one selects a Grpl and/or Grpla moiety and a means of attachment to the HBA/HBD moiety. It is desirable to confirm that Grpl and/or Grpla so attached is within the requisite distance to HBA and HBD, and is capable of forming satisfactory interactions with its gyrase binding site environment as described above. Confirming that the satisfactory interactions would be achievable is within the knowledge of one skilled in the art using computational methods such as those described above. In a like manner, one may build the rest of the inhibitor by selecting from at least two groups of Grps 2-4 and corresponding means of attachment to provide the desired distances between groups and satisfactory interactions. The following process may be used to identify gyrase inhibitors of this invention. (1) One or more molecular structures are..provided individually or as members of any suitable commercial or proprietary structure-searchable database of chemical compounds. A 2-D substructure searching program (such as Daylight®, CIS, Santa Fe, NM) is applied to select one or more structures containing HBA/HBD pairs wherein there is one to four bonds separating HBA and HBD (which will typically allow HBA and HBD to be separated by up to 4.0 A when converted below to a three-dimensional structure) . (2) The molecular structures selected from step (1) are then converted to their respective three-dimensional ■ structures (for example, by using CORINA software available from Molecular Networks, GmbH, Germany) . Using a standard docking method (such as the previously referenced DOCK method) , the selected molecules may be placed into the active site of gyrB such that the HBA/HBD moiety is constrained to make the appropriate hydrogen bond interactions. Under this constraint HBD is capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Asp81 and/or HBA is capable of forming a water-bridged hydrogen bond with Asp81 and is in the vicinity of the sidechain oxygen of Thrl73. (3) The remainder of the constrained molecular structure is then analyzed to determine if it contains a suitably placed moiety or moieties corresponding to Grpl and/or Grpla. The docking method allows one to confirm whether the group (s) fit appropriately into the region of the ATP binding site defined above for Grpl and/or Grpla. (4) After selecting a molecular structure from step (3) (that is constrained with respect to the HBA/HBD, Grpl and/or Grpla interactions) , the remainder of the structure is then analyzed to determine whether at least two of the Grp2 , Grp3 and Grp4 features are present . The docking method allows one to confirm whether these group (s) fit appropriately into the respective regions of the ATP binding site defined above. The distances and the polar/non-polar surface areas are checked to determine whether they are within the specified ranges. It would be apparent to one skilled in the art that the above steps do not need to be performed in the above order. In a related manner, one may use molecular fragments to design new bacterial DNA gyrase inhibitors. For Grpl to Grp4 , molecular fragments are selected that have the appropriate buried polar and non-polar surface areas described above. The following steps describe this process. (1) HBA/HBD moieties are provided as molecular fragments. Table 1 lists a number of suitable fragments. Alternatively, these may be identified by searching a database of compounds as described in the first step of the previous process and selecting all molecules containing HBA/HBD pairs where there is one to four bonds separating HBA and HBD. (2) This step is similar to the second step of the previous method, except that the HBA/HBD moiety is docked as a molecular fragment rather than as a whole compound. The HBA/HBD moiety is constrained to make the appropriate hydrogen bond interactions in the gyrB ATP site. (3) Molecular fragments possessing suitably placed Grpl and/or Grpla features are selected. Molecular fragments each possessing at least one of the Grp2, Grp3 or Grp4 features are also selected such that at least two of these features are represented among the fragments. These molecular fragments may be obtained by reference to the generic and specific examples provided in this application or by searching other structures that have the required intergroup distances and buried polar and non-polar surf ce areas . (4) The molecular fragments are connected to form a compound comprising the following features: (a) HBA, (b) HBD, (c) Grpl and/or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4. For this purpose one may use connection programs such as the aforementioned HOOK or CAVEAT as well as a database of linker groups, such as the linker groups described above. Bacterial DNA gyrase inhibitors may also be obtained by modifying compound structures to include the pharmacophore features described above. Accordingly, one embodiment of this invention relates to a method of designing a bacterial DNA gyrase inhibitor comprising the steps of: (a) providing a first structure that comprises HBA, HBD, and zero to four features selected from Grpl, Grpla, Grp2, Grp3, or Grp4 , and (b) modifying the first structure to provide a gyrase inhibitor comprising the features present in the first structure and at least one additional feature not present in the first structure and selected from Grpl, Grpla, Grp2 , Grp3 , or Grp4 ; wherein the gyrase inhibitor comprises the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 ; wherein: HBA is a hydrogen bond acceptor and HBD is a hydrogen bond donor; Grpl is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40- 160 (A) 2 ; Grpla is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 35-260 (A) 2 and a buried polar surface area in the range of about 0- 110 (A) 2 ; Grp2 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0-150 (A) 2 ; Grp3 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25-140 (A) 2 ; Grp4 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0-100 (A) 2 , provided that Grp4 is other than a coumarin ring; and the distances in angstroms between the features are in the following ranges: Below are examples of the use of the pharmacophore features and methods described herein to provide new bacterial DNA gyrase inhibitors . From the weakly active lead structure below, lacking Grpl and Grpla in particular, the applicants designed novel gyrase inhibitors having the general formula I: wherein: R 1 is an optionally substituted group selected from a Cι- 6 aliphatic group, -C (R 4 ) 2 (CH 2 ) n NRC0R, -C(R 4 )=N-0R, -C(R 4 )=N-0C(=0) (Cι_ 6 aliphatic) , -C (R 4 ) =NNRC0 2 ( L - S aliphatic) , -C (R 4 ) =NNRC0R, -C (R 4 ) =NN(R) 2 , -C(R 4 ) 2 (CH 2 ) n NRC0 2 (Cι- 6 aliphatic) , -C0 2 (C 1-6 aliphatic) , -C0N(R) 2 , -C(R 4 ) 2 (CH 2 ) n C0N(R) 2 , -C (R 4 ) _ (CH 2 ) n S0 2 N (R) 2 , -CONH-OR, -S0 2 N(R) 2 , or -C (R 4 ) 2 (CH 2 ) n NRS0 2 (C 1-6 aliphatic) ; n is zero or one; each R is independently selected from- hydrogen or an optionally substituted Cι- 6 aliphatic group; R 2 is selected from hydrogen or, when R 1 is -C0 2 (Cι_ 3 aliphatic) or -CONH(Cι -3 aliphatic), R 2 is further selected from -halo, -CN, -Cι_ 4 aliphatic, a three to five-membered heterocyclyl, or a five-membered heteroaryl ; Ring A is a heteroaryl ring selected from thiazole, oxazole, imidazole or pyrazole, wherein said imidazole is optionally attached by a Cι_ 3 bridge from an imidazole ring nitrogen to Ar to form a five- to seven- membered fused ring; Z is C-R 3 or N-R 3 ; R 3 is - (CH 2 ) P N(R 5 ) _ or an optionally substituted group selected from C 1-8 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; each R 4 is indepependently selected from hydrogen, an optionally subtituted Cι_ 6 aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring; each R 5 is independently selected from hydrogen, an optionally subtituted Cι_ 4 aliphatic group, or two R 5 taken together with the nitrogen to which they are attached form a five or six membered heterocyciic ring; p is an integer from zero to four when Z is C-R 3 or an integer from one to four when Z is N-R 3 ; and Ar is an optionally substituted aryl, heteroaryl, or heterocyclyl ring. Compounds of formula I illustrate selected examples of compounds that were designed to contain the pharmacophore features of the present invention. The pyrazole ring of formula I is a moiety that contains both HBA and HBD. R 1 is attached to the HBA/HBD moiety by a valence bond and satisfies the Grpl and/or Grpla requirements; R 2 satisfies the Grp2 requirements; Ring A including R 3 satisfies the Grp3 requirements; and Ar is a Grp4 moiety. Such compounds are useful in methods of treating bacterial infections. As used herein, the following definitions shall apply unless otherwise indicated. The term "aliphatic" as used herein means straight chained, branched or cyclic C1-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl . The term "alkyl" and "alkoxy" used alone or as part of a larger moiety refers to both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, CI , Br, or I. The term "heteroatom" means N, O or S . The nitrogen-containing compounds of this invention also include the corresponding N-oxides of the compounds as well as those having a quarternized form of any basic nitrogen. Rings having one to four heteroatoms .selected from N, 0, or S include heterocyciic aromatic (or heteroaryl) rings and non-aromatic heterocyciic rings. Examples of aromatic heterocyciic rings include 2- furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2- thienyl, or 3-thienyl. Examples of non-aromatic heterocyciic rings include 2-tetrahydrofuranyl, 3- tetrahydrofuranyl , 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl , 2 -morpholino, 3 -morpholino, 4- morpholino, 2-thiomorpholino, 3-thiomorpholino, 4- thiomorpholino, 1-pyrrolidinyl, 2 -pyrrolidinyl, 3- pyrrolidinyl, 1-piperazinyl, 2 -piperazinyl, 1- piperidinyl, 2 -piperidinyl, 3 -piperidinyl, 4 -piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1- phthalimidinyl, benzoxane, benzotriazol-1-yl , benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolane , tetrahydroisoquinoline , decahydroisoquinoline, and benzothiane. An aryl group (carbocyclic and heterocyciic) or an aralkyl group, such as benzyl or phenethyl, may contain one or more substituents. Examples of suitable substituents on an unsaturated carbon atom of an aryl group include halogen, -R, -OR, -OH, -SH, -SR, protected OH (such as acyloxy) , phenyl (Ph) , substituted Ph, -OPh, substituted -OPh, substituted or unsubstituted five to six membered ring having one to four heteroatoms, -N0 2 , -CN, -NH 2 , -NHR, -N(R) 2 , -NHCOR, -NHCONHR, -NHC0N(R) 2 , -NRCOR, -NHC0 2 R, -C0 2 R, -C0 2 H, -COR, -CONHR, -C0N(R) 2 , -S(0) 2 R, -SONH 2 , -S(0)R, -S0 2 NHR, or -NHS(0) 2 R, where, R is an aliphatic group or a substituted aliphatic group . An aliphatic group or a non-aromatic heterocyciic ring may contain one or more substituents. Examples of suitable substituents on a saturated carbon of an aliphatic group or of a non-aromatic heterocyciic ring include those listed above for the unsaturated carbon as well as the following: =0, =S, =NNHR, =NNR 2 , =N-0R, =NNHC0R, =NNHC0 2 R, =NNHS0 2 R, or =NR. An alkylidene chain is a hydrocarbon chain that may be saturated or unsaturated such as -(CH 2 ) n - / ~ (CH=CH) m (CH 2 ) n - , or - (C≡C) m (CH 2 ) n - , where m and n are integers from zero to six. An alkylidene chain may be substituted in the same manner as an aliphatic group. A substitutable nitrogen on an aromatic or non- aromatic heterocyciic ring may be optionally substituted. Suitable substituents on the nitrogen include R, COR, S(0) 2 R, and C0 2 R, where R is an aliphatic group or a substituted aliphatic group. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such forms of the compounds being within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include all- stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. This invention also relates to a method of treating a bacterial infection in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of a compound having the formula I . Subsets of compounds of this invention include I-A, I-B, I-C, I-D and I-E shown below: I-A I-B I-C I-D I-E where R 1 , R 2 , R 3 , and Ar are as described above and R 7 is hydrogen or a Cι -6 aliphatic group. Compounds of formula I-A are novel. Preferred R 1 groups include -C (R 4 ) 2 NHCOR, -C(R 4 ) 2 NHC0 2 R, -C0 2 R, and -CONHR where R is an optionally substituted Cι_ 4 aliphatic group and each R 4 is independently selected from hydrogen, a Cι_ 3 alkyl group, or two R 4 taken together with the carbon to which they are attached form a three or four membered aliphatic ring. Examples of preferred R include -Cι_ 4 alkyl, -Cι_ 4 haloalkyl, -allyl, -CH 2 C≡CR 6 , -CH (C 1-3 alkyl) C≡CR 6 , and -C (Me) 2 C≡CR 6 , where R 6 is hydrogen, -Cι -4 aliphatic, -CH 2 N(Me) 2 , or -CH 2 0(C 1 . 3 alkyl) . A preferred R 2 group is hydrogen. When R 1 is -CONH(Cι- 3 alkyl) or -C0 2 (Cι_ 3 alkyl), other preferred R 2 are halo, -CN and -Cι_ 4 alkyl groups. Preferred R 3 groups include Cι- 6 aliphatic optionally substituted by alkoxy, alkylamino or dialkylamino, optionally substituted morpholinyl, piperazinyl, piperidinyl, pyridyl, phenyl or benzyl. Preferred Ar groups are aryl and heteroaryl groups including optionally substituted phenyl, pyridyl, and pyrimidinyl rings. Examples of optional substituents attached to Ar include one or more of the following: alkyl, alkoxy, hydroxy, carboxy, . halo, S0 2 R, S0 2 NHR, amino, alkylamino, dialkylamino, and pyridyl. Selected compounds of formula I are shown in Table 3 (R 2 is hydrogen) . The numbering of these examples is based on the subsets described above: IA refers to ring A thiazoles (X is sulfur) IB to oxazoles (X is oxygen) , IC to imidazoles (X is NH) , ID to pyrazoles (Y is nitrogen) and IE to pyrazoles (Z is nitrogen) . The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds and by referring to the synthetic schemes shown below. A general reference is Katritzky and Rees, Comprehensive Heterocyciic Chemistry, vol. 5, 1984, Pergamon Press. In the routes shown below, the Ar group of formula I may be represented by a phenyl ring. It will be apparent to one skilled in the art that these routes are generally applicable to compounds having aryl groups other than phenyl . Scheme I Reagents and conditions : (a) (Et0 2 C) 2 CHBr, pyridine , toluene , heat (b) trif lie anhydride , 2 , 6-lutidine , CH 2 C1 2 , 0°C (c) Me 2 AlCl , MeNHOMe - HCl , CH 2 C1 2 / 0°C (d) piperidine, toluene, heat (e) LiCsCCH 2 N (Li ) C0 2 t-Bu, THF, 0°C → RT (f ) H 2 NNH 2 , EtOH, RT (g) trifluoroacetic acid, CH 2 C1 2 (h) imidazole-1-carboxylic acid methyl ester, acetonitrile , heat . Scheme I above shows a route for the preparation of thiazole compounds of this invention where the 4-position (R 3 ) of the thiazole ring is substituted by an amino group, illustrated here where Ar is phenyl and R 3 is piperidine. It will be apparent to one skilled in the art that the piperidine reactant in step (d) may be replaced by other amines to provide other 4- (amino group-substituted) thiazoles . Scheme II 8 Reagents and conditions: (a) Et0 2 CCH (CI) C (=0) R 3 , EtOH, heat (b) Me 2 AlCl, MeNHOMe-HCl, CH 2 C1 2 , 0°C (c) LiC≡CCH 2 N(Li)C0 2 t-Bu, THF, 0°C → RT (d) H 2 NNH 2 , EtOH, RT (e) trifluoroacetic acid, CH 2 C1 2 (f) imidazole-1- carboxylic acid methyl ester, acetonitrile, heat. Scheme II above shows a general route to thiazole compounds of formula IA wherein R 3 is an alkyl or aryl group. Scheme III 13 Reagents and conditions: (a) Et0 2 CCH(Cl) COCH 2 OCH 3 , EtOH, heat (b) Me 2 AlCl, MeNHOMe-HCl, CH 2 C1 2 , 0°C (c) MeMgBr, THF, 0°C (d) KOtBu, diethyl oxalate, THF, RT (e) H 2 NNH 2 , acetic acid, EtOH (f) BBr 3 , CH 2 C1 2 (g) (R 4 ) 2 NH, THF (h) LiAlH 4 , THF (i) S0C1 2 , CH 2 C1 2 , 0°C (j) NH 3 , dioxane (k) imidazole-1-carboxylic acid methyl ester, acetonitrile, heat (1) EtNH 2 , MeOH, heat. Scheme III above shows a general route to compounds of formula IA where R 3 is (CH 2 ) P N(R ) 2 and p is one. Scheme IV 17 18 19 20 Reagents and conditions: (a) Et0 2 CCHS + (Me) 2 Br ~ , 60%NaH, THF (b) decalin, 195°C (c) triflic anhydride, 2,6- lutidine, CH 2 C1 2 , 0°C (d) Me 2 AlCl, MeNHOMe-HCl, CH 2 C1 2 , 0°C → RT (e) piperidine, toluene, 90°C (f) CH≡CCH 2 NHC0 2 tBu, n- BuLi, -15°C → 10°C (g) H 2 NNH 2 -H 2 0, EtOH, RT (h) (4:1) CH 2 C1 2 -TFA (i) ClC0 2 Me, EtOAc, 1. ON NaHC0 3 Scheme IV above shows a route for the preparation of oxazole compounds IB of this invention where the 4 -position (R 3 ) of the oxazole ring is substituted by an amino group, illustrated here where Ar is phenyl and R 3 is piperidine. The formation of the oxazolone ring according to steps (a) and (b) is based on the method reported in Tetrahedron, Vol.29, 1983-1990 (1973) . Scheme V 23 24 Reagents and conditions: (a) (C0C1) 2 , benzene, CH 2 Cl 2 , RT (b) MeNHOMe-HCl, Et 3 N, 0°C—>RT (c) piperidine, toluene, 90°C (d) CH≡CCH 2 NHC0 2 tBu, n-BuLi, -15°C → 10°C (e) H 2 NNH 2 -H 2 0, EtOH, RT (f) (4:1) CH 2 Cl 2 -TFA (i) ClC0 2 Me, EtOAc, 1.0N NaHC0 3 Scheme V above shows a route for the preparation of oxazoles IB where the 4-position of the oxazole ring (R 3 ) is substituted by various groups, for example, an aliphatic group. The formation of the oxazole ring according to step (a) is based on the method reported in J. Chem. Soc, Chem. Commun., 29-30 (1995). Scheme VI 25 26 27 Reagents and conditions: (a) C1S0 2 C1, CH 2 C1 2 , RT (b) PhCONH2, neat, 150°C (c) 2N NaOH, dioxane (d) i. carbonyldi imidazole, THF; ii. MeNHOMe-HCl, Et 3 N (e) CH≡CCH 2 NHC0 2 tBu, n-BuLi, -15°C → 10°C (f) H 2 NNH 2 -H 2 0, EtOH, RT (g) (4:1) CH 2 C1 2 -TFA (h) ClC0 2 Me, EtOAc, 1. ON NaHC0 3 Scheme VI above shows a route for the preparation of IB compounds where the 4-position of the oxazole ring (R 3 ) is substituted by an aryl group, as illustrated here using a phenyl group. Scheme VII 40 41 Reagents and conditions: (a) PhNHNH 2 , Et 2 0, RT (b) aq. NaOH, MeOH (c) carbonyldiimidazole, THF (d) MeNHOMe-HCl, diisopropylethylamine, DMF, 80°C (e) LiC≡CCH 2 N (Li) C0 2 tBu, THF, 0°C -> RT (f) H 2 NNH 2 , EtOH, RT (g) CH 2 C1 2 , TFA (h) 1- imidazolecarboxylic acid methyl ester, acetonitrile, heat Scheme VII above shows a general route to formula ID pyrazoles. This route is particularly suitable for compounds where the R 3 substituent is aliphatic or aryl. Scheme VIII Reagents and conditions: (a) KOtBu, diethyloxalate, THF, RT (b) (i) H 2 NNHR, -HOAc, EtOH (ii) separate (c) aq. NaOH, MeOH (d) carbonyldiimidazole, THF (e) MeNHOMe-HCl, diisopropylethylamine, DMF, 80°C (f) LiC≡CCH 2 N(Li) C0 2 tBu, THF, 0°C → RT (g) H 2 NNH 2 , EtOH, RT (h) CH 2 C1 2 , TFA (i) 1- imidazolecarboxylic acid methyl ester, acetonitrile, heat Scheme VIII above shows a general route for the preparation of formula IE pyrazoles. The pharmaceutical compositions and methods of this invention will be useful generally for controlling bacterial infections in vivo . Examples of bacterial organisms that may be controlled by the compositions and methods of this invention include, but are not limited to the following organisms: Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae , Enterobacter sps . , Proteus sps., Pseudomonas aeruginosa, E. coli , Serratia marcesens, S. aureus, Coag. Neg. Staph. , Acinetobacter sps., Salmonella sps, Shigella sps., Helicobacter pylori , Mycobacterium tuberculosis , Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium kansasii , Haemophilus influenzae, Stenotrophomonas maltophilia, and Streptococcus agalactiae. The compositions and methods will therefore be useful for controlling, treating or reducing the advancement, severity or effects of nosocomial or non- nosocomial infections. Examples of nosocomial infection uses include, but are not limited to, urinary tract infections, pneumonia, surgical wound infections, bone and joint infections, and bloodstream infections. Examples of non-nosocomial uses include but are not limited to urinary tract infections, pneumonia, prostatitis, skin and soft tissue infections, bone and joint infections, intra-abdominal infections, meningitis, brain abscess, infectious diarrhea and gastrointestinal infections, surgical prophylaxis, and therapy for febrile neutropenic patients. The term "non-nosocomial infections" is also referred to as community acquired infections. Pharmaceutical compositions of this invention comprise a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Such compositions may optionally comprise an additional therapeutic agent. Such agents include, but are not limited to, an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound. The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof . Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, ■ waxes, polyethylene-polyoxypropylene-block polymers, wool fat and self-emulsifying drug delivery systems (SEDDS) such as α-tocopherol, polyethyleneglycol 1000 succinate, or other similar polymeric delivery matrices. In pharmaceutical composition comprising only a compound of formula I as the active component, methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent. Such agents include, but are not limited to, an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant , an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound. The term "pharmaceutically effective amount" or "therapeutically effect amount" refers to an amount effective in treating or ameliorating a bacterial infection in a patient. The term "prophylactically effective amount" refers to an amount effective in preventing or substantially lessening a bacterial infection in a patient. The compounds of this invention may be employed in a conventional manner for controlling bacterial infections levels in vivo and for treating diseases or reducing the advancement or severity of effects which are mediated by bacteria. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques . For example, a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from a bacterial infection or disease in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of that infection or disease. Alternatively, the compounds of this invention may be used in compositions and methods for treating or protecting individuals against bacterial infections or diseases over extended periods of time. The compounds may be employed in such compositions either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of enzyme inhibitors in pharmaceutical compositions. For example, a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against bacterial infections or diseases. The compounds of formula I may also be co- administered with other antibiotics to increase the effect of therapy or prophylaxis against various bacterial infections. When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention comprise a combination of a compound of formula I and another therapeutic or prophylactic agent . The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, via ophthalmic solution or ointment, rectally, nasally, buccally, vaginally or via an implanted reservoir. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial , intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol . Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution- and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides . Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica, or a similar alcohol. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and solutions and propylene glycol are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to-, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-administered transdermal patches are also included in this invention. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art . Dosage levels of between about 0.01 and about " 100 mg/kg body weight per day, preferably between 0.5 and about 75 mg/kg body weight per day and most preferably between about 1 and 50 mg/kg body weight per day of the active ingredient compound are useful in a monotherapy for the prevention and treatment of bacterial infections caused by bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes , Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps . Pseudomonas aeruginosa, E. coli , Serratia marcesens, S. aureus, and Coagr. Neg. Staph. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w) . Preferably, such preparations contain from about 20% to about 80% active compound. When the compositions of this invention comprise a combination of a compound of formula I and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 10% to 80% of the dosage normally administered in a monotherapy regime. Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage, dosage form, or frequency of administration, or both, may need to be modified. in some .cases, patients may, however, require intermittent treatment on a long-term basis upon any recurrence or disease symptoms. As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, and the patient's disposition to the disease and the judgment of the treating physician. One embodiment of this invention provides a method for treating or preventing a bacterial infection or disease in a subject comprising the step of administering to the subject any compound, pharmaceutical composition, or combination described herein and a pharmaceutically acceptable carrier. The compounds of this invention are also useful as commercial reagents which effectively bind to the gyrase B enzyme. As commercial reagents, the compounds of this invention, and their derivatives, may be used to block gyrase B activity in biochemical or cellular assays for bacterial gyrase B or its homologs or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial gyrase B inhibitors will be evident to those of ordinary skill in the art . In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. Synthetic Examples Example 1.— 2-Phenyl-4-trifluoromethanesulfonyloxy- thiazole-5-carboxylic acid ethyl ester The starting material 4-hydroxy-2-phenyl- thiazole-5-σarboxylic acid ethyl ester was prepared according to the procedure described by Kedersky et al . , J. Med. Chem. , 34, 2158 (1991). To a solution of the starting material (2.3 mmol) in CH 2 C1 2 (10 mL) at 0°C was successively added 2,6-lutidine (2.53 mmol) and trifluoromethanesulfonic anhydride (2.53 mmol). The reaction was stirred from 0°C to room temperature over a two hours period. The reaction mixture was diluted with CH 2 C1 2 and washed successively with 5% NaHS0 4 , water, NaHC0 3 , and saturated brine, then dried over MgS0 4 and concentrated in vacuo. Silica gel chromatography of the crude material provided 82% of the desired product the title compound as a white crystalline solid with consistent X H NMR (CDCl 3 ) : δ 1.4(t,3H), 4.4(q,2H), 7.4- 7.6(m,3H) , 7.95(m,2H) . Example 2. 2-Phenyl-4-piperidin~l-yl-thiazole-5- carboxylic acid ethyl ester To a solution of the above-prepared 2-phenyl- - trifluoromethanesulfonyloxy-thiazole-5-carboxylic acid ethyl ester (0.75 mmol) in toluene (5mL) was added piperidine -"" (4.5 mmol) . The reaction mixture was heated to 80°C for 2 hours. The mixture was then diluted in.,, ethyl acetate, washed successively with water and brine, and dried over MgS0. Silica gel chromatography of the crude mixture provided title compound (96%) as a yellowish oil. Example 3. 2-Phenyl-4-piperidin-l-yl-thiazole-5- carboxylic acid methoxy-methyl-amide A solution of N, O-dimethylhydroxylamine hydrochloride(3.62 mmol) in dry CH 2 C1 2 (5ml) at 0°C was treated dropwise with neat dimethylaluminum chloride (3.62 mmol) and the resulting mixture stirred at 0°C for 0.5 hours. The mixture was then allowed to warm to room temperature before adding the above-prepared 2-phenyl-4- piperidin-l-yl-thiazole-5-carboxylic acid ethyl ester (0.724 mmol) in CH 2 C1 2 (2 ml) dropwise. The yellow mixture was then stirred at room temperature under nitrogen for one hour and re-cooled to 0°C. The mixture was quenched slowly by adding 2. ON NaOH dropwise, warmed to room temperature, and extracted with two portions of CH 2 C1 2 . The organic phase was washed successively with 1. ON NaOH and brine, dried over MgS0 4 , and concentrated in vacuo to give a yellow oil. Silica gel chromatography provided 3 as a yellow waxy crystalline solid (98% yield) . X H NMR (CDC1 3 ) : δ 3.35 (s,3H) , 1.6-1.8 (m, 6H) , 3.3(s,3H) , 3.5 (m,4H) , 3.7(s,3H) , 7.3-7.4 (m, 3H) , 7.95 (m, 2H) . Example 4. 1- (2-Phenyl-4-piperidin-l-yl-thiazol-5~yl) ethanone To a solution of the above-prepared 2-phenyl-4- piperidin-l-yl-thiazole-5-carboxylic acid methoxy-methyl- amide (0.754 mmol) in THF (5mL) was added at 0°C MeLi-LiBr (0.83 mmol) . The reaction mixture was stirred until the reaction was complete, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and concentrated in vacuo to give a brown oil. Silica gel chromatography provided the title compound (72%) as a yellowish oil. ^Η NMR (CDCl 3 ) : δ 1.6- 1.8(m,6H), 2.45(s,3H), 3.5 (m, 4H) , 7.4-7.5 (m, 3H) , 8.0(m, 2H) . Example 5. 5- (2-Phenyl-4-piperidin-l-yl-thiazol-5-yl) - 2fl-pyrazole-3 -carboxylic acid ethyl ester To a solution of the above-prepared 1- (2- phenyl-4-piperidin-l-yl-thiazol-5-yl) -ethanone (0.545 mmol) in dry THF (5 mL) was treated dropwise with a 1. OM potassium t-butoxide in THF solution (0.654 mmol). The suspension was stirred at room temperature under nitrogen for 15 minutes. Diethyl oxalate (0.600 mmol) was added, and the brown suspension was diluted with additional THF (6 mL) and allowed to stir at room temperature for 30 minutes. The reaction mixture was quenched by adding glacial acetic acid (0.710 mmol) and ethanol (5 mL) . The solvent was removed in vacuo leaving a residual oil that was dissolved in absolute EtOH (5 mL) . The ethanolic solution was treated with hydrazine monohydrate (0.655 mmol) and the mixture heated at 80°C for 1 hour. The resulting yellow suspension was concentrated in vacuo leaving a residual oil that was dissolved in ethyl acetate. This organic phase was washed with water, saturated NaHC0 3 and brine, then dried over MgS0 4 and evaporated in vacuo to give a yellow oily solid. Silica gel chromatography provided the title compound (59%) as a yellow solid. U NMR(CDC1 3 ) : δ 1.4(t,3H), 1.6-1.9 (6H) , 3.1 (m, 4H) , 4.4(q,2H), 6.9 (broad s, IH) , 7.4-7.5 (m, 3H) , 7.9 (m,2H) . Example 6. 4-Methoxymethyl-2-phenyl-thiazole-5- carboxylic acid methyl ester A solution of CH 3 0 2 CCH (CI) C0CH 2 0CH 3 (68mmole, 1.2eq), prepared according to De Kimpe et al . , Synthesis, 188 (1986) , in absolute EtOH (75ml) was treated with thiobenzamide (7.8g, 56.7mmole, l.Oeq) and the resulting brown mixture refluxed under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate and saturated NaHC0 3 . The organic layer was washed with water twice and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography eluting with (9:1) hexanes- ethyl acetate provided 6.98g (47%) of title compound as a yellow crystalline solid. X H NMR (CDC1 3 ) : δ 3.6(s,3H), 3.9(s,3H), 4.95(s, 2H) , 7.4-7.5 (m,3H), 8.0 (m,2H). Example 7. 4-Methoxymethyl-2-phenyl-thiazole-5- carboxylic acid methoxy-methyl amide A solution of N, O-dimethylhydroxylamine hydrochloride(13.3g, 136.3 mmole, 6. Oeq) in dry CH 2 Cl 2 (250 ml) at 0°C was treated dropwise with neat dimethylaluminum chloride (12.7 ml, 136.3 mmole, 6. Oeq) and the resulting mixture stirred at 0°C for 2 hours then allowed to warm to RT. To this mixture was added dropwise a solution of the above-prepared 4- methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methyl ester (5.98g, 22.71mmole, l.Oeq) in CH 2 Cl 2 (20 ml). The yellow mixture was then stirred at room temperature under nitrogen for one hour and re-cooled to 0°C. The mixture was quenched slowly by adding 2. ON NaOH dropwise, warmed to room temperature, and extracted with two portions of CH 2 C1 . The organic phase was washed successively with 1.0N NaOH and brine, dried over MgS0 4 , and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with (4:1) hexanes-ethyl acetate to give 6.5g (97%) of the title compound as a yellow waxy crystalline solid. α H NMR (CDC1 3 ) : δ 3.35 (s,3H), 3.5(s,3H), 3.7(s,3H), 4.95(s,2H), 7.4-7.5 (m, 3H) , 8.0 (m, 2H) . Example 8. 1- (4-Methoxymethyl-2-phenyl-thiazol-5-yl) - ethanone H,C OCH 3 To a solution of the above-prepared 4- methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methoxy-methyl amide (6.706g, 22.9mmole, l.Oeq) in dry THF (25ml) at 0°C was added dropwise a solution of 1.4M methylmagnesium bromide in (3 :1) toluene-THF (32.7ml, 45.8mmole, 2. Oeq). The resulting tan suspension was stirred under nitrogen at room temperature for 30 minutes, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography using a gradient elution of (9:1) to (4:1) hexanes-ethyl acetate provided the title compound (6.033g, 81%) as a yellow crystalline solid. X H NMR (CDC1 3 ) : δ 2.7(s,3H), 3.5(s,3H), 4.9(s,2H), 7.4-7.5(m,3H) , 8.0 (m, 2H) . Example 9. 5- (4-Methoxymethyl-2-phenyl-thiazol-5-yl) -2H- pyrazole-3 -carboxylic acid ethyl ester To a solution of the above-prepared l-(4- methoxymethyl-2-phenyl-thiazol-5-yl) -ethanone (5.22g, 21.12mmole, l.Oeq) in dry THF (100ml) at -15°C was added dropwise a solution of 1.0M potassium t-butoxide in THF (31.7ml, 31.7mmole, 1.5eq) and the suspension stirred at room temperature under nitrogen for one hour. Diethyl oxalate (4.4ml, 31.7mmole, 1.5eq) was added, the brown suspension diluted with additional THF (60ml) and allowed to stir at room temperature for 30 minutes. The mixture was quenched by adding glacial acetic acid (3.2ml, 2.6eq) . THF was removed in vacuo, and the residual oil was dissolved in absolute ethanol (175ml) and treated with hydrazine monohydrate (1.4ml , 30mmole, 1.4eq). This mixture was heated at 70°C for 3 hours. The resulting yellow suspension was concentrated in vacuo leaving a residual oil that was dissolved in ethyl acetate. The organic phase was washed with water, saturated NaHC0 3 and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oily solid. Silica gel chromatography using a gradient elution of (9:1) -(4:1) hexanes-ethyl acetate provided a yellow solid which was triturated with hexanes, filtered and dried in vacuo to give 3.69g (51%) of the title compound as an off- white solid. H NMR(CDC1 3 ) : δ 1.4(t,3H), 3.5(s,3H), 4.4(q,2H), 4.8(s,2H), 7.0(s,lH), 7.4(m,3H), 7.9- 8.0(m,2H) . Example 10. 5- (4-Bromomethyl-2-phenyl-thiazol-5-yl) - 2H- pyrazole-3 -carboxylic acid ethyl ester A -78°C solution of the above-prepared 5- (4- methoxymethyl-2-phenyl-thiazol-5-yl) - 2H-pyrazole-3 - carboxylic acid ethyl ester (1.5g, 4.37mmole, l.Oeq) in dry CH 2 C1 2 (20ml) was treated with a solution of 1. OM BBr 3 in CH 2 C1 2 (5.24ml, 5.24mmole, 1.2eq) and the mixture stirred at -78 °C for 45 minutes, then allowed to warm to room temperature and stirred for one hour. The reaction mixture was quenched by adding saturated NaHC0 3 , stirred for 30 minutes then extracted twice with CH 2 C1 2 . The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Silica gel chromatography using a gradient elution of (3:2)- (1:1) hexanes-ethyl acetate provided 610mg (36%) of the title compound as an off white solid. ^-H NMR(CDC1 3 ) : δ l.4(t,3H), 4.4(q,2H), 4.9(s,2H), 7.2(s,lH), 7.4(m,3H), 7.95(m,2H), 11.1 (bs,lH). Example 11. 5- (4-Morpholin-4-ylmethyl-2-phenyl-thiazol- 5-yl) -2H-pyrazole-3 -carboxylic acid ethyl ester A solution of the above-prepared 5- (4- bromomethyl-2 -phenyl-thiazol-5-yl) -2H-pyrazole-3 - carboxylic acid ethyl ester (20mg) in dry THF (1.0ml) was treated with morpholine (2 drops) and Et 3 N (1 drop) and the mixture stirred at room temperature under nitrogen for 2.5 hours . The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oily solid. Silica gel chromatography using a gradient elution of (9:1)- (4:1) hexanes-acetone provided 18mg (89%) of the title compound as a white solid. a H NMR(CDC1 3 ): δ 1.45(t,3H), 2.7(bm,4H), 3.8(bm,4H), 3.9(s,2H), 4.45(q,2H), 6.95(s,lH), 7.45(m,3H), 7.9(m,2H). Example 12. 1- (2-Phenyl-thiazol-5-yl) -ethanone A mixture of 10. Og (72.9 mmol) of thiobenzamide and 17.4g (146 mmol) dimethylformamide dimethyl acetal was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure. The residue was dissolved in ethanol (40ml) . To this solution was added l.Og (109 mmol) of chloroacetone and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate and washed twice with aqueous sodium bicarbonate, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 3:97 acetone: hexanes as eluant to give 3.5g of the title compound (25%). α H NMR (500MHz, CDC1 3 ) δ 8 . 36 ( s , lH) , 8 . 01 (d , 2H) , 7 . 49 (m, 3H) , 2 . 61 ( S , 1H) . Example 13. 5- (2-Phenyl-thiazol-5-yl) -2H-pyrazole-3- carboxylic acid ethyl ester To a solution of 0.10g (0.49 mmol) of the above-prepared 1- (2-phenyl-thiazol-5-yl) -ethanone was added O.llg (0.98 mmol) of IM potassium tert-butoxide in tetrahydrofuran. The solution was allowed to stir for 0.5 hours. 0.15g (0.98 mmol) of diethyl oxalate was added and the solution was allowed to stir for 2 hours. The reaction was quenched with aqueous ammonium chloride and partitioned with ethyl acetate. The organic phase was twice washed with aqueous ammonium chloride, once with water, once with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (10ml) . To the ethanolic solution was added 0.04g (0.64 mmol) of glacial acetic acid followed by 0.03g (0.64 mmol) of hydrazine monohydrate. The solution was allowed to stir for 3 hours at room temperature . The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 9:1 hexanes : ethyl acetate as eluant to give 75mg of the title compound (51%). a H NMR (500MHz, CDC1 3 ) δ 8.10 (s,lH) 7.98 (m,2H) 7.47 (m,3H) 7.10 (s,lH) 4.42 (q,2H) 1.42 (t,3H). Example 14. 4-Bromo-5- (2-phenyl-thiazol-5-yl) -2H- pyrazole-3-carboxylic acid ethyl ester To a mixture of 0.03g (0.10 mmol) of the above- prepared 5- (2-phenyl-thiazol-5-yl) -2iT-pyrazole-3- ' carboxylic acid ethyl ester in acetonitrile (2ml) and dimethylformamide (1.5ml) was added 0.02g (0.10 mmol) of N-bromosuccinamide. The reaction was allowed to stir for 2 hours and diluted with ethyl acetate. The solution was washed 3 times with aqueous sodium bicarbonate, once with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 9:1 hexanes : ethyl acetate as eluant to give 28mg of the title compound (74%). X H NMR (500MHz, CDC1 3 ) δ 8.53 (s,lH) 8.01 (d,2H) 7.48 (m,3H) 4.47 (q,2H) 1.44 (t,3H). Example 15. 4-Chloro-5- (2-phenyl-thiazol-5-yl) -2H- pyrazole-3 -carboxylic acid ethyl ester To a solution of 25mg (0.084 mmol) of the above-prepared 5- (2-phenyl-thiazol-5-yl) -2H-pyrazole-3- carboxylic acid ethyl ester in dichloromethane was added 23mg (0.168 mmol) of sulfuryl chloride and allowed to stir overnight at room temperature. The solution was diluted with ethyl acetate, washed once with aqueous sodium bicarbonate, once with water once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 7:93 ethyl acetate : hexanes as eluant to give 23mg of the title compound (82%) . a H NMR (500MHz, CDCl 3 ) δ 8.39 (s,lH) 7.94 (d, 2H) 7.40 (m,2H) 4.40 (q, 2H) 1.38 (t,3H) . Example 16. 4-Chloro-5- (2-phenyl-thiazol-5-yl) -2H- pyrazole-3-carboxylic acid ethyl amide N <X CONHEt To 15mg (0.045 mmol) of the above-prepared 4- chloro-5- (2-phenyl-thiazol-5-yl) -2H-pyrazole-3-carboxylic acid ethyl ester was added 45mg (1.0 mmol) of 2M ethylamine in tetrahydrofuran followed by the addition of 2 drops of water. The mixture was heated to 60°C in a sealed tube and allowed to stir overnight. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 2:5 ethyl acetate .-hexanes as eluant to give 5mg of the title, compound (33%). NMR (500MHz, CDC1 3 ) δ 8.39 (s,lH) 8.00 (d,2H) 7.47 (m,3H) 6.78 (m, IH) 3.58 (m, 2H) 1.32 (t,3H). Example 17. 2-Phenyl-thiazole-5-carboxylic acid methoxy- methyl-amide To a solution of 3.72g (93 mmol) of sodium hydroxide in water (20ml) at 0°C. was added 3.72g (23.2 mmol) of bromine dropwise. The reaction was allowed to warm to room temperature and stir for 15 minutes. The solution was added to 1.05g (5.17 mmol) of the above- prepared 1- (2-phenyl-thiazol-5-yl) -ethanone in dioxane (50ml) and allowed to stir for 3 hours. The solution was poured onto ice, acidified with IN hydrochloric acid, and was twice extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give l.Olg (4.9 mmol) of the carboxylic acid. To the acid in THF (10ml) was added 1.04g (6.4 mmol) of 1,1- carbonyldiimidazole. The solution was heated to 50°C and allowed to stir for 1 hour. The solution was cooled to room temperature. 0.79g (7.9 mmol) of triethylamine and 0.672g (6.9 mmol) of N, O-dimethylhydroxylamine hydrochloride was added and allowed to stir overnight. The solution was diluted with ethyl acetate and washed once with aqueous potassium hydrogen sulfate, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 7:93 ethyl acetate :hexanes as eluant to give 0.66g of the title compound (54%). X H NMR (500MHz, CDC1 3 ) δ 8.58 (S,1H) 8.00 (m,2H) 7.46 (m,3H) 3.82(s,3H) 3.40 (s,3H). Example 18. 1- (2-Phenyl-thiazol-5-yl) -propan-1-one To a solution of 0.32g (1.3 mmol) of the above- prepared 2-phenyl-thiazole-5-carboxylic acid methoxy- methyl-amide in tetrahydrofuran at room temperature was added 0.34g (2.6 mmol) of IM ethyl magnesium bromide in tetrahydrofuran. The reaction mixture was allowed to stir for one hour. The reaction was quenched with aqueous ammonium chloride and partitioned with ethyl acetate. The organic phase was washed once with aqueous ammonium chloride, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:19 ethyl acetate:hexanes to give 0.26g of the title compound (93%). 2 H NMR (500MHz, CDCl 3 ) δ 8.36 (s,lH) 8.0 (m, 2H) 7.49 (m,3H) 2.98 (q,2H) 1.27 (t,3H). Example 19. 2-Hydroxy-3-methyl-4-oxo-4- (2-phenyl- thiazol-5-yl) -butyric acid ethyl ester && C0 2 Et OH To a -78°C solution of 0.26g (1.2 mmol) of the above-prepared 1- (2-phenyl-thiazol-5-yl) -propan-1-one was added 0.24g (1.4 mmol) of IM lithium bis (trimethylsilyl) amide in tetrahydrofuran. The mixture was allowed to stir for 0.5 hours and then 0.38g (1.5 mmol) of IM chlorotitanium triisopropoxide in hexanes was added. The reaction was allowed to warm to -20°C and stirred for 15 minutes . The reaction was recooled to -78°C and 0.25g (0.24 mmol) of ethyl glyoxalate in toluene (50%) was added. The solution was warmed to room temperature and allowed to stir for 0.5 hours. The reaction was quenched with aqueous potassium sodium tartrate tetrahydrate and partitioned with ethyl acetate. The organic phase was twice washed with aqueous potassium sodium tartrate tetrahydrate, once with water, once with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:9 ethyl acetate:hexanes to give 0.15g of the title compound (40%) . ^Η NMR (500MHz, CDCl 3 ) δ 8.42 (s,lH) 8.01 (d,2H) 7.48 (m,3H) 5.8 (m, IH) 4.27 (q, 2H) 3.75 (m, IH) 3.28 (m,lH) 1.37 " (d,3H) 1.26 (t,3H) . Example 20. 4-Methyl-5- (2-phenyl-thiazol-5-yl) -2H- pyrazole-3-carboxylic acid ethyl ester A mixture of 0.39g (0.91 mmol) of Dess-Martin periodinane and 0.07g (0.91 mmol) of tert-butyl alcohol in dichloromethane (2ml) was allowed to stir at room temperature for 20 minutes. The solution was cooled to ■ 0°C and to this was added 0.15g (0.45 mmol) of the above- prepared 2-hydroxy-3-methyl-4-oxo-4- (2-phenyl-thiazol-5~ yl) -butyric acid ethyl ester in dichloromethane (2ml) . The reaction was stirred at 0°C for 3 hours and quenched with sodium bisulfite in 50% aqueous sodium bicarbonate. The mixture was diluted with dichloromethane and allowed to stir for 20 minutes at room temperature. The organic phase was washed twice with aqueous sodium bicarbonate, once with water, once with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and dissolved in ethyl alcohol (5ml) . 41mg (0.68 mmol) of glacial acetic acid was added followed by the addition of 34mg (0.68 mmol) of hydrazine monohydrate. The solution was allowed to stir at room temperature for 4 hours . The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 1:99 ethyl alcohol .-dichloromethane as eluant to give 0.035g of the title compound (25%). X H NMR ( 500MHz , CDCl 3 ) δ 8 . 08 ( s , lH) 8 . 00 ( d, 2H) 7 . 47 (m, 3H) 4 . 45 (q, 2H) 2 . 54 ( s , 3H) 1 . 44 ( t , 3H) . Example 21. 4-Methyl-2-phenyl-oxazole-5-carboxylic acid methoxy-methyl-amide A suspension of commercially available N- benzoyl-DL-alanine (3.0g, 15.5mmole, 1. Oeq) in dry benzene (62 ml) and dry dichloromethane (23 ml) was treated dropwise with neat oxalyl chloride (13.5 ml, 155 mmole, lOeq) and the white suspension stirred overnight under nitrogen- at room temperature. The resulting homogeneous yellow mixture was then evaporated in vacuo to an oil, azeotroped twice with benzene and evaporated to give crude acid chloride as a yellow oil. This was used immediately in next step without further purification. See Crooks et al . , J. Chem. Soc, Chem. Comm. , 2335 (1995) . A 0°C solution of the above crude acid chloride (15.5 mmole, 1.0 eq) in dry THF (50ml) was treated with N,0-dimethylhydroxylamine hydrochloride (2.27 g, 23.3 mmole, 1.5eq) followed by Et 3 N (6.5ml, 46.5 mmole, 3. Oeq) and the dark brown suspension was stirred overnight under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic phase was washed successively with 5% KHS0 4 solution, water and brine, then dried over anhydrous sodium sulfate. Concentration in vacuo provided a crude brown oil. The crude oil was chromatographed on silica gel using a gradient elution of (4:1) to (7:3) hexanes-ether to give 1.82g (48%) of the title compound as a yellow crystalline solid. ^Η NMR: (CDCI 3 ) δ 2.5 (s,3H) , 3.35 (s,3H) , 3.9 (s,3H) , 7.4-7.5 (m,3H) , 8.05 (m,2H) . Example 22. [4- (4-Methyl-2-phenyl-oxazol-5-yl) -4-oxo- but-2-ynyl] -carbamic acid tert-butyl ester A -15°C solution of N-BOC propargyl amine (651mg, 4.2 mmole, 3.5eq) in dry THF (12ml) was treated dropwise with a 1.6M n-BuLi in hexanes solution (5.25ml, 8.4mmole, 7. Oeq) and the pale yellow dianion solution was stirred at -15°C for 30 minutes under nitrogen. A dry THF solution (3 ml) of the above-prepared 4-methyl-2- phenyl-oxazole-5-carboxylic acid methoxy-methyl-amide (296mg, 1.2mmole, l.Oeq) was added dropwise to the dianion solution at -15°C and the mixture stirred at 0°C for 2 hours under nitrogen. The mixture was quenched by adding a solution of 2M NaH 2 P0 (5 ml) , warmed to room temperature, and then extracted with ethyl acetate. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate and concentrated in vacuo to provide the title compound as a crude brown oil. The crude oil was used immediately in the next step without further purification. Example 23. [5- (4-Methyl-2-phenyl-oxazol-5-yl) -2H- pyrazol-3-ylmethyl] -carbamic acid tert-butyl ester A solution of the above-prepared [4- ( -methyl- 2-phenyl-oxazol-5-yl) -4-oxo-but-2-ynyl] -carbamic acid tert-butyl ester (~1.2mmole) in absolute ethanol (7 ml) was treated with excess hydrazine monohydrate (6 drops) and the brown mixture stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo to an oil and chromatographed on silica gel using a gradient elution of (4:1) hexanes-ethyl acetate. Obtained 258mg (61%) of 3 as a pale yellow solid with good IH NMR (CDC1 3 ) : ? 1.55 (s, 9H) , 2.5 (s, 3H) , 4.35 (d, 2H) , 5.2 (bt, IH) , 6.45 (s, IH) , 7.4-7.5 (m, 3H) , 8.05 (m, 2H) . Example 24. C- [5- (4-Methyl-2-phenyl-oxazol-5-yl) -2H- pyrazol-3-yl] -methylamine A solution of the above-prepared [5- (4-Methyl-2- phenyl-oxazol-5-yl) -2H-pyrazol-3-ylmethyl] -carbamic acid tert-butyl ester (258mg, 0.728mmole, l.Oeq) in dry CH 2 Cl 2 (4 ml) was treated with trifluoroacetic acid (1 ml, excess) and the brown homogeneous mixture stirred under nitrogen at room temperature for one hour. The mixture was partitioned between CH 2 C1 2 and 1. ON NaOH, the organic phase washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 177 mg (96%) of the title compound as an off-white solid. The crude solid was used without further purification. Example 25. [5- (4-Methyl-2-phenyl-oxazol-5-yl) -2H- pyrazol-3-ylmethyl] -carbamic acid ethyl ester A heterogeneous mixture' of the above-prepared C- [5- (4-Methyl-2-phenyl-oxazol-5-yl) -2H-pyrazol-3-yl] - methylamine (31 mg, 0.122 mmole, l.Oeq) in ethyl acetate (0.5ml) and 1. ON NaHC0 3 (0.5ml) was treated with excess methyl chloroformate (5 drops) and the mixture stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and saturated NaHC0 3 . The organic phase was washed with water and brine, then dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow solid. Silica gel chromatography eluting with (4:1) hexanes-acetone provided 28 mg (74%) of the title compound as a white solid. ^H NMR (DMSO-d 6 ) : δ 2.6 (s,3H), 3.6 (s,3H), 4.25 (m, 2H) , 6.5 (s,lH), 7.5 (m,3H), 7.7 (bm,lH), 8.0 (m, 2H) . Example 26. 2 , 4-Diphenyl-oxazole-5-carboxylic acid ethyl ester The starting ketoester PhCOCH(Cl) C0 2 Et was prepared according to De Kimpe, et al . , Synthesis, 188 (1986). The starting ketoester (-27 mmole, l.Oδeq) and benzamide (3.0 g, 25.0 mmole, leq) were heated neat at 150 °C for 4 hours. The mixture was then partitioned between CH 2 C1 2 and saturated NaHC0 3 . The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Residual benzamide was precipitated out with ether. The filtrate was concentrated and then chromatographed on silica gel eluting with (95:5) hexanes-ether to provide 500mg of the title compound as a white solid. 1 H-NMR(CDC1 3 ) : δ 1.4 (t,3H), 4.4 (q,2H), 7.4-7.6 (m, 3H) , 8.1 (dd, IH) , 8.25 (dd,lH) . Example 27. 2 , 4-Diphenyl-oxazole-5-carboxylic acid A solution of the above-prepared 2 , 4-diphenyl- oxazole-5-carboxylic acid ethyl ester (500 mg, 1.70 mmole, l.Oeq) in dioxane (6 ml) was treated with 2N NaOH (1.7 ml, 3.4 mmole, 2. Oeq) and the mixture stirred at room temperature overnight under nitrogen. The mixture was then partitioned between ethyl acetate and 2. ON HCI. The organic phase washed with 0.5N HCI and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 426mg of the title compound as a crude yellow solid. The product was used directly in the next step, without purification. Example 28. 2, 4-Diphenyl-oxazole-5-carboxylic acid methoxy-methyl-amide A solution of the. above-prepared 2, 4-diphenyl- oxazole-5-carboxylic acid (427mg, 1.61 mmole, l.Oeq) in dry THF was treated with carbonyldiimidazole (34Omg, 2.09mmole, 1.3eq) and the mixture heated at 50°C for 3 hours . Triethylamine (360uL, 2.58mmole, 1.6eq) and N,0- dimethylhydroxylamine-HCl (236mg, 2.42 mmole, 1.5eq) were added and the mixture heated at 50°C for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHS0 and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil. The crude oil was chromatographed on silica gel eluting with (7:3) hexanes-ether to give 371 mg (75%) of the title compound as a brown crystalline solid. X H NMR (CDC1 3 ) δ 3.35 (s,3H), 3.8 (s,3H), 7.3-7.6 (m, 6H) , 7.95 (dd, 2H) , 8.15 (dd, 2H) . Example 29. [4- (2 , 4-Diphenyl-oxazol-5-yl) -4-oxo~but-2- ynyl] -carbamic acid tert-butyl ester A -15°C solution of N-BOC propargyl amine (641 mg, 4.13 mmole, 3.5eq) in dry THF (12ml) was treated dropwise with a 1.6M n-BuLi in hexanes solution (5.16 ml, 8.3 mmole, 7. Oeq) and the resulting pale yellow dianion solution stirred at -15°C for 30 minutes under nitrogen. A dry THF solution (3 ml) of the above-prepared 2,4- Diphenyl-oxazole-5-carboxylic acid methoxy-methyl-amide (365 mg, 1.18 mmole, l.Oeq) was added dropwise to the dianion solution at -15°C and the mixture stirred at 0°C for 2 hours under nitrogen. The mixture was quenched by adding a solution of 2M NaH 2 P0 4 (5 ml) , then warmed to room temperature and extracted with 'ethyl acetate. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a crude brown oil. The crude oil without purification was used immediately in next step. Example 30. [5- (2 , 4-Diphenyl-oxazol-5-yl) -2H-pyrazol-3- ylmethyl] -carbamic acid tert-butyl ester A solution of the above-prepared [4- (2,4- diphenyl-oxazol-5-yl) -4-oxo-but-2-ynyl] -carbamic acid tert-butyl ester (-1.2 mmole) in absolute ethanol (7 ml) was treated with excess hydrazine monohydrate (6 drops) and the brown mixture stirred at room temperature overnight . The mixture was concentrated in vacuo to an oil and chromatographed on silica gel eluting with (4:1) hexanes-ethyl acetate. The title compound (251 mg) was obtained as a pale yellow solid. X H NMR (CDCl 3 ) : δ 1.50 (s, 9H) , 2.5 (s, 3H) , 4.3 (m, 2H) , 5.2 (bt, IH) , 6.5 (s, IH) , 7.3-7.5 (m, 6H) , 7.9 (m, 2H) , 8.15 (m, 2H) . Example 31. [5- (2 , 4-Diphenyl-oxazol-5-yl) -2H-pyrazol-3- ylmethyl] -carbamic acid methyl ester A solution of the above-prepared [5- (2,4- Diphenyl-oxazol-5-yl) -2H-pyrazol-3 -ylmethyl] -carbamic acid tert-butyl ester (251mg, l.Oeq) in dry CH 2 C1 2 (8 ml) was treated with trifluoroacetic acid (2 ml, excess) and the brown homogeneous mixture stirred under nitrogen at room temperature for 1.5 hours . The mixture was partitioned between CH 2 C1 2 and 1. ON NaOH. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 181mg of crude benzylamine as a light brown solid. The crude benzylamine was used without further purification. A heterogeneous mixture of benzylamine (32 mg, 0.101 mmole, l.Oeq) in ethyl acetate (1.5 ml) and 1. ON NaHC0 3 (1.5 ml) was treated with excess methyl chloroformate (5 drops) and the mixture stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and saturated NaHC0 3 . The organic phase was washed with water and brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil. Chromatography on silica gel with a gradient elution of (85:15) to (4:1) hexanes-acetone provided 24mg of the title compound as a white solid. 1 H NMR (DMS0-d 6 ) : δ 3.6 (s,3H), 4.3 (3,2H), 6.5 (s,lH), 7.35-7.6 (m, 6H) , 7.7 (bm, IH) , 8.1 (m, 2H) , 8.2(m,2H). Example 32. 5-Phenyl-2H-pyrazole-3 -carboxylic acid ethyl ester To a room temperature mixture of acetophenone (1.0 mL, 8.57 mmoles) and diethyl oxalate (1.75 mL, 1,2.86 mmoles) in THF (15 mL) was added potassium t-butoxide (8.57 mL of a 1.0 M solution in t-BuOH) under a nitrogen atmosphere. The resulting dark mixture was stirred at room temperature for two hours. The crude reaction was then diluted with ethyl acetate, quenched with 6 N HCI, and then diluted with brine and enough water to dissolve all solids. The phases were separated and the organic phase was dried over Na 2 S0 , filtered, and concentrated in vacuo. The crude diketoester was diluted EtOH (10 mL) , then treated sequentially with acetic acid (2 mL) and hydrazine (1 mL) and stirred at room temperature for 1 hour. The crude reaction was concentrated in vacuo to a thick oil, diluted with ethyl acetate, washed sequentially with water and brine, dried over Na 2 S0 4 , filtered, concentrated in vacuo, and flash chromatographed (silica gel, hexanes/ethyl acetate gradient) to give the title compound (1.76 g, 95% yield) as a yellow solid. 2 H NMR (CDCl 3 , 400 MHz): 7.83 (d, 2H) ; 7.25 (dd, 2H) ; 7.28 (dd, IH) ; 7.09 (s, IH) ; 4.59 (q, 2H) ; 1.39 (t, 3H) Example 33. 2-Ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester To a 0 °C mixture of the above-prepared 5- phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (350 mg, 1.62 mmoles) and iodoethane (260 μL, 3.23 mmoles) in DMF (3 mL) was added neat LiH (spatula tip, excess) under a nitrogen atmosphere. The resulting mixture was warmed up to room temperature and stirred overnight . The crude reaction was cooled to 0 °C, quenched with aqueous NH 4 C1, diluted with ethyl acetate and enough water to dissolve all solids. The phases were separated, and the organic phase was washed sequentially with water and brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The regioisomeric products separated and purified by flash chromatography (silica gel, hexanes/ethyl acetate gradient) to give the title compound (167 mg , 42% yield, higher Rf in hexanes/ethyl acetate) and the undesired regioisomer (175 mg, 44% yield) as white solids. 1 H NMR (CDC1 3 , 400 MHz): 7.81 (d, 2H) ; 7.40 (dd, 2H) ; 7.29 (dd, IH) ; 7.13 (s, IH) ; 4.63 (q, 2H) ; 4.37 (q, 2H) ; 1.47 (t, 3H) ; 1.41 (t, 3H) . Example 34. 2 -Ethyl-5-phenyl-2H-pyrazole-3 -carboxylic acid methoxy-methyl-amide To a room temperature solution of the above- prepared 2-ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (165 mg, 675 μmoles) in MeOH (2 mL) was added aqueous NaOH (215 μL of a 10 N solution, 215 μmoles) under a nitrogen atmosphere. The resulting mixture was allowed to stir at room temperature overnight. The reaction was acidified with 6 N HCI, diluted with ethyl acetate and brine, and the phases were separated. The organic phase was dried over Na 2 S0 , filtered, and concentrated in vacuo. The crude acid was suspended in THF (2 mL) , and carbonyldiimidazole was added (140 mg, 860 μmoles) , and the mixture was stirred overnight at room temperature. The resulting acylimidazolide was treated with a preformed mixture of MeON(H) Me -HCI (140 mg, 1.43 mmole) and isoprσpylethylamine (250 μL, 1.43 mmoles) in DMF (1 L) and the resulting mixture heated to 90 °C overnight. The reaction was then cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 1 M NaHS0 4 (3x) , brine, dried over Na 2 S0 , filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (130 mg, 74% yield) as a thick oil. Example 35. [4- (2-Ethyl-5-phenyl-2H-pyrazol-3-yl) -4-oxo- but-2-ynyl] -carbamic acid tert-butyl ester To a -10 °C solution of N-t-butoxycarbonyl propargylamine (502 mg, 3.24 mmoles) in THF (5 mL) was added nBuLi (3.7 mL of a 1.6 M solution in hexanes, 5.94 mmoles) dropwise over 10 minutes. The resulting dianion mixture was stirred at -10 °C for 15 minutes, then treated with a THF solution (2 mL) of the above-prepared 2-ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid methoxy- methyl-amide (125 mg, 482 μmoles) , allowed to warm to room temperature, and stirred at room temperature for 2 hours. The resulting mixture was cooled to 0 °C, quenched with 2 M NaH 2 P0, diluted with ethyl acetate, and vigorously stirred for 5 minutes. The phases were separated, the organic phase dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The crude title compound was used directly in the next step. Example 36. (2 ' -Ethyl-5 ' -phenyl-IH, 2 'H- [3,3'] bipyrazolyl-5-ylmethyl) -carbamic acid tert-butyl ester To the above-prepared [4- (2-ethyl-5-phenyl-2H- pyrazol-3-yl) -4-oxo-but-2-ynyl] -carbamic acid tert-butyl ester in EtOH (5 mL) , hydrazine monohydrate was added (excess, 5 drops) , and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to a thick oil, diluted with ethyl acetate, washed sequentially with water and brine, dried over Na 2 S0 , filtered, and' concentrated in vacuo . Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (175 mg, 98% yeild) as a white foam. K NMR (CDC1 3 , 400 MHz): 7.86 (d, 2H) ; 7.39 (dd, 2H) ; 7.28 (dd, IH) ; 6.72 (s, IH) ; 6.36 (s, IH) ; 5.12 (broad dd, IH) ; 4.58 (q, 2H) ; 4.31 (d, 2H) ; 1.49 (s, 9H) . Example 37. (2 ' -Ethyl-5' -phenyl-IH, 2 'H- [3 , 3 '] bipyrazolyl-5-ylmethyj) -carbamic acid methyl ester To a room temperature solution of the above- prepared (2' -ethyl-5' -phenyl -IH, 2'H- [3,3' ] bipyrazolyl-5- ylmethyl) -carbamic acid tert-butyl ester (25 mg, 68 μmoles) in CH 2 C1 2 (2 mL) was added trifluoroacetic acid (0.5 mL, excess). The resulting solution was stirred at room temperature for one hour, then concentrated and azeotroped with acetonitrile (3x) in vacuo . To the resulting crude deprotection product in acetonitrile was added triethylamine, then 1-methoxycarbonyl imidazole (26 mg, 204 μmoles) and the mixture was heated to 90 °C for two hours . The reaction was then cooled to room temperature, diluted with ethyl acetate and 1 M NaHS0 4 , and stirred vigorously for 20 minutes. The organic phase was washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo . Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound as a white solid. X H NMR (CDCl 3 , 400 MHz): 7.87 (d, 2H) ; 7.41 (dd, 2H) ; 7.37 (dd, IH) ; 6.75 (s, IH) ; 6.42 (s, IH) ; 5.30 (dd, IH) ; 4.68 (q, 2H) ; 4.40 (d, 2H) ; 3.73 (s, 3H) ; 1.51 (t, 3H) . Example 38. 1 ' - (3-Chloro-phenyl) -5 ' -methyl-IH, 1 'H- [3 , 4 ' ] bipyrazolyl-5-carboxylic acid ethyl ester (Compound ID-28) To a solution of 47 mg (0.2 mmol) of l-[l-(3- chlorophenyl) -5-methyl-lH-pyrazol-4-yl] ethan-1-one (commercially available) in 2 mL of THF was added successively 0.4 mL (0.4 mmol) of IM KOtBu in THF and 54 μL (0.4 mmol) of diethyl oxalate. The mixture was stirred at room temperature overnight, quenched with water, and diluted with ethyl acetate. The solution was washed successively with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated in vacuo . The residue was diluted with 2 mL of ethanol, and 15 mL (0.3 mmol) of hydrazine monohydrate was added followed by 15 mL (0.3 mmol) of acetic acid. The mixture was stirred at room temperature for 2 hours, and concentrated in vacuo . The residue was purified by reverse phase preparative HPLC to afford 8 mg of the title compound as the trifluoroacetic acid salt. MS m/e expected M+l 333.18, found m/e 333.01. X H NMR (DMSO-d 6 ) δ 14.0 (s, 0.45H), 13.8 (s, 0.55H), 8.05 (s, IH) , 7.75 (s, IH) , 7.55 (m, 3H) , 7.1 (br s, 0.45H), 6.8 (br s, 0.55H), 4.3 (br s, 2H) , 2.65 (br s, 1.4H), 2.4 (br s, 1.6H), 1.3 (t, 3H) . Biological Methods Method A. Susceptibility Testing in Liquid Media Compounds of this invention may also be tested for antimicrobial activity by susceptibility testing in liquid media. Such assays may be performed within the guidelines of the latest NCCLS document governing such practices: "M7-A5 Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Fifth Edition (2000)". Other publications such as "Antibiotics in Laboratory Medicine" (Edited by V. Lorian, Publishers Williams and Wilkins, 1996) provide essential practical techniques in laboratory antibiotic testing. Essentially, several discrete bacterial colonies (3 to 7) from a freshly streaked plate are transferred to an appropriate rich broth medium such as MHB, supplemented where appropriate for the more fastidious organisms. This is grown overnight to high density followed by a 1 or 2-thousand- fold dilution to give an inoculation density of between 5 x 10 5 and 5 x 10 s CFU per mL. Alternatively, the freshly picked colonies can be incubated at 37C for about 4 to 8 hrs until the culture equals or exceeds a turbidity of a 0.5 McFarland standard (approximately 1.5 x 10 8 cells per mL) and diluted to give the same CFU per mL as above. In a more convenient method, the inoculum can be prepared using a commercially available mechanical device (the BBL PROMPT System) that involves touching five colonies directly with a wand, containing Crosshatch grooves at its bottom, followed by suspension of the bacteria in an appropriate volume of saline. Dilution to the appropriate inoculum cell density can be made from this cell suspension. The broth used for testing consists of MHB supplemented with 50 mg per L of Ca 2+ and 25 mg per L of Mg 2+ . Standard dilution panels of control antibiotics are made and stored as in the NCCLS standard M7-A5, the dilution range typically being in the 128 μg per mL to 0.015 μg per mL (by 2-fold serial dilution) . The test compounds are dissolved and diluted fresh for experimentation on the same day; the same or similar ranges of concentration as above being used. The test compounds and controls are dispensed into a multiwell plate and test bacteria added such that the final inoculation is approximately 5 x 10 4 CFU per well and the final volume is 100 μL. The plates are incubated at 35C overnight (16 to 20 hr) and checked by eye for turbidity using a test reading mirror or quantitated with a multiwell plate reader. The endpoint minimal inhibitory concentration (MIC) is the lowest concentration of drug at which the microorganism tested does not grow. Such determinations are also compared to the appropriate tables contained in the above two publications to ensure that the range of antibacterial activity is within the acceptable range for this standardized assay. Selected compounds of this invention were found to be active in the above Susceptibility Testing in Liquid Media. Method B. ATPase Assay The ATP hydrolysis activity of DNA gyrase was measured by coupling the production of ADP through pyruvate kinase/lactate dehydrogenase to the oxidation of NADH. This method has been described previously. (Tamura and Gellert, 1990, J. Biol. Chem.265, 21342- 21349) . ATPase assays were carried out at 30°C in buffered solutions containing 100 mM TRIS pH 7.6, 1.5 mM MgCl 2 , and 150 mM KCl . The coupling system contained (final concentrations) 2.5 mM phosphoenol pyruvate, 200 μM nicotinamide adenine dinucleotide (NADH) , 1 mM DTT, 30 ug/ml pyruvate kinase, and 10 ug/ml lactate dehydrogenase. 40 nM enzyme (374 kDa Gyr A2B2 from E coli) and a DMSO solution of the inhibitor to a final concentration of 4% were added and the reaction mixture allowed to incubate for 10 minutes at 30°C. The reaction was then started by the addition of ATP to a final concentration of 0.9 mM and the rate of NADH disappearance at 340 nm, measured over the course of 10 minutes . K^ values were determined from rate versus . inhibitor concentration profiles. Table 4 shows the activities of representative compounds tested in an E. coli gyrase A 2 B 2 ATPase assay. Compounds having a Ki less than 500 nM are rated "A", compounds having a Ki between 500 nM and 1500 nM are rated "B" and compounds having a Ki greater than 1500 nM are rated "C" . While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products and processes of this invention.

Claims: We claim : 1. An enzyme-inhibitor complex comprising a bacterial DNA gyrase and a bacterial DNA gyrase inhibitor, said inhibitor comprising the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2 , Grp3 or Grp4 wherein: HBA is a hydrogen bond acceptor; HBD is a hydrogen bond donor; Grpl is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40-160 (A) 2 ,- Grpla is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (A) 2 and a buried polar surface area in the range of about 0-110 (A) 2 ,- Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0-150 (A) 2 ; Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25-140 (A) 2 ; Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0-100 (A) 2 , provided that Grp4 is other than a coumarin ring; and the distances in angstroms between the features are in the following ranges : 2. The enzyme-inhibitor complex of claim 1 wherein the bacterial DNA gyrase inhibitor comprises the following features: (a) HBA, (b) HBD, (σ) Grpl and/or Grpla, and (d) at least three features selected from Grp2 , Grp3 or Grp4. 3. The enzyme-inhibitor complex of claim 2 wherein the bacterial DNA gyrase inhibitor comprises the following features: (a) HBA, (b) HBD, (c) Grpl and/or Grpla, and (d) Grp2, Grp3 and Grp4. 4. The enzyme-inhibitor complex of claim 3 wherein the HBA/HBD feature is selected from one of the following: d m s t u v w X y ae af ag ah ai a: ak al am an ao 5. The enzyme- inhibitor complex of claim 1 wherein: Grpl is selected from -CH(R 4 ) 2 , -C0 2 (Cι- 6 aliphatic), -C0N(R) 2 , -CONH-OR, -S0 2 R, or -S0 2 N(R) 2 , where each R is independently selected from hydrogen or a C 1-6 aliphatic group, and each R 4 is independently selected from hydrogen, an optionally substituted Cι_6 aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring; Grpla is selected from Ci-β aliphatic group, -CH 2 (CH 2 ) n NRCOR, -CH 2 (CH 2 ) n NRC0 2 (Cι- 6 aliphatic) , -CH 2 (CH 2 ) π CON(R) 2 , -CH 2 (CH 2 ) n S0 2 N(R) 2/ -CH 2 (CH 2 ) „NRS0 2 (C 1-6 aliphatic), -CH=N-OR, -CH=N-OC (=0) (Cι_ 6 aliphatic), -CH=NNRC0 2 (Ci- 6 aliphatic), -CH=NNRC0R, and -CH=NN(R) 2 , where n is zero or one; Grp2 is selected from hydrogen, -Cχ_ 4 aliphatic, -CONHR, -CN, -halo, -C0 2 R, -S0 2 R, -COR, -C0N(R) 2 , -S0 2 N(R) 2 , -NRS0 2 R, -NRS0 2 N(R) 2 , -Q, -C0Q, -S0 2 Q, -CONHQ, -S0 2 NRQ, -NRS0 2 Q, and -NRS0 2 NRQ, where R is a C α _ 3 aliphatic group and Q is a three to five-membered heterocyclyl or a five- or six-membered heteroaryl ring; Grp3 is selected from R, -SR, -S0 2 R, -S0 2 NHR, -CONHR, -C0NR 2 , -COR, -NHS0 2 R, -NHR, aryl, heteroaryl or heterocyclyl, where each R is a hydrogen or a Cι- 6 aliphatic group optionally substituted by one or more halogens, =0 or C . 6 alkyl; and Grp4 is selected from -R, -SR, -S0 2 R, -S0 2 NHR, -CONHR, -C0NR 2 , -COR, -NHS0 2 R, -NHR, -halo, or -Ar; where R is a hydrogen or a Cι- 6 aliphatic group optionally substituted by one or more halogens, =0 or Cι_ 6 alkyl ; and Ar is an optionally substituted aryl, heteroaryl, or heterocyclyl ring. 6. The enzyme-inhibitor complex of claim 5 wherein the Grpl and Grpla moieties are selected from -C(R) 2 (CH 2 ) n NRC0R, -C (R 4 ) 2 (CH 2 ) n NRC0 2 (Cι_ 6 aliphatic), -C (R 4 ) 2 (CH 2 ) n CON (R) 2 , -C (R 4 ) 2 (CH 2 ) n S0 2 N (R) _ , -C(R 4 ) 2 (CH 2 ) n NRS0 2 (C 1 . 6 aliphatic), -C(R 4 )=N-0R, -C(R 4 )=N-0C(=0) (Cι-6 aliphatic), -C (R 4 ) =NNRC0 2 (C x . 6 aliphatic), -C (R 4 ) =NNRCOR, -C (R 4 ) =NN(R) _ , or -C (R 4 ) 2 (CH 2 ) n NRS0 2 (Cι- 6 aliphatic) where n is zero or one, each R is independently selected from hydrogen or a Cι_ 6 aliphatic group, and each ' R 4 is independently selected from hydrogen, an optionally substituted Cι- 6 aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring. 7. A bacterial DNA gyrase inhibitor, said inhibitor when bound to the ATP site of a bacterial DNA gyrase B subunit comprises the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 wherein: HBA is a hydrogen bond acceptor; HBD is a hydrogen bond donor; Grpl is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40-160 (A) 2 ; Grpla is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (A) 2 and a buried polar surface area in the range of about 0-110 (A) 2 ; Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0-150 (A) 2 ; Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25-140 (A) 2 ; Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0-100 (A) 2 , provided that Grp4 is other than a coumarin ring; and the distances in angstroms between the features are in the following ranges: 8. A method of treating a bacterial infection in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amόunt of a bacterial DNA gyrase inhibitor, said inhibitor capable of forming an enzyme-inhibitor complex comprising a bacterial DNA gyrase and the inhibitor, wherein the complexed inhibitor comprises the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 wherein: HBA is a hydrogen bond acceptor; HBD is a hydrogen bond donor; Grpl is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40-160 (A) 2 ; Grpla is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (A) and a buried polar surface area in the range of about 0-110 (A) 2 ,- Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0-150 (A) 2 ; Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25-140 (A) 2 ; Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0-100 (A) 2 , provided that Grp4 is other than a coumarin ring; and the distances in angstroms between the features are in the following ranges: 9. The method of claim 8 wherein the complexed bacterial DNA gyrase inhibitor comprises the following _fea£ure.s_:__(al .HBA, (b.) HBD, (c)_ at-leas-t-one- feature selected from Grpl or Grpla, and (d) at least three features selected from Grp2 , Grp3 or Grp4. 10. The method of claim 9 wherein the complexed bacterial DNA gyrase inhibitor comprises the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) Grp2, Grp3 and Grp4 , 11. The method of claim 10 wherein the HBA/HBD feature is selected from one of the following: d g j r t u w X y aa ab ac ad ae af ag ah ai a ak al am an ao 12. The method of claim 11 wherein: Grpl is selected from -CH(R 4 ) 2 , -C0 2 (Cι_ 6 aliphatic), -CON(R) 2 , -CONH-OR, -S0 2 R, or -S0 2 N(R) 2 , where each R is independently selected from hydrogen or a C 1-6 aliphatic group, and each R 4 is independently selected from hydrogen, an optionally substituted Cι- 6 aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring; Grpla is selected from Cι -6 aliphatic group, -CH 2 (CH 2 ) n NRCOR, -CH 2 (CH 2 ) n NRC0 2 (Cχ- 6 aliphatic) , -CH 2 (CH 2 ) n CON(R) 2 , -CH 2 (CH 2 ) n S0 2 N(R) 2 , -CH 2 (CH 2 ) π NRS0 2 (Cχ-6 aliphatic), -CH=N-OR, -CH=N-OC (=0) (Cι_ 6 aliphatic) , -CH=NNRC0 2 (C 1 - 6 aliphatic), -CH=NNRC0R, and -CH=NN(R) 2 , where n is zero or one; Grp2 is selected from hydrogen, -C_._ aliphatic, -CONHR, -CN, -halo, -C0 2 R, -S0 2 R, -COR, -C0N(R) 2 , -S0 2 N(R) 2 , -NRS0 2 R, -NRΞ0 2 N(R) 2 , -Q, -COQ, -S0 2 Q, -CONHQ, -S0 2 NRQ, -NRS0 2 Q, and -NRS0 2 NRQ, where R is a Cι -3 aliphatic group and Q is a three to five-membered heterocyclyl or a five- or six-membered heteroaryl ring; Grp3 is selected from R, -SR, -S0 2 R, -S0 2 NHR, -CONHR, -CONR 2 , -COR, -NHS0 2 R, -NHR, aryl, heteroaryl or heterocyclyl, where each R is a hydrogen or a Cι_ 6 aliphatic group optionally substituted by one or more halogens, =0 or Cι-6 alkyl; and Grp4 is selected from -R, -SR, -S0 2 R, -S0 2 NHR, -CONHR, - C0NR 2/ -COR, -NHS0 2 R, -NHR, -halo, or -Ar; where R is a hydrogen or a Cα- 6 aliphatic group optionally • substituted by one or more halogens, =0 or Cι- 6 alkyl; and Ar is an optionally substituted aryl, heteroaryl, or heterocyclyl ring. 13. The method of claim 12 wherein the Grpl and Grpla moieties are selected from -C (R 4 ) _ (CH 2 ) n NRCOR, -C(R 4 ) 2 (CH 2 ) n NRC0 2 (C 1-6 aliphatic), -C (R) 2 (CH 2 ) n C0N(R) 2 , -C(R 4 ) 2 (CH 2 ) n S0 2 N(R) 2 , -C(R) 2 (CH 2 ) n NRS0 2 (C 1 _ 6 aliphatic), -C(R 4 )=N-OR, -C(R 4 )=N-OC(=0) (Ci-g aliphatic), -C(R 4 )=NNRC0 2 (C 1-S aliphatic) , -C (R 4 ) =NNRCOR, or -C (R 4 ) =NW(R) 2 , where n is zero or one, each R is independently selected from hydrogen or a C ._ aliphatic group, and each R 4 is independently selected from hydrogen, an optionally substituted Ci-s aliphatic group, or two R 4 taken together with the carbon to which they are attached form a three to six membered aliphatic ring. 14. The method according to any of claims 8-13 wherein the bacterial infection to be treated is selected from one or more of the following: Streptococcus pneumoniae, Streptococcus pyogenes , Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae , Enterobacter sps., Proteus sps., Pseudomonas aeruginosa, E. coli , Serratia marcesens, S. aureus, Coag. Neg. Staph. , Acinetobacter sps., Salmonella sps, Shigella sps., Helico acter pylori , Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare , Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium kansasii, Haemophilus influenzae, Stenotrophomonas maltophilia, and .Streptococcus agalactiae . 15. The method according to any of claim 8-13 wherein the bacterial infection to be treated is selected from one or more of the following: surgical wound infections, bloodstream infections, urinary tract infections, pneumonia, prostatitis, skin and soft tissue infections, bone and joint infections, intra-abdominal infections, meningitis, brain abscess, infectious diarrhea and gastrointestinal infections, surgical prophylaxis, and therapy for febrile neutropenic patients . 16. A method of designing a bacterial DNA gyrase inhibitor comprising the steps of: (a) providing a first structure that comprises HBA, HBD, and zero to four features selected from Grpl, Grpla, Grp2 , Grp3 , or Grp4 , and (b) modifying the first structure to provide a gyrase inhibitor comprising the features present in the first structure and at least one additional feature not present in the first structure and selected from Grpl, Grpla, Grp2, Grp3, or Grp4; wherein the gyrase inhibitor comprises the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4 ; HBA is a hydrogen bond acceptor and HBD is a hydrogen bond donor; Grpl is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 30-250 (A) 2 and a buried polar surface area in the range of about 40- 160 (A) 2 ; Grpla is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 35-260 (A) 2 and a buried polar surface area in the range of about 0- 110 (A) 2 ; Grp2 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 50-300 (A) 2 and a buried polar surface area in the range of about 0- 150 (A) 2 ; Grp3 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area -in the range of about 215-500 (A) 2 and a buried polar surface area in the range of about 25- 140 (A) 2 ; Grp4 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 150-350 (A) 2 and a buried polar surface area in the range of about 0- 100 (A) 2 , provided that Grp4 is other than a coumarin ring,- and • the distances in angstroms between the features are in the following ranges : 17. A method of determining whether a compound inhibits bacterial DNA gyrase, said method comprising the steps of : (a) determining whether the compound comprises an HBA/HBD pair wherein there is one to four bonds separating HBA and HBD; (b) docking a three-dimensional structure of the compound into the ATP binding site of bacterial DNA gyrase subunit B such that the HBA/HBD moiet such that (i) HBD is capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Aspδl and (ii) HBA is capable of forming a water-bridged hydrogen bond with the side chain carboxyl oxygens of Asp81 and is in the vicinity of the sidechain oxygen of Thr173; (c) determining whether the constrained structure . from step ' (b) ι further comprises at least one feature selected from Grpl or Grpla and at least two features selected from Grp2, Grp3 or Grp4; and (d) determining whether said features, if present, are within suitable distances of each other and the HBA/HBD groups and are capable of forming suitable binding interactions in the gyrB binding site. 18. A method of designing a new bacterial DNA gyrase inhibitor comprising the steps of: (a) providing a molecular fragment comprising an HBA/HBD moiety wherein HBA and HBD are separated by up to 4.0 A; (b) constraining the HBA/HBD moiety within the gyrB ATP site so that (i) HBD is capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Aspδl and (ii) HBA is capable of forming a water-bridged hydrogen bond with the side chain carboxyl oxygens of Aspδl and is in the vicinity of the sidechain oxygen of Thrl73; (c) providing a molecular fragment possessing at least one of Grpl or Grpla features, and molecular fragments each possessing at least one of the Grp2 , Grp3 or Grp4 features such that at least two of these features are represented among the fragments; and (d) connecting the fragments selected in step (3) to form a compound comprised of the following features: (a) HBA, (b) HBD, (c) at least one feature selected from Grpl or Grpla, and (d) at least two features selected from Grp2, Grp3 or Grp4.

Inventors: BADIA MICHAEL, BELLON STEVE, CHARIFSON PAUL, GRILLOT ANNE-LAURE, MURCKO MARK, RONKIN STEVEN, STAMOS DEAN, TRUDEAU MARTIN, BADIA, MICHAEL, BELLON, STEVE, CHARIFSON, PAUL, GRILLOT, ANNE-LAURE, MURCKO, MARK, RONKIN, STEVEN, STAMOS, DEAN, TRUDEAU, MARTIN
Applicants: BADIA MICHAEL, BELLON STEVE, CHARIFSON PAUL, GRILLOT ANNE LAURE, MURCKO MARK, RONKIN STEVEN, STAMOS DEAN, TRUDEAU MARTIN, VERTEX PHARMA, BADIA, MICHAEL, BELLON, STEVE, CHARIFSON, PAUL, GRILLOT, ANNE-LAURE, MURCKO, MARK, RONKIN, STEVEN, STAMOS, DEAN, TRUDEAU, MARTIN, VERTEX PHARMACEUTICALS INCORPORATED
Application year: 2001
Main classification: A61K31
IPC codes: A61K31, A61P31, C12Q1, G06F19